Understanding Pathophysiology [7 ed.] 9780323639088

Table of contents :
Title Page
Table of Contents
Copyright
Contributors
Reviewers
Preface
Organization and Content for the Seventh Edition
Features to Promote Learning
Art Program
Teaching/Learning Package
Acknowledgments
Dedication
Introduction to Pathophysiology
Part 1 Basic Concepts of Pathophysiology
Unit 1 The Cell
1 Cellular Biology
Prokaryotes and Eukaryotes
Cellular Functions
Structure and Function of Cellular Components
Cell-to-Cell Adhesions
Cellular Communication and Signal Transduction
Cellular Metabolism
Membrane Transport: Cellular Intake and Output
Cellular Reproduction: The Cell Cycle
Tissues
Summary Review
Key Terms
References
2 Genes and Genetic Diseases
DNA, RNA, and Proteins: Heredity at the Molecular Level
Chromosomes
Elements of Formal Genetics
Transmission of Genetic Diseases
Linkage Analysis and Gene Mapping
Multifactorial Inheritance
Summary Review
Key Terms
References
3 Epigenetics and Disease
Epigenetic Mechanisms
Epigenetics and Human Development
Epigenetics in Genomic Imprinting
Environmental Impacts on Epigenetic Information
Epigenetics and Cancer
Future Directions
Summary Review
Key Terms
References
Additional Readings
4 Altered Cellular and Tissue Biology
Cellular Adaptation
Cellular Injury
Manifestations of Cellular Injury
Cellular Death
Aging and Altered Cellular and Tissue Biology
Somatic Death
Summary Review
Key Terms
References
5 Fluids and Electrolytes, Acids and Bases
Distribution of Body Fluids and Electrolytes
Alterations in Water Movement
Sodium, Chloride, and Water Balance
Alterations in Sodium, Chloride, and Water Balance
Alterations in Potassium and Other Electrolytes
Acid–Base Balance
Pediatric Considerations
Geriatric Considerations
Summary Review
Key Terms
References
Unit 2 Mechanisms of Self-Defense
6 Innate Immunity
Human Defense Mechanisms
Innate Immunity
Acute and Chronic Inflammation
Wound Healing
Pediatric Considerations
Geriatric Considerations
Summary Review
Key Terms
References
7 Adaptive Immunity
Overview of Adaptive Immunity
Antigens and Immunogens
Immune Response: Collaboration of B Cells and T Cells
Humoral Immunity (Antibodies)
Cell-Mediated Immunity
Pediatric Considerations
Geriatric Considerations
Summary Review
Key Terms
References
8 Alterations in Immunity
Hypersensitivity Reactions
Immunologic Mechanisms of Hypersensitivity Reactions
Deficiencies in Immunity
Secondary (Acquired) Immune Deficiencies
Summary Review
Key Terms
References
9 Infection
Microorganisms and Humans: a Dynamic Relationship
Infectious Disease
Antibiotic/Antimicrobial Resistance
Vaccines and Protection Against Infection
Summary Review
Key Terms
References
10 Stress and Disease
Background and General Concepts of Stress
The Stress Systems
Chronic Stress at an Early Age Increases the Risk of Developing Long-Lasting Pathophysiologic Alterations Linked to Poor Health and to Disease
Negative Effects of Stress on Telomere Length, Aging, and Disease
Coping and Intervention Strategies
Summary Review
Key Terms
References
Unit 3 Cellular Proliferation: Cancer
11 Cancer Biology
Cancer Terminology and Characteristics
The Biology of Cancer Cells
Clinical Manifestations of Cancer
Diagnosis and Staging of Cancer
Treatment of Cancer
Summary Review
Key Terms
References
12 Cancer Epidemiology
Genetics, Epigenetics, and Tissue
In Utero and Early Life Conditions
Environmental-Lifestyle Factors
Summary Review
Key Terms
References
13 Cancer in Children and Adolescents
Incidence, Etiology, and Types of Childhood Cancer
Prognosis
Summary Review
Key Terms
References
Part 2 Body Systems and Diseases
Unit 4 The Neurologic System
14 Structure and Function of the Neurologic System
Overview and Organization of the Nervous System
Cells of the Nervous System
The Nerve Impulse
Central Nervous System
Blood Supply
Peripheral Nervous System
Autonomic Nervous System
Geriatric Considerations
Summary Review
Key Terms
References
15 Pain, Temperature, Sleep, and Sensory Function
Pain
Temperature Regulation
Sleep
The Special Senses
Geriatric Considerations
Geriatric Considerations
Somatosensory Function
Summary Review
Key Terms
References
16 Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function
Alterations in Cognitive Systems
Alterations in Cerebral Hemodynamics
Alterations in Neuromotor Function
Alterations in Complex Motor Performance
Extrapyramidal Motor Syndromes
Summary Review
Key Terms
References
17 Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction
Central Nervous System Disorders
Peripheral Nervous System and Neuromuscular Junction Disorders
Tumors of the Central Nervous System
Summary Review
Key Terms
References
18 Alterations of Neurologic Function in Children
Development of the Nervous System in Children
Structural Malformations
Alterations in Function: Encephalopathies
Cerebrovascular Disease in Children
Childhood Tumors
Summary Review
Key Terms
References
Unit 5 The Endocrine System
19 Mechanisms of Hormonal Regulation
Mechanisms of Hormonal Regulation
Structure and Function of the Endocrine Glands
Geriatric Considerations
Summary Review
Key Terms
References
20 Alterations of Hormonal Regulation
Mechanisms of Hormonal Alterations
Alterations of the Hypothalamic–Pituitary System
Alterations of Thyroid Function
Alterations of Parathyroid Function
Dysfunction of the Endocrine Pancreas: Diabetes Mellitus
Alterations of Adrenal Function
Summary Review
Key Terms
References
21 Obesity, Starvation, and Anorexia of Aging
Adipose Tissue
Obesity
Starvation
Anorexia of Aging
Summary Review
Key Terms
References
Unit 6 The Hematologic System
22 Structure and Function of the Hematologic System
Components of the Hematologic System
Development of Blood Cells
Mechanisms of Hemostasis
Pediatrics and Blood
Aging and Blood
Summary Review
Key Terms
References
23 Alterations of Hematologic Function
Anemia
Myeloproliferative Red Cell Disorders
Alterations of Leukocyte Function
Alterations of Lymphoid Function
Alterations of Splenic Function
Hemorrhagic Disorders and Alterations of Platelets and Coagulation
Summary Review
Key Terms
References
24 Alterations of Hematologic Function in Children
Disorders of Erythrocytes
Disorders of Coagulation and Platelets
Neoplastic Disorders
Summary Review
Key Terms
References
Unit 7 The Cardiovascular and Lymphatic Systems
25 Structure and Function of the Cardiovascular and Lymphatic Systems
Circulatory System
Heart
Systemic Circulation
The Lymphatic System
Summary Review
Key Terms
References
26 Alterations of Cardiovascular Function
Diseases of the Veins
Diseases of the Arteries
Disorders of the Heart Wall
Manifestations of Heart Disease
Shock
Summary Review
Key Terms
References
27 Alterations of Cardiovascular Function in Children
Congenital Heart Disease
Acquired Cardiovascular Disorders
Summary Review
Key Terms
References
Unit 8 The Pulmonary System
28 Structure and Function of the Pulmonary System
Structures of the Pulmonary System
Function of the Pulmonary System
Geriatric Considerations
Summary Review
Key Terms
References
29 Alterations of Pulmonary Function
Clinical Manifestations of Pulmonary Alterations
Pulmonary Disorders
Summary Review
Key Terms
References
30 Alterations of Pulmonary Function in Children
Disorders of the Upper Airways
Disorders of the Lower Airways
Sudden Infant Death Syndrome
Summary Review
Key Terms
References
Unit 9 The Renal and Urologic Systems
31 Structure and Function of the Renal and Urologic Systems
Structures of the Renal System
Renal Blood Flow and Glomerular Filtration
Kidney Function
Tests of Renal Function
Pediatric Considerations
Geriatric Considerations
Summary Review
Key Terms
References
32 Alterations of Renal and Urinary Tract Function
Urinary Tract Obstruction
Urinary Tract Infection
Glomerular Disorders
Acute Kidney Injury
Chronic Kidney Disease
Summary Review
Key Terms
References
33 Alterations of Renal and Urinary Tract Function in Children
Structural Abnormalities
Glomerular Disorders
Nephroblastoma
Bladder Disorders
Urinary Incontinence
Summary Review
Key Terms
References
Unit 10 The Reproductive Systems
34 Structure and Function of the Reproductive Systems
Development of the Reproductive Systems
The Female Reproductive System
Structure and Function of the Breast
The Male Reproductive System
Aging and Reproductive Function
Summary Review
Key Terms
References
35 Alterations of the Female Reproductive System
Abnormalities of the Female Reproductive Tract
Alterations of Sexual Maturation
Disorders of the Female Reproductive System
Disorders of the Female Breast
Summary Review
Key Terms
References
36 Alterations of the Male Reproductive System
Alterations of Sexual Maturation
Disorders of the Male Reproductive System
References
Disorders of the Male Breast
Sexually Transmitted Infections
Summary Review
Key Terms
References
Unit 11 The Digestive System
37 Structure and Function of the Digestive System
The Gastrointestinal Tract
Accessory Organs of Digestion
Geriatric Considerations
Summary Review
Key Terms
References
38 Alterations of Digestive Function
Disorders of the Gastrointestinal Tract
Disorders of the Accessory Organs of Digestion
Cancer of the Digestive System
Summary Review
Key Terms
References
39 Alterations of Digestive Function in Children
Congenital Impairment of Motility in the Gastrointestinal Tract
Acquired Impairment of Motility in the Gastrointestinal Tract
Impairment of Digestion, Absorption, and Nutrition
Diarrhea
Disorders of the Liver
Summary Review
Key Terms
References
Unit 12 The Musculoskeletal and Integumentary Systems
40 Structure and Function of the Musculoskeletal System
Structure and Function of Bones
Structure and Function of Joints
Structure and Function of Skeletal Muscles
Aging & the Musculoskeletal System
Summary Review
Key Terms
References
41 Alterations of Musculoskeletal Function
Musculoskeletal Injuries
Disorders of Bones
Disorders of Joints
References
Disorders of Skeletal Muscle
Musculoskeletal Tumors
Summary Review
Key Terms
References
42 Alterations of Musculoskeletal Function in Children
Congenital Defects
Bone and Joint Infection
Juvenile Idiopathic Arthritis
Osteochondroses
Scoliosis
Neuromuscular Disorders
Musculoskeletal Tumors
Nonaccidental Trauma
Summary Review
Key Terms
References
43 Structure, Function, and Disorders of the Integument
Structure and Function of the Skin
Disorders of the Skin
Disorders of the Hair
Disorders of the Nail
Geriatric Considerations
Summary Review
Key Terms
References
44 Alterations of the Integument in Children
Acne Vulgaris
Dermatitis
Infections of the Skin
Insect Bites and Parasites
Cutaneous Hemangiomas and Vascular Malformations
Other Skin Disorders
Summary Review
Key Terms
References
Index
Prefixes and Suffixes Used in Medical Terminology
Word Roots Commonly Used in Medical Terminology

Citation preview

Understanding Pathophysiology

SEVENTH EDITION

Sue E. Huether MS, PhD Professor Emerita, College of Nursing, University of Utah, Salt Lake City, Utah

Kathryn L. McCance MS, PhD Professor Emerita, College of Nursing, University of Utah, Salt Lake City, Utah

Valentina L. Brashers MD, FACP, FNAP Professor Emerita, University of Virginia, Charlottesville, Virginia

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Table of Contents Cover image Title Page Copyright Contributors Reviewers Preface Organization and Content for the Seventh Edition Features to Promote Learning Art Program Teaching/Learning Package Acknowledgments Dedication Introduction to Pathophysiology

Part 1 Basic Concepts of Pathophysiology Unit 1 The Cell 1 Cellular Biology

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Prokaryotes and Eukaryotes Cellular Functions Structure and Function of Cellular Components Cell-to-Cell Adhesions Cellular Communication and Signal Transduction Cellular Metabolism Membrane Transport: Cellular Intake and Output Cellular Reproduction: The Cell Cycle Tissues Summary Review Key Terms References 2 Genes and Genetic Diseases DNA, RNA, and Proteins: Heredity at the Molecular Level Chromosomes Elements of Formal Genetics Transmission of Genetic Diseases Linkage Analysis and Gene Mapping Multifactorial Inheritance Summary Review Key Terms References 3 Epigenetics and Disease Epigenetic Mechanisms Epigenetics and Human Development

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Epigenetics in Genomic Imprinting Environmental Impacts on Epigenetic Information Epigenetics and Cancer Future Directions Summary Review Key Terms References Additional Readings 4 Altered Cellular and Tissue Biology Cellular Adaptation Cellular Injury Manifestations of Cellular Injury Cellular Death Aging and Altered Cellular and Tissue Biology Somatic Death Summary Review Key Terms References 5 Fluids and Electrolytes, Acids and Bases Distribution of Body Fluids and Electrolytes Alterations in Water Movement Sodium, Chloride, and Water Balance Alterations in Sodium, Chloride, and Water Balance Alterations in Potassium and Other Electrolytes Acid–Base Balance

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Pediatric Considerations Geriatric Considerations Summary Review Key Terms References

Unit 2 Mechanisms of Self-Defense 6 Innate Immunity Human Defense Mechanisms Innate Immunity Acute and Chronic Inflammation Wound Healing Pediatric Considerations Geriatric Considerations Summary Review Key Terms References 7 Adaptive Immunity Overview of Adaptive Immunity Antigens and Immunogens Immune Response: Collaboration of B Cells and T Cells Humoral Immunity (Antibodies) Cell-Mediated Immunity Pediatric Considerations Geriatric Considerations

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Summary Review Key Terms References 8 Alterations in Immunity Hypersensitivity Reactions Immunologic Mechanisms of Hypersensitivity Reactions Deficiencies in Immunity Secondary (Acquired) Immune Deficiencies Summary Review Key Terms References 9 Infection Microorganisms and Humans: a Dynamic Relationship Infectious Disease Antibiotic/Antimicrobial Resistance Vaccines and Protection Against Infection Summary Review Key Terms References 10 Stress and Disease Background and General Concepts of Stress The Stress Systems Chronic Stress at an Early Age Increases the Risk of Developing Long-Lasting Pathophysiologic Alterations Linked to Poor Health and to Disease Negative Effects of Stress on Telomere Length, Aging, and Disease

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Coping and Intervention Strategies Summary Review Key Terms References

Unit 3 Cellular Proliferation: Cancer 11 Cancer Biology Cancer Terminology and Characteristics The Biology of Cancer Cells Clinical Manifestations of Cancer Diagnosis and Staging of Cancer Treatment of Cancer Summary Review Key Terms References 12 Cancer Epidemiology Genetics, Epigenetics, and Tissue In Utero and Early Life Conditions Environmental-Lifestyle Factors Summary Review Key Terms References 13 Cancer in Children and Adolescents Incidence, Etiology, and Types of Childhood Cancer

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Prognosis Summary Review Key Terms References

Part 2 Body Systems and Diseases Unit 4 The Neurologic System 14 Structure and Function of the Neurologic System Overview and Organization of the Nervous System Cells of the Nervous System The Nerve Impulse Central Nervous System Blood Supply Peripheral Nervous System Autonomic Nervous System Geriatric Considerations Summary Review Key Terms References 15 Pain, Temperature, Sleep, and Sensory Function Pain Temperature Regulation Sleep The Special Senses Geriatric Considerations

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Geriatric Considerations Somatosensory Function Summary Review Key Terms References 16 Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function Alterations in Cognitive Systems Alterations in Cerebral Hemodynamics Alterations in Neuromotor Function Alterations in Complex Motor Performance Extrapyramidal Motor Syndromes Summary Review Key Terms References 17 Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction Central Nervous System Disorders Peripheral Nervous System and Neuromuscular Junction Disorders Tumors of the Central Nervous System Summary Review Key Terms References 18 Alterations of Neurologic Function in Children Development of the Nervous System in Children Structural Malformations

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Alterations in Function: Encephalopathies Cerebrovascular Disease in Children Childhood Tumors Summary Review Key Terms References

Unit 5 The Endocrine System 19 Mechanisms of Hormonal Regulation Mechanisms of Hormonal Regulation Structure and Function of the Endocrine Glands Geriatric Considerations Summary Review Key Terms References 20 Alterations of Hormonal Regulation Mechanisms of Hormonal Alterations Alterations of the Hypothalamic–Pituitary System Alterations of Thyroid Function Alterations of Parathyroid Function Dysfunction of the Endocrine Pancreas: Diabetes Mellitus Alterations of Adrenal Function Summary Review Key Terms References

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21 Obesity, Starvation, and Anorexia of Aging Adipose Tissue Obesity Starvation Anorexia of Aging Summary Review Key Terms References

Unit 6 The Hematologic System 22 Structure and Function of the Hematologic System Components of the Hematologic System Development of Blood Cells Mechanisms of Hemostasis Pediatrics and Blood Aging and Blood Summary Review Key Terms References 23 Alterations of Hematologic Function Anemia Myeloproliferative Red Cell Disorders Alterations of Leukocyte Function Alterations of Lymphoid Function Alterations of Splenic Function

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Hemorrhagic Disorders and Alterations of Platelets and Coagulation Summary Review Key Terms References 24 Alterations of Hematologic Function in Children Disorders of Erythrocytes Disorders of Coagulation and Platelets Neoplastic Disorders Summary Review Key Terms References

Unit 7 The Cardiovascular and Lymphatic Systems 25 Structure and Function of the Cardiovascular and Lymphatic Systems Circulatory System Heart Systemic Circulation The Lymphatic System Summary Review Key Terms References 26 Alterations of Cardiovascular Function Diseases of the Veins Diseases of the Arteries

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Disorders of the Heart Wall Manifestations of Heart Disease Shock Summary Review Key Terms References 27 Alterations of Cardiovascular Function in Children Congenital Heart Disease Acquired Cardiovascular Disorders Summary Review Key Terms References

Unit 8 The Pulmonary System 28 Structure and Function of the Pulmonary System Structures of the Pulmonary System Function of the Pulmonary System Geriatric Considerations Summary Review Key Terms References 29 Alterations of Pulmonary Function Clinical Manifestations of Pulmonary Alterations Pulmonary Disorders

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Summary Review Key Terms References 30 Alterations of Pulmonary Function in Children Disorders of the Upper Airways Disorders of the Lower Airways Sudden Infant Death Syndrome Summary Review Key Terms References

Unit 9 The Renal and Urologic Systems 31 Structure and Function of the Renal and Urologic Systems Structures of the Renal System Renal Blood Flow and Glomerular Filtration Kidney Function Tests of Renal Function Pediatric Considerations Geriatric Considerations Summary Review Key Terms References 32 Alterations of Renal and Urinary Tract Function Urinary Tract Obstruction

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Urinary Tract Infection Glomerular Disorders Acute Kidney Injury Chronic Kidney Disease Summary Review Key Terms References 33 Alterations of Renal and Urinary Tract Function in Children Structural Abnormalities Glomerular Disorders Nephroblastoma Bladder Disorders Urinary Incontinence Summary Review Key Terms References

Unit 10 The Reproductive Systems 34 Structure and Function of the Reproductive Systems Development of the Reproductive Systems The Female Reproductive System Structure and Function of the Breast The Male Reproductive System Aging and Reproductive Function Summary Review

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Key Terms References 35 Alterations of the Female Reproductive System Abnormalities of the Female Reproductive Tract Alterations of Sexual Maturation Disorders of the Female Reproductive System Disorders of the Female Breast Summary Review Key Terms References 36 Alterations of the Male Reproductive System Alterations of Sexual Maturation Disorders of the Male Reproductive System References Disorders of the Male Breast Sexually Transmitted Infections Summary Review Key Terms References

Unit 11 The Digestive System 37 Structure and Function of the Digestive System The Gastrointestinal Tract Accessory Organs of Digestion

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Geriatric Considerations Summary Review Key Terms References 38 Alterations of Digestive Function Disorders of the Gastrointestinal Tract Disorders of the Accessory Organs of Digestion Cancer of the Digestive System Summary Review Key Terms References 39 Alterations of Digestive Function in Children Congenital Impairment of Motility in the Gastrointestinal Tract Acquired Impairment of Motility in the Gastrointestinal Tract Impairment of Digestion, Absorption, and Nutrition Diarrhea Disorders of the Liver Summary Review Key Terms References

Unit 12 The Musculoskeletal and Integumentary Systems 40 Structure and Function of the Musculoskeletal System Structure and Function of Bones

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Structure and Function of Joints Structure and Function of Skeletal Muscles Aging & the Musculoskeletal System Summary Review Key Terms References 41 Alterations of Musculoskeletal Function Musculoskeletal Injuries Disorders of Bones Disorders of Joints References Disorders of Skeletal Muscle Musculoskeletal Tumors Summary Review Key Terms References 42 Alterations of Musculoskeletal Function in Children Congenital Defects Bone and Joint Infection Juvenile Idiopathic Arthritis Osteochondroses Scoliosis Neuromuscular Disorders Musculoskeletal Tumors Nonaccidental Trauma

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Summary Review Key Terms References 43 Structure, Function, and Disorders of the Integument Structure and Function of the Skin Disorders of the Skin Disorders of the Hair Disorders of the Nail Geriatric Considerations Summary Review Key Terms References 44 Alterations of the Integument in Children Acne Vulgaris Dermatitis Infections of the Skin Insect Bites and Parasites Cutaneous Hemangiomas and Vascular Malformations Other Skin Disorders Summary Review Key Terms References Index Prefixes and Suffixes Used in Medical Terminology

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Word Roots Commonly Used in Medical Terminology

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Contributors Barbara J. Boss RN, PhD, CFNP, CANP Professor of Nursing Retired University of Mississippi Jackson, Mississippi Valentina L. Brashers MD, FACP, FNAP Professor Emerita University of Virginia Charlottesville, Virginia Lois E. Brenneman MSN, FNP Adjunct Faculty Fairleigh Dickinson University Florham Park, New Jersey Russell J. Butterfield MD, PhD Assistant Professor Neurology and Pediatrics University of Utah Salt Lake City, Utah Sara J. Fidanza MS, RN, CNS-BC, CPNP-PC, DHI Digestive Health Institute Advanced Practice Nurse Children's Hospital Colorado Aurora, Colorado Diane P. Genereux PhD Research Scientist Vertebrate Genome Biology Broad Institute of MIT and Harvard Cambridge, Massachusetts Sue E. Huether MS, PhD Professor Emerita Nursing University of Utah Salt Lake City, Utah Lynn B. Jorde PhD Mark and Kathie Miller Presidential Professor and Chair

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Department of Human Genetics University of Utah School of Medicine Salt Lake City, Utah Lauri A. Linder PhD, APRN, CPON Assistant Professor College of Nursing University of Utah Salt Lake City, Utah Clinical Nurse Specialist Cancer Transplant Center Primary Children's Hospital Salt Lake City, Utah Kathryn L. McCance MS, PhD Professor Emerita Nursing University of Utah Salt Lake City, Utah Sue Ann McCann MSN, RN Programmatic Nurse Specialist Nursing University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Clinical Research Coordinator Dermatology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Noreen Heer Nicol PhD, RN, FNP, NEA-BC Associate Professor College of Nursing University of Colorado Denver, Colorado Jennifer Peterson PhD, RN, CCNS Sue and Bill Gross School of Nursing University of California, Irvine Irvine, California Nancy Pike PhD, CPNP-PC/AC, FAAN Associate Professor UCLA School of Nursing Los Angeles, California Pediatric Nurse Practitioner Cardiothoracic Surgery Children's Hospital Los Angeles

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Los Angeles, California Geri C. Reeves PhD, APRN, FNP-BC Assistant Professor School of Nursing Vanderbilt University Nashville, Tennessee Patricia Ring RN, MSN, PNP, BC Retired Renal/Voiding Improvement Program Children's Hospital Wisconsin Milwaukee, Wisconsin George W. Rodway PhD, APRN Associate Clinical Professor UC Davis School of Nursing Sacramento, California Neal S. Rote PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology University Hospitals Case Medical Center Case Western Reserve University School of Medicine Cleveland, Ohio Sharon Sables-Baus PhD, RN, MPA, PCNS-BC, CPPS, FAAN Associate Professor University of Colorado College of Nursing and School of Medicine, Department Pediatrics Denver, Colorado Benjamin A. Smallheer PhD Assistant Professor School of Nursing Duke University, Durham North Carolina Acute Care Nurse Practitioner Critical Care Medicine Duke Raleigh Hospital Raleigh, North Carolina Lorey K. Takahashi PhD Professor of Psychology Department of Psychology University of Hawaii at Manoa Honolulu, Hawaii

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Karen Turner BS Freelance Editor Editorial TurnKey Content Melbourne, Florida

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Reviewers Jennifer B. Drexler MSN, RN, CCRN Clinician Faculty Educator College of Nursing University of New Mexico College of Nursing Albuquerque, New Mexico Linda Phillips FNP-C Clinical Associate Professor Herzing University Brookfield, Wisconsin Shawn Theobald EdD(c), MS(N), MBA, RN Assistant Professor College of Health Sciences - Nursing University of Arkansas – Fort Smith Fort Smith, Arkansas Linda Turchin MSN, CNE Associate Professor of Nursing Fairmont State University Fairmont, West Virginia

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Preface The updates for the seventh edition of Understanding Pathophysiology, include a simplification of the content to make it less complex and easier for student comprehension. The primary focus of the text is the pathophysiology associated with the most common diseases. Some of the molecular and cellular content has been rewritten into more general explanations of disease processes. The text has also been written to assist students with the translation of the concepts and processes of pathophysiology into clinical practice and to promote lifelong learning. For preparatory knowledge, students need to have a good understanding of human organ system anatomy and physiology. Because of the rapidly evolving discovery of disease mechanisms and treatment at the molecular and cellular level, students also need to have a working understanding of cell structure and function. We continue to include discussions of the following interconnected topics to highlight their importance for clinical practice:

• Pathophysiologic alterations of organ and cell function related to mechanisms of disease • A life-span approach that includes special sections on aging and separate chapters on children • Epidemiology and incidence rates showing regional and worldwide differences that reflect the importance of environmental and lifestyle factors on disease initiation and progression • Sex differences that affect epidemiology and pathophysiology • Clinical manifestations, summaries of treatment, and health promotion/risk reduction strategies

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Organization and Content for the Seventh Edition The book is organized into two parts: Part One, Basic Concepts of Pathophysiology, and Part Two, Body Systems and Diseases. All content has been updated and includes the most common content related to mechanisms of disease.

Part One: Basic Concepts of Pathophysiology Part One introduces basic principles and processes that are important for a contemporary understanding of the pathophysiology of common diseases. The concepts include descriptions of cell structure, cellular transport and communication; forms of cell injury; genes and genetic disease; epigenetics; fluid and electrolytes and acid and base balance; immunity, inflammation and wound healing; mechanisms of infection; stress, coping, and illness; tumor biology and cancer epidemiology. We separated the content on infection into a new chapter, Chapter 9.

Part Two: Body Systems and Diseases Part Two presents the pathophysiology of the most common alterations according to body system. To promote readability and comprehension, we have used a logical sequence and uniform approach in presenting the content of the units and chapters. Each unit focuses on a specific organ system and contains chapters related to anatomy and physiology, the pathophysiology of the most common diseases, and common alterations in children. The anatomy and physiology content is presented as a review to enhance the learner's understanding of the structural and functional changes inherent in pathophysiology. A brief summary of normal aging effects is included at the end of these review chapters. The general organization of each disease/disorder discussion includes an introductory paragraph on relevant risk factors and epidemiology, a significant focus on pathophysiology and clinical manifestations, and then a brief review of evaluation and treatment. A new chapter was added with content related to obesity, starvation, and anorexia of aging, Chapter 21.

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Features to Promote Learning A number of features are incorporated into this text that guide and support learning and understanding, including:

• Chapter Outlines including page numbers for easy reference • Quick Check questions strategically placed throughout each chapter to help readers confirm their understanding of the material; answers are included on the textbook's Evolve website • Risk Factors boxes for selected diseases • Did You Know boxes • End-of-chapter Summary Reviews that condense the major concepts of each chapter into an easy-to-review list format; printable versions of these are available on the textbook's Evolve website • Key Terms set in blue boldface in text and listed, with page numbers, at the end of each chapter • Special boxes for Aging and Pediatrics content that highlight discussions of life-span alterations

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Art Program All of the figures and photographs have been carefully reviewed, revised, or updated. This edition features approximately 100 new or heavily revised illustrations and photographs with a total of approximately 1000 images. The figures and algorithms are designed to help students visually understand sometimes difficult and complex material. High-quality photographs show actual pathologic features of disease. Micrographs show normal and abnormal cellular structure. The combination of illustrations, algorithms, photographs, and use of color for tables and boxes allows a more complete understanding of essential information.

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Teaching/Learning Package For Students The free electronic Student Resources on Evolve include review questions and answers, numerous animations, answers to the Quick Check questions in the book, chapter summary reviews, and bonus case studies with questions and answers. These electronic resources enhance learning options for students. Go to http://evolve.elsevier.com/Huether. The newly rewritten Study Guide includes many different question types, aiming to help the broad spectrum of student learners. Question types include the following: Choose the Correct Words Complete These Sentences Categorize These Clinical Examples Explain the Pictures Teach These People about Pathophysiology Plus many more… Answers are found in the back of the Study Guide for easy reference for students.

For Instructors The electronic Instructor Resources on Evolve are available free to instructors with qualified adoptions of the textbook and include the following: TEACH Lesson Plans with case studies to assist with clinical application; a Test Bank of more than 1200 items; PowerPoint Presentations for each chapter, with integrated images, audience response questions, and case studies; and an Image Collection of approximately 1000 key figures from the text. All of these teaching resources are also available to instructors on the book's Evolve site. Plus the Evolve Learning System provides a comprehensive suite of course communication and organization tools that allow you to upload your class calendar and syllabus, post scores and announcements, and more. Go to http://evolve.elsevier.com/Huether. The most exciting part of the learning support package is Pathophysiology Online, a complete set of online modules that provide thoroughly developed lessons on the most important and difficult topics in pathophysiology supplemented with illustrations, animations, interactive activities, interactive algorithms, self-assessment reviews, and exams. Instructors can use it to enhance traditional classroom lecture courses or for distance and online-only courses. Students can use it as a self-guided study tool.

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Acknowledgments This book would not be possible without the knowledge and collaboration of our contributing authors, both those who have worked with us through previous editions and the new members of our team. Their reviews and synthesis of the evidence and clear concise presentation of information is a strength of the text. We thank them. The reviewers for this edition provided excellent recommendations for focus of content and revisions. We appreciate their insightful work. Tina Brashers, MD, is our section editor and a contributing author. Tina is a distinguished teacher and has received numerous awards for her teaching and work with nursing and medical students and faculty. She is nationally known for her leadership and development in promoting and teaching interprofessional collaboration and is the founder of the Center for Academic Strategic Partnerships for Interprofessional Research and Education (ASPIRE) at the University of Virginia. Tina brings innovation and clarity to the subject of pathophysiology. Her contributions to the online course continue to be intensive and creative, and a significant learning enhancement for students. Thank you, Tina, for the outstanding quality of your work. Karen Turner joined our team with a new role for this edition. She assisted with the editing of several chapters, managed the revision of artwork, and organized the flow of content for the Summary Reviews. She is an experienced and dedicated editor and made significant contributions to this edition. Thank you, Karen. Kellie White was our Executive Content Strategist for the first year of the revision until she was promoted to another position. We appreciate her helpful leadership and guidance not only for this edition but, for the past years that she has worked with us. Thank you, Kellie. Jennifer Wade was our Content Development Specialist. Jennifer kept us on track and managed the multiple tasks of acquiring images and getting the manuscript ready for copy editing and page proofs. Thank you, Jennifer. We are particularly grateful to Cassie Carey who jumped into the copy edit process and kept us going when Beth Welch, our long time copy editor, had to take medical leave. We appreciate the work you both contributed to this edition. The internal layout, selection of colors, and design of the cover were done by our Designer, Maggie Reid. Great work, Maggie! Thanks to the team from Graphic World, who created many new images and managed the cleanup and scanning of artwork obtained from many resources. Rich Barber was our Senior Project Manager and brought us into the home stretch and took us through copy edit to final page proofs. Thank you, Rich. Tamara Meyers, Director of Traditional Nursing Programs, provided the oversight for the entire 7th edition revision. We are thankful for her exceptional leadership, coordination and problem solving in bringing this project to completion. We thank the Department of Dermatology at the University of Utah School of Medicine, which provided numerous photos of skin lesions. Thank you to our many colleagues and friends at the University of Utah College of Nursing and Health Sciences Center for their suggestions and content critiques. We extend gratitude to those who contributed to the book supplements. Linda Felver has created an all new inventive and resourceful Study Guide. Thank you, Linda, for your very

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astute edits. A special thanks to Amber Ballard and Karen Turner for their thorough approach in preparing the materials for the Evolve website. Tina Brashers, Amber Ballard, and Linda Turchin also updated the interactive online lessons and activities for Pathophysiology Online. Sincerely and with great affection we thank our families, especially Mae and John. Always supportive, you make the work possible! Sue E. Huether Kathryn L. McCance

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Dedication We dedicate this book to Sue Anne Meeks, who has been our manuscript manager since the first edition of Understanding Pathophysiology and for all of the editions of our more extensive book, Pathophysiology: The Biologic Basis of Disease in Adults and Children. The behind-the-scene processes for the development and revision of a major textbook is extensive and requires coordination, attention to detail, organizational skills, good communication, and lots of laughter. Sue is prodigious; she has been a tireless, dedicated, and exceptionally fun person. She is now ready for retirement. We will forever be grateful for her colossal work. We could not have done it without her at our side for the past 30 years. We wish her continuing joy and happiness as she begins her next life adventure.

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Introduction to Pathophysiology The word root “patho” is derived from the Greek word pathos, which means suffering. The Greek word root “logos” means discourse or, more simply, system of formal study, and “physio” refers to functions of an organism. Altogether, pathophysiology is the study of the underlying changes in body physiology (molecular, cellular, and organ systems) that result from disease or injury. Important, however, is the inextricable component of suffering and the psychological, spiritual, social, cultural, and economic implications of disease. The science of pathophysiology seeks to provide an understanding of the mechanisms of disease and to explain how and why alterations in body structure and function lead to the signs and symptoms of disease. Understanding pathophysiology guides healthcare professionals in the planning, selection, and evaluation of therapies and treatments. Knowledge of human anatomy and physiology and the interrelationship among the various cells and organ systems of the body is an essential foundation for the study of pathophysiology. Review of this subject matter enhances comprehension of pathophysiologic events and processes. Understanding pathophysiology also entails the utilization of principles, concepts, and basic knowledge from other fields of study including pathology, genetics, epigenetics, immunology, and epidemiology. A number of terms are used to focus the discussion of pathophysiology; they may be used interchangeably at times, but that does not necessarily indicate that they have the same meaning. Those terms are reviewed here for the purpose of clarification. Pathology is the investigation of structural alterations in cells, tissues, and organs, which can help identify the cause of a particular disease. Pathology differs from pathogenesis, which is the pattern of tissue changes associated with the development of disease. Etiology refers to the study of the cause of disease. Diseases may be caused by infection, heredity, gene–environment interactions, alterations in immunity, malignancy, malnutrition, degeneration, or trauma. Diseases that have no identifiable cause are termed idiopathic. Diseases that occur as a result of medical treatment are termed iatrogenic (for example, some antibiotics can injure the kidney and cause renal failure). Diseases that are acquired as a consequence of being in a hospital environment are called nosocomial. An infection that develops as a result of a person's immune system being depressed after receiving cancer treatment during a hospital stay would be defined as a nosocomial infection. Diagnosis is the naming or identification of a disease. A diagnosis is made from an evaluation of the evidence accumulated from the presenting signs and symptoms, health and medical history, physical examination, laboratory tests, and imaging. A prognosis is the expected outcome of a disease. Acute disease is the sudden appearance of signs and symptoms that last only a short time. Chronic disease develops more slowly and the signs and symptoms last for a long time, perhaps for a lifetime. Chronic diseases may have a pattern of remission and exacerbation. Remissions are periods when symptoms disappear or diminish significantly. Exacerbations are periods when the symptoms become worse or more severe. A complication is the onset of a disease in a person who is already coping

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with another existing disease (for example, a person who has undergone surgery to remove a diseased appendix may develop the complication of a wound infection or pneumonia). Sequelae are unwanted outcomes of having a disease or are the result of trauma, such as paralysis resulting from a stroke or severe scarring resulting from a burn. Clinical manifestations are the signs and symptoms or evidence of disease. Signs are objective alterations that can be observed or measured by another person, measures of bodily functions such as pulse rate, blood pressure, body temperature, or white blood cell count. Some signs are local, such as redness or swelling, and other signs are systemic, such as fever. Symptoms are subjective experiences reported by the person with disease, such as pain, nausea, or shortness of breath; and they vary from person to person. The prodromal period of a disease is the time during which a person experiences vague symptoms such as fatigue or loss of appetite before the onset of specific signs and symptoms. The term insidious symptoms describes vague or nonspecific feelings and an awareness that there is a change within the body. Some diseases have a latent period, a time during which no symptoms are readily apparent in the affected person, but the disease is nevertheless present in the body; an example is the incubation phase of an infection or the early growth phase of a tumor. A syndrome is a group of symptoms that occur together and may be caused by several interrelated problems or a specific disease; severe acute respiratory syndrome (SARS), for example, presents with a set of symptoms that include headache, fever, body aches, an overall feeling of discomfort, and sometimes dry cough and difficulty breathing. A disorder is an abnormality of function; this term also can refer to an illness or a particular problem such as a bleeding disorder. Epidemiology is the study of tracking patterns or disease occurrence and transmission among populations and by geographic areas. Incidence of a disease is the number of new cases occurring in a specific time period. Prevalence of a disease is the number of existing cases within a population during a specific time period. Risk factors, also known as predisposing factors, increase the probability that disease will occur, but these factors are not the cause of disease. Risk factors include heredity, age, gender, race, environment, and lifestyle. A precipitating factor is a condition or event that does cause a pathologic event or disorder. For example, asthma is precipitated by exposure to an allergen, or angina (pain) is precipitated by exertion. Pathophysiology is an exciting field of study that is ever-changing as new discoveries are made. Understanding pathophysiology empowers healthcare professionals with the knowledge of how and why disease develops and informs their decision making to ensure optimal healthcare outcomes. Embedded in the study of pathophysiology is understanding that suffering is a personal, individual experience and a major component of disease.

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PA R T 1

Basic Concepts of Pathophysiology OUTLINE Unit 1 The Cell Unit 2 Mechanisms of Self-Defense Unit 3 Cellular Proliferation: Cancer

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UNIT 1

The Cell OUTLINE 1 Cellular Biology 2 Genes and Genetic Diseases 3 Epigenetics and Disease 4 Altered Cellular and Tissue Biology 5 Fluids and Electrolytes, Acids and Bases

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Cellular Biology Kathryn L. McCance

CHAPTER OUTLINE Prokaryotes and Eukaryotes, 1 Cellular Functions, 1 Structure and Function of Cellular Components, 2 Nucleus, 3 Cytoplasmic Organelles, 3 Plasma Membranes, 4 Cellular Receptors, 10 Cell-to-Cell Adhesions, 11 Extracellular Matrix and Basement Membrane, 12 Specialized Cell Junctions, 12 Cellular Communication and Signal Transduction, 13 Cellular Metabolism, 17 Role of Adenosine Triphosphate, 17 Food and Production of Cellular Energy, 17 Oxidative Phosphorylation, 18 Membrane Transport: Cellular Intake and Output, 18 Electrolytes as Solutes, 20 Transport by Vesicle Formation, 23 Movement of Electrical Impulses: Membrane Potentials, 26 Cellular Reproduction: The Cell Cycle, 27 Phases of Mitosis and Cytokinesis, 27 Control of Cell Division and Cell Growth: Mitogens, Growth Factors, and Survival Factors, 28 DNA Damage Response: Blocks Cell Division 28 Tissues, 28 Tissue Formation and Differentiation, 29

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All body functions depend on the integrity of cells. Therefore an understanding of cellular biology is increasingly necessary to comprehend disease processes. An overwhelming amount of information reveals how cells behave as a multicellular “social” organism. At the heart of it all is cellular communication (cellular “crosstalk”)—how messages originate and are transmitted, received, interpreted, and used by the cell. Streamlined conversation between, among, and within cells maintains cellular function and specialization. Cells must demonstrate a “chemical fondness” for other cells to maintain the integrity of the entire organism. When they no longer tolerate this fondness, the conversation breaks down, and cells either adapt (sometimes altering function) or become vulnerable to isolation, injury, or disease.

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Prokaryotes and Eukaryotes Living cells generally are divided into eukaryotes and prokaryotes. The cells of higher animals and plants are eukaryotes, as are the single-celled organisms, fungi, protozoa, and most algae. Prokaryotes include cyanobacteria (blue-green algae), bacteria, and rickettsiae. Prokaryotes traditionally were studied as core subjects of molecular biology. Today emphasis is on the eukaryotic cell; much of its structure and function have no counterpart in bacterial cells. Eukaryotes (eu = good; karyon = nucleus; also spelled “eucaryotes”) are larger and have more extensive intracellular anatomy and organization than prokaryotes. Eukaryotic cells have a characteristic set of membrane-bound intracellular compartments, called organelles, that includes a well-defined nucleus. The prokaryotes contain no organelles, and their nuclear material is not encased by a nuclear membrane. Prokaryotic cells are characterized by lack of a distinct nucleus. Besides having structural differences, prokaryotic and eukaryotic cells differ in chemical composition and biochemical activity. The nuclei of prokaryotic cells carry genetic information in a single circular chromosome, and they lack a class of proteins called histones, which in eukaryotic cells bind with deoxyribonucleic acid (DNA) and are involved in the supercoiling of DNA. Eukaryotic cells have several or many chromosomes. Protein production, or synthesis, in the two classes of cells also differs because of major structural differences in ribonucleic acid (RNA)–protein complexes. Other distinctions include differences in mechanisms of transport across the outer cellular membrane and in enzyme content.

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Cellular Functions Cells become specialized through the process of differentiation, or maturation, so that some cells eventually perform one kind of function and other cells perform other functions. Cells with a highly developed function, such as movement, often lack some other property, such as hormone production, which is more highly developed in other cells. The eight chief cellular functions are as follows: 1. Movement. Muscle cells can generate forces that produce motion. Muscles that are attached to bones produce limb movements, whereas those muscles that enclose hollow tubes or cavities move or empty contents when they contract (e.g., the colon). 2. Conductivity. Conduction as a response to a stimulus is manifested by a wave of excitation, an electrical potential that passes along the surface of the cell to reach its other parts. Conductivity is the chief function of nerve cells. 3. Metabolic absorption. All cells can take in and use nutrients and other substances from their surroundings. 4. Secretion. Certain cells, such as mucous gland cells, can synthesize new substances from substances they absorb and then secrete the new substances to serve, as needed, elsewhere. 5. Excretion. All cells can rid themselves of waste products resulting from the metabolic breakdown of nutrients. Membrane-bound sacs (lysosomes) within cells contain enzymes that break down, or digest, large molecules, turning them into waste products that are released from the cell. 6. Respiration. Cells absorb oxygen, which is used to transform nutrients into energy in the form of adenosine triphosphate (ATP). Cellular respiration, or oxidation, occurs in organelles called mitochondria. 7. Reproduction. Tissue growth occurs as cells enlarge and reproduce themselves. Even without growth, tissue maintenance requires that new cells be produced to replace cells that are lost normally through cellular death. Not all cells are capable of continuous division. (see Chapter 4). 8. Communication. Communication is vital for cells to survive as a society of cells. Appropriate communication allows the maintenance of a dynamic steady state.

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Structure and Function of Cellular Components Fig. 1.1, A, shows a “typical” eukaryotic cell, which consists of three components: an outer membrane called the plasma membrane, or plasmalemma; a fluid “filling” called cytoplasm (see Fig. 1.1, B); and the “organs” of the cell—the membrane-bound intracellular organelles, among them the nucleus.

FIGURE 1.1 Typical Components of a Eukaryotic Cell and Structure of the Cytoplasm. A, Artist's interpretation of cell structure. Note the many mitochondria known as the

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“power plants” of the cell. Note, too, the innumerable dots bordering the endoplasmic reticulum. These are ribosomes, the cell's “protein factories.” B, Color-enhanced electron micrograph of a cell showing the cell is crowded. (B, from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)

Nucleus The nucleus, which is surrounded by the cytoplasm and generally is located in the center of the cell, is the largest membrane-bound organelle. Two pliable membranes compose the nuclear envelope (Fig. 1.2, A). The nuclear envelope is pockmarked with pits, called nuclear pores, which allow chemical messages to exit and enter the nucleus (see Fig. 1.2, B). The outer membrane is continuous with membranes of the endoplasmic reticulum (see Fig. 1.1). The nucleus contains the nucleolus (a small dense structure composed largely of RNA), most of the cellular DNA, and the DNA-binding proteins (i.e., the histones) that regulate its activity. The DNA “chain” in eukaryotic cells is so long that it is easily broken. Therefore the histones that bind to DNA cause DNA to fold into chromosomes (see Fig. 1.2, C), which decreases the risk of breakage and is essential for cell division in eukaryotes.

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FIGURE 1.2 The Nucleus. The nucleus is composed of a double membrane, called a nuclear envelope, which encloses the fluid-filled interior, called nucleoplasm. The chromosomes are suspended in the nucleoplasm (illustrated here much larger than actual size to show the tightly packed deoxyribonucleic acid [DNA] strands). Swelling at one or more points of the chromosome, shown in A, occurs at a nucleolus where genes are being copied into ribonucleic acid (RNA). The nuclear envelope is studded with pores. B, The pores are visible as dimples in this freeze-etch of a nuclear envelope. C, Histone-folding DNA in chromosomes. (A, C, from McCance KL, Huether S: Pathophysiology: the biologic basis for disease in adults and children, St. Louis, 2019, Elsevier. B, from Raven PH, Johnson GB: Biology, St Louis, 1992, Mosby.)

The primary functions of the nucleus are cell division and control of genetic information. Other functions include the replication and repair of DNA and the transcription of the information stored in DNA. Genetic information is transcribed into RNA, which can be processed into messenger, transport, and ribosomal RNAs and introduced into the cytoplasm, where it directs cellular activities. Most of the processing of RNA occurs in the nucleolus. (The roles of DNA and RNA in protein synthesis are discussed in Chapter 2.)

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Cytoplasmic Organelles Cytoplasm is an aqueous solution (cytosol) that fills the cytoplasmic matrix—the space between the nuclear envelope and the plasma membrane. The cytosol represents about half the volume of a eukaryotic cell. It contains thousands of enzymes involved in intermediate metabolism and is crowded with ribosomes making proteins (see Fig. 1.1, B). Newly synthesized proteins remain in the cytosol if they lack a signal for transport to a cell organelle.1 The organelles suspended in the cytoplasm are enclosed in biologic membranes, so they can simultaneously carry out functions requiring different biochemical environments. Many of these functions are directed by coded messages carried from the nucleus by RNA. The functions include synthesis of proteins and hormones and their transport out of the cell, isolation and elimination of waste products from the cell, performance of metabolic processes, breakdown and disposal of cellular debris and foreign proteins (antigens), and maintenance of cellular structure and motility. The cytosol is a storage unit for fat, carbohydrates, and secretory vesicles. Table 1.1 lists the principal cytoplasmic organelles. TABLE 1.1 Principal Cytoplasmic Organelles Organelle Ribosomes

Characteristics and Description Ribonucleic acid (RNA)–protein complexes (nucleoproteins) synthesized in nucleolus and secreted into cytoplasm. Provide sites for cellular protein synthesis. Endoplasmic Network of tubular channels (cisternae) that extend throughout outer nuclear membrane. Specializes reticulum in synthesis, folding, and transport of protein and lipid components of most organelles. A new role is sensing cellular stress.

(From McCance KL, Huether S: Pathophysiology: the biologic basis for disease in adults and children, St. Louis, 2019, Elsevier.)

Golgi complex

Network of smooth membranes and vesicles located near nucleus. Responsible for processing and packaging proteins onto secretory vesicles that break away from the complex and migrate to various intracellular and extracellular destinations, including plasma membrane. Best-known vesicles are those that have coats largely made of the protein clathrin. Proteins in the complex bind to the

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cytoskeleton, generating tension that helps organelle function and keep its stretched shape intact. The complex is a refining plant and directs traffic.

(From McCance KL, Huether S: Pathophysiology: the biologic basis for disease in adults and children, St. Louis, 2019, Elsevier.)

Lysosomes

Sac-like structures that contain enzymes for digesting most cellular substances to their basic form, such as amino acids, fatty acids, and carbohydrates (sugars). Cellular injury leads to release of lysosomal enzymes that cause cellular self-destruction. A new function of lysosomes is signaling hubs of a sophisticated network for cellular adaptation.

(From McCance KL, Huether S: Pathophysiology: the biologic basis for disease in adults and children, St. Louis, 2019, Elsevier.)

Peroxisomes

Similar to lysosomes in appearance but contain several oxidative enzymes (e.g., catalase, urate oxidase)

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Mitochondria

that produce hydrogen peroxide; reactions detoxify various wastes (see Fig. 1.1, A). Contain metabolic machinery needed for cellular energy metabolism. Enzymes of respiratory chain (electron-transport chain), found in inner membrane of mitochondria, generate most of cell's adenosine triphosphate (ATP) (oxidative phosphorylation). Have a role in osmotic regulation, pH control, calcium homeostasis, and cell signaling.

(From McCance KL, Huether S: Pathophysiology: the biologic basis for disease in adults and children, St. Louis, 2019, Elsevier.)

Cytoskeleton

“Bone and muscle” of cell. Composed of a network of protein filaments, including microtubules and actin filaments (microfilaments); forms cell extensions (microvilli, cilia, flagella). Intermediate filaments bridge the cytoplasm from one cell junction to another strengthening and supporting the sheet of epithelium.

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(From McCance KL, Huether S: Pathophysiology: the biologic basis for disease in adults and children, St. Louis, 2019, Elsevier.)

Quick Check 1.1 1. Why is the process of differentiation essential to specialization? Give an example. 2. Describe at least two cellular functions.

Plasma Membranes Every cell is contained within a membrane with gates, channels, and pumps. Membranes surround the cell or enclose an intracellular organelle and are exceedingly important to normal physiologic function because they control the composition of the space, or compartment, they enclose. Membranes can allow or exclude various molecules, and because of selective transport systems, they can move molecules in or out of the space (Fig. 1.3). By controlling the movement of substances from one compartment to another, membranes exert a powerful influence on metabolic pathways. Directional transport is facilitated by polarized domains, distinct apical and basolateral domains. Cell polarity, the direction of cellular transport, maintains normal cell and tissue structure for numerous functions (e.g., movement of nutrients in and out of the cell) and becomes altered with diseases (Fig. 1.4). The plasma membrane also has an important role in cell-to-cell recognition. Other functions of the plasma membrane include cellular mobility and the maintenance of cellular shape (Table 1.2).

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FIGURE 1.3 Functions of Plasma Membrane Proteins. The plasma membrane proteins illustrated here show a variety of functions performed by the different types of plasma membranes. (From Raven PH, Johnson GB: Understanding biology, ed 3, Dubuque, IA, 1995, Brown.)

FIGURE 1.4 Cell Polarity of Epithelial Cells. Schematic of cell polarity (cell direction) of epithelial cells. Shown are the directions of the basal side and the apical side. Organelles and cytoskeleton are also arranged directionally to enable, for example, intestinal cell secretion and absorption. (Adapted from Life science web textbook, The University of Tokyo.)

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TABLE 1.2 Plasma Membrane Functions Cellular Membrane Functions Mechanism Structure Usually thicker than membranes of intracellular organelles Containment of cellular organelles Maintenance of relationship with cytoskeleton, endoplasmic reticulum, and other organelles Maintenance of fluid and electrolyte balance (ion channels) Outer surfaces of plasma membranes in many cells are not smooth but are dimpled with cave-like indentations called caveolae; they are also studded with cilia or even smaller cylindrical projections called microvilli; both are capable of movement Protection Barrier to toxic molecules and macromolecules (proteins, nucleic acids, polysaccharides) Barrier to foreign organisms and cells Activation Hormones (regulation of cellular activity) of cell Mitogens (cellular division; see Chapter 2) Antigens (antibody synthesis; see Chapter 7) Growth factors (proliferation and differentiation; see Chapter 11) Storage Storage site for many receptors Transport (e.g., sodium [Na+] pump) Diffusion and exchange diffusion Endocytosis (pinocytosis, phagocytosis) Exocytosis (secretion) Active transport Cell-to-cell Communication, anchors (integrins), and attachment at junctional complexes interaction Symbiotic nutritive relationships Release of enzymes and antibodies to extracellular environment Relationships with extracellular matrix

Modified from King DW, Fenoglio CM, Lefkowitch JH: General pathology: principles and dynamics, Philadelphia, 1983, Lea & Febiger.

Membrane Composition The basic structure of cell membranes is the lipid bilayer, composed of two apposing leaflets and proteins that span the bilayer or interact with the lipids on either side of the two leaflets (Fig. 1.5). Lipid research is growing and principles of membrane organization are being overhauled. In short, the main constituents of cell membranes are lipids and proteins. Historically, the plasma membrane was described as a fluid lipid bilayer (fluid mosaic model) composed of a uniform lipid distribution with inserted moving proteins. Although the notion is controversial, it now appears that the lipid bilayer is a much more complex structure where lipids and proteins are not uniformly distributed but may separate into discrete units called microdomains, differing in their protein and lipid compositions. Different membranes have varying percentages of lipids and proteins. Intracellular membranes may have a higher percentage of proteins than do plasma membranes, presumably because most enzymatic activity occurs within organelles. The membrane organization is achieved through noncovalent bonds that allow different physical states called phases (solid gel, fluid liquid–crystalline, and liquid ordered). These phases can change under physiologic factors, such as temperature and pressure fluctuations. Carbohydrates are mainly associated with plasma membranes, in which they are chemically combined with lipids, forming glycolipids, and with proteins, forming glycoproteins (see Fig. 1.5).

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FIGURE 1.5 Lipid Bilayer Membranes. A, Concepts of biologic membranes have markedly changed in the last two decades, from the classic fluid mosaic model to the current model that lipids and proteins are not evenly distributed but can isolate into microdomains, differing in their protein and lipid composition. Important for pathophysiology is the proposal that protein–lipid interactions can be critical for correct insertion, folding, and orientation of membrane proteins. For example, diseases related to lipids that interfere with protein folding are becoming more prevalent. B, Each phospholipid molecule consists of a phosphate functional group and two fatty acid chains attached to a glycerol molecule. C, The fatty acid chains and glycerol form nonpolar, hydrophobic “tails,” and the phosphate functional group forms the polar, hydrophilic “head” of the phospholipid molecule. When placed in water, the hydrophobic tails of the molecule face inward, away from the water, and the hydrophilic head faces outward, toward the water. D, The cell membrane is not static but is always moving. Observed for the first time from measurements taken at the National Institute of Standards and Technology (NIST) and France's Institute Laue-Langevin (ILL). (A & D, adapted from Bagatolli LA et al: An outlook on organization of lipids in membranes: searching for a realistic connection with the organization of biological membranes, Prog Lipid Res 49[4]:378–389, 2010; Contreras FX et al: Specificity of intramembrane protein-lipid interactions, Cold Spring Harb Perspect Biol 3[6]:pii a004705, 2011; Cooper GM: The cell—a molecular approach, ed 2, Sunderland, MA, 2000, Sinauer Associates; Defamie N, Mesnil M: Biochim Biophys Acta 1818(8):1866–1869, 2012; Woodka AC et al: Phys Rev Lett 9(5):058102, 2012. B & C, from Raven PH, Johnson GB: Understanding biology, ed 3, Dubuque, IA, 1995, Brown.)

The outer surface of the plasma membrane in many types of cells, especially endothelial cells and adipocytes, is not smooth but dimpled with flask-shaped invaginations known as caveolae (“tiny caves”). Caveolae are thought to serve as a storage site for many receptors, provide a route for transport into the cell and may act as the initiator for relaying signals from several extracellular chemical messengers into the cell's interior. Lipids. Each lipid molecule is said to be polar, or amphipathic, which means that one part is hydrophobic (uncharged, or “water hating”) and another part is hydrophilic (charged, or “water loving”) (see Fig. 1.5, B). The membrane spontaneously organizes itself into two layers because of these two incompatible solubilities. The hydrophobic region (hydrophobic tail) of each lipid molecule is protected from water, whereas the hydrophilic region (hydrophilic head) is immersed in it. The bilayer serves as a barrier to the diffusion of water and hydrophilic substances, while allowing lipid-soluble molecules, such as oxygen (O2) and carbon dioxide (CO2), to diffuse through the membrane readily. A major component of the plasma membrane is a bilayer of lipid molecules—

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glycerophospholipids, sphingolipids, and sterols (e.g., cholesterol). The most abundant lipids are phospholipids. Phospholipids have a phosphate-containing hydrophilic head connected to a hydrophobic tail. Phospholipids and glycolipids form self-sealing lipid bilayers. Lipids along with protein assemblies act as “molecular glue” for the structural integrity of the membrane. Investigators are studying the concept of lipid rafts, which may be structurally and functionally distinct regions of the plasma membrane. Proteins. Proteins perform most of the plasma membrane's tasks. A protein is made from a chain of amino acids, known as polypeptides. There are 20 types of amino acids in proteins and each type of protein has a unique sequence of amino acids. After translation (the synthesis of protein from RNA, see Chapter 2) of a protein, posttranslational modifications (PTMs) are the methods used to diversify the limited numbers of proteins generated. These modifications alter the activity and functions of proteins and have become very important in understanding diseases. Researchers have known for decades that pathogens interfere with the host's PTMs. New approaches are being used to understand changes in proteins— a field called proteomics is the study of the proteome, or entire set of proteins expressed by a genome from synthesis, translocation, and modification (e.g., folding), and the analysis of the roles of proteomes in a staggering number of diseases. Membrane proteins associate with the lipid bilayer in different ways (Fig. 1.6), including:

FIGURE 1.6 Proteins Attach to the Plasma Membrane in Different Ways. A, Transmembrane proteins extend through the membrane as a single α helix, as multiple α helices, or as a rolled-up barrel-like sheet called a β barrel. B, Some membrane proteins are anchored to the cytosolic side of the lipid bilayer by an amphipathic α helix. C, Some proteins are linked on either side of the membrane by a covalently attached lipid molecule. D, Proteins are attached by weak noncovalent interactions with other membrane proteins. (D, adapted from Alberts B et al: Essential cell biology, ed 4, New York, 2014, Garland.)

1. Transmembrane proteins that extend across the bilayer and exposed to an aqueous environment on both sides of the membrane (see Fig. 1.6, A) 2. Proteins located almost entirely in the cytosol and associated with the cytosolic half

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of the lipid bilayer by an α helix exposed on the surface of the protein (see Fig. 1.6, B) 3. Proteins that exist outside the bilayer, on one side or the other, and attached to the membrane by one or more covalently attached lipid groups (see Fig. 1.6, C) 4. Proteins bound indirectly to one or the other bilayer membrane face and held in place by their interactions with other proteins (see Fig. 1.6, D).1. Proteins directly attached to the membrane bilayer can be removed by dissolving the bilayer with detergents called integral membrane proteins. The remaining proteins that can be removed by gentler procedures that interfere with protein–protein interactions but do not dissolve the bilayer are known as peripheral membrane proteins. Proteins exist in densely folded molecular configurations rather than straight chains; thus most hydrophilic units are at the surface of the molecule, and most hydrophobic units are inside. Membrane proteins, like other proteins, are synthesized by the ribosome and translocate, called trafficking, to different membrane locations of a cell. Trafficking puts unique demands on membrane proteins for folding, translocation, and stability. Therefore much research is now being done to understand misfolded proteins (e.g., as a cause of disease; Box 1.1).

Box 1.1

Endoplasmic Reticulum, Protein Folding, and Endoplasmic Reticulum Stress Protein folding in the endoplasmic reticulum (ER) is critical for humans. As the biologic workhorses, proteins perform vital functions in every cell. To do these tasks, proteins must fold into complex three-dimensional structures (see figure). Most secreted proteins fold and are modified in an error-free manner, but ER or cell stress, mutations, or random (stochastic) errors during protein synthesis can decrease the folding amount or the rate of folding. Pathophysiologic processes, such as viral infections, environmental toxins, and mutant protein expression, can perturb the sensitive ER environment. Natural processes also can perturb the environment, such as the large protein-synthesizing load placed on the ER. These perturbations cause the accumulation of immature and abnormal proteins in cells, leading to ER stress. Fortunately, the ER is loaded with protective ways to help folding, for example, protein so-called chaperones that facilitate folding and prevent the formation of off-pathway types. Because specialized cells produce large amounts of secreted proteins, the movement or flux through the ER is tremendous. Therefore misfolded proteins not repaired in the ER are observed in some diseases and can initiate apoptosis, or cell death. It has recently been shown that the ER mediates intracellular signaling pathways in response to the accumulation of unfolded or misfolded proteins; collectively, the adaptive pathways are known as the unfolded-protein response (UPR). Investigators are studying UPR-associated inflammation and how the UPR is coupled to inflammation in health and disease. Specific diseases include Alzheimer disease, Parkinson disease, prion disease, amyotrophic lateral sclerosis, diabetes mellitus, and sepsis. Additionally being studied is ER stress and how it may accelerate age-related dysfunction. Overall, ER is a major organelle for protein quality control.

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Protein Folding. Each protein exists as an unfolded polypeptide (left) or random coil after the process of translation from a sequence of messenger ribonucleic acid (mRNA) to a linear string of amino acids. From amino acids interacting with each other they produce a three-dimensional structure called the folded protein (right) that is its native state. Data from Alberts B et al: Molecular biology of the cell, ed 6, New York, 2015; Brodsky J, Skach WR: Curr Opin Cell Biol 23:464–475, 2011; Jäger R et al: Biol Cell 104(5):259–270, 2012; Khan MM, Yang VVL, Wang P: Shock 44(4):294–304, 2015; Shah SZ et al: J Mol Neurosci 57(4):529– 537, 2015. Although membrane structure is determined by the lipid bilayer, membrane functions are determined largely by proteins. Proteins act as: 1. Recognition and binding units (receptors) for substances moving into and out of the cell 2. Pores or transport channels for various electrically charged particles, called ions or electrolytes, and specific carriers for amino acids and monosaccharides 3. Specific enzymes that drive active pumps to promote concentration of certain ions, particularly potassium (K+), within the cell while keeping concentrations of other ions (e.g., sodium [Na+]), less than concentrations found in the extracellular environment; 4. Cell surface markers, such as glycoproteins (proteins attached to carbohydrates), which identify a cell to its neighbor 5. Cell adhesion molecules (CAMs), or proteins that allow cells to hook together and form attachments of the cytoskeleton for maintaining cellular shape 6. Catalysts of chemical reactions (e.g., conversion of lactose to glucose (see Fig. 1.3). Membrane proteins are key components of energy transduction, converting chemical energy into electrical energy, or electrical energy into either mechanical energy or synthesis of ATP. Investigators are studying ATP enzymes and the changes in shape of biologic membranes, particularly mitochondrial membranes, and their relationship to aging and disease. In animal cells, the plasma membrane is stabilized by a meshwork of proteins attached to

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the underside of the membrane called the cell cortex. Human red blood cells have a cell cortex that maintains their flattened biconcave shape.1 Protein regulation in a cell: proteostasis. The cellular protein pool is in constant change or flux. Proteostasis is a state of cell balance of the processes of protein synthesis, folding, and dehydration. It is vital to health. This adaptable system depends on how quickly proteins are made, how long they survive, or when they are broken down. The proteostasis network comprises ribosomes (makers); chaperones (helpers); and two protein breakdown systems or proteolytic systems— lysosomes and the ubiquitin–proteasome system (UPS). These systems regulate protein homeostasis under a large variety of conditions, including variations in nutrient supply, the existence of oxidative stress or cellular differentiation, changes in temperature, and the presence of heavy metal ions and other sources of stress. Malfunction or failure of the proteostasis network is associated with human (Fig. 1.7).

FIGURE 1.7 Protein Homeostasis System and Outcomes. A main role of the protein homeostasis network (proteostasis) is to minimize protein misfolding and protein aggregation. The network includes ribosome-mediated protein synthesis, chaperone (folding helpers in the ER) and enzyme mediated folding, breakdown systems of lysosome and proteasome-mediated protein degradation, and vesicular trafficking. The network integrates biologic pathways that balance folding, trafficking, and protein degradation depicted by arrows a, b, c, d, e, f, g, h, and i. ER, Endoplasmic reticulum. (Adapted from Lindquist SL, Kelly JW: Cold Spring Harb Perspect Biol 3[12]:pii: a004507, 2011.)

Carbohydrates. The short chains of sugars or carbohydrates (oligosaccharides) contained within the plasma membrane are mostly bound to membrane proteins (glycoproteins) and lipids (glycolipids). Long polysaccharide chains attached to membrane proteins are called proteoglycans. All of

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the carbohydrate on the glycoproteins, proteoglycans, and glycolipids is located on the outside of the plasma membrane and the carbohydrate coating is called the glycocalyx. The glycocalyx helps protect the cell from mechanical damage.1 Additionally, the layer of carbohydrate gives the cell a slimy surface that assists the mobility of other cells, such as leukocytes, to squeeze through the narrow spaces.1 Other functions of carbohydrates include specific cell-to-cell recognition and adhesion. Intercellular recognition is an important function of membrane oligosaccharides; for example, the transmembrane proteins called lectins, which bind to a particular oligosaccharide, recognize neutrophils at the site of bacterial infection. This recognition allows the neutrophil to adhere to the blood vessel wall and migrate from blood into the infected tissue to help eliminate the invading bacteria.1

Cellular Receptors Cellular receptors are protein molecules on the plasma membrane, in the cytoplasm, or in the nucleus that can recognize and bind with specific smaller molecules called ligands (from the Latin ligare, “to bind”) (Fig. 1.8). The region of a protein that associates with a ligand is called its binding site. Hormones, for example, are ligands. Numerous receptors are found in most cells, and ligand binding to receptors activates or inhibits the receptor's associated signaling or biochemical pathway (see the Cellular Communication and Signal Transduction section). Recognition and binding depend on the chemical configuration of the receptor and its smaller ligand, which must fit together somewhat like the pieces of a jigsaw puzzle (see Chapter 19). Binding selectively to a protein receptor with high affinity to a ligand depends on formation of weak, noncovalent interactions—hydrogen bonds, electrostatic attractions, and van der Waals attractions—and favorable hydrophobic forces.1

FIGURE 1.8 Cellular Receptors. A, 1. Plasma membrane receptor for a ligand (here, a hormone molecule) on the surface of an integral protein. A neurotransmitter can exert its effect on a postsynaptic cell by means of two fundamentally different types of receptor proteins. 2. Channel-linked receptors. 3. Non–channel-linked receptors. Channel-linked receptors are also known as ligand-gated channels. B, Example of ligand-gated ion channels. The channel structure is changed when, for example, a neurotransmitter binds and ions can now enter.

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Plasma membrane receptors protrude from or are exposed at the external surface of the membrane and are important for cellular uptake of ligands (see Fig. 1.8). The ligands that bind with membrane receptors include hormones, neurotransmitters, antigens, complement components, lipoproteins, infectious agents, drugs, and metabolites. Many new discoveries concerning the specific interactions of cellular receptors with their respective ligands have provided a basis for understanding disease. Although the chemical nature of ligands and their receptors differs, receptors are classified on the basis of their location and function. Cellular type determines overall cellular function, but plasma membrane receptors determine which ligands a cell will bind with and how the cell will respond to the binding. Specific processes also control intracellular mechanisms. Receptors for different drugs are found on the plasma membrane, in the cytoplasm, and in the nucleus. Membrane receptors have been found for certain anesthetics, opiates, endorphins, enkephalins, antibiotics, cancer chemotherapeutic agents, digitalis, and other drugs. Membrane receptors for endorphins, which are opiate-like peptides isolated from the pituitary gland, are found in large quantities in pain pathways of the nervous system (see Chapters 14 and 15). With binding to the receptor, the endorphins (or drugs, e.g., morphine) change the cell's permeability to ions, increase the concentration of molecules that regulate intracellular protein synthesis, and initiate molecular events that modulate pain perception. Receptors for infectious microorganisms, or antigen receptors, bind bacteria, viruses, and parasites to the cell membrane. Antigen receptors on white blood cells (lymphocytes, monocytes, macrophages, granulocytes) recognize and bind with antigenic microorganisms and activate the immune and inflammatory responses (see Chapter 6).

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Cell-to-Cell Adhesions Cells are small and squishy, not like bricks. They are enclosed only by a flimsy membrane, yet the cell depends on the integrity of this membrane for its survival. How can cells be connected strongly, with their membranes intact, to form a muscle that can lift this textbook? Plasma membranes not only serve as the outer boundaries of all cells but also allow groups of cells to be held together robustly, in cell-to-cell adhesions, to form tissues and organs (Box 1.2). Once arranged, cells are linked by three different means: (1) cell adhesion molecules in the cell's plasma membrane, (2) the extracellular matrix (ECM), and (3) specialized cell junctions.

Box 1.2

Cell Adhesion Molecules Cell adhesion molecules (CAMs) are cell surface proteins that bind the cell to an adjacent cell and to components of the extracellular matrix (ECM). CAMs include four protein families: (1) the integrins, (2) the cadherins, (3) the selectins, and (4) the immunoglobulin superfamily CAMs (IgSF CAMs). Integrins are receptors within the ECM and regulate cell-ECM interactions with collagen. Cadherins are calcium (Ca++)–dependent glycoproteins throughout tissue, for example, epithelial (E-cadherin). Selectins are proteins that bind some carbohydrates, for example, mucins. The IgSF CAMs bind integrins and other IgSF CAMs.

Extracellular Matrix and Basement Membrane Cells can be united by attachment to one another or through the ECM (including the basement membrane), which the cells secrete around themselves. The extracellular matrix (ECM) is an intricate meshwork of fibrous proteins embedded in a watery, gel-like substance composed of complex carbohydrates (Fig. 1.9). The basement membrane (BM) (also known as basal lamina) is a specialized type of ECM. This sheet of matrix is very thin, tough, and flexible; lies beneath epithelial cells; occurs between two cell sheets (kidney glomerulus); and surrounds individual muscle cells, fat cells, and Schwann cells (which wrap around peripheral nerve cell axons) (Fig. 1.10). The ECM is similar to glue; however it provides a pathway for diffusion of nutrients, wastes, and other water-soluble substances between the blood and tissue cells. Interwoven within the matrix are three groups of large molecules or macromolecules: (1) fibrous structural proteins, including collagen and elastin; (2) adhesive glycoproteins, such as fibronectin; and (3) proteoglycans and hyaluronic acid.

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FIGURE 1.9 Extracellular Matrix. Tissues are not just cells but also extracellular space. The extracellular space is an intricate network of macromolecules called the extracellular matrix (ECM). The macromolecules that constitute the ECM are secreted locally (by mostly fibroblasts) and assembled into a meshwork in close association with the surface of the cell that produced them. Two main classes of macromolecules include proteoglycans, which are bound to polysaccharide chains called glycosaminoglycans; and fibrous proteins (e.g., collagen, elastin, fibronectin, and laminin), which have structural and adhesive properties. Together the proteoglycan molecules form a gel-like ground substance in which the fibrous proteins are embedded. The gel permits rapid diffusion of nutrients, metabolites, and hormones between blood and the tissue cells. Matrix proteins modulate cell–matrix interactions, including normal tissue remodeling (which can become abnormal, for example, with chronic inflammation). Disruptions of this balance result in serious diseases such as arthritis, tumor growth, and other pathologic conditions. (Adapted from Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

FIGURE 1.10 Three Ways Basement Membranes (Basal Laminae) Are Organized. Basal laminae (yellow) surround certain cells like skeletal cells, underlie epithelia, and occur between two cell sheets (kidney glomerulus). (Adapted from Alberts B et al: Essential cell biology, ed 4, New York, 2014, Garland.)

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1. Collagen forms cable-like fibers or sheets that provide tensile strength or resistance to longitudinal stress. Collagen breakdown, such as occurs in osteoarthritis, destroys the fibrils that give cartilage its tensile strength. 2. Elastin is a rubber-like protein fiber most abundant in tissues that must be capable of stretching and recoiling, such as found in the lungs. 3. Fibronectin, a large glycoprotein, promotes cell adhesion and cell anchorage. Reduced amounts have been found in certain types of cancerous cells; this allows cancer cells to travel, or metastasize, to other parts of the body. All of these macromolecules occur in intercellular junctions and cell surfaces and may assemble into two different components: interstitial matrix and BM (see Fig. 1.9). The ECM is secreted by fibroblasts (“fiber formers”) (Fig. 1.11), local cells that are present in the matrix. The matrix and the cells within it are known collectively as connective tissue because they interconnect cells to form tissues and organs. Human connective tissues are enormously varied. They can be hard and dense, for example, bone; flexible, for example, tendons or the dermis of the skin; resilient and shock absorbing, for example, cartilage; or soft and transparent, similar to the jelly-like substance that fills the eye. In all these examples, the majority of the tissue is composed of ECM, and the cells that produce the matrix are scattered within it like raisins in a pudding (see Fig. 1.11).

FIGURE 1.11 Fibroblasts in Connective Tissue. This micrograph shows tissue from the cornea of a rat. The extracellular matrix surrounds the fibroblasts (F). (From Nishida T et al: The extracellular matrix of animal connective tissues, Invest Ophthalmol Vis Sci 29:1887–

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1880, 1998.)

The matrix is not just passive scaffolding for cellular attachment but also helps regulate the function of the cells with which it interacts. The matrix helps regulate important functions, such as cell growth and differentiation.

Specialized Cell Junctions Cells in direct physical contact with neighboring cells are often interconnected at specialized plasma membrane regions called cell junctions. Cell junctions are classified by their function: 1. To hold cells together and form a tight seal (tight junctions) 2 To provide strong mechanical attachments (adherens junctions, desmosomes, hemidesmosomes) 3 To provide a special type of chemical communication (e.g., inorganic ions and small water-soluble molecules to move from the cytosol of one cell to the cytosol of another cell), such as those causing an electrical wave (gap junctions) 4 To maintain apico-basal polarity of individual epithelial cells (tight junctions) (Fig. 1.12)

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FIGURE 1.12 Junctional Complex. A, Schematic drawing of a belt desmosome between epithelial cells. This junction, also called zonula adherens, encircles each interacting cell. The spot desmosomes and hemidesmosomes, like the belt desmosomes, are adhering junctions. The tight junction is an impermeable junction that holds cells together but seals them in such a way that molecules cannot leak between them. The gap junction, as a communicating junction, mediates the passage of small molecules from one interacting cell to the other. B, Electron micrograph of desmosomes. C, Connexons. The connexin gap junction proteins have four transmembrane domains and they play a vital role in maintaining cell and tissue function and homeostasis. Cells connected by gap junctions are considered ionically (electrically) and metabolically coupled. Gap junctions coordinate the activities of adjacent cells; for example, they are important for synchronizing contractions of heart muscle cells through ionic coupling and for permitting action potentials to spread rapidly from cell to cell in neural tissues. The reason gap junctions occur in tissues that are not electrically active is unknown. Although most gap junctions are associated with junctional complexes, they sometimes exist as independent structures. (A and B, from Raven PH, Johnson GB: Biology, St Louis, 1992, Mosby; C adapted from Gartner LP, Hiatt JL: Color textbook of histology, ed 3, St Louis, 2006, Saunders Elsevier; Sherwood L: Learning, ed 8, Belmont, California, 2013, Brooks/Cole CENGAGE.)

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In summary, cell junctions make the epithelium leak-proof and mediate mechanical attachment of one cell to another, allow communicating tunnels and maintaining cell polarity. Cell junctions can be classified as symmetric and asymmetric. Symmetric junctions include tight junctions (zonula occludens), the belt desmosome (zonula adherens), desmosomes (macula adherens), and gap junctions (also called intercellular channel or communicating junctions). An asymmetric junction is the hemidesmosome (see Fig. 1.12, A). Together they form the junctional complex. Desmosomes unite cells either by forming continuous bands or belts of epithelial sheets or by developing button-like points of contact. Desmosomes also act as a system of braces to maintain structural stability. Tight junctions are barriers to diffusion, prevent the movement of substances through transport proteins in the plasma membrane, and prevent the leakage of small molecules between the plasma membranes of adjacent cells. Gap junctions are clusters of communicating tunnels or connexons that allow small ions and molecules to pass directly from the inside of one cell to the inside of another. Connexons are hemichannels that extend outward from each of the adjacent plasma membranes (see Fig. 1.12, C). Multiple factors regulate gap junction intercellular communication, including voltage across the junction, intracellular pH, intracellular calcium (Ca++) concentration, and protein phosphorylation. The junctional complex is a highly permeable part of the plasma membrane where permeability is controlled by a process called gating. Increased levels of cytoplasmic calcium cause decreased permeability at the junctional complex. Gating enables uninjured cells to protect themselves from injured neighbors. Calcium is released from injured cells.

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Cellular Communication and Signal Transduction Cells need to communicate with each other to maintain a stable internal environment, or homeostasis; to regulate their growth and division; to oversee their development and organization into tissues; and to coordinate their functions. Cells communicate by using hundreds of kinds of signal molecules, for example, insulin-like growth factor 1. Cells communicate in three main ways: 1. They display plasma membrane–bound signaling molecules (receptors) that affect the cell itself and other cells in direct physical contact (Fig. 1.13, A).

Cellular Communication. Three primary ways (A–C) cells communicate with one another. (B, adapted from Alberts B et al: Molecular biology of the cell, ed 5, New York,

FIGURE 1.13

2008, Garland.)

2. They affect receptor proteins inside the target cell and the signal molecule has to enter the cell to bind to them (see Fig. 1.13, B). 3. They form protein channels (gap junctions) that directly coordinate the activities of adjacent cells (see Fig. 1.13, C). Alterations in cellular communication affect disease onset and progression. In fact, if a cell cannot perform gap junctional intercellular communication, normal growth control and cell differentiation is compromised, thereby favoring cancerous tumor development (see Chapter 11). Secreted chemical signals involve communication locally and at a distance. Primary modes of intercellular signaling are contact-dependent, paracrine, hormonal, neurohormonal, and neurotransmitter. Autocrine stimulation occurs when the secreting cell targets itself (Fig. 1.14).

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FIGURE 1.14 Primary Modes of Chemical Signaling. Five forms of signaling mediated by secreted molecules. Hormones, paracrines, neurotransmitters, and neurohormones are all intercellular messengers that accomplish communication between cells. Autocrines bind to receptors on the same cell. Not all neurotransmitters act in the strictly synaptic mode shown; some act in a contact-dependent mode as local chemical mediators that influence multiple target cells in the area.

Contact-dependent signaling requires cells to be in close membrane-to-membrane contact. In paracrine signaling, cells secrete local chemical mediators that are quickly taken up, destroyed, or immobilized. Paracrine signaling usually involves different cell types; however cells also can produce signals to which they alone respond, and this is called autocrine signaling (see Fig. 1.14). For example, cancer cells use this form of signaling to stimulate their survival and proliferation. The mediators act only on nearby cells. Hormonal signaling involves specialized endocrine cells that secrete chemicals called hormones; hormones are released by one set of cells and travel through the bloodstream to produce a response in other sets of cells (see Chapter 19). In neurohormonal signaling hormones are released into blood by neurosecretory neurons. Like endocrine cells, neurosecretory neurons release blood-borne chemical messengers, whereas ordinary neurons secrete short-range neurotransmitters into a small discrete space (i.e., synapse). Neurons communicate directly with the cells they innervate by releasing chemicals or neurotransmitters at specialized junctions called chemical synapses; the neurotransmitter diffuses across the synaptic cleft and acts on the postsynaptic target cell (see Fig. 1.14). Many of these same signaling molecules are receptors used in hormonal, neurohormonal, and paracrine signaling. Important differences lie in the speed and selectivity with which the signals are delivered to their targets.1 Plasma membrane receptors belong to one of three classes that are defined by the signaling (transduction) mechanism used. Table 1.3 summarizes these classes of receptors. Cells respond to external stimuli by activating a variety of signal transduction pathways, which are communication pathways, or signaling cascades (Fig. 1.15). Signals are passed

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between cells when a particular type of molecule is produced by one cell—the signaling cell—and received by another—the target cell—by means of a receptor protein that recognizes and responds specifically to the signal molecule (see Fig. 1.15, A and B). In turn, the signaling molecules activate a pathway of intracellular protein kinases that results in various responses, such as growing and reproducing, dying, surviving, or differentiating (see Fig. 1.15). If deprived of appropriate signals, most cells undergo a form of cell suicide known as programmed cell death, or apoptosis (see Chapter 4). TABLE 1.3 Classes of Plasma Membrane Receptors Type of Description Receptor Channel Also called ligand-gated channels; involve rapid synaptic signaling between electrically excitable cells. Channels linked open and close briefly in response to neurotransmitters, changing ion permeability of plasma membrane of postsynaptic cell. Catalytic Once activated by ligands, function directly as enzymes. Composed of transmembrane proteins that function intracellularly as tyrosine-specific protein kinases. GIndirectly activate or inactivate plasma membrane enzyme or ion channel; interaction mediated by protein guanosine triphosphate (GTP)–binding regulatory protein (G protein). When activated, a chain of linked reactions occurs that alters concentration of intracellular messengers, such as cyclic adenosine monophosphate (cAMP) and calcium, or signaling molecules. Behaviors of other target proteins are also altered. May also interact with inositol phospholipids, which are significant in cell signaling, and molecules involved in the inositol-phospholipid transduction pathway. A G-protein–linked receptor activates the enzyme phosphoinositide-specific phospholipase, which, in turn, generates two intracellular messengers: (1) inositol triphosphate (IP3) releases calcium (Ca++), and (2) diacylglycerol remains in the plasma membrane and activates protein kinase C. Protein kinase C further activates various cell proteins. Several different plasma membrane receptors are known to use the inositol–phospholipid transduction pathway.

Data from Alberts B et al: Molecular biology of the cell, ed 5, New York, 2008, Garland.

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FIGURE 1.15 Schematic of a Signal Transduction Pathway. Like a telephone receiver that converts an electrical signal into a sound signal, a cell converts an extracellular signal. A, An extracellular signal molecule (ligand) binds to a receptor protein located on the plasma membrane, where it is transduced into an intracellular signal. This process initiates a signaling cascade that relays the signal into the cell interior, amplifying and distributing it during transit. Amplification is often achieved by stimulating enzymes. Steps in the cascade can be modulated by other events in the cell. B, Different cell behaviors rely on multiple extracellular signals.

Binding of the extracellular signaling messenger (i.e., ligand), or first messenger, to the membrane receptors causes (1) opening or closing of specific channels in the membrane to regulate the movement of ions into or out of the cell; and (2) transfer of the signal to an intracellular messenger or second messenger, which triggers a cascade of biochemical events within the cell (Fig. 1.16).

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FIGURE 1.16 First and Second Messengers. The first messenger or ligand attaches to the membrane receptor relaying the message across the membrane and intracellular messengers or second messengers trigger the cascade of intracellular events. The two major second-messenger pathways are cyclic adenosine monophosphate (cAMP) and calcium (Ca++). A large number of human disorders involve problematic signaling.

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Cellular Metabolism All of the chemical tasks of maintaining essential cellular functions are referred to as cellular metabolism. The energy-using process of metabolism is called anabolism (ana = upward), and the energy-releasing process is known as catabolism (kata = downward). Metabolism provides the cell with the energy it needs to produce cellular structures. Dietary proteins, fats, and starches (i.e., carbohydrates) are hydrolyzed in the intestinal tract into amino acids, fatty acids, and glucose, respectively. These constituents are then absorbed, circulated, and incorporated into the cell, where they may be used for various vital cellular processes, including the production of ATP. The process by which ATP is produced is one example of a series of reactions called a metabolic pathway. A metabolic pathway involves several steps whose end products are not always detectable. A key feature of cellular metabolism is the directing of biochemical reactions by protein catalysts or enzymes. Each enzyme has a high affinity for a substrate, a specific substance converted to a product of the reaction.

Role of Adenosine Triphosphate What is best known about ATP is its role as a universal “fuel” inside living cells. This fuel or energy drives biologic reactions necessary for cells to function. For a cell to function, it must be able to extract and use the chemical energy in organic molecules. When 1 mole (mol) of glucose metabolically breaks down in the presence of oxygen into CO2 and water, 686 kilocalories (kcal) of chemical energy are released. The chemical energy lost by one molecule is transferred to the chemical structure of another molecule by an energy-carrying or energy-transferring molecule, such as ATP. The energy stored in ATP can be used in various energy-requiring reactions and in the process is generally converted to adenosine diphosphate (ADP) and inorganic phosphate (Pi). The energy available as a result of this reaction is about 7 kcal/mol of ATP. The cell uses ATP for muscle contraction and active transport of molecules across cellular membranes. ATP not only stores energy but also transfers it from one molecule to another. Energy stored by carbohydrate, lipid, and protein is catabolized and transferred to ATP. Emerging understandings are the role of ATP outside cells—as a messenger. In animal studies, using the newly developed ATP probe, ATP has been measured in pericellular spaces. New research is clarifying the role of ATP as an extracellular messenger and its role in many physiologic processes, including inflammation.2,3

Food and Production of Cellular Energy Catabolism of the proteins, lipids, and polysaccharides found in food can be divided into the following three phases (Fig. 1.17):

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FIGURE 1.17 Three Phases of Catabolism, Which Lead From Food to Waste Products. These reactions produce adenosine triphosphate (ATP), which is used to power other processes in the cell.

Phase 1: Digestion. Large molecules are broken down into smaller subunits: proteins into amino acids, polysaccharides into simple sugars (i.e., monosaccharides), and fats into fatty acids and glycerol. These processes occur outside the cell and are activated by secreted enzymes. Phase 2: Glycolysis and oxidation. The most important part of phase 2 is glycolysis, the splitting of glucose. Glycolysis produces two molecules of ATP per glucose molecule through oxidation, or the removal and transfer of a pair of electrons. The total process is called oxidative cellular metabolism and involves 10 biochemical reactions (see Fig. 1.17). Phase 3: Citric acid cycle (Krebs cycle, tricarboxylic acid cycle). Most of the ATP is

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generated during this final phase, which begins with the citric acid cycle and ends with oxidative phosphorylation. About two-thirds of the total oxidation of carbon compounds in most cells is accomplished during this phase. The major end products are CO2 and two dinucleotides—reduced nicotinamide adenine dinucleotide (NADH) and the reduced form of flavin adenine dinucleotide (FADH2)—both of which transfer their electrons into the electron-transport chain.

Oxidative Phosphorylation Oxidative phosphorylation occurs in the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and proteins is transferred to ATP. During the breakdown (catabolism) of foods, many reactions involve the removal of electrons from various intermediates. These reactions generally require a coenzyme (a nonprotein carrier molecule), such as nicotinamide adenine dinucleotide (NAD), to transfer the electrons and thus are called transfer reactions. Molecules of NAD and flavin adenine dinucleotide (FAD) transfer electrons they have gained from the oxidation of substrates to molecular O2. The electrons from reduced NAD and FAD, NADH and FADH2, respectively, are transferred to the electron-transport chain on the inner surfaces of the mitochondria with the release of hydrogen ions. Some carrier molecules are brightly colored, iron-containing proteins known as cytochromes, which accept a pair of electrons. These electrons eventually combine with molecular oxygen. If oxygen is not available to the electron-transport chain, ATP will not be formed by the mitochondria. Instead, an anaerobic (without oxygen) metabolic pathway synthesizes ATP. This process, called substrate phosphorylation or anaerobic glycolysis, is linked to the breakdown (glycolysis) of carbohydrate (Fig. 1.18). Because glycolysis occurs in the cytoplasm of the cell, it provides energy for cells that lack mitochondria. The reactions in anaerobic glycolysis involve the conversion of glucose to pyruvic acid (pyruvate) with the simultaneous production of ATP. With the glycolysis of one molecule of glucose, two ATP molecules and two molecules of pyruvate are liberated. If oxygen is present, the two molecules of pyruvate move into the mitochondria, where they enter the citric acid cycle (Fig. 1.19).

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FIGURE 1.18 Glycolysis. Sugars are important for fuel or energy and they are oxidized in small steps to carbon dioxide (CO2) and water. Glycolysis is the process for oxidizing sugars or glucose. Breakdown of glucose. A, Anaerobic catabolism, to lactic acid and little ATP. B, Aerobic catabolism, to carbon dioxide, water, and lots of ATP. (From Herlihy B: The human body in health and illness, ed 5, St Louis, 2015, Saunders.)

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FIGURE 1.19 What Happens to Pyruvate, the Product of Glycolysis? In the presence of oxygen, pyruvate is oxidized to acetyl coenzyme A (Acetyl CoA) and enters the citric acid cycle. In the absence of oxygen, pyruvate instead is reduced, accepting the electrons extracted during glycolysis and carried by reduced nicotinamide adenine dinucleotide (NADH). When pyruvate is reduced directly, as it is in muscles, the product is lactic acid. When carbon dioxide (CO2) is first removed from pyruvate and the remainder is reduced, as it is in yeasts, the resulting product is ethanol.

If oxygen is absent, pyruvate is converted to lactic acid, which is released into the extracellular fluid (ECF). The conversion of pyruvic acid to lactic acid is reversible; therefore once oxygen is restored, lactic acid is quickly converted back to either pyruvic acid or glucose. The anaerobic generation of ATP from glucose through glycolysis is not as efficient as the aerobic generation process. Adding an oxygen-requiring stage to the catabolic process (phase 3; see Fig. 1.18) provides cells with a much more powerful method for extracting energy from food molecules.

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Membrane Transport: Cellular Intake and Output Cell survival and growth depend on the constant exchange of molecules with their environment. Cells continually import nutrients, fluids, and chemical messengers from the extracellular environment and expel metabolites, or the products of metabolism, and end products of lysosomal digestion. Cells also must regulate ions in their cytosol and organelles. Simple diffusion across the lipid bilayer of the plasma membrane occurs for such important molecules as O2 and CO2. However the majority of molecular transfer depends on specialized membrane transport proteins that span the lipid bilayer and provide private conduits for select molecules.1 Membrane transport proteins occur in many forms and are present in all cell membranes.1 Transport by membrane transport proteins is sometimes called mediated transport. Most of these transport proteins allow selective passage (e.g., Na+ but not K+, or K+ but not Na+). Each type of cell membrane has its own transport proteins that determine which solute can pass into and out of the cell or organelle.1 The two main classes of membrane transport proteins are transporters and channels. These transport proteins differ in the type of solute—small particles of dissolved substances—they transport. A transporter is specific, allowing only those ions that fit the unique binding sites on the protein (Fig. 1.20, A). A transporter undergoes conformational changes to enable membrane transport. A channel, when open, forms a pore across the lipid bilayer that allows ions and selective polar organic molecules to diffuse across the membrane (see Fig. 1.20, B). Transport by a channel depends on the size and electrical charge of the molecule. Some channels are controlled by a gate mechanism that determines which solute can move into it. Ion channels are responsible for the electrical excitability of nerve and muscle cells and play a critical role in the membrane potential.

FIGURE 1.20 Inorganic Ions and Small, Polar Organic Molecules Can Cross a Cell Membrane Through Either a Transporter or a Channel. (Adapted from Alberts B et al: Essential cell biology, ed 4, New York, 2014, Garland.)

The mechanisms of membrane transport depend on the characteristics of the substance to be transported. In passive transport, water and small, electrically uncharged molecules move easily through pores in the plasma membrane's lipid bilayer (see Fig. 1.20). This

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process occurs naturally through any semipermeable barrier. Molecules will easily flow “downhill” from a region of high concentration to a region of low concentration; this movement is called passive because it does not require expenditure of energy or a driving force. It is driven by osmosis, hydrostatic pressure, and diffusion, all of which depend on the laws of physics and do not require life. Other molecules are too large to pass through pores or are ligands bound to receptors on the cell's plasma membrane. Some of these molecules are moved into and out of the cell by active transport, which requires life, biologic activity, and the cell's expenditure of metabolic energy (Fig. 1.21). Unlike passive transport, active transport occurs across only living membranes that have to drive the flow “uphill” by coupling it to an energy source). Movement of a solute against its concentration gradient occurs by special types of transporters called pumps (see Fig. 1.21). These transporter pumps must harness an energy source to power the transport process. Energy can come from ATP hydrolysis, a transmembrane ion gradient, or sunlight (see Fig. 1.21). The best-known energy source is the Na+-K+–dependent adenosine triphosphatase (ATPase) pump (see Fig. 1.26 later in the chapter). It continuously regulates the cell's volume by controlling leaks through pores or protein channels and maintaining the ionic concentration gradients needed for cellular excitation and membrane conductivity (see the Active Transport of Na+ and K+ section). The maintenance of intracellular K+ concentrations is required also for enzyme activity, including enzymes involved in protein synthesis. Large molecules (macromolecules), along with fluids, are transported by endocytosis (taking in) and exocytosis (expelling) (see the Transport by Vesicle Formation section). Receptor-macromolecule complexes enter the cell by means of receptor-mediated endocytosis.

FIGURE 1.21 Pumps Carry Out Active Transport in Three Ways. 1. Coupled pumps link the uphill transport of one solute to the downhill transport of another solute. 2. ATPdriven pumps drive uphill transport from hydrolysis of ATP. 3. Light-driven pumps are mostly found in bacteria and use energy from sunlight to drive uphill transport. (Adapted from Alberts B et al: Essential cell biology, ed 4, New York, 2014, Garland.)

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Mediated transport systems can move solute molecules singly or two at a time. Two molecules can be moved simultaneously in one direction (a process called symport; e.g., sodium–glucose in the digestive tract) or in opposite directions (called antiport; e.g., the sodium–potassium pump in all cells), or a single molecule can be moved in one direction (called uniport; e.g., glucose) (Fig. 1.22).

FIGURE 1.22 Mediated Transport. Illustration shows simultaneous movement of a single solute molecule in one direction (Uniport), of two different solute molecules in one direction (Symport), and of two different solute molecules in opposite directions (Antiport).

Electrolytes as Solutes Body fluids are composed of electrolytes, which are electrically charged and dissociate into constituent ions when placed in solution, and nonelectrolytes, such as glucose, urea, and creatinine, which do not dissociate. Electrolytes account for approximately 95% of the solute molecules in body water. Electrolytes exhibit polarity by orienting themselves toward the positive or negative pole. Ions with a positive charge are known as cations and migrate toward the negative pole, or cathode, if an electrical current is passed through the electrolyte solution. Anions carry a negative charge and migrate toward the positive pole, or anode, in the presence of electrical current. Anions and cations are located in both the intracellular fluid (ICF) and the ECF compartments, although their concentration depends on their location. (Fluid and electrolyte balance between body compartments is discussed in Chapter 5.) For example, Na+ is the predominant extracellular cation, and K+ is the principal intracellular cation. The difference in ICF and ECF concentrations of these ions is important to the transmission of electrical impulses across the plasma membranes of nerve and muscle cells. Electrolytes are measured in milliequivalents per liter (mEq/L) or milligrams per deciliter (mg/dL). The term milliequivalent indicates the chemical-combining activity of an

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ion, which depends on the electrical charge, or valence, of its ions. In abbreviations, valence is indicated by the number of plus or minus signs. One milliequivalent of any cation can combine chemically with 1 mEq of any anion: one monovalent anion will combine with one monovalent cation. Divalent ions combine more strongly than monovalent ions. To maintain electrochemical balance, one divalent ion will combine with two monovalent ions (e.g., Ca++ + 2Cl− {ReversReact} Calcium dichloride [CaCl2]).

Passive Transport: Diffusion, Filtration, and Osmosis Diffusion. Diffusion is the movement of a solute molecule from an area of greater solute concentration to an area of lesser solute concentration. This difference in concentration is known as a concentration gradient. Although particles in a solution move randomly in any direction, if the concentration of particles in one part of the solution is greater than that in another part, the particles distribute themselves evenly throughout the solution. According to the same principle, if the concentration of particles is greater on one side of a permeable membrane than on the other side, the particles diffuse spontaneously from the area of greater concentration to the area of lesser concentration until equilibrium is reached. The higher the concentration on one side, the greater is the diffusion rate. The diffusion rate is influenced by differences of electrical potential across the membrane (see the Movement of Electrical Impulses: Membrane Potentials section). Because the pores in the lipid bilayer are often lined with Ca++, other cations (e.g., Na+ and K+) diffuse slowly because they are repelled by positive charges in the pores. The rate of diffusion of a substance depends also on its size (diffusion coefficient) and its lipid solubility (Fig. 1.23). Usually, the smaller the molecule and the more soluble it is in oil, the more hydrophobic or nonpolar it is and the more rapidly it will diffuse across the bilayer. O2, CO2, and steroid hormones (e.g., androgens and estrogens) are all nonpolar molecules. Water-soluble substances, such as glucose and inorganic ions, diffuse very slowly, whereas uncharged lipophilic (“lipid-loving”) molecules, such as fatty acids and steroids, diffuse rapidly. Ions and other polar molecules generally diffuse across cellular membranes more slowly compared with lipid-soluble substances.

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FIGURE 1.23 Passive Diffusion of Solute Molecules Across the Plasma Membrane. Oxygen, nitrogen, water, urea, glycerol, and carbon dioxide can diffuse readily down the concentration gradient. Macromolecules are too large to diffuse through pores in the plasma membrane. Ions may be repelled if the pores contain substances with identical charges. If the pores are lined with cations, for example, other cations will have difficulty diffusing because the positive charges will repel one another. Diffusion can still occur, but it occurs more slowly.

Water readily diffuses through biologic membranes because water molecules are small and uncharged. The dipolar structure of water allows it to rapidly cross the regions of the bilayer containing the lipid head groups. The lipid head groups constitute the two outer regions of the lipid bilayer. Filtration: hydrostatic pressure. Filtration is the movement of water and solutes through a membrane because of a greater pushing pressure (force) on one side of the membrane than on the other side. Hydrostatic pressure is the mechanical force of water pushing against cellular membranes (Fig. 1.24, A). In the vascular system, hydrostatic pressure is the blood pressure generated in vessels when the heart contracts. Blood reaching the capillary bed has a hydrostatic pressure of 25 to 30 millimeters of mercury (mm Hg), which is sufficient force to push water across the thin capillary membranes into the interstitial space. Hydrostatic pressure is partially balanced by osmotic pressure, whereby water moving out of the capillaries is partially balanced by osmotic forces that tend to pull water into the capillaries (see Fig. 1.24, B). Water that is not osmotically attracted back into the capillaries moves into the lymph system (see the discussion of Starling forces in Chapter 5).

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FIGURE 1.24 Hydrostatic Pressure and Oncotic Pressure in Plasma. 1. Hydrostatic pressure in plasma. 2. Oncotic pressure exerted by proteins in the plasma usually tends to pull water into the circulatory system. 3. Individuals with low protein levels (e.g., starvation) are unable to maintain a normal oncotic pressure; therefore water is not reabsorbed into the circulation and, instead, causes body edema.

Osmosis. Osmosis is the movement of water “down” a concentration gradient—that is, across a semipermeable membrane from a region of higher water concentration to one of lower concentration. For osmosis to occur, (1) the membrane must be more permeable to water than to solutes, and (2) the concentration of solutes on one side of the membrane must be greater than that on the other side so that water moves more easily. Osmosis is directly related to both hydrostatic pressure and solute concentration but not to particle size or weight. For example, particles of the plasma protein albumin are small but are more concentrated in body fluids compared with the larger and heavier particles of globulin. Therefore albumin exerts a greater osmotic force compared with globulin. Osmolality controls the distribution and movement of water between body compartments. The terms osmolality and osmolarity often are used interchangeably in reference to osmotic activity, but they define different measurements. Osmolality measures the number of milliosmoles per kilogram (mOsm/kg) of water, or the concentration of molecules per weight of water. Osmolarity measures the number of milliosmoles per liter of solution, or the concentration of molecules per volume of solution. In solutions that contain only dissociable substances, such as Na and chloride (Cl−), the difference between the two measurements is negligible. When considering all the different

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solutes in plasma (e.g., proteins, glucose, lipids), however, the difference between osmolality and osmolarity becomes more significant. Less of plasma's weight is water, and the overall concentration of particles is therefore greater. The osmolality will be greater than the osmolarity because of the smaller proportion of water. Osmolality is thus preferred in human clinical assessment. The normal osmolality of body fluids ranges from 280 to 294 mOsm/kg. The osmolalities of ICF and ECF tend to equalize, providing a measure of body fluid concentration and thus the body's hydration status. Hydration is affected also by hydrostatic pressure because the movement of water by osmosis can be opposed by an equal amount of hydrostatic pressure. The amount of hydrostatic pressure required to oppose the osmotic movement of water is called the osmotic pressure of the solution. Factors that determine osmotic pressure are the type and thickness of the plasma membrane, the size of the molecules, the concentration of molecules or the concentration gradient, and the solubility of molecules within the membrane. Effective osmolality is sustained osmotic activity and depends on the concentration of solutes remaining on one side of a permeable membrane. If the solutes penetrate the membrane and equilibrate with the solution on the other side of the membrane, the osmotic effect will be diminished or lost. Plasma proteins influence osmolality because they have a negative charge (see Fig. 1.24, B). The principle involved is known as Gibbs-Donnan equilibrium; it occurs when the fluid in one compartment contains small, diffusible ions, such as Na+ and Cl−, together with large, nondiffusible, charged particles, such as plasma proteins. Because the body tends to maintain an electrical equilibrium, the nondiffusible protein molecules cause asymmetry in the distribution of small ions. Anions such as Cl− are thus driven out of the cell or plasma, and cations, such as Na+, are attracted to the cell. The protein-containing compartment maintains a state of electroneutrality, but the osmolality is higher. The overall osmotic effect of colloids, such as plasma proteins, is called the oncotic pressure, or colloid osmotic pressure. Tonicity describes the effective osmolality of a solution. (The terms osmolality and tonicity may be used interchangeably.) Solutions have relative degrees of tonicity. An isotonic solution (or isosmotic solution) has the same osmolality or concentration of particles (285 mOsm) as ICF or ECF. A hypotonic solution has a lower concentration and is thus more dilute than body fluids (Fig. 1.25). A hypertonic solution has a concentration of more than 285 to 294 mOsm/kg. The concept of tonicity is important when correcting water and solute imbalances by administering different types of replacement solutions (see Fig. 1.25 and Chapter 5).

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FIGURE 1.25 Tonicity. Tonicity is important, especially for red blood cell function. A, Isotonic solution. B, Hypotonic solution. C, Hypertonic solution. (From Waugh A, Grant A: Ross and Wilson anatomy and physiology in health and illness, ed 12, London, 2012, Churchill Livingstone.)

Quick Check 1.2 1. What does glycolysis produce? 2. Define membrane transport proteins. 3. What are the differences between passive and active transport? 4. Why do water and small, electrically charged molecules move easily through pores in the plasma membrane?

Active Transport of Na+ and K+ The active transport system for Na+ and K+ is found in virtually all mammalian cells. The Na+-K+–antiport system (i.e., Na+ moving out of the cell and K+ moving into the cell) uses the direct energy of ATP to transport these cations. The transporter protein is ATPase, which requires Na+, K+, and magnesium (Mg++) ions. The concentration of ATPase in plasma membranes is directly related to Na+-K+–transport activity. Approximately 60% to 70% of the ATP synthesized by cells, especially muscle and nerve cells, is used to maintain the Na+-K+–transport system. Excitable tissues have a high concentration of Na+-K+ ATPase, as do other tissues that transport significant amounts of Na+. For every ATP molecule hydrolyzed, three molecules of Na+ are transported out of the cell, whereas only two molecules of K+ move into the cell. The process leads to an electrical potential and is called electrogenic, with the inside of the cell more negative than the outside. Although the exact mechanism for this transport is uncertain, it is possible that ATPase induces the transporter protein to undergo several conformational changes, causing Na+ and K+ to move short distances (Fig. 1.26). The conformational change lowers the affinity for Na+ and K+ to the ATPase transporter, resulting in the release of the cations after transport.

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FIGURE 1.26 Active Transport and the Sodium–Potassium (Na+–K+) Pump. 1. Three sodium (Na+) ions bind to Na-binding sites on the carrier's inner face. 2. At the same time, an energy-containing adenosine triphosphate (ATP) molecule produced by the cell's mitochondria binds to the carrier. Adenosine triphosphate (ATP) dissociates, transferring its stored energy to the carrier, and changes shape. 3 and 4. The ATP releases the three Na+ ions to the outside of the cell, and attracts two potassium (K+) ions to its potassium-binding sites. 5. The carrier then returns to its original shape, releasing the two K+ ions and the remnant of the ATP molecule to the inside of the cell. The carrier is now ready for another pumping cycle.

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Table 1.4 summarizes the major mechanisms of transport through pores and protein transporters in the plasma membranes. Many disease states are caused or manifested by loss of these membrane transport systems. TABLE 1.4 Major Transport Systems in Mammalian Cells Substance Transported Carbohydrates Glucose Fructose

Mechanism of Transport*

Tissues

Passive: protein channel Active: symport with Na+ Active: symport with Na+

Most tissues

Passive Amino Acids Amino acid specific transporters All amino acids except proline Specific amino acids

Small intestines and renal tubular cells Intestines and liver

Coupled channels Active: symport with Na+ Active: group translocation Passive

Intestines, kidney, and liver Liver Small intestine

Active: symport with Na+

Intestines

Antiport with counter-organic anion

Mitochondria of liver cells

Antiport transport of nucleotides; can be active

Mitochondria of liver cells

Inorganic Ions Na+ Na+/H+

Passive Active antiport, proton pump

Na+/K+ Ca++ H+/K+

Active: ATP driven, protein channel Active: ATP driven, antiport with Na+ Active

Cl−/HCO3 (perhaps other anions)

Mediated: antiport (anion transporter– band 3 protein) Osmosis passive

Distal renal tubular cells Proximal renal tubular cells and small intestines Plasma membrane of most cells All cells, antiporter in red cells Parietal cells of gastric cells secreting H+ Erythrocytes and many other cells

Other Organic Molecules Cholic acid, deoxycholic acid, and taurocholic acid Organic anions (e.g., malate, αketoglutarate, glutamate) ATP-ADP

Water

All tissues

*NOTE:

The known transport systems are listed here; others have been proposed. Most transport systems have been studied in only a few tissues and their sites of activity may be more limited than indicated. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; Ca++, calcium; Cl−/HCO3, chloride/bicarbonate; H+, hydrogen; K+, potassium; Na+, sodium. Data from Alberts B et al: Molecular biology of the cell, ed 4, New York, 2001, Wiley; Alberts B et al: Essential cell biology, ed 4, New York, 2014, Garland; Devlin TM, editor: Textbook of biochemistry: with clinical correlations, ed 3, New York, 1992, Wiley; Raven PH, Johnson GB: Understanding biology, ed 3, Dubuque, IA, 1995, Brown.

Transport by Vesicle Formation Endocytosis and Exocytosis The active transport mechanisms by which the cells move large proteins, polynucleotides, or polysaccharides (macromolecules) across the plasma membrane are very different from

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those that mediate small solute and ion transport. Transport of macromolecules involves the sequential formation and fusion of membrane-bound vesicles. In endocytosis, a section of the plasma membrane enfolds substances from outside the cell, invaginates (folds inward), and separates from the plasma membrane, forming a vesicle that moves into the cell (Fig. 1.27, A). Two types of endocytosis are designated based on the size of the vesicle formed. Pinocytosis (cell drinking) involves the ingestion of fluids, bits of the plasma membrane, and solute molecules through formation of small vesicles; and phagocytosis (cell eating) involves the ingestion of large particles, such as bacteria, through formation of large vesicles (vacuoles).

FIGURE 1.27 Endocytosis and Exocytosis. A, Endocytosis and fusion with lysosome and exocytosis. B, Electron micrograph of exocytosis. (B, from Raven PH, Johnson GB: Biology, ed 5, New York, 1999, McGraw-Hill.)

Because most cells continually ingest fluid and solutes by pinocytosis, the terms pinocytosis and endocytosis often are used interchangeably. In pinocytosis, the vesicle containing fluids, solutes, or both fuses with a lysosome, and lysosomal enzymes digest the vesicle's contents for use by the cell. Vesicles that bud from membranes have a particular protein coat on their cytosolic surface and are called coated vesicles. The best studied are those that have an outer coat of bristle-like structures—the protein clathrin. Pinocytosis occurs mainly by the clathrin-coated pits and vesicles (Fig. 1.28). After the coated pits pinch off from the plasma membrane, they quickly shed their coats and fuse with an endosome. An endosome is a vesicle pinched off from the plasma membrane from which its contents can be recycled to the plasma membrane or sent to lysosomes for digestion. In phagocytosis, the large molecular substances are engulfed by the plasma membrane and enter the cell so that they can be isolated and destroyed by lysosomal enzymes (see Chapter

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6). Substances that are not degraded by lysosomes are isolated in residual bodies and released by exocytosis. Both pinocytosis and phagocytosis require metabolic energy and often involve binding of the substance with plasma membrane receptors before membrane invagination and fusion with lysosomes in the cell. New data are revealing that endocytosis has an even larger and more important role than previously known (Box 1.3). Exosomes are small membrane vesicles of endocytic origin containing protein, lipid, and RNA species in a single unit. Exosomes are secreted by many cell types and confer messages between cells as mediators of cell-to-cell communication. Researchers are revealing this communication through exosomes, including those released from cancer cells, taken up by neighboring cells, and capable of inducing pathways involved in cancer initiation and progression (Fig. 1.29).4

FIGURE 1.28 Ligand Internalization by Means of Receptor-Mediated Endocytosis. A, The ligand attaches to its surface receptor (through the bristle coat or clathrin coat (1) and receptor-mediated endocytosis), invagination (2) and coated pit (3), and enters the cell. The ingested material fuses (4) with an endosome and lysosomes (6) and is processed by hydrolytic lysosomal enzymes (7). Processed molecules can then be transferred to other cellular components (8 and 9). B, Electron micrograph of a coated pit showing different sizes of filaments of the cytoskeleton (×82,000). (B, from Erlandsen SL, Magney JE: Color atlas of histology, St Louis, 1992, Mosby.)

Box 1.3

The New Endocytic Matrix An explosion of new data is disclosing a much more involved role for endocytosis than just a simple way to internalize nutrients and membrane-associated molecules. These new data show that endocytosis not only is a master organizer of signaling pathways but also has a

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major role in managing signals in time and space. Endocytosis appears to control signaling; therefore it determines the net output of biochemical pathways. This occurs because endocytosis modulates the presence of receptors and their ligands as well as effectors at the plasma membrane or at intermediate stations of the endocytic route. The overall processes and anatomy of these new functions are sometimes called the “endocytic matrix.” All of these functions ultimately have a large impact on almost every cellular process, including the nucleus.

FIGURE 1.29 Exosomes and Cell Signaling: Cancer. From a model of cancer cell signaling, exosomes are secreted with characteristic protein and ribonucleic acid (RNA) components. Exosomes are released from cancer cells and taken up by neighboring cells and are capable of inducing pathways in cancer initiation and progression. A growing interest in defining the clinical relevance of exosomes in cancers is based partially on their ability to alter tumor microenvironment by regulating immunity, angiogenesis, and metastasis. (From Henderson M, Azorsa D: The genomic and proteomic content of cancer cell-derived exosomes, Front Oncol 2:38, 2012.)

In eukaryotic cells, secretion of macromolecules almost always occurs by exocytosis (see Fig. 1.27). Exocytosis has two main functions: (1) replacement of portions of the plasma membrane that have been removed by endocytosis and (2) release of molecules synthesized by the cells into the ECM.

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Receptor-Mediated Endocytosis The internalization process, called receptor-mediated endocytosis (ligand internalization), is rapid and enables the cell to ingest large amounts of receptor-macromolecule complexes in clathrin-coated vesicles without ingesting large volumes of extracellular fluid (see Fig. 1.28). The cellular uptake of cholesterol, for example, depends on receptor-mediated endocytosis. Additionally, many essential metabolites (e.g., vitamin B12 and iron) depend on receptor-mediated endocytosis and, unfortunately, the influenza virus.

Movement of Electrical Impulses: Membrane Potentials All body cells are electrically polarized, with the inside of the cell more negatively charged compared with the outside. The difference in electrical charge, or voltage, is known as the resting membrane potential and is about −70 to −85 millivolts (mV). The difference in voltage across the plasma membrane results from the differences in ionic composition of ICF and ECF. Sodium ions are more concentrated in ECF, and potassium ions are in greater concentration in ICF. The concentration difference is maintained by the active transport of Na+ and K+ (the sodium–potassium [Na+-K+] pump), which transports Na+ outward and K+ inward (Fig. 1.30). Because the resting plasma membrane is more permeable to K+ than to Na+, K+ diffuses easily from ICF to ECF. Because both Na+ and K+ are cations, the net result is an excess of anions inside the cell, resulting in the resting membrane potential.

FIGURE 1.30 Sodium–Potassium (Na+–K+) Pump and Propagation of an Action Potential. A, Concentration difference of sodium (Na+) and potassium (K+) intracellularly and extracellularly. The direction of active transport by the Na+–K+ pump is also shown. B, The left diagram represents the polarized state of a neuronal membrane when at rest. The middle and right diagrams represent changes in sodium and potassium membrane permeabilities with depolarization and repolarization.

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Nerve and muscle cells are excitable and can change their resting membrane potential in response to electrochemical stimuli. Changes in resting membrane potential convey messages from cell to cell. When a nerve or muscle cell receives a stimulus that exceeds the membrane threshold value, a rapid change occurs in the resting membrane potential, known as the action potential. The action potential carries signals along the nerve or muscle cell and conveys information from one cell to another in a domino-like fashion. Nerve impulses are described in Chapter 14. When a resting cell is stimulated through voltage-regulated channels, the cell membranes become more permeable to Na+, so a net movement of Na+ into the cell occurs and the membrane potential decreases, or moves forward, from a negative value (in mV) to zero. This decrease is known as depolarization. The depolarized cell is more positively charged, and its polarity is neutralized. To generate an action potential and the resulting depolarization, the threshold potential must be reached. Generally this occurs when the cell has depolarized by 15 to 20 mV. When the threshold is reached, the cell will continue to depolarize with no further stimulation. The Na+ gates open, and sodium rushes into the cell, causing the membrane potential to drop to zero and then become positive (depolarization). The rapid reversal in polarity results in the action potential. During repolarization, the negative polarity of the resting membrane potential is reestablished. As the voltage-gated Na+ channels begin to close, voltage-gated potassium channels open. Membrane permeability to Na+ decreases and K+ permeability increases, so K+ ions leave the cell. The Na+ gates close and, with the loss of K+ the membrane potential, becomes more negative. The Na+-K+ pump then returns the membrane to the resting potential by pumping K+ back into the cell and Na+ out of the cell. During most of the action potential, the plasma membrane cannot respond to an additional stimulus. This time is known as the absolute refractory period and is related to changes in permeability to Na+. During the latter phase of the action potential, when permeability to K+ increases, a stronger-than-normal stimulus can evoke an action potential; this time is known as the relative refractory period. When the membrane potential is more negative than normal, the cell is in a hyperpolarized state (less excitable: decreased K+ levels within the cell). A stronger-thannormal stimulus is then required to reach the threshold potential and generate an action potential. When the membrane potential is more positive than normal, the cell is in a hypopolarized state (more excitable than normal: increased K+ levels within the cell) and a weaker-than-normal stimulus is required to reach the threshold potential. Changes in the intracellular and extracellular concentrations of ions or a change in membrane permeability can cause these alterations in membrane excitability.

Quick Check 1.3 1. Identify examples of molecules transported in one direction (symport) and opposite directions (antiport). 2. If oxygen is no longer available to make ATP, what happens to the transport of Na+? 3. Define the differences between pinocytosis, phagocytosis, and receptor-mediated

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endocytosis. 4. Define exosome communication.

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Cellular Reproduction: The Cell Cycle Humans must make millions of cells every second to just survive.5 In most tissues, new cells are created as fast as old cells die. Continuity of life depends on constant rounds of cell growth and division; the cycle of repeated rounds of duplication and division is called the cell cycle. Reproduction of gametes (sperm and egg cells) occurs through a process called meiosis, which is described in Chapter 2. The reproduction, or division, of other body cells (somatic cells) involves two sequential phases—mitosis, or nuclear division, and cytokinesis, or cytoplasmic division. Before a cell can divide, however, it must double its mass and duplicate all its contents. Most of the work preparing for division occurs during the growth phase, called interphase. The cell cycle drives the alternation between mitosis and interphase in all tissues with cellular turnover (Fig. 1.31).

FIGURE 1.31 The Cell Cycle. A, Simplified figure of schematic cell with one green chromosome and one yellow chromosome to show how two genetically identical daughter cells are produced in each cycle. B, Cell cycle events: mitosis and cytokinesis. (Adapted from Alberts B et al: Molecular biology of the cell, ed 6, New York, 2015, Garland Science.)

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The four designated phases of the cell cycle (Fig. 1.32) are (1) the G1 phase (G = gap), which is the period between the M phase and the start of DNA synthesis; (2) the S phase (S = synthesis), in which DNA is synthesized in the cell nucleus; (3) the G2 phase, in which RNA and protein synthesis occurs, the period between the completion of DNA synthesis and the next phase (M); and (4) the M phase (M = mitosis), which includes both nuclear and cytoplasmic division.

FIGURE 1.32 Interphase and the Phases of Mitosis. A, The G1/S checkpoint is to “check” for cell size, nutrients, growth factors, and deoxyribonucleic acid (DNA) damage. See text for resting phases. The G2/M checkpoint checks for cell size and DNA replication. B, The orderly progression through the phases of the cell cycle is regulated by cyclins (so called because levels rise and fall) and cyclin-dependent protein kinases (CDKs) and their inhibitors. When cyclins are complexed with CDKs, cell cycle events are triggered.

Phases of Mitosis and Cytokinesis Interphase (the G1, S, and G2 phases) is the longest phase of the cell cycle. During interphase, the chromatin consists of very long, slender rods jumbled together in the nucleus. Late in interphase, strands of chromatin (the substance that gives the nucleus its granular appearance) begin to coil, causing shortening and thickening. The M phase of the cell cycle, mitosis and cytokinesis, begins with prophase, the first appearance of chromosomes. As the phase proceeds, each chromosome is seen as identical halves called chromatids, which lie together and are attached by a spindle site called a centromere. (The two chromatids of each chromosome, which are genetically identical, are sometimes called sister chromatids.) The nuclear membrane, which surrounds the nucleus,

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disappears. Spindle fibers are microtubules formed in the cytoplasm. They radiate from two centrioles located at opposite poles of the cell and pull the chromosomes to opposite sides of the cell, beginning the metaphase. Next, the centromeres become aligned in the middle of the spindle, which is called the equatorial plate (or metaphase plate) of the cell. In this stage, chromosomes are easiest to observe microscopically because they are highly condensed and arranged in a relatively organized fashion. The anaphase begins when the centromeres split and the sister chromatids are pulled apart. The spindle fibers shorten, causing the sister chromatids to be pulled, centromere first, toward opposite sides of the cell. With sister chromatid separation, each is considered to be a chromosome. Thus the cell has 92 chromosomes during this stage. By the end of the anaphase, there are 46 chromosomes lying at each side of the cell. Barring mitotic errors, each of the two groups of 46 chromosomes is identical to the original 46 chromosomes present at the start of the cell cycle. During the telophase, the final stage, a new nuclear membrane is formed around each group of 46 chromosomes, the spindle fibers disappear, and the chromosomes begin to uncoil. Cytokinesis causes the cytoplasm to divide into almost equal parts during this phase. At the end of the telophase, two identical diploid cells, called daughter cells, have been formed from the original cell.

Control of Cell Division and Cell Growth: Mitogens, Growth Factors, and Survival Factors Organ size and body size are determined by three main processes: (1) cell growth, (2) cell division, and (3) cell survival.5 These processes are tightly regulated by intracellular programs and extracellular signal molecules, usually soluble proteins, proteins bound to cells, or molecules of the ECM. The molecules comprise three main classes: (1) mitogens, (2) growth factors, and (3) survival factors. A mitogen is a chemical agent that induces or stimulates mitosis (cell division). Mitogens act as an extracellular signal and they usually come from another neighboring cell. Mitogens can stimulate cell growth, differentiation, migration, and survival.5 Growth factors (also called cytokines) stimulate an increase in cell mass or cell growth by fostering the synthesis of proteins and other macromolecules and inhibiting their breakdown (Table 1.5), including examples of mitogens and growth factors. Survival factors promote cell survival by inhibiting programmed cell death, or apoptosis (see Chapter 4). TABLE 1.5 Examples of Mitogens and Growth Factors and Their Actions Growth Factor Platelet-derived growth factor (PDGF) Epidermal growth factor (EGF) Insulin-like growth factor 1 (IGF-1) Insulin-like growth factor 2 (IGF-2) Transforming growth factor-beta (TGF-β)

Physiologic Actions Stimulates proliferation of connective tissue cells and neuroglial cells Stimulates proliferation of epidermal cells and other cell types Collaborates with PDGF and EGF; stimulates proliferation of fat cells and connective tissue cells Collaborates with PDGF and EGF; stimulates proliferation of fat cells and connective tissue cells Stimulates or inhibits response of most cells to other growth factors; regulates differentiation of some cell types (e.g., cartilage)

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Fibroblast growth factor (FGF) Interleukin-2 (IL-2) Nerve growth factor (NGF) Hematopoietic cell growth factors (IL-3, GMCSF, M-CSF, G-CSF, erythropoietin)

Stimulates proliferation of fibroblasts, endothelial cells, myoblasts, and other cell types Stimulates proliferation of T lymphocytes Promotes axon growth and survival of sympathetic and some sensory and CNS neurons Promotes growth of white and red blood cells

CNS, Central nervous system; CSF, colony-stimulating factor; G, granulocyte; GM, granulocyte-macrophage; M, macrophage.

DNA Damage Response: Blocks Cell Division The DNA damage response occurs when DNA is damaged with recruitment of protein kinases to the site of damage and signaling that promotes a stop to the progression of the cell cycle, called cell cycle arrest (Fig. 1.33).

FIGURE 1.33 Deoxyribonucleic Acid (DNA) Damage Response. Several injurious agents can damage DNA. These include exogenous agents such as ultraviolet light; ionizing radiation; chemicals; and endogenous agents; oxidative damage; and replicative stress. Protein kinases are activated and serve as sensors and transducers causing many effector responses. The cell cycle arrest prevents entry into mitosis and several cell fates occur including DNA repair and apoptosis or cell death.

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Tissues Cells of common structure and function are organized into tissues, of which there are four primary types: muscle, neural, epithelial, and connective. Epithelial, connective, and muscle tissues are summarized in Tables 1.6, 1.7, and 1.8, respectively. Different types of neurons have special characteristics that depend on their distribution and function within the nervous system (see Chapter 14). Different types of tissues compose organs. Finally, organs are integrated to perform complex functions as tracts or systems. TABLE 1.6 Characteristics of Epithelial Tissues Simple Squamous Epithelium Structure Single layer of cells Location and Function Lining of blood vessels leads to diffusion and filtration Lining of pulmonary alveoli (air sacs) leads to separation of blood from fluids in tissues Bowman's capsule (kidney), where it filters substances from blood, forming urine

Simple Squamous Epithelial Cell. Photomicrograph of simple squamous epithelial cell in parietal wall of Bowman's capsule in kidney. (From Erlandsen SL, Magney JE: Color atlas of histology, St Louis, 1992, Mosby.)

Stratified Squamous Epithelium Structure Two or more layers, depending on location, with cells closest to basement membrane tending to be cuboidal Location and Function Epidermis of skin and linings of mouth, pharynx, esophagus, and anus provide protection and secretion

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Cornified Stratified Squamous Epithelium. Diagram of stratified squamous epithelium of skin. (Copyright Ed Reschke. Used with permission.)

Transitional Epithelium Structure Vary in shape from cuboidal to squamous depending on whether basal cells of bladder are columnar or are composed of many layers; when bladder is full and stretched, the cells flatten and stretch like squamous cells Location and Function Linings of urinary bladder and other hollow structures stretch, allowing expansion of the hollow organs

Stratified Squamous Transitional Epithelium. Photomicrograph of stratified squamous transitional epithelium of urinary bladder. (Copyright Ed Reschke. Used with permission.)

Simple Cuboidal Epithelium Structure Simple cuboidal cells; rarely stratified (layered) Location and Function Glands (e.g., thyroid, sweat, salivary) and parts of the kidney tubules and outer covering of ovary secrete fluids

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Simple Cuboidal Epithelium. Photomicrograph of simple cuboidal epithelium of pancreatic duct. (From Erlandsen SL, Magney JE: Color atlas of histology, St Louis, 1992, Mosby.)

Simple Columnar Epithelium Structure Large amounts of cytoplasm and cellular organelles Location and Function Ducts of many glands and lining of digestive tract allow secretion and absorption from stomach to anus

Simple Columnar Epithelium. Photomicrograph of simple columnar epithelium. (Copyright Ed Reschke. Used with permission.)

Ciliated Simple Columnar Epithelium Structure Same as simple columnar epithelium but ciliated Location and Function Linings of bronchi of lungs, nasal cavity, and oviducts allow secretion, absorption, and propulsion of fluids and particles Stratified Columnar Epithelium Structure Small and rounded basement membrane (columnar cells do not touch basement membrane) Location and Function Linings of epiglottis, part of pharynx, anus, and male urethra provide protection Pseudostratified Ciliated Columnar Epithelium Structure All cells in contact with basement membrane

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Nuclei found at different levels within cell, giving stratified appearance Free surface often ciliated Location and Function Linings of large ducts of some glands (parotid, salivary), male urethra, respiratory passages, and eustachian tubes of ears transport substances

Pseudostratified Ciliated Columnar Epithelium. Photomicrograph of pseudostratified ciliated columnar epithelium of trachea. (Copyright Robert L. Calentine. Used with permission.)

TABLE 1.7 Connective Tissues Loose or Areolar Tissue Structure Unorganized; spaces between fibers Most fibers collagenous, some elastic and reticular Includes many types of cells (fibroblasts and macrophages most common) and large amount of intercellular fluid Location and Function Attaches skin to underlying tissue; holds organs in place by filling spaces between them; supports blood vessels Intercellular fluid transports nutrients and waste productsFluid accumulation causes swelling (edema)

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Loose Areolar Connective Tissue. (Copyright Ed Reschke. Used with permission.)

Dense Irregular Tissue Structure Dense, compact, and areolar tissue, with fewer cells and greater number of closely woven collagenous fibers than in loose tissue Location and Function Dermis layer of skin; acts as protective barrier

Dense, Irregular Connective Tissue. (Copyright Ed Reschke. Used with permission.)

Dense, Regular (White Fibrous) Tissue Structure Collagenous fibers and some elastic fibers, tightly packed into parallel bundles, with only fibroblast cells Location and Function Forms strong tendons of muscle, ligaments of joints, some fibrous membranes, and fascia that surrounds organs and muscles

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Dense, Regular (White Fibrous) Connective Tissue. (Copyright Phototake. Used with permission.)

Elastic Tissue Structure Elastic fibers, some collagenous fibers, fibroblasts Location and Function Lends strength and elasticity to walls of arteries, trachea, vocal cords, and other structures

Elastic Connective Tissue. (From Erlandsen SL, Magney JE: Color atlas of histology, St Louis, 1992, Mosby.)

Adipose Tissue Structure Fat cells dispersed in loose tissues; each cell containing a large droplet of fat flattens nucleus and forces cytoplasm into a ring around cell's periphery Location and Function Stores fat, which provides padding and protection

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Adipose Tissue. A, Fat storage areas—distribution of fat in male and female bodies. B, Photomicrograph of adipose tissue. (A from Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby; B copyright Ed Reschke. Used with permission.)

Cartilage (Hyaline, Elastic, Fibrous) Structure Collagenous fibers embedded in a firm matrix (chondrin); no blood supply Location and Function Gives form, support, and flexibility to joints, trachea, nose, ear, vertebral disks, embryonic skeleton, and many internal structures

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Cartilage. A, Hyaline cartilage. B, Elastic cartilage. C, Fibrous cartilage. (A and C, copyright Robert L. Calentine. B, copyright Ed Reshke. Used with permission.)

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Bone Structure Rigid connective tissue consisting of cells, fibers, ground substances, and minerals Location and Function Lends skeleton rigidity and strength

Bone. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 10, St. Louis, 2019, Elsevier.)

Special Connective Tissues Plasma Structure Fluid Location and Function Serves as matrix for blood cells Macrophages in Tissue, Reticuloendothelial, or Macrophage System Structure Scattered macrophages (phagocytes) called Kupffer cells (in liver), alveolar macrophages (in lungs), microglia (in central nervous system) Location and Function Facilitate inflammatory response and carry out phagocytosis in loose connective, lymphatic, digestive, medullary (bone marrow), splenic, adrenal, and pituitary tissues

TABLE 1.8 Muscle Tissues Skeletal (Striated) Muscle Structure Characteristics of Cells Long, cylindrical cells that extend throughout length of muscles Striated myofibrils (proteins) Many nuclei on periphery Location and Function Attached to bones directly or by tendons and provide voluntary movement of skeleton and maintenance of posture

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Skeletal (Striated) Muscle. (From Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)

Cardiac Muscle Structure Characteristics of Cells Branching networks throughout muscle tissue Striated myofibrils Location and Function Cells attached end-to-end at intercalated disks with tissue forming walls of heart (myocardium) to provide involuntary pumping action of heart

Cardiac Muscle. (Copyright Ed Reschke. Used with permission.)

Smooth (Visceral) Muscle Structure Characteristics of Cells Long spindles that taper to a point Absence of striated myofibrils Location and Function Walls of hollow internal structures, such as digestive tract and blood vessels (viscera), provide voluntary and involuntary contractions that move substances through hollow structures

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Smooth (Visceral) Muscle. (From Young B, Woodford P: Wheater's functional histology, ed 6, Philadelphia, 2014, Churchill Livingstone.)

All cells are in contact with a network of extracellular macromolecules known as the ECM (see the Extracellular Matrix and Basement Membrane section). This matrix not only holds cells and tissues together but also provides an organized latticework within which cells can migrate and interact with one another.

Tissue Formation and Differentiation To form tissues, cells must exhibit intercellular recognition and communication, adhesion, and memory. Specialized cells sense their environment through signals, such as growth factors, from other cells. This type of communication ensures that new cells are produced only when and where they are required. Different cell types have different adhesion molecules in their plasma membranes, sticking selectively to other cells of the same type. They can also adhere to the ECM components. Because cells are tiny and squishy and enclosed by a flimsy membrane, it is remarkable that they form a strong human being. Strength can occur because of the ECM and the strength of the cytoskeleton with cell-to-cell adhesions to neighboring cells. Cells have memory because of specialized patterns of gene expression evoked by signals that acted during embryonic development. Memory allows cells to autonomously preserve their distinctive character and pass it on to their progeny.1 Fully specialized, or terminally differentiated, cells that are lost are regenerated from proliferating precursor cells. These precursor cells have been derived from a smaller number of stem cells.1 Stem cells are cells with the potential to develop into many different cell types during early development and growth. In many tissues, stem cells serve as an internal repair and maintenance system, dividing indefinitely. These cells can maintain themselves over very long periods, an ability that is referred to as self-renewal, and can generate all the differentiated cell types of the tissue or multipotency. This stem cell–driven tissue renewal is very evident in the epithelial lining of the intestine, stomach, blood cells, and skin, which is continuously exposed to environmental factors. When a stem cell divides, each daughter cell has a choice: It can remain as a stem cell, or it can follow a pathway that results in terminal differentiation (Fig. 1.34).

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FIGURE 1.34 Properties of Stem Cell Systems. A, Stem cells have three characteristics: self-renewal, proliferation, and differentiation into mature cells. Stem cells are housed in niches consisting of stromal cells that provide factors for their maintenance. Stem cells of the embryo can give rise to cell precursors that generate all the tissues of the body. This property defines stem cells as multipotent. Stem cells are difficult to identify anatomically. Their identification is based on specific cell surface markers (cell surface antigens recognized by specific monoclonal antibodies) and on the lineage they generate following transplantation. B, Wnt signaling fuels tissue renewal. (A, from Kierszenbaum A: Histology and cell biology: an introduction to pathology, ed 3, St Louis, 2012, Elsevier. B, from Clevers H, et al: Science 346(6205):1248012, 2014.)

Quick Check 1.4 1. What is the cell cycle? 2. Describe the DNA damage response 3. Discuss the five types of intracellular communication. 4. Why is the ECM important for tissue cells?

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Summary Review Prokaryotes and Eukaryotes 1. Eukaryotes are the cells of higher animals and plants, fungi, protozoa, and most algae. These cells are larger and have membrane bound intracellular compartments (organelles) and a well-defined nucleus. Genetic information is contained in several or many chromosomes. 2. Prokaryotes include blue-green algae, bacteria, and rickettsiae. They contain no organelles and their nucleus is not well defined. Genetic information is contained in a single circular chromosome.

Cellular Functions 1. Cells become specialized through the process of differentiation, or maturation, so that they perform one kind of function. 2. The eight specialized cellular functions are movement, conductivity, metabolic absorption, secretion, excretion, respiration, reproduction, and communication.

Structure and Function of Cellular Components 1. The eukaryotic cell consists of three general components: the plasma membrane, the cytoplasm, and the intracellular organelles. 2. The nucleus is the largest membrane-bound organelle and is found usually in the cell's center. The chief functions of the nucleus are cell division and control of genetic information. 3. Cytoplasm, or the cytoplasmic matrix, is an aqueous solution (cytosol) that fills the space between the nucleus and the plasma membrane. It represents about half of the volume of the cell. 4. The organelles are suspended in the cytoplasm and are enclosed in biologic membranes. 5. Ribosomes are RNA-protein complexes that provide sites for cellular protein synthesis. 6. The endoplasmic reticulum is a network of tubular channels (cisternae) that extend throughout the outer nuclear membrane. It specializes in the synthesis, folding, and transport of protein and lipid components of most of the organelles, as well as in sensing cellular stress. 7. The Golgi complex is a network of smooth membranes and vesicles located near the nucleus. The Golgi complex is responsible for processing and packaging proteins into secretory vesicles that break away from the Golgi complex and migrate to a variety of intracellular and extracellular destinations, including the plasma membrane. 8. Lysosomes are saclike structures that contain digestive enzymes. These enzymes are responsible for digesting most cellular substances to their basic form, such as

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amino acids, fatty acids, and carbohydrates (sugars). Cellular injury leads to a release of the lysosomal enzymes, causing cellular self-digestion. They also serve as signaling hubs in a network for cellular adaptation. 9. Peroxisomes appear similar to lysosomes but contain several enzymes that either produce or use hydrogen peroxide and their reactions detoxify waste products. 10. Mitochondria contain the metabolic machinery necessary for cellular energy metabolism. The enzymes of the respiratory chain (electron-transport chain), found in the inner membrane of the mitochondria, generate most of the cell's ATP. 11. The cytoskeleton is the “bone and muscle” of the cell. The internal skeleton is composed of a network of protein filaments, including microtubules and actin filaments (microfilaments). They also form cell extensions (microvilli, cilia, flagella). 12. The plasma membrane encloses the cell and, by controlling the movement of substances across it, exerts a powerful influence on metabolic pathways. Other important functions include cell-to-cell recognition, cellular mobility, and maintenance of cellular shape. 13. The basic structure of plasma membrane is the lipid bilayer, which is studded with various proteins. Carbohydrates contained within the plasma membrane are generally bound to membrane proteins (glycoproteins) and lipids (glycolipids). 14. The lipid bilayer determines the structure of the membrane. Each lipid molecule is polar, or amphipathic: the head is hydrophilic (“water loving”) and the tail is hydrophobic (“water hating”). The membrane is organized in two layers, with the tails inward and the heads outward. This provides a barrier to the diffusion of hydrophilic substances, while allowing lipid-soluble molecules to diffuse through readily. 15. Membrane proteins can extend across the bilayer, be in the bilayer but primarily on one side or the other, or can exist outside of the bilayer. Membrane proteins, like other proteins, are synthesized by the ribosome and then translocate, called trafficking, to different locations in the cell. Trafficking places unique demands on membrane proteins for folding, translocation, and stability. Misfolded proteins are emerging as an important cause of disease. 16. Proteins determine the functions of the membrane. Proteins perform most of the plasma membrane's tasks. Proteins act as recognition and binding units for substances moving in and out of the cell, pores and transport channels, enzymes that drive pumps or maintain ion concentrations, cell surface markers, cell adhesion molecules, and catalysts of chemical reactions. Proteins form cellular receptors that recognize and bind with smaller molecules called ligands. 17. Proteostasis is the state of cell balance of the processes of protein synthesis, folding, and dehydration (protein homeostasis). The proteostasis network is composed of ribosomes (makers), chaperones (helpers), and protein breakdown or proteolytic systems. Malfunction of these systems is associated with disease. 18. The carbohydrates on the outside of the plasma membrane form a coating (glycocalyx) that protects the cell from mechanical damage and creates a slimy surface that assists in mobility. Carbohydrates also function in cell-cell recognition and adhesion.

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Cell-to-Cell Adhesions 1. Cell-to-cell adhesions are formed on plasma membranes, thereby allowing the formation of tissues and organs. Cells are held together by three different means: (1) the extracellular membrane, (2) cell adhesion molecules in the cell's plasma membrane, and (3) specialized cell junctions. 2. The extracellular matrix (ECM) is secreted by cells and is a meshwork of fibrous proteins in a gel-like substance. It provides a pathway for diffusion of nutrients, wastes, and other water-soluble substances. The ECM includes three groups of macromolecules: (1) fibrous structural proteins (collagen and elastin), (2) adhesive glycoproteins, and (3) proteoglycans and hyaluronic acid. The matrix helps regulate cell growth, movement, and differentiation. 3. Basement membrane is a specialized type of ECM that is very thin, tough, and flexible. It lies under the epithelium of many organs and is also called the basal lamina. 4. Cell junctions are the contacts between neighboring cells. They can hold cells together with a tight seal, provide strong mechanical attachments, provide a chemical communication, and maintain polarity of cells. Cell junctions can be classified as symmetric and asymmetric. Symmetric junctions include tight junctions, the belt desmosome, desmosomes, and gap junctions. An asymmetric junction is the hemidesmosome.

Cellular Communication and Signal Transduction 1. Cells communicate in three main ways: (1) they form protein channels (gap junctions); (2) they display receptors that affect intracellular processes or other cells in direct physical contact; and (3) they use receptor proteins inside the target cell. 2. Primary modes of intercellular signaling include contact-dependent, paracrine, hormonal, neurohormonal, and neurotransmitter. 3. Signal transduction involves signals or instructions from extracellular chemical messengers that are conveyed to the cell's interior for execution. If deprived of appropriate signals, cells undergo a form of cell suicide known as programmed cell death or apoptosis. 4. Binding of the extracellular signaling messenger (first messenger) to the membrane receptors causes 1) the opening or closing of channels that regulate ion movement and 2) the transfer of the signal to an intracellular messenger (second messenger) that triggers a cascade of events in the cell.

Cellular Metabolism 1. The chemical tasks of maintaining essential cellular functions are referred to as cellular metabolism. Anabolism is the energy-using process of metabolism, whereas catabolism is the energy-releasing process. 2. Adenosine triphosphate (ATP) functions as an energy-transferring molecule. It is fuel for cell survival. Energy is stored by molecules of carbohydrate, lipid, and

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protein, which, when catabolized, transfers energy to ATP. The phases of catabolism are digestion, glycolysis and oxidation, and the citric acid cycle. 3. Oxidative phosphorylation occurs in the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and proteins is transferred to ATP.

Membrane Transport: Cellular Intake and Output 1. Cell survival and growth depends on the constant exchange of molecules with their environment. The majority of molecular transfer depends on specialized membrane transport proteins. The two main classes of membrane transport proteins are transporters and channels. 2. Passive transport does not require the expenditure of energy; rather, it is driven by physical effects. Passive transport mechanisms include diffusion, filtration, and osmosis. Water and small, electrically uncharged molecules move through pores in the plasma membrane's lipid bilayer via passive transport. 3. Diffusion is the passive movement of a solute from an area of greater solute concentration to an area of lesser solute concentration, a difference known as the concentration gradient. 4. Filtration is the movement of water and solutes through a membrane because of a greater pushing pressure on one side. Hydrostatic pressure is the force of water pushing against a cellular membrane. 5. Osmosis is the movement of water across a semipermeable membrane from a region of lower solute concentration to a region of higher solute concentration. The amount of hydrostatic pressure required to oppose the osmotic movement of water is called the osmotic pressure of solution. The overall osmotic effect of colloids, such as plasma proteins, is called the oncotic pressure or colloid osmotic pressure. 6. Active transport requires expenditure of metabolic energy by the cell by means of ATP. Larger molecules and molecular complexes are moved into the cell by active transport. 7. The active transport of Na+ and K+ is found in virtually all cells. Around 60-70% of ATP synthesized by cells is used to maintain the transport of Na+ and K+. 8. The largest molecules (macromolecules) and fluids are transported by membranebound vesicles through the processes of endocytosis (ingestion) and exocytosis (expulsion). 9. Endocytosis, or vesicle formation, is when the substance to be transported is engulfed by a segment of the plasma membrane, forming a vesicle that moves into the cell. Pinocytosis is a type of endocytosis in which fluids and solute molecules are ingested through formation of small vesicles. Phagocytosis is a type of endocytosis in which large particles, such as bacteria, are ingested through formation of large vesicles, called vacuoles. 10. In receptor-mediated endocytosis, the plasma membrane receptors are clustered, along with bristlelike structures, in specialized areas called coated pits. Endocytosis occurs when the coated pits invaginate, internalizing ligand-receptor complexes in coated vesicles. 11. Inside the cell, lysosomal enzymes process and digest material ingested by

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endocytosis. 12. In exocytosis, a membrane bound vesicle carries macromolecules to the outer cell membrane. It has two main functions: it releases molecules synthesized by the cells into the extracellular matrix and replaces portions of the plasma membrane that have been removed by endocytosis. 13. Two types of solutes exist in body fluids: electrolytes and nonelectrolytes. Electrolytes are electrically charged and dissociate into constituent ions when placed in solution. Nonelectrolytes do not dissociate when placed in solution. 14. All body cells are electrically polarized, with the inside of the cell more negatively charged than the outside. The difference in voltage across the plasma membrane is the resting membrane potential. 15. When an excitable (nerve or muscle) cell receives an electrochemical stimulus, cations enter the cell and cause a rapid change in the resting membrane potential known as the action potential. The action potential “moves” along the cell's plasma membrane and is transmitted to an adjacent cell. This is how electrochemical signals convey information from cell to cell.

Cellular Reproduction: The Cell Cycle 1. Cellular reproduction in body tissues involves mitosis (nuclear division) and cytokinesis (cytoplasmic division). 2. Only mature cells are capable of division. Maturation occurs during a stage of cellular life called interphase (growth phase). 3. The cell cycle is the reproductive process that begins after interphase in all tissues with cellular turnover. There are four phases of the cell cycle: (1) the G1 phase (G = gap), the period between the M phase and the start of DNA synthesis; (2) the S phase (S = synthesis), during which DNA synthesis takes place in the cell nucleus; (3) the G2 phase, the period between the completion of DNA synthesis and the next phase in which RNA and protein synthesis occurs; and (4) the M phase (M = mitosis), which involves both nuclear and cytoplasmic division. 4. The M phase (mitosis) involves four stages: prophase, metaphase, anaphase, and telophase. 5. Cellular division and growth are regulated by intracellular programs and several extracellular signal molecules. Mitogens induces or simulates mitosis. Growth factors stimulate an increase in cell mass or cell growth. Survival factors inhibit the programmed cell death called apoptosis.

Tissues 1. Cells of one or more types are organized into tissues, and different types of tissues compose organs. Organs are organized to function as tracts or systems. 2. Three key factors that maintain the cellular organization of tissues are (1) recognition and cell communication, (2) selective cell-to-cell adhesion, and (3) memory. 3. Fully specialized or terminally differentiated cells that are lost are generated from proliferating precursor cells and they, in turn, have been derived from a smaller

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number of stem cells. Stem cells are cells with the potential to develop into many different cell types during early development and growth. In many tissues, stem cells serve as an internal repair and maintenance system dividing indefinitely. These cells can maintain themselves over very long periods of time, called selfrenewal, and can generate all the differentiated cell types of the tissue or multipotency. 4. The four basic types of tissues are epithelial, muscle, nerve, and connective tissues. 5. Neural tissue is composed of highly specialized cells called neurons that receive and transmit electrical impulses rapidly across junctions called synapses. 6. Epithelial tissue covers most internal and external surfaces of the body. The functions of epithelial tissue include protection, absorption, secretion, and excretion. 7. Connective tissue binds various tissues and organs together, supporting them in their locations and serving as storage sites for excess nutrients. 8. Muscle tissue is composed of long, thin, highly contractile cells or fibers. Muscle tissue that is attached to bones enables voluntary movement. Muscle tissue in internal organs enables involuntary movement, such as the heartbeat.

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Key Terms Absolute refractory period, 26 Action potential, 26 Active transport, 19 Amphipathic, 4 Anabolism, 17 Anaphase, 28 Anion, 20 Antiport, 20 Autocrine signaling, 14 Basal lamina, 12 Basement membrane (BM), 12 Binding site, 10 Cadherin, 11 Catabolism, 17 Cation, 20 Cell adhesion molecule (CAM), 9 Cell cortex, 9 Cell cycle, 27 Cell cycle arrest, 28 Cell junction, 12 Cell polarity, 4 Cell-to-cell adhesion, 11 Cellular metabolism, 17 Cellular receptor, 10 Centromere, 28 Channel, 19 Chemical synapse, 14 Chromatid, 28 Chromatin, 28 Citric acid cycle (Krebs cycle, tricarboxylic acid cycle), 17 Clathrin, 23 Coated vesicle, 23 Collagen, 12 Concentration gradient, 20 Connexons, 13 Contact-dependent signaling, 14 Cytokinesis, 27 Cytoplasm, 2 Cytoplasmic matrix, 3 Cytochrome, 18 Cytosol, 3 Daughter cell, 28 Depolarization, 26

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Desmosome, 13 Differentiation, 1 Diffusion, 20 Digestion, 17 DNA damage response, 28 Effective osmolality, 21 Elastin, 12 Electrolyte, 20 Electron-transport chain, 18 Endocytosis, 23 Endosome, 23 Equatorial plate (metaphase plate), 28 ER stress, 10 Eukaryote, 1 Exocytosis, 24 Exosome, 23 Extracellular matrix (ECM), 12 Fibroblast, 12 Fibronectin, 12 Filtration, 20 First messenger, 15 G1 phase, 27 G2 phase, 27 Gap junction, 13 Gating, 13 Glycocalyx, 10 Glycolipid, 4 Glycolysis, 17 Glycoprotein, 4, 9 Growth factor, 28 Homeostasis, 13 Hormonal signaling, 14 Hydrostatic pressure, 20 Hyperpolarized state, 26 Hypopolarized state, 26 Immunoglobulin superfamily (CAM), 11 Integral membrane protein, 9 Integrin, 11 Interphase, 27 Ion, 9, 20 Junctional complex, 13 Ligand, 10 Lipid bilayer, 4 M phase, 27 Macromolecule, 12 Mediated transport, 19 Membrane transport protein, 18

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Metabolic pathway, 17 Metaphase, 28 Mitogen, 28 Mitosis, 27 Multipotency, 29 Neurohormonal signaling, 14 Neurotransmitter, 14 Nuclear envelope, 3 Nuclear pores, 3 Nucleolus, 3 Nucleus, 3 Oncotic pressure (colloid osmotic pressure), 22 Organelle, 3 Osmolality, 21 Osmolarity, 21 Osmosis, 20 Osmotic pressure, 21 Oxidation, 17 Oxidative phosphorylation, 18 Paracrine signaling, 14 Passive transport, 19 Peripheral membrane protein, 9 Phagocytosis, 23 Phospholipid, 6 Pinocytosis, 23 Plasma membrane (plasmalemma), 2 Plasma membrane receptor, 10 Polarity, 20 Polypeptide, 7 Posttranslational modification (PTM), 7 Prokaryote, 1 Prophase, 28 Protein, 7 Proteolytic, 9 Proteome, 7 Proteomic, 7 Proteostasis, 9 Receptor protein, 15 Receptor-mediated endocytosis (ligand internalization), 24 Relative refractory period, 26 Repolarization, 26 Resting membrane potential, 26 S phase, 27 Second messenger, 15 Selectin, 11 Self-renewal, 29 Signal transduction pathway, 15

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Signaling cell, 15 Solute, 19 Spindle fiber, 28 Stem cell, 29 Substrate, 17 Substrate phosphorylation (anaerobic glycolysis), 18 Symport, 20 Target cell, 15 Telophase, 28 Terminally differentiated, 29 Threshold potential, 26 Tight junction, 13 Tissue, 28 Tonicity, 22 Transfer reaction, 18 Transmembrane protein, 9 Transporter, 19 Unfolded-protein response (UPR), 10 Uniport, 20 Valence, 20

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References 1. Alberts B, et al. Essential cell biology. ed 4. Garland: New York; 2014. 2. Ramdani G, Langsley G. ATP, an extracellular signaling molecule in red blood cells: a messenger for malaria? Biomed J. 2014;37(5):284–292. 3. Dou L, et al. Extracellular ATP signaling and clinical relevance. Clin Immunol. 2018;188:67–73. 4. Soung YH, et al. Exosomes in cancer diagnostics. Cancers (Basel). 2017;9(1). 5. Alberts B, et al. Molecular biology of the cell. ed 6. Garland Science: New York; 2015.

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Genes and Genetic Diseases Lynn B. Jorde

CHAPTER OUTLINE DNA, RNA, and Proteins: Heredity at the Molecular Level, 40 Definitions, 40 From Genes to Proteins, 41 Chromosomes, 44 Chromosome Aberrations and Associated Diseases, 44 Elements of Formal Genetics, 51 Phenotype and Genotype, 51 Dominance and Recessiveness, 51 Transmission of Genetic Diseases, 51 Autosomal Dominant Inheritance, 52 Autosomal Recessive Inheritance, 54 X-Linked Inheritance, 56 Linkage Analysis and Gene Mapping, 58 Classic Pedigree Analysis, 58 Complete Human Gene Map: Prospects and Benefits, 58 Multifactorial Inheritance, 59

Genetics is the study of biologic inheritance. An understanding of genetics is essential to study human, animal, plant, or microbial life. In the nineteenth century, microscopic studies of cells led scientists to suspect the nucleus of the cell contained the important mechanisms of inheritance. Scientists found chromatin, the substance giving the nucleus a granular appearance, is observable in nondividing cells. Just before the cell divides, the chromatin condenses to form discrete, dark-staining organelles, which are called chromosomes. (Cell division is discussed in Chapter 1.) With the rediscovery of Mendel's important breeding experiments at the turn of the twentieth century, it soon became apparent the chromosomes contained genes, the basic units of inheritance (Fig. 2.1).

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FIGURE 2.1

Successive Enlargements From a Human to the Genetic Material.

The primary constituent of chromatin is deoxyribonucleic acid (DNA). Genes are composed of sequences of DNA. By serving as the blueprints of proteins in the body, genes ultimately influence all aspects of body structure and function. Humans have approximately 20,000 protein-coding genes and at least an additional 9000 to 10,000 genes that encode various types of ribonucleic acid (RNA; see below) that are not translated into proteins. An error in one of these genes often leads to a recognizable genetic disease. To date, more than 20,000 genetic traits and diseases have been identified and cataloged. As infectious diseases continue to be more effectively controlled, the proportion of beds in pediatric hospitals occupied by children with genetic diseases has risen. In addition to genetic diseases in children, many common diseases primarily affecting adults, such as hypertension, coronary heart disease, diabetes, and cancer, are now known to have important genetic components. Great progress is being made in the diagnosis of genetic diseases and in the understanding of genetic mechanisms underlying them. With the huge strides being made in molecular genetics, “gene therapy”—the utilization of normal genes to correct genetic disease—has begun.

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DNA, RNA, and Proteins: Heredity at the Molecular Level Definitions Composition and Structure of DNA Genes are composed of DNA, which has three basic components: the five-carbon monosaccharide deoxyribose; a phosphate molecule; and four types of nitrogenous bases. Two of the bases, cytosine and thymine, are single carbon-nitrogen rings called pyrimidines. The other two bases, adenine and guanine, are double carbon-nitrogen rings called purines. The four bases are commonly represented by their first letters: A (adenine), C (cytosine), T (thymine), and G (guanine). Watson and Crick demonstrated how these molecules are physically assembled as DNA, proposing the double-helix model, in which DNA appears like a twisted ladder with chemical bonds as its rungs (Fig. 2.2). The two sides of the ladder consist of deoxyribose and phosphate molecules, united by strong phosphodiester bonds. Projecting from each side of the ladder, at regular intervals, are the nitrogenous bases. The base projecting from one side is bound to the base projecting from the other by a weak hydrogen bond. Therefore the nitrogenous bases form the rungs of the ladder; adenine pairs with thymine, and guanine pairs with cytosine. Each DNA subunit—consisting of one deoxyribose molecule, one phosphate group, and one base—is called a nucleotide.

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FIGURE 2.2 Watson-Crick Model of the Deoxyribonucleic Acid (DNA) Molecule. The DNA structure illustrated here is based on that published by James Watson (photograph, left) and Francis Crick (photograph, right) in 1953. Note that each side of

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the DNA molecule consists of alternating sugar and phosphate groups. Each sugar group is bonded to the opposing sugar group by a pair of nitrogenous bases (adenine– thymine or cytosine–guanine). The sequence of these pairs constitutes a genetic code that determines the structure and function of a cell. (Illustration from Herlihy B: The human body in health and illness, ed 5, St Louis, 2015, Saunders.)

DNA as the Genetic Code DNA directs the synthesis of all the body's proteins. Proteins are composed of one or more polypeptides (intermediate protein compounds), which in turn consist of sequences of amino acids. The body contains 20 different types of amino acids; they are specified by the four nitrogenous bases. To specify (code for) 20 different amino acids with only four bases, different combinations of bases, occurring in groups of three (triplets), are used. These triplets of bases are known as codons. Each codon specifies a single amino acid in a corresponding protein. Because there are 64 (4 × 4 × 4) possible codons but only 20 amino acids, there are many cases in which several codons correspond to the same amino acid. The genetic code is universal: all living organisms use precisely the same DNA codes to specify proteins except for mitochondria, the cytoplasmic organelles in which cellular respiration takes place (see Chapter 1)—they have their own extranuclear DNA. Several codons of mitochondrial DNA encode different amino acids, compared with the same nuclear DNA codons.

Replication of DNA DNA replication consists of breaking the weak hydrogen bonds between the bases, leaving a single strand with each base unpaired (Fig. 2.3). The consistent pairing of adenine with thymine and of guanine with cytosine, known as complementary base pairing, is the key to accurate replication. The unpaired base attracts a free nucleotide only if the nucleotide has the proper complementary base. When replication is complete, a new double-stranded molecule identical to the original is formed. The single strand is said to be a template, or molecule on which a complementary molecule is built, and is the basis for synthesizing the new double strand.

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FIGURE 2.3 Replication of Deoxyribonucleic Acid (DNA). The two chains of the double helix separate and each chain serves as the template for a new complementary chain. (From Herlihy B: The human body in health and illness, ed 5, St Louis, 2015, Saunders.)

Several different proteins are involved in DNA replication. The most important of these proteins is an enzyme known as DNA polymerase. This enzyme travels along the single DNA strand, adding the correct nucleotides to the free end of the new strand and checking to ensure that its base is actually complementary to the template base. This mechanism of DNA proofreading substantially enhances the accuracy of DNA replication.

Mutation A mutation is any alteration of genetic material. One type of mutation is the base pair substitution, in which one base pair replaces another. This replacement can result in a change in the amino acid sequence. However, because of the redundancy of the genetic code, many of these mutations do not change the amino acid sequence and thus have no consequence. Such mutations are called silent mutations. Base pair substitutions altering amino acids consist of two basic types: missense mutations, which produce a change (i.e., the “sense”) in a single amino acid; and nonsense mutations, which produce one of the three stop codons (UAA, UAG, or UGA) in the messenger RNA (mRNA) (Fig. 2.4). Missense mutations (see Fig. 2.4, A) produce a single amino acid change, whereas nonsense mutations (see Fig. 2.4, B) produce a premature stop codon in the mRNA. Stop codons terminate translation of the polypeptide.

FIGURE 2.4 Base Pair Substitution. Missense mutations (A) produce a single amino acid change, whereas nonsense mutations (B) produce a stop codon in the messenger ribonucleic acid (mRNA). Stop codons terminate translation of the polypeptide. (From

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Jorde L et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)

The frameshift mutation involves the insertion or deletion of one or more base pairs of the DNA molecule. As Fig. 2.5 shows, these mutations change the entire “reading frame” of the DNA sequence because the deletion or insertion is not a multiple of three base pairs (the number of base pairs in a codon). Frameshift mutations can thus greatly alter the amino acid sequence. (In-frame insertions or deletions, in which a multiple of three bases is inserted or lost, tend to have less severe disease consequences than do frameshift mutations.)

FIGURE 2.5 Frameshift Mutations. Frameshift mutations result from the addition or deletion of a number of bases that is not a multiple of 3. This mutation alters all of the codons downstream from the site of insertion or deletion. (From Jorde L et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)

Agents known as mutagens increase the frequency of mutations. Examples include radiation and chemicals, such as nitrogen mustard, vinyl chloride, alkylating agents, formaldehyde, and sodium nitrite. Mutations are rare events. The rate of spontaneous mutations (those occurring in the absence of exposure to known mutagens) in humans is about 10−4 to 10−7 per gene per generation. This rate varies from one gene to another. Some DNA sequences have particularly high mutation rates and are known as mutational hot spots.

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From Genes to Proteins DNA is formed and replicated in the cell nucleus, but protein synthesis takes place in the cytoplasm. The DNA code is transported from nucleus to cytoplasm, and subsequent protein is formed through two basic processes: transcription and translation. These processes are mediated by ribonucleic acid (RNA), which is chemically similar to DNA except the sugar molecule is ribose rather than deoxyribose, and uracil rather than thymine is one of the four bases. The other bases of RNA, as in DNA, are adenine, cytosine, and guanine. Uracil is structurally similar to thymine, so it also can pair with adenine. DNA usually occurs as a double strand, whereas RNA usually occurs as a single strand.

Transcription In transcription, RNA is synthesized from a DNA template, forming messenger RNA (mRNA). RNA polymerase binds to a promoter site, a sequence of DNA that specifies the beginning of a gene. RNA polymerase then separates a portion of the DNA, exposing unattached DNA bases. One DNA strand then provides the template for the sequence of mRNA nucleotides. The sequence of bases in the mRNA is thus complementary to the template strand, and except for the presence of uracil instead of thymine, the mRNA sequence is identical to that of the other DNA strand. Transcription continues until a termination sequence, codons that act as signals for the termination of protein synthesis, is reached. Then the RNA polymerase detaches from the DNA, and the transcribed mRNA is freed to move out of the nucleus and into the cytoplasm (Figs. 2.6 and 2.7).

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FIGURE 2.6 General Scheme of Ribonucleic Acid (RNA) Transcription. In transcription of messenger RNA (mRNA), a deoxyribonucleic acid (DNA) molecule “unzips” in the region of the gene to be transcribed. RNA nucleotides already present in the nucleus temporarily attach themselves to exposed DNA bases along one strand of the unzipped DNA molecule according to the principle of complementary pairing. As the RNA nucleotides attach to the exposed DNA, they bind to each other and form a chainlike RNA strand called a messenger RNA (mRNA) molecule. Note that the new mRNA strand is an exact copy of the base sequence on the opposite side of the DNA molecule. As in all metabolic processes, the formation of mRNA is controlled by an enzyme—in this case, the enzyme is called RNA polymerase. (From Ignatavicius DD, Workman LD: Medical-surgical nursing, ed 6, St Louis, 2010, Saunders.)

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FIGURE 2.7

Protein Synthesis. The site of transcription is the nucleus and the site of translation is the cytoplasm. See the text for details.

Gene Splicing When the mRNA is first transcribed from the DNA template, it reflects exactly the base sequence of the DNA. In eukaryotes, many RNA sequences are removed by nuclear enzymes, and the remaining sequences are spliced together to form the functional mRNA that migrates to the cytoplasm. The excised sequences are called introns (intervening sequences), and the sequences that are left to code for proteins are called exons.

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In translation, RNA directs the synthesis of a polypeptide (see Fig. 2.7), interacting with transfer RNA (tRNA), a cloverleaf-shaped strand of about 80 nucleotides. The tRNA molecule has a site where an amino acid attaches. The three-nucleotide sequence at the opposite side of the cloverleaf is called the anticodon. It undergoes complementary base pairing with an appropriate codon in the mRNA, which specifies the sequence of amino acids through tRNA. The site of actual protein synthesis is in the ribosome, which consists of approximately equal parts of protein and ribosomal RNA (rRNA). During translation, the ribosome first binds to an initiation site on the mRNA sequence and then binds to its surface, so that base pairing can occur between tRNA and mRNA. The ribosome then moves along the mRNA sequence, processing each codon and translating an amino acid by way of the interaction of mRNA and tRNA. The ribosome provides an enzyme that catalyzes the formation of covalent peptide bonds between the adjacent amino acids, resulting in a growing polypeptide. When the ribosome arrives at a termination signal on the mRNA sequence, translation and polypeptide formation cease; the mRNA, ribosome, and polypeptide separate from one another; and the polypeptide is released into the cytoplasm to perform its required function.

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Chromosomes Human cells can be categorized into gametes (sperm and egg cells) and somatic cells, which include all cells other than gametes. Each somatic cell nucleus has 46 chromosomes in 23 pairs (Fig. 2.8). These are diploid cells, and the individual's father and mother each donate one chromosome per pair. New somatic cells are formed through mitosis and cytokinesis. Gametes are haploid cells: They have only 1 member of each chromosome pair, for a total of 23 chromosomes. Haploid cells are formed from diploid cells by meiosis (Fig. 2.9).

FIGURE 2.8

From Molecular Parts to the Whole Somatic Cell.

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FIGURE 2.9

Phases of Meiosis and Comparison to Mitosis. (From Jorde LB et al: Medical genetics, ed 5, St Louis, 2016, Elsevier.)

In 22 of the 23 chromosome pairs, the two members of each pair are virtually identical in microscopic appearance: thus they are homologous (Fig. 2.10, B). These 22 chromosome pairs are homologous in both males and females and are termed autosomes. The remaining pair of chromosomes, the sex chromosomes, consists of two homologous X chromosomes in females and a nonhomologous pair, X and Y, in males.

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FIGURE 2.10 Karyogram of Chromosomes. A, Human karyogram. B, Homologous chromosomes and sister chromatids. (From Raven PH et al: Biology, ed 8, New York, 2008, McGraw-Hill.)

Fig. 2.10, A, illustrates a metaphase spread, which is a photograph of the chromosomes as they appear in the nucleus of a somatic cell during metaphase. (Chromosomes are easiest to visualize during this stage of mitosis.) In Fig. 2.10, A, the chromosomes are arranged according to size, with the homologous chromosomes paired. The 22 autosomes are numbered according to length, with chromosome 1 being the longest and chromosome 22 the shortest. A karyotype, or karyogram, is an ordered display of chromosomes. Some natural variation in relative chromosome length can be expected from person to person, so it is not always possible to distinguish each chromosome by its length. Therefore the position of the centromere (region of DNA responsible for movement of the replicated chromosomes into the two daughter cells during mitosis and meiosis) also is used to classify chromosomes (see Fig. 2.10, B, and Fig. 2.11).

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FIGURE 2.11 Structure of Chromosomes. A, Human chromosomes 2, 5, and 13. Each is replicated and consists of two chromatids. Chromosome 2 is a metacentric chromosome because the centromere is close to the middle; chromosome 5 is submetacentric because the centromere is set off from the middle; chromosome 13 is acrocentric because the centromere is at or very near the end. B, During mitosis, the centromere divides and the chromosomes move to opposite poles of the cell. At the time of centromere division, the chromatids are designated as chromosomes.

The chromosomes in Fig. 2.10 were stained with Giemsa stain, resulting in distinctive chromosome bands. These form various patterns in the different chromosomes so that each chromosome can be distinguished easily. Using banding techniques, researchers can number chromosomes and study individual variations. Missing or duplicated portions of chromosomes, which often result in serious diseases, also are readily identified. More recently, techniques have been devised permitting each chromosome to be visualized with a different color.

Chromosome Aberrations and Associated Diseases Chromosome abnormalities are the leading known cause of intellectual disability and miscarriage. Estimates indicate that a major chromosome aberration occurs in at least 1 in 12 conceptions. Most of these fetuses do not survive to term; about 50% of all recovered first-trimester spontaneous abortuses have major chromosome aberrations.1 The number of live births affected by these abnormalities is, however, significant; approximately 1 in 150 has a major diagnosable chromosome abnormality.1

Polyploidy Cells with a multiple of the normal number of chromosomes are euploid cells (Greek eu = good or true). Because normal gametes are haploid and most normal somatic cells are diploid, they are both euploid forms. When a euploid cell has more than the diploid number of chromosomes, it is said to be a polyploid cell. Several types of body tissues, including some liver, bronchial, and epithelial tissues, are normally polyploid. A zygote

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that has three copies of each chromosome, rather than the usual two, has a form of polyploidy called triploidy. Nearly all triploid fetuses are spontaneously aborted or stillborn. The prevalence of triploidy among live births is approximately 1 in 10,000. Tetraploidy, a condition in which euploid cells have 92 chromosomes, has been found primarily in early abortuses, although occasionally affected infants have been born alive. Like triploid infants, however, they do not survive. Triploidy and tetraploidy are relatively common conditions, accounting for approximately 10% of all known miscarriages.2

Aneuploidy A cell that does not contain a multiple of 23 chromosomes is an aneuploid cell. A cell containing three copies of one chromosome is said to be trisomic (a condition termed trisomy) and is aneuploid. Monosomy, the presence of only one copy of a given chromosome in a diploid cell, is the other common form of aneuploidy. Among the autosomes, monosomy of any chromosome is lethal, but newborns with trisomy of chromosomes 13, 18, 21, or X can survive. This difference illustrates an important principle: In general, loss of chromosome material has more serious consequences than duplication of chromosome material. Aneuploidy of the sex chromosomes is less serious than that of the autosomes. Very little genetic material—only about 40 genes—is located on the Y chromosome. For the X chromosome, inactivation of extra chromosomes (see the X-linked Inheritance section) largely diminishes their effect. A zygote bearing no X chromosome, however, will not survive. Aneuploidy is usually the result of nondisjunction, an error in which homologous chromosomes or sister chromatids fail to separate normally during meiosis or mitosis (Fig. 2.12). Nondisjunction produces some gametes that have two copies of a given chromosome and others that have no copies of the chromosome. When such gametes unite with normal haploid gametes, the resulting zygote is monosomic or trisomic for that chromosome. Occasionally, a cell can be monosomic or trisomic for more than one chromosome.

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FIGURE 2.12 Nondisjunction. Nondisjunction causes aneuploidy when chromosomes or sister chromatids fail to divide properly. (From Jorde LB et al: Medical genetics, ed 5, St Louis, 2016, Elsevier.)

Autosomal aneuploidy. Trisomy can occur for any chromosome, but fetuses with other trisomies of chromosomes (other than 13, 18, 21, or X) do not survive to term. Trisomy 16, for example, is the most common trisomy among abortuses, but it is not seen in live births. Partial trisomy, in which only an extra portion of a chromosome is present in each cell, can occur also. The consequences of partial trisomies are not as severe as those of complete trisomies. Trisomies may occur in only some cells of the body. Individuals thus affected are said to be chromosomal mosaics, meaning that the body has two or more different cell lines, each of which has a different karyotype. Mosaics are often formed by early mitotic nondisjunction occurring in one embryonic cell but not in others. The best-known example of aneuploidy in an autosome is trisomy of chromosome 21, which causes Down syndrome (named after J. Langdon Down, who first described the syndrome in 1866). Down syndrome is seen in approximately 1 in 800 to 1 in 1000 live births; its principal features are shown and outlined in Fig. 2.13 and Table 2.1.

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FIGURE 2.13

Child with Down Syndrome. (Courtesy Drs. A. Olney and M. MacDonald, University of Nebraska Medical Center, Omaha, Neb.)

TABLE 2.1 Characteristics of Various Chromosome Disorders Disease/Disorder Features Down Syndrome Trisomy of Chromosome 21 Intelligence Usually ranges from 20 to 70 (intellectual disability) quotient (IQ) Male/female Virtually all males are sterile; some females can reproduce findings Face Distinctive: low nasal bridge, epicanthal folds, protruding tongue, low-set ears Musculoskeletal Poor muscle tone (hypotonia), short stature system Systemic Congenital heart disease (one-third to half of cases), reduced ability to fight respiratory tract disorders infections, increased susceptibility to leukemia—overall reduced survival rate; by age 40 years usually develop symptoms similar to those of Alzheimer disease Mortality About 75% of fetuses with Down syndrome abort spontaneously or are stillborn; 20% of infants die before age 10 years; those who live beyond 10 years have life expectancy of about 60 years Causative factors 97% caused by nondisjunction during formation of one of parent's gametes or during early embryonic development; 3% result from translocations; in 95% of cases, nondisjunction occurs when mother's egg cell is formed; remainder involve paternal nondisjunction; 1% are mosaics—these have a large number of normal cells, and effects of trisomic cells are attenuated and symptoms are generally less severe Turner Syndrome (45,X) Monosomy of X Chromosome IQ Not considered to be intellectually disabled, although some impairment of spatial and mathematical reasoning ability is found Male/female Found only in females findings Musculoskeletal Short stature common, characteristic webbing of neck, widely spaced nipples, reduced carrying angle system at elbow Systemic Coarctation (narrowing) of aorta, edema of feet in newborns, usually sterile and have gonadal streaks disorders rather than ovaries; streaks are sometimes susceptible to cancer Mortality About 15%-20% of spontaneous abortions with chromosome abnormalities have this karyotype, most

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common single-chromosome aberration; highly lethal during gestation, only about 0.5% of these conceptions survive to term Causative factors 75% inherit X chromosome from mother, thus caused by meiotic error in father; frequency low compared with other sex chromosome aneuploidies (1 : 5000 newborn females); 50% have simple monosomy of X chromosome; remainder have more complex abnormalities; combinations of 45, X cells with XX or XY cells common Klinefelter Syndrome (47,XXY) XXY Condition IQ Moderate degree of mental impairment may be present Male/female Have a male appearance but usually sterile; 50% develop female-like breasts (gynecomastia); occurs findings in 1 : 1000 male births Face Voice somewhat high pitched Systemic Sparse body hair, sterile, small testicles disorders Causative factors 50% of cases the result of nondisjunction of X chromosomes in mother, frequency rises with increasing maternal age; also involves XXY and XXXY karyotypes with degree of physical and mental impairment increasing with each added X chromosome; mosaicism fairly common with most prevalent combination of XXY and XY cells

The risk of having a child with Down syndrome increases greatly with maternal age. As Fig. 2.14 demonstrates, women younger than 30 years of age have a risk ranging from about 1 in 1000 births to 1 in 2000 births. The risk begins to rise substantially after age 35 years, and reaches 3% to 5% for women older than 45 years of age. This dramatic increase in risk is caused by the age of maternal egg cells, which are held in an arrested state of prophase I from the time they are formed in the female embryo until they are shed in ovulation. Thus an egg cell formed by a 45-year-old woman is itself 45 years old. This long suspended state causes defects to accumulate in the cellular proteins responsible for meiosis, leading to nondisjunction. The risk of Down syndrome, as well as other trisomies, does not increase with paternal age.

FIGURE 2.14

Down Syndrome Increases With Maternal Age. Rate is per 1000 live births related to maternal age.

Sex chromosome aneuploidy.

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The incidence of sex chromosome aneuploidies is fairly high. Among live births, about 1 in 500 males and 1 in 900 females have a form of sex chromosome aneuploidy. Because these conditions are generally less severe than autosomal aneuploidies, all forms except complete absence of any X chromosome material allow at least some individuals to survive. One of the most common sex chromosome aneuploidies, affecting about 1 in 1000 newborn females, is trisomy X. Instead of two X chromosomes, these females have three X chromosomes in each cell. Most of these females have no overt physical abnormalities, although sterility, menstrual irregularity, or intellectual disability is sometimes seen. Some females have four X chromosomes, and they are more often intellectually disabled. Those with five or more X chromosomes generally have more severe intellectual disability and various physical defects. A condition that leads to somewhat more serious problems is the presence of a single X chromosome and no homologous X or Y chromosome, so that the individual has a total of 45 chromosomes. The karyotype is usually designated 45,X, and it causes a set of symptoms known as Turner syndrome (Fig. 2.15; see Table 2.1). Individuals with at least two X chromosomes and one Y chromosome in each cell (47,XXY karyotype) have a disorder known as Klinefelter syndrome (Fig. 2.16; see Table 2.1).

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FIGURE 2.15 Turner Syndrome. A, A sex chromosome is missing, and the person's chromosomes are 45,X. Characteristic signs are short stature, female genitalia, webbed neck, shield-like chest with underdeveloped breasts and widely spaced nipples, and imperfectly developed ovaries. B, As this karyotype shows, Turner syndrome results from monosomy of sex chromosomes (genotype XO). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby. Courtesy Nancy S. Wexler, PhD, Columbia University.)

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FIGURE 2.16 Klinefelter Syndrome. This young man exhibits many characteristics of Klinefelter syndrome: small testes, some development of the breasts, sparse body hair, and long limbs. This syndrome results from the presence of two or more X chromosomes with one Y chromosome (genotypes XXY or XXXY, for example). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Mosby. Courtesy Nancy S. Wexler, PhD, Columbia University.)

Abnormalities of Chromosome Structure In addition to the loss or gain of whole chromosomes, parts of chromosomes can be lost or duplicated as gametes are formed, and the arrangement of genes on chromosomes can be altered. Unlike aneuploidy and polyploidy, these changes sometimes have no serious consequences for an individual's health. Some of them can even remain entirely unnoticed, especially when very small pieces of chromosomes are involved. Nevertheless, abnormalities of chromosome structure can also produce serious disease in individuals or their offspring. During meiosis and mitosis, chromosomes usually maintain their structural integrity, but chromosome breakage occasionally occurs. Mechanisms exist to “heal” these breaks and usually repair them perfectly with no damage to the daughter cell. However, some breaks remain or heal in a way that alters the chromosome's structure. The risk of chromosome breakage increases with exposure to harmful agents called clastogens (e.g., ionizing radiation, viral infections, or some types of chemicals). Deletions. Broken chromosomes and lost DNA cause deletions (Fig. 2.17). Usually, a gamete with a deletion unites with a normal gamete to form a zygote. The zygote thus has one

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chromosome with the normal complement of genes and one with some missing genes. Because many genes can be lost in a deletion, serious consequences result, even though one normal chromosome is present. The most often cited example of a disease caused by a chromosomal deletion is the cri du chat syndrome. The term literally means “cry of the cat” and describes the characteristic cry of the affected child. Other symptoms include low birth weight, severe intellectual disability, microcephaly (smaller than normal head size), and heart defects. The disease is caused by a deletion of part of the short arm of chromosome 5.

FIGURE 2.17 Abnormalities of Chromosome Structure. A, Deletion occurs when a chromosome segment is lost. B, Normal crossing over. C, The generation of duplication and deletion through unequal crossover.

Duplications. A deficiency of genetic material is more harmful than an excess, so duplications usually have less serious consequences than deletions. For example, a deletion of a region of chromosome 5 causes cri du chat syndrome, but a duplication of the same region causes intellectual disability, but less serious physical defects. Inversions. An inversion occurs when two breaks take place on a chromosome, followed by the reinsertion of the missing fragment at its original site but in inverted order. Therefore a

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chromosome symbolized as ABCDEFG might become ABEDCFG after an inversion. Unlike deletions and duplications, no loss or gain of genetic material occurs, so inversions are “balanced” alterations of chromosome structure, and they often have no apparent physical effect. Some genes are influenced by neighboring genes, however, and this position effect, a change in a gene's expression caused by its position, sometimes results in physical defects in these persons. Inversions can cause serious problems in the offspring of individuals carrying the inversion because the inversion can lead to duplications and deletions in the chromosomes transmitted to the offspring. Translocations. The interchange of genetic material between nonhomologous chromosomes is called translocation. A reciprocal translocation occurs when breaks take place in two different chromosomes and the material is exchanged (Fig. 2.18, A). As with inversions, the carrier of a reciprocal translocation is usually normal, but his or her offspring can have duplications and deletions.

FIGURE 2.18 Normal and Abnormal Chromosome Translocation. A, Normal chromosomes and reciprocal translocation. B, Pairing at meiosis. C, Consequences of translocation in gametes; unbalanced gametes result in zygotes that are partially trisomic and partially monosomic and consequently develop abnormally.

A second and clinically more important type of translocation is Robertsonian translocation. In this disorder, the long arms of two nonhomologous chromosomes fuse at the centromere, forming a single chromosome. Robertsonian translocations are confined to chromosomes 13, 14, 15, 21, and 22 because the short arms of these chromosomes are very small and contain no essential genetic material. The short arms are usually lost during subsequent cell divisions. Because the carriers of Robertsonian translocations lose no important genetic material, they are unaffected, although they have only 45 chromosomes in each cell. Their offspring, however, may have serious monosomies or trisomies. For example, a common Robertsonian translocation involves the fusion of the long arms of chromosomes 21 and 14. An offspring who inherits a gamete carrying the fused

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chromosome can receive an extra copy of the long arm of chromosome 21 and develop Down syndrome. Robertsonian translocations are responsible for approximately 3% to 5% of Down syndrome cases. Parents who carry a Robertsonian translocation involving chromosome 21 have an increased risk for producing multiple offspring with Down syndrome. Fragile sites. A number of areas on chromosomes develop distinctive breaks and gaps (observable microscopically) when the cells are cultured. Most of these fragile sites do not appear to be related to disease. However, one fragile site, located on the long arm of the X chromosome, is associated with fragile X syndrome. The most important feature of this syndrome is intellectual disability. With a relatively high population prevalence (affecting approximately 1 in 4000 males and 1 in 8000 females), fragile X syndrome is the second most common genetic cause of intellectual disability (after Down syndrome). In fragile X syndrome, females who inherit the mutation do not necessarily express the disease condition, but they can pass it on to descendants who do express it. Ordinarily, a male who inherits a disease gene on the X chromosome expresses the condition because he has only one X chromosome. An uncommon feature of this disease is that about one-third of carrier females are affected, although less severely than males. Unaffected transmitting males have been shown to have more than about 50 repeated DNA sequences near the beginning of the fragile X gene. These trinucleotide sequences, which consist of CGG sequences duplicated many times, cause fragile X syndrome when the number of copies exceeds 200.3 The number of these repeats can increase from generation to generation. More than 20 other genetic diseases, including Huntington disease and myotonic dystrophy, also are caused by this mechanism.4

Quick Check 2.1 1. What is the major composition of DNA? 2. Define the terms mutation, autosomes, and sex chromosomes. 3. What is the significance of mRNA? 4. What is the significance of chromosomal translocation?

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Elements of Formal Genetics The mechanisms by which an individual's set of paired chromosomes produces traits are the principles of genetic inheritance. Mendel's work with garden peas first defined these principles. Later geneticists have refined Mendel's work to explain patterns of inheritance for traits and diseases that appear in families. Analysis of traits that occur with defined, predictable patterns has helped geneticists assemble the pieces of the human gene map. Current research focuses on determining the RNA or protein products of each gene and understanding the way they contribute to disease. Eventually, diseases and defects caused by single genes can be traced and therapies to prevent and treat such diseases can be developed. Traits caused by single genes are called mendelian traits (after Gregor Mendel). Each gene occupies a position along a chromosome, known as a locus. The genes at a particular locus can have different forms (i.e., they can be composed of different nucleotide sequences) called alleles. A locus that has two or more alleles that each occur with an appreciable frequency in a population is said to be polymorphic (or to have a polymorphism). Because humans are diploid organisms, each chromosome is represented twice, with one member of the chromosome pair contributed by the father and one by the mother. At a given locus, an individual has one allele whose origin is paternal and one whose origin is maternal. When the two alleles are identical, the individual is homozygous at that locus. When the alleles are not identical, the individual is heterozygous at that locus.

Phenotype and Genotype The composition of genes at a given locus is known as the genotype. The outward appearance of an individual, which is the result of both genotype and environment, is the phenotype. For example, an infant who is born with an inability to metabolize the amino acid phenylalanine has the single-gene disorder known as phenylketonuria (PKU) and thus has the PKU genotype. If the condition is left untreated, abnormal metabolites of phenylalanine will begin to accumulate in the infant's brain and irreversible intellectual disability will occur. Intellectual disability is thus one aspect of the PKU phenotype. By imposing dietary restrictions to exclude food that contains phenylalanine, however, intellectual disability can be prevented. Foods high in phenylalanine include proteins found in milk, dairy products, meat, fish, chicken, eggs, beans, and nuts. Although the child still has the PKU genotype, a modification of the environment (in this case, the child's diet) produces an outwardly normal phenotype.

Dominance and Recessiveness In many loci, the effects of one allele mask those of another when the two are found together in a heterozygote. The allele whose effects are observable is said to be dominant. The allele whose effects are hidden is said to be recessive (from the Latin root for “hiding”). Traditionally, for loci having two alleles, the dominant allele is denoted by an uppercase letter and the recessive allele is denoted by a lowercase letter. When one allele is dominant over another, the heterozygote genotype Aa has the same phenotype as the dominant

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homozygote AA. For the recessive allele to be expressed, it must exist in the homozygote form, aa. A carrier is an individual who has a disease gene but is phenotypically normal. Many genes for a recessive disease occur in heterozygotes, who carry one copy of the gene but do not express the disease. When recessive genes are lethal in the homozygous state, they are eliminated from the population when they occur in homozygotes. By “hiding” in carriers, however, recessive genes for diseases are passed on to the next generation.

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Transmission of Genetic Diseases The pattern in which a genetic disease is inherited through generations is termed the mode of inheritance. Knowing the mode of inheritance can reveal much about the diseasecausing gene itself, and members of families with the disease can be given reliable genetic counseling. The known single-gene diseases can be classified into four major modes of inheritance: autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. The first two types involve genes known to occur on the 22 pairs of autosomes. The last two types occur on the X chromosome; very few disease-causing genes occur on the Y chromosome. The pedigree chart summarizes family relationships and shows which members of a family are affected by a genetic disease (Fig. 2.19). Generally the pedigree begins with one individual in the family, the proband. This individual is usually the first person in the family diagnosed or seen in a clinic.

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FIGURE 2.19

Symbols Commonly Used in Pedigrees. (From Jorde LB et al: Medical genetics, ed 5, St Louis, 2016, Elsevier.)

Autosomal Dominant Inheritance Characteristics of Pedigrees Diseases caused by autosomal dominant genes are rare, with the most common occurring in fewer than 1 in 500 individuals. Therefore it is uncommon for two individuals who are both affected by the same autosomal dominant disease to produce offspring together. Fig. 2.20, A, illustrates this unusual pattern. Affected offspring are usually produced by the union of a normal parent with an affected heterozygous parent. The Punnett square in Fig. 2.20, B, illustrates this mating. The affected parent can pass either a disease-causing allele or a normal allele to the next generation. On average, half the children will be heterozygous and will express the disease, and half will be normal.

FIGURE 2.20 Punnett Square and Autosomal Dominant Traits. A, Punnett square for the mating of two individuals with an autosomal dominant gene. Here both parents are affected by the trait. B, Punnett square for the mating of a normal individual with a carrier for an autosomal dominant gene.

The pedigree in Fig. 2.21 shows the transmission of an autosomal dominant allele. Several important characteristics of this pedigree support the conclusion that the trait is

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caused by an autosomal dominant gene:

FIGURE 2.21 Pedigree Illustrating the Inheritance Pattern of Postaxial Polydactyly, an Autosomal Dominant Disorder. Affected individuals are represented by shading. (From Jorde LB et al: Medical genetics, ed 5, St Louis, 2016, Elsevier.)

1. The two sexes exhibit the trait in approximately equal proportions; males and females are equally likely to transmit the trait to their offspring. 2. No generations are skipped. If an individual has the trait, one parent must also have it. If neither parent has the trait, none of the children will have it (with the exception of new mutations, as discussed later). 3. Affected heterozygous individuals transmit the trait to approximately half their children, and because gamete transmission is subject to chance fluctuations, all or none of the children of an affected parent may have the trait. When large numbers of matings of this type are studied, however, the proportion of affected children closely approaches one-half.

Recurrence Risks Parents at risk for producing children with a genetic disease nearly always ask the question, “What is the chance that our child will have this disease?” The probability that an individual will develop a genetic disease is termed the recurrence risk. When one parent is affected by an autosomal dominant disease (and is a heterozygote) and the other is unaffected, the recurrence risk for each child is one-half. An important principle is that each birth is an independent event, much like a coin toss. Thus even though parents may have already had a child with the disease, their recurrence risk remains one-half. Even if they have produced several children, all affected (or all unaffected) by the disease, the law of independence dictates that the probability their next child will have the disease is still one-half. Parents’ misunderstanding of this principle is a common problem encountered in genetic counseling. If a child is born with an autosomal dominant disease and there is no history of the disease in the family, the child is probably the product of a new mutation. The gene transmitted by one of the parents has thus undergone a mutation from a normal allele to a

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disease-causing allele. The alleles at this locus in most of the parent's other germ cells are still normal. In this situation, the recurrence risk for the parent's subsequent offspring is not greater than that of the general population. The offspring of the affected child, however, will have a recurrence risk of one-half (probability of 0.5). Because these diseases often reduce the potential for reproduction, many autosomal dominant diseases result from new mutations.

Delayed Age of Onset One of the best-known autosomal dominant diseases is Huntington disease, a neurologic disorder whose main features are progressive dementia and increasingly uncontrollable limb movements (chorea; discussed further in Chapter 16). A key feature of this disease is its delayed age of onset: Symptoms usually are not seen until 40 years of age or later. Thus those who develop the disease often have borne children before they become aware that they have the disease-causing mutation. If the disease was present at birth, nearly all affected persons would die before reaching the reproductive age, and the occurrence of the disease-causing allele in the population would be much lower. An individual whose parent has the disease has a 50% chance of developing it during middle age. He or she is thus confronted with a torturous question: Should I have children, knowing that there is a 50 : 50 chance that I may have this disease-causing gene and will pass it to half my children? A DNA test can now be used to determine whether an individual has inherited the trinucleotide repeat mutation that causes Huntington disease.

Penetrance and Expressivity The penetrance of a trait is the percentage of individuals with a specific genotype who also exhibit the expected phenotype. Incomplete penetrance means individuals who have the disease-causing genotype may not exhibit the disease phenotype at all, even though the genotype and the associated disease may be transmitted to the next generation. A pedigree illustrating the transmission of an autosomal dominant mutation with incomplete penetrance is provided in Fig. 2.22. Retinoblastoma, the most common malignant eye tumor affecting children, typically exhibits incomplete penetrance. About 10% of the individuals who are obligate carriers of the disease-causing mutation (i.e., those who have an affected parent and affected children and therefore must themselves carry the mutation) do not have the disease. The penetrance of the disease-causing genotype is then said to be 90%.

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FIGURE 2.22 Pedigree for Retinoblastoma Showing Incomplete Penetrance. Female with marked arrow in line II must be heterozygous, but she does not express the trait.

The gene responsible for retinoblastoma is a tumor-suppressor gene: The normal function of its protein product is to regulate the cell cycle so cells do not divide uncontrollably. When the protein is altered because of a genetic mutation, its tumorsuppressing capacity is lost and a tumor can form5 (see Chapters 11 and 18). Expressivity is the extent of variation in phenotype associated with a particular genotype. If the expressivity of a disease is variable, penetrance may be complete but the severity of the disease can vary greatly. A good example of variable expressivity in an autosomal dominant disease is neurofibromatosis type 1, or von Recklinghausen disease. As in retinoblastoma, the mutations that cause neurofibromatosis type 1 occur in a tumorsuppressor gene.6 The expression of this disease varies from a few harmless café-au-lait (light brown) spots on the skin to numerous neurofibromas, scoliosis, seizures, gliomas, neuromas, malignant peripheral nerve sheath tumors, hypertension, and learning disorders (Fig. 2.23).

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FIGURE 2.23 Neurofibromatosis: Tumors. The most common is sessile or pedunculated. Early tumors are soft, dome-shaped papules or nodules that have a distinctive violaceous hue. Most are benign. (From Habif et al: Skin disease: diagnosis and treatment, ed 2, St Louis, 2005, Mosby.)

Several factors cause variable expressivity. Genes at other loci sometimes modify the expression of a disease-causing gene. Environmental (i.e., nongenetic) factors also can influence expression of a disease-causing gene. Finally, different mutations at a locus can cause variation in severity. For example, a mutation that alters only one amino acid of the factor VIII gene usually produces a mild form of hemophilia A, whereas a “stop” codon (premature termination of translation) usually produces a more severe form of this blood coagulation disorder.

Epigenetics and Genomic Imprinting Although this chapter focuses on DNA sequence variation and its consequence for disease, there is increasing evidence that the same DNA sequence can produce dramatically different phenotypes because of chemical modifications altering the expression of genes (these modifications are collectively termed epigenetic; see Chapter 3). An important example of such a modification is DNA methylation, the attachment of a methyl group to a cytosine base followed by a guanine base in the DNA sequence (Fig. 2.24). These sequences, which are common near many genes, are termed CpG islands. When the CpG islands located near a gene become heavily methylated, the gene is less likely to be transcribed into mRNA. In other words, the gene becomes transcriptionally inactive. One study showed that identical (monozygotic) twins accumulate different methylation patterns in the DNA

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sequences of their somatic cells as they age, causing increasing numbers of phenotypic differences. Intriguingly twins with more differences in their lifestyles (e.g., smoking versus nonsmoking) accumulated larger numbers of differences in their methylation patterns. The twins, despite having identical DNA sequences, become more and more different as a result of epigenetic changes, which, in turn, affect the expression of genes (see Fig. 3.5).

FIGURE 2.24 Epigenetic Modifications. Because deoxyribonucleic acid (DNA) is a long molecule, it needs packaging to fit in the tiny nucleus. Packaging involves coiling of the DNA in a “left-handed” spiral around spools, made of four pairs of proteins individually known as histones and collectively termed the histone octamer. The entire spool is called a nucleosome (also see Fig. 1.2). Nucleosomes are organized into chromatin, the repeating building blocks of a chromosome. Histone modifications are correlated with methylation, are reversible, and occur at multiple sites. Methylation occurs at the 5 position of cytosine and provides a “footprint” or signature as a unique

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epigenetic alteration (red). When genes are expressed, chromatin is open or active; however, when chromatin is condensed because of methylation and histone modification, genes are inactivated.

Epigenetic alteration of gene activity can have important disease consequences. For example, a major cause of one form of inherited colon cancer (termed hereditary nonpolyposis colorectal cancer [HNPCC]) is the methylation of a gene whose protein product repairs damaged DNA. When this gene becomes inactive, damaged DNA accumulates, eventually resulting in colon tumors. Epigenetic changes are also discussed in Chapters 3, 11, and 12. Approximately 100 human genes are thought to be methylated differently, depending on which parent transmits the gene. This epigenetic modification, characterized by methylation and other changes, is termed genomic imprinting. For each of these genes, one of the parents imprints the gene (inactivates it) when it is transmitted to the offspring. An example is the insulin-like growth factor 2 gene (IGF2) on chromosome 11, which is transmitted by both parents, but the copy inherited from the mother is normally methylated and inactivated (imprinted). Thus only one copy of IGF2 is active in normal individuals. However the maternal imprint is occasionally lost, resulting in two active copies of IGF2. This causes excess fetal growth and contributes to a condition known as Beckwith-Weidemann syndrome (see Chapter 3). A second example of genomic imprinting is a deletion of part of the long arm of chromosome 15 (15q11–q13), which, when inherited from the father, causes the offspring to manifest a disease known as Prader-Willi syndrome (short stature, obesity, hypogonadism). When the same deletion is inherited from the mother, the offspring develop Angelman syndrome (intellectual disability, seizures, ataxic gait). The two different phenotypes reflect the fact that different genes are normally active in the maternally and paternally transmitted copies of this region of chromosome 15.

Autosomal Recessive Inheritance Characteristics of Pedigrees Like autosomal dominant diseases, diseases caused by autosomal recessive genes are rare in populations, although there can be numerous carriers. Cystic fibrosis, the most common lethal recessive disease in white children, occurs in about 1 in 2500 births. Approximately 1 in 25 whites carries a copy of a mutation that causes cystic fibrosis (see Chapter 30). Carriers are phenotypically unaffected. Some autosomal recessive diseases are characterized by delayed age of onset, incomplete penetrance, and variable expressivity. Fig. 2.25 shows a pedigree for cystic fibrosis. The gene responsible for cystic fibrosis encodes a chloride ion channel in some epithelial cells. Defective transport of chloride ions leads to a salt imbalance, which results in secretions of abnormally thick, dehydrated mucus. Some digestive organs, particularly the pancreas, become obstructed, causing malnutrition, and the lungs become clogged with mucus, making them highly susceptible to bacterial infections. Death from lung disease or heart failure occurs before age 40 years in about half the individuals with cystic fibrosis.

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FIGURE 2.25 Pedigree for Cystic Fibrosis. Cystic fibrosis is an autosomal recessive disorder. The double bar denotes a consanguineous mating. Because cystic fibrosis is relatively common in European populations, most cases do not involve consanguinity.

The important criteria for discerning autosomal recessive inheritance include the following: 1. Males and females are affected in equal proportions. 2. Consanguinity (marriage between related individuals) is sometimes present, especially in cases of rare recessive diseases. 3. The disease may be seen in siblings of affected individuals but usually not in their parents. 4. On average, one-fourth of the offspring of carrier parents will be affected.

Recurrence Risks In most cases of recessive disease, both of the parents of affected individuals are heterozygous carriers. On average, one-fourth of their offspring will be normal homozygotes, half will be phenotypically normal carrier heterozygotes, and one-fourth will be homozygotes with the disease (Fig. 2.26). Thus the recurrence risk for the offspring of carrier parents is 25%. However, in any given family, there are chance fluctuations.

FIGURE 2.26

Punnett Square for the Mating of Heterozygous Carriers Typical of Most Cases of Recessive Disease.

If two parents have a recessive disease, they each must be homozygous for the disease. Therefore all their children also must be affected. This distinguishes recessive from

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dominant inheritance because two parents both affected by a dominant gene are nearly always both heterozygotes, and thus one-fourth of their children will be unaffected. Because carrier parents usually are unaware that they both carry the same recessive allele, they often produce an affected child before becoming aware of their condition. Carrier detection tests can identify heterozygotes by analyzing the DNA sequence to reveal a mutation. Some recessive diseases for which carrier detection tests are routinely used include PKU, sickle cell disease, cystic fibrosis, Tay-Sachs disease, hemochromatosis, and galactosemia.

Consanguinity Consanguinity and inbreeding are related concepts. Consanguinity refers to the mating of two related individuals, and the offspring of such matings are said to be inbred. Consanguinity is sometimes an important characteristic of pedigrees for recessive diseases because relatives share a certain proportion of genes received from a common ancestor. The proportion of shared genes depends on the closeness of their biologic relationship. Consanguineous matings produce a significant increase in recessive disorders and are seen most often in pedigrees for rare recessive disorders.

X-Linked Inheritance Some genetic conditions are caused by mutations in genes located on the sex chromosomes, and this mode of inheritance is termed sex linked. Only a few diseases are known to be inherited as X-linked dominant or Y chromosome traits, so only the more common X-linked recessive diseases are discussed here. Because females receive two X chromosomes, one from the father and one from the mother, they can be homozygous for a disease allele at a given locus, homozygous for the normal allele at the locus, or heterozygous. Males, having only one X chromosome, are hemizygous for genes on this chromosome. If a male inherits a recessive disease gene on the X chromosome, he will be affected by the disease because the Y chromosome does not carry a normal allele to counteract the effects of the disease gene. Because a single copy of an X-linked recessive gene will cause disease in a male, whereas two copies are required for disease expression in females, more males are affected by X-linked recessive diseases than are females.

X Inactivation In the late 1950s, Mary Lyon proposed that one X chromosome in the somatic cells of females is permanently inactivated, a process termed X inactivation.7 This proposal, the Lyon hypothesis, explains why most gene products coded by the X chromosome are present in equal amounts in males and females, even though males have only one X chromosome and females have two X chromosomes. This phenomenon is called dosage compensation. The inactivated X chromosomes are observable in many interphase cells as highly condensed intranuclear chromatin bodies, termed Barr bodies (after Barr and Bertram, who discovered them in the late 1940s). Normal females have one Barr body in each somatic cell, whereas normal males have no Barr bodies. X inactivation occurs very early in embryonic development—approximately 7 to 14 days after fertilization. In each somatic cell, one of the two X chromosomes is inactivated. In

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some cells, the inactivated X chromosome is the one contributed by the father; in other cells, it is the one contributed by the mother. Once the X chromosome has been inactivated in a cell, all the descendants of that cell have the same chromosome inactivated (Fig. 2.27). Thus inactivation is said to be random but fixed.

FIGURE 2.27 The X Inactivation Process. The maternal (m) and paternal (p) X chromosomes are both active in the zygote and in early embryonic cells. X inactivation then takes place, resulting in cells having either an active paternal X or an active maternal X. Females are thus X chromosome mosaics, as shown in the tissue sample at the bottom of the page. (From Jorde LB et al: Medical genetics, ed 5, St Louis, 2016, Elsevier.)

Some individuals do not have the normal number of X chromosomes in their somatic cells. For example, males with Klinefelter syndrome typically have two X chromosomes and one Y chromosome. These males do have one Barr body in each cell. Females whose cell nuclei have three X chromosomes have two Barr bodies in each cell, and females whose cell nuclei have four X chromosomes have three Barr bodies in each cell. Females with Turner syndrome have only one X chromosome and no Barr bodies. Thus the number of Barr bodies is always one less than the number of X chromosomes in the cell. All but one X chromosome are always inactivated. Persons with abnormal numbers of X chromosomes, such as those with Turner syndrome or Klinefelter syndrome, are not physically normal. This situation presents a puzzle because they presumably have only one active X chromosome, the same as individuals with normal numbers of chromosomes. This is probably because the distal tips of the short and long arms of the X chromosome, as well as several other regions on the chromosome arm, are not inactivated. Thus X inactivation is also known to be incomplete. The inactivated X chromosome DNA is heavily methylated. Inactive X chromosomes can

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be at least partially reactivated in vitro by administering 5-azacytidine, a demethylating agent.

Sex Determination The process of sexual differentiation, in which the embryonic gonads become either testes or ovaries, begins during the sixth week of gestation. A key principle of mammalian sex determination is that one copy of the Y chromosome is sufficient to initiate the process of gonadal differentiation that produces a male fetus. The number of X chromosomes does not alter this process. For example, an individual with two X chromosomes and one Y chromosome in each cell is still phenotypically a male. Thus the Y chromosome contains a gene that begins the process of male gonadal development. This gene, termed SRY (for “sex-determining region on the Y”), has been located on the short arm of the Y chromosome.8 The SRY gene lies just outside the pseudoautosomal region (Fig. 2.28), which pairs with the distal tip of the short arm of the X chromosome during meiosis and exchanges genetic material with it (crossover), just as autosomes do. The DNA sequences of these regions on the X and Y chromosomes are highly similar. The rest of the X and Y chromosomes, however, do not exchange material and are not similar in DNA sequence.

FIGURE 2.28 Distal Short Arms of the X and Y Chromosomes Exchange Material During Meiosis in the Male. The region of the Y chromosome in which this crossover

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occurs is called the pseudoautosomal region. The SRY gene, which triggers the process leading to male gonadal differentiation, is located just outside the pseudoautosomal region. Occasionally, the crossover occurs on the centromeric side of the SRY gene, causing it to lie on an X chromosome instead of a Y chromosome. An offspring receiving this X chromosome will be an XX male, and an offspring receiving the Y chromosome will be an XY female.

Other genes that contribute to male differentiation are located on other chromosomes. Thus SRY triggers the action of genes on other chromosomes. This concept is supported by the fact that the SRY protein product is similar to other proteins known to regulate gene expression. Occasionally, the crossover between X and Y occurs closer to the centromere than it should, placing the SRY gene on the X chromosome after crossover. This variation can result in offspring with an apparently normal XX karyotype but a male phenotype. Such XX males are seen in about 1 in 20,000 live births and resemble males with Klinefelter syndrome. Conversely, it is possible to inherit a Y chromosome that has lost the SRY gene (the result of either a crossover error or a deletion of the gene). This situation produces an XY female. Such females have gonadal streaks rather than ovaries and have poorly developed secondary sex characteristics.

Quick Check 2.2 1. Why is the influence of environment significant to phenotype? 2. Discuss the differences between a dominant allele and a recessive allele. 3. Why are the concepts of variable expressivity, incomplete penetrance, and delayed age of onset so important in relation to genetic diseases? 4. What is the recurrence risk for autosomal dominant inheritance and recessive inheritance?

Characteristics of Pedigrees X-linked pedigrees show distinctive modes of inheritance. The most striking characteristic is that females seldom are affected. To express an X-linked recessive trait fully, a female must be homozygous: either both her parents are affected, or her father is affected and her mother is a carrier. Such matings are rare. The following are important principles of X-linked recessive inheritance: 1. The trait is seen much more often in males than in females. 2. Because a father can give a son only a Y chromosome, the trait is never transmitted from father to son. 3. The gene can be transmitted through a series of carrier females, causing the appearance of one or more “skipped generations.” 4. The gene is passed from an affected father to all his daughters, who, as phenotypically normal carriers, transmit it to approximately half their sons, who are affected.

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A relatively common X-linked recessive disorder is Duchenne muscular dystrophy (DMD), which affects approximately 1 in 3500 males. As its name suggests, this disorder is characterized by progressive muscle degeneration. Affected individuals usually are unable to walk by age 10 or 12 years. The disease affects the heart and respiratory muscles, and death caused by respiratory or cardiac failure usually occurs before age 20 years. Identification of the disease-causing gene (on the short arm of the X chromosome) has greatly increased our understanding of the disorder.9 The DMD gene is the largest gene ever found in humans, spanning more than 2 million DNA bases. It encodes a previously undiscovered muscle protein, termed dystrophin. Extensive study of dystrophin indicates that it plays an essential role in maintaining the structural integrity of muscle cells: it may also help regulate the activity of membrane proteins. When dystrophin is absent, as in DMD, the cell cannot survive, and muscle deterioration ensues. Most cases of DMD are caused by frameshift deletions of portions of the DMD gene and thus involve alterations of the amino acids encoded by the DNA following the deletion.

Recurrence Risks The most common mating type involving X-linked recessive genes is the combination of a carrier female and a normal male (Fig. 2.29, A). On average, the carrier mother will transmit the disease-causing allele to half her sons (who are affected) and half her daughters (who are carriers).

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FIGURE 2.29 Punnett Square and X-Linked Recessive Traits. A, Punnett square for the mating of a normal male (XHY) and a female carrier of an X-linked recessive gene (XHXh). B, Punnett square for the mating of a normal female (XHXH) with a male affected by an X-linked recessive disease (XhY). C, Punnett square for the mating of a female who carries an X-linked recessive gene (XHXh) with a male who is affected with the disease caused by the gene (XhY).

The other common mating type is an affected father and a normal mother (see Fig. 2.29, B). In this situation, all the sons will be normal because the father can transmit only his Y chromosome to them. Because all the daughters must receive the father's X chromosome, they will all be heterozygous carriers. Because the sons must receive the Y chromosome and the daughters must receive the X chromosome with the disease gene, these are precise outcomes and not probabilities. None of the children will be affected. The final mating pattern, less common than the other two, involves an affected father and a carrier mother (see Fig. 2.29, C). With this pattern, on average, half the daughters will be heterozygous carriers, and half will be homozygous for the disease allele and thus affected. Half the sons will be normal, and half will be affected. Some X-linked recessive diseases, such as DMD, are fatal or incapacitating before the affected individual reaches reproductive age, and therefore affected fathers are rare.

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A sex-limited trait can occur in only one sex, often because of anatomic differences. Inherited uterine and testicular defects are two obvious examples. A sex-influenced trait occurs much more often in one sex than in the other. For example, male-pattern baldness occurs in both males and females but is much more common in males. Autosomal dominant breast cancer, which is much more commonly expressed in females than in males, is another example of a sex-influenced trait.

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Linkage Analysis and Gene Mapping Locating genes on specific regions of chromosomes has been one of the most important goals of human genetics. The location and identification of a gene can tell much about the function of the gene, the interaction of the gene with other genes, and the likelihood that certain individuals will develop a genetic disease.

Classic Pedigree Analysis During the first meiotic stage, the arms of homologous chromosome pairs intertwine and sometimes exchange portions of their DNA (Fig. 2.30) in a process known as crossover. During crossover, new combinations of alleles can be formed. For example, two loci on a chromosome have alleles A and a and alleles B and b. Alleles A and B are located together on one member of a chromosome pair, and alleles a and b are located on the other member. The genotype of this individual is denoted as AB/a0b.

FIGURE 2.30

Genetic Results of Crossover. A, No crossing over. B, Crossing over with recombination.

As Fig. 2.30, A, shows, the allele pairs would be transmitted together when no crossover occurs. However, when crossover occurs (see Fig. 2.30, B), all four possible pairs of alleles can be transmitted to the offspring. The process of forming such new arrangements of alleles is called recombination. Loci that are located very close to one another are unlikely to experience recombination and are said to demonstrate linkage. The frequency of recombination can be assessed in families and is used to determine the relative positions of loci on chromosomes (the gene map, discussed below).

Complete Human Gene Map: Prospects and Benefits The major goals of the Human Genome Project were to find the locations of all human genes (the “gene map”) and to determine the entire human DNA sequence. These goals

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have now been accomplished, and the genes responsible for approximately 5000 mendelian conditions have been identified1,10 (Fig. 2.31). This has greatly increased our understanding of the mechanisms that underlie many diseases, such as retinoblastoma, cystic fibrosis, neurofibromatosis, and Huntington disease. The project also has led to more accurate diagnosis of these conditions and, in some cases, more effective treatment.11

FIGURE 2.31

Example of Diseases: A Gene Map. ADA, Adenosine deaminase; ALD, adrenoleukodystrophy; PKU, phenylketonuria.

DNA sequencing has become much less expensive and more efficient in recent years. Consequently hundreds of thousands of individuals have now been sequenced, leading, in some cases, to the identification of disease-causing genes10 (see Did You Know? Gene Therapy).

Did You Know? Gene Therapy Thousands of subjects are currently enrolled in gene therapy clinical trials, and several gene therapy treatments have been approved by the U.S. Food and Drug Administration (FDA). Most trials and treatments involve the genetic alteration of cells to combat various types of cancer. Others involve the treatment of inherited diseases, such as β-thalassemia,

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hemophilia B, severe combined immunodeficiency, and retinitis pigmentosa. Data from: Dunbar CE et al: Science 359(6372), 2018.

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Multifactorial Inheritance Not all traits are produced by single genes; some traits result from several genes acting together. These are called polygenic traits. When environmental factors influence the expression of the trait (as is usually the case), the term multifactorial inheritance is used. Many multifactorial and polygenic traits tend to follow a normal distribution in populations (the familiar bell-shaped curve). Fig. 2.32 shows how three loci acting together can cause grain color in wheat to vary in a gradual way from white to red, exemplifying multifactorial inheritance. If both alleles at each of the three loci are white alleles, the color is pure white. If most alleles are white but a few are red, the color is somewhat darker; if all are red, the color is dark red.

FIGURE 2.32

Multifactorial Inheritance. Analysis of mode of inheritance for grain color

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in wheat. The trait is controlled by three independently assorted gene loci.

Other examples of multifactorial traits include height and intelligent quotient (IQ). Although both height and IQ are determined, in part, by genes, they are also influenced by environment. For example, the average height of many human populations has increased by 5 to 10 cm in the past 100 years because of improvements in nutrition and health care. Also, IQ scores can be improved by exposing individuals (especially children) to enriched learning environments. Thus both genes and environment contribute to variation in these traits. A number of diseases do not follow the bell-shaped distribution. Instead they appear to be either present in or absent from an individual. Yet they do not follow the patterns expected of single-gene diseases. Many of these are probably polygenic or multifactorial, but a certain threshold of liability must be crossed before the disease is expressed. Below the threshold the individual appears normal; above it, the individual is affected by the disease (Fig. 2.33).

FIGURE 2.33

Threshold of Liability for Pyloric Stenosis in Males and Females.

A good example of such a threshold trait is pyloric stenosis, a disorder characterized by a narrowing or obstruction of the pylorus, the area between the stomach and small intestine. Chronic vomiting, constipation, weight loss, and electrolyte imbalance can result from the condition, but it is easily corrected with surgery. The prevalence of pyloric stenosis is about

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3 in 1000 live births in whites. This disorder is much more common in males than in females, affecting 1 in 200 males and 1 in 1000 females. The apparent reason for this difference is the threshold of liability is much lower in males than females, as shown in Fig. 2.33. Thus fewer defective alleles are required to generate the disorder in males. This situation also means the offspring of affected females are more likely to have pyloric stenosis because affected females necessarily carry more disease-causing alleles compared with most affected males. A number of other common diseases are thought to correspond to a threshold model. They include cleft lip and cleft palate, neural tube defects (anencephaly, spina bifida), clubfoot (talipes), and some forms of congenital heart disease. Although recurrence risks can be given with confidence for single-gene diseases (e.g., 50% for autosomal dominant diseases, 25% for autosomal recessive diseases), it is considerably more difficult to do so for multifactorial diseases. The number of genes contributing to the disease is not known, the precise allelic constitution of the biologic parents is not known, and the extent of environmental effects can vary from one population to another. For most multifactorial diseases, empirical risks (i.e., those based on direct observation) have been derived. To determine empirical risks, a large sample of biologic families in which one child has developed the disease is examined. The siblings of each child are then surveyed to calculate the percentage who also develop the disease. Another difficulty is distinguishing polygenic or multifactorial diseases from single-gene diseases having incomplete penetrance or variable expressivity. Large data sets and good epidemiologic data often are necessary to make the distinction. Box 2.1 lists the criteria commonly used to define multifactorial diseases.

Box 2.1

Criteria Used to Define Multifactorial Diseases 1. The recurrence risk becomes higher if more than one family member is affected. For example, the recurrence risk for neural tube defects in a family increases to 10% if two siblings have been born with the disease. By contrast, the recurrence risk for single-gene diseases remains the same regardless of the number of siblings affected. 2. If the expression of the disease is more severe, the recurrence risk is higher. This is consistent with the liability model; a more severe expression indicates that the individual is at the extreme end of the liability distribution. Relatives of the affected individual are thus at a higher risk for inheriting disease genes. Cleft lip or cleft palate is a condition in which this has been shown to be true. 3. Relatives of probands of the less commonly affected are more likely to develop the disease. As with pyloric stenosis, this occurs because an affected individual of the less susceptible sex is usually at a more extreme position on the liability distribution. 4. Generally, if the population frequency of the disease is f, the risk for offspring and siblings of probands is approximately . This does not usually hold true for single-gene traits. 5. The recurrence risk for the disease decreases rapidly in more remotely related

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relatives. Although the recurrence risk for single-gene diseases decreases by 50% with each degree of relationship (e.g., an autosomal dominant disease has a 50% recurrence risk for siblings, 25% for uncle–nephew relationship, 12.5% for first cousins), the risk for multifactorial inheritance decreases much more quickly. The genetics of common disorders, such as hypertension, heart disease, and diabetes, is complex and often confusing. Nevertheless, the public health impact of these diseases, together with the evidence for hereditary factors in their etiology, demands that genetic studies be pursued. Thousands of genes contributing to susceptibility for these diseases have been discovered, and the next decade will undoubtedly witness substantial advancements in our understanding of these disorders.

Quick Check 2.3 1. Define linkage analysis; cite an example. 2. Why is “threshold of liability” an important consideration in multifactorial inheritance? 3. Discuss the concept of multifactorial inheritance, and include two examples.

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Summary Review DNA, RNA, and Proteins: Heredity at the Molecular Level 1. Genes, the basic units of inheritance, are composed of sequences of deoxyribonucleic acid (DNA) and are located on chromosomes. 2. Each subunit of DNA, called a nucleotide, is composed of one deoxyribose, a phosphate molecule, and one of four types of nitrogenous bases. The physical structure of DNA is a double helix. The two strands connect by the nitrogenous bases, with thymine bonding to adenine, and guanine bonding to cytosine. 3. The four DNA bases code for amino acids, which in turn make up proteins. The amino acids are specified by triplet sets of nitrogenous bases in specific orders, called codons. Several codons correspond to the same amino acid in many cases. 4. DNA replication is based on complementary base pairing, in which a single strand of DNA serves as the template for attracting complementary bases that form a new strand of DNA. 5. DNA polymerase is the primary enzyme involved in replication. It adds bases to the new DNA strand and performs “proofreading” functions. 6. A mutation is an alteration of genetic material (e.g., base pair substitution, frameshift mutation). Substances that cause mutations are called mutagens. 7. Mutations are rare events, and the rate of mutations varies from gene to gene. Mutational hot spots are DNA sequences with particularly high mutation rates. 8. Transcription and translation, the two basic processes in which proteins are specified by DNA, both involve ribonucleic acid (RNA). RNA is chemically similar to DNA, but it is single stranded, has a ribose sugar molecule, and has uracil rather than thymine as one of its four nitrogenous bases (uracil pairs with the base adenine). 9. Transcription is the process by which a DNA template synthesizes a RNA, thus forming messenger RNA (mRNA). 10. Much of the RNA sequence is spliced from the mRNA before the mRNA leaves the nucleus. The excised sequences are called introns, and those that remain to code for proteins are called exons. 11. Translation is the process by which RNA directs the synthesis of polypeptides. This process takes place in the ribosomes, which consist of proteins and ribosomal RNA (rRNA). 12. During translation, mRNA interacts with transfer RNA (tRNA), a molecule that has an attachment site for a specific amino acid and an anticodon, a region that matches up with a 3-base codon on the mRNA. The ribosome moves along the mRNA, matching different tRNAs to codons on the mRNA, and forming a growing chain of amino acids called a polypetide.

Chromosomes 1. Human cells consist of diploid somatic cells (body cells with 23 pairs of chromosomes, 46 total) and haploid gametes (sperm and egg cells with 23 total

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chromosomes). 2. Humans have 23 pairs of chromosomes. Twenty-two of these pairs are autosomes, ones that appear virtually identical (homologous) between males and females). The remaining pair consists of the sex chromosomes. Females have two homologous X chromosomes as their sex chromosomes; males have an X and a Y chromosome. 3. A karyogram is an ordered display of chromosomes arranged according to length and the location of the centromere. The karyogram is the visual representation of the individual's chromosome karyotype. 4. Various types of stains can be used to make chromosome bands more visible. Chromosome bands can be used to identify chromosomes and identify variations. 5. About 1 in 150 live births has a major diagnosable chromosome abnormality. Chromosome abnormalities are the leading known cause of intellectual disability and miscarriage. 6. Euploid cells are ones with the normal number of chromosomes. Polyploidy is a condition in which a cell has some multiple of the normal number of chromosomes. Humans have been observed to have triploidy (three copies of each chromosome) and tetraploidy (four copies of each chromosome); both conditions are lethal. 7. Aneuploidy is when a cell does not have a multiple of 23 chromosomes: there is an extra or missing single chromosome. Trisomy is a type of aneuploidy in which one chromosome is present in three copies. A partial trisomy is one in which only part of a chromosome is present in three copies. Monosomy is a type of aneuploidy in which one chromosome is present in only one copy. 8. In general, monosomies cause more severe physical defects than do trisomies, illustrating the principle that the loss of chromosome material has more severe consequences than the duplication of chromosome material. 9. Down syndrome, a trisomy of chromosome 21, is the best-known disease caused by a chromosome aberration. It affects 1 in 800 to 1 in 1000 live births. 10. Most aneuploidies of the sex chromosomes have less severe consequences than those of the other chromosomes. 11. The most commonly observed sex chromosome aneuploidies are the 47,XXX karyotype, 45,X karyotype (Turner syndrome), 47,XXY karyotype (Klinefelter syndrome), and 47,XYY karyotype. 12. Abnormalities of chromosome structure include deletions, duplications, inversions, and translocations.

Elements of Formal Genetics 1. Mendelian traits are caused by single genes, each of which occupies a position, or locus, on a chromosome. 2. Alleles are different forms of genes located at the same locus on a chromosome. 3. At any given locus in a somatic cell, an individual has two genes, one from each parent. An individual may be homozygous (alleles are identical) or heterozygous (alleles are different) for a locus. 4. An individual's genotype is his or her genetic makeup, and the phenotype reflects the interaction of genotype and environment.

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5. In a heterozygote, a dominant gene's effects mask those of a recessive gene. The recessive gene is expressed only when it is present in two copies.

Transmission of Genetic Diseases 1. Genetic diseases caused by single genes usually follow autosomal dominant, autosomal recessive, X-linked dominant, or X-linked recessive modes of inheritance. Pedigree charts are important tools in the analysis of modes of inheritance. 2. Autosomal dominant inheritance affects males and females are equally likely and the two sexes are equally likely to transmit to their offspring. Skipped generations are not seen in classic autosomal dominant pedigrees. Affected heterozygous individuals transmit the trait to approximately half their children. 3. Recurrence risks specify the probability that future offspring will inherit a genetic disease. For single-gene diseases, recurrence risks remain the same for each offspring, regardless of the number of affected or unaffected offspring. 4. Many genetic diseases have a delayed age of onset: symptoms are not seen until some time after birth. 5. The penetrance of a trait is the percentage of individuals with a specific genotype who also exhibit the expected phenotype. A gene that is not always expressed phenotypically is said to have incomplete penetrance. 6. Expressivity is the extent of variation in phenotype associated with a particular genotype. If the expressivity of a disease is variable, penetrance may be complete but the severity of the disease can vary greatly. 7. Epigenetics involves changes, such as the methylation of DNA bases, that do not alter the DNA sequence but can alter the expression of genes. 8. Genomic imprinting, which is associated with methylation, results in differing expression of a disease gene, depending on which parent transmitted the gene. 9. Autosomal recessive inheritance affect males are females in equal proportions. Consanguinity (mating of related individuals) is sometimes present in families with autosomal recessive diseases, and it becomes more prevalent with rarer recessive diseases. The disease may be seen in siblings but not their parents. The recurrence risk for autosomal recessive diseases is 25%. 10. Most commonly, biologic parents of children with autosomal recessive diseases are both heterozygous carriers of the disease gene. 11. Carrier detection tests for autosomal recessive diseases are routinely available. 12. In each normal female somatic cell, one of the two X chromosomes is inactivated early in embryonic development. X inactivation is random, fixed, and incomplete (i.e., only part of the chromosome is actually inactivated) and involves methylation. 13. Gender is determined embryonically by the presence of the SRY gene on the Y chromosome. Embryos that have a Y chromosome (and thus the SRY gene) become males, whereas those lacking the Y chromosome become females. When the Y chromosome lacks the SRY gene, an XY female can be produced. Similarly, an X chromosome that contains the SRY gene can produce an XX male. 14. Sex linked inheritance is caused by mutations in genes on sex chromosomes. X-

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linked genes are those that are located on the X chromosome. Nearly all known Xlinked diseases are caused by X-linked recessive genes. 15. Males are hemizygous for genes on the X chromosome. If a male inherits a recessive disease gene on the X chromosome, he will be affected by the disease because the Y chromosome does not carry a normal allele to counteract the effects. 16. X-linked recessive inheritance produces traits more often in males than in females because males need only one copy of the gene to express the disease. Because a father can give a son only a Y chromosome, biologic fathers cannot pass X-linked genes to their sons. Skipped generations often are seen in X-linked recessive disease pedigrees because the gene can be transmitted through carrier females. The gene is passed from an affected father to his daughters, who transmit to approximately half of their sons. 17. Recurrence risks for X-linked recessive diseases depend on the carrier and affected status of the mother and father. 18. A sex-limited trait is one that occurs only in one sex (gender). A sex-influenced trait is one that occurs more often in one sex than in the other.

Linkage Analysis and Gene Mapping 1. During meiosis I, crossover occurs and can cause recombinations of alleles located on the same chromosome. Loci that are located very close to one another are unlikely to experience recombination and are said to demonstrate linkage. 2. The major goals of the Human Genome Project were to find the locations of all human genes (the “gene map”) and to determine the entire human DNA sequence. These goals have now been accomplished and the genes responsible for approximately 5000 mendelian conditions have been identified.

Multifactorial Inheritance 1. Traits that result from the combined effects of several loci are polygenic. When environmental factors also influence the trait, it is multifactorial. 2. Many multifactorial traits have a threshold of liability. Once the threshold of liability has been crossed, the disease may be expressed. 3. Recurrence risks are difficult to determine for multifactorial inheritance. Empirical risks, which are based on direct observation of large numbers of families, are used to estimate recurrence risks.

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Key Terms Adenine, 40 Allele, 51 Amino acid, 41 Aneuploid cell, 44 Anticodon, 43 Autosome, 44 Barr body, 56 Base pair substitution, 41 Carrier, 51 Carrier detection test, 56 Chromosomal mosaic, 46 Chromosome, 40 Chromosome band, 44 Chromosome breakage, 48 Clastogen, 48 Codon, 41 Complementary base pairing, 41 Consanguinity, 56 CpG islands, 54 Cri du chat syndrome, 49 Crossover, 58 Cytokinesis, 44 Cytosine, 40 Delayed age of onset, 53 Deletion, 48 Deoxyribonucleic acid (DNA), 40 Diploid cell, 44 DNA methylation, 54 DNA polymerase, 41 Dominant, 51 Dosage compensation, 56 Double-helix model, 40 Down syndrome, 46 Duplication, 49 Dystrophin, 57 Empirical risk, 59 Epigenetic, 54 Euploid cell, 44 Exon, 43 Expressivity, 53 Fragile site, 51 Frameshift mutation, 41 Gamete, 44

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Gene, 40 Genetics, 40 Genomic imprinting, 54 Genotype, 51 Guanine, 40 Haploid cell, 44 Hemizygous, 56 Heterozygote, 51 Heterozygous, 51 Homologous, 44 Homozygote, 51 Homozygous, 51 Inbreeding, 56 Intron, 43 Inversion, 49 Karyotype (karyogram), 44 Klinefelter syndrome, 47 Linkage, 58 Locus, 51 Meiosis, 44 Messenger RNA (mRNA), 41 Metaphase spread, 44 Methylation, 54 Missense, 41 Mitosis, 44 Mode of inheritance, 51 Multifactorial inheritance, 59 Mutagen, 41 Mutation, 41 Mutational hot spot, 41 Nondisjunction, 45 Nonsense, 41 Nucleotide, 40 Obligate carrier, 53 Partial trisomy, 46 Pedigree, 52 Penetrance, 53 Phenotype, 51 Polygenic trait, 59 Polymorphic (polymorphism), 51 Polypeptide, 41 Polyploid cell, 44 Position effect, 49 Proband, 52 Promoter site, 41 Pseudoautosomal, 56 Purine, 40

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Pyrimidine, 40 Recessive, 51 Reciprocal translocation, 49 Recombination, 58 Recurrence risk, 52 Ribonucleic acid (RNA), 41 Ribosomal RNA (rRNA), 43 Ribosome, 43 RNA polymerase, 41 Robertsonian translocation, 49 Sex-influenced trait, 57 Sex-limited trait, 57 Sex linked (inheritance), 56 Silent mutation, 41 Somatic cell, 44 Spontaneous mutation, 41 Template, 41 Termination sequence, 43 Tetraploidy, 44 Threshold of liability, 59 Thymine, 40 Transcription, 41 Transfer RNA (tRNA), 43 Translation, 43 Translocation, 49 Triploidy, 44 Trisomy, 44 Tumor-suppressor gene, 53 Turner syndrome, 47 X inactivation, 56

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References 1. Jorde LB, et al. Medical genetics. ed 5. Elsevier: St Louis; 2016. 2. Gardner RJM, Amor DJ. Gardner and Sutherland's chromosome abnormalities and genetic counseling. ed 5. Oxford University Press: Oxford; 2018. 3. Mila M, et al. Fragile X syndrome: an overview and update of the FMR1 gene. Clin Genet. 2017;93(2):197–205. 4. Hannan AJ. Tandem repeats mediating genetic plasticity in health and disease. Nat Rev Genet. 2018;19(5):286–298. 5. Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302–308. 6. Kresak JL, Walsh M. Neurofibromatosis: a review of NF1, NF2, and schwannomatosis. J Pediatr Genet. 2016;5(2):98–104. 7. Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152(6):1308– 1323. 8. Larney C, et al. Switching on sex: transcriptional regulation of the testis-determining gene Sry. Development. 2014;141(11):2195–2205. 9. Flanigan KM. The muscular dystrophies. Semin Neurol. 2012;32(3):255–263. 10. Boycott KM, et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am J Hum Genet. 2017;100(5):695–705. 11. Rehm HL. Evolving health care through personal genomics. Nat Rev Genet. 2017;18(4):259–267.

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Epigenetics and Disease Diane P. Genereux

CHAPTER OUTLINE Epigenetic Mechanisms, 64 DNA Methylation, 64 Histone Modifications, 64 Epigenetics and Human Development, 65 Epigenetics in Genomic Imprinting, 66 Prader-Willi and Angelman Syndromes, 66 Beckwith-Wiedemann Syndrome, 67 Russell-Silver Syndrome, 67 Environmental Impacts on Epigenetic Information, 67 Epigenetics and Nutrition, 67 Epigenetics and Maternal Care, 68 Twin Studies Provide Insights on Epigenetic Modification, 68 Molecular Approaches to Understand Epigenetic Disease, 68 Epigenetics and Cancer, 69 DNA Methylation and Cancer, 69 Epigenetic Screening for Cancer, 70 Emerging Strategies for the Treatment of Epigenetic Disease, 70 Future Directions, 71

Human beings exhibit great diversity in physical and behavioral features. Much of this diversity is because of genetic variation. Epigenetic (“upon genetic”) information is another contributor. This information, which is encoded by chemical modifications to DNA and associated histone proteins, helps determine which of an individual's genes are active in which cells. Epigenetic information is critical for normal human development. Abnormal changes in epigenetic information can occur spontaneously or through environmental exposures. Some of these changes lead to disease.

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Epigenetic Mechanisms DNA Methylation DNA methylation (Fig. 3.1) occurs when a methyl group (CH3) is attached to a cytosine. Methylation within a gene generally renders it inactive. Methylation usually occurs only at cytosines that are followed by a guanine base known as a CpG dinucleotide, and the fraction of CpG dinucleotides that are methylated is variable across the genome. In human embryonic stem cells, methylation also can occur at cytosines outside of the CpG context (see Fig. 2.24).

FIGURE 3.1 Three Types of Epigenetic Processes. Investigators are studying three epigenetic mechanisms: (1) DNA methylation. (2) Histone modifications. (3) RNA based-mechanisms. See text for discussion.

DNA methylation plays a prominent role in human development and disease. For example, in each cell of a normal human female, one of the two X chromosomes is silenced by dense methylation and associated molecular marks, whereas the other X chromosome is transcriptionally active and largely devoid of methylation (see Chapter 2). During early

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embryonic development, one of the two X chromosomes in each cell is inactivated. Random inactivation of the X chromosome inherited from the mother or the father occurs independently in each cell of the embryo, and the methylation state is inherited by all subsequent copies. If a woman's two X chromosomes carry different alleles at a given locus, random X inactivation can lead to cells with different traits. Striking examples include the patchy coloration of calico cats and anhidrotic ectodermal dysplasia, a condition characterized by patchy presence and absence of sweat glands in the skin of human females. Abnormal changes to DNA methylation are involved in several human cancers, including cancers of the breast and ovary (Box 3.1).

Box 3.1

Cancer of Ovary and Breast Can Arise Through Epigenetic Silencing of Tumor-Suppressor Gene BRCA1. Inherited mutations in the coding region of the BRCA1 and BRCA2 genes are known to increase risk of breast, ovarian, and prostate cancer. Such mutations, however, cannot explain all cases of breast cancer. Many families have a high incidence of breast cancer but no known pathogenic variants in the coding regions of the BRCA1 gene. Researchers sought to identify epimutations (errors in epigenetic gene repression) that could potentially account for breast cancer in these families. Evans et al. used bisulfite sequencing to examine the promoter region of the BRAC1 or BRCA2 genes in 49 women who had breast or ovarian cancer but did not have mutations in the coding regions of either gene. Abnormal, dense DNA methylation in the BRCA1 promoter was found in two of these women. Both women also had a single mutation in the promoter of the gene. Examination of DNA from other women in the families of these women revealed that the point mutation was strongly associated with DNA methylation and transcriptional silencing of the BRCA1 gene. In conclusion, point mutations in the promoter region of the BRCA1 gene can increase the probability of dense methylation. This dense methylation can lead to gene inactivation, indicating that epigenetic mechanisms driven by noncoding mutations can lead to breast cancer through loss of BRCA1 function. Data from Evans GR et al: Inherited BRCA1 epimutation as a novel cause of breast and ovarian cancer. Available at: https://doi.org/10.1101/246934, 2018; Garett D et al: A dominantly inherited 5’ UTR variant causing methylation-associated silencing of BRCA1 as a cause of breast and ovarian cancer, Am J Human Genet 103:213-220, 2018.

Histone Modifications Histone modifications (see Fig. 3.1) are chemical changes to the histone proteins around which DNA is coiled. The coiling, or extreme compaction of DNA, enables it to fit into the nucleus of a cell. Histone modifications can up-regulate or down-regulate nearby gene expression by increasing or decreasing the tightness of the interaction between DNA and histones. The material made of DNA in association with histones is called chromatin.

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Histone modifications of a given region of DNA can undergo dramatic changes during cellular differentiation and organismal development. Certain modifications characterize specific cell types. Accrual of specific sets of histone modifications enable diverse types of differentiated cells to differentiate from a founder stem cell. Mutations that impair histone modification have been implicated in congenital heart disease, thus highlighting histone modification states as critical for normal development. In contrast to the vast majority of other cell types, including oocytes, sperm cells do not have histones. Instead, they have closely related proteins called protamines. DNA coils on the right side or more “rightly” around protamines, making sperm-cell nuclei smaller, and facilitate sperm movement.

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Epigenetics and Human Development Each of the cells in the early embryo has the potential to give rise to a somatic cell of any type. These embryonic stem cells are therefore said to be totipotent (“possessing all powers”). Epigenetic modifications that arise during development ensure that specific genes are expressed only in the cells and tissue types in which their gene products normally function. Only a small percentage of genes, termed housekeeping genes, escape epigenetic silencing and remain transcriptionally active in all or nearly all cells.

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Epigenetics in Genomic Imprinting For every gene not encoded on a sex chromosome, a child inherits two copies: one from the mother and one from the father. For a large subset of these, expression is biallelic, meaning that both copies contribute to phenotype. For a few genes, expression is stochastically (randomly) monoallelic, meaning that the maternal copy is randomly chosen for inactivation in some somatic cells and the paternal copy is randomly chosen for inactivation in other somatic cells. As discussed earlier, the process whereby monoallelic expression is established is much like that of random inactivation of the X chromosomes. For a third and smaller subset of autosomes (about 1%), either the maternal copy or the paternal copy is imprinted, meaning that either the sperm or the egg carries an inactive copy (see Chapter 2). This imprinted, or inactive, state persists in all of the somatic cells of the individual. Many of the genes subject to imprinting regulate growth. The genetic conflict hypothesis is useful to explain the imprinting pattern. Because a mother makes a large physiologic investment in each child, it is in her evolutionary best interest to limit the flow of energetic resources to any given child, thus preserving her ability to have subsequent children. Contrarily, it is in the best biologic interests of the father for his child to extract maximal resources from the mother. In general, imprinting of maternally inherited genes tends to reduce offspring size; imprinting of paternally inherited genes tends to increase offspring size. One hallmark of imprinting-associated disease is that the phenotype of affected individuals is critically dependent on whether the mutation is inherited from the mother or from the father. Some examples are included in the following syndromes.

Prader-Willi and Angelman Syndromes When a deletion of about 4 million base (Mb) pairs of the long arm of chromosome 15 is inherited from the father, a child manifests Prader-Willi syndrome. The characteristics of this syndrome include short stature, hypotonia, small hands and feet, obesity, mild to moderate intellectual disability, and hypogonadism (Fig. 3.2, A). The same 4-Mb deletion, when inherited from the mother, causes Angelman syndrome, which is characterized by severe intellectual disability, seizures, and an ataxic gait (see Fig. 3.2, B). These diseases are each observed in about 1 of every 15,000 live births; chromosome deletions are responsible for about 70% of cases of both diseases. The deletions that cause Prader-Willi and Angelman syndromes are indistinguishable at the DNA sequence level.

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FIGURE 3.2 Prader-Willi and Angelman Syndromes. A, A child with Prader-Willi syndrome (truncal obesity, small hands and feet, inverted V-shaped upper lip). B, A child with Angelman syndrome (characteristic posture, ataxic gait, bouts of uncontrolled laughter). (From Jorde LB, Carey JC, Bamshad MJ: Medical genetics, ed 4, Philadelphia, 2010, Mosby.)

The 4-Mb deletion (the critical region) contains several genes that are normally transcribed only on the copy of chromosome 15 that is inherited from the father. These genes are transcriptionally inactive (imprinted) on the copy of chromosome 15 inherited from the mother. Similarly, other genes in the critical region are transcriptionally active only on the chromosome copy inherited from the mother and are inactive on the chromosome inherited from the father. Thus several genes in this region are normally active on only one chromosome copy (Fig. 3.3). If the single active copy of one of these genes is lost because of a chromosome deletion, then no gene product is produced, resulting in disease.

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FIGURE 3.3 Prader-Willi Syndrome Pedigrees. These pedigrees illustrate the inheritance patterns of Prader-Willi syndrome, which can be caused by a 4-million base pairs (Mb) deletion of chromosome 15q when inherited from the father. In contrast, Angelman syndrome can be caused by the same deletion but only when it is inherited from the mother. The reason for this difference is that different genes in this region are normally imprinted (inactivated) in the copies of 15q transmitted by the mother and the father. (From Jorde LB, Carey JC, Bamshad MJ: Medical genetics, ed 4, Philadelphia, 2010, Mosby.)

Beckwith-Wiedemann Syndrome Another well-known example of imprinting is Beckwith-Wiedemann syndrome, an overgrowth condition accompanied by an increased predisposition to cancer. BeckwithWiedemann syndrome is usually identifiable at birth by the large size for gestational age, neonatal hypoglycemia, large tongue, creases on the earlobe, and birth defects of the intestines. Children with Beckwith-Wiedemann syndrome have an increased risk of developing Wilms tumor or hepatoblastoma. Both these tumors can be treated effectively if they are detected early; thus screening at regular intervals is an important part of management. Some children with Beckwith-Wiedemann syndrome also develop asymmetric overgrowth of a limb or one side of the face or trunk (hemihyperplasia). As in Angelman syndrome, in some individuals, Beckwith-Wiedemann syndrome (about 20%–30%) is caused by the inheritance of two copies of a chromosome from the father and no copy of the chromosome from the mother (uniparental disomy, in this case affecting chromosome 11). Several genes on the short arm of chromosome 11 are imprinted on either the paternally or the maternally transmitted chromosome. These genes are found in two separate, differentially methylated regions (DMRs). In DMR1, the gene that encodes insulin-like growth factor 2 (IGF2) is inactive on the maternally transmitted chromosome but active on the paternally transmitted chromosome. Thus a normal individual has only one active copy of IGF2. When two copies of the paternal chromosome are inherited (i.e., paternal uniparental disomy) or there is loss of imprinting on the maternal copy of IGF2, an active IGF2 gene is present in double dose. These changes produce increased levels of IGF2 during fetal development, contributing to the overgrowth features of Beckwith-Wiedemann syndrome. Note that in contrast to Prader-Willi and Angelman syndromes, which are produced by a missing gene product, Beckwith-Wiedemann syndrome is caused, in part, by

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overexpression of a gene product.

Russell-Silver Syndrome Characteristics of Russell-Silver syndrome include growth retardation, proportionate short stature, leg length discrepancy, and a small, triangular face. About one-third of RussellSilver syndrome cases are caused by imprinting abnormalities of chromosome 11p15.5 that lead to down-regulation of IGF2 and therefore diminished growth. Another 10% of cases are caused by maternal uniparental disomy. Thus whereas up-regulation, or extra copies, of active IGF2 causes overgrowth in Beckwith-Wiedemann syndrome, down-regulation of IGF2 causes the diminished growth seen in Russell-Silver syndrome.

Quick Check 3.1 1. Define epigenetics. 2. What are the two types of epigenetic mechanisms? 3. What is meant by the genetic conflict hypothesis? 4. Compare and contrast the molecular and phenotypic features of Prader-Willi and Angelman syndromes.

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Environmental Impacts on Epigenetic Information Imprinted genes are not the only loci for which epigenetic modifications persist over time. Conditions encountered in utero, during childhood, and even during adolescence or later can have long-term impacts on epigenetic states, sometimes with impacts that can be transmitted across generations. A few such examples are listed below.

Epigenetics and Nutrition During the winter of 1943, millions of people in the Netherlands suffered starvation conditions as a result of a Nazi blockade that interfered with the shipping of food. This era is now called “The Dutch Hunger Winter.” Researchers found individuals who were in utero during the Dutch Hunger Winter were more likely to suffer from obesity and diabetes as adults compared with those who had not experienced nutritional deprivation during gestation. More recent work has identified similar consequences in mice exposed to famine conditions in utero. The specific molecular mechanisms that may mediate these apparent relationships between nutritional deprivation and disease are largely unknown. From some animal models, it seems that the IGF2 gene is a possible target of epigenetic modifications. Exposure in utero and through lactation to some chemicals also seems to lead to epigenetic modifications similar to those that arise through nutritional deprivation in early life. Effects on offspring epigenetics also can arise through parental exposure to chemicals, including bisphenol A (a constituent of plastics sometimes used in food preparation and storage), and cold temperatures (Box 3.2).

Box 3.2

Epigenetics Could Explain Correlation Between Birth Month and Body Mass Index (BMI). It has long been observed that people conceived during cold times of the year tend to have lower body mass index (BMI) compared with people conceived during warmer times of the year. Sun et al. exposed male and female mice to cold temperatures before mating, then assessed the body mass and gene expression in their offspring. Their findings confirmed data from human populations. Offspring of male mice exposed to cold before mating tend to have larger amounts of brown adipose, a tissue with very high metabolic rate, as well as a lower overall probability of diet-induced obesity. Exposing female mice to cold before mating had no impact on brown adipose or obesity risk in their offspring. Exploration of DNA methylation in the sperm of cold-exposed male mice revealed methylation in the promoters of several genes involved in the production of brown adipose tissue. In conclusion, the sperm of male mice exposed to cold have reduced methylation in several genes relevant to the development of brown adipose tissue by a yet unknown mechanism. The offspring of these cold-exposed males have higher expression of these genes, resulting in higher amounts of brown adipose tissue, higher metabolic rate, and

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lowering risk of diet-induced obesity. Future work could focus on potential applications of cold exposure in the treatment or prevention of obesity. Data from Sun W et al: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in offspring, Nat Med 24(9):1372-1383, 2018.

Epigenetics and Maternal Care It is increasingly clear that parenting style can affect epigenetic states and that this information can be transmitted from one generation to the next. Mice and other rodents can exhibit two alternative styles of nursing behavior: (1) frequent arched-back nursing with a high level of licking and grooming behavior or (2) infrequent arched-back nursing with reduced licking and grooming behavior. Offspring of rodent mothers that engage in frequent arched-backed nursing have significantly lower methylation levels and higher transcription activity of a glucocorticoid receptor–encoding locus. Because the glucocorticoid receptor is involved in a pathway that intensifies fearfulness and response to stress, these findings suggest that alteration to methylation states could help explain how stress early in life can impact behavior in adulthood. These findings also highlight the concept that epigenetic processes can help store information about the environment with lasting consequences.

Epigenetics and Ethanol Exposure in Utero The impact of ethanol exposure in utero on skeletal and neural development was first reported in 1973 and led to broad awareness of fetal alcohol syndrome. Recently population-based and molecular-level studies began to clarify the epigenetic signals that mediate these impacts. Culturing neural stem cells in the presence of ethanol leads to dense methylation and inactivation of loci typically active in neurons. One possible explanation is that maternal ethanol exposure alters fetal expression of the DNA methyltransferases (DNMTs).

Epigenetics and Genetic Abnormalities In some diseases, both genetic and epigenetic factors contribute to abnormal phenotypes. For example, a range of abnormal phenotypes can arise in individuals with mutations at the fragile X locus FMR1 (Fig. 3.4, A). Some of these phenotypes arise in individuals for whom epigenetic changes are coincident with genetic changes. The promoter of the FMR1 genes contains a series of cytosine–guanine (CGG) dinucleotide repeats. Normal individuals have ≈35 CGG repeats. Females with >35 repeats are at risk for fragile X–associated primary ovarian insufficiency, which can lead to early menopause. Males with moderate expansions are at risk of fragile X tremor ataxia syndrome (FXTAS), which is characterized by a lateonset intention tremor. Both conditions seem to arise through accumulation of excess FMR1 messenger RNAs (mRNAs) in cellular nuclei. Individuals with 200 repeats increase the risks of dense methylation of the region and fragile X syndrome. These risks are characterized by reduced intelligence quotient (IQ) and various behavioral abnormalities. Although excessive CGG repeats in the FMR1 promoters increase the probability of fragile X syndrome, the presence of an atypically large number of repeats does not, itself, lead to the syndrome. For example, fragile X syndrome also can be present in a male with excessive

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repeats but absent in brothers who also inherited the full mutation allele. How can this be? Methylation-based silencing at FMR1 is stochastic, meaning that a large number of CGG repeats increases the probability of silencing but does not guarantee it. It remains to be seen whether dietary or environmental factors shape the probability of fragile syndrome in individuals who inherit the full-length allele.

FIGURE 3.4 Comparing the Molecular Mechanisms of Fragile X and Facioscapulohumeral Muscular Dystrophy (FSHD). A, FMR1 in normal, expanded permutation, and full-mutation states. B, DUX4 in normal and contracted states.

In another genetic-epigenetic disease, fascioscapulohumeral muscular dystrophy (FSHMD) (see Fig. 3.4, B), the disease phenotype arises through a genetic deletion, not expansion, in the DUX4 gene. This eventually leads to loss of methylation in a region that is densely methylated in normal individuals (see Fig. 3.4, A). Symptoms include adverse impacts on skeletal musculature. Although life span is not typically decreased, wheelchair use eventually becomes necessary for some individuals. Together, fragile X syndrome and FSHMD highlight that both abnormal gain and abnormal loss of epigenetic modifications can result in disease.

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Twin Studies Provide Insights on Epigenetic Modification Identical (monozygotic) twins, whose DNA sequences are essentially the same, offer a unique opportunity to isolate and examine the impacts of epigenetic modifications. As twins age, they accrue substantial genetic differences in their somatic cells. Twins— especially those with significant lifestyle differences, such as smoking versus nonsmoking —tend to accumulate differences in their methylation patterns. These results suggest that changes in epigenetic patterns may be an important part of the aging process (Fig. 3.5).

FIGURE 3.5 Twins and Aging. A, Twins as babies look very much alike but, B, as adults, have slight differences in appearance, possibly because of epigenetics. (A, vgm/Shutterstock. B, Stacey Bates/Shutterstock.)

Molecular Approaches to Understand Epigenetic Disease Epigenetic information is not encoded by DNA sequences but instead by chemical

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modifications. As a result, conventional genome sequencing approaches are not sufficient to screen epigenetic states and to identify differences between normal individuals and those with disease. To collect information on DNA methylation states of individual nucleotides, DNA is typically subjected to bisulfite conversion before sequencing. Bisulfite treatment deaminates unmethylated, but not methylated, cytosines to uracil. Because uracil complements adenine, not guanine, methylated and unmethylated cytosines can be distinguished in resulting sequence data as long as the genetic sequence is known. Histone modification states can be assayed through the use of antibodies specific for histones with various modifications.

Quick Check 3.2 1. Evaluate the statement: “Epigenetic information is highly dynamic in early development.” 2. How does the epigenetic regulation of imprinted genes compare with that of the rest of the genome? 3. Compare and contrast the molecular mechanisms leading to FX syndrome and to FSHMD.

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Epigenetics and Cancer DNA Methylation and Cancer Some of the most extensive evidence for the role of epigenetic modification in human disease comes from studying cancer (Fig. 3.6). Tumor cells often exhibit two abnormalities of DNA: (1) methylation hypomethylation in the promoters genes that promote cell division and cancer, leading to their silencing; and (2) hypermethylation in the promoter regions of the tumor-suppressor genes that work to keep cell division in check. For example, hypermethylation of the promoter region of the RB1 gene is often seen in retinoblastoma; hypermethylation of the BRCA1 gene is seen in some cases of inherited breast cancer (see Box 3.1 for data on epigenetics and breast cancer, and Chapter 35)

FIGURE 3.6 Global Changes in Three Processes Relevant to Cancer. Three processes—DNA cytosine methylation, histone modification, and nucleosomal remodeling—are intimately linked. Alterations in these processes result in permanent silencing of cancer-relevant genes. (From Jones PA, Baylin SB: The epigenomics of cancer, Cell 128(4):683-692, 2007.)

Colon cancer cells often have the hypermethylation in the promoter region of the MLH1 gene that encodes a protein that repairs DNA damage. When MLH1 becomes inactive, DNA damage accumulates, giving rise to colon tumors.1,2 Abnormal methylation of tumorsuppressor genes also is common in Barrett esophagus, a condition in which the lining of the esophagus is replaced by abnormal cells.

Epigenetic Screening for Cancer The finding that epigenetic alterations are common in tumors raises the possibility that epigenetic screening approaches could be useful for detecting cancer. For example, in some

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cases, epigenetic screening could be done by using bodily fluids (e.g., urine or sputum), eliminating the need for the more invasive, costly, and risky strategies currently in place. Other epigenetics-based screening approaches have shown promise for detection of cancers of the bladder, lung, and prostate.

Emerging Strategies for the Treatment of Epigenetic Disease Epigenetic modifications are potentially reversible: DNA can be demethylated, and histones can be modified to change the transcriptional state of nearby DNA. This raises the prospect of treating epigenetic disease with pharmaceutical agents that directly reverse the changes associated with disease. In recent years, such interventions have shown considerable promise for the treatment of disease.

DNA Demethylating Agents 5-Azacytidine (Fig. 3.7) has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome. The cytosine analogue 5-azacytidine is incorporated into DNA opposite its complementary nucleotide, guanine. 5-Azacytidine differs from cytosine because it has nitrogen, instead of carbon, in the fifth position of its cytidine ring. As result, the DNMTs cannot add methyl groups to 5-azacytidine, and DNAs that contain 5azacytidine decline in their methylation density over successive rounds of DNA replication. Administration of 5-azacytidine is associated with various side effects, including digestive disturbance, but it has shown promise in the treatment of diseases, including pancreatic cancer and myelodysplastic syndromes.

FIGURE 3.7 5-Azacytosine as Demethylating Agent. A, Unmethylated cytosines in DNA are typically subject to the addition of methyl groups by DNA methyltransferase 1 (DNMT1), a DNA methyltransferase, using methyl groups supplied by the methyl donor S-adenosylmethionine. B, In 5-azacytosine, the 5′ carbon of cytosine is replaced with a nitrogen. This chemical difference is sufficient both to block the addition of a methyl

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group and to confer irreversible binding to DNMT1. Incorporation of 5-azacytosine into DNA is therefore sufficient to drive passive loss of methylation from replicating DNA and thus to reactivate hypermethylated loci. 5-Azacytosine, bound to a sugar, can be integrated into DNA, and has been administered with some success in treating epigenetic diseases that arise through hypermethylation of individual loci.

Histone Deacetylase Inhibitors The activity of the histone deacetylases (HDACs) increases chromatin compaction, decreasing transcriptional activity (see Fig. 3.7). In many cases, excessive activity of HDACs results in transcriptional inactivation of tumor-suppressor genes, leading ultimately to the development of tumors. Treatment with HDAC inhibitors, either alone or in combination with other drugs, has shown promise in the treatment of cancers of the breast and prostate but only very limited success in the treatment of pancreatic cancer.

Quick Check 3.3 1. Assess the statement that cancer is, in many cases, an epigenetic disease. 2. Describe a potential strategy for the treatment of epigenetic disease.

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Future Directions Emerging experimental data are clarifying the role of epigenetics in determining cell fates and disease phenotypes. The well-documented involvement of epigenetic abnormalities in carcinogenesis and the mounting evidence for these epigenetic changes in other common diseases (discussed in other chapters) will likely elucidate possibilities for reversing the epigenetic abnormalities and possibly preventing their establishment in utero.

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Summary Review Epigenetic Mechanisms 1. Epigenetic (“upon genetic”) information is encoded by chemical modifications to DNA and associated histone proteins. It helps determine which of an individual's genes are active in which cells. 2. DNA methylation, which results from attachment of a methyl group to a cytosine, generally renders a gene inactive. One of the two X chromosomes in a female is silenced by methylation. Abnormal changes to DNA methylation are involved in several human cancers. 3. Histone modifications are chemical changes to the histone protein around which DNA is coiled for extreme compaction. This alters gene expression by increasing or decreasing the tightness of the interaction between DNA and histones.

Epigenetics and Human Development 1. Embryonic stem cells have the potential to give rise to any type of somatic cell. 2. Epigenetic modifications that arise during early development ensure that specific genes are expressed only in the cells and tissue types in which their gene products normally function. 3. Housekeeping genes escape epigenetic silencing and remain active.

Epigenetics in Genomic Imprinting 1. In biallelic expression, both inherited copies of a gene contribute to phenotype. In monoallelic expression, one copy of a gene (from either the mother or father) is randomly inactivated in some somatic cells. 2. For some human genes, one copy of an inherited chromosome is transcriptionally inactive: either the sperm or the egg carries the inactive copy. This process of gene silencing, in which genes are silenced depending on which parent transmits them, is known as imprinting; the transcriptionally silenced genes are said to be “imprinted.” The imprinted state persists in all somatic cells of the individual. 3. Many genes subject to imprinting regulate growth. Generally, imprinting of maternally inherited genes tends to reduce offspring size; imprinting of paternally inherited genes tends to increase offspring size. 4. The phenotype of individuals affected by imprinting is critically dependent on whether the mutation is inherited from the mother or from the father. When the deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15 is inherited from the father, the child manifests Prader-Willi syndrome. The same 4 Mb deletion, when inherited from the mother, causes Angelman syndrome. 5. Beckwith-Wiedemann syndrome is an overgrowth condition caused by imprinting that is accompanied by an increased predisposition to cancer. 6. Up-regulation, or extra copies, of active IGF2 causes overgrowth in Beckwith-

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Wiedemann syndrome. Down-regulation of IGF2 causes the diminished growth seen in Russell-Silver syndrome.

Environmental Impacts on Epigenetic Information 1. Events encountered in utero, in childhood, and in adolescence can result in specific epigenetic changes that yield a wide range of phenotypic abnormalities, and can be transmitted across generations. 2. Widespread nutritional deprivation (such as during times of war) has been shown to increase obesity and diabetes in the next generation due to epigenetic changes to individuals who were in utero during the deprivation. 3. Fetal alcohol syndrome, which results from ethanol exposure in utero, may be mediated by the repressive impact of ethanol on the DNA methyltransferases. 4. Both abnormal gain of methylation, as in the case of fragile X syndrome, and abnormal loss of methylation, as in the case of FSHMD, can produce disease phenotypes. Both phenotypes arise through epigenetic abnormalities that occur secondary to a genetic mutation. 5. Identical twins have DNA sequences that are essentially the same. As twins age, they accrue substantial genetic in their somatic cells, especially when they have significantly different lifestyles (e.g., smoking versus nonsmoking). 6. Epigenetic information is encoded by chemical modifications, not DNA sequences, so conventional genome sequencing approaches cannot screen for epigenetic states.

Epigenetics and Cancer 1. The best evidence for epigenetic effects on disease risk comes from studies of human cancer. 2. Methylation densities change as tumors progress. These changes can increase the activity of oncogenes and decrease the activity of tumor-suppressor genes, causing tumors to progress to malignancy. 3. Epigenetics-based screening approaches have shown promise for the detection of some cancers. 4. Epigenetic modifications can be reversed through pharmaceutical intervention. For example, 5-azacytidine, a demethylating agent, has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome. Histone deacetylase inhibitors have shown promise in treating cancers of the breast and prostate.

Future Directions 1. Emerging experimental data are clarifying the roles of epigenetic states in determining cell fates and disease phenotypes. 2. The well-documented involvement of epigenetic abnormalities in cancer and the mounting evidence for these epigenetic changes in other common diseases will

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likely elucidate new therapies with the possibilities of reversing the epigenetic abnormalities.

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Key Terms 5-Azacytidine, 70 Angelman syndrome, 66 Beckwith-Wiedemann syndrome, 67 Biallelic, 66 CpG dinucleotide, 64 DNA methylation, 64 Embryonic stem cell, 65 Epigenetic, 64 Fascioscapulohumeral muscular dystrophy (FSHMD), 68 Fragile X, 68 Histone modification, 64 Housekeeping genes, 66 Imprinted, 66 Monoallelic, 66 Prader-Willi syndrome, 66 Protamine, 65 Russell-Silver syndrome, 67

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References 1. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919–932. 2. Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol. 2011;5(3):385–399.

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Additional Readings Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018;378(14):1323– 1334. Sillanpää E, et al. Leisure-time physical activity and DNA methylation age—twin study. Clin Epigenetics. 2019;11(1):12. Wang J, et al. DNA methylation patterns of adult survivors of adolescent/young adult Hodgkin lymphoma compared to their unaffected monozygotic twin. Leuk Lymphoma. 2019;22:1– 9. Wang Y, et al. Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins. Epigenetics. 2018;13(9):975–987. Webster AP, et al. Increased DNA methylation variability in rheumatoid arthritis-discordant monozygotic twins. Genome Med. 2018;10(1):64.

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Altered Cellular and Tissue Biology Kathryn L. McCance, Lois E. Brenneman

CHAPTER OUTLINE Cellular Adaptation, 74 Atrophy, 74 Hypertrophy, 75 Hyperplasia, 75 Dysplasia: Not a True Adaptive Change, 76 Metaplasia, 76 Cellular Injury, 77 General Mechanisms of Cell Injury, 77 Ischemic and Hypoxic Injury, 77 Ischemia–Reperfusion Injury, 78 Free Radicals and Reactive Oxygen Species—Oxidative Stress, 79 Chemical or Toxic Injury, 82 Unintentional and Intentional Injuries, 90 Infectious Injury, 93 Immunologic and Inflammatory Injury, 94 Manifestations of Cellular Injury, 94 Cellular Manifestations: Accumulations, 94 Water, 95 Lipids and Carbohydrates, 95 Glycogen, 96 Proteins, 96 Pigments, 97 Calcium, 97 Urate, 99 Systemic Manifestations of Cellular Injury, 99 Cellular Death, 99 Necrosis, 100 Apoptosis, 102 Autophagy, 103

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Aging and Altered Cellular and Tissue Biology, 104 Normal Life Span and Life Expectancy, 105 Frailty, 105 Somatic Death, 106

The majority of diseases are caused by multiple factors acting together (multifactorial) or a single factor interacting with a genetically susceptible person. Injury to cells or their surrounding environment, the extracellular matrix (ECM), leads to tissue and organ damage. Although the normal cell is characterized by a narrow range of structural and functional constraints, cells can adapt to increased demands and stress so as to maintain a steady state, called homeostasis. Adaptation is a reversible response involving structural or functional modifications to accommodate both physiologic (normal) demands and pathologic (adverse) conditions. For example, the uterus adapts to pregnancy—a normal physiologic state—by enlarging. Pregnancy triggers an increase in the size and number of cells to accommodate a growing fetus. Adaptation to a pathologic condition occurs with high blood pressure or hypertension. Myocardial cells become enlarged, resulting in a larger, thicker left ventricle to accommodate the increased workload of the heart. Cellular adaptations to pathologic conditions are usually only temporarily successful. Severe or long-term stressors commonly overwhelm the adaptive processes, resulting in cellular injury or death. Common sources of cell stress include structural damage, neoplasia, fluid/solute accumulations, genetic influences, and aging. Altered cellular and tissue biology can result from adaptation. Cellular injury can result from any factor that disrupts cellular structures or deprives the cell of oxygen and essential nutrients. Resultant injury may be sublethal (reversible) or lethal (irreversible). Common sources of cell injury are classified broadly as ischemic–hypoxic (lack of sufficient oxygen), ischemia–reperfusion, free radical, immunologic, infectious, intentional or unintentional, and inflammatory. Clinical manifestations and alteration to normal physiology will vary with the type of injury. Stress from metabolic derangements is linked to intracellular excessive accumulations of carbohydrate, protein, and lipids. Cell death can result in calcium accumulation within surrounding tissue, a condition referred to as pathologic calcification. The two main types of cell death are necrosis and apoptosis. A third process, autophagy, occurs during times of cellular stress and is typically triggered by deficiency of nutrients or growth factors. The various forms of cell death are discussed in greater detail later in this chapter. Cellular aging causes structural and functional changes that may result in decreased capacity to recover from injury and, ultimately, cell death. The exact mechanisms governing cellular aging is unclear; distinguishing pathologic changes from age-associated physiologic changes can be challenging. Aging clearly results in alterations to cellular structure and function, yet senescence (growing old) is both inevitable and normal.

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Cellular Adaptation Cells adapt to their environment to avoid injury. An adapted cell is neither normal nor injured; its status falls somewhere between these two states. Adaptations are reversible changes affecting the size, number, phenotype, metabolic activity, or function of cells.1 Adaptive responses have limits; additional stress can compromise essential cell functions leading to cell injury or death. Cell adaptation may be the central component in many disease states. In the early stages of successful adaptation, cells may have enhanced function making it difficult to distinguish a pathologic response from vigorous adaptation. Over time, the adaptive response may fail and pathology will ensue. The most significant adaptive changes in cells include the following:

• Atrophy—decrease in cell size • Hypertrophy—increase in cell size • Hyperplasia—increase in cell number • Metaplasia—reversible replacement of one mature cell type by another, less mature cell type or a change in cell phenotype • Dysplasia—or deranged cellular growth, is not considered a true cellular adaptation but rather atypical hyperplasia These changes are shown in Fig. 4.1.

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FIGURE 4.1

Adaptive and Dysplastic Alterations in Simple Cuboidal Epithelial Cells.

Atrophy Atrophy refers to decrease in cell size. If atrophy affects a sufficient number of cells, the affected organ shrinks in size and is said to be atrophic. Atrophy can affect any organ, but it occurs most commonly in skeletal muscle, heart muscle, secondary sex organs, and the brain. Atrophy is classified as either physiologic or pathologic, depending on the underlying cause. Identical changes to cellular structure will occur regardless of whether atrophy results from normal or pathologic conditions. Physiologic atrophy occurs with early development, such as the thymus gland during early childhood; the atrophy is a normal event. Age-related atrophic changes to the gonads occur secondary to decreases in hormonal stimulation. The ovaries atrophy in postmenopausal women secondary to a lack of estrogenic stimulation. Aging results in atrophic changes to brain cells. Pathologic atrophy occurs in organs as a result of decreases in workload, pressure, use, blood supply, nutrition, hormonal stimulation, or neural stimulation (Fig. 4.2). Pathologic atrophy to muscle will occur when a limb is placed in a cast. This form of atrophy, known as disuse atrophy, also occurs with prolonged bed rest or other immobilization.

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FIGURE 4.2 Atrophy. A, Normal brain of a young adult. B, Atrophy of the brain in an 82-year-old male with atherosclerotic cerebrovascular disease, resulting in reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the surface of the brain. (From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

Atrophic muscle cells contain less endoplasmic reticulum (ER), fewer mitochondria, and fewer myofilaments (the contractile components of the muscle fiber) compared with normal cells. Muscle atrophy, caused by decreased neural stimulation, results in reduced oxygen consumption and decreased amino acid uptake. The mechanisms of atrophy for such changes include a decrease in protein synthesis, an increase in protein degradation, or both. The degradation of proteins occurs mainly by the ubiquitin–proteosome pathway (see Chapter 1). Current research emphasis is related to misfolded proteins, abnormalities in protein degradation, and a host of diseases, especially neurodegenerative diseases. Atrophy, secondary to chronic malnutrition, is associated with a process called autophagy (“self-eating”), where self-destructive autophagic vacuoles are created within the cell. These membrane-bound vesicles contain cellular debris and hydrolytic enzymes that degrade substances into simple units of fat, carbohydrate, or protein. Isolation of these enzymes within autophagic vacuoles prevents uncontrolled cell destruction in neighboring cells and tissue. Some substances contained within autophagic vacuole may resist destruction, persisting as membrane-bound residual bodies within tissues. Lipofuscin refers to yellow-brown pigmented granules; lipid-containing residue that persists after lysosomal destruction. These granules tend to accumulate in liver, myocardial, renal, retinal, adrenal, and neural tissues as individuals age. When they accumulate in the skin, they are the basis of the so-called age spots appearing in older individuals.

Hypertrophy Hypertrophy is a compensatory increase in the size of cells, occurring in response to mechanical load or stress, and results in increased size of the affected organ. Common triggers include repetitive stretching, chronic pressure, and volume overload (Fig. 4.3). The cells of the heart and kidneys are particularly prone to enlargement. Hypertrophy, as an

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adaptive response, occurs in the striated muscle cells of both the heart and skeletal muscles. It presents clinically as muscle enlargement. In the case of cardiac muscle hypertrophy, typically left ventricular hypertrophy (LVH), an increased synthesis of cardiac muscle proteins follows, allowing muscle fibers to do more work. Hypertrophy may be physiologic or pathologic. Physiologic hypertrophy results from increased demand, stimulation by hormones, and growth factors. An example of physiologic hypertrophy is enlargement secondary to aerobic exercise or a “runner's heart.” In this case, no pathology is present and normal structure and function is preserved. Pathologic hypertrophy results from chronic hemodynamic overload, such as from hypertension or heart valve dysfunction. When LVH occurs secondary to hypertension, it represents pathologic hypertrophy. The initial adaptation, in the form of cardiac enlargement with dilated ventricles, is short lived. Prolonged cardiac hypertrophy progresses to contractile dysfunction and, finally, heart failure. In contrast to physiologic hypertrophy, where the myocardial matrix is preserved, pathologic hypertrophy is associated with increased interstitial fibrosis, cell death, and abnormal cardiac function (see Fig. 4.3). After a unilateral nephrectomy (removal of one kidney), compensatory hypertrophy occurs in the remaining kidney, which preserves renal structure and function.

FIGURE 4.3 Hypertrophy of Cardiac Muscle in Response to Valve Disease. A, Transverse slices of a normal heart and a heart with hypertrophy of the left ventricle (L, normal thickness of left ventricular wall; T, thickened wall from heart in which severe narrowing of aortic valve caused resistance to systolic ventricular emptying). B, Histology of cardiac muscle from the normal heart. C, Histology of cardiac muscle from a hypertrophied heart. (From Stevens A, Lowe J: Pathology: illustrated review in color, ed 2, Edinburgh, 2000, Mosby.)

Hyperplasia Hyperplasia is an increase in the number of cells, resulting from an increased rate of cellular division. As a response to injury, hyperplasia occurs when the damage is severe or prolonged or when it results in cell death. Hyperplasia requires that cells undergo mitosis, a process wherein a single cell divides into two identical cells. The main mechanism for hyperplasia is the production of growth factors, which stimulate the remaining cells after

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injury or cell loss to synthesize new cell components and, ultimately, to divide. Another mechanism is increased output of new cells from tissue stem cells. For example, if liver cells are injured, new cells can regenerate from intrahepatic stem cells.2 Mature cells have differing capacity for hyperplastic (mitotic) growth. Although hyperplasia and hypertrophy have distinct processes, they can occur together within the same tissue. Two types of physiologic (normal) hyperplasia occur: compensatory hyperplasia and hormonal hyperplasia. Compensatory hyperplasia is an adaptive mechanism that enables organs to regenerate. Removal of part of the liver leads to rapid hyperplasia of the remaining hepatocytes (liver cells). Even with removal of 70% of liver mass, regeneration is complete in about 2 weeks. Significant compensatory hyperplasia readily occurs in epidermal and intestinal epithelia, hepatocytes, bone marrow cells, and fibroblasts. Loss of cells within an organ triggers deoxyribonucleic acid (DNA) synthesis, mitotic division, and hyperplasia. To a lesser extent, hyperplasia occurs in bone, cartilage, and smooth muscle cells. A callus, or thickening of the skin, is an example of compensatory hyperplasia. It occurs in response to injury from a mechanical stimulus. Another example is the response to wound healing secondary to the inflammation process. Hormonal hyperplasia occurs in organs that respond to endocrine hormonal stimulation. For example, during the follicular phase of the menstrual cycle, estrogen secretion by the ovary results in hyperplasia and endometrial proliferation. Hormonal secretion from a variety of endocrine organs maintains normal structure and function of target organs. (Hormone function is discussed further in Chapters 19, 20, 34, and 35.) Pathologic hormonal hyperplasia is the abnormal proliferation of normal cells, usually in response to excessive hormonal stimulation or to the action of growth factors on target cells (Fig. 4.4). A common example is pathologic hyperplasia of the uterine endometrium (lining of the uterus) that occurs from an imbalance between estrogen and progesterone levels (see Chapter 35). The resulting endometrial hyperplasia commonly presents as erratic or excessive uterine bleeding, known as dysfunctional uterine bleeding. Left unchecked, the regular growth-inhibiting control mechanisms can fail over time, producing malignant transformation or endometrial cancer. Benign prostatic hyperplasia (BPH) is another example of pathologic hyperplasia. The incidence of BPH increases with age, secondary to age-related hormonal imbalances that result in epithelial and stromal proliferation or impaired apoptosis. Similarly, thyroid enlargement, including thyroid goiters, can result from excessive levels of pituitary thyroid-stimulating hormone (TSH). In the absence of malignant transformation, when the predisposing factors are corrected, pathologic hyperplasia will typically regress.

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FIGURE 4.4 Hyperplasia of the Prostate With Secondary Thickening of the Obstructed Urinary Bladder (Bladder Cross-Section). The enlarged prostate is seen protruding into the lumen of the bladder, which appears trabeculated. These “trabeculae” result from hypertrophy and hyperplasia of smooth muscle cells that occur in response to increased intravesical pressure caused by urinary obstruction. (From Damjanov I: Pathology for the health professions, ed 4, St Louis, 2012, Saunders.)

Dysplasia: Not a True Adaptive Change Dysplasia refers to abnormal changes in the size, shape, and organization of mature cells (Fig. 4.5). Dysplasia is not considered a true adaptive process but is related to hyperplasia and is often referred to as atypical hyperplasia. Although dysplastic tissue appears disorderly, the term dysplasia does not refer to cancer. Dysplastic changes are common in the epithelial tissue of the uterine cervix, the endometrium, and the gastrointestinal and respiratory tract mucosa. Dysplasias that do not involve the entire thickness of epithelium may be completely reversible.2 When dysplastic changes penetrate the basement membrane, it is considered an invasive neoplasm. Dysplasia is described as “low grade” or “high grade,” depending on the degree of variation from normal. If the triggering stimulus is removed—for example, certain hormonal stimuli—dysplastic transformation may be reversible. (Dysplasia is discussed further in Chapter 11.)

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FIGURE 4.5 Dysplasia. Abnormal changes in the size, shape, and organization of cells. Dysplasia is related to hyperplasia and called atypical hyperplasia. (Adapted from Biology of Cancer modules, Boston University, School of Public Health. Available at sphweb.bumc.bu.edu.)

Metaplasia Metaplasia is the reversible replacement of one mature cell type (epithelial or mesenchymal) by another cell type, frequently one less differentiated. It is found in association with tissue damage, repair, and regeneration.2 It is thought to develop as an adaptive response wherein the new cell type may be better suited to withstand an adverse environment. Usually, however, the change is not beneficial. For example, in the long-term cigarette smoker, the chronic irritation from smoke causes the normal ciliated columnar epithelial cells of the trachea and bronchi to become replaced by stratified squamous epithelial cells (Fig. 4.6). The newly formed squamous epithelial cells do not secrete mucus or have cilia, causing a loss of a critical protective mechanism.

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FIGURE 4.6

Reversible Changes in Cells Lining the Bronchi.

Metaplasia results from a reprogramming of stem cells present in most epithelia or of undifferentiated mesenchymal (tissue from embryonic mesoderm) cells present in connective tissue.2 These precursor cells mature along a different pathway with metaplastic change. Differentiation of stem cells from a particular cell lineage responds to signals generated by growth factors, cytokines, and ECM components in the cell's environment.

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Cellular Injury Injury to cells and to the ECM leads to injury of tissues and organs and ultimately determines the structural patterns of disease. Cellular injury occurs when the cell is unable to maintain homeostasis (a normal or adaptive steady state). The injury may be reversible injury (the cell can recover) or irreversible injury (cellular death). Loss of function is the result of cell and ECM injury and cell death. Cellular injury may occur secondary to a variety of factors: chemical agents, lack of sufficient oxygen (hypoxia), free radicals, infectious agents, physical and mechanical factors, immunologic reactions, genetic factors, and nutritional imbalances. Types of injuries and their responses are summarized in Table 4.1 and Fig. 4.7. TABLE 4.1 Types of Progressive Cell Injury and Responses Type Adaptation Active cell injury Reversible Irreversible Necrosis Apoptosis, or programmed cell death Autophagy Chronic cell injury (subcellular alterations) Accumulations or infiltrations Pathologic calcification

Responses Atrophy, hypertrophy, hyperplasia, metaplasia Immediate response of “entire” cell Loss of ATP, cellular swelling, detachment of ribosomes, autophagy of lysosomes “Point of no return” structurally when severe vacuolization of mitochondria occurs and Ca++ moves into cell Common type of cell death with severe cell swelling and breakdown of organelles Cellular self-destruction for elimination of unwanted cell populations Eating of self, cytoplasmic vesicles engulf cytoplasm and organelles, recycling factory Persistent stimuli response may involve only specific organelles or cytoskeleton (e.g., phagocytosis of bacteria) Water, pigments, lipids, glycogen, proteins Dystrophic and metastatic calcification

ATP, Adenosine triphosphate; Ca++, calcium.

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FIGURE 4.7 Stages of Cellular Adaptation, Injury, and Death. The normal cell responds to physiologic and pathologic stresses by adapting (atrophy, hypertrophy, hyperplasia, metaplasia). Cell injury occurs if the adaptive responses are exceeded or compromised by injurious agents, stress, and mutations. The injury is reversible if it is mild or transient, but if the stimulus persists, the cell suffers irreversible injury and eventually death.

The extent of cellular injury is a function of cell type, level of differentiation, and adaptive mechanisms of the cell. Also important is the nature, severity, and duration of the injury. Fully differentiated, mature cells are more susceptible to injury than are cell precursors. Two individuals exposed to an identical stimulus may incur varying degrees of cellular injury. Individual differences, including genetics, nutritional status, and immunologic competency, can profoundly influence the extent of cell injury. The precise “point of no return” with respect to cell death remains unclear. Once changes to the nucleus have occurred or cell membranes are disrupted, or both, irreversible injury and cell death are inevitable.

General Mechanisms of Cell Injury Regardless of the cause of injury, a host of biochemical events result in cell injury and death. Such events include adenosine triphosphate (ATP) depletion, damage from oxygenderived free radicals, and alterations in calcium level. Injury to cell components includes membrane damage, protein folding defects, mitochondrial compromise, and DNA damage (Table 4.2). The most common forms of cell injury include (1) ischemic and hypoxic injury, (2) ischemia–reperfusion injury, (3) oxidative stress or accumulation of oxygen-derived free

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radicals-induced injury, and (4) chemical injury. TABLE 4.2 Common Themes in Cell Injury and Cell Death Theme ATP depletion Reactive oxygen species (↑ROS) Ca++ entry

Comments Loss of mitochondrial ATP and decreased ATP synthesis; results include cellular swelling, decreased protein synthesis, decreased membrane transport, and lipogenesis, all changes that contribute to loss of integrity of plasma membrane Lack of oxygen is key in progression of cell injury in ischemia (reduced blood supply); activated oxygen species (ROS, , H O , OH ) cause destruction of cell membranes and cell structure 2

2

−

Normally intracellular cytosolic calcium concentrations are very low; ischemia and certain chemicals cause an increase in cytosolic Ca++ concentrations; sustained levels of Ca++ continue to increase with damage to plasma membrane; Ca++ causes intracellular damage by activating a number of enzymes Mitochondrial Can be damaged by increases in cytosolic Ca++, ROS; two outcomes of mitochondrial damage are loss of damage membrane potential, which causes depletion of ATP and eventual death or necrosis of cell, and activation of another type of cell death (apoptosis) (see p. 102) Membrane Early loss of selective membrane permeability found in all forms of cell injury, lysosomal membrane damage damage with release of enzymes causing cellular digestion Protein Proteins may misfold, triggering unfolded protein response that activates corrective responses; if misfolding, overwhelmed, response activates cell suicide program or apoptosis; DNA damage (genotoxic stress) also DNA damage can activate apoptosis (see p. 102)

ATP, Adenosine triphosphate; Ca++, calcium; DNA, deoxyribonucleic acid; H2O2, hydrogen peroxide;

,

superoxide radical; OH−, hydroxyl radical; ROS, reactive oxygen species.

Ischemic and Hypoxic Injury Hypoxia, or the lack of sufficient oxygen within cells, is the single most common cause of cellular injury (Fig. 4.8). Hypoxia can result from a number of circumstances, such as reduced oxygen content in the ambient air, loss of hemoglobin, decreased red blood cell (RBC) production, respiratory and cardiovascular diseases, and poisoning of the cellular oxidative enzymes (cytochromes). The most common cause of hypoxia is ischemia or a reduced supply of blood and therefore oxygen. Hypoxia negatively impacts normal physiologic processes: differentiation, angiogenesis, proliferation, erythropoiesis, and overall cell viability. Mitochondria are the primary consumers of oxygen. Hypoxia triggers the mitochondrial complex to produce reactive oxygen species (ROS). From a physiologic perspective, ROS can be both beneficial and harmful, for example, by promoting oxidative stress, which can damage cells (oxidative stress is discussed in the next section). The relationship between hypoxia and inflammation has been linked to inflammatory bowel disease, certain cancers, and infection (Fig. 4.9). Ongoing research seeks to clarify how tumors adapt to low oxygen levels, including angiogenesis, increasing glucose consumption, and promoting the metabolic state of glycolysis.

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FIGURE 4.8 Hypoxic Injury Induced by Ischemia. A, Consequences of decreased oxygen delivery or ischemia with decreased adenosine triphosphate (ATP). The structural and physiologic changes are reversible if oxygen is delivered quickly. Significant decreases in ATP result in cell death, mostly by necrosis. B, Mitochondrial damage can result in changes in membrane permeability, loss of membrane potential, and decrease in ATP concentration. Between the outer and inner membranes of the mitochondria are proteins that can activate the cell's suicide pathways, called apoptosis. C, Calcium ions are critical mediators of cell injury. Calcium ions (Ca++) are usually maintained at low concentrations in the cell's cytoplasm; thus ischemia and certain toxins can initially cause an increase in the release of Ca++ from intracellular stores and later an increased movement (influx) across the plasma membrane. (Adapted from Kumar V et al, editors: Pathology, St Louis, 2014, Elsevier.)

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FIGURE 4.9 Hypoxia and Inflammation. Shown is a simplified drawing of clinical conditions characterized by tissue hypoxia that causes inflammatory changes (left) and inflammatory diseases that ultimately lead to hypoxia (right). These diseases and conditions are discussed in more detail in their respective chapters. (Adapted from Eltzschig HK, Carmeliet P: Hypoxia and inflammation, N Engl J Med 364:656–665, 2011.)

Arteriosclerosis (narrowing of blood vessels) and thrombus (blood clots within vessels) can result in localized tissue ischemia. Progressive hypoxia, caused by gradual arterial narrowing, is better tolerated than the acute anoxia (total lack of oxygen) caused by an acute obstruction, or a thrombus. An acute obstruction in a coronary artery can result in a rapidly evolving myocardial infarction (“heart attack”) if the blood supply is not restored. Irreversible myocardial cell death, with loss of heart function, will follow. Gradual onset of ischemia, however, usually results in myocardial adaptation. Myocardial infarction and

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stroke are frequent causes of mortality in the United States. These events typically result from ischemia. Cellular responses to hypoxic injury occur rapidly. Within 1 minute after the blood supply to the myocardium is interrupted, the heart becomes pale and dysfunctional and unable to contract normally. Within 3 to 5 minutes, mitochondrial compromise occurs, resulting in insufficient ATP production. At this point, the compromised portion of the myocardium ceases to contract. The abrupt lack of contraction is caused by a rapid decrease in mitochondrial phosphorylation, which results in insufficient ATP production. Lack of ATP leads to an increase in anaerobic metabolism, which generates ATP from glycogen when there is insufficient oxygen. When glycogen stores are depleted, even anaerobic metabolism ceases. Ischemia-induced reduction in ATP levels causes a failure of the plasma membrane's sodium–potassium (Na+-K+) pump and sodium–calcium (Na+-Ca++) exchange mechanisms. Sodium and calcium influx into and accumulate in the cell. Potassium (K+) diffuses out of the cell. Without the pump mechanism, sodium and water can freely enter the cell resulting in cellular swelling and dilation of the ER. With dilation, ribosomes detach from the rough ER, reducing protein synthesis. If hypoxia persists, the entire cell becomes markedly swollen. These disruptions are reversible if oxygen (O2) is restored. If oxygen is not restored, vacuolation (formation of vacuoles) occurs within the cytoplasm (see Manifestations of Cellular Injury section). The damaged outer membrane causes lysosomes to swell; marked swelling occurs to the mitochondria. With continued hypoxia, cell death rapidly follows as calcium accumulates within the cell, essential metabolic processes cease, and cell membranes become dysfunctional (see Figs. 4.8, C, and, late in the chapter, Fig. 4.21). Influx of calcium into the cell activates enzymes that trigger apoptosis (see Figs. 4.23 and 4.28 later in the chapter). Restoration of blood flow and oxygen can actually result in additional injury known as ischemia–reperfusion injury.

Ischemia–Reperfusion Injury Restoration of blood flow and oxygen to ischemic tissues can increase recovery of cells reversibly injured, but paradoxically result in additional injury known as ischemia– reperfusion injury (reperfusion [reoxygenation] injury) and cause cell death (Fig. 4.10). Reperfusion is a serious complication and an important mechanism of injury in instances of tissue transplantation and other ischemic syndromes (e.g., hepatic, intestinal, renal). Several mechanisms are proposed for reperfusion injury, including the following:

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FIGURE 4.10 Reperfusion Injury. Without oxygen, or in anoxia, the cells display hypoxic injury and become swollen. With reoxygenation, risk of reperfusion injury increases because of the formation of reactive oxygen radicals that can cause cell necrosis. (Redrawn from Damjanov I: Pathology for the health professions, ed 3, St Louis, 2006, Saunders.)

• Oxidative stress: Reoxygenation induces oxidative stress by generating highly ROS and nitrogen species. Reactive oxygen intermediates include hydroxyl radical (OH−), superoxide radical ( ), and hydrogen peroxide (H2O2). Nitrogen-based free radicals present mostly in the form of nitric oxide (NO) and are generated by endothelial cells, macrophages, neurons, and other cells. The radicals further damage the already compromised membrane and facilitate calcium overload within the mitochondria. Additionally, reperfusion injury promotes proinflammatory neutrophil adhesion to the endothelium where they release toxic oxidants and harmful proteases. Antioxidant agents, such as vitamin C and vitamin E, reverse neutrophil adhesion. They also reverse neutrophil-mediated reperfusion injury in cardiac muscle.3,4 • Increased intracellular calcium concentration: Intracellular and mitochondrial calcium accumulate within the cell during acute ischemia. Reperfusion results in even more calcium influx because of damaged cell membranes and ROS-mediated injury to 223

the sarcoplasmic reticulum. The increased calcium enhances mitochondrial permeability; damaged mitochondria have decreased or ceased production of ATP. • Inflammation: Ischemic injury promotes inflammation. Dead cells stimulate immune cells to release cytokine-mediated danger signals, thus initiating an inflammatory response. • Complement activation: Complement activation may exacerbate damage which has occurred secondary to reperfusion injury.2 Quick Check 4.1 1. When does a cell become irreversibly injured? 2. Discuss the pathogenesis of hypoxic injury? 3. What are the mechanisms of ischemia–reperfusion injury?

Free Radicals and Reactive Oxygen Species—Oxidative Stress Free radicals are an important mechanism of cellular injury, especially injury caused by ROS. This form of injury is called oxidative stress. Reactive oxygen species (ROS) are reactive molecules from molecular oxygen formed as a natural oxidant species in cells during mitochondrial respiration and energy generation. Oxidative stress is caused by an increase in different reactive species, depletion of antioxidant defense, or both. Oxidative stress results in detrimental oxidation of different molecules, including proteins, lipids, nucleic acids, and others. Oxidative stress can activate several intracellular signaling pathways because ROS can regulate enzymes and transcription factors. This process is an important mechanism of cell damage in many conditions. A free radical is an electrically uncharged atom, or group of atoms, which has an unpaired electron. Having one unpaired electron makes the molecule unstable; the molecule becomes stabilized either by donating or by accepting an electron from another molecule. The free radical has the potential to form a damaging chemical bond with proteins, lipids, and carbohydrates found within the cell membrane. Free radicals are highly reactive. They have low chemical specificity—that is, they can react with most molecules in their proximity. Reactions involving free radicals are difficult to control, and they initiate chain reactions. Free radicals are generated in a variety of conditions, including chemical and radiation injury, ischemia–reperfusion injury, cellular aging, and microbial destruction by phagocytes. Free radicals are generated within cells by a number of mechanisms. These mechanisms are as follows: 1. Reduction–oxidative reactions (redox reactions): An oxidative-reduction reaction is a type of biochemical reaction involving the transfer of elections between two species (molecule, atom, or ion). A species may either gain or lose an electron. All biologic membranes contain redox systems, which serve to support cellular

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activity. 2. Absorption of extreme energy sources (ultraviolet light, radiation) produces free radicals. 3. Enzymatic metabolism of exogenous chemicals or drugs: Many exogenous (outside the body) substances within the environment readily generate free radicals. As an example, CCL3, a byproduct of carbon tetrachloride [CCl4]), forms free radicals known to damage the liver, predisposing this organ to cancer. Accordingly, CCL4 is classified by the International Agency for Research on Cancer (IARC; Group 2B) as a possible carcinogenic and by the Environmental Protection Agency (EPA) as a probable human carcinogen. Many reported cases of CCL4 toxicity are associated with drinking alcohol. 4. Transition metals (iron and copper) donate or accept free electrons during intracellular reactions, generating free radicals in the process. As an example, the Fenton reaction, involving iron and H2O2, produces the potentially damaging hydroxyl radical and higher oxidation states of the iron. It has been implicated in iron accumulation disease. 5. NO, a colorless gas, acts as an intermediate in reactions involving endothelial cells, neurons, macrophages, and other cell types. NO can act as a free radical and convert to highly reactive compounds, including peroxynitrite anion (ONOO−), nitrogen dioxide (NO2), and nitrate (NO3). Table 4.3 describes the most significant free radicals. TABLE 4.3

Biologically Relevant Free Radicals Reactive oxygen species (ROS) Superoxide radical Hydrogen peroxide (H2O2) Or Oxidases present in peroxisomes O2 peroxisome Hydroxyl radicals (OH−) Or

Generated either (1) directly during autoxidation in mitochondria or (2) enzymatically by enzymes in cytoplasm, such as xanthine oxidase or cytochrome p450; once produced, it can be inactivated spontaneously or more rapidly by enzyme superoxide dismutase (SOD): Generated by SOD or directly by oxidases in intracellular peroxisomes (NOTE: SOD is considered an antioxidant because it converts superoxide to H2O2); catalase (another antioxidant) can then decompose H2O2 to O2 + H2O.)

Generated by hydrolysis of water caused by ionizing radiation or by interaction with metals—especially iron (Fe) and copper (Cu); iron is important in toxic oxygen injury because it is required for maximal oxidative cell damage

Or Nitric oxide (NO)

NO by itself is an important mediator that can act as a free radical; it can be converted to another radical—peroxynitrite anion (ONOO ), as well as nitrogen dioxide ( ) and carbonate −

radical (

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)

Data from Cotran RS et al: Robbins pathologic basis of disease, ed 6, Philadelphia, 1999, Saunders.

Free radicals also cause several damaging effects, such as the following: 1. Lipid peroxidation—the destruction of polyunsaturated lipids, which leads to membrane damage and increased permeability. This same process causes fats to become rancid. 2. Protein alteration—a process whereby polypeptide chains become fragmented leading to protein loss, protein misfolding, and alters protein–protein interaction. 3. DNA damage—results in mutations (Fig. 4.11; also see Chapter 2).

FIGURE 4.11 The Role of Reactive Oxygen Species (ROS) in Cell Injury. The production of ROS can be initiated by many cell stressors, such as radiation, toxins, and reperfusion of oxygen. Free radicals are removed by normal decay and enzymatic systems. ROS accumulates in cells because of insufficient removal or excess production leading to cell injury, including lipid peroxidation, protein modifications, and DNA damage or mutations. (Adapted from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

4. Mitochondrial effects—mitochondria are organelles that generate ATP. They can become damaged by ROS compromising available energy for the cell. Increases in intracellular calcium also damage mitochondria (see Fig. 4.8). Box 4.1 summarizes the major types of mitochondrial damage. Cell damage from ROS can extend to neighboring cells. Box 4.1

T h r e e M a j o r Ty p e s a n d C o n s e q u e n c e s o f M i t o c h o n d r i a l Damage 1. Damage to the mitochondria results in the formation of the mitochondrial permeability transition pore, a high-conductance channel or pore. The opening of this channel results in the loss of mitochondrial membrane potential, causing failure of oxidative phosphorylation, depletion of adenosine triphosphate (ATP), and damage to mitochondrial DNA (mtDNA), leading to necrosis of the cell.

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2. Altered oxidative phosphorylation leads to the formation of reactive oxygen species (ROS) that can damage cellular components. 3. Because mitochondria store several proteins between their membranes, increased permeability of the outer membrane may result in leakage of proapoptotic proteins and cause cell death by apoptosis. Data from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.

The toxicity of certain drugs and chemicals can be attributed to free radicals. The drug/chemical may be converted to a free radical or it may generate oxygen-derived metabolites. Free radicals have been either directly or indirectly linked with a growing number of diseases and disorders (Box 4.2). The body has various mechanisms to eliminate free radicals. As an example, the oxygen free radical superoxide may spontaneously decay into oxygen and hydrogen peroxide. Table 4.4 summarizes other methods that contribute to inactivation or termination of free radicals.

Box 4.2

Diseases and Disorders Linked to Oxygen-Derived Free Radicals Deterioration noted in aging Atherosclerosis Ischemic brain injury Alzheimer disease Neurotoxins Cancer Cardiac myopathy Chronic granulomatous disease Diabetes mellitus Eye disorders Macular degeneration Cataracts Inflammatory disorders Iron overload Lung disorders Asbestosis Oxygen toxicity Emphysema Nutritional deficiencies Radiation injury Reperfusion injury Rheumatoid arthritis Skin disorders Toxic states Xenobiotics (tetrachloride [CCl4], paraquat, cigarette smoke, etc.) Metal irons (nickel [Ni], copper [Cu], iron [Fe], etc.)

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TABLE 4.4 Methods Contributing to Inactivation or Termination of Free Radicals Method Process Antioxidants Endogenous or exogenous; either blocks synthesis or inactivates (e.g., scavenges) free radicals; includes vitamin E, vitamin C, cysteine, glutathione, albumin, ceruloplasmin, transferrin, γ-lipoacid, others Enzymes Superoxide dismutase,* which converts superoxide to hydrogen peroxide (H2O2); catalase* (in peroxisomes) decomposes H2O2; glutathione peroxidase* decomposes hydroxyl radical (OH−) and H2O2 *These

enzymes are important in modulating the cellular destructive effects of free radicals; also released in inflammation.

Chemical or Toxic Injury Humans are exposed to thousands of chemicals that have insufficient toxicologic data.5 Time, cost, and an interest in reducing animal testing dictate the need to develop new methods for toxicity testing. In an effort to meet public health concerns, many agencies have partnered to investigate how chemicals interact with biologic systems. Investigators are aided by advances in molecular and systems biology, computational toxicology, and bioinformatics. Mechanisms of cell stress from chemical agents include oxidative stress, ER stress, heat shock response, DNA damage response, mental stress, inflammation, and osmotic stress (sudden change in solute concentration). Chemicals are being classified under these types of cell stress mechanisms. Xenobiotics (from Greek xenos, “foreign”; bios, “life”) are compounds and chemicals that have toxic, mutagenic, or carcinogenic properties (Fig. 4.12). Some of these chemicals are found in the human diet, for example, the fungal mycotoxin, aflatoxin B1. Many xenobiotics are hepatotoxic (toxic to the liver). The liver is the initial site of contact for many ingested compounds—xenobiotics, drugs, and alcohol—predisposing this organ to chemically induced injury. Once absorbed by the gastrointestinal (GI) tract, the liver is the initial site of contact. This dynamic is called first-pass effect. A frequent cause for withdrawing medications from the market is hepatotoxicity. Herbal products are less subject to regulation by the U.S. Food and Drug Administration (FDA). The compounds chaparral and ma huang, marketed as herbal medicines, are potent hepatotoxins.6 Many chemical compounds used in household cleaning, insect control, outdoor maintenance, or chemical manufacturing are potential carcinogens. Many such agents are absorbed in the body through the skin or by inhalation; ubiquitous in the environment, some agents have been linked with liver and other organ damage. The extent of chemically induced liver injury varies from minor liver injury to acute liver failure, cirrhosis, and liver cancer.7

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FIGURE 4.12 Human Exposure to Pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, gastrointestinal tract, and skin. In the body, the pollutants may act at the site of absorption but are generally transported through the bloodstream to various organs where they can be stored or metabolized. Metabolism of xenobiotics may result in the formation of water-soluble compounds that are excreted, or a toxic metabolite may be created by activation of the agent. (From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier).

Hepatic detoxification occurs through enzyme-mediated biotransformation and

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antioxidant systems. Biotransformation is a process whereby enzymatic reactions convert one chemical into a less toxic or nontoxic compound. The liver has the highest supply of biotransformation enzymes of all organs and plays a key role in protecting the host from chemical toxicity (Fig. 4.13). Fig. 4.14 provides a summary of chemically induced liver injury.

FIGURE 4.13 Chemical Liver Injury. Liver injury is a result of genetic, environmental, biologic, and dietary factors. Certain chemicals can form toxic or chemically reactive metabolites. The risk of liver injury also can increase with increasing doses of a toxicant. Xenobiotic enzyme induction can lead to altered metabolism of chemicals, and drugs can either inhibit or induce drug-metabolizing enzymes. These changes can lead to greater toxicity. The dose at the site of action is controlled by phase I to III xenobiotic metabolites and metabolizing enzymes are encoded by numerous different genes. Therefore the metabolism and toxicity outcomes can vary greatly among individuals. Additionally all aspects of xenobiotic metabolism are regulated by certain transcription factors (cellular mediators of gene regulation). Overall the extent of cell damage depends on the balance between reactive chemical species and protective responses aimed at decreasing oxidative stress, repairing macromolecular damage, or preserving cell health by inducing apoptosis or cell death. Significant clinical outcomes of chemicalinduced liver injury occur with necrosis and the immune response. Covalent binding of reactive metabolites to cellular proteins can produce new antigens (haptens) that initiate autoantibody production and cytotoxic T-cell responses. Necrosis, a form of cell death

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(see the Cellular Death section), can result from extensive damage to the plasma membrane with altered ion transport, changes of membrane potential, cell swelling, and eventual dissolution. Altogether the pathogenesis of chemically induced liver injury is determined by genetics, environmental factors, and other underlying pathologic conditions. Green arrows are pathways leading to cell recovery; red arrows indicate pathways to cell damage or death; black arrows are pathways leading to chemically induced liver injury. (Adapted from Gu X, Manautou JE: Molecular mechanisms underlying chemical liver injury, Exp Rev Mol Med 14:e4, 2013.)

FIGURE 4.14 Chemical Injury of Liver Cells Induced by Carbon Tetrachloride (CCl4) Poisoning. Light blue boxes are mechanisms unique to chemical injury, purple boxes involve hypoxic injury, and green boxes are clinical manifestations.

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Antioxidants are molecules that inhibit the oxidation of other molecules, thereby preventing the formation of free radicals. Antioxidants often terminate a chain reaction, which would otherwise result in free radical formation. Endogenous antioxidants are antioxidants produced by the body. The five most powerful endogenous antioxidants are superoxide dismutase (SOD), alpha lipoic acid (ALA), catalase, coenzyme Q 10 (CoQ10), and glutathione peroxidase (GPX). Exogenous antioxidants are antioxidants that originate from outside the body, typically from dietary sources, such as vitamin C. Foods rich in antioxidants are appropriately encouraged as part of a healthy diet.

Chemical Agents Including Drugs Numerous chemical agents cause cellular injury. Minute amounts of some, such as arsenic and cyanide, can rapidly destroy cells and cause death of the individual. Chronic exposure to air pollutants, insecticides, and herbicides can cause cell injury (see Fig. 4.12). Carbon tetrachloride, alcohol, and social drugs can significantly alter cellular function and injure cellular structures. Over-the-counter (OTC) and prescribed drugs are an important cause of cellular injury. The abuse and addiction to opioids, such as heroin, morphine, and fentanyl, and other prescription pain relievers are a serious global problem that affects all societies. Millions of people abuse opioids worldwide. The issue has become a public health crisis. In the United States, drug overdoses have dramatically increased over the last two decades, with deaths more than tripling between 1999 and 2016; and approximately 72,000 deaths in 2017.8 The leading cause of poisoning in children is medications, including inappropriate administration of OTC preparations containing acetaminophen (paracetamol). Acetaminophen is one of the most common causes of poisonings worldwide when used as an analgesic. The liver is the most common site for chemically induced injury. Common drugs of abuse are listed in Table 4.5 and social or street drugs in Table 4.6. TABLE 4.5 Common Drugs of Abuse Class Opioid narcotics

Molecular Target Mu (µ) opioid receptor (agonist)

Sedative-hypnotics

GABAA receptor (agonist)

Psychomotor stimulants

Dopamine transporter (antagonist) Serotonin receptors (toxicity)

Phencyclidine-like drugs Cannabinoids

NMDA glutamate receptor channel (antagonist) CB1 cannabinoid receptors (agonist)

Hallucinogens

Serotonin 5-HT2 receptors (agonist)

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Example Heroin, hydromorphone (Dilaudid) Oxycodone (Percodan, Percocet, OxyContin) Fentanyl Methadone (Dolophine) Meperidine (Demerol) Barbiturates Ethanol Methaqualone (Quaalude) Glutethimide (Doriden) Ethchlorvynol (Placidyl) Cocaine Amphetamines 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) Phencyclidine (PCP, angel dust) Ketamine Marijuana Hashish Lysergic acid diethylamide (LSD) Mescaline Psilocybin

CB1, Cannabinoid receptor type 1; GABA, γ-aminobutyric acid; 5-HT2, 5-hydroxytryptamine; NMDA, N-methyl-Daspartate. From Kumar V et al: Cellular responses to stress and toxic insults: adaptation, injury, and death. In Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, St Louis, 2014, Saunders; Hyman SE: A 28year-old man addicted to cocaine. JAMA 286:2586, 2001.

TABLE 4.6 Social or Street Drugs and Their Effects Type of Drug Marijuana (pot)

Description and Effects Active substance: ∆9-Tetrahydrocannabinol (THC), found in resin of Cannabis sativa plant. With smoking (e.g., “joints”), about 5%–10% is absorbed through lungs; with heavy use, the following adverse effects have been reported: alterations of sensory perception; impairment of cognitive and psychomotor judgments (e.g., inability to judge time, speed, distance); increases in heart rate and blood pressure; increases susceptibility to laryngitis, pharyngitis, bronchitis; causes cough and hoarseness; may contribute to lung cancer (dosages levels not determined); contains large number of carcinogens; data from animal studies only indicate reproductive changes include reduced fertility, decreased sperm motility, and decreased levels of circulatory testosterone; fetal abnormalities include low birth weight; increased frequency of infectious illness is thought to be result of depressed cell-mediated and humoral immunity; beneficial effects include decreased nausea secondary to cancer chemotherapy and decreased pain in certain chronic conditions. Methamphetamine An amine derivation of amphetamine (C10H15N) used as crystalline hydrochloride (“meth”) CNS stimulant; in large doses causes irritability, aggressive (violent) behavior, anxiety, excitement, auditory hallucinations, and paranoia (delusions and psychosis); mood changes are common and abuser can swiftly change from being friendly to being hostile; paranoiac swings can result in suspiciousness, hyperactive behavior, and dramatic mood swings. Appeals to abusers because body's metabolism is increased and produces euphoria, alertness, and perception of increased energy Stages: Low intensity: User is not psychologically addicted and uses methamphetamine by swallowing or snorting. Binge and high intensity: User has psychological addiction and smokes or injects to achieve a faster, stronger high. Tweaking: Most dangerous stage; user is continually under the influence, not sleeping for 3–15 days, extremely irritated, and paranoid. Cocaine and crack Extracted from leaves of cocoa plant and sold as a water-soluble powder (cocaine hydrochloride) liberally diluted with talcum powder or other white powders; extraction of pure alkaloid from cocaine hydrochloride is “free-base” called crack because it “cracks” when heated. Crack is more potent than cocaine; cocaine is widely used as an anesthetic, usually in procedures involving oral cavity; it is a potent CNS stimulant, blocking reuptake of neurotransmitters norepinephrine, dopamine, and serotonin; also increases synthesis of norepinephrine and dopamine; dopamine induces sense of euphoria, and norepinephrine causes adrenergic potentiation, including hypertension, tachycardia, and vasoconstriction; cocaine can therefore cause severe coronary artery narrowing and ischemia; reason cocaine increases thrombus formation is unclear; other cardiovascular effects include dysrhythmias, sudden death, dilated cardiomyopathy, rupture of descending aorta (i.e., secondary to hypertension); effects on fetus include premature labor, retarded fetal development, stillbirth, hyperirritability. Heroin Opiate closely related to morphine, methadone, and codeine Highly addictive, and withdrawal causes intense fear (“I'll die without it”); sold “cut” with similar-looking white powder; dissolved in water it is often highly contaminated; feeling of tranquility and sedation lasts only a few hours and thus encourages repeated intravenous or subcutaneous injections; acts on the receptors enkephalins, endorphins, and dynorphins, which are widely distributed throughout body with high affinity to CNS; effects can include infectious complications, especially Staphylococcus aureus infections, granulomas of lung, septic embolism, and pulmonary edema—in addition, viral infections from casual exchange of needles and HIV; sudden death is related to overdosing secondary to respiratory depression, decreased cardiac output, and severe pulmonary edema.

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Fentanyl

Synthetic opioid analgesic similar to morphine but is 50-100 times more potent. The synthetic opioid fentanyl and its analogs have risen across the United States in a variety of forms. Currently, it is documented in connection with a growing number of overdoses and overdose deaths.

CNS, Central nervous system; HIV, human immunodeficiency virus. Data from Kumar V, Abbas A, Aster J: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders; Nahas G et al: Review of marihuana and medicine, N Engl J Med 343(7):514, 2000.

Common Environmental Toxins Air pollution. The world's largest single environmental health risk is air pollution.9 According to the State of Global Air 2018, which provides evidence as part of the Global Burden of Disease (GBD) project,10 seven billion people, or more than 95% of the world's population, live in areas of unhealthy air. Air pollution is the leading environmental cause of death worldwide.10 Air pollution from both indoor and outdoor exposure contributed to 6.1 million premature deaths from stroke, heart attack, lung cancer, and chronic lung disease.10 For the first time, worldwide estimates of exposure to and health effects of indoor pollution or burning solid fuel in homes resulted in a total of 2.5 billion people, or one in three global persons, exposed to household pollution from the use of solid fuels (e.g., coal, charcoal, wood, dung, or other biomass) for heating and cooking. These people live mostly in low- and middleincome countries and together with outdoor pollution face a double health burden10 Fig. 4.15. Over half of the total global attributable deaths were found to be from China and India together.10 India is now similar to China for the highest air pollution health burdens worldwide with both countries having 1.1 million deaths from outdoor air pollution.10

FIGURE 4.15

Numbers of Deaths Attributable to Ambient PM2.5. (From GDB 2016 Risk

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Factors Collaborators: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990– 2016: a systematic analysis for the Global Burden of Disease Study 2016, Lancet 390(10100):1345–1422, 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28919119.

Ambient particulate matter is particulate matter less than or equal to 2.5 micrometers in aerodynamic matter, or PM2.5 Fig. 4.16. Ambient particulate matter is ranked as the sixth highest risk factor for early death. Another component of outdoor air pollution is ozone, a special form of oxygen in a deep layer in the stratosphere, whose levels are increasing around the world and contributes to 234,000 deaths from chronic lung disease.10

FIGURE 4.16

Particle Sizes and Pollution. (From Environmental Protection Agency: Particulate matter updated March 18, 2013, Washington, DC, 2013, Author.)

Heavy Metals as Environmental Pollutants The most common heavy metals associated with harmful effects in humans include lead, mercury, arsenic, and cadmium. Damage from metals includes involvement of DNA repair mechanisms, tumor suppressor functions, and interference with signal transduction pathways. Lead. Lead (Pb) is a heavy toxic metal present in paint of older homes, the environment, and the workplace. The organ systems most affected by lead include the nervous, hematopoietic (organs and tissues that produce blood cells), reproductive, GI, cardiovascular, musculoskeletal systems and the kidneys. Exposure occurs through inhalation, ingestion, and, less frequently, skin contact. Lead induces cellular damage by increasing oxidative stress.11 The key underlying effects of lead exposure in humans is disruption of cellular ion status, and disruption of protein function from displacement of metal enzyme cofactors. Lead inhibits several enzymes involved in hemoglobin synthesis and causes a microcytic,

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hypochromic anemia. Renal lesions can cause tubular dysfunction resulting in glycosuria (glucose in the urine), aminoaciduria (amino acids in the urine), and hyperphosphaturia (excess phosphate in urine). GI symptoms are less severe and include nausea, loss of appetite, weight loss, and abdominal cramping. Low lead levels can increase the levels of other metals and also may be a risk factor for hypertension.12 Lead may be found in hazardous concentrations in food, water, and air, and is one of the most common sources of overexposures injuries found in industry. Older buildings, where lead-based paint is peeling from the walls, is a particular hazard to children (see Did You Know? CDC Update: Primary Prevention of Lead Exposures for Children). Lead-based paint has a sweet taste and toddlers are prone to find paint chips on the floor and put them into their mouths.

Did You Know? CDC Update: Primary Prevention of Lead Exposures in Children

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In 2012, the Centers for Disease Control and Prevention (CDC) updated recommendations on children's blood lead levels. The shift is to focus on primary prevention of lead exposure to reduce or eliminate dangerous and toxic sources in children's environments. At least 4 million households have children living in houses where they are being exposed to high levels of lead. Experts now use a reference level of 5 micrograms per deciliter (mcg/dL) to identify children with blood lead levels that are much higher than most children's levels. (This new level is based on the US population of children ages 1 to 5 years who are in the highest percentile [2.5% of children] when tested for lead.) The CDC will update the reference value every 4 years using the most recent National Health and Nutrition Examination Survey (NHANES) based on the 97.5th percentile of blood lead distribution in children. The recommendation for when medical treatment is advised for children with high blood lead levels has not changed. Chelation therapy is recommended in a child with blood lead test result showing ≥ 45 mcg/dL. Data from Centers for Disease Control and Prevention (CDC): Lead, Atlanta, GA, 2017, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, updated February 9, 2017; Centers for Disease Control and Prevention (CDC): Lead: what do parent's need to know to protect their children? Atlanta, GA, Author, updated March 15, 2016. The neurologic effect of lead in exposed children is the driving force for reducing lead levels in the environment. Children are more susceptible than adults to the effects of lead for several reasons: 1. Children have increased hand-to-mouth behavior and thus are prone to putting objects found in their environment into their mouths. 2. The blood–brain barrier in children is immature during fetal development, contributing to greater accumulation in the developing brain. 3. Infant absorption of lead is greater than that in adults. In adults, the body burden of lead is found in bone. In children, growth results in a rapid turnover in skeletal bone causing a continuous leaching of lead into blood.13,14 In cases of compromised nutrition, where dietary intake of iron and calcium is insufficient, children are more likely to have elevated blood lead levels.13 Elevated blood lead levels in children are linked to cognitive deficits and behavioral changes, including antisocial behavior, acting out in school, and attention deficits.13 These deficits can persist even after the individuals are no longer exposed to lead within their environment. Lead interferes with the normal remodeling of cartilage and bone in children (remodeling increases lead reintroduction). Radiologic studies often reveal lead lines in children. Lead accumulates in gums, causing hyperpigmentation. Particularly worrisome is lead exposure during pregnancy because the developing fetal nervous system is especially vulnerable to lead toxicity. Lead exposure in utero can result in significant cognitive impairment and subsequent learning disabilities. Main methods of treatment are removal

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of the source of exposure and for those with high blood lead levels, chelation therapy. Additional treatment may include correcting deficiencies for iron, calcium, and zinc; irrigating the bowel; removing strategic bullets or shrapnel; and medications for seizures. Cadmium and arsenic. See Table 4.7 for a summary of the toxic effects of cadmium and arsenic. TABLE 4.7 Summary of Toxic Effects of Cadmium and Arsenic Metals Arsenic

Key Concepts Arsenic salts were the poison of choice during the Renaissance in Italy. Deliberate poisoning by arsenic is rare today; however, its exposure is an important health concern in many areas worldwide. Arsenic is found naturally in soils and water and used in products (wood preservers, herbicides, agricultural products). It can be released from mines and smelting industries and may be present in some Chinese and Indian herbal medicines. Inorganic arsenic may be present in ground water with large concentrations found in Bangladesh, Chile, and China. Most toxic forms are the trivalent compounds arsenic trioxide, sodium arsenite, and arsenic trichloride. Arsenic trioxide is used as a therapy for acute promyelocytic leukemia; ingestion of large quantities of arsenic causes acute gastrointestinal, cardiovascular, and CNS toxicities that often are fatal. These effects are partially attributed to replacement of phosphates in ATP and interference of mitochondrial oxidative phosphorylation and the function of some proteins. Chronic exposure causes skin lesions (hyperpigmentation, hyperkeratosis) and the development of cancers (lung, bladder, skin). The mechanism for arsenic carcinogenesis has not been fully defined. Arsenic present in drinking water has been correlated with nonmalignant respiratory disease. Cadmium Compared with the other metals discussed, cadmium poisoning is a more modern problem. Pollution in the environment and occupationally is from mining, electroplating, and production of nickel-cadmium batteries, which are often disposed of in household waste. Food is an important source of cadmium because cadmium can contaminate soil and plants directly or from fertilizers and irrigation water. The most probable mechanism of toxicity is the generation of ROS. The main toxic effects of excess cadmium is obstructive lung disease and renal tubular damage. It also can cause skeletal abnormalities associated with calcium loss. In Japan, cadmium-containing water used to irrigate rice fields caused a disease in postmenopausal women known as “Itai-Itai” (ouch-ouch), a combination of osteoporosis and osteomalacia associated with renal disease. Cadmium is associated with higher risk of lung cancer in populations living near zinc smelters.

ATP, adenosine triphosphate; CNS, central nervous system; ROS, reactive oxygen species. Data from Kumar V, Abbas A, Aster J, editors: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.

Mercury. Mercury (quicksilver) is a neurotoxic elemental metal liquid at room temperature and widely present in the environment. Mercury is a global threat to human and environmental health. It can be released into the air, water, and soil through industrial processes, including mining, metal and cement production, fuel extraction, and combustions of fossil fuels. Sources of exposure include natural geologic sources, vehicle emissions, consumer products, industrial waste, and landfills and disposal sites. Mercury also is found in dental amalgam; some vaccine preservatives; food products (e.g., rice); and terrestrial and marine

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animals, some of which are consumed by humans. The previously common practice of allowing school children to handle mercury in chemistry classes is no longer permitted. Similarly, the once ubiquitous mercury-filled household thermometer is being phased out of production. There is debate among experts as to exactly how much direct mercury ingestion from the food supply or environmental vapor inhalation results in health hazards to humans or animals. There is little debate, however, concerning the hazards of mercury exposure during pregnancy. Mercury negatively impacts fetal brain development, so pregnant women are well advised to avoid dietary sources of mercury. Climate change and thawing of enormous areas of frozen lands may release long-stored mercury into lakes, rivers, and oceans.15 Ethanol. Alcohol (ethanol) is the primary choice of mood-altering drugs available in the United States. It is estimated there are more than 10 million chronic alcoholics in the United States. Alcohol contributes to more than 100,000 deaths annually, with 50% of these deaths resulting from drunk driving accidents, alcohol-related homicides, and suicides.2 A blood concentration of 80 mg/dL is the legal definition for driving while intoxicated in the United States. The amount of alcohol intake required to achieve this blood level will vary, depending on age, sex, percent body fat, metabolic rate, and genetically controlled factors influencing alcohol metabolism. A large intake of alcohol has implications for nutritional status. Major nutritional deficiencies associated with alcohol abuse include those of magnesium, vitamin B6, thiamine, folic acid, and phosphorus. Folic acid deficiency, in particular, is problematic in persons consuming large quantities of alcohol. Ethanol alters folic acid (folate) homeostasis by decreasing intestinal absorption of folate, increasing liver retention of folate, and increasing the loss of folate through urinary and fecal excretion. Folic acid deficiency becomes especially serious when alcohol is consumed during pregnancy and may contribute to fetal alcohol syndrome. Thiamine deficiencies result in major neurologic sequela, common in persons with alcohol abuse. Most of the alcohol ingested is metabolized to acetaldehyde in the liver. Acetaldehyde is a highly toxic substance and known carcinogen, with particular implications for head and neck cancer. It is responsible for both the acute effects of alcohol ingestion and for numerous disease processes associated with chronic alcohol consumption. The major effects of acute alcoholism involve the central nervous system (CNS). After alcohol is ingested, it is absorbed, unaltered, from the stomach and small intestine. Fatty foods and milk slow absorption. After absorption, alcohol is distributed to all body tissues and fluids in direct proportion to blood concentration levels. Individuals differ widely in their capability to metabolize alcohol. Genetic differences in the hepatic metabolism of alcohol are related to levels of hepatic aldehyde dehydrogenases. There is considerable variability in alcohol tolerance among different ethnic groups. Persons with chronic alcoholism tend to develop an increased tolerance because of the enhanced production of metabolic enzymes. Numerous studies have validated the so-called J-curve or U-shaped inverse association between alcohol and overall or cardiovascular mortality, including myocardial infarction and ischemic stroke. Both irregular and chronic heavy drinking has a detrimental impact on most cardiovascular diseases. Among light to moderate drinkers, in the absence of binge

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drinking, mortality rates tend to be lower than in nondrinkers; mortality rates are higher among heavy drinkers. These findings, however, may be confounded by medical care and social relationships. Experts hold that further research is indicated. They also recommend that people who do not consume alcohol should not be encouraged to start drinking for purposes of health maintenance. The proposed mechanisms for observed cardiovascular benefit includes one or more of the following effects: increased levels of high-density lipoprotein–cholesterol (HDL-C), decrease in levels of low-density lipoprotein (LDL), prevention of clot formation, reduction in platelet aggregation, decrease in blood pressure, increase in coronary vessel vasodilation, increase in coronary blood flow, decrease in coronary inflammation, decrease in atherosclerosis, limited ischemia–reperfusion injury, and decreased diabetic vessel pathology. The American Heart Association recommends no more than two drinks per day for men and no more than one drink per day for women. One drink is defined as 12 oz beer, 4 oz of wine, 1.5 oz of 80-proof spirits, or 1 oz of 100-proof spirits. Consuming alcohol in greater than recommended amounts is associated with numerous health hazards, including increased risk for alcoholism, high blood pressure, obesity, stroke, breast cancer, suicide, and accidents. Acute alcohol intoxication (drunkenness) primarily affects the CNS, causing dose-related CNS depression. Alcohol consumption induces varying levels of sedation, drowsiness, loss of motor coordination, delirium, altered behavior, and loss of consciousness. Toxic blood levels (300–400 mg/dL) result in a lethal coma or respiratory arrest caused by medullary center depression. Additionally, acute alcoholism may induce reversible hepatic and gastric changes.1. Binge drinking, defined as four standard alcoholic drinks on one occasion for women and five drinks for men, has significant health hazards. Chronic drinking and binge drinking cause alcoholic liver disease (ALD) with the spectrum ranging from hepatic steatosis (fatty change) and steatohepatitis (fatty and inflammatory changes) to cirrhosis of the liver. These alterations can lead to hepatocellular carcinoma. Alcohol can induce damage to mitochondrial DNA, lipid accumulation, and oxidative stress. Additionally, there is evidence that alcohol drinking in adolescents, especially binge drinking, can result in neurocognitive changes affecting both gray and white brain matter and may result in risk-taking behaviors. Chronic alcoholism causes structural alterations in practically all organs and tissues in the body. The most significant changes, however, occur in the liver. Alcohol is the leading cause of liver-related morbidity and mortality.16 Hepatic changes, initiated by acetaldehyde, are far reaching and include inflammation, fat deposition, and liver enlargement. On the cellular level, changes include protein transport malfunctions, increased intracellular water, decreased mitochondrial fatty acid oxidation, excessive membrane rigidity, and liver cell necrosis. Chronic, excessive alcohol consumption typically results in cirrhosis of the liver and the associated portal hypertension (Fig. 4.17). Other disorders associated with chronic alcoholism include alcoholic cardiomyopathy; increased risk of hypertension, gastritis, and pancreatitis; regressive changes in skeletal muscle; and an increased risk for oral, liver, esophageal and breast cancer. Ethanol is implicated in the onset of a variety of immune defects, including cytokine production, inflammation, increased susceptibility to infection, and enhanced progression of human immunodeficiency disease.17

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FIGURE 4.17 Alcoholic Hepatitis. Chicken-wire fibrosis extending between hepatocytes (Mallory trichrome stain). (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)

Alcohol ingestion during pregnancy is associated with cognitive deficiencies and neurobehavioral disorders, including fetal alcohol syndrome (FAS). Fetal alcohol spectrum disorders (FASDs) are a range of health effects or disorders of prenatal alcohol exposure with FAS at the more severe end of the spectrum. FAS syndrome is characterized by growth retardation, facial anomalies, cognitive impairment, and ocular malformations (Fig. 4.18). Research suggests that alcohol-induced epigenetic alterations may be carried through the male germline for multiple generations.18 Alcohol readily crosses the placenta, reaching the fetus in 1 to 2 hours, and produces fetal blood levels that are equivalent to maternal alcohol levels.19 Amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure.19 Overall, maternal ingestion of alcohol can be catastrophic for the developing fetus.

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FIGURE 4.18 Diagnostic Facial Features of Fetal Alcohol Syndrome (FAS). Three diagnostic facial features of FAS: (1) short palpebral fissure lengths, (2) smooth philtrum, and (3) thin upper lip. (© 2017 Susan Astley, PhD, University of Washington.)

Quick Check 4.2 1. Why are children more susceptible to the toxic effects of lead exposure? 2. Discuss the nutritional implications of chronic alcoholism. 3. Discuss the mechanisms of cell injury related to chronic alcoholism. 4. What are the sources of mercury exposure? 5. Why has air pollution become a leading cause of morbidity and mortality?

Social or Street Drugs The social or recreational use of psychoactive and narcotic drugs is a major problem in many parts of the world. Popular drugs are methamphetamine (“meth”); marijuana; cocaine, heroin; and, increasingly, fentanyl. Many of these drugs have a high risk for addiction and dependence, and some can cause respiratory distress and death. Opiates both prescription and illicit are the main causes of drug overdose deaths.20 Opiates were involved in 42,249 deaths in 2016; opiate overdose deaths were five times higher in 2016 than in 199920 (see Table 4.6 for a summary of the effects of these drugs).

Unintentional and Intentional Injuries Unintentional and intentional injuries are an important health problem in the United States. In 2016, there were 231,991injury deaths, an injury death rate of 71.8 per 100,000.21 The number of deaths because of poisoning was 68,995, at a rate of 21.4 deaths per 100,000.

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Motor vehicle accident–related deaths accounted for 38,804, with a rate of 12 deaths per 100,000. Deaths caused by all firearms were 38,658, with a rate of 12 deaths per 100,000. From data reported in 2016, drug poisoning deaths occurred at a rate of 19.7 per 100,000.21 Rates of drug overdose deaths continues to increase. The 10 drugs most frequently involved in overdose deaths included the following opioids: heroin, oxycodone, methadone, morphine, hydrocodone, and fentanyl; the following benzodiazephines: alprazolam and diazepam; and the following stimulants: cocaine and methamphetamine. The rate of drug overdose deaths involving fentanyl more than doubled in a single year (from 2013 to 2014).22 Increases in drug overdose deaths are seen for both males and females and the largest percentage increase is for adults aged 55 to 64. Rates had a fivefold increase in this age group. Overall, 70,237 drug overdose deaths occurred in the United States in 2017. The opioid epidemic continues to worsen because of the continuing increase in deaths from synthetic opioids.23 Death rates because of falls increased 30%.24 Each year 3 million older people are treated in emergency departments for fall injuries. More than 95% of hip fractures are caused by falls and falls are the leading cause of traumatic brain injuries (TBI). Sexual violence affects millions of people each year in the United States. Specifically, 1 in 3 women and 1 in 4 men experience sexual violence.25 Sports- and recreation-related injury account for an estimated 3.2 million visits to emergency rooms each year for children 5 to 14 years. Injuries from organized and unorganized sports account for 775,000 emergency room visits annually for this same age group. Sports-related injuries are the leading cause of emergency room visits in 12- to 17-year-olds.26 Death from all injury is significantly more common among men than among women. Significant racial differences are noted in mortality rates, with mortality rate of whites at 64.85 per 100,000, that of blacks at 56.20 per 100,000, and that of other racial groups at a combined rate of 28.96 per 100,000. There also is a bimodal age distribution for injury-related deaths, with peaks in the young adult and elderly age groups. Unintentional injury is the leading cause of death among those between ages 1 and 34 years; intentional injury (suicide, homicide) ranks between the second and fourth leading causes of death in these age groups. A 1999 report published by the Institute of Medicine (IOM) indicated that 44,000 to 98,000 unnecessary deaths per year occurred in hospitals alone as a result of errors made by health care professionals. Death and injury from medical care itself is a very important issue and a main concern is the lack of a comprehensive, nationwide system for estimating premature deaths and unintentional injury associated with preventable harm to people.27 Subsequent data to the IOM report suggest that the magnitude of the problem may have been underestimated and that hospital-acquired infections alone explained more than 90,000 deaths per year.28 In 2013, a review of studies estimated that the true number of premature deaths associated with preventable harm to individuals was far higher than the IOM report with an estimate of more than 400,000 per year.29 From the Agency for Health Care Research and Quality (AHRQ) on hospitalacquired conditions approximately 75,000 preventable hospital deaths occurred in 2013.27 Getting close to the real number is absolutely necessary to assist educators, clinicians, administrators, and boards of trustees to guarantee a culture of safety for individuals. The more common terms used to describe and classify unintentional and intentional injuries and brief descriptions of important features of these injuries are presented in Table 4.8. TABLE 4.8

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Unintentional and Intentional Injuries Type of Injury BLUNT-FORCE INJURIES

Description Mechanical injury to body resulting in tearing, shearing, or crushing; most common type of injury seen in healthcare settings; caused by blows or impacts; motor vehicle accidents and falls most common cause (see Photo A) Contusion (bruise): Bleeding into skin or underlying tissues; initial color will be red-purple, then blue-black, then yellow-brown or green (see Fig. 4.22); duration of bruise depends on extent, location, and degree of vascularization; bruising of soft tissue may be confined to deeper structures; hematoma is collection of blood in soft tissue; subdural hematoma is blood between inner surface of dura mater and surface of brain; can result from blows, falls, or sudden acceleration/deceleration of head as occurs in shaken baby syndrome; epidural hematoma is collection of blood between inner surface of skull and dura; is most often associated with a skull fracture Laceration: Tear or rip resulting when tensile strength of skin or tissue is exceeded; is ragged and irregular with abraded edges; an extreme example is avulsion, where a wide area of tissue is pulled away; lacerations of internal organs are common in blunt-force injuries; lacerations of liver, spleen, kidneys, and bowel occur from blows to abdomen; thoracic aorta may be lacerated in sudden deceleration accidents; severe blows or impacts to chest may rupture heart with lacerations of atria or ventricles Fracture: Blunt-force blows or impacts can cause bone to break or shatter (see Chapter 40) Cutting and piercing injuries accounted for 2734 deaths in 2007; men have a higher rate (1.37/100,000) compared with women (0.44/100,000); differences

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by race are as follows: whites 0.71/100,000; blacks 2.12/100,000; and other groups 0.80/100,000 Incised wound: A wound that is longer than it is deep; wound can be straight or jagged with sharp, distinct edges without abrasion; usually produces significant external bleeding with little internal hemorrhage; these wounds are noted in sharp-force injury suicides; in addition to a deep, lethal cut, there will be superficial incisions in same area called hesitation marks (see Photo B) Stab wound: A penetrating sharp-force injury that is deeper than it is long; if a sharp instrument is used, depths of wound are clean and distinct but can be abraded if object is inserted deeply and wider portion (e.g., hilt of a knife) impacts skin; depending on size and location of wound, external bleeding may be surprisingly small; after an initial spurt of blood, even if a major vessel or heart is struck, wound may be almost completely closed by tissue pressure, thus allowing only a trickle of visible blood despite copious internal bleeding Puncture wound: Instruments or objects with sharp points but without sharp edges produce puncture wounds; classic example is wound of foot after stepping on a nail; wounds are prone to infection, have abrasion of edges, and can be very deep Chopping wound: Heavy, edged instruments (axes, hatchets, propeller blades) produce wounds with a combination of sharp- and blunt-force characteristics Accounted for > 33,636 deaths in the United States in 2015; men more likely to die compared with women (18.16 vs. 2.73/100,000); black men ages 15 to 24 years have greatest death rate (86.95/100,000); gunshot wounds are either penetrating (bullet remains in body) or perforating (bullet exits body); bullet also can fragment; most important factors or appearances are whether it is an entrance or exit wound and range

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of fire Entrance wound: All wounds share some common features; overall appearance is most affected by range of fire Contact range entrance wound: Distinctive type of wound when gun is held so muzzle rests on or presses into skin surface; there is searing of edges of wound from flame and soot or smoke on edges of wound in addition to hole; hard contact wounds of head cause severe tearing and disruption of tissue (because of thin layer of skin and muscle overlying bone); wound is gaping and jagged, known as blow back; can produce a patterned abrasion that mirrors weapon used (see Photo C) Intermediate (distance) range entrance wound: Surrounded by gunpowder tattooing or stippling; tattooing results from fragments of burning or unburned pieces of gunpowder exiting barrel and forcefully striking skin; stippling results when gunpowder abrades but does not penetrate skin (see Photo D) Indeterminate range entrance wound: Occurs when flame, soot, or gunpowder does not reach skin surface but bullet does; indeterminate is used rather than distant because appearance may be same regardless of distance; for example, if an individual is shot at close range through multiple layers of clothing the wound may look the same as if the shooting occurred at a distance Exit wound: Has the same appearance regardless of range of fire; most important factors are speed of projectile and degree of deformation; size cannot be used to determine whether hole is an exit or entrance wound; usually has clean edges that can often be reapproximated to cover defect; skin is one of toughest structures for a bullet to penetrate; thus it is not uncommon for a bullet to pass entirely through body but stopped just beneath skin on “exit” side Wounding potential of bullets: Most

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damage done by a bullet is a result of amount of energy transferred to tissue impacted; speed of bullet has much greater effect than increased size; some bullets are designed to expand or fragment when striking an object, for example, hollow-point ammunition; lethality of a wound depends on what structures are damaged; wounds of brain may not be lethal; however, they are usually immediately incapacitating and lead to significant long-term disability; a person with a “lethal” injury (wound of heart or aorta) also may not be immediately incapacitated

Asphyxiation Asphyxial injuries are caused by the failure of cells to receive or use oxygen. Deprivation of oxygen may be partial (hypoxia) or total (anoxia). Asphyxiation can be grouped into four general categories: suffocation, strangulation, chemical asphyxiants, and drowning. Suffocation. Suffocation, or the process of dying as a result of lack of oxygen, can result from either a lack of oxygen in the environment or from a blockage of the respiratory airways (see Choking Asphyxiation section below). Persons can become entrapped in an enclosed space that is lacking in adequate oxygen. This scenario would occur if a child becomes trapped in an abandoned refrigerator or if a toddler's head becomes entangled in a plastic bag. Both scenarios have been linked to fatalities. Suffocation also can occur when another gas displaces oxygen in the environment. Methane, the largest component of sewer gas, has caused fatal asphyxiation when it has displaced atmospheric oxygen. Children have died from methane asphyxiation shortly after falling into a pit containing sewage; rescue workers have a very narrow time frame in which to save the child. Volcanos have been known to belch carbon dioxide (CO2) gas in amounts sufficient to displace the normal oxygen level in the atmosphere for several miles, resulting in widespread death of humans and animals within the area. Normal ambient oxygen level in the atmosphere is 21%. A reduction to a level of 16% poses immediate danger. If the level drops below 5%, death can ensue within minutes. History and forensic examination are important in diagnosing suspected asphyxiation, because even autopsy may not demonstrate specific physical findings in such cases. Choking asphyxiation occurs when there is an obstruction of the pulmonary airways. An object may become lodged in a large airway, directly obstructing breathing. Injury or disease also may result from soft tissue swelling surrounding the airway, leading to a partial or complete obstruction and subsequent asphyxiation. Treatment requires locating and removing the obstructing object immediately or, in the case of airway swelling, reversing the swelling before asphyxiation occurs. Compressional asphyxiation occurs when mechanical compression of the chest or abdomen prevents normal respiratory movements. Usual signs and symptoms include florid facial congestion and petechiae (pinpoint

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hemorrhages) of the eyes and face. An individual entrapped beneath a heavy object, which impairs chest expansion, may become asphyxiated. Strangulation. Strangulation is caused by compression of the blood vessels and air passages resulting from external pressure on the neck. The compression causes hypoxia from impaired blood flow to the brain. The amount of force needed to compress the jugular veins (2 kg) or carotid arteries (5 kg) is significantly less than the force required to crush the trachea (15 kg). Injury or death, which occurs secondary to strangulation results from the impaired cerebral blood flow, not from lack of airflow. With a complete blockage of the carotid arteries, unconsciousness will typically occur within 10 to 15 seconds. Hanging strangulation occurs when a noose or similar object is placed around the neck after which the support under the victim's feet is suddenly removed so that the body falls freely. Death or severe injury results as the noose tightens, cutting off air flow through the trachea. Hanging strangulation is usually an intentional event, such as suicide, homicide, or a judicial hanging. However it can also be accidental. This form of strangulation typically produces severe soft tissue injury and cervical spinal trauma. The body does not need to be completely suspended for death to occur. Hanging may cause petechiae in the eyes or face; however this finding is uncommon. More typically, an inverted V–shaped ligature mark about the neck is seen at autopsy. Ligature strangulation does not require suspension. Instead some form of cord encircles and tightens about the neck. This event may be intentional, as in the case of homicide with use of a garrote from behind the victim. It also may be accidental, as when a child becomes accidentally entangled in cords of window blinds. Autopsy will reveal a horizontal mark about the neck, without an inverted V pattern. Petechiae are more common in this scenario because intermittent opening and closure of the blood vessels may occur as a result of the victim's struggle. Internal injuries of the neck are rare. Manual strangulation occurs when an assailant's hands compress the neck of the victim to the point where death by asphyxiation occurs. There is evidence of variable amounts of external trauma to the neck. Contusions and abrasions are either caused directly by the assailant or by the victim clawing at their own neck in an attempt to remove the assailant's hands. Internal damage can be quite severe; bruising of deep structures, including fractures of the hyoid bone, the tracheal cartilage, and the cricoid cartilages, are seen. Petechiae are common. Chemical asphyxiants. A number of substances can act as chemical asphyxiants. They either prevent the delivery of oxygen to the tissues or block oxygen utilization. Carbon monoxide is the most common chemical asphyxiant. Carbon monoxide (CO) is an odorless, colorless, nonirritating, and undetectable gas; it is often mixed with a visible or odorous compound. CO is produced by incomplete combustion of fuels, such as gasoline. CO produces hypoxic injury, specifically, oxygen deprivation. As a systemic asphyxiant, CO causes death by inducing CNS depression. Normally, oxygen molecules are carried to tissues bound to the hemoglobin in RBCs. Because the affinity of CO for hemoglobin is 300 times greater than that of oxygen, CO quickly binds with hemoglobin, preventing oxygen molecules from binding to hemoglobin, and they are thus transported to tissues. Minute amounts of CO can produce a significant percentage of carboxyhemoglobin (carbon monoxide bound with hemoglobin).

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With increasing levels of carboxyhemoglobin, hypoxia occurs insidiously, evoking widespread ischemic changes in the CNS. Individuals are often unaware of exposure. Death may occur in an individual who believes he is simply feeling sleepy, thus no evasive action is taken. The use of CO monitors in homes is therefore strongly recommended. Diagnosis can be made from the measurement of carboxyhemoglobin levels in blood. Victims of CO poisoning may have a cherry red coloration to the skin and mucous membranes. Symptoms related to CO poisoning include headache, giddiness, tinnitus (ringing in the ears), chest pain, confusion, nausea, weakness, and vomiting. CO is an environmental air pollutant found in combustion fumes produced by cars and trucks, small gasoline engines, stoves, gas ranges, gas refrigerators, heating systems, lanterns, burning charcoal or wood, and cigarette smoke. Chronic exposure can occur in people working in confined spaces, such as underground garages and tunnels. Fumes can accumulate in enclosed or semienclosed spaces. Individuals most susceptible to CO poisoning are fetuses, infants, and people with chronic heart disease, respiratory problems, and anemia. Cyanide is an extremely toxic salt. Cyanide acts as an asphyxiant by combining with the ferric (iron) ion in hemoglobin, facilitating its transport to tissues. When present in tissues, cyanide inhibits the formation of cytochrome oxidase by interrupting the electron transport chain within the mitochondria. As a result, the mitochondria can no longer aerobically generate ATP, and oxygen can no longer bind to the final molecule in the electron transport chain. The host dies from oxygen deprivation, even though abundant oxygen may be present. As with CO poisoning, victims of cyanide poisoning may have a cherry red coloration to the skin and mucus membranes. With the presence of cyanide, an odor of bitter almonds may be detected; however the ability to smell cyanide is a genetic trait that is present in only 20% to 40% of the general population. Hydrogen sulfide, one of several sewer gases, is a chemical asphyxiant and neurotoxin; it interferes with the body's ability to carry oxygen. It has a characteristic “rotten egg” odor that is detectable even at very low levels. Victims of hydrogen sulfide poisoning may have brown-tinged blood, in addition to the nonspecific signs of asphyxiation. Methane, another sewer gas, is nontoxic but readily causes asphyxiation by displacing oxygen. Because of the presence of asphyxiant gases, caution is indicated when working in areas containing septic tanks, cesspools, and manure pits. Numerous fatalities have occurred in persons working in these environments. Drowning. Drowning is death from inhalation of and suffocation by a liquid, usually water. The CDC has reported that between 2005 and 2014, an average of 3536 fatal, unintentional drownings occurred annually. The major mechanism of injury is hypoxemia (low blood oxygen levels). Contrary to previous prevailing views, there is no evidence that drowning deaths result from fluid and electrolyte disturbances or from blood hemolysis. In freshwater drownings, large amounts of water can pass through the alveolar–capillary interface. Even in this setting, there is no evidence that an increase in blood volume results in either hemolysis or electrolyte derangements. With drowning, airway obstruction is the more important consideration because in as many as 15% of drownings, little or no water enters the lungs. Vagal-mediated laryngospasms may close off the airway producing a phenomenon known as dry-lung drowning. Regardless of the mechanism, cerebral hypoxia leads to unconsciousness in a matter of

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minutes. Whether this status progresses to death depends on a number of factors, including the age and the health of the individual. One of the most important determinants is water temperature. Irreversible injury develops much more rapidly in warm water than in cold water. Survival after up to 1 hour has been reported in children who were submerged in very cold water. Complete submersion is not enough to cause drowning. An incapacitated or helpless individual (e.g., persons with epilepsy or alcoholism, infants) may drown in water that is only a few inches deep. No specific or diagnostic findings prove that a person, recovered from the water, is actually a drowning victim. In cases where water has entered the lung, there may be large amounts of foam exiting the nose and mouth. This same phenomenon, however, could occur with other causes of death, including drug overdoses. A body recovered from water could have been that of a victim of some other type of fatal injury. Drowning may represent an effort to obscure the actual cause of death. When treating a living victim recovered from water, it is essential to keep an index of suspicion for any underlying condition that may have predisposed the person to become incapacitated, causing him or her to fall into the water.

Quick Check 4.3 1. Give examples of intentional and unintentional asphyxia cases in the United States. 2. What are common chemical asphyxiants, and why are they lethal? 3. How does CO cause death? 4. What is the major mechanism of injury with drowning?

Infectious Injury The pathogenicity (virulence) of microorganisms lies in their ability to survive and proliferate within the host. The disease-producing potential of a microorganism is a function of its ability to (1) invade and destroy cells, (2) produce toxins, and (3) produce damaging hypersensitivity reactions. (Chapter 8 contains a description of infection and infectious microorganisms.)

Immunologic and Inflammatory Injury Cellular membranes are injured as a result of direct contact with immune or inflammatorymediated responses, such as phagocytes (lymphocytes and monocytes) and biochemical substances generated during an inflammatory response. Potentially injurious biochemical agents include histamine, antibodies, lymphokines, complement system products, and proteases (see Chapter 6). A variety of mechanisms for potential cellular injury exist. The complement system is responsible for several membrane alterations associated with immunologic injury. Membrane alterations can facilitate a rapid leakage of potassium out of the cell, along with an influx of water. Antibodies can bind and occupying receptor molecules located on the plasma membrane, interfering with its function. Antibodies also can block or destroy cellular junctions, obstructing intercellular communication. Other mechanisms include genetic and epigenetic factors, nutritional imbalances, and physical agents. These are summarized in Table 4.9.

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TABLE 4.9 Mechanisms of Cellular Injury Mechanism Characteristics Genetic Alter cell's nucleus and plasma membrane's structure, shape, factors receptors, or transport mechanisms Epigenetic factors Nutritional imbalances

Induction of mitotically heritable alterations in gene expression without changing DNA Pathophysiologic cellular effects develop when nutrients are not consumed in diet and transported to body's cells or when excessive amounts of nutrients are consumed and transported

Examples Sickle cell anemia, Huntington disease, muscular dystrophy, abetalipoproteinemia, familial hypercholesterolemia Gene silencing in cancer Protein deficiency, protein-calorie malnutrition, glucose deficiency, lipid deficiency (hypolipidemia), hyperlipidemia (increased lipoproteins in blood causing deposits of fat in heart, liver, and muscle), vitamin deficiencies

Physical Agents Temperature Hypothermic injury results from chilling or freezing of cells, Frostbite extremes creating high intracellular sodium concentrations; abrupt drops in temperature lead to vasoconstriction and increased viscosity of blood, causing ischemic injury, infarction, and necrosis; reactive oxygen species (ROS) are important in this process Hyperthermic injury is caused by excessive heat and varies in Burns, burn blisters, heat cramps severity according to nature, intensity, and extent of heat usually from vigorous exercise with water and salt loss; heat exhaustion with salt and water loss causes heme contraction; heat stroke is lifethreatening with a clinical rectal temperature of 106° F Tissue injury caused by compressive waves of air or fluid Blast injury (air or immersion), impinging on body, followed by sudden wave of decreased decompression sickness (caisson pressure; changes may collapse thorax, rupture internal solid disease or “the bends”); recently organs, and cause widespread hemorrhage: carbon dioxide and reported in a few individuals with nitrogen that are normally dissolved in blood precipitate from subdural hematomas after riding highsolution and form small bubbles (gas emboli), causing hypoxic speed roller coasters injury and pain Ionizing Refers to any form of radiation that can remove orbital electrons X-rays, γ-rays, and α- and β-particles radiation from atoms; source is usually environment and medical use; cause skin redness, skin damage, damage is to DNA molecule, causing chromosomal aberrations, chromosomal damage, cancer chromosomal instability, and damage to membranes and enzymes; also induces growth factors and extracellular matrix remodeling; uncertainty exists regarding effects of low levels of radiation Illumination Fluorescent lighting and halogen lamps create harmful oxidative Eyestrain, obscured vision, cataracts, stresses; ultraviolet light has been linked to skin cancer headaches, melanoma Mechanical Injury is caused by physical impact or irritation; they may be Faulty occupational biomechanics, stresses overt or cumulative leading to overexertion disorders Noise Can be caused by acute loud noise or cumulative effects of Hearing impairment or loss; tinnitus, various intensities, frequencies, and duration of noise; considered temporary threshold shift (TTS), or a public health threat loss can occur as a complication of critical illness, from mechanical trauma, ototoxic medications, infections, vascular disorders, and noise

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Manifestations of Cellular Injury Cellular Manifestations: Accumulations Metabolic disturbances can result from cell injury, particularly where there is excessive intracellular accumulation of biochemical substances. Cellular accumulations, also known as infiltrations, can occur with both sustained cell injury and with normal but inefficient cell function. Two categories of substances can produce infiltrations: 1. Normal cellular substances—excess water, proteins, lipids, and carbohydrates 2. Abnormal substances—including endogenous substances (products of abnormal metabolism and synthesis) and exogenous substances (infectious agents or minerals) Products can accumulate transiently or permanently, and can be toxic or harmless. Infiltrations may occur in the cytoplasm, typically within the lysosomes, and they also can occur in the nucleus. Most accumulations result from four types of mechanisms, all of which are abnormal (Fig. 4.19). The four mechanisms are:

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FIGURE 4.19

Mechanisms of Intracellular Accumulations. (From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

1. Insufficient removal of the normal substance because of altered configuration or transport. Example: steatosis, fatty changes in the liver. 2. Accumulation of abnormal substance because of defects in protein folding, transport, or abnormal degradation. Such occurrences are usually secondary to gene mutation. 3. Inadequate metabolism of an endogenous (physiologic) substance, usually because of a lack of a lysosomal enzyme. Example: storage diseases. 4. Harmful exogenous materials. Example: heavy metals and mineral dust inhalation and ingestion or the presence of pathogenic microorganisms. In all storage diseases, the cells attempt to digest, or catabolize, the “stored” substances resulting in excessive amounts of metabolites accumulating within the cells. These metabolites are expelled into the ECM where they are attacked by phagocytic cells, usually macrophages (see Chapter 6). Some of these scavenger cells circulate throughout the body; others remain fixed in tissues, particularly in liver or spleen tissue. Affected tissues swell resulting in organ enlargement as increasing numbers of phagocytes migrate to tissues. Hepatomegaly or splenomegaly occurs in many storage diseases.

Water Cellular swelling is the most common degenerative change; it results from a shift of extracellular water into the cells. In hypoxic injury, the movement of fluid and ions into the cell is associated with acute metabolic failure and the loss of ATP production. The energydependent sodium pump, which transports sodium ions out of the cell, requires ATP. Adenosine triphosphatase (ATPase) is the active transport enzyme; it is reduced with hypoxia. Inadequate levels of ATP and ATPase permit sodium to accumulate within the cell while potassium diffuses outward. Increased intracellular sodium concentration raises osmotic pressure, drawing yet more water into the cell. The cisternae of the ER become distended and are predisposed to rupture. Once ruptured, the cisternae reunite, forming large vacuoles that isolate water, a process called vacuolation. Progressive vacuolation results in cytoplasmic swelling, termed oncosis (hydropic degeneration) or vacuolar degeneration (Fig. 4.20). Where cellular swelling affects the majority of cells within an organ, the affected organ becomes expanded; the weight of the organ increases and it takes on a pale appearance.

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FIGURE 4.20

The Process of Oncosis (Formerly Referred to as “Hydropic Degeneration”). ATP, Adenosine triphosphate.

Cellular swelling is reversible or sublethal. It is an early manifestation of almost all types of cellular injury, including injuries that are severe or lethal. Cellular swelling is associated with high fever, hypokalemia (decreased blood potassium), and certain infections.

Lipids and Carbohydrates Certain metabolic disorders result in an abnormal intracellular accumulation of carbohydrates and lipids. These substances may accumulate throughout the body, but they are found primarily in the spleen, liver, and CNS. Accumulations within CNS cells are associated with neurologic deficits and severe intellectual impairment. Lipids accumulate in Tay-Sachs disease, Niemann-Pick disease, and Gaucher disease. When carbohydrates accumulate, mucopolysaccaride diseases (mucopolyaccharidoses) result. Mucopolysaccharidoses are progressive disorders, typically affecting multiple organs and, particularly, the liver, spleen, heart, and blood vessels. Mucopolysaccharides accumulate at a variety of sites throughout the body: reticuloendothelial cells, endothelial cells, intimal smooth muscle cells, and fibroblasts. Carbohydrate accumulations are associated with cataracts (corneal clouding), joint stiffness, intellectual deficits, and the characteristic eye changes seen in Graves disease (hyperthyroidism). The most common site of intracellular lipid accumulation is the liver where steatosis or fatty changes of the liver occur (Fig. 4.21). Other sites include heart, muscle, and kidney cells. Lipid accumulation in the liver results in deficits to hepatic functioning. As lipids accumulate in the cells, increased vacuolation pushes the nucleus and other organelles aside. The outward appearance of the liver becomes yellow and greasy. In developed countries, the most common cause of fatty changes to the liver is alcohol abuse. Other causes include diabetes mellitus, protein malnutrition, toxins, anoxia, and obesity. Mechanisms for lipid accumulation in the liver include the following:

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FIGURE 4.21

Fatty Liver. The liver appears yellow. (From Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)

1. Increased movement of free fatty acids into the liver (for example, starvation increases triglyceride metabolism in adipose tissue and fatty acids are released and enter liver cells) 2. Failure to convert fatty acids to phospholipids results in (preferential) conversion into triglycerides 3. Increased synthesis of triglycerides from fatty acids 4. Decreased synthesis of apoproteins (lipid-acceptor proteins) 5. Failure of lipids to bind with apoproteins to form lipoproteins 6. Failure of mechanisms that transport lipoproteins out of the cell 7. Direct damage to the ER by free radicals released by alcohol's toxic effects Many pathologic states show accumulation of cholesterol and cholesterol esters. Atherosclerosis is characterized by plaques containing lipids, cholesterol, calcium, macrophages, and other substances. The coronary and carotid arteries are particularly prone to plaques. Their presence in these vessels can result in myocardial infarction and stroke. Cholesterol-rich deposits in the gallbladder commonly lead to obstruction from cholelithiasis (gall stones). Niemann-Pick disease is characterized by lipid accumulation in the spleen, liver, lungs, bone marrow, and brain, secondary to a genetic lack of sphingomyelinase, an enzyme that affects cholesterol transport.

Glycogen Glycogen is the storage form of glucose, with 90% found in the liver. Glycogen serves as a readily available source of energy needed for normal cell function. Intracellular accumulations of glycogen are seen in a large group of genetic disorders called glycogen storage diseases. Accumulations also are noted disorders affecting glucose and glycogen metabolism. Glycogen storage diseases have profound detrimental effects on growth and development, and they negatively impact a variety of organ and body system functions. As with water and lipid accumulation, glycogen accumulation results in excessive vacuolation in the cytoplasm. Excess glycogen accumulation is evident in 80% of persons with diabetes.

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The high levels of blood glucose and excess glycogen cause a multiplicity of problems in the individual with diabetes (see Chapter 20).

Proteins Proteins provide cellular structure and account for most of the cell's dry weight. Proteins are synthesized on ribosomes from the essential amino acids. Intracellular accumulation of excess protein damages cells in two ways. First, protein metabolism results in the release of lysosomal enzymes, which can damage cellular organelles. Second, excessive amounts of protein in the cytoplasm crowd cell organelles, disrupting their function and intracellular communication. Protein excess accumulates primarily in two locations: in the epithelial cells of the renal convoluted tubules and in the antibody-producing B lymphocytes. A variety of renal disorders result in excessive excretion of protein molecules into urine (proteinuria). Normally, protein is conserved with little or no protein escaping into urine. Proteinuria suggests cellular injury or altered cellular function, or both. As a function of the immune response, protein complexes are elaborated as B lymphocytes (plasma cells) synthesize antibodies. Excess protein aggregates, called Russell bodies, have been identified in multiple myeloma, which is a cancer of the plasma cells. A number of disease states result from mutations, which impair protein folding; partially folded intermediates accumulate within the cell. Emphysema, without a history of smoking, can result from α1-antitrypsin deficiency, a genetic mutation that impairs protein folding. Cell injury also is associated with the accumulation of cytoskeleton proteins. The neurofibrillary tangle found in the brain in Alzheimer disease contains these types of proteins.

Pigments Pigment accumulations may be normal or abnormal, endogenous (produced within the body), or exogenous (produced outside the body). Endogenous pigments, derived from amino acids (tyrosine, tryptophan), include melanin and blood proteins (porphyrins, hemoglobin, and hemosiderin). Lipofuscin, a lipid-rich pigment, known as the “aging pigment,” imparts a yellow-brown color to cells, which are undergoing slow, regressive, or atrophic changes. The most common exogenous pigment is carbon black (coal dust), a pervasive air pollutant in urban areas. Inhaled carbon black interacts with lung macrophages. Lymphatics transport it to regional pulmonary lymph nodes where it accumulates. This accumulation blackens lung tissues and pulmonary nodes causing a variety of respiratory disorders. Other exogenous pigments include mineral dusts: silica, iron particles, lead, silver salts, and dyes used for tattoos.

Melanin Melanin is a brown-black pigment derived from the amino acid tyrosine. Melanin is synthesized by epidermal cells called melanocytes and is stored in membrane-bound cytoplasmic vesicles, called melanosomes. It accumulates in epithelial cells (keratinocytes) of the skin and retina, where it serves to protect the tissue from the harmful effects of prolonged exposure to sunlight. Melanin is essential in the prevention of skin cancer. Persons with absent or low levels of melanin (lighter-skinned persons) are more susceptible

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to skin cancer (see Chapters 12 and 43). Particularly hazardous are episodes of sunburn during the early years of life because these events increase the life-long risk for developing skin cancer. Ultraviolet radiation from nonnatural sources (tanning salon lamps) also is associated with an increased risk for skin cancer. Individuals who have more darkly pigmented skin because of the presence of higher levels of melanin are proportionately less susceptible to skin cancers. Ultraviolet light, from sunlight and other sources, stimulates the synthesis of melanin. Melanin absorbs ultraviolet rays during subsequent exposures. Melanin also may serve to trap harmful free radicals, derived by the action of ultraviolet light on skin. Melanin accounts for the brown to black coloration seen in pigmented nevi, benign skin moles. Melanin also is found in cancerous skin lesions, particularly malignant melanoma, a highly aggressive and lethal form of skin cancer. It is characterized by irregular black skin lesions, which rapidly metastasize to other organs. Albinism is a congenital inherited disorder characterized by the complete or partial absence of melanin. These individuals are extremely predisposed to developing skin cancer because they experience sunburn upon even minimal exposure to sunlight. In humans, the disorder is inherited as either an autosomal recessive or a sex-linked recessive genetic disorder, depending on the type of albinism involved. The mechanism for albinism is a defect in tyrosinase, a copper-containing enzyme, which catalyzes the production of melanin from the amino acid tyrosine.

Hemoproteins Hemoproteins are essential endogenous pigments. They include hemoglobin and oxidative enzymes, the cytochromes. Numerous disorders result from abnormalities involving these pigments, particularly, iron uptake, metabolism, excretion, and storage (see Chapter 22). Excessive intracellular iron storage results from accumulations of hemoprotein, originating when this substance is transferred from the bloodstream into cells. Iron enters blood from three primary sources: (1) tissue stores, (2) the intestinal mucosa, and (3) macrophages. Macrophages remove and destroy dead or defective RBCs. The amount of iron in blood plasma also depends on the metabolism of the major iron-transport protein, transferrin. Iron is stored in tissue cells in two forms: ferritin, the major vehicle for iron storage and, with greater levels of iron present, as hemosiderin, an intracellular, yellow-brown pigment. Excess accumulation of hemosiderin usually occurs in the mononuclear phagocyte systems (MPSs) and, to a lesser extent, in the liver, kidneys, lungs, spleen, lymph nodes, and bone marrow. Iron overload, also known as hemochromatosis, refers to an accumulation of iron within the body and results from a variety of mechanisms (see Chapter 23). In contrast to hemochromatosis, a chronic and systemic disorder, hemosiderosis is a transient, localized deposition of iron. It usually does not result in tissue damage. Transient hemosiderin accumulation within tissues can be seen in bruising where ruptured blood vessels result in RBCs exiting the circulatory system. The RBCs diffuse into tissues surrounding the site of injury. A local hemorrhage (bruise) forms after a contusion. The skin surrounding the site of impact injury first appears red or dark blue, or both, or, in lay terminology, “black and blue” as blood accumulates under the skin. Depending on the nature of the trauma, the color change can be quite profound (deep, blackish blue) and extend over a large area. Over the course of a few days to several weeks, the blue coloration is gradually replaced by characteristic color changes—green, yellow, and brown-

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pigmentation to the skin. The colors reflect the sequential degradation of hemoglobin (red– blue) to biliverdin (green) to bilirubin (yellow) and, finally, to hemosiderin (golden brown) (Fig. 4.22). Eventually the abnormal pigmentation resolves, and the normal skin color returns.

FIGURE 4.22

Hemosiderin Accumulation Is Noted as the Color Changes in a “Black Eye.”

Bilirubin is a normal, yellow-to-green pigment of bile derived from the porphyrin structure of hemoglobin. Excess bilirubin within cells and tissues causes jaundice (icterus), a yellowing of the skin and sclera of eye. Jaundice occurs when the bilirubin level exceeds 1.5 to 2 mg/dL of plasma, compared with the normal values of 0.4 to 1 mg/dL. Hyperbilirubinemia develops because of one of several mechanisms: (1) destruction of RBCs causing hemolytic jaundice; (2) diseases affecting the metabolism and excretion of bilirubin in the liver; and (3) diseases causing obstruction of the common bile duct, such as gallstones or pancreatic tumors. Various drugs can cause the obstruction of normal bile flow through the liver, increasing blood levels of bilirubin.

Calcium Calcium salts accumulate in both injured and dead tissues (Fig. 4.23), a process that results in cellular calcification. An important mechanism for cellular calcification is the influx of extracellular calcium of the mitochondria. Another mechanism involves the excretion of acid leading to the production of hydroxyl ions. These hydroxyl irons precipitate calcium hydroxide (Ca[OH]2) and hydroxyapatite (Ca3[PO4]2)3•Ca(OH)2) into a mixed salt. Injury occurs when clustered calcium salts harden, interfering with normal structure and function of the cell. This process is often identified in the pulmonary alveoli, gastric epithelium, and renal tubules.

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FIGURE 4.23 Free Cytosolic Calcium: A Destructive Agent. Normally, calcium is removed from the cytosol by adenosine triphosphate (ATP)–dependent calcium pumps. In normal cells, calcium is bound to buffering proteins, such as calbindin or parvalbumin, and is contained in the endoplasmic reticulum and the mitochondria. If there is abnormal permeability of calcium ion channels, direct damage to membranes, or depletion of ATP (i.e., hypoxic injury), calcium increases in the cytosol. If the free calcium cannot be buffered or pumped out of cells, uncontrolled enzyme activation takes place, causing further damage. Uncontrolled entry of calcium into the cytosol is an important final common pathway in many causes of cell death.

Dystrophic calcification refers to calcification occurring in dying or necrotic tissues. This form of calcification is commonly noted in chronic pulmonary tuberculosis. Other sites affected include lymph nodes, advanced atherosclerotic cardiovascular plaques, and injured heart valves (Fig. 4.24). Calcification impedes the smooth opening or closing of heart valves and presents clinically as a heart murmur (see Chapter 26). Dystrophic calcification is frequently found in the center of tumors. Over time, necrosis and subsequent calcification occurs in the inner regions of growing tumors as they are progressively deprived of oxygen. Calcium salts appear as gritty, clumped granules that can become stone-like. Psammoma bodies (named for the Greek word denoting “sand”) are laminated, calcified structures, which resemble grains of sand. They are concentric and commonly found within tumors; however the exact mechanism responsible for their formation remains unclear.

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FIGURE 4.24 Aortic Valve Calcification. A, This calcified aortic valve is an example of dystrophic calcification. B, This algorithm shows the dystrophic mechanism of calcification. (A, from Damjanov I: Pathology for the health professions, ed 4, St Louis, 2012, Saunders.)

Metastatic calcification consists of mineral deposits that occur in undamaged, normal tissues secondary to hypercalcemia (excess calcium in the blood). Frequent causes of hypercalcemia include hyperparathyroidism, toxic levels of vitamin D, hyperthyroidism, Addison disease (adrenocortical insufficiency), and excess calcium supplementation. Hypercalcemia can develop secondary to the increased bone demineralization, resulting from bone tumors, leukemia, and disseminated cancers. It also may occur in advanced renal failure with phosphate retention. As phosphate levels increase, the activity of the

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parathyroid gland increases resulting in higher levels of circulating calcium.

Urate In humans, uric acid (urate) is the major end product of purine catabolism. Humans lack the enzyme urate oxidase present in most other mammals. This enzyme is needed to convert uric acid to allantoin. Because urate crystals are not degraded by lysosomal enzymes, they persist in dead cells. Normally, serum urate concentration is stable measuring approximately 5 mg/dL in postpubertal males and 4.1 mg/dL in postpubertal females. With elevated serum urate levels, sodium urate crystals accumulate in tissues, leading to a group of painful disorders collectively called gout. These disorders include acute arthritis, chronic gouty arthritis, tophi (firm, nodular, subcutaneous deposits of urate crystals surrounded by fibrosis), and nephritis (inflammation of the nephron). In all of these disorders, cell injury and inflammation are characteristic findings (see Chapter 41).

Systemic Manifestations of Cellular Injury Dead and injured cells initiate local inflammation and, with more severe injury, cause systemic inflammation. Inflammation promotes systemic manifestations of cellular injury, including fatigue, malaise, altered appetite, and fever. Fever may occur because of endogenous pyrogens (fever-inducing substances) released during the inflammatory response. Table 4.10 summarizes the most significant systemic manifestations of cellular injury. TABLE 4.10 Systemic Manifestations of Cellular Injury Manifestation Fever Increased heart rate Increase in leukocytes (leukocytosis) Pain Presence of cellular enzymes Lactate dehydrogenase (LDH) (LDH isoenzymes) Creatine kinase (CK) (CK isoenzymes) Aspartate aminotransferase (AST/ serum glutamic-oxaloacetic transaminase [SGOT]) Alanine aminotransferase (ALT/ serum glutamic pyruvic transaminase [SGPT]) Alkaline phosphatase (ALP) Amylase Aldolase

Cause Release of endogenous pyrogens (interleukin-1, tumor necrosis factor-α, prostaglandins) from bacteria or macrophages; acute inflammatory response Increase in oxidative metabolic processes resulting from fever Increase in total number of white blood cells because of infection; normal is 5000–9000/mm3 (increase is directly related to severity of infection) Various mechanisms, such as release of bradykinins, obstruction, pressure Release of enzymes from cells of tissue* in extracellular fluid Release from red blood cells, liver, kidney, skeletal muscle Release from skeletal muscle, brain, heart Release from heart, liver, skeletal muscle, kidney, pancreas Release from liver, kidney, heart Release from liver, bone Release from pancreas Release from skeletal muscle, heart

*The

rapidity of enzyme transfer is a function of the weight of the enzyme and the concentration gradient across the cellular membrane. The specific metabolic and excretory rates of the enzymes determine how long levels of enzymes remain elevated.

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Cellular Death With sufficient structural or physiologic damage, cell injury becomes irreversible and cells die. Historically, cell death has been attributed to either necrosis or apoptosis (Fig. 4.25 and Table 4.11). Necrosis is a form of cell destruction characterized by rapid loss of plasma membrane structure, swelling of organelles, mitochondrial dysfunction, and the lack of typical features of apoptosis.30 Apoptosis is known as a regulated or programmed cell process discussed below. Until recently, necrosis was considered passive or accidental, occurring after severe and sudden injury. It is now understood that necrosis can be driven by regulated or programmed molecular pathways. Hence the new term is programmed necrosis, or necroptosis.

FIGURE 4.25 Schematic Illustration of the Morphologic Changes in Cell Injury Culminating in Necrosis or Apoptosis. Myelin figures come from degenerating cellular membranes and are noted within the cytoplasm or extracellularly. (From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

TABLE 4.11 Features of Necrosis and Apoptosis

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Features of Necrosis and Apoptosis Feature Cell size Nucleus Plasma membrane Cellular contents Adjacent inflammation Physiologic or pathologic role

Necrosis Apoptosis Enlarged (swelling) Reduced (shrinkage) Pyknosis → karyorrhexis → Fragmentation into nucleosome-size fragments karyolysis Disrupted Intact; altered structure, especially orientation of lipids Enzymatic digestion; may leak out of cell Frequent

Intact; may be released in apoptotic bodies

Invariably pathologic (culmination of irreversible cell injury)

Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially deoxyribonucleic acid (DNA) damage

No

From Kumar V et al: Cellular responses to stress and toxic insults: adaptation, injury, and death. In Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.

Necrosis Cellular death leads to necrosis, the dissolution of cellular components. Necrosis is the sum of cellular changes occurring after local cell death. It is characterized by autolysis or autodigestion, a process of cellular self-digestion (see Fig. 4.25). Cellular death is initiated long before any necrotic changes can be detected by light microscopy.31 Dense clumping of nuclear material and the progressive disruption of plasma and organelle membranes portend irreversible injury, and necrosis follows. As membrane integrity is lost, necrotic cell contents leak into the surrounding intracellular spaces, where they trigger an inflammatory response within the tissue. In the later stages of necrosis, when most organelles are disrupted, karyolysis (enzymatic hydrolysis of nuclear chromatin) is well underway. In some cells, pyknosis, a process where the nucleus shrinks into a small, dense mass of genetic material, occurs. Eventually, lysosomal enzymes break up the pyknotic nucleus. Karyorrhexis is fragmentation of the nucleus into small particles or “nuclear dust.” Different types of necrosis tend to occur in different organs or tissues, sometimes indicating the mechanism or cause of cellular injury. The four major forms of necrosis are coagulative, liquefactive, caseous, and fatty (Fig. 4.26). Another form, gangrenous necrosis, is not a distinctive type of cell death but, instead, refers to large areas of tissue death. These forms of necrosis occur mostly in the kidneys, heart, and adrenal glands. Necrosis commonly results from hypoxia secondary to severe ischemia or chemical injury. Necrosis also is particularly common after the ingestion of mercuric chloride.

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FIGURE 4.26 Types of Necrosis. A, Coagulative necrosis of myocardium of posterior wall of left ventricle of heart. A large anemic (white) infarct is readily apparent; note also the necrosis of papillary muscle. B, Liquefactive necrosis of the brain. The area of infarction is softened as a result of liquefactive necrosis. C, Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris. D, Fat necrosis of pancreas. Interlobular adipocytes are necrotic; these are surrounded by acute inflammatory cells. (A and D, from Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby. B, from Damjanov I: Pathology for the health professions, ed 5, St Louis, 2016, Saunders. C, from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

Coagulative necrosis occurs as a result of protein denaturation, where albumin is transformed from a gelatinous, transparent state into a firm, opaque substance (see Fig. 4.26, A). The area of coagulative necrosis is called an infarct. Liquefactive necrosis commonly results from ischemic injury to neurons and glial cells in the brain (see Fig. 4.26, B). Dead brain tissue is readily subjected to liquefactive necrosis because brain cells are rich in digestive hydrolytic enzymes and lipids. Additionally the brain contains little connective tissue. Cells are digested by their own hydrolases as the tissue becomes soft and liquefied. In response, cysts form segregating this material from healthy tissue. Liquefactive necrosis is often triggered by bacterial infection, especially staphylococci, streptococci, and Escherichia coli. Caseous necrosis commonly results from pulmonary tuberculosis or infection caused by Mycobacterium tuberculosis (see Fig. 4.26, C). It combines elements of both coagulative and liquefactive necrosis. Dead cells disintegrate, but the debris is not completely hydrolyzed. Instead a granulomatous inflammatory response ensues. Soft and granular tissues form the

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end-product, resembling clumped cheese. An inflammatory wall encloses the areas of caseous necrosis forming the characteristic granulomas of pulmonary tuberculosis (see Chapter 29). Fatty necrosis is cellular dissolution caused by lipases, potent enzymes found in the breast and abdominal structures, especially within the pancreas (see Fig. 4.26, D). Lipases break down triglycerides, releasing free fatty acids. The fatty acids combine with calcium, magnesium, and sodium ions creating soaps, a process known as saponification. The necrotic tissue formed appears opaque and chalky white. Gangrenous necrosis refers to tissue death but does not denote a specific pattern of cell death. It results from severe hypoxic injury, commonly secondary to the blockage of major arterial vessels supplying a region of the body. Gangrenous necrosis is particularly common with severely compromised circulation of the lower leg, either from acute or chronic disorders. With hypoxia, bacterial invasion, which enters a wound, can readily result in gangrenous necrosis. Dry gangrene typically results from coagulative necrosis. The skin becomes very dry and shriveled, and skin coloration in such cases is brown or black. Wet gangrene, the more lethal form, develops secondary to necrotizing bacterial infections, particularly infection with gram-positive cocci, gram-negative rods, or anaerobic microorganisms, especially Clostridium spp. These microorganisms invade the site, causing a liquefactive necrosis. Wet gangrene causes the affected tissues to become cold, swollen, and black, and a foul odor is present. Wet gangrene also can affect internal organs, usually secondary to hypoxia. The presentation is similar regardless of the site involved. Wet gangrene is an aggressive disorder, which spreads rapidly to surrounding tissue. Left untreated, it rapidly can progress to death. Gas gangrene refers to a type of wet gangrene caused by tissue infection with Clostridium spp., most commonly Clostridium perfringens. These microorganisms are widely present in soil and proliferate under conditions of low oxygen tension. Deep puncture wounds from soil-contaminated objects are common sources of infection. Once established at the site of infection, the microorganisms produce hydrolytic enzymes and toxins, which destroy tissue and cause bubbles of gas to form in the affected region. The infection progresses rapidly, spreading to adjacent tissue. Untreated, death typically occurs within 12 hours secondary to overwhelming sepsis, shock, and renal shutdown

Apoptosis Apoptosis (“dropping off”) is a distinct type of cell death that differs from necrosis in several ways (see Fig. 4.25 and Table 4.11). Apoptosis is an active process of cellular selfdestruction, resulting in programmed cell death. It has been implicated in both normal and pathologic tissue changes. Cells die as a part of a normal physiologic process. Were it otherwise, endless cell proliferation would result in large and unwieldy anatomy. In the average adult, 10 billion new cells may be created every day, and the same number of cells are destroyed daily. Death by apoptosis also causes loss of cells in many pathologic states, including the following:

• Severe cell injury: When cell injury exceeds the capacity for repair mechanisms, cell signaling triggers apoptosis. • Accumulation of misfolded proteins: This condition results from 267

either genetic mutations or free radicals. Excessive accumulation of misfolded proteins in the ER leads to a condition known as endoplasmic reticulum stress (ER stress) (see Chapter 1). ER stress culminates in cell death secondary to apoptosis. This mechanism has been linked to several degenerative diseases of the CNS and other organs (Fig. 4.27).

FIGURE 4.27 The Unfolded Protein Response, Endoplasmic Stress, and Apoptosis. A, In normal or healthy cells the newly made proteins are folded with help from chaperones and then incorporated into the cell or secreted. B, Various stressors can cause endoplasmic reticulum (ER) stress whereby the cell is challenged to cope with the increased load of misfolded proteins. The accumulation of the protein load initiates the unfolded protein response in the ER; if restoration of the protein fails, the cell dies by apoptosis. An example of a disease caused by misfolding of proteins is Alzheimer disease. (From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

• Infections (particularly viral infections): Apoptosis may be the result of the host's immune response to the presence of a virus infecting the cell. Cytotoxic T lymphocytes respond to viral infections by inducing apoptosis, thus eliminating infectious cells. This process, however, can result in tissue damage. The same mechanism can result in cell death in tumor-related disease and organ transplant rejection. • Obstruction in tissue ducts: Obstruction of blood flow to an 268

organ results in pathologic atrophy, a process commonly noted in the pancreas, kidney, or parotid gland. Excessive or insufficient apoptosis is known as dysregulated apoptosis. A low rate of apoptosis can encourage survival of abnormal cells, particularly mutated cells, which predispose the individual to developing cancer. Similarly, defective apoptosis may fail to eliminate lymphocytes implicated in attacking host tissue (self-antigens), thus leading to autoimmune disorders. Excessive apoptosis occurs in several neurodegenerative diseases and with ischemic injury, such as with myocardial infarction and stroke, and in the context of virus-infected cells. Initiation of apoptosis requires tightly regulated cell signaling. Key components involve proteases, enzymes that divide other proteins. Caspases are a family of aspartic acid– specific enzymes that trigger proteolytic activity in response to signals, which induce apoptosis. Specifically, activated caspases cleave other proteins within the system, initiating a series of sequential reactions known as the “suicide” cascade. The cascade results in a rapid and contained cell death. Caspase activation triggers two different but convergent pathways: the mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway (Fig. 4.28). Cells undergoing apoptosis release chemical factors, which recruit phagocytes. The phagocytes quickly engulf cellular remnants, reducing their potential to induce damaging inflammation. Cell death secondary to necrosis is less contained because injured cells swell and burst spilling their contents into the extracellular spaces, triggering an inflammatory response.

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FIGURE 4.28 Mechanisms of Apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of “executioner” caspases. The induction of apoptosis by the mitochondrial pathway involves the Bcl-2 family, which causes leakage of mitochondrial proteins. The regulators of the death receptor pathway involve the proteases, called caspases. (Adapted from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)

Autophagy The Greek term autophagy means “eating of self.” Autophagy is a “recycling factory” as well as a survival mechanism. It is a self-destructive process that delivers cytoplasmic contents to the lysosome for degradation. Box 4.3 includes terminology used to describe autophagy.

Box 4.3

The Major Forms of Autophagy 270

Macroautophagy, the most common term to refer to autophagy, involves the sequestration and transportation of parts (cargo) of the cytosol in an autophagic vacuole (autophagosome). Microautophagy is the inward invagination of the lysosomal membrane for cargo delivery. Chaperone-mediated autophagy is the chaperone-dependent proteins that direct cargo across the lysosomal membrane. When cells are starved or nutrient deprived, autophagy initiates a “cannibalization response,” which digests the cell and recycles the contents. Autophagy can maintain cellular metabolism under conditions of starvation. Under conditions of stress, autophagy removes damaged organelles, thus enhancing the likelihood of survival. Autophagy also has been implicated in cancer, heart disease, neurodegeneration diseases, inflammation, and infection.32 Although somewhat controversial, the process is thought to begin with a cup-shaped, curved membrane known as a phagophore (Fig. 4.29). This membrane expands and engulfs intracellular contents—organelles, ribosomes, and proteins—forming a double membrane autophagosome. The autophagosome fuses with the lysosome, forming an autophagolysosome. Lysosomal acid proteases then degrade the autophagosome into amino acids and other elemental substances. These end-products are transported out of the cytoplasm, where they are subsequently utilized for the synthesis of macromolecules or for fueling metabolism.

FIGURE 4.29 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes that create vacuoles in which cellular organelles are sequestered and

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then degraded following fusion of the vesicles with lysosomes. The digested materials are recycled to provide nutrients for the cell. (Adapted from Mexcelom Bioscience Collometer.)

Autophagy holds promise for formulating new therapeutic strategies in treating disease. Evidence also suggests that autophagy may be the last immune defense against infectious microorganisms that have invaded the intracellular environment.33 The “garbage collecting” and recycling functions, characterizing autophagy, becomes less efficient and less discriminating in aging individuals. Consequently harmful agents accumulate and cause increasing cell damage as people age. Failure to clear protein products in neurons of the CNS has been linked with dementia. Similarly failure to clear mitochondria, which generates ROS, can lead to nuclear DNA mutations and cancer. These processes may even partially define normal aging. Enhancing autophagy may serve to decrease the incidence of cancer and prevent the development of particular degenerative diseases.

Quick Check 4.4 1. Why is an increase in the concentration of intracellular calcium injurious? 2. Compare and contrast necrosis and apoptosis. 3. Why is apoptosis significant? 4. Autophagy may become less efficient with aging. Why is this harmful?

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Aging and Altered Cellular and Tissue Biology Aging is defined as a normal physiologic process, which is universal and inevitable. Life span is the period from birth to death and its study offers insight into the aging process. Aging is associated with a gradual loss of homeostatic mechanisms. It is a complex process involving a multiplicity of factors; however the underlying cause of aging is not entirely clear. Investigators have focused on genetic, inflammatory, oxidative, and metabolic parameters of aging. Active investigation includes the study of genetic signatures in humans with exceptional longevity. Current research is focused on epigenetic mechanisms that modulate gene expression and the role of intrauterine environment. Lifelong patterns of health, the effects of personality, behavioral patterns, and social support also are thought to be relevant. Investigators have studied the influence of biochemical factors believed to impact aging, particularly the role of insulin and insulin-like growth factor 1 (IGF-1) signaling on senescence; mitochondrial dysfunction; and an inflammatory microenvironment leading to chronic disease, frailty, and decreased lifespan. Coagulation is part of the inflammatory response and may be responsible for thickening (hypercoagulable) blood with aging leading to arterial and venous clot formation in the elderly. The microbiota plays a role in the induction of the immune system, adaptive immunity declines with age, and innate immunity may result in mild hyperactivity.34 Senescence is a process leading to permanent proliferative arrest of cells in response to various stressors. Senescent cells accumulate with time and contribute to tissue dysfunction. A recent study in immune factors in identical twins found increasing differences between identical twins, suggesting the influence of nonheritable factors or environmental factors.35 Diet is believed to play a major role on both the development and the prevention of age-related diseases. A major research challenge has been to separate the causes of cell and tissue aging from the changes that characterize it. Understanding the physiology of aging supports public health efforts to promote healthy aging and delay the progression to vulnerability and frailty. Traditionally aging has not been considered a disease; rather it has been regarded as a normal process. Disease has been defined as deviation from the normal state secondary to injury or abnormal function. Conceptually this distinction has been clear; however issues involving cellular injury or damage challenge traditional views. Life span can be altered in animals. But extending life span is not equivalent to delaying aging.36 For example, death can be prevented through treatment of an acute infection, but the rate of aging continues. What is critical is extending a person's health span, which results in an increase in life span and a decrease in time spent in a frail state.37 The passage of time cannot be stopped (chronologic aging), but it may be possible to delay the decline in health, or biologic aging. Table 4.12 presents degenerative changes, cellular changes, and tissue and systemic aging. TABLE 4.12 Aging: Degenerative Extracellular Changes, Cellular Changes, and Tissue and Systemic Aging Degenerative extracellular changes

Binding of collagen; increase in free radicals; alterations of tendons, ligaments, bones and joints; development of peripheral vascular disease, particularly, arteriosclerosis Extracellular matrix with increased cross-linking, decreased synthesis, and increased degradation of

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Cellular aging

Tissue and Systemic Aging

collagen Oxidative stress damages cellular function Development of cardiovascular diseases with endothelial cell shifts to proinflammatory, proproliferative, and procoagulative state Atrophy, decreased function, loss of cells possibly by apoptosis Compensatory mechanisms of hypertrophy and hyperplasia can lead to metaplasia, dysplasia, and neoplasia deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and cellular proteins and membranes susceptible to injuries Lack of DNA repair leads to increase in mutations Increased production of reactive oxygen species (ROS) Cumulative damage to mitochondrial DNA (mtDNA) Progression of common diseases (diabetes, cancer, heart failure Progressive stiffness or rigidity affects many systems (arterial, pulmonary, musculoskeletal) Peripheral resistance to blood flow Thymus atrophy occurs at puberty causing a decreased response to T-dependent antigens (foreign proteins), increased formation of autoantibodies and immune complexes decreasing effectiveness of immune function later in life Reproductive system loss of ova and spermatogenesis decreased in men Responsiveness to hormones decreases in the breast and endometrium Stomach decreases in the rate of emptying and secretion of hormones and hydrochloric acid Muscular atrophy decreases motor tone and contractility Sarcopenia or loss of muscle mass and strength Decrease in height Reduction in circumference of the neck, thighs, and arms; widening of the pelvis; lengthening of the nose and ears Increase in body weight in middle age followed by a decrease in stature, weight, fat-free mass, and body mass As the amount of fat increases, the percentage of total body water decreases. Increased body fat distribution (abdominal) is associated with non-insulin-dependent diabetes and heart disease. Total body potassium concentration decreases

Studies have suggested the possibility of altering the “aging clock” by changing the cell's differentiation program. Causes of aging may be largely epigenetic or influences on gene expression.

Normal Life Span and Life Expectancy The maximal life span of humans is 80 to 100 years, and it does not vary significantly among populations. Life expectancy is the average number of years of life remaining at a given age (Box 4.4).

Box 4.4

Life Expectancy Differences Across the United States • Improved public health strategies and health advances in the United States between the years 1900 and 2000 added about 30 years to life expectancy • The increase in life expectancy, however, does not apply to all Americans. • Women outnumber men in each successive age group from 65 years and older. • The historic advances in life expectancy resulted in a larger older adult population and, for some, problems of disability, disease, and socioeconomic hardship. • Although U.S. spending on health care far exceeds that of other countries, rates of life

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expectancy and key measures of health lag behind those of other high-income countries. • The National Center for Health Statistics has reported that Americans, on average, have a life expectancy of 78.8 years, a decline from 78.9 in 2014. • The decline in life expectancy is attributed to rising fatalities from heart disease and stroke; diabetes; drug overdoses; accidents, including unintentional injuries; and other conditions. • Chronic health problems associated with modifiable risk factors, such as smoking, poor nutrition, overweight, and lack of physical activity, represent 6 of the 10 costliest in terms of health care burden. • The preventable conditions lead to injuries and diseases and cause soaring medical and labor costs that burden U.S. employers and bankrupt families. • All of these conditions are highly amenable to population-based preventive strategies. • The current generation of children and young adults in the United States could become the first generation to have shorter life spans, multiple medical conditions, and fewer years of healthy life.

Frailty Frailty, a common clinical syndrome in older adults, is characterized by overall weakness, decreased stamina, and functional decline. The individual is susceptible to falls, disability, disease, and death. This presentation is often described as frailty syndrome. Criteria indicating compromised functioning include low grip strength, slowed walking speed, low physical activity, and unintentional weight loss.38 The pathophysiology of frailty includes several interrelated physiologic systems (Fig. 4.30). It is complex, with multiple aging mechanisms influenced by genetic factors, epigenetic factors, or both, as well as environmental factors. Frailty also can involve such alterations as osteopenia, cognitive impairment, and anemia. Differences between men and women in presentation include the following: (1) Higher baseline levels of muscle mass in men may be protective against frailty; (2) testosterone and growth hormone can provide advantages to men in muscle mass maintenance; (3) cortisol is more dysregulated, especially in older women; (4) alterations in immune function and immune responsiveness to sex steroids make men more susceptible to sepsis and infection and make women more susceptible to chronic inflammatory conditions and loss of muscle mass; and (5) lower levels of activity and caloric intake may increase the risk of frailty in women. Sarcopenia and cachexia are common sequelae of aging and also occur secondary to many chronic illnesses.

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FIGURE 4.30 Frailty. Frailty is a disorder of multiple interrelated physiologic systems. A gradual decline progresses with aging, but in frailty this decline becomes accelerated. Homeostatic mechanisms begin to fail, and vulnerability becomes disproportionate to changes in health status after a relatively minor stressor event. (From Clegg A et al: Frailty in elderly people, Lancet 381[9868]:752–762, 2013.)

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Somatic Death Somatic death is systemic death of the entire body. Unlike the changes that follow cellular death, postmortem change is diffuse and does not involve an inflammatory response. Within minutes after death, postmortem changes appear, and it becomes readily evident that death has occurred. The most immediate manifestations are the complete cessation of respiration and circulation, followed rapidly by a host of other changes. The surface of the skin becomes pale and yellowish, marking the first stage after death known as pallor mortis. In instances of death secondary to carbon monoxide poisoning, drowning, or chloroform poisoning, this phenomenon may not be apparent; instead, a lifelike coloration of the cheeks and lips may persist even after death has occurred.39 The second stage after death, algor mortis, is defined as a decrease in body temperature after death. Body temperature falls gradually, immediately after death, then decreases more rapidly (approximately 1.0° F–1.5° F/hr) until body temperature equals environmental temperature.40 In cases of death caused by certain infective diseases, body temperature may transiently rise for a short time. The third stage after death, rigor mortis, is characterized by stiffening of muscles. Within 6 hours after death, acidic compounds accumulate within the muscles secondary to degradation of carbohydrates and the depletion of ATP. With lack of ATP, the detachment of myosin from actin (contractile proteins) fails, resulting in muscle rigidity. The smaller muscles are usually affected first, particularly the muscles of the jaws. Many factors affect the onset of rigor mortis, which begins 0 to 8 hours after death and peaks at approximately 8 to 12 hours from onset. The body remains stiff for another 12 to 24 hours, after which the rigor begins to dissipate with muscle flexibility returning after 24 to 36 hours. Livor mortis is the fourth stage after death. Gravity causes blood to settle in dependent (anatomically low areas) tissues, resulting in a prominent blue-purple discoloration of the skin over these regions. During this stage, blood pressure within the retinal vessels decreases, causing muscle tension to decrease and the pupils to dilate. The face, nose, and chin become sharp or peaked-looking as blood and fluids drain from these areas.39 The process begins immediately after death but is not readily apparent to the human eye until 2 hours after death. It reaches a maximum peak 8 to 12 hours after death. Incisions made during this time frame usually will not cause bleeding. The skin loses elasticity and transparency. Appreciation of the changes that occur during this stage is very useful to forensic pathologists because it enables them to determine the approximate time of death and whether the body has been moved or repositioned. Putrefaction is the fifth stage after death when tissues and organs of the body lose cohesiveness as they break down into gaseous and liquid matter. This process is largely driven by the action of bacteria present both within the body and in the external environment. Visible signs of putrefaction are generally obvious about 24 to 48 hours after death. The rate at which putrefactive changes occur varies, depending on the environmental temperature surrounding the body. Changes will occur more rapidly in warm environments (e.g., hot summer days or nights). Putrefaction occurs most rapidly in ambient air. The rate is sequentially slower in water and earth. The first sign is usually a greenish discoloration of the skin, particularly over the abdomen. Discoloration is thought to occur because of the diffusion of hemolyzed blood into tissues and the production of

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denatured hemoglobin derivatives. Slippage or loosening of the skin from underlying tissues occurs during this phase. Black discoloration to the tissues follow, and gases with characteristic noxious odors are released. As the process progresses, gas builds within body structures resulting in swelling or bloating. Gas buildup will eventually lead to bursting of organs and body cavity openings. Liquefactive changes occur as internal organs begin to liquefy. Decomposition is the sixth stage after death. It occurs when the organic matter of the body is broken down into elemental matter and recycled into the earth's biosphere. The body's own enzymes and chemicals drive this process. Putrification may be ongoing simultaneously. Skeletonization, the seventh and final stage after death, occurs when the various tissues of the body have degraded and decayed to the point of exposing the skeleton. When all of the organic matter of the body is gone, the process is complete, and only disarticulated bones will remain. Depending on the environment surrounding the skeleton, bones can persist for periods lasting from several years to relatively indefinitely. Under rare circumstances, an eighth stage, fossilization, may occur. At this stage, the bones are infiltrated and replaced with inorganic mineral deposits. If this process transpires, the fossilized bones will have the permanence of rocks, thus accounting for many museum specimens. Fossilization is uncommon and only occurs under select and relatively unusual environmental conditions.

Quick Check 4.5 1. Aging is a complex process. Discuss the many mechanisms of aging. 2. What are the body composition changes that occur with aging? 3. Define frailty and possible endocrine–immune system involvement.

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Summary Review Cellular Adaptation 1. Cellular adaptation is a reversible event involving a structural or functional response to both physiologic (normal) conditions and to pathologic (adverse) conditions. Cells adapt to meet physiologic demands and stress in an effort to maintain a steady state called homeostasis. 2. The most significant adaptive changes include atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia. 3. Atrophy is a decrease in cellular size caused by aging, disuse, or insufficient blood supply. Insufficient hormonal or neural stimulation also can cause atrophy. Endoplasmic reticulum, mitochondria, and microfilaments decrease with atrophy. Mechanisms predisposing the cell to atrophy include decreased protein synthesis or increased protein catabolism, or both. 4. Hypertrophy is an increase in the size of cells in response to mechanical stimuli (e.g., stretching, pressure, or volume overload) and results in increased size of the affected organ. Hypertrophy can be either physiologic or pathologic, depending on the circumstances. 5. Hyperplasia is an increase in the number of cells caused by an increased rate of mitosis (cell division). Hyperplasia can be physiologic (compensatory and hormonal) or pathologic hormonal. 6. Metaplasia is the reversible replacement of one mature cell type with another less mature cell type. It is found in association with tissue damage, repair, and regeneration. 7. Dysplasia, or atypical hyperplasia, is an abnormal change in the size, shape, and organization of mature tissue cells. It is considered an atypical rather than a true adaptation response.

Cellular Injury 1. Injury to cells and to the extracellular matrix leads to tissue and organ injury. This injury affects the structural patterns of disease. Cellular injury occurs when the cell fails to maintain homeostasis (normal or adaptive steady state) secondary to insult or stress. Injured cells may recover (reversible injury) or die (irreversible injury). 2. Biochemical events result in characterize cell injury and death, including: (1) ATP depletion, resulting in mitochondrial damage; (2) accumulation of oxygen and radical oxygen species (ROS) which cause membrane damage;(3) increased intracellular calcium concentration and the loss of calcium steady state; (4) mitochondrial damage causing loss of membrane potential and activation of cell death; (5) membrane damage; and (6) protein folding defects. 3. The most common forms of cell injury include ischemic and hypoxic injury, ischemia-reperfusion injury, oxidative stress or accumulation of oxygen-derived free radical-induced injury, and chemical injury. 4. Hypoxia is the lack of sufficient oxygen in cells and is the most common cause of

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cellular injury. The most common cause of hypoxia is ischemia, or a reduced supply of blood. 5. Restoration of oxygen in ischemic states can result in additional injury, called reperfusion injury. The mechanisms for such injury include oxidative stress, increased intracellular calcium concentration, inflammation, and complement activation. 6. Free radicals have an unpaired electron making the molecule unstable. Seeking stability, they may form chemical bonds with proteins, lipids, and carbohydrates located within membranes and nucleic acids (DNA), causing injury. The damaging effects of free radicals is termed oxidative stress. Mechanisms include (1) peroxidation of lipids, (2) alteration of ion pumps and transport mechanisms, (3) fragmentation of DNA, and (4) damage to mitochondria, releasing calcium into the cytosol. 7. Humans are exposed to thousands of chemicals for which there is inadequate toxicologic data. Potential mechanisms for injury include oxidative stress, heat shock proteins, DNA damage, hypoxia, ER stress, mental stress, inflammation, and osmotic stress. 8. The world's largest single environmental health risk is air pollution. Millions of deaths and diseases occur because of indoor and outdoor air pollution. 9. The most common heavy metals associated with cell injury include lead, mercury, arsenic, and cadmium. Damage from metals affects DNA repair mechanisms, tumor suppressor functions, and signal transduction pathways. 10. Alcohol contributes to cell injury by altering nutritional status, causing the metabolism of acetaldehyde (toxic and known carcinogen), and effecting the liver, CNS, and other body tissues. Chronic alcoholism and binge drinking have significant health hazards including alcoholic liver disease, cirrhosis, and hepatocellular carcinoma. 11. Fetal alcohol spectrum disorders are a range of health effects or disorders of prenatal alcohol exposure. Maternal ingestion of alcohol can be catastrophic for the developing fetus. 12. The use of psychoactive and narcotic drugs is a major problem in many parts of the world. Both prescription and illicit opiates are the main causes of drug overdose deaths. 13. Unintentional and intentional injuries are a major health problem in the United States. Death as a result of these injuries is more common for men than women and there are differences among ethnic/racial groups. 14. Injuries by blunt force are the result of the application of mechanical energy to the body, resulting in tearing, shearing, or crushing of tissues. These include contusions (bruises), lacerations (tears or rips in the skin), and fractures of bone. The most common causes of blunt-force injuries include motor vehicle accidents and falls. 15. Injuries by sharp force are the result of cutting or piercing. Examples of this include incised, stab, puncture, and chopping wounds. 16. Gunshot wounds may be either penetrating (bullet is retained in the body) or perforating (bullet exits the body). The most important factors determining the appearance of a gunshot injury are whether it is an entrance or an exit wound and the range at which the bullet was fired.

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17. Asphyxial injuries are caused by mechanisms that prevent oxygen from entering the body and reaching the cells. These injuries can be grouped into four general categories: suffocation, strangulation, chemical asphyxiation, and drowning. 18. Activation of inflammation and immunity that follows cell injury or infection produces powerful biochemical reactions and proteins capable of damaging normal cells. 19. Genetic disorders result in cellular injury by altering the nucleus and the plasma membrane (structure, shape, receptors, or transport mechanisms). 20. Deprivation and excessive consumption of essential nutrients (proteins, carbohydrates, lipids, vitamins) can result in cellular injury by altering cellular structure and function. 21. Environmental factors can result in cellular injury. Common triggers include temperature extremes, changes in atmospheric pressure, ionizing radiation, illumination, mechanical stresses, and excessive noise.

Manifestations of Cellular Injury 1. Metabolic derangements can trigger cellular injury, especially cellular accumulations. Intracellular accumulation of substances is called infiltration. Infiltrations include (1) excess accumulation of normal cellular substances (water, proteins, lipids, and carbohydrate excesses), and (2) concentration or accumulation of abnormal substances which can be either endogenous (produced within the body, such as from abnormal metabolism) or exogenous (derived from outside the body, like a virus). 2. Most accumulations occur secondary to one of four mechanisms: (1) a normal substances that is insufficiently removed due to altered transport; (2) an abnormal substance, often secondary to a gene mutation, accumulates; (3) an endogenous substance that is inadequately catabolized; and (4) an inhaled or ingested harmful exogenous substance accumulates or is produced secondary to an infection. 3. Protein accumulations injure cells by “crowding” the organelles and producing potentially harmful metabolites. Metabolites are released into the cytoplasm or expelled in the extracellular matrix. They may be abnormal substances or normal metabolites produced in excessive amounts. 4. Oncosis is a type of cell death that occurs secondary to cellular swelling with water. It is seen in many types of cellular injury and occurs as a result of a failure of the transport mechanisms to regulate water flow into and out of the cell. 5. Certain metabolic disorders result in abnormal intracellular accumulations of carbohydrates and lipids, primarily in the spleen, liver, and CNS. 6. Glycogen (the storage form of glucose) is an important source of energy in normal cell function, but intracellular accumulations of it can have detrimental effects on growth and development. 7. Protein accumulations primarily occur in epithelial cells of renal convoluted tubules and in the antibody B-lymphocytes. 8. Pigment accumulations can be endogenous (e.g., melanin and blood proteins) or exogenous (e.g., coal dust and other mineral dusts). 9. Dystrophic calcification is the accumulation of calcium salts in injured or dead cells,

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and is a sign of pathologic change. Metastatic calcification occurs in uninjured cells secondary to hypercalcemia. 10. Gout, a very common and painful disorder, results from disturbances in urate metabolism. It occurs secondary to hyperuricemia where sodium urate crystals are deposited into tissues. 11. Systemic manifestations of cellular injury initiate inflammation with associated manifestations, including fever, leukocytosis, increased heart rate, pain, and serum elevations of plasma enzymes. 12. Inflammation promotes systemic manifestations of cellular injury, including fever, fatigue, malaise, pain, altered appetite, increased heart rate, increased number of leukocytes, or the presence of cellular enzymes.

Cellular Death 1. Historically, cell death has been classified as either necrosis or apoptosis. Necrosis is characterized by a rapid loss of the plasma membrane structure, organelle swelling, mitochondrial dysfunction, and the lack of any hallmark features of apoptosis. Apoptosis is known as regulated or programmed cell death and is characterized by the “dropping off” of cellular fragments, called apoptotic bodies. 2. It is now understood that under certain conditions, necrosis is regulated or programmed, hence, the new term programmed necrosis or necroptosis. 3. There are four major types of necrosis: coagulative, liquefactive, caseous, and fatty. Different types of necrosis occur in different tissues and under differing disease circumstances. 4. Gangrenous necrosis, or gangrene, is not a type of cell death but rather refers to large areas of tissue death. It is tissue necrosis caused by hypoxia and subsequent infection with anaerobic bacteria. 5. Structural signs which indicate irreversible injury with subsequent progression to necrosis are (1) dense clumping and disruption of nuclear genetic material and (2) disruption of plasma and organelle membranes. 6. Apoptosis is a distinct type of selective cellular self-destruction that occurs in both normal and pathologic tissue changes. Death by apoptosis results in the loss of cells and occurs in many pathologic states: (1) severe cell injury, (2) accumulation of misfolded proteins, (3) infections, and (4) obstruction in tissue ducts. 7. Excessive or insufficient apoptosis is known as dysregulated apoptosis. 8. Autophagy, defined as the “eating of self,” is a self-destructive process. It serves as a survival mechanisms and has been compared to a “recycling factory.” When cells are starved or nutrient deprived, autophagy initiates cannibalization to recycle digested contents. Autophagy can maintain cellular metabolism under conditions of starvation and can remove damaged organelles under stress conditions. Autophagy declines and becomes less efficient as cells age, a dynamic, which contributes to the aging process.

Aging and Altered Cellular and Tissue Biology 1. It is difficult to distinguish physiologic (normal) from pathologic (abnormal)

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changes associated with aging. Investigators are focused on genetic, inflammatory, oxidation, and metabolic origins of aging. 2. Important factors in aging include increased damage to cells, reduced capacity for mitosis, reduced ability to repair DNA damage, and defective nitrogen balance. 3. Frailty is a common clinical syndrome in older adults characterized by overall weakness, decreased stamina, and functional decline. This leaves the individual vulnerable to falls, functional decline, disability, disease, and, eventually, death. Sarcopenia and cachexia are common sequela of aging.

Somatic Death 1. Somatic death is death of the entire organism. Postmortem changes are diffuse, predictable, and do not involve an inflammatory response. 2. Manifestations of somatic death are progressive, occurring in a sequenced manner. Death typically begins with the cessation of respiration and circulation and characteristic dilation of the pupils and culminates with the skeletonization of the body. The seven stages of death are (1) pallor mortis, (2) algor mortis, (3) rigor mortis, (4) livor mortis, (5) putrefaction, (6) decomposition, and (7) skeletonization. 3. Depending on the environment surrounding the bones, a rare eighth stage, fossilization, may occur.

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Key Terms Adaptation, 73 Aging, 104 Albinism, 97 Algor mortis, 106 Ambient particulate matter, 85 Anoxia, 78 Antioxidant, 83 Apoptosis, 102 Asphyxial injury, 91 Atrophy, 74, 74 Autolysis, 100 Autophagic vacuole, 74 Autophagy, 103 Bilirubin, 97 Binge drinking, 89 Biotransformation, 83 Callus, 75 Carbon monoxide (CO), 93 Caseous necrosis, 101 Caspase, 103 Cellular accumulation (infiltration), 94 Cellular swelling, 95 Chemical asphyxiant, 93 Choking asphyxiation, 92 Coagulative necrosis, 100 Compensatory hyperplasia, 75 Cyanide, 93 Cytochrome, 97 DNA damage, 80 Decomposition, 106 Disuse atrophy, 74 Drowning, 93 Dry-lung drowning, 93 Dysplasia (atypical hyperplasia), 74, 76 Dystrophic calcification, 98 Endoplasmic reticulum stress (ER stress), 102 Ethanol, 86 Fatty necrosis, 101 Ferritin, 97 Fetal alcohol spectrum disorder (FASD), 89 Fetal alcohol syndrome (FAS), 89 Fossilization, 107 Frailty, 105

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Frailty syndrome, 105 Free radical, 79 Gangrenous necrosis, 101 Gas gangrene, 102 Gout, 99 Hanging strangulation, 92 Hemochromatosis, 97 Hemoprotein, 97 Hemosiderin, 97 Hemosiderosis, 97 Hormonal hyperplasia, 75 Hydrogen sulfide, 93 Hyperplasia, 74, 75 Hypertrophy, 74, 75 Hypoxia, 77 Infarct, 100 Irreversible injury, 77 Ischemia, 77 Ischemia-reperfusion injury (reperfusion [reoxygenation] injury), 78 Karyolysis, 100 Karyorrhexis, 100 Lead (Pb), 85 Life expectancy, 105 Life span, 104 Ligature strangulation, 92 Lipid peroxidation, 80 Lipofuscin, 75 Liquefactive necrosis, 100 Livor mortis, 106 Manual strangulation, 93 Maximal life span, 105 Melanin, 97 Mesenchymal (tissue from embryonic mesoderm) cell, 77 Metaplasia, 74, 76 Metastatic calcification, 98 Mercury (quicksilver), 85 Methane, 93 mitochondrial DNA (mtDNA), 82 Mitochondrial effect, 81 Necrosis, 100 Oncosis (vacuolar degeneration), 95 Oxidative stress, 79 Ozone, 85 Pallor mortis, 106 Pathologic atrophy, 74 Pathologic hormonal hyperplasia, 75 Pathologic hypertrophy, 75

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Physiologic atrophy, 74 Physiologic hypertrophy, 75 Postmortem change, 106 Programmed necrosis (necroptosis), 100 Protein alteration, 80 Psammoma body, 98 Putrefaction, 106 Pyknosis, 100 Reactive oxygen species (ROS), 79 Reversible injury, 77 Rigor mortis, 106 Senescence, 104 Skeletonization, 107 Somatic death, 106 Strangulation, 92 Steatosis, 96 Suffocation, 91 Urate, 99 Vacuolation, 78 Xenobiotic, 82

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clusters of risks, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1345–1422 [Available at] https://www.ncbi.nlm.nih.gov/pubmed/28919119. 11. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283:65–87. 12. Abadin H, et al. Toxicological profile for lead. Agency for Toxic Substances and Disease Registry (US): Atlanta, GA; 2007. 13. Neal AP, Guilarte TR. Mechanisms of lead and manganese neurotoxicity. Toxicol Res. 2013;2:99–114. 14. Centers for Disease Control and Prevention (CDC). Blood lead levels in children aged 1-5 years—United States, 1999-2010. Author: Atlanta, GA; 2013. 15. United Nations Environmental Programme (UNEP). Global mercury assessment 2013: sources, emissions, releases and environmental transport. UNEP Chemicals Branch: Geneva, Switzerland; 2013. 16. Nassir F, Ibdah JA. Role of mitochondria in alcoholic liver disease. World J Gastroenterol. 2014;20(9):2136–2142. 17. Curtis BJ, et al. Epigenetic targets for reversing immune defects caused by alcohol exposure. Alcohol Res. 2013;35(1):97– 113. 18. Govorko D, et al. Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations. Biol Psychiatry. 2012;72:378–388. 19. Burd L, et al. Prenatal alcohol exposure, blood alcohol concentrations and alcohol elimination rates for the mother, fetus and newborn. J Perinatol. 2012;32(9):652–659. 20. Centers for Disease Control and Prevention (CDC). Drug overdose death data. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Unintentional Injury Prevention, U.S. Department of Health & Human Services: Atlanta GA; 2017 [Available at] https://www.cdc.gov/drugoverdose/data/statedeaths.html. 21. Centers for Disease Control and Prevention (CDC). CDC 24/7: 288

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Fluids and Electrolytes, Acids and Bases Lois E. Brenneman, Sue E. Huether

CHAPTER OUTLINE Distribution of Body Fluids and Electrolytes, 111 Water Movement Between Plasma and Interstitial Fluid, 112 Water Movement Between ICF and ECF, 113 Alterations in Water Movement, 113 Edema, 113 Sodium, Chloride, and Water Balance, 115 Alterations in Sodium, Chloride, and Water Balance, 117 Isotonic Alterations, 118 Hypertonic Alterations, 118 Hypotonic Alterations, 119 Alterations in Potassium and Other Electrolytes, 120 Potassium, 120 Other Electrolytes—Calcium, Phosphate, and Magnesium, 123 Acid–Base Balance, 123 Hydrogen Ion and pH, 123 Buffer Systems, 125 Acid–Base Imbalances, 127 PEDIATRIC CONSIDERATIONS: Distribution of Body Fluids, 130 GERIATRIC CONSIDERATIONS: Distribution of Body Fluids, 130

The cells of the body live in a fluid environment where electrolyte and acid–base concentrations are maintained within a narrow range. Changes in electrolyte concentration affect the electrical activity of nerve and muscle cells, resulting in fluid shifts from one compartment to another. Alterations in acid–base balance disrupt cell functions. Fluid fluctuations also affect blood volume. Disturbances in these functions are common and can be life-threatening. Understanding how alterations occur and how the body compensates for the disturbance is key to understanding many pathophysiologic conditions.

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Distribution of Body Fluids and Electrolytes The sum of all fluids within body compartments constitutes the total body water (TBW)— about 60% of body weight in adults (Table 5.1). The volume of TBW is usually expressed as a percentage of body weight in kilograms. One liter of water weighs 2.2 lb (1 kg). The remainder of the body weight is composed of fat and fat-free solids, particularly bone. The total volume of body water for a person weighing 154 lb (70 kg) is about 42 liters. TABLE 5.1 Total Body Water as a Percentage of Body Weight Body Build

Adult Male

Adult Female

Normal Lean Obese

60 70 50

50 60 42

Child (1–10 yr) 65 50–60 50

Infant (1 mo–1 yr) 70 80 60

Newborn (Up to 1 mo) 70–80

Body fluids are distributed among functional compartments, sometimes called spaces, and provide a transport medium for cellular and tissue function. Intracellular fluid (ICF) is all the fluid within cells and comprises about two-thirds of TBW. The distribution of intracellular water in females is less due to larger amounts of subcutaneous tissue and smaller muscle mass. Extracellular fluid (ECF) is all the fluid outside the cells and comprises about one-third of TBW. ECF includes the interstitial fluid, the intravascular fluid, and the various transcellular fluids (Table 5.2). The interstitial fluid is the fluid found in the spaces between cells but not within the blood vessels. The intravascular fluid is the fluid found within blood vessels; it is more commonly known as the blood plasma. The transcellular fluids, the smallest component of extracellular fluids, are the fluids contained within epithelial-lined cavities of the body. Examples of transcellular fluid include synovial fluid, cerebral spinal fluid, gastrointestinal fluids, pleural fluids, pericardial fluids, peritoneal fluids, and urine. Sweat is yet another component of the extracellular fluid. Derived directly from the interstitial fluid, sweat is released through pores onto the skin in varying amounts as a function of physiologic and environmental conditions. Sweating and lung ventilation are two major sources of insensible fluid loss. Insensible losses must be replaced regularly, usually by drinking fluids, to maintain fluid balance. TABLE 5.2 Distribution of Body Water (70-kg Adult) Fluid Compartment Intracellular fluid (ICF) Extracellular fluid (ECF) Interstitial Intravascular Total body water (TBW)

% of Body Weight 40 (males) 30 (females) 20 male and female 15 5 60 (males) 50 (females)

Volume (L) 28 21 14 11 3 42 35

Electrolytes and other solutes are distributed throughout the intracellular and

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extracellular fluids (Table 5.3). Note that the extracellular fluid contains a large amount of sodium and chloride and smaller amounts of potassium. Intracellular fluid contains larger amounts of potassium with smaller amounts of sodium and chloride. An active energyrequiring physiologic pump maintains these differences in the electrolyte concentration. The concentrations of phosphates and magnesium are greater in the intracellular fluid; the concentration of calcium is greater in the extracellular fluid. These differences in electrolyte concentration are important in maintaining several physiologic functions: electroneutrality between the extracellular and intracellular compartments, the transmission of electrical impulses, and the movement of water among body compartments (see Chapter 1). TABLE 5.3 Representative Distribution of Electrolytes in Body Compartments* Electrolytes Cations Sodium Potassium Calcium Magnesium TOTAL

Anions Bicarbonate Chloride Phosphate Proteins Other anions TOTAL *Values

ECF (mEq/L)

ICF (mEq/L)

142 4.2 5 2 153.2

12 150 0 24 186

24 103 2 16 8 153

12 4 100 65 6 187

may vary slightly among different laboratories.

ECF, Extracellular fluid; ICF, intracellular fluid.

Although the amount of fluid within the various compartments is relatively constant, solutes and water are exchanged between compartments to maintain their unique compositions. The percentage of TBW varies with the amount of body fat and age. Fat is hydrophobic (water repelling), and very little water is contained in adipose (fat) cells. Individuals with more body fat have proportionately less TBW and tend to be more susceptible to dehydration. The distribution and the amount of TBW change with age (see the Pediatric Considerations and Geriatric Considerations boxes). Although daily fluid intake may fluctuate widely, the body regulates water volume within a relatively narrow range. Water obtained from drinking fluids and ingesting foods and from secondary to oxidative metabolism are the primary sources of body water. Most water is lost through renal excretion; relatively smaller amounts are lost through stool and through insensible loss from perspiration and ventilation (Table 5.4). TABLE 5.4 Normal Water Gains and Losses (70-kg Adult)

Drinking

Daily Intake (mL) 1400–1800

Urine

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Daily Output (mL) 1400–1800

Water in food Water of oxidation

700–1000 300–400

Stool Skin Lungs

TOTAL

2400–3200

TOTAL

100 300–500 600–800 2400–3200

Water Movement Between Plasma and Interstitial Fluid The distribution of water and the movement of nutrients and waste products between the capillary and interstitial spaces occur as a result of changes in hydrostatic pressure and osmotic/oncotic pressure. Hydrostatic pressure pushes water out of the capillaries; osmotic/oncotic pressure pulls water into the capillaries (see Fig. 1.24). Water, sodium, and glucose readily move across the capillary membrane. Under normal conditions, proteins (particularly albumin) do not cross the capillary membrane. They maintain physiologic osmolality by generating oncotic pressure within the plasma. Filtration refers to fluid movement out of the capillary and into the interstitial space. Reabsorption refers to fluid movement into the capillary from the interstitial space. As plasma flows from the arterial to the venous end of the capillary, four forces determine whether the net effect is filtration or reabsorption. These forces, acting in concert, are described as net filtration or Starling forces: 1. Capillary hydrostatic pressure (blood pressure) facilitates the movement of water from the capillary into the interstitial space. 2. Capillary (plasma) oncotic pressure osmotically attracts water from the interstitial space into the capillary. 3. Interstitial hydrostatic pressure facilitates the inward movement of water from the interstitial space into the capillary. 4. Interstitial oncotic pressure osmotically attracts water from the capillary into the interstitial space. The forces controlling the movement of fluid across the capillary wall are summarized by these equations:

At the arterial end of the capillary, hydrostatic pressure exceeds capillary oncotic pressure; thus fluid moves into the interstitial space (filtration). At the venous end of the capillary,

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oncotic pressure within the capillary exceeds capillary hydrostatic pressure; thus fluids move into the capillary to enter into the circulation (reabsorption). Interstitial hydrostatic pressure promotes the movement of approximately 10% of the interstitial fluid, along with small amounts of protein, into the lymphatics. Once the fluid enters the lymphatic system, it travels through progressively larger lymphatic vessels until it enters the systemic circulation. These two systems, the lymphatic and circulatory systems, connect at a location near the left internal jugular vein where the lymphatic thoracic duct joins the left subclavian vein. Because albumin does not normally cross the capillary membrane, interstitial oncotic pressure normally is minimal. Fig. 5.1 illustrates net filtration.

FIGURE 5.1 Net Filtration—Fluid Movement Between Plasma and Interstitial Space. The movement of fluid between the vascular, interstitial spaces and the lymphatics is the result of net filtration of fluid across the semipermeable capillary membrane. Capillary hydrostatic pressure is the primary force for fluid movement out of the arteriolar end of the capillary and into the interstitial space. At the venous end, capillary oncotic pressure (from plasma proteins) attracts water back into the vascular space. Interstitial hydrostatic pressure promotes the movement of fluid and proteins into the lymphatics. Osmotic pressure accounts for the movement of fluid between the interstitial space and the intracellular space. Normally intracellular and extracellular fluid osmotic pressures are equal (280 to 294 mOsm), and water is equally distributed between the interstitial and intracellular compartments.

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Water Movement Between ICF and ECF Water moves between ICF and ECF compartments primarily as a function of osmotic forces (see Chapter 1). Water moves freely by diffusion through the lipid bilayer cell membrane and through aquaporins, a class of water channel proteins that are permeable to water.1 Sodium is responsible for the osmotic balance of the ECF, and potassium maintains the ICF osmotic balance. The osmotic force of ICF proteins and other nondiffusible substances is balanced by the active transport of ions out of the cell. Water crosses cell membranes freely, thus the osmolality of TBW normally is at equilibrium. Under normal conditions, the ICF is not subject to rapid changes in osmolality; however, when the ECF osmolality changes, water moves from one compartment to another until osmotic equilibrium is reestablished (see Fig. 5.8).

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Alterations in Water Movement Edema Edema is the excessive accumulation of fluid within the interstitial spaces. It results from a shift of fluid from the capillaries (intravascular fluid) or lymphatic vessels into the tissues (Fig. 5.2). Physiologic conditions that promote fluid flow into the tissues include (1) increased capillary hydrostatic pressure, (2) decreased plasma oncotic pressure, (3) increased capillary membrane permeability, and (4) lymphatic channel obstruction.

FIGURE 5.2

Mechanisms of Edema Formation.

Pathophysiology Capillary hydrostatic pressure increases as a direct result of either venous obstruction or salt and water retention. Venous obstruction results in an increased hydrostatic pressure behind the obstruction, pushing fluid from the capillaries into the interstitial spaces. Common causes of venous obstruction include thrombophlebitis (inflammation of veins), hepatic obstruction, tight clothing around the extremities, and prolonged standing. Similarly, excessive salt and water retention results in edema secondary to plasma volume overload. The overload produces an increased capillary hydrostatic pressure. Common predisposing causes include congestive heart failure, renal failure, and cirrhosis of the liver. Decreased plasma oncotic pressure occurs when production of plasma proteins, especially albumin, is lost or diminished. Plasma albumin functions to attract and hold water within blood vessels. Decreased albumin—commonly seen in liver disease or protein malnutrition

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—results in a decrease of plasma oncotic pressure. Fluid remains in the interstitial spaces instead of filtering into the systemic circulation through the capillaries. As fluid accumulates within the tissues, edema worsens. Common causes of plasma protein loss include glomerular diseases of the kidney, serous drainage from open wounds, hemorrhage, burns, and cirrhosis of the liver. Increased capillary membrane permeability, resulting in edema, occurs with inflammation and immune responses. The increased vessel permeability permits proteins to escape from within blood vessels (the vascular space) into the interstitial space, producing edema. This edema results from decreased capillary oncotic pressure and interstitial fluid protein accumulation. Common triggers include trauma, especially burns or crushing injuries; neoplastic disease; and allergic reactions. Inflammation invariably results in some measure of increased vascular permeability with edema at the site of the injury. The extent of the edema typically is a function of the amount of tissue damage. Allergic reactions can produce profound edema, including life-threatening laryngeal edema (closed-off airway), depending on the extent of vascular permeability. Lymphatic channel obstruction, causing edema, occurs when lymphatic channels are blocked.2 The lymphatic system normally absorbs interstitial fluid, along with small amounts of protein. These substances travel through a one-way system of progressively larger lymphatic vessels until they are returned to the systemic circulation. When lymphatic channels are blocked or surgically removed, proteins and fluid accumulate within the interstitial space, causing lymphedema. Lymphedema of the arm or, less commonly, the leg can occur after surgical removal of axillary or femoral lymph nodes, a procedure commonly performed during resection (cutting out) of malignant tumors (Fig. 5.3). Other causes of lymphedema include radiation therapy, obstruction from malignant tumors, and infection.

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FIGURE 5.3 Lymphedema of the Arm. Secondary lymphedema of the upper extremity in an 82-year-old female with right upper extremity lymphedema 2 years after mastectomy, radiation therapy, and lymphadenectomy for breast cancer. (From Slavin SA, Schook CC, Greene AK: Lymphedema management. In Davis MP et al, editors: Supportive oncology, Philadelphia, 2011, Elsevier/Saunders, pp 211-210. Available at www.sciencedirect.com: http://dx.doi.org/10.1016/B978-1-4377-1015-1.00021-7.)

Clinical Manifestations Edema can be can be identified by pressing on tissues overlying bony prominences. An indentation or pit left in the skin indicates the presence of edema, hence the term pitting edema (Fig. 5.4). Edema may be localized or generalized. Localized edema usually is limited to a single body region, often at the site where trauma has occurred, as might be seen with a sprained ankle. Localized edema also may occur within an organ of the body. Common examples include cerebral, pulmonary, and laryngeal edema. Fluid accumulation within a body cavity or space is referred to as an effusion. Examples include a pleural effusion (fluid accumulation in the pleural space) and a pericardial effusion (fluid accumulation within the membrane surrounding the heart). Localized edema can be life-threatening when vital organs are involved (e.g., the brain, lung, or larynx). Generalized edema is characterized by a more uniform distribution of fluid within the interstitial spaces throughout the body. Anasarca refers to a severe generalized edema. Dependent edema occurs when fluid accumulates in gravity-dependent areas of the body and may be a precursor to more generalized edema. Dependent edema appears in the feet and legs when standing and in the sacral area and buttocks when supine.

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FIGURE 5.4

Pitting Edema. (From Bloom A, Ireland J: Color atlas of diabetes, ed 2, St Louis, 1992, Mosby.)

Edema is associated with weight gain, swelling and puffiness, tight-fitting clothes or shoes, and limited movement of affected joints. It usually presents along with symptoms associated with the underlying pathologic condition. Fluid accumulations increase the distance required for nutrients and waste products to travel between capillaries and tissues. Blood flow may be impaired. Accordingly, wounds heal more slowly, and the risk of infection or decubiti (pressure sores) increase. The region where edematous fluid accumulates is referred to as a third space (interstitial space); the term third spacing sometimes is used to refer to the process of edema formation. Fluid trapped in such spaces is unavailable for metabolic processes or perfusion. Common third space sites include interstitial regions, pleural membranes (pleural effusion), and the space between the heart the pericardial membrane (pericardial effusion). Although the person with generalized edema appears swollen because of excess fluid, dehydration can develop as a result of the fluid sequestering. When severe edema is treated with diuretics (a drug or drug class that promotes kidney excretion of sodium and water), it is not uncommon for an individual to appear cachectic (severe loss of weight and muscle mass) after the excess fluid has been eliminated. With severe burns, large amounts of vascular fluid are lost into the interstitial spaces and shock often occurs secondary to the resulting reduced blood volume (see Chapter 26). Clinically, lymphedema presents differently from edema secondary to fluid accumulation from the capillaries. With edema from capillary sources, the edematous tissue is easily compressed (i.e., pitting edema). By contrast, lymphedema is firm and noncompressible. In severe cases, lymphedema can be profound and causes gross enlargement and distortion of the body parts affected. Evaluation and Treatment

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Medical treatment for edema varies, depending on the underlying conditions that cause fluid retention. Edema may be treated symptomatically, commonly with diuretics, until the underlying disorder has been corrected. In addition to diuretics, symptomatic treatment includes elevating edematous limbs, applying compression stockings, avoiding prolonged standing, and restricting salt intake. Administration of intravenous (IV) albumin may be required in severe cases.

Quick Check 5.1 1. How does an increase in capillary hydrostatic pressure cause edema? 2. How does a decrease in capillary oncotic pressure cause edema? 3. What are possible consequences of edema? How is edema treated?

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Sodium, Chloride, and Water Balance The combined influences of the renal and endocrine systems have a central role in maintaining sodium and water balance. Because water follows the osmotic gradients established by changes in salt concentration, the sodium concentration and water balance are integrally related. The sodium concentration is regulated by the renal effects of aldosterone (see Fig. 31.9). Water balance is regulated primarily by antidiuretic hormone (ADH), also known as vasopressin, and is discussed in the Water Balance section. Sodium (Na+) accounts for 90% of the ECF cations (positively charged ions) (see Table 5.3). Sodium in concert with chloride and bicarbonate, the two major anions (negatively charged ions), acts to regulate water balance by contributing to extracellular osmotic forces. Sodium has an important role in several other physiologic functions, including nerve impulse conduction (see Fig. 1.31), regulation of the acid–base balance, cellular biochemistry, and the transport of substances across the cellular membrane. The serum sodium concentration normally is maintained within a narrow range (135 to 145 mEq/L) by renal tubular reabsorption within the kidney in response to neural and hormonal influences. Hormonal regulation of sodium (and potassium) balance is mediated by aldosterone, a mineralocorticoid synthesized and secreted from the adrenal cortex. Aldosterone is a component of the renin-angiotensin-aldosterone system (see Chapters 19 and 31). Aldosterone secretion is influenced by a number of factors, including circulating blood volume, blood pressure, and plasma concentrations of sodium and potassium. When the circulating blood volume or blood pressure is reduced, renin, an enzyme secreted by the juxtaglomerular cells of the kidney, is released. Renin also is released when sodium levels are depressed or potassium levels are increased. Once released, renin stimulates the formation of angiotensin I, an inactive polypeptide, from angiotensinogen, a substance secreted by the liver. Angiotensin-converting enzyme (ACE), found primarily in pulmonary vessels and to a lesser extent in endothelial and renal epithelial cells, converts angiotensin I to angiotensin II, a potent vasoconstrictor. Vasoconstriction elevates blood pressure and restores renal perfusion. Restoring renal perfusion inhibits further release of renin. Angiotensin II also stimulates both the secretion of aldosterone from the adrenal cortex and antidiuretic hormone from the posterior pituitary. Aldosterone promotes sodium and water reabsorption, in addition to the excretion of potassium within the renal tubules. The net effect is to increase blood volume (Fig. 5.5; also see Fig. 31.9).

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FIGURE 5.5 The Renin-Angiotensin-Aldosterone System. BP, blood pressure; ECF, extracellular fluid; Na+, sodium ion. (Modified from Herlihy B, Maebius N: The human body in health and disease, ed 4, Philadelphia, 2011, Saunders. Borrowed from Lewis SL et al: Medical-surgical nursing: assessment and management of clinical problems, ed 9, St Louis, 2014, Mosby.)

Drugs used for the treatment of hypertension include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, which are well-tolerated. Both of these classes of drugs inhibit the renin-angiotensin-aldosterone system and lower blood pressure. Direct renin inhibitors are a third class of antihypertensive drugs. They are used less commonly because of their less favorable safety profile. Natriuretic peptides are hormones primarily produced by the myocardium. Atrial natriuretic hormone (ANH) is produced by the atria. B-type natriuretic peptide (BNP) is produced by the ventricles. Urodilatin (an ANP analogue) is synthesized within the kidney. Natriuretic peptides are released when the transmural atrial pressure increases (increased volume), which commonly occurs with congestive heart failure or when the mean arterial pressure increases (Fig. 5.6). Measurement of BNP is used as a means to assist with the initial diagnosis and management of people with congestive heart failure.3 These hormones are natural antagonists to the renin-angiotensin-aldosterone system. Natriuretic peptides cause vasodilation and increase sodium and water excretion, decreasing blood pressure. Natriuretic peptides sometimes are called a “third factor” in sodium regulation. An increased glomerular filtration rate is considered to be the first factor, and aldosterone is considered to be the second factor.

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FIGURE 5.6

The Natriuretic Peptide System. ANH, Atrial natriuretic hormone; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; Na+, sodium ion.

Chloride (Cl−) is the major anion in the ECF and provides electroneutrality, particularly in relation to sodium. Chloride transport generally is passive and follows the active transport of sodium. Increases or decreases in chloride concentration are proportional to changes in sodium concentration. Chloride concentration tends to vary inversely with changes in the concentration of bicarbonate ( ), the other major anion. Water balance is regulated by the secretion of ADH, also known as vasopressin. ADH is produced in the posterior pituitary and secreted when plasma osmolality increases or circulating blood volume decreases, causing a drop in blood pressure (Fig. 5.7). Increased Plasma osmolality occurs when there is a decrease in water or an excess concentration of sodium in relation to total body water. The increased osmolality stimulates hypothalamic osmoreceptors, resulting in thirst. Thirst, in turn, stimulates the individual to consume

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liquids, thus increasing total body water. In addition to stimulating thirst, the osmoreceptors signal the posterior pituitary gland to release ADH, a hormone that increases water reabsorption from the renal distal tubules and collecting ducts into the plasma (see Chapter 31). The net effect of both increased water intake and increased renal reabsorption of water is to decrease plasma osmolality, returning it to a normal status. Urine concentration increases as less water is excreted into the urine.

FIGURE 5.7

The Antidiuretic Hormone (ADH) System.

With dehydration (fluid loss) secondary to vomiting, diarrhea, or excessive sweating, a decrease in systemic blood volume and blood pressure often follows. Volume-sensitive receptors and baroreceptors, both of which are nerve endings sensitive to changes in blood volume and pressure, also stimulate thirst and the release of pituitary ADH, which prompts fluid consumption. The volume receptors are located in the right and left atria and in the thoracic vessels; baroreceptors are found in the aorta, pulmonary arteries, and carotid sinus. Additionally, ADH secretion is increased when atrial pressure drops. Such pressure drops occur with a decrease in blood volume (see Fig. 31.9). ADH-mediated reabsorption of water follows, restoring normal status for plasma volume and blood pressure (see Fig. 5.7).

Quick Check 5.2 305

1. What forces promote net filtration? 2. How do hormones regulate salt and water balance? 3. Where are volume and baroreceptors located and how do they function?

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Alterations in Sodium, Chloride, and Water Balance Alterations in sodium and water balance are closely related. Sodium imbalances occur with gains or losses of body water. Water imbalances develop with gains or losses of salt. These alterations can be classified as changes in tonicity (i.e., the change in the concentration of solutes in relation to the amount of water present). Normal plasma osmolality is 280 milliosmoles [mOsm)/kg. Solutions are classified as isotonic, hypertonic, or hypotonic as a function of the solute concentration compared with that of normal body cells (Table 5.5 and Fig. 5.8; also see Fig. 1.25. Isotonic solutions have solute concentrations that are equal to that of normal cells; hypertonic or hypotonic solutions have more or less solute concentration, respectively. Changes in tonicity (solute concentration) affect the volume of water within the intracellular and extracellular compartments, resulting in isovolemia, hypervolemia, or hypovolemia—that is, normal volume, excess volume, or less than normal volume in the blood, respectively. TABLE 5.5 Water and Solute Imbalances Tonicity Isotonic (isoosmolar) imbalance Serum osmolality = 280–294 mOsm/kg Hypertonic (hyperosmolar) imbalance Serum osmolality >294 mOsm/kg Hypotonic (hypoosmolar) imbalance Serum osmolality 0.9% salt solution (i.e., water loss or solute gain); cells shrink in hypertonic fluid

Imbalance that results in ECF 300 different HLA-A molecules are expressed in the population.

FIGURE 8.8 Human Leukocyte Antigens (HLAs). The major histocompatibility complex (MHC) is located on the short arm of chromosome 6 and contains genes (genetic loci) that code for class I antigens (found mostly on nucleated cells), class II antigens (found mostly on dendritic cells, macrophages and B lymphocytes), and class III proteins (i.e., complement proteins and cytokines). (From Peakman M, Vergani D: Basic and clinical immunology, ed 2, London, 2009, Churchill Livingstone; and Abbas AK, Lichtman AH, Pillai S: Basic Immunology, ed 4, St Louis, 2014, Elsevier.)

Human leukocyte antigens (HLAs). Clearly, not every allele is expressed in the same individual. Humans have two copies of each MHC locus (one inherited from each parent) that are codominant so that molecules encoded by each parent's genes are expressed on the surface of every cell, except erythrocytes (Fig. 8.9). The tremendous number of possible alleles that can be expressed

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throughout the population makes it highly unlikely that any two unrelated individuals will have the same MHC antigens.

FIGURE 8.9 Inheritance of Human Leukocyte Antigen (HLA). HLA alleles are inherited in a codominant fashion; both maternal and paternal antigens are expressed. Specific HLA alleles are commonly given numbers to indicate different antigens. In this example, the mother has linked genes for HLA-A3 and HLAB12 on one chromosome 6 and genes for HLA-A10 and HLA-B5 on the second chromosome 6. The father has HLA-A28 and HLA-B7 on one chromosome and HLA-A1 and HLA-B35 on the second chromosome. The children from this pairing may have one of four possible combinations of maternal and paternal HLA.

Inheritance of HLA. The diversity of MHC molecules becomes clinically relevant during organ transplantation. The recipient of a transplant can mount an immune response against the foreign HLA antigens on the donor tissue, resulting in rejection. To minimize the chance of tissue rejection, the donor and recipient are often tissue-typed beforehand to identify differences in HLA antigens. It is highly unlikely that a perfect match can be found between someone who needs a transplant and a potential donor from the general population, but the more similar the two individuals are in their HLA tissue type, the more likely it is that transplantation will be successful. The chance of finding a match among siblings is much higher (25%) than the general population and, clearly, the most successful transplants would be between identical twins because they are identical genetically. Transplant rejection may be classified as hyperacute, acute, or chronic, depending on the amount of time that elapses between transplantation and rejection. Hyperacute rejection is immediate and rare. Hyperacute rejection occurs because of the presence of preexisting antibodies (type II reaction) to HLA antigens on the vascular endothelial cells in the grafted tissue. These preexisting antigens are usually found in individuals who have received multiple blood transfusions or previous transplants. When the circulation is reestablished to the grafted area, the graft may immediately turn white (the so-called white graft) instead

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of a normal pink color. Hyperacute rejection can be avoided by testing the recipient for preexisting antibodies prior to transplantation. Acute rejection is a cell-mediated immune response that occurs within days to months after transplantation. This type of rejection occurs when the recipient develops an immune response against unmatched HLA antigens after transplantation. A biopsy of the rejected organ usually shows an infiltration of lymphocytes and macrophages characteristic of a type IV reaction, although antibodies to the graft vasculature also occur. Acute rejection is treated with a combination of corticosteroids and antirejection drugs which block adaptive immune function. Chronic rejection may occur after a period of months or years of normal function. It is characterized by slow, progressive organ failure. Chronic rejection usually results from chronic inflammation and a weak cell-mediated (type IV) reaction against minor histocompatibility antigens on the grafted tissue. It occurs most often in recipients who were poorly matched to their donor, have comorbidities (e.g., diabetes, hypertension), who received a graft that was damaged during the transplantation procedure, or who have required treatment for multiple acute rejection episodes. Once chronic rejection is well established, there are few effective treatments, and it may be necessary to replace the graft with a new transplanted organ.

Quick Check 8.2 1. Why do certain drugs become immunogenic to the host? 2. Why is an individual with type O blood considered a universal blood donor? 3. Why is SLE considered an autoimmune disease? 4. Define the different types of graft rejection.

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Deficiencies in Immunity Immune deficiency is the failure of the immune or inflammatory response to function normally, resulting in increased susceptibility to infections. Primary (congenital) immune deficiency is caused by a genetic defect, whereas secondary (acquired) immune deficiency is caused by another condition, such as cancer, infection, or normal physiologic changes, such as aging. Acquired forms of immune deficiency are far more common than the congenital forms.

Initial Clinical Presentation The clinical hallmark of immune deficiency is a tendency to develop unusual or recurrent, severe infections. The most severe primary immune deficiencies develop in young children 2 years of age and younger. Potential immune deficiencies should be considered if the individual has experienced severe, documented bouts of pneumonia, otitis media, sinusitis (sinus infection), bronchitis, septicemia (blood infection), or meningitis or infections with rare opportunistic microorganisms (e.g., Pneumocystis jiroveci). Infections are generally recurrent, and multiple simultaneous infections are common. Invasive fungal infections are rare in healthy individuals and strongly indicate a defective immune system. Children frequently present with failure to thrive because of chronic diarrhea and other chronic symptoms. A familial history of immune deficiency may be found in some types of primary deficiency. Routine care of individuals with immune deficiencies must be tempered with the knowledge that the immune system may be totally ineffective. Prolonged antibiotic use is commonly ineffective by oral or injected routes and may necessitate intravenous administration. It is unsafe to administer many conventional immunizing agents to many of these individuals because of the risk of causing an uncontrolled infection. Infection is a particular problem when attenuated vaccines that contain live but weakened microorganisms are used (e.g., live polio vaccine; vaccines against measles, mumps, and rubella). The type of recurrent infections may indicate the type of immune defect. Deficiencies in T-cell immune responses are associated with recurrent infections caused by certain viruses (e.g., varicella herpes, cytomegalovirus), fungi, and yeasts (e.g., Candida, Histoplasma), or atypical microorganisms (e.g., P. jiroveci). B-cell deficiencies and phagocyte deficiencies, however, are suggested if the individual has documented, recurrent infections with microorganisms that require opsonization (e.g., encapsulated bacteria, such as Pneumococcus) or those with viruses against which humoral immunity is normally effective (e.g., rubella virus). Some complement deficiencies resemble defects in antibody or phagocyte function, but others are associated with disseminated infections with bacteria of the genus Neisseria (Neisseria meningitides and Neisseria gonorrhoeae).

Primary (Congenital) Immune Deficiencies Most primary immune deficiencies are the result of single gene defects. Generally the mutations are sporadic and not inherited: a family history exists in only about 25% of individuals. The sporadic mutations occur before birth, but the onset of symptoms may be

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early or later, depending on the particular syndrome. In some instances, symptoms of immune deficiency appear within the first 2 years of life. Other immune deficiencies are progressive, with the onset of symptoms appearing in the second or third decade of life. Individually, primary immune deficiencies are rare. The prevalence of primary immune deficiency diseases was approximately 30 to 50 new cases per year in the United States from 2001 to 2007.2 However, 354 inborn errors of immunity were identified as of February 2017.3 Together, primary immune deficiencies are more common than cystic fibrosis, hemophilia, childhood leukemia, or many other well-known diseases. Many are subtle with minor deficiencies, but several result from major defects and lead to recurrent lifethreatening infections. Sex distribution is about even, although some specific diseases have a male or female predominance. The three most commonly diagnosed deficiencies are common variable immune deficiency (34% of individuals with primary immune deficiencies), selective IgA deficiency (24%), and IgG subclass deficiency (17%). Primary immune deficiencies have recently been reclassified into nine groups, based on the principal component of the immune or inflammatory systems that is defective.3 Of these nine groups, the most common disorders are included within combined immunodeficiencies (affecting both cellular and humoral immunity), with or without associated or syndromic features. They are predominantly antibody deficiencies, defects in phagocyte number or function, defects in innate immunity, and complement defects. To provide a better understanding of the diversity and severity of primary immune deficiencies, a few select examples will be discussed.

Combined Deficiencies Combined deficiencies include the most life-threatening disorders and result from defects that directly affect the development of both T and B lymphocytes. However, the severity depends on the degree to which B and T cells are affected. The most severe disorders are called severe combined immunodeficiencies (SCIDs). Most individuals with SCIDs have few detectable lymphocytes in the circulation and secondary lymphoid organs (spleen, lymph nodes). The thymus usually is underdeveloped because of the absence of T cells. Immunoglobulin levels, especially IgM and IgA, are absent or greatly reduced. Several forms of SCID are caused by autosomal recessive enzymatic defects that result in the accumulation of toxic metabolites, and rapidly dividing cells, such as lymphocytes, are especially sensitive. For instance, deficiency of adenosine deaminase (ADA deficiency) results in the accumulation of toxic purines. X-linked SCID results from a common defect in most of the important interleukin (IL) receptors needed for lymphocyte maturation (e.g., IL-2, IL-4, IL-7, and others). Even if nearly adequate numbers of B and T cells are produced, their cooperation may be defective. Bare lymphocyte syndrome is the immune deficiency characterized by the inability of lymphocytes and macrophages to produce MHC class I or class II molecules. Without MHC molecules, antigen presentation and intercellular cooperation cannot occur effectively. Children with this deficiency develop serious, life-threatening infections and usually die before age 5 years. Some combined immune deficiencies are associated with other features. Wiskott-Aldrich syndrome (WAS), an X-linked recessive disorder, is a condition in which IgM antibody production is greatly depressed. Antibody responses against antigens that primarily elicit an IgM response, such as polysaccharide antigens from bacterial cell walls (e.g., P.

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aeruginosa, S. pneumoniae, Haemophilus influenzae, and other microorganisms with polysaccharide outer capsules), are deficient. WAS results from a mutation of the WAS gene that also affects the actin cytoskeleton, which is important for platelet function. Thus WAS is a combined immune deficiency with an associated major defect in platelet function. Clinical manifestations include bleeding secondary to thrombocytopenia (low platelet counts), eczema, and recurrent infections (e.g., otitis media, pneumonia, herpes simplex, cytomegalovirus). DiGeorge syndrome (22q11.2 deletion syndrome) is a combined immunodeficiency with syndromic features. It is caused by the lack or partial lack of the thymus, resulting in greatly decreased T-cell numbers and function. Defective development of the third and fourth pharyngeal pouches during embryonic development results in thymic defects and the absence of the parathyroid gland (causing inability to regulate calcium concentration). Low blood calcium levels cause the development of tetany or involuntary rigid muscular contraction. DiGeorge syndrome is frequently associated with abnormal development of facial features that are controlled by the same embryonic pouches; these include low-set ears, fish-shaped mouth, and other altered features (Fig. 8.10). There are numerous other combined immune deficiencies, including defects in CD3 resulting in the loss of T-cell receptor intracellular signaling, defective somatic gene rearrangement of variable region genes or constant region genes, IL-2 receptor defects, and defects in DNA repair.

FIGURE 8.10 Facial Anomalies Associated With DiGeorge Syndrome. Note the wideset eyes (B), low-set ears (A and B), shortened structure of the upper lip (B), and underdeveloped chin (A and B). (From Male D et al: Immunology, ed 8, Philadelphia, 2013, Mosby.)

Predominantly Antibody Deficiencies Predominantly antibody deficiencies result from defects in B-cell maturation or function and are the most common of immune deficiencies. T-cell immune responses are not affected in pure B-lymphocyte deficiencies. The results are lower levels of circulating

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immunoglobulins (hypogammaglobulinemia) or occasionally totally or nearly absent immunoglobulins (agammaglobulinemia). Some defects may involve a particular class of antibody, such as selective IgA deficiency, in which only IgA is suppressed. This occurs in 1 in 700 to 1 in 400 individuals and may result from failure to class-switch to IgA and mature into IgA-producing plasma cells. Many individuals are asymptomatic, although others have a history of recurring sinus, pulmonary, and gastrointestinal infections. Individuals with IgA deficiency often have chronic intestinal candidiasis (infection with C. albicans). Complications of IgA deficiency include severe allergic disease and autoimmune diseases. Secretory IgA normally may prevent the uptake of allergens from the environment; therefore IgA deficiency may lead to a more intense challenge to the immune system by environmental antigens. Bruton agammaglobulinemia (X-linked agammaglobulinemia) is caused by blocked development of mature B cells in bone marrow. There are few or no circulating B cells, although T-cell number and function are normal, resulting in repeated bacterial infections, such as otitis media, streptococcal sore throat, and conjunctivitis, as well as more serious conditions, such as septicemia. Other predominantly antibody deficiencies include severe reduction in particular classes or subclasses of antibody; defects in B-cell surface receptors, such as CD21 and CD40; and defects in class-switch, which may result in hyper-IgM syndrome.

Phagocyte Defects Phagocyte defects range from inadequate numbers of phagocytes (e.g., severe congenital neutropenia) to defects in phagocyte function that can result in recurrent infections with the same group of microorganisms (encapsulated bacteria). Chronic granulomatous disease (CGD) is a severe defect in the myeloperoxidase–hydrogen peroxide system—a major means of bacterial destruction using the enzyme myeloperoxidase, halides (e.g., chloride ion), and hydrogen peroxide (H2O2). Deficient production of hydrogen peroxide and other oxygen products needed for phagocytic killing results in recurrent severe pneumonias; tumor-like granulomata in the lungs, skin, and bones; and other infections with some opportunistic microorganisms, such as Staphylococcus aureus, Serratia marcescens, and Aspergillus species. Other phagocytic deficiencies include defects in various leukocyte adhesion molecules, defects in the phagocytosis process or bacterial killing, and defects in cytokine receptors.

Defects in Innate Immunity Some immune deficiencies are characterized by a defect in the capacity to produce an immune response against a particular antigen. In chronic mucocutaneous candidiasis, interaction between the Th17 lymphocytes and macrophages is ineffective related to a specific infectious agent, C. albicans. Thus the macrophage cannot be activated, and these individuals usually have mild to extremely severe recurrent Candida infections involving the mucous membranes and skin. Other defects in innate immunity include defects in Tolllike receptors and NK cells. Other primary defects in innate immunity result in susceptibility to infections with mycobacteria, salmonella, and viruses (Epstein Barr, Herpes, influenza viruses).

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Complement Deficiencies Many complement deficiencies have been described. C3 deficiency is the most severe defect because of its central role in the complement cascade. Loss of C3b and C3a production and the inability to activate C5 result in recurrent life-threatening infections with encapsulated bacteria (e.g., Haemophilus influenzae and Streptococcus pneumoniae) at an early age. Deficiencies of any of the terminal components of the complement cascade (C5, C6, C7, C8, or C9 deficiencies) are associated with increased infections with only one group of bacteria—those of the genus Neisseria (Neisseria meningitides or N. gonorrhoeae). Neisseria species usually cause localized infections (meningitis or gonorrhea), but terminal pathway defects result in an 8000-fold increased risk for systemic infections with atypical strains of these microorganisms. Mannose-binding lectin (MBL) deficiency is the primary defect of the lectin pathway of complement activation. This defect, as well as defects in the alternative pathway, results in increased risk of infection with microorganisms that have polysaccharide capsules rich in mannose, particularly the yeast Saccharomyces cerevisiae and encapsulated bacteria, such as N. meningitidis and S. pneumoniae. Other complement deficiencies include defects in the components C1, C4, C2, C5, C1 inhibitor, factor B, factor D, properdin, complement control factors, MASP, or complement receptors.

Evaluation and Care of Those With Primary Immune Deficiency A review of clinical characteristics can help select the appropriate tests. A basic screening test is a complete blood count (CBC) with a differential. The CBC provides information on the numbers of red blood cells, white blood cells, and platelets, and the differential indicates the quantities of lymphocytes, granulocytes, and monocytes in blood. Quantitative determination of immunoglobulins (IgG, IgM, IgA) is a screening test for antibody production, and an assay for total complement (total hemolytic complement, CH50) is useful if a complement defect is suspected.

Replacement Therapies for Primary Immune Deficiencies Many primary immune deficiencies can be successfully treated by replacing the missing component of the immune system. Individuals with B-cell deficiencies that cause hypogammaglobulinemia or agammaglobulinemia are usually treated by administration of intravenous immunoglobulin (IVIG), antibody-rich fractions prepared from plasma pooled from large numbers of donors. Administration of IVIG replaces the individual's antibodies temporarily; these antibodies have a half-life of 3 to 4 weeks. Thus individuals must be treated repeatedly to maintain a protective level of antibodies in blood. Gene therapy would provide long-term replacement of specific immune factors. Trials have verified immune reconstitution in individuals with ADA deficiency, X-linked SCID, CGD, and WAS and progress is promising for this form of treatment.4 Defects in lymphoid cell development in the primary lymphoid organs (e.g., SCID, WAS) can sometimes be treated by replacement of stem cells through transplantation of bone marrow, umbilical cord cells, or other cell populations that are rich in stem cells. Thymic defects (e.g., DiGeorge syndrome, chronic mucocutaneous candidiasis) may be treated with transplantation of fetal thymus tissue or thymic epithelial cells (the cells that produce thymic hormones). However, in most cases, improvement is only temporary.

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Enzymatic defects that cause SCID (e.g., adenosine deaminase deficiency) have been treated successfully with transfusions of glycerol frozen-packed erythrocytes. The donor erythrocytes contain the needed enzyme and can, at least temporarily, provide sufficient enzyme for normal lymphocyte function. Bone marrow transplants containing hematopoietic stem cells are routinely used to treat SCID. However, individuals with SCID are at risk for graft-versus-host disease (GVHD). This occurs if T cells in a transplanted graft (e.g., transfused blood, bone marrow transplants) are mature and therefore capable of cell-mediated immunity against the recipient's HLA. The primary targets for GVHD are the skin (e.g., rash, loss or increase of pigment, thickening of skin), liver (e.g., damage to bile duct, hepatomegaly), mouth (e.g., dry mouth, ulcers, infections), eyes (e.g., burning, irritation, dryness), and gastrointestinal tract (e.g., severe diarrhea) and the disease may lead to death from infections. The risk of GVHD can be diminished by removing mature T cells from tissue used to treat individuals with immune deficiencies. Mesenchymal stem cells (MSCs) are present in all adult tissues and may be useful in treating GVHD. MSCs have potent immunosuppressive properties. Several clinical trials have demonstrated complete suppression of GVHD in a large number of recipients of MSCs.5

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Secondary (Acquired) Immune Deficiencies Secondary, or acquired, immune deficiencies are far more common than primary deficiencies. These deficiencies are complications of other physiologic or pathophysiologic conditions. Some conditions that are known to be associated with acquired deficiencies are summarized in Box 8.1.

Box 8.1

Some Conditions Known to Be Associated With Acquired Immunodeficiencies Normal Physiologic Conditions Pregnancy Infancy Aging

Psychologic Stress Emotional trauma Eating disorders

Dietary Insufficiencies Malnutrition caused by insufficient intake of large categories of nutrients, such as protein or calories Insufficient intake of specific nutrients, such as vitamins, iron, or zinc

Infections Congenital infections, such as rubella, cytomegalovirus, hepatitis B Acquired infections, such as acquired immunodeficiency syndrome (AIDS)

Malignancies Malignancies of lymphoid tissues, such as Hodgkin disease, acute or chronic leukemia, or myeloma Malignancies of nonlymphoid tissues, such as sarcomas and carcinomas

Physical Trauma 470

Burns

Medical Treatments Stress caused by surgery Anesthesia Immunosuppressive treatment with corticosteroids or antilymphocyte antibodies Splenectomy Cancer treatment with cytotoxic drugs or ionizing radiation

Other Diseases or Genetic Syndromes Diabetes Alcoholic cirrhosis Sickle cell disease Systemic lupus erythematosus (SLE) Chromosome abnormalities, such as trisomy 21

Some Conditions Known to Be Associated With Secondary (Acquired) Immune Deficiencies Although secondary deficiencies are common, many are not clinically relevant. In many cases, the degree of the immune deficiency is relatively minor and without any apparent increased susceptibility to infection. Alternatively, the immune system may be substantially suppressed, but only for a short duration, thus minimizing the incidence of clinically relevant infections. Some secondary immune deficiencies (e.g., malignancy, immunosuppressive treatments, AIDS), however, can be severe and may result in recurrent life-threatening infections.

Malignancies. Virtually all malignancies are complicated by immunosuppression, either through the effect of the disease itself on the body's defense mechanisms or as the result of treatment. Cancer cells are capable of protecting themselves by directly suppressing T lymphocytes. T lymphocytes seek to destroy cancer cells through a variety of inhibitory signals and secreted immunosuppressive chemicals (see Chapter 11). Virtually all late-stage malignancies result in generalized deficiency of the immune response and greatly increased susceptibility to developing life-threatening infections. Mechanisms include replacement of bone marrow by cancer cells, decreased NK and T lymphocyte function, and the release of soluble immunosuppressive chemicals. In fact, many people with malignancies die as a result of infections rather than of the direct effects of the tumor. Some malignancies (e.g., lymphomas, leukemias, plasmacytomas) present with an early and specific immune depression through a direct effect on B cells.

Immunosuppressive treatments. The list of medications that affect the immune response is ever increasing and includes

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anesthetics, analgesics, antithyroid medications, anticonvulsants, antihistamines, antimicrobial agents, antilymphocyte antibodies, and tranquilizers. The most profound immunosuppressive treatments are those that are intentionally used to suppress the immune system to manage immune-mediated disease, to treat malignancy, or to prevent rejection of transplanted tissues. Corticosteroids are intentionally used to control hypersensitivity diseases (especially autoimmune disease) or to prevent rejection of transplants. They predominantly inhibit T cell function, prevent lymphocyte proliferation, inhibit production of critical cytokines, and suppress monocyte/macrophage functions but do not affect neutrophils. Because of their nonspecific activity, however, immune responses against infectious agents also can be suppressed, increasing an individual's susceptibility to infection. Many drugs and other treatments that are used to treat cancer (e.g., chemotherapeutic agents, irradiation) are not specific for cancer cells but are designed to attack cells at susceptible stages in their cell cycles or to attack rapidly proliferating cells, including the cells of the immune system as well as malignant cells. Depending on the dose of chemotherapy and/or irradiation administered, the entire immune system may be depleted. Antirejection drugs are used to prevent immune-mediated rejection of transplanted tissue. Although more targeted treatments are becoming available, most antirejection regimens still cause generalized immune suppression and increase the likelihood of infection and even cancer. A careful therapeutic balance must be maintained between protecting the graft and preventing these complications.

Acquired immunodeficiency syndrome. AIDS is secondary immune deficiency that develops in response to viral infection. Human immunodeficiency virus (HIV) infects and destroys the CD4-positive (CD4+) Th cells, which are necessary for the development of both B cells (humoral immunity) and cytotoxic T cells (cellular immunity). There are two types of HIV: HIV-1 (the most common [95% of HIV infections]) and HIV-2 (less common and less infectious). The discussion in this section is related to HIV-1 and will be referred to as “HIV.” HIV suppresses the immune response against itself and secondarily creates a generalized immune deficiency by suppressing the development of immune responses against other pathogens and opportunistic microorganisms. Acquired immunodeficiency syndrome (AIDS) is the most advanced stage of HIV infection. Despite major efforts by health care agencies around the world, the number of cases and deaths from HIV infection and AIDS (HIV/AIDS) remains a major health concern. In 2017, 36.9 million people were living with HIV/AIDS, including 1.8 million children. Approximately 70% of these people live in Sub-Saharan Africa in middle and low income countries. An estimated 1.8 million people became infected worldwide in 2016. About 75% of people with HIV know their status. By the end of 2017, 21.7 million people in the world were accessing antiretroviral therapy.6 With the advent of effective therapy to stabilize progression of the disease in the mid-1990s, HIV infection has become a chronic disease in the United States, with fewer deaths. An estimated 1.1 million people in the United States were reported to be living with HIV at the end of 2015.7 HIV infection is a bloodborne infection, with typical routes of transmission: blood or blood products, intravenous drug abuse, sexual activity, and maternal–child transmission

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before or during birth. Although the disease first gained attention in the United States related to sexual transmission between males, the most common route worldwide and in the United States is through heterosexual activity. Worldwide, women constitute more than half of those living with HIV/AIDS. Hundreds of thousands of cases of HIV/AIDS have been reported in children who contracted the virus from their mothers across the placenta, through contact with infected blood during delivery, or through the milk during breastfeeding. Pathogenesis of AIDS. HIV is a member of a family of viruses called retroviruses, which carry genetic information in the form of two identical copies of single-stranded ribonucleic acid RNA rather than DNA. RNA—along with the viral enzymes reverse transcriptase, integrase, and protease— is packaged within the viral particle inside a capsid. The capsid is encased in an envelope which displays glycoprotein 120 (gp120) on its surface connected to a transmembrane glycoprotein 41 (gp41) (Fig. 8.11).

FIGURE 8.11 Human Immunodeficiency Virus-1 (HIV-1) Structure. The HIV-1 virion consists of a core of two identical strands of viral ribonucleic acid (RNA) molecules of viral enzymes (reverse transcriptase [RT], protease [PR], integrase [IN]) enveloped in a core capsid structure consisting primarily of the structural viral protein p24. The capsid is further encased in a matrix consisting primarily of viral protein p17. The outer surface is an envelope consisting of the plasma membrane of the cell from which the virus budded (lipid bilayer) and two viral glycoproteins: a transmembrane glycoprotein, gp41, and a noncovalently attached surface glycoprotein, gp120 (site of viral attachment). (Modified from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

HIV-1 structure. The first step in the life cycle of HIV is attachment to the target cell (Fig. 8.12). After transmission from one person to another, the virus attaches to dendritic cells, which then carry the virus into the lymph nodes, where it can infect its primary target cell, the Th

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lymphocyte. For both dendritic cells and Th cells, the process of viral attachment begins with the binding of gp120 to CD4 molecules present on the surface of these cells. Further viral attachment requires binding to chemokine coreceptors. The coreceptor is CCR5 on macrophages and dendritic cells. On T-helper cells, the coreceptor is CCR4. Fusion of the virus to the cellular membrane requires that the gp120/CD4 molecule complex undergoes conformational changes that allow the transmembrane gp41 to fuse with the target cell. At this point, the viral envelope and the cellular membrane are fully fused and the viral capsid is released into the target cell cytoplasm. A group of antiretroviral medications are used to block these steps in viral attachment and fusion (see Fig. 8.12).Once the virus has been released into the target cell cytoplasm, the viral enzyme HIV reverse transcriptase converts RNA into dsDNA. Using a second viral enzyme, HIV integrase, the new DNA is inserted into the infected cell's genetic material. If the cell is activated, transcription and translation of the viral information are initiated, resulting in the production of a long strand of viral components which is then processed by the viral enzyme HIV protease. Assembly of the virion core follows. Antiretroviral medications have been developed that prevent the action of all three HIV enzymes (see Fig. 8.12).

FIGURE 8.12 Human Immunodeficiency Virus-1 (HIV-1) Life Cycle and Sites of Drug Intervention. The HIV virion consists of a core of two identical strands of viral ribonucleic acid (RNA) enveloped in a protein structure with viral glycoproteins gp41 and gp120 on its surface (envelope). (1) HIV infection begins when a virion attaches to CD4 and chemokine co-receptors (e.g., CCR5) on dendritic and T-helper cells. (2) Conformational changes in the gp120/CD4 complex allow for fusion of the virus to the cell membrane and entry into a cell. (3) Reverse transcription (a deoxyribonucleic acid [DNA] copy of the viral RNA). (4) Integration into the nucleus. (5) Synthesis of HIV proteins (protease) and viral assembly. (6) Budding and release from the cell. The HIV life cycle is susceptible to blockage at several sites (see the text for further information), including attachment and fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. (Modified from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

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The final step in the HIV lifecycle is the formation and release of new virions. As the virus buds, it takes some of the host cell membrane with it, making the virus less vulnerable to adaptive immune attack. New viruses infect mature Th cells in the circulation, as well as bone marrow precursor cells and lymphoid cells in the gastrointestinal tract. T cytotoxic cells target these infected cells leading to a gradual loss of Th cells over time. When Th cells are lost, they can no longer be replaced by healthy Th cells from bone marrow and the thymus. The result is immunosuppression. If an infected Th cell is relatively dormant (e.g., memory cells), then few new viruses are made and the cell survives the HIV infection. In these cells, the viral genetic material remains in the cell's chromosomes for the life of the individual, and new viruses will be made when that Th cell is activated at a later time.

Clinical manifestations of AIDS. The clinical manifestations of HIV infection and AIDS are primarily the result of depletion of Th cells, and this has a profound effect on the immune system, causing a severely diminished response to a wide array of infectious pathogens and cancers (Box 8.2). At the time of diagnosis, the individual may present with one of several different conditions: serologically negative (no detectable antibody), serologically positive (positive for antibody against HIV proteins) but asymptomatic, early stages of HIV disease, or AIDS (Fig. 8.13).

Box 8.2

AIDS-Defining Opportunistic Infections and Neoplasms Found in Individuals With HIV Infection Infections Protozoal and Helminthic Infections Cryptosporidiosis or isosporiasis (enteritis) Pneumocystosis (pneumonia or disseminated infection) Toxoplasmosis (pneumonia or CNS infection) Fungal Infections Candidiasis (esophageal, tracheal, or pulmonary) Coccidioidomycosis (disseminated) Cryptococcosis (CNS infection) Histoplasmosis (disseminated) Bacterial Infections Mycobacteriosis (“atypical,” e.g., Mycobacterium avium-intracellulare, disseminated or extrapulmonary M. tuberculosis, disseminated or extrapulmonary)

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Nocardiosis (pneumonia, meningitis, disseminated) Salmonella infections (septicemia, recurrent) Viral Infections Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS) Herpes simplex virus (localized or disseminated) Progressive multifocal leukoencephalopathy Varicella-zoster virus (localized or disseminated)

Neoplasms Invasive cancer of the uterine cervix Kaposi sarcoma Non-Hodgkin lymphomas (Burkitt, immunoblastic) Primary lymphoma of brain AIDS, Acquired immunodeficiency syndrome; CNS, Central nervous system; HIV, human immunodeficiency virus. From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.

FIGURE 8.13 Typical Progression From Human Immunodeficiency Virus (HIV) Infection to Acquired Immunodeficiency Syndrome (AIDS) in Untreated Persons. Clinical progression begins within weeks after infection; the person may experience symptoms of acute HIV syndrome. During this early period, the virus progressively infects T cells and other cells and spreads to the lymphoid organs, with a sharp decrease in the number of circulating CD4+ T cells. During a period of clinical latency, the virus replicates and T-cell destruction continues, although the person is generally asymptomatic. The individual may develop HIVrelated disease (constitutional symptoms)—a variety of symptoms of acute viral infection that do not involve opportunistic infections or malignancies. When the number of CD4+ cells is critically suppressed,

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the individual becomes susceptible to a variety of opportunistic infections and cancers with a diagnosis of AIDS. The length of time for progression from HIV infection to AIDS may vary considerably from person to person. (Redrawn from Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related conditions. In Fauci AS et al, editors: Harrison's principles of internal medicine, ed 14, New York, 1997, McGraw-Hill; Saunders.)

Current CDC recommendations for screening of HIV infection in all health care settings should be performed routinely for all persons 13 to 64 years of age after the individual is notified orally or in writing that testing will be performed unless the individual declines (known as opt-out screening). Screening also is recommended for men who have sex with men (MSM), pregnant women, and those with other sexually transmitted diseases (STDs) or tuberculosis (TB).8 HIV is diagnosed by the measurement of both HIV antibodies and HIV p24 antigen in blood. If positive, these tests are confirmed by HIV DNA (nucleic acid tests [NATs]). The amount of virus in the blood (viral load) and the Th cell count are used to determine what is called the “set point,” which describes the severity of infection and the level of risk for rapid progression to AIDS. Those with the early stages of HIV disease (early-stage disease) usually initially present with relatively mild and nonspecific symptoms resembling influenza, such as headaches, fever, or fatigue. These symptoms disappear after 1 to 6 weeks, and although the infection appears to be in clinical latency, it is actively proliferating in lymph nodes. As the disease progresses, more serious symptoms and signs appear. The diagnosis of AIDS is made when the HIV infection becomes associated with various clinical conditions (Fig. 8.14; also see Box 8.2). These conditions include atypical or opportunistic infections and cancers, as well as indications of debilitating chronic disease (e.g., wasting syndrome, recurrent fevers). Most commonly, new cases of AIDS are diagnosed initially by decreased CD4+ T cell numbers. A diagnosis of AIDS can be made if the CD4+ T cell numbers decrease to < 200/mm3. Without treatment, the average time from infection to development of AIDS is just over 10 years.

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FIGURE 8.14 Clinical Symptoms of Acquired Immunodeficiency Syndrome (AIDS). A, Severe weight loss and anorexia. B, Kaposi sarcoma lesions. C, Perianal lesions of herpes simplex infection. D, Deterioration of vision from cytomegalovirus retinitis leading to areas of infection, which can lead to blindness. (A and D, from Taylor PK: Diagnostic picture tests in sexually transmitted diseases, London, 1995, Mosby; B and C, from Morse SA et al, editors: Atlas of sexually transmitted diseases and AIDS, ed 4, London, 2011, Saunders.)

Treatment and prevention of AIDS. HIV/AIDS treatment guidelines are published by the National Institutes of Health (NIH) and are revised frequently as new antiretroviral medications are approved.9 Approved AIDS medications are classified by mechanism of action: chemokine receptor inhibitors (CCR5 antagonist prevents viral attachment), HIV fusion inhibitors (prevent CD4-gp 120 conformational changes during binding), reverse transcriptase inhibitors (nucleoside and nonnucleoside inhibitors of reverse transcriptase), HIV integrase inhibitors (inhibitors of viral integration into host genome), and HIV protease inhibitors (inhibitors of the proteases HIV uses for assembly of new virus) (see Fig. 8.12). The current regimen for the

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treatment of HIV infection is a combination of drugs, termed antiretroviral therapy (ART). ART protocols require a combination of synergist drugs from different classes, and specific regimens (e.g., timing of drug administration, doses, drug combinations) are adapted on the basis of the age of the individual, secondary clinical symptoms (renal or hepatic insufficiency), CD4+ T-cell levels, viral load, specific coinfections, preexisting cardiac risk factors, past history of treatment failure, suspected drug resistance, and other parameters. The clinical benefits of ART are profound. Death resulting from AIDS-related diseases has been reduced significantly since the introduction of ART. However, resistant variants to these drugs are increasing and may be found even in individuals when they are first diagnosed with HIV infection. The U.S. Food and Drug Administration (FDA) recently approved the first humanized monoclonal antibody for the treatment of multidrug-resistant HIV-1/AIDS (see Did You Know? Iblaizumab-Uiyk and Multidrug-Resistant Human Immunodeficiency Virus-1). Drug therapy for AIDS is not curative because HIV incorporates into the genetic material of the host, particularly CD4+ T memory cells, and may never be removed by antimicrobial therapy. Therefore drug administration to control the virus may have to continue for the lifetime of the individual. Additionally HIV may persist in organs where the antiviral drugs are not as effective, such as the central nervous system (CNS).

Did You Know? Iblaizumab-Uiyk and Multidrug-Resistant Human Immunodeficiency Virus-1 The U.S. Food and Drug Administration (FDA) has recently approved ibalizumab-uiyk (Trogarzo) in combination with other antiretrovirals for treatment of multidrug-resistant human immunodeficiency virus (HIV). Ibalizumab is a drug that blocks HIV-1 entry into CD4+ T cells while preserving normal immunologic function. It is the first CD4-directed postattachment HIV-1 inhibitor and the first humanized monoclonal antibody for the treatment of HIV infection and acquired immunodeficiency syndrome (HIV/AIDS). It has a unique specificity for domain 2 of CD4 and leads to conformational changes of the CD4 T cell receptor–glycoprotein 120 (gp120) complex and prevents HIV fusion and entry. Thus this antibody potently blocks HIV-1 infection by inhibiting a critical step required for viral entry, but without interfering with major histocompatibility complex class II (MHC II)– mediated T-helper cell activation. In clinical trials, for individuals with drug-resistant HIV1, ibalizumab has demonstrated anti–HIV-1 activity without causing immunosuppression. A potential life-threatening side effect is immune reconstitution inflammatory syndrome (IRIS). IRIS can occur when the immune system is recovering after treatment for HIV, and there is an overwhelming inflammatory response. For example, pulmonary IRIS is associated with opportunistic infections, such as Mycobacterium tuberculosis and Pneumocystis jiroveci infections, with high morbidity and mortality. Data from: Food and Drug Administration (FDA): FDA approves new HIV treatment for patients who have limited treatment options. March 6, 2018. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm599657.htm;

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Gopal R, Rapaka RR, Kolls JK: Immune reconstitution inflammatory syndrome associated with pulmonary pathogens, Eur Respir Rev 26(143):160042, 2017; Kaplon H, Reichert JM: Antibodies to watch in 2018, MAbs 10(2):183-203, 2018; Markham A. Ibalizumab: first global approval, Drugs 78(7):781–785, 2018. The chronic nature of HIV/AIDS resulting from successful ART has led to additional concerns. Long-term toxicity of ART drugs has resulted in increased risk for cardiovascular disease, metabolic disorders, and organ failure. Some individuals receiving treatment fail to fully reconstitute their immune system or develop chronic immune activation characterized by activation of monocytes and T cells, production of proinflammatory cytokines, and depletion of Th17 cells and CD4+ T-cells.10 Chronic immune activation tends to exacerbate clinical disease in adults and neonates.

Pediatric AIDS and central nervous system involvement. HIV can be transmitted from mother to child during pregnancy, at the time of delivery, or through breastfeeding, although the risk of mother-to-child transmission has dropped precipitously since the introduction of ART in pregnant women. The clinical diagnosis of HIV infection in young children born to HIV-infected mothers is very often a difficult task because the presence of maternal antibodies may result in a misleading false-positive result on tests for antibodies against HIV for as long as 18 months after birth. Testing for antibody against HIV can be performed recurrently from birth until 18 months; if the test results become negative and remain so after 12 months, the child can be considered uninfected. The protocol for diagnosis of HIV infection in infants and children younger than 18 months of age has been published by the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV.11 HIV infection in babies is generally more aggressive than in adults; on average, an untreated child will die by his or her second birthday. Neurologic involvement occurs more commonly in children than in adults and results from CNS involvement, rather than from the effects on peripheral portions of the CNS. HIV encephalopathy occurs with varying degrees of severity and is a clinical component in the diagnosis of AIDS in children. Most newborns with HIV infection appear normal but may progressively develop signs of CNS involvement. These usually appear as failure to attain, or loss of, developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; acquired symmetric motor deficits, seen in children older than 1 month of age; impaired brain growth or acquired microcephaly, demonstrated by head circumference measurements; or brain atrophy, demonstrated by serial imaging and required in children younger than 2 years of age. It may be difficult to completely differentiate the effect of HIV infection on the CNS from other risk factors, including prenatal drug exposure, prematurity, chronic illness, and chaotic social conditions. The pathogenesis of HIV encephalopathy in children is poorly understood, but the presence of inflammatory mediators may be a contributing factor. Because HIV infection in infants progresses very rapidly, treatment must begin at the diagnosis of infection. In older children, the criteria for treatment are similar to those used in adults. A growing number of investigational protocols are available for treatment of children with HIV infection. In general, treatment is focused on the preservation and maintenance of the immune system, aggressive response to opportunistic infections, support and relief of symptomatic occurrences, and administration of ART.

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Quick Check 8.3 1. Why is the development of recurrent or unusual infections the clinical hallmark of immunodeficiency? 2. Compare and contrast the most common infections in individuals with defects in cell-mediated immune response and those with defects in humoral immune response. 3. How does HIV cause immune suppression?

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Summary Review Hypersensitivity: Allergy, Autoimmunity, and Alloimmunity 1. Hypersensitivity is an immune response misdirected against the host's own tissues (autoimmunity) or directed against beneficial foreign tissues, such as transfusions or transplants (alloimmunity); or it can be exaggerated responses against environmental antigens (allergy). 2. Mechanisms of hypersensitivity are classified as type I (immunoglobulin E [IgE]– mediated) reactions, type II (tissue-specific) reactions, type III (immune complex– mediated) reactions, and type IV (cell-mediated) reactions. 3. Hypersensitivity reactions can be immediate (developing within seconds or hours) or delayed (developing within hours or days). 4. Anaphylaxis, the most rapid immediate hypersensitivity reaction, is an explosive reaction that occurs within minutes of reexposure to the antigen and can lead to shock. 5. Type I (IgE-mediated) reactions occur after antigen reacts with IgE on mast cells, leading to mast cell degranulation and the release of histamine and other inflammatory substances. 6. Type II (tissue-specific) reactions are caused by four possible mechanisms: complement-mediated lysis, opsonization and phagocytosis, antibody-dependent cell-mediated cytotoxicity, and modulation of cellular function. 7. Type III (immune complex–mediated) reactions are caused by the formation of immune complexes that are deposited in target tissues, where they activate the complement cascade, generating chemotactic fragments that attract neutrophils into the inflammatory site. 8. Immune complex disease can be a systemic reaction, such as serum sickness (e.g., Raynaud phenomenon), or localized, such as the Arthus reaction. 9. Type IV (cell-mediated) reactions are caused by specifically sensitized T cells, which either kill target cells directly or release lymphokines that activate other cells, such as macrophages. 10. Allergens are antigens that cause allergic responses, usually a type I hypersensitivity response. 11. Autoimmune disease is loss of tolerance to self-antigens. There can be a genetic predisposition, and the diseases can be a type II or type III hypersensitivity reaction. 12. Alloimmunity is the immune system's reaction against antigens on the tissues of other members of the same species. 13. Alloimmune disorders include transient neonatal disease, in which the maternal immune system becomes sensitized against antigens expressed by the fetus; and transplant rejection and transfusion reactions, in which the immune system of the recipient of an organ transplant or blood transfusion reacts against foreign antigens on the donor's cells.

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1. Immunodeficiency is the failure of mechanisms of self-defense to function in their normal capacity. 2. Immunodeficiencies are either primary or secondary. Congenital immunodeficiencies are caused by genetic defects that disrupt lymphocyte development, whereas acquired immunodeficiencies are secondary to disease or other physiologic alterations. 3. The clinical hallmark of immunodeficiency is a propensity to unusual or recurrent severe infections. The type of infection usually reflects the immune system defect. 4. The most common infections in individuals with defects of cell-mediated immune response are fungal and viral, whereas infections in individuals with defects of the humoral immune response or complement function are primarily bacterial. 5. Severe combined immunodeficiency (SCID) is a total lack of T-cell function and a severe (either partial or total) lack of B-cell function. 6. Wiskott-Aldrich syndrome (WAS) is caused by decreased production of IgM antibody. 7. DiGeorge syndrome is characterized by complete or partial lack of the thymus (resulting in depressed T-cell immunity), frequently associated with diminished or absent parathyroid gland activity (resulting in hypocalcemia) and cardiac anomalies. 8. Antibody deficiencies result from defects in B-cell maturation or function and range from a complete lack of the human bursal equivalent, the lymphoid organs required for B-cell maturation (as in Bruton agammaglobulinemia), to deficiencies in a single class of immunoglobulins (e.g., selective IgA deficiency). 9. Phagocyte defects include inadequate numbers or alteration in function, such as inadequate adhesion to bacteria or ineffective killing. 10. Complement and mannose-binding lectin deficiencies also are rare causes of increased risk for infection. 11. Primary immunodeficiency syndromes are usually treated with replacement therapy. Deficient antibody production is treated by replacement of missing immunoglobulins with commercial gamma-globulin preparations. Lymphocyte deficiencies are treated by the replacement of host lymphocytes with transplants of bone marrow, fetal liver, or fetal thymus from a donor. There are ongoing trials for gene therapy. 12. Acquired immunodeficiencies are caused by superimposed conditions, such as malnutrition, malignancy, medical therapies, physical or psychologic trauma, or infections. 13. Malignancy is associated with both local and generalized immune suppression that can result in life-threatening infections. 14. Treatments for hypersensitivity disorders, malignancy, and transplant rejection cause profound immune suppression and the benefits of these treatments must be carefully balanced with the risks. 15. Acquired immunodeficiency syndrome (AIDS) is acquired dysfunction of the immune system caused by a retrovirus (HIV) that infects and destroys CD4+ lymphocytes (T-helper cells).

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Key Terms ABO blood group, 184 Acquired immunodeficiency syndrome (AIDS), 189 Acute rejection, 186 Adenosine deaminase (ADA deficiency), 187 Agammaglobulinemia, 187 Allergen, 181 Allergy (atopy), 181 Alloantigen, 184 Alloimmunity (isoimmunity), 183 Anaphylaxis, 174 Antiretroviral therapy, (ART), 192 Arthus reaction, 178 Atopic, 176 Autoimmune disease, 182, 182 Autoimmunity, 182 Bare lymphocyte syndrome, 187 Blood group antigen, 184 Bruton agammaglobulinemia, 187 C3 deficiency, 188 Chemokine receptor inhibitor, 191 Chronic granulomatous disease (CGD), 187 Chronic mucocutaneous candidiasis, 188 Chronic rejection, 186 Combined deficiency, 187 Complement deficiency, 188 Contact dermatitis, 180 Cryoglobulin, 178 Delayed hypersensitivity reaction, 174 Delayed hypersensitivity skin test, 180 Desensitization, 182 DiGeorge syndrome, 187 Erythema, 180 Graft-versus-host disease (GVHD), 188 HIV fusion inhibitor, 191 HIV integrase, 190 HIV integrase inhibitor, 191 HIV protease, 190 HIV protease inhibitor, 191 HIV reverse transcriptase, 190 Human immunodeficiency virus (HIV), 189 Human leukocyte antigen (HLA), 185 Hyperacute rejection, 186 Hypogammaglobulinemia, 187

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Immediate hypersensitivity reaction, 174 Immune deficiency, 186 Induration, 180 Isohemagglutinin, 184 Major histocompatibility complex (MHC), 185 Mannose-binding lectin (MBL) deficiency, 188 Mesenchymal stem cell (MSC), 188 Phagocyte defect, 187 Predominantly antibody deficiency, 187 Primary (congenital) immune deficiency, 186 Raynaud phenomenon, 178 Reverse transcriptase inhibitor, 191 Rh blood group, 184 Secondary (acquired) immune deficiency, 186 Selective IgA deficiency, 187 Serum sickness, 178 Severe combined immunodeficiency (SCID), 187 Severe congenital neutropenia, 187 Systemic lupus erythematosus (SLE), 182 Tissue-specific antigen, 177 Tolerance, 182 Type I hypersensitivity, 175 Type II hypersensitivity, 177 Type III hypersensitivity, 178 Type IV hypersensitivity, 178 Universal donor, 184 Universal recipient, 184 Urticaria (hives), 176 Wheal and flare reaction, 176 Wiskott-Aldrich syndrome (WAS), 187 X-linked SCID, 187

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References

1. Thong B, Olsen NJ. Systemic lupus erythematosus diagnosis and management. Rheumatology (Oxford). 2017;56(suppl_1):i3– i13. 2. Kobrynski L, Powell RW, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 20012007. J Clin Immunol. 2014;34(8):954–961. 3. Picard C, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96–128. 4. Kuo CY, Kohn DB. Gene therapy for the treatment of primary immune deficiencies. Curr Allergy Asthma Rep. 2016;16(5):39. 5. Dunavin N, et al. Mesenchymal stromal cells: what is the mechanism in acute graft-versus-host disease. Biomedicines. 2017;5(3):E39. 6. World Health Organization. HIV/AIDS, Data and statistics. [Available at] https://www.who.int/hiv/data/en/. 7. Centers for Disease Control and Prevention (CDC). HIV/AIDS, basic statistics. [Last updated March 13, 2019; Available at] https://www.cdc.gov/hiv/basics/statistics.html.2017a. 8. Centers for Disease Control and Prevention (CDC). HIV testing guidelines. [Page last reviewed March 16, 2018; Available at] https://www.cdc.gov/hiv/guidelines/testing.html. 9. National Institutes of Health. NIH guidelines for antiretroviral agents in adults and adolescents. Last updated October 15, 2018. [Available at] https://aidsinfo.nih.gov/contentfiles/lvguidelines/AA_Recommendatio 10. Paiardini M, Müller-Trutwin M. HIV-associated chronic immune activation. Immunol Rev. 2013;254(1):78–101. 11. U.S. Department of Health and Human Services (DHHS). AIDSinfo: guidelines for the use of antiretroviral agents in pediatric 486

HIV infection: diagnosis of HIV infection in infants and children. [U.S. Department of Health and Human Services, Last updated December 14, 2018; Available at] https://aidsinfo.nih.gov/guidelines/html/2/pediatricarv/55/diagnosis-of-hiv-infection-in-infants-and-children.

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Infection Valentina L. Brashers, Sue E. Huether

CHAPTER OUTLINE Microorganisms and Humans: a Dynamic Relationship, 196 The Process of Infection, 196 Stages of Infection, 198 Infectious Disease, 199 Bacterial Infection, 199 Viral Infection, 201 Fungal Infection, 204 Parasitic Infection, 204 Antibiotic/Antimicrobial Resistance, 206 Vaccines and Protection Against Infection, 207 Active Immunization, 207 Passive Immunotherapy, 208

Modern health care has shown great progress in preventing and treating infectious diseases. However, infectious disease continues to be a threat to human health because of the emergence of previously unknown infections, the reemergence and spread of old infections that were thought to be under control, and the development of infectious agents that are resistant to multiple antibiotics. Endemic diseases, such as chronic hepatitis, human immunodeficiency virus (HIV) infection, other sexually transmitted infections, and foodborne infections, remain major challenges in the United States. Most deaths related to infections occur in individuals whose immune systems are compromised (young children, the elderly, and those with chronic disease).

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Microorganisms and Humans: a Dynamic Relationship For many microorganisms, the human body is a hospitable site in which to grow and flourish because of sufficient nutrients and appropriate conditions of temperature and moisture. Only a small number of microorganisms are capable of causing disease. The relationship between humans and microorganisms is summarized in Box 9.1. The symbiotic microorganisms make up the normal human microbiome—the resident microorganisms found in different parts of the body, including the skin, mouth, gastrointestinal tract, respiratory tract, and genital tract. For instance, the normal bacterial microbiome of the human gut is provided with nutrients from ingested food and produces enzymes that facilitate the digestion and use of many of the more complex molecules found in the human diet. It also produces antibacterial factors that prevent colonization by pathogenic microorganisms and produces usable metabolites (e.g., vitamins K and B).

Box 9.1

Relationships Between Humans and Microorganisms Symbiosis: Benefits only the human; no harm to the microorganism Mutualism: Benefits the human and the microorganism Commensalism: Benefits only the microorganism; no harm to the human Pathogenicity: Benefits the microorganism; harms the human Opportunism: A situation in which benign microorganisms become pathogenic because of decreased human host resistance or translocation to other body sites. The symbiotic relationship between the body and the human microbiome is maintained by physical barriers (e.g., skin and lining of respiratory, intestinal and genital tracts) and the complex interaction of the microbiome and inflammatory and immune systems. Microorganisms that may cause infection if the protective barriers are breached or defensive systems are weakened are referred to as opportunistic microorganisms. For example, alterations in the microbiome by antibiotics may allow local overgrowth of opportunistic microorganisms that can cause disease (e.g., Clostridium difficile, Candida albicans). Individuals with immune deficiencies also become easily infected with opportunistic microorganisms. The concepts and processes of infection are presented in this chapter. Specific infections are presented in Part Two of the book with the organ system chapters (i.e., infections that occur in the cardiovascular, pulmonary, genitourinary tract, gastrointestinal tract, and skin).

The Process of Infection Infectious diseases are caused by pathogenic microorganisms. Classes of pathogenic microorganisms and their characteristics are summarized in Table 9.1. The process of infection includes encounter and transmission, colonization, invasion, dissemination, and

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cellular or tissue damage by the pathogenic microorganisms. There are several different ways that an individual can encounter or come in contact with microorganisms. Endogenous microorganisms are already present in the body and part of the normal microbiome. Exogenous microorganisms are transmitted from an external source (e.g., contaminated water, food, or from another human, animals or insects). TABLE 9.1 Classes of Microorganisms Infectious to Humans Class

Size

Virus

20-300 nm

Bacteria

0.8-15 mcg

Fungi

2-200 mcg

Protozoa

1-50 mm

Helminths 3 mm to 10 m

Site of Reproduction Intracellular

Example

Human immunodeficiency virus, hepatitis A and B, chicken pox, measles Skin Staphylococcal wound infection Mucous membranes Cholera Extracellular Streptococcal pneumonia Mycoplasma pneumonia Intracellular Tuberculosis, chlamydiasis Skin Tinea pedis (athlete's foot) Mucous membranes Candidiasis (e.g., thrush) Extracellular Sporotrichosis Intracellular Histoplasmosis Mucosal Giardiasis Extracellular African trypanosomiasis (sleeping sickness) Intracellular Trichinosis Extracellular Filariasis

Transmission of microorganisms can occur in several different ways: Direct transmission or contact: Vertical transmission from mother to child across the placenta (e.g., Listeria monocytogenes, cytomegalovirus [CMV]), during delivery from the birth canal (e.g., group B Streptococcus, Escherichia coli, Chlamydia trachomatis), or from breast milk (e.g., Staphylococcus aureus); horizontal transmission from one person to another through exposure to blood and body fluids (e.g., HIV, Neisseria gonorrhoeae); or zoonotic infections directly transmitted from animals (e.g., giardiasis, toxoplasmosis). Indirect transmission: Occurs from contact with infected materials, such as towels, toys, bandages and contact lenses (e.g., cellulitis, conjunctivitis); inhalation or droplet infection (e.g., common cold, pneumonia); ingestion of contaminated food or water (e.g., gastroenteritis, cholera); or inoculation (e.g., malaria, tetanus). Colonization is the ability of a pathogenic microorganism to survive and multiply on or within the human environment. They must be able to compete with the symbiotic microorganisms and resist local defenses. Table 9.2 summarizes mechanisms used by pathogens to resist immune defenses. The multiple layers of defense against pathogens are described in Chapters 6 and 7. The estimated minimum number of microorganisms needed to cause infection (minimum infective dose) varies greatly with the particular pathogen: Vibrio cholerae (103-108 microorganisms), norovirus and rotavirus (10-100), Giardia lamblia parasitic diarrhea (10), and Mycobacterium tuberculosis (40° C [104° F]), the regulatory center ceases to function and the body's heat loss mechanisms fail. Symptoms include high core temperature, absence of sweating, rapid pulse rate, confusion, agitation, and coma. Complications include cerebral edema, degeneration of the CNS, swollen dendrites, renal tubular necrosis, and hepatic failure with delirium, coma, and eventually death if treatment is not undertaken.36 4. Malignant hyperthermia—a potentially lethal hypermetabolic complication of a rare inherited muscle disorder that may be triggered by inhaled anesthetics and depolarizing muscle relaxants.37 The syndrome involves altered calcium function in muscle cells with hypermetabolism, uncoordinated muscle contractions, increased muscle work, increased oxygen consumption, and a raised level of lactic acid production. Acidosis develops, and body temperature rises, with resulting tachycardia and cardiac dysrhythmias, hypotension, decreased cardiac output, and cardiac arrest. Signs resemble those of coma—unconsciousness, absent reflexes, fixed pupils, apnea, and occasionally a flat electroencephalogram. Oliguria and anuria are common. It is most common in children and adolescents.

Hypothermia Hypothermia (core body temperature less than 35° C [95° F]) produces depression of the CNS and respiratory system, vasoconstriction, alterations in microcirculation and coagulation, and ischemic tissue damage. Hypothermia may be accidental or therapeutic (Box 15.3). Most tissues can tolerate low temperatures in controlled situations, such as surgery. However, in severe hypothermia, ice crystals form on the inside of the cell, causing cells to rupture and die. Tissue hypothermia slows cell metabolism, increases the blood viscosity, slows microcirculatory blood flow, facilitates blood coagulation, and stimulates profound vasoconstriction (also see Frostbite, Chapter 43).

Box 15.3

Defining Characteristics of Hypothermia Accidental Hypothermia The unintentional decrease in core temperature to less than 35° C (95° F) results from sudden immersion in cold water, prolonged exposure to cold environments, diseases that diminish the ability to generate heat, or altered thermoregulatory mechanisms. It is most common among young and elderly persons.

Factors That Increase Risk 1. Hypothyroidism 2. Hypopituitarism 3. Malnutrition 4. Parkinson disease 5. Rheumatoid arthritis

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6. Chronic increased vasodilation 7. Failure of thermoregulatory control resulting from cerebral injury, ketoacidosis, uremia, sepsis, and drug overdose

Response Mechanisms 1. Peripheral vasoconstriction—shunts blood away from cooler skin to core to decrease heat loss and produces peripheral tissue ischemia 2. Intermittent reperfusion of extremities (Lewis phenomenon) helps preserve peripheral oxygenation until core temperature drops dramatically 3. Hypothalamic center induces shivering; thinking becomes sluggish, and coordination is depressed 4. Stupor; heart rate and respiratory rate decline; cardiac output diminishes; metabolic rate falls; acidosis; eventual ventricular fibrillation and asystole occur at 30° C (86° F) and lower

Treatment 1. Most changes are reversible with rewarming 2. Core temperature greater than 30° C (86° F)—active rewarming (external) 3. Core temperature less than 30° C (86° F) or with severe cardiovascular problems— active core rewarming (internal)

Therapeutic Hypothermia (Targeted Temperature Management) Used to slow metabolism and preserve ischemic tissue during surgery (e.g., limb reimplantation) and after cardiac arrest. Studies are in progress to evaluate outcomes of hypothermia for management of neurologic injury.

Effects and Cautions 1. Stresses the heart, leading to ventricular fibrillation and cardiac arrest (may be desired outcome in open heart surgery when heart must be stopped) 2. Exhausts liver glycogen stores by prolonged shivering 3. Surface cooling may cause burns, frostbite, and fat necrosis 4. Immunosuppression with increased infection risk 5. Slows drug metabolism From Carwell M: Crit Care Nurs Q 41(2):102-108, 2018; Kraft J, Karpenko A, Rincon F: Curr Neurol Neurosci Rep 16(2):18, 2016.

Trauma and Temperature Major body trauma can affect temperature regulation through various mechanisms. Damage to the CNS, inflammation, increased intracranial pressure, or intracranial bleeding typically produces a body temperature of greater than 39° C (102.2° F). This sustained

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noninfectious fever, often referred to as a central fever, appears with or without bradycardia. A central fever does not induce sweating and is very resistant to antipyretic therapy.38 Other traumatic mechanisms that produce temperature alterations include accidental injuries, hemorrhagic shock, major surgery, and thermal burns. The severity and type of alteration (hyperthermia or hypothermia) vary with the severity of the cause and the body system affected.

Quick Check 15.2 1. Why is temperature regulation important? 2. What are the principal heat production methods? Heat loss methods? 3. How does the hypothalamus alter its set point to change body temperature? 4. Compare and contrast hyperthermia and hypothermia and their effects on the body.

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Sleep Sleep is an active multiphase process that provides restorative functions and promotes memory consolidation. Complex neural circuits, interacting hormones, and neurotransmitters involving the hypothalamus, thalamus, brainstem, and cortex control the timing of the sleep-wake cycle and coordinate this cycle with circadian rhythms (24-hour rhythm cycles).39 Normal sleep has two primary phases that can be documented by electroencephalogram (EEG), a test that detects electrical activity in your brain: rapid eye movement (REM) sleep (20% to 25% of sleep time) and slow-wave (non-REM) sleep. NonREM sleep is further divided into three stages (N1, N2, N3) from light to deep sleep. REM cycles do not typically start to occur until about 90 minutes into sleep. Four to six cycles of REM and non-REM sleep occur each night in an adult.40 The hypothalamus is a major sleep center, and the hypocretins (orexins), acetylcholine, and glutamate are neuropeptides secreted by the hypothalamus that promote wakefulness. Prostaglandin D2, adenosine, melatonin, serotonin, L-tryptophan, gamma-aminobutyric acid (GABA), and growth factors promote sleep. The pontine reticular formation is primarily responsible for generating REM sleep, and projections from the thalamocortical network produce non-REM sleep.41 Rapid eye movement (REM) sleep is initiated by REM-on and REM-off neurons in the pons and mesencephalon. REM sleep occurs about every 90 minutes beginning 1 to 2 hours after non-REM sleep begins. This sleep is known as paradoxical sleep because the EEG pattern is similar to that of the normal awake pattern and the brain is very active with dreaming. REM and non-REM sleep alternate throughout the night, with lengthening intervals of REM sleep and fewer intervals of deeper stages of non-REM sleep toward morning. The changes associated with REM sleep include increased parasympathetic activity and variable sympathetic activity associated with rapid eye movement; muscle relaxation; loss of temperature regulation; altered heart rate, blood pressure, and respiration; penile erection in men and clitoral engorgement in women; release of steroids; and many memorable and often bizarre, dreams. Respiratory control appears largely independent of metabolic requirements and oxygen variation. Loss of normal voluntary muscle control in the tongue and upper pharynx may produce respiratory obstruction which, in turn, can precipitate apneic events. Cerebral blood flow increases. REM sleep is associated with memory consolidation.42 Non-REM sleep accounts for 75% to 80% of sleep time in adults and is initiated when inhibitory signals are released from the hypothalamus. Sympathetic tone is decreased, and parasympathetic activity is increased during non-REM sleep, creating a state of reduced activity. The basal metabolic rate falls by 10% to 15%; temperature decreases 0.5° to 1° C (0.9° to 1.8° F); heart rate, respiration, blood pressure, and muscle tone decrease; and knee jerk reflexes are absent. Pupils are constricted. During the various stages, cerebral blood flow to the brain decreases and growth hormone is released, with corticosteroid and catecholamine levels depressed. Box 15.4 summarizes sleep characteristics in infants and elderly persons.

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Box 15.4

Sleep Characteristics of Infants, Children, and Elderly Persons Infants • Infants sleep 10 to 16 hours per day: 50% REM (active) sleep, 25% non-REM (inactive) sleep. • Infant sleep cycles are 50 to 60 minutes in length; 10 to 45 minutes of REM sleep accompanied by movement of the arms, legs, and facial muscles followed by about 20 minutes of non-REM sleep. • At 1 year, REM and non-REM sleep cycles are about equal in length and infants sleep through the night with about two naps per day.

Children • Children assume an adult sleep pattern between 3 and 5 years and sleep about 9 to 10 hours per night. • Inadequate sleep in adolescents is associated with obesity, depression, and poor academic performance.

Elderly Persons • Total sleep time is decreased with a longer time to fall asleep and poorer-quality sleep. • Total time in slow-wave and final phase of non-REM sleep decreases by 15% to 30%. • Increases in stage 1 and 2 non-REM sleep, attributable to an increased number of spontaneous arousals. • Elderly individuals tend to go to sleep earlier in the evening and wake earlier in the morning because of a phase advance in their normal circadian sleep cycle. • Alterations in sleep patterns occur about 10 years later in women than in men. • Sleep disorders are more likely in the elderly and increase risks of morbidity, mortality, and changes in cognitive function. REM, rapid eye movement; non-REM, non-rapid eye movement From Gulia KK, Kumar VM: Psychogeriatrics 18(3):155-165, 2018; Owens J; Pediatrics 134(3):e921-e932, 2014; Scullin MK, Bliwise DL: Perspect Psychol Sci 10(1):97-137, 2015.

Sleep Disorders Because classification of sleep disorders is complex, a system has been established by the American Academy of Sleep Medicine and includes six classifications: (1) insomnia, (2) sleep-related breathing disorders, (3) central disorders of hypersomnolence, (4) circadian

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rhythm sleep-wake disorders, (5) parasomnias, (6) sleep-related movement disorders.43 The most common disorders are summarized here.

Common Dyssomnias Insomnia is the inability to fall or stay asleep; it is accompanied by fatigue, malaise, and difficulty with performance during wakefulness and may be mild, moderate, or severe. It may be transient, lasting a few days or months (primary insomnia), and related to travel across time zones or caused by acute stress, or very commonly inadequate “sleep hygiene.” Sleep hygiene simply refers to behavioral and environmental practices that are intended to promote better-quality sleep (e.g., avoiding all-nighters and caffeine late in the evening). Chronic insomnia can be idiopathic, start at an early age, and be associated with drug or alcohol abuse, chronic pain disorders, chronic depression, the use of certain drugs, obesity, aging, genetics, and environmental factors that result in hyperarousal.44 Obstructive sleep apnea syndrome (OSAS) is the most commonly diagnosed sleep disorder and occurs in all age groups. However, the incidence of OSAS increases with age beyond 60 years. Major risk factors include obesity, male sex, older age, and postmenopausal status (not on hormone therapy) in women, and increased size of tonsillar and adenoid tissue.45 A lack of daytime sleepiness often lessens awareness of a potential sleep disorder, and many persons are never properly diagnosed and treated.46 OSAS results from partial or total upper airway obstruction to airflow recurring during sleep with excessive loud snoring, gasping, and multiple apneic episodes that last 10 seconds or longer. Central sleep apnea is the temporary absence or diminution of ventilatory effort during sleep with decreased sensitivity to carbon dioxide and oxygen tensions, and decreased airway dilator muscle activation. Obesity hypoventilation syndrome may be related to leptin resistance because leptin also is a respiratory stimulant. The periodic breathing eventually produces arousal, which interrupts the sleep cycle, reducing total sleep time and producing sleep and REM deprivation. Sleep apnea produces hypercapnia and low oxygen saturation and if left untreated, eventually leads to polycythemia, pulmonary hypertension, systemic hypertension, stroke, right-sided congestive heart failure, dysrhythmias, liver congestion, cyanosis, and peripheral edema. Hypersomnia (excessive daytime sleepiness) is associated with OSAS. Individuals may fall asleep while driving a car, working, or even while conversing, with significant safety concerns.47 Sleep deprivation also can result in impaired mood and cognitive function characterized by impairments of attention, episodic memory, working memory, and executive functions (i.e., decision-making ability). Polysomnography is needed to diagnose OSAS, in addition to the history and physical examination. Treatments include use of nasal continuous positive airway pressure (CPAP) and dental devices, surgery of the upper airway and jaw in selected individuals, and management of obesity.48 Adenotonsillar hypertrophy is the major cause of obstructive sleep apnea in children, and obesity increases the risk. Adenotonsillectomy is the treatment of choice.49 Narcolepsy is a primary hypersomnia with disruption in sleep-wake cycles characterized by hallucinations, sleep paralysis and, rarely, cataplexy (brief spells of muscle weakness). Narcolepsy is usually sporadic or can occur in families. Type I narcolepsy (narcolepsy with cataplexy) is associated with immune-mediated destruction of hypocretin (orexin)-secreting

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cells in the hypothalamus. Orexins stimulate wakefulness. Type II narcolepsy (narcolepsy without cataplexy) is associated with normal levels of orexins (hypocretins) and the cause is unknown.50 Circadian rhythm sleep disorders are common disorders of the 24-hour sleep-wake schedule (circadian rhythm sleep disorders). They can result from extrinsic causes, such as rapid time zone changes (or jet-lag syndrome), alternating the sleep schedule (rotating work shifts) involving 3 hours or more in sleep time, or changing the total sleep time from day to day. Intrinsic causes include advanced sleep phase disorder (early morning waking– early evening sleeping) resulting in sleep loss if social requirements are for late sleeping, or delayed sleep phase disorder (late morning waking–late night to early morning sleeping) with loss of sleep because of required early morning rising (common in adolescents). These changes desynchronize the circadian rhythm, which can depress the degree of vigilance, performance of psychomotor tasks, and arousal. A circadian rhythm sleep disorder known as shift work sleep disorder affects many shift workers who rotate or swing long shifts (such as nurses), particularly between the hours of 2200 (10 PM) and 0600 (6 AM). Our sleepwake cycle is driven by circadian rhythms, and the disruption of this circadian influence may cause problems in the short term, such as cognitive deficits and difficulty concentrating. However, long-term health consequences of shift work sleep disorder may be quite serious and include depression/anxiety, increased risk for cardiovascular disease, and increased all-cause mortality. Sleep cycle phenotype also has a genetic basis and influences the timing and cycles of sleep and can affect advances or delays in sleep-wake times.51,52

Common Parasomnias Parasomnias are unusual behaviors occurring during non-REM stage 3 (slow-wave) sleep (non-REM parasomnias).53 These behaviors include sleepwalking, having night terrors, rearranging furniture, eating food, exhibiting sleep sex or violent behavior, and having restless legs syndrome. REM sleep behavior disorder (RBD) is manifested by loss of REM paralysis, leading to potentially injurious dream enactment. Nonmotor symptoms are nonspecific and include olfactory dysfunction, abnormal color vision, autonomic dysfunction, excessive daytime sleepiness, depression, and cognitive impairment. RBD is a common prodromal manifestation of Parkinson disease.54 Two dysfunctions of sleep (somnambulism and night terrors) are common in children and may be related to CNS immaturity. Somnambulism (sleepwalking) is a non-REM parasomnia disorder primarily of childhood and appears to resolve within a few years. Sleepwalking is therefore not associated with dreaming, and the child has no memory of the event on awakening. Sleepwalking in adults is often associated with sleep-disordered breathing. Night terrors are characterized by sudden apparent arousals in which the child expresses intense fear or emotion. However, the child is not awake and can be difficult to arouse. Once awakened, the child has no memory of the night terror event. Night terrors are not associated with dreams. Although this problem occurs most often in children, adults also may experience it with corresponding daytime anxiety.

Restless Leg Syndrome Restless legs syndrome (RLS)/Willis Ekbom disease is a common sensorimotor disorder

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associated with unpleasant sensations (prickling, tingling, crawling) and nonvolitional periodic leg movements that occurs at rest and is worse in the evening or at night. There is a compelling urge to move the legs for relief, with a significant effect on sleep and quality of life. The disorder is more common in women, during pregnancy, the elderly, and individuals with iron deficiency. RLS has a familial tendency and is associated with a circadian fluctuation of dopamine in the substantia nigra. Iron is a cofactor in dopamine production, and some individuals respond to iron administration as well as dopamine agonists. Diagnostic and treatment guidelines have been established to assist with disease management.55

Quick Check 15.3 1. Describe REM and non-REM sleep. 2. What is the major difference between the dyssomnias and parasomnias?

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The Special Senses Vision The eyes are complex sense organs responsible for vision. Within a protective casing, each eye has receptors, a lens system for focusing light on the receptors, and a system of nerves for conducting impulses from the receptors to the brain. Visual dysfunction may be caused by abnormal ocular movements or alterations in visual acuity, refraction, color vision, or accommodation. Visual dysfunction also may be the secondary effect of another neurologic disorder.

The Eye The wall of the eye consists of three layers: (1) sclera, (2) choroid, and (3) retina (Fig. 15.5). The sclera is the thick, white, outermost layer. It becomes transparent at the cornea—the portion of the sclera in the central anterior region that allows light to enter the eye. The choroid is the deeply pigmented middle layer that prevents light from scattering inside the eye. The iris, part of the choroid, has a round opening, the pupil, through which light passes. Smooth muscle fibers control the size of the pupil so that it adjusts to bright light or dim light and to close or distant vision.

FIGURE 15.5

Internal Anatomy of the Eye. (Adapted from Patton KT, Thibodeau GA: Structure & function of the human body, ed 13, St Louis, 2008, Mosby.)

The retina is the innermost layer of the eye and contains millions of rods and cones— special photoreceptors that convert light energy into nerve impulses. Rods mediate peripheral and dim light vision and are densest at the periphery. Cones are color and detail receptors, and densest in the center of the retina. There are no photoreceptors where the

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optic nerve leaves the eyeball; this creates the optic disc, or blind spot. Lateral to each optic disc is the macula lutea, the area of most distinct vision, and in the center is the fovea centralis, a tiny area that contains only cones and provides the greatest visual acuity (see Fig. 15.5). Nerve impulses pass through the optic nerves (second cranial nerve) to the optic chiasm (see Fig. 15.8). The nerves from the inner (nasal) halves of the retinas cross to the opposite side and join fibers from the outer (temporal) halves of the retinas to form the optic tracts (see Fig. 15.8). The fibers of the optic tracts synapse in the dorsal lateral geniculate nucleus and pass by way of the optic radiation (or geniculocalcarine tract) to the primary visual cortex in the occipital lobe of the brain. Some fibers terminate in the suprachiasmatic nucleus (SCN) of the hypothalamus (located above the optic chiasm) and are involved in circadian regulation of the sleep-wake cycle. Light entering the eye is focused on the retina by the lens—a flexible, biconvex, crystal-like structure. The flexibility of the lens allows a change in curvature with contraction of the ciliary muscles, called accommodation, and allows the eye to focus on objects at different distances. The lens divides the anterior chamber into (1) the aqueous chamber and (2) the vitreous chamber. Aqueous humor fills the aqueous chamber and helps maintain pressure inside the eye, as well as provide nutrients to the lens and cornea. Aqueous humor is secreted by the ciliary processes and reabsorbed into the canal of Schlemm. If drainage is blocked, intraocular pressure increases, causing glaucoma. The vitreous chamber is filled with a gel-like substance called vitreous humor that cannot regenerate. Vitreous humor helps prevent the eyeball from collapsing inward. The central retinal artery provides blood to the inner retinal surface, and the choroid supplies nutrients to the outer surface of the retina. Six extrinsic eye muscles allow gross eye movements and permit eyes to follow a moving object (Fig. 15.6).

FIGURE 15.6 Extrinsic Muscles of the Right Eye. A, Superior view. B, Lateral view. (From Dutton JJ: Atlas of clinical and surgical orbital anatomy, ed 2, Philadelphia, 2011, Saunders.)

Visual Dysfunction Alterations in ocular movements. Abnormal ocular movements result from oculomotor, trochlear, or abducens cranial nerve

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dysfunction (see Table 14.6). The three types of eye movement disorders are (1) strabismus, (2) nystagmus, and (3) paralysis of individual extraocular muscles. In strabismus, one eye deviates from the other when the person is looking at an object. This is caused by a weak or hypertonic muscle in one eye. The deviation may be upward, downward, inward (entropia), or outward (extropia). Strabismus in children requires early intervention to prevent amblyopia (reduced vision in the affected eye caused by cerebral blockage of the visual stimuli). The primary symptom of strabismus is diplopia (double vision). Causes include neuromuscular disorders of the eye muscle, diseases involving the cerebral hemispheres, or thyroid disease. Nystagmus is an involuntary unilateral or bilateral rhythmic movement of the eyes. It may be present at rest or when the eye moves. Pendular nystagmus is characterized by a regular back and forth movement of the eyes. In jerk nystagmus, one phase of the eye movement is faster than the other. Nystagmus may be caused by imbalanced reflex activity of the inner ear, vestibular nuclei, cerebellum, medial longitudinal fascicle, or nuclei of the oculomotor, trochlear, and abducens cranial nerves (see Table 14.6 and Fig. 14.25). Drugs, retinal disease, diseases involving the cervical cord, stroke syndromes, brain tumors, and brain trauma also may produce nystagmus. Paralysis of specific extraocular muscles may cause limited abduction, abnormal closure of the eyelid, ptosis (drooping of the eyelid), or diplopia (double vision) as a result of unopposed muscle activity. Trauma or pressure in the area of the cranial nerves or diseases such as diabetes mellitus and myasthenia gravis also paralyze specific extraocular muscles. Alterations in visual acuity. Visual acuity is the ability to see objects in sharp detail. With advancing age, the lens of the eye becomes less flexible and adjusts slowly, and there is altered refraction of light by the cornea and lens. Thus visual acuity declines with age. Table 15.6 contains a summary of changes in the eye caused by aging. Specific causes of visual acuity changes are (1) amblyopia, (2) scotoma (blind spot in visual field), (3) cataracts, (4) papilledema, (5) dark adaptation, (6) glaucoma, (7) retinal detachment, and (8) macular degeneration (Table 15.7). TABLE 15.6 Changes in the Eye Caused by Aging Structure Cornea Formation of gray ring at edge of cornea (arcus senilis) Anterior chamber Lens Ciliary muscles Retina

*The

Change Thicker and less curved Not detrimental to vision

Consequence Increase in astigmatism

Decrease in size and volume caused Occasionally exerts pressure on Schlemm canal and may by thickening of lens lead to increased intraocular pressure and glaucoma Increase in opacity Decrease in refraction with increased light scattering (blurring) and decreased color vision (green and blue); can lead to cataracts Reduction in pupil diameter, Persistent constriction (senile miosis); decrease in critical atrophy of radial dilation muscles flicker frequency* Reduction in number of rods at Increase in minimum amount of light necessary to see an periphery, loss of rods and object associated nerve cells

rate at which consecutive visual stimuli can be presented and still be perceived as separate.

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TABLE 15.7 Causes of Visual Acuity Changes Disorder Amblyopia

Description Reduced or dimmed vision; cause unknown Associated with strabismus Accompanies such diseases as diabetes mellitus, renal failure, and malaria and use of drugs such as alcohol and tobacco Scotoma Circumscribed defect of central field of vision Often associated with retrobulbar neuritis and multiple sclerosis, compression of optic nerve by tumor, inflammation of optic nerve, pernicious anemia, methyl alcohol poisoning, and use of tobacco Cataract Cloudy or opaque area in ocular lens—the leading cause of blindness Incidence increases with age because most commonly a result of degeneration; other causes are congenital Papilledema Edema and inflammation of optic nerve where it enters eyeball Caused by obstruction of venous return from retina by one of three main sources: increased intracranial pressure, retrobulbar neuritis, or changes in retinal blood vessels Dark With age, eye does not adapt as readily to dark adaptation Also, changes in quantity and quality of rhodopsin are causative; vitamin A deficiencies can produce this at any age Glaucoma Increased intraocular pressures (>12-20 mm Hg) Loss of acuity results from pressure on optic nerve, which blocks flow of nutrients to optic nerve fibers, leading to their death; second leading cause of blindness Retinal Tear or break in retina with accumulation of fluid and separation from underlying tissue; seen as floaters, detachment flashes of light, or a curtain over visual field; risks include extreme myopia, diabetic retinopathy, sickle cell disease

A cataract is a cloudy or opaque area in the ocular lens and leads to visual loss when located on the visual axis (see Fig. 15.5). It is the leading cause of blindness in the world. The incidence of cataracts increases with age as lens proteins break down, leading to opacification. Cataracts develop because of alterations of metabolism and transport of nutrients within the lens. Although the most common form of cataract is degenerative, cataracts also may occur congenitally or as a result of infection, radiation, trauma, drugs, or diabetes mellitus. Cataracts cause decreased visual acuity, blurred vision, glare, and decreased color perception. Cataracts are treated by removal of the entire lens and replacement with an intraocular artificial lens. Glaucomas are the second leading cause of blindness and are characterized by intraocular pressures greater than 12 to 20 mm Hg with death of retinal ganglion cells and their axons and irreversible loss of vision.56 There are three primary types of glaucoma: 1. Open angle. This type of glaucoma is characterized by outflow obstruction of aqueous humor at the trabecular meshwork or canal of Schlemm even though there is adequate space for drainage; often this is an inherited disease and is a leading cause of blindness with few preliminary symptoms. 2. Angle closure or narrow angle. In this type of glaucoma there is displacement of the iris toward the cornea with obstruction of the trabecular meshwork and obstruction of outflow of aqueous humor from the anterior chamber; it may occur acutely with a sudden rise in intraocular pressure, causing pain and visual disturbances. 3. Congenital closure. This is a rare disease associated with congenital malformations and other genetic anomalies.

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Angle closure glaucoma is a medical emergency. Both medical and surgical therapies are available to control intraocular pressure for all types of glaucoma. Age-related macular degeneration (AMD) is a severe and irreversible loss of vision and a major cause of blindness in older individuals. Hypertension, cigarette smoking, diabetes mellitus, and a family history of AMD are risk factors. The degeneration usually occurs after the age of 60 years. There are two forms: atrophic (dry, nonexudative) and neovascular (wet, exudative). The atrophic form is more common and is slowly progressive with inflammation and accumulation of lipofuscin (a lysosomal pigmented residue) and drusen (waste products from photoreceptors) in the retina and may include limited night vision and difficulty reading. The neovascular form includes accumulation of drusen and lipofuscin, abnormal choroidal blood vessel growth, leakage of blood or serum, retinal detachment, fibrovascular scarring, loss of photoreceptors, and more severe and rapid loss of central vision. Treatment includes anti–vascular endothelial growth factor (anti-VEGF) injection for wet macular degeneration and antioxidant vitamins for dry macular degeneration. Daily high doses of vitamins C and E, beta-carotene, and the minerals zinc and copper—called the AREDS formulation—can help slow the progression to advanced AMD.57 Alterations in accommodation. Accommodation refers to changes in the shape of the lens and allows for a change of focus from distant to near images. Accommodation is mediated through the oculomotor nerve. Pressure, inflammation, age, and disease of the oculomotor nerve may alter accommodation, causing diplopia, blurred vision, and headache. Loss of accommodation with advancing age is termed presbyopia, a condition in which the ocular lens becomes larger, firmer, and less elastic. The major symptom is reduced near vision, causing the individual to hold reading material at arm's length. Treatment includes corrective forward, contact, and intraocular lenses or laser refractive surgery for monovision.58 Alterations in refraction. Alterations in refraction are the most common visual problem. Causes include irregularities of the corneal curvature, the focusing power of the lens, and the length of the eye. The major symptoms of refraction alterations are blurred vision and headache. Three types of refraction alterations are as follows (Fig. 15.7):

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FIGURE 15.7 Alterations in Refraction. A, Myopic eye. Parallel rays of light are brought to a focus in front of the retina. B, Hyperopic eye. Parallel rays of light come to a focus behind the retina in the unaccommodative eye. C, Simple myopic astigmatism. The vertical bundle of rays is focused on the retina; the horizontal rays are focused in front of the retina. (From Stein HA et al: The ophthalmic assistant: a text for allied and associated ophthalmic personnel, ed 9, Philadelphia, 2013, Saunders.)

Myopia—nearsightedness: Light rays are focused in front of the retina when the person is looking at a distant object. Hyperopia—farsightedness: Light rays are focused behind the retina when a person is looking at a near object. Astigmatism—unequal curvature of the cornea: Light rays are bent unevenly and do not come to a single focus on the retina. Astigmatism may coexist with myopia, hyperopia, or presbyopia. Alterations in color vision. Normal sensitivity to color diminishes with age because of the progressive yellowing of the lens that occurs with aging. All colors become less intense, although color discrimination for blue and green is greatly affected. Color vision deteriorates more rapidly for individuals with diabetes mellitus than for the general population. Abnormal color vision also may be caused by color blindness and is an X-linked genetic trait.59 Congenital color blindness affects 6% to 8% of the male population and about 0.5% of the female population. Although many forms of color blindness exist, most commonly the affected individual cannot distinguish red from green. In the most severe form (achromatopsia) individuals see only shades of gray, black, and white. Acquired color vision deficiency occurs with ocular, neurologic, or systemic disease. Neurologic disorders causing visual dysfunction. Vision may be disrupted at many points along the visual pathway, causing various defects in the visual field. Visual changes may cause defects or blindness in the entire visual field or in half of a visual field (hemianopia). Fig. 15.8 illustrates the many areas along the visual

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pathway that may be damaged and the associated visual changes. Injury to the optic nerve causes same-side blindness. Injury to the optic chiasm (the X-shaped crossing of the optic nerves) can cause various defects, depending on the location of the injury.

FIGURE 15.8

Visual Pathways and Defects. (Modified from Thompson JM et al: Mosby's clinical nursing, ed 5, St Louis, 2002, Mosby.)

External Eye Structure and Disorders Protective external eye structures include the eyelids (palpebrae), conjunctivae, and lacrimal apparatus. The eyelids control the amount of light reaching the eyes, and the conjunctiva lines the eyelids. Tears released from the lacrimal apparatus bathe the surface of the eye and prevent friction, maintain hydration, and wash out foreign bodies and other irritants (Fig. 15.9).

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FIGURE 15.9 Lacrimal Apparatus. Fluid produced by lacrimal glands (tears) streams across the eye surface, enters the canals, and then passes through the nasolacrimal duct to enter the nose. (From Applegate E: The anatomy and physiology learning system, ed 4, St Louis, 2011, Saunders.)

Infection and inflammatory responses are the most common conditions affecting the supporting structures of the eyes. Blepharitis is an inflammation of the eyelids caused by Staphylococcus or seborrheic dermatitis. A hordeolum (stye) is an infection (usually staphylococcal) of the sebaceous glands of the eyelids, usually centered near an eyelash. A chalazion is a noninfectious lipogranuloma of the meibomian (oil-secreting) gland that often occurs in association with a hordeolum and appears as a deep nodule within the eyelid. These conditions present with redness, swelling, and tenderness and are treated symptomatically. Entropion is a common eyelid malposition in which the lid margin turns inward against the eyeball. There are both surgical and nonsurgical treatments to reposition the lid margin. Conjunctivitis is an inflammation of the conjunctiva (mucous membrane covering the front part of the eyeball) caused by viruses (most common), bacteria, allergies, or chemical irritants.60 Acute bacterial conjunctivitis (pinkeye) is highly contagious and often caused by Staphylococcus, Haemophilus, Streptococcus pneumoniae, and Moraxella catarrhalis, although other bacteria may be involved (Fig. 15.10). In children younger than 6 years, Haemophilus infection often leads to otitis media (conjunctivitis-otitis syndrome). Preventing the spread of the microorganism with meticulous hand washing and use of separate towels is important. The disease also is treated with antibiotics.

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FIGURE 15.10 Bacterial Conjunctivitis. Staphylococcal conjunctivitis of the left eye with mild erythema and inflammatory edema of the eyelids. Purulent exudate can be seen at the lateral canthus. (From Durkin SR et al: Recurrent staphylococcal conjunctivitis associated with facial impetigo contagiosa, Am J Ophthalmol 141(1):189-190, 2006. Available at https://doi.org/10.1016/j.ajo.2005.07.079.)

Viral conjunctivitis is caused by an adenovirus. It, too, is contagious, with symptoms of watering, redness, and photophobia. Allergic conjunctivitis is associated with a variety of antigens, including pollens. Chronic conjunctivitis results from any persistent conjunctivitis. Trachoma (chlamydial conjunctivitis) is caused by Chlamydia trachomatis and often is associated with poor hygiene and leads to corneal scarring. It is the leading cause of preventable blindness in the world. Keratitis is an infection of the cornea caused by bacteria or viruses. Bacterial infections can cause corneal ulceration, and type 1 herpes simplex virus can involve both the cornea and the conjunctiva. Acanthamoeba keratitis can occur from contact lens wear because of poor hygiene. Severe ulcerations with residual scarring require corneal transplantation.

Hearing The Normal Ear The ear is divided into three areas: (1) the external ear, involved only with hearing; (2) the middle ear, involved only with hearing; and (3) the inner ear, involved with both hearing and equilibrium. The external ear is composed of the pinna (auricle), which is the visible portion of the ear, and the external auditory canal, a tube that leads to the middle ear (Fig. 15.11). The external auditory canal is surrounded by the bones of the cranium. The opening (meatus) of the canal is just above the mastoid process. The air-filled sinuses, called mastoid air cells, of the mastoid process promote conductivity of sound between the external and the middle ear. The tympanic membrane separates the external ear from the middle ear. Sound waves entering the external auditory canal hit the tympanic membrane (eardrum) and cause it to vibrate.

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FIGURE 15.11 External, Middle, and Inner ears. (Anatomic structures are not drawn to scale.) (From Applegate E: The anatomy and physiology learning system, ed 4, St Louis, 2011, Saunders.)

The middle ear is composed of the tympanic cavity, a small chamber in the temporal bone. Three ossicles (small bones known as the malleus [hammer], incus [anvil], and stapes [stirrup]) transmit the vibration of the tympanic membrane to the inner ear. When the tympanic membrane moves, the malleus moves with it and transfers the vibration to the incus, which passes it on to the stapes. The stapes presses against the oval window, a small membrane of the inner ear. The movement of the oval window promotes movement of the round window and sets the fluids of the inner ear in motion (Fig. 15.12).

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FIGURE 15.12 The Inner Ear. A, The bony labyrinth (tan) is the hard outer wall of the entire inner ear and includes the semicircular canals, vestibule, and cochlea. Within the bony labyrinth is the membranous labyrinth (purple), which is surrounded by perilymph and filled with endolymph. Each ampulla in the vestibule contains a crista ampullaris that detects changes in head position and sends sensory impulses through the vestibular nerve to the brain. B, Section of the membranous cochlea. Hair cells in the organ of Corti detect sound and send the information through the cochlear nerve. The vestibular and cochlear nerves join to form the eighth cranial nerve. (From Applegate E: The anatomy and physiology learning system, ed 4, St Louis, 2011, Saunders.)

The eustachian (pharyngotympanic) tube connects the middle ear with the thorax. Normally flat and closed, the eustachian tube opens briefly when a person swallows or yawns, and it equalizes the pressure in the middle ear with atmospheric pressure. Equalized pressure permits the tympanic membrane to vibrate freely. Through the eustachian tube the mucosa of the middle ear is continuous with the mucosal lining of the throat. The inner ear is a system of osseous labyrinths (bony, mazelike chambers) filled with a

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fluid, the perilymph. The bony labyrinth is divided into the cochlea, the vestibule, and the semicircular canals (see Fig. 15.12). Suspended in the perilymph is the endolymph-filled membranous labyrinth that basically follows the shape of the bony labyrinth. Within the cochlea is the organ of Corti, which contains hair cells (hearing receptors). Sound waves that reach the cochlea through vibrations of the tympanic membrane, ossicles, and oval window set the cochlear fluids into motion. Receptor cells on the basilar membrane are stimulated when their hairs are bent or pulled by fluid movement. Once stimulated, hair cells transmit impulses along the cochlear nerve (a division of the vestibulocochlear nerve) to the auditory cortex of the temporal lobe in the brain (see Fig. 15.12 and view an animation at https://www.youtube.com/watch?v=46aNGGNPm7s). This is where interpretation of the sound occurs. The semicircular canals and vestibule of the inner ear contain equilibrium receptors. In the semicircular canals the dynamic equilibrium receptors respond to changes in direction of movement. Within each semicircular canal is the crista ampullaris, a receptor region composed of a tuft of hair cells covered by a gelatinous cupula. When the head is rotated, the endolymph in the canal lags behind and moves in the direction opposite to the head's movement. The hair cells are stimulated, and impulses are transmitted through the vestibular nerve (a division of the vestibulocochlear nerve) to the cerebellum. The vestibule in the inner ear contains maculae—receptors essential to the body's sense of static equilibrium. As the head moves, otoliths (small pieces of calcium salts) move in a gel-like material in response to changes in the pull of gravity. The otoliths pull on the gel, which in turn pulls on the hair cells in the maculae. Nerve impulses in the hair cells are triggered and transmitted to the brain (see Fig. 15.12). Thus the ear not only permits the hearing of a large range of sounds but also assists with maintaining balance through the sensitive equilibrium receptors (see animation at https://www.youtube.com/watch? v=YMIMvBa8XGs).

Auditory Dysfunction Between 5% and 10% of the general population have impaired hearing, and it is the most common sensory defect. The major categories of auditory dysfunction are conductive hearing loss, sensorineural hearing loss, mixed hearing loss, and functional hearing loss. Hearing loss may range from mild to profound. Auditory changes caused by aging are common and incremental (see the box Geriatric Considerations: Aging & Changes in Hearing).

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Geriatric Considerations Aging & Changes in Hearing* Changes in Structure Cochlear hair cell degeneration

Changes in Function Inability to hear high-frequency sounds (presbycusis, sensorineural loss); interferes with understanding speech; hearing may be lost in both ears at different times Loss of auditory neurons in spiral Inability to hear high-frequency sounds (presbycusis, sensorineural loss); interferes ganglia of organ of Corti with understanding speech; hearing may be lost in both ears at different times Degeneration of basilar (cochlear) Inability to hear at all frequencies but more pronounced at higher frequencies conductive membrane of cochlea (cochlear conductive loss) Decreased vascularity of cochlea Equal loss of hearing at all frequencies (strial loss); inability to disseminate localization of sound Loss of cortical auditory neurons Equal loss of hearing at all frequencies (strial loss); inability to disseminate localization of sound

*Hearing

loss affects about 33% of older people. Hearing loss is associated with declining cognitive function, changes in perception, comprehension, and memory, but causal mechanisms are not clearly known. Data from Frisina RD: Ann N Y Acad Sci 1170:708-717, 2009; Jayakody DMP et al: Front Neurosci 12:125, 2018; Roth TN: Handb Clin Neurol 129:357-373, 2015. Conductive hearing loss. A conductive hearing loss occurs when a change in the outer or middle ear impairs conduction of sound from the outer to the inner ear. Conditions that commonly cause a conductive hearing loss include impacted cerumen, foreign bodies lodged in the ear canal, benign tumors of the middle ear, carcinoma of the external auditory canal or middle ear, eustachian tube dysfunction, otitis media, acute viral otitis media, chronic suppurative otitis media, cholesteatoma (accumulation of keratinized epithelium), and otosclerosis. Symptoms of conductive hearing loss include diminished hearing and soft speaking voice. The voice is soft because often the individual hears his or her voice, conducted by bone, as loud. Sensorineural hearing loss. A sensorineural hearing loss is caused by impairment of the organ of Corti or its central connections. The loss may occur gradually or suddenly. Conditions causing sensorineural loss include congenital and hereditary factors, noise exposure, aging, Ménière disease, ototoxicity, systemic disease (syphilis, Paget disease, collagen diseases, diabetes mellitus), neoplasms, and autoimmune processes.61 Congenital and neonatal sensorineural hearing loss may be caused by maternal rubella, ototoxic drugs, prematurity, traumatic delivery, erythroblastosis fetalis, bacterial meningitis, and congenital hereditary malfunction. Diagnosis often is made when delayed speech development is noted. Sudden onset bilateral

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sensorineural hearing loss is a medical emergency. Presbycusis is the most common form of sensorineural hearing loss in elderly people. Its cause may be atrophy of the basal end of the organ of Corti, loss of auditory receptors, changes in vascularity, or stiffening of the basilar membranes. Drug ototoxicities (drugs that cause destruction of auditory function) have been observed after exposure to various chemicals; for example, antibiotics such as streptomycin, neomycin, gentamicin, and vancomycin; diuretics such as ethacrynic acid and furosemide; and chemicals such as salicylate, quinine, carbon monoxide, nitrogen mustard, arsenic, mercury, gold, tobacco, and alcohol. In most instances, the drugs and chemicals listed initially cause tinnitus (ringing in the ear), followed by a progressive high-tone sensorineural hearing loss that is permanent. Mixed and functional hearing loss. A mixed hearing loss is caused by a combination of conductive and sensorineural losses. With functional hearing loss, which is rare, the individual does not respond to voice and appears not to hear. It is thought to be caused by emotional or psychologic factors. Ménière disease. Ménière disease (endolymphatic hydrops is an episodic chronic disorder of the middle ear with an unknown etiology that can be unilateral or bilateral. There is excessive endolymph and pressure in the membranous labyrinth that disrupts both vestibular and hearing functions. There are four symptoms: recurring episodes of vertigo (often accompanied by severe nausea and vomiting), hearing loss, ringing in the ears (tinnitus), and a feeling of fullness in the ear. Treatment is symptomatic with medical management or surgical management when medications fail.62

Ear Infections Otitis externa. Otitis externa is the most common inflammation of the outer ear and may be acute or chronic, infectious or noninfectious. The most common origins of acute infections are bacterial microorganisms including Pseudomonas, Staphylococcus aureus, and, less commonly, Escherichia coli. Fungal infections are less common. Infection usually follows prolonged exposure to moisture (swimmer's ear). The earliest symptoms are inflammation with pruritus, swelling, and clear drainage, progressing to purulent drainage with obstruction of the canal. Tenderness and pain with earlobe retraction accompany inflammation. Acidifying solutions are used for early treatment and prevention. Topical antimicrobials usually provide effective treatment for later stages of disease.63 Chronic infections are more often related to allergy or skin disorders. Otitis media. Otitis media is a common infection of infants and children. Most children have one episode by 3 years of age. The most common pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Predisposing factors include allergy, sinusitis, submucosal cleft palate, adenoidal hypertrophy, eustachian tube dysfunction, and immune deficiency. Breast-feeding is a protective factor. Recurrent acute otitis media may be

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genetically determined.64 Acute otitis media (AOM) is associated with ear pain, fever, irritability, inflamed tympanic membrane, and fluid in the middle ear. The appearance of the tympanic membrane progresses from erythema to opaqueness with bulging as fluid accumulates. There is an increasing prevalence of AOM caused by penicillin-resistant microorganisms. Otitis media with effusion (OME) is the presence of fluid in the middle ear without symptoms of acute infection (Fig. 15.13).

FIGURE 15.13 Otitis Media. A, Obstructing wax or foreign bodies in external ear canal (see arrow) precluding visualization of the TM to establish an OM diagnosis. B, A normal TM (n-TM) showing a semitransparent pearly white TM, triangular shaped light reflex, and malleus bone clearly visible (red ring and line, respectively). C, Acute otitis media showing a bulging TM with red color (see arrow). D, Otitis media with effusion (see arrow) showing a retracted TM and fluid in the middle ear (see arrow). E, Chronic suppurative otitis media showing a TM perforation (see arrow). TM, tympanic membrane. (From Myburgh HC et al: Otitis media diagnosis for developing countries using tympanic membrane image-analysis, EBioMedicine 5:156–160, 2016. Available at https://www.sciencedirect.com/science/article/pii/S2352396416300500.)

Treatment includes symptom management, particularly of pain, with watchful waiting, antimicrobial therapy for severe illness, and placement of tympanostomy tubes when there is persistent bilateral effusion and significant hearing loss. Complications include mastoiditis, brain abscess, meningitis, and chronic otitis media with hearing loss. Persistent middle ear effusions may affect speech, language, and cognitive abilities. Multivalent vaccines for influenza result in modest prevention of acute otitis media.65

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Olfaction (smell) is a function of cranial nerve I and part of cranial nerve V. Taste (gustation) is a function of multiple nerves in the tongue, soft palate, uvula, pharynx, and upper esophagus innervated by cranial nerves VII and IX. Both of these cranial nerves are influenced by hormones within the sensory cells. Dysfunctions of smell and taste may occur separately or jointly. The strong relationship between smell and taste creates the sensation of flavor. If either sensation is impaired, the perception of flavor is altered. Olfactory structures are illustrated in Fig. 15.14.

FIGURE 15.14 Olfaction. Midsagittal section of the nasal area shows the location of major olfactory sensory structures. (From Patton KT, Thibodeau GA, Douglas MM: Essentials of anatomy & physiology, St Louis, 2012, Mosby.)

Olfactory cells, located in the olfactory epithelium, are the receptor cells for smell. Seven different primary classes of olfactory stimulants have been identified: (1) camphoraceous, (2) musky, (3) floral, (4) peppermint, (5) ethereal, (6) pungent, and (7) putrid. The primary sensations of taste are (1) sour, (2) salty, (3) sweet, (4) bitter, and (5) umami (savory taste of glutamate). Taste buds (fungiform, foliate, and circumvallate) sensitive to each of the primary sensations are located in specific areas of the tongue: sweet near the tip, salty on frontal sides, sour on the posterior sides, bitter on the very back, and umami overall surface of tongue. Sensitivity to odors declines steadily with aging. (See the box Geriatric Considerations: Aging & Changes in Olfaction and Taste for a summary of changes in olfaction and taste with aging.)

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Geriatric Considerations Aging & Changes in Olfaction and Taste • Decline in sensitivity to odors, usually after age 80, occurs. • Loss of olfaction may diminish appetite, taste, and food selection and may affect nutrition. • Inability to smell toxic fumes or gases can pose a safety hazard. • Decline in taste sensitivity is more gradual than decline in sense of smell. • Higher concentrations of flavors required to stimulate taste. • Taste may be influenced by decreased salivary secretion.

Olfactory and Taste Dysfunctions Olfactory dysfunctions include the following: 1. Hyposmia—impaired sense of smell 2. Anosmia—complete loss of sense of smell 3. Olfactory hallucinations—smelling odors that are not really present 4. Parosmia—abnormal or perverted sense of smell The sense of taste can be impaired by injury. Altered taste may be attributed to impaired smell associated with injury near the hippocampus. Hypogeusia is a decrease in taste sensation, whereas ageusia is an absence of the sense of taste. These disorders result from cranial nerve injuries and can be specific to the area of the tongue innervated. Dysgeusia is a perversion of taste in which substances possess an unpleasant flavor (i.e., metallic). Alterations in taste may compromise adequate nutrition or cause anorexia.66

Quick Check 15.4 1. List the major structures of the eye. 2. Visual disorders fall into several categories; name them. 3. How does fluid accumulate in the middle ear during otitis media? 4. What factors are involved in the sensation of flavor?

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Somatosensory Function Touch The sensation of touch involves four afferent fiber types that mediate tactile sensation, and there may be an additional sensory nerve that transmits pleasurable touch.67 Receptors sensitive to touch are present in the skin with high densities in the fingers and lips. Meissner and pacinian corpuscles sense movement across the skin and vibration, respectively. Merkel disks sense sustained light touch, and Ruffini endings respond to deep sustained pressure, stretch, and joint position. Specific sensory input is carried to the higher levels of the CNS by the dorsal column of the spinal cord and the anterior spinothalamic tract. The cutaneous senses develop before birth, but structural growth continues into early adulthood. Then a gradual decline occurs, with loss in tactile discrimination with advancing age.68 Abnormal tactile perception may be caused by alterations at any level of the nervous system, from the receptor to the cerebral cortex. Factors that interrupt or impair reception, transmission, perception, or interpretation of touch—including trauma, tumor, infection, metabolic changes, vascular changes, and degenerative diseases—may cause tactile dysfunction. In addition, most tactile sensations evoke affective responses that determine whether the sensation is unpleasant, pleasant, or neutral.

Proprioception Proprioception is the awareness of the position of the body and its parts. It depends on impulses from the inner ear and from receptors in joints and ligaments. Sensory data are transmitted to higher centers, primarily through the dorsal columns and the spinocerebellar tracts, with some data passing through the medial lemnisci and thalamic radiations to the cortex. These stimuli are necessary for the coordination of movements, the grading of muscular contraction, and the maintenance of equilibrium. As with tactile dysfunction, any factor that interrupts or impairs the reception, transmission, perception, or interpretation of proprioceptive stimuli also alters proprioception and increases the risk for falls and injury. A progressive loss of proprioception has been reported in elderly persons with an increased risk for falls and injury.69 Two common causes are vestibular dysfunction and neuropathy. Specific vestibular dysfunctions are vestibular nystagmus and vertigo. Vestibular nystagmus is the constant, involuntary movement of the eyeball and develops when the semicircular canal system is overstimulated. Vertigo is the sensation of spinning that occurs with inflammation of the semicircular canals in the ear. The individual may feel either that he or she is moving in space or that the world is revolving. Vertigo often causes loss of balance, and nystagmus may occur. Ménière disease can cause loss of proprioception during an acute attack, so that standing or walking is impossible. Peripheral neuropathies also can cause proprioceptive dysfunction. They may be caused by several conditions and commonly are associated with renal disease and diabetes mellitus. Although the exact sequence of events is unknown, neuropathies cause a diminished or absent sense of body position or position of body parts. Gait changes often occur.

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Quick Check 15.5 1. How are different touch receptors distributed over the body? 2. What are two causes of alterations in proprioception?

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Summary Review Pain 1. Pain (nociception) is a complex, sensory experience involving emotion, cognition, and motivation. Acute pain is protective, promoting withdrawal from painful stimuli. 2. Three portions of the nervous system are responsible for the sensation, perception, and response to pain: (1) the afferent pathways, (2) the interpretive centers in the central nervous system, and (3) the efferent pathways. 3. Nociception involves four phases: transduction, transmission, perception, and modulation. 4. Pain transduction begins when nociceptors (pain receptors) are activated by noxious stimulants. There are two types of nociceptors: mylinated Aδ fibers transmit sharp, “fast” pain; smaller, unmyelinated C fibers more slowly transmit dull, less localized pain. 5. Pain transmission is the conduction of pain impulses along the nociceptors into the spinal cord and eventually to the brain. 6. Pain perception is the conscious awareness of pain. It occurs with the integration of three systems. The sensory-discriminative system (mediated by the somatosensory cortex) identifies the location and intensity of pain. The affective-motivational system (mediated by the reticular formation, limbic system, and brain stem) controls emotional and affective responses to pain. The cognitive-evaluative system (mediated by the cortex) coordinates the meaning an experience of pain. 7. Pain threshold is the lowest intensity of pain that a person can recognize. Pain tolerance is the greatest level of pain that an individual is prepared to tolerate. Both are subjective and influenced by many factors. 8. Pain modulation increases or decreases the transmission of pain signals throughout the nervous system. Neuromodulators of pain include substances that (1) stimulate pain nociceptors (e.g., prostaglandins, bradykinins, lymphokines, substance P, glutamate) and (2) suppress pain (e.g., GABA, endogenous opioids, endocannabinoids). Some substances excite peripheral nerves but inhibit central nerves (e.g., serotonin, norepinephrine). 9. Endogenous opioids inhibit pain transmission and include enkephalins, endorphins, dynorphins, and endomorphins. They are produced in the central nervous system and by immune cells. 10. Descending inhibitory and facilitatory pathways and nuclei inhibit or facilitate pain. Efferent pathways from the ventromedial medulla and periaqueductal gray inhibit pain impulses at the dorsal horn. The rostroventromedial medulla (RVM) stimulates efferent pathways that facilitate or inhibit pain in the dorsal horn 11. Segmental pain inhibition occurs when impulses from Aβ fibers (touch and vibration sensations) arrive at the same spinal level as impulses from Aδ or C fibers. 12. Diffuse noxious inhibitory control occurs when pain signals from two different sites are transmitted simultaneously and inhibit pain through a spinal-medullary-

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spinal pathway. 13. Because of the complex nature of pain, classifications of pain often overlap, and more than one description is often used. 14. Acute pain is a signal to the person of a harmful stimulus and may be (1) somatic (skin, joints, muscles), (2) visceral (inner organs, body cavities), or (3) referred (present in an area distant from its origin). The area of referred pain is supplied by the same spinal segment as the actual site of pain. 15. Chronic pain is pain lasting well beyond the expected normal healing time and may be ongoing (e.g., low back pain) or intermittent (e.g., migraine headaches). Psychologic, behavioral, and physiologic responses to chronic pain include depression, sleep disorders, preoccupation with pain, lifestyle changes, and physiologic adaptation. 16. Neuropathic pain is increased sensitivity to painful or nonpainful stimuli and results from abnormal processing of pain information in the peripheral or central nervous system.

Temperature Regulation 1. Temperature regulation (thermoregulation) is achieved through precise balancing of heat production, heat conservation, and heat loss. Body temperature is maintained in a range around 37° C (98.6° F). 2. Temperature regulation is mediated by the hypothalamus and endocrine system through peripheral thermoreceptors in the skin, liver, and skeletal muscle and central thermoreceptors in the hypothalamus, spinal cord, viscera, and great veins. 3. Heat is produced through chemical reactions of metabolism and skeletal muscle contraction. Heat is distributed by the circulatory system. 4. Heat is lost through radiation, conduction, convection, vasodilation, decreased muscle tone, evaporation of sweat, increased respiration, voluntary mechanisms, and adaptation to warmer climates. 5. Infants do not conserve heat well because of their greater body surface/mass ratio and decreased amounts of subcutaneous fat. Elderly persons have poor responses to environmental temperature extremes as a result of slowed blood circulation, structural and functional changes in the skin, and overall decrease in heatproducing activities. 6. Fever involves the “resetting of the hypothalamic thermostat” to a higher level. When the fever breaks, the set point returns to normal. Fever is triggered by the release of exogenous pyrogens from bacteria or the release of endogenous pyrogens (cytokines) from phagocytic cells. 7. Fever of unknown origin is a body temperature greater than 38.3° C (101° F) for longer than 3 weeks that remains undiagnosed after 3 days of investigation. 8. Fever production aids responses to infectious processes. Higher temperatures kill many microorganisms, promote immune responses, and decrease serum levels of iron, zinc, and copper, which are needed for bacterial replication. 9. Hyperthermia (marked warming of core temperature) can produce nerve damage, coagulation of cell proteins, and death. Therapeutic hyperthermia may be used to promote natural immune processes or promote tumor blood flow. Forms of

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accidental hyperthermia include heat cramps, heat exhaustion, heat stroke, and malignant hyperthermia. Heat stroke and malignant hyperthermia are potentially lethal. 10. Hypothermia (marked cooling of core temperature) slows the rate of cell metabolism, increases the viscosity of the blood, slows blood flow through the microcirculation, facilitates blood coagulation, and stimulates profound vasoconstriction. Hypothermia may be accidental or therapeutic. 11. 11. Major body trauma can affect temperature regulation by damaging the CNS or causing inflammation, increased intracranial pressure, or intracranial bleeding. It results in a sustained, noninfectious fever called central fever.

Sleep 1. Sleep is an active process that provides restorative functions and promotes memory consolidation. Sleep is divided into rapid eye movement (REM) and non-REM stages, each of which has its own series of stages. While asleep, an individual progresses through REM and non-REM (slow wave) sleep multiple times in a predictable cycle. 2. REM sleep is controlled by mechanisms in the pons and mesencephalon. It is known as paradoxical sleep because the EEG pattern is similar to that of an awake person. The brain is very active with dreaming. 3. Non-REM sleep is controlled by release of inhibitory signals from the hypothalamus and accounts for 75% to 80% of sleep time. The body is in a state of reduced activity. 4. The sleep patterns of the newborn and young child vary from those of the adult in total sleep time, cycle length, and percentage of time spent in each sleep cycle. Elderly persons experience a total decrease in sleep time. 5. The restorative, reparative, and growth processes occur during slow-wave (nonREM) sleep. Sleep deprivation can cause profound changes in personality and functioning. 6. Sleep disorders include (1) dyssomnias, which are disorders of initiating or maintaining sleep (i.e., insomnia, obstructive sleep apnea syndrome, hypersomnia, or disorders of the sleep-wake schedule) and (2) parasomnias, which are unusual behaviors during sleep (i.e., sleepwalking or night terrors and restless legs syndrome).

The Special Senses 1. The special senses include vision, hearing, olfaction, and taste. 2. The eyes are responsible for vision. The wall of the eye has three layers: sclera, choroid, and retina. The retina contains millions of baroreceptors known as rods and cones that receive light through the lens and then convey signals to the optic nerve and subsequently to the visual cortex of the brain. 3. The eye is filled with vitreous and aqueous humor, which prevent it from collapsing. 4. The major alterations in ocular movement include strabismus, nystagmus, and

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paralysis of the extraocular muscles. 5. Alterations in visual acuity (the ability to see objects in sharp detail) can be caused by amblyopia, scotoma, cataracts, papilledema, dark adaptation, glaucoma, retinal detachment, and macular degeneration. Visual acuity decreases with age due to structural eye changes. 6. A cataract is a cloudy or opaque area in the ocular lens and leads to visual loss when located on the visual axis. Cataracts are the leading cause of blindness in the world. 7. Glaucomas are characterized by intraocular pressures with death of retinal ganglion cells and their axons. 8. Age-related macular degeneration is irreversible loss of vision with atrophic (dry) or neovascular (wet) forms. 9. Alterations in accommodation (changes in lens shape that changes focus from distant to near images) develop with increased intraocular pressure, inflammation, age, and disease of the oculomotor nerve. Presbyopia is loss of accommodation caused by loss of elasticity of the lens with aging. 10. Alterations in refraction, including myopia, hyperopia, and astigmatism, are the most common visual disorders. 11. Alterations in color vision can be related to yellowing of the lens with aging and color blindness, an inherited trait. 12. Trauma or disease of the optic nerve pathways can cause defects or blindness in the entire visual field or in half of the visual field (hemianopia). 13. The eyelids, conjunctivae, and lacrimal apparatus protect the eye externally. Infections are the most common disorders; they include blepharitis, conjunctivitis, chalazion, and hordeolum. 14. Blepharitis is an inflammation of the eyelid; a hordeolum (stye) is an infection of the eyelid's sebaceous gland; and a chalazion is an infection of the eyelid's meibomian gland. 15. Conjunctivitis is an inflammation of the conjunctiva, and can be acute or chronic, bacterial, viral, or allergic. Redness, edema, pain, and lacrimation are common symptoms. Trachoma (chlamydial conjunctivitis) is the leading cause of preventable blindness in the world and is associated with poor hygiene. 16. Keratitis is a bacterial or viral infection of the cornea that can lead to corneal ulceration. 17. The ears are responsible for hearing. The ear is composed of external, middle, and inner structures. 18. The external ear structures are the pinna, auditory canal, and tympanic membrane. The external ear is only involved in hearing. 19. The middle ear is composed of the tympanic cavity (containing three bones: the malleus, the incus, and the stapes), oval window, eustachian tube, and fluid. These transmit sound vibrations to the inner ear. The middle ear is only involved in hearing. 20. The inner ear is involved in both hearing and equilibrium. It includes the bony and membranous labyrinths that transmit sound waves through the cochlea and to the cochlear nerve and ultimately to the brain. The semicircular canals and vestibule help maintain balance through the equilibrium receptors. 21. Impaired hearing is the most common sensory defect, occurring in 5% to 10% of

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the general population. 22. Hearing loss can be classified as conductive, sensorineural, mixed, or functional. 23. Conductive hearing loss occurs when sound waves cannot be conducted through the middle ear. 24. Sensorineural hearing loss develops with impairment of the organ of Corti or its central connections. Presbycusis is the most common form of sensorineural hearing loss in elderly people. 25. A combination of conductive and sensorineural loss is a mixed hearing loss. Loss of hearing with no known organic cause is a functional hearing loss. 26. Ménière disease is a disorder of the middle ear that affects hearing and balance. 27. Otitis externa is an infection of the outer ear associated with prolonged exposure to moisture. 28. Otitis media is an infection of the middle ear that is common in children. Accumulation of fluid (effusion) behind the tympanic membrane is a common finding. 29. Olfaction (smell) is a function of cranial nerve I and part of cranial nerve V. Taste (gustation) is a function of multiple nerves in the tongue, soft palate, uvula, pharynx, and upper esophagus innervated by cranial nerves VII and IX 30. The perception of flavor is altered if olfaction or taste dysfunctions occur. Sensitivity to odor and taste decreases with aging. 31. Hyposmia is an impaired sense of smell, and anosmia is the complete loss of the sense of smell. 32. Hypogeusia is a decrease in taste sensation, and ageusia is the absence of the sense of taste.

Somatosensory Function 1. The sensation of touch is a function of receptors present in the skin, and the sensory response is conducted to the brain through the dorsal column and anterior spinothalamic tract. 2. Alterations in touch can result from alterations at any level of the nervous system. 3. Proprioception is the awareness of the position and location of the body and its parts. Proprioceptors are located in the inner ear, joints, and ligaments. Proprioceptive stimuli are necessary for balance, coordinated movement, and grading of muscular contraction. 4. Disorders of proprioception can occur at any level of the nervous system and result in impaired balance and lack of coordinated movement. Vestibular nystagmus is the constant, involuntary movement of the eyeball and develops when the semicircular canal system is overstimulated. Vertigo is the sensation of spinning that occurs with inflammation of the semicircular canals in the ear.

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Key Terms A-beta (Aβ) fiber, 330 Accidental hyperthermia, 335 Accommodation, 340 Acute bacterial conjunctivitis (pinkeye), 342 Acute otitis media (AOM), 344 Acute pain, 330 A-delta (Aδ) fiber, 328 Affective-motivational system, 329 Age-related macular degeneration (AMD), 340 Ageusia, 345 Allergic conjunctivitis, 342 Allodynia, 332 Amblyopia, 338 Anosmia, 344 Aqueous humor, 338 Astigmatism, 340 Blepharitis, 341 Cannabinoid, 330 Cannabis, 330 Cataract, 339 Central fever, 335 Central neuropathic pain, 332 Central sensitization, 332 C fiber, 328 Chalazion, 341 Choroid, 338 Chronic conjunctivitis, 342 Chronic pain, 331 Circadian rhythm sleep disorder, 337 Cochlea, 343 Cognitive-evaluative system, 329 Color blindness, 341 Conductive hearing loss, 343 Cone, 338 Conjunctivitis, 341 Cornea, 338 Crista ampullaris, 343 Descending inhibitory pathway, 330 Diffuse noxious inhibitory control (DNIC), 330 Diplopia, 338 Dynorphin, 329 Dysgeusia, 345 Endocannabinoid, 330

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Endogenous opioid, 329 Endogenous pyrogen, 333 Endomorphin, 329 Endorphin, 329 Enkephalin, 329 Entropion, 341 Equilibrium receptor, 343 Eustachian (pharyngotympanic) tube, 342 Excitatory neurotransmitter, 329 Exogenous pyrogen, 333 Expectancy-related cortical activation, 330 External auditory canal, 342 Facilitatory pathway, 330 Fever, 333 Fever of unknown origin (FUO), 334 Fovea centralis, 338 Functional hearing loss, 344 Glaucoma, 339 Hair cell, 343 Heat cramp, 335 Heat exhaustion, 335 Heat stroke, 335 Heterosegmental pain inhibition or conditioned pain modulation, 330 Hordeolum (stye), 341 Hyperopia, 340 Hypersomnia, 337 Hyperthermia, 335 Hypogeusia, 345 Hyposmia, 344 Hypothermia, 335 Incus (anvil), 342 Inhibitory neurotransmitter, 329 Insomnia, 336 Iris, 338 Jerk nystagmus, 338 Keratitis, 342 Lens, 338 Macula lutea, 338 Maculae, 343 Malignant hyperthermia, 335 Malleus (hammer), 342 Mastoid air cell, 342 Mastoid process, 342 Meissner corpuscle, 345 Ménière disease (endolymphatic hydrops), 344 Merkel disk, 346 Mixed hearing loss, 344

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Myopia, 340 Narcolepsy, 337 Neuropathic pain, 331 Night terrors, 337 Nociceptin/orphanin FQ, 329 Nociception, 327 Nociceptive pain, 327 Nociceptor, 327 Non-REM sleep, 336 Nystagmus, 338 Obstructive sleep apnea syndrome (OSAS), 336 Olfaction (smell), 344 Olfactory hallucination, 344 Optic chiasm, 341 Optic disc, 338 Optic nerve, 338 Organ of Corti, 343 Otitis externa, 344 Otitis media, 344 Otitis media with effusion (OME), 344 Otolith, 343 Oval window, 342 Pacinian corpuscle, 346 Pain modulation, 329 Pain perception, 328 Pain threshold, 329 Pain tolerance, 329 Pain transduction, 328 Pain transmission, 328 Parasomnia, 337 Parosmia, 344 Pendular nystagmus, 338 Perceptual dominance, 329 Perilymph, 342 Peripheral neuropathic pain, 332 Peripheral sensitization, 332 Persistent pain, 331 Pinna, 342 Presbycusis, 343 Presbyopia, 340 Proprioception, 346 Pupil, 338 Rapid eye movement (REM) sleep, 336 Referred pain, 331 Restless legs syndrome (RLS)/Willis Ekbom disease, 337 Retina, 338 Rod, 338

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Ruffini ending, 346 Sclera, 338 Segmental pain inhibition, 330 Semicircular canal, 343 Sensorineural hearing loss, 343 Sensory-discriminative system, 329 Shift work sleep disorder, 337 Sleep, 335 Somatic pain, 330 Somnambulism (sleepwalking), 337 Stapes (stirrup), 342 Strabismus, 338 Taste (gustation), 344 Temperature regulation (thermoregulation), 333 Therapeutic hyperthermia, 335 Thermoregulation, 333 Tinnitus, 343 Touch, 345 Trachoma, 342 Tympanic cavity, 342 Tympanic membrane, 342 Vertigo, 346 Vestibular nystagmus, 346 Vestibule, 343 Viral conjunctivitis, 342 Visceral pain, 331 Vitreous humor, 338

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56. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. J Am Med Assoc. 2014;311(18):1901–1911. 57. Chew EY, et al. Long-term effects of vitamins C, E, betacarotene and zinc on age related macular degeneration, AREDS Report No. 35. Ophthalmology. 2013;120(8):1604–1611. 58. Liu HH, Hu Y, Cui HP. Femtosecond laser in refractive and cataract surgeries. Int J Ophthalmol. 2015;8(2):419–426. 59. Simunovic MP. Colour vision deficiency. Eye (Lond). 2010;24(5):747–755. 60. Alfonso SA, Fawley JD, Alexa Lu X. Conjunctivitis. Prim Care. 2015;42(3):325–345. 61. Lasak JM, et al. Hearing loss: diagnosis and management. Prim Care. 2014;41(1):19–31. 62. Nevoux J, et al. International consensus (ICON) on treatment of Ménière's disease. Eur Ann Otorhinolaryngol Head Neck Dis. 2018;135(1S):S29–S32. 63. Hajioff D, MacKeith S. Otitis externa. BMJ Clin Evid. 2015;2015 [pii 0510]. 64. Rye MS, et al. Genetic susceptibility to otitis media in childhood. Laryngoscope. 2012;122(3):665–675. 65. Norhayati MN, Ho JJ, Azman MY. Influenza vaccines for preventing acute otitis media in infants and children. Cochrane Database Syst Rev. 2017;(10) [CD010089]. 66. Visvanathan R, Chapman IM. Undernutrition and anorexia in the older person. Gastroenterol Clin North Am. 2009;38(3):393– 409. 67. McGlone F, Reilly D. The cutaneous sensory system. Neurosci Biobehav Rev. 2010;34(2):148–159. 68. Norman JF, et al. Aging and curvature discrimination from static and dynamic touch. PLoS ONE. 2013;8(7):e68577. 69. Sohn J, Kim S. Falls study: proprioception, postural stability, and slips. Biomed Mater Eng. 2015;26(Suppl 1):S693–S703.

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Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function Barbara J. Boss, Sue E. Huether

CHAPTER OUTLINE Alterations in Cognitive Systems, 351 Alterations in Arousal, 351 Alterations in Awareness, 357 Data-Processing Deficits, 359 Seizure Disorders, 365 Alterations in Cerebral Hemodynamics, 367 Increased Intracranial Pressure, 367 Cerebral Edema, 369 Hydrocephalus, 369 Alterations in Neuromotor Function, 370 Alterations in Muscle Tone, 370 Alterations in Muscle Movement, 372 Upper and Lower Motor Neuron Syndromes, 375 Motor Neuron Diseases, 377 Amyotrophic Lateral Sclerosis, 377 Alterations in Complex Motor Performance, 378 Disorders of Posture (Stance), 378 Disorders of Gait, 379 Disorders of Expression, 379 Extrapyramidal Motor Syndromes, 379

Intellectual and behavioral functions are achieved by integrated processes of cognitive systems, sensory systems, and motor systems. The purpose of this chapter is to present the concepts and processes of alterations in these systems as an approach to understanding the manifestations of neurologic dysfunction that can occur with disease or injury. Some specific diseases also are presented here (i.e., Parkinson disease, Huntington disease, and

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amyotrophic lateral sclerosis) because they best fit here. (Specific disorders of the central and peripheral nervous system are presented in Chapter 17. Alterations in sensory function were presented in Chapter 15.) The neural systems essential to cognitive function are (1) attentional systems that provide arousal and maintenance of attention over time; (2) memory and language systems by which information is remembered and communicated; and (3) affective or emotive systems that mediate mood, emotion, and intention. These core systems are fundamental to the processes of abstract thinking and reasoning. The products of abstraction and reasoning are organized and made operational through executive attentional networks. The normal functioning of these networks manifests through the motor network in a behavioral array viewed by others as appropriate to human activity and successful living.

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Alterations in Cognitive Systems Consciousness is a state of awareness both of oneself and of the environment, and a set of responses to that environment. Consciousness has two distinct components: arousal (state of awakeness or alertness) and awareness (content of thought). Arousal is mediated by the reticular activating system, which regulates aspects of attention and information processing and maintains consciousness. Awareness encompasses all cognitive functions and is mediated by attentional systems, memory systems, language systems, and executive systems.

Alterations in Arousal Alterations in level of arousal may be caused by structural, metabolic, or psychogenic (functional) disorders. Pathophysiology Structural alterations in arousal are divided according to the primary location of the pathologic condition. Causes include infection, vascular alterations, neoplasms, traumatic injury, congenital alterations, degenerative changes, polygenic traits, and metabolic disorders. Supratentorial disorders (above the tentorium cerebelli) produce changes in arousal by either diffuse or localized dysfunction. Diffuse dysfunction may be caused by disease processes affecting the cerebral cortex or the underlying subcortical white matter (e.g., encephalitis). Disorders outside the brain but within the cranial vault (extracerebral) that can produce diffuse dysfunction include neoplasms, closed-head trauma with subsequent subdural bleeding, and accumulation of pus in the subdural space. Localized dysfunction occurs when masses develop within the brain substance (intracerebral). The sources of these masses include bleeding, infarcts, emboli, and tumors. Such localized destructive processes directly impair function of the thalamic or hypothalamic activating systems or secondarily compress these structures in a process of herniation. Infratentorial disorders (below the tentorium cerebelli) produce a decline in arousal by (1) direct destruction or compression of the reticular activating system and its pathways (e.g., demyelinating disorders or accumulations of blood or pus and growth of tumors) or (2) the brainstem (midbrain, pons, medulla) may be destroyed either by direct invasion or by indirect impairment of its blood supply. Metabolic disorders produce a decline in arousal by alterations in delivery of energy substrates as occurs with hypoxia, electrolyte disturbances, or hypoglycemia. Metabolic disorders caused by liver or renal failure cause alterations in neuronal excitability because of failure to metabolize or eliminate drugs and toxins. All the systemic diseases that eventually produce nervous system dysfunction are part of this metabolic category. Psychogenic alterations in arousal (unresponsiveness), although uncommon, may signal general psychiatric disorders. Despite apparent unconsciousness, the person actually is physiologically awake, and the neurologic examination reflects normal responses. Clinical Manifestations and Evaluation Five patterns of neurologic function are critical to the evaluation of consciousness: (1) level

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of consciousness, (2) pattern of breathing, (3) pupillary reaction, (4) oculomotor responses, and (5) motor responses. Patterns of clinical manifestations help in determining the extent of brain dysfunction and serve as indexes for identifying increasing or decreasing central nervous system (CNS) function. Distinctions are made between metabolic and structurally induced manifestations (Table 16.1). The types of manifestations suggest the mechanism of the altered arousal state (Table 16.2). TABLE 16.1 Clinical Manifestations of Metabolic and Structural Causes of Altered Arousal Manifestations Blink to threat (cranial nerves II, VII) Optic discs (cranial nerve II) Extraocular movement (cranial nerves III, IV, VI) Pupils (cranial nerves II, III) Corneal reflex (cranial nerves V, VII) Grimace to pain (cranial nerve VII) Motor function movement Muscle tone

Metabolically Induced Equal

Structurally Induced Asymmetric

Flat, good pulsation

Papilledema

Roving eye movements; normal doll's eyes and calorics

Gaze paresis, nerve palsy

Equal and reactive; may be dilated (e.g., atropine), pinpoint (e.g., opiates), or midposition and fixed (e.g., glutethimide [Doriden]) Symmetric response

Asymmetric or nonreactive; may be midposition (midbrain injury), pinpoint (pons injury), large (tectal injury) Asymmetric response

Symmetric response

Asymmetric response

Symmetric

Asymmetric

Symmetric

Posture

Symmetric

Deep tendon reflexes Babinski sign Sensation

Symmetric

Paratonic (rigid), spastic, flaccid, especially if asymmetric Decorticate, especially if symmetric; decerebrate, especially if asymmetric (see Fig. 16.6) Asymmetric

Absent or symmetric response Symmetric

Present Asymmetric

TABLE 16.2 Differential Characteristics of States Causing Altered Arousal Mechanism Supratentorial mass lesions compressing or displacing diencephalon or brainstem

Manifestations Initiating signs usually of focal cerebral dysfunction: vomiting, headache, hemiparesis, ocular signs, seizures, coma Signs of dysfunction progress rostral to caudal Neurologic signs at any given time point to one anatomic area (e.g., diencephalon, mesencephalon, medulla) Motor signs often asymmetric Infratentorial mass of destruction causing coma History of preceding brainstem dysfunction or sudden onset of coma Localizing brainstem signs precede or accompany onset of coma and always include oculovestibular abnormality Cranial nerve palsies usually manifest “bizarre” respiratory patterns that appear at onset

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Metabolic coma Exogenous toxins (drugs) Endogenous toxins (organ system failure)

Psychiatric unresponsiveness

Confusion and stupor commonly precede motor signs Motor signs usually are symmetric Pupillary reactions usually are preserved Asterixis, myoclonus, tremor, and seizures are common Acid–base imbalance with hyperventilation or hypoventilation is common Lids close actively; pupils reactive or dilated (cycloplegics) Oculocephalic reflexes are unpredictable; oculovestibular reflexes are physiologic (nystagmus is present) Motor tone is inconsistent or normal Eupnea or hyperventilation is usual No pathologic reflexes are present Electroencephalogram (EEG) is normal

Level of consciousness is the most critical clinical index of nervous system function, with changes indicating either improvement or deterioration of the individual's condition. A person who is alert and oriented to self, others, place, and time is considered to be functioning at the highest level of consciousness, which implies full use of all the person's cognitive capacities. From this normal alert state, levels of consciousness diminish in stages from confusion and disorientation (can occur simultaneously) to coma, each of which is clinically defined (Table 16.3). TABLE 16.3 Levels of Altered Consciousness State Definition Confusion Loss of ability to think rapidly and clearly; impaired judgment and decision making Disorientation Beginning loss of consciousness; the person may exhibit restlessness, anxiety, and irritation; disorientation to time occurs first, followed by disorientation to place and familiar others (family members) and impaired memory; recognition of self is lost last Lethargy Limited spontaneous movement or speech; easy arousal with normal speech or touch; may or may not be oriented to time, place, or person Obtundation Mild to moderate reduction in arousal (awakeness) with limited response to environment; falls asleep unless stimulated verbally or tactilely; answers questions with minimal response Stupor Condition of deep sleep or unresponsiveness from which person may be aroused or caused to open eyes only by vigorous and repeated stimulation; response is often withdrawal or grabbing at stimulus Light coma Associated with purposeful movement on stimulation Coma Associated with nonpurposeful movement only on stimulation Deep coma Associated with unresponsiveness or no response to any stimulus

Patterns of breathing help evaluate the level of brain dysfunction and coma (Fig. 16.1). Rate, rhythm, and pattern should be evaluated. Breathing patterns can be categorized as hemispheric or brainstem patterns (Table 16.4).

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FIGURE 16.1 Abnormal Respiratory Patterns With Corresponding Level of Central Nervous System Activity. A, Posthyperventilation apnea is seen with bilateral cerebral dysfunction. B, Cheyne-Stokes respiration is seen with metabolic injury and lesions in the forebrain and diencephalon. C, Central neurogenic hyperventilation is most commonly seen with metabolic encephalopathies (lesion of midbrain, pons or medulla). D, Apneustic breathing (inspiratory pauses) is seen in patients with bilateral pontine lesions. E, Cluster breathing and ataxic breathing are seen in lesions at the pontine medullary junction. F, Ataxic breathing occurs when the medullary ventral respiratory nuclei are injured. (From Urden LD et al: Critical care nursing: diagnosis and management, ed 6, St Louis, 2010, Mosby.)

TABLE 16.4 Patterns of Breathing Breathing Pattern Description Hemispheric Breathing Patterns Normal After a period of hyperventilation that lowers arterial carbon dioxide pressure (PaCO2), individual continues to breathe regularly but with reduced depth. Posthyperventilation Respirations stop after hyperventilation has lowered apnea the concentration of carbon dioxide in the blood (PCO2) level below normal. Rhythmic breathing returns when PCO2 level returns to normal. Cheyne-Stokes Breathing pattern has a smooth increase (crescendo) in rate respirations and depth of breathing (hyperpnea), which peaks and is followed by a gradual smooth decrease (decrescendo) in rate and depth of breathing to point of apnea, when cycle repeats itself. Hyperpneic phase lasts longer than apneic phase. Brainstem Breathing Patterns Central neurogenic A sustained, deep, rapid, but regular pattern (hyperpnea) hyperventilation occurs, with a decreased PaCO2 and a corresponding increase in pH and the partial pressure of oxygen in the arterial blood (PaO2). Apneusis

Location of Injury Response of nervous system to an external stressor—not associated with injury to CNS Associated with diffuse bilateral metabolic or structural disease of cerebrum

Bilateral dysfunction of deep cerebral or diencephalic structures; seen with supratentorial injury and metabolically induced coma states

May result from CNS damage or disease that involves midbrain and upper pons; seen after increased intracranial pressure and blunt head trauma A prolonged inspiratory cramp (a pause at full inspiration) Indicates damage to respiratory occurs; a common variant of this is a brief end-inspiratory control mechanism located at pontine pause of 2 or 3 sec, often alternating with an endlevel; most commonly associated expiratory pause. with pontine infarction but

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Cluster breathing Ataxic breathing Gasping breathing pattern (agonal gasps)

documented with hypoglycemia, anoxia, and meningitis A cluster of breaths has a disordered sequence with Dysfunction in lower pontine and irregular pauses between breaths. high medullary areas Completely irregular breathing occurs, with random Originates from a primary shallow and deep breaths and irregular pauses. Rate is dysfunction of medullary neurons often slow. controlling breathing A pattern of deep “all-or-none” breaths is accompanied by Indicative of a failing medullary a slow respiratory rate. respiratory center

CNS, Central nervous system.

With normal breathing, a neural center in the forebrain (cerebrum) produces a rhythmic pattern. When consciousness decreases, lower brainstem centers regulate the breathing pattern by responding only to changes in arterial carbon dioxide (PaCO2) levels. This pattern is called posthyperventilation apnea. Cheyne-Stokes respiration is an abnormal rhythm of ventilation with alternating periods of tachypnea and apnea with a crescendodecrescendo pattern. Increases in PaCO2 levels lead to tachypnea. The PaCO2 level then decreases to below normal, and breathing stops (apnea) until the carbon dioxide reaccumulates and again stimulates tachypnea (see Fig. 16.1). In cases of opiate or sedative drug overdose, the respiratory center is depressed, so the rate of breathing gradually decreases until respiratory failure occurs. Pupillary changes indicate the presence and level of brainstem dysfunction because brainstem areas that control arousal are adjacent to areas that control the pupils (Fig. 16.2). For example, severe ischemia and hypoxia usually produce dilated, fixed pupils. Hypothermia may cause fixed pupils.

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FIGURE 16.2

Appearance of Pupils at Different Levels of Consciousness.

Some drugs affect the pupils and must be considered in evaluating individuals in comatose states. Large doses of atropine and scopolamine (drugs that block parasympathetic stimulation) fully dilate and fix the pupils. Doses of sedatives in sufficient amounts to produce coma cause the pupils to become midposition or moderately dilated, unequal, and commonly fixed to light. Opiates cause pinpoint pupils. Severe barbiturate intoxication may produce fixed pupils. Oculomotor responses are resting, spontaneous, and reflexive eye movements. They change at various levels of brain dysfunction in comatose individuals. Persons with metabolically induced coma, except with barbiturate-hypnotic and phenytoin poisoning, generally retain ocular reflexes even when other signs of brainstem damage are present. Destructive or compressive injury to the brainstem causes specific abnormalities of the oculocephalic and oculovestibular reflexes (Figs. 16.3 and 16.4). Injuries that involve an oculomotor nucleus or nerve (cranial nerve III) cause the involved eye to deviate outward, producing a resting dysconjugate lateral position of the eye.

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FIGURE 16.3 Test for Oculocephalic Reflex Response (Doll Eyes Phenomenon). A, Normal response— eyes turn together to side opposite from turn of head. B, Abnormal response—eyes do not turn in conjugate manner. C, Absent response—eyes move in direction of head movement (brainstem injury). (From Rudy EB: Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)

FIGURE 16.4

Test for Oculovestibular Reflex (Caloric Ice Water Test). A, Ice water is injected into the ear

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canal. Normal response—conjugate eye movements. B, Abnormal response—dysconjugate or asymmetric eye movements. C, Absent response—no eye movements.

Assessment of motor responses helps evaluate the level of brain dysfunction and determine the most severely damaged side of the brain. The patterns of response may be (1) purposeful; (2) inappropriate, generalized motor movement; or (3) not present. Motor signs indicating loss of cortical inhibition that are commonly associated with decreased consciousness include primitive reflexes and rigidity (paratonia) (Fig. 16.5). Primitive reflexes include grasping, reflex sucking, snout reflex, and palmomental reflex, all of which are normal in the newborn but disappear in infancy. Abnormal flexor and extensor responses in the upper and lower extremities are defined in Table 16.5 and illustrated in Fig. 16.6.

FIGURE 16.5

Pathologic Reflexes. A, Grasp reflex. B, Snout reflex. C, Palmomental reflex. D, Suck reflex.

TABLE 16.5 Abnormal Motor Responses With Decreased Responsiveness Motor Response Decorticate posturing/rigidity: upper extremity flexion, lower extremity extension Decerebrate posturing/rigidity: upper and lower extremity extensor responses

Description Location of Injury Slowly developing flexion of arm, wrist, and fingers Hemispheric damage above with adduction in the upper extremity and extension, midbrain releasing medullary internal rotation, and plantar flexion of lower extremity and pontine reticulospinal systems Opisthotonos (hyperextension of vertebral column) with Associated with severe damage clenching of teeth; extension, abduction, and involving midbrain or upper hyperpronation of arms; and extension of lower pons extremities In acute brain injury, shivering and hyperpnea may Acute brain injury often causes accompany unelicited recurrent decerebrate spasms limb extension regardless of location Extensor responses in upper Pons extremities accompanied by flexion in lower extremities Flaccid state with little or no Lower pons and upper medulla motor response to stimuli

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FIGURE 16.6 Decorticate and Decerebrate Posture/Responses. A, Decorticate posture/response. Flexion of arms, wrists, and fingers with adduction in upper extremities. Extension, internal rotation, and plantar flexion in lower extremities. Both sides. B, Decerebrate posture/response. All four extremities in rigid extension, with hyperpronation of forearms and plantar extension of feet. (From deWit SC, Kumagai CK: Medical-surgical nursing, ed 2, St Louis, 2013, Saunders.)

Vomiting, yawning, and hiccups are complex reflex-like motor responses that are integrated by neural mechanisms in the lower brainstem. These responses may be produced by compression or diseases involving tissues of the medulla oblongata (e.g., infection, tumors, infarction). They also may occur when there is benign stimuli to the vagal nerve (i.e., from the gut, liver, and kidney). Most CNS disorders produce nausea and vomiting. Vomiting without nausea indicates direct involvement of the central neural mechanism (or pyloric obstruction; see Chapters 38 and 39). Vomiting often accompanies CNS injuries that (1) involve the vestibular nuclei (cranial nerve VIII) or its immediate projections, particularly when double vision (diplopia) also is present; (2) impinge directly on the floor of the fourth ventricle; or (3) produce brainstem compression secondary to increased intracranial pressure.

Quick Check 16.1 1. Why are structural as well as metabolic factors capable of producing coma? 2. Why is level of consciousness the most critical index of central nervous system function? 3. How do changes in PaCO2 cause Cheyne-Stokes respirations in coma? 4. What level of brain injury is associated with oculomotor changes?

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Outcomes of Alterations in Arousal Outcomes of alterations in arousal fall into two categories: extent of disability (morbidity) and mortality. Outcomes depend on the cause and extent of brain damage and the duration of coma. Some individuals may recover consciousness and an original level of function, some may have permanent disability, and some may never regain consciousness and experience neurologic death. Two forms of neurologic death—brain death and cerebral death—result from severe pathologic conditions and are associated with irreversible coma. Other possible outcomes are a vegetative state, a minimally conscious state, or locked-in syndrome. The extent of disability has four subcategories: recovery of consciousness, residual cognitive function, psychologic function, and vocational function. Brain death (total brain death) occurs when the brain is damaged so completely that it can never recover (irreversible) and cannot maintain the body's internal homeostasis. State laws define brain death as irreversible cessation of function of the entire brain, including the brainstem and cerebellum. On postmortem examination, the brain is autolyzing (selfdigesting) or already autolyzed. Brain death has occurred when there is no evidence of brain function for an extended period.1 The abnormality of brain function must result from structural or known metabolic disease and must not be caused by a depressant drug, alcohol poisoning, or hypothermia. An isoelectric, or flat, electroencephalogram (EEG) (electrocerebral silence) for 6 to 12 hours in a person who is not hypothermic and has not ingested depressant drugs indicates brain death. The clinical criteria used to determine brain death are noted in Box 16.1. A task force for determination of brain death in children recommended the same criteria as for adults, but with a longer observation period.2

Box 16.1

Criteria for Brain Death 1. Completion of all appropriate diagnostic and therapeutic procedures with no possibility of brain function recovery 2. Unresponsive coma (no motor or reflex movements) 3. No spontaneous respiration (apnea) 4. No brainstem functions (ocular responses to head turning or caloric stimulation; dilated, fixed pupils; no gag or corneal reflex [see Figs. 16.3 and 16.4]) 5. Isoelectric (flat) electroencephalogram (EEG) (electrocerebral silence) 6. Persistence of these signs for an appropriate observation period Summarized from Wijdicks EF et al: Neurology 74(23):1911-1918, 2010. Cerebral death, or irreversible coma, is death of the cerebral hemispheres exclusive of the brainstem and cerebellum. Brain damage is permanent, and the individual is forever unable to respond behaviorally in any significant way to the environment. The brainstem may continue to maintain internal homeostasis (i.e., body temperature, cardiovascular functions, respirations, and metabolic functions). The survivor of cerebral death may remain in a coma or emerge into a persistent vegetative state (VS) or a minimally conscious state. In coma, the eyes are usually closed with no eye opening. The person does not follow

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commands, speak, or have voluntary movement. A persistent vegetative state is complete unawareness of the self or surrounding environment and complete loss of cognitive function. The individual does not speak any comprehensible words or follow commands. Sleep-wake cycles are present, eyes open spontaneously, and blood pressure and breathing are maintained without support. Brainstem reflexes (pupillary, oculocephalic, chewing, swallowing) are intact, but cerebral function is lost. There is bowel and bladder incontinence. Recovery is unlikely if the state persists for 12 months. In a minimally conscious state (MCS, minimally preserved consciousness) individuals may follow simple commands, manipulate or reach for objects, gesture or give yes/no responses, have intelligible speech, and have movements such as blinking or smiling. Individuals may remain permanently in this state or progress to minimal ability to understand and communicate.3 With locked-in syndrome there is complete paralysis of voluntary muscles with the exception of eye movement. Content of thought and level of arousal are intact, but the efferent pathways are disrupted. The injury is at the base of the pons with the reticular formation intact and often is caused by basilar artery occlusion.4 Thus the individual cannot communicate through speech or body movement but is fully conscious, with intact cognitive function. Vertical eye movement and blinking are a means of communication.

Alterations in Awareness Awareness (content of thought) encompasses all cognitive functions, including awareness of self, environment, and affective states (i.e., moods). Awareness is mediated by all of the core networks under the guidance of executive attention networks, including selective attention and memory. Executive attention networks involve abstract reasoning, planning, decision making, judgment, error correction, and self-control. Each attentional function is a network of interconnected brain areas and not localized to a single brain area. Selective attention (orienting, focusing) refers to the ability to select specific information to be processed from available, competing environmental and internal stimuli, and to focus on that stimulus (i.e., to concentrate on a specific task without being distracted).5 Selective visual attention is the ability to select objects from multiple visual stimuli and process them to complete a task (i.e., selecting a square red object from among various objects when sorting objects according to configuration and color). Selective auditory or hearing attention is the ability to select or filter specific sounds and process them to complete a task (i.e., listening to a person's verbal directions and blocking out background music or traffic noise). Multiple areas of the brain are involved in selective attention including cortical areas, thalamic nuclei, and the limbic system. Selective attention deficits can be temporary, permanent, or progressive. Disorders associated with selective attention deficits include seizure activity, parietal lobe contusions, subdural hematomas, stroke, gliomas or metastatic tumor, late Alzheimer dementia, frontotemporal dementia, and psychotic disorders. Memory is the recording, retention, and retrieval of information. Working memory (short-term memory) is remembering temporary information long enough to make a decision or complete a task (seconds to a few minutes). For example, remembering the first sentences in a paragraph in order to understand the concepts included by the end of the paragraph. Long-term memory can last indefinitely and last a lifetime. Amnesia is the loss of memory and can be mild or severe. Two types of amnesia are retrograde amnesia and

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anterograde amnesia. The person experiencing retrograde amnesia has difficulty retrieving or recalling past personal history memories (i.e., place of birth or high school graduation) or past factual memories (i.e., current address or phone number). Anterograde amnesia is the inability to form new personal or factual memories (i.e., where a car is parked or recognize a person one has met in the preceding minutes) but memories of the distant past are retained and retrieved. Global amnesia is a combination of anterograde and retrograde amnesia. Such individuals may not be able to recall where they are, how they arrived there, where or when they were born, or recognize family and friends. Image processing is a higher level of memory function and includes the ability to integrate sensory data and language to form concepts, assign meaning, and make abstractions. Alterations in image processing include an inability to form concepts and generalizations or to reason. Thinking is very concrete. For example, a person will not understand the abstract phrase “walking on eggs shells” and may look at his or her feet for the eggshells. These memory disorders may be temporary (e.g., after a seizure) or permanent (e.g., after severe head injury or in Alzheimer disease). There may be only the memory disorder, or the memory disorder may be associated with other cognitive disorders, including an inability to make decisions or sustain attention. Table 16.6 contains the clinical manifestations of alterations in attention and memory. TABLE 16.6 Clinical Manifestations of Alterations in Attention and Memory Deficit Attention Selective attention (orienting)

Clinical Signs

Symptoms

Inability to focus attention; decreased eye, head, and body movements associated with focusing on stimuli; decreased search and scanning; faulty orientation to stimuli, causing safety problems

Person reports inability to focus attention, failure to perceive objects and other stimuli (history of injuries, falls, safety problems); can exhibit neglect syndrome (i.e., unilateral neglect with failure to groom or recognize one side of the body)

Left hemisphere: disorientation to time, situation, place, name, person (verbal identification); impaired language memory (e.g., names of objects); impaired semantic memory Right hemisphere: disorientation to self, person (visual), place (visual); impaired episodic memory (personal history); impaired emotional memory Either or both hemispheres: confusion; behavioral change Retrograde Left hemisphere: inability to retrieve personal history, amnesia past medical history; unaware of recent current events (loss of past Right hemisphere: inability to recognize persons, places, memories) objects, music, and so on from past Image Inability to categorize (identify similarities and processing differences) or sort; inability to form concepts; inability to analyze relationships; misinterpretations; inability to interpret proverbs Inability to perform deductive reasoning (convergent reasoning); inability to perform inductive reasoning (divergent reasoning); inability to abstract; concrete reasoning demonstrated; delusions Executive Attention Deficits Vigilance Failure to stay alert and orient to stimuli

Person reports disorientation, confusion, “not listening,” “not remembering”; reports by others of person being disoriented, not able to remember, not able to learn new information

Memory Antegrade amnesia (inability to form new memories)

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Person reports remote memory problems; others report that person cannot recall formerly known information

Reports by others of frequent misinterpretation of data, failure to conceptualize or generalize information Reports by others of predominantly concrete thinking; lack of understanding of everyday situations, healthcare regimens, and such; delusional thinking Person reports decreased alertness or ability to

Detection

Mild Severe

Lack of initiative (anergy); lack of ambition; lack of motivation; flat affect; no awareness of feelings; appears depressed, apathetic, and emotionless; fails to appreciate deficit; disinterested in appearance; lacks concern about childish or crude behavior Responds to immediate environment but no new ideas; grooming and social graces are lacking Motionless; lack of response to even internal cues; does not respond to physical needs; does not interact with surroundings Inability to use feedback regarding behavior; failure to recognize omissions and errors in self-care, speech, writing, and arithmetic; impaired cue utilization; overestimation of performance Failure to shift response set; failure to change behavior when conditions change; cue utilization may be impaired Inability to set goals or form goals; indecisiveness

orient Reports by others of laziness or apathy, flat affect, or lack of emotional expression; failure to exhibit or be aware of feelings Reports by others of lack of ambition, motivation, or initiative; failure to carry out adult tasks; lack of social graces and new ideas Reports by others of failure to groom or toilet self, unawareness of surroundings and own physical needs Reports by others of not changing behavior when requested; unawareness of limitations; does not recognize and correct errors in dressing, grooming, toileting, eating, and such; fails to recognize speech and arithmetic errors; careless speech Reports by others of failure to use feedback; inability to incorporate feedback (does not correct when feedback is given) Reports by others of failure to set goals, indecisiveness Reports by others of failure to plan, impulsiveness, “does not think things through”

Working memory (recent or Failure to make plans; inability to produce a complete short-term line of reasoning; inability to make up a story; appears memory) impulsive Failure to initiate behavior; failure to maintain Reports by others of not knowing where to begin, behavior; failure to discontinue behavior; slowness to inability to carry out sequential acts (maintain a alternate response for the next step; motor behavior), inability to cease a behavior perseveration

Executive attention deficits include the inability to maintain sustained attention and a working memory deficit. Sustained attention deficit is an inability to set goals and recognize when an object meets a goal. A working memory deficit is an inability to remember instructions and information needed to guide behavior. Executive attention deficits may be temporary, progressive, or permanent. ADHD is a common disorder of childhood that can continue through adulthood (Box 16.2).

Box 16.2

Attention-Deficit/Hyperactivity Disorder Initially attention-deficit/hyperactivity disorder (ADHD) was viewed as a neurodevelopmental disorder of childhood. It is now recognized that 50% to 75% of persons diagnosed in childhood have continuing symptoms into adulthood. Often the diagnosis is first made in adolescence or young adulthood, when behavioral control and self-organization are expected of the person. The ability to function at work, at home, and in social situations is often impaired because of inattentiveness, hyperactivity, impulsivity, and problems with executive function. Continued treatment, including medications for symptomatic adults, is supported. The multifactorial patterns of inheritance and gene– environment interactions are under investigation, as are the pathogenesis and pathophysiology of this complex disorder. Findings from structural and functional neuroimaging suggest the involvement of developmentally abnormal brain networks related to cognition, attention, emotion, and sensorimotor functions. Hopefully new findings will lead to improved prevention, diagnosis, treatment options, and functional

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outcomes. Data from Bonvicini C, Faraone SV, Scassellati C: Mol Psychiatry 21(7):872-884, 2016; Gallo EF, Posner J: Lancet Psychiatry 3(6):555-567, 2016; Leahy LG: Arch Psychiatr Nurs 32(6), 2018. Pathophysiology Very generally, the primary pathophysiologic mechanisms that operate in disorders of awareness are (1) direct destruction caused by ischemia and hypoxia or indirect destruction resulting from compression and (2) the effects of toxins and chemicals or metabolic disorders. Disorders of selective attention, at least as they relate to visual orienting behavior, are produced by disease that involves portions of the midbrain. For example, disease affecting the superior colliculus (associated with retinal signals) manifests as a slowness in orienting attention. Parietal lobe disease may produce unilateral neglect syndrome or lack of awareness of one side of the body or lack of response to stimuli on one side of the body. It can occur after a stroke. An individual may groom or dress on only one side or eat food from only one side of the plate. Sensory inattentiveness is a form of neglect. The person is able to recognize individual sensory input from the dysfunctional side when asked but ignores the sensory input from the dysfunctional side when stimulated from both sides (extinction). The entire complex of denial of dysfunction, loss of recognition of one's own body parts, and extinction sometimes is referred to as hemineglect or neglect syndrome. A disorder in vigilance may be produced by disease in the prefrontal areas. Dysfunction in the right anterior cingulate gyrus (part of the “emotional” limbic system) and basal ganglia (coordination of fluid movement) may cause detection problems (i.e., being able to choose among objects without making an error). Problems with working memory may be produced with left lateral frontal lobe injury. Anterograde amnesia originates from pathologic conditions in the hippocampus and related temporal lobe structures; the diencephalic region, including the thalamus; and the basal forebrain. Retrograde amnesia and higher-level memory deficits originate from pathologic conditions in the widely distributed association areas of the cerebral cortex (see Fig. 14.8, C). Executive attention deficits are associated with alterations in the frontal and prefrontal cortex (cognitive functions) including the anterior cingulate gyrus, supplementary motor area, and portions of the basal ganglia. Clinical Manifestations Clinical manifestations of selective attention deficits, memory deficits, and executive attention function deficits are presented in Table 16.6. Evaluation and Treatment Immediate medical management is directed at diagnosing the cause and treating reversible factors. Rehabilitative measures generally focus on compensatory or restorative activities and recently have been greatly facilitated by computer technology and other electronic devices.

Quick Check 16.2 851

1. Why is irreversible coma different from brain death? 2. What is the difference between anterograde and retrograde amnesia? 3. What is an example of neglect syndrome?

Data-Processing Deficits Data-processing deficits are problems associated with recognizing and processing sensory information. These deficits include agnosia, aphasia, and acute confusional states.

Agnosia Agnosia is a defect of pattern recognition—a failure to recognize the form and nature of objects. Agnosia can be tactile, visual, or auditory, but generally only one sense is affected. For example, an individual may be unable to identify a safety pin by touching it with a hand but is able to name it when looking at it. Agnosia may be as minimal as a finger agnosia (failure to identify by name the fingers of one's hand) or more extensive, such as a color agnosia (an inability to name and distinguish colors, for example describing a brown dog as pink). Although agnosia is associated most commonly with cerebrovascular accidents, it may arise from any pathologic process that injures specific areas of the brain.

Aphasia Aphasia is impairment of comprehension or production of language with impaired communication. The terms aphasia and dysphasia are often used interchangeably; the term aphasia is used here. Comprehension or use of symbols, in either written or verbal language, is disturbed or lost. Aphasia results from dysfunction in the left cerebral hemisphere, including the inferior frontal gyrus and superior temporal gyrus, and the subcortical and cortical connecting networks (Fig. 16.7). Aphasias usually are associated with a cerebrovascular accident involving the middle cerebral artery or one of its many branches. Language disorders, however, may arise from a variety of injuries and diseases including vascular, neoplastic, traumatic, degenerative, metabolic, or infectious causes. Most language disorders result from acute processes or a chronic residual deficit of the acute process.

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FIGURE 16.7 Right Cortical, Subcortical, and Brainstem Areas of the Brain Mediating Cognitive Function. (From Boss GJ, Wilkerson R: Communication: language and pragmatics. In Hoeman SP, editor: Rehabilitation nursing; prevention, intervention & outcomes, ed 4, p 508, St Louis, 2008, Mosby.)

Aphasias have been classified anatomically (i.e., Wernicke [sensory speech area] or Broca area [motor speech area] aphasias) or functionally as disorders of fluency (quality and content of speech). Expressive aphasia, also known as Broca, motor, or nonfluent aphasia, involves loss of the ability to produce spoken or written language, with slow or difficult speech. Verbal comprehension is usually present. Expressive aphasia is differentiated from dysarthria, in which words cannot be articulated clearly as a result of cranial nerve damage or muscle impairment. Receptive aphasia, also known as Wernicke, sensory, or fluent aphasia, involves an inability to understand written or spoken language. Speech is fluent, flowing at a normal rate, but words and phrases have no meaning. Anomic aphasia is a sensory aphasia distinguished by difficulty finding words and naming a person or object. Circumlocution, or describing an object as a way of trying to name something, is common in anomic aphasia. Auditory comprehension is present in conductive aphasia, but there is impaired verbatim repetition. Naming also can be impaired. The person recognizes the errors and tries to correct them. Speech is fluent, but words and sounds may be transposed. Damage is in the left hemisphere to networks that connect the Broca and Wernicke areas. Transcortical aphasias are rare and can be motor, sensory, or mixed. They involve areas of the brain that connect into the language centers. Global aphasia is the most severe aphasia and involves both expressive and receptive aphasia. The individual is nonfluent or mute; cannot read or write; and has impaired comprehension, naming, reading, and writing. Global aphasia is usually associated with a cerebrovascular accident involving the middle cerebral artery. Table 16.7 compares types of aphasias, and Table 16.8 illustrates some of the language disturbances. Pure aphasias are rare and are often mixed, making diagnosis difficult. All types of aphasia usually improve with speech rehabilitation. TABLE 16.7 Major Types of Aphasia

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Type

Expression

Expressive Broca, Cannot find nonfluent or words, difficulty motor writing aphasia

Transcortical Halting speech motor, nonfluent aphasia Receptive Wernicke, receptive fluent or sensory aphasia

Conductive dysphasia

Meaningless verbal language, inappropriate words or unable to monitor language for correctness so errors are not recognized Intonation, accent, cadence, rhythm, and articulation normal Difficulty repeating words, phrases spoken to them; naming is impaired

Anomic aphasia

Hesitancy, difficulty recalling names, objects, or numbers Transcortical Repeats words sensory, and phrases fluent spoken to them aphasia

Other Transcortical Repeats words mixed motor and phrases and sensory, spoken to them

Verbal Reading Repetition Writing Comprehension Comprehension

Location of Lesion

Cause of Lesion

Relatively intact Impaired

Variable

Intact

Intact

Impaired

Impaired; disturbance in understanding all language

Impaired

Impaired

Impaired Left posterosuperior temporal lobe (Wernicke area)

Intact

Severely impaired

Variable

Variable

Intact

Impaired

Variable

Intact except for anomia

Poor

Intact

Impaired

Impaired Posterior temporal lobe

Occlusion at the border zone between two cerebral arterial territories

Impaired

Intact

Impaired

Impaired Left cerebral hemisphere; spares the

Occlusion at the border zone

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Impaired Left posteroinferior frontal lobe (Broca area)

Occlusion of one or several branches of left middle cerebral artery supplying inferior frontal gyrus Impaired Anterior Occlusion at superior frontal the border lobe zone between two arterial territories Occlusion of inferior division of left middle cerebral artery

Inferior and posterior temporal lobe; parietotemporal junction

Occlusion in distributions of left middle cerebral artery Left Diffuse left temporoparietal hemisphere zones; arcuate brain fasciculus disease

nonfluent

Global or Mute nonfluent; summation of motor and sensory aphasia

perisylvian cortex

Impaired

Impaired

Impaired

between two cerebral arterial territories Impaired Large areas of Occlusion of the left cortex left middle and subcortical cerebral regions artery of left internal carotid artery, tumors, other mass lesions, hemorrhage, embolic occlusion of ascending parietal or posterior temporal branch of middle cerebral artery

TABLE 16.8 Examples of Aphasia Disorder Wernicke/Fluent/Sensory Aphasia Verbal paraphasia

Wernicke/Fluent/Sensory Aphasia Literal paraphasia Wernicke/Fluent/Sensory Aphasia Neologism Anomic dysphasia (circumlocution example)

Broca or Motor Aphasia Telegraphic style

Example Question: What did the car do? Patient: The car would spit sweetly down the road. (The car sped swiftly down the road.) Request: Say, “Persistence is essential to success.” Patient: Mesastence is instans to success. Question: What do you call this? (Pointing to a plant.) Patient: It's a logper. Question: What do you call this? (Pointing to a plant.) Patient: Something that grows. Patient: It's… Or Question: What did you do this morning? Patient: Reading. Question: Were you reading a book or newspaper? Patient: One of those. Question: Where is your daughter? Patient: New Orleans … home … Monday.

From Boss BJ: J Neurosurg Nurs 16(3):151-160, 1984.

Acute Confusional States and Delirium Acute confusional states (ACSs) (also may be known as delirium or acute organic brain

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syndromes or acute brain failure) are transient disorders of cognitive function, consciousness, or perception and may have either a sudden or a gradual onset. Delirium can be considered as a type of acute confusional state, but for this discussion acute confusional states and delirium are considered to be synonymous. There are many medical conditions associated with delirium, and they are summarized in Box 16.3. Acute confusional states arise from disruption of widely distributed brain networks rather than in a discrete area of the brain. Most metabolic disturbances (i.e., hypoglycemia, thyroid disorders, liver or kidney disease) that produce delirium interfere with neuronal metabolism or synaptic transmission. Several neurotransmitters are involved, including decreased acetylcholine and excess dopamine. Many drugs and toxins also interfere with neurotransmission function at the synapse. The types of delirium include hyperactive and hypoactive states. Some individuals fluxuate between the two states and have mixed delirium.

Box 16.3

Conditions Causing Acute Confusional States/Delirium Drug intoxication Alcohol or drug withdrawal Metabolic disorders (e.g., hypoglycemia, thyroid storm) Brain trauma or surgery or tumors Meningoencephalitis Postanesthesia Febrile illnesses or heat stroke Electrolyte imbalance, dehydration Heart, kidney, or liver failure Sepsis and proinflammatory cytokines Pathophysiology and Clinical Manifestations Delirium (hyperactive confusional state) is an acute disturbance in attention and awareness, associated with autonomic nervous system overactivity and typically develops over 2 to 3 days.6 It commonly occurs in critical care units, after surgery, during withdrawal from CNS depressants (i.e., alcohol or narcotic agents), and in hospitalized elderly.7 Risk factors include medications (i.e., narcotics, benzodiazepines, anticholinergic medications), acute infection or sepsis, surgery, electrolyte disturbances, hypoxia, and metabolic disorders (liver or kidney disease, hypoglycemia, and thyroid disorders). Delirium initially manifests as restlessness, irritability, difficulty in concentrating, insomnia, tremulousness, and poor appetite. Some persons experience seizures. Unpleasant, even terrifying dreams or hallucinations may occur. In a fully developed delirium state, the individual is completely inattentive and perceptions are grossly altered, with extensive misperception and misinterpretation. The person appears distressed and often perplexed; conversation is incoherent. Frank tremor and high levels of restless movement are common. The individual cannot sleep, is flushed, and has dilated pupils, a rapid pulse rate (tachycardia), elevated temperature, and profuse sweating (diaphoresis). Delirium usually abates suddenly or gradually in 2 to 3 days, although occasionally

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delirium states persist for weeks. Excited delirium syndrome (ExDS), also known as agitated delirium, is a type of hyperactive delirium that can lead to sudden death. Its symptoms include altered mental status, combativeness, aggressiveness, tolerance to significant pain, rapid breathing, sweating, severe agitation, elevated temperature, noncompliance or poor awareness to direction from police or medical personnel, inability to become fatigued, unusual or superhuman strength, and inappropriate clothing for the current environment. Hypoactive delirium (hypoactive confusional state) is associated with right-sided frontal-basal ganglion disruption (an area of the brain associated with coordinated movement and alertness).It may occur in individuals who have fevers or metabolic disorders (i.e., chronic liver or kidney failure), or who are under the influence of CNS depressants. The individual exhibits decreases in alertness, attention span, accurate perception, interpretation of the environment, and reaction to the environment. Forgetfulness and apathy are prominent, speech may be slow, and the individual dozes frequently with little spontaneous movement. Evaluation and Treatment The initial goals are to (1) establish that the individual is confused and (2) determine the cause of the confusion (organic or functional) (Table 16.9). The next step is to differentiate whether the confusion is delirium or an underlying dementia; the syndromes can overlap. Individuals with dementia are at increased risk for developing delirium. Table 16.10 contains a comparison of the features differentiating delirium and dementia. A complete history, physical examination, laboratory tests (electrocardiogram and blood, urine, cerebrospinal fluid, and radiologic studies), and review of medications are needed. Several assessment scales are available to guide evaluation (such as the Nursing Delirium Screening Scale and Confusion Assessment Method).8,9 Once the cause is established, treatment is directed at controlling the primary disorder with supportive measures used as appropriate. Delirium is preventable in some individuals.10 TABLE 16.9 Differences Between Organic and Functional Confusion Factor Memory impairment Disorientation Time Place Person

Hallucinations Illusions Delusions Confused

Organic Confusion Recent more impaired than remote

Functional Confusion No consistent difference between recent and remote

Within own lifetime or reasonably near future Familiar place or one where person might easily be found Sense of identity usually preserved Misidentification of others as familiar

May not be related to person's lifetime Bizarre or unfamiliar places

Visual, vivid Animals and insects common Common Concern everyday occurrences and people Spotty confusion Clear intervals mixed with confused episodes Worse at night

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Sense of identity diminished Misidentification of others based on delusion system Auditory more frequent Bizarre and symbolic Not prominent Bizarre and symbolic More consistent No tendency to become worse at night

From Morris M, Rhodes M: Am J Nurs 72(9):1632, 1972.

TABLE 16.10 Comparison of Delirium and Dementia Feature Age Onset

Delirium Usually older Acute—common during hospitalization

Associated Urinary tract infection, thyroid disorders, hypoxia, hypoglycemia, conditions toxicity, fluid-electrolyte imbalance, renal insufficiency, trauma, postsurgical anesthesia Course Fluctuating/reversible with treatment Duration Attention Sleep-wake cycle Alertness Orientation Behavior Speech

Hours to days and months in some cases Inability to focus or sustain attention Disrupted Impaired Impaired Agitated, withdrawn/depressed Incoherent, disorganized

Dementia Usually older Usually insidious and progressive; acute in some cases of strokes/trauma May have no other conditions Brain trauma Chronic slow decline—more stable Months to years Intact early; often impaired late Disturbances are common There may be fluctuations Intact early; impaired late Intact early Word-finding problems or aphasia Impoverished Usually intact early

Thoughts Disorganized, delusions Perceptions Hallucinations/illusions

Adapted from Fong TG et al: Lancet Neurol 14(8):823-832, 2015.

Quick Check 16.3 1. What are two types of dysphasia? 2. How does dysphasia differ from dysarthria? 3. What are some causes of delirium?

Dementia Dementia is an acquired deterioration and a progressive failure of many cerebral functions that includes impairment of intellectual processes with a decrease in orienting, memory, language, judgment, and decision making. Because of declining intellectual ability, the individual may exhibit alterations in behavior, for example, agitation, wandering, and aggression. Pathophysiology Mechanisms leading to dementia include neuron degeneration, compression of brain tissue, atherosclerosis of cerebral vessels, brain trauma, infection, and neuroinflammation. Genetic predisposition is associated with neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson diseases. CNS infections, including the human immunodeficiency virus (HIV) and slow-growing viruses associated with Creutzfeldt-

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Jakob disease, also lead to nerve cell degeneration and brain atrophy. Clinical Manifestations The onset of dementia is generally slow, and symptoms are usually irreversible. Clinical manifestations of the major dementias are presented in Table 16.11. TABLE 16.11 Clinical Manifestations of the Major Degenerative Dementias Disease

Mental Status

Neurobehavior

Alzheimer disease

Memory loss, disorientation to place and time, loss of facial recognition Variable, frontal/executive, focal cortical, memory

Initially normal; progressive cognitive, language, abstraction, and judgment impairment

Creutzfeldt-Jakob disease Dementia with Lewy body (Lewy body dementia)

Initially affects concentration and attention, then memory or cognition loss but unpredictable levels of ability, attention, or alertness; delirium prone Frontotemporal Primary progressive disorders/degeneration/dementia aphasia variant Language loss with talking less and speech becoming hesitant or loss of understanding of language, may precede memory loss; spares drawing Huntington disease Subtle decline in decision making, planning, organizing and recognizing emotion of others several years prior to motor symptoms Vascular dementia Frontal/executive, cognitive slowing; memory can be intact

Neurologic Examination Initially normal

Depression, anxiety, decreased Myoclonus, cognitive function and memory rigidity, loss parkinsonism Visual hallucinations, depression, Parkinsonism sleep disorder, delusions, Changes in transient loss of consciousness walking or movement may present first Behavioral variant frontotemporal dementia Loss of empathy (emotional blunting), apathy, increased inappropriate or decline in personal or social conduct, loss of judgment and reasoning, hyperorality, euphoria, depression Apathy, loss of interest early; impaired cognition, judgment, and memory can occur as prodromal manifestations; loss of smell recognition; decline of finger tapping speed. Often but not always sudden, usually within 3 months of a stroke; variable; apathy, falls, focal weakness, delusions, anxiety

Caused by corticobasal degeneration and progressive supranuclear palsy variants

Chorea, bradykinesia, dystonia

Usually motor slowing, spasticity; can be normal or may have symptom improvement with stroke recovery

Data from Bott NT et al: Neurodegener Dis Manag 4(6):439-454, 2014; Darrow MD: Prim Care 42(2):195-204, 2015; Hugo J, Ganguli M: Clin Geriatr Med 30(3):421-442, 2014; Nordberg A: Nat Rev Neurol 11(2):69-70, 2015.

Evaluation and Treatment Establishing the cause for dementia may be complicated, but individuals with clinical manifestations of dementia should be evaluated with laboratory and neuropsychological testing to identify underlying conditions that may be treatable. Unfortunately, no specific cure exists for most progressive dementias. Therapy is directed at maintaining and maximizing use of the remaining capacities, restoring functions if possible, and

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accommodating to lost abilities. Helping the family understand the process and to learn ways to assist the individual are essential.

Alzheimer Disease Alzheimer disease (AD) (dementia of Alzheimer type [DAT], senile disease complex) is the leading cause of severe cognitive dysfunction in older persons. The three forms of AD are nonhereditary sporadic or late-onset AD (70% to 90%), early-onset familial AD (FAD), and early-onset AD (very rare). In 2019, an estimated 5.8 million Americans had AD; about two-thirds were women.11 Pathophysiology The exact cause of AD is unknown, but both early onset and late onset have genetic associations. Early-onset FAD has been linked to three genes with mutations on chromosome 21 (abnormal amyloid precursor protein 14 [APP14], abnormal presenilin 1 [PSEN1], and abnormal presenilin 2 [PSEN2]). Late-onset AD may be related to the involvement of chromosome 19 with the apolipoprotein E gene-allele 4 (APOE4). Sporadic late-onset AD is the most common, and does not have a specific genetic association; however, the cellular pathology is the same as that for gene-associated early- and late-onset AD.12 DNA methylation is a potential epigenetic marker for AD.13 Pathologic alterations in the brain include the accumulation of extracellular neuritic plaques containing a core of amyloid beta protein and intraneuronal neurofibrillary tangles of tau protein. Neuritic plaques disrupt nerve impulse transmission and cause death of neurons (Fig. 16.8). They are more concentrated in the cerebral cortex and hippocampus (an area of the brain associated with memory). Loss of synapses, acetylcholine, and other neurotransmitters contributes to the decline of memory and attention and the loss of other cognitive functions associated with AD. The loss of neurons results in brain atrophy with widening of sulci and shrinkage of gyri (see Fig. 16.8).

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FIGURE 16.8 Common Pathologic Findings in Alzheimer Disease. A, Comparison of Normal and Alzheimer Brain. The brain decreases in volume and weight, the sulci widen, and the gyri thin, especially in the temporal and frontal lobes. The ventricles enlarge to fill the space. B, Common pathologic findings in Alzheimer disease. (A from National Institute on Aging Scientific Images: Brain images. Available at https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet#changes.)

Clinical Manifestations AD has a long preclinical and prodromal course. Pathophysiologic changes can occur decades before the appearance of the clinical dementia syndrome. The disease progresses from mild short-term memory deficits and culminates in total loss of cognitive and executive functions. Initial clinical manifestations are insidious and often are attributed to forgetfulness, emotional upset, or other illness. The individual becomes progressively more forgetful over time, particularly in relation to recent events. Memory loss increases as the disorder advances. The person becomes disoriented and confused and loses the ability to concentrate. Abstraction, problem solving, and judgment gradually deteriorate with failure

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in mathematic calculation ability, language, and visuospatial orientation. The mental status changes induce behavioral changes, including irritability, agitation, and restlessness. Mood changes also result from the deterioration in cognition. The person may become anxious, depressed, hostile, emotionally labile, and prone to mood swings. Motor changes may occur if the posterior frontal lobes are involved, causing rigidity and flexion posturing. Weight loss can be significant. Great variability in age of onset, intensity and sequence of symptoms, and location and extent of brain abnormalities is common. Stages for the progression of AD are summarized in Table 16.12. TABLE 16.12 Progression of Alzheimer Disease Mild Cognitive Impairment Cognitive Mild memory loss Stage

Functional Possibly depression (vs. apathy); mild anxiety

Early Stage

Middle Stage

Late Stage End Stage

Measurable shortterm memory loss; difficulty with word finding; other cognition problems compared with previous behavior Mild IADL problems

Moderate to severe cognitive problems: impaired reasoning, judgment, and problem solving; disorientation to time, place, and person; difficulty planning and organizing; progressive memory loss IADL-dependent; some ADL problems

Little cognitive ability; language not clear

No significant cognitive function; loss of orientation to self

ADLNonambulatory/bedbound; dependent; unable to eat related to incontinent failure to sense hunger or thirst, difficulty swallowing

ADL, (Basic) activities of daily living; IADL, instrumental activities of daily living (independent performance of activities). Adapted from National Conference of Gerontological Nurse Practitioners and the National Gerontological Nursing Association: Counseling Points 1(1):6, 2008; Peña-Casanova J et al: Arch Med Res 43(8):686-693, 2012.

Evaluation and Treatment The diagnosis of AD is made by ruling out other causes. Clinical criteria have been developed to assist diagnosis.14 The clinical history, including mental status examinations (mini–mental status examination, clock drawing; and geriatric depression scale); laboratory tests; brain imaging of structure, blood flow, and metabolism; and the course of the illness (which may span 5 years or more), is used to assess progression of the disease. Efforts are in progress to identify imaging and biochemical markers for risk assessment and early diagnosis and progression of Alzheimer type and other neurodegenerative causes of dementia15 (see Did You Know? Biomarkers and Neurodegenerative Dementia).

Did You Know? Biomarkers and Neurodegenerative Dementia Neurodegenerative disease processes that lead to dementia begin many years before clinical manifestations are evident for Alzheimer disease, Huntington disease, and

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Parkinson disease. Efforts are under way to identify neuroimaging techniques to visualize Aβ deposits and neurodegenerative lesions. Predictive biomarkers for tau protein, amyloid β peptides, and apolipoprotein E4 in the brain, spinal fluid, and blood will guide a more comprehensive understanding of the etiology and biologic pathways that mediate neurodegeneration. Identification and profiling of such images and molecules will promote early identification of risk factors, enhance preventive and protective measures, provide alerts for progression from mild to advanced stages, and accelerate development of presymptomatic and personalized treatment for these diseases. Data from Zetterberg H et al: Mol Brain March 28, 12(1):26, 2019; Hampel H et al: Nat Rev Neurol 14(11):639-652, 2018; Mahalingam S, Chen MK: Semin Neurol 39(2):188-199, 2019. Treatment is directed at using devices to compensate for the impaired cognitive function, such as memory aids; maintaining unimpaired cognitive functions; and maintaining or improving the general state of hygiene, nutrition, and health. Cholinesterase inhibitors have shown a modest effect on cognitive function in mild to moderate AD. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, blocks glutamate activity and may slow progression of disease in moderate to severe AD. Treatments, beginning in the preclinical stage, are being developed to prevent, modify, or halt disease pathology.16

Vascular Dementia Vascular dementia is the second most common cause of dementia after AD. It is a consequence of cerebrovascular disease. Vascular dementia is associated with large artery disease, cardioembolism, small vessel disease of the brain, and stroke, all of which can cause hypoperfusion in the brain. It is more common in men. Risk factors include diabetes, hypercholesterolemia, hypertension, and smoking. Treatment is directed at preventing these risk factors.17

Frontotemporal Dementia Frontotemporal dementia (FTD), previously known as Pick disease, is a rare disease. There is a familial association with an age of onset less than 60 years. The majority of cases involve mutations of genes encoding tau protein. There is degeneration of the frontal and anterior frontal lobes. Three distinct clinical syndromes are presented in frontotemporal degeneration, depending on the site of atrophy: (1) behavioral variant of frontotemporal dementia (changes in personality and judgment), (2) progressive nonfluent aphasia (problems with language and writing skills), and (3) semantic dementia (problems forming words and sentences).18 There is no specific treatment.

Seizure Disorders Seizure disorders represent a manifestation of disease and not a specific disease entity. A seizure is a sudden, transient disruption in brain electrical function caused by abnormal excessive discharges of cortical neurons. Epilepsy is a disease of the brain with recurrence of unpredictable seizures. The term convulsion is sometimes applied to seizures and refers to the tonic-clonic (jerky, contract-relax) movement associated with some seizures. (Seizures in children are presented in Chapter 18.)

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Conditions Associated With Seizure Disorders Any disorder that alters the neuronal environment may cause seizure activity. Conditions that may produce a seizure are metabolic disorders, congenital malformations, genetic predisposition, perinatal injury, postnatal trauma, myoclonic syndromes (sudden involuntary jerking of muscles), infection, brain tumor, vascular disease, and drug or alcohol abuse. The onset of seizures also may indicate the presence of an ongoing primary neurologic disease. Metabolic and structural causes of recurrent seizures in adults are summarized in Table 16.13. The cause of seizures is often unknown. TABLE 16.13 Structural/Metabolic Causes of Recurrent Seizures in Adults Age at Onset Young adults (18 to 35 yr)

Older adults (>35 yr)

Probable Cause Alcohol or drug withdrawal (e.g., barbiturates, benzodiazepines) Brain tumor Idiopathic Illicit drug use (e.g., cocaine, amphetamine) Posttraumatic brain injury Perinatal insults Alcohol or drug withdrawal (e.g., barbiturates, benzodiazepines) Brain tumor Cerebrovascular disease (e.g., stroke, aneurysm, arteriovenous malformations, infection) CNS degenerative diseases (e.g., Alzheimer disease, multiple sclerosis) Idiopathic Metabolic disorders (e.g., uremia, hepatic failure, electrolyte abnormalities, hypoglycemia) Posttraumatic brain injury

CNS, Central nervous system. Data from Daroff RB et al: Bradley's neurology in clinical practice, ed 6, Saunders, 2012, Philadelphia.

The threshold for seizures may be lowered by hypoglycemia, fatigue or lack of sleep, emotional or physical stress, fever, large amounts of water ingestion, constipation, use of antipsychotic drugs (i.e., chlorpromazine and clozapine) especially when combined with alcohol, withdrawal from depressant drugs (including alcohol), or hyperventilation (respiratory alkalosis). Some environmental stimuli, such as blinking lights, a poorly adjusted television screen, loud noises, certain music, certain odors, or merely being startled, have been known to initiate a seizure. Women may have increased seizure activity immediately before or during menses.

Types of Seizure Seizures are classified in different ways: by clinical manifestations, site of origin, EEG correlates, or response to therapy. Types of seizures and clinical manifestations are presented in Table 16.14. Terms used to describe seizure activity are defined in Table 16.15. The International League Against Epilepsy also has developed a framework to assist with classifying epilepsy (Fig. 16.9).19 TABLE 16.14 Types of Seizures and Clinical Manifestations

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Type Focal seizures (previously partial seizures)

Clinical Manifestations Seizures originating in one area of the brain; an aura is common Motor Tonic: stiffening of body muscles with falling; loss of consciousness; can occur in sleep; more common in infants and children Atonic: sudden, brief loss of muscle tone with falling (drop attacks); usually no loss of consciousness Myoclonic: sudden brief shock-like jerks or twitches of the arms and/or legs; may drop things; no impairment of consciousness; frequently occurs shortly after awakening Tonic-clonic: Abrupt loss of consciousness, body stiffening (tonic) and then shaking (clonic); may begin with sudden cry, sometimes loss of bladder control or biting of tongue; usually lasts about 2 minutes, followed by a period of confusion, agitation, and fatigue; headaches and soreness are common afterwards Hypermotor: bimanual or bipedal motor activity such a kicking and thrashing, clapping and rubbing of both hands, hugging, sometimes with sexual automatisms and autonomic changes with or without preserved awareness Nonmotor Sensory: numbness, tingling or burning sensation, flashing lights, auditory experiences Cognitive: aphasia, hallucination, memory or attention impairment Emotional or affective: fear, agitation, anger, crying, laughing, paranoia Autonomic: blushing, pallor, increased or decreased heart-rate, hyper- or hypoventilation nausea Without loss of Recall, responsiveness, and consciousness are intact awareness Impaired Loss of consciousness or awareness; vague or dreamlike state awareness (also known as complex focal seizure) Awareness Unable to determine awareness unknown Focal to Begins in one part of brain (focal seizure) and spreads to both sides of brain followed by generalized bilateral tonic- tonic-clonic seizure; loss of consciousness clonic seizure Generalized Seizures originating in both sides of the brain simultaneously; can include tonic, atonic, clonic, seizures myoclonic, myoclonic-atonic, clonic-tonic-clonic activity (see above descriptions) Epileptic Episodes of sudden flexion or extension involving neck, trunk, and extremities; clinical manifestations spasms range from subtle head nods to violent body contractions (jackknife seizures); onset between 3 and 12 (formerly months of age; may occur after infancy, may be idiopathic, genetic, result of metabolic disease, or in known as response to CNS insult; spasms occur in clusters of 5 to 150 times per day; EEG shows large-amplitude, infantile chaotic, and disorganized pattern called “hypsarrhythmia” spasms) Epilepsy Seizure disorder that displays a group of signs and symptoms that occur collectively and characterize or syndromes indicate a particular condition; usually associated with genetic or developmental cause (examples) Neonatal Wide variety of abnormal clinical activity, including rhythmic eye movements, chewing, and swimming seizures movements; common in neonatal seizures; there are 5 main types of neonatal seizures: (1) subtle seizures (50%), (2) tonic seizures (5%), (3) clonic seizures (25%), (4) myoclonic seizures (20%), (5) nonparoxysmal repetitive behaviors LennoxEpileptic syndrome with onset in early childhood, 1 to 5 years of age; includes various generalized Gastaut seizures (tonic-clonic, atonic [drop attacks], akinetic, absence, and myoclonic); EEG has characteristic syndrome “slow spike and wave” pattern; results in mental retardation and delayed psychomotor developments Juvenile Generalized epilepsy syndrome with onset in adolescence; multifocal myoclonus; seizures often occur myoclonic early in morning, aggravated by lack of sleep or after excessive alcohol intake; occasional generalized epilepsy convulsions; requires long-term medication treatment Unclassified Etiology remains unknown; seizures do not have distinct clinical and EEG features Epileptic Seizures Simple febrile Common in children younger than 5 to 6 years of age; brief (less than a few minutes) generalized seizures convulsions associated with high fever; important to exclude meningitis as cause of seizures; usually do not develop epilepsy Pseudoseizures Nonepileptic phenomena that look like epileptic seizures; diagnosis often requires video-EEG monitoring to capture spells, and determine that EEG is normal during clinical events; frequently occurs in setting of child abuse Status Continuing or recurring seizure activity in which recovery from seizure activity is incomplete;

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Epilepticus

unrelenting seizure activity can last 30 min or more; other forms can evolve into status epilepticus; medical emergency that requires immediate intervention

CNS, Central nervous system; EEG, electroencephalogram. Data from: Fisher RS et al: Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 58(4):522-530, 2017. Available at https://www.ilae.org/news-and-media/news-about-ilae/new-ilae-seizure-classification. Accessed July 7, 2019.

TABLE 16.15 Terminology Applied to Phases of a Seizure Disorder Term Definition Preictal Phase Prodroma Early clinical manifestation (such as malaise, headache, a sense of depression or alterations in smell, taste, hearing or vision) that may occur a few days to hours before onset of a seizure Aura A partial seizure experienced as a peculiar sensation preceding onset of generalized seizure that may take the form of gustatory, visual, or auditory experience or a feeling of dizziness, numbness, or just “a funny feeling” Ictal The event of the seizure Phase Tonic A state of muscle contraction in which there is excessive muscle tone Phase Clonic A state of alternating contraction and relaxation of muscles Phase Postictal Time period immediately following cessation of seizure activity Phase

FIGURE 16.9

Framework for Classification of Epilepsy. *Due to inadequate information or inability to place in other categories.

Pathophysiology Epilepsy is the result of the interaction of complex genetic mutations with environmental effects. These effects cause abnormalities in synaptic transmission, an imbalance in the brain's excitatory and inhibitory neurotransmitters, the development of abnormal nerve connections, or loss of nerves after injury.20 A group of neurons may exhibit a sudden, depolarization shift, triggering a discharge of action potentials and function as an epileptogenic focus. These epileptogenic neurons are hypersensitive and are more easily activated by triggers, such as hyperthermia, hypoxia, hypoglycemia, hyponatremia,

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repeated sensory stimulation, and certain sleep phases. Epileptogenic neurons fire more frequently and with greater amplitude. When the intensity of firing reaches a threshold point, the excitation spreads across the brain. Excitation of the subcortical, thalamic, and brainstem areas corresponds to the tonic phase (muscle contraction with increased muscle tone) and is associated with loss of consciousness. The clonic phase (alternating contraction and relaxation of muscles) begins when inhibitory neurons in the cortex, anterior thalamus, and basal ganglia react to the cortical excitation. The seizure discharge is interrupted, producing intermittent muscle contractions that gradually decrease and finally cease. The epileptogenic neurons are then exhausted. During seizure activity, oxygen is consumed at a high rate—about 60% greater than normal. Although cerebral blood flow also increases, oxygen is rapidly depleted, along with glucose, and lactate accumulates in brain tissue. Thus continued severe seizure activity has the potential for progressive brain injury and irreversible damage. In addition, if a seizure focus in the brain is active for a prolonged period, a mirror focus may develop in contralateral normal tissue and cause more widespread seizure activity across the brain. Clinical Manifestations The clinical manifestations associated with seizure depend on its type (see Table 16.14). Two types of symptoms signal the preictal phase of a generalized tonic-clonic seizure: prodroma, early manifestations occurring hours to days before a seizure and may include anxiety, depression, or inability to think clearly; and an aura, unusual sensory experiences or a partial seizure that immediately precedes the onset of a generalized tonic-clonic seizure. Both symptoms may become familiar to the person experiencing recurrent generalized seizures and may enable the person to prevent injuries during the seizure. The ictus is the episode of the epileptic seizure with tonic-clonic activity. Relaxation of urinary and bowel sphincters may occur, leading to bladder and bowel incontinence. Airway maintenance needs to be ensured. The postictal state follows an epileptic seizure and can include signs of headache, confusion, dysphasia, memory loss, and paralysis that may last hours or a day or two. Deep sleep also is common. Status epilepticus in adults is a state of continuous seizures lasting more than 5 minutes, or rapidly recurring seizures before the person has fully regained consciousness from the preceding seizure, or a single seizure lasting more than 30 minutes. Evaluation and Treatment The health history, a physical examination, and laboratory tests of blood and urine (concentrations of blood glucose, serum calcium, blood urea nitrogen, and urine sodium; and creatinine clearance time) can identify systemic diseases known to promote seizures. Brain imaging and cerebrospinal fluid (CSF) examination help identify neurologic diseases associated with seizures. The EEG is used to assess the type of seizure and determine its focus in brain tissue. Treatment for a seizure disorder is to first correct or control its cause if possible. If this is not possible, the major means of management is the judicious administration of antiseizure medications. Dietary treatments (e.g., ketogenic and Atkins diet) are effective for some individuals.21 Surgical interventions can improve seizure control and quality of life in people with drug-resistant epilepsy.

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Quick Check 16.4 1. What are some major difference between delirium and dementia? 2. What is an eliptogenic focus? 3. What is epilepsy?

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Alterations in Cerebral Hemodynamics An injured brain reacts with structural, chemical, and pathophysiologic changes. Primary brain injury is the original trauma, and secondary brain injury is a consequence of alterations in cerebral blood flow, intracranial pressure, and oxygen delivery. Target values for relevant cerebral blood flow parameters are summarized in Box 16.4).

Box 16.4

Cerebral Hemodynamics Cerebral blood flow (CBF) to the brain is normally maintained at a rate that matches the local metabolic needs of the brain. Cerebral perfusion pressure (CPP) (70-90 mm Hg) is the pressure required to perfuse the cells of the brain. Cerebral blood volume (CBV) is the amount of blood in the intracranial vault at a given time. Cerebral blood oxygenation is measured by oxygen saturation in the internal jugular vein. Intracranial pressure (ICP) normally is 1 to 15 mm Hg, or 60 to 180 cm H2O. Alterations in cerebral blood flow (CBF) are related to three injury states: inadequate cerebral perfusion, normal cerebral perfusion but with an elevated intracranial pressure, and excessive cerebral blood volume (CBV). Treatments for these injury states are directed at improving or maintaining cerebral perfusion pressure (CPP), as well as controlling intracranial pressure. (The pathophysiology specific to primary and secondary traumatic brain injury is discussed in Chapter 17.)

Increased Intracranial Pressure Increased intracranial pressure (IICP) may result from an increase in intracranial content as occurs with tumor growth, cerebral edema, excess CSF, or hemorrhage. An increase in intracranial content necessitates an equal reduction in volume of the other cranial contents to maintain cerebral perfusion. The most readily displaced content is CSF. If intracranial pressure remains high after CSF displacement out of the cranial vault, CBV and CBF are altered. There are four progressive stages of IICP. In stage 1 of intracranial hypertension, vasoconstriction and external compression of the venous system occur in an attempt to further decrease the intracranial pressure. Thus during the first stage of intracranial hypertension, intracranial pressure (ICP) may not change because of the effective compensatory mechanisms, and there may no detectable symptoms (Fig. 16.10). Small increases in volume, however, cause an increase in pressure, and the pressure may take longer to return to baseline. This pressure change can be detected with ICP monitoring.

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FIGURE 16.10 Clinical Correlates of Compensated and Uncompensated Stages of Intracranial Hypertension. (From Beare PG, Myers JL: Principles and practice of adult health nursing, ed 3, St Louis, 1998, Mosby.)

In stage 2 of intracranial hypertension, there is continued expansion of intracranial contents. The resulting increase in ICP may exceed the ability of the brain's compensatory mechanisms to adjust. The pressure begins to compromise neuronal oxygenation. Systemic arterial vasoconstriction occurs in an attempt to elevate the systemic blood pressure sufficiently to overcome the IICP and maintain perfusion. Clinical manifestations at this stage usually are subtle and transient, including episodes of confusion, restlessness, drowsiness, and slight pupillary and breathing changes (see Fig. 16.10). Interventions at this stage reduce ICP and promote better clinical outcomes. In stage 3 of intracranial hypertension, ICP begins to approach arterial pressure. The brain tissues begin to experience hypoxia and hypercapnia, and the individual's condition rapidly deteriorates. Clinical manifestations include decreasing levels of arousal or central neurogenic hyperventilation, widened pulse pressure, bradycardia, and small, sluggish pupils (see Fig. 16.10). Dramatic sustained rises in ICP are not seen until all compensatory mechanisms have been exhausted. Then dramatic rises in ICP occur over a very short period. Autoregulation is the compensatory alteration in the diameter of the intracranial blood vessels designed to maintain a constant blood flow during changes in cerebral perfusion pressure. Autoregulation is lost with progressively increased ICP. Accumulating carbon dioxide may still cause vasodilation locally, but without autoregulation this vasodilation causes the blood pressure in the vessels to drop and the blood volume to increase. The brain volume is thus further increased, and ICP continues to rise. Small increases in volume cause dramatic increases in ICP, and the pressure takes much longer to return to baseline. As the ICP begins to approach systemic blood pressure, cerebral perfusion pressure falls and cerebral perfusion slows dramatically. The brain tissues experience severe hypoxia, hypercapnia,

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and acidosis. In stage 4 of intracranial hypertension, brain tissue shifts (herniates) from the compartment of greater pressure to a compartment of lesser pressure. IICP in one compartment of the cranial vault is not evenly distributed throughout the other vault compartments (see Figs. 16.10 and 16.11). With this shift in brain tissue, the herniating brain tissue's blood supply is compromised, causing further ischemia and hypoxia in the herniating tissues. The volume of content within the lower-pressure compartment increases, exerting pressure on the brain tissue that normally occupies that compartment, and thus impairs its blood supply. For example, herniation into the brainstem impairs the vital cardiovascular and respiratory regulatory centers and can cause death. The herniation process markedly and rapidly increases ICP. Mean systolic arterial pressure soon equals ICP, and CBF ceases at this point. The types of herniation syndromes are outlined in Box 16.5.

FIGURE 16.11 Brain Herniation Syndromes. Herniations can occur both above and below the tentorial membrane. Supratentorial: 1, uncal (transtentorial); 2, central; 3, cingulate; 4, transcalvarial (external herniation through an opening in the skull). Infratentorial: 5, upward herniation of cerebellum; 6, cerebellar tonsillar move down through foramen magnum.

Box 16.5

Brain Herniation Syndrome Supratentorial Herniation 1. Uncal herniation. Occurs when the uncus or hippocampal gyrus, or both, shifts from the middle fossa through the tentorial notch into the posterior fossa, compressing the ipsilateral third cranial nerve, the contralateral third cranial nerve, and the

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mesencephalon. Uncal herniation generally is caused by an expanding mass in the lateral region of the middle fossa. The classic manifestations of uncal herniation are a decreasing level of consciousness, pupils that become sluggish before fixing and dilating (first the ipsilateral, then the contralateral pupil), Cheyne-Stokes respirations (which later shift to central neurogenic hyperventilation), and the appearance of decorticate and then decerebrate posturing. 2. Central herniation. Occurs when there is a straight downward shift of the diencephalon through the tentorial notch. It may be caused by injuries or masses located around the outer perimeter of the frontal, parietal, or occipital lobes; extracerebral injuries around the central apex (top) of the cranium; bilaterally positioned injuries or masses; and unilateral cingulate gyrus herniation. The individual rapidly becomes unconscious; moves from Cheyne-Stokes respirations to apnea; develops small, reactive pupils and then dilated, fixed pupils; and passes from decortication to decerebration. 3. Cingulate gyrus herniation. Occurs when the cingulate gyrus shifts under the falx cerebri. Little is known about its clinical manifestations. 4. Transcalvarial. The brain shifts through a skull fracture or a surgical opening in the skull. This type of external herniation may occur during a craniectomy—surgery in which a flap of skull is removed. This type of herniation prevents the piece of skull from being replaced.

Infratentorial Herniation 1. The most common syndrome is cerebellar tonsillar herniation. The cerebellar tonsil shifts through the foramen magnum because of increased pressure within the posterior fossa. The clinical manifestations are an arched, stiff neck, paresthesias in the shoulder area, decreased consciousness, respiratory abnormalities, and pulse rate variations. Occasionally the force produces an upward transtentorial herniation of a cerebellar tonsil or the lower brainstem. There is increased intracranial pressure (ICP) but no specific set of clinical manifestations associated with infratentorial herniation.

Cerebral Edema Cerebral edema is an increase in the fluid content of brain tissue (Fig. 16.12). The result is increased extracellular or intracellular tissue volume. It occurs after brain insult from trauma, infection, hemorrhage, tumor growth, ischemia, infarction, or hypoxia. The harmful effects of cerebral edema are caused by distortion of blood vessels, displacement of brain tissues, increase in ICP, and eventual herniation of brain tissue to a different brain compartment.

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FIGURE 16.12 Brain Edema. This coronal section of the cerebrum demonstrates marked compression in the lateral ventricles (long arrows) and flattening of gyri (short arrows) from extensive bilateral cerebral edema. Edema increases intracranial pressure, leading to herniation. (From Klatt EC: Robbins and Cotran atlas of pathology, ed 2, Philadelphia, 2010, Saunders.)

There are three types of cerebral edema: (1) vasogenic edema, (2) cytotoxic (metabolic) edema, and (3) interstitial/hydrocephalic edema.22 There is often overlap among the three types of edema. Vasogenic edema is clinically the most important and common type. It is caused by increased permeability of the capillaries that comprise the blood–brain barrier. Consequently, plasma proteins leak into the extracellular spaces, drawing water to them, and increasing the water content of the brain interstitial spaces. Vasogenic edema begins in the area of injury (brain trauma, tumors, inflammation) and spreads, with fluid accumulating in the white matter at the site of injury. Edema promotes more edema because of ischemia from the increasing ICP. Clinical manifestations of vasogenic edema include focal neurologic deficits, disturbances of consciousness, and a severe increase in ICP. Vasogenic edema resolves by slow diffusion of fluid back into the bloodstream. In cytotoxic edema (cellular brain edema), the accumulation of fluid is in the cells of the brain (neuronal, glial, and endothelial cells) rather than in the interstitial spaces. The blood– brain barrier is intact. Accumulation of toxic factors directly causes failure of the active transport systems. The cells lose their potassium and gain larger amounts of sodium. Water follows by osmosis into the cells, so that the cells swell. Cytotoxic edema occurs principally in the gray matter and may contribute to vasogenic edema. It occurs with head injury, hypoxia, and arterial infarction. Interstitial/hydrocephalic edema is most often seen with noncommunicating hydrocephalus. The edema is caused by the movement of CSF from the lining of the ventricles into the extracellular spaces of the brain tissues (transependymal edema). The brain fluid volume increases predominantly around the ventricles, with increased hydrostatic pressure within the white matter. The size of the white matter is reduced because of the rapid disappearance of myelin lipids. Treatment of cerebral edema is directed at decreasing IICP. Treatment can include the use of oxygen, osmotherapy (e.g., mannitol), diuretics, the placement of a CSF drain tube, and maintenance of systemic blood pressure with fluid management. Steroids (dexamethasone) may be used to treat edema associated with brain tumors.

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Hydrocephalus The term hydrocephalus refers to various conditions characterized by excess fluid in the cerebral ventricles, subarachnoid space, or both. Hydrocephalus occurs because of interference with CSF flow caused by increased fluid production, obstruction within the ventricular system, or defective reabsorption of the fluid. A tumor of the choroid plexus may, in rare instances, cause overproduction of CSF. The types of hydrocephalus are reviewed in Table 16.16. TABLE 16.16 Types of Hydrocephalus Type Mechanism Noncommunicating Obstruction of CSF flow between ventricles Aqueduct stenosis Arnold-Chiari malformation (brain extension through foramen magnum) Compression by tumor Communicating Impaired absorption of CSF within subarachnoid space Compression of subarachnoid space by a tumor High venous pressure in sagittal sinus Head injury Congenital malformation Increased CSF secretion by choroid plexus

Cause Congenital abnormality

Infection with inflammatory adhesions

Secreting tumor

CSF, Cerebrospinal fluid.

Hydrocephalus may develop from infancy through adulthood. Communicating hydrocephalus is defective resorption of CSF from the cerebral subarachnoid space and is found more often in adults. Noncommunicating hydrocephalus (internal hydrocephalus, intraventricular hydrocephalus) is obstruction within the ventricular system and is seen more often in children (see Fig. 18.7). Congenital hydrocephalus is ventricular enlargement before birth and is rare. Pathophysiology The obstruction of CSF flow associated with hydrocephalus produces increased pressure and dilation of the ventricles proximal to the obstruction. The increased pressure and dilation cause atrophy of the cerebral cortex and degeneration of the white matter tracts. Selective preservation of gray matter occurs. Clinical Manifestations Most cases of hydrocephalus develop gradually and insidiously over time. Acute hydrocephalus presents with signs of rapidly developing IICP. The person quickly deteriorates into a deep coma if not promptly treated. Normal-pressure hydrocephalus (dilation of the ventricles without increased pressure) develops slowly and occurs more commonly in the elderly. The individual or family members may notice declining memory and cognitive function. The triad symptoms of an unsteady, broad-based gait with a history of falling, incontinence, and dementia is common.23 Evaluation and Treatment

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The diagnosis is based on the physical examination and imaging procedures. Hydrocephalus can be treated by surgery to resect cysts, neoplasms, or hematomas or by ventricular bypass into the normal intracranial channel or into an extracranial compartment using a shunting procedure. Excision or coagulation of the choroid plexus is a treatment option to reduce formation of CSF or when a papilloma (a benign tumor) is present. In normal-pressure hydrocephalus, reduction in CSF is achieved through diuresis or placement of a ventriculoperitoneal shunt.

Quick Check 16.5 1. What are the four stages of increased intracranial pressure? 2. How does supratentorial herniation differ from infratentorial herniation? 3. What is the major difference between vasogenic and cytotoxic cerebral edema? 4. How is communicating hydrocephalus different from noncommunicating hydrocephalus?

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Alterations in Neuromotor Function Movements are complex patterns of activity controlled by the cerebral cortex, the pyramidal system, the extrapyramidal system, and the motor neurons in muscles (motor units). Dysfunction in any of these areas can cause motor dysfunction. General neuromotor dysfunctions are associated with changes in muscle tone, movement, and complex motor performance.

Alterations in Muscle Tone Normal muscle tone involves a slight resistance to passive movement. Throughout the range of motion, the resistance is smooth, constant, and even. The alterations of muscle tone and their characteristics and causes are summarized in Table 16.17. TABLE 16.17 Alterations in Muscle Tone Alterations Hypotonia

Characteristics Passive movement of a muscle mass with little or no resistance

Muscles may be moved rapidly without resistance Flaccidity Associated with limp, atrophied muscles, and paralysis Hypertonia Increased muscle resistance to passive movement May be associated with paralysis May be accompanied by muscle hypertrophy Spasticity A gradual increase in tone causing increased resistance until tone suddenly diminishes, which results in clasp-knife phenomenon; increased deep tendon reflexes (hyperreflexia); clonus (spread of reflexes) Paratonia Resistance to passive movement, which varies in (gegenhalten) direct proportion to force applied Dystonia Sustained involuntary muscle contraction with twisting movement Rigidity Plastic or lead-pipe rigidity Cogwheel rigidity Gamma rigidity Alpha rigidity

Cause Thought to be caused by decreased muscle spindle activity as a result of decreased excitability of neurons (e.g., muscular dystrophy, cerebral palsy)

Occurs typically when nerve impulses necessary for muscle tone are lost Results when lower motor unit reflex arc continues to function but is not mediated or regulated by higher centers (e.g., stroke, brain tumors, multiple sclerosis) Exact mechanism unclear; appears to arise from an increased excitability of alpha motor neurons to any input because of absence of descending inhibition of pyramidal systems (e.g., multiple sclerosis, brain trauma, cerebral palsy) Exact mechanism unclear; associated with frontal lobe injury (e.g., progressive Alzheimer dementia) Produced by slow muscular contraction; lack of reciprocal inhibition of muscle (e.g., neuroleptic drug side effects, meningitis) Occurs as a result of constant, involuntary contraction of muscle—usually involves extrapyramidal tracts (e.g., Parkinson disease) Associated with basal ganglion damage (e.g., Parkinson disease)

Muscle resistance to passive movement of a rigid limb that is uniform in both flexion and extension throughout the motion Increased muscular tone relatively independent of degree of force used in passive movement; does not vary throughout the passive movement Uniform resistance may be interrupted by a Associated with basal ganglion damage series of brief jerks, resulting in movements much like a ratchet, “cogwheel” phenomenon Characterized by extensor posturing Loss of excitation of extensor inhibitory areas by (decerebrate rigidity) cerebral cortex decreasing inhibition of alpha and gamma motor neurons Impaired relaxation characterized by extensor Loss of cerebellum input to lateral vestibular nuclei rigidity of skeletal muscle after contraction

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Hypotonia Hypotonia is decreased muscle tone. With passive muscle movement there is little or no resistance. Normally there is some resistance or tone to relaxed muscles. Causes include cerebellar damage and pure pyramidal tract damage (a rare occurrence). Hypotonia manifests with minimal weakness and normal or slightly exaggerated reflexes. Cerebellar damage contributes to ataxia (loss of control of body movements) and intention tremor. A pure pyramidal tract injury produces hypotonia and weakness. Hypotonia also occurs when nerve impulses needed for muscle tone are lost, such as in spinal cord injury or cerebrovascular accident. Individuals with hypotonia tire easily or are weak. They may have difficulty rising from a sitting position, sitting down without using arm support, and walking up and down stairs. They may have an inability to stand on their toes. Because of their weakness, accidents during ambulatory and self-care activities are common. The joints become hyperflexible, so persons with hypotonia may be able to assume positions that require extreme joint mobility. The joints may appear loose. The muscle mass atrophies because of decreased input entering the motor unit, and muscles appear flabby and flat. Muscle cells are gradually replaced by connective tissue and fat. Fasciculations (muscle twitches) may be present in some cases.

Hypertonia Hypertonia is increased muscle tone. With passive movement of a muscle there is resistance to stretch. Hypertonia is caused by upper motor neuron damage with loss of inhibitory control (see the section Upper Motor Neuron Syndromes). The four types of hypertonia are spasticity (usually corticospinal in origin) (Figs. 16.13 and 16.15), paratonia (gegenhalten), dystonia (Fig. 16.14), and rigidity (usually extrapyramidal in origin). Four types of rigidity are described: plastic or lead-pipe, cogwheel, gamma (independent of stretch reflex pathways), and alpha (dependent on stretch reflex pathways) (see Table 16.17).

FIGURE 16.13

Paroxysm of Left-Sided Hemifacial Spasm. (From Perkin GD: Mosby's color atlas and text of neurology, ed 2, London, 2002, Mosby.)

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FIGURE 16.15 Spasmodic Torticollis. A characteristic head posture related to spasticity. (From Perkin GD: Mosby's color atlas and text of neurology, ed 2, London, 2002, Mosby.)

FIGURE 16.14

Dystonic Posturing of the Hand and Foot. (From Perkin GD: Mosby's color atlas and text of neurology, ed 2, London, 2002, Mosby.)

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Individuals with hypertonia tire easily or are weak. Passive movement and active movement are affected equally, except in paratonia, in which more active than passive movement is possible. As a result of hypertonia and weakness, accidents occur during ambulatory and self-care activities. The muscles may atrophy because of decreased use. However, hypertrophy occasionally occurs as a result of the overstimulation of muscle fibers. Overstimulation occurs when the motor unit reflex arc remains intact and functioning but is not inhibited by higher centers. This causes continual muscle contraction, resulting in enlargement of the muscle mass and the development of firm muscles.

Alterations in Muscle Movement Movement requires a change in the contractile state of muscles. Abnormal movements occur when CNS dysfunction alters muscle innervation. The neurotransmitter dopamine has a role in several movement disorders. Some movement disorders (e.g., the akinesias) result from too little dopaminergic activity, whereas others (e.g., chorea, ballism, tardive dyskinesia) result from too much dopaminergic activity. Still others are not primarily related to dopamine function. Movement disorders are not necessarily associated with muscle mass, strength, or tone but are neurologic dysfunctions that result in insufficient or excessive movement or involuntary movement. Movement disorders can be idiopathic or associated with specific diseases of the CNS, such as Parkinson disease and Huntington disease. Hyperkinesia is excessive, purposeless movement. Within this category are a number of specific dysfunctions, including tremors (Table 16.18). Also included under the general category of hyperkinesias are dyskinesias and abnormal involuntary movements. Huntington disease symptoms are the hallmark of hyperkinesia (see the section Huntington Disease). TABLE 16.18 Types of Hyperkinesia and Tremor Type Hyperkinesia Chorea*

Athetosis*

Ballism

Characteristics

Causes

Nonrepetitive muscular contractions, usually of extremities or face; random pattern of irregular, involuntary rapid contractions of groups of muscles; disappears with sleep, decreases with resting; increases with emotional stress and attempted voluntary movement Disorder of distal muscle postural fixation; slow, sinuous, irregular movements most obvious in distal extremities, more rhythmic than choreiform movements and always much slower; movements accompany characteristic hand posture; slowly fluctuating grimaces Disorder of proximal muscle postural fixation with wild flinging movement of limbs; movement is severe and stereotyped, usually lateral; does not lessen with sleep; ballism is most common on one side of body, a condition termed hemiballism

Associated with excess concentration of or supersensitivity to dopamine within basal ganglia

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Occurs most commonly as result of injury to putamen of basal ganglion; exact pathophysiologic mechanism is not known

Results from injury to subthalamic nucleus (one of nuclei that comprise basal ganglia); thought to be caused by reduced inhibitory influence in nucleus, a release phenomenon; hemiballism results from injury to contralateral subthalamic nucleus

Hyperactivity

Wandering Akathisia

Tremor at Rest Parkinsonian tremor

State of prolonged, generalized, increased activity that May be caused by frontal and reticular is largely involuntary but may be subject to some activating system injury voluntary control; not highly stereotyped but rather manifests as continuous changes in total body posture or in excessive performance of some simple activity, such as pacing under inappropriate circumstances Tendency to wander without regard for environment “Release phenomenon” associated with bilateral injury to globus pallidus or putamen Special type of hyperactivity; mild compulsion to Dopaminergic transmission may be involved move (usually more localized to legs); severe, frenzied motion possible; movements are partly voluntary and may be transiently suppressed; carrying out movement brings sense of relief; frequent complication of antipsychotic drugs Rhythmic, oscillating movement affecting one or more body parts Regular, rhythmic, slower flexion-extension contraction; involves principally metacarpophalangeal and wrist joints; alternating movements between thumb and index finger described as “pill rolling”; disappears during voluntary movement

Postural Tremor Asterixis Irregular flapping movement of hands accentuated by (tremor of outstretching arms hepatic encephalopathy) Metabolic Rapid, rhythmic tremor affecting fingers, lips, and tongue; accentuated by extending body part; enhanced physiologic tremor

Essential (familial)

Tremor of fingers, hands, and feet; absent at rest but accentuated by extension of body part, prolonged muscular activity, and stress

Caused by regular contraction of opposing groups of muscles Loss of inhibitory influence of dopamine in the basal ganglia, causing instability of basal ganglial feedback circuit within cerebral cortex

Exact mechanisms responsible unknown; thought to be related to accumulation of products normally detoxified by liver (e.g., ammonia) Occurs in conditions associated with disturbed metabolism or toxicity, as in thyrotoxicosis (hyperthyroidism), alcoholism, and chronic use of barbiturates, amphetamines, lithium, or amitriptyline (Elavil); exact mechanism responsible unknown Not associated with any other neurologic abnormalities; cause unknown

Intention Tremor Cerebellar Tremor initiated by movement, maximal toward end of movement

Rubral

Myoclonus

*Choreoathetosis

Occurs in disease of dentate nucleus (one of deep cerebellar nuclei responsible for efferent output) and superior cerebellar peduncle (stalklike structure connected to pons); caused by errors in feedback from periphery and errors in preprogramming goal-directed movement Rhythmic tremor of limbs that originates proximally Results from lesions involving by movement dentatorubrothalamic tract (a spinothalamic tract connecting red nucleus in reticular formation and dentate nucleus in cerebellum) Series of shocklike, nonpatterned contractions of Associated with an irritable nervous system portion of a muscle, entire muscle, or group of and spontaneous discharge of neurons; muscles that cause throwing movements of a limb; structures associated with myoclonus include usually appear at random but frequently triggered by cerebral cortex, cerebellum, reticular sudden startle; do not disappear during sleep formation, and spinal cord

involves both chorea and athetosis; precise pathophysiology is unknown.

Paroxysmal dyskinesias are rare abnormal, episodic, involuntary movements that occur as spasms. The type of dyskinesia varies depending on the specific disorder. These involuntary movements include dystonia (uncontrollable twisting, repetitive movement resulting in abnormal posture), chorea (abnormal jerky movements), athetosis (writhing movements), and ballism (flailing limb movements), or a combination of these.

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Tardive dyskinesia is the involuntary movement of the face, lip, tongue, trunk, and extremities. Although the condition occurs occasionally in individuals with Parkinson disease, it usually occurs as a side effect of prolonged antipsychotic drug therapy. The most common symptom of tardive dyskinesia is rapid, repetitive, stereotypic movements, such as continual chewing with intermittent protrusions of the tongue, lip smacking, and facial grimacing. The symptoms also are called extrapyramidal symptoms because the extrapyramidal system controls involuntary reflexes and coordination of movement and posture. Other movement disorders in this category are (1) complex repetitive movements, including automatism (unconscious behavior), stereotypy (ritualistic behavior such as rocking), complex tics such as Tourette syndrome (see Did You Know? Tourette Syndrome), compulsions, perseverations, and mannerisms; (2) excessive reactions to certain stimuli; and (3) paroxysmal excessive activity, including cataplexy (a sudden and uncontrollable muscle weakness or paralysis often triggered by a strong emotion, such as excitement or laughter) and excessive startle reaction.

Did You Know? Tourette Syndrome There is growing evidence that Tourette syndrome (TS) occurs worldwide and has common features across all races and cultures. The hallmark of TS is the presence of motor tics (sudden, rapid, repetitive nonrhythmic movements) and vocal tics. The tics may be either simple, involving only an individual muscle group (e.g., eye blinking or grunting), or complex, requiring coordinated movement of muscle groups (e.g., head banging or repeating of another person's words). Sensory tics involve unpleasant sensations in the face, head, and neck areas. Probably underdiagnosed, the onset of TS is typically between the ages of 2 and 15 years, with the tics lessening in adulthood. The syndrome has a complex multifactorial etiology with undetermined genetic, environmental, immune, and hormonal factors. The pathophysiology of TS is unclear and currently under study. There is evidence of cortico-striato-thalamocortical dysfunction with loss of inhibition and, in some cases, altered dopaminergic neurotransmission. TS is often diagnosed in association with anxiety, depression, ADHD, and obsessive-compulsive disorder. Habit reversal therapy is the most common behavioral therapy, and all behavioral therapy needs further investigation. Pharmacologic treatments target symptoms and include dopamine blocking agents. New drugs are being evaluated to identify the best outcomes. Deep brain stimulation is an alternative treatment for drug resistant cases. Data from Hallett M: Brain Dev 2015 Aug;37(7):651-655, 2015; Novotny M, Valis M, Klimova B: Front Neurol 9:139, 2018.

Huntington Disease Huntington disease (HD), also known as Huntington chorea, is a relatively rare, hereditary, degenerative hyperkinetic movement disorder. The onset of HD is usually between 35 and 44 years of age, when the trait may already have been passed to the person's children. The

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disorder has a prevalence rate of approximately 3 to 7 per 100,000 people of European ancestry, but it occurs in all races.24 Pathophysiology HD is inherited from one or both parents who have the autosomal dominant trait with high penetrance. The genetic defect of HD is on chromosome 4. There is an abnormally long polyglutamine tract in the huntingtin (htt) protein that is toxic to neurons. The age of symptom onset is related to the length of the repeat sequences and mechanisms of toxicity. Repeat lengths greater than 60 cause the juvenile form of the disease.25 Fathers, but not mothers, with high normal alleles do not develop HD but are at risk of transmitting potentially penetrant HD alleles (≥36) to their offspring, who can develop HD.26 The principal pathologic feature of HD is severe degeneration of the basal ganglia, particularly the caudate nucleus, with progression to involve other parts of the brain. Tangles of huntingtin protein collect in the brain cells. Depletion of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, is the principal biochemical alteration in Huntington disease. It alters the integration of motor and mental function. Clinical Manifestations Symptoms of HD progress slowly over 15 to 20 years. Symptoms are extrapyramidal and include involuntary hyperkinetic movements, such as chorea, athetosis, and ballism (Table 16.18). Chorea, the most common type of jerky abnormal movement, begins in the face and arms, eventually affecting the entire body. There is emotional lability and progressive dysfunction of intellectual and thought processes that may precede motor symptoms. Any one of these features may mark the onset of the disease. Cognitive deficits include slow thinking, loss of working memory, and reduced capacity to plan, organize, and sequence. Restlessness, disinhibition, and irritability are common. Apathy, depression, and anxiety can be disabling. Evaluation and Treatment The diagnosis of HD is based on the family history and clinical presentation of the disorder. Genetic testing confirms the diagnosis. Neuroradiologic abnormalities can be demonstrated up to 15 years before clinical symptoms. No known treatment is effective in halting the degeneration or progression of symptoms, and the disease is fatal. Symptomatic drug therapies are available.27,28

Hypokinesia Hypokinesia (decreased movement) is loss of voluntary movement despite preserved consciousness and normal peripheral nerve and muscle function. Types of hypokinesia include akinesia, bradykinesia, and loss of associated movement. Parkinson disease symptoms are the hallmark of hypokinesia. Akinesia is a decrease in voluntary and associated movements. It is related to dysfunction of the extrapyramidal system and caused by either a deficiency of dopamine or a defect of the postsynaptic dopamine receptors, which occurs in parkinsonism. Bradykinesia is slowness of voluntary movements. All voluntary movements become slow, labored, and deliberate, with difficulty in (1) initiating movements, (2) continuing movements smoothly, and (3) performing synchronous (at the same time) and consecutive

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tasks. Both akinesia and bradykinesia involve a delay in the time it takes to start to perform a movement. Loss of associated movement accompanies hypokinesia. The normal, habitually associated movements that provide skill, grace, and balance to voluntary movements are lost. Decreased associated movements accompanying emotional expression cause an expressionless face, a statue-like posture, absence of speech inflection, and absence of spontaneous gestures. Decreased associated movements accompanying locomotion cause reduction in arm and shoulder movements, hip swinging, and rotary motion of the cervical spine.

Parkinson Disease Parkinson disease (PD) is a complex motor disorder accompanied by systemic nonmotor and neurologic symptoms. Etiologic classification of parkinsonism includes primary parkinsonism (hereditary and sporadic) and secondary parkinsonism. Primary PD begins after the age of 40 years, with the incidence increasing after 60 years. It is more prevalent in males and a leading cause of neurologic disability in individuals older than 60 years. Approximately 60,000 new cases are diagnosed in the United States each year.29 The familial form represents about 10% of PD; however, the majority of cases are sporadic or idiopathic. Secondary parkinsonism is parkinsonism caused by disorders other than PD (i.e., head trauma, infection, neoplasm, atherosclerosis, toxins, drug intoxication). Druginduced parkinsonism, caused by neuroleptics, antiemetics, and antihypertensives, is the most common secondary form and usually is reversible. Pathophysiology The pathogenesis of primary PD is unknown. Several gene mutations have been identified that influence nerve function in PD. Gene–environment interactions are probable causes of neurodegeneration in PD. The primary pathology is degeneration of the basal ganglia (see Fig. 14.10) with accumulation of dysfunctional or misfolded α-synuclein protein and loss of dopamine-producing neurons in the substantia nigra and dorsal striatum. The resulting depletion of dopamine, an inhibitory neurotransmitter, and relative excess of cholinergic (excitatory) activity in the feedback circuit are manifested by hypertonia (tremor and rigidity) and hypokinesia, producing a syndrome of abnormal movement called parkinsonism (Parkinson syndrome, parkinsonian syndrome, paralysis agitans) (Fig. 16.16). Neuroimaging shows degeneration of dopaminergic neurons preceding the onset of motor symptoms by as long as 3 to 6 years.30 Collections of α-synuclein protein form Lewy bodies resulting in neurodegeneration and dementia after years of the disease.31 Loss of cholinergic subcortical input into the cortex is associated with nonmotor symptoms of PD.32

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FIGURE 16.16

Pathophysiology of Parkinson Disease.

Clinical Manifestations The classic manifestations of PD are resting tremor, rigidity, bradykinesia/akinesia, postural disturbance, dysarthria, and dysphagia. They may develop alone or in combination, but as the disease progresses, all are usually present. There is no true paralysis. The symptoms are always bilateral but usually involve one side early in the illness. Because the onset is insidious, the beginning of symptoms is difficult to document. Early in the disease, reflex status, sensory status, and mental status usually are normal. Loss of smell can be an early nonmotor symptom. Postural abnormalities (flexed, forward leaning), difficulty walking, and weakness develop as neurodegeneration progresses (Fig. 16.17). Speech may be slurred.

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FIGURE 16.17

Stooped Posture of Parkinson Disease. (From Perkin DG: Mosby's color atlas and text of neurology, ed 2, London, 2002, Mosby.)

Disorders of equilibrium result from postural abnormalities. The person with Parkinson disease cannot make the appropriate postural adjustment to tilting or falling and falls like a post when starting to tilt. The short, accelerating steps of the individual with Parkinson disease are an attempt to maintain an upright position while walking. Individuals are also unable to right themselves when changing from a reclining or crouching position to a standing position and when rolling over from a supine to a lateral or prone position. Nonmotor symptoms are common. Sleep disorders and excessive daytime sleepiness are commonly experienced. Sensory disturbances (pain and impaired smell and vision), urinary urgency, difficulty concentrating, depression, and hallucinations are some of the nonmotor symptoms of PD. Autonomic-neuroendocrine changes also contribute to nonmotor symptoms and include inappropriate diaphoresis, orthostatic hypotension, drooling, gastric retention, constipation, and urinary retention. Progressive dementia is more common in persons older than 70 years. Mental status may be further compromised by the side effects of the medication taken to control symptoms. Evaluation and Treatment The diagnosis of PD is based on the history and clinical features of the disease. Causes of secondary parkinsonism are first excluded. Specific gene panels and imaging studies are evolving for early diagnosis.33,34

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Treatment of PD is symptomatic, with drug therapy to decrease dyskinesia. Because of troublesome side effects and loss of effectiveness, however, drug therapy may not be started until the symptoms become incapacitating. Deep brain stimulation (i.e., subthalamic neurostimulation) is replacing surgery to treat persons unresponsive to drug therapy. Implants of stem cells and fetal cells, as well as gene therapy, are strategies for future treatments.35,36 Dysphagia and general immobility are special problems of the individual with PD, requiring interdisciplinary efforts to improve nutrition and functional status.

Upper and Lower Motor Neuron Syndromes Upper Motor Neuron Syndromes Upper motor neuron syndromes are the result of injury to motor pathways that descend from the motor cortex (Figs. 16.18 and 16.19). The nerves travel in the pyramidal (corticospinal) tracts and synapse on lower motor neurons in the brainstem or anterior spinal cord. Upper motor neuron injury may be in the cerebral cortex, the subcortical white matter, the internal capsule, the brainstem, or the spinal cord but above the anterior horn cell. Injury may be caused by trauma, a stroke, or tumors (these are discussed in Chapter 17). The injury causes upper motor neuron signs and symptoms that are summarized in Table 16.19.

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FIGURE 16.18 Structures of the Upper Motor Neuron, or Pyramidal, System. Pyramidal system fibers are shown to originate primarily in cells in the precentral gyrus of the motor cortex; to converge at the internal capsule; to descend to form the central third of the cerebral peduncle; to descend further through the pons, where small fibers supply cranial nerve motor nuclei along the way; to form pyramids at the medulla, where most of the fibers decussate (cross over); and then to continue to descend in the lateral column of white matter of the spinal cord. A few fibers descend without crossing at the level of the medulla (i.e., the ventral (anterior) corticospinal tract).

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FIGURE 16.19 Motor Function Syndromes. Disturbances in motor function are classified pathologically along upper and lower motor neuron structures. It should be noted that the same pathologic condition occurs at more than one site in an upper motor neuron (top right). A few pathologic conditions involve both upper and lower motor neuron structures, as in amyotrophic lateral sclerosis, for example. Other lesion sites include myoneural junction and primary muscle, making it possible to classify conditions as neuromuscular and muscular, respectively.

TABLE 16.19 Upper and Lower Motor Neuron Syndromes Signs and Symptoms Lower Motor Neuron (Cranial Nerve Nuclei— Brainstem; Ventral Horn—Spinal Cord) Individual muscles may be affected Mild weakness (paresis) Flaccid paralysis Marked muscle atrophy Fasciculations Hyporeflexia, decreased muscle stretch reflexes

Upper Motor Neuron (Pyramidal Cells—Motor Cortex)

Muscle groups are affected Mild weakness (paresis) Spastic paralysis Minimal disuse muscle atrophy No fasciculations Hyperreflexia, increased muscle stretch reflexes (clasp-knife spasticity; resistance to passive flexion that releases abruptly to allow easy flexion) Clonus may be present Clonus not present

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Hypertonia, spasticity Pathologic reflexes (Babinski and Hoffmann signs, loss of abdominal reflexes) Often initial impairment of only skilled movements

Hypotonia, flaccidity No Babinski sign Asymmetric and may involve one limb only in beginning to become generalized as disease progresses

Paresis (weakness) is partial paralysis with incomplete loss of muscle power. Paralysis is loss of motor function so that a muscle group is unable to overcome gravity. Different terms are used to describe the location of the paralysis (Box 16.6). Upper motor neuron paresis (weakness) or paralysis is also known as spastic paresis/paralysis. Upper motor neuron injury initially causes flaccid paralysis. However, within a few weeks there is a gradual return of motor function that is overactive. Upper motor neuron paresis/paralysis involves a series of motor dysfunctions resulting from interruption of the pyramidal system. The clinical manifestations reflect muscle overactivity and include excessive, regularly occurring movements, such as clonus (rhythmic contractions) and spasms. They are the result of loss of descending inhibitory control. There is great variation, depending on the suddenness of onset and the age of the individual.

Box 16.6

Location of Paresis/Paralysis Hemiparesis/hemiplegia is paresis/paralysis of the upper and lower extremities on one side. Diplegia is paralysis of corresponding parts of both sides of the body as a result of cerebral hemisphere injuries. Paraparesis/paraplegia is weakness/paralysis of the lower extremities as a result of lower spinal cord injury. Quadriparesis/quadriplegia is paresis/paralysis of all four extremities as a result of upper spinal cord injury. If the pyramidal system is interrupted above the level of the pons, the hand and arm muscles are greatly affected. Paralysis rarely involves all the muscles on one side of the body, even when the hemiplegia results from complete damage to the internal capsule. Bilateral movements, such as those of the eye, jaw, and larynx, as well as those of the trunk, are affected only slightly, if at all. Predominantly the limbs are affected. Paralysis associated with an upper motor neuron syndrome rarely remains flaccid for a prolonged time. After a few days or weeks, a gradual return of spinal reflexes marks the end of spinal shock (see Chapter 17). Hypertonia and hyperreflexia occur particularly in antigravity muscles (e.g., the soleus muscles of the leg, the hamstrings of the leg, the gluteus maximus, the quadriceps femoris, and spinal erector muscles of the back). Spasticity is common, although rigidity occasionally occurs. Most often, passive range-ofmotion movements cause “clasp-knife” rigidity, probably by activating the stretch receptors in the muscle spindles and the Golgi tendon organ. (Muscle function is discussed in Chapter 40.) With pyramidal motor syndrome, the flexors of the arms and the extensors of the legs are predominantly affected.

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Lower Motor Neuron Syndromes Alpha motor neurons are the large motor neurons with their cell bodies in the anterior horn of the spinal cord and the motor nuclei of the brainstem. These lower motor neurons bring nerve impulses from upper motor neurons to skeletal muscles through the anterior spinal roots or cranial nerves and cause muscle contraction (Fig. 16.20). Damage to alpha motor neurons can occur in the anterior horn cell, nerve root, nerve plexus, or peripheral nerve. The damage causes lower motor neuron syndromes and impairs both voluntary and involuntary movement in the muscles innervated by the involved nerves (see Table 16.19 and Fig. 16.19). The degree of paralysis or paresis is proportional to the number of lower motor neurons affected. If only some of the motor units that supply a muscle are affected, only partial paralysis or paresis results. If all motor units are affected, complete paralysis results. Other clinical manifestations also are proportional to the degree of dysfunction, but the precise manifestations depend on the location of the dysfunction in the motor unit and in the CNS.

FIGURE 16.20 Structures Composing Lower Motor Neuron, Including Motor (Efferent) and Sensory (Afferent) Elements. (Top) Anterior horn cell (alpha motor neuron with cell body in anterior gray column of spinal cord), axon terminates in motor end plate as it innervates extrafusal muscle fibers in quadriceps muscle. (Detailed enlargement) Sensory and motor elements of gamma loop system. Gamma efferent fibers shown innervating the muscle spindle (sensory receptor of skeletal muscle). Contraction of muscle spindle fibers stretches the central portion of the spindle and causes the gamma afferent spindle fiber to transmit impulse centrally to the cord. Muscle spindle gamma afferent fibers in turn synapse on the anterior horn cell, and impulses are transmitted by way of alpha efferent fibers to skeletal (extrafusal) muscle, causing it to contract. Muscle spindle discharge is interrupted by active contraction of skeletal muscle fibers.

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Small motor (gamma) neurons maintain muscle tone, protect the muscle from injury, and are needed for normal motor movement. Gamma neurons depend on input from the muscle spindle in skeletal muscle (see Fig. 16.20). Dysfunction in this motor system (the gamma loop) impairs tone and reduces tendon reflexes, causing hyporeflexia. The muscles become susceptible to damage from hyperextensibility. Generally, the large and small motor neuron systems are equally affected. Therefore the muscle has reduced tone or hypotonia and is accompanied by hyporeflexia or areflexia (loss of tendon reflexes) and flaccid paresis/paralysis. Denervated muscles (i.e., muscles that have lost their nervous system input) atrophy over weeks to months, mostly from disuse, and demonstrate fasciculations (muscle rippling or quivering under the skin). Occasionally, denervated muscles cramp. Fibrillation is isolated contraction of a single muscle fiber because of metabolic changes in denervated muscle and is not clinically visible.

Motor Neuron Diseases Motor neuron diseases result from progressive degeneration of upper or lower motor neurons in the spinal cord, brainstem, or cortex. The pathologic processes that give rise to motor neuron diseases can be sporadic or inherited. Sporadic inflammatory processes (virally induced, postinfectious, or postvaccination) may injure or destroy anterior horn cells or cranial nerve cell bodies (e.g., polio, Guillain-Barré syndrome (see Chapter 17), or amyotrophic lateral sclerosis [see the next section]). Some inflammatory processes are mild and can be followed by rapid cellular recovery (e.g., facial nerve [Bell] palsy) (Box 16.7).

Box 16.7

Facial Nerve (Bell) Palsy Facial nerve (Bell) palsy is an acute unilateral lower motor neuron paralysis of cranial nerve VII. The etiology remains unknown. There is usually an inflammatory reaction compressing the facial nerve, particularly in the narrowest segment, followed by demyelinating neural change. The most distressing signs are unilateral facial weakness and the inability to smile or whistle. Facial palsy may be caused by reactivation of herpesviruses in cranial nerve VII (facial), geniculate ganglia, or an autoimmune response. The signs usually have an acute onset (within 72 hours). Herpes simplex type 1 has been detected in up to 78% of cases and herpes zoster in 30% of cases. Severe pain with facial palsy and a vesicular rash in the ear or mouth suggest herpes zoster infection. Ramsay Hunt syndrome (herpes zoster oticus) is rare, but complete recovery is less than 50%. Recovery from facial palsy is usually complete. Both disorders may be treated with combination antivirals and oral steroids. Treatment should be individualized according to severity of symptoms. Data from Baugh RF et al: Otolaryngol Head Neck Surg 149(3 Suppl):S1-S27, 2013; De Ru JA, Van Benthem PP: Evid Based Med 19(1):15, 2014; Eviston TJ et al: J Neurol Neurosurg Psychiatry 86(12):1356-1361, 2015; Glass GE, Tzafetta K: Fam Pract 31(6):631-642, 2014. Damage to one or more of the cranial nerve nuclei is called cranial nerve palsy. It may be

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caused by vascular occlusion, tumor, aneurysm, tuberculosis, or hemorrhage. A group of rare degenerative disorders principally cause progressive lower motor neuron atrophy. Spinal muscular atrophy (SMA) is an inherited autosomal recessive degenerative disease of the anterior horn cells of the spinal cord. SMA causes weakness and atrophy of skeletal muscles. A bulbar palsy involves the cranial nerves in the motor nuclei of the medulla (cranial nerves IX [glossopharyngeal], X [vagus], XI [accessory], and XII [hypoglossal]). The term bulb was so named because the medulla was originally called the bulb. Progressive bulbar palsy involves degeneration of the glossopharyngeal, vagus, and hypoglossal cranial nerves. The clinical manifestations of bulbar palsies include paresis or paralysis of the jaw, face, pharynx, and tongue musculature. All these manifestations become progressively worse, leading to aspiration, malnutrition, possible dehydration, and an inability to communicate verbally.

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis ([ALS], sporadic motor neuron disease, sporadic motor system disease, motor neuron disease [MND], Lou Gehrig disease) is a worldwide neurodegenerative disorder that diffusely involves lower and upper motor neurons, resulting in progressive muscle weakness. Amyotrophic (without muscle nutrition or progressive muscle wasting) refers to the predominant lower motor neuron component of the syndrome. Lateral sclerosis, scarring of the pyramidal (corticospinal) tract in the lateral column of the spinal cord, refers to the upper motor neuron component of the syndrome. ALS may begin at any time from the fourth decade of life; its peak occurrence is between 60 and 69 years, with about 1 to 2.6 cases per 100,000 population in the United States. The prevalence is higher in males.37 Most cases of ALS are sporadic. A subset (about 5% to 10%) of persons has a familial form with genetic mutations that contribute to the neurotoxicity affecting motor neurons. Gene and environmental interactions are being evaluated as a cause of ALS.38 ALS is fatal from respiratory failure, usually within 3 years of diagnosis. A small percentage of individuals live 5 to 10 years or longer. Pathophysiology The cause of ALS is unknown. The principal pathologic feature of ALS is degeneration of lower and upper motor neurons. There is a decrease in large motor neurons in the spinal cord, brainstem, and cerebral cortex (premotor and motor areas), with ongoing degeneration in the remaining motor neurons. Death of the motor neuron results in axonal degeneration and secondary demyelination with glial proliferation and sclerosis (scarring). Widespread neural degeneration of nonmotor neurons in the spinal cord and motor cortices, as well as in the premotor, sensory, and temporal cortices, has been found, including areas that involve cognition. Lower motor neuron degeneration denervates motor units. Adjacent, still viable lower motor neurons attempt to compensate by distal intramuscular sprouting, reinnervation, and enlargement of motor units. Clinical Manifestations The initial symptoms of the disease are heterogeneous and may be related to lower or upper motor neuron dysfunction or both. About 60% of individuals have a spinal form of the disease, with focal muscle weakness beginning in the arms and legs and progressing to

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muscle atrophy, spasticity, and loss of manual dexterity and gait. No associated mental, sensory, or autonomic symptoms are present. ALS with progressive bulbar palsy presents with difficulty speaking and swallowing. Peripheral muscle weakness and atrophy usually occur within 1 to 2 years, including the muscles of ventilation. These individuals have an improved response to treatment with non-invasive ventilation.39 The lower motor neuron syndrome consists of weakness of individual muscles, progressing to flaccid paralysis, associated with hypotonia, and primary muscle atrophy (i.e., atrophy caused by denervation). Frontotemporal dementia may occur concurrently.40 Evaluation and Treatment Diagnosis of the syndrome is based predominantly on the history and physical examination with no evidence of other neuromuscular disorders. Genetic testing is available. Electromyography and muscle biopsy results verify lower motor neuron degeneration and denervation. Imaging studies and CSF biomarkers can assist in making the diagnosis. There is no curative treatment. Riluzole (Rilutek), an antiglutamate and edaravone (Radicava) a free-radical scavenger, are the only drugs approved by the U.S. Food and Drug Administration for treatment of ALS, and they prolong life for months. Supportive and rehabilitative management are directed toward preventing complications of malnutrition and immobility. Psychologic support of the affected individual and the family is extremely important.

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Alterations in Complex Motor Performance The alterations in complex motor performance include disorders of posture (stance), disorders of gait, and disorders of expression.

Disorders of Posture (Stance) An inequality of tone in muscle groups, because of a loss of normal postural reflexes, results in a posturing of limbs. Equilibrium and balance are disrupted. Many reflex systems govern tone and posture, but the most important factor in posture control is the stretch reflex, in which extensor (antigravity) muscle stretching causes increased extensor tone and inhibited flexor tone. Four types of disorders of posture are (1) dystonic posture, (2) decorticate posture, (3) decerebrate posture/response, and (4) basal ganglion posture. Dystonia is the maintenance of an abnormal posture through muscular contractions. When muscular contractions are sustained for several seconds, they are called dystonic movements. When contractions last for longer periods, they are called dystonic postures. Dystonic postures may last for weeks, causing permanent, fixed contractures. Dystonia has been associated with basal ganglia abnormality, but the exact pathophysiologic mechanisms are unknown. One dystonic posture is decorticate posture/response (striatal posture or upper motor neuron dysfunction posture), which may be unilateral or bilateral. Decorticate posture/response (also referred to as antigravity posture or hemiplegic posture) is characterized by upper extremities flexed at the elbows and held close to the body and by lower extremities that are externally rotated and extended (see Fig. 16.6). Decorticate posture/response is thought to occur when the brainstem is not inhibited by the cerebral cortex motor area. Upper motor neuron posture is more commonly described as the arm flexed at the elbow with a wrist drop, the leg inadequately bent at the knee, the hip excessively circumabducted, and the presence of footdrop. Decerebrate posture/response refers to increased tone in extensor muscles and trunk muscles, with active tonic neck reflexes. When the head is in a neutral position, all four limbs are rigidly extended (see Fig. 16.6). The decerebrate posture is caused by severe injury to the brain and brainstem, resulting in overstimulation of the postural righting and vestibular reflexes. Basal ganglion posture refers to a stooped, hyperflexed posture with a narrow-based, short-stepped gait. Basal ganglion dysfunction accounts for this posture. This posture abnormality results from the loss of normal postural reflexes and not from defects in proprioceptive, labyrinthine, or visual function. Dysfunctional equilibrium results when the individual loses stability and cannot make the appropriate postural adjustment to tilting or loss of balance, falling instead. Dysfunctional righting is the inability to right oneself when changing from a lying or crouching to a standing position or when rolling from the supine to the lateral or prone position. Dysfunctional postural fixation is the involuntary flexion of the head and neck, causing the person difficulty in maintaining an upright trunk position while standing or walking.

Disorders of Gait Four predominant types of gait associated with neurologic disorders are (1) upper motor

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neuron dysfunction gait (spastic gait), (2) cerebellar (ataxic) gait, (3) basal ganglion gait, and (4) frontal lobe ataxic gait. As with posture, equilibrium and balance are affected with gait disturbances.41 Several upper motor neuron gaits exist. Injury to the pyramidal (cortocospinal) system with loss of accompanying inhibitory control accounts for these gaits (e.g., stroke, cerebral palsy, multiple sclerosis, spinal cord tumor). With mild forms, the individual may have footdrop with fatigue and hip and leg pain. A spastic gait, which is associated with unilateral injury, manifests by a shuffling gait with the leg extended and held stiff, causing a scraping over the floor surface. The leg swings improperly around the body rather than being appropriately lifted and placed. The foot may drag on the ground, and the person tends to fall to the affected side. A scissors gait is associated with bilateral injury and spasticity. The legs are adducted so they touch each other. As the person walks, the legs are swung around the body but then cross in front of each other because of adduction. A cerebellar (ataxic) gait is wide-based with the feet apart and often turned outward or inward for greater stability. The pelvis is held stiff, and the individual staggers when walking. Cerebellar dysfunction with loss of coordination accounts for this particular gait. A basal ganglion gait is a broad-based gait in which the person walks with small steps and a decreased arm swing. The head and body are flexed and the arms semiflexed and abducted, whereas the legs are flexed and rigid in more advanced states. The basal ganglia modulate and coordinate motor function; dysfunction accounts for this gait. It is associated with Parkinson disease. A frontal lobe ataxic gait is associated with start hesitation, gait ignition failure, a widebased gait, body sway and falls, loss of control of truncal motion, shuffling, and freezing. The gait is associated with bilateral frontal lobe damage or degeneration. Power and coordination of the legs is normal when tested in the seated or lying position. The pattern may change as the frontal disease progresses. The slowness of walking, lack of heel-shin or upper limb ataxia, dysarthria, or nystagmus distinguishes the wide stance from cerebellar gait ataxia.42 Gait disorders are often accompanied by balance, coordination, and sensory dysfunction that further alter mobility and increase risk for falls. Assessment and intervention strategies are important for prevention of injury.

Disorders of Expression Disorders of expression involve the motor aspects of communication and include (1) hypermimesis, (2) hypomimesis, and (3) apraxia/dyspraxia. Hypermimesis commonly manifests as pathologic laughter or crying. Pathologic laughter is associated with right hemisphere injury, and pathologic crying is associated with left hemisphere injury. The exact pathophysiology is not known. Hypomimesis manifests as aprosody—the loss of emotional language. Receptive aprosody involves an inability to understand emotion in speech and facial expression. Expressive aprosody involves the inability to express emotion in speech and facial expression. Aprosody is associated with right hemisphere damage. Apraxia/dyspraxia is a disorder of learned skilled movements with difficulty planning and executing coordinated motor movements. The term is often used interchangeably with dyspraxia. It can be developmental, beginning at birth (developmental apraxia), or associated with vascular disorders (common in stroke), trauma, tumors, degenerative disorders, infections, or metabolic disorders. People with apraxia have difficulty

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performing tasks requiring motor skills, including speaking, writing, using tools or utensils, playing sports, following instructions, and focusing.43 True apraxias occur when the connecting pathways between the left and right cortical areas are interrupted. Apraxias may result from any pathologic process that disrupts the cortical areas necessary for the conceptualization and execution of a complex motor act or the communication pathways within the left hemisphere or between the hemispheres.43,44

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Extrapyramidal Motor Syndromes Because the extrapyramidal system encompasses all the motor pathways except the pyramidal system, two types of motor dysfunction make up the extrapyramidal motor syndromes: (1) the basal ganglia motor syndromes and (2) the cerebellar motor syndromes. Unlike pyramidal motor syndromes, both extrapyramidal motor syndromes result in movement or posture disturbance without significant paralysis, along with other distinctive symptoms (Table 16.20). TABLE 16.20 Pyramidal Versus Extrapyramidal Motor Syndrome Manifestations Unilateral movement Tendon reflexes Babinski sign Involuntary movements Muscle tone

Pyramidal Motor Syndrome Paralysis of voluntary movement Increased tendon reflexes

Extrapyramidal Motor Syndrome Little or no paralysis of voluntary movement Normal or slightly increased tendon reflexes

Present Absent Absence of involuntary Presence of tremor, chorea, athetosis, or dystonia movements Spasticity in muscles (e.g., Plastic rigidity (equal throughout movement) or intermittent— clasp-knife phenomenon) cogwheel rigidity (generalized but predominantly in flexors of Hypertonia present in limbs and trunk) flexors of arms and Hypotonia, weakness and gait disturbances in cerebellar disease extensors of legs

Basal ganglia motor syndromes are caused by an imbalance of dopaminergic and cholinergic activity in the corpus striatum. A relative excess of cholinergic activity produces hypokinesia (decreased movement) and hypertonia. A relative excess of dopaminergic activity produces hyperkinesia and hypotonia. Symptoms associated with Parkinson and Huntington diseases are exemplary of disorders of the basal ganglia. Cerebellar motor syndromes are associated with ataxia and other symptoms affecting coordinated movement and balance. Cerebellar disorders primarily influence the same side of the body, so that damage to the right cerebellum generally causes symptoms on the right side of the body.

Quick Check 16.6 1. What are three symptoms of upper motor neuron disease? 2. What are three symptoms of lower motor neuron disease? 3. How does decerebrate posture differ from decorticate posture? 4. What motor symptoms would be characteristic of extrapyramidal diseases?

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Summary Review Alterations in Cognitive Systems 1. The neural systems essential to cognitive function are: (1) attentional systems that provide arousal and maintenance of attention over time; (2) memory and language systems by which information is remembered and communicated; and (3) affective or emotive systems that mediate mood, emotion, and intention. 2. Consciousness is a state of awareness of oneself and the environment, and a set of responses to that environment. 3. Consciousness has two components: arousal (state of awakeness or alertness) and awareness (content of thought). 4. An altered level of arousal occurs by pathologies that alter localized or diffuse brain structure and metabolic disorders that alter delivery of energy substrates. The five patterns of neurologic function critical to the evaluation of consciousness are level of consciousness, pattern of breathing, pupillary reaction, oculomotor responses, and motor responses. 5. Level of consciousness is the most critical index of nervous system function. From a normal alert state, consciousness can diminish in stages through confusion, disorientation, lethargy, obtundation, stupor, and coma. 6. Breathing pattern, rate, and rhythm help evaluate brain dysfunction and coma. 7. Pupillary changes reflect changes in level of brainstem function, drug action, and response to hypoxia and ischemia. 8. Oculomotor responses are resting, spontaneous, and reflexive eye movements and reflect alterations in brainstem function. 9. Level of brain function manifests by changes in generalized motor responses or no responses. The most severely damaged side of the brain can be determined by assessing motor response. 10. Loss of cortical inhibition associated with decreased consciousness produces abnormal flexor and extensor movements. 11. Brain death results from irreversible brain damage, with an inability to maintain internal homeostasis. 12. Cerebral death or irreversible coma represents permanent brain damage, with an ability to maintain cardiac, respiratory, and other vital functions. 13. A persistent vegetative state is complete unawareness of the self or surrounding environment and complete loss of cognitive function. Brainstem reflexes (pupillary, oculocephalic, chewing, swallowing) are intact but cerebral function is lost. 14. Locked-in syndrome is complete paralysis of voluntary muscles, with the exception of eye movement, with retention of consciousness. 15. Alterations in awareness include alterations in executive attention (abstract reasoning, planning, decision making, judgment, error correction, and self-control) and memory. 16. With a deficit in selective attention, mediated by midbrain, thalamus, and parietal lobe structures, the individual cannot focus on selective stimuli and thus neglects

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those stimuli. 17. In amnesia, some past memories are lost (retrograde amnesia) and new memories cannot be stored (anterograde amnesia). Global amnesia is a combination of anterograde and retrograde amnesia. 18. Frontal areas mediate vigilance, detection, and working (short-term) memory. 19. With vigilance deficits, the person cannot maintain sustained concentration. 20. With detection deficits, the person is unmotivated and unable to set goals and plan. 21. Data-processing deficits are problems associated with recognizing and processing sensory information, and include agnosias, dysphasias, acute confusional states, and dementias. 22. Agnosias are defects of pattern recognition and may be tactile, visual, or auditory. 23. Aphasia (dysphasia) is an impairment of comprehension or production of language. Aphasia may be expressive or receptive. 24. Acute confusional states are characterized chiefly by transient disorders of awareness. 25. Delirium can be hyperactive (excited delirium syndrome) with intense autonomic nervous system activation, or hypoactive with frontal basal ganglia disruption. 26. Dementia is a slowly progressive deterioration in cerebral function with loss of intellectual processes and memory. 27. Alzheimer disease is a chronic irreversible dementia that is related to altered production or failure to clear amyloid from the brain with plaque formation and formation of neurofibrillary tangles. 28. Vascular dementia is a consequence of cerebrovascular disease, and treatment is directed at preventing the risk factors of diabetes, hypercholesterolaemia, hypertension, and smoking. 29. Frontotemporal dementias are rare early-onset degenerative diseases similar to Alzheimer disease. 30. Seizures represent a sudden, chaotic discharge of cerebral neurons with transient alterations in brain function. Seizures may be generalized or focal and can result from metabolic disorders, congenital malformations, genetic predisposition, perinatal injury, postnatal trauma, myoclonic syndromes, infection, brain tumor, vascular disease, and drug or alcohol abuse.

Alterations in Cerebral Hemodynamics 1. Alterations in cerebral blood flow are related to inadequate cerebral perfusion, normal cerebral perfusion but with an elevated intracranial pressure, and excessive cerebral blood volume. 2. Increased intracranial pressure (IICP) may result from edema, excess cerebrospinal fluid, hemorrhage, or tumor growth. When intracranial pressure approaches arterial pressure, hypoxia and hypercapnia produce brain damage. 3. The herniation process rapidly increases ICP. Types of supratentorial herniation include (1) uncal (uncus and/or hippocampal gyrus shift from the middle fossa through the tentorial notch into the posterior fossa), (2) central (downward shift of the diencephalon through the tentorial notch), (3) cingulate gyrus (cingulate gyrus

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shifts under the falx cerebri), and (4) transcalvarial (brain shifts through a skull fracture or a surgical opening in the skull). 4. The most common infratentorial herniation is a shift of the cerebellar tonsils through the foramen magnum. 5. Cerebral edema is an increase in the fluid content of the brain resulting from trauma, infection, hemorrhage, tumor growth, ischemia, infarction, or hypoxia. The three types of cerebral edema are vasogenic, cytotoxic, and interstitial. 6. Hydrocephalus comprises a variety of disorders characterized by an excess of fluid within the ventricles, subarachnoid space, or both. Hydrocephalus occurs because of interference with cerebrospinal fluid flow caused by increased fluid production, obstruction within the ventricular system, or defective reabsorption of the fluid.

Alterations in Neuromotor Function 1. General neuromotor dysfunctions are associated with changes in muscle tone, movement, and complex motor performance. 2. Normal muscle tone involves a slight resistance that is smooth, constant, and even to passive movement. Hypotonia and hypertonia are the main categories of altered tone. 3. Hypotonia is decreased muscle tone. It is associated with pyramidal tract or cerebellar injury. Muscles are flaccid and weak with atrophy. 4. Hypertonia is increased muscle tone. The four types of hypertonia are spasticity, paratonia, dystonia, and rigidity. 5. Alterations in muscle movements occur when CNS dysfunction alters muscle innervation. Movement disorders are not necessarily associated with muscle mass, strength, or tone but are neurologic dysfunctions that result in insufficient or excessive movement or involuntary movement. Movement disorders can be idiopathic or associated with specific diseases of the central nervous system, such as Parkinson disease and Huntington disease. 6. Hyperkinesia is excessive purposeless movement, including chorea, athetosis, ballism, akathisia, tremor, and myoclonus. Paroxysmal dyskinesias are rare abnormal, episodic, involuntary movements that occur as spasms. 7. Huntington disease is a rare, hereditary movement disorder involving severe degeneration of the basal ganglia and cerebral cortex that commonly manifests between 25 and 45 years of age. An excess of dopaminergic activity causes involuntary hyperkinetic movements, such as chorea (jerky, abnormal movement), athetosis (slow, sinuous, irregular movements), and ballism (violent flailing movement of the limbs). 8. Hypokinesia is loss of voluntary movement despite preserved consciousness and normal peripheral nerve and muscle function. Akinesia is a decrease in voluntary movements; bradykinesia is a slowness of voluntary movements. 9. Parkinson disease is a degenerative disorder of the basal ganglia with loss of dopamine-secreting neurons. Dopamine depletion and excess cholinergic activity cause tremor, rigidity, and akinesia. Progressive dementia may be associated with an advanced stage of the Parkinson disease. 10. Upper motor neuron syndromes are the result of injury to motor pathways that

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descend from the motor cortex. Injury may occur in the cerebral cortex, the subcortical white matter, the internal capsule, the brainstem, or the spinal cord. Upper motor neuron syndromes are characterized by paresis (partial paralysis), paralysis, hypertonia, and hyperreflexia. 11. Lower motor neuron syndromes involve damage to the alpha motor neurons—the large motor neurons in the anterior horn of the spinal cord and the motor nuclei of the brainstem. Lower motor neuron syndromes manifest by impaired voluntary and involuntary movements and flaccid paresis or paralysis. 12. Motor neuron diseases result from progressive degeneration of upper or lower motor neurons in the spinal cord, brainstem, or cortex (e.g., polio, Gullian-Barré syndrome, or amyotrophic lateral sclerosis). 13. Amyotrophic lateral sclerosis involves degeneration of both upper and lower motor neurons with progressive muscle weakness and atrophy. No associated mental, sensory, or autonomic symptoms are present.

Alterations in Complex Motor Performance 1. Alterations in complex motor performance include disorders of posture (stance), disorders of gait, and disorders of expression. 2. Inequality of tone in muscle groups results in abnormal posturing of the limbs. Disorders of posture include dystonic posture, decerebrate posture/response, basal ganglion posture, and senile posture. 3. Disorders of gait associated with neurologic disorders include upper motor neuron dysfunction gait (spastic gait), cerebellar (ataxic) gait, basal ganglion gait, and frontal lobe ataxic gait. 4. Disorders of expression include hypermimesis (pathologic laughter or crying), hypomimesis (loss of emotional language/communication), and apraxia/dyspraxia. Apraxia is an impairment of the conceptualization or execution of a complex motor act.

Extrapyramidal Motor Syndromes 1. Extrapyramidal motor syndromes include basal ganglia and cerebellar motor syndromes. 2. Basal ganglia disorders are caused by an imbalance of dopaminergic and cholinergic activity. A relative excess of cholinergic activity produces hypokinesia and hypertonia; a relative excess of dopaminergic activity produces hyperkinesia and hypotonia. 3. Cerebellar motor syndromes are associated with ataxia and other symptoms affecting coordinated movement and balance, usually on the same side of the body as the side of the cerebellar lesion.

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Key Terms Acute confusional state (ACS), 360 Acute hydrocephalus, 370 Agnosia, 359 Akinesia, 374 Alzheimer disease (AD) (dementia of Alzheimer type [DAT], senile disease complex), 362 Amnesia, 357 Amyotrophic lateral sclerosis ([ALS] sporadic motor neuron disease, sporadic motor system disease, motor neuron disease [MND], Lou Gehrig disease), 377 Anterograde amnesia, 357 Aphasia, 359 Apraxia/dyspraxia, 379 Arousal, 351 Aura, 367 Autoregulation, 368 Awareness (content of thought), 357 Basal ganglia motor syndrome, 379 Basal ganglion gait, 379 Basal ganglion posture, 378 Bradykinesia, 374 Brain death (total brain death), 355 Bulbar palsy, 377 Cerebellar (ataxic) gait, 379 Cerebellar motor syndrome, 380 Cerebral death (irreversible coma), 355 Cerebral edema, 369 Cerebral perfusion pressure (CPP), 367 Clonic phase, 367 Communicating hydrocephalus, 370 Congenital hydrocephalus, 370 Consciousness, 351 Convulsion, 365 Cytotoxic edema, 369 Decerebrate posture/response, 378 Decorticate posture/response (antigravity posture, hemiplegic posture), 378 Delirium (hyperactive confusional state), 360 Dementia, 362 Dystonia, 378 Dystonic movement, 378 Dystonic posture, 378 Epilepsy, 365 Epileptogenic focus, 365 Excited delirium syndrome (ExDS), 360

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Executive attention deficit, 357 Extinction, 359 Extrapyramidal motor syndrome, 379 Fasciculation, 377 Fibrillation, 377 Flaccid paresis/paralysis, 377 Frontal lobe ataxic gait, 379 Frontotemporal dementia (FTD) (Pick disease), 365 Global amnesia, 357 Hiccup, 353 Huntington disease (HD), 372 Hydrocephalus, 369 Hyperkinesia, 372 Hypermimesis, 379 Hypertonia, 370 Hypokinesia, 374 Hypoactive delirium (hypoactive confusional state), 360 Hypomimesis, 379 Hypotonia, 370 Ictus, 367 Image processing, 357 Increased intracranial pressure (IICP), 367 Interstitial/hydrocephalic edema, 369 Level of consciousness, 352 Locked-in syndrome, 357 Long-term memory, 357 Loss of associated movement, 374 Lower motor neuron syndrome, 377 Memory, 357 Minimally conscious state ([MCS], minimally preserved consciousness), 357 Mirror focus, 367 Motor response, 353 Neglect syndrome, 359 Neuritic plaque, 362 Neurofibrillary tangle, 362 Noncommunicating hydrocephalus (internal hydrocephalus, intraventricular hydrocephalus), 370 Normal-pressure hydrocephalus, 370 Oculomotor response, 353 Paralysis, 375 Paratonia (gegenhalten), 370 Paresis, 375 Parkinson disease (PD), 374 Parkinsonism (Parkinson syndrome, parkinsonian syndrome, paralysis agitans), 374 Paroxysmal dyskinesia, 372 Patterns of breathing, 352 Persistent vegetative state, 357

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Postictal state, 367 Preictal phase, 367 Prodroma, 367 Progressive bulbar palsy, 377 Psychogenic alterations in arousal (unresponsiveness), 352 Pupillary change, 352 Retrograde amnesia, 357 Rigidity, 370 Secondary parkinsonism, 374 Seizure, 365 Selective attention, 357 Selective attention deficit, 357 Sensory inattentiveness, 359 Spasticity, 370 Spinal muscular atrophy (SMA), 377 Status epilepticus, 367 Structural alterations in arousal, 351 Tardive dyskinesia, 372 Tonic phase, 367 Tourette syndrome, 372 Upper motor neuron gait, 379 Upper motor neuron paresis (weakness)/paralysis, 375 Upper motor neuron syndrome, 375 Vascular dementia, 365 Vasogenic edema, 369 Vomiting, 353 Working memory (short-term memory), 357 Yawning, 353

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12. Loy CT, et al. Genetics of dementia. Lancet. 2014;383(9919):828–840. 13. Qazi TJ, et al. Epigenetics in Alzheimer's disease: perspective of DNA methylation. Mol Neurobiol. 2018;55(2):1026–1044. 14. Cummings JL, et al. International Work Group criteria for the diagnosis of Alzheimer disease. Med Clin North Am. 2013;97(3):363–368. 15. Aisen PS, et al. On the path to 2025: understanding the Alzheimer's disease continuum. Alzheimers Res Ther. 2017;9(1):60. 16. Epperly T, Dunay MA, Boice JL. Alzheimer disease: pharmacologic and nonpharmacologic therapies for cognitive and functional symptoms. Am Fam Physician. 2017;95(12):771– 778. 17. Tariq S, Barber PA. Dementia risk and prevention by targeting modifiable vascular risk factors. J Neurochem. 2018;144(5):565– 581. 18. Olney NT, Spina S, Miller BL. Frontotemporal dementia. Neurol Clin. 2017;35(2):339–374. 19. Fisher RS, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522–530 [Available at] https://www.ilae.org/news-and-media/news-aboutilae/new-ilae-seizure-classification. 20. Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med. 2015;5(6). 21. Nei M, et al. Ketogenic diet in adolescents and adults with epilepsy. Seizure. 2014;23(6):439–442. 22. Michinaga S, Koyama Y. Pathogenesis of brain edema and investigation into anti-edema drugs. Int J Mol Sci. 2015;16(5):9949–9975. 23. Williams MA, Malm J. Diagnosis and treatment of idiopathic normal pressure hydrocephalus. Continuum (Minneap Minn). 2016;22(2 Dementia):579–599. 24. Agostinho LA, et al. A systematic review of the 906

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Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction Barbara J. Boss, Sue E. Huether

CHAPTER OUTLINE Central Nervous System Disorders, 384 Traumatic Brain and Spinal Cord Injury, 384 Degenerative Disorders of the Spine, 392 Cerebrovascular Disorders, 395 Primary Headache Syndrome, 400 Infection and Inflammation of the Central Nervous System, 401 Demyelinating Disorders, 403 Peripheral Nervous System and Neuromuscular Junction Disorders, 405 Peripheral Nervous System Disorders, 405 Neuromuscular Junction Disorders, 405 Tumors of the Central Nervous System, 406 Brain Tumors, 406 Spinal Cord Tumors, 409

Alterations in central nervous system (CNS) function are caused by traumatic injury, vascular disorders, tumor growth, infectious and inflammatory processes, and metabolic derangements, including nutritional deficiencies and drugs or chemicals. Alterations in peripheral nervous system function involve the nerve roots, a nerve plexus, the peripheral nerves, or the neuromuscular junction.

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Central Nervous System Disorders Traumatic Brain and Spinal Cord Injury Traumatic Brain Injury Traumatic brain injury (TBI) is an alteration in brain function or other evidence of brain pathology caused by an external force. The most common causes are falls for children and older adults followed by unintentional blunt trauma and motor vehicle accidents. Males have the highest incidence in every age group. The incidence of TBI is highest among American Indian/Alaska Natives and African Americans and in lower- and medianincome families.1 In recent years, individuals with TBI have shown improved survival. Advancements have been made in enhanced safety measures (e.g., passive seat restraints, air bags, protective head gear), reduced transport time to hospitals or trauma centers, improved on-scene medical management, imaging of brain injury, prevention and management of secondary brain injury, and a better understanding of all degrees of brain injury severity. TBI can be classified as primary or secondary. Primary brain injury is caused by a direct impact. The injury can be a focal brain injury, affecting only one area of the brain, or a diffuse brain injury (diffuse axonal injury [DAI]), which involves more than one area of the brain. Both types of injury can be associated with the same initiating event. Focal brain injury and DAI each account for about half of all injuries. Focal brain injury accounts for more than two-thirds of head injury deaths. More severely disabled survivors, including those surviving in an unresponsive state or reduced level of consciousness, have DAI. Secondary injury is an indirect consequence of the primary injury. It includes systemic and brain tissue responses with a cascade of cellular and molecular cerebral events (Table 17.1). TBI can be mild, moderate, or severe. The Glasgow Coma Scale (GCS) is used to grade severity of injury (Table 17.2). Most TBIs are mild. The hallmark of a severe TBI is loss of consciousness for 6 hours or more.2 TABLE 17.1 Classification of Brain Injuries Type of Injury Mechanism Primary Brain Injury Focal Brain Injury Localized injury from impact Closed injury Blunt trauma Coup Injury is directly below site of forceful impact Contrecoup Injury is on opposite side of brain from site of forceful impact Epidural Vehicular accidents, minor falls, sporting accidents (extradural) hematoma Subdural Forceful impact: vehicular accidents or falls, especially in elderly persons or persons with chronic hematoma alcohol abuse Subarachnoid Bleeding caused by forceful impact, usually vehicular accidents or long distance falls hemorrhage Open injury Penetrating trauma: missiles (bullets) or sharp projectiles (knives, ice picks, axes, screwdrivers) Compound Objects strike head with great force or head strikes object forcefully; temporal blows, occipital fracture blows, upward impact of cervical vertebrae (basilar skull fracture)

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Diffuse Axonal Traumatic shearing forces; tearing of axons from twisting and rotational forces with injury over Injury (can occur widespread brain areas; moving head strikes hard, unyielding surface or moving object strikes with focal injury) stationary head; torsional head motion without impact Secondary Brain Injury Systemic processes Hypotension, hypoxia, anemia, hypercapnia, and hypocapnia Intracerebral Inflammation, cerebral edema, increased intracranial pressure (IICP), brain herniation, decreased processes cerebral perfusion pressure, ischemia Cellular processes Release of excitatory neurotransmitters (glutamate); failure of cell ion pumps, mitochondrial failure; disruption of blood brain barrier

TABLE 17.2 Glasgow Coma Scale (GCS)* Score† 1 2 3 4 5 6

Best Eye Response Score (4) No eye opening Eye opening to pain Eye opening to verbal command Eyes open spontaneously NA NA

Best Verbal Response Score (5) No verbal response Incomprehensible sounds Inappropriate words Confused Oriented NA

Best Motor Response Score (6) No motor response Extension to pain Flexion to pain Withdrawal from pain Localizing pain Obeys commands

*The

GCS is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of the sum of three parameters: Best Eye Response (E), Best Verbal Response (V), and Best Motor Response (M). Mild Brain Injury = 13 or higher; Moderate Brain Injury = 9 to 12; Severe Brain Injury = 8 or lower. †It

is important to break the scoring report into its components, for example, E3V3M5 = GCS 11. A total score is meaningless without this information. Age affects the GCS. Elderly individuals with a traumatic brain injury (TBI) have higher (better) GCS scores than younger individuals with a TBI of similar anatomic severity. Data from Teasdale G, Jennett B: Lancet 2:81-84, 1974; Salottolo K et al: J Am Med Assoc Surg 149(7):727-734, 2014.

Primary brain injury Focal brain injury. Focal brain injury can be caused by closed (blunt) trauma or open (penetrating) trauma. Closed injury is more common and involves either the head striking a hard surface (e.g., motor vehicle accidents or falls), a rapidly moving object striking the head (e.g., a baseball or falling objects), or by blast waves. The dura remains intact, and brain tissues are not exposed to the environment. Focal brain injuries include contusions, subdural hematomas, epidural hematomas, and intracerebral hemorrhage. Blunt trauma may result in both focal brain injuries and DAIs, and they can occur at the same time (see Table 17.1). Open injury occurs with penetrating trauma or skull fracture. A break in the dura results in exposure of the cranial contents to the environment. Closed brain injuries are specific, grossly observable brain lesions that occur in a precise location; most blunt trauma injuries are mild. Injury to the cranial vault, vessels, and supporting structures can produce more severe damage, including contusions and epidural, subdural, and intracerebral hematomas. The injury may be a coup injury (injury at site of impact) or a contrecoup injury (injury from brain rebounding and hitting the opposite side of skull) (Fig. 17.1). Compression of the skull at the point of impact produces contusions or brain bruising from blood leaking from an injured vessel. The severity of contusion varies with the amount of energy transmitted by the skull to underlying brain

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tissue. The smaller the area of impact, the more severe the injury because of the concentration of force. Brain edema forms around and in damaged neural tissues, contributing to increasing intracranial pressure (see Chapter 16). Multiple hemorrhages, edema, infarction, and necrosis can occur within the contused areas. The tissue has a pulpy quality. The maximal effects of these injuries peak 18 to 36 hours after severe head injury.

FIGURE 17.1 Coup and Contrecoup Focal Injury With Acceleration/Deceleration Axonal Shearing. A, Sagittal force causing coup (c) and contrecoup injury (cc). B, Lateral force causing coup (c) and contrecoup (cc) injury. C, Axial or rotational injury with shearing of axons, particularly at base of brain. Acceleration/deceleration axonal shearing injury occurs throughout the brain (red and blue directional arrows in all three images). (Borrowed from Pascual JM, Preito R: Surgical management of severe closed head injury in adults. In Quinones-Hinojosa A, editor: Schmidek and Sweet operative neurosurgical techniques, ed 6, vol 2, pp 1513-1538, Philadelphia, 2012, Saunders. Originally redrawn from Adams JH: Brain damage in fatal non-missile head injury in man. In Braakman R, editor: Handbook of clinical neurology, head injury, vol 13, pp 43-63, Amsterdam, 1990, Elsevier Science Publishers BV; Gennarelli TA

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et al: Ann Neurol 12:564-574, 1982.)

Contusions occur most commonly in the frontal lobes, the temporal lobes, and at the frontotemporal junction. Injuries in these areas cause changes in attention, memory, intellectual function, affect, emotion, and behavior. Less commonly, contusions occur in the parietal and occipital lobes. Focal cerebral contusions are usually superficial, involving just the brain gyri. Hemorrhagic contusions may coalesce into a large confluent intracranial hematoma. A contusion may be evidenced by immediate loss of consciousness (generally accepted to last no longer than 5 minutes), loss of reflexes (individual falls to the ground), transient cessation of respiration, brief period of bradycardia, and decrease in blood pressure (lasting 30 seconds to a few minutes). Vital signs may stabilize to normal values in a few seconds; reflexes then return, and the person regains consciousness over minutes to days. With more severe injury, residual deficits may persist, and some persons never regain a full level of consciousness. Evaluation is based on the results of the health history, level of consciousness according to the GCS (see Table 17.2), outcomes of imaging studies, and assessment of vital parameters (e.g., intracranial pressure [ICP] and electroencephalogram [EEG]). Large contusions and lacerations with hemorrhage may be surgically excised. Treatment is otherwise directed at controlling intracranial pressure, neuroprotection, and managing symptoms. An epidural (extradural) hematoma is bleeding between the dura mater and the skull. It represents 1% to 2% of major head injuries and occurs in all age groups, but most commonly in those 20 to 40 years old. The temporal fossa is the most common site of epidural hematoma caused by injury, commonly to the middle meningeal artery and less commonly to the meningeal vein or dural sinus (see Fig. 17.2). Both sites of hematoma can result in brain herniation (see Fig. 16.11).

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FIGURE 17.2

Brain Hematomas.

Individuals with temporal epidural hematomas lose consciousness at injury. If a vein is bleeding (a slower bleed), one-third of those affected then become lucid for a few minutes to a few days. As the hematoma accumulates, a headache of increasing severity, vomiting, drowsiness, confusion, and seizure occur. The expanding hematoma causes temporal lobe herniation, and the level of consciousness is rapidly lost, with ipsilateral pupillary dilation and contralateral hemiparesis. Imaging usually is needed to diagnose epidural hematoma. The prognosis is good if intervention is initiated before bilateral dilation of the pupils occurs. Epidural hematomas are medical emergencies requiring evaluation, monitoring, and surgical evacuation of the hematoma.3 A subdural hematoma is bleeding between the dura mater and the arachnoid membrane covering the brain and is caused by tearing of veins.4 It is the most common cause of a traumatic intracranial mass lesion, occurring in about 10% to 20% of individuals. Nontraumatic subdural hematoma can rarely develop in association with anticoagulant therapy or vascular malformations. Acute subdural hematomas develop rapidly, commonly within hours, and usually are located at the top of the skull. Subacute subdural hematomas develop more slowly, often over 48 hours to 2 weeks. Chronic subdural hematomas develop over weeks to months. These subdural hematomas act like expanding masses, increasing ICP that eventually compresses the bleeding vessels (see Fig. 17.2). Brain herniation can result. With a chronic subdural hematoma, the existing subdural space gradually fills with blood. A vascular membrane forms around the hematoma in approximately 2 weeks. Further enlargement may take place. In acute, rapidly developing subdural hematomas, the expanding clots directly compress the brain. As the ICP rises, bleeding veins are compressed. Thus bleeding can be selflimiting, although cerebral compression and displacement of brain tissue can cause

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temporal lobe herniation. An acute subdural hematoma classically begins with headache, drowsiness, restlessness or agitation, slowed cognition, and confusion. These symptoms worsen over time and progress to loss of consciousness, respiratory pattern changes, and pupillary dilation (i.e., the symptoms of temporal lobe herniation). Homonymous hemianopia (loss of vision in either the right or the left field [see Fig. 15.8]), dysconjugate gaze, and gaze palsies also may occur. Severity of injury is measured using the GCS, ICP monitoring, and brain imaging. Generally, clinical deterioration, a clot thickness greater than 10 mm, or a midline shift greater than 5 mm are suggested as critical parameters for surgery to remove the clot.5 Of those individuals affected by chronic subdural hematomas, 80% have chronic headaches and tenderness over the hematoma on palpation. Most persons appear to have a progressive dementia with generalized rigidity (paratonia). Chronic subdural hematomas require clot evacuation. Intracerebral hematomas (bleeding within the brain) occur in 2% to 3% of persons with head injuries. The hematomas may be single or multiple and are associated with contusions. Although most commonly located in the frontal and temporal lobes, they may occur in the hemispheric deep white matter. Penetrating injury or shearing forces traumatize small blood vessels. The intracerebral hematoma then acts as an expanding mass, increasing the ICP, compressing brain tissues, and causing edema (see Fig. 17.2). Delayed intracerebral hematomas may appear 3 to 10 days after the head injury. Intracerebral hematomas also can occur with nontraumatic brain injury, such as hemorrhagic stroke. Intracerebral hematomas cause a decreasing level of consciousness. Coma or a confusional state from other injuries, however, can make the cause of this increasing unresponsiveness difficult to detect. Contralateral hemiplegia also may develop and, as the ICP rises, temporal lobe herniation may occur. In delayed intracerebral hematoma, the presentation is similar to that of a hypertensive brain hemorrhage—sudden, rapidly progressive decreased level of consciousness with pupillary dilation, breathing pattern changes, hemiplegia, and bilateral positive Babinski reflexes (stroking the lateral side of the sole of the foot causes extension of the big toe—moves up—with fanning of the other toes). The history and physical examination help establish the diagnosis, and imaging confirms it. Surgical evacuation of a hematoma is performed, considering clinical signs and symptoms, size and location of the hematoma, and associated comorbid conditions. Otherwise, treatment is directed at reducing the ICP and allowing the hematoma to reabsorb slowly. Open brain injury (trauma that penetrates the dura mater) produces both focal and diffuse injuries and includes compound skull fractures and missile injuries (e.g., bullets, rocks, shell fragments, knives, and blunt instruments). A compound skull fracture opens a communication between the cranial contents and the environment and should be investigated whenever lacerations of the scalp, tympanic membrane, sinuses, eye, or mucous membranes are present. Such fractures may involve the cranial vault or the base of the skull (basilar skull fracture). Cranial nerve damage and spinal fluid leak may occur with a basilar skull fracture. The mechanisms of open brain trauma are crush injury (laceration and crushing of whatever the missile touches) and stretch injury (blood vessels and nerves damaged without direct contact as a result of stretching). The tangential injury is to the coverings and the brain (scalp and brain lacerations) and may also include skull fractures and meningeal

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or cerebral lacerations from projectiles and debris driven into the brain substance. Most persons lose consciousness with open brain injury. The depth and duration of the coma are related to the location of injury, extent of damage, and amount of bleeding. Open brain injury often requires débridement of the traumatized tissues to prevent infection and to remove blood clots, thereby reducing ICP. The ICP also is managed with dehydrating agents, osmotic diuretics, or a combination of these drugs. Broad-spectrum antibiotics are administered to prevent infection. A compound fracture may be diagnosed through physical examination, skull X-ray films, or both. Basilar skull fracture is determined on the basis of clinical findings, such as spinal fluid leaking from the ear or nose. Skull X-rays often do not demonstrate the fracture, although intracranial air or air in the sinuses on imaging is indirect evidence of a basilar skull fracture. Bed rest and close observation for meningitis and other complications are prescribed for a basilar skull fracture. Diffuse brain injury. Diffuse brain injury (diffuse axonal injury [DAI]) involves widespread areas of the brain and occurs with all severities of brain injury. DAI is defined clinically as coma lasting 6 or more hours after TBI. In mild DAI, coma lasts 6 to 24 hours. In moderate DAI, coma lasts longer than 24 hours but without abnormal posturing. In severe cases of DAI, coma duration is longer than 24 hours, with signs of brainstem impairment. Mechanical effects from high levels of acceleration and deceleration injury, such as whiplash, or rotational forces cause shearing of delicate axonal fibers and white matter tracts that project to or from the cerebral cortex (see Fig. 17.1). The most severe axonal injuries are located more peripheral to the brainstem, causing extensive cognitive and affective impairments, as seen in survivors of TBI from motor vehicle crashes. Axonal damage reduces the speed of information processing and responding and causes behavioral, cognitive, and physical changes.6 Pathophysiologically, axonal damage can be seen only with an electron microscope and involves numerous axons, either alone or in conjunction with actual tissue tears. Advanced imaging techniques assist in defining areas of injury. Areas where axons and small blood vessels are torn appear as small hemorrhages. More damaged axons are visible 12 hours to several days after the initial injury. The severity of diffuse injury correlates with how much shearing force was applied to the brainstem. DAI is not associated with intracranial hypertension immediately after injury; however, acute brain swelling, caused by vasodilation, increased intravascular blood flow within the brain, and increased cerebral blood volume, is seen often and can result in hypoxic-ischemic injury and death. DAI may induce long-term neurodegenerative processes. These changes may continue for years after injury, with the development of chronic traumatic encephalopathy and Alzheimer disease– like pathologic changes.7 Secondary brain injury. Secondary brain injury is an indirect result of primary brain injury, including trauma and stroke syndromes. Both systemic and cerebral processes are contributing factors. Systemic processes include hypotension, hypoxia, anemia, hypercapnia, and hypocapnia. Cerebral contributions include inflammation, cerebral edema, increased intracranial pressure (IICP), decreased cerebral perfusion pressure, cerebral ischemia, and brain herniation. Cellular and molecular brain damage from the effects of primary injury develops hours to days later and

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causes disruption of the blood–brain barrier and neuronal death. Mechanisms include oxidative stress, excitotoxicity (excessive stimulation by excitatory neurotransmitters, such as glutamate), and mitochondrial failure. The management of secondary brain injury is related to prevention of hypoxia and maintenance of cerebral perfusion pressure. Management includes removal of hematomas and treatment of hypotension, hypoxemia, anemia, intracranial pressure, fluid and electrolyte balance, body temperature, and ventilation. The development of neuroprotective agents is in progress but is difficult because of the complexity of multiple interacting secondary injury cascades.8 Nutrition management has emerged as critically important in the care of individuals with severe brain injury.9 Long-term recovery and mortality can be influenced by systemic complications, such as pneumonia, fever, infections, and immobility, that contribute to further brain injury and delays in repair and recovery. Categories of traumatic brain injury. Several categories of TBI exist and are presented here as mild, moderate, and severe. The terms concussion and traumatic brain injury are often used interchangeably. The severity of TBI commonly considers the duration of loss of consciousness, the GCS score, posttraumatic amnesia, and brain imaging results.10 Mild traumatic brain injury (mild concussion) is characterized by immediate but transitory clinical manifestations. There may be no loss of consciousness, or loss of consciousness may last less than 30 minutes. Most blunt trauma injuries cause mild concussion. The GCS score is 13 to 15. The initial confusional state lasts for 1 to several minutes, possibly with amnesia for events preceding the trauma (retrograde amnesia). Persons may experience headache, nausea, vomiting, impaired ability to concentrate, and difficulty sleeping for up to a few days. A blood test to evaluate for the presence of mild TBI in adults is available to determine if there is a need for a computed tomography (CT) scan.11 Moderate traumatic brain injury (moderate concussion) is any loss of consciousness lasting more than 30 minutes and up to 6 hours. The GCS score is 9 to 12. A basal skull fracture may be present, but there is no brainstem injury; however, there is transitory decerebration or decortication (see Fig. 16.6). The person is confused and experiences posttraumatic amnesia that lasts for more than 24 hours. There often are permanent deficits in selective attention, vigilance, detection, working memory, data processing, vision or perception, and language, as well as mood and affect changes ranging from mild to severe. Brain imaging is abnormal. Severe traumatic brain injury (severe concussion) is loss of consciousness lasting more than 6 hours. The GCS is 3 to 8. Frequently there are associated signs of brainstem damage, including changes in pupillary reaction, cardiac and respiratory symptoms, decorticate or decerebrate posturing (see Fig. 16.6), and abnormal reflexes. Brain imaging is abnormal. IICP appears 4 to 6 days after injury. Pulmonary complications occur frequently, with profound sensorimotor and cognitive system deficits. Severely compromised coordinated movements and verbal and written communication, inability to learn and reason, and inability to modulate behavior also are evident. Severe injury causes permanent neurologic deficits, and some individuals remain in a vegetative state or die as a result of brain injury or secondary complications. The goal of treating TBI is to maintain cerebral perfusion and oxygenation and promote

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neuroprotection. Implementation of management guidelines for TBI decreases death and improves neurologic outcome. The Corticosteroid Randomization After Significant Head Injury (CRASH) trial showed corticosteroids increase mortality with acute TBI; consequently, these drugs are no longer used.12

Complications of Traumatic Brain Injury Many complications are associated with TBI and are related to the severity of injury and the parts of the brain that are affected. Altered states of consciousness can range from confusion to deep coma (see Table 16.3). Cognitive deficits; hydrocephalus; sensory-motor disorders, including pain, paresis, and paralysis; and loss of coordination may be present. Three of the most common posttraumatic brain syndromes are summarized below. Postconcussion syndrome, including headache, dizziness, fatigue, nervousness or anxiety, irritability, insomnia, depression, inability to concentrate, and forgetfulness, may last for weeks to months after a mild concussion. Treatment entails reassurance and symptomatic relief in addition to 24 hours of close observation after the concussion in the event bleeding or swelling in the brain occurs. Symptoms requiring further evaluation and treatment include drowsiness or confusion, nausea or vomiting, severe headache, memory deficit, seizures, drainage of cerebrospinal fluid from the ear or nose, weakness or loss of feeling in the extremities, asymmetry of the pupils, and double vision. Guidelines for the management of pediatric and adult concussion are available.13-15 Guidelines have been published for the management of sports-related concussion.16 Posttraumatic seizures (epilepsy) occur in about 10% to 20% of TBIs, with the highest risk among open brain injuries. Seizures can occur early, within days, and up to 2 to 5 years or longer after the trauma. Causal mechanisms are poorly understood. Seizure prevention using drugs, such as phenytoin, is initiated for moderate to severe TBI at the time of injury. Studies are ongoing to test drugs that prevent the development of posttraumatic seizures.17 Chronic traumatic encephalopathy (CTE) (previously called dementia pugilistica) is a progressive dementing disease that develops with repeated brain injury associated with sporting events, blast injuries in soldiers, or work-related head trauma. Hyperphosphorylated tau neurofibrillary tangles are present in the brain, and research is in progress to discover the mechanistic link between neurotrauma and CTE. CTE is associated with violent behaviors, loss of control, depression, suicide, memory loss, cognitive change, and change in motor function. It is diagnosed from history and clinical evaluation and at autopsy.18

Quick Check 17.1 1. How is a concussion different from a contusion? 2. How does focal brain injury differ from diffuse brain injury? 3. Why is head motion the principal causative mechanism of diffuse brain injury?

Spinal Cord and Vertebral Injury Each year 17,700 persons experience serious spinal cord injury. Male sex and ages 16 to 30

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years are strong risk factors. Motor vehicle crashes are the leading cause of injury, followed by falls and then violence, other events, and sports activities.19 Elderly people are particularly at risk for trauma that results in serious spinal cord injury because of preexisting degenerative vertebral disorders. Pathophysiology Primary spinal cord injury occurs with the initial mechanical trauma and immediate tissue destruction. Injuries to the cord are summarized in Table 17.3. Primary spinal cord injury occurs if an injured spine is not adequately immobilized immediately following injury. Primary spinal cord injury also may occur in the absence of vertebral fracture or dislocation and is related to longitudinal stretching of the cord with or without flexion or extension of the vertebral column, or both. The stretching causes altered axon transport, edema, myelin degeneration, and retrograde or Wallerian neural degeneration (see Chapter 14). TABLE 17.3 Spinal Cord Injuries Injury Cord concussion Cord contusion Cord compression Laceration Transection Complete Incomplete Preserved sensation only Preserved motor nonfunctional Preserved motor functional Hemorrhage Damage or obstruction of spinal blood supply

Description Results in temporary disruption of cord-mediated functions Bruising of neural tissue causes swelling and temporary loss of cord-mediated functions Pressure on cord causes ischemia to tissues; must be relieved (decompressed) to prevent permanent damage to spinal cord Tearing of neural tissues of spinal cord; may be reversible if only slight damage sustained by neural tissues; may result in permanent loss of cord-mediated functions if spinal tracts are disrupted Severing of spinal cord causes permanent loss of function All tracts in spinal cord are completely disrupted; all cord-mediated functions below transection are completely and permanently lost Some tracts in spinal cord remain intact, together with functions mediated by these tracts; has potential for recovery although function is temporarily lost Some demonstrable sensation below level of injury Preserved motor function without useful purpose; sensory function may or may not be preserved Preserved voluntary motor function that is functionally useful Bleeding into neural tissue as a result of blood vessel damage; usually no major loss of function Causes local ischemia

Secondary spinal cord injury is a complex pathophysiologic cascade of vascular, cellular, and biochemical events that begins within a few minutes after injury and continues for weeks. Secondary injury includes hemorrhages, inflammation, edema, and ischemia. Hemorrhages develop in the central gray matter, and edema develops in the white matter, impairing the microcirculation of the cord. The hemorrhages and edema are followed by vasospasm and vascular occlusion, reduced perfusion, and development of ischemic areas, which are maximal at the level of injury and two cord segments above and below it. Cord swelling increases the individual's degree of dysfunction, making it difficult to distinguish functions permanently lost from those temporarily impaired. In the cervical region at C1C4, cord swelling may be life-threatening because cardiovascular and respiratory control functions can be lost. Excitotoxicity (excessive stimulation by excitatory neurotransmitters,

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such as glutamate), intracellular calcium overload, oxidative damage, and cell death occur similarly to those previously described for TBI. Spared neurons continue to be chronically injured, with death of oligodendrocytes and myelin degeneration, axonal disruption, glial scarring, cystic cavitation, and release of inhibitory mediators. The process presents a physical and chemical barrier to regeneration.20 Vertebral injuries result from acceleration, deceleration, or deformation forces occurring at impact. These forces cause vertebral fractures, dislocations, and penetration of bone fragments that can cause compression to the tissues, pull or exert traction (tension) on the tissues, or cause shearing of tissues so they slide into one another (Figs. 17.3 to 17.6). Vertebral injuries can be classified as (1) simple fracture—a single break usually affecting transverse or spinous processes; (2) compressed (wedged) vertebral fracture—vertebral body compressed anteriorly; (3) comminuted (burst) fracture—vertebral body shattered into several fragments; and (4) dislocation.

FIGURE 17.3

Hyperextension Injuries of the Spine. Hyperextension injuries of the spine can result in fracture or nonfracture injuries with spinal cord damage.

FIGURE 17.4 Flexion Injury of the Spine. Hyperflexion produces translation (subluxation) of vertebrae that compromises the central canal and compresses spinal cord parenchyma or vascular structures.

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FIGURE 17.5 Axial Compression Injuries of the Spine. In axial compression injuries of the spine, the spinal cord is contused directly by retropulsion of bone or disk material into the spinal canal.

FIGURE 17.6

Flexion-Rotation Injuries of the Spine.

The vertebrae fracture readily with both direct and indirect trauma. When the supporting ligaments are torn, the vertebrae move out of alignment, and dislocations occur. A horizontal force moves the vertebrae straight forward; if the individual is in a flexed position at the time of injury, the vertebrae are then angulated. Flexion and extension injuries may result in dislocations. (Bone, ligament, and joint injuries are presented in Table 17.4.) TABLE 17.4 Mechanisms of Vertebral Injury Involving Bone, Ligaments, and Joints Mechanism of Injury

Location of Vertebral Injury

Forces of Injury

Hyperextension Fracture and dislocation of posterior elements, Results from forces of such as spinous processes, transverse acceleration/deceleration and sudden processes, laminae, pedicles, or posterior reduction in anteroposterior diameter of

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Location of Injury Cervical area

Hyperflexion

Vertical compression (axial loading) Rotational forces (flexionrotation)

ligaments Fracture or dislocation of vertebral bodies, disks, or ligaments Shattering fractures Rupture support ligaments in addition to producing fractures

spinal cord Results from sudden and excessive force that propels neck forward or causes an exaggerated lateral movement of neck to one side Results from a force applied along an axis from top of cranium through vertebral bodies Add shearing force to acceleration forces

Cervical area T12 to L2 Cervical area

Vertebral injuries in adults occur most often at vertebrae C1 to C2 (cervical), C4 to C7 (cervical), and T10 (thoracic) to L2 (lumbar) (see Fig. 14.11), the most mobile portions of the vertebral column. The spinal cord also occupies most of the vertebral canal in the cervical and lumbar regions, so it can be easily injured in these locations. Clinical Manifestations Spinal shock is the temporary loss of spinal cord functions below the lesion. Spinal shock develops immediately after injury because of loss of continuous tonic discharge from the brain or brainstem and inhibition of central descending impulses that control and modulate spinal cord neurons. It is caused by cord hemorrhage, edema, or anatomic transection. Normal activity of spinal cord cells at and below the level of injury ceases, with complete loss of reflex function, flaccid paralysis, absence of sensation, loss of bladder and rectal control, transient drop in blood pressure, bradycardia, and poor venous circulation. The condition also results in disturbed thermal control because the sympathetic nervous system is damaged. The hypothalamus cannot regulate body heat through vasoconstriction and increased metabolism; therefore the individual assumes the temperature of the air (poikilothermia). Spinal shock generally lasts 2 to 3 days. It terminates with the reappearance of reflex activity, hyperreflexia, spasticity, and reflex emptying of the bladder, all of which may take weeks to months. Table 17.5 summarizes the clinical manifestations of spinal cord injury. TABLE 17.5 Clinical Manifestations of Spinal Cord Injury Stage Spinal Shock Stage Complete spinal cord transection

Partial spinal cord transection

Manifestations Loss of motor function 1. Quadriplegia with injuries of cervical spinal cord 2. Paraplegia with injuries of thoracic spinal cord Muscle flaccidity Loss of all reflexes below level of injury Loss of pain, temperature, touch, pressure, and proprioception below level of injury Pain at site of injury caused by zone of hyperesthesia above injury Atonic bladder and bowel Paralytic ileus with abdominal distention Loss of vasomotor tone in lower body parts; low and unstable blood pressure Loss of perspiration below level of injury Loss or extreme depression of genital reflexes, such as penile erection and bulbocavernous reflex Dry and pale skin; possible ulceration over bony prominences Respiratory impairment Asymmetric flaccid motor paralysis below level of injury Asymmetric reflex loss Preservation of some sensation below level of injury

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Heightened Reflex Activity Stage

Vasomotor instability less severe than that seen with complete cord transection Bowel and bladder impairment less severe than that seen with complete cord transection Preservation of ability to perspire in some portions of body below level of injury Brown-Séquard syndrome (associated with penetrating injuries, hyperextension and flexion, locked facets, and compression fractures) 1. Ipsilateral paralysis or paresis below level of injury 2. Ipsilateral loss of touch, pressure, vibration, and position sense below level of injury 3. Contralateral loss of pain and temperature sensations below level of injury Cauda equina syndrome (compression of nerve roots below L1 caused by fracture and dislocation of spine or large posterocentral intervertebral disk herniation) 1. Lower extremity motor deficits 2. Variable sensorimotor dysfunction 3. Variable reflex dysfunction 4. Variable bladder, bowel, and sexual dysfunction Emergence of Babinski reflexes Hyperactive ankle and knee reflexes Reflex urinary incontinence and defecation Episodes of hypertension Defective heat-induced sweating Development of extensor reflexes, first in muscles of hip and thigh, later in leg

Neurogenic shock, also called vasogenic shock, occurs with cervical or upper thoracic cord injury above T6 and may be seen in addition to spinal shock. Neurogenic shock is caused by the absence of sympathetic activity through loss of supraspinal control and unopposed parasympathetic tone mediated by the intact vagus nerve. Symptoms include vasodilation, hypotension, bradycardia, and failure of body temperature regulation. Neurogenic shock may be complicated by hypovolemic or cardiogenic shock if there is concurrent heart failure or blood loss (see Chapter 26). Loss of motor and sensory function depends on the extent and level of injury. Paralysis of the lower half of the body with both legs involved is termed paraplegia. Paralysis involving all four extremities is termed quadriplegia (tetraplegia). In complete quadriplegia, the level of injury is above C6 and all upper extremity function is lost. In incomplete quadriplegia, function at or above C6 is preserved, leaving the shoulder, upper arm, and some forearm muscle control intact. The initial clinical manifestations associated with acute spinal cord injury are related to spinal shock described above and include (1) rapid development of flaccid paralysis below the level of injury, (2) loss of sensations in the lower extremities and possibly lower trunk (depending on the level of injury), and (3) loss of spinal and autonomic reflexes below the level of injury. The duration of this areflexic state is highly variable. In most persons, reflex activity returns in about a week. Return of spinal neuron excitability occurs slowly. Depending on the degree of damage, either of the following can occur: (1) motor, sensory, reflex, and autonomic functions return to normal; or (2) autonomic neural activity in the isolated segment develops. Spasticity is common, with hyperreflexia, clonus, and painful muscle spasms. Sometimes after several months, episodes of autonomic hyperreflexia occur. Autonomic hyperreflexia (dysreflexia) is a syndrome of sudden, massive reflex sympathetic discharge associated with spinal cord injury at level T6 or above. It occurs because descending inhibition is blocked (Fig. 17.7). It may occur after spinal shock resolves and be a recurrent complication. Characteristics include paroxysmal hypertension (up to 300 mm Hg, systolic), a pounding headache, blurred vision, sweating above the level of the lesion, with flushing of the skin, nasal congestion, nausea, piloerection caused by pilomotor spasm, and bradycardia (30 to 40 beats/min). The symptoms may develop singly or in combination. The condition can cause serious complications (stroke, seizures, myocardial ischemia, and death) and requires immediate treatment.

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FIGURE 17.7 Autonomic Hyperreflexia. A, Normal response pathway. B, Autonomic hyperreflexia pathway. SA, Sinoatrial. (Modified from Rudy EB: Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)

In autonomic hyperreflexia, sensory receptors below the level of the cord lesion are stimulated. The intact autonomic nervous system reflexively responds with an arteriolar spasm that increases blood pressure. Baroreceptors in the cerebral vessels, the carotid sinus, and the aorta sense the hypertension and stimulate the parasympathetic system. The heart

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rate decreases, but the visceral and peripheral vessels do not dilate because efferent impulses cannot pass through the cord. The most common cause is a distended bladder or rectum; however, any sensory stimulation (i.e., skin or pain receptors) can elicit autonomic hyperreflexia. Intravenous fluids may be required to maintain blood pressure. Drug therapy may be required to lower blood pressure and reduce complications. Bladder, bowel, and skin care management are important preventive strategies. Education of the individual and family regarding triggers and acute management is important, as is wearing a medic alert tag.21 Evaluation and Treatment Diagnosis of spinal cord injury is based on physical examination and imaging studies. Neurogenic shock must be differentiated from other kinds of shock (i.e., hypovolemic shock). For a suspected or confirmed vertebral fracture or dislocation, regardless of the presence or absence of spinal cord injury, the immediate intervention is immobilization of the spine to prevent further injury. Decompression and surgical fixation may be necessary. Blood pressure control, lung function, nutrition, skin integrity, prevention of pressure ulcers, and bladder and bowel management must be addressed. Plans for rehabilitation need early consideration. Both neuroprotective and neuroregenerative strategies are under clinical investigation.22,23

Degenerative Disorders of the Spine Low Back Pain Low back pain (LBP) affects the area between the lower rib cage and gluteal muscles and often radiates into the thighs. About 80% of the population experiences LBP at some time during their lives, and about 25% of the adult population has experienced LBP in the past 3 months.24 The burdens of disability include psychological, financial, occupational, and social effects on the person and family members. Risk factors include occupations that require repetitious lifting in the forward bent-and-twisted position, exposure to vibrations caused by vehicles or industrial machinery, obesity, osteoporosis, and cigarette smoking. Pathophysiology Most cases of LBP are idiopathic or nonspecific, and no precise diagnosis is possible. Acute LBP is often associated with muscle or ligament strain and is more common in individuals younger than 50 years of age without a history of cancer. The interspinous bursae can be a source of pain, particularly in the lumbar vertebrae. The ligaments of the spine are supplied with pain receptors, and all of these ligaments are vulnerable to traumatic tears (sprains) and fracture. Diskogenic pain also may be related to inflammation and nerve sprouting within the disk25 (Fig. 17.8, A).

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FIGURE 17.8 Spinal Ligaments, Degenerating Disk, and Herniated Disk. A, Ligaments of the spine. B, Bulging disk with spinal nerve compression and degenerative disk showing collapse of vertebral body. C, Herniated disk with spinal nerve compression.

Common causes of chronic LBP include degenerative disk disease, spondylolysis (vertebral stress fracture), spondylolisthesis (vertebra slides forward or slips in relation to a vertebra below), spinal osteochondrosis (abnormal bone growth), spinal stenosis, and lumbar disk herniation (see Fig. 17.8, B and C). Other causes include tension caused by tumors or disk prolapse, bursitis, synovitis, spinal immobility, inflammation caused by infection (as in osteomyelitis), and pain referred from viscera or the posterior peritoneum. Systemic causes of LBP include bone diseases, such as osteoporosis or osteomalacia, and hyperparathyroidism. Anatomically, LBP must originate from innervated structures, but deep pain is widely referred and varies. The nucleus pulposus has no intrinsic innervation, but when extruded or herniated through a prolapsed disk, it irritates the spinal nerve and causes pain referred to the segmental area (see Fig. 17.8, C). Clinical Manifestations Some individuals with acute LBP have pain along the distribution of a lumbar nerve root (radicular pain), most commonly involving the sciatic nerve (sciatica). Sciatica is often accompanied by neurosensory and motor deficits, such as tingling, numbness, and weakness in various parts of the leg and foot. Chronic LBP may be associated with progressive motor or sensory deficits, cauda equina syndrome (new-onset bowel or bladder incontinence or urinary retention, loss of anal sphincter tone, and saddle anesthesia), a history of cancer metastasis to bone, and suspected spinal infection. Evaluation and Treatment Diagnosis of LBP is based on the history and physical examination. Imaging and nerve conduction studies are obtained with severe neurologic deficit or serious underlying disease. Diagnosis and treatment guidelines are available to plan therapy.26 Most individuals with acute LBP benefit from a nonspecific short-term treatment regimen of rest, analgesic medications, exercises, physical therapy, and education. Surgical treatments, specifically diskectomy and spinal fusions, are used for individuals not responding to medical management or for emergency management of cauda equina syndrome.

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Individuals with chronic LBP may benefit from antiinflammatory and muscle relaxant medications, exercise programs, massage, topical heat, spinal manipulation, acupuncture, cognitive-behavioral therapies, and interdisciplinary care. There is scant evidence for efficacy of opioids for chronic LBP, but a high risk for addiction. The complexity of causes contributes to the difficulty in defining pathogenesis and clearly defining the most effective therapies.

Degenerative Joint Disease Degenerative disk disease. Degenerative disk disease (DDD) is common in individuals 30 years of age and older. It is, in part, a process of normal aging as a response to continuous vertical compression of the spine (axial loading). DDD includes a genetic component, involving genes that code for spinal cartilage. The combination of environmental interactions and genetic predisposition increases susceptibility to lumbar disk disease by disrupting normal building and maintenance of cartilage, with inflammation and physical compression of the intervertebral disk tissue.27 The annulus (outer fibrous ring) can tear, and the disk can herniate, pinching nerves or placing strain on the spine. The pathologic findings in DDD include disk protrusion, spondylolysis and/or subluxation (spondylolisthesis), degeneration of vertebrae, and spinal stenosis. Lumbar disk disease commonly affects adults at some point in their lives. However, only a small percentage of people with degenerative disk disease have any functional incapacity because of pain. Spondylolysis. Spondylolysis is a structural defect (degeneration, fracture, or developmental defect) in the pars interarticularis of the vertebral arch (the joining of the vertebral body to the posterior structures). The lumbar spine at L5 is affected most often. Mechanical pressure may cause an anterior or posterior displacement of the deficient vertebra (spondylolisthesis). Heredity plays a significant role, and spondylolysis is associated with an increased incidence of other congenital spinal defects. Symptoms include lower back and lower limb pain. Spondylolisthesis. Spondylolisthesis, an osseous defect of the pars interarticularis, allows a vertebra to slide anteriorly in relation to the vertebra below. This commonly occurs at L5-S1. Spondylolisthesis is graded from 1 to 4 based on the percentage of slip that occurs. Grades 1 and 2 have symptoms of pain in the lower back and buttocks, muscle spasms in the lower back and legs, and tightened hamstrings. Conservative management includes exercise, rest, and back bracing. Vertebral slippage in grades 3 and 4 usually requires surgical intervention. Spinal stenosis. Spinal stenosis is a narrowing of the spinal canal that causes pressure on the spinal nerves or cord. It can be congenital or acquired (more common) and is associated with trauma or arthritis. Spinal stenosis is categorized by the area of the spine affected: cervical, thoracic, or lumbar. Acquired conditions include a bulging disk, facet hypertrophy, or a thick, ossified posterior longitudinal ligament. Symptoms are related to the area of the spine affected and

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can produce pain; numbness; and tingling in the neck, hands, arms, or legs, with weakness and difficulty walking. Surgical decompression is recommended for those with chronic symptoms and those who do not respond to medical management.

Herniated Intervertebral Disk Herniation of an intervertebral disk is a displacement of the nucleus pulposus or annulus fibrosus beyond the intervertebral disk space (see Fig. 17.8, C). Rupture of an intervertebral disk usually is caused by trauma, degenerative disk disease, or both. Risk factors are weight-bearing sports, light weight lifting, and certain work activities, such as repeated lifting. Men are affected more often than women, with the highest incidence in the 30- to 50year age group. Most commonly affected are the lumbosacral disks L4-L5 and L5-S1. Disk herniation occasionally occurs in the cervical area, usually at C5-C6 and C6-C7. Herniations at the thoracic level are extremely rare. The herniation may occur immediately, within a few hours, or months to years after injury. Pathophysiology In a herniated disk, the ligament and posterior capsule of the disk are usually torn, allowing the nucleus pulposus to extrude and compress the nerve root. The vascular supply may be compromised and cause inflammatory changes in the nerve root (radiculitis). Occasionally, the injury tears the entire disk loose, causing the disk capsule and nucleus pulposus to protrude onto the nerve root or compress the spinal cord. Clinical Manifestations The location and size of the herniation into the spinal canal, together with the amount of space in the canal, determine the clinical manifestations associated with the injury (Fig. 17.9). Compression or inflammation, or both, of a spinal nerve resulting from disk herniation follows a dermatomal distribution called radiculopathy (Fig. 17.10). A herniated disk in the lumbosacral area is associated with pain that radiates along the sciatic nerve course over the buttock and into the calf or ankle. The pain occurs with straining, including coughing and sneezing, and usually on straight leg raising. Other clinical manifestations include limited range of motion of the lumbar spine; tenderness on palpation in the sciatic notch and along the sciatic nerve; impaired pain, temperature, and touch sensations in the L4-L5 or L5-S1 dermatomes of the leg and foot; decreased or absent ankle jerk reflex; and mild weakness of the foot. More rarely, there is development of cauda equine syndrome (see Table 17.5).

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FIGURE 17.9

Clinical Features of Herniated Nucleus Pulposus.

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FIGURE 17.10 Sensory Nerve Distribution of Skin Dermatomes. (Redrawn from Patton HD et al, editors: Introduction to basic neurology, Philadelphia, 1976, WB Saunders. Borrowed from Canale ST, Beaty JH: Campbell's operative orthopaedics, ed 12, St Louis, 2013, Mosby.)

With the herniation of a lower cervical disk, paresthesias (sensation of tingling, numbness, or burning) and pain are present in the upper arm, forearm, and hand along the affected nerve root distribution. Neck motion and straining, including coughing and sneezing, may increase neck and nerve root pain. Neck range of motion is diminished. Slight weakness and atrophy of biceps or triceps muscles may occur; the biceps or triceps reflex may decrease. Occasionally, signs of both corticospinal and sensory tract impairments appear, including motor weakness of the lower extremities, sensory disturbances in the lower extremities, and presence of a Babinski reflex. Evaluation and Treatment Diagnosis of a herniated intervertebral disk is made through the history and physical examination, imaging, electromyography, and nerve conduction studies. Evidenced-based practice guidelines have been published to guide treatment options.28 Most herniated disks heal spontaneously over time and do not require surgery. Diskectomy is indicated if there is evidence of severe compression (weakness or decreased deep tendon, bladder, or bowel reflexes) or if a conservative approach is unsuccessful. Cauda equina syndrome rarely develops and requires emergency surgical evaluation and long-term follow-up.29

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Cerebrovascular Disorders Cerebrovascular disease (CVD) is any abnormality of the brain caused by a pathologic process in the blood vessels. CVD is the most frequently occurring neurologic disorder and frequently requires hospitalization. Included in this category are lesions of the vessel wall, occlusion of the vessel lumen by thrombus or embolus, rupture of the vessel, and alteration in blood quality, such as increased blood viscosity. The brain abnormalities induced by cerebrovascular disease are either (1) ischemia with or without infarction (death of brain tissues) or (2) hemorrhage. The common clinical manifestation of CVD is a cerebrovascular accident or stroke. The symptoms occur suddenly and are focal (i.e., slurred speech, difficulty swallowing, limb weakness, or paralysis). In its mildest form, a cerebrovascular accident is so minimal that it is almost unnoticed. In its most severe form, hemiplegia, coma, and death result.

Cerebrovascular Accidents (Stroke Syndromes) Cerebrovascular accidents (CVAs, stroke syndromes) are the leading cause of disability; they are the third leading cause of death in women and the fifth leading cause of death in men in the United States. Of all strokes, 87% are ischemic and 13% are hemorrhagic (intracerebral 10% and subarachnoid 3%). About 25% of strokes are recurrent strokes. Although hemorrhagic strokes are less common, they account for about 40% of strokerelated deaths. About 75% of CVAs occur among those older than 65 years. The incidence is greater in African Americans than in other ethnic groups. Persons with both hypertension and type 2 diabetes mellitus have an increase in stroke incidence and an increase in stroke mortality.30 CVAs are classified pathophysiologically as ischemic or hemorrhagic. If there is no identifiable cause of an ischemic stroke, it is classified as undetermined or cryptogenic. Risk factors for stroke are summarized in Box 17.1.

Box 17.1

Risk Factors for Stroke • Poorly controlled or uncontrolled arterial hypertension • Smoking, which increases the risk of stroke by 2 to 4 times • Insulin resistance and diabetes mellitus • Atrial fibrillation • Polycythemia (excess red blood cells) and thrombocythemia (excess platelets) • High total cholesterol or low high-density lipoprotein (HDL) cholesterol, elevated lipoprotein-a • Congestive heart disease and peripheral vascular disease • Hyperhomocysteinemia • Sickle cell disease • Postmenopausal hormone therapy • High sodium intake >2300 mg; low potassium intake 1 cm in diameter) or giant (>4 cm in diameter) prolactinomas. Clinical Manifestations Women with hyperprolactinemia generally present with galactorrhea (nonpuerperal milk production) and menstrual disturbances, including amenorrhea. Estrogen deficiency also may cause hirsutism, and fractures may occur because of osteopenia or osteoporosis. Hyperprolactinemia in men causes gynecomastia, hypogonadism, and erectile dysfunction, although they often are not diagnosed until they develop symptoms related to the increasing size of the adenoma (i.e., headache or visual impairment). Evaluation and Treatment The diagnostic evaluation of hyperprolactinemia includes a careful history to exclude medications that may cause elevations in prolactin concentration. Screening for hypothyroidism is mandatory. MRI scanning of the pituitary is indicated to determine the size and location of an adenoma. Dopaminergic agonists (cabergoline) are the treatment of choice for prolactinomas. Decreases in tumor size and restoration of fertility in previously anovulatory women are common. In individuals resistant or intolerant to these medications, transsphenoidal surgery and radiotherapy are options. New chemotherapeutic and targeted molecular therapies are being explored in selected cases.

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Alterations of Thyroid Function Disorders of thyroid function develop as a result of primary dysfunction or disease of the thyroid gland or, secondarily, as a result of pituitary or hypothalamic alterations. Primary thyroid disorders result in either increased or decreased thyroid hormone (TH) levels. These disorders also cause secondary feedback effects on pituitary TSH. For example, when there are primary elevations in the TH level, the TSH level will secondarily decrease because of negative feedback. When the TH level is decreased because of a condition affecting the thyroid gland, the TSH level will be elevated. Central (secondary) thyroid disorders are related to disorders of pituitary gland TSH production. When there is excessive TSH production, the TH level is elevated secondary to the primary elevation of the TSH concentration. The reverse is true with inadequate TSH production. The majority of primary thyroid diseases are idiopathic and caused by autoimmune mechanisms that affect the gland. Although the exact genetic and environmental influences are not known, some individuals experience a predominantly cellular autoimmune response (some antithyroid autoantibodies also are involved) with resultant destruction of the thyroid gland, leading to hypothyroidism. Others experience a predominantly antibody-mediated autoimmune response that stimulates the gland, leading to hyperthyroidism. The most common autoimmune hypothyroid condition is called Hashimoto thyroiditis,6 and the most common autoimmune hyperthyroid condition is called Graves disease7 (Fig. 20.4).

FIGURE 20.4

Autoimmune Mechanisms in Primary Thyroid Disease.

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Thyrotoxicosis/Hyperthyroidism Pathophysiology Thyrotoxicosis is a condition that results from any cause of increased TH levels and can result from dysfunction of the pituitary, the thyroid gland, ectopic thyroid tissue, or the ingestion of excessive amounts of TH medication. Hyperthyroidism is a form of thyrotoxicosis in which excess amounts of TH are secreted from the thyroid gland8 (Fig. 20.5). Primary hyperthyroidism results from thyroid gland dysfunction and is most commonly caused by Graves disease, toxic multinodular goiter, and solitary toxic adenoma. Central (secondary) hyperthyroidism is less common and is caused by TSH-secreting pituitary adenomas. Each condition is associated with a specific pathophysiology and manifestations; however, all forms of thyrotoxicosis share some common characteristics.

FIGURE 20.5 Common Causes of Hyperthyroidism. Hyperthyroidism may have several causes, among them: 1, Graves disease; 2, toxic multinodular goiter; 3, follicular adenoma; 4, thyroid medication. (Adapted from Damjanov I: Pathology for the health professions, ed 4, St Louis, 2012, Saunders.)

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Clinical Manifestations The clinical features of thyrotoxicosis are attributable to the metabolic effects of increased circulating levels of thyroid hormones. This results in an increased metabolic rate, with heat intolerance and increased tissue sensitivity to stimulation by the sympathetic nervous system. The major manifestations are summarized in Fig. 20.6.

FIGURE 20.6

Clinical Manifestations of Hyperthyroidism and Hypothyroidism. (From Damjanov I: Pathology for the health professions, ed 4, St Louis, 2012, Saunders.)

Elevated serum thyroxine (T4) and triiodothyronine (T3) levels and suppressed serum TSH levels are diagnostic for primary hyperthyroidism. By contrast, central (secondary)

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hyperthyroidism caused by TSH-secreting pituitary tumors is characterized by normal to increased TSH levels despite elevated TH concentrations. Treatment is directed at controlling excessive TH production, secretion, or action and involves antithyroid drug therapy, radioactive iodine therapy (absorbed only by thyroid tissue, causing death of cells), or surgical removal of nodules or part of the thyroid gland. A major complication of all forms of treatment for hyperthyroidism is excessive ablation of the gland, leading to hypothyroidism.

Hyperthyroid Conditions Graves disease. Graves disease is the underlying cause of 50% to 80% of cases of hyperthyroidism with a prevalence of approximately 3% of women and 0.5% of men in the United States.9 Although the exact cause of Graves disease is not known, genetic factors interacting with environmental triggers play an important role in the pathogenesis. Graves disease is classified as an autoimmune disease and results from a form of type II hypersensitivity (see Chapter 8) in which there is stimulation of the thyroid by autoantibodies directed against the TSH receptor. These autoantibodies, called thyroid-stimulating immunoglobulins (TSIs; also called thyroid-stimulating antibodies [TSAbs] or thyroid receptor antibodies [TRAbs]), override the normal regulatory mechanisms. TSI stimulation of TSH receptors in the gland results in hyperplasia of the gland (goiter) and increased synthesis of TH, especially of triiodo-L-thyronine (T3). Increased levels of TH result in the classic signs and symptoms of hyperthyroidism illustrated in Fig. 20.6. TSH production by the pituitary is inhibited through the usual negative feedback loop. Autoimmunity also contributes to the two major distinguishing clinical manifestations of Graves disease (ophthalmopathy and dermopathy [pretibial myxedema]) (Fig. 20.7). Two categories of ophthalmopathy associated with Graves disease are (1) functional abnormalities resulting from hyperactivity of the sympathetic division of the autonomic nervous system (lag of the globe on upward gaze and of the upper lid on downward gaze) and (2) infiltrative changes involving the orbital contents with enlargement of the ocular muscles. These changes affect more than half of individuals with Graves disease. Orbital connective tissue accumulation, inflammation, and edema of the orbital contents result in exophthalmos (protrusion of the eyeball), periorbital edema, and extraocular muscle weakness leading to diplopia (double vision). The individual may experience irritation, pain, lacrimation, photophobia, blurred vision, decreased visual acuity, papilledema, visual field impairment, exposure keratosis, and corneal ulceration.

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FIGURE 20.7 Ophthalmopathy and Pretibial Edema in Graves Disease. A, Exophthalmos (large and protruding eyeballs, often in association with a large goiter). B, Pretibial myxedema associated with Graves disease; note lumpy and swollen appearance from accumulation of connective tissue and pinkish purple discoloration. (A from Belchetz P, Hammond P: Mosby's color atlas and text of diabetes and endocrinology, Edinburgh, 2003, Mosby; B from Habif T: Clinical dermatology, ed 5, St Louis, 2009, Mosby.)

A small number of individuals with Graves disease who have very high levels of TSI experience pretibial myxedema (Graves dermopathy), characterized by subcutaneous swelling on the anterior portions of the legs and by indurated and erythematous skin. Graves dermopathy is associated with TSI stimulation of fibroblasts and T lymphocytes, causing excessive amounts of hyaluronic acid production in the dermis and subcutaneous tissue. These manifestations occasionally appear on the hands, giving the appearance of clubbing of the fingers (thyroid acropachy). Fig. 20.8 provides an overview of the pathophysiology of Graves disease.

FIGURE 20.8 Pathophysiology of Graves Disease. TSI, Thyroid-stimulating immunoglobulins (antibodies); TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, tetraiodothyronine.

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Hyperthyroidism resulting from nodular thyroid disease. The thyroid gland normally enlarges in response to the increased demand for TH that occurs in puberty, pregnancy, and iodine-deficient states, as well as in individuals with immunologic, viral, or genetic disorders. When the condition resulting in increased TH resolves, TSH secretion normally subsides and the thyroid gland returns to its original size. Irreversible changes can occur in some follicular cells so that these cells form nodules that function autonomously and produce excessive amounts of TH. Toxic multinodular goiter occurs when there are several hyperfunctioning nodules leading to hyperthyroidism. Unlike Graves disease, there is absence of an autoimmune stimulus. If only one nodule is hyperfunctioning, it is termed toxic adenoma. The classic clinical manifestations of hyperthyroidism (see Fig. 20.6) usually develop slowly, and exophthalmos and pretibial myxedema do not occur. Nodules may be palpable on physical examination, and there is increased uptake of radioactive iodine. There is an increased incidence of malignancy in toxic nodular goiter, so most individuals should undergo a fine-needle aspiration biopsy of suspicious nodules before treatment. Treatment consists of a combination of radioactive iodine (may increase risk of solid cancer-related death, including breast cancer death9a), surgery, and antithyroid medications. Thyrotoxic crisis. Thyrotoxic crisis (thyroid storm) is a rare but dangerous worsening of the thyrotoxic state in which TH levels rise dramatically and death can occur within 48 hours without treatment. The condition may develop spontaneously but usually occurs in individuals who have undiagnosed or partially treated Graves disease and who are subjected to physiologic stress, such as infection, pulmonary or cardiovascular disorders, trauma, seizures, surgery (especially thyroid surgery), obstetric complications, or dialysis. The systemic manifestations of thyrotoxic crisis include hyperthermia; tachycardia, especially atrial tachydysrhythmias; heart failure; agitation or delirium; and nausea, vomiting, or diarrhea contributing to fluid volume depletion. Treatment includes drugs that block TH synthesis (i.e., propylthiouracil or methimazole), beta blockers, glucocorticoids, iodine, and supportive care.

Hypothyroidism Hypothyroidism results from deficient production of TH by the thyroid gland. Hypothyroidism is the most common disorder of thyroid function, affecting approximately 3.7% of the U.S. population, and occurs more commonly in women.10 It may be primary or central. Primary hypothyroidism accounts for the majority of all cases. Central (secondary) hypothyroidism is much less common and is related to either pituitary or hypothalamic failure. Subclinical hypothyroidism is a mild thyroid failure estimated to occur in 4% to 8% of U.S. adults.11 It is defined as an elevation in TSH levels with normal levels of circulating TH. Pathophysiology In primary hypothyroidism, loss of thyroid function leads to decreased production of TH and increased secretion of TSH and TRH. The most common causes of primary hypothyroidism in adults include autoimmune thyroiditis (Hashimoto disease), iatrogenic loss of thyroid

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tissue after surgical or radioactive treatment for hyperthyroidism or after head and neck radiation therapy, medications (e.g., lithium and amiodarone), and endemic iodine deficiency. Infants and children may present with hypothyroidism because of congenital defects. Central (secondary) hypothyroidism is caused by the pituitary's failure to synthesize adequate amounts of TSH or a lack of TRH. Pituitary tumors that compress surrounding pituitary cells or the consequences of their treatment are the most common causes of central hypothyroidism. Other causes include traumatic brain injury, subarachnoid hemorrhage, or pituitary infarction. Hypothalamic dysfunction results in low levels of TH, TSH, and TRH. Clinical Manifestations Hypothyroidism generally affects all body systems and occurs insidiously over months or years. Decreased TH levels lower energy metabolism and heat production. The individual develops a low basal metabolic rate, cold intolerance, lethargy, and slightly lowered basal body temperature (see Fig. 20.6). The decrease in the level of TH leads to excessive TSH production, which stimulates thyroid tissue and causes goiter. The characteristic sign of severe or long-standing hypothyroidism is myxedema, which results from the altered composition of the dermis and other tissues. The connective tissue fibers are separated by large amounts of protein and mucopolysaccharide. This complex binds water, producing nonpitting, boggy edema, especially around the eyes, hands, and feet and in the supraclavicular fossae (Fig. 20.9). The tongue and laryngeal and pharyngeal mucous membranes thicken, producing thick, slurred speech and hoarseness. Myxedema coma, a medical emergency, is a diminished level of consciousness associated with severe hypothyroidism. Signs and symptoms include hypothermia without shivering, hypoventilation, hypotension, hypoglycemia, and lactic acidosis. Older individuals with comorbid conditions, such as pulmonary or urinary infections, congestive heart failure, or cerebrovascular accident, and with moderate or untreated hypothyroidism are particularly at risk for developing myxedema coma. It also may occur after overuse of narcotics or sedatives or after an acute illness in hypothyroid individuals. Symptoms of hypothyroidism in older adults should not be attributed to normal aging changes.

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FIGURE 20.9

Myxedema. Note edema around eyes and facial puffiness. The hair is dry. (From Bolognia JL et al: Dermatology, ed 3, St Louis, 2012, Mosby.)

Evaluation and Treatment The diagnosis of primary hypothyroidism is made by documentation of the clinical symptoms of hypothyroidism and measurement of increased levels of TSH and decreased levels of TH (total T3 and both total and free T4). Central hypothyroidism is diagnosed by finding low TH and low serum TSH levels. Hormone replacement therapy with the hormone levothyroxine is the treatment of choice for both primary and central thyroid disorders.

Hypothyroid Conditions Hashimoto disease. The most common cause of primary hypothyroidism in the U.S. is autoimmune thyroiditis (Hashimoto disease), which results in gradual, inflammatory destruction of thyroid tissue. This disorder is linked with several genetic risk factors and is often associated with other autoimmune conditions. Infiltration of the thyroid with autoreactive T lymphocytes, antithyroid antibodies (antithyroid peroxidase and antithyroglobulin antibodies), and natural killer cells induces inflammation, glandular apoptosis, and tissue destruction (Fig. 20.10).

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FIGURE 20.10

Pathophysiology of Hashimoto Thyroiditis. TSH, Thyroid-stimulating hormone; T3, triiodothyronine; T4, tetraiodothyronine.

Uncommon causes of hypothyroidism. Other, less common causes of hypothyroidism are subacute thyroiditis and postpartum thyroiditis. Subacute thyroiditis (de Quervain thyroiditis) is a rare nonbacterial inflammation of the thyroid gland often preceded by a viral infection. It is accompanied by fever, tenderness, and enlargement of the thyroid gland and transient hypothyroidism before the gland recovers normal activity. Symptoms may last for 2 to 4 months, and nonsteroidal antiinflammatory drugs or corticosteroids usually resolve symptoms. Postpartum thyroiditis generally occurs up to 6 months after birthing with a course similar to that seen in subacute thyroiditis. Iatrogenic hypothyroidism results from ablation of the thyroid gland during treatment for hyperthyroid conditions. Congenital hypothyroidism. Hypothyroidism in infants occurs when thyroid tissue is absent (thyroid dysgenesis) or with hereditary defects in TH synthesis. Thyroid dysgenesis occurs more often in female infants, with permanent abnormalities in 1 of every 4000 live births. The affected fetus is dependent on maternal thyroxine for the first 20 weeks of gestation, then becomes deficient in TH. TH is essential for fetal growth and for the development of brain tissue, so the infant will suffer developmental and cognitive disabilities if left untreated. Hypothyroidism may not be evident at birth. Symptoms may include high birth weight, hypothermia, delay in passing meconium, and neonatal jaundice. Cord blood can be examined in the first days of life for measurement of T4 and TSH levels. The probability of normal growth and intellectual function is high if treatment with levothyroxine is started before the child is 3 or 4 months old. The earlier thyroid hormone replacement is initiated, the better the child's outcome. Without early screening, hypothyroidism may not be evident until after 4 months of age.

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Symptoms include difficulty eating, hoarse cry, and protruding tongue caused by myxedema of oral tissues and vocal cords; hypotonic muscles of the abdomen with constipation, abdominal protrusion, and umbilical hernia; subnormal temperature; lethargy; excessive sleeping; slow pulse rate; and cold, mottled skin. Skeletal growth is stunted because of impaired protein synthesis, poor absorption of nutrients, and lack of bone mineralization. The child will be dwarfed with short limbs, if not treated. Dentition is often delayed. Cognitive disability varies with the severity of hypothyroidism and the length of delay before treatment is initiated.

Thyroid Carcinoma Thyroid carcinoma is the most common endocrine malignancy and is the sixth most common cancer in the U.S in women.12 Exposure to ionizing radiation, especially during childhood, is the most consistent causal factor. Papillary and follicular thyroid carcinomas are the most frequent, and medullary and anaplastic thyroid carcinomas are less common. The cancer is typically discovered as a small thyroid nodule or metastatic tumor in the lungs, brain, or bone. Changes in voice and swallowing and difficulty breathing are related to tumor growth impinging on the trachea or esophagus. The diagnosis of thyroid cancer is generally made by ultrasonography and then by fine-needle aspiration of a thyroid nodule. Most individuals with thyroid carcinoma have normal T3 and T4 levels and are therefore euthyroid. Treatment may include partial or total thyroidectomy, TSH suppression therapy (levothyroxine), radioactive iodine therapy (in iodine-concentrating tumors), postoperative radiation therapy, and chemotherapy (especially in anaplastic carcinoma).13 New insights into the molecular pathogenesis of thyroid carcinoma are leading to new therapies.

Quick Check 20.2 1. Compare the clinical manifestations of hyperthyroidism and hypothyroidism. 2. What is Graves disease? 3. What is Hashimoto disease? 4. How does thyroid carcinoma present clinically?

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Alterations of Parathyroid Function Hyperparathyroidism Hyperparathyroidism is characterized by greater than normal secretion of parathyroid hormone (PTH) with associated hypercalcemia. Hyperparathyroidism is classified as primary, secondary, or tertiary. Pathophysiology Primary hyperparathyroidism is characterized by inappropriate excess secretion of PTH by one or more of the parathyroid glands.14 It is one of the most common endocrine disorders. Approximately 80% to 85% of cases are caused by parathyroid adenomas, another 10% to 15% result from parathyroid hyperplasia, and approximately 1% of cases are caused by parathyroid carcinoma. In addition, primary hyperparathyroidism may be caused by a variety of genetic causes, especially the genes that cause multiple endocrine neoplasia. In primary hyperparathyroidism, PTH secretion is increased and is not under the usual feedback control mechanisms. The calcium level in the blood rises because of increased bone resorption and gastrointestinal absorption of calcium but fails to inhibit PTH secretion by the parathyroid gland. Some individuals with primary hyperparathyroidism maintain normal levels of calcium despite elevated levels of PTH and are diagnosed only when they develop osteoporosis. Secondary hyperparathyroidism is a compensatory response of the parathyroid glands to chronic hypocalcemia, which is commonly associated with decreased activation of vitamin D in individuals with renal failure (see Chapter 32). Secretion of PTH is elevated, but PTH cannot achieve normal calcium levels because of insufficient levels of activated vitamin D. Other causes of secondary hyperparathyroidism include a dietary deficiency of vitamin D or calcium; decreased intestinal absorption of vitamin D or calcium; and ingestion of drugs, such as phenytoin, phenobarbital, and laxatives, which either accelerate the metabolism of vitamin D or decrease intestinal absorption of calcium. Tertiary hyperparathyroidism can develop after any long-standing period of hypocalcemia, such as is seen with chronic dialysis, renal transplantation, or gastrointestinal malabsorption. Parathyroid chief cell hyperplasia leads to is excessive secretion of PTH and may cause hypercalcemia. Clinical Manifestations Hypercalcemia and hypophosphatemia are the hallmarks of primary hyperparathyroidism. Hypercalcemia and hypophosphatemia may be asymptomatic, or affected individuals may present with symptoms related to the muscular, nervous, and gastrointestinal systems, including fatigue, headache, depression, anorexia, and nausea and vomiting. Excessive osteoclastic and osteocytic activity causes bone resorption, resulting in osteoporosis, pathologic fractures, kyphosis of the dorsal spine, and compression fractures of the vertebral bodies. (Bone resorption is discussed in Chapter 40.) Hypercalcemia means that the renal tubules must filter large amounts of calcium, leading to hypercalciuria and production of an abnormally alkaline urine. PTH hypersecretion enhances renal phosphate excretion and results in hypophosphatemia and hyperphosphaturia (see Chapter 5). The combination of these three variables—

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hypercalciuria, alkaline urine, and hyperphosphaturia—predisposes the individual to the formation of calcium stones, particularly in the renal pelvis or renal collecting ducts. These stones may be associated with infections and impaired renal function. Chronic hypercalcemia also is associated with mild insulin resistance, necessitating increased insulin secretion to maintain normal glucose levels. Secondary hyperparathyroidism caused by renal disease presents clinically not only with the complications of bone resorption but also with the symptoms of hypocalcemia and hyperphosphatemia, such as muscle spasms and cardiovascular complications (see Chapter 5) Evaluation and Treatment The diagnosis of primary hyperparathyroidism is suggested by the concurrent findings of elevated PTH levels and an increased ionized calcium concentration. Imaging procedures are used to localize adenomas before surgery. Observation of asymptomatic individuals with mild hypercalcemia is recommended; these individuals are advised to avoid dehydration and limit dietary calcium intake. Definitive treatment of more severe primary hyperparathyroidism involves surgical removal of the solitary adenoma or, in the case of hyperplasia, complete removal of three and partial removal of the fourth hyperplastic parathyroid glands. If the serum calcium concentration is low despite elevated levels of PTH, secondary hyperparathyroidism is likely. Evaluation for renal function may indicate chronic renal disease. Treatment for secondary hyperparathyroidism in chronic renal disease requires calcium replacement, dietary phosphate restriction and phosphate binders, and vitamin D replacement. Treatment also may include calcimimetics, which work to increase parathyroid calcium receptor sensitivity, thus lowering PTH levels.

Hypoparathyroidism Hypoparathyroidism (abnormally low PTH levels) is most commonly caused by damage to the parathyroid glands during thyroid surgery. This occurs because of the anatomic proximity of the parathyroid glands to the thyroid (see Fig. 19.11). Hypomagnesemia is another cause of low PTH levels. Hypoparathyroidism also is associated with genetic syndromes, including familial hypoparathyroidism and DiGeorge syndrome (see Chapter 8). There is an inherited condition called pseudohypoparathyroidism that causes a defect in tissue responsiveness to PTH. Pseudohypoparathyroidism is associated with hypocalcemia despite normal to elevated levels of PTH. Pathophysiology No matter the cause, the absence of PTH impairs resorption of calcium from bone and the renal tubules, leading to hypocalcemia. Deficient PTH also stimulates increased renal reabsorption of phosphate, leading to hyperphosphatemia. Hyperphosphatemia further lowers the calcium concentration by inhibiting the activation of vitamin D, thereby lowering the gastrointestinal absorption of calcium. Hypomagnesemia inhibits PTH secretion. Hypomagnesemia may be related to chronic alcoholism, malnutrition, malabsorption, increased renal clearance of magnesium caused by the use of aminoglycoside antibiotics or certain chemotherapeutic agents, or prolonged magnesium-deficient parenteral nutritional therapy. When serum magnesium levels return

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to normal, however, PTH secretion returns to normal. Clinical Manifestations Symptoms associated with hypoparathyroidism are primarily those of hypocalcemia (see Chapter 5). Hypocalcemia causes muscle spasms, which can progress to tetany, dry skin, and loss of body and scalp hair. Irreversible complications include hypoplasia of developing teeth, horizontal ridges on the nails, cataracts, basal ganglia calcifications (which may be associated with a parkinsonian syndrome), and bone deformities, including brachydactyly and bowing of the long bones. Evaluation and Treatment A low PTH level, along with a low serum calcium concentration and a high phosphorus level in the absence of renal failure, intestinal disorders, or nutritional deficiencies, suggests hypoparathyroidism. Measurement of the serum magnesium level and urinary calcium excretion also can help in diagnosis. Treatment is directed toward alleviation of the hypocalcemia. In acute states, this involves parenteral administration of calcium, which corrects the serum calcium concentration within minutes. Chronic maintenance of the serum calcium level is achieved with pharmacologic doses of cholecalciferol (vitamin D3) and oral calcium. PTH hormone replacement with recombinant human parathyroid hormone (rhPTH) is safe and effective.

Quick Check 20.3 1. How does excessive parathyroid hormone (PTH) affect bones? 2. What are the results of a lack of circulating PTH?

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Dysfunction of the Endocrine Pancreas: Diabetes Mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In 2015, an estimated 30.3 million people (9.4%) in the U.S. had diabetes, and another 7.2 million were estimated to be undiagnosed.15 The American Diabetes Association (ADA)16 classifies four categories of diabetes mellitus17: 1. Type 1 diabetes (caused by autoimmune beta-cell destruction, usually leading to absolute insulin deficiency)17 2. Type 2 diabetes (caused by progressive loss of beta-cell insulin secretion, frequently with a background of insulin resistance)18 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. Specific types of diabetes mellitus due to other causes Specific types of diabetes include monogenic diabetes syndromes (e.g., neonatal diabetes and maturity-onset diabetes of the young [MODY]), disease of the exocrine pancreas (e.g., cystic fibrosis), and drug- or chemical-induced diabetes (e.g., glucocorticoid use in the treatment of human immunodeficiency virus [HIV] infection and/or acquired immunodeficiency syndrome [AIDS] or after organ transplantation). The diagnosis of diabetes mellitus is based on glycosylated hemoglobin (HbA1C) levels; fasting plasma glucose (FPG) levels; oral glucose tolerance testing (OGTT); or random glucose levels in an individual with symptoms16 (Box 20.1). Glycosylated hemoglobin refers to the permanent attachment of glucose to hemoglobin molecules and reflects the average plasma glucose exposure over the life of a red blood cell (approximately 120 days). It provides a more accurate measure for monitoring long-term control of blood glucose levels.

Box 20.1

Diagnostic Criteria for Diabetes Mellitus 1. HbA1C (as measured in a DCCT-referenced assay) ≥6.5% OR 2. FPG ≥126 mg/dl (7 mmol/L); fasting is defined as no caloric intake for at least 8 hr OR 3. 2-hr plasma glucose ≥200 mg/dl (11.1 mmol/L) during OGTT OR 4. In an individual with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/L)

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In the absence of unequivocal hyperglycemia, criteria 1 through 3 diagnosis requires two abnormal test results from the same sample or in two separate test samples

Categories of Increased Risk for Diabetes 1. FPG 100 to 125 mg/dl 2. 2-hr PG 140 to 199 mg/dl during OGTT 3. HbA1C 5.7% to 6.4%

DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; HbA1C, hemoglobin A1C or glycosylated hemoglobin; OGTT, oral glucose tolerance testing; PG, plasma glucose. Data from American Diabetes Association: Classification and diagnosis of diabetes: standards of medical care in diabetes—2019, Diabetes Care 42(Suppl 1):S13-S28, 2019. Available at http://care.diabetesjournals.org/content/42/Supplement_1/. The ADA classification “categories at increased risk for diabetes” (or prediabetes) describes nondiabetic elevations of the HbA1C, FPG, or 2-hour plasma glucose value during an OGTT16 (see Box 20.1). The Centers for Disease Control and Prevention (CDC) estimates that 84.1 million U.S. adults (34%) aged 18 years or older have prediabetes.15 This classification includes impaired glucose tolerance (IGT), which results from diminished insulin secretion; and impaired fasting glucose (IFG), which is caused by enhanced hepatic glucose output. Individuals with IGT and IFG are at increased risk of cardiovascular disease and premature death and carry up to a 50% 5-year risk of developing diabetes, particularly type 2 diabetes. Thus prevention of diabetes with lifestyle interventions is essential.

Types of Diabetes Mellitus Type 1 Diabetes Mellitus Type 1 diabetes mellitus accounts for 5% to 10% of diabetes cases and is the most common pediatric chronic disease. It currently affects approximately 1.25 million U.S. children, and the incidence is increasing.15 Between 10% and 13% of individuals with newly diagnosed type 1 diabetes have a first-degree relative (parent or sibling) with type 1 diabetes, and there is a 50% concordance rate in twins. Diagnosis is rare during the first 9 months of life and peaks at 12 years of age (see Table 20.3). TABLE 20.3 Epidemiology and Etiology of Diabetes Mellitus in the United States Type 1 Diabetes: Primary Beta-Cell Defect or Failure Incidence Frequency

5-10% of all cases of diabetes mellitus

Type 2 Diabetes: Insulin Resistance With Inadequate Insulin Secretion Accounts for most cases (≈90-95%)

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Prevalence rate is 0.17% Change in Incidence is increasing incidences Characteristics Age at Peak onset at age 11-13 yr (slightly earlier for girls onset than for boys); rare in children younger than 9 mos and adults older than 30 yrs Sex Similar in males and females Racial Rates for whites 1.5-2 times higher than for other distribution ethnic groups Weight Generally normal or underweight Etiology Common theory

Presence of antibody Insulin resistance Insulin secretion

Autoimmune: genetic and environmental factors, resulting in gradual process of autoimmune destruction in genetically susceptible individuals Nonautoimmune: Unknown

Prevalence rate for adults is 9.3% Incidence in adults more than tripled in the past 3 decades. Risk of developing diabetes increases after age 40 yr Similar in males and females Risk is highest for African Americans and Native Americans Obesity is common and is a frequent contributing factor to precipitate type 2 diabetes among those susceptible Genetic susceptibility (polygenic) combined with environmental determinants; defects in beta-cell function combined with insulin resistance Associated with long-duration obesity Autoantibodies not present

Autoantibodies to insulin and to glutamic acid decarboxylase (GAD65) Insulin resistance at diagnosis is unusual, but may Insulin resistance is virtually universal and occur as individual ages and gains weight multifactorial in origin Severe insulin deficiency or no insulin secretion at all Typically increased at time of diagnosis, but progressively declines over course of illness

Data from American Diabetes Association: Diabetes Care 40(Suppl 1): S11-S24, 2017. Available at: http://care.diabetesjournals.org/content/diacare/suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf); Centers for Disease Control: National diabetes statistics report 2017. Available at https://www.cdc.gov/diabetes/data/statistics/statistics-report.htm.

Pathophysiology Two distinct types of type 1 diabetes have been identified: idiopathic and autoimmune. Idiopathic type 1 diabetes mellitus is far less common than autoimmune diabetes, has a strong genetic component, and occurs mostly in people of Asian or African descent. Affected individuals have no evidence of beta-cell autoimmunity and have varying degrees of insulin deficiency. Autoimmune type 1 diabetes mellitus is a slowly progressive disease that destroys beta cells of the pancreas. There are strong genetic associations with histocompatibility leukocyte antigen (HLA) class II alleles HLA-DQ and HLA-DR. Environmental factors that have been implicated include exposure to certain drugs, foods, and viruses. These gene-environment interactions result in the formation of autoantigens that are expressed on the surface of pancreatic beta cells and circulate in the bloodstream and lymphatics (Fig. 20.11). Cellular immunity (T-cytotoxic cells and macrophages) and humoral immunity (autoantibodies against islet cells, insulin, glutamic acid decarboxylase [GAD], and other cytoplasmic proteins) are stimulated, resulting in beta-cell destruction and apoptosis. Over time, 80% to 90% of the insulin-secreting beta cells of the islet of Langerhans are destroyed, insulin synthesis declines, and hyperglycemia develops.

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FIGURE 20.11

Pathophysiology of Type 1 Diabetes Mellitus.

Insulin normally suppresses secretion of glucagon, and thus hypoinsulinemia leads to a marked increase in glucagon secretion. In addition to the decline in insulin secretion, there is decreased secretion of amylin (another beta-cell hormone), which also leads to an increase in glucagon. Glucagon, a hormone produced by the alpha cells of the islets, acts in the liver to increase the blood glucose level by stimulating glycogenolysis and gluconeogenesis.. Thus both a lack of insulin and a relative excess of glucagon contribute to hyperglycemia in type 1 diabetes. The natural history of type 1 diabetes involves a long preclinical period before insulin deficiency and hyperglycemia develop. Glucose accumulates in the blood and appears in the urine as the renal threshold for glucose is exceeded, producing an osmotic diuresis and symptoms of polyuria and thirst (Table 20.4). Wide fluctuations in blood glucose levels occur. Insulin deficiency also causes protein and fat breakdown, resulting in weight loss. Excessive metabolism of fats and proteins leads to high levels of circulating ketones, causing a condition known as diabetic ketoacidosis (DKA) (see the Acute Complications of Diabetes section). TABLE 20.4 Clinical Manifestations and Mechanisms for Type 1 Diabetes Mellitus Manifestation Polydipsia Polyuria Polyphagia Weight loss

Rationale Because of elevated blood glucose levels, water is osmotically attracted from body cells, resulting in intracellular dehydration and stimulation of thirst in hypothalamus Hyperglycemia acts as an osmotic diuretic; amount of glucose filtered by glomeruli of kidney exceeds that which can be reabsorbed by renal tubules; glycosuria results, accompanied by large amounts of water lost in urine Depletion of cellular stores of carbohydrates, fats, and protein results in cellular starvation and a corresponding increase in hunger Weight loss occurs because of fluid loss in osmotic diuresis and loss of body tissue as fats and proteins are used for energy

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Fatigue

Metabolic changes result in poor use of food products, contributing to lethargy and fatigue Recurrent infections (e.g., boils, Growth of microorganisms is stimulated by increased glucose levels; tissue ischemia carbuncles, and bladder and neuropathy contribute to the risk of infection; diabetes also is associated with infection) systemic immunocompromise. Prolonged wound healing Impaired blood supply hinders healing Genital pruritus Hyperglycemia and glycosuria favor fungal growth; candidal infections, resulting in pruritus, are a common presenting symptom in women Visual changes Blurred vision occurs as water balance in eye fluctuates because of elevated blood glucose levels; microvascular disease resulting in diabetic retinopathy may ensue Paresthesias Paresthesias are common manifestations of diabetic neuropathies Cardiovascular symptoms (e.g., Diabetes contributes to macrovascular disease with formation of atherosclerotic chest pain, extremity pain, and plaques that involve coronary, peripheral, and cerebral vessels neurologic deficits)

Although most individuals with type 1 diabetes are of normal or decreased weight, there are increasing numbers of individuals who have both type 1 diabetes and the clinical manifestations of metabolic syndrome, including obesity, dyslipidemia, and hypertension (Box 20.2). These individuals are at high risk for chronic complications of diabetes, including heart disease and stroke.

Box 20.2

Criteria for the Diagnosis of Metabolic Syndrome Three of these five traits must be present: 1. Increased waist circumference as determined by population and countryspecific definitions (>40 inches in men; >35 inches in women in the United States) 2. Plasma triglycerides ≥150 mg/dl 3. Plasma high-density lipoprotein (HDL) cholesterol 38° C (100.4° F), drenching night sweats, or weight loss >10% of body weight *NOTE:

The number of lymph node regions involved may be indicated by a subscript (e.g., II3).

From National Comprehensive Cancer Network: Hodgkin lymphoma. In NCCN practice guidelines, Version 2.2014: Hodgkin lymphoma (originally adapted from Carbono PP et al: Cancer Res 31[11]:1860-1861, 1971).

The effectiveness of treatment is related to the age, sex, and general health of the individual; signs and symptoms; stage of the disease; blood test results; type of HL; and classification of the disease as recurrent or progressive. HL in adults usually can be cured with early diagnosis and treatment.21 Three types of treatment are used: chemotherapy, radiation therapy, and surgery. Treatment for pregnant women includes watchful waiting and steroid therapy. Newer treatments undergoing testing include chemotherapy and

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radiation therapy with stem cell transplant and monoclonal antibody therapy.21 Treatment with chemotherapy or radiation therapy, or both, may increase the risk of second cancers, cardiovascular disease, and other health problems for many months or years after treatment.

Non-Hodgkin Lymphomas Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoid tissue neoplasms with differing biologic and clinical patterns of activity and responses to treatment. For unknown reasons, NHL incidence rates increased worldwide from 1950 to 2000, tripling in adults older than 65 years of age. The previously used generic classification of NHL has been reclassified in the WHO/REAL scheme into (1) B-cell neoplasms, which include a variety of lymphomas and myelomas that originate from B cells at various stages of differentiation; and (2) T-cell and NK-cell neoplasms, which include lymphomas that originate from either T or NK cells. These cancers are differentiated from HL by lack of RS cells and other cellular changes not characteristic of HL. More than 74,200 new cases of NHL and 19,970 deaths are predicted for 2019.12 The median age of diagnosis is 67 years, with a higher occurrence in men than women. The highest incidences are in North America, Europe, Oceania, and several African countries. Part of the increased incidence has been attributed to diagnostic improvements as well as AIDS-related cancers after the HIV epidemic. Conversely, the mortality has risen at a slower rate. It is thought that newer treatment modalities are improving survival rates. Risk factors for adult NHL include being older, male, or white and having one of the following: afflicted by certain inherited immune disorders, an autoimmune disease, or HIV/AIDS; exposure to a variety of mutagenic chemicals or certain pesticides; infection with certain cancer-related viruses (e.g., EBV, HIV, HTLV-1, hepatitis C, and human herpesvirus-8); and immune suppression related to organ transplantation. Gastric infection with H. pylori increases the risk for gastric lymphomas. NHL is a disease of middle age, usually found in persons more than 50 years old. Pathophysiology NHL is a progressive clonal expansion of B cells, T cells, or NK cells. B cells account for 85% to 90% of NHLs, with most of the remainder being T cells and rarely NK cells. A very small percentage originates from macrophages. Oncogenes may be activated by chromosomal translocations or the tumor-suppressor loci may be inactivated by deletion or mutation of chromosomes. Certain subtypes may have altered genomes by oncogenic viruses. Various subtypes of NHL are identified by specific diagnostic markers related to various cytogenetic lesions. The most common type of chromosomal alteration in NHL is translocation, which disrupts the genes encoded at the breakpoints. Unlike HL, NHL spreads in a less predictable way and spreads widely early. Clinical Manifestations Clinical manifestations of NHL usually begin as localized or generalized lymphadenopathy, similar to HL. Differences in clinical features are noted in Table 23.10. The cervical, axillary, inguinal, and femoral lymph node chains are the most commonly affected sites. Generally, the swelling is painless and the nodes have enlarged and transformed over a period of months or years. Other sites of involvement are the

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nasopharynx, GI tract, bone, thyroid, testes, and soft tissue. Some individuals have retroperitoneal and abdominal masses with symptoms of abdominal fullness, back pain, ascites (fluid in the peritoneal cavity), skin rash or itchy skin, fatigue, fever of unknown origin, drenching night sweats, and leg swelling. TABLE 23.10 Clinical Differences Between Non-Hodgkin Lymphoma and Hodgkin Lymphoma Characteristics Nodal involvement

Non-Hodgkin Lymphoma Multiple peripheral nodes Mesenteric nodes and Waldeyer ring commonly involved Noncontiguous Uncommon Common

Spread B symptoms* Extranodal involvement Extent of disease Rarely localized *Fever,

Hodgkin Lymphoma Localized to single axial group of nodes (i.e., cervical, mediastinal, paraaortic) Mesenteric nodes and Waldeyer ring rarely involved Orderly spread by contiguity Common Rare Often localized

weight loss, night sweats.

Lymphomas are classified as low, intermediate, or high grade. A low-grade lymphoma, which also may be termed indolent, has a slow progression. Individuals with low-grade lymphoma commonly present with a painless, peripheral adenopathy. Spontaneous regression of these nodes may occur, mimicking the presence of an infection. Night sweats with an elevated temperature (more than 38° C [100.4° F]) and weight loss, as well as extranodular involvement, are not commonly present in the early stages but are common in advanced or end-stage disease. Cytopenia, or reduction in the number of blood cells, reflective of bone marrow involvement is often observed. Hepatomegaly is common; splenomegaly is present in approximately 40% of individuals. Fatigue and weakness are more prevalent with advanced stages. Intermediate and high-grade lymphomas, which are more aggressive, have a more varied clinical presentation. A high-grade lymphoma also may be termed aggressive. Evaluation and Treatment The primary means for diagnosis of NHL is biopsy. A common finding in NHL is noncontiguous lymph node involvement, which is not common in HL. Staging is determined from radiologic studies, biopsy, and examination of bone marrow aspirate. Treatment for NHL is quite diverse and depends on type (B cell or T cell), tumor stage, histologic status (low, intermediate, or high grade), symptoms, age, and presence of comorbidities. Depending on the type (B cell or T cell) of the tumor, stage of disease, and aggressiveness of the tumor, treatment is usually initiated at the time of diagnosis. However, because treatment is not curative for some low-grade indolent lymphomas that are widely disseminated, observation without treatment may be the most appropriate choice. These indolent tumors are often not symptomatic for the individual, and this approach improves quality of life. In some cases the disease may be so slow growing that treatment is not needed for an extended period of time. Treatment with chemotherapy alone may be adequate for many individuals, although radiation therapy is often included. Low-dose chemotherapy has been followed by autologous stem cell transplantation in some NHLs or for recurrent disease. Treatment

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using monoclonal antibody alone or in combination with radiation therapy (radioimmunotherapy) also is being used. Individuals with NHL can survive for extended periods. A partial remission may be achieved in some cases in which evidence of the disease remains but the disease does not progress. Survival with nodular lymphoma ranges up to 15 years, but those with diffuse disease generally do not survive as long. Overall, the survival rates of NHL are less than those for HL. Survival rates for NHL are 77% at 1 year, 59% at 5 years, and 42% at 10 years. Burkitt lymphoma. Burkitt lymphoma (BL) is a B-cell NHL with unique clinical and epidemiologic features. It is highly aggressive and is the fastest growing human tumor. There are three main types of BL: endemic, sporadic, and immunodeficiency-related. Endemic BL commonly occurs in Africa and is linked to the EBV, and sporadic BL occurs worldwide. Immunodeficiency-related BL is most often seen in individuals with AIDS. BL occurs most often in children and young adults. Endemic cases, usually from Africa, involve a rapidly growing tumor of the jaw and facial bones (Fig. 23.15). In the United States, BL is rare, usually involves the abdomen, and is characterized by extensive bone marrow invasion and replacement.

FIGURE 23.15 Burkitt Lymphoma. Burkitt lymphoma involving the jaw in a young African boy. (Courtesy I. Magrath, MD, Bethesda, MD. From Zitelli BJ et al: Zitelli and Davis’ atlas of pediatric physical diagnosis, ed 6, Philadelphia, 2012, Saunders.)

Pathophysiology Almost all cases of BL are associated with EBV. Perhaps suppression of the immune system by other illnesses (e.g., HIV infection, chronic malaria) increases the individual's susceptibility to EBV. B cells are particularly sensitive because of specific surface receptors

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for EBV. As a result, the B cell undergoes chromosomal translocations that result in overexpression of the c-MYC proto-oncogene and loss of control of cell growth (Fig. 23.16). The most common translocation (75% of individuals) is between chromosomes 8 (containing the c-MYC gene) and 14 (containing the immunoglobulin heavy chain genes). Other translocations have been reported between chromosome 8 and chromosomes 2 or 22, which contain genes for immunoglobulin light chains.

FIGURE 23.16

Burkitt Lymphoma Cells. The 8,14 chromosomal translocation and associated oncogenes in Burkitt lymphoma.

Clinical Manifestations In non-African BL the most common presentation is abdominal swelling. Manifestations of most tumors occur at extranodal sites. More advanced disease may involve the eye, ovaries, kidneys, or glandular tissue (breast, thyroid, tonsils) and presents with type B symptoms (night sweats, fever, weight loss). Common manifestations may include nausea and vomiting; loss of appetite or change in bowel habits, or both; GI bleeding; symptoms of an acute abdominal condition; intestinal perforation; and renal failure. Evaluation and Treatment Usually indicative of BL is the presence of tumors in the jaw and facial bones, enlarged lymph nodes, and bone marrow containing malignant B cells. Laboratory studies include CBC, electrolytes, liver and renal function tests, lactate dehydrogenase, hepatitis B, HIV, and uric acid.24 Treatment is aggressive multidrug regimens, such as combination chemotherapy. There is no role for radiation therapy in people with BL.24 Lymphoblastic lymphoma. Lymphoblastic lymphoma (LL) is a relatively rare variant of NHL overall (2% to 4%) but accounts for almost one-third of cases of NHL in children and adolescents, with a male predominance. The vast majority of LL (90%) is of T-cell origin; the remainder arises from B

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cells. LL is similar to acute lymphoblastic leukemia and may be considered a variant of that disease. Pathophysiology The disease arises from a clone of relatively immature T cells that becomes malignant in the thymus. As with most lymphoid tumors, LL is frequently associated with translocations, primarily of the chromosomes that encode for the T-cell receptor (chromosomes 7 and 14). These aberrations result in increased expression of a variety of transcription factors and loss of growth control. Clinical Manifestations The first sign of LL is usually a painless lymphadenopathy in the neck. Peripheral lymph nodes in the chest become involved in about 70% of individuals. Involved nodes are located mostly above the diaphragm. LL is a very aggressive tumor that presents as stage IV in most people. T-cell LL is associated with a unique mediastinal mass (up to 75%) because of the apparent origin of the tumor in the thymus. The mass results in dyspnea and chest pain and may cause compression of bronchi or the superior vena cava. The tumor may infiltrate the bone marrow in about half of those affected, and suppression of bone marrow hematopoiesis leads to increased susceptibility to infections. Other organs, including the liver, kidney, spleen, and brain, also may be affected. Many individuals express type B symptoms: fever, night sweats, and significant weight loss. Evaluation and Treatment The most common therapeutic approach is combined chemotherapy (intensive therapy). In early stages of the disease, the response rate is high, with increased survival; the 5-year survival in children is 80% to 90% and 45% to 55% in adults. Although LL is easily treated, there is a high relapse rate: 40% to 60% of adults.

Plasma Cell Malignancy Multiple Myeloma Multiple myeloma (MM) is a clonal plasma cell cancer characterized by the slow proliferation of tumor cell masses in the bone marrow (Fig. 23.17). These masses are associated with lytic bone lesions (round, punched out regions of bone) (Fig. 23.18). Uncommon variants include solitary myeloma (plasmacytoma) with a single mass in bone or soft tissue and smoldering myeloma, which is defined by a lack of symptoms and a high plasma abnormal antibody called the M protein.

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FIGURE 23.17 Multiple Myeloma, Bone Marrow Aspirate. Normal marrow cells are largely replaced by plasma cells, including atypical forms with multiple nuclei (arrow), and cytoplasmic droplets containing immunoglobulin. (From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

FIGURE 23.18 Osteolytic Lesions in Individuals With Multiple Myeloma. A, Radiograph showing skull lesions in a client with myeloma. B, Radiograph of femur showing extensive bone destruction caused by tumor. Note absence of reactive bone formation. (A from Abeloff M et al: Abeloff's clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone. B from Kissane JM, editor: Anderson's pathology, ed 9, St Louis, 1990, Mosby.)

Myeloma cells reside in the bone marrow and are usually not found in the peripheral blood. As the number of myeloma cells increases, fewer red blood cells, white blood cells, and platelets are produced. It may occasionally spread to other tissues, especially in very advanced stages of the disease. For unknown reasons, the reported incidence of MM has doubled in the past 2 decades. About 32,110 new cases and 12,960 deaths are estimated for 2019.12 MM occurs in all races, but the incidence in blacks is about twice that of whites. It

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rarely occurs before the age of 40 years—the peak age of incidence is between 65 and 70 years. It is slightly more common in men (7.7 estimated new cases per 100,000 persons) than in women (4.9 new cases per 100,000 persons). Other risk factors include exposure to radiation or certain chemicals, including pesticides, and a history of monoclonal gammopathy of undetermined significance (MGUS; see Clinical Manifestations) or plasmacytoma. Pathophysiology MM is a plasma cell neoplasia that causes lytic bone lesions (bony disease; radiologically appears as punched-out defects), hypercalcemia, renal failure, anemia, and immune abnormalities. It is a biologically complex disease with significant heterogeneity (wide range of genetic abnormalities, differences in clinical response, and survival in those with the same treatment). Multiple mutations in different pathways alter the intrinsic biology of the plasma cell, generating the features of myeloma. Defining the main, or driver, mutations and heterogeneity is essential for treatment decisions. Many myelomas are aneuploid and, in most individuals with myeloma, chromosomal translocations are the most common. Development of further secondary genetic alterations increases progression to an aggressive MM. Investigators are studying various epigenetic alterations and interactions with extracellular matrix proteins. For example, myeloma cells interact and secrete peptides that adhere to stromal cells, inducing cytokines that possibly promote inflammation. Myeloma cells are prone to the accumulation of misfolded protein, such as unpaired immunoglobulin chains. Misfolded proteins activate apoptosis. Malignant plasma cells arise from one clone of B cells that produce abnormally large amounts of one class of immunoglobulin (usually IgG, occasionally IgA, and rarely IgM, IgD, or IgE). The malignant transformation may begin early in B-cell development, possibly before encountering antigen in the secondary lymphoid organs. The myeloma cells return either to the bone marrow or to other soft tissue sites. Cytokines, particularly IL-6, have been identified as essential factors that promote the growth and survival of MM cells. (Lymphocytes and cytokines are described in Chapter 6.) IL-6 in particular acts as an osteoclast-activating factor and stimulates osteoclasts to reabsorb bone. This process results in bone lesions and hypercalcemia (high calcium levels in the blood) attributable to the release of calcium from the breakdown of bone. The antibody produced by the transformed plasma cell is frequently defective, containing truncations, deletions, and other abnormalities, and is often referred to as a paraprotein (abnormal protein in the blood). Because of the large number of malignant plasma cells, the abnormal antibody, or M protein, becomes the most prominent protein in the blood (see Fig. 23.19). Suppression of normal plasma cells by the myeloma results in diminished or absent normal antibodies. The excessive amount of M protein also may contribute to many of the clinical manifestations of the disease. Frequently, the myeloma produces free immunoglobulin light chain (Bence Jones protein) that is present in the blood and urine and contributes to damage of renal tubular cells.

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FIGURE 23.19 M Protein. Serum protein electrophoresis (PEL) is used to screen for M proteins in multiple myeloma (MM). A, In normal serum the proteins separate into several regions between albumin (Alb) and a broad band in the gamma (γ) region, where most antibodies (gamma globulins) are found. Immunofixation (IFE) can identify the location of IgG (G), IgA (A), IgM (M), and kappa (κ), and lambda (λ) light chains. B, Serum from an individual with MM contains a sharp M protein (M spike). The M protein is monoclonal and contains only one heavy chain and one light chain. In this instance the IFE identifies the M protein as an IgG containing a lambda light chain. C, Serum and urine protein electrophoretic patterns in an individual with MM. Serum demonstrates an M protein (Immunoglobulin) in the gamma region, and the urine has a large amount of the smaller sized light chains with only a small amount of the intact immunoglobulin. (A and B from Abeloff M et al: Abeloff's clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone. C from McPherson R, Pincus M: Henry's clinical diagnosis and management by laboratory methods, ed 22, Edinburgh, 2012, Saunders.)

Clinical Manifestations MM is characterized by elevated levels of calcium in the blood (hypercalcemia), renal failure, anemia, and bone lesions. The hypercalcemia and bone lesions result from infiltration of the bone by malignant plasma cells and stimulation of osteoclasts to reabsorb bone. This process results in the release of calcium (hypercalcemia) and the development of lytic lesions of bone (see Fig. 23.18). Destruction of bone tissue causes pain, the most common presenting symptom, and pathologic fractures. The bones most commonly involved, in decreasing order of frequency, are the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Spinal cord compression, because of the weakened vertebrae, occurs in about 10% of individuals. A condition called amyloidosis may occur, in which antibody proteins increase and stick together in peripheral nerves and organs, such as the kidney and heart. Signs and symptoms of amyloidosis include fatigue, purple spots on the skin, enlarged tongue, diarrhea, edema, and numbness or tingling in the legs and feet. Proteinuria is observed in 90% of individuals. Renal failure may be either acute or chronic and is usually secondary to the hypercalcemia. Bence Jones protein may lead to

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damage of the proximal tubules. Anemia is usually normocytic and normochromic and results from inhibited erythropoiesis caused by tumor cell infiltration of the bone marrow. The high concentration of paraprotein in the blood may lead to hyperviscosity syndrome. The increased viscosity interferes with blood circulation to various sites (brain, kidneys, extremities). Hyperviscosity syndrome is observed in up to 20% of persons. Additional neurologic symptoms (e.g., confusion, headaches, blurred vision) may occur secondary to hypercalcemia or hyperviscosity. Suppression of the humoral (antibody-mediated) immune response results in repeated infections, primarily pneumonias, and pyelonephritis. The most commonly involved microorganisms are encapsulated bacteria that are particularly sensitive to the effects of antibody; pneumonia caused by Streptococcus pneumoniae, Staphylococcus aureus, or Klebsiella pneumoniae; or pyelonephritis caused by Escherichia coli or other gram-negative organisms. Cell-mediated (T-cell) function is relatively normal. Overwhelming infection is the leading cause of death from MM. MM is a progressive disorder and is often preceded by a condition known as monoclonal gammopathy of undetermined significance (MGUS). MGUS is diagnosed by the presence of an M protein in the blood or urine without additional evidence of MM.25 MGUS is present in approximately 1% of the general population and in 3% of individuals older than 70 years. Although MGUS is considered nonpathologic and requires no treatment, about 2% of individuals with MGUS progress to malignant plasma cell disorders. Progression of MM after MGUS advances to asymptomatic MM and finally symptomatic MM. Asymptomatic MM also may be referred to as smoldering myeloma and indolent myeloma.25 Smoldering myeloma is usually characterized by the presence of an M protein and clonal bone marrow plasma cells, but with no indication of end-organ damage. Evaluation and Treatment Diagnosis of MM is made by symptoms and radiographic and laboratory studies; a definitive diagnosis requires a bone marrow biopsy. The International Myeloma Working Group's new criteria25 for the diagnosis of MM and smoldering MM is presented in Box 23.2. Several types of radiologic studies document the presence of bone lesions and areas of destruction. Quantitative measurements of immunoglobulins (IgG, IgM, IgA) are usually done, and serum electrophoretic analysis reveals increased levels of M protein. Bence Jones protein may be observed in the urine or serum by immunoelectrophoresis, or in the serum using available enzyme-linked immunosorbent assays (ELISAs). However, variants of MM include individuals in which only free light chain is produced and a rare variant that produces only free heavy chain; about 1% of cases are nonsecretory so that neither M protein nor Bence Jones protein is produced. Measurement of another protein, free β2microglobulin, is used as an indicator of prognosis or effectiveness of therapy.

Box 23.2

Revised International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Smoldering Multiple Myeloma 1266

Definition of Multiple Myeloma Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* and any one or more of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL) Renal insufficiency: creatinine clearance >40 mL per min† or serum creatinine >177 µml/L (>2 mg/dL) Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value 1 focal lesion on MRI studies¶

Definition of Smoldering Multiple Myeloma Both criteria must be met: Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500/24 hr and/or clonal bone marrow plasma cells 10% to 60% Absence of myeloma-defining events or amyloidosis

*Clonality

should be established by showing κ/A-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of disparity between the aspirate and core biopsy, the highest value should be used. †Measured

or estimated by validated equations.

‡If

bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement. §These

values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L. ¶Each

focal lesion must be ≥5 mm or more in size. PET-CT, 18F-Labeled fluorodeoxyglucose PET with CT. From Rajkumar SV et al: Lancet Oncol 15(12):e538-e548, 2014. Treatment options include combinations of chemotherapy; other drug therapy; targeted therapy; high-dose chemotherapy with stem cell transplant; biologic therapy; radiation

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therapy (bone lesions of the spine); and, sometimes, surgery. New therapies, called proteasome inhibitors, are emerging. Dose intensification improves outcomes in younger persons; however, long-term remissions occur in a minority of people. Gene expression profiling (GEP) helps improve the treatment of MM because it identifies prognostic subgroups and defines the molecular pathways associated with these subgroups. Newer agents (e.g., bortezomib, lenalidomide) have expanded therapeutic regimens for end-stage myeloma. The median survival for all stages of MM is 3 years. Approval of new drugs has changed the management of MM, and research for survival improvement is ongoing.

Quick Check 23.4 1. What are the risk factors for adult NHL? 2. Discuss why multiple myeloma (MM) causes bone lesions and increases the risk of fractures. 3. What are the main pathologic features of MM?

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Alterations of Splenic Function The complexities of splenic function are not totally understood, and its mysteries are still being studied. The normal functions of the spleen that may affect disease states include (1) phagocytosis of blood cells and particulate matter (e.g., bacteria), (2) antibody production, (3) hematopoiesis, and (4) sequestration of formed blood elements. The spleen is part of the mononuclear phagocyte system and is involved in all systemic inflammations, hematopoietic disorders, and many metabolic disorders. In the past, splenomegaly (enlargement of the spleen) has been associated with various disease states. It is now recognized that splenomegaly is not necessarily pathologic; an enlarged spleen may be present in certain individuals without any evidence of disease. Splenomegaly may be, however, one of the first physical signs of underlying conditions, and its presence should not be ignored. In conditions in which splenomegaly is present, the normal functions of the spleen may become overactive, producing a syndrome known as hypersplenism. Current criteria indicating the presence of hypersplenism include (1) cytopenias (anemia, leukopenia, thrombocytopenia, or combinations of these), (2) cellular bone marrow, (3) splenomegaly, and (4) improvement after splenectomy. Some individuals may seek treatment for problems even though they have not met all of these clinical criteria; therefore the relevance and significance of hypersplenism are still uncertain. Primary hypersplenism is recognized when no etiologic factor has been identified; secondary hypersplenism occurs in the presence of another condition. Pathophysiology Specific conditions causing splenomegaly and resulting hypersplenism are many (Box 23.3). Different pathologic processes that produce splenomegaly are described briefly.

Box 23.3

Diseases Related to Classification of Splenomegaly Inflammation or Infection Acute: viral (hepatitis, infectious mononucleosis, cytomegalovirus), bacterial (Salmonella, gram negative), parasitic (typhoid) Subacute or chronic: bacterial (subacute bacterial endocarditis, tuberculosis), parasitic (malaria), fungal (histoplasmosis), Felty syndrome, systemic lupus erythematosus, rheumatoid arthritis, thrombocytopenia

Congestive Cirrhosis, heart failure, portal vein obstruction (portal hypertension), splenic vein obstruction

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Infiltrative Gaucher disease, amyloidosis, diabetic lipemia

Tumors or Cysts Malignant: polycythemia rubra vera, chronic or acute leukemias, Hodgkin lymphoma, metastatic solid tumors

Nonmalignant: Hamartoma Cysts: true cysts (lymphangiomas, hemangiomas, epithelial, endothelial); false cysts (hemorrhagic, serous, inflammatory) Acute inflammatory or infectious processes cause splenomegaly because of an increased demand for defensive activities. An acutely enlarged spleen secondary to infection may become so filled with erythrocytes that their natural rubbery resilience is lost and they become fragile and vulnerable to blunt trauma. Splenic rupture is a complication associated with IM; rupture occurs mostly in males between days 4 and 21 of acute illness. Congestive splenomegaly is accompanied by ascites, portal hypertension, and esophageal varices and is most commonly seen in those with hepatic cirrhosis. Splenic hyperplasia develops in disorders that increase splenic workload and is associated most commonly with various types of anemia (hemolytic) and CMPDs (i.e., PV). Infiltrative splenomegaly is caused by engorgement by the macrophages with indigestible materials associated with various “storage diseases.” Tumors and cysts cause actual growth of the spleen. Metastatic tumors in the spleen are rare and may result from primary tumors of the skin, lung, breast, and cervix. Clinical Manifestations Overactivity of the spleen results in hematologic alterations that affect all blood components. Sequestering of red blood cells, granulocytes, and platelets results in a reduction of all circulating blood cells. The spleen may sequester up to 50% of the red blood cell population, thereby upsetting the normal physiologic concentration of red blood cells in the circulation. The rate of splenic pooling is directly related to spleen size and the degree of increased blood flow through it. Sequestering exposes the red blood cells to splenic conditions that accelerate destruction, further contributing to the decreased red blood cell concentration. Anemia is the result of these combined activities. Anemia may be further potentiated by an increase in blood volume, which produces a dilutional effect on the already reduced concentration of red blood cells. The dilutional effect, as well as the removal and destruction of red blood cells, depends primarily on the degree of splenomegaly. White blood cells and platelets also are affected by sequestering, although not to the same degree as the red blood cell. Again, the size of the spleen is the determining factor in the number of cells sequestered. Evaluation and Treatment

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Treatment for hypersplenism is splenectomy; however, it may not be always indicated. A splenectomy is considered necessary to alleviate the destructive effects on red blood cells. Clinical indicators should determine the need for splenectomy, not necessarily specific conditions. Splenectomy for splenic rupture is no longer considered mandatory because of the possibility of overwhelming sepsis after removal. Repair and preservation are now considered before the decision to remove the spleen. Splenectomy also may be performed as treatment for hairy cell leukemia, Felty syndrome, agnogenic myeloid metaplasia, thalassemia major, Gaucher disease, hemodialysis, splenomegaly, splenic venous thrombosis, and thrombotic thrombocytopenia purpura (TTP). Individuals are able to lead normal lives after splenectomy but blood cell abnormalities often exist after removal of the spleen (i.e., red blood cells become thinner, broader, and wrinkled; white blood cell counts initially increase and then plateau; platelet counts rise after surgery and then stabilize). A major postoperative complication after splenectomy is OPSI. Unless treated in time, OPSI may rapidly progress to septic shock and possibly disseminated intravascular coagulation (DIC).

Quick Check 23.5 1. Contrast the principal features of Hodgkin lymphoma with those of non-Hodgkin lymphoma. 2. What is Burkitt lymphoma? 3. Identify the major causes of splenomegaly. How does it differ from hypersplenism?

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Hemorrhagic Disorders and Alterations of Platelets and Coagulation The arrest of bleeding, or hemostasis, depends on adequate numbers of platelets, normal levels of coagulation factors, and absence of defects in vessels walls. The spectrum of abnormal bleeding varies widely from massive bleeds, such as rupture of large vessels such as the aorta, to small bleeds in skin or mucosal membranes. Diminished or excessive levels of coagulation factors can lead to defective hemostasis or spontaneous and unnecessary clotting. (Hemostasis is discussed in Chapter 22.) Diminished hemostasis results in either internal or external hemorrhage, defined as copious or heavy discharge of blood from blood vessels. A classification of hemorrhagic disorders is included in Table 23.11. TABLE 23.11 Classification of Hemorrhagic Disorders Type of Defect Defects of primary hemostasis

Example

Manifestation

Platelet defects or von Willebrand disease Coagulation factor defects

Usually present with small bleeds in skin or mucosal membrane; bleeds are usually petechiae (3-mm red-purple discolorations); common in capillaries; also includes epistaxis (nose bleeds), GI bleeds, or excessive menstruation

Defects of Bleeds into soft tissue, muscle, or joints; intracranial bleeds may occur secondary hemostasis Generalized Palpable Extravasated blood creates a palpable mass (or palpable purpura), ecchymoses (simply defects of purpura and called a bruise), or a larger palpable lesion (or hematoma); systemic disorders disrupt small small ecchymoses blood vessels, called vasculitis vessels

Purpuric disorders, red or purple discolored spots on skin, occur when there is a deficiency of normal platelets necessary to plug damaged vessels or prevent leakage from the tiny tears that occur daily in capillaries. More serious internal bleeding occurs from events that simply overwhelm hemostatic mechanisms, such as rupture of large blood vessels, trauma, and diseases associated with massive hemorrhage including abdominal aneurysm (also see the Anemias of Blood Loss section). Between these smaller bleeds and massive bleeds are deficiencies of coagulation factors found with the hemophilias (see Chapter 22). Disorders that result in spontaneous clotting can develop from genetic disorders of the clotting system components or from acquired diseases that activate clotting. These disorders are known collectively as thromboembolic disease. Additionally, any disorder of the blood that predisposes to clotting of blood or thrombosis is called hypercoagulability (thrombophilia).

Disorders of Platelets Quantitative or qualitative abnormalities of platelets can interrupt normal blood coagulation and prevent hemostasis. The quantitative abnormalities are thrombocytopenia, a decrease in the number of circulating platelets, and thrombocythemia, an increase in the

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number of platelets. Qualitative disorders affect the structure or function of individual platelets and can coexist with the quantitative disorders. Qualitative disorders usually prevent platelet adherence and aggregation, preventing formation of a platelet plug.

Thrombocytopenia Thrombocytopenia is defined as a platelet count less than 150,000 platelets/µl of blood, although most health care providers do not consider the decrease significant unless it falls below 100,000 platelets/µl of blood.26 Hemorrhage associated with minor trauma does not appreciably increase until the count falls below 50,000 platelets/µl. Spontaneous bleeding without trauma can occur with counts ranging from 10,000 platelets/µl to 15,000 platelets/ µl, resulting in skin manifestations (i.e., petechiae, ecchymoses, and larger purpuric spots) or frank bleeding from mucous membranes. Severe spontaneous bleeding may result if the count is less than 10,000 platelets/µl and can be fatal if it occurs in the GI tract, respiratory tract, or CNS. Before the diagnosis of thrombocytopenia is made, pseudothrombocytopenia must be ruled out. This phenomenon occurs in approximately 1 in 1000 to 1 in 10,000 laboratory samples and results from an error in platelet counting when a blood sample is analyzed by an automated cell counter. Platelets in the blood sample may become nonspecifically agglutinated by immunoglobulins in the presence of ethylenediaminetetraacetic acid (EDTA), a preservative in banked blood. The agglutinated platelets are not counted, thus giving an apparent, but false, thrombocytopenia. Thrombocytopenia also may be falsely diagnosed because of a dilutional effect observed after massive transfusion of platelet-poor packed cells to treat a hemorrhage. This occurs when more than 10 units of blood have been transfused within a 24-hour period. The hemorrhage that necessitated the transfusion also accelerates the loss of platelets, contributing to the pseudothrombocytopenic state. Splenic sequestering of platelets in hypersplenism (congestive) also induces an apparent thrombocytopenia, as does hypothermia (less than 25° C [77° F]), which is reversed when temperatures return to normal, suggesting an increased platelet sequestration in response to chilling. Pathophysiology Thrombocytopenia results from decreased platelet production, increased consumption, or both. The condition may be either congenital or acquired and may be either primary or secondary to other acquired or congenital conditions. Thrombocytopenia secondary to congenital conditions occurs in a large number of different diseases, although each is relatively rare. Acquired thrombocytopenia is more common and may occur as a result of decreased platelet production secondary to viral infections (e.g., EBV, rubella, CMV, HIV), drugs (e.g., thiazides, estrogens, quinine-containing drugs, chemotherapeutic agents, ethanol), nutritional deficiencies (vitamin B12 or folic acid in particular), chronic renal failure, bone marrow hypoplasia (e.g., AA), radiation therapy, or bone marrow infiltration by cancer. Most common forms of thrombocytopenia are the result of increased platelet consumption. Examples include heparin-induced thrombocytopenia, idiopathic (immune) TTP, TTP, and DIC (discussed in the Disorders of Coagulation section). Heparin-induced thrombocytopenia.

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Heparin is a common cause of drug-induced thrombocytopenia. Approximately 4% of individuals treated with unfractionated heparin develop heparin-induced thrombocytopenia (HIT). The incidence is lower (about 0.1%) with the use of lowmolecular-weight heparin. HIT is an immune-mediated, adverse drug reaction caused by IgG antibodies against the heparin–platelet factor 4 complex leading to platelet activation through platelet Fc γIIa receptors. The release of additional platelet factor 4 from activated platelets and activation of thrombin lead to increased platelet consumption and a decrease in platelet counts beginning 5 to 10 days after administration of heparin. Clinical Manifestations The hallmark of HIT is thrombocytopenia. A decrease of approximately 50% in the platelet count is observed in more than 95% of individuals. However, 30% or more of those with thrombocytopenia are also at risk for venous or arterial thrombosis because a prothrombotic state is caused by antibody binding to platelets, inducing activation, aggregation, and consumption (thus the term thrombocytopenia in the syndrome name) of platelets. Venous thrombosis is more common and results in deep venous thrombosis (DVT) and pulmonary emboli. Arterial thrombosis affects the lower extremities, causing limb ischemia. Arterial thrombosis may lead to cerebrovascular accidents and myocardial infarctions. Other major arteries also may be affected (e.g., renal, mesenteric, upper limb). Although platelet counts are low, bleeding is uncommon. Evaluation and Treatment Diagnosis is primarily based on clinical observations. The individual presents with dropping platelet counts after 5 days or longer of heparin treatment. On average, platelet counts may fall to 60,000/µl. Because most individuals have undergone surgery and the onset of symptoms, including thrombosis, may be delayed until after release from the hospital, other possible causes of thrombocytopenia (e.g., infection, other drug reactions) must be considered. Tests are available to measure anti-heparin–platelet factor 4 antibodies. The sensitivity of this test is extremely high (>90%), but the specificity is less because of false-positive reactions (e.g., those receiving dialysis). Treatment is the withdrawal of heparin and use of alternative anticoagulants. Immune thrombocytopenia purpura. The most common cause of thrombocytopenia secondary to increased platelet destruction is immune thrombocytopenic purpura (ITP). The incidence of ITP is estimated to range from 5.8 to 6.6 per 100,000 in the general population and tends to increase with age. ITP may be acute or chronic. The acute form is frequently observed in children and typically lasts 1 to 2 months with a complete remission. In some instances it may last for up to 6 months, and some children (7% to 28%) may progress to the chronic condition (see Chapter 24). Acute ITP is usually secondary to infections (particularly viral) or other conditions that lead to large amounts of antigen in the blood, such as drug allergies or SLE. Under these conditions, the antigen usually forms immune complexes with circulating antibody; it is thought that the immune complexes bind to Fc receptors on platelets, leading to their destruction in the spleen. The acute form of ITP usually resolves as the source of antigen is resolved (infection) or removed (drugs). Chronic ITP is caused by autoantibodies against platelet-specific antigens. This form is more commonly observed in adults, being most prevalent in women between 20 and 40

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years of age, although it can be found in all ages. The chronic form tends to get progressively worse. It can occur from a variety of predisposing conditions or exposures (secondary) or have no known risk factors (primary). The autoantibodies are generally of the IgG class and are against one or more of several platelet glycoproteins (e.g., GPIIb/IIIa, GPIIb/IX, GPIa/IIa). The antibodies bind directly to the platelet antigens, after which the antibody-coated platelets are recognized and removed from the circulation by macrophages in the spleen. Clinical Manifestations Initial manifestations range from minor bleeding problems (development of petechiae and purpura) over the course of several days to major hemorrhage from mucosal sites (epistaxis, hematuria, menorrhagia, bleeding gums). Rarely will an individual present with intracranial bleeding or other sites of internal bleeding. During pregnancy, a woman with ITP may have a newborn that is also thrombocytopenic. If the fetal platelets express the same antigen as the mother, the maternal antibody will coat the platelets, potentially resulting in thrombocytopenia in utero. A variant of neonatal thrombocytopenia (neonatal alloimmune thrombocytopenia) occurs when the mother does not have ITP but makes IgG antibodies against an antigen inherited from the father found on fetal platelets but not on maternal platelets. Evaluation and Treatment Diagnosis of ITP is based on a history of bleeding and associated symptoms (weight loss, fever, headache). Physical examination includes notations on the type, location, and severity of bleeding. In addition, evidence of infections (bacterial, HIV and other viral), medication history, family history, and evidence of thrombosis are assessed. Other diagnostic tests include CBC and peripheral blood smear. Unlike some other forms of thrombocytopenia, there is usually no evidence of splenectomy. Testing for antiplatelet antibodies is usually not helpful. Although most cases of ITP are associated with elevated levels of IgG on platelets, other forms of thrombocytopenia also have a high incidence of platelet-associated antibodies; thus the specificity is low (50% to 65%).27 In addition, some cases of ITP will not present with elevated platelet-associated antibodies. The sensitivity is 75% to 94%; therefore a negative test does not rule out ITP. The acute form of ITP usually resolves without major clinical consequences, but the chronic form, like many autoimmune diseases, is variable with multiple remissions and exacerbations. Treatment is palliative, not curative, and focuses on prevention of platelet destruction. Initial therapy for ITP is glucocorticoids (e.g., prednisone), which suppress the immune response and prevent sequestering and further destruction of platelets. If steroid therapy is ineffective, other reagents have been used. Treatment with intravenous immunoglobulin (IVIG) is used to prevent major bleeding. The response rate is 80%, but the effects are transient, lasting only days to a few weeks. Anti-Rho(D) immune globulin (antiD) has been used with limited success to treat individuals who are Rh-positive. Newer drug therapies are now available. If other therapies are ineffective, splenectomy is considered to remove the site of platelet destruction. However, splenectomy is not without risks and approximately 10% to 20% of individuals who undergo a splenectomy suffer a relapse and require further treatment. In that situation, it is thought that the liver has become the site for platelet destruction. If splenectomy is unsuccessful and life-threatening thrombocytopenia persists, more

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aggressive immunosuppressive medications (e.g., azathioprine, cyclophosphamide) are usually recommended. Because of potential complications, these medications are reserved for individuals who are severely thrombocytopenic and refractive to other therapies. Thrombotic thrombocytopenia purpura. Thrombotic thrombocytopenia purpura (TTP; also known as Moschcowitz disease) is a multisystem disorder characterized by thrombotic microangiopathy (TMA) (small or microvessel disease) in which platelets aggregate and cause occlusion of arterioles and capillaries within the microcirculation. Aggregation may lead to increased platelet consumption and organ ischemia. TTP is relatively uncommon, occurring in about 5 per 1 million individuals per year. The incidence is increasing and does appear to be an actual increase and not just the result of improved recognition. One suspected etiologic factor for TMA, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome is druginduced, and a recent report found definite evidence from three drugs: quinine, cyclosporine, and tacrolimus.28 There are two types of TTP: familial and acquired idiopathic. The familial type is the more rare type and is usually chronic, relapsing, and typically seen in children. When the disease is recognized and treated early, the child experiences predictable recurring episodes at approximately 3-week intervals that are responsive to treatment. Acquired TTP is more common and more acute and severe. It occurs mostly in females in their thirties and is rarely observed in infants or older adults. Platelet aggregation and microthrombi formation is found throughout the entire vascular system, causing damage to multiple organs. The most susceptible organs for damage include the kidney, brain, and heart. Also affected are the pancreas, spleen, and adrenal glands. The thrombi are composed of platelets with minimal fibrin and red cells, differentiating them from thrombi secondary to intravascular coagulation. Most cases of TTP are related to a dysfunction of the plasma metalloprotease ADAMTS13 (Fig. 23.20). This enzyme is responsible for digesting large precursor molecules of von Willebrand factor (vWF) produced by endothelial cells into smaller molecules. Defects in ADAMTS13 result in expression of large-molecular-weight vWF on the endothelial cell surface and the formation of large aggregates of platelets, which can break off and form occlusions in smaller vessels. People with TTP (about 80%) have less than 5% of normal plasma ADAMTS13 levels. Most individuals with familial TTP are homozygous for mutations in ADAMTS13. Acquired TTP of unexplained origin is associated in most people with an IgG autoantibody against ADAMTS13 that is able to neutralize the enzyme's activity and accelerate its clearance from the plasma.

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FIGURE 23.20 Thrombotic Thrombocytopenic Purpura. A, A microvessel (arteriole or capillary) in a healthy individual. Normal proteolysis by ADAMTS13 of ultra-large von Willebrand factor (vWF) strings anchored to or secreted from stimulated microvascular endothelial cells. B, A microvessel in thrombotic thrombocytopenic purpura (TTP). Cleavage of secreted or anchored ultralarge vWF is severely reduced when ADAMTS13 activity is less than 10% of normal level. The results include excessive microthrombi formation, shear stress injury to red blood cells (schistocytes) flowing through microvessels that are partially occluded by platelet clumps (producing hemolysis), and perhaps damage from activation of the alternative complement pathway on the uncleaved ultralarge vWF strings. (From Kremer Hovinga JA et al: Nat Rev Dis Primers 3:17020, 2017.)

Clinical Manifestations Chronic relapsing TTP is a rare familial form of TTP observed in children and usually recognized and successfully treated. The acquired acute idiopathic TTP is much more common and more severe. Early diagnosis and treatment is essential because TTP may prove fatal within 90 days of onset. TTP is clinically related to and must be distinguished from other thrombotic microangiopathic conditions, including hemolytic uremic syndrome (HUS), malignant hypertension, preeclampsia, and pregnancy-induced HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Acute idiopathic TTP is characterized by a pathognomonic pentad (characteristic for a particular disease; group of five). However, only 20% to 30% of those with acute idiopathic TTP present with the classic pentad. These include (1) extreme thrombocytopenia (less than 20,000 platelets/µl), (2) intravascular hemolytic anemia, (3) ischemic signs and symptoms most often involving the CNS (about 65% present with memory disturbances, behavioral irregularities, headaches, or coma), (4) kidney failure (affecting about 65% of individuals), and (5) fever (present in about 33% of individuals with TTP). It is not mandatory that all five be present to begin treatment. Evaluation and Treatment A routine blood smear usually shows fragmented red cells (schizocytes) produced by shear forces when red cells are in contact with the fibrin mesh in clots that form in the vessels. As a result of tissue injury, serum levels of lactate dehydrogenase (LDH) may be very high, and low-density lipoprotein (LDL) levels may be elevated. Tests for antibody on red cells are negative, excluding immune hemolytic anemia. Importantly, prompt treatment can significantly reduce the death rate. Plasma exchange with fresh frozen plasma, which replenishes functional ADAMTS13, is the treatment of choice, achieving a 70% to 85% response rate. Additionally, steroids (glucocorticoids) are

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administered. In the absence of major organ damage, this approach may lead to complete recovery with no long-term complications. The anti-CD20 monoclonal antibody rituximab has shown some success in people who are refractory to plasma exchange.29 Relapses do occur at a rate of 13% to 36%, and recurrences have been reported, sometimes delayed until 9 years after treatment. Individuals who do not respond to conventional treatment may be candidates for splenectomy; however, postoperative hemorrhage remains a dangerous complication. Immunosuppression therapy has been successful in some individuals.

Thrombocythemia Thrombocythemia (also called thrombocytosis) is defined as a platelet count greater than 450,000/µl of blood.30 Thrombocythemia may be primary or secondary (reactive) and is usually asymptomatic until the count exceeds 1 million/µl. Then intravascular clot formation (thrombosis), hemorrhage, or other abnormalities can occur. Pathophysiology Essential (primary) thrombocythemia (ET) is a chronic, myeloproliferative neoplasm (MPN) characterized by excessive platelet production resulting from a defect in the bone marrow megakaryocyte progenitor cells. Abnormal blood clotting commonly occurs in individuals with essential thrombocythemia causing many clinical manifestations. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, itching (or pruritus), and risk of leukemic or bone marrow fibrotic transformation. The most common mutated genes in ET are the Janus kinase 2 (JAK2) and calreticulin (CALR) genes. Other mutated genes also can occur and contribute to ET. The JAK2 mutation induces overactivity in cell signaling from JAK2 protein. JAK2, a tyrosine kinase, is an essential player downstream of cytokine receptors, such as the thrombopoietin (TPO, affects platelet proliferation) and erythropoietin (EPO, affects erythrocyte proliferation) receptors. More simply, both EPO and TPO convey their signals and consequent proliferation through JAK2. Along with increased platelets, there may be a concomitant increase in the number of red cells, indicating a myeloproliferative disorder; however, the increase in red cells is not to the extent seen in PV. Red blood cells in ET tend to aggregate and adhere to the endothelium and contribute to the blockage of flow in the microvasculature and altered interactions between platelets and the vascular endothelium. The JAK2 (V617F) mutation is present in 50% to 60% of persons with ET. It is more common in middle-age individuals, with the majority of cases occurring between ages 50 and 60 years. There is no known sex preference. There also is a rare hereditary type of ET called familial essential thrombocythemia (FET) that is inherited in an autosomal dominant pattern. Secondary thrombocythemia may occur after splenectomy because platelets that normally would be stored in the spleen remain in circulating blood. The increase in platelets may be gradual, with thrombocythemia not occurring for up to 3 weeks after splenectomy. Reactive thrombocythemia may occur during some inflammatory conditions, such as rheumatoid arthritis and cancers. In these conditions, excessive production of some cytokines (e.g., IL-6, IL-11) may induce increased production of thrombopoietin in the liver, resulting in increased megakaryocyte proliferation. Reactive thrombocythemia also may occur during a variety of physiologic conditions, such as after exercise. Clinical Manifestations

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Clinical manifestations vary among individuals. Those with ET are at risk for large-vessel arterial or venous thrombosis, although the most common complication is microvasculature thrombosis leading to ischemia in the fingers, toes, or cerebrovascular regions. The primary presenting symptoms of microvasculature thrombosis are erythromelalgia, headache, and paresthesias. Erythromelalgia is unilateral or bilateral warm, congested, red hands and feet with painful burning sensations, particularly in the forefoot sole and one or more toes. The lower extremities are affected more often, and only one side may be involved. The pain is initiated by standing, exercise, or warmth and relieved by elevation and cooling. In extreme situations, acrocyanosis (bluish or purple coloring of hands or feet) and gangrene may result. Arterial thrombosis is more common than venous thrombosis and may involve the coronary and renal arteries. DVT of the lower extremities and pulmonary embolism are the major sites for venous involvement. Other common venous sites include intra-abdominal venous thrombosis (portal and hepatic). People older than 60 years of age or those with prior history of thrombotic events have as much as a 25% chance of developing a cerebral, cardiac, or peripheral arterial thrombus and, less often, developing a pulmonary embolism or DVT.31,32 Conversion to acute leukemia is found in less than 10%.33 Symptoms related to microvascular thrombosis in the CNS include headache, dizziness with paresthesias, transient ischemic attacks (TIAs), strokes, visual disturbances, and seizures. Major thrombotic events, not directly related to the platelet count, occur in about 20% to 30% of individuals with ET. Prior history of thrombotic events, advanced age, and duration of thrombocytosis are predictors of future thrombotic complications. Individuals older than age 60 are at greatest risk. Although thrombosis is the more common symptom, hemorrhage can also occur. Sites for bleeding include the GI tract, skin, mucous membranes, urinary tract, gums, teeth sockets after extraction, joints, eyes, and brain. GI bleeding may be mistaken for a duodenal ulcer. Hemorrhage is not severe and generally occurs in the presence of very high platelet counts; transfusions are required only occasionally. Bleeding and clotting may occur simultaneously, and individuals will not necessarily be “bleeders” or “clotters.” Evaluation and Treatment Initial diagnosis is not difficult, and as many as two-thirds of cases are diagnosed from a routine CBC. Secondary thrombocytosis also may occur as a moderate rise in the platelet count that resolves with treatment or resolution of the underlying condition. The WHO criteria for the diagnosis of ET require the following four criteria be met: (1) sustained platelet count of at least 450 × 109/L; (2) bone marrow biopsy showing proliferation of enlarged mature megakaryocytes and no increase of granulocyte or erythrocyte precursors; (3) failure to meet the criteria of PV, myelofibrosis, CML, or other myelodysplastic syndrome; and (4) presence of JAK2 617F or another clonal marker or evidence of reactive thrombocytosis.34 Because ET can be mistaken for CML, careful differentiation is necessary because treatment varies significantly. Treatment of ET is directed toward preventing thrombosis or hemorrhage. Reducing the platelet count remains a significant treatment issue. Hydroxyurea, a nonalkylating myelosuppressive agent, has been the drug of choice to suppress platelet production; however, long-term use may cause progression to other myelodysplastic disorders, particularly AML or myelofibrosis.35 Another drug used to treat ET is IFN. IFN has a

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response rate of 80% but may not be effective for everyone because of side effects. Anagrelide interferes with platelet maturation rather than production, thus not interfering with red and white cell growth and development. Low-dose aspirin may be effective to alleviate erthromyalgia and transient neurologic manifestations. ET is not necessarily considered life-threatening but, in those older than age 60 and who have had previous incidences of thrombosis, complications are more common and have a higher risk of mortality.

Alterations of Platelet Function Qualitative alterations in platelet function are characterized by an increased bleeding time in the presence of a normal platelet count. Associated clinical manifestations include spontaneous petechiae and purpura, and bleeding from the GI tract, genitourinary tract, pulmonary mucosa, and gums. Congenital alterations in platelet function (thrombocytopathies) are quite rare and may be categorized into several types of disorders (also see Chapter 24). Acquired disorders of platelet function are more common than the congenital disorders and may be categorized into three principal causes: (1) drugs, (2) systemic inflammatory conditions, and (3) hematologic alterations. Multiple drugs are known to interfere with platelet function in several ways: inhibition of platelet membrane receptors, inhibition of prostaglandin pathways, and inhibition of phosphodiesterase activity. Aspirin is the most commonly used drug that affects platelets. It irreversibly inhibits cyclooxygenase function for several days after administration. Nonsteroidal antiinflammatory drugs also affect cyclooxygenase, although in a reversible fashion. Systemic disorders that affect platelet function are chronic renal disease, liver disease, cardiopulmonary bypass surgery, and severe deficiencies of iron or folate and antiplatelet antibodies associated with autoimmune disorders. Hematologic disorders associated with platelet dysfunction include CMPDs, MM, leukemias, myelodysplastic syndromes, and dysproteinemias.

Disorders of Coagulation Disorders of coagulation are usually caused by defects or deficiencies of one or more of the clotting factors. (Normal function of the clotting factors is described in Chapter 22.) Qualitative or quantitative abnormalities interfere with or prevent the enzymatic reactions that transform clotting factors, circulating as plasma proteins, into a stable fibrin clot (see Fig. 22.17). Some clotting factor defects are inherited and involve a single factor, such as the hemophilias and von Willebrand disease, caused by deficiencies of specific clotting factors. Other coagulation defects are acquired and tend to result from deficient synthesis of clotting factors by the liver. Causes include liver disease and dietary deficiency of vitamin K. Other coagulation disorders are attributed to pathologic conditions that trigger coagulation inappropriately, engaging the clotting factors and causing detrimental clotting within blood vessels. For example, any cardiovascular abnormality that alters normal blood flow by acceleration or deceleration or obstruction can create conditions in which coagulation proceeds within the vessels. An example of this is thromboembolic disease, in which blood clots obstruct blood vessels. Coagulation is also stimulated by the presence of

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tissue factor that is released by damaged or dead tissues. Vasculitis, or inflammation of the blood vessels, along with vessel damage activates platelets, which in turn activates the coagulation cascade. In extensive or prolonged vasculitis, blood clot formation can suppress mechanisms that normally control clot formation and dissolution, leading to clogging of the vessels. In each of these acquired conditions, normal hemostatic function proves detrimental to the body by consuming coagulation factors excessively or by overwhelming normal control of clot formation and breakdown (fibrinolysis) (see Fig. 22.19).

Impaired Hemostasis Impaired hemostasis, or the inability to promote coagulation and the development of a stable fibrin clot, is commonly associated with liver dysfunction, which may be caused by either specific liver disorders or lack of vitamin K. Vitamin K deficiency. Vitamin K, a fat-soluble vitamin, is required for the synthesis and regulation of prothrombin, the procoagulant factors (VII, IX, X), and the anticoagulant factors within the liver (proteins C and S).36 Unknown is the contribution of vitamin K to the overall supply by the intestinal flora. The primary source of vitamin K is found in green leafy vegetables. The most common cause of vitamin deficiency is parenteral nutrition in combination with antibiotics that destroy normal gut flora. Rarely is the deficiency caused by a lack of dietary intake; however, bulimia can suppress vitamin K–dependent activity. Parenteral administration of vitamin K is the treatment of choice and usually results in correction of the deficiency within 8 to 12 hours. Fresh frozen plasma also may be administered but is usually reserved for individuals with life-threatening hemorrhages or those who require emergency surgery. Liver disease. Liver disease (e.g., acute or chronic hepatocellular diseases, cirrhosis), vitamin K deficiency, or liver surgery includes hemostatic derangements with defects in the clotting or fibrinolytic systems and platelet function. The hepatic (parenchyma) cells produce most of the factors involved in hemostasis; therefore damage to the liver frequently results in diminished production of factors involved in clotting. Factor VII level is the first to decline after liver damage because of its rapid turnover. Factor IX levels are less affected and do not decline until the liver destruction is well advanced. The liver also is a major site for production of plasminogen and α2-antiplasmin of the fibrinolytic system, as well as thrombopoietin and the metalloprotease ADAMTS13. Diminished thrombopoietin may lead to thrombocytopenia from decreased platelet production. Decreased production of ADAMTS13 results in increased levels of large precursor molecules of vWF, which leads to the formation of large aggregates of platelets. With severe liver disease, such as cirrhosis, most clotting factors are significantly depressed. Levels of clotting system regulators, such as antithrombin, protein C, protein S, and fibrinogen, also are diminished. The fibrolytic system is commonly active because of plasmin inhibitor and other activators that are unaffected. Thrombocytopenia occurs in affected individuals because of diminished thrombopoietin and ADAMTS13, as well as increased sequestration (pooling) of platelets in the spleen, which is frequently enlarged in cirrhosis and is associated with portal hypertension. Thus these individuals may appear to

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have a condition similar to DIC (see the Consumptive Thrombohemorrhagic Disorders section). Treatment of hemostasis alterations in liver disease must be comprehensive to cover all aspects of dysfunctions. Fresh frozen plasma administration is the treatment of choice; however, not all individuals tolerate the volume needed to adequately replace all deficient factors. Alternative modalities include the addition of exchange transfusions and platelet concentration to plasma administration.

Consumptive Thrombohemorrhagic Disorders Consumptive thrombohemorrhagic disorders are a heterogeneous group of conditions that demonstrate the entire spectrum of hemorrhagic and thrombotic pathologic findings. Symptoms range from the subtle to the devastating and generally are considered to be intermediary disease processes that complicate a vast number of primary disease states. These disorders are also characterized by confusion and controversy related to their diagnosis, treatment, and management. No one definition can cover all possible varieties of these disorders; however, DIC is most commonly used in the clinical setting to describe a pathologic condition associated with hemorrhage and thrombosis. Disseminated intravascular coagulation. Disseminated intravascular coagulation (DIC) is an acquired clinical syndrome characterized by widespread activation of coagulation resulting in formation of fibrin clots in medium and small vessels or microvasculature throughout the body. Widespread clotting may lead to blockage of blood flow to organs, resulting in multiple organ failure. The excess clotting may result in consumption of platelets and clotting factors, leading to tendency to bleed despite widespread clots. The clinical course of DIC is largely determined by the stimulus intensity, host response, and comorbidities and ranges from an acute, severe, life-threatening process that is characterized by massive hemorrhage and thrombosis to a chronic, low-grade condition. The chronic condition includes subacute hemorrhage and diffuse microcirculatory thrombosis. DIC may be localized to one specific organ or generalized, involving multiple organs. The diagnosis of DIC has been challenging because of the complexity and wide variations in clinical manifestations. Diagnostic criteria have been established and include a systemic thrombohemorrhagic disorder with laboratory evidence of (1) clotting activation, (2) fibrinolytic activation, (3) coagulation inhibitor consumption, and (4) biochemical evidence of end-organ damage or failure. DIC is secondary to a wide variety of well-defined clinical conditions, specifically those capable of activating the clotting cascade (see Pathophysiology). Sepsis is the most common condition associated with DIC. Gram-negative microorganisms, as well as some gram-positive microorganisms, fungi, protozoa (malaria), and viruses (influenza, herpes), are capable of precipitating DIC by causing damage to the vascular endothelium. Gram-negative endotoxins are the primary cause of endothelial damage; DIC may occur in up to 50% of individuals with gram-negative sepsis. DIC occurs in approximately 10% to 20% of individuals with metastatic cancer or acute leukemia. The adenocarcinomas most frequently associated with DIC include the lung, pancreas, colon, and stomach. Direct tissue damage (e.g., massive trauma, extensive surgery, severe burns)

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also results in release of tissue factor (TF), an initiator of DIC, by the endothelium. Severe trauma, especially to the brain, can induce DIC. DIC occurs in about two-thirds of individuals with a systemic inflammatory response to trauma. Some complications of pregnancy also are associated with DIC; incidences range from 50% for women with placental abruptions to less than 10% for severe preeclampsia. Other causes of DIC have been identified, most notably blood transfusion. Transfused blood dilutes the clotting factors, as well as circulating naturally occurring antithrombins. In hemolytic transfusion reactions, the endothelium is damaged by complement-mediated reactions. Pathophysiology DIC results from abnormally widespread and ongoing activation of clotting—coagulopathy —in small and midsize vessels that alters the microcirculation, leading to ischemic necrosis in various organs, particularly the kidney and lung. Concomitantly, DIC can be caused by the imbalance between the coagulant system and the fibrinolytic system (which generates plasmin) to maintain normal circulation. DIC can cause widespread deposition of fibrin in the microcirculation that leads to ischemia, microvascular thrombotic obstruction, and organ failure (Fig. 23.21).

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FIGURE 23.21

Pathophysiology of Disseminated Intravascular Coagulation. See text.

Seemingly paradoxical, DIC involves both widespread clotting and bleeding because of simultaneous procoagulant activation, fibrinolytic activation, and consumption of platelets and coagulation factors, which results directly in serious bleeding (see Fig. 23.21). DIC is not a disease but is secondary to a variety of conditions (Box 23.4) because of activation of the clotting cascade. The common pathway for DIC appears to be excessive and widespread exposure to TF. This may occur by several mechanisms:

Box 23.4

Clinical Conditions Associated With Disseminated Intravascular Coagulation Sepsis or Severe Infection Potentially from any microorganism, including malaria

Trauma Serious head injury Head injury Fat metabolism Burns

Liver Diseases Fulminant hepatitis Severe liver cirrhosis

Heat Stroke Organ Destruction Severe pancreatitis

Malignancy Solid tumors Hematologic cancers

Obstetrical Calamities Preeclampsia or eclampsia

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Placental abruption Amniotic fluid embolism HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome Acute fatty liver Sepsis during pregnancy

Vascular Abnormalities Hemangioma Leaking or ruptured aneurysm (such as in the aorta) Aortic aneurysm Kasabach-Merritt syndrome Other vascular malformations

Severe Toxic or Immunologic Reactions Snake bite Recreational drug use Severe transfusion reaction Transplant rejection Data from Gando S et al: Nat Rev Dis Primers 2:16037, 2016. 1. Damage to the vascular endothelium results in exposure to TF. 2. When stimulated by inflammatory cytokines, endothelial cells and monocytes express surface TF. 3. Endotoxin triggers the release of many cytokines that can both promote and cause progression of DIC. 4. Sepsis is associated with many cytokines, interleukins, and platelet activating factor (PAF) that promote DIC as well as activate endothelial cells that stimulate thrombi development. 5. TF may be released directly into the bloodstream from circulating white blood cells. TF binds clotting factor VII, which leads to conversion of prothrombin to thrombin and formation of fibrin clots (see Fig. 22.19). This pathway appears to be the primary route by which DIC is initiated. Not only is the clotting system extensively activated in DIC, but also the activities of the predominant natural anticoagulants (tissue factor pathway inhibitor, antithrombin III, protein C) are greatly diminished. During DIC, the activation of clotting is prolonged and is a result of certain conditions (e.g., bacteremia or endotoxemia); thrombin generation is increased and is insufficiently balanced by impaired anticoagulant systems, such as antithrombin and protein C. The overall result is fibrin generation and deposition in the vascular system. In early DIC, plasmin (naturally occurring clot busting or fibrinolytic agent) produced from endothelial cells causes fibrinolysis to maintain circulation. Bleeding can occur with excess fibrinolytic activity. However, fibrinolysis becomes blunted by high levels of plasminogen activator inhibitor-1 (PAI-1), a fibrinolytic inhibitor. Over time the

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activity of plasmin is diminished by PAI-1. Although some fibrinolytic activity remains, the level is inadequate to control the systemic deposition of fibrin. The slow breakdown of fibrin by plasmin produces fibrin split products (FSPs) (also known as fibrin degradation products [FDPs]). These products are powerful anticoagulants that are normally removed from blood by fibronectin and macrophages. FSPs, along with thrombin, induce further cytokine release from monocytes, contributing to endothelial damage and TF release. During DIC, the presence of FSPs is prolonged. Low levels of fibronectin suggest a poor prognosis. Although thrombosis is generalized and widespread, individuals with DIC are paradoxically at risk for hemorrhage. Hemorrhage is secondary to the abnormally high consumption of clotting factors and platelets, as well as the anticoagulant properties of FSPs, which interfere with fibrin mesh formation or polymerization. Both thrombin and FSPs have a high affinity for platelets and cause platelet activation and aggregation—an event that occurs early in the development of DIC—which facilitates microcirculatory coagulation and obstruction in the initial phase. However, platelet consumption exceeds production, resulting in a thrombocytopenia that increases bleeding. Activation of clotting also leads to activation of other inflammatory pathways, including the kallikrein-kinin and complement systems (see Chapter 6). Activation of these systems contributes to increased vascular permeability, hypotension, and shock. Activated complement components also induce platelet destruction, which initially contributes to the thrombosis and later to the thrombocytopenia. The deposition of fibrin clots in the circulation interferes with blood flow, causing widespread organ hypoperfusion. This condition may lead to ischemia, infarction, and necrosis, further potentiating and complicating the existing DIC process by causing further release of TF and eventually organ failure. Manifestations of multisystem organ dysfunction and failure ultimately result. In addition to initiation of clotting by TF, DIC may be precipitated by direct proteolytic activation of factor X. This has been described as “thrombin mimicry” and is the result of proteases directly converting fibrinogen to fibrin. These proteases may come from snake venom, some tumor cells, or the pancreas and liver, where they are respectively released during episodes of pancreatitis and various stages of liver disease. Direct proteolytic activity appears to be independent of any type of damage to the endothelium or tissue. Whatever initiates the process of DIC, the cycle of thrombosis and hemorrhage persists until the underlying cause of the DIC is removed or appropriate therapeutic interventions are used. Clinical Manifestations Clinical signs and symptoms of DIC present a wide spectrum of possibilities, depending on the underlying disease process that initiates DIC and whether the DIC is acute or chronic (see Box 23.4). Most symptoms are the result of either bleeding or thrombosis. Acute DIC presents with rapid development of hemorrhaging (oozing) from venipuncture sites, arterial lines, or surgical wounds or development of ecchymotic lesions (purpura, petechiae) and hematomas. Other sites of bleeding include the eyes (sclera, conjunctiva), the nose, and the gums. Most individuals with DIC demonstrate bleeding at three or more unrelated sites, and any combination may be observed. Shock of variable intensity, out of proportion to the amount of blood loss, also may be observed. Hemorrhaging into closed compartments of the body can occur and may precede the development of shock.

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Manifestations of thrombosis are not always as evident, even though it is often the first pathologic alteration to occur. The initial observations may be bleeding and sometimes very extensive hemorrhage. Several organ systems are susceptible to microvascular thrombosis associated with dysfunction: cardiovascular, pulmonary, central nervous, renal, and hepatic systems. Acute and accurate clinical interpretations are critical to preventing progression of DIC that may lead to multisystem organ dysfunction and failure. (Multiple organ dysfunction and failure are discussed further in Chapter 26.) Indicators of multisystem dysfunction include changes in level of consciousness or behavior, confusion, seizure activity, oliguria, hematuria, hypoxia, hypotension, hemoptysis, chest pain, and tachycardia. Symmetric cyanosis of fingers and toes (blue finger/toe syndrome), nose, and breast may be observed and indicates macrovascular thrombosis. This may lead to infarction and gangrene that may require amputation. Jaundice also is observed and most likely results from red cell destruction rather than liver dysfunction. Individuals with chronic or low-grade DIC do not present with the overt manifestations of hemorrhaging and thrombosis but instead have subacute bleeding and diffuse thrombosis; these individuals are described as having compensated DIC, or non-overt DIC. The major characteristic of this state is an increased turnover and decreased survival time of the components of hemostasis: platelets and clotting factors. Occasionally, diffuse or localized thrombosis develops, but this is infrequent. Evaluation and Treatment No single laboratory test can be used to effectively diagnose DIC. Diagnosis is based primarily on clinical symptoms and confirmed by a combination of laboratory tests. The person must present with a clinical condition that is known to be associated with DIC. The most commonly used combination of laboratory tests usually confirms thrombocytopenia or a rapidly decreasing platelet count on repeated testing, prolongation of clotting times, the presence of fibrin split products, and decreased levels of coagulation inhibitors. Platelet counts below 100,000/µl or a progressive decrease in platelet counts is very sensitive for DIC, although not greatly specific. These changes usually indicate consumption of platelets. The standard coagulation tests (e.g., prothrombin time [PT], activated partial thromboplastin time [aPTT]) also have a high degree of sensitivity, but they are not highly specific for DIC. As a result of consumption of circulating clotting factors, these tests are usually abnormal, ranging from shortened to prolonged times. However, conditions other than DIC may prolong clotting times. Detection of fibrin split products is more specific for DIC. Detection of D-dimers is a widely used test for DIC. A D-dimer is a molecule produced by plasmin degradation of cross-linked fibrin in clots. D-Dimers in the blood can be quantified using ELISA tests that include commercially available and highly specific monoclonal antibody against the Ddimer. Agglutination tests for other fibrin split products are available. Levels of fibrin split products are elevated in the plasma in 95% to 100% of cases; however, they are less specific and only document the presence of plasmin and its action on fibrin. ELISAs for markers of thrombin activity are sometimes used. Levels of coagulation inhibitors (e.g., antithrombin III [AT-III], protein C) can be measured by assays that rely on function or by ELISAs that quantify the amount of the specific inhibitor. AT-III levels can provide key information for diagnosing and monitoring therapy of DIC. Initial levels of functional AT-III are low in DIC because thrombin is irreversibly complexed with activated clotting factors and AT-III.

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Treatment of DIC is directed toward (1) eliminating the underlying pathologic condition, (2) controlling ongoing thrombosis, and (3) maintaining organ function. Elimination of the underlying pathologic condition is the initial intervention in the treatment phase in order to remove the trigger for activation of clotting. Once the stimulus is gone, production of coagulation factors in the liver leads to restoration of normal plasma levels within 24 to 48 hours. Control of thrombosis is more difficult to attain. Heparin has been used for this; however, its use is controversial because its mechanism of action is binding to and activating AT-III, which is deficient in many types of DIC. Currently, heparin is indicated only in certain types of situations related to DIC. For instance, heparin seems to be effective in DIC caused by a retained dead fetus or associated with acute promyelocytic leukemia. Organ function is compromised by microthrombi, and there is a risk of losing an extremity because of vascular occlusion; thus heparin is also indicated in these conditions. Heparin's usefulness, however, for DIC that is precipitated by septic shock has not been established and so is contraindicated in that instance; heparin is also contraindicated when there is evidence of postoperative bleeding, peptic ulcer, or CNS bleeding. Replacement of deficient coagulation factors, platelets, and other coagulation elements is gaining recognition as an effective treatment modality. Their use is not without controversy, however, because a major concern with replacement therapy is the possible risk of adding components that will increase the rate of thrombosis. Clinical judgment is the key factor in determining whether replacement is to be used as a treatment modality. Several clinical trials are evaluating replacement of anticoagulants (i.e., AT-III, protein C). Antifibrinolytic drugs also are used in treatment but are limited to instances of lifethreatening bleeding that have not been controlled by blood component replacement therapy. Maintenance of organ function is achieved by fluid replacement to sustain adequate circulating blood volume and maintain optimal tissue and organ perfusion. Fluids may be required to restore blood pressure, cardiac output, and urine output to normal parameters.

Thromboembolic Disorders Certain conditions within the blood vessels predispose an individual to develop clots spontaneously. A stationary clot attached to the vessel wall is called a thrombus (Fig. 23.22). A thrombus is composed of fibrin and blood cells and can develop in either the arterial or the venous system. Arterial thrombi form under conditions of high blood flow and are composed mostly of platelet aggregates held together by fibrin strands. Venous thrombi form under conditions of low flow and are composed mostly of red cells with larger amounts of fibrin and few platelets.

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FIGURE 23.22 Thrombus. Thrombus arising in valve pocket at upper end of superficial femoral vein (arrow). Postmortem clot on the right is shown for comparison. (From McLachlin J, Paterson JC: Surg Gynecol Obstet 93[1]:1-8, 1951.)

A thrombus eventually reduces or obstructs blood flow to tissues or organs, such as the heart, brain, or lungs, depriving them of essential nutrients critical to survival. A thrombus also has the potential to detach from the vessel wall and circulate within the bloodstream (referred to as an embolus). The embolus may become lodged in smaller blood vessels, blocking blood flow into the local tissue or organ and leading to ischemia. Whether episodes of thromboembolism are life-threatening depends on the site of vessel occlusion. Therapy consists of removal or dissolution of the clot and supportive measures. Anticoagulant therapy is effective in treating or preventing venous thrombosis; it is not as useful in treating or preventing arterial thrombosis. Parenteral heparin is the major anticoagulant used to treat thromboembolism. Oral coumarin drugs also are widely used, including a newer direct factor Xa inhibitor (rivaroxaban). More aggressive therapy may be indicated for such conditions as pulmonary embolism, coronary thrombosis, or thrombophlebitis. Streptokinase, tissue plasminogen activator (t-PA), and urokinase activate the fibrinolytic system and are administered to accelerate the lysis of known thrombi. These drugs are known as fibrinolytic or thrombolytic therapy and are prescribed with a high degree of caution because they can cause hemorrhagic complications. The risk for developing spontaneous thrombi is related to several factors, referred to as the Virchow triad: (1) injury to the blood vessel endothelium, (2) abnormalities of blood flow, and (3) hypercoagulability of the blood. Endothelial injury to blood vessels can result from atherosclerosis (plaque deposits on arterial walls) (see Chapter 26). Atherosclerosis initiates platelet adhesion and aggregation, promoting the development of atherosclerotic plaques that enlarge, causing further damage and occlusion. Other causes of vessel endothelial injury may be related to hemodynamic

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alterations associated with hypertension and turbulent blood flow. Injury is also caused by radiation injury, exogenous chemical agents (e.g., toxins from cigarette smoke), endogenous agents (e.g., cholesterol), bacterial toxins or endotoxins, or immunologic mechanisms. Sites of turbulent blood flow in the arteries and stasis of blood flow in the veins increase the risk for thrombus formation. In areas of turbulence, platelets and endothelial cells may be activated, leading to thrombosis. In sites of stasis, platelets may remain in contact with the endothelium for prolonged lengths of time, and clotting factors that would normally be diluted with fresh flowing blood are not diluted and may become activated. The most common clinical conditions that predispose to venous stasis and subsequent thromboembolic phenomena are major surgery (e.g., orthopedic surgery), acute myocardial infarction, CHF, limb paralysis, spinal injury, malignancy, advanced age, the postpartum period, and bed rest longer than 1 week. Turbulence and stasis occur with ulcerated atherosclerotic plaques hyperviscosity (polycythemia) and conditions with deformed red cells (sickle cell anemia). Hypercoagulability, or thrombophilia, increases the risk for venous thrombosis. Hypercoagulability is differentiated according to whether it results from primary (hereditary) or secondary (acquired) causes. Hereditary thrombophilias. Thrombophilias can result from both inherited conditions and, more commonly, acquired conditions. Several inherited conditions increase the risk of developing thrombosis, and most are autosomal dominant. Thus individuals who are homozygous for the mutation are at greatest risk for thrombosis. These include mutations in platelet receptors, coagulation proteins, fibrinolytic proteins, and other factors. The particular mutations that have been most strongly linked as risk factors for venous thrombosis or for arterial thrombosis involving coronary artery disease or stroke include those that affect fibrinogen, prothrombin (G20210A variant), and factor V (factor V Leiden) of the coagulation system. Other inherited thrombophilias are risk factors mostly for venous thrombosis and include deficiencies in protein C, protein S, and AT-III.37,38 Other hereditary thrombophilias are less common. Tests to diagnose inherited thrombophilias include prothrombin time; partial thromboplastin time; and levels of protein C, protein S, and AT-III. More elaborate tests to detect precise mutations in factor V, prothrombin, or MTHFR may be indicated. Acquired hypercoagulability. Deficiencies in proteins S and C and AT-III may be acquired and contribute to a hypercoagulable state. Conditions associated with an acquired protein deficiency include DIC, liver disease, infection, DVT, acute respiratory distress syndrome, L-asparaginase therapy, HUS, and TTP. The postoperative state also predisposes an individual to protein C or S deficiency; however, its role in contributing to DVT remains unclear. Acquired hypercoagulable states include antiphospholipid syndrome (APS). APS is an autoimmune syndrome characterized by autoantibodies against plasma membrane phospholipids and phospholipid-binding proteins. As with most autoimmune diseases, the predominantly affected individual is female and of reproductive age. Those with APS are at risk for both arterial and venous thrombosis and a variety of obstetric complications, including pregnancy loss and preeclampsia/eclampsia. In severe cases the individual may die from recurrent major thrombus formation. The pathophysiology is related to

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autoantibodies directly reacting with platelets or endothelial cells (increasing the risk for thrombosis) or the placental surface (resulting in damage to the placenta). The predominant diagnostic tests measure prolongation of laboratory blood coagulation tests related to an antibody inhibitor (lupus anticoagulant) and specific ELISAs for antibodies against phospholipids (e.g., anticardiolipin antibody) or proteins that bind to phospholipids (e.g., β2-glycoprotein I). Highly effective therapy (i.e., unfractionated or low-molecular-weight heparin with low-dose aspirin) is available to prevent the obstetric complications.

Quick Check 23.6 1. Identify three pathologic causes of DIC, and describe the manifestations associated with DIC. 2. Compare and contrast thrombocytopenia with thrombocytosis. 3. Why does vitamin K deficiency predispose an individual to a coagulation disorder? 4. Compare and contrast a thrombus with an embolus.

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Summary Review Anemia 1. Anemia is defined as a reduction in the number or volume of circulating red cells or a decrease in the quality or quantity of hemoglobin. 2. The most common classification of anemias is based on changes in the cell size— represented by the cell suffix -cytic—and changes in the cell's hemoglobin content —represented by the suffix -chromic. 3. Clinical manifestations of anemia can be found in all organs and tissues throughout the body. Decreased oxygen delivery to tissues causes fatigue, dyspnea, dizziness, compensatory tachycardia, and organ dysfunction. 4. Posthemorrhagic anemia is caused by acute blood loss, often caused by trauma. Complete recovery is possible if acute blood loss is not severe. 5. Macrocytic (megaloblastic) anemias are characterized by unusually large stem cells (megaloblasts) in the marrow that mature into very large erythrocytes (macrocytic). Macrocytic anemias are caused most commonly by deficiency of vitamin B12 or folate. Pernicious anemia can be fatal, usually because of heart failure, unless vitamin B12 replacement is given (lifelong replacement is required). Folate deficiency anemia is treated with folate supplements, but long-term therapy is not necessary if dietary adjustments are made to increase folate intake. 6. Microcytic-hypochromic anemias are characterized by abnormally small red cells with unusually reduced hemoglobin content. The most common cause is iron deficiency. 7. Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide. The causes of IDA include (1) dietary deficiency, (2) impaired absorption, (3) increased requirement, (4) chronic blood loss, (5) impaired absorption, and (6) chronic diarrhea. 8. IDA usually develops slowly, with a gradual, insidious onset of nonspecific symptoms, including fatigue, weakness, shortness of breath, and pale earlobes, palms, and conjunctivae. Once the source of blood loss is identified and corrected, iron replacement therapy can be initiated. 9. Anemia of chronic disease results from decreased production of red blood cells and impaired iron utilization in people with chronic systemic diseases or inflammation. It is a common anemia found in hospitalized individuals and is usually in the mild to moderate range of anemias. 10. Normocytic-normochromic anemias are characterized by insufficient numbers of normal erythrocytes. Aplastic anemia is caused by a reduction in the effective production of mature cells by the bone marrow, causing a reduction or absence of all three blood cell types (pancytopenia). Hemolytic anemia is the premature accelerated destruction of erythrocytes.

Myeloproliferative Red Cell Disorders

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1. Myeloproliferative disorders involve an overproduction of cells resulting from abnormal regulation of hematopoietic stem cells. Polycythemia is an excessive red cell production. 2. Polycythemia vera is a slow-growing blood cancer in which the bone marrow makes too many red blood cells. It is a stem cell disorder with hyperplastic and neoplastic bone marrow alterations characterized by abnormal uncontrolled proliferation of erythrocytes, frequently with increased white blood cells and platelets. Polycythemia is responsible for most of the clinical symptoms, including increased blood volume and viscosity. 3. Treatment of polycythemia vera includes frequent phlebotomies and aspirin in low-risk individuals. Hydroxyurea is the drug of choice for myelosuppression. Use of radioactive phosphorus has been helpful in suppressing erythropoiesis. Polycythemia vera may spontaneously convert to acute myelogenous leukemia. 4. Hereditary hemochromatosis is a common inherited disorder of iron metabolism characterized by increased gastrointestinal iron absorption with subsequent iron deposition in the liver, pancreas, heart, joints, and endocrine glands. Periodic phlebotomy is effective at removing excess iron.

Alterations of Leukocyte Function 1. Quantitative alterations of leukocytes (too many or too few) can be caused by bone marrow dysfunction or premature destruction of cells in the circulation. Many quantitative changes in leukocytes occur in response to invasion by microorganisms. 2. Leukocytosis is a condition in which the leukocyte count is higher than normal and is usually a response to physiologic stressors and pathologic conditions, such as malignancies and hematologic disorders. 3. Leukopenia is present when the leukocyte count is lower than normal and is caused by radiation, anaphylactic shock, autoimmune disease, immune deficiencies, and certain drugs. A decrease in neutrophils increases the risk for infection. 4. Granulocytosis (or neutrophilia) is an increase in circulating granulocytes— neutrophils, eosinophils, or basophils—that occurs in response to infection and inflammation. Granulocytopenia (or neutrophilia), a significant decrease in the number of neutrophils, is often caused by chemotherapeutic agents, severe infection, and radiation. Agranulocytosis is a complete absence of granulocytes in the blood. 5. Eosinophilia (increase in circulating eosinophils) results most commonly from allergic disorders and parasitic invasion. Eosinopenia (decrease in circulating eosinophils) is generally caused by the migration of eosinophils into inflammatory sites. 6. Basophilia (increase in circulating basophils) is rare and generally is a response to inflammation and immediate hypersensitivity reactions. Basopenia (decrease in circulating basophils) is seen in hyperthyroidism, acute infection, ovulation and pregnancy, and long-term steroid therapy. 7. Monocytosis (increase in circulating monocytes) is often transient and occurs

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during the late or recuperative phase of infection. Monocytopenia (decrease in circulating monocytes) is rare but may occur with hairy cell leukemia and prednisone therapy. 8. Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood and is most commonly caused by viral infections. Lymphocytopenia is a decrease in the number of circulating lymphocytes and is associated with neoplasias, immune deficiencies, and destruction by drugs, viruses, or radiation. 9. Infectious mononucleosis (IM) is an acute, self-limiting infection of B lymphocytes most commonly associated with the Epstein-Barr virus (EBV), which is transmitted through saliva from close personal contact. The classic symptoms of IM are pharyngitis, lymphadenopathy, and fever. The proliferation of infected B cells may be uncontrolled and lead to B-cell lymphomas. Treatment of IM consists of rest and symptomatic treatment. 10. The common pathologic feature of all forms of leukemia is an uncontrolled proliferation of malignant leukocytes, overcrowding the bone marrow and resulting in decreased production and function of the other blood cell lines. 11. The classification of leukemias is complex, because the once discrete categories of lymphoma and leukemia have been blurred. 12. The World Health Organization (WHO) groups lymphoid neoplasms into five categories defined by cell of origin: (1) precursor B-cell neoplasms (immature B cells), (2) peripheral B-cell neoplasms (mature B cells), (3) precursor T-cell neoplasms (immature T cells), (4) peripheral T-cell and NK (natural killer)-cell neoplasms (mature T cells and NK cells), and (5) Hodgkin lymphoma (ReedSternberg cell and variants). 13. Acute leukemia is characterized by undifferentiated or immature cells. The onset of disease is abrupt and rapid, and, without treatment, disease progression results in a short survival time. In chronic leukemia, the predominant cell is more differentiated but does not function normally, with a relatively slow progression. 14. All leukemias have certain pathophysiologic features in common. Abnormal immature white blood cells, called leukemic blasts, fill the bone marrow and spill into the blood. The blasts overcrowd the marrow and cause cellular proliferation of the other cell lines to cease. 15. Acute leukemias include acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). 16. Increased risk for ALL has been linked to prenatal exposure to x-rays, postnatal exposure to ionizing radiation, past treatment with chemotherapy, and certain genetic conditions. AML is the most frequently reported secondary cancer after high doses of chemotherapy. 17. The major clinical manifestations of acute leukemia include fatigue caused by anemia, bleeding caused by thrombocytopenia, fever secondary to infection, anorexia, and weight loss. 18. Treatment varies depending on the type of leukemia and includes chemotherapy, radiation therapy, stem cell transplant, and other drug therapy. 19. Chronic leukemias include chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). 20. The only known cause of CML is exposure to ionizing radiation, and the cause of CLL is unknown.

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21. Most individuals with chronic leukemia are asymptomatic at the time of diagnosis, but the most common finding is lymphadenopathy. 22. Treatment of CLL ranges from periodic observation with treatment of infection, hemorrhage, or immunologic complications. Treatments for CML do not cure the disease, but include chemotherapy, biologic response modifiers, and stem cell transplant.

Alterations of Lymphoid Function 1. Lymphadenopathy is enlarged lymph nodes. Lymphadenopathy results from four types of conditions: (1) neoplastic disease, (2) immunologic or inflammatory conditions, (3) endocrine disorders, or (4) lipid storage diseases. 2. Lymphomas consist of a diverse group of neoplasms that develop from the proliferation of malignant lymphocytes in the lymphoid system. The WHO classification of lymphomas based on the cell type it originated from include Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Classification based on morphology and cell lineage include B-cell neoplasms, T-cell neoplasms, and natural killer (NK) cell neoplasms. Two basic categories of lymphomas are HL and NHL. 3. In general, lymphomas are the result of genetic mutations or viral infection. Malignant transformation produces a cell with uncontrolled and excessive growth that accumulates in the lymph nodes and other sites, producing tumor masses. 4. HL is a malignant lymphoma that progresses from one group of lymph nodes to another and is characterized by abnormal cells called Reed-Sternberg cells, which are infected with EBV in most cases. 5. An enlarged, painless lymph node, most commonly in the neck, is an initial sign of HL; however, asymptomatic lymphadenopathy can progress undetected for years. 6. Treatment of HL includes chemotherapy, radiation therapy, and surgery. Treatment with chemotherapy or radiation therapy, or both, may increase the risk of second cancers, cardiovascular disease, and other health problems months or years after treatment. 7. The NHLs are a heterogeneous group of lymphoid tissue neoplasms. NHL is a progressive clonal expansion of B cells, T cells, or NK cells, with B cells accounting for the majority of NHLs. Oncogenes may be activated by chromosomal translocation or by deletion of tumor-suppressor genes. Certain subtypes may have altered genomes by oncogenic viruses. 8. Generally, with NHL, the swelling of lymph nodes is painless and the nodes enlarge and transform over a period of months or years. The cervical, axillary, inguinal, and femoral lymph node chains are the most commonly affected sites. 9. Treatment for NHL may include chemotherapy, radiation therapy, monoclonal antibody therapy, and watchful waiting. 10. Burkitt lymphoma (BL) is a B-cell NHL. It is highly aggressive and is the fastest growing human tumor. There are three main types of BL: endemic (common in Africa and linked to EBV), sporadic (occurs worldwide), and immunodeficiencyrelated (found in individuals with AIDS). The rapidly growing tumor involves the jaw and facial bones and sometimes the abdomen.

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11. Treatment for BL is aggressive multidrug regimens, such as combination chemotherapy. 12. Lymphoblastic lymphoma is a rare variant of NHL, with the vast majority originating from the T cell. Painless lymphadenopathy in the neck is the first sign; peripheral lymph nodes in the chest become involved in most people. The most common treatment is combined chemotherapy. 13. Multiple myeloma (MM) is a clonal plasma cell cancer in the bone marrow. It is characterized by multiple malignant tumor masses of plasma cells scattered throughout the skeletal system (lytic bone lesions) and sometimes found in soft tissue. The common presentation of MM is characterized by elevated levels of calcium in the blood, renal failure, anemia, and lytic bone lesions. 14. Multiple mutations in different pathways alter the intrinsic biology of the plasma cell, generating the features of myeloma. The exact cause of MM is unknown, but risk factors include radiation, certain chemicals, and a history of monoclonal gammopathy of undetermined significance (MGUS). 15. Treatment options for MM include combinations of chemotherapy; other drug therapy; targeted therapy; high-dose chemotherapy with stem cell transplant; biologic therapy; radiation therapy; and, sometimes, surgery.

Alterations of Splenic Function 1. Splenomegaly (enlargement of the spleen) may be considered normal in certain individuals, but its presence is associated with various diseases. 2. Splenomegaly results from (1) acute inflammatory or infectious processes, (2) congestive disorders, (3) infiltrative processes, and (4) tumors or cysts. 3. Hypersplenism (overactivity of the spleen) results from splenomegaly. Hypersplenism results in sequestering of the blood cells, causing increased destruction of red blood cells, leukopenia, and thrombocytopenia.

Hemorrhagic Disorders and Alterations of Platelets and Coagulation 1. The arrest of bleeding is called hemostasis. Copious or heavy discharge of blood from blood vessels is called hemorrhage. 2. Quantitative or qualitative abnormalities of platelets can interrupt normal blood coagulation and prevent hemostasis. 3. Thrombocytopenia is characterized by a platelet count below 150,000/µl of blood; this is considered significant when the count is less than 100,000 platelets/µl, and a count less than 50,000/µl increases the potential for hemorrhage associated with minor trauma. A count less than 15,000 platelets/µl can cause spontaneous bleeding without trauma. 4. Thrombocytopenia exists in primary or secondary forms and can be congenital or acquired. Acquired thrombocytopenia is associated with viral infections, drugs, nutritional deficiencies, chronic renal failure, cancer, radiation therapy, and bone marrow hypoplasia. 5. Common forms of thrombocytopenia include heparin-induced thrombocytopenia,

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idiopathic (immune) thrombocytopenia purpura, thrombotic thrombocytopenia purpura, and disseminated intravascular coagulation. 6. Thrombocythemia is characterized by a platelet count more than 450,000 platelets/ µl of blood and is symptomatic when the count exceeds 1 million/µl, at which time the risk for intravascular clotting (thrombosis) is high. 7. Thrombocythemia is a myeloproliferative neoplasm characterized by excessive platelet production resulting from a defect in the bone marrow megakaryocyte progenitor cells. It also can include an increase in red blood cell production. 8. Qualitative alterations in normal platelet function prevent platelet plug formation and may result in prolonged bleeding times. Acquired disorders of platelet function are more common than congenital disorders. 9. Disorders of coagulation are usually caused by defects or deficiencies of one or more clotting factors. Coagulation is stimulated by the presence of tissue factor that is released by damaged or dead tissues. 10. Coagulation is impaired when there is a deficiency of vitamin K because of insufficient production of prothrombin and synthesis of clotting factors VII, IX, and X, often associated with liver diseases. 11. Disseminated intravascular coagulation (DIC) is an acquired clinical syndrome characterized by widespread activation of coagulation, resulting in formation of fibrin clots in medium and small vessels or microvasculature throughout the body. Widespread clotting may lead to blockage of blood flow to organs, resulting in multiple organ failure. The excessive clotting may result in consumption of platelets and clotting factors, leading to a tendency to bleed despite widespread clots. 12. DIC is secondary to a wide variety of clinical conditions, with sepsis being the most common. 13. For a diagnosis of DIC, the person must present with a clinical condition that is known to be associated with DIC. The most commonly used combination of laboratory tests usually confirms thrombocytopenia, or a rapidly decreasing platelet count on repeated testing, prolongation of clotting times, the presence of fibrin split products, and decreased levels of coagulation inhibitors. 14. Treatment of DIC is directed toward (1) eliminating the underlying pathologic condition, (2) controlling ongoing thrombosis, and (3) maintaining organ function. 15. Thromboembolic disease results from a fixed (thrombus) or moving (embolus) clot that blocks flow within a vessel, denying nutrients to tissues distal to the occlusion; death can result when clots obstruct blood flow to the heart, brain, or lungs. 16. The Virchow triad refers to three factors that influence the risk of developing spontaneous thrombi: (1) injury to the blood vessel endothelium, (2) abnormalities of blood flow, and (3) hypercoagulability of the blood.

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Key Terms Absolute polycythemia, 514 Acute idiopathic TTP, 537 Acute leukemia, 521 Acute lymphocytic leukemia (ALL), 523 Acute myelogenous leukemia (AML), 523 Agranulocytosis, 518 Amyloidosis, 532 Anemia, 505 Anemia of chronic disease (ACD; anemia of inflammation [AI]), 512 Anisocytosis, 505 Aplastic anemia (AA), 514 Apoferritin, 513 Arterial thrombus (pl., thrombi), 543 β2-Microglobulin, 533 Basopenia, 518 Basophilia, 518 B-cell neoplasm, 529 Bence Jones protein, 532 Blast cell, 521 Burkitt lymphoma, 530 Chronic leukemia, 521 Chronic lymphocytic leukemia (CLL), 525 Chronic myelogenous leukemia (CML), 525 Chronic relapsing TTP, 537 Congestive splenomegaly, 534 Consumptive thrombohemorrhagic disorder, 540 D-Dimer, 542 Disseminated intravascular coagulation (DIC), 540 Embolus, 543 Eosinopenia, 518 Eosinophilia, 518 Eryptosis, 507 Erythromelalgia, 538 Essential (primary) thrombocythemia (ET), 538 Fibrin degradation product (FDP), 541 Fibrin split product (FSP), 541 Folate (folic acid), 511 Granulocytopenia, 518 Granulocytosis, 518 Hemochromatosis, 516 Hemolysis, 507 Hemolytic anemia, 514 Hemorrhage, 535

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Hemostasis, 535 Heparin-induced thrombocytopenia (HIT), 536 Hepcidin, 517 Hereditary hemochromatosis (HH), 516 Hodgkin lymphoma (HL), 527 Hypercoagulability (thrombophilia), 536 Hypersplenism, 534 Hypoxemia, 507 Immune thrombocytopenic purpura (ITP), 536 Impaired hemostasis, 539 Infectious mononucleosis (IM), 520 Infiltrative splenomegaly, 534 Intrinsic factor (IF), 507 Iron deficiency anemia (IDA), 507 Janus kinase 2 gene (JAK2 gene), 515 Koilonychia, 512 Lactoferrin, 513 Leukemia, 521 Leukemic blast, 523 Leukocytosis, 517 Leukopenia, 517 Lymphadenopathy, 527 Lymphoblastic lymphoma (LL), 531 Lymphocytopenia, 519 Lymphocytosis (absolute lymphocytosis), 518 Macrocytic (megaloblastic) anemia, 507 Microvasculature thrombosis, 538 Monoclonal gammopathy of undetermined significance (MGUS), 533 Monocytopenia, 518 Monocytosis, 518 M protein, 531 Multiple myeloma (MM), 531 Neutropenia, 518 Neutrophilia, 518 NK-cell neoplasm, 529 Non-Hodgkin lymphoma (NHL), 529 Normocytic-normochromic anemia (NNA), 507 Pancytopenia, 514, 523 Pernicious anemia (PA), 509 Philadelphia chromosome, 523 Poikilocytosis, 505 Polycythemia, 514 Polycythemia vera (PV [primary polycythemia]), 514 Posthemorrhagic anemia, 507 Pseudothrombocytopenia, 536 Purpuric disorder, 535 Qualitative leukocyte disorder, 517

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Quantitative leukocyte disorder, 517 Reduced oxygen-carrying capacity, 505 Reed-Sternberg (RS) cell, 527 Relative polycythemia, 514 Secondary thrombocythemia, 538 Shift-to-the-left (leukemoid reaction), 518 Shift-to-the-right, 518 Small lymphocytic lymphoma (SLL; CLL/SLL), 525 Smoldering myeloma, 533 Splenomegaly, 534 T-cell neoplasm, 529 Thrombocythemia (thrombocytosis), 538 Thrombocytopenia, 536 Thromboembolic disease, 535 Thrombosis, 536 Thrombotic thrombocytopenia purpura (TTP, Moschcowitz disease), 537 Thrombus, 543 Trauma, 507 Vasculitis, 539 Venus thrombus (pl., thrombi), 543 Virchow triad, 543

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References 1. Rossaint R, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100. 2. World Health Organization (WHO). Injuries and violence: the facts. [Available from:] http://whqlibdoc.who.int/publications/2010/9789241599375_eng.pdf 2010. 3. Lang E, et al. Killing me softly—suicidal erythrocyte death. Int J Biochem Cell Biol. 2012;44(8):1236–1243. 4. Ainger E, Feldman A, Datz C. Obesity as an emerging risk factor for iron deficiency. Nutrients. 2014;6(9):3587–3600. 5. Drüeke TB. Anemia treatment in patients with chronic kidney disease. N Engl J Med. 2013;368(4):387–389. 6. Jing Z, et al. Hemoglobin targets for chronic kidney disease patients with anemia: a systematic review and meta-analysis. PLoS ONE. 2012;7(8):1–9. 7. Asare K. Anemia of critical illness. Pharmacotherapy. 2008;28(10):1267–1282. 8. U.S. Department of Health & Human Services (USDHHS), National Institutes of Health. Genetics home reference hereditary hemochromatosis. Author: Bethesda, MD; 2018. 9. U.S. Department of Health & Human Services (USDHHS), National Institutes of Health. Genetics home reference HFE gene. Author: Bethesda, MD; 2018. 10. Genetic Testing Registry: Hereditary hemochromatosis, Bethesda MD, National Center for Biotechnology Information, U.S. National Library of Medicine. Accessed 10/21/2018. 11. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 2004;350(13):1328–1337. 12. American Cancer Society (ACS). Cancer facts & figures 2019. Author: Atlanta, Ga; 2019. 13. SEER cancer statistics review 1975-2008. [Bethesda MD; 1301

National Institutes of Health, U.S. Department of Health and Human Services] 2011. 14. Talpaz M, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531–2541. 15. Wakeford R, Little MP, Kendall GM. Risk of childhood leukemia after low-level exposure to ionizing radiation. Expert Rev Hematol. 2010;3(3):251–254. 16. PDQ® Adult Treatment Editorial Board. PDQ adult acute lymphoblastic leukemia treatment. [Bethesda, MD, National Cancer Institute. Updated 03/16/2017; Available from:] https://www.cancer.gov/types/leukemia/hp/adult-alltreatment-pdq. 17. Friese CR, et al. Timeliness and quality of diagnostic care for Medicare recipients with chronic lymphocytic leukemia. Cancer. 2011;117(7):1470–1477. 18. National Cancer Institute (NCI). Chronic lymphocytic leukemia treatment (PDQ®). [Bethesda MD; National Cancer Institute, National Institutes of Health. Date last modified December 30, 2004; Available from:] http://cancer.gov/cancertopics/pdq/treatment/CLL/Patient 2014. 19. Helgason GV, Young GAR, Holyoake TL. Targeting chronic myeloid leukemic stem cells. Curr Hematol Malig Rep. 2010;5(2):81–87. 20. Canellos GP, Freedman AS, Rosmarin AG. Staging and prognosis of Hodgkin lymphoma, UpToDate. Wolters Kluwer; 2018. 21. PDQ® Adult Treatment Editorial Board. Adult Hodgkin lymphoma treatment (PDQ®). [Bethesda MD, National Cancer Institute. Date last modified February 25, 2015; Available from:] http://cancer.gov/cancertopics/pdq/treatment/adulthodgkins/Health 22. PDQ® Adult Treatment Editorial Board. Adult Hodgkin lymphoma treatment (PDQ®). [Bethesda MD, National Cancer Institute. Date last modified January 9, 2015; Available from:] 1302

http://cancer.gov/cancertopics/pdq/treatment/adulthodgkins/Patient 23. PDQ® Adult Treatment Editorial Board. PDQ adult Hodgkin lymphoma treatment. [Bethesda, MD, National Cancer Institute. Updated 08/15/2018; Available from:] https://www.cancer.gov/types/lymphoma/hp/adulthodgkin-treatment-pdq. 24. Freedman AS, Friedberg JW. Treatment of Burkitt leukemia/lymphoma, UpToDate. Wolters Kluwer; 2018 [Accessed 11/01/2018]. 25. Rajkumar SV, et al. Haematological cancer: redefining myeloma. Nat Rev Clin Oncol. 2012;9(9):494–496. 26. Thrombocytopenia. [Bethesda MD; National Institutes of Health, U.S. Department of Health and Human Services; Available from:] http://www.nhlbi.nih.gov/health/dci/Diseases/thcp/thcp_all.html 2008. 27. Bennett CM, et al. Targeted ITP strategies: do they elucidate the biology of ITP and related disorders? Pediatr Blood Cancer. 2006;47(Suppl 5):706–709. 28. Al-Nouri ZL, et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125(4):616–618. 29. Scully M, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746–1753. 30. National Institutes of Health (NIH). Thrombocytopenia & thrombocytosis. [Bethesda MD; National Institutes of Health, U.S. Department of Health and Human Services; Available from:] http://www.nhlbi.nih.gov/health/dci/Diseases/thrm/thrm_all.html 2008. 31. Harrison C, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798. 32. Passamonti F, et al. A prognostic model to predict survival in 867 World Health Organization-defined essential 1303

thrombocythemia at diagnosis: as study by the International Working Group on Myelofibrosis Research and Treatment. Blood. 2012;120(6):1197–1201. 33. Wolanskyj AP, et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006;81(2):159–166. 34. Tefferi A, et al. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009;115(17):3842–3847. 35. Barbui T, et al. Front-line therapy in polycythemia vera and essential thrombocythemia. Blood Rev. 2012;26(5):205–211. 36. Lisman T, et al. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol. 2010;53(2):362– 371. 37. Nakashima MO, Rogers HJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res. 2014;49(2):85–94. 38. Bruce A, Massicotte MP. Thrombophilia screening: whom to test. Blood. 2012;120(7):1353–1355.

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Alterations of Hematologic Function in Children Lauri A. Linder, Kathryn L. McCance

CHAPTER OUTLINE Disorders of Erythrocytes, 548 Acquired Disorders, 548 Inherited Disorders, 551 Disorders of Coagulation and Platelets, 557 Inherited Hemorrhagic Disease, 557 Antibody-Mediated Hemorrhagic Disease, 557 Neoplastic Disorders, 558 Leukemia, 558 Lymphomas, 559

This chapter will include conditions in children that affect red blood cells, the coagulation process and platelets, as well as disorders involving white blood cells. Discussions of both acquired conditions and inherited conditions also are presented.

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Disorders of Erythrocytes Anemia is the most common blood disorder in children. As do adult anemias, anemias occurring in children result from inadequate erythropoiesis or early destruction of erythrocytes. Iron deficiency is the most common cause of inadequate erythropoiesis. Iron deficiency can result from insufficient dietary intake or chronic loss of iron caused by bleeding. The hemolytic anemias of childhood are either inherited or acquired. They may be divided into disorders that result from destruction caused by (1) intrinsic abnormalities of the erythrocytes and (2) damaging factors external to the erythrocytes. The most dramatic form of acquired congenital hemolytic anemia is hemolytic disease of the fetus and newborn (HDFN), also termed erythroblastosis fetalis. HDFN results when maternal blood and fetal blood are incompatible, causing the mother's immune system to produce antibodies against fetal erythrocytes. Intracellular defects in red blood cells include enzyme deficiencies, the most common of which is glucose-6-phosphate dehydrogenase (G6PD) deficiency, and defects of hemoglobin synthesis, which manifest as sickle cell disease or thalassemia, depending on which component of hemoglobin is defective. These and other causes of childhood anemia are listed in Table 24.1. TABLE 24.1 Anemias of Childhood Examples of Anemic Condition

Cause Blood Loss Trauma Gastrointestinal lesion Parasitic infestation Hemorrhagic disease Decreased Red Cell Production or Hemoglobin Synthesis Decreased stem cell population in marrow (congenital or acquired pure red cell aplasia)

Iron deficiency anemia

Normocyticnormochromic anemia Decreased erythropoiesis despite normal stem cell population in marrow (infection, inflammation, Normocyticcancer, chronic renal disease, congenital dyserythropoiesis) normochromic anemia Deficiency of a Factor or Nutrient Needed for Erythropoiesis Cobalamin (vitamin B12), folate Megaloblastic anemia Iron Microcytichypochromic anemia Increased or Premature Hemolysis Alloimmune disease (maternal-fetal Rh, ABO, or minor blood group incompatibility) Autoimmune hemolytic anemia Autoimmune disease (idiopathic autoimmune hemolytic anemia, symptomatic systemic lupus Autoimmune erythematosus, lymphoma, drug-induced autoimmune processes) hemolytic anemia Inherited defects of plasma membrane structure (spherocytosis, elliptocytosis, stomatocytosis) or Hemolytic anemia cellular size or both (pyknocytosis) Infection (bacterial sepsis, congenital syphilis, malaria, cytomegalovirus infection, rubella, Hemolytic anemia toxoplasmosis, disseminated herpes) Intrinsic and inherited enzymatic defects (deficiencies) of G6PD, pyruvate kinase, 5′-nucleotidase, Hemolytic anemia glucose phosphate isomerase Inherited Defects of Hemoglobin Synthesis

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Structurally abnormal globins Deficient globin synthesis Other Anemias Disseminated intravascular coagulation (see Chapter 23) Galactosemia Prolonged or recurrent respiratory or metabolic acidosis Blood vessel disorders (cavernous hemangiomas, large vessel thrombus, renal artery stenosis, severe coarctation of aorta)

Sickle cell anemia Thalassemia Hemolytic anemia Hemolytic anemia Hemolytic anemia Hemolytic anemia

ABO; type A, type B, type O blood; G6PD; glucose-6-phosphate dehydrogenase

Acquired Disorders Iron Deficiency Anemia Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide, with the highest incidence occurring between 6 months and 2 years of age. Its prevalence in the United States is greatest among toddlers, adolescent girls, and women of childbearing age. Iron is critical to the developing child, especially for normal brain development. Without it the damage from the periods of IDA is irreversible. The clinical manifestations of IDA are mostly related to inadequate hemoglobin synthesis. IDA can result from (1) dietary lack of iron, (2) problems with iron absorption, (3) blood loss, and (4) increased requirement for iron. During the first few years of life, IDA most often results from inadequate iron intake. During childhood and adolescence, blood loss is the most common cause of IDA. Dietary lack of iron is not common in developed countries, where iron is readily absorbed from heme found in meat. In developing countries, food may be less available. Although iron is found in plants, it is a more poorly absorbed form.1 Infants are at increased risk for IDA because milk has only very small amounts of iron. The bioavailability of iron from breast milk is higher than that from cow's milk. Impaired absorption is found in chronic diarrhea, fat malabsorption, and sprue (see Did You Know? A Significant Number of Children Develop and Suffer from Severe Iron Deficiency Anemia).

Did You Know? A Significant Number of Children Develop and Suffer From Severe Iron Deficiency Anemia A recent study in the United States found that children aged 36 months to 15 years are particularly vulnerable to iron deficiency anemia (IDA), especially those consuming excessive quantities of whole cow's milk. The prevalence of IDA in infancy has not changed in the past four decades and remains about 7%. Several children who were not anemic at 12 months of age went on to develop IDA as their iron stores became depleted. These children had typical signs of anemia, although their parents were not aware of the abnormalities. Chronic severe IDA in the first years of life increases the risk of irreversible cognition problems, as well as affective and motor development. The American Academy of Pediatrics (AAP) recommends screening for IDA with hemoglobin concentration and clinical assessment at about 1 year of age, and the Centers for Disease Control and

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Prevention (CDC) recommends that all children aged 2 through 5 years be assessed annually for risk factors for IDA and screened appropriately. IDA is a preventable disease. Data from Paoletti G et al: Pediatrics 53(4):1352-1358, 2014. Blood loss may not always be obvious; for example, blood loss caused by a gastrointestinal lesion, parasitic infestation, or hemorrhagic disease can be occult (hidden) and result in chronic IDA. Chronic parasitic infections are an important risk factor for IDA among children in developing countries. Treating these parasitic infections results in improved appetite and growth, as well as reduction of anemia. Infants and young children who consume excessive amounts of cow's milk also may develop IDA as a result of chronic intestinal blood loss. A heat-labile protein in cow's milk may induce inflammation that damages the intestinal mucosa causing diffuse, chronic microhemorrhage. Cellular components of both innate and adaptive immunity may play significant roles in the development of cow's milk allergy. The association between IDA and lead poisoning is controversial. Newer areas of investigation include iron deficiency in overweight children and the association of Helicobacter pylori infection with IDA. Pathophysiology No matter the cause, a deficiency of iron produces a hypochromic-microcytic anemia. In the early stages, however, the body may respond by increasing red blood cell activity in the bone marrow, which may temporarily prevent the development of anemia. As the body's iron stores are depleted, anemia develops. Low serum levels of ferritin and transferrin saturation lead to lowered hemoglobin and hematocrit levels. Clinical Manifestations The symptoms of mild anemia—listlessness and fatigue—may go unnoticed in infants and young children, who are unable to describe these symptoms. Clinical indicators of anemia also are nonspecific, such as general irritability, decreased activity tolerance, weakness, and lack of interest in play, and may be attributed to other causes. As a result, parents may not note persistent changes in the child's behavior until moderate anemia has developed. Other clinical manifestations, such as pallor, anorexia, tachycardia, and systolic murmurs, are often not present until hemoglobin levels fall below 5 g/dl. Other symptoms and signs of chronic IDA include splenomegaly, widened skull sutures, decreased physical growth, developmental delays, pica (a behavior in which nonfood substances, such as clay, are eaten), and altered neurologic and intellectual functions, especially those involving attention span, alertness, and learning ability. Evaluation and Treatment The diagnosis of IDA is confirmed by laboratory tests. These tests include hemoglobin, hematocrit, serum iron, and ferritin levels and determination of the total iron binding capacity. Obtaining a thorough history of the child's present illness and dietary history and performing a complete physical examination also are essential to the evaluation and subsequent clinical management of IDA. Treatment of IDA is similar in children and adults (see Chapter 23). Oral administration of a simple ferrous salt is usually sufficient. Taking iron supplements with a vitamin C source helps promote absorption.2 If liquid iron

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supplements are used, they should be given with a straw or a dropper placed back on the tongue to prevent staining the teeth. Dietary modification, including increasing intake of iron-rich food sources, is required to prevent recurrences of iron deficiency anemia. The intake of cow's milk should be restricted to the recommended daily allowance for age.

Hemolytic Disease of the Fetus and Newborn The most common cause of hemolytic anemia in newborns is alloimmune disease. Hemolytic disease of the fetus and newborn (HDFN) (erythroblastosis fetalis) can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. Most cases are caused by ABO incompatibility, which occurs if the mother and fetus have different ABO blood types. About 1 in 3 cases of HDFN is caused by Rh incompatibility, which occurs when the fetus is Rh-positive and the mother is Rh-negative. Some minor blood antigens also may be involved (see Chapter 8). ABO incompatibility occurs in about 20% to 25% of all pregnancies. Only 1 in 10 of these cases results in HDFN. Rh incompatibility occurs in less than 10% of pregnancies. It rarely causes HDFN in the first incompatible fetus. During this first pregnancy, erythrocytes from the fetus cause the mother's immune system to produce antibodies. These antibodies can affect fetuses in subsequent incompatible pregnancies. Even after five or more pregnancies, however, only 5% of women have babies with hemolytic disease. Pathophysiology Three conditions need to be met for HDFN to occur: 1. the mother's blood contains preformed antibodies against fetal erythrocytes or produces them when exposed to fetal erythrocytes, 2. sufficient amounts of antibody (usually immunoglobulin G [IgG] class) cross the placenta and enter fetal blood, and 3. IgG binds with sufficient numbers of fetal erythrocytes to cause widespread antibody-mediated hemolysis or splenic removal (antibody-mediated cellular destruction is described in Chapter 8). In most cases of HDFN, the mother has blood type O and the fetus has blood type A or B. Maternal antibodies also may be formed against type B erythrocytes if the mother is type A or against type A erythrocytes if the mother is type B. ABO incompatibility can cause HDFN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy. This occurs because the blood of most adults already contains anti-A or anti-B antibodies. These antibodies are produced on exposure to certain foods or infection by gram-negative bacteria. As a result, IgG against type A or B erythrocytes is usually already present in maternal blood and can enter the fetal circulation during the first incompatible pregnancy. Anti-O antibodies do not exist because type O erythrocytes are not antigenic. Anti-Rh antibodies, on the other hand, form only in response to the presence of Rhpositive erythrocytes from the fetus in the blood of an Rh-negative mother. This exposure typically occurs when fetal blood is mixed with the mother's blood at the time of delivery. Exposure may also occur through transfused blood, and, rarely, previous sensitization of the mother by her own mother's incompatible blood (Fig. 24.1).

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FIGURE 24.1 Hemolytic Disease of the Fetus and Newborn (HDFN). A, Before or during delivery, Rhpositive erythrocytes from the fetus enter the blood of an Rh-negative woman through a tear in the placenta. B, The mother is sensitized to the Rh antigen and produces Rh antibodies. Because this usually happens after delivery, there is no effect on the fetus in the first pregnancy. C, During a subsequent pregnancy with an Rh-positive fetus, Rh-positive erythrocytes cross the placenta, enter the maternal circulation, and (D) stimulate the mother to produce antibodies against the Rh antigen. (Modified from Seeley RR et al: Anatomy and physiology, ed 3, St Louis, 1995, Mosby.)

The first Rh-incompatible pregnancy generally presents no difficulties for the fetus. This is because few fetal erythrocytes cross the placental barrier during the pregnancy. When the placenta detaches at birth, a large number of fetal erythrocytes often enter the mother's bloodstream. If the mother is Rh-negative and the fetus is Rh-positive, the mother produces anti-Rh antibodies. These anti-Rh antibodies persist in the mother's bloodstream for a long time. If the next offspring is Rh-positive, the mother's anti-Rh antibodies can enter the bloodstream of the fetus and destroy the erythrocytes. Antibody-coated fetal erythrocytes are usually destroyed in the spleen. As hemolysis proceeds, the fetus becomes anemic. Erythropoiesis accelerates, particularly in the liver and spleen. Immature nucleated cells (erythroblasts) are released into the bloodstream (hence the name erythroblastosis fetalis). The degree of anemia depends on several factors: (1) the length of time the antibody has been in the fetal circulation, (2) the concentration of the antibody, and (3) the ability of the fetus to compensate for increased hemolysis. During the pregnancy, unconjugated (indirect) bilirubin, which forms during the breakdown of hemoglobin, is transported across the placental barrier into the maternal circulation and is

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excreted by the mother. Hyperbilirubinemia occurs in the neonate after birth because bilirubin is no longer excreted through the placenta. HDFN is typically more severe in Rh incompatibility than in ABO incompatibility. Rh incompatibility is more likely to result in severe or even life-threatening anemia, death in utero, or damage to the central nervous system. Severe anemia alone can cause death as a result of cardiovascular complications. Extensive hemolysis can result in increased levels of unconjugated bilirubin in the neonate's circulation. If bilirubin levels exceed the liver's ability to conjugate and excrete bilirubin, it can be deposited in the brain, a condition known as kernicterus, causing cellular damage and, eventually, death if the neonate does not receive exchange transfusions. Fetuses that do not survive anemia in utero are usually stillborn, with gross edema in the entire body, a condition called hydrops fetalis. Death can occur as early as 17 weeks’ gestation and results in spontaneous abortion. Clinical Manifestations Neonates with mild HDFN may appear healthy or slightly pale, with slight enlargement of the liver or spleen. Pronounced pallor, splenomegaly, and hepatomegaly indicate severe anemia, which predisposes the neonate to cardiovascular failure and shock. Lifethreatening symptoms as a consequence of Rh incompatibility, however, are rare, largely because of the routine use of Rh immunoglobulin. Because the maternal antibodies remain in the neonate's circulatory system after birth, erythrocyte destruction can continue. Without exchange transfusions, in which the neonate receives Rh-negative red blood cells, severe hyperbilirubinemia and icterus neonatorum (neonatal jaundice) can develop shortly after birth. If kernicterus develops, it can cause cerebral damage, including intellectual disabilities, cerebral palsy, or high-frequency deafness. It may even cause death (icterus gravis neonatorum). Evaluation and Treatment Fetuses and neonates with ABO incompatibility typically do not require additional monitoring or treatment. Fetuses and infants at risk for HDFN as a consequence of Rh incompatibility may require additional monitoring and treatment. Routine evaluation of fetuses at risk for HDFN includes the Coombs test. The indirect Coombs test measures antibody in the mother's circulation and indicates whether the fetus is at risk for HDFN. The direct Coombs test measures antibody already bound to the surfaces of fetal erythrocytes. It is used primarily to confirm the diagnosis of antibody-mediated HDFN. If a prior history of fetal hemolytic disease is present, additional diagnostic tests are done to determine risk with the current pregnancy. These include maternal antibody titers, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment. Prevention is the key to managing HDFN that results from Rh incompatibility. Immunoprophylaxis through the use of Rh immune globulin (RhoGAM), a preparation of antibody against Rh antigen D (anti-D Ig), prevents an Rh-negative woman from producing antibodies. If an Rh-negative woman is given Rh immune globulin within 72 hours of exposure to Rh-positive erythrocytes, she will not produce antibody against the D antigen. As a result, the next Rh-positive baby she conceives will be protected. Updated United States and United Kingdom guidelines also state that if anti-D Ig is not given within 72 hours, every effort should be made to administer it within 10 days.3,4

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Inherited Disorders Sickle Cell Disease Sickle cell disease is a group of autosomal recessive disorders characterized by the production of hemoglobin S (Hb S; sickle hemoglobin) within the erythrocytes. Hb S is formed as a result of a genetic mutation in which one amino acid (valine) replaces another (glutamic acid) (Fig. 24.2). Under conditions of decreased oxygen tension and dehydration, Hb S stretches and elongates, causing the erythrocyte to assume a characteristic sickle shape. These sickled cells also die prematurely, resulting in hemolytic anemia (Fig. 24.3).

FIGURE 24.2 Sickle Cell Hemoglobin. A, Sickle cell hemoglobin is produced by a recessive allele of the gene encoding the β-chain of the protein hemoglobin. It represents a single amino acid change—from glutamic acid to valine at the sixth position of the chain. In this model of a hemoglobin molecule, the

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position of the mutation can be seen near the end of the upper arm. B, Color-enhanced electron micrograph shows normal erythrocytes and sickled blood cell. C, Brief summary of the process of cell sickling. (A from Raven PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby; B copyright Dennis Kunkel Microscopy, Inc; C from Kierszenbaum A, Tres L: Histology and cell biology: an introduction to pathology, ed 3, St Louis, 2012, Mosby.)

FIGURE 24.3 Normal and Sickle-Shaped Blood Cells. Scanning electron micrograph of normal and sickle-shaped red blood cells. The irregularly shaped cells are the sickle cells; the circular cells are the normal blood cells. (From Raven PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby.)

The most prevalent types of sickle cell disease are sickle cell anemia, sickle cell– thalassemia disease, and sickle cell–Hb C disease (Table 24.2). (See Chapter 2 for a discussion of genetic inheritance of disease.) Sickle cell anemia, a homozygous form, is the most severe. It results when the individual inherits two copies of Hb S. Sickle cell– thalassemia and sickle cell–Hb C disease are compound heterozygous forms in which the child inherits Hb S from one parent and another type of abnormal hemoglobin from the other parent. Sickle cell trait occurs when the child inherits Hb S from one parent and normal hemoglobin (Hb A) from the other. This heterozygous carrier state rarely has clinical manifestations. All forms of sickle cell disease are lifelong conditions. TABLE 24.2 Inheritance of Sickle Cell Disease Hemoglobin Hemoglobin Inherited From Inherited From Second Parent First Parent Hb S (an abnormal Hb S hemoglobin) Hb S Hb S Hb S

Defective or insufficient α- or βchains of Hb A (alpha- or betathalassemia) Hb C or D (both abnormal hemoglobins) Normal hemoglobins (mostly Hb A)

Form of Sickle Cell Disease in Child Sickle cell anemia: homozygous inheritance in which child's hemoglobin is mostly Hb S, with remainder Hb F (fetal hemoglobin) Sickle cell–thalassemia disease (heterozygous inheritance of Hb S and alpha- or beta-thalassemia) Sickle cell–hemoglobin C (or D) disease (heterozygous inheritance of hemoglobin S and either C or D) Sickle cell trait, carrier state (heterozygous inheritance of Hb S and normal hemoglobin)

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Sickle cell disease is most common among persons with ancestry from sub-Saharan Africa. Although less common, it also is present among individuals with ancestry from Mediterranean countries, the Arabian Peninsula, parts of India, and Spanish-speaking areas of South America. In the United States, sickle cell anemia is most common in black people, with a reported incidence of around 1 : 365 live births.5 In the general population, the risk of two black parents having a child with sickle cell anemia is 0.7%. Sickle cell–Hb C disease occurs in 1 in 800 births, and sickle cell–thalassemia is even less common (1 in 1700 births). Sickle cell trait occurs in 7% to 13% of African Americans. Its prevalence in African countries, such as Nigeria and the Democratic Republic of Congo, may be as high as 30%.6 The sickle cell trait may provide protection against lethal forms of malaria. This results in a genetic advantage for carriers who reside in regions of the world that are endemic for malaria, such as sub-Saharan Africa and some Mediterranean countries. Pathophysiology Hb S is soluble and usually causes no problem when it is properly oxygenated. When oxygen tension decreases, the abnormal β-globin chain of Hb S polymerizes, forming abnormal fluid polymers. As these polymers realign, they cause the red cell to form into the sickle shape. Decreased oxygenation (hypoxemia) and pH, as well as dehydration, trigger the sickling process. Acute illness, stress, temperature changes, and living at altitude can cause decreased oxygen tension, leading to sickling. Sickled erythrocytes tend to plug the blood vessels. This increases the viscosity of the blood, which slows circulation, and causes vascular occlusion, pain, and organ infarction. The increased blood viscosity also increases the time that erythrocytes are exposed to less oxygenation, which promotes further sickling. Sickled cells undergo hemolysis in the spleen or become sequestered there, causing blood pooling and infarction of splenic vessels. The anemia that follows these sickling episodes triggers erythropoiesis in the marrow and, in extreme cases, in the liver (Fig. 24.4).

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FIGURE 24.4

Sickling of Erythrocytes. O2, Oxygen; Po2, partial pressure of oxygen

Sickling usually is not permanent. Most sickled erythrocytes regain a normal shape after reoxygenation and rehydration. Irreversible sickling is caused by irreversible plasma membrane damage caused by sickling. In persons with sickle cell anemia, in which the erythrocytes contain a high percentage of Hb S (75% to 95%), up to 30% of the erythrocytes can become irreversibly sickled. Clinical Manifestations The clinical manifestations of sickle cell disease can vary. Some individuals have mild symptoms; others suffer from repeated vasoocclusive crises. The general manifestations of hemolytic anemia from the sickling process include pallor, fatigue, jaundice, and irritability. Extensive sickling can precipitate four types of acute crises: 1. Vasoocclusive crisis (thrombotic crisis). This crisis type begins with sickling in the microcirculation. As blood flow is obstructed by sickled cells, vasospasm occurs and a logjam effect blocks all blood flow through the vessel. Unless the process is reversed, thrombosis and infarction of local tissue occur. Vasoocclusive crisis is extremely painful and may last for days or even weeks, with an average duration of 4 to 6 days. The frequency of this type of crisis is variable and unpredictable. Vasoocclusion in vessels to the brain can result in stroke. Chronic vasoocclusion in vessels to the kidneys results in end-stage renal disease. 2. Sequestration crisis. This type of crisis is typically seen only in children less than 5 years of age. Large amounts of blood become acutely pooled in the liver and spleen. Because the spleen can hold as much as one-fifth of the body's blood

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supply at one time, the risk of mortality is high if the condition is not recognized and managed appropriately. Approximately half of children who experience sequestration crises will have recurrent episodes. 3. Aplastic crisis. Profound anemia is caused by lowered erythropoiesis despite an increased need for new erythrocytes. In sickle cell anemia, erythrocyte survival is only 10 to 20 days. Normally the bone marrow is able to compensate to replace the cells lost through premature hemolysis. When this compensatory response is compromised, often after a viral infection, aplastic crisis develops. This type of crisis typically lasts 7 to 10 days. 4. Hyperhemolytic crisis. Although unusual, this type of crisis may occur in association with certain drugs or infections. It has also been reported as an acute or chronic reaction following a blood transfusion. The clinical manifestations of sickle cell disease usually do not appear until the infant is at least 6 months old. At this time, postnatal concentrations of Hb F decrease, causing concentrations of Hb S to rise (Fig. 24.5). Infection is the most common cause of death related to sickle cell disease. Sepsis and meningitis develop in as many as 10% of children with sickle cell anemia during the first 5 years of life. Advances in identification of sickle cell disease and supportive care have improved survival of children with sickle cell disease.

FIGURE 24.5 Differences between effects of normal (A) and sickled (B) red blood cells on blood circulation and selected consequences in a child. C, Tissue effects of

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sickle cell anemia. CVA, Cerebrovascular accident. (A and B adapted from Hockenberry MJ et al, editors: Wong's nursing care of infants and children, ed 10, St Louis, 2015, Mosby.)

Sickle cell–Hb C disease is usually milder than sickle cell anemia. The main clinical problems are related to vasoocclusive crises, which are thought to result from higher hematocrit values and viscosity. In older children, sickle cell retinopathy, renal necrosis, and aseptic necrosis of the femoral heads can occur along with obstructive crises. Sickle cell–thalassemia has the mildest clinical manifestations of all the sickle cell diseases. The normal hemoglobins, particularly Hb F, inhibit sickling. The erythrocytes tend to be small (microcytic) and to contain relatively little hemoglobin (hypochromic), making them less likely to occlude the microcirculation, even when in a sickled state. Evaluation and Treatment The parents’ hematologic history and clinical manifestations may suggest that a child has sickle cell disease, but hematologic tests are necessary for diagnosis. If the sickle solubility test confirms the presence of Hb S in peripheral blood, hemoglobin electrophoresis provides information about the amount of Hb S in erythrocytes. Prenatal diagnosis can be made after chorionic villus sampling as early as 8 to 10 weeks’ gestation or by amniotic fluid analysis at 15 weeks’ gestation (Fig. 24.6). Hemoglobinopathies, including sickle cell disease, are now included as part of routine newborn screening in all 50 states and the District of Columbia.

FIGURE 24.6 Prepregnancy Sickle Cell Test. This technique has potential for detection of other inherited diseases. 1, Fertilization produces several embryos. 2, The embryos are tested for the presence of the gene. 3, The embryos without the gene are implanted. 4, Amniocentesis confirms whether the fetus (or fetuses) has the sickle cell gene. 5, Woman has a normal child.

Sickle cell trait typically does not affect life expectancy or interfere with daily activities. On rare occasions, however, severe hypoxia caused by shock, vigorous exercising at high altitudes, flying at high altitudes in unpressurized aircraft, or undergoing anesthesia is associated with vasoocclusive episodes in persons with sickle cell trait. These cells form an ivy shape instead of a sickle shape. Advances in supportive care have led to decreased morbidity and mortality among children with sickle cell disease. Supportive care emphasizes preventing consequences of anemia and avoiding crises, including adequate hydration, infection prevention, and pain management. Genetic counseling and psychologic support are important for the child and

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family. A common treatment for sickle cell disease is hydroxyurea. Hydroxyurea inhibits deoxyribonucleic acid (DNA) synthesis, which causes an increase in Hb F concentration. It also provides an antiinflammatory effect by decreasing leukocyte production. These outcomes are thought to decrease crises. Transfusion therapy can decrease morbidity and mortality associated with sickle cell disease, particularly in those at increased risk for stroke.7 Despite these benefits, it can result in iron overload, which can cause liver damage and fibrosis, delayed physical and sexual development, and heart disease. Chelation therapy to remove excess iron is often required. Hematopoietic stem cell transplantation offers the only cure for sickle cell disease; however, it is not without important risks. Current research is seeking to reduce the toxicities associated with transplantation while optimizing long-term outcomes.

Thalassemias The alpha- and beta-thalassemias are autosomal recessive disorders that result in impaired synthesis of one of the two chains—α or β—of adult hemoglobin (Hb A). Beta-thalassemia is most prevalent among Greek, Italian, some Arab, and Sephardic Jewish people. Alphathalassemia is most common among Chinese, Vietnamese, Cambodian, and Laotian people. Both alpha- and beta-thalassemias are common among Black people. Beta-thalassemias are more common than alpha-thalassemias. Both types are further classified as major or minor. The classification is based on the number of genes that control α- or β-chain synthesis. It also is based on the combination of mutations and whether they are homozygous (thalassemia major) or heterozygous (thalassemia minor). The anemic manifestation of both alpha- and beta-thalassemia is microcytic-hypochromic hemolytic anemia. Pathophysiology The beta-thalassemias are caused by mutations that decrease the synthesis of β-globin chains, leading to anemia, tissue hypoxia, and red cell hemolysis. β-Globin chain production is depressed moderately in the heterozygous form, beta-thalassemia minor, and severely in the homozygous form, beta-thalassemia major (also called Cooley anemia). As a result, erythrocytes have a reduced amount of hemoglobin and free α-chains accumulate (Fig. 24.7). Free α-chains are unstable and easily precipitate in the cell. Most erythroblasts that contain precipitates are destroyed by mononuclear phagocytes in the marrow. Destruction results in ineffective erythropoiesis and anemia. Some of the precipitate-carrying cells mature and enter the bloodstream. These cells are destroyed prematurely in the spleen, resulting in mild hemolytic anemia.

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FIGURE 24.7 Pathogenesis of Beta-Thalassemia Major. The aggregates of unpaired α-globin chains are a hallmark of the disease. Blood transfusions can diminish the anemia, but they add to the systemic iron overload. (From Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

There are four forms of alpha-thalassemia: (1) alpha trait (the heterozygous carrier state), in which a single α-chain–forming gene is defective; (2) alpha-thalassemia minor, in which two genes are defective; (3) hemoglobin H disease, in which three genes are defective; and (4) alpha-thalassemia major, in which all four α-forming genes are defective. Alphathalassemia major is fatal, often in utero, because α-chains are not produced and oxygen cannot be released to the tissues. Clinical Manifestations Beta-thalassemia minor causes mild to moderate microcytic-hypochromic anemia. The degree of reticulocytosis depends on the severity of the anemia and results in skeletal changes. Hemolysis of immature (and therefore fragile) erythrocytes may cause a slight elevation in serum iron and indirect bilirubin levels. Persons with beta-thalassemia minor may experience mild splenomegaly, bronze coloring of the skin, and hyperplasia of the bone marrow, but they are less likely to experience life-threatening complications. Persons with beta-thalassemia major may become quite ill and show impaired physical growth and development. The severe anemia resulting from this condition can cause a

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significant cardiovascular burden with high-output congestive heart failure. In the past, death resulted from cardiac failure, often by age 20. Today, blood transfusions can increase the life span by one to two decades. Death is usually caused by consequences of hemochromatosis resulting from chronic transfusions. Liver enlargement occurs as a result of progressive hemosiderosis, and enlargement of the spleen is caused by extramedullary hemopoiesis and increased destruction of red blood cells. Skeletal changes begin in infancy and include spinal impairment that retards linear growth and subsequent upper and lower limb-length discrepancy. Deformity of the facial bones in response to hyperplastic marrow results in a characteristic chipmunk-like facial appearance. Persons who inherit the mildest form of alpha-thalassemia (the alpha trait) usually are symptom free or have mild microcytosis. Alpha-thalassemia minor has clinical manifestations that are virtually identical to those of beta-thalassemia minor: mild microcytic-hypochromic reticulocytosis, bone marrow hyperplasia, increased serum iron concentrations, and moderate splenomegaly. Signs and symptoms of alpha-thalassemia minor are similar to those of beta-thalassemia minor but milder. Moderate microcytic-hypochromic anemia, enlargement of the liver and spleen, and bone marrow hyperplasia are evident. Alpha-thalassemia major causes hydrops fetalis, whereby the developing fetus suffers from severe tissue anoxia and may develop fulminant intrauterine congestive heart failure. Signs of fetal distress became evident by the third trimester of pregnancy. In the past, severe tissue anoxia led to death in utero; now many such infants are saved by intrauterine transfusions. Evaluation and Treatment Evaluation of thalassemia is based on the familial disease history, clinical manifestations, and blood tests. Diagnostic tests include peripheral blood smears that show microcytosis and hemoglobin electrophoresis that demonstrates diminished amounts of α- or β-chains. Prenatal diagnosis is sometimes done, and families are referred for genetic counseling. Identification of thalassemia is now included as part of routine newborn screening for hemoglobinopathies in all 50 states and the District of Columbia. Molecular genetic testing of at-risk siblings should be offered to allow for early diagnosis and appropriate treatment. Treatment is largely supportive and involves a regular transfusion program and chelation therapy to reduce transfusion iron overload. Milder forms of thalassemia rarely require transfusion. The only available definitive cure for thalassemia major is allogeneic hematopoietic stem cell transplantation (HSCT) from a matched family or unrelated donor or cord blood transplantation from a related donor.8 Optimal clinical management may decrease the need for splenectomy.

Quick Check 24.1 1. Why is Rh incompatibility rare today? 2. Why do clinical manifestations of sickle cell disease not appear until the infant is at least 6 months old? 3. Why do children with thalassemia major develop cardiovascular complications?

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Disorders of Coagulation and Platelets Inherited Hemorrhagic Disease Hemophilias The hemophilias are a group of inherited bleeding disorders resulting from mutations in coagulation factors. The focus of this section will be hemophilia A and hemophilia B, both of which are X-linked recessive conditions. A third type of hemophilia, hemophilia C, is an autosomal recessive condition that results from a deficiency of factor XI. Table 24.3 lists the coagulation factors and deficiencies associated with clinical bleeding. TABLE 24.3 The Coagulation Factors and Associated Disorders Clotting Factors I II V VII VIII IX X XI XII XIII

Synonym

Disorder

Fibrinogen

Congenital deficiency (afibrinogenemia) and dysfunction (dysfibrinogenemia) Congenital deficiency or dysfunction Congenital deficiency (parahemophilia) Congenital deficiency Congenital deficiency is hemophilia A (classic hemophilia) Congenital deficiency is hemophilia B Congenital deficiency Congenital deficiency, sometimes referred to as hemophilia C

Prothrombin Labile factor or proaccelerin Stable factor or proconvertin AHF Christmas factor Stuart-Prower factor Plasma thromboplastin antecedent Hageman factor Fibrin-stabilizing factor

Congenital deficiency is not associated with clinical symptoms Congenital deficiency

AHF; antihemophilic factor.

Hemophilia A results from a mutation in the F8 gene, which codes for factor VIII, an essential cofactor for factor IX in the coagulation cascade. It is the most common hereditary disease associated with life-threatening bleeding. Hemophilia B results from a mutation in the F9 gene, which codes for factor IX. Because both factors VIII and IX function together to activate factor X, hemophilia A and B are clinically indistinguishable. The incidence of hemophilia A is approximately 1 in 5000 male births. Hemophilia B is five times less common, with an incidence of approximately 1 in 30,000 male births. The worldwide prevalence of hemophilia it is estimated to be at more than 400,000 people.9 All racial groups are equally affected. Pathophysiology As X-linked recessive conditions, hemophilia A and B are most frequently inherited from a mother who is heterozygous for a mutation in either the F8 or F9 gene. Approximately 30% of cases, however, result from a new mutation. This new mutation can occur in either a carrier female or in an affected male. More than 1300 mutations have been associated with factor VIII and IX deficiency. Affected individuals within the same family will have the same mutation; however, the mutation causing hemophilia may be different across families.10

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The F8 and F9 genes are located on the long arm of the X chromosome. A mutation in either of these genes typically results in either deficient or abnormal function of the corresponding clotting factor. Because males have only one copy of the X chromosome, the mutation results in the clinical manifestations of hemophilia. In females, the second copy of the X chromosome usually produces a sufficient quantity of normal functioning clotting factor. Females who are heterozygous carriers typically do not experience excessive bleeding. Because X-inactivation, or lyonization (see Chapter 2), is a random process, phenotypes of women who are heterozygous carriers can vary. Fifty percent of female carriers have lower than normal clotting factor levels. Although very uncommon, it is plausible for a female to be homozygous for mutations in the F8 or F9 gene and therefore have hemophilia.10 Clinical Manifestations The clinical manifestations and severity of hemophilia depend largely on the level of factor VIII and IX activity. Joint bleeding is the most characteristic type of bleeding in hemophilia. The joints most often affected are the knees, ankles, and elbows. Bleeding into muscles, usually from trauma, also can occur. Oral bleeding is common in the setting of dental surgery. Spontaneous painless hematuria is relatively common in hemophilia; it does not result in significant blood loss but requires evaluation. Hematuria accompanied by pain requires prompt evaluation and treatment. Intracranial bleeds, bleeding of internal organs, and bleeding into the tissues of the neck, chest, or abdomen are all life-threatening. Delayed or suboptimal treatment of these bleeds may lead to permanent brain injury, loss of organ function, or death. Evaluation and Treatment A positive family history may expedite a diagnosis of hemophilia. When a mother who is a known or suspected carrier is pregnant, prenatal genetic testing through chorionic villus sampling (CVS) or amniocentesis may reveal a diagnosis of hemophilia. In the absence of a positive family history, a personal bleed history, laboratory testing, family history, and physical assessment contribute to a thorough evaluation and accurate diagnosis. In general, those with hemophilia A or B will have a prolonged partial thromboplastin time (PTT) and the prothrombin time (PT) will be normal. Measuring factor VIII and factor IX levels also is necessary for diagnosis. The majority of children with hemophilia A can be treated with recombinant factor VIII. The majority of children with hemophilia B can be treated with recombinant factor IX. Recombinant factor is reconstituted in a small volume of diluent, administered by slow intravenous push, and raises the factor level almost immediately. Emerging therapies for hemophilia include the use of PEGylated factor. Adding a polyethylene glycol (PEG) molecule results in an extended half-life of the involved factor.11

Antibody-Mediated Hemorrhagic Disease Antibody-mediated hemorrhagic diseases are caused by the immune response. Antibodymediated destruction of platelets or antibody-mediated inflammatory reactions to allergens damage blood vessels and cause seepage into tissues. The thrombocytopenic purpuras may be intrinsic or idiopathic. They also may be transient phenomena transmitted from mother to fetus. The inflammatory, or “allergic,” purpuras, although rare, occur in response to

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allergens in the blood. All of these disorders first appear during infancy or childhood.

Primary Immune Thrombocytopenia Primary immune thrombocytopenia (ITP) (previously referred to as idiopathic thrombocytopenic purpura) is the most common disorder of platelet consumption. Autoantibodies bind to the plasma membranes of platelets, causing platelet sequestration and destruction by mononuclear phagocytes in the spleen and other lymphoid tissues at a rate that exceeds the ability of the bone marrow to produce them. The destruction of platelets is triggered by drugs, infections, lymphomas, or an unknown cause. Pathophysiology The autoantibodies that produce the destruction are often of the IgG class and are usually against the platelet membrane glycoproteins (IIb-IIIa or Ib-IX). Approximately 70% of cases of ITP are preceded by a viral illness (e.g., cytomegalovirus [CMV], Epstein-Barr virus [EBV], parvovirus, or respiratory tract infection) prior to the eruption of petechiae or purpura by 1 to 3 weeks. Clinical Manifestations Bruising and a generalized petechial rash often occur about 1 to 3 weeks after a viral illness. Petechiae can develop into ecchymoses. Asymmetric bruising is typical and is found most often on the legs and trunk. Hemorrhagic bullae of the gums, lips, and other mucous membranes may be prominent. Epistaxis (nose bleeding) may be severe and difficult to control. Except for signs of bleeding, the child appears well. The principal changes are found in the spleen, bone marrow, and blood. The acute phase lasts 1 to 2 weeks, but thrombocytopenia often persists. Intracranial hemorrhage is the most serious complication of ITP, however, the incidence is less than 1%. In some cases, the onset is more gradual, and clinical manifestations consist of moderate bruising and a few petechiae. Evaluation and Treatment Laboratory examination reveals an isolated low platelet count. The few platelets observed on a smear are large, reflecting increased bone marrow production. The Ivy bleeding time is prolonged. Bone marrow aspiration is not recommended for children with typical features of ITP. The primary treatment for children with ITP is observation regardless of the platelet count. When bleeding is present, primary treatment is with an infusion of intravenous immune globulin (IVIG) or a short course of corticosteroids. Even without treatment, the prognosis for children with ITP is excellent: 75% recover completely within 3 months. After the initial acute phase, spontaneous clinical manifestations subside. By 6 months after onset, 80% to 90% of affected children have regained normal platelet counts. ITP that persists longer than 12 months in children is considered chronic, and immunosuppressive therapies are used.

Quick Check 24.2 1. List the major disorders of coagulation and platelets found in children.

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2. What is the mechanism of inheritance associated with hemophilia and how does it contribute to the clinical manifestations associated with factor VIII or IX deficiency in males and females? 3. What are the most common sites of bleeding in individuals with hemophilia? 4. What is the primary abnormality in primary immune thrombocytopenia (ITP)?

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Neoplastic Disorders Leukemia Leukemia is cancer of the blood-forming tissues, such as the bone marrow, that most often produces abnormal white blood cells called leukemic cells. Once in the blood, leukemic cells can spread to other organs, such as the lymph nodes, spleen, and brain. Leukemia is the most common malignancy in children and teens. The four most common types of leukemia are (1) acute lymphoblastic leukemia (ALL), (2) acute myeloid leukemia (AML), (3) chronic lymphocytic leukemia (CLL), and (4) chronic myeloid leukemia (CML)12 (see Chapter 23). About 75% of leukemias among children and teens are ALL; the remaining cases are classified as AML and related neoplasms. Chronic leukemias are rare in children and account for fewer than 5% of cases. ALL is most common in early childhood, peaking between 2 and 4 years of age. AML is slightly more common during the first 2 years of life and during the teenage years and occurs about equally among boys and girls of all races. ALL is more common in boys than girls and among Hispanic and white children than among black and Asian American children. The cause of most childhood cancer, including leukemia, is unknown. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations that predispose the child to cancer development can occur during fetal development. Genetic conditions associated with leukemia include Down syndrome, neurofibromatosis, ShwachmanDiamond syndrome, Bloom syndrome, and ataxia-telangiectasia. Epigenetic modifications, including DNA methylation, have been proposed as mediating events between environmental exposures and subsequent disease development.13 Many studies have shown that exposure to ionizing radiation (prenatal exposure to xrays and postnatal exposure to high doses) can lead to the development of childhood leukemia and possibly other cancers.14 There is recent concern for performing computed tomography (CT) scans in children. The increased use of these scans combined with wide variability in radiation doses has resulted in many children receiving a high dose of radiation.15 Studies of other possible environmental risk factors, including parental exposure to cancer-causing chemicals, prenatal exposure to pesticides, childhood exposure to common infectious agents, and living near a nuclear power plant, have so far produced inconsistent results. Higher risks of cancer have not been seen in children of individuals treated for sporadic cancer (cancer not caused by an inherited mutation).16,17 Pathophysiology ALL is composed of immature B (pre-B) or T (pre-T) cells called lymphoblasts. As leukemia develops, the bone marrow becomes dense with lymphoblasts that replace the normal marrow and disrupt normal function. Many of the chromosomal abnormalities documented in ALL cause dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development.18 The mutations can include both gain of function and loss of function that are required for normal development. AML is caused by acquired oncogenic mutations that impair differentiation, resulting in

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the accumulation of immature myeloid blasts in the marrow and other organs. Epigenetic alterations are frequent in AML and have a central role. The bone marrow crowding by blast cells produces marrow failure and complications, including anemia, thrombocytopenia, and neutropenia. AML is very heterogeneous because myeloid cell differentiation is very complex. Leukemia, ALL or AML, is typically distinguished from lymphoma by the presence of greater than 20% leukemic blasts in the bone marrow. Clinical Manifestations The onset of leukemia may be abrupt or insidious. Children with leukemia may present with symptoms only 1 week before diagnosis. Regardless of how leukemia develops, the most common symptoms reflect consequences of bone marrow failure. These include decreased levels of red blood cells and platelets, as well as changes in white blood cells. Pallor, fatigue, petechiae, purpura, bleeding, and fever generally are present. Approximately 45% of children present with a hemoglobin level below 7 g/dl. Epistaxis often occurs in children with severe thrombocytopenia. Fever can be present as a result of (1) infection associated with the decrease in functional neutrophils and (2) hypermetabolism associated with the ongoing rapid growth and destruction of leukemic cells. White blood cell counts greater than 200,000/mm3 can cause leukostasis, an intravascular clumping of cells resulting in infarction and hemorrhage, usually in the brain and lung. Renal failure as a result of hyperuricemia (high uric acid levels) can be associated with ALL, particularly at diagnosis or during the initial phase of treatment. Extramedullary invasion with leukemic cells can occur in nearly all body tissue. The central nervous system (CNS) is a common site of infiltration of extramedullary leukemia. Less than 10% of children with ALL, however, will have CNS involvement at diagnosis. The most common symptoms of CNS involvement relate to increased intracranial pressure, causing early morning headaches, nausea, vomiting, irritability, and lethargy. Gonadal involvement, with testicular infiltration, also may occur. Leukemic infiltration into bones and joints is common. Reports of bone or joint pain actually lead to the diagnosis of leukemia in some children. In most children, bone pain is characterized as migratory, vague, and without areas of swelling or inflammation. In some cases, however, joint pain is the primary symptom and some swelling is associated with the pain. Occasionally, these children are initially misdiagnosed as having rheumatoid arthritis. Other organs reported to be sites of leukemic invasion include the kidneys, heart, lungs, thymus, eyes, skin, and gastrointestinal tract. Evaluation and Treatment Leukemia is diagnosed through blood tests and examination of peripheral blood smears. A bone marrow aspiration is usually performed to further characterize the leukemia. The blast cell is the hallmark of acute leukemia (Fig. 24.8). Healthy children have less than 5% blast cells in the bone marrow and none in the peripheral blood. In ALL, the bone marrow often is replaced by 80% to 100% blast cells. Counts of normally developing red blood cells, granulocytes, and platelets are typically reduced. Occasionally, the marrow appears hypocellular, making the diagnosis difficult to differentiate from aplastic anemia. When this occurs, bone marrow biopsy or biopsy of extramedullary sites is necessary to confirm the diagnosis.

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FIGURE 24.8 Monoblasts From Acute Monoblastic Leukemia. Monoblasts in a marrow smear from an individual with acute monoblastic leukemia. The monoblasts are larger than myeloblasts and usually have abundant cytoplasm, often with delicate scattered azurophilic granules (an element that stains well with blue aniline dyes). (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)

Approximately 85% of children with ALL will become 5-year survivors of their illness. Chemotherapy, using a combination of medications, is the treatment of choice for acute leukemia. Radiation of the CNS is used only in selected cases. Identification of various risk groups among children with ALL has led to the development of different intensities of drug protocols. As a result, treatment can be targeted specifically for a particular risk group. For children who experience relapses of ALL, treatment with chimeric antigen receptor T cells (CAR-T cells) is showing promise.19,19a AML is more difficult to treat than ALL. Combination chemotherapy is the most common approach to treatment. Those children with unfavorable cytogenetic markers and those who experience a relapse of their disease will often undergo hematopoietic stem cell transplantation.20 CML accounts for less than 5% of childhood leukemias. Biologically targeted therapies, specifically tyrosine kinase inhibitors (TKIs), are becoming the mainstay of treatment, specifically for individuals whose disease has the BCR/ABL translocation21 (see Chapter 23). TKIs are administered orally, and several are now approved for use in children. Treatment requires continued adherence to the medication regimen, and the health impact of longterm TKI therapy is not yet known.21

Lymphomas Lymphoma (Hodgkin lymphoma [HL] and non-Hodgkin lymphoma [NHL]) develops from the proliferation of malignant lymphocytes in the lymphoid system (see Chapters 12 and 23). Lymphomas arise from discrete tissue masses. Lymphoid neoplasms involve some recognizable stage of lymphocyte B- or T-cell differentiation. Some lymphomas occasionally have leukemic presentations, and evolution to “leukemia” is not unusual during the progression of incurable “lymphomas.” The terms therefore merely reflect the usual tissue distribution. The World Health Organization (WHO) provides a classification scheme for lymphoma that was updated in 201622 (also see

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Chapter 23). NHL and HL constitute about 11% of all cases of childhood cancer. Approximately 1800 children younger than 20 years of age are diagnosed with lymphoma in the United States each year.23 NHL (including Burkitt lymphoma) occurs more often than Hodgkin lymphoma. Either group of diseases is rare before the age of 5 years, and the relative incidence increases throughout childhood. Boys are more likely to be diagnosed with lymphoma than are girls. Children with inherited or acquired immunodeficiency syndromes, such as Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Bloom syndrome, are at particular risk for developing NHL.

Non-Hodgkin Lymphoma Non-Hodgkin lymphomas (NHLs) are cancers of immune cells. NHLs are a large and diverse group of tumors. Some tumors develop more slowly, whereas others develop more quickly and aggressively. Childhood NHL typically becomes evident as a diffuse disease and can be further subdivided into four major types: (1) B-cell non-Hodgkin lymphoma (Burkitt and Burkitt-like lymphoma and Burkitt leukemia); (2) diffuse large B-cell lymphoma; (3) lymphoblastic lymphoma; and (4) anaplastic large cell lymphoma.24 The common types of NHL in children are different from those in adults. The most common types of NHL in children are Burkitt lymphoma (40%), lymphoblastic lymphoma (25% to 30%), and large cell lymphoma (10%). Pathophysiology Burkitt lymphoma will be discussed as an example of the pathogenesis of NHL in children. All forms of Burkitt lymphoma are associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels.25 MYC is a transcriptional regulator that increases the expression of genes required for aerobic glycolysis, called the Warburg effect (see Chapter 11). Most Burkitt lymphomas are latently infected with the EBV.26 EBV also is present in about 25% of tumors associated with human immunodeficiency virus (HIV) infection and in 15% to 20% of sporadic cases.27 Clinical Manifestations NHL can arise from any lymphoid tissue. Signs and symptoms therefore are specific for the involved site. Associated signs of NHL include swelling of the lymph nodes in the neck, underarm, stomach, or groin; trouble swallowing; a painless lump or swelling in a testicle; weight loss for unknown reason; night sweats; and possibly trouble breathing. Involvement of facial bones, particularly the jaw, is common in African Burkitt lymphoma. Evaluation and Treatment Diagnosis is made by physical exam and health history, followed by a needle biopsy of disease sites, usually the involved lymph nodes, tonsils, spleen, liver, bowel, or skin. Burkitt lymphoma is very aggressive and responds well to treatment. With intensive chemotherapy, most children and young adults can be cured.

Hodgkin Lymphoma Hodgkin lymphoma (HL) is a group of lymphoid cancers. In contrast to NHL, HL arises in

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a single chain of lymph nodes and spreads first in a contiguous way to lymphoid tissue. HL is characterized by the presence of Reed-Sternberg cells, which are large cells derived from the germinal center of B cells (Fig. 24.9; also see Chapter 23). WHO has identified five types of HL: (1) nodular sclerosis, (2) mixed cellularity, (3) lymphocyte rich, (4) lymphocyte depletion, and (5) lymphocyte predominance. The first four types are considered the classic types of HL with similar expression of Reed-Sternberg cells. In the lymphocytepredominance type, the Reed-Sternberg cell is distinctive but different from the others. HL is more common among adolescents, relative to younger childhood, and young adults.

FIGURE 24.9 Diagnostic Reed-Sternberg Cell. A large multinucleated or multilobated cell with inclusion body–like nucleoli (arrow) surrounded by a halo of clear nucleoplasm. (From Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)

Pathophysiology The Reed-Sternberg cells fail to express most of the normal B-cell markers, as well as those of T-cells. The causes of the genetic rearrangements or reprogramming are not fully known but are thought to be the result of widespread epigenetic changes. The abnormal pattern of gene expression in Reed-Sternberg cells suggests that the activity of many transcription factors is also altered.28 Abnormalities in the activation of the transcription factor nuclear factor-kappa B (NF-κB) may be influenced by EBV infection. NF-κB is involved in many biologic processes, including inflammation, immunity, cell growth, differentiation, and apoptosis. EBV-infected B cells, resembling Reed-Sternberg cells, are found in lymph nodes in individuals with infectious mononucleosis, suggesting that the EBV proteins may have a role in changes of the B cells into Reed-Sternberg cells.29 Loss-of-function mutations in major histocompatibility class I antigens may allow ReedSternberg cells to avoid the normal host immune response.30 Clinical Manifestations Painless lymphadenopathy in the lower cervical chain, with or without fever, is the most common symptom in children. Other lymph nodes and organs also may be involved (Fig.

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24.10). Mediastinal involvement can cause pressure on the trachea or bronchi, leading to airway obstruction. Extranodal primary sites in Hodgkin lymphoma are rare. Initial symptoms consist of anorexia, malaise, and fatigue. Intermittent fever is present in 30% of children, and weight loss also may be present. Hodgkin lymphoma has a well-defined staging system that considers the extent and location of disease and the presence of fever, weight loss, or night sweats at diagnosis.

FIGURE 24.10 Main Areas of Lymphadenopathy and Organ Involvement in Hodgkin Lymphoma. (From Hockenberry MJ et al, editors: Wong's nursing care of infants and children, ed 10, St Louis, 2015, Mosby.)

Evaluation and Treatment Treatment for Hodgkin lymphoma includes chemotherapy and radiation therapy. Historically, survivors had a much greater risk of developing a secondary cancer, such as lung cancer, melanoma, and breast cancer. Treatment protocols have been modified to minimize the use of radiotherapy and use less toxic chemotherapy. Targeted therapies, including monoclonal antibodies such as brentuximab vedotin and immune checkpoint inhibitors, may have a greater role in treating Hodgkin lymphoma.

Quick Check 24.3 1. List the childhood leukemias in order of incidence.

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2. Why do children with leukemia experience bone or joint pain? 3. What are the common types of non-Hodgkin lymphoma (NHL) in children?

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Summary Review Disorders of Erythrocytes 1. Anemia is the most common blood disorder in children. Like the anemias of adulthood, the anemias of childhood are caused by ineffective erythropoiesis or premature destruction of erythrocytes. 2. Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide. Its incidence is greatest among children between 6 months and 2 years of age. Iron is critical for the developing child and without it damage from the periods of IDA is irreversible. 3. Regardless of its cause, IDA produces a hypochromic-microcytic anemia. Symptoms of mild anemia are often nonspecific, so parents may not notice changes until moderate anemia has developed. 4. Hemolytic disease of the fetus and newborn (HDFN) results from incompatibility between the maternal and the fetal Rh factors or blood type (ABO)Maternal antibodies (anti-Rh antibodies) form in response to the presence of fetal incompatible (Rh-positive) erythrocytes in the blood of an Rh-negative mother. The maternal antibodies then enter the fetal circulation and cause hemolysis of fetal erythrocytes. ABO incompatibility can cause HDFN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy. 5. The key to treatment of HDFN resulting from Rh incompatibilities lies in prevention or immunoprophylaxis. 6. Sickle cell disease is a group of disorders characterized by the production of abnormal hemoglobin S (Hb S) within the erythrocytes. It is most common among people with ancestry from sub-Saharan Africa. 7. Sickle cell disease is an inherited, autosomal recessive disorder expressed as sickle cell anemia, sickle cell–thalassemia disease, or sickle cell–Hb C disease, depending on mode of inheritance. Sickle cell anemia, in which the individual is homozygous for Hb S, is the most severe. Sickle cell–thalassemia and sickle cell–Hb C disease are compound heterozygous forms in which the child inherits Hb S from one parent or another type of abnormal hemoglobin from the other parent. All forms of sickle cell disease are lifelong conditions. 8. Sickle cell trait, in which the child inherits Hb S from one parent and normal hemoglobin (Hb A) from the other, is a heterozygous carrier state that rarely has clinical manifestations. 9. Sickle cell disease causes a change in the shape of red blood cells into the sickle shape. Sickling is triggered by decreased oxygen or dehydration. Most sickled erythrocytes regain a normal shape after reoxygenation and rehydration. 10. The alpha- and beta-thalassemias are inherited autosomal recessive disorders. These conditions result in an impaired rate of synthesis of one of the two chains— α or β—of adult hemoglobin (Hb A).

Disorders of Coagulation and Platelets 1333

1. Hemorrhagic diseases can be either inherited (hemophilias) or antibody-mediated (primary immune thrombocytopenia [ITP]). 2. The hemophilias are a group of inherited bleeding disorders resulting from mutations in coagulation factors. 3. Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are caused by mutations in the genes coding for factors VIII and IX, factors essential in the coagulation cascade. Because factors VIII and IX function together, hemophilia A and B are clinically indistinguishable. Hemophilia A is the most common hereditary disease associated with life-threatening bleeding. 4. Hemophilias A and B are inherited as X-linked recessive conditions. Approximately one-third of cases, however, are the result of a spontaneous mutation in the involved gene. 5. The antibody-mediated hemorrhagic diseases are a group of disorders caused by the immune response. Antibody-mediated destruction of platelets or antibodymediated inflammatory reactions to allergens damage blood vessels and cause seepage into tissues. 6. ITP is the most common disorder of platelet consumption in which antiplatelet antibodies bind to the plasma membranes of platelets. ITP results in platelet sequestration and destruction by mononuclear phagocytes at a rate that exceeds the ability of the bone marrow to produce them.

Neoplastic Disorders 1. Leukemia is cancer of the blood-forming tissues, such as the bone marrow, that most often produces abnormal white blood cells called leukemic cells. 2. About 75% of childhood leukemias are acute lymphoblastic leukemia (ALL). The remaining cases are classified as acute myeloid leukemia (AML) and related neoplasms. Chronic leukemias are rare in children. 3. The cause of most childhood cancer, including leukemia, is unknown. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations that predispose the child to cancer development can occur during fetal development. 4. Exposure to ionizing radiation can lead to the development of childhood leukemia and possible other cancers. 5. ALL causes dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development. 6. Epigenetic alterations are frequent in AML and have a central role in its development. 7. The onset of leukemia may be abrupt or insidious. The most common symptoms reflect consequences of bone marrow failure and can include decreased levels of red blood cells and platelets, as well as changes in white blood cells. 8. Lymphomas are proliferations of malignant lymphocytes that arise from discrete tissue masses. Lymphoid neoplasms involve some recognizable stage of lymphocyte B- or T-cell differentiation. 9. Some lymphomas occasionally have leukemic presentations, and evolution to leukemia is not unusual during the progression of incurable lymphoma. 10. The lymphomas of childhood are Hodgkin lymphoma (HL) and non-Hodgkin

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lymphoma (NHL). 11. NHLs are cancers of immune cells. Children with inherited or acquired immunodeficiency syndromes have an increased risk of developing NHL. 12. The most common types of NHL in children are Burkitt lymphoma, lymphoblastic lymphoma, and large cell lymphoma. Most Burkitt lymphomas are latently infected with the Epstein-Barr virus (EBV). 13. HL is a group of lymphoid cancers. HL arises in a single chain of lymph nodes and spreads first in a contiguous way to lymphoid tissue. 14. HL is characterized by the presence of Reed-Sternberg cells, which are large cells derived from the germinal center of B cells.

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Key Terms Alpha trait, 555 Alpha-thalassemia, 555 Alpha-thalassemia major, 555 Alpha-thalassemia minor, 555 Aplastic crisis, 554 Beta-thalassemia, 555 Beta-thalassemia major (Cooley anemia), 555 Beta-thalassemia minor, 555 Blast cell, 559 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 548 Hemoglobin H disease, 555 Hemoglobin S (Hb S; sickle hemoglobin), 551 Hemolytic anemia, 548 Hemolytic disease of the fetus and newborn (HDFN; erythroblastosis fetalis), 550 Hemophilia A, 557 Hemophilia B, 557 Hodgkin lymphoma (HL), 560 Hydrops fetalis, 550, 550 Hyperbilirubinemia, 550 Hyperhemolytic crisis, 554 Icterus gravis neonatorum, 550 Icterus neonatorum (neonatal jaundice), 550 Immune thrombocytopenic purpura (ITP; idiopathic thrombocytopenic purpura), 557 Kernicterus, 550 Leukemia, 558 Leukemic cell, 558 Lymphoblast, 558 Lymphoma, 559 Non-Hodgkin lymphoma (NHL), 559 Sequestration crisis, 554 Sickle cell anemia, 551 Sickle cell disease, 551 Sickle cell trait, 551 Sickle cell–Hb C disease, 551 Sickle cell–thalassemia, 551 Vasoocclusive crisis (thrombotic crisis), 553

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References 1. Cerami C. Iron nutriture of the fetus, neonate, infant, and child. Ann Nutr Metab. 2017;71(Suppl 3):8–14. 2. Shah M, et al. Effect of orange and apple juice on iron absorption in children. Arch Pediatr Adolesc Med. 2003;157:1232–1236. 3. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Obstetrics, practice bulletin no 181: prevention of RhD alloimmunization. Obstet Gynecol. 2017;130:e57–e70. 4. McBain RD, et al. Anti-D Anti-D administration in pregnancy for preventing Rhesus alloimmunization. Cochrane Database Syst Rev. 2015;(9) [CD000020]. 5. National Heart, Lung, & Blood Institute (NHLBI). Sickle cell disease. [Available at] https://www.nhlbi.nih.gov/healthtopics/sickle-cell-disease. 6. DeBaun MR, Galadanci NA. Sickle cell disease in sub-Saharan Africa. UpToDate. [Available at] https://www.uptodate.com/contents/sickle-cell-disease-insub-saharan-africa [Topic last updated April 23, 2018]. 7. Fortin PM, et al. Red blood cell transfusion to treat or prevent complications in sickle cell disease: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2018;(8) [CD012082]. 8. Caocci G, et al. Long term survival of beta-thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. Am J Hematol. 2017;92:1303–1310. 9. National Hemophilia Foundation (NHF). Fast facts: about bleeding disordes. Author: New York, NY; 2018 [Available at] https://www.hemophilia.org/About-Us/Fast-Facts. 10. Johnsen JM, et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017;1:824–834. 11. Wynn TT, Gumuscu B. Potential role of a new PEGylated 1337

recombinant factor VIII for hemophilia A. J Blood Med. 2016;7:121–128. 12. American Cancer Society (ACS). What is childhood leukemia. Author: Atlanta, GA; 2018 [Available at] https://www.cancer.org/cancer/leukemia-inchildren/about/what-is-childhood-leukemia.html. 13. Timms JA, et al. DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia. Epigenomics. 2016;8:519–536. 14. Berrington de Gonzalez A, et al. Relationship between paediatric CT scans and subsequent risk of leukaemia and brain tumours: assessment of the impact of underlying conditions. Br J Cancer. 2016;114:388–394. 15. Baysson H, et al. Exposure to CT scans in childhood and longterm cancer risk: a review of epidemiological studies. Bull Cancer. 2016;103:190–198. 16. Kenney LB, et al. Improving male reproductive health after childhood, adolescent, and young adult cancer: progress and future directions for survivorship research. J Clin Oncol. 2018;36:2160–2168. 17. van Dorp W, et al. Reproductive function and outcomes in female survivors of childhood, adolescent, and young adult cancer: a review. J Clin Oncol. 2018;36:2169–2180. 18. Weimels JL, et al. GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21. Nat Commun. 2018;9(1):286. 19. Santiago R, et al. Novel therapy for childhood acute lymphoblastic leukemia. Expert Opin Pharmacother. 2017;18:1081–1099. 19a. PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Lymphoblastic Leukemia Treatment. [Bethesda, MD: National Cancer Institute. Updated 23 July; Available at:] https://www.cancer.gov/types/leukemia/patient/child-alltreatment-pdq; 2019 26389385. 20. National Cancer Institute (NCI). PDQ® childhood acute lymphoblastic leukemia treatment. Author: Bethesda, Md; 2018 1338

[Available at] http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfe [Date last modified September 28, 2018]. 21. National Cancer Institute (NCI). PDQ® childhood acute myeloid leukemia/other myeloid malignancies treatment. Author: Bethesda, MD; 2018 [Available at] http://cancer.gov/cancertopics/pdq/treatment/childAML/HealthProf [Date last modified August 28, 2018]. 22. Swerdlow SH, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. 23. American Cancer Society (ACS). What are the key statistics for non-Hodgkin lymphoma in children?. Author: Atlanta, GA; 2017 [Available at] https://www.cancer.org/cancer/childhoodnon-hodgkin-lymphoma/about/key-statistics.html [Date last modified August 1, 2017]. 24. National Cancer Institute (NCI). PDQ® childhood non-Hodgkin lymphoma treatment. Author: Bethesda, MD; 2018 [Available at] https://www.cancer.gov/types/lymphoma/patient/childnhl-treatment-pdq [Last modified September 28, 2018]. 25. Haberl S, et al. MYC rearranged B-cell neoplasms: impact of genetics on classification. Cancer Genet. 2016;209:431–439. 26. Naeini YB, et al. Aggressive B-cell lymphomas: frequency, immunophenotype, and genetics in a reference laboratory population. Ann Diagn Pathol. 2016;25:7–14. 27. Mbulaiteye SM, et al. Epstein-Barr virus patterns in U.S. Burkitt lymphoma tumors from the SEER Residual Tissue Repository during 1979-2009. APMIS. 2014;122:5–15. 28. Mata E, et al. Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets. Oncotarget. 2017;8:111386– 111395. 29. Carbone A, et al. The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis. Int J Cancer. 2017;140:1233–1245. 1339

30. Reichel J, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood. 2015;125:1061–1072.

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UNIT 7

The Cardiovascular and Lymphatic Systems OUTLINE 25 Structure and Function of the Cardiovascular and Lymphatic Systems 26 Alterations of Cardiovascular Function 27 Alterations of Cardiovascular Function in Children

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25

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Structure and Function of the Cardiovascular and Lymphatic Systems Kathryn L. McCance

CHAPTER OUTLINE Circulatory System, 563 Heart, 563 Structures That Direct Circulation Through the Heart, 564 Structures That Support Cardiac Metabolism: Coronary Circulation, 567 Structures That Control Heart Action, 568 Factors Affecting Cardiac Output, 574 Systemic Circulation, 577 Structure of Blood Vessels, 577 Factors Affecting Blood Flow, 577 Regulation of Blood Pressure, 581 Regulation of the Coronary Circulation, 585 Lymphatic System, 585

The functions of the circulatory system include delivery of oxygen, nutrients, hormones, immune system components, and other substances to body tissues and removal of the waste products of metabolism. Delivery and removal are achieved by an extensive array of tubes—the blood and lymphatic vessels—connected to a pump—the heart. The heart continuously pumps blood through the blood vessels in collaboration with other systems, particularly the nervous and endocrine systems, which regulate the heart and blood vessels. Immune system components, nutrients, and oxygen are supplied by the immune, digestive, and respiratory systems; gaseous wastes of metabolism are expired through the lungs; and other wastes are removed by the kidneys and digestive tract. The vascular endothelium also is a key component of the circulatory system and is sometimes considered a separate endocrine organ. This endothelium is a multifunctional tissue whose health is essential to normal vascular, immune, and hemostatic system function. Endothelial dysfunction is a critical factor in the development of vascular and other diseases.1

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Circulatory System The heart is composed of two conjoined pumps moving blood through two separate circulatory systems in sequence: one pump supplies blood to the lungs, whereas the second pump delivers blood to the rest of the body. Structures on the right side, or right heart, pump blood through the lungs. This system is termed the pulmonary circulation and is described in Chapter 28. The left side, or left heart, sends blood throughout the systemic circulation, which supplies all of the body except the lungs (Fig. 25.1). These two systems are serially connected; thus the output of one becomes the input of the other.

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FIGURE 25.1 Diagram of the Pulmonary and Systemic Circulatory Systems and Flow Chart of the Direction of Blood Flow. A, The right heart pumps unoxygenated blood (blue) through the pulmonary circulation, where oxygen enters the blood and carbon dioxide is exhaled, and the left heart pumps oxygenated (red) blood to and from all the other organ systems in the body. B, Blood flow begins at the left ventricle of the heart; the blood flows to the arteries, arterioles, capillaries of each body organ, venules, veins, right atrium, right ventricle, pulmonary artery, lung capillaries, pulmonary veins, and left atrium and then returns to the left ventricle (A from Patton KT, Thibodeau GA, Douglas MM: Essentials of anatomy & physiology, St Louis, 2012, Elsevier. B adapted from Patton KT, Thibodeau GA: The human body in health & disease, ed 7, St Louis, 2018, Mosby).

Arteries carry blood from the heart to all parts of the body, where they branch into arterioles and even smaller vessels, ultimately becoming a fine meshwork of capillaries. Capillaries allow the closest contact and exchange between the blood and the interstitial space, or interstitium—the environment in which cells live. Venules and then veins next carry blood from the capillaries back to the heart. Some of the plasma or liquid part of the blood passes through the walls of the capillaries into the interstitial space. This fluid, lymph, is returned to the cardiovascular system by vessels of the lymphatic system. The lymphatic system is a critical component of the immune system as described in Chapters 6 and 7.

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Heart The adult heart is about the size of a fist and weighs between 200 and 350 grams. The heart lies obliquely (diagonally) in the mediastinum, the area above the diaphragm and between the lungs. Heart structures can be categorized by function: 1. Structural support of heart tissues and circulation of pulmonary and systemic blood through the heart. This category includes the heart wall and fibrous skeleton enclosing and supporting the heart and dividing it into four chambers; the valves directing flow through the chambers; and the great vessels conducting blood to and from the heart. 2. Maintenance of cardiac metabolism. This category includes all the vessels of the coronary circulation—the arteries and veins that serve the metabolic needs of all the heart cells—and the heart's lymphatic vessels. 3. Stimulation and control of heart action. Among these structures are the nerves and specialized muscle cells that direct the rhythmic contraction and relaxation of the heart muscles, propelling blood throughout the pulmonary and systemic circulatory systems.

Structures That Direct Circulation Through the Heart Heart Wall The three layers of the heart wall—the epicardium, myocardium, and endocardium—are enclosed in a double-walled membranous sac, the pericardium (Fig. 25.2, B). The pericardial sac has three main functions: it prevents displacement of the heart during gravitational acceleration or deceleration, it serves as a physical barrier to protect the heart against infection and inflammation coming from the lungs and pleural space, and it contains pain receptors and mechanoreceptors that can cause reflex changes in blood pressure and heart rate. The two layers of the pericardium, the parietal and the visceral pericardia (see Fig. 25.2), are separated by a fluid-containing space called the pericardial cavity. The pericardial fluid (about 20 ml) is secreted by cells of the mesothelial layer of the pericardium and lubricates the membranes that line the pericardial cavity, enabling them to slide smoothly over one another with minimal friction as the heart beats. The amount and character of the pericardial fluid are altered if the pericardium is inflamed (see Chapter 26).

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FIGURE 25.2 Structures That Direct Blood Flow Through the Heart and Wall of the Heart. A, The arrows indicate the path of blood through the chambers, valves, and major vessels. B, This section of the heart wall shows the fibrous pericardium, the parietal and visceral layers of the serous pericardium (with the pericardial space between them), the myocardium, and the endocardium. Note the fatty connective tissue between the visceral layer of the serous pericardium (epicardium) and the myocardium. Note also that the endocardium covers tubular projections of myocardial muscle tissue called trabeculae. (Revised from Applegate E: The anatomy and physiology learning system, ed 4, St Louis, 2011, Saunders.)

The smoothness of the outer layer of the heart, the epicardium, also minimizes the friction between the heart wall and the pericardial sac. The thickest layer of the heart wall, the myocardium, is composed of cardiac muscle and is anchored to the heart's fibrous skeleton. The heart muscle cells, cardiomyocytes, provide the contractile force needed for blood to flow through the heart and into the pulmonary and systemic circulations. About 0.5% to 1% of the cardiomyocytes are replaced annually; thus over a lifetime only about half of these muscle cells are replaced.2 There is great interest in finding therapies that will increase the rate of cardiomyocyte replacement for persons who have suffered a myocardial infarction or have heart failure from another cause because the limited myocyte turnover is insufficient to restore contractile function. The internal lining of the myocardium, the endocardium, is composed of connective tissue and squamous cells (see Fig. 25.2, B). This lining is continuous with the endothelium that lines all the arteries, veins, and capillaries of the body, creating a continuous, closed circulatory system.

Great Vessels Blood moves into and out of the heart through several large veins and arteries (see Fig. 25.2). The right heart receives venous blood from the systemic circulation through the superior and inferior venae cavae, which join and then enter the right atrium. Blood leaving the right ventricle enters the pulmonary circulation through the pulmonary artery, which divides into right and left branches to transport deoxygenated blood from the right heart to the lungs. The pulmonary arteries branch further into the pulmonary capillary beds, where oxygen and carbon dioxide exchange occurs. Four pulmonary veins, two from the right lung and two from the left lung, carry oxygenated blood from the lungs to the left side of the heart. The oxygenated blood moves through the left atrium and ventricle, out into the aorta that subsequently branches into the

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systemic arteries that supply the body.

Chambers of the Heart The heart has four chambers: the left atrium, the right atrium, the right ventricle, and the left ventricle. These chambers form two pumps in series: the right heart is a low-pressure system pumping blood through the lungs, and the left heart is a high-pressure system pumping blood to the rest of the body (see Fig. 25.2, A). The atria are smaller than the ventricles and have thinner walls. The ventricles have a thicker myocardial layer and constitute much of the bulk of the heart. The ventricles are formed by a continuum of muscle fibers originating from the fibrous skeleton at the base of the heart. The wall thickness of each cardiac chamber depends on the amount of pressure or resistance it must overcome to eject blood. The two atria have the thinnest walls because they are low-pressure chambers that serve as storage units and channels for blood that is emptied into the ventricles. Normally, there is little resistance to flow from the atria to the ventricles. The ventricles, on the other hand, must propel the blood all the way through the pulmonary or systemic vessels. The mean pulmonary artery pressure, the force the right ventricle must overcome, is only 15 mm Hg, whereas the mean arterial pressure the left ventricle must pump against is about 92 mm Hg. Because the pressure is markedly higher in the systemic circulation, the wall of the left ventricle is about three times thicker than that of the right ventricle. The right ventricle is shaped like a crescent or triangle, enabling a bellows-like action that efficiently ejects large volumes of blood through the pulmonary semilunar valve into the low-pressure pulmonary system. The larger left ventricle is bullet shaped, which allows it to generate enough pressure to eject blood through a relatively larger aortic semilunar valve into the high-pressure systemic circulation. Blood normally does not flow between the chambers of the right and left sides of the heart. The atria are separated by the interatrial septum, and the ventricles by the interventricular septum. However, because the fetus does not depend on the lungs for oxygenation, there is an opening before birth between the right and left atria, called the foramen ovale, that facilitates circulation. This opening closes functionally at the time of birth as the higher pressure in the left atrium pushes a flap, the septum primum, over the hole. In 75% to 80% of infants these septa are permanently fused within the first year of life3,4 (see Chapter 27).

Valves of the Heart Four valves in the heart direct blood flow in one direction through the heart chambers (Fig. 25.3). The atrioventricular (AV) valves are termed such because they fall between the atria and ventricles. The AV valve openings are composed of tissue flaps called leaflets or cusps, which are attached at the upper margin to a ring in the heart's fibrous skeleton and by the chordae tendineae at the lower end to the papillary muscles (see Fig. 25.2, A). The papillary muscles, extensions of the myocardium, help hold the cusps together and downward at the onset of ventricular contraction, thus preventing their backward expulsion or prolapse into the atria. The AV valve in the right heart is called the tricuspid valve because it has three cusps. The left atrioventricular valve is a bicuspid (two-cusp) valve called the mitral valve. The tricuspid and mitral valves function as a unit because the atria, fibrous rings, valvular

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tissue, chordae tendineae, papillary muscles, and ventricular walls are connected. Collectively, these six structures are known as the mitral and tricuspid complex. Damage to any one of the six components of this complex can alter function significantly and contribute to heart failure.

FIGURE 25.3 Blood Flow Through the Heart During a Single Cardiac Cycle. A, During diastole, blood flows into atria, the atrioventricular valves are pushed open, and blood begins to fill the ventricles. Atrial systole squeezes the blood remaining in the atria into the ventricles. B, During ventricular systole, the ventricles contract, pushing the blood out through the semilunar valves into the pulmonary artery (right ventricle) and the aorta (left ventricle). (From Patton KT, Thibodeau GA: Structure & function of the body, ed 15, St Louis, 2016, Elsevier.)

The other two valves in the heart are called the semilunar valves. These valves have three cup-shaped cusps that arise from the fibrous skeleton. Blood leaves the right ventricle through the pulmonary semilunar valve, and it leaves the left ventricle through the aortic semilunar valve (see Figs. 25.2 and 25.3).

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Fibrous Skeleton of the Heart Four rings of dense fibrous connective tissue provide a firm anchorage for the attachments of the atrial and ventricular musculature, as well as the valvular tissue (see Fig. 25.3). The fibrous rings are adjacent and form a central, fibrous supporting structure collectively termed the annuli fibrosi cordis.

Intracardiac Pressures Four heart valves, four chambers, and the pressure gradients they maintain ensure that blood only flows one way through the heart. When the ventricles are relaxed, the two AV valves open and blood flows from the relatively higher pressure in the atria to the lower pressure in the ventricles. As the ventricles contract, ventricular pressure increases and causes these valves to close and prevent backflow into the atria. The semilunar valves of the heart open when intraventricular pressure exceeds aortic and pulmonary pressures, and blood flows out of the ventricles and into the pulmonary and systemic circulations. After ventricular contraction and ejection, intraventricular pressure decreases and the pulmonary and aortic semilunar valves close when the pressure in the vessels is greater than the pressure in the ventricles, thus preventing backflow into the right and left ventricles, respectively. The actions of the heart valves are shown in Figs. 25.2 and 25.3. Normal intracardiac pressures are shown in Table 25.1. TABLE 25.1 Normal Intracardiac Pressures

Right atrium Right Ventricle Systolic End-diastolic Left atrium Left Ventricle Systolic End-diastolic

Mean (mm Hg) 4

Range (mm Hg) 0-8

24 4 7

15-28 0-8 4-12

130 7

90-140 4-12

Blood Flow during the Cardiac Cycle The pumping action of the heart consists of contraction and relaxation of the heart muscle, or myocardium. Each ventricular contraction and the relaxation that follows it constitute one cardiac cycle. (Blood flow through the heart during a single cardiac cycle is illustrated in Fig. 25.3.) During the period of relaxation, termed diastole, blood fills the ventricles. The ventricular contraction that follows, termed systole, propels the blood out of the ventricles and into the pulmonary and systemic circulations. Contraction of the left ventricle occurs slightly earlier than contraction of the right ventricle. The five phases of the cardiac cycle are said to begin with the opening of the mitral and tricuspid valves and atrial contraction (Figs. 25.4 and 25.5). Closing of the mitral and tricuspid valves as passive ventricular filling begins marks the end of one cardiac cycle.

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FIGURE 25.4 The Five Phases of the Cardiac Cycle. 1, Atrial systole. The atria contract, pushing blood through the open tricuspid and mitral valves into the ventricles. The semilunar valves are closed. 2, Beginning of ventricular systole. The ventricles contract, increasing pressure within the ventricles. The tricuspid and mitral valves close, causing the first heart sound. 3, Period of rising pressure. The semilunar valves open when pressure in the ventricle exceeds that in the arteries. Blood spurts into the aorta and pulmonary arteries. 4, Beginning of ventricular diastole. Pressure in the relaxing ventricles drops below that in the arteries. The semilunar valves snap shut, causing the second heart sound. 5, Period of falling pressure. Blood flows from the veins into the relaxed atria. The tricuspid and mitral valves open when pressure in the ventricles falls below that in the atria. (Adapted from Solomon E: Introduction to human anatomy and physiology, ed 4, St Louis, 2016, Saunders.)

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FIGURE 25.5

Composite Chart of Heart Function. This chart is a composite of several diagrams of heart

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function (cardiac pumping cycle, blood pressure, blood flow, volume, heart sounds, venous pulse, and an electrocardiogram [ECG]), all on the same time scale.

Quick Check 25.1 1. Why are the two separate circulatory systems said to be “serially connected”? 2. What are the functions of the pericardial sac? 3. Why is the thickness of the myocardium different in the right and left ventricles? 4. Trace the flow of blood through the heart during one cardiac cycle.

Structures That Support Cardiac Metabolism: Coronary Circulation The myocardium and other heart structures are supplied with oxygen and nutrients by the coronary circulation, which is the part of the systemic circulation that occurs within the blood vessels of the heart muscles. The coronary arteries originate at the upper edge of the aortic semilunar valve cusps (Fig. 25.6, A and B) and receive blood through openings in the aorta called the coronary ostia. The cardiac veins empty into the right atrium through another ostium, the opening of a large vein called the coronary sinus (see Fig. 25.6, C). (The Regulation of the Coronary Circulation section describes the regulation of this mechanism, which is similar to regulation of flow through systemic and pulmonary vessels.)

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FIGURE 25.6 Coronary Circulation. A, Arteries. B, Coronary artery openings from the aorta. C, Veins. Both A and C are anterior views of the heart. Vessels near the anterior surface are more darkly colored than vessels of the posterior surface seen through the heart. (A and C from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby. B, Patton KT, Thibodeau GA: The human body in health & disease, ed 6, St Louis, 2014, Mosby.)

Coronary Arteries The major coronary arteries, the right coronary artery (RCA) and the left coronary artery (LCA) (see Fig. 25.6, A), traverse the epicardium, myocardium, and endocardium and branch to become arterioles and then capillaries. The LCA arises from a single ostium behind the left cusp of the aortic semilunar valve. It generally divides into the left anterior descending (LAD) artery, or anterior interventricular artery (supplies blood to portions of the left and right ventricles and much of the interventricular septum), and the circumflex artery (supplies blood to the left atrium and the lateral wall of the left ventricle). The RCA originates from an ostium behind the right aortic cusp. It branches into the conus (supplies blood to the upper right ventricle), right marginal branch (supplies the right ventricle to the apex), and posterior descending branch (supplies smaller branches to both ventricles). Because women's hearts weigh proportionally less than men's hearts, the coronary arteries are smaller in women.

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Collateral Arteries Collateral arteries are connections, or anastomoses, between branches of the same coronary artery or connections of branches of the right coronary artery with branches of the left. The epicardium contains more collateral vessels than the endocardium. New collateral vessels are formed through two processes: arteriogenesis (new artery growth branching from preexisting arteries) and angiogenesis (growth of new capillaries within a tissue). This collateral growth is stimulated by shear stress, an increased blood flow speed within and just beyond areas of stenosis, or narrowing, as well as the production of growth factors and cytokines. The collateral circulation assists in supplying blood and oxygen to myocardium that has become ischemic following gradual stenosis of one or more major coronary arteries (coronary artery disease). Unfortunately, diabetes, which predisposes to coronary artery disease, also impedes collateral formation because of increased production of antiangiogenic factors, such as endostatin and angiostatin.

Coronary Capillaries The heart requires an extensive capillary network to function. Blood travels from the arteries to the arterioles and then into the capillaries, where oxygen and other nutrients enter the myocardium while waste products enter the blood. At rest, the heart extracts 70% to 80% of the oxygen delivered to it, and coronary blood flow is directly correlated with myocardial oxygen consumption. Any alteration of the cardiac muscles dramatically affects blood flow in the capillaries.

Coronary Veins and Lymphatic Vessels After passing through the capillary network, blood from the coronary arteries drains into the cardiac veins located alongside the arteries. Most of the venous drainage of the heart occurs through veins in the visceral pericardium. The veins then feed into the great cardiac vein and coronary sinus on the posterior surface of the heart, between the atria and ventricles, in the coronary sulcus (see Fig. 25.6, C). There is an extensive system of lymphatic capillaries and collecting vessels within the layers of the myocardium and the valves. With cardiac contraction, the lymphatic vessels drain fluid to lymph nodes in the anterior mediastinum that empty into the superior vena cava. The lymphatics are important for protecting the myocardium against infection and injury.

Structures That Control Heart Action Life depends on continuous repetition of the cardiac cycle (systole and diastole), which requires the transmission of electrical impulses, termed cardiac action potentials, through the myocardium.5 (Action potentials are described in Chapters 1 and 5.) The muscle fibers of the myocardium are electrically coupled so that action potentials pass from cell to cell rapidly and efficiently. The myocardium contains its own conduction system—a collection of specialized cells that enable the myocardium to generate and transmit action potentials without input from the nervous system (Fig. 25.7). Cells that initiate signals are called pacemakers. The pacemaker cells are concentrated at two sites in the myocardium, called nodes: the sinoatrial

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node and the atrioventricular node. The cardiac cycle is stimulated by these nodes of specialized cells. Although the heart is innervated by the autonomic nervous system (both sympathetic and parasympathetic fibers), neural impulses are not needed to maintain the cardiac cycle. Thus the heart will beat in the absence of any innervation, one of the many factors that allow heart transplantation to be successful.

FIGURE 25.7 The Cardiac Conduction System. Specialized cardiac muscle cells in the heart wall rapidly conduct an electrical impulse throughout the myocardium. The signal is initiated by the sinoatrial (SA) node (pacemaker) and spreads through the atrial myocardium to the atrioventricular (AV) node. The AV node then initiates a signal that is conducted through the ventricular myocardium by way of the atrioventricular bundle (of His) and Purkinje fibers. (From Koeppen BM, editor: Berne & Levy physiology, ed 6, St Louis, 2010, Mosby.)

Heart action is also influenced by substances delivered to the myocardium in coronary blood. Nutrients and oxygen are needed for cellular survival and normal function. Hormones and biochemical substances, including medications, can affect the strength and duration of myocardial contraction and the degree and duration of myocardial relaxation. Normal or appropriate function depends on the supply of these substances, which is why coronary artery disease can seriously disrupt heart function.

Conduction System Normally, electrical impulses arise in the sinoatrial (SA) node (sinus node), the usual pacemaker of the heart. The SA node is located at the junction of the right atrium and superior vena cava, just superior to the tricuspid valve. The SA node is heavily innervated by both sympathetic and parasympathetic nerve fibers.6 In the resting adult the SA node generates about 60 to 100 action potentials per minute, depending on the age and physical condition of the person. Each action potential travels rapidly from cell to cell and through the atrial myocardium, carrying the action potential onward to the atrioventricular (AV) node, as well as causing both atria to contract, beginning systole.6 The AV node, located in the right atrial wall superior to the tricuspid valve and anterior to the ostium of the coronary sinus, conducts the action potentials onward to the ventricles.

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It is innervated by nerves from the autonomic parasympathetic ganglia that serve as receptors for the vagus nerve and cause slowing of impulse conduction through the AV node. Conducting fibers from the AV node converge to form the bundle of His (atrioventricular bundle), within the posterior border of the interventricular septum. The bundle of His then gives rise to the right and left bundle branches. The right bundle branch (RBB) is thin and travels without much branching to the right ventricular apex. Because of its thinness and relative lack of branches, the RBB is susceptible to interruption of impulse conduction by damage to the endocardium. The left bundle branch (LBB) divides into two branches, or fascicles. The left anterior bundle branch (LABB) passes the left anterior papillary muscle and the base of the left ventricle and crosses the aortic outflow tract. Damage to the aortic valve or the left ventricle can interrupt this branch. The left posterior bundle branch (LPBB) travels posteriorly, crossing the left ventricular inflow tract to the base of the left posterior papillary muscle. This branch spreads diffusely through the posterior inferior left ventricular wall. Blood flow through this portion of the left ventricle is relatively nonturbulent, so the LBB is somewhat protected from injury caused by wear and tear. The Purkinje fibers are the terminal branches of the RBB and LBB. They extend from the ventricular apexes to the fibrous rings and penetrate the heart wall to the outer myocardium. The first areas of the ventricles to be excited are portions of the interventricular septum. The septum is activated from both the RBB and the LBB. The extensive network of Purkinje fibers promotes the rapid spread of the impulse to the ventricular apexes. The basal and posterior portions of the ventricles are the last to be activated. Propagation of cardiac action potentials. Electrical activation of the muscle cells, termed depolarization, is caused by the movement of ions, including sodium, potassium, calcium, and chloride, across cardiac cell membranes. Deactivation, called repolarization, occurs the same way. (Movement of ions across cell membranes is described in Chapter 1; electrical activation of muscle cells is described in Chapter 40.) Movement of ions into and out of the cell creates an electrical (voltage) difference across the cell membrane, called the membrane potential. During depolarization, the inside of the cell becomes less negatively charged as positive ions move inside. In cardiac cells, as in other excitable cells, when the resting membrane potential (in millivolts) becomes less negative with depolarization and reaches the threshold potential for cardiac cells, a cardiac action potential is fired. The various phases of the cardiac action potential are related to changes in the permeability of the cell membrane to sodium, potassium, chloride, and calcium. Threshold is the point at which the cell membrane's selective permeability to these ions is temporarily disrupted, leading to an “all or nothing” depolarization. Drugs that alter the movement of these ions (e.g., calcium) have profound effects on the action potential and can alter heart rate. If the resting membrane potential becomes more negative because of a decrease in the extracellular potassium concentration (hypokalemia), it is termed hyperpolarization. Refractory periods, during which no new cardiac action potential can be initiated by a normal stimulus, follow depolarization. Abnormal refractory periods as a result of disease can cause abnormal heart rhythms or dysrhythmias, including ventricular fibrillation and

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cardiac arrest (see Chapter 26). The electrocardiogram. An electrocardiogram originates from myocardial cell electrical activity as recorded by skin electrodes and is the summation of all the cardiac action potentials (Fig. 25.8). The P wave represents atrial depolarization. The PR interval is a measure of time from the onset of atrial activation to the onset of ventricular activation. The PR interval represents the time necessary for electrical activity to travel from the sinus node through the atrium, AV node, and His-Purkinje system to activate ventricular myocardial cells. The QRS complex represents the sum of all ventricular muscle cell depolarization. The configuration and amplitude of the QRS complex may vary considerably among individuals. During the ST interval, the entire ventricular myocardium is depolarized. The QT interval is sometimes called the “electrical systole” of the ventricles but the time it takes varies inversely with the heart rate. The T wave represents ventricular repolarization.

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FIGURE 25.8 Electrocardiogram (ECG) and Cardiac Electrical Activity. A, Normal ECG. Depolarization and repolarization. B, ECG intervals among P, QRS, and T waves. C, Schematic representation of ECG and its relationship to cardiac electrical activity. AV, Atrioventricular; LA, left atrium; LBB, left bundle branch; LV, left ventricle; RA, right atrium; RBB, right bundle branch; RV, right ventricle.

Automaticity. Automaticity, or the property of generating spontaneous depolarization to threshold, enables the SA and AV nodes to generate cardiac action potentials without any external stimulus. Cells capable of spontaneous depolarization are called automatic cells. The automatic cells of the cardiac conduction system can stimulate the heart to beat even when it is transplanted and thus has no innervation. Spontaneous depolarization is possible in automatic cells because the membrane potential of these special cells does not actually “rest” during return to the resting membrane potential. Instead, it slowly depolarizes toward threshold during the diastolic phase of the cardiac cycle. Because threshold is approached during diastole, return to the resting membrane potential in automatic cells is called diastolic depolarization. The electrical impulse normally begins in the SA node because its cells depolarize more rapidly than other automatic cells. Rhythmicity. Rhythmicity is the regular generation of an action potential by the heart's conduction system. The SA node sets the pace because normally it has the fastest rate. The SA node depolarizes spontaneously 60 to 100 times per minute. If the SA node is damaged, the AV node can become the heart's pacemaker at a rate of about 40 to 60 spontaneous depolarizations per minute. Eventually, however, conduction cells in the atria usually take over from the AV node. Purkinje fibers are capable of spontaneous depolarization but at an even slower rate than the AV node.

Quick Check 25.2 1. Describe the structures and importance of coronary circulation. 2. What are the pathways of conduction through the heart? 3. What do the P wave, QRS complex, and T wave on the electrocardiogram represent? 4. Define automaticity and rhythmicity.

Cardiac Innervation: Sympathetic and Parasympathetic Nerves Although the heart's nodes and conduction system are able to generate action potentials independently, the autonomic nervous system influences both the rate of impulse generation (firing), depolarization, and repolarization of the myocardium; and the strength of atrial and ventricular contraction. Autonomic neural transmission produces changes in the heart and circulatory system faster than metabolic or humoral agents. Speed is important, for example, in stimulating the heart to increase its pumping action with increased physical activity or during times of stress and fear—the so-called fight or flight response. Although increased delivery of oxygen, glucose, hormones, and other blood-

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borne factors sustains increased cardiac activity, the rapid initiation of increased activity depends on the sympathetic and parasympathetic fibers of the autonomic nervous system. Sympathetic and parasympathetic nerve fibers innervate all parts of the atria and ventricles and the SA and AV nodes. In general, sympathetic stimulation increases electrical conductivity and the strength of myocardial contraction, and vagal parasympathetic nerve activity does the opposite, slowing the conduction of action potentials through the heart and reducing the strength of contraction. Thus the sympathetic and parasympathetic nerves affect the speed of the cardiac cycle (heart rate, or beats per minute) (Fig. 25.9). Sympathetic nervous activity enhances myocardial performance. Stimulation of the SA node by the sympathetic nervous system rapidly increases heart rate. The sympathetic nervous system may also induce an increased influx of calcium (Ca2+), which increases the contractile strength of the heart and the speed of electrical impulses through the heart muscle and the nodes. Finally, sympathetic nerves influence the diameter of the coronary vessels. Increased sympathetic discharge dilates the coronary vessels by causing the release of vasodilating metabolites resulting from increased myocardial contraction.

FIGURE 25.9

Autonomic Innervation of the Cardiovascular System. Input to the cardiovascular center and output to the heart.

The parasympathetic nervous system affects the heart through the vagus nerve, which releases acetylcholine. Acetylcholine causes a decreased heart rate and slows conduction through the AV node.

Myocardial Cells Cardiomyocytes are composed of long, narrow fibers that contain bundles of longitudinally arranged myofibrils; a nucleus; mitochondria; an internal membrane system (the sarcoplasmic reticulum); cytoplasm (sarcoplasm); and a plasma membrane (the sarcolemma), which encloses the cell (Fig. 25.10). Cardiac and skeletal muscle cells also have an “external” membrane system made up of transverse tubules (T tubules) formed by inward pouching of the sarcolemma. The sarcoplasmic reticulum forms a network of channels that surrounds the muscle fiber.

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FIGURE 25.10 Cardiac Muscle Fiber. Unlike other types of muscle fibers, cardiac muscle fibers are typically branched with junctions, called intercalated disks, between adjacent myocytes. Like skeletal muscle cells, cardiac muscle cells contain sarcoplasmic reticula and T tubules, although these structures are not as highly organized as in skeletal muscle fibers.

Because the myofibrils in both cardiac and skeletal fibers consist of alternating light and dark bands of protein, the fibers appear striped, or striated. The dark and light bands of the myofibrils create repeating longitudinal units, called sarcomeres, which are between 1.6 and 2.2 µm long (Fig. 25.11). The length of these sarcomeres determines the limits of myocardial stretch at the end of diastole and subsequently the force of contraction during systole. Alterations in sarcomere size are seen in both physiologic and pathologic myocardial hypertrophy.

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FIGURE 25.11 Structure of a Sarcomere, Myofilaments, and Myosin. A, The sarcomere is the basic contractile unit of a muscle cell. The Z disk is the anchor for the contractile elements actin and myosin. Actin attaches directly to the Z disk, whereas myosin is attached to it by elastic titin filaments. The myosin filaments are connected to each other by M-protein at the M line. The A, H, and I bands refer to parts of the sarcomere as they were originally seen by light microscopy. B, Thin myofilaments and thick myofilament. C, Mysosin molecule.

There are a number of differences between cardiac and muscle cells. Cardiac cells are arranged in branching networks throughout the myocardium, whereas skeletal muscle cells tend to be arranged in parallel units throughout the length of the muscle. Cardiac fibers have only one nucleus, whereas skeletal muscle cells have many nuclei. Differences between cardiac and skeletal muscle often relate to heart function. Some of these functions include: 1. Transmit action potentials quickly from cell to cell. Electrical impulses are transmitted rapidly from cardiac fiber to cardiac fiber because the network of fibers connects at intercalated disks, which are thickened portions of the sarcolemma. The intercalated disks contain three junctions: desmosomes, or macula adherens; fascia adherens, which mechanically attach one cell to another; and gap junctions, which allow the electrical impulse to spread from cell to cell through a low-resistance pathway (see Chapter 1). Changes in the function of these junctional elements may cause an increased risk of arrhythmias.6 2. Maintain high levels of energy synthesis. Unlike skeletal muscle, the heart cannot rest and is in constant need of energy, which is supplied by molecules such as adenosine triphosphate (ATP). Therefore, the cytoplasm surrounding the bundles of myofibrils in each cardiomyocyte contains a large number of mitochondria (25% to 35% of cell volume, versus 3% to 8% of cell volume in skeletal muscle). Cardiac muscle cells have more mitochondria than do skeletal muscle cells to provide the necessary respiratory enzymes for aerobic metabolism and supply quantities of ATP sufficient for the constant action of the myocardium.7 3. Gain access to more ions, particularly sodium and potassium, in the extracellular environment. Cardiac fibers contain more T tubules than do skeletal muscle fibers (see Fig. 25.10). This increased closeness to the T tubules gives each myofibril in the myocardium faster access to molecules needed for the transmission of action potentials, a process that involves transport of sodium and potassium through the walls of the T tubules. Because the T tubule system is continuous with the extracellular space and the interstitial fluid, it facilitates the rapid transmission of the electrical impulses from the surface of the sarcolemma to the myofibrils inside the fiber. This rapid transmission activates all the myofibrils of one fiber simultaneously. The sarcoplasmic reticulum is located around the myofibrils. As an action potential is transmitted through the T tubules, it induces the sarcoplasmic reticulum to release its stored calcium, thus activating the contractile proteins actin and myosin. The sarcomere. Within each myocardial sarcomere are myosin and actin molecules that are grouped together to form filaments. Myosin molecules resemble golf clubs with two large, ovoid

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heads at one end of the shaft (see Fig. 25.11, B). About 200 myosin molecules are bundled together with their heads facing outward, forming a single thick filament. Actin molecules resemble beads, and they are strung into two chains that wind around each other, forming a thin filament. A tropomyosin molecule (a relaxing protein) lies alongside actin molecules. Troponin, another relaxing protein, associates with the tropomyosin molecule. The sarcomere also contains a giant elastic protein, titin, which attaches myosin to the Z line, acts as a spring, and influences myocardial stiffness.7 The titin structure affects myocardial diastolic filling and has been found to play a role in heart failure.8 Where thick filaments overlap with thin filaments, a central dark band is formed, called the A band (see Fig. 25.11, A). The light bands of the sarcomere, called I bands, contain only actin molecules and no myosin. The center of the sarcomere is a less dense region called the H band, which contains only myosin molecules and no actin. Thick filaments are held together by M-protein molecules that form a central thin, dark M line.7 Thin filaments of actin extend from each side of the Z line, a dense fibrous structure at the center of each I band. The area from one Z line to the next Z line defines one sarcomere. Myocardial metabolism. Cardiomyocytes depend on the constant production of ATP, which is synthesized within the mitochondria mainly from glucose, fatty acids, and lactate. If the myocardium is underperfused because of coronary artery disease, anaerobic metabolism must be used for energy (see Chapter 1). Energy produced by metabolic processes fuels muscle contraction and relaxation, electrical excitation, membrane transport, and synthesis of large molecules. Normally, the amount of ATP produced supplies sufficient energy to pump blood throughout the system. Cardiac work is expressed as myocardial oxygen consumption (MV̇O2), which is closely correlated with total cardiac energy requirements. The MV̇O2 is determined by three major factors: (1) the amount of wall stress during systole, estimated by measuring the systolic blood pressure; (2) the duration of systolic wall tension, measured indirectly by the heart rate; and (3) the contractile state of the myocardium, which is not measured clinically. The coronary arteries deliver oxygen (O2) to the myocardium. Approximately 70% to 75% of this O2 is used immediately by cardiac muscle, leaving little O2 in reserve. Because the O2 content of the blood and the amount of O2 extracted from the blood cannot be increased under normal circumstances, any increased energy needs can be met only by increasing coronary blood flow. The MV̇O2 increases with exercise and decreases with hypotension and hypothermia. As myocardial metabolism and consumption of O2 increase, the local concentration of local vasoactive metabolic factors increases. Some of these, such as adenosine, nitric oxide, and prostaglandins, dilate coronary arterioles, thus increasing coronary blood flow.9

Myocardial Contraction and Relaxation Myocardial contractility is a change in developed tension at a given resting fiber length, which basically is the ability of the heart muscle to shorten. Each sarcomere serves as the basic contractile unit of a muscle cell. The outward-facing heads of myosin molecules are called cross-bridges because they can form force-generating bridges by binding with exposed actin molecules. Once bound, the myosin molecules effectively pull the thin filaments

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toward the center of the sarcomere, shortening the sarcomere and resulting in contraction. This process is known as the cross-bridge theory of muscle contraction (Fig. 25.12). The degree of shortening depends on the amount of overlap between the thick and thin filaments.

FIGURE 25.12 Cross-Bridge Theory of Muscle Contraction. A, Each myosin cross-bridge in the thick filament moves into a resting position after an adenosine triphosphate (ATP) molecule binds and transfers its energy. B, Calcium ions released from the sarcoplasmic reticulum bind to troponin in the thin filament, allowing tropomyosin to shift from its position blocking the active sites of actin molecules. C, Each myosin cross-bridge then binds to an active site on a thin filament, displacing the remnants of ATP hydrolysis—adenosine diphosphate (ADP) and inorganic phosphate (Pi). D, The release of stored energy from step A provides the force needed for each cross-bridge to move back to its original position, pulling actin along with it. Each cross-bridge will remain bound to actin until another ATP molecule binds to it and pulls it back into its resting position (A). (Adapted from Thibodeau GA, Patton KT: Anatomy & physiology, ed 4, St Louis, 1999, Mosby.)

Calcium and excitation-contraction coupling. Excitation-contraction coupling is the process by which an action potential arriving at the muscle fiber plasma membrane triggers the cycle, leading to cross-bridge formation and contraction. Cycle activation depends on calcium availability, and the amount of force developed is regulated by how much the concentration of calcium ions increases within the cardiomyocytes. Calcium enters the myocardial cell from the interstitial fluid after electrical excitation that increases membrane calcium permeability. Calcium entering the cell triggers the release of additional calcium from the two storage sites within the sarcomere. Calcium ions then diffuse toward the myofibrils, where they bind with troponin. The calcium-troponin complex interaction facilitates the contraction process. In the resting state, troponin is bound to actin and the tropomyosin molecule covers the sites where the myosin heads bind to actin, thereby preventing interaction between actin and myosin. Calcium binds to troponin, which ultimately results in tropomyosin moving troponin, thus uncovering the binding sites. Myosin and actin can now form cross-bridges, and ATP can be dephosphorylated to adenosine diphosphate (ADP). Under these circumstances, sliding of the thick and thin filaments can occur, and the muscle contracts.7 Myocardial relaxation. Relaxation is as vital to optimal cardiac function as contraction; and calcium, troponin, and tropomyosin also facilitate relaxation. After contraction, free calcium ions are actively pumped out of the cell back into the interstitial fluid or taken back into storage by the sarcoplasmic reticulum and tubule system. As the concentration of calcium within the

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sarcomere decreases, troponin releases its bound calcium. The tropomyosin complex moves and blocks the active sites on the actin molecule, preventing cross-bridge formation with the myosin heads. If the ability of the myocardium to relax is impaired, it can lead to increased diastolic filling pressures and eventually heart failure.10

Quick Check 25.3 1. What features distinguish myocardial cells from skeletal cells? 2. Describe the interactions of actin and myosin in controlling heart function. 3. Define excitation-contraction coupling.

Factors Affecting Cardiac Output Cardiac performance can be evaluated by measuring the cardiac output. Cardiac output is calculated by multiplying the heart rate in beats per minute (beats/min) by the stroke volume (volume of blood ejected during systole) in liters per beat. Normal adult cardiac output is about 5 L/min at rest, given a heart rate of about 70 beats/min and a normal stroke volume of about 70 ml. With each heartbeat, the ventricles eject much of their blood volume, and the amount ejected per beat is called the ejection fraction. The ejection fraction is calculated by dividing the stroke volume by the end-diastolic volume. The end-diastolic volume of the normal ventricle is about 70 to 80 ml/m2, and the normal ejection fraction of the resting heart, measured with gated myocardial perfusion imaging, was 66% ± 8% for women and 58% ± 8% for men.11 The ejection fraction is increased by factors that increase contractility, such as increased sympathetic nervous system activity. A decrease in the ejection fraction may indicate ventricular failure. The effects of aging on cardiovascular function are summarized in Table 25.2. TABLE 25.2 Cardiovascular Function in Elderly Adults Determinant Cardiac output Heart rate Stroke volume Ejection fraction Afterload End-diastolic volume End-systolic volume Contraction Myocardial wall stiffness Maximum oxygen consumption Plasma catecholamines *Changes

Resting Cardiac Performance Unchanged Slight decrease Slight increase Unchanged Increased Unchanged Unchanged Decreased velocity Increased Not applicable —

Exercise Cardiac Performance* Decreases because of a decrease in maximum heart rate Increases less than in younger people No change Decreased Increased Increased Increased Decreased Increased Decreased Increased

in healthy men and women up to age 80 years as compared to those 20 years of age.

Data from Lakatta EG et al: Aging and cardiovascular disease in the elderly. In Fuster V et al, editors: Hurst's the heart, ed 13, Philadelphia, 2011, McGraw-Hill.

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The factors that determine cardiac output are (1) preload, (2) afterload, (3) myocardial contractility, and (4) heart rate. Preload, afterload, and contractility all affect stroke volume (Fig. 25.13).

FIGURE 25.13 Factors Affecting Cardiac Performance. Cardiac output, the amount of blood (in liters) ejected by the heart per minute, depends on the heart rate (beats per minute) and stroke volume (milliliters of blood ejected during ventricular systole).

Preload Preload is the volume and pressure inside the ventricle at the end of diastole (ventricular end-diastolic volume [VEDV] and pressure [VEDP]). Preload is determined by two primary factors: (1) the amount of blood left in the ventricle after systole (end-systolic volume) and (2) the amount of venous blood returning to the ventricle during diastole. End-systolic volume is dependent on the strength of ventricular contraction and the resistance to ventricular emptying. Venous return is dependent on blood volume and flow through the venous system and the atrioventricular valves. Clinically, preload is estimated by measuring the central venous pressure (CVP) for the right side of the heart and the pulmonary artery wedge pressure (cross-sectional pressure) for the left side. Normal values for these two estimates are 1 to 5 mm Hg and 4 to 12 mm Hg, respectively.12 The Laplace law states that wall tension generated in the wall of the ventricle (or any chamber or vessel) to produce a given intraventricular pressure depends directly on ventricular size (internal radius) and inversely on ventricular wall thickness. The VEDV, which determines the size of the ventricle and the stretch of the cardiac muscle fibers, therefore affects the tension (or force) for contraction. The Frank-Starling law of the heart indicates that the volume of blood in the heart at the end of diastole, as the volume determines the length of its muscle fibers, is directly related to the force of contraction

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during the next systole. Muscle fibers have an optimal resting length from which to generate the maximum amount of contractile strength. Within a physiologic range of muscle stretching, increased preload increases stroke volume (and therefore cardiac output and stroke work) (Fig. 25.14, curve B). Excessive ventricular filling and preload (increased VEDV) stretches the heart muscle beyond optimal length, and stroke volume begins to fall. Factors that increase contractility cause the heart to operate on a higher length-tension curve (see Fig. 25.14, curve A). Factors that decrease contractility cause the heart to operate at a lower length-tension curve (see Fig. 25.14, curve C).

FIGURE 25.14 Frank-Starling Law of the Heart. The relationship between length and tension in the heart. The end-diastolic volume determines the end-diastolic length of ventricular muscle fibers and is proportional to tension generated during systole, as well as to cardiac output, stroke volume, and stroke work. A change in myocardial contractility causes the heart to perform on a different length-tension curve. A, Increased contractility; B, normal contractility; C, heart failure or decreased contractility. (See text for further explanation.)

Increases in preload (VEDV) may not only cause a decline in stroke volume, but also result in increases in the VEDP. These changes can lead to heart failure (see Chapter 26). An increased VEDP causes pressures to increase, or “back up,” into the pulmonary or systemic venous circulation, thus increasing the movement of plasma out through vessel walls, causing fluid to accumulate in lung tissues (pulmonary edema; see Chapter 29) or in peripheral tissues (peripheral edema).

Afterload Ventricular afterload is the resistance to ejection of blood from the ventricle. It is the load the muscle must move during contraction. The aortic systolic pressure is an index of afterload. Pressure in the ventricle must exceed the aortic pressure before blood can be pumped out during systole. Low aortic pressures (decreased afterload) enable the heart to contract more rapidly and efficiently, whereas high aortic pressures (increased afterload) slow contraction and cause higher workloads against which the heart must function to eject blood. Increased aortic pressure is usually the result of increased systemic vascular resistance (SVR), sometimes referred to as total peripheral resistance (TPR). In individuals with hypertension, increased SVR means that afterload is chronically elevated, resulting in increased ventricular workload and hypertrophy of the myocardium. SVR is calculated by dividing the mean arterial pressure by the cardiac output; the normal range is 700 dyne/sec/cm−5.5,12 The most sensitive measure of afterload is SVR.

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Myocardial Contractility Stroke volume, or the volume of blood ejected per beat during systole, also depends on the force of contraction, myocardial contractility, or the degree of myocardial fiber shortening. Three major factors determine the force of contraction (see Fig. 25.13): 1. Changes in the stretching of the ventricular myocardium caused by changes in VEDV (preload). As discussed previously, increased venous return to the heart distends the ventricle, thus increasing preload, which increases the stroke volume and, subsequently, cardiac output, up to a certain point. However, an excessive increase in preload leads to decreased stroke volume. 2. Alterations in the inotropic stimuli of the ventricles. Hormones, neurotransmitters, or medications that affect contractility are called inotropic agents. The most important endogenous positive inotropic agents are epinephrine and norepinephrine released from the sympathetic nervous system. The most important negative inotropic agent is acetylcholine released from the vagus nerve. Many medications have positive or negative inotropic properties that can have significant effects on cardiac function. In sepsis, a variety of cytokines, including tumor necrosis factor-alpha (TNF-α), and interleukin-1β, have been shown to impair myocardial contractility.13 3. Adequacy of myocardial oxygen supply. O2 and carbon dioxide levels (tensions) in the coronary blood also influence contractility. With severe hypoxemia (arterial O2 saturation less than 50%), contractility is decreased. Moderate degrees of hypoxemia may increase contractility by enhancing the myocardial response to circulating catecholamines.14 Preload, afterload, and contractility all interact with one another to determine stroke volume and cardiac output. Changes in any one of these factors can result in deleterious effects on the others, resulting in heart failure (see Chapter 26).

Heart Rate As described previously, SA node activity is the primary determinant of the heart rate. The average heart rate in healthy adults is about 70 beats/min. This rate diminishes by 10 to 20 beats/min during sleep and can accelerate to more than 100 beats/min during muscular activity or emotional excitement. In well-conditioned athletes, the resting heart rate is normally about 50 to 60 beats/min. In highly trained or elite athletes, the resting heart rate can be below 50 beats/min; these athletes also have a greater stroke volume and lower peripheral resistance in active muscles than they had before training. The control of heart rate includes activity of the central nervous system, autonomic nervous system, neural reflexes, atrial receptors, and hormones (see Fig. 25.13). Cardiovascular control centers in the brain. The cardiovascular vasomotor control center is in the medulla and pons areas of the brainstem, with additional areas in the hypothalamus, cerebral cortex, and thalamus.15 The hypothalamic centers regulate cardiovascular responses to changes in temperature, the cerebral cortex centers adjust cardiac reaction to a variety of emotional states, and the

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brainstem control center regulates heart rate and blood pressure. The nerve fibers from the cardiovascular control center synapse with autonomic neurons that influence the rate of firing of the SA node. As previously discussed, an increased heart rate occurs with sympathetic (adrenergic) stimulation. When the parasympathetic nerves to the heart are stimulated (primarily via the vagus nerve), the heart rate slows and the sympathetic nerves to the heart, arterioles, and veins are inhibited.6 At rest, the heart rate in healthy individuals is primarily under the control of parasympathetic stimulation. Administration of drugs that block parasympathetic function (anticholinergic) or physical interruption of the vagus nerve causes significant tachycardia (abnormally fast heart rate) because this inhibitory parasympathetic influence is lost. Neural reflexes. Output from the baroreceptor reflexes influences short-term regulation of the vascular smooth muscle of resistance arteries, myocardial contractility, and heart rate, all components of blood pressure control. The baroreceptors or pressoreceptors are located in the aortic arch and carotid arteries. If blood pressure decreases, the baroreceptor reflex accelerates the heart rate, increases myocardial contractility, and increases vascular smooth muscle contraction in the arterioles, thus raising blood pressure. This reflex is critical to maintaining adequate tissue perfusion. When the blood pressure increases, the baroreceptors increase their rate of discharge, sending neural impulses over a branch of the glossopharyngeal nerve (cranial nerve IX) and through the vagus nerve to the cardiovascular control centers in the medulla. These reflexes increase parasympathetic activity and decrease sympathetic activity, causing the resistance arteries to dilate, decreasing myocardial contractility and the heart rate. The role of baroreceptors in influencing blood pressure is discussed in more detail later in this chapter. Atrial receptors. Mechanoreceptors that influence the heart rate exist in both atria. They are located where the veins, venae cavae, and pulmonary veins enter their respective atria. The Bainbridge reflex is the name for the changes in the heart rate that may occur after intravenous infusions of blood or other fluid. The change in heart rate is thought to be caused by a reflex mediated by these atrial volume receptors that are innervated by the vagus nerve (volume receptors are thought to respond to increased plasma volume). Although this reflex can be elicited in humans, its relevance is uncertain at this time.16 Stimulation of these atrial receptors also increases urine volume, presumably because of a neurally mediated reduction in antidiuretic hormone. In addition, peptides of the atrial natriuretic family are released from atrial tissue in response to the increases in blood volume. These peptides have diuretic and natriuretic (salt excretion) properties, resulting in decreased blood volume and pressure. The atrial natriuretic peptides also have been shown to relax vascular smooth muscle and oppose myocardial hypertrophy, leading to measurement of blood levels to evaluate clinical status and raising interest in their use as therapeutic agents.17 Hormones and biochemicals. Hormones and other biochemically active substances affect the arteries, arterioles, venules, capillaries, and contractility of the myocardium. Norepinephrine, mainly released as a neurotransmitter from the adrenal medulla, dilates vessels of the liver and skeletal muscle

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and also causes an increase in myocardial contractility. Some adrenocortical hormones, such as hydrocortisone, increase the effects of the catecholamines—norepinephrine and epinephrine. Thyroid hormones enhance sympathetic activity and increase cardiac output. Growth hormone, working together with insulin-like growth factor-1 (IGF-1), also has been shown to increase myocardial contractility.18 Decreases in levels of growth hormone or thyroid hormone may result in bradycardia (heart rate below 60 beats/min), reduced cardiac output, and low blood pressure. (Other hormones are discussed in the Regulation of Blood Pressure section.)

Quick Check 25.4 1. Explain four ways that aging impacts the cardiovascular system. 2. Why is the Frank-Starling law of the heart important to the understanding of heart failure? 3. Discuss the baroreceptor reflex and explain its influence on blood pressure and heart rate.

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Systemic Circulation The arteries and veins of the systemic circulation are illustrated in Fig. 25.15. Oxygenated blood leaves the left side of the heart through the aorta and flows into the systemic arteries. These arteries branch into small arterioles, which branch into the smallest vessels, the capillaries, where nutrient and waste product exchange between the blood and tissues occurs. Blood from the capillaries then enters tiny venules that join to form the larger veins, which return venous blood to the right heart (see Fig. 25.1, B). Peripheral vascular system is the term used to describe the part of the systemic circulation that supplies the skin and the extremities, particularly the legs and feet.

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FIGURE 25.15 Circulatory System. A, Principal arteries of the body. B, Principal veins of the body. (From Patton KT, Thibodeau GA, Douglas MM: Essentials of anatomy & physiology, St Louis, 2012, Elsevier.)

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Structure of Blood Vessels Blood vessel walls are composed of three layers: (1) the tunica intima (innermost, or intimal, layer), (2) the tunica media (middle, or medial, layer), and (3) the tunica externa or adventitia (outermost, or external, layer), which also contains nerves and lymphatic vessels. These layers are illustrated in Fig. 25.16. Blood vessel walls vary in thickness, depending on the thickness or absence of one or more of these three layers. Cells of the larger vessel walls are nourished by the vasa vasorum, small vessels located in the tunica externa.

FIGURE 25.16 Structure of the Blood Vessels. The tunica externa of the veins (blue) and the arteries (red). (From Patton KT, Thibodeau GA: Structure & function of the body, ed 15, St Louis, 2016, Elsevier.)

Arterial Vessels An artery is a thick-walled, pulsating blood vessel transporting blood away from the heart. In the systemic circulation, arteries carry oxygenated blood. When the iron in hemoglobin is oxygenated, it turns bright red, which is why arterial vessels are often color-coded red in illustrations. Arterial walls are composed of elastic connective tissue, fibrous connective tissue, and smooth muscle. There are two types of arteries: elastic and muscular. Elastic arteries have a thick tunica media with more elastic fibers than smooth muscle fibers. Elastic arteries are located close to the heart and include the aorta and its major branches and the pulmonary trunk. Elasticity allows the vessel to absorb energy and stretch as blood is ejected from the heart during systole. During diastole, elasticity promotes recoil of the arteries, maintaining blood pressure within the vessels. Muscular arteries, medium and small size arteries, are farther from the heart than the

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elastic arteries. They contain more muscle fibers and fewer elastic fibers than the elastic arteries and they function to distribute blood to arterioles throughout the body (see Fig. 25.16, A). Because their smooth muscle can contract or relax, they play a role in blood flow control and in directing flow to body parts with the highest need at any point in time. Contraction narrows the vessel lumen (the internal cavity of the vessel), which diminishes flow through the vessel (vasoconstriction). When the smooth muscle layer relaxes, more blood flows through the vessel lumen (vasodilation). An artery becomes an arteriole where the diameter of its lumen narrows to less than 0.5 mm. Arterioles are mainly composed of smooth muscle and regulate the flow of blood into the capillaries by constricting or dilating to either slow or increase the flow of blood into the capillaries (Fig. 25.17). The thick smooth muscle layer of the arterioles is a major determinant of the resistance blood encounters as it flows through the systemic circulation.

FIGURE 25.17 Microcirculation. Control of local blood flow through a capillary network is regulated by altering the tone of precapillary sphincters surrounding arterioles and metarterioles. In the diagram, the sphincters are relaxed, permitting blood flow to enter the capillary bed. (From Patton KT, Thibodeau GA, Douglas MM: Essentials of anatomy & physiology, St Louis, 2012, Elsevier.)

The capillary network is composed of connective channels called metarterioles and “true” capillaries (see Fig. 25.17). Metarterioles have discontinuous smooth muscle cells in their tunica media, whereas capillaries have no smooth muscle cells. There is a ring of smooth muscle called the precapillary sphincter at the point where capillaries branch from metarterioles. As the sphincters contract and relax, they regulate blood flow through the capillary beds. The precapillary sphincters help to maintain arterial pressure and regulate selective flow to vascular beds. Capillaries are composed solely of a layer of endothelial cells surrounded by a basement

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membrane. Their thin walls and unique structure make possible the rapid exchange of water; small soluble molecules; some larger molecules, such as albumin; and cells of the innate and adaptive components of the immune system between the blood and the interstitial fluid. In some capillaries, the endothelial cells contain oval windows or pores termed fenestrations covered by a thin diaphragm. Substances pass between the capillary lumen and the interstitial fluid (1) through junctions between endothelial cells, (2) through fenestrations in endothelial cells, (3) in vesicles moved by active transport across the endothelial cell membrane, or (4) by diffusion through the endothelial cell membrane. A single capillary may be only 0.5 to 1 mm in length and 0.01 mm in diameter, but the capillaries are so numerous their total surface area may be more than 600 m2 (about 100 football fields).

Endothelium The vascular endothelium, or blood vessel lining, is important to several body functions and is sometimes considered a separate endocrine organ. All tissues depend on a blood supply, and the blood supply depends on endothelial cells, which form the lining, or endothelium, of the blood vessel (Fig. 25.18). In addition to substance transport, the vascular endothelium has important roles in coagulation, antithrombogenesis, and fibrinolysis; immune system function; tissue and vessel growth and wound healing; and vasomotion, the contraction and relaxation of vessels. Table 25.3 summarizes some of the more important endothelial functions. Endothelial injury and dysfunction are central processes in many of the most common and serious cardiovascular disorders, including hypertension and atherosclerosis (see Chapter 26).

FIGURE 25.18

Vascular Endothelium. The endothelial cells arrange themselves as a single-layer lining that has numerous critical functions (see Table 25.3).

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TABLE 25.3 Functions of the Endothelium Function Filtration and permeability

Actions Involved Facilitates transport of large molecules via vesicular transport movement through intercellular junctions Facilitates transport of small molecules via movement of vesicles, through opening of tight junctions, and across cytoplasm Vasomotion Stimulates vascular relaxation through production of nitric oxide, prostacyclin, and other vasodilators Stimulates vascular constriction through production of endothelin-1 and of angiotensin II by the action of endothelial angiotensin-converting enzyme on angiotensin I Hemostatic balance Endothelial surface is normally antithrombotic and maintains a balance between procoagulant and anticoagulant factors, as well as profibrinolytic and antifibrinolytic factors Anticoagulant factors include prostacyclin, nitric oxide, antithrombin, thrombomodulin, tissue factor pathway inhibitor, and heparins Procoagulant factors include tissue factor (factor VII), factor VIII, factor V, and plasminogen activator inhibitor-1 (PAI-1) Profibrinolytic factors are tissue- and urokinase-type plasminogen activating factor and PAI-1 Antifibrinolytic factor is tissue plasminogen activator Inflammation/immunity Expresses chemotactic agents and adhesion molecules that support white blood cells (including monocytes, neutrophils, and lymphocytes) moving into tissues Expresses receptors for oxidized lipoproteins, allowing them to enter vascular intima Angiogenesis/vessel Releases growth factors, such as endothelin-1, and heparins for vascular smooth muscle cells growth Lipid metabolism Expresses receptors for lipoprotein lipase and low-density lipoproteins (LDLs)

From Griendling KK et al: Biology of the vessel wall. In Fuster et al, editors: Hurst's the heart, ed 13, Philadelphia, 2011, McGraw-Hill; Rajendran P et al: Int J Biol Sci 9(10):1057-1069, 2013.

Veins Compared with arteries, veins are thin walled with more fibrous connective tissue and have a larger diameter (see Fig. 25.16, B). Veins also are more numerous than arteries. The smallest venules downstream from the capillaries have an endothelial lining and are surrounded by connective tissue. The largest venules have some smooth muscle fibers in their thin tunica media. The venous tunica externa has less elastic tissue than that in arteries, so veins do not recoil as much or as rapidly after distention. Like arteries, veins receive nourishment from tiny vasa vasorum. Veins contain valves to facilitate the one-way flow of blood toward the heart (Fig. 25.19). These valves are folds of the tunica intima and resemble the semilunar valves of the heart. When a person stands up, contraction of the skeletal muscles of the legs compresses the deep veins of the legs and assists the flow of blood toward the heart. This important mechanism of venous return is called the muscle pump (see Fig. 25.19, B).

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FIGURE 25.19 Venous Valves and the Muscle Pump. In veins, one-way valves aid circulation by preventing backflow of venous blood when pressure in a local area is low. A, Blood is moved toward the heart as valves in the veins are forced open by pressure from volume of blood downstream and the neighboring muscles are relaxed. B, When pressure below the valve drops, blood begins to flow backward but fills the “pockets” formed by the valve flaps, pushing the flaps together and thus blocking further backward flow. Contraction in the adjacent muscles and the valves of the systemic veins assist in the return of unoxygenated blood to the right heart.

Factors Affecting Blood Flow Blood flow, the amount of fluid moved per unit of time, is usually expressed as liters or milliliters per minute (L/min or ml/min). Factors that influence blood flow include pressure, resistance, velocity, laminar versus turbulent flow, and compliance, with the most important of these being pressure and resistance.

Pressure and Resistance Pressure in a liquid system is the force exerted on the liquid per unit area and is expressed clinically as millimeters of mercury (mm Hg), or torr (1 torr = 1 mm Hg). Blood flow to an organ depends partly on the pressure difference between the arterial and venous vessels supplying that organ. Fluid moves from the arterial “side” of the capillaries where the pressure is higher to the venous side where the pressure is lower. Resistance is the opposition to blood flow. Most opposition to blood flow results from the diameter and length of the vessels. Changes in blood flow through an organ result from changes in the vascular resistance within the organ because of increases or decreases in vessel diameter and the opening or closing of vascular channels. Resistance in a vessel is inversely related to blood flow—that is, increased resistance leads to decreased blood flow. The Poiseuille law indicates that resistance is directly related to tube length and blood viscosity and inversely related to the radius of the tube to the fourth power (r4). Because blood flow is inversely related to resistance, the greater the resistance the lower the blood flow will be. Resistance to flow cannot be measured directly, but it can be calculated if the pressure difference and flow volumes are known. Resistance to blood flow in a single vessel is determined by the radius and length of the blood vessel and by the blood viscosity.

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Clinically, the most important factor determining resistance in a single vessel is the radius or diameter of the vessel's lumen. Small changes in the lumen's radius or diameter lead to large changes in vascular resistance. Clinically, vasoconstriction will contribute to an increase in resistance, whereas vasodilation will cause a decrease in resistance that may be reflected by a fall in blood pressure. Because vessel length is relatively constant but lumen size is quite variable, length is not as important as lumen size in determining flow through a single vessel. Blood vessel radius is usually the key factor in determining the TPR because viscosity, the consistency of the fluid, is relatively constant. Thick fluids move more slowly and cause greater resistance to flow than thin fluids—just think of honey as compared to water. The viscosity of blood depends on the red cell content. The greater the percentage of red cells in the blood, the more viscous the blood. This relationship is expressed as the hematocrit. A high hematocrit value reduces flow through the blood vessels, particularly the microcirculation (arterioles, capillaries, venules). An elevated hematocrit level is relatively rare. Conditions with elevated hematocrits include a lack of body water, cyanotic congenital heart disease (see Chapter 27), or polycythemia (see Chapter 23), and can lead to increased cardiac work as a result of increased vascular resistance. Resistance to flow through a system of vessels, or total resistance, depends not only on characteristics of individual vessels, but also on whether the vessels are arranged in series (end to end) or in parallel (side to side) and on the total cross-sectional area of the system. Vessels arranged in parallel provide less resistance than vessels arranged in series. Blood flowing through the distributing arteries, beginning with branches off the aorta and ending at arterioles in the capillary bed, encounters more resistance than blood flowing through the capillary bed itself, where flow is distributed among many short, tiny branches arranged in parallel (Fig. 25.20). The total cross-sectional area of the arteriolar system is greater than that of the arterial system, yet the greater number of arterioles arranged in series leads to great resistance to flow in the arteriolar system. In contrast, the capillary system has a larger number of vessels arranged in parallel than the arteriolar system, and the total cross-sectional area is much greater; thus there is lower resistance overall through the capillary system. The resulting slow velocity of flow in each capillary is optimal for capillary-tissue exchange.

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FIGURE 25.20 Relationship between Cross-Sectional Area and Velocity of Blood Flow. A, Small and large cross-sectional areas and their relationship to velocity changes. B, Total cross-sectional area of different kinds of blood vessels with velocity of blood flow (ml/sec). Blood flows with great speed in the large arteries. However, branching of arterial vessels increases the total cross-sectional area of the arterioles and capillaries, reducing the flow rate. When capillaries merge into venules and venules merge into veins, the total cross-sectional area decreases, causing the flow rate to increase. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Elsevier.)

Velocity Blood velocity, or speed, is the distance blood travels in a unit of time, usually centimeters per second (cm/sec). It is directly related to blood flow (the amount of blood moved per unit of time) and inversely related to the cross-sectional area of the vessel in which the blood is flowing (see Fig. 25.20). As blood moves from the aorta to the capillaries, the total cross-sectional area of the vessels increases and the velocity decreases.

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Flow through a tubular system can be either laminar or turbulent. Blood flow through the vessels, except where vessels split or branch, is usually laminar. In laminar flow, concentric layers of molecules move “straight ahead,” with each layer flowing at a slightly different velocity (Fig. 25.21, A). The cohesive attraction between the fluid and the vessel wall prevents the molecules of blood that are in contact with the wall from moving at all. The next thin layer of blood is able to slide slowly past the stationary layer and so on until, at the center, the blood velocity is greatest. Large vessels have room for a large center layer; therefore they have less resistance to flow and greater flow and velocity than smaller vessels.

FIGURE 25.21 Laminar and Turbulent Blood Flow. A, Laminar flow. Fluid flows in long, smooth-walled tubes as if it is composed of a large number of concentric layers. B, Turbulent flow. Turbulent flow is caused by numerous small currents flowing crosswise or oblique to the long axis of the vessel, resulting in flowing whorls and eddy currents.

Where flow is obstructed, the vessel turns or branches, or blood flows over rough surfaces, the flow becomes turbulent with whorls or eddy currents that produce noise, causing a murmur to be heard on auscultation (see Fig. 25.21, B). Resistance increases with turbulence, which frequently occurs in areas with atherosclerotic plaque (see Chapter 26).

Vascular Compliance 1383

Vascular compliance is the increase in volume a vessel can accommodate with a given increase in pressure. Compliance depends on factors related to the nature of a vessel wall, such as the ratio of elastic fibers to muscle fibers in the wall. Elastic arteries are more compliant than muscular arteries. The veins are more compliant than either type of artery, and they can serve as storage areas for the circulatory system. Compliance determines a vessel's response to pressure changes. For example, a large volume of blood can be accommodated by the venous system with only a small increase in pressure. In the less compliant arterial system, where smaller volumes and higher pressures are normal, even small changes in blood volume can cause significant changes in arterial pressure. Stiffness is the opposite of compliance. Several conditions and disorders can cause stiffness, with the most common being aging and atherosclerosis (see Chapter 26).

Quick Check 25.5 1. What is the function of the arterioles? 2. Identify the functions of the endothelium. 3. Why does the total cross-sectional area in the capillary system lower the resistance to flow?

Regulation of Blood Pressure Arterial Pressure The arterial blood pressure is determined by the cardiac output multiplied by the peripheral resistance (Fig. 25.22). The systolic blood pressure is the highest arterial blood pressure after ventricular contraction or systole. The diastolic blood pressure is the lowest arterial blood pressure that occurs during ventricular filling or diastole. The mean arterial pressure (MAP), which is the average pressure in the arteries throughout the cardiac cycle, depends on the elastic properties of the arterial walls and the mean volume of blood in the arterial system. MAP can be approximated from the measured values of the systolic (Ps) and diastolic (Pd) pressures as follows:

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FIGURE 25.22

Factors Regulating Blood Pressure. O2, Oxygen; K+, potassium; CO2, carbon dioxide; H, hydrogen.

The normal range for MAP is 70 to 110 mm Hg. The difference between the systolic pressure and the diastolic pressure (Ps − Pd) is called the pulse pressure and typically is between 40 and 50 mm Hg. The pulse pressure is directly related to arterial wall stiffness and stroke volume. During a wide range of physiologic conditions, including changes in body position, muscular activity, and circulating blood volume, arterial pressure is regulated within a fairly narrow range to maintain tissue perfusion, or blood supply to the capillary beds. The major factors and relationships that regulate arterial blood pressure are summarized in Fig. 25.22.

Effects of Cardiac Output The cardiac output (minute volume) of the heart can be changed by alterations in the heart rate, stroke volume (volume of blood ejected during each ventricular contraction), or both. An increase in cardiac output without a decrease in peripheral resistance will cause the MAP and flow rate to increase. The higher arterial pressure increases blood flow through the arterioles. On the other hand, a decrease in the cardiac output causes a drop in the MAP

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and arteriolar flow if peripheral resistance stays constant.

Effects of Total Peripheral Resistance Total resistance in the systemic circulation, known as either SVR or TPR, is primarily a function of arteriolar diameter. If cardiac output remains constant, arteriolar constriction raises the MAP by reducing the flow of blood into the capillaries, whereas arteriolar dilation has the opposite effect. Reflex control of total cardiac output and peripheral resistance includes (1) sympathetic stimulation of the heart, arterioles, and veins; and (2) parasympathetic stimulation of the heart (Fig. 25.23). The cardiovascular center in the medulla receives input from arterial baroreceptors and chemoreceptors throughout the vascular system and then modifies vagal and sympathetic output to control heart rate and contractility, plus vascular diameter. Vasoconstriction is regulated by an area of the brainstem that maintains a constant (tonic) output of norepinephrine from sympathetic fibers in the peripheral arterioles. This tonic activity is essential for maintenance of blood pressure.

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FIGURE 25.23 Baroreceptors and Chemoreceptor Reflex Control of Blood Pressure. A, Baroreceptor reflexes. B, Vasomotor chemoreflexes. CN, Cranial nerve; O2, oxygen; CO2, carbon dioxide; H+, hydrogen. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Elsevier.)

Baroreceptors. As discussed previously, baroreceptors are stretch receptors located predominantly in the aorta and in the carotid sinus (see Fig. 25.23, A). They respond to changes in smooth muscle fiber length by altering their rate of discharge and supply sensory information to the cardiovascular center in the brainstem. When activated (stretched), the baroreceptors decrease cardiac output by lowering the heart rate, stroke volume, and peripheral resistance, and thus lower blood pressure. Arterial chemoreceptors. Specialized areas within the aortic arch and carotid arteries are sensitive to concentrations of O2, carbon dioxide (CO2), and hydrogen ions (pH) in the blood (see Fig. 25.23, B). Although these chemoreceptors are most important for respiratory control, they also transmit impulses to the medullary cardiovascular centers that regulate blood pressure. A decrease in arterial oxygen concentration (hypoxemia), an increase in arterial PaCO2 concentration, or to a lesser extent a decrease in arterial blood pH causes a reflexive increase in heart rate, stroke volume, and blood pressure.

Effects of Hormones Hormones influence blood pressure regulation through their effects on vascular smooth muscle and blood volume. By constricting or dilating the arterioles in organs, hormones can (1) increase or decrease the flow in response to the body's needs, (2) redistribute blood volume during hemorrhage or shock, and (3) regulate heat loss. The key vasoconstrictor hormones include angiotensin II, vasopressin (or antidiuretic hormone), epinephrine, and norepinephrine. The main vasodilator hormones are the atrial natriuretic hormones. By causing fluid retention or loss, aldosterone, vasopressin, and the natriuretic hormones can influence stroke volume and thus blood pressure.

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Vasoconstrictor hormones. The vasoconstrictor hormones include epinephrine; norepinephrine; angiotensin II, which is part of the renin-angiotensin-aldosterone system; and vasopressin (also known as antidiuretic hormone). Epinephrine, the catecholamine hormone released from the adrenal medulla, causes vasoconstriction in most vascular beds except the coronary, liver, and skeletal muscle circulations. Norepinephrine mainly acts as a neurotransmitter; however, some also is released from the adrenal medulla. When released into the circulation, it is a more potent vasoconstrictor than epinephrine. Although angiotensin II and vasopressin are vasoconstrictors, they are not thought to have a major role in blood pressure control in normal circumstances. Vasopressin and aldosterone, however, affect blood pressure by increasing blood volume through their influence on fluid reabsorption in the kidney and by stimulating thirst. Vasopressin causes the reabsorption of water from tubular fluid in the distal tubule and collecting duct of the nephron. Aldosterone, the end product of the renin-angiotensinaldosterone system, stimulates the reabsorption of sodium, chloride, and water from the same locations in the kidney (Fig. 25.24; also see Chapters 5 and 20).

FIGURE 25.24 Three Mechanisms That Influence Total Plasma Volume. Antidiuretic hormone (ADH) mechanism and renin-angiotensin-aldosterone system (RAAS) tend to increase water, sodium, and

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chloride retention and thus increase total plasma volume. The atrial natriuretic hormone (ANH) mechanism antagonizes these mechanisms by promoting water, sodium, and chloride loss, thus promoting a decrease in total plasma volume. ACE, Angiotensin-converting enzyme; Na+, sodium. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Elsevier.)

Vasodilator hormones. The natriuretic peptides (NPs) or hormones (see Fig. 25.24), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin, function as both vasodilators and regulators of sodium and water excretion (natriuresis and diuresis). Increased pressure or diastolic volume in the heart stimulates the release of these peptide hormones. Increased levels of BNP predict increased risk of a poor outcome in heart failure, pulmonary embolism, valvular heart disease, and chronic coronary artery disease.19

Effects of Other Mediators A variety of other mediators have been demonstrated to cause arteriolar vasodilation or vasoconstriction. Some of the vasodilating mediators include nitric oxide (NO), adrenomedullin (ADM), the endothelins, and prostacyclin. These mediators are being investigated to determine if they or their inhibitors might be useful drugs for the treatment of cardiovascular diseases or if their levels might be useful in determining the prognosis of persons with known disease. Nitric oxide (NO), an intercellular and intracellular signaling molecule produced in endothelial cells, has a variety of roles in vascular function including acting as a vasodilator and inhibitor of smooth muscle proliferation. NO also has been called endothelium-derived relaxing factor (EDRF). One way that diabetes may contribute to hypertension is through inhibition of NO production by impeding a family of enzymes—the NO synthases. Understanding the role of NO in producing vasodilation explains why sublingual nitroglycerin has been a useful treatment for coronary artery spasm. Adrenomedullin (ADM), a peptide with powerful vasodilatory activity, is present in numerous tissues. Although it has been found to have numerous cardiovascular effects, including a role in fetal cardiovascular system development and vasodilation, its exact role in adult human cardiovascular function and disease is unclear. Some research indicates that elevated ADM levels may be useful disease indicators. The endothelins are a family of three structurally similar peptides (ET-1, ET-2, and ET-3) and four receptors produced in cells in the vascular smooth muscle, the endothelium, the kidneys, and other organs. Understanding the physiologic and pathologic roles of these peptides has been complicated by the fact that endothelin binding to some receptors causes vasodilation and natriuresis, whereas binding to other receptors causes the opposite response—vasoconstriction plus sodium and water retention. Inhibitors to ET-1 have been approved for the treatment of pulmonary hypertension. Prostacyclin is a vasodilator that is produced by the actions of cyclooxygenases (COX-1 and COX-2) on arachidonic acid. It has the additional properties of opposing clot formation (antithrombotic), decreasing platelet activity, and inhibiting the release of growth factors from macrophages and the endothelial cells. Nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit these cyclooxygenases have been associated with cardiovascular disease risk in healthy people and in those with a known cardiovascular disease.20,21

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Venous Pressure The main determinants of venous blood pressure are (1) the volume of fluid within the veins and (2) the compliance (distensibility) of the vessel walls. The venous system typically accommodates about 66% of the total blood volume at any time, with venous pressure averaging less than 10 mm Hg. The systemic arteries accommodate about 11% of the total blood volume, with an average arterial pressure (blood pressure) of about 100 mm Hg; the remainder of the blood volume is within the heart, capillaries, and pulmonary circulation. The sympathetic nervous system controls venous compliance. The walls of the veins are highly innervated by sympathetic fibers that control venous smooth muscle. Rather than constriction that would occur in the arteries, smooth muscle contraction in the veins results in stiffening of the vessel walls. This stiffening reduces venous distensibility and increases venous blood pressure, thus forcing more blood through the veins and into the right heart. Two other mechanisms that increase venous pressure and venous return to the heart are (1) the skeletal muscle pump and (2) the respiratory pump. During skeletal muscle contraction, the veins within the muscles are partially compressed, causing decreased venous capacity and increased return to the heart (see Fig. 25.19, B). The respiratory pump acts during inspiration, when the veins of the abdomen are partially compressed by the downward movement of the diaphragm. Increased abdominal pressure moves blood toward the heart.

Regulation of the Coronary Circulation Coronary blood flow is directly proportional to the perfusion pressure and inversely proportional to the vascular resistance of the coronary bed. Coronary perfusion pressure is the difference between pressure in the aorta and pressure in the coronary vessels. Thus, aortic pressure is the driving pressure for the arteries and arterioles that perfuse the myocardium. Vasodilation and vasoconstriction maintain coronary blood flow despite stresses imposed by the constant contraction and relaxation of the heart muscle and despite shifts (within a physiologic range) of coronary perfusion pressure. Several unique anatomic factors influence coronary blood flow. Because of their anatomic location, the aortic valve cusps can obstruct coronary blood flow by occluding the openings of the coronary arteries during systole. Also during systole, the coronary arteries are compressed by ventricular contraction. The resulting systolic compressive effect is particularly evident in the subendocardial layers of the left ventricular wall and can greatly increase resistance to coronary blood flow, with the result that most left ventricular coronary blood flow occurs during diastole. During the period of systolic compression, when flow is slowed or stopped, myoglobin, a protein in heart muscle that binds O2, provides the supply of O2 to the myocardium. Myoglobin's O2 levels are replenished during diastole.

Autoregulation Autoregulation (automatic self-regulation) enables organs to regulate blood flow by altering the resistance (diameter) in their arterioles. Autoregulation in the coronary circulation maintains the blood flow at a nearly constant rate at perfusion pressures (MAP) between 60 and 140 mm Hg when other influencing factors are held constant. Thus autoregulation helps to ensure constant coronary blood flow despite shifts in the perfusion

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pressure within the stated range. Given that blood flow is directly related to pressure and inversely related to resistance, for flow to stay constant as pressure decreases, resistance also has to decrease; therefore the mechanisms underlying autoregulation must be related to control of smooth muscle contraction in the arteriolar walls.

Autonomic Regulation Although the coronary vessels themselves contain sympathetic (α- and β-adrenergic) and parasympathetic neural receptors, coronary blood flow during regular activity is regulated locally by the factors that cause autoregulation. During exercise, however, the vasodilating effects of β2-receptors on the smaller coronary resistance arteries are responsible for about 25% of any increase in blood flow. At the same time, α-adrenergic receptors in larger arteries cause vasoconstriction to direct the blood flow to the inner layers of the myocardium.

Quick Check 25.6 1. Identify the factors regulating blood pressure. 2. Why is capillary flow increased with increased mean arterial pressure? 3. Define natriuretic peptides and adrenomedullin.

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The Lymphatic System The lymphatic system is a one-way network of lymphatic vessels and the lymph nodes (Figs. 25.25 and 25.26) that is important for immune function, fluid balance, and transport of lipids, hormones, and cytokines and is considered to be part of the circulatory system. Every day about 3 liters of fluid filters out of venous capillaries in body tissues and is not reabsorbed. This fluid becomes the lymph that is carried by the lymphatic vessels to the chest, where it enters the venous circulation. The lymphatic vessels run in the same sheaths with the arteries and veins. (Lymph nodes and lymphoid tissues are described in Chapter 7.) The lymphatic capillaries are closed at the distal ends, as shown in Fig. 25.27.

FIGURE 25.25 Role of the Lymphatic System in Fluid Balance. Fluid from plasma flowing through the capillaries moves into interstitial spaces. Although most of this interstitial fluid is either absorbed by tissue cells or reabsorbed by blood capillaries, some of the fluid tends to accumulate in the interstitial spaces. This lymph then diffuses into the lymphatic vessels that carry it to the lymph nodes and then into the systemic venous blood. Green is used to diagram the lymphatic vessels although the lymphatic vessels, particularly the smaller ones, are almost transparent. (Modified from Thibodeau GA, Patton KT: Structure & function of the body, ed 13, St Louis, 2008, Elsevier.)

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FIGURE 25.26

Principal Organs of the Lymphatic System. (From VanMeter KC, Hubert RJ: Microbiology for the healthcare professional, St Louis, 2010, Mosby.)

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FIGURE 25.27

Lymphatic Capillaries. A, Schematic representation of lymphatic capillaries. B, Anatomic components of microcirculation.

In this pumpless system, a series of valves ensures one-way flow of the excess interstitial fluid (now called lymph) toward the heart. Lymph consists primarily of water and small amounts of dissolved proteins, mostly albumin, that are too large to be reabsorbed into the less permeable blood capillaries. Lymph also carries two types of immune system cells: lymphocytes and antigen-presenting cells. The antigen-presenting cells are carried to the next lymph node in the system, whereas lymphocytes traffic between lymph nodes. Once within the lymphatic system, lymph travels through lymphatic venules and veins that drain into one of two large ducts in the thorax: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains lymph from the right arm and the right side of the head and thorax, whereas the larger thoracic duct receives lymph from the rest of the body

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(see Fig. 25.23). The right lymphatic duct and the thoracic duct drain lymph into the right and left subclavian veins, respectively. Lymphatic veins are thin walled like the veins of the cardiovascular system. In larger lymphatic veins, endothelial flaps form valves similar to those in blood-carrying veins (see Fig. 25.27). The valves allow lymph to flow in only one direction, because lymphatic vessels are compressed intermittently by skeletal muscle contraction, pulsating expansion of the artery in the same sheath, and contraction of the smooth muscles in the walls of the lymphatic vessels. As lymph is transported toward the heart, it is filtered through thousands of beanshaped lymph nodes clustered along the lymphatic vessels (see Fig. 25.26). Lymph enters the nodes through afferent lymphatic vessels, filters through the sinuses in the node, and leaves by way of efferent lymphatic vessels. Lymph flows slowly through a node, allowing phagocytosis of foreign substances within the node and delivery of lymphocytes. (Phagocytosis is described in Chapter 6.)

Quick Check 25.7 1. Why is the lymphatic system considered a circulatory system? 2. What happens to lymph in lymph nodes?

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Summary Review Circulatory System 1. The circulatory system is part of the body's transport and communication systems. It delivers O2, nutrients, metabolites, hormones, neurochemicals, proteins, and blood cells, including lymphocytes and leukocytes, throughout the body and carries metabolic wastes to the kidneys, lungs, and liver for excretion. 2. The circulatory system consists of the heart and the blood and lymphatic vessels and is made up of two separate but conjoined, serially connected pump systems: the pulmonary circulation and the systemic circulation. The lymphatic system is a one-way network consisting of lymphatic vessels and lymph nodes. 3. The low-pressure pulmonary circulation is driven by the right side of the heart; its function is to deliver blood to the lungs for oxygenation. 4. The higher pressure systemic circulation is driven by the left side of the heart and functions to provide oxygenated blood, nutrients, and other key substances to body tissues and transport waste products to the lungs, kidneys, and liver for excretion. 5. The lymphatic vessels collect fluids from the interstitium and return the fluids to the circulatory system; lymphatic vessels also deliver antigens, microorganisms, and cells to the lymph nodes.

Heart 1. The heart consists of four chambers (two atria and two ventricles), four valves (two atrioventricular valves and two semilunar valves), a muscular wall, a fibrous skeleton, a conduction system, nerve fibers, systemic vessels (the coronary circulation), and openings where the great vessels enter the atria and ventricles. 2. The heart wall, which encloses the heart and divides it into chambers, is made up of three layers: the epicardium (outer layer), the myocardium (muscular layer), and the endocardium (inner lining). The heart lies within the pericardium, a doublewalled sac. 3. The myocardial layer of the two atria, which receive blood entering the heart, is thinner than the myocardial layer of the ventricles, which have to be stronger to squeeze blood out of the heart. 4. The right and left sides of the heart are separated by portions of the heart wall called the interatrial septum and the interventricular septum. 5. Deoxygenated (venous) blood from the systemic circulation enters the right atrium through the superior and inferior venae cavae. From the right atrium, the blood passes through the right atrioventricular (tricuspid) valve into the right ventricle. In the ventricle, the blood flows from the inflow tract to the outflow tract and then through the pulmonary semilunar valve (pulmonary valve) into the pulmonary artery, which delivers it to the lungs for oxygenation. 6. Oxygenated blood from the lungs enters the left atrium through the four

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pulmonary veins (two from the left lung and two from the right lung). From the left atrium, the blood passes through the left atrioventricular valve (mitral valve) into the left ventricle. In the ventricle, the blood flows from the inflow tract to the outflow tract and then through the aortic semilunar valve (aortic valve) into the aorta, which delivers it to systemic arteries of the entire body. 7. There are four heart valves. The atrioventricular valves ensure one-way flow of blood from the atria to the ventricles. The semilunar valves ensure one-way blood flow from the right ventricle to the pulmonary artery and from the left ventricle to the aorta. The valves are supported by a fibrous skeleton. 8. The pumping action of the heart consists of two phases: diastole, during which the myocardium relaxes and the ventricles fill with blood; and systole, during which the myocardium contracts, forcing blood out of the ventricles. A cardiac cycle consists of one systolic contraction and the diastolic relaxation that follows it. Each cardiac cycle represents one heartbeat. 9. Coronary circulation provides O2 and nutrients to the myocardium and other heart structures. Oxygenated blood enters the coronary arteries through openings from the aorta, and deoxygenated blood from the coronary veins enters the right atrium through the coronary sinus. 10. The conduction system of the heart generates and transmits electrical impulses (cardiac action potentials) that stimulate systolic contractions. The autonomic nerves (sympathetic and parasympathetic fibers) can adjust heart rate and force of contraction, but they do not originate the heartbeat. 11. The normal electrocardiogram is the sum of all cardiac action potentials. The P wave represents atrial depolarization; the QRS complex is the sum of all ventricular cell depolarizations. The ST interval occurs when the entire ventricular myocardium is depolarized. 12. Cardiac action potentials are generated by the sinoatrial node at a rate of 60 to 100 impulses per minute. The impulses can travel through the conduction system of the heart, stimulating myocardial contraction as they go. 13. Each cardiac action potential travels from the SA node to the AV node to the bundle of His (atrioventricular bundle), through the bundle branches, and finally to the Purkinje fibers and ventricular myocardium, where the impulse stops. It is prevented from reversing its path by the refractory period of cells that have just been polarized. The refractory period ensures that diastole (relaxation) will occur, thereby completing the cardiac cycle. 14. Cells of the cardiac conduction system have the properties of automaticity and rhythmicity. Automatic cells return to threshold and depolarize rhythmically without an outside stimulus. The cells of the sinoatrial node depolarize faster than other automatic cells, making it the natural pacemaker of the heart. If the SA node is disabled, the next fastest pacemaker, the AV node, takes over. 15. Adrenergic receptor number, type, and function govern autonomic (sympathetic) regulation of heart rate, contractile force, and the dilation or constriction of coronary arteries. The presence of specific receptors on the myocardium and coronary vessels determines the effects of the neurotransmitters norepinephrine and epinephrine. 16. Unique features that distinguish myocardial cells from skeletal cells enable myocardial cells to transmit action potentials faster (through intercalated disks),

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synthesize more ATP (because of a large number of mitochondria), and have readier access to ions in the interstitium (because of an abundance of transverse tubules). These combined differences enable the myocardium to work constantly, which is not required by skeletal muscle. 17. Cross-bridges between actin and myosin enable contraction. Calcium ions interacting with the troponin complex help initiate the contraction process. Subsequently, myocardial relaxation begins as troponin releases calcium ions. 18. Cardiac performance is affected by preload, afterload, myocardial contractility, and heart rate. 19. Preload, or pressure generated in the ventricles at the end of diastole, depends on the amount of blood in the ventricle. Afterload is the resistance to ejection of the blood from the ventricle. Afterload depends on pressure in the aorta. 20. Myocardial stretch determines the force of myocardial contraction; thus the greater the stretch, the stronger the contraction up to a certain point. This relationship is known as the Frank-Starling law of the heart. 21. Contractility is the potential for myocardial fiber shortening during systole. It is determined by the amount of stretch during diastole (i.e., preload) and by sympathetic stimulation of the ventricles. 22. The heart rate is determined by the sinoatrial node and by components of the autonomic nervous system, including cardiovascular control centers in the brain, receptors in the aorta and carotid arteries, and hormones, including catecholamines (epinephrine, norepinephrine).

Systemic Circulation 1. Blood flows from the left ventricle into the aorta and from the aorta into arteries that eventually branch into arterioles and capillaries, the smallest of the arterial vessels. O2, nutrients, and other substances needed for cellular metabolism pass from the capillaries into the tissues, where they are taken up by the cells. Capillaries also absorb metabolic waste products from the tissues. 2. Venules, the smallest veins, receive capillary blood. From the venules, the venous blood flows into larger and larger veins until it reaches the venae cavae, through which it enters the right atrium. 3. Vessel walls have three layers: the tunica intima (inner layer), the tunica media (middle layer), and the tunica externa (the outer layer). 4. Layers of the vessel wall differ in thickness and composition from vessel to vessel, depending on the vessel's size and location within the circulatory system. In general, the tunica media of arteries close to the heart has more elastic fibers (elastic arteries) because these arteries must be able to distend during systole and recoil during diastole. Arteries farther from the heart contain more smooth muscle fibers (muscular arteries) because they constrict and dilate to control blood pressure and volume within specific capillary beds. 5. Blood flow into the capillary beds is controlled by the contraction and relaxation of smooth muscle bands (precapillary sphincters) at junctions between metarterioles and capillaries. 6. Endothelial cells line the blood vessels. The endothelium is a life-support tissue; it

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functions as a filter (altering permeability), changes in vasomotion (constriction and dilation), and is involved in clotting and inflammation. 7. Blood flow through the veins is assisted by the contraction of skeletal muscles (the muscle pump), and backward flow is prevented by one-way valves, which are particularly important in the deep veins of the legs. 8. Blood flow is affected by blood pressure, resistance to flow within the vessels, velocity of the blood, anatomic features that may cause turbulent or laminar flow, and compliance (distensibility) of the vessels. 9. The Poiseuille law states that resistance is directly related to tube length and blood viscosity, and inversely related to the radius of the tube. 10. Total resistance, or the resistance to flow within the entire systemic circulatory system, depends on the combined lengths and radii of all the vessels within the system and on whether the vessels are arranged in series (greater resistance) or in parallel (lesser resistance). 11. Blood flow is also influenced by neural stimulation (vasoconstriction or vasodilation) and by autonomic features that cause turbulence within the vascular lumen (e.g., protrusions from the vessel wall, twists and turns, vessel branching). 12. Arterial blood pressure is influenced and regulated by factors that affect cardiac output (heart rate, stroke volume), total resistance within the system, and blood volume. 13. ADH, the RAAS system, and NPs can all alter blood volume and thus blood pressure. 14. Venous blood pressure is influenced by blood volume within the venous system and compliance of the venous walls. 15. Blood flow through the coronary circulation is governed by the same principles as flow through other vascular beds plus two adaptations dictated by cardiac dynamics. First, blood flows into the coronary arteries during diastole rather than systole, because during systole the cusps of the aortic semilunar valve block the openings of the coronary arteries. Second, systolic contraction inhibits coronary artery flow by compressing the coronary arteries. 16. Autoregulation enables the coronary vessels to maintain optimal perfusion pressure despite systolic compression. 17. Myoglobin in heart muscle stores O2 for use during the systolic phase of the cardiac cycle.

The Lymphatic System 1. The vessels of the lymphatic system run in the same sheaths as the arteries and veins. 2. Lymph (interstitial fluid) is absorbed by lymphatic venules in the capillary beds and travels through ever larger lymphatic veins until it empties through the right lymphatic duct or thoracic duct into the right or left subclavian veins, respectively. 3. As lymph travels toward the thoracic ducts, it passes through thousands of lymph nodes clustered around the lymphatic veins. The lymph nodes are sites of immune function and are ideally placed to sample antigens and cells carried by the lymph from the periphery of the body into the central circulation.

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Key Terms A band, 572 Actin, 572 Adrenomedullin (ADM), 584 Afferent lymphatic vessel, 587 Afterload, 575 Angiogenesis, 568 Aorta, 565 Aortic semilunar valve, 566 Arteriogenesis, 568 Arteriole, 577 Artery, 577 Atrioventricular node (AV) node, 569 Atrioventricular (AV) valve, 565 Automatic cell, 570 Automaticity, 570 Autoregulation, 585 Bainbridge reflex, 576 Baroreceptor reflex, 576 Blood flow, 577 Blood velocity, 581 Bundle of His (atrioventricular bundle), 569 Capillary, 577 Cardiac action potential, 568 Cardiac cycle, 567 Cardiac output, 574 Cardiac vein, 567 Cardiomyocyte, 564 Cardiovascular vasomotor control center, 576 Chordae tendineae, 565 Circumflex artery, 568 Collateral artery, 568 Conduction system, 568 Coronary artery, 567 Coronary circulation, 567 Coronary ostium (pl., ostia), 567 Coronary perfusion pressure, 585 Coronary sinus, 567 Cross-bridge theory of muscle contraction, 573 Depolarization, 570 Diastole, 567 Diastolic blood pressure, 582 Diastolic depolarization, 570 Efferent lymphatic vessel, 587

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Ejection fraction, 574 Elastic artery, 577 Endocardium, 564 Endothelial cell, 577 Endothelium, 577 Epinephrine, 583 Excitation-contraction coupling, 573 Fenestration, 577 Frank-Starling law of the heart, 575 Great cardiac vein, 568 H band, 573 Heart rate, 571 Hematocrit, 579 I band, 572 Inferior vena cava (pl., cavae), 565 Inotropic agent, 576 Intercalated disk, 571 Laminar flow, 581 Laplace law, 574 Left anterior descending (LAD) artery, 567 Left atrium, 565 Left bundle branch (LBB), 569 Left coronary artery (LCA), 567 Left heart, 563 Left ventricle, 565 Lumen, 577 Lymph, 586 Lymph node, 587 Lymphatic vein, 586 Lymphatic venule, 586 M line, 573 Mean arterial pressure (MAP), 582 Mediastinum, 563 Metarteriole, 577 Mitral and tricuspid complex, 566 Mitral valve, 566 Muscle pump, 577 Muscular artery, 577 Myocardial contractility, 573 Myocardial oxygen consumption (MV̇O2), 573, 573 Myocardium, 564 Myoglobin, 585 Myosin, 572 Natriuretic peptide (NP), 583 Nitric oxide (NO), 584 P wave, 570 Pacemaker, 568

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Papillary muscle, 565 Perfusion, 582 Pericardial cavity, 564 Pericardial fluid, 564 Pericardial sac, 564 Pericardium, 564 Peripheral vascular system, 577 Poiseuille law, 578 PR interval, 570 Precapillary sphincter, 577 Preload, 574 Pressure, 578 Prolapse, 565 Pulmonary artery, 565 Pulmonary circulation, 563 Pulmonary semilunar valve, 566 Pulmonary vein, 565 Pulse pressure, 582 Purkinje fiber, 570 QRS complex, 570 QT interval, 570 Radius (diameter), 578 Refractory period, 570 Repolarization, 570 Resistance, 578 Rhythmicity, 570 Right atrium, 565 Right bundle branch (RBB), 569 Right coronary artery (RCA), 567 Right heart, 563 Right lymphatic duct, 586 Right ventricle, 565 Sarcomere, 573 Semilunar valve, 566 Shear stress, 568 Sinoatrial node (SA node, sinus node), 569 Stenosis, 568 ST interval, 570 Stroke volume, 574 Superior vena cava (pl., cavae), 565 Systemic circulation, 563 Systemic vascular resistance (SVR), 576 Systole, 567 Systolic blood pressure, 581 Systolic compressive effect, 585 T wave, 570 Thoracic duct, 586

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Titin, 572 Total peripheral resistance (TPR), 576 Total resistance, 579 Tricuspid valve, 565 Tropomyosin molecule, 572 Troponin, 572 Tunica externa (adventitia), 577 Tunica intima, 577 Tunica media, 577 Turbulent (flow), 581 Vasa vasorum, 577 Vascular compliance, 581 Vasoconstriction, 577 Vasodilation, 577 Vein, 577 Venule, 577 Viscosity, 579 Z line, 573

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References 1. Rajendran P, et al. The vascular endothelium and human diseases. Int J Biol Sci. 2013;9(10):1057–1069. 2. Lin Z, Pu WT. Strategies for cardiac regeneration and repair. Sci Transl Med. 2014;6(239):239rv1. 3. Kutty S, et al. Patent foramen ovale: the known and the to be known. J Am Coll Cardiol. 2012;59(19):1665–1671. 4. Tobis J, Shenoda M. Percutaneous treatment of patent foramen ovale and atrial septal defects. J Am Coll Cardiol. 2012;60(19):1722–1732. 5. Klabunde RE. Cardiovascular physiology concepts. ed 2. Lippincott, Williams & Wilkins: Baltimore; 2012. 6. Rubart M, Zipes DP. Genesis of cardiac arrhythmias. Mann DL, et al. Braunwald's heart disease: a textbook of cardiovascular medicine. ed 10. Saunders: Philadelphia; 2015:629–661 [pp 33]. 7. Opie LH, Bers DM. Mechanisms of cardiac contraction and relaxation. Mann DL, et al. Braunwald's heart disease: a textbook of cardiovascular medicine. ed 10. Saunders: Philadelphia; 2015:429–453. 8. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114:1052– 1068. 9. Deussen A, et al. Mechanisms of metabolic coronary flow regulation. J Mol Cell Cardiol. 2012;52(4):794–801. 10. Sakata Y, et al. Left ventricular stiffening as therapeutic target for heart failure with preserved ejection fraction. Circ J. 2013;77(4):886–892. 11. Ababneh AA, et al. Normal limits for left ventricular ejection fraction and volumes estimated with gated myocardial perfusion imaging in patients with normal exercise test results: influence of tracer, gender, and acquisition camera. J Nucl Cardiol. 2000;7(6):661–668. 12. Davidson CJ, Bonow RO. Cardiac catheterization. Mann DL, et al. Braunwald's heart disease: a textbook of cardiovascular 1404

medicine. ed 10. Saunders: Philadelphia; 2015:364–391. 13. Flynn A, et al. Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms. Heart Fail Rev. 2010;15(6):605– 611. 14. Goegel B, et al. Impact of acute normobaric hypoxia on regional and global myocardial function: a speckle tracking echocardiography study. Int J Cardiovasc Imaging. 2013;29(3):561–567. 15. Hoit BD, Walsh RA. Normal physiology of the cardiovascular system. Fuster V, et al. Hurst's the heart. ed 13. McGraw-Hill: Philadelphia; 2011. 16. Crystal GJ, Salem MR. The Bainbridge and the “reverse” Bainbridge reflexes: history, physiology, and clinical relevance. Anesth Analg. 2012;114(3):520–532. 17. Volpe M, et al. Natriuretic peptides in cardiovascular diseases: current use and perspectives. Eur Heart J. 2014;35(7):419–425. 18. Perkel D, et al. The potential effects of IGF-1 and GH on patients with chronic heart failure. J Cardiovasc Pharmacol Ther. 2012;17(1):72–78. 19. Bergler-Klein J, et al. The role of biomarkers in valvular heart disease: focus on natriuretic peptides. Can J Cardiol. 2014;30(9):1027–1034. 20. Schjerning Olsen AM, et al. The impact of NSAID treatment on cardiovascular risk—insight from Danish observational data. Basic Clin Pharmacol Toxicol. 2014;115(2):179–184. 21. Singh BK, et al. Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity. Expert Opin Drug Metab Toxicol. 2014;10(2):143–156.

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Alterations of Cardiovascular Function Valentina L. Brashers

CHAPTER OUTLINE Diseases of the Veins, 591 Varicose Veins and Chronic Venous Insufficiency, 591 Thrombus Formation in Veins, 591 Superior Vena Cava Syndrome, 592 Diseases of the Arteries, 592 Hypertension, 592 Orthostatic (Postural) Hypotension, 596 Aneurysm, 596 Thrombus Formation, 597 Embolism, 598 Peripheral Vascular Disease, 598 Atherosclerosis, 599 Peripheral Artery Disease, 601 Coronary Artery Disease, Myocardial Ischemia, and Acute Coronary Syndromes, 602 Disorders of the Heart Wall, 611 Disorders of the Pericardium, 611 Disorders of the Myocardium: the Cardiomyopathies, 613 Disorders of the Endocardium, 614 Manifestations of Heart Disease, 620 Heart Failure, 620 Dysrhythmias, 623 Shock, 624 Impairment of Cellular Metabolism, 624 Clinical Manifestations of Shock, 627 Treatment for Shock, 628 Types of Shock, 628 Multiple Organ Dysfunction Syndrome, 632

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Our understanding of the pathophysiology of cardiovascular diseases is evolving rapidly. Neurohumoral, genetic, inflammatory, and metabolic factors are now the focus. This new information is leading to improvements in prevention and treatment.

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Diseases of the Veins Varicose Veins and Chronic Venous Insufficiency A varicose vein is a vein in which blood has pooled, producing distended, tortuous, and palpable vessels (Fig. 26.1). Risk factors include age, female sex, family history of varicose veins, obesity, pregnancy, deep venous thrombosis (DVT), and previous leg injury. Varicose veins typically involve the saphenous veins of the leg and are caused by (1) injury or disease involving the saphenous veins that damages one or more valves or (2) gradual venous distention caused by the action of gravity on blood in the legs.

FIGURE 26.1 Varicose Veins of the Leg (Arrow). (From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 8, Philadelphia, 2010, Saunders. Courtesy Dr. Magruder C. Donaldson, Brigham and Women's Hospital, Boston, Mass.)

If a valve is damaged, volume and pressure increase within the vessel. The vein swells as it becomes engorged and surrounding tissue becomes edematous because increased hydrostatic pressure pushes plasma through the stretched vessel wall. Venous distention develops over time, especially in individuals who habitually stand for long periods, wear constricting garments, or cross the legs at the knees, which diminishes the action of the muscle pump (see Fig. 25.19). Eventually the pressure in the vein damages venous valves, rendering them incompetent and unable to maintain normal venous pressure. Varicose veins and valvular incompetence can progress to chronic venous insufficiency, especially in obese individuals. Chronic venous insufficiency (CVI) is inadequate venous return over a long period. Venous hypertension, circulatory stasis, and tissue hypoxia cause an inflammatory reaction in vessels and tissue leading to fibrosclerotic remodeling of the

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skin and then to ulceration. Symptoms include edema of the lower extremities and hyperpigmentation of the skin of the feet and ankles. Poor circulation makes tissues vulnerable to trauma and infection resulting in the formation of venous stasis ulcers (Fig. 26.2) and cellulitis.

FIGURE 26.2

Venous Stasis Ulcer. (From Rosai J: Ackerman's surgical pathology, ed 7, vol 2, St Louis, 1989, Mosby.)

Treatment of varicose veins and CVI begins conservatively with elevating the legs, wearing compression stockings, and performing physical exercise. Invasive management includes endovenous ablation, sclerotherapy or surgical ligation, and conservative vein resection.

Thrombus Formation in Veins A thrombus is a blood clot that remains attached to a vessel wall (see Fig. 23.22). A detached thrombus is a thromboembolus. Venous thrombi are more common than arterial thrombi because flow and pressure are lower in the veins than in the arteries. Deep venous thrombosis (DVT) occurs primarily in the lower extremity. Three factors (triad of Virchow) promote venous thrombosis: (1) venous stasis (e.g., immobility, age, heart failure), (2) venous endothelial damage (e.g., trauma, surgery, intravenous medications), and (3) hypercoagulable states (e.g., inherited disorders, malignancy, pregnancy, use of oral contraceptives or hormone replacement therapy). Orthopedic trauma or surgery, spinal cord injury, and obstetric/gynecologic conditions are associated with a high likelihood of DVT. Inherited hypercoagulability states increase the risk for DVT, especially in association with other risk factors, such as immobility or pregnancy. The most common inherited abnormality is factor V Leiden mutation, which affects 3% to 8% of the population. Other inherited hypercoagulability states are caused by prothrombin mutations and deficiencies of protein C, protein S, and antithrombin. Accumulation of clotting factors and platelets leads to thrombus formation in the vein, often near a venous valve. Inflammation around the thrombus promotes further platelet aggregation, and the thrombus propagates (grows) proximally. This inflammation may cause pain and redness, but is usually not accompanied by clinical symptoms or signs. If

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the thrombus creates significant obstruction to venous blood flow, increased pressure in the vein behind the clot may lead to edema of the extremity. Most thrombi will eventually dissolve without treatment; however, untreated DVT is associated with a high risk of thromboembolization to the lung (pulmonary embolism) (see Chapter 29). Persistent venous obstruction may lead to CVI and postthrombotic syndrome with associated pain, edema, and ulceration of the affected limb. Because DVT is usually asymptomatic and difficult to detect clinically, prevention is important in at-risk individuals and includes early ambulation, pneumatic devices, and prophylactic anticoagulation. If thrombosis does occur, diagnosis is confirmed by a combination of serum D-dimer measurement and Doppler ultrasonography. Management most often consists of anticoagulation therapy using heparin (low-molecular-weight heparin) and warfarin. New oral anticoagulant therapies, such as factor Xa inhibitors and direct thrombin inhibitors, have been shown to have a more favorable benefit-to-risk ratio and are rapidly becoming the treatments of choice.1 Thrombolytic therapy or placement of an inferior vena cava filter may be indicated in selected individuals.

Superior Vena Cava Syndrome Superior vena cava syndrome (SVCS) is a progressive occlusion of the superior vena cava (SVC) that leads to venous distention in the upper extremities and head. The most common cause is bronchogenic cancer followed by lymphomas and metastasis of other cancers. Other less common causes include tuberculosis, mediastinal fibrosis, and cystic fibrosis. Invasive therapies (pacemaker wires, central venous catheters, and pulmonary artery catheters) with associated thrombosis now account for nearly half of cases. The SVC is a relatively low-pressure vessel that lies in the closed thoracic compartment; therefore spaceoccupying lesions can easily compress the SVC. The SVC is surrounded by lymph nodes and abuts the right mainstem bronchus, which commonly becomes involved in thoracic cancers and compresses the SVC during tumor growth. Clinical manifestations of SVCS are edema and venous distention in the upper extremities and face, including the ocular beds. Affected persons complain of a feeling of fullness in the head or tightness of shirt collars, necklaces, and rings. Cerebral edema may cause headache, visual disturbance, and impaired consciousness. The skin of the face and arms may become purple and taut, and capillary refill time is prolonged. Respiratory distress may be present because of bronchial compression. In infants, SVCS can lead to hydrocephalus. Diagnosis is made by chest X-ray, Doppler studies, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound. SVCS is an oncologic emergency. Treatment for malignant disorders can include radiation therapy, surgery, chemotherapy, and the administration of diuretics, steroids, and anticoagulants, as necessary. Treatment for nonmalignant causes may include bypass surgery using various grafts, thrombolysis (both locally and systemically), balloon angioplasty, and placement of intravascular stents.

Quick Check 26.1 1. What is chronic venous insufficiency, and how does it present clinically?

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2. What are the major risk factors for deep venous thrombosis? 3. Name three causes of superior vena cava syndrome.

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Diseases of the Arteries Hypertension Hypertension is consistent elevation of systemic arterial blood pressure. It has recently been redefined as a sustained systolic blood pressure (SBP) of 130 mm Hg or a diastolic blood pressure (DBP) of 80 mm Hg or greater2 (Table 26.1). One in three Americans has hypertension, and more than two thirds of those older than age 60 are affected.3 The chance of developing primary hypertension increases with age, although children are being diagnosed with increasing frequency (see Chapter 27). The prevalence of hypertension is higher in African Americans and in those with diabetes. Those who fall into the new category called elevated blood pressure are at risk for developing hypertension unless lifestyle modification and treatment are instituted. All stages of hypertension are associated with increased risk for target organ disease events, such as myocardial infarction (MI), kidney disease, and stroke. TABLE 26.1 Classification of Blood Pressure for Adults Age 18 Years and Older Category Normal Elevated Stage 1 hypertension Stage 2 hypertension Hypertensive crisis

Systolic (mm Hg) men after 55) Black race High dietary sodium intake Low dietary intake of potassium, calcium, magnesium Glucose intolerance Pathophysiology Hypertension results from a sustained increase in peripheral vascular resistance (PVR), an increase in circulating blood volume, or both.

Primary Hypertension Primary hypertension is the result of an extremely complicated interaction of genetics and the environment mediated by a host of neurohumoral effects that influence intravascular volume and PVR. Multiple pathophysiologic mechanisms mediate these effects, including the SNS, the RAAS, and natriuretic peptides. Inflammation, endothelial dysfunction, obesity-related hormones, and insulin resistance also contribute. Increased vascular volume is related to a decrease in renal excretion of salt, often referred to as a shift in the pressurenatriuresis relationship (Fig. 26.3). This means that for a given blood pressure, individuals with hypertension tend to secrete less salt in their urine.

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FIGURE 26.3 Factors That Cause a Shift in the Pressure-Natriuresis Relationship. Numerous factors have been implicated in the pathogenesis of sodium retention in individuals with hypertension. These factors cause less renal excretion of salt than would normally occur with increased blood pressure. This is called a shift in the pressure-natriuresis relationship and is thought to be a central process in the pathogenesis of primary hypertension. RAAS, Renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

Increased SNS activity causes increased heart rate and systemic vasoconstriction. This increases both cardiac output and peripheral vascular resistance, thus raising the blood pressure. Additional mechanisms of SNS-induced hypertension include structural changes in blood vessels (vascular remodeling), renal sodium retention (shift in pressure-natriuresis curve), insulin resistance, increased renin and angiotensin levels, and procoagulant effects. In hypertensive individuals, overactivity of the RAAS directly causes salt and water retention and increased vascular resistance (see Fig. 25.24). High levels of renin, angiotensin II (Ang II), and aldosterone also contribute to endothelial dysfunction, insulin resistance, platelet aggregation, and arteriolar remodeling. Remodeling is structural change in vessel walls that results in permanent increases in PVR and contributes to atherogenesis. The RAAS is associated with end-organ effects of hypertension, including coronary artery disease (CAD), renal disease, cardiac hypertrophy, and heart failure. Medications, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone blockers oppose the activity of the RAAS and are effective in reducing blood pressure and protecting against target organ damage. A second RAAS also has been described that has cardiovascular, cerebrovascular, and metabolic protective effects. Its discovery may lead to new and more effective medications (see Did You Know? The ReninAngiotensin-Aldosterone System [RAAS] and Cardiovascular Disease).

Did You Know? The Renin-Angiotensin-Aldosterone System (RAAS) and Cardiovascular Disease 1415

The RAAS has multiple effects on the cardiovascular system. There are two primary RAA systems. The best known includes the release of renin, the synthesis of Ang II through ACE, stimulation of the AT1 receptor (AT1R), and secretion of aldosterone. This system contributes to systemic vasoconstriction, renal salt and water retention, and remodeling of blood vessels, kidney, and the heart. Drugs that block this RAAS include ACE inhibitors, direct renin inhibitors, Ang II receptor blockers (ARBs), and aldosterone inhibitors. In contrast, the second RAAS serves a counterregulatory system. Activation of a second ACE pathway (ACE2) leads to the synthesis of angiotensin 1-7 from Ang II. Angiotensin 1-7 stimulates Mas receptors and has vasodilatory, antiproliferative, antifibrotic, and antithrombotic effects. These protective effects lead to lower blood pressure, less vascular inflammation and clotting, and decreased tissue remodeling and damage to target organ tissues. Research is underway to develop pharmacologic interventions, such as synthetic Mas agonists, Ang(1-7) formulations, and ACE2 activators that will stimulate these protective RAAS pathways. Data from Bahramali E et al: Clin Exp Hypertens 39(4):371-376, 2017; Carey RM: Am J Hypertens 30(4), 339-347, 2017; Mirabito Colafella KM, Danser AHJ: Hypertension 69(6):994999, 2017; Schmull S et al: Curr Hypertens Rev 12(3):170-180, 2016; Williams B: Ther Adv Cardiovasc Dis 10(3):118-125, 2016. The natriuretic hormones include atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin. They modulate renal sodium (Na+) excretion and require adequate potassium, calcium, and magnesium intake to function properly. Dysfunction of these hormones, along with alterations in the RAA system and the SNS, causes a shift in the pressure-natriuresis relationship leading to increased blood volume and blood pressure. With inadequate natriuretic function, a compensatory increase occurs in natriuretic peptide serum levels. High levels of these peptides therefore indicate dysfunction and are linked to an increased risk for ventricular hypertrophy, atherosclerosis, and heart failure in individuals with hypertension. Salt restriction combined with adequate intake of dietary potassium, magnesium, and calcium improves natriuretic peptide function. Innate and adaptive immunity with associated inflammation play a role in the pathogenesis of hypertension. Activation of immunity results in chronic inflammation with damage to endothelial cells, decreased production of vasodilators (such as nitric oxide), vascular remodeling, and smooth muscle contraction. Inflammation also contributes to insulin resistance, decreased natriuresis, and autonomic dysfunction. Obesity is recognized as an important risk factor for hypertension in both adults and children and contributes to many of the neurohumoral, metabolic, renal, and cardiovascular processes that cause hypertension. Obesity causes changes in the adipokines (i.e., leptin and adiponectin) and also is associated with increased activity of the SNS and RAAS. Obesity is linked to inflammation, endothelial dysfunction, insulin resistance, and an increased risk for cardiovascular complications from hypertension (see Did You Know? Obesity and Hypertension).

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Obesity and Hypertension Obesity is a well-known risk factor for hypertension. Obesity and increased caloric intake contribute to adipocyte dysfunction and ectopic fat deposition throughout the cardiovascular system. Adipocytes secrete adipokines, including leptin and adiponectin. The primary function of leptin is to interact with the hypothalamus to control body weight through appetite inhibition and increased metabolic rate. Chronically high levels of leptin noted in obesity, however, result in resistance to these weight-reducing functions. Adiponectin is a protein produced by adipose tissue but is reduced in obesity. With obesity, increased leptin and decreased adiponectin have been found to increase sympathetic nervous system and renin-angiotensin-aldosterone system activity, contribute to insulin resistance, decrease renal sodium excretion, promote inflammation, and stimulate myocyte hypertrophy. Other adipokines that are altered in obesity-related cardiovascular diseases include resistin, omentin, visfatin, and perivascular adipose tissue–derived relaxing factor. Obesity also is linked with endothelial dysfunction and release of vascular growth factors, which contribute to arterial remodeling. Taken together, these obesity-related changes result in vasoconstriction, salt and water retention, and renal dysfunction that contribute to the development of hypertension. Weight loss is an essential treatment for obesity-related hypertension. In severe obesity, bariatric surgery has been shown to cause long-standing remission of hypertension in many individuals. Data from Cabandugama PK et al: Med Clin North Am 101(1):129-137, 2017; Faulkner JL, Belin de Chantemele EJ: Hypertension 71(1):15-21, 2018; Jakobsen GS et al: J Am Med Assoc 319(3):291-301, 2018; Nizar JM, Bhalla V: Curr Hypertens Rep 19(8):60, 2017; Schutten MT et al: Physiology 32(3):197-209, 2017; Seravalle G, Grassi G: Pharmacol Res 122:1-7, 2017. Insulin resistance is common in hypertension, even in individuals without clinical diabetes. Insulin resistance is associated with decreased endothelial release of nitric oxide and other vasodilators. It also affects renal function and causes renal salt and water retention. Insulin resistance promotes overactivity of the SNS and RAAS. The interactions among obesity, hypertension, insulin resistance, and lipid disorders in metabolic syndrome result in a high risk of cardiovascular disease. It is likely that primary hypertension is an interaction among many of these factors, leading to sustained increases in blood volume and PVR. The pathophysiology of primary hypertension is summarized in Fig. 26.4.

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FIGURE 26.4 Pathophysiology of Hypertension. Numerous genetic vulnerabilities have been linked to hypertension and these, in combination with environmental risks, cause neurohumoral dysfunction (sympathetic nervous system [SNS], renin-angiotensin-aldosterone [RAA] system, natriuretic hormones) and promote inflammation and insulin resistance. Insulin resistance and neurohumoral dysfunction contribute to sustained systemic vasoconstriction and increased peripheral vascular resistance. Inflammation contributes to renal dysfunction, which, in combination with the neurohumoral alterations, results in renal salt and water retention and increased blood volume. Increased peripheral vascular resistance and increased blood volume are two primary causes of sustained hypertension.

Secondary Hypertension Secondary hypertension is caused by an underlying disease process or medication that raises PVR or cardiac output. Examples include renal vascular or parenchymal disease, adrenocortical tumors, adrenomedullary tumors (pheochromocytoma), and drugs (oral contraceptives, corticosteroids, antihistamines). If the cause is identified and removed before permanent structural changes occur, blood pressure returns to normal.

Complicated Hypertension As hypertension becomes more severe and chronic, tissue damage can occur in the blood vessels and tissues leading to target organ damage in the heart, kidney, brain, and eyes. Cardiovascular complications of sustained hypertension include left ventricular hypertrophy, angina pectoris, heart failure, coronary artery disease, myocardial infarction,

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and sudden death. Myocardial hypertrophy is mediated by the SNS and RAAS. Hypertrophy is characterized by a myocardium that is thickened, scarred, and less able to relax during diastole, leading to heart failure with preserved ejection fraction. Over time, the increased size of the heart muscle increases demand for oxygen delivery, the contractility of the heart is impaired, and the individual is at risk for myocardial infarction and heart failure with reduced ejection fraction. Vascular complications include hyaline sclerosis and accelerated atherosclerosis that can affect perfusion to any vascular bed. Hypertension also can contribute to the formation, dissection, and rupture of aneurysms (outpouchings in vessel walls). Renal manifestations of complicated hypertension include nephrosclerosis, renal arteriosclerosis, and renal insufficiency or failure. Microalbuminuria (small amounts of protein in the urine) occurs in many individuals with HTN and is now recognized as an early sign of impending renal dysfunction and increased risk for cardiovascular events. Complications specific to the retina include retinal vascular sclerosis, exudation, and hemorrhage. Cerebrovascular complications include transient ischemia, stroke, cerebral thrombosis, aneurysm, hemorrhage, and dementia. The pathologic effects of complicated hypertension are summarized in Table 26.2. TABLE 26.2 Pathologic Effects of Sustained, Complicated Primary Hypertension Site of Injury Mechanism of Injury Heart Myocardium Increased workload combined with diminished blood flow through coronary arteries Coronary Accelerated atherosclerosis (coronary artery disease) arteries Kidneys Reduced blood flow, increased arteriolar pressure, RAAS and SNS stimulation, and inflammation Brain Reduced blood flow and oxygen supply; weakened vessel walls, accelerated atherosclerosis Eyes (retinas) Retinal vascular sclerosis, increased retinal artery pressures Aorta Weakened vessel wall Arteries of Reduced blood flow and high pressures in lower arterioles, accelerated atherosclerosis extremities

Pathologic Effect Left ventricular hypertrophy, myocardial ischemia, heart failure Myocardial ischemia, myocardial infarction, sudden death Glomerulosclerosis and decreased glomerular filtration, end-stage renal disease Transient ischemic attacks, cerebral thrombosis, aneurysm, hemorrhage, acute brain infarction Hypertensive retinopathy, retinal exudates and hemorrhages Dissecting aneurysm Intermittent claudication, gangrene

RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

Hypertensive crisis is rapidly progressive hypertension in which systolic pressure is ≥180 mmHg and or diastolic pressure is ≥120 mmHg. It can occur in those with primary hypertension, but the reason why some people develop this complication and others do not is unknown. Other causes include complications of pregnancy, cocaine or amphetamine use, reaction to certain medications, adrenal tumors, and alcohol withdrawal. High arterial pressure renders the cerebral arterioles incapable of regulating blood flow to the cerebral capillary beds. High hydrostatic pressures in the capillaries cause vascular fluid to exude into the interstitial space. If blood pressure is not reduced, cerebral edema and cerebral dysfunction (encephalopathy) increase until death occurs. Besides encephalopathy, hypertensive crisis can cause papilledema, cardiac failure, uremia, retinopathy, and cerebrovascular accident and is considered a medical emergency.

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Clinical Manifestations The early stages of hypertension have no clinical manifestations other than elevated blood pressure; for this reason, hypertension is called a silent disease. Some hypertensive individuals never develop signs, symptoms, or complications, whereas others become very ill, and hypertension can be a cause of death. If elevated blood pressure is not detected and treated, it becomes established, setting the stage for the complications of hypertension that begin to appear during the fourth, fifth, and sixth decades of life. Most clinical manifestations of hypertensive disease are caused by complications that damage organs and tissues outside the vascular system. Besides elevated blood pressure, the signs and symptoms therefore tend to be specific for the organs or tissues affected. Evidence of heart disease, renal insufficiency, central nervous system dysfunction, impaired vision, impaired mobility, vascular occlusion, or edema can all be caused by sustained hypertension. Evaluation and Treatment Diagnosis of hypertension requires the measurement of blood pressure on at least two separate occasions, averaging two readings at least 2 minutes apart, with the following conditions: the person is seated, the arm is supported at heart level, the person must be at rest for at least 5 minutes, and the person should not have smoked or ingested any caffeine in the previous 30 minutes. Diagnostic tests for further evaluation of hypertension include 24-hour blood pressure monitoring in selected individuals; measurement of electrolytes, glucose, and lipids; and an electrocardiogram (ECG). Individuals who have elevated blood pressure are assumed to have primary hypertension unless their history, physical examination, or initial diagnostic screening indicates secondary hypertension. Once the diagnosis is made, a careful evaluation for other cardiovascular risk factors and for endorgan damage should be done. Treatment of primary hypertension depends on its severity. Management begins with lifestyle modification including exercise, dietary modifications including reducing salt intake, smoking cessation, and weight loss. Pharmacologic treatment is recommended for individuals who have existing or are at high risk for atherosclerotic cardiovascular disease, or for those who have Stage 2 hypertension.2 Commonly recommended medications include thiazide diuretics, ACE inhibitors or ARBs, and calcium channel blockers. Careful follow-up to support continued adherence, determine the response, and monitor for potential side effects of these medications is important.

Orthostatic (Postural) Hypotension The term orthostatic (postural) hypotension (OH) refers to a decrease in SBP of at least 20 mm Hg or a decrease in DBP of at least 10 mm Hg within 3 minutes of moving to a standing position. OH is usually associated with disorders that affect autonomic nervous function, affects men more often than women, and usually occurs between the ages of 40 and 70 years. It is a significant risk factor for falls and associated injury and for increased mortality. Normally when an individual stands, the gravitational changes on the circulation are compensated by a baroreceptor-mediated reflex that stimulates the SNS. This causes arteriolar and venous constriction and increased heart rate upon standing. Other compensatory mechanisms include mechanical factors, such as the closure of valves in the

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venous system, contraction of the leg muscles, and a decrease in intrathoracic pressure. These mechanisms are dysfunctional or inadequate in individuals with orthostatic hypotension; consequently, upon standing, blood pools in the lower extremities and normal arterial pressure cannot be maintained. Orthostatic hypotension may be acute or chronic. Acute orthostatic hypotension is common in the elderly and occurs when the normal regulatory mechanisms are inadequate as a result of (1) altered body chemistry, (2) drug action (e.g., antihypertensives, antidepressants), (3) prolonged immobility, (4) starvation, (5) physical exhaustion, (6) volume depletion (e.g., dehydration, diuresis, potassium or sodium depletion), or (7) any condition that results in venous pooling (e.g., pregnancy, extensive varicosities of the lower extremities). Chronic orthostatic hypotension may be (1) secondary to a specific disease or (2) primary (idiopathic). The conditions that cause secondary orthostatic hypotension are endocrine disorders (e.g., adrenal insufficiency, diabetes), metabolic disorders (e.g., porphyria), or diseases of the central or peripheral nervous systems (e.g., Parkinson disease, multiple system atrophy, intracranial tumors, cerebral infarcts, Wernicke encephalopathy, peripheral neuropathies). Cardiovascular autonomic neuropathy is a common cause of OH in persons with diabetes and is a serious and often overlooked complication. OH is often accompanied by dizziness, blurring or loss of vision, and syncope or fainting. When possible, acute OH and secondary chronic OH are managed by correction of the underlying condition. Primary OH and irreversible secondary OH are managed with a combination of nondrug (fluid and salt intake, thigh-high stockings) and drug therapies (mineralocorticoids and vasoconstrictors).

Quick Check 26.2 1. What are the major risk factors for hypertension? 2. Summarize the pathophysiology of primary hypertension. 3. What are the causes of orthostatic hypotension?

Aneurysm An aneurysm is a localized dilation or outpouching of a vessel wall or cardiac chamber (Fig. 26.5). The law of Laplace (discussed in detail in Chapter 25) can provide an understanding of the hemodynamics of an aneurysm. True aneurysms involve weakening in all three layers of the arterial wall (Fig. 26.6, A). Most are fusiform and circumferential, whereas saccular aneurysms are basically spherical in shape. False aneurysms are an extravascular hematoma that communicates with the intravascular space. A common cause of this type of lesion is a leak between a vascular graft and a natural artery.

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FIGURE 26.5

Aneurysm. A three-dimensional CT scan shows the aneurysm (A) involves the ascending thoracic aorta. D, Descending aorta; LV, left ventricle.

FIGURE 26.6 Longitudinal Sections Showing Types of Aneurysms. A, The fusiform circumferential and fusiform saccular aneurysms are true aneurysms, caused by weakening of the vessel wall. False and saccular aneurysms involve a break in the vessel wall, usually caused by trauma. B, Dissecting aneurysm of thoracic aorta (arrow). (B from Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)

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Vascular aneurysms most commonly occur in the thoracic or abdominal aorta. The aorta is particularly susceptible to aneurysm formation because of constant stress on the vessel wall and the absence of penetrating vasa vasorum in the media layer. Atherosclerosis is the most common cause of arterial aneurysms because plaque formation erodes the vessel wall and contributes to inflammation and release of proteinases that can further weaken the vessel. Hypertension also contributes to aneurysm formation by increasing wall stress. Collagen-vascular disorders (e.g., Marfan syndrome), syphilis, and other infections that affect arterial walls also can cause aneurysms. Cardiac aneurysms most commonly form after MI when intraventricular tension stretches the noncontracting infarcted muscle. The stretching produces infarct expansion, a weak and thin layer of necrotic muscle, and fibrous tissue that bulges with each systole. Clinical manifestations depend on where the aneurysm is located. Aortic aneurysms often are asymptomatic until they rupture and then cause severe pain and hypotension. Thoracic aortic aneurysms can cause dysphagia (difficulty swallowing) and dyspnea (breathlessness). An aneurysm that impairs flow to an extremity causes symptoms of ischemia. Cerebral aneurysms, which often occur in the circle of Willis, are associated with signs and symptoms of increased intracranial pressure and stroke. (Cerebral aneurysms are described in Chapter 17.) Aneurysms in the heart present with dysrhythmias, heart failure, and embolism of clots to the brain or other vital organs. The diagnosis of an aneurysm is usually confirmed by ultrasonography, CT, MRI, or angiography. Medical treatment is indicated for slow-growing aortic aneurysms, particularly in early stages, and includes cessation of smoking, reduction of blood pressure and blood volume, and implementation of β-adrenergic blockade. For aneurysms that are dilating rapidly or have become large, surgical treatment is indicated and usually includes replacement with a prosthetic graft. Aortic aneurysms can be complicated by the acute aortic syndromes, which include aortic dissection, hemorrhage into the vessel wall, or vessel rupture. Dissection of the layers of the arterial wall occurs when there is a tear in the intima and blood enters the wall of the artery (see Fig. 26.6, B). Dissections can involve any part of the aorta (ascending, arch, or descending) and can disrupt flow through arterial branches. Symptoms include severe pain in the neck, jaw, chest, back, or abdomen. Emergent evaluation and surgical intervention is critical.

Thrombus Formation As in venous thrombosis, arterial thrombi tend to develop when intravascular conditions promote activation of coagulation or when there is stasis of blood flow. These conditions include those in which there is intimal irritation or roughening (such as in surgical procedures and trauma), inflammation, infection, low intravascular volume and pressures, or obstructions that cause blood stasis and pooling within the vessels. (Mechanisms of coagulation are described in Chapter 22.) Inflammation of the endothelium leads to activation of the clotting cascade, causing platelets to adhere readily. An anatomic change in an artery (such as an aneurysm) can contribute to thrombus formation, particularly if the change results in a pooling of arterial blood. Valvular thrombi are most commonly associated with inflammation of the endocardium (endocarditis) and rheumatic heart disease. Widespread arterial thrombus formation can occur in shock when systemic

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inflammation activates the intrinsic and extrinsic pathways of coagulation, resulting in microvascular thrombosis throughout the systemic arterial circulation. Arterial thrombi pose two potential threats to the circulation. First, the thrombus may grow large enough to occlude the artery, causing ischemia in tissue supplied by the artery. Second, the thrombus may dislodge, becoming a thromboembolus that travels through the vascular system until it occludes flow into a distal systemic vascular bed. Diagnosis of arterial thrombi is usually accomplished through the use of Doppler ultrasonography and angiography. Pharmacologic treatment involves the administration of anticoagulants or thrombolytics. A balloon-tipped catheter can be used to remove or compress an arterial thrombus.

Embolism Embolism is the obstruction of a vessel by an embolus—a bolus of matter circulating in the bloodstream. The embolus may consist of a dislodged thrombus; an air bubble; an aggregate of amniotic fluid; an aggregate of fat, bacteria, or cancer cells; or a foreign substance. The types of emboli are summarized in Table 26.3. Most emboli arise from venous or arterial thrombi and travel in the bloodstream until they reach a vessel through which they cannot pass. Pulmonary emboli originate on the venous system (mostly from the deep veins of the legs) or in the right heart; arterial emboli most commonly originate in the left heart and are associated with thrombus formation associated with MI, valvular disease, left heart failure, endocarditis, and dysrhythmias. TABLE 26.3 Types of Emboli Type Arteries Arterial thromboembolism Veins Venous thromboembolism Air embolism Amniotic fluid embolism Bacterial embolism Fat embolism Foreign matter

Characteristics Dislodged thrombus; source is usually from heart; most common sites of obstruction are lower extremities (femoral and popliteal arteries), coronary arteries, and cerebral vasculature Dislodged thrombus; source is usually from lower extremities; obstructs branches of pulmonary artery Bolus of air displaces blood in vasculature; source usually room air entering circulation through IV lines; trauma to chest also may allow air from lungs to enter vascular space Bolus of amniotic fluid; extensive intra-abdominal pressure attending labor and delivery can force amniotic fluid into bloodstream of mother; introduces antigens, cells, and protein aggregates that trigger inflammation, coagulation, and immune responses Aggregates of bacteria in bloodstream; source is subacute bacterial endocarditis or abscess Globules of fat floating in bloodstream associated with trauma to long bones; lungs in particular are affected Small particles or fibers introduced during trauma or through an IV or intra-arterial line; coagulation cascade is initiated and thromboemboli form around particles

Embolism causes ischemia or infarction in tissues distal to the obstruction, producing organ dysfunction and pain. Infarction and subsequent necrosis of a central organ are lifethreatening. For example, occlusion of a coronary artery will cause an MI whereas occlusion of a cerebral artery causes a stroke (see Chapter 17).

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Quick Check 26.3 1. What are the major complications of aneurysms? 2. What is a thrombus? 3. Why are emboli dangerous?

Peripheral Vascular Disease Thromboangiitis Obliterans (Buerger Disease) Thromboangiitis obliterans (Buerger disease) is an autoimmune disease of the peripheral arteries. It is strongly associated with smoking. Thromboangiitis obliterans is characterized by the formation of thrombi filled with inflammatory and immune cells. Inflammatory cytokines and toxic oxygen free radicals contribute to accompanying vasospasm. Over time, these thrombi become organized and fibrotic and result in permanent occlusion of smalland medium-sized arteries in the feet and sometimes in the hands. The chief symptom of thromboangiitis obliterans is pain and tenderness of the affected part, usually affecting more than one extremity. Clinical manifestations include rubor (redness of the skin), which is caused by dilated capillaries under the skin, and cyanosis, which is caused by tissue ischemia. Chronic ischemia causes the skin to become thin and shiny and the nails to become thickened and malformed. In advanced disease, profound ischemia of the extremities can cause gangrene necessitating amputation. Thromboangiitis obliterans also has been associated with cerebrovascular disease (stroke), mesenteric disease, and rheumatic symptoms (joint pain). Diagnosis of thromboangiitis obliterans is made by identification of the following common features—age 40 years.3 The risk factors for PAD are the same as those previously described for atherosclerosis. It is especially prevalent in smokers and elderly individuals with diabetes. Lower extremity ischemia resulting from arterial obstruction in PAD can be gradual or acute. In most individuals, gradually increasing atherosclerotic obstruction to arterial blood flow in the iliofemoral vessels can result in leg pain with ambulation called intermittent claudication. If a thrombus forms over the atherosclerotic lesion, complete obstruction of blood flow can occur acutely, causing severe pain, loss of pulses, and skin color changes in the affected extremity. Evaluation for PAD requires a careful history and physical examination that focuses on finding evidence of atherosclerotic disease (e.g., bruits), determining a difference in blood pressure measured at the ankle versus the arm (ankle-brachial index), and measuring blood flow using duplex ultrasound, CT angiography, or magnetic resonance angiography. Treatment includes risk factor reduction (smoking cessation, exercise, and treatment of diabetes, hypertension, and dyslipidemia) and antiplatelet therapy. Symptomatic PAD should be managed with vasodilators in combination with antiplatelet or antithrombotic medications and cholesterol-lowering medications.4 If acute or refractory symptoms occur, emergent invasive catheterization followed by percutaneous or surgical revascularization may be indicated.

Coronary Artery Disease, Myocardial Ischemia, and Acute Coronary Syndromes Coronary artery disease (CAD) caused by atherosclerosis is the primary cause of heart disease in the United States. CAD can diminish the myocardial blood supply until

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deprivation impairs myocardial metabolism enough to cause myocardial ischemia, a local state in which the cells are temporarily deprived of blood supply. The cells remain alive but cannot function normally. Persistent ischemia or the complete occlusion of a coronary artery causes the acute coronary syndromes, including MI (heart attack).

Development of Coronary Artery Disease CAD accounts for 1 in 7 deaths in the United States, with an estimated 366,800 deaths each year.3 Risk factors for CAD are the same as those for atherosclerosis and can be categorized as conventional (major) versus nontraditional (novel) and as modifiable versus nonmodifiable. Conventional or major risk factors for CAD that are nonmodifiable include (1) advanced age, (2) male sex or women after menopause, and (3) family history. Aging and menopause are associated with increased exposure to risk factors and poor endothelial healing. Family history may contribute to CAD through genetics and shared environmental exposures. Many gene polymorphisms have been associated with CAD and its risk factors. Modifiable major risks include (1) dyslipidemia, (2) hypertension, (3) cigarette smoking, (4) diabetes and insulin resistance, (5) obesity, (6) sedentary lifestyle, and (7) atherogenic diet. Fortunately, modification of these factors can dramatically reduce the risk for CAD. Dyslipidemia. The link between CAD and abnormal levels of lipoproteins is well documented. The term lipoprotein refers to lipids, phospholipids, cholesterol, and triglycerides bound to carrier proteins. The cycle of lipoprotein synthesis is complex. Dietary fat is packaged into particles known as chylomicrons in the small intestine. Chylomicrons primarily contain triglycerides. Some of the triglycerides may be removed and either stored by adipose tissue or used by muscle as an energy source. The chylomicron remnants, composed mainly of cholesterol, are taken up by the liver. A series of chemical reactions in the liver results in the production of several lipoproteins that vary in density and function. These include verylow-density lipoproteins (VLDLs), primarily triglycerides and protein; low-density lipoproteins (LDLs), mostly cholesterol and protein; and high-density lipoproteins (HDLs), mainly phospholipids and protein. Although lipoproteins are necessary for many physiologic functions, they can accumulate in the serum. Dyslipidemia (or dyslipoproteinemia) refers to abnormal concentrations of serum lipoproteins as defined by the Third Report of the National Cholesterol Education Program.5 (Table 26.4). It is estimated that nearly half of the U.S. population has some form of dyslipidemia, especially among Caucasian and Asian populations.3 These abnormalities are the result of a combination of genetic and dietary factors. Primary or familial dyslipoproteinemias result from genetic defects that cause abnormalities in lipidmetabolizing enzymes and abnormal cellular lipid receptors. Secondary causes of dyslipidemia include the existence of several common systemic disorders, such as diabetes, hypothyroidism, pancreatitis, and renal nephrosis, as well as the use of certain medications, such as some diuretics, glucocorticoids, interferons, and antiretrovirals. TABLE 26.4 Criteria for Dyslipidemia*

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Total cholesterol Low-density lipoprotein Triglycerides High-density lipoprotein *All

Optimal

Near-Optimal

5 times the 99th percentile URL in patients with normal baseline values. In patients with elevated pre-procedure cTn in whom the cTn levels are stable (≤20% variation) or falling, the post-procedure cTn must rise by >20%. However, the absolute postprocedural value must still be at least five times the 99th percentile URL. In addition, one of the following elements is required: • New ischemic ECG changes; • Development of new pathological Q waves; • Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major epicardial artery or a side branch occlusion/thrombus, disruption of collateral flow or distal embolization. • Coronary artery bypass grafting (CABG)-related MI is arbitrarily defined as elevation of cTn values >10 times the 99th percentile URL in patients with normal baseline cTn values. In patients with elevated pre-procedure cTn in whom cTn levels are stable (≤20% variation) or falling, the post-procedure cTn must rise by >20%. However, the absolute post-procedural value still must be >10 times the 99th percentile URL. In

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addition, one of the following elements is required: • Development of new pathological Q waves; • Angiographic documented new graft occlusion or new native coronary artery occlusion; • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology. • It is increasingly recognized that there is a group of MI patients with no angiographic obstructive coronary artery disease (≥50% diameter stenosis in a major epicardial vessel), and the term “myocardial infarction with non-obstructive coronary arteries (MINOCA)” has been coined for this entity. • Patients may have elevated cTn values and marked decreases in ejection fraction due to sepsis caused by endotoxin, with myocardial function recovering completely with normal ejection fraction once the sepsis is treated. Arriving at a diagnosis of MI using the criteria set forth in this document requires integration of clinical findings, patterns on the ECG, laboratory data, observations from imaging procedures, and on occasion pathological findings, all viewed in the context of the time horizon over which the suspected event unfolds. Data from Thygesen K et al: J Am Coll Cardiol 72(18):2231-2264, 2018. MI can occur in various regions of the heart wall and may be described as anterior, inferior, posterior, lateral, subendocardial, or transmural, depending on the anatomic location and extent of tissue damage from infarction. Twelve-lead ECGs help localize the affected area through identification of changes in ST segments and T waves (Fig. 26.17). The infarcted myocardium is surrounded by a zone of hypoxic injury, which may progress to necrosis or return to normal, and adjacent to this zone of hypoxic injury is a zone of reversible ischemia (see Fig. 26.17). A characteristic Q wave often develops on ECG some hours later in STEMI.

FIGURE 26.17

Electrocardiographic Alterations Associated With the Three Zones of Myocardial Infarction.

Cardiac troponin I (cTnI) is the most specific indicator of MI, and measurement of its level should be performed on admission to the emergency department. cTnI level elevation is detectable 2 to 4 hours after onset of symptoms. Additional measurements within 6 to 9 hours and again at 12 to 24 hours are recommended if clinical suspicion is high and previous samples were negative. Troponin levels also can be used to estimate infarct size and therefore the likelihood of complications. Additional laboratory data may reveal leukocytosis and elevated C-reactive protein (CRP), both of which indicate inflammation.

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The individual's blood glucose level is usually elevated and the glucose tolerance level may remain abnormal for several weeks. Acute MI requires admission to the hospital, often directly into a coronary care unit. The individual should be given an aspirin immediately (ticlopidine if allergic to aspirin) along with nitrates and morphine for pain. Continuous monitoring of cardiac rhythms and enzymatic changes is essential, because the first 24 hours after onset of symptoms is the time of highest risk for sudden death. Non-STEMI is treated in the same way as unstable angina including antithrombotics, anticoagulation or PCI, or both.8 STEMI is best managed with emergent PCI or thrombolytics and antithrombotics.9 Hyperglycemia is treated with insulin. Once the person is stabilized, further management includes ACE inhibitors, betablockers, and statins. Individuals who are in shock require aggressive fluid resuscitation, ionotropic drugs, and possible emergent invasive procedures. Bed rest, followed by gradual return to activities of daily living, reduces the myocardial oxygen demands of the compromised heart. Individuals not receiving thrombolytic or heparin infusion must receive DVT prophylaxis as long as their activity is significantly limited. Stool softeners are given to eliminate the need for straining. Education regarding appropriate diet and caffeine intake, smoking cessation, exercise, and other aspects of risk factor reduction is crucial for secondary prevention of recurrent myocardial ischemia.

Quick Check 26.6 1. Describe the coronary artery disease–myocardial ischemia continuum. 2. Describe the pathophysiology of myocardial infarction. 3. What complications are associated with the period after infarction?

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Disorders of the Heart Wall Disorders of the Pericardium Pericardial disease is a localized manifestation of another disorder, such as infection (bacterial, viral, fungal, rickettsial, or parasitic); trauma or surgery; neoplasm; or a metabolic, immunologic, or vascular disorder (uremia, rheumatoid arthritis, systemic lupus erythematosus, periarteritis nodosa). The pericardial response to injury from these diverse causes may consist of acute pericarditis, pericardial effusion, or constrictive pericarditis.

Acute Pericarditis Acute pericarditis is acute inflammation of the pericardium. The etiology of acute pericarditis is most often idiopathic or caused by viral infection by coxsackie, influenza, hepatitis, measles, mumps, varicella viruses, or human immunodeficiency virus (HIV). Other causes include MI, trauma, neoplasm, surgery, uremia, bacterial infection (especially tuberculosis), connective tissue disease (especially systemic lupus erythematosus and rheumatoid arthritis), or radiation therapy. The pericardial membranes become inflamed and roughened, and a pericardial effusion may develop that can be serous, purulent, or fibrinous (Fig. 26.18). Possible sequelae of pericarditis include recurrent pericarditis, pericardial constriction, and cardiac tamponade.

FIGURE 26.18 Acute Pericarditis. Note shaggy coat of fibers covering the surface of heart. (From Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)

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Symptoms may follow several days of fever and usually begin with the sudden onset of severe retrosternal chest pain that worsens with respiratory movements and when assuming a recumbent position. The pain may radiate to the back as a result of irritation of the phrenic nerve (innervates the trapezius muscles) as it traverses the pericardium. Individuals with acute pericarditis also report dysphagia, restlessness, irritability, anxiety, weakness, and malaise. Physical examination often discloses low-grade fever ( male Normal Decreased Probable

Pulmonary congestion with cardiomegaly S3

Pulmonary congestion without cardiomegaly S4

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Modified from Jessup M, Brozena S: N Engl J Med 348(20):2007-2018, 2003.

Management is aimed at improving ventricular relaxation and prolonging diastolic filling times to reduce diastolic pressure. Nitrates, β-blockers, ACE inhibitors, and ARBs have been used with only varying success, and current guidelines focus on treating hypertension, ischemia, or valvular disease.12 Outcomes for individuals with HFpEF are as poor as those with HFrEF, and there has been little improvement in prognosis despite numerous new treatment trials.

Right Heart Failure Right heart failure is defined as the inability of the right ventricle to provide adequate blood flow into the pulmonary circulation at a normal central venous pressure. It can result from left heart failure when an increase in left ventricular filling pressure is reflected back into the pulmonary circulation. As pressure in the pulmonary circulation rises, the resistance to right ventricular emptying increases (Fig. 26.34). The right ventricle is poorly prepared to compensate for this increased afterload and will dilate and fail. When this happens, pressure will rise in the systemic venous circulation, resulting in peripheral edema and hepatosplenomegaly. Treatment relies on management of the left ventricular dysfunction as just outlined.

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FIGURE 26.34

Right Heart Failure. RA, Right atrial; RV, right ventricular.

When right heart failure occurs in the absence of left heart failure, it is typically attributable to diffuse hypoxic pulmonary disease such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and acute respiratory distress syndrome (ARDS). These disorders result in pulmonary vasoconstriction, pulmonary hypertension, and an increase in right ventricular afterload. The mechanisms for this type of right ventricular failure (cor pulmonale) are discussed in Chapter 29. Finally, MI, cardiomyopathies, and pulmonic valvular disease interfere with right ventricular contractility and can lead to right heart failure.

High-Output Failure High-output failure is the inability of the heart to adequately supply the body with bloodborne nutrients, despite adequate blood volume and normal or elevated myocardial contractility. In high-output failure, the heart increases its output but the body's metabolic needs are still not met. Common causes of high-output failure are anemia, septicemia, hyperthyroidism, and beriberi (Fig. 26.35).

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FIGURE 26.35

High-Output Failure. SVR, Systemic vascular resistance.

Anemia decreases the oxygen-carrying capacity of the blood. Metabolic acidosis occurs as the body's cells switch to anaerobic metabolism (see Chapter 5). In response to metabolic acidosis, heart rate and stroke volume increase in an attempt to improve tissue perfusion. If anemia is severe, however, even maximum cardiac output does not supply the cells with enough oxygen for metabolism. In septicemia, disturbed metabolism, bacterial toxins, and the inflammatory process cause systemic vasodilation and fever. Faced with a lowered systemic vascular resistance (SVR) and an elevated metabolic rate, cardiac output increases to maintain blood pressure and prevent metabolic acidosis. In overwhelming septicemia, however, the heart may not be able to raise its output enough to compensate for vasodilation. Body tissues show signs of inadequate blood supply despite a high cardiac output. Hyperthyroidism accelerates cellular metabolism through the actions of elevated levels of thyroxine from the thyroid gland. This may occur chronically (thyrotoxicosis) or acutely (thyroid storm). Because the body's increased demand for oxygen threatens to cause metabolic acidosis, cardiac output increases. If blood levels of thyroxine are high and the metabolic response to thyroxine is vigorous, even an abnormally elevated cardiac output may be inadequate. In the United States, beriberi (thiamine deficiency) usually is caused by malnutrition secondary to chronic alcoholism. Beriberi actually causes a mixed type of heart failure. Thiamine deficiency impairs cellular metabolism in all tissues, including the myocardium. In the heart, impaired cardiac metabolism leads to insufficient contractile strength. In blood vessels, thiamine deficiency leads to peripheral vasodilation, which decreases SVR. Heart failure ensues as decreased SVR triggers increased cardiac output, which the impaired myocardium is unable to deliver. The strain of demands for increased output in the face of

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impaired metabolism may deplete cardiac reserves until low-output failure begins.

Dysrhythmias A dysrhythmia, or arrhythmia, is a disturbance of heart rhythm. Normal heart rhythms are generated by the SA node and travel through the heart's conduction system, causing the atrial and ventricular myocardium to contract and relax at a regular rate that is appropriate to maintain circulation at various levels of physical activity (see Chapter 25). Dysrhythmias range in severity from occasional “missed” or rapid beats to serious disturbances that impair the pumping ability of the heart, contributing to heart failure and death. Dysrhythmias can be caused either by an abnormal rate of impulse generation (Table 26.8) from the SA node or other pacemaker or by the abnormal conduction of impulses (Table 26.9) through the heart's conduction system, including the myocardial cells themselves. TABLE 26.8 Disorders of Impulse Formation Type Sinus bradycardia

Electrocardiogram Effect P rate ≤60 Increased preload PR interval Decreased mean normal arterial pressure QRS for each P

Pathophysiology Hyperkalemia: slows depolarization Vagal hyperactivity: unknown Digoxin toxicity common Late hypoxia: lack of adenosine triphosphate (ATP) Simple sinus tachycardia P rate 100-150 Decreased filling Catecholamines: rise in PR interval times resting potential and normal Decreased mean calcium influx QRS for each P arterial pressure Fever: unknown Increased Early failure and lung myocardial disease: hypoxic cell demand metabolism Hypercalcemia Premature atrial Early P waves that Occasional Electrolyte disturbances: contractions (PACs) or may have decreased filling decrease in all phases beats* morphologic time and mean Hypoxia and elevated changes arterial pressure preload: cell PR interval membrane normal disturbances QRS for each P Hypercalcemia Sinus dysrhythmias Rate varies Variable filling times Unknown P-P regularly Variable mean Common in young irregular, short arterial pressure children and young with inspiration, Variable oxygen adults long with demand exhalation PR interval normal QRS for each P Atrial tachycardia P rate 151-250; Decreased filling Same as PACs: leads to (includes premature atrial morphology time increased atrial tachycardia if onset is may differ from Decreased mean automaticity, atrial abrupt) sinus PPR arterial pressure reentry interval normal Increased Digoxin toxicity: P/QRS ratio myocardial common

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Treatment If hypotensive, treat cause and support Follow with sympathomimetics, cardiotonics, and pacer Vagolytics Oxygen, bed rest Calcium channel blockers

Treat underlying cause Digoxin

None

Control ventricular rate Digoxin, calcium channel blockers, vagus stimulation Pace to override

Atrial flutter*

Atrial fibrillation*

Idiojunctional rhythm

Junctional bradycardia

variable P rate 251-300; morphology may vary from sinus P PR interval usually not observable P/QRS ratio variable P rate >300 and usually not observable No PR interval QRS rate variable and rhythm irregular P absent or independent QRS normal, rate 41-59, regular

demand Decreased filling time Decreased mean arterial pressure

Same as atrial tachycardia Aging

Same as atrial flutter Same as atrial tachycardia Aging

Same as atrial tachycardia Synchronous cardioversion

Same as atrial tachycardia

Decreased cardiac Atrial and sinus Same as sinus output from loss of bradycardia, standstill, bradycardia atrial contribution or block to ventricular preload Decreased mean atrial pressure as a result of bradycardia Same as Same as idiojunctional Same as sinus idiojunctional rhythm bradycardia rhythm Vagal hyperactivity

P absent or independent QRS normal, rate 40 or less Premature junctional Early beats Decreased cardiac contractions (PJCs) or without P waves output from loss of beats QRS morphology atrial contribution normal to ventricular preload for that beat Accelerated junctional P absent or Decreased cardiac rhythm independent output from loss of QRS morphology atrial contribution normal, rate 60to ventricular 99 preload Junctional tachycardia P absent or Decreased cardiac independent output from loss of QRS morphology atrial contribution normal, rate 100 to ventricular or more preload Increased myocardial demand because of tachycardia Idioventricular rhythm† P absent or Same as independent idiojunctional QRS >0.11 and rhythm rate 20-39 Ventricular bradycardia† P absent or Same as independent idiojunctional QRS >0.11 and rhythm rate 60-21 Agonal P absent or Absent or barely rhythm/electromechanical independent present cardiac dissociation† QRS >0.11 and output and pulse rate ≤20 Not compatible with life

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Hyperkalemia (6-5.4 mEq/L) Hypercalcemia, hypoxia, and elevated preload (see PACs)

Same as PACs

Same as PJCs

Same as PACs

Same as PJCs

Same as PACs

Sinus, atrial, and Same as sinus junctional bradycardia, bradycardia standstill, or block Same as idiojunctional rhythm

Same as sinus bradycardia

Depolarization and contraction not coupled: electrical activity present with little or no mechanical

Vigorous pharmacologic treatment aimed at restoring rate and force

Ventricular standstill or asystole† Premature ventricular contractions (PVCs) or depolarizations*

Accelerated ventricular rhythm Ventricular tachycardia†

Ventricular fibrillation†

*Most

Usually ineffective activity Usually caused by May attempt to pace profound hypoxia P absent or No cardiac output Profound ischemia, Same as agonal independent Not compatible with hyperkalemia, acidosis rhythm, including QRS absent life electrical defibrillation Early beats with P Same as PJCs Same as PJCs, including Pharmacology to waves aging and induction of change thresholds, QRS occasionally anesthesia refractory periods; opposite in Impulse originates in reduce myocardial deflection from cell outside normal demand, increase usual QRS conduction system and supply spreads through Removal of cause intercalated disks P absent or Same as accelerated Same as PVCs Same as PVCs independent junctional rhythm QRS >0.11 and rate of 41-99 P absent or Same as junctional Same as PVCs Same as PVCs, independent tachycardia including electrical QRS >0.11 and cardioversion rate 100 or more P absent Same as ventricular Same as PVCs Same as PVCs, QRS >300 and standstill Rapid infusion of including electrical usually not potassium defibrillation observable

common in adults.

†Life-threatening

in adults.

TABLE 26.9 Disorders of Impulse Conduction Type Sinus block

First-degree block*

Electrocardiogram Effect Occasionally absent Occasional P, with loss of QRS decrease in for that beat cardiac output Increase in preload for following beat PRI interval >0.2 None

Second-degree Progressive block, Mobitz I, prolongation of or Wenckebach* PRI interval until one QRS is dropped Pattern of prolongation resumes

Same as sinus block

Pathophysiology Local hypoxia, scarring of intraatrial conduction pathways, electrolyte imbalances Increased atrial preload

Same as sinus block Hyperkalemia (>7 mEq/L) Hypokalemia (44 mm Hg) (see Table 28.2 for a definition of gas partial pressures and other pulmonary abbreviations). This results in a fall in the pH of the blood (respiratory acidosis) that can affect the function of many tissues throughout the body. Hypoventilation is often overlooked until it is severe because the breathing pattern and ventilatory rate may appear to be normal, and changes in the tidal volume can be difficult to detect clinically. Measurement of the PaCO2 (i.e., blood gas analysis) or in the inspired and expired air (capnography) reveals the hypoventilation. Severe hypoventilation can cause secondary hypoxemia, somnolence, and disorientation. Hyperventilation is alveolar ventilation exceeding metabolic demands. The lungs remove CO2 faster than it is produced by cellular metabolism, resulting in a decreased PaCO2, or hypocapnia (PaCO2 90 ml/min) II Mild kidney damage, mild reduction in GFR (60-89 ml/min) III IV

V

Moderate kidney damage GFR 30-59 ml/min Severe kidney damage GFR 15-29 ml/min

End-stage kidney disease Established kidney failure GFR 38.3° C (>101° F) Mucopurulent cervical or vaginal discharge, or cervical friability Numerous white blood cells on saline wet prep Elevated C-reactive protein Elevated erythrocyte sedimentation rate Documented infection with Chlamydia trachomatis or Neisseria gonorrhoeae

Definitive Criteria (Not Needed for Treatment) Transvaginal ultrasound, magnetic resonance imaging, or Doppler studies showing thickened and fluid-filled tubes Laparoscopic visualization of PID-related abnormalities Endometrial biopsy with evidence of endometritis From Centers for Disease Control and Prevention (CDC): Pelvic inflammatory disease (PID) treatment and care, Atlanta, 2015, U.S. Department of Health and Human Services. The complications of PID can be significant, therefore, rapid treatment is recommended even before the causative pathogen can be identified. Because treatment is empiric, it needs to be effective against a broad range of pathogens, especially chlamydiae, gonococci and anaerobic bacteria. Treatment is usually done on an outpatient basis unless the woman has symptoms of advanced infection, cannot take oral medications, is pregnant, or exhibits other pathologies that cannot be excluded. The outpatient regimen recommended by the CDC is shown in Box 35.6.

Box 35.6

CDC-Recommended Treatment for Pelvic Inflammatory Disease: Intramuscular/Oral Regimens Ceftriaxone 250 mg IM in a single dose Doxycycline 100 mg PO twice a day for 14 days WITH or WITHOUT Metronidazole 500 mg PO twice a day for 14 days Cefoxitin 2g IM in a single dose and Probenecid, 1 g orally administered concurrently In a single dose PLUS Doxycycline 100 mg orally twice a day for 14 days WITH or WITHOUT Metronidazole 500 mg orally twice a day for 14 days OR Other parenteral third-generation cephalosporin (e.g., ceftizoxime or cefotaxime) PLUS Doxycycline 100 mg orally twice a day for 14 days

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WITH* or WITHOUT Metronidazole 500 mg orally twice a day for 14 days

*

The recommended third-generation cephalsporins are limited in the coverage of anaerobes. Therefore, until it is known that extended anaerobic coverage is not important for treatment of acute PID, the addition of metronidazole to treatment regimens with thirdgeneration cephalosporins should be considered. These regimens provide coverage against frequent etiologic agents of PID, but the optimal choice of a cephalosporin is unclear. Cefoxitin, a second-generation cephalosporin, has better anaerobic coverage than ceftriaxone, and in combination with probenecid and doxycycline has been effective in short-term clinical response in women with PID. Ceftriaxone has better coverage against N. gonorrhoeae. The addition of metronidazole also will effectively treat BV, which is frequently associated with PID. CDC, Centers for Disease Control and Prevention; IM, intramuscularly; PO, orally. Data from Centers for Disease Control and Prevention (CDC): Pelvic inflammatory disease (PID) treatment and care, Atlanta, 2015, U.S. Department of Health and Human Services; Walker CK, Wiesenfeld HC: Clin Infect Dis 28(Supp 1):S29–S36, 2007. To prevent recurrence, sexual partners of women with PID should also receive treatment, even if they are asymptomatic. Women receiving treatment should be reevaluated by their care provider in 3 days to ensure that the antibiotic treatment is effective. Because women with a history of PID are at increased risk for ectopic pregnancy, they should seek care as soon as they know they are pregnant, because ectopic pregnancy is a major cause of maternal mortality. All sexually active women younger than age 25 should receive, at minimum, annual screening for chlamydia and gonorrhea, as should women older than age 25 who have a new sexual partner, more than one sexual partner, a partner who has been diagnosed with an STI, or a partner with more than one sexual partner.

Vaginitis Vaginitis is irritation or inflammation of the vagina, typically caused by infection, irritants, pathologies, or disruption of the normal vaginal flora. Vaginitis is characterized by complaints of vaginal irritation, itching, burning, odor, or abnormal discharge. Clinically, it is characterized by an increase in white blood cells or abnormal cells, or both, observed on a saline wet prep examination. The major causes of vaginitis are overgrowth of normal flora, STIs, and vaginal irritation related to low estrogen levels during menopause (a condition known as atropic vaginitis). The primary forms of vaginitis are vulvovaginal candidiasis, or yeast vaginitis, and bacterial vaginosis, or trichomoniasis. Bacterial vaginosis is a noninflammatory condition resulting from an overgrowth of anaerobic bacteria. The overgrowth causes a shift in the composition of the vaginal flora and produces a malodorous vaginal discharge. Pain and itching are common manifestations. The development of vaginitis is related to alterations in the vaginal environment. This includes changes with complications in local defense mechanisms, such as skin integrity, immune reaction and, particularly, vaginal pH. The pH of the vagina (normally 4 to 4.5) depends on cervical secretions and the presence of normal flora that help maintain an acidic

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environment. Changes in the vaginal pH may predispose a woman to infection. Variables that affect the vaginal pH, and therefore the bactericidal nature of secretions and the predisposition to infection, include semen and the use of douches, soaps, spermicides, feminine hygiene sprays, and deodorant menstrual pads or tampons. Another variable is having a condition associated with an increased glycogen content of vaginal secretions, such as pregnancy and diabetes. Antibiotics often destroy normal vaginal flora, facilitating the overgrowth of Candida albicans and causing a yeast infection. Increased vaginal alkalinity also may enhance susceptibility to trichomoniasis and BV. Unusual changes in the amount, color, or texture of the vaginal discharge may signal an infection, especially if the discharge is malodorous, irritating, or copious. The diagnosis is based on the history, physical examination, and examination of the discharge by wet mount. Infection is suggested by a marked change in color or by a discharge that becomes copious, malodorous, or irritating. Treatment involves developing and maintaining an acidic environment, relieving symptoms (usually pruritus and irritation), and administering antimicrobial or antifungal medications to eradicate the infectious organism. If the infection can be sexually transmitted, the woman's partner will also need to be treated. Research suggests that probiotics, especially Lactobacillus rhamnosus, can encourage the proliferation of normal vaginal flora and reduce the incidence of vaginitis in women at risk for this disease.

Cervicitis Cervicitis is a nonspecific term used to describe inflammation of the cervix. The CDC defines cervicitis as having two major diagnostic signs: a purulent or mucopurulent discharge from the cervical os, or endocervical bleeding (or both), induced by gently introducing a cotton swab into the cervix.6 Cervicitis can have infectious or noninfectious causes; about half of all cases are caused by sexually transmitted pathogens. Chemicals and substances introduced into the vagina can cause cervicitis, as can disruptions in the normal vaginal flora. However, conflicting definitions of cervicitis are used clinically and in research. Age and risk factors are important in assessing a woman with cervicitis. Younger women are at risk for STIs and should be tested for chlamydia, gonorrhea, and trichomoniasis. Older women with cervicitis may have STIs but are at risk for irritation from abnormal vaginal flora related to low vaginal estrogen levels. Even if no infectious agent is identified, pharmacologic therapy may still be effective. Mucopurulent cervicitis (MPC) is usually caused by one or more sexually transmitted pathogens, such as Trichomonas, Neisseria, Chlamydia, Mycoplasma, or Ureaplasma spp. Infection causes the cervix to become red and edematous. A mucopurulent (mucus and pus containing) exudate drains from the external cervical os, and the individual may report vague pelvic pain, bleeding, or dysuria. The cervix often becomes friable, and bleeding can occur during sexual intercourse or with pelvic examinations (or both) and Pap smears. Because mucopurulent cervicitis is a symptom of PID, women at risk for STIs, especially those younger than age 26, should receive treatment for PID while awaiting the results of microbial testing.7 If the woman is not at risk for STIs, a thorough evaluation often reveals another cause for the inflammation.

Vulvodynia 1888

Vulvodynia (VV) (also referred to as vulvitis, vestibulitis, or vulvovestibulitis) is chronic pain of at least 3 months duration and inflammation of the vulva or vaginal vestibule (entrance of vagina), or both. The classification of vulvodynia is based on the location of the pain, whether it is localized or generalized, and whether the pain is provoked, unprovoked, or mixed. Localized is characterized by pain from a cause that usually does not cause pain (allodynia) to the vulvar vestibule area. Generalized is a diffuse pain pattern involving all of the pudendal nerve distribution and beyond. Provoked means any touch or stimulation that elicits pain, unprovoked is pain that occurs in the absence of touch or stimulation, and mixed is pain that varies with or without touch or stimulation. Individuals describe the pain as burning, stinging, soreness, irritation, dyspareunia, throbbing, itching, or rawness. Vulvodynia is fairly common, with lifetime estimates of prevalence ranging from 10% to 28% among reproductive-age women, across races. It also can affect girls. The cause of VV is unknown. Theories suggest it is multifactorial in origin, including embryonic factors, chronic inflammation, genetic immune factors, nerve pathways, increased sensitivity to environmental factors (infection, trauma, irritants), hormonal changes, human papillomavirus (HPV), and oxalates.8 Although the inflammation of VV may be caused by contact dermatitis (i.e., exposure to soaps, detergents, lotions, sprays, shaving, menstrual pads/tampons, perfumed toilet paper, tight-fitting clothes), the condition may be more complex and represent abnormalities in three interdependent systems: the vestibular mucosa, pelvic floor musculature, and CNS pain regulatory pathways. The condition also may represent an autoimmune reaction or genetic and psychological links. Recent data suggest site-specific inflammatory responses and the production of proinflammatory mediators.9 The mechanisms are poorly understood, making the condition difficult to evaluate and treat. An important trigger is chronic inflammation caused by contact irritants, recurrent infections, hormonal changes, and chronic skin conditions. Overall, with normal sensations there is a heightened sensitivity. VV can occur in the context of other pain conditions, such as irritable bowel syndrome, interstitial cystitis, recurrent yeast infections, and fibromyalgia. Cotton swab testing is used to identify painful areas. For vulvar pain, treatment is focused on identifying and treating any infectious cause or comorbid contributor. However, laboratory tests and imaging are rarely required for VV. Women are advised to avoid potential irritants; wear loose, cotton clothing; use mild soaps; and apply a vaginal emollient (e.g., coconut oil or vegetable oil) after bathing. Hot water may incite vulvar symptoms. Studies on treatments are limited but suggest that women may benefit from topical lidocaine (Xylocaine), estrogen cream, topical or systemic antidepressants, or anxiolytics; Botox injections into the affected nerve; dietary modifications; physical therapy; behavioral or sexual counseling (or both); acupuncture; or vestibulectomy. Biofeedback may help to relax the muscles of the pelvic floor and reduce pain.

Bartholinitis Bartholinitis, or Bartholin cyst, is an acute inflammation of one or both of the ducts that lead from the introitus (vaginal opening) to the Bartholin/greater vestibular glands (Fig. 35.8). Most lesions of the Bartholin gland are cysts or abscesses. The usual causes are microorganisms that infect the lower female reproductive tract, such as streptococci, staphylococci, and sexually transmitted pathogens. Acute bartholinitis may be preceded by

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an infection, such as cervicitis, vaginitis, or urethritis.

FIGURE 35.8 Inflammation of Bartholin Gland. (Modified from Gershenson DM et al: Operative gynecology, ed 2, Philadelphia, 2001, Saunders; Fuller JK: Surgical technology, ed 6, Philadelphia, 2013, Saunders.)

Infection or trauma causes inflammatory changes that narrow the distal portion of the duct, leading to obstruction and stasis of glandular secretions. The obstruction, or cyst, varies from 1 to 8 cm in diameter and is located in the posterolateral portion of the vulva. The affected area is usually red and painful, and pus may be visible at the opening of the duct. This exudate should be cultured. The individual may have fever and malaise. The diagnosis is based on the clinical manifestations and the identification of infectious microorganisms. Chronic bartholinitis is characterized by the presence of a small cyst that is slightly tender but otherwise asymptomatic. Most Bartholin cysts require no treatment. However, if they are uncomfortable or show signs of infection, treatment is advised to prevent abscess formation. Treatment is controversial but involves broad-spectrum antibiotics. Some clinicians attempt to drain the cyst using hot soaks, needle aspiration, insertion of a catheter, or marsupialization (cutting a slit and suturing the edges) of the infected gland. No single treatment has proved superior for both relief and prevention of recurrence. Lesions in the form of carcinomas are a rare type of gynecologic tumor and are carefully monitored among postmenopausal women, who are more prone to Bartholin malignancy.

Pelvic Organ Prolapse The bladder, urethra, and rectum are supported by the endopelvic fascia and perineal muscles. This muscular and fascial tissue loses tone and strength with aging and may fail to maintain the pelvic organs in the proper position. Progressive descent of the pelvic support structures may cause pelvic floor disorders, such as urinary and fecal incontinence, and

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pelvic organ prolapse. Pelvic organ prolapse (POP) is the descent of one or more of these structures: the vaginal wall, the uterus, or the apex of the vagina (after a hysterectomy). Although more than 50% of women have some version of POP on physical examination, most women have no symptoms. When prolapse becomes severe, the function of the surrounding organs can be altered. POP is thought be caused by direct trauma (e.g., childbirth); pelvic floor surgery; obesity; constipation; pelvic organ cancers; or damage to the pelvic innervation, particularly the pudendal nerve. Risk factors in nulliparous women, however, include occupational activities that require heavy lifting or chronic medical conditions, such as chronic lung disease or refractory constipation (chronically increased intra-abdominal pressure). The most frequently cited risk factors are aging, obesity, and hysterectomy. Other risk factors include a strong familial tendency (from family and twin studies) and possibly a multifactorial genetic component. Prolapse of the bladder, urethra, rectum, or uterus may occur many years after an initial injury to the supporting structure. Uterine prolapse is descent of the cervix or entire uterus into the vaginal canal, and in severe cases the uterus falls completely through the vagina and protrudes from the introitus, creating ulceration and obvious discomfort. Fig. 35.9 illustrates the different degrees (grades) of uterine prolapse, showing descent of the cervix or the entire uterus into the vaginal canal. Grade 1 prolapse is not treated unless it causes discomfort. Grades 2 and 3 prolapse usually cause feelings of fullness, heaviness, and collapse through the vagina. Symptoms of other pelvic floor disorders also may be present.

FIGURE 35.9 Degrees of Uterine Prolapse. Grade 1 prolapse is minimal and rarely requires correction. Grade 2 prolapse has moderate symptoms. Grade 3 prolapse is severe; the uterus is so low the cervix protrudes from the vagina. (From Phillips N: Berry & Kohn's operating room technique, ed 12, Philadelphia, 2013, Mosby.)

A common first-line treatment is a pessary, a removable mechanical device that holds the uterus in position. The pelvic fascia may be strengthened through Kegel exercises (repetitive isometric tightening and relaxing of the pubococcygeal muscles) or by estrogen therapy in menopausal women. Maintaining a healthy body mass index, preventing constipation, and treating chronic cough may help prevent prolapse. Surgical repair, with

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or without hysterectomy, is the treatment of last resort. Fig. 35.10 shows pelvic organ prolapse associated with cystocele and rectocele. Cystocele is descent of a portion of the posterior bladder wall and trigone into the vaginal canal and is usually caused by childbirth. In severe cases, the bladder and anterior vaginal wall bulge outside the introitus. Symptoms are usually insignificant in mild to moderate cases. Increased bulging and descent of the anterior vaginal wall and urethra can be aggravated by vigorous activity, prolonged standing, sneezing, coughing, or straining and can be relieved by rest or by assumption of a recumbent or prone position. If the prolapse is large, women may complain of vaginal pressure. Medical management can include a vaginal pessary, Kegel exercises, and estrogen therapy for postmenopausal women. Surgical treatment is used for severe injury that is unresponsive to medical treatment (see Did You Know? Vaginal Mesh).

FIGURE 35.10 Cystocele and Rectocele. A, Grade 2 (moderate form): anterior vaginal wall prolapse (i.e., cystocele). B, Grade 4: prolapse. C, Grade 2: posterior wall prolapse (i.e., rectocele). D, Grade 4: associated with ulceration of the vaginal wall. Grades 1 and 3 are not shown. (A and C from Seidel HM et al: Mosby's guide to physical examination, ed 4, St Louis, 1999, Mosby; B and D from Symonds EM, Macpherson MBA: Color atlas of obstetrics and gynecology, London, 1994, Mosby-Wolfe.)

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Did You Know? Vaginal Mesh Because pelvic organ prolapse is often a result of weakened pelvic fascia and musculature, a surgical mesh was developed to improve pelvic support. This mesh was designed to be placed surgically along the area needing support. The goal was to have the woman's tissues grow through the mesh and provide consistent, long-term support. However, women who received the surgical mesh had a high rate of complications, including infection and persistent postoperative pain. In many cases the mesh eroded through the tissue, protruding into the vagina and perforating other organs. In addition, the mesh may shrink over time, causing vaginal shortening, tightening, and pain. Some large studies have shown a benefit from mesh use for some women. However, once implanted, the mesh is difficult to remove if it is ineffective, resulting in long-term pain and the need for intensive surgeries and repairs. The U.S. Food and Drug Administration has issued several warnings about the mesh to caution women and practitioners and encourage fully informed consent about the risks and benefits of mesh placement. On April 16, 2019, the FDA ordered the manufacturers of all remaining surgical mesh products for transvaginal repair of pelvic organ prolapse to stop selling and distributing their products in the U.S. immediately. Data from Food and Drug Administration: FDA takes action to protect women's health, orders manufacturers of surgical mesh intended for transvaginal repair of pelvic organ prolapse to stop selling all devices, Silver Spring, MD, 2019, Author. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/um636114.htm. Retrieved June 17, 2019; Maher C et al: Cochrane Database Syst Rev 4:CD004014, 2013; U.S. Food and Drug Administration: FDA study communication: UPDATE on serious complications associated with transvaginal placement of surgical mesh for pelvic organ prolapse, 2010. Available at www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm2362435.htm. A rectocele is the bulging of the rectum and posterior vaginal wall into the vaginal canal. Childbirth may increase damage, ultimately leading to a rectocele, but symptoms may not appear until after menopause. Genetic and familial predisposition and bowel habits contribute to rectocele development. Lifelong chronic constipation and straining may produce or aggravate a rectocele. A large rectocele may cause vaginal pressure, rectal fullness, and incomplete bowel evacuation. Defecation may be difficult and can be facilitated by applying manual pressure to the posterior vaginal wall. Medical treatment focuses on the management and prevention of constipation and, if needed, the use of a pessary. Rectocele alone (without associated enterocele, uterine prolapse, and cystocele) seldom requires surgery. An enterocele is a herniation of the rectouterine pouch into the rectovaginal septum (between the rectum and the posterior vaginal wall). It can be congenital or acquired. Congenital enterocele rarely causes symptoms or progresses in size, but an acquired enterocele can result from muscular weakness caused by previous surgery, especially those through the vagina, or from pelvic relaxation disorders, such as uterine prolapse, cystocele, and rectocele. Most large enteroceles are found in grossly obese and older adults. Treatment is surgical. Box 35.7 summarizes the symptoms and treatment of POP.

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Box 35.7

Pelvic Organ Prolapse: Symptoms and Treatments Symptoms Urinary Sensation of incomplete emptying of bladder Urinary incontinence Urinary frequency/urgency Bladder “splinting” to accomplish voiding Bowel Constipation or feeling of rectal fullness or blockage Difficult defecation Stool or flatus incontinence Urgency Manual “splinting” of posterior vaginal wall to accomplish defecation Pain and Bulging Vaginal, bladder, rectum Pelvic pressure, bulging, pain Lower back pain Sexual Dyspareunia Decreased sensation, lubrication, arousal

Treatment Depending on age of woman and cause and severity of condition: • Isometric exercises to strengthen pubococcygeal muscles (Kegel exercises) • Estrogen to improve tone and vascularity of fascial support (postmenopausal) • Pessary (a removable device) to hold pelvic organs in place Surgical Reconstructive: autologous grafts; synthetic mesh/sling Obliterative (most extreme) Weight loss Avoidance of constipation Treatment of cough/lung conditions

Benign Growths and Proliferative Conditions Benign Ovarian Cysts Benign cysts of the ovary may occur at any time during the life span but are most common during the reproductive years and, in particular, at the extremes of those years (Fig. 35.11). An increase in benign ovarian cysts occurs when hormonal imbalances are more common, around puberty and menopause. Benign ovarian cysts are quite common, comprising one third of gynecologic hospital admissions. Two common causes of benign ovarian enlargement in ovulating women are follicular cysts and corpus luteum cysts. These cysts are called functional cysts because they are caused by variations of normal physiologic events. Follicular and corpus luteum cysts are unilateral. They are typically 5 to 6 cm in diameter but can grow as large as 8 to 10 cm. Most women are asymptomatic.

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FIGURE 35.11

Depiction of an Ovarian Cyst.

Benign cysts of the ovary are produced when a follicle or a number of follicles are stimulated but no dominant follicle develops and completes the maturation process. Every month about 120 follicles are stimulated, and generally, only 1 succeeds in ovulation of a mature ovum. Normally, in the early follicular phase of the menstrual cycle, follicles of the ovary respond to hormonal signals from the pituitary gland. The pituitary gland produces FSH to mature follicles in the ovary. If the dominant follicle develops properly before ovulation, the corpus luteum becomes vascularized and secretes progesterone. Progesterone arrests development of other follicles in both ovaries in that cycle. LH, proteolytic enzymes, and prostaglandins trigger follicular rupture and release of the ovum. Follicular cysts (also called ovarian or functional cysts) are filled with fluid and can be caused by a transient condition in which the dominant follicle fails to rupture or one or more of the nondominant follicles fail to regress. This disturbance is not well understood. It may be that the hypothalamus does not receive or send a message strong enough to increase FSH levels to the degree necessary to develop or mature a dominant follicle. The hypothalamus monitors blood levels of estradiol and progesterone; when the FSH level is low, the estradiol concentration does not increase enough to stimulate LH. Research indicates that when progesterone is not being produced, the hypothalamus releases GnRH to increase the FSH level. FSH continues to stimulate follicles to mature; the granulosa cells grow and, presumably, the estradiol level increases. This abnormal cycle continues to stimulate follicular size and causes follicular cysts to develop. Although individuals may experience no symptoms, some have pelvic pain, a sensation of feeling bloated, tender breasts, and heavy or irregular menses. After several subsequent cycles in which hormone levels once again follow a regular cycle and progesterone levels are restored, cysts usually are absorbed or regress. Follicular cysts can be random or recurrent events. A corpus luteum cyst may normally form by the granulosa cells left behind after ovulation. This cyst is highly vascularized but usually limited in size, and with the normal menstrual cycle it spontaneously regresses. With an imbalance in hormones, low LH and progesterone levels may cause an abnormal or hemorrhagic cyst. In some cases, large cysts can rupture and cause hemorrhage. Corpus luteum cysts are less common than follicular cysts, but luteal cysts typically cause more symptoms, particularly if they rupture. Manifestations include dull pelvic pain and amenorrhea or delayed menstruation, followed by irregular or heavier than normal bleeding. Rupture occasionally occurs and can cause massive bleeding, with excruciating

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pain; immediate surgery may be required. Corpus luteum cysts usually regress spontaneously in nonpregnant women. Oral contraceptives may be used to prevent cysts from forming in the future. Dermoid cysts are ovarian teratomas that contain elements of all three germ layers; they are common ovarian neoplasms. These growths may contain mature tissue including skin, hair, sebaceous and sweat glands, muscle fibers, cartilage, and bone. Dermoid cysts are usually asymptomatic and are found incidentally on pelvic examination. Dermoid cysts have malignant potential and need careful evaluation for removal. Torsion of the ovary is a rare complication of ovarian cysts or tumors or enlargement of the ovary; it can occur in girls or women. If a cyst is sufficiently large, it can cause the ovary to twist on its ligaments, reducing the blood supply to the ovary and causing extreme pain. Ovarian torsion is rare, but it is a gynecologic emergency. It usually presents with acute, severe, unilateral abdominal or pelvic pain and is treated surgically.

Quick Check 35.3 1. Why is prompt treatment of pelvic inflammatory disease (PID) critical to reproductive health? 2. Why do benign ovarian cysts develop in women who ovulate? 3. What is the difference between a follicular cyst and a corpus luteum cyst?

Endometrial Polyps An endometrial polyp is a benign mass of endometrial tissue that contains a variable amount of glands, stroma, and blood vessels. Endometrial polyps are usually solitary and can occur anywhere within the uterus. Polyps are structurally diverse and are usually classified as hyperplastic, atrophic (or inactive), or functional. Hyperplastic polyps are often pedunculated (stalk or mushroom-like) and may be mistaken for endometrial hyperplasia or, if large, for adenosarcoma (Fig. 35.12). Although polyps most often develop in women between the ages of 40 and 50 years, they can occur at all ages. Risk factors include advancing age, obesity, nulliparity, early menarche or late menopause (or both), diabetes, estrogenic states (i.e., anovulatory cycles and unopposed estrogen), treatment with tamoxifen, and hypertension.

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FIGURE 35.12

Uterine Polyps Visible Through Hysteroscopy. (From Cheng C et al: J Minim Invasive Gynecol 16[6]:739-342, 2009.)

Endometrial polyps are a common cause of intermenstrual bleeding or even excessive menstrual bleeding. The diagnosis is made by transvaginal sonography or hysteroscopy. The lesions can be removed with small, curved forceps, but there is a high rate of spontaneous resolution. The coexistence of a separate endometrial atypical hyperplasia or adenocarcinoma is possible, but malignancy is extremely rare.

Leiomyomas Leiomyomas, commonly called myomas or uterine fibroids, are benign tumors that develop from smooth muscle cells in the myometrium. Leiomyomas are the most common benign tumors of the uterus, affecting 70% to 80% of all women, and most remain small and asymptomatic. The prevalence increases in women ages 30 to 50 years but decreases with menopause. The incidence of leiomyomas in black and Asian women is two to five times higher than that in white women. On average, the age of onset for black women is 10 years earlier than it is for white women. The cause of uterine leiomyomas is unknown, although their size appears to be related to estrogen and progesterone, growth factors, and reduced apoptosis. Because leiomyomas are estrogen and progesterone sensitive, uterine leiomyomas are not seen before menarche, are common during the reproductive years, and generally shrink after menopause. Tumors in pregnant women enlarge rapidly but often decrease in size after the end of the pregnancy. Risk factors include heredity, nulliparity, obesity, PCOS, black race, postmenopausal hormone use, and hypertension. Lifestyle factors are risk factors and include diet, caffeine and alcohol consumption, smoking, lack of physical activity, and stress. Pathophysiology

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Most leiomyomas occur in multiples in the fundus of the uterus, although they often can occur singly and throughout the uterus. Leiomyomas are classified as subserous, submucous, or intramural, according to their location within the various layers of the uterine wall (Fig. 35.13). Mutations in the Mediator Subcomplex 12 (MED12) gene have been identified in about 70% of uterine leiomyomas. Uterine leiomyomas are usually firm and surrounded by a connective tissue layer. Degeneration and necrosis may occur when the leiomyoma outgrows its blood supply, which is more common in larger tumors and is frequently accompanied by pain.

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FIGURE 35.13 Leiomyomas. A, Uterine section showing the whorl-like appearance and locations of leiomyomas (also called uterine fibroids). B, Sagittal section showing multiple leiomyomas. Typical, wellcircumscribed, solid, light gray nodules distort the uterus. (B from Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)

Clinical Manifestations The major clinical manifestations of leiomyomas are abnormal vaginal bleeding, pain, and symptoms related to pressure on nearby structures. Fibroids also may contribute to infertility and subfertility, as well as obstruction during birth if the fibroids are large enough. The leiomyoma can make the uterine cavity larger, thereby increasing the endometrial surface area. This enlargement may account for the increased menstrual bleeding associated with leiomyomas. Although pain is not an early symptom, it occurs with the devascularization of larger leiomyomas and is associated with blood vessel compression that limits the blood supply to adjacent structures. Because the fibroid is relatively slow growing, enabling adjacent structures to adapt to pressure, symptoms of abdominal pressure develop slowly. Pressure on the bladder may contribute to urinary frequency, urgency, and dysuria. Pressure on the ureter may cause it to become distended “upstream” from the pressure point; rectosigmoid pressure may lead to constipation. Larger fibroids may cause a sensation of abdominal or genital heaviness. Evaluation and Treatment Uterine leiomyomas are suspected when bimanual examination discloses irregular, nontender nodularity of the uterus. Pelvic sonography or MRI confirms the diagnosis. Treatment depends on the symptoms and tumor size, and the woman's age, reproductive status, preference, and overall health. Most leiomyomas are asymptomatic and can be managed by observation only. Medical treatment is aimed at shrinking the myoma or reducing the symptoms. The use of hormonal contraceptives may shrink or enhance growth and should be closely monitored. Mifepristone (formerly RU-486), a progesterone receptor agonist, and ulipristal acetate may be useful in shrinking fibroids. Shrinking is sometimes done prior to surgical treatment. Nonpharmalogic therapies include green tea extract, curcumin (the active ingredient in turmeric), vitamin D, and herbal preparations used in Chinese medicines. Surgical treatments are commonly used but may be decreasing in frequency. Hysterectomy is commonly performed for fibroid-related bleeding and pain. Myomectomy, or removal of the fibroid from the muscle of the uterus, may be less invasive than a full hysterectomy and remains the standard of cure for women wishing to preserve their fertility. Other treatments, such as uterine artery embolization (UAE), laser ablation, and the levonorgestrel-intrauterine system (LNG-IUS), all hold promise. A Cochrane review found that UAE appears to have an overall satisfaction rate similar to hysterectomy and myomectomy.10 UAE is associated with a higher rate of minor complications and a much higher risk of requiring future surgical intervention within 2 to 5 years of the initial procedure.10 Benefits and risks of all treatments should be carefully considered, as should a woman's desire for future pregnancy.

Adenomyosis Adenomyosis is the presence of endometrial tissue within the uterine myometrium.

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Migration of endometrial cells into the myometrial layers occurs as a result of an unknown mechanism. The diagnosis of adenomyosis often is made during the late reproductive years, however, because it is commonly diagnosed after hysterectomy (30% to 60% of normal women), the time of diagnosis may not be associated with the onset. Incidence rates are higher for women taking tamoxifen. Parity also increases the risk for adenomyosis and for women who are pregnant; the outcomes can include preterm labor, preterm rupture of membranes, and low birth weight. Adenomyosis may be asymptomatic or may be associated with abnormal menstrual bleeding, anemia, dysmenorrhea, uterine enlargement, uterine tenderness during menstruation, chronic pelvic pain, and infertility. Secondary dysmenorrhea becomes increasingly severe as the disease progresses. On examination, the uterus is enlarged, globular, and most tender just before or after menstruation. The diagnosis is confirmed by ultrasonography or MRI. Treatment is symptomatic and includes NSAIDs, hormonal contraceptives, and the LNG-IUD. Other promising treatments include estrogen receptor modulators, high-dose progestins, selective progesterone receptor modulators, aromatase inhibitors, and GnRH agonists. Surgical treatments include resection or, if severe, hysterectomy. Further testing is needed for uterine artery embolization and uterine ablation. Treatment decisions are based on managing symptoms and preserving future fertility.

Endometriosis Endometriosis is the presence of functioning endometrial tissue or implants outside the uterus. The ectopic (out of place) endometrium responds to the normal hormonal fluctuations of the menstrual cycle. Common sites of implantation of ectopic tissue include the pelvic peritoneum, ovaries, uterine ligaments, and rectovaginal septum. Many other sites of implantation have been identified (Fig. 35.14). Endometriosis primarily affects younger (premenopausal) women, with a peak incidence in the third decade. The incidence of endometriosis, however, is difficult to determine, especially in asymptomatic adolescent and fertile women. About 50% of women evaluated for pelvic pain, infertility, or a pelvic mass are diagnosed with endometriosis. It is the third most common reason for hysterectomy and is associated with a higher risk for cancers, especially ovarian cancer.

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FIGURE 35.14 Endometriosis. The uterus is distended, and retrograde spillage of menstrual loss has led to the development of endometriosis (dark purple patches). (From Symonds EM, Macpherson MBA: Color atlas of obstetrics and gynecology, London, 1994, Mosby-Wolfe.)

The cause of endometriosis is not known, and many theories exist. One commonly accepted theory, proposed in 1927, suggests that endometriosis results from the implantation of endometrial cells during retrograde menstruation, in which menstrual fluids move through the fallopian tubes and into the pelvic cavity. Women with obstructed menstrual flow do have a higher incidence of endometriosis. However, it is now known that retrograde menstruation occurs in almost all women, but not all women develop endometriosis. Other theories include alterations in cytokine and growth factor signaling, coelomic metaplasia (peritoneal mesothelium, the müllerian ducts, and the germinal epithelium of the ovary all are derived from coelomic wall epithelium), embryonic cell rest (primitive “at rest” embryonic cells become activated), possible spread of endometrial cells outside the uterus during fetal organogenesis, iatrogenic mechanical transplantation, and lymphatic and vascular dissemination.11 A genetic predisposition to endometriosis has been documented, and genetic polymorphisms have been identified. Disruption of gene expression during embryogenesis may contribute to endometriosis. Pathophysiology The growth of endometrial lesions depends on estrogen. Endometrial lesions are affected by ovarian hormones as endometrial tissue within the uterus, however, endometriosis cells have marked progesterone resistance. The cyclic changes are influenced by blood supply and the presence of glandular and stromal cells. With an adequate blood supply. the ectopic endometrium proliferates, breaks down, and bleeds with the normal menstrual cycle. The response to the bleeding is inflammation triggering many inflammatory cascades, including cytokines, chemokines, growth factors, and protective factors (leukocyte protease inhibitor and superoxide dismutase). Eventually, the inflammation leads to fibrosis, scarring, adhesions, and pain. Clinical Manifestations The clinical manifestations of endometriosis vary in frequency and severity and can mimic other pelvic diseases (i.e., PID, ovarian cysts, and irritable bowel syndrome). Symptoms

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include infertility, pelvic pain, dyschezia (pain on defecation), dyspareunia, (pain on intercourse) and, less commonly, constipation and abnormal vaginal bleeding. If implants are located within the pelvis, an asymptomatic pelvic mass having irregular, movable nodules and a fixed, retroverted uterus are found on examination. Most symptoms can be explained by the proliferation, breakdown, and bleeding of the ectopic endometrial tissue, with subsequent formation of adhesions. In most instances, however, the degree of endometriosis is not related to the frequency or severity of symptoms. Dysmenorrhea, for example, does not appear to be related to the degree of endometriosis. With involvement of the rectovaginal septum or the uterosacral ligaments, dyspareunia develops. Dyschezia, a hallmark symptom of endometriosis, occurs with bleeding of ectopic endometrium in the rectosigmoid musculature and subsequent fibrosis. About 25% to 40% of women with infertility have endometriosis. The relationship between endometriosis and infertility is strong; however, the degree of disease is not as closely associated. More simply, women with untreated minimal to mild disease may have high pregnancy rates or may experience infertility. The exact reason for infertility in women with endometriosis is unknown. Evaluation and Treatment A presumptive diagnosis is based on the previously described symptoms, but pelvic laparoscopy is required for a definitive diagnosis. A uniform classification system that includes both extent and severity has been developed, including stage I, minimal; stage II, mild; and stage III, moderate. The classification, however, still does not correlate well with a woman's symptoms. Treatment is based on preventing progression of the disease, alleviating pain, and restoring fertility. Medical therapies include suppression of ovulation with various medications, such as the noncyclic estrogen-progestin–combined oral contraceptive pill, depot medroxyprogesterone acetate (DMPA), danazol, GnRH agonists/analogs, mifepristone or gestrinone, and promotion of atrophy of the endometrium with progestins or an LNG-IUD. Conservative surgical treatment includes laparoscopic removal of endometrial implants with conventional or laser techniques. All treatments have risks or side effects, and recurrent symptoms develop in most women within a few years, even with surgical treatments. Women should be fully informed of all options and understand the risk-to-benefit ratio of treatments, especially nonreversible treatments.

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Cancer Malignant tumors of the female reproductive system are common. Because the pelvis and abdomen are poorly innervated and designed to accommodate a growing fetus, cancers of the female reproductive tract can often grow large before causing pain. Reproductive cancers are likely to be diagnosed early if there are symptoms; for example, vaginal bleeding prompts women to seek treatment.

Cervical Cancer Cancer of the cervix has the highest incidence in Africa, Latin America, and the Caribbean, and the lowest incidence in North America and Oceania.12 In the United States in 2019, an estimated 13,170 new cases of invasive cervical cancer will be diagnosed with an estimated 4250 deaths.13 Cervical cancer incidence rates declined by more than half between 1975 (14.8 per 100,000) and 2014 (6.9 per 100,000). The decline is attributed to the widespread use of screening, primarily with the Papanicolaou (Pap) test. In the United States, Hispanic women are most likely to get cervical cancer, followed by black women, Asians and Pacific Islanders, and whites. In the United States, American Indians and Alaskan Natives have the lowest risk of cervical cancer.14 Human papillomavirus (HPV) infection is almost exclusively the cause of cervical cancer. It is a necessary condition in the development of almost all precancerous and cancerous cervical lesions. Risk factors for cervical cancer include multiple sexual partners, a male partner with multiple previous or current sexual partners, young age at first sexual intercourse, high parity, persistent infection with HPV-16 or HPV-18, immunosuppression, a long history of the use of oral contraceptives, certain human leukocytic antigen (HLA) subtypes, and use of nicotine. Factors affecting the integrity of the immune system may affect a later risk of cervical cancer, including poor nutrition, chronic stress, and immunosuppressant medications. High-risk types of HPV (16 and 18) are found more frequently in women coinfected with chlamydia or gonorrhea. Women who use vaginal douches seemed to have a higher risk of HPV infections, possibly caused by the alteration in the cervicovaginal microbiome.15 Healthy vaginal microbiomes, marked by adequate quantities of lactobacilli, seem to have a decreased prevalence and increased clearance of HPV.16 Pathophysiology There are multiple subtypes of HPV, and the “high risk” (oncogenic) types of HPV (predominantly 16 and 18) have been most closely associated with high-grade dysplasia and cancer (also see Chapters 11 and 12). HPV-16 accounts for about 60% of cervical cancer cases and HPV-18 for about another 10%; other types contribute less than 5% of cases. The precancerous lesion, or dysplasia, also called cervical intraepithelial neoplasia (CIN) and cervical carcinoma in situ (CIS), is a more advanced form of the cell changes and can progress to invasive cancer. Importantly, cervical dysplasia can be detected noninvasively through examination of the cervical cells. If dysplasia is detected early, treatment is available to prevent invasive cancer. Progress to invasive cancer can be very slow. About 30% to 70% of those untreated for CIS will develop invasive carcinoma over 10 to 12 years, however, in about 10% of women, progression from in situ to invasive cancer can occur in less than 1

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year.17 The cervix is lined by two types of epithelial cells: squamous cells at the outer aspect and columnar glandular cells along the inner canal (Fig. 35.15). The site of the cellular transformation zone, called the squamocolumnar junction, is illustrated in Fig. 35.16. The transformation zone is very vulnerable to the oncogenic effects of HPV and is the site where CIS is most likely to develop. HPVs infect immature basal cells of the squamous epithelium in the areas of epithelial breaks or injury, or immature metaplastic squamous cells present at the squamocolumnar junction. Establishing HPV infection in the mature squamous cells that cover the ectocervix, vagina, or vulva requires damage to the surface epithelium. The cervix, with its large areas of immature epithelium, is very vulnerable to HPV infection.

FIGURE 35.15

The Two Types of Epithelial Cells Lining the Cervix: Squamous Cells and Columnar Glandular Cells.

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FIGURE 35.16 Cervical Intraepithelial Neoplasia (CIN). A, Normal multiparous cervix, including the transformation zone, where precancerous and cancerous changes occur. CIN stage I—note the white appearance of part of the anterior lip of the cervix; this is associated with neoplastic changes. CIN stage II —lesions also are reflected in distant capillaries. CIN stage III—lesions are predominantly around the external os. B, Normal epithelium, then human papillomavirus (HPV) infection progressing to CIN stage I. With more time, persistent HPV infections progress to precancerous lesions CIN II and CIN III and eventually to cervical cancer. Most cervical lesions do not progress to cervical cancer. (A from Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders; B from Symonds EM, Macpherson MBA: Color atlas of obstetrics and gynecology, London, 1994, Mosby.)

Although HPV is a causative factor for cervical cancer, it is not the only factor. Other important cocarcinogens must play a role, because in spite of the high percentage of young women infected with one or more HPV types during their reproductive years, only a few develop cancer. The other factors that appear to be associated include immune responses, hormonal responses, and other environmental factors that determine regression or persistence of the HPV infection. Like other cancers, cervical cancer requires the accumulations of genetic alterations for carcinogenesis to occur. Cervical cancer is a slowly progressive disease that moves from normal cervical epithelial cells to dysplasia to CIS and, eventually, to invasive cancer (see Fig. 35.16, B). Table 35.3 summarizes the staging of cervical cancer. Testing for high-risk HPV is often positive for many years (10 years or more) before dysplasia progresses to high-grade squamous intraepithelial lesions (HSILs) that can develop into invasive cervical cancer (CIN III, Table 35.4). TABLE 35.3 International Federation of Gynecology and Obstetrics (FIGO) Clinical Staging of Cancer of the Cervix Stage 0 I IA IA1

Characteristics Cancer in situ, intraepithelial carcinoma; earliest stage of cancer; cancer confined to its original site Carcinoma confined to cervix (extension to corpus disregarded) Earliest form of stage I; very small amount of cancer, which is visible only under a microscope Area of invasion is 3 cm in diameter), circumscribed, and encapsulated, glistening appearance, varies in color; two types: pure and mixed; pure tumor is surrounded by mucin; infrequent; found in lateral half of breast; tends to occur in women after age 70 Medullary Encapsulated and grows very large (7-8 cm in diameter); commonly surrounded by lymphocytic inflammatory infiltrate; occurs after age 50 Tubular Well-differentiated with orderly tubules in center (stroma) of mass; can be associated with noninfiltrating ductal carcinoma; occurs in women about age 50; nodal metastasis infrequent; occurrence is rare Adenoid Very rare; well-circumscribed, painless mass arising from nipple and areola cystic Metaplastic Involves cartilage or bone, mixed tumors or osteogenic sarcomas Squamous Frequent in black people; originates in ductal epithelium cell Carcinoma of the Mammary Lobules

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Lobular carcinoma in situ Infiltrating lobular Paget disease

Found in individuals with fibrocystic disease; localized to upper breast quadrants; 15%-35% risk of becoming invasive; occurs frequently in mid-40s; infiltrating variety occurs in early 50s Infiltrates from duct; firm mass with chalky streaks

Eczema of nipple that extends to areola; cancer usually found underneath nipple; poorly circumscribed; large Paget cells arise from duct and directly invade nipple; history of scaly, red rash spreading from nipple; lesion palpable beneath nipple, often bilateral; occurs in middle age Inflammatory Not a histologic type; fairly diffuse within breast tissue, diffuse edema of overlying skin; extremely carcinoma undifferentiated, very rare; most metastasize to axilla Sarcoma of the Breast Cystosarcoma Usually large (>17 cm in diameter); mostly localized but can rupture through skin; rarely metastasizes to phyllodes lymph nodes; history of painless nodule present for years before it forms a large mass; ulceration and bleeding of skin often present; occurs in wide age range (13-77 years) Fibrosarcoma Well-circumscribed, firm, and usually does not involve skin or nipple; well-differentiated to extremely undifferentiated; arises from connective tissue; extremely rare (e.g., liposarcoma, angiosarcoma)

Gene expression profiling studies have identified major subtypes classified as luminal A, luminal B, HER2+, basal-like, Claudin-low, and normal breast. Tumors can be classified with gene expression profiles, such as Oncotype Dx, Prosigna, and MammaPrint, on the basis of genomic profiles. This information helps personalize breast cancer treatment and determine which women need aggressive systemic treatment for high-risk cancers and close surveillance for dormant tumors. Many models of breast carcinogenesis have been suggested and include (1) gene addiction; (2) phenotype plasticity; and (3) cancer stem cells; and (4) hormonal outcomes affecting cell turnover of mammary epithelium, stem cells, ECM, and immune function (see previous sections Reproductive Factors: Pregnancy; Lobular Involution, Age, and Postlactational Involution; and Hormonal Factors). Cancer gene addiction includes oncogene addiction, whereby these driver genes (e.g., HER2 and MYC) play key roles in breast cancer development and progression, and nononcogene addiction, whereby these genes may not initiate cancer but play roles in cancer development and progression. Once a founding tumor clone is established, genomic instability may assist through the establishment of other subclones and contribute both to tumor progression and to therapy resistance. Phenotypic plasticity is exemplified by a distinctive phenotype called epithelialto-mesenchymal transition (EMT) (see Chapter 11). EMT is involved in the generation of tissues and organs during embryogenesis, is essential for driving tissue plasticity during development, and is an unintentional process during cancer progression. The EMTassociated reprogramming is involved in many cancer cell characteristics, including suppression of cell death or apoptosis and senescence, is reactivated during wound healing, and is resistant to chemotherapy and radiation therapy. Remodeling or reprogramming of the breast during postpregnancy involution is important because it involves inflammatory and “wound healing–like” tissue reactions known as reactive stroma or inflammatory stroma. These tissue reactions increase the risk for tumor invasion and may facilitate the transition of CIS to invasive carcinoma. Activation of an EMT program during cancer development often requires signaling between cancer cells and neighboring stromal cells. In advanced primary carcinomas, cancer cells recruit a variety of cell types into the surrounding stroma, including fibroblasts, myofibroblasts, granulocytes, macrophages, mesenchymal stem cells, and lymphocytes (Fig. 35.30). Overall, increasing evidence suggests that interactions of cancer cells with adjacent tumor-associated stromal cells induce malignant cell phenotypes (Fig. 35.31).

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FIGURE 35.30 Cells of the Tumor Microenvironment. A, Distinct cell types constitute most solid tumors, including breast tumors. Both the main cellular tissue, called parenchyma, and the surrounding tissue, or stroma, of tumors contain cell types that enable tumor growth and progression. For example, the immuneinflammatory cells present in tumors can include both tumor-promoting and tumor-killing subclasses of cells. B, The microenvironment of tumors. Multiple stromal cell types create a succession of tumor microenvironments that change as tumors invade normal tissue, eventually seeding and colonizing distant tissues. The organization, numbers, and phenotypic characteristics of the stromal cell types and the extracellular matrix (hatched background) evolve during progression and enable primary, invasive, and metastatic growth. (The premalignant stages are not shown.) (Data from Hanahan D, Weinberg R: Cell 144:646-674, 2011.)

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FIGURE 35.31 Signaling Interactions in the Tumor Microenvironment During Malignant Progression. Upper panel, Numerous cell types constitute the tumor microenvironment and are orchestrated and maintained by reciprocal interactions. Lower panel, The reciprocal interactions between the breast main tissue (parenchyma) and the surrounding stroma are important for cancer progression and growth. Certain organ sites of “fertile soil” or “metastasis niches” facilitate metastatic seeding and colonization. Cancer stem cells are involved in some or all stages of tumor development and progression. (Adapted from Hanahan D, Weinberg R: Cell 144:646-674, 2011.)

Research is ongoing to define cancer stem cells in breast carcinogenesis, including their origin and renewability properties. Studies have begun to identify the role of mammary stem cells (MaSCs) and to describe how they drive development of the gland and maintain homeostasis, the many cycles of proliferation and apoptosis needed to expand and maintain the breast during pregnancy, and return it to a quiet (quiescent) state after involution. EMT generates multiple epithelial cell subsets with different states of stemness relative to more differentiated cells. The ECM and the basement membrane (BM), in particular, are no longer just considered the “bricks and mortar” of a tissue but now a place

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where stem cells reside; and correct tissue architecture, together with the reservoir of growth factors, cytokines, and proteinases, is critical for mammary tissue to develop and function properly. Many of the biologic traits of high-grade malignancy—motility, invasiveness, and self-renewal—have been traced to subpopulations of stem cells within carcinomas. Hormones may act as accelerators, as well as initiators, delay involution, and influence the susceptibility of the breast epithelium to environmental carcinogens because hormones control the differentiation of the mammary gland epithelium and, thereby, regulate the rate of stem cell division. Invasion of cancer cells typically involves the collective migration of large unified groups of cells into adjacent tissue rather than the scattering of individual cancer cells (Fig. 35.32). Still unknown are the exact events that occur at the invasive edge of the tumor. It is critical to understand these events at the invasive edge as they relate to treatment. Displacement of tumor cells from a biopsy needle track is a concern and, although reported as low incidence, so is mechanical disruption from surgery that leads to displacement and seeding of tumor cells. Dormant cells appear to perpetuate carcinogenesis and form the precursors of eventual metastatic relapse and, sometimes, rapid recurrence. These dormant cells are called minimal residual disease (MRD). MRD may remain after initial chemotherapy, radiotherapy, and surgery. Current treatments preferentially kill proliferating cells, but dormant cells are not proliferating, which renders them more resistant to almost all current treatments.86 The benefit of surgery is that it eliminates cancer bulk and the diversity of cancer cells, including therapy-resistant cells.86

FIGURE 35.32 Invasion. Invasion of carcinoma cells occurs through two mechanisms: by single cell dissemination through an epithelial-mesenchymal transition (EMT) (gray arrow), or by collective

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dissemination of a cluster of tumor cells. Emerging evidence suggests that the leader cells of tumor groups or clusters undergo EMT-associated phenotypic changes. Clusters of migrating cells are commonly noted at the borders of invasive carcinomas and are best documented in the breasts and lungs. (Adapted from Lambert AW, Pattabiraman DR, Weinberg RA: Cell 168[4]:670-691, 2017.)

Cancer metastases require that primary tumor cells evolve the ability to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites. Investigators developed a mouse model of breast tumor heterogeneity and isolated a distinct clone of specialized cells that efficiently enter the vasculature and express two proteins, Serpine2 and Slpi, which were necessary and sufficient to program these cells for vascular mimicry. Vascular mimicry is a blood supply pathway in tumors that is formed by tumor cells and is independent of endothelial cell–lined blood vessels—thus it mimics real blood vessels (Fig. 35.33). This blood supply pathway facilitates perfusion of the primary tumors and correlates with a poor clinical outcome. The increase in these blood supply pathways was associated with an increase in circulating tumor cells (CTCs) and a subsequent increase in lung metastases. Additionally, treatment with the anticoagulant warfarin increased the number of CTCs and lung metastases, suggesting that the anticoagulant function of Serpine2 and Slpi both maintains blood flow through the extravascular network and promotes intravasation. These remarkable findings identify Serpine2- and Slpi-driven vascular mimicry as a critical mechanism or driver of metastatic progression in cancer.87

FIGURE 35.33 Vascular Mimicry Drives Metastasis. The steps to accomplish metastasis include intravasation, in which tumor cells escape from the primary tumor into the vasculature and move through the bloodstream; or extravasation, in which tumor cells escape from the vasculature to colonize in distant tissue. Metastasis is promoted by vascular mimicry, whereby tumor cells adopt characteristics similar to those of the endothelial cells that line blood vessels, and mimic vascular-like networks within tumors and between tumors and blood vessels. Wagenblast and colleagues found that two proteins, Serpine2 and Slpi, promoted metastasis by stimulating vascular mimicry. Tumor cells expressing these proteins (green) form the vascular-like network that allows other tumor cells (purple, blue) to move to secondary sites. (Adapted from Hendrix MJC: Nature 520:300-302, 2015; Wagenblast E et al: Nature 520:358-362, 2015.)

Carcinoma cells may promote the growth of lymphatic vessels through the process of lymphoangiogenesis, a process correlated with disease progression. Metastases may occur early in the process of neoplastic transformation. One explanation is the presence of preneoplastic cells living within inflammatory microenvironments and, from signaling, can

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activate EMT programs, causing the development of invasive phenotypes. In other cases, and traditionally understood, is metastases as a late event.

Ductal and Lobular Carcinoma in Situ Ductal carcinoma in situ (DCIS) is a heterogeneous group of proliferative lesions limited to breast ducts and lobules without invasion of the BM (Fig. 35.34). When DCIS breaches the BM and invades adjacent stroma, microinvasion (MI) is said to be present. About 84% of all in situ disease is DCIS; the remainder is mostly LCIS. DCIS occurs predominantly in females but can occur in males. Since 1980 the widespread adoption of screening mammography has led to an epidemic of diagnoses of DCIS88 (also see Did You Know? Breast Cancer Screening Mammography).

FIGURE 35.34 Ductal Carcinoma In Situ (DCIS). Illustration shows the location of DCIS. Given the low breast cancer mortality from DCIS, new approaches are needed for managing this disease. (From National Cancer Institute: Risk of breast cancer death is low after a diagnosis of ductal carcinoma in situ, Besthesda, Md, 2015, Author. With permission from Terese Winslow.)

Perspectives on DCIS are changing. Because DCIS looks like invasive cancer, the presumption was that these lesions were the precursors of cancer and early removal and treatment would reduce cancer incidence and mortality.89 Long-term epidemiologic studies have demonstrated that the removal of 50,000 to 60,000 DCIS lesions annually has not been accompanied by a reduction in the incidence of invasive cancer.90 The understanding is emerging that breast cancer has a range of behaviors, aggressive to indolent (idle), and screening mammography increases the likelihood of indolent lesions surfacing.89 A large study by Narod and colleagues has added to the growing concern to rethink the strategy for detecting and treating DCIS.91 Their study of 100,000 women with a diagnosis of DCIS showed that the risk of dying from breast cancer was very low.91 Less than 1% of women in this 20-year study died of breast cancer (compared to 5% of women who died of other causes). Surprisingly, the overall death rate for women with DCIS is lower than that for women in the population as a whole.92,93 Aggressive treatment of almost all DCIS does

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not lead to a reduction in breast cancer mortality, confirming the conclusions from the NSABP trials.94 In summary, based on large numbers of subjects and long-term study follow-up, and given the low breast cancer mortality risk, DCIS is not an emergency. The detection and treatment of nonpalpable DCIS often represent overdiagnosis and overtreatment.93 Data now suggest these measures: 1. In general, DCIS should be considered a “risk factor” for invasive cancer and should prompt targeting for preventive strategies. 2. Radiation therapy should not be routinely offered after lumpectomy for DCIS lesions that are not high-risk, because the absolute risk reduction in mortality was only 0.27% (relative risk reduction in mortality of 23%); Giannakease and colleagues state, “It is doubtful whether a benefit of this size is large enough to warrant radiotherapy.”95 3. Low- to intermediate-grade DCIS does not need to be a target for screening or early detection. 4. Continuing study is needed, both for the biologic nature of the highest-risk DCIS (large, high-grade, hormone receptor negative) and protein HER2 positive, especially in very young and black women. Studies of target approaches to reduce death from breast cancer also are needed.89 DCIS represents an opportunity to alter the breast environment with increased exercise, decreased alcohol intake, and avoidance of postmenopausal hormone therapy with progesterone-containing regimens. Stratification of DCIS lesions may be accomplished through available tools, such as Oncotype DCIS; unfortunately genetic testing is performed only for about half of such women. Lobular carcinoma in situ (LCIS) originates from the terminal duct lobular unit (see Fig. 35.25, B). Unlike DCIS, LCIS has a uniform appearance—the cells expand but do not distort involved spaces; thus the lobular structure is preserved. The cells grow in noncohesive (discohesive) clusters, usually because of a loss of the tumor-suppressive adhesion protein E-cadherin. LCIS is found as an incidental lesion from a biopsy and not from mammography because it is not associated with calcifications or stromal reactions that produce mammographic densities. LCIS has an incidence of about 1% to 6% of all carcinomas and does not increase with mammographic screening. With biopsies in both breasts, LCIS is bilateral in 20% to 40% of cases, compared with 10% to 20% of cases of DCIS. The cells of atypical hyperplasia, LCIS, and invasive lobular carcinoma are structurally identical. Loss of cellular adhesion because of dysfunction of E-cadherin results in a rounded shape without attachment to adjacent cells, increasing the risk of invasion. Ecadherin functions as a tumor-suppressor protein and may be lost in neoplastic proliferations from various mechanisms, including mutation. LCIS is a risk factor for invasive carcinoma and develops in 25% to 35% of women over a period of 20 to 30 years. Unlike DCIS, the risk is almost as high in the contralateral breast as in the ipsilateral breast. Treatments include close clinical follow-up and mammographic screening, tamoxifen, and bilateral prophylactic mastectomy. Clinical Manifestations

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The majority of carcinomas of the breast occur in the upper outer quadrant, where most of the glandular tissue of the breast is located. The lymphatic spread of cancer to the opposite breast, to lymph nodes in the base of the neck, and to the abdominal cavity is caused by obstruction of the normal lymphatic pathways or destruction of lymphatic vessels by surgery or radiotherapy (see Fig. 34.11). The less common, inner quadrant tumors may spread to mediastinal nodes or Rotter nodes, which are located between the pectoral muscles (see Fig. 34.11). Internal mammary chain nodes also are common sites of metastasis. Metastases from the vertebral veins can involve the vertebrae, pelvic bones, ribs, and skull. The lungs, kidneys, liver, adrenal glands, ovaries, and pituitary gland are also sites of metastasis. The first sign of breast cancer is usually a painless lump. Lumps caused by breast tumors do not have any classic characteristics. Other presenting signs include palpable nodes in the axilla, retraction of tissue (dimpling) (Fig. 35.35), or bone pain caused by metastasis to the vertebrae. Table 35.11 summarizes the clinical manifestations of breast cancers. Manifestations vary according to the type of tumor and stage of disease.

FIGURE 35.35 Retraction of Nipple Caused by Carcinoma. (From del Regato JA et al: Ackerman and del Regato's cancer: diagnosis, treatment, and prognosis, ed 6, St Louis, 1985, Mosby.)

TABLE 35.11 Clinical Manifestations of Breast Cancer Clinical Manifestation Local pain Dimpling of skin

Pathophysiology Local obstruction caused by tumor Can occur with invasion of dermal lymphatics because of retraction of Cooper

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Nipple retraction Skin retraction Edema Nipple/areolar eczema Pitting of skin (similar to surface of an orange [peau d'orange]) Reddened skin, local tenderness, and warmth Dilated blood vessels Nipple discharge in a nonlactating woman Ulceration Hemorrhage Edema of arm Chest pain

ligament or involvement of pectoralis fascia Shortening of mammary ducts Involvement of suspensory ligament Local inflammation or lymphatic obstruction Paget disease Obstruction of subcutaneous lymphatics, resulting in accumulation of fluid Inflammation Obstruction of venous return by a fast-growing tumor; obstruction dilates superficial veins Spontaneous and intermittent discharge caused by tumor obstruction Tumor necrosis Erosion of blood vessels Obstruction of lymphatic drainage in axilla Metastasis to lung

Evaluation and Treatment Clinical breast examination, mammography, ultrasound, thermography, MRI, biopsy, hormone receptor assays, and gene expression profiling are used in evaluating breast alterations and cancer. Most states in the U.S. enacted laws mandating that mammography facilities report breast density, but inconsistent guidelines have caused confusion and anxiety among individuals and health care providers.96 Case-control and cohort studies provide indirect evidence for the effectiveness of screening, yet they can be limited by selection bias and healthy volunteer bias. Individuals who undergo screening have been shown to have lower mortality from causes unrelated to that screening then do those who did not undergo screening, likely caused by better overall health behavior profiles; thus, observed differences in survival or mortality by screening history could be caused by these other factors and not the actual screening.96,97 Treatment is based on the extent or stage of the cancer. The extent of the tumor at the primary site, the presence and extent of lymph node metastases, and the presence of distant metastases are all evaluated to determine the stage of disease. Treatment can include surgery, radiation, chemotherapy, hormone, and targeted therapy.

Quick Check 35.5 1. What types of fibrocystic breast changes increase the risk of breast cancer? 2. What is the role of hormones and growth factors in the pathophysiology of breast cancer? 3. Why are reproductive factors, such as early menarche and late menopause, important for the pathogenesis of breast cancer? 4. Why is complete breast involution important for reducing the risk of breast cancer? 5. Discuss the role of the microenvironment or stromal tissue on breast cancer development.

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Summary Review Abnormalities of the Female Reproductive Tract 1. Normal development of the female reproductive tract requires the absence of testosterone during embryonic and fetal life. 2. Alterations in the normal process include errors in cellular sensitivity to testosterone (androgen insensitivity) or failures of cell line migration that result in changes in the structure of the reproductive organs. 3. AIS is a disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype or male genotype. 4. Other abnormalities of the uterus, cervix, and fallopian/uterine tubes have multifactorial origins, often the result of an interaction between genetic predisposition and environmental factors.

Alterations of Sexual Maturation 1. Sexual maturation, or puberty, is marked by the development of secondary sex characteristics, rapid growth and ultimately, the ability to reproduce. The normal range for the onset of puberty is now 8 to 13 years of age and can vary geographically. 2. Delayed puberty is the onset of sexual maturation after these ages; precocious puberty is the onset before these ages. Treatment depends on the cause.

Disorders of the Female Reproductive System 1. The female reproductive system can be altered by hormonal imbalances, infectious microorganisms, inflammation, structural abnormalities, and benign or malignant proliferative conditions. 2. Primary dysmenorrhea is painful menstruation not associated with pelvic disease. It results from excessive synthesis of PGF2α. Secondary dysmenorrhea results from endometriosis, pelvic adhesions, inflammatory disease, uterine fibroids, or adenomyosis. 3. Primary amenorrhea is the continued absence of menarche and menstrual function by 13 years of age without the development of secondary sex characteristics or by 15 years of age if these changes have occurred. 4. Secondary amenorrhea is the absence of menstruation for a time equivalent to three or more cycles in women who have previously menstruated. Secondary amenorrhea is associated with many disorders and physiologic conditions. 5. DUB is heavy or irregular bleeding in the absence of organic disease. 6. PCOS is a condition in which excessive androgen production is triggered by inappropriate secretion of gonadotropins. This hormonal imbalance prevents ovulation and causes enlargement and cyst formation in the ovaries, excessive endometrial proliferation, and often hirsutism. Insulin resistance and

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hyperinsulinemia play a key role in androgen excess. 7. PMS is the cyclic recurrence of physical, psychological, or behavioral changes distressing enough to disrupt normal activities or interpersonal relationships. Emotional symptoms, particularly depression, anger, irritability, and fatigue, are reported as the most distressing symptoms; physical symptoms tend to be less problematic. Treatment is symptomatic and includes stress reduction, exercise, biofeedback, lifestyle changes, counseling, and medication. 8. Infection and inflammation of the female genitalia can result from microorganisms that are present in the environment and often are sexually transmitted or from overproliferation of microorganisms that normally populate the genital tract. 9. PID is an acute inflammatory process caused by infection. Many infections are sexually transmitted, and microorganisms that comprise the vaginal flora are implicated. PID is a substantial health risk to women and untreated PID can lead to infertility. 10. Vaginitis is irritation or inflammation of the vagina, typically caused by infection. It is usually caused by sexually transmitted pathogens or Candida albicans, which causes candidiasis. 11. Cervicitis, which is infection of the cervix, can be acute (mucopurulent cervicitis) or chronic. Its most common cause is a sexually transmitted pathogen. 12. VV is chronic vulvar pain lasting 3 months or longer. The cause of VV is unknown; theories include embryonic factors, chronic inflammation, genetic immune factors, nerve pathways, increased sensitivity to environmental factors, infection with HPV, and hormonal changes. 13. Bartholinitis, also called Bartholin cyst, is an infection of the ducts that lead from the Bartholin glands to the surface of the vulva. Infection blocks the glands, preventing the outflow of glandular secretions. 14. The pelvic relaxation disorders—uterine displacement, uterine prolapse, cystocele, rectocele, and urethrocele—are caused by the relaxation of muscles and fascial supports, usually as a result of advancing age or after childbirth or other trauma. They are more likely to occur in women with a familial or genetic predisposition. 15. Benign ovarian cysts develop from mature ovarian follicles that do not release their ova (follicular cysts) or from a corpus luteum that persists abnormally instead of degenerating (corpus luteum cyst). Cysts usually regress spontaneously. 16. Endometrial polyps consist of benign overgrowths of endometrial tissue and often cause abnormal bleeding in the premenopausal woman. 17. Leiomyomas, also called myomas or uterine fibroids, are benign tumors arising from the smooth muscle layer of the uterus, the myometrium. 18. Adenomyosis is the presence of endometrial glands and stroma within the uterine myometrium. 19. Endometriosis is the presence of functional endometrial tissue (i.e., tissue that responds to hormonal stimulation) at sites outside the uterus. Endometriosis causes an inflammatory reaction at the site of implantation and is a cause of infertility. Information is emerging on the relationship between endometriosis and ovarian cancer. 20. Cancers of the female genitalia involve the uterus (particularly the endometrium), the cervix, and the ovaries. Cancer of the vagina is rare. 21. Cervical cancer arises from the cervical epithelium and is triggered by HPV. The

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cellular transformational zone is called the squamocolumnar junction. The progressively serious neoplastic alterations are CIN (cervical intraepithelial neoplasia, also known as cervical dysplasia), cervical CIS (carcinoma in situ), and invasive cervical carcinoma. Cocarcinogens include immune responses, hormonal responses, and other environmental factors that determine regression or persistence of the HPV infection. 22. Primary cancer of the vagina is rare. Risk factors include age 60 or older, exposure to DES, infection with HPV type 16, infection with HIV, and genital warts. The relationship of developing precancerous cell changes (called vaginal intraepithelial neoplasia) is controversial. 23. Risk factors for vulvar cancer include infection with HPV type 16 (cause), HIV, HPV-18 (probable cause), advancing age, previous cancer (untreated high-grade VIN), cervical cancer survivor, previous CIN, certain autoimmune conditions, organ transplant recipients (perhaps because of immunosuppression to clear HPV), and tobacco use (may relate to inability to clear HPV infection). 24. Carcinoma of the endometrium is the most common type of uterine cancer and most prevalent gynecologic malignancy. Primary risk factors for endometrial cancer include exposure to unopposed estrogen (e.g. estrogen-only hormone replacement therapy, tamoxifen, early menarche, late menopause, nulliparity, failure to ovulate), chronic hyperinsulinemia, hyperglycemia, body fatness and adult weight gain, chronic inflammation, lack of physical exercise. 25. Risk factors for ovarian cancer include advancing age, genetic factors, family history, overweight and obesity, height, reproductive/hormonal factors, HRT, endometriosis, diabetes, previous cancer, smoking, asbestos, use of talc-based powder, and ionizing radiation. Ovarian cancer causes more deaths than any other genital cancer in women. 26. Ovarian cancer is heterogeneous, and the biology of this type of cancer is changing.

Sexual Dysfunction 1. Sexual dysfunction is the lack of satisfaction with sexual function as a result of pain or a deficiency in sexual desire, arousal, or orgasm/climax. 2. Sexual function and dysfunction result from a complex set of personal and biologic factors that interact with the culture. Both organic and psychosocial disorders can be implicated in sexual dysfunction.

Impaired Fertility 1. Infertility, or the inability to conceive after 1 year of unprotected intercourse, affects approximately 15% of all couples. Fertility can be impaired by factors in the male, female, or both partners. 2. Female infertility results from dysfunction of the normal reproductive process: menses and ovulation, fallopian tube function (transport of the egg to the uterus, and the tube as a site of fertilization), ovarian dysfunction, and implantation of the fertilized egg into a receptive endometrium.

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Disorders of the Female Breast 1. Most disorders of the breast are disorders of the mammary gland—that is, the female breast. 2. Galactorrhea, or inappropriate lactation, is the persistent secretion of a milky substance by the breasts of a woman who is not in the postpartum state or nursing an infant. Its most common cause is nonpuerperal hyperprolactinemia—a rise in serum prolactin levels. 3. Benign breast conditions are numerous and involve both ducts and lobules. Benign epithelial lesions can be broadly classified according to their future risk of developing breast cancer as (1) nonproliferative breast lesions, (2) proliferative breast disease, and (3) atypical (atypia) hyperplasia. 4. Nonproliferative lesions include simple breast cysts, papillary apocrine change, and mild hyperplasia of the usual type. 5. Proliferative breast lesions without atypia are diverse and include usual ductal hyperplasia, intraductal papillomas, sclerosing adenosis, radial scar, and simple fibroadenoma. 6. Proliferative breast lesions with atypia include ADH and ALH. 7. DCIS refers to a heterogeneous group of proliferations limited to breast ducts and lobules without invasion of the basement membrane. LCIS originates from the duct lobular unit. 8. Breast cancer is the most common form of cancer in women and second to lung cancer as the most common cause of cancer death. However, the inclusion of DCIS with invasive breast cancer statistics is controversial. Breast cancer is a heterogeneous disease with diverse molecular, phenotypic, and pathologic changes. 9. The major risk factors for breast cancer are reproductive factors, such as nulliparity; hormonal factors and growth factors (e.g., excessive estradiol and IGF-1), familial factors (e.g., a family history of breast cancer) and environmental factors (e.g.,ionizing radiation). Two factors that have emerged as important are delayed involution of the mammary gland and breast density. Physical activity and avoiding postmenopausal weight gain may be risk-reducing factors. 10. A dominating belief in the field of cancer research is that epithelial function depends on the entire tissue, including the stroma or microenvironment. Breast cancer is now known as a tissue-based disease with a possible abnormal, aberrant wound healing and inflammatory stromal (reactive stroma) component. 11. Models of breast carcinogenesis include three interrelated themes: gene addiction, phenotype plasticity, and cancer stem cells. The exact molecular events leading to breast cancer invasion are complex and not completely understood. These events involve genetic and epigenetic alterations and cancer cell and stromal interactions. New concepts for breast cancer metastases include tumor dormancy and vascular mimicry. 12. Most breast cancers arise from the ductal epithelium and then may metastasize to the lymphatics, opposite breast, abdominal cavity, lungs, bones, kidneys, liver, adrenal glands, ovaries, and pituitary glands. 13. The first clinical manifestation of breast cancer is usually a small, painless lump in

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the breast. Other manifestations include palpable lymph nodes in the axilla, dimpling of the skin, nipple and skin retraction, nipple discharge, ulcerations, reddened skin, and bone pain associated with bony metastases.

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Key Terms Abnormal uterine bleeding (AUB), 784 Adenomyosis, 796 Amenorrhea, 783 Androgen insensitivity syndrome (AIS), 780 Anorgasmia (orgasmic dysfunction), 806 Atypia, 808 Atypical ductal hyperplasia (ADH), 809 Atypical hyperplasia (AH), 808 Atypical lobular hyperplasia (ALH), 809 Bacterial vaginosis, 790 Bartholinitis (Bartholin cyst), 791 Benign breast disease (BBD), 808 BRCA1, 819 BRCA2, 819 Carcinoma in situ (CIS), 819 Cervicitis, 790 Complete androgen insensitivity syndrome (CAIS), 780 Complete precocious puberty, 782 Corpus luteum cyst, 794 Cyst, 793, 808 Cystocele, 792 Delayed puberty, 782 Dermoid cyst, 794 Diffuse papillomatosis, 808 Disorders of desire (hypoactive sexual desire, decreased libido), 806 Ductal carcinoma in situ (DCIS), 821 Dyspareunia (painful intercourse), 806 E-cadherin, 824 Endometrial polyp, 794 Endometriosis, 796 Enterocele, 793 Epithelial-to-mesenchymal transition (EMT), 820 Fibrocystic change (FCC), 808 Follicular cyst, 794 Functional cyst, 794 Galactorrhea (inappropriate lactation), 807 Genetic heterogeneity, 819 Human papillomavirus (HPV), 797 Hirsutism, 784 Infertility, 807 Inflammatory stroma, 820 Intraductal papilloma, 808 Leiomyoma (myoma, uterine fibroid), 795

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Lobular carcinoma in situ (LCIS), 824 Lobular involution, 813 Mammographic density (MD), 816 Mild hyperplasia of the usual type, 808 Minimal residual disease (MRD), 821 Mixed precocious puberty, 782 Mucopurulent cervicitis (MPC), 791 Nonpuerperal hyperprolactinemia, 807 Nonpuerperal prolactinemia, 807 Oophoritis, 788 Ovarian torsion, 794 Papillary apocrine change, 808 Pelvic inflammatory disease (PID), 788 Pelvic organ prolapse (POP), 792 Pessary, 792 Phenotypic heterogeneity, 819 Polycystic ovary syndrome (PCOS), 785 Precocious puberty, 782 Pregnancy-associated breast cancer (PABC), 813 Premenstrual dysphoric disorder (PMDD), 786 Premenstrual syndrome (PMS), 786 Primary amenorrhea, 783 Primary dysmenorrhea, 783 Prolactin-inhibiting factor (PIF), 807 Proliferative breast lesion without atypia, 808 Puberty, 781 Radial scar (RS), 808 Reactive stroma, 820 Rectocele, 793 Retrograde menstruation, 796 Salpingitis, 788 Sclerosing adenosis, 808 Secondary amenorrhea, 783 Secondary dysmenorrhea, 783 Sexual dysfunction, 806 Simple fibroadenoma, 808 Terminal duct lobular unit (TDLU), 813 Thelarche, 781 Transformation zone, 797 Unopposed estrogen, 801 Usual ductal hyperplasia (UDH), 808 Uterine prolapse, 792 Vaginismus, 806 Vaginitis, 790 Vascular mimicry, 821 Vulvodynia (VV), 791 Xenoestrogen, 819

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References 1. Geffner ME. Androgen insensitivity syndrome (AIS). Shahram Yazdano, et al. Chronic complex diseases of childhood: a practical guide for clinicians. Universal Publishers: Boca Raton, Fla; 2011. 2. National Institutes of Health (NIH). Genetics home reference: androgen insensitivity syndrome. U.S. Department of Health & Human Services, National Institutes of Health, U.S. National Library of Medicine: Bethesda MD; 2018 [(Accessed 24 July 2018)]. 3. Kreisel K, et al. Prevalence of pelvic inflammatory disease in sexually experienced women of reproductive age—United States, 2013-2014. MMWR Morb Mortal Wkly Rep. 2017;66:80– 83. 4. Kumar V, et al. Robbins & Cotran pathologic basis of disease. ed 9. Elsevier/Saunders: Philadelphia; 2015. 5. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases (STDs). Author: Atlanta; 2015. 6. Centers for Disease Control and Prevention (CDC). Diseases characterized by urethritis and cervicitis, STD sexually transmitted disease treatment guidelines. Author: Atlanta; 2014. 7. Centers for Disease Control and Prevention (CDC). STD treatment guidelines. Author: Atlanta; 2014. 8. Shah M, Hoffstetter S. Vulvodynia. Obstet Gynecol Clin North Am. 2014;41:453–464. 9. Falsetta ML, et al. A review of the available clinical therapies for vulvodynia management and new data implicating proinflammatory mediators in pain elicitation. BJOG. 2017;124(2):210–218. 10. Gupta JK, et al. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014;(12) [CD005073]. 11. Forte A, et al. Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic 1964

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Transl Med. 2014;3(1):1–8. 24. Romero I, Bast RC. Minireview: human ovarian cancer biology, current management, and paths to personalizing therapy. Endocrinology. 2012;153(4):1593–1602. 25. Nik NN, et al. Origin and pathogenesis of pelvic (ovarian, tubal, and primary peritoneal) serous carcinoma. Annu Rev Pathol. 2014;9:27–45. 26. National Cancer Institute. PDQ® ovarian, fallopian tube, and primary peritoneal cancer screening. Author.: Bethesda, Md; 2015 [Date last modified March 3, 2015; Available at] www.cancer.gov/types/ovarian/hp/ovarian-screening-pdq. 27. U.S. Preventive Services Task Force (USPSTF). Screening for ovarian cancer: U.S. Preventive services task force reaffirmation recommendation statement. Ann Intern Med. 2012;157(12):900–904. 28. Giede KC, et al. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol. 2005;99(2):447–461. 29. Mercado C, et al. Quality of care in advanced ovarian cancer: the importance of provider specialty. Gynecol Oncol. 2010;117(1):18–22. 30. Barbieri RL. Female infertility. Strauss JF, Barbieri RL. Yen and Jaffe's reproductive endocrinology. ed 7. Elsevier: Philadelphia PA; 2014:512–517. 31. Marshburn PB. Counseling and diagnostic evaluation for the infertile couple. Obstet Gynecol Clin North Am. 2015;42(1):1–14. 32. Boulet SL, et al. Assisted reproductive technology and birth defects among liveborn infants in Florida, Massachusetts, and Michigan, 2000-2010. JAMA Pediatr. 2016;170(6):e154934. 33. Sabel MS. Overview of benign breast disease. [Available at UpToDate Individual Web] www.uptodate.com; 2018. 34. Lester S. The breast. Kumar V, et al. Robbins & Cotran pathologic basis of disease. ed 9. Elsevier Saunders: Philadelphia; 2015. 35. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146– 151. 1966

36. Page DL, et al. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer. 1985;55:2698– 2708. 37. Sanders M, et al. Continued observation of the natural history of low-grade ductal carcinoma in situ reaffirms proclivity for local recurrence even after more than 30 years of follow-up. Mod Pathol. 2015;28(5):662–669. 38. Hartmann LC, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353:229–237. 39. Page DL, et al. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet. 2003;361(9352):125–129 [Erratum: Lancet 361(9373), 1994.]. 40. Menes TS, et al. Subsequent breast cancer risk following diagnosis of atypical ductal hyperplasia on needle biopsy. JAMA Oncol. 2017;3(1):36–41. 41. Hartmann LC, et al. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res (Phila). 2014;7:211– 217. 42. Hollowell JG, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and II (1971-1974 and 1988-1994). J Clin Endocrinol Metab. 1998;83(10):3401–3408. 43. Li Y, et al. Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanism. Int J Cancer. 2009;125(2):286–296. 44. Islam MA, et al. Deconjugation of soy isoflavone glucuronides needed for estrogenic activity. Toxicol In Vitro. 2015;29(4):706– 715. 45. North American Menopause Society (NAMS). The role of soy isoflavones in menopausal health: report of the North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL. Menopause. 2011;18(7):732–753. 1967

46. Iodine monograph. Altern Med Rev. 2010;15(3):273–278. 47. Centers for Disease Control and Prevention (CDC). Breast cancer statistics, updated June 12, 2018. Division of Cancer Prevention and Control, Centers for Disease Control and Prevention: Atlanta GA; 2018 [(Accessed 14 September 18)]. 48. International Agency for Research on Cancer (IARC). Breast GLOBOCAN 2018. World Health Organization, International Agency for Research on Cancer, Global Cancer Observatory: Lyon, France; 2018. 49. Albrektsen G, et al. The short-term and long-term effect of pregnancy on breast cancer risk: a prospective study of 802,457 parous Noregian women. Br J Cancer. 1995;72(2):480– 484. 50. Callihan EB, et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res Treat. 2013;138:549–559. 51. Johansson AL, et al. Increased mortality in women with breast cancer detected during pregnancy and different periods postpartum. Cancer Epidemiol Biomarkers Prev. 2011;20(9):1865– 1872. 52. Schedin P, et al. Microenvironment of the involuting mammary gland mediates mammary cancer progression. J Mammary Gland Biol Neoplasia. 2007;12:71–82. 53. Martinson HA, et al. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression. Int J Cancer. 2015;136(8):1803–1813. 54. Barton M, et al. Molecular pathways involved in pregnancyinduced prevention against breast cancer. Front Endocrinol (Lausanne). 2014;5:213. 55. Milanese TR, et al. Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst. 2006;98(2):1600–1607. 56. Jindal S, et al. Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling. Breast Cancer Res. 2014;16(2):R31. 57. Geschickter CD. Diseases of the breast. ed 2. Lippincott: 1968

Philadelphia; 1945. 58. Vorrherr H. The breast: morphology, physiology, and lactation. Academic Press: New York; 1974. 59. Khodr ZG, et al. Circulating sex hormones and terminal duct lobular unit involution of the normal breast. Cancer Epidemiol Biomarkers Prev. 2014;23(12):2765–2773. 60. Martinson HA, et al. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression. Int J Cancer. 2015;136(8):1803–1813. 61. Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6:281–291. 62. World Health Organization (WHO). A review of human carcinogens. B. Biological agents IARC monographs on the evaluation of carcinogenic risks to humans, IARC Monographs, vol 100(B). Author: Geneva, Switzerland; 2015. 63. Grant MD, et al. Menopausal symptoms: comparative effectiveness of therapies, Blue Cross and Blue Shield Association Technology Evaluation Center, Evidence-Based Practice Center. Agency for Healthcare Research and Quality: Rockville, Md; 2015. 64. Ahmadieh H, Azar ST. Type 2 diabetes oral diabetic medications, insulin therapy, and overall breast cancer risk. ISRN Endocrinol. 2013;2013:181240. 65. Suissa S, et al. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011;54(9):2254–2262. 66. Wu J, et al. Light at night activates IGF-1R/PDK1 signaling and accelerates tumor growth in human breast cancer xenografts. Cancer Res. 2011;71(7):2622–2631. 67. IARC Special Report. Policy: a review of human carcinogens— Part A: pharmaceuticals. Lancet. 2009;10:13–14. 68. Institute of Medicine (IOM) of the National Academies. Breast cancer and the environment: a life course approach. The National Academies Press: Washington, DC; 2011. 69. National Cancer Institute (NCI). Radiation risks and pediatric computed tomography (CT): a guide for health care providers. [Available at] www.cancer.gov; 2002. 70. Ginsburg ON, et al. Mammographic density, lobular 1969

involution, and risk of breast cancer. Br J Cancer. 2008;4(99):1369–1374. 71. Smith-Bindman R. Environmental causes of breast cancer and radiation from medical imaging. Arch Intern Med. 2012;172(13):1023–1027. 72. Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277– 2284. 73. Schwab SA, et al. X-ray induced formation of γ-H2AX foci after full-field digital mammography and digital breast tomosynthesis. PLoS ONE. 2013;8(7):e70660. 74. Colin C, et al. DNA double-strand breaks induced by mammographic screening procedures in human mammary epithelial cells. Int J Radiat Biol. 2011;87(11):1103–1112. 75. Colin C, Foray N. DNA damage induced by mammography in high family risk patients: only one single view in screening. Breast. 2012;21:409–410. 76. Colin C, et al. Update relevance of mammographic screening modalities in women previously treated with chest irradiation for Hodgkin disease. Radiology. 2012;265(3):669–676. 77. Frankenberg-Schwager M, et al. Chromosomal instability carriers. Int J Radiat Biol. 2012;88:846–857. 78. Ng J, et al. Predicting the risk of secondary lung malignancies associated with whole-breast radiation therapy. Int J Radiat Oncol Biol Phys. 2012;83(4):1101–1106. 79. Broach RB, et al. A cost-effective handheld breast scanner for use in low-resource environments: a validation study. World J Surg Oncol. 2016;14(1):277. 80. Somashekhar SP, et al. Noninvasive and low-cost technique for early detection of clinically relevant breast lesions using a handheld point-of–care medical device (iBreastExam): prospective three-arm triple-blinded comparative study. Indian J Gynecologic Oncol. 2016;14:26. 81. Xu X, et al. Breast tumor detection using piezoelectric fingers: first clinical report. J Am Coll Surg. 2013;216(6):1168–1173. 82. Aune D, et al. Dietary fiber and breast cancer risk: a systematic 1970

review and meta-analysis of prospective studies. Ann Oncol. 2012;23(6):1394–1402. 83. Nechuta SJ, et al. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of U.S. and Chinese women. Am J Clin Nutr. 2012;96(1):123–132. 84. Vaino H, Bianchini F. IARC. International Agency for Research on Cancer. Weight control and physical activity. IARC Press: Lyon; 2002. 85. Bennett LM, Davis BJ. Identification of mammary carcinogens in rodent bioassays. Environ Mol Mutagen. 2002;39(2-3):150– 157. 86. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168(4):670–691. 87. Wagenblast E, et al. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature. 2015;520:358–362. 88. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;41:139–141. 89. Esserman L, Yau C. Rethinking the standard for ductal carcinoma in situ treatment. JAMA Oncol. 2015;1(7):881–883. 90. Lin C, et al. The majority of locally advanced breast cancers are interval cancers. J Clin Oncol. 1503;27:2009. 91. Narod SA, et al. Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. 2015;1(7):888–896. 92. Lester S. The breast. Kumar V, Abbas AK, Fausto N. Robbins and Cotran pathologic basis of disease. ed 9. Elsevier Saunders: Philadelphia; 2015. 93. National Cancer Institute (NCI). PDQ® breast cancer screening. Author.: Bethesda, Md; 2015 [Date last modified May 14, 2015; Available at] www.cancer.gov/types/breast/hp/breast-screening-pdq. 94. Wapnir IL, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478–488. 1971

95. Giannakeas V, et al. Association of radiotherapy with survival in women treated for ductal carcinoma in situ with lumpectomy or mastectomy. JAMA Netw Open. 2018;1(4):e181100. 96. National Cancer Institute (NCI), PDQ® Screening and Prevention Editorial Board. PDQ® cancer screening overview. Author.: Bethesda, Md; 2019 [Updated 05/31/2019; Available at] https://www.cancer.gov/about-cancer/screening/hpscreening-overview-pdq. 97. Pierre-Victor D, Pinsky PF. Association of nonadherence to cancer screening examinations with mortality from unrelated causes: a secondary analysis of the PLCO Cancer Screening Trial. JAMA Intern Med. 2019;179(2):196–203.

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36

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Alterations of the Male Reproductive System George W. Rodway

CHAPTER OUTLINE Alterations of Sexual Maturation, 830 Delayed or Absent Puberty, 830 Precocious Puberty, 830 Disorders of the Male Reproductive System, 831 Disorders of the Urethra, 831 Disorders of the Penis, 831 Disorders of the Scrotum, Testis, and Epididymis, 834 Disorders of the Prostate Gland, 838 Sexual Dysfunction, 849 Disorders of the Male Breast, 852 Gynecomastia, 852 Carcinoma, 852 Sexually Transmitted Infections, 853

Alterations of the reproductive system span a wide range of concerns, from delayed sexual development and suboptimal sexual performance to structural and functional abnormalities. Many common male reproductive disorders carry potentially serious physiologic or psychological consequences. For example, sexual or reproductive dysfunction, such as impotence or infertility, can dramatically affect self-concept, relationships, and overall quality of life. Conversely, organic and psychosocial problems, such as alcoholism, depression, situational stressors, chronic illness, and medications, can affect sexual performance and may be risk factors for the development of some types of reproductive tract cancers. Aside from skin cancer, prostate cancer is the second leading cause of cancer deaths and is the most frequently diagnosed cancer in men. The incidence rates for prostate cancer changed substantially between the mid-1980s and the mid-1990s and have since fluctuated widely from year to year, in large part reflecting changes in prostate cancer screening with the prostate-specific antigen (PSA) blood test. As with disorders of the female reproductive system, the diagnosis and treatment of male

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reproductive system disorders are often complicated by the stigma and symbolism associated with the reproductive organs and emotion-laden beliefs and behaviors related to reproductive health. The diagnosis or treatment for any problem may be delayed because of embarrassment, guilt, fear, or denial.

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Alterations of Sexual Maturation The process of sexual maturation, or puberty, is marked by the development of secondary sex characteristics, rapid growth, and, ultimately, the ability to reproduce. A variety of congenital and endocrine disorders can disrupt the timing of puberty. Puberty that occurs too late (delayed puberty) or too early (precocious puberty) is caused by the inappropriate onset of sex hormone production. While the average age of pubertal onset appears to be decreasing for girls, the age of pubertal onset has remained essentially unchanged for boys.

Delayed or Absent Puberty About 3% of children living in North America experience delayed development of secondary sex characteristics.1 Normally, boys tend to mature later than girls, around 14 to 14.5 years of age. In boys, the first sign of maturity is enlargement of the testes and thinning of the scrotal skin. In delayed puberty, these secondary sex characteristics develop later. In about 95% of cases, delayed puberty is a normal physiologic event. Hormonal levels are normal, the hypothalamic-pituitary-gonadal axis is intact, and maturation is slowly occurring. Treatment is seldom needed unless the delayed puberty is causing psychosocial problems.2 The other 5% of cases are caused by the disruption of the hypothalamic-pituitary-gonadal axis or by the outcomes of a systemic disease. Treatment depends on the cause (Box 36.1), and referral to a pediatric endocrinologist is necessary.

Box 36.1

Causes of Delayed Puberty Hypergonadotropic Hypogonadism: Low Testosterone, Increased Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) 1. Gonadal dysgenesis, most commonly Turner syndrome (45,X/46,XX; structural X or Y abnormalities, or mosaicism) 2. Klinefelter syndrome (47,XXY) 3. Bilateral gonadal failure a. Traumatic or infectious b. Postsurgical, postirradiation, or postchemotherapy c. Autoimmune d. Idiopathic empty scrotum or vanishing testes syndrome (congenital anorchia)

Hypogonadotropic Hypogonadism: Low Testosterone, Decreased LH, Depressed FSH 1976

1. Reversible a. Physiologic delay b. Weight loss/anorexia c. Strenuous exercise d. Severe obesity e. Illegal drug use; also use of marijuana in particular f. Primary hypothyroidism g. Congenital adrenal hyperplasia h. Cushing syndrome i. Prolactinomas 2. Irreversible a. Gonadotropin-releasing hormone (GnRH) deficiency (Kallmann syndrome) or idiopathic hypogonadotropic hypogonadism (IHH) b. Hypopituitarism c. Congenital central nervous system defects d. Other pituitary adenomas e. Craniopharyngioma f. Malignant pituitary tumors

Precocious Puberty Precocious puberty is a rare event, affecting fewer than 1 in 50,000 boys. Precocious puberty for boys of all ethnic and racial groups is defined as sexual maturation occurring before age 9.3 The mean ages of beginning male genital and pubic hair growth and early testicular volumes are leaning toward younger ages than earlier studies have suggested, although this seems to be dependent on race and/or ethnicity. Precocious puberty may be caused by many conditions (Box 36.2), including lethal central nervous system tumors. All cases of precocious puberty require thorough evaluation.

Box 36.2

Primary Forms of Precocious Puberty Complete Precocious Puberty Premature development of appropriate characteristics for the child's sex Hypothalamic-pituitary-ovarian axis functioning normally but prematurely In about 10% of cases, lethal central nervous system tumor may be the cause

Partial Precocious Puberty Partial development of appropriate secondary sex characteristics Premature adrenarche (growth of axillary and pubic hair), which tends to occur between 5 and 8 years of age Can progress to complete precocious puberty; may be caused by estrogen-secreting

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neoplasms or may be a variant of normal pubertal development

Mixed Precocious Puberty Causes the child to develop some secondary sex characteristics of the opposite sex Common causes: adrenal hyperplasia or androgen-secreting tumors Data from Burchett MLR et al: Endocrine and metabolic diseases. In Burns CE et al, editors: Pediatric primary care, St Louis, 2009, Saunders; Jospe N: Disorders of pubertal development. In Osborn LM et al, editors: Pediatrics, Philadelphia, 2005, Mosby. All forms of precocious puberty are treated by identifying and removing the underlying cause or administering appropriate hormones. In many cases, precocious puberty can be reversed. However, complete precocious puberty (development consistent with the sex of the individual) is difficult to treat and can cause long bones to stop growing before the child has reached normal height.

Quick Check 36.1 1. Why does puberty occur too late or too early in some individuals? 2. Why do all forms of precocious puberty require evaluation?

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Disorders of the Male Reproductive System Disorders of the Urethra Urethritis and urethral strictures are common disorders of the male urethra. Urethral carcinoma, an extremely rare form of cancer, can occur in men older than 60 years.

Urethritis Urethritis is an inflammatory process that is usually, but not always, caused by a sexually transmitted microorganism. Infectious urethritis caused by Neisseria gonorrhoeae is often called gonococcal urethritis (GU); urethritis caused by other microorganisms is called nongonococcal urethritis (NGU). Nonsexual origins of urethritis include inflammation or infection as a result of urologic procedures, insertion of foreign bodies into the urethra, anatomic abnormalities, or trauma. Noninfectious urethritis is rare and is associated with the ingestion of wood or ethyl alcohol or turpentine. It is also seen with reactive arthritis. Symptoms of urethritis include urethral tingling or itching or a burning sensation, and frequency and urgency with urination. The individual may note a purulent or clear mucuslike discharge from the urethra. Nucleic acid detection amplification tests allow early detection of N. gonorrhoeae and Chlamydia trachomatis in urine studies. Treatment consists of appropriate antibiotic therapy for infectious urethritis and avoidance of future exposure or mechanical irritation.

Urethral Strictures A urethral stricture is a narrowing of the urethra caused by scarring. The scars may be congenital but can be present at any age and have a wide range of etiologic factors, including untreated urethral infection, trauma, and urologic instrumentation. Infections also can occur from long-term use of indwelling catheters. Prostatitis and infection secondary to urinary stasis are common complications. Severe and prolonged obstruction can result in hydronephrosis and renal failure. The clinical manifestations of urethral stricture are caused by bladder outlet obstruction. Urethral stricture often manifests itself as lower urinary tract symptoms or urinary tract infections with significant impairment in the quality of life. The primary symptom is diminished force and caliber of the urinary system; other symptoms include urinary frequency and hesitancy, mild dysuria, double urinary stream or spraying, and dribbling after voiding. Urethral stricture is diagnosed on the basis of the history, physical examination, flow rates, and cystoscopy. Treatment is usually surgical and may involve urethral dilation, urethrotomy, or a variety of open surgical techniques. The choice of surgical intervention depends on the age of the individual and the severity of the problem.

Disorders of the Penis Phimosis and Paraphimosis Phimosis and paraphimosis are both disorders in which the foreskin (prepuce) is “too

1979

tight” to move easily over the glans penis. Phimosis is a condition in which the foreskin cannot be retracted back over the glans, whereas paraphimosis is the opposite: the foreskin is retracted and cannot be moved forward (reduced) to cover the glans (Fig. 36.1). Both conditions can cause penile pathologic conditions.

FIGURE 36.1 Phimosis and Paraphimosis. A, Phimosis: the foreskin has a narrow opening that is not large enough to permit retraction over the glans. B, Lesions on the prepuce secondary to infection cause swelling, and retraction of the foreskin may be impossible. Circumcision is usually required. C, Paraphimosis: the foreskin is retracted over the glans but cannot be reduced to its normal position. Here it has formed a constricting band around the penis. D, Ulcer on the retracted prepuce with edema. (A and C from Monahan FD et al: Phipps’ medical-surgical nursing: health and illness perspectives, ed 8, St Louis, 2007, Mosby; B from Taylor PK: Diagnostic picture tests in sexually transmitted diseases, St Louis, 1995, Mosby; D from Morse SA et al: Atlas of sexually transmitted diseases and AIDS, ed 4, London, 2011, Saunders.)

The inability to retract the foreskin is normal in infancy and is caused by congenital adhesions. During the first 3 years of life, congenital adhesions (between the foreskin and glans) separate naturally with penile erections and are not an indication for circumcision. Phimosis can occur at any age and is most commonly caused by poor hygiene and chronic infection. It rarely occurs with normal foreskin.

1980

Reasons for seeking treatment include edema, erythema, and tenderness of the prepuce and purulent discharge; inability to retract the foreskin is a less common complaint. Circumcision, if needed, is performed after infection has been eradicated. Complications of phimosis include inflammation of the glans (balanitis) or prepuce (posthitis) and paraphimosis. There is a higher incidence of penile carcinoma in uncircumcised males, but chronic infection and poor hygiene are usually the underlying factors in such cases. Approximately 60% of invasive penile carcinomas are attributable to human papillomavirus (HPV).4 Paraphimosis, in which the foreskin is retracted, can constrict the penis, causing edema of the glans. If the foreskin cannot be reduced manually, surgery must be performed to prevent necrosis of the glans caused by constricted blood vessels. Severe paraphimosis is a surgical emergency.

Peyronie Disease Peyronie disease (“bent nail” syndrome) is a fibrotic condition that causes lateral curvature of the penis during erection (Fig. 36.2). Peyronie disease develops slowly and is characterized by tough fibrous thickening of the fascia in the erectile tissue of the corpora cavernosa. A dense, fibrous plaque is usually palpable on the dorsum of the penile shaft. The problem usually affects middle-aged men and is associated with painful erection, painful intercourse (for both partners), and poor erection distal to the involved area. In some cases, impotence or unsatisfactory penetration occurs. When the penis is flaccid, there is no pain.

FIGURE 36.2 Peyronie Disease. This person complained of pain and deviation of his penis to one side on erection. (From Taylor PK: Diagnostic picture tests in sexually transmitted diseases, London, 1995, Mosby.)

A local vasculitis-like inflammatory reaction occurs, and decreased tissue oxygenation results in fibrosis and calcification. The exact cause is unknown. Peyronie disease is

1981

associated with Dupuytren contracture (a flexion deformity of the fingers or toes caused by shortening or fibrosis of the palmar or plantar fascia), diabetes, tendency to develop keloids, and, in rare cases, use of beta-blocker medications. There is no definitive treatment for Peyronie disease; however, treatment can include pharmacologic agents and surgery. Spontaneous remissions occur in as many as 50% of individuals. However, men suffering with Peyronie disease who have a significant penile deformity that precludes successful coitus should be appraised for surgical correction.

Priapism Priapism is an uncommon condition of prolonged penile erection. It is usually painful and is not associated with sexual arousal (Fig. 36.3). Priapism is idiopathic in 60% of cases; the remaining 40% of cases can be associated with spinal cord trauma, sickle cell disease, leukemia, pelvic tumors, infections, or penile trauma.

FIGURE 36.3

Priapism. (From Lloyd-Davies RW et al: Color atlas of urology, ed 2, London, 1994, Wolfe Medical.)

Priapism must be considered a urologic emergency. Treatment within hours is effective and prevents impotence. Conservative approaches include iced saline enemas, ketamine administration, and spinal anesthesia. Needle aspiration of blood from the corpus through the dorsal glans is often effective and is followed by catheterization and pressure dressings to maintain decompression. More aggressive surgical treatments include the creation of vascular shunts to maintain blood flow. Erectile dysfunction results in up to 50% of prolonged cases.

Balanitis 1982

Balanitis is an inflammation of the glans penis (Fig. 36.4) that usually occurs in conjunction with posthitis, an inflammation of the prepuce. (Inflammation of the glans and the prepuce is called balanoposthitis.) Balanitis is associated with poor hygiene and phimosis. The accumulation under the foreskin of glandular secretions (smegma), sloughed epithelial cells, and Mycobacterium smegmatis can irritate the glans directly or lead to infection. Skin disorders (e.g., psoriasis, lichen planus, eczema) and candidiasis must be differentiated from inflammation resulting from poor hygienic practices. Balanitis is most commonly seen in men with poorly controlled diabetes and candidiasis. The infection is treated with antimicrobials. After the inflammation has subsided, circumcision can be considered to prevent recurrences.

FIGURE 36.4

Balanitis. (From Taylor PK: Diagnostic picture tests in sexually transmitted diseases, London, 1995, Mosby.)

Tumors of the Penis Tumors of the penis are not common. The most frequent are the benign epithelial tumor condyloma acuminatum and penile carcinomas. Condyloma acuminatum is a benign tumor caused by HPV, a microorganism that causes a sexually transmitted infection (STI). HPV type 6 and, less often, type 11, are the most frequent types and can cause a common wart and moist surface of the external genitalia. Giant condylomata (Buschke-Löwenstein) affect older men and may be 5 to 10 cm in size. Atypia may be evident in long-standing giant condylomata, and assessment of other HPV subtypes may be indicated to distinguish the lesion from a noninvasive warty carcinoma.

Penile Cancer Carcinoma of the penis is rare in the United States, affecting about 1 in 100,000 men. However, it does account, for about 10% of cancers in African and South American men. It can affect men 40 to 70 years of age; two thirds of men are diagnosed at 65 years of age or

1983

older. In the United States about four out of five cases of the disease are diagnosed in men more than 55 years of age. Although the exact cause is unknown, risk factors may include HPV infection, AIDS (weakened immune system), smoking, and treatment (psoralens and ultraviolet A) for psoriasis. Circumcision at birth appears to decrease the risk of penile cancer, and penile cancer is more common in men with phimosis.5 Squamous cell carcinoma accounts for 95% of invasive penile cancers. Other premalignant lesions, or in situ forms of epidermal carcinoma, that occur on the penis include leukoplakia (white plaque), Paget disease (red, inflamed areas), erythroplasia of Queyrat (raised red areas), and Buschke-Löwenstein patches (large venous areas). HPV 6 and HPV 11 associated with genital warts (condylomata acuminata) have low cancer risks. At times, the penis might be the site of metastatic spread of solid tumors from the bladder, prostate, rectum, or kidney. Early squamous cell carcinoma and premalignant epidermal lesions are easily treated, but delays in seeking treatment are attributed to denial, embarrassment, failure to detect lesions under a phimotic foreskin, fear, guilt, and ignorance. When diagnosed early (stage 0, stage I, and stage II), penile cancer is highly curable. Squamous cell carcinoma usually begins as a small, flat, ulcerative or papillary lesion on the glans or foreskin that grows to involve the entire penile shaft. Extensive lesions are associated with metastases and a poor prognosis. The regional femoral and iliac lymph nodes are common metastatic sites; the urethra and bladder are rarely involved. Weight loss, fatigue, and malaise accompany chronic suppurative lesions. The specific diagnosis is made by biopsy after examination to document the location, size, and fixation of the lesion. After a positive biopsy, the extent of cancer spread is determined by imaging studies. Distant metastases are uncommon. Stages of carcinoma of the penis are presented in Box 36.3.

Box 36.3

Staging for Penile Cancer In this system, T stands for primary tumor size, N stands for regional lymph nodes, and M stands for distant metastasis.

Stage 0: Tis or Ta, N0, M0 The cancer has not grown into tissue below the top layers of skin and has not spread to lymph nodes or distant sites.

Stage I: T1a, N0, M0 The cancer has grown into tissue just below the superficial layer of skin but has not grown into blood or lymph vessels. It is a grade 1 or 2. It has not spread to lymph nodes or distant sites.

Stage II: Any of the Following: T1b, N0, M0 The cancer has grown into tissue just below the superficial layer of skin and is high grade or has grown into blood or lymph vessels. It has not spread to lymph nodes or distant

1984

sites. Or T2, N0, M0 The cancer has grown into one of the internal chambers of the penis (the corpus spongiosum or corpora cavernosa). The cancer has not spread to lymph nodes or distant sites. Or T3, N0, M0 The cancer has grown into the urethra. It has not spread to lymph nodes or distant sites.

Stage IIIA: T1 to T3, N1, M0 The cancer has grown into tissue below the superficial layer of skin (T1). It also may have grown into the corpus spongiosum, the corpora cavernosa, or the urethra (T2 or T3). The cancer has spread to a single groin lymph node (N1). It has not spread to distant sites.

Stage IIIB: T1 to T3, N2, M0 The cancer has grown into the tissues of the penis and may have grown into the corpus spongiosum, the corpora cavernosa, or the urethra (T1 to T3). It has spread to two or more groin lymph nodes. It has not spread to distant sites.

Stage IV: Any of the Following: T4, any N, M0 The cancer has grown into the prostate or other nearby structures. It may or may not have spread to groin lymph nodes. It has not spread to distant sites. Or Any T, N3, M0 The cancer has spread to lymph nodes in the pelvis or spread in the groin lymph nodes and grown through the lymph nodes’ outer covering and into surrounding tissue. The cancer has not spread to distant sites. Or Any T, any N, M1 The cancer has spread to distant sites. Penile carcinoma is managed primarily with surgery. Newer, innovative surgical techniques can preserve as much penile tissue as possible without compromising cancer control. A multimodal approach with chemotherapy is under study. Palliative treatment with radiation or chemotherapy may be used when the disease is inoperable and bulky inguinal metastases have occurred. Options for individuals with carcinoma in situ include local excision, radiation, laser surgery, cryosurgery, chemosurgery, or chemotherapy.

Quick Check 36.2 1. Why are priapism and severe paraphimosis considered urologic emergencies? 2. What are the risk factors for cancer of the penis?

1985

Disorders of the Scrotum, Testis, and Epididymis Disorders of the Scrotum Men may seek treatment for painful or painless scrotal masses. Masses may be serious (cancer or torsion) or benign (hydrocele or cyst) and may require immediate surgical intervention or allow for careful observation. Varicocele, hydrocele, and spermatocele are common intrascrotal disorders. A varicocele is an abnormal dilation of the testicular vein and the pampiniform plexus within the scrotum; it is classically described as a “bag of worms” (Fig. 36.5). Varicoceles are one of the most commonly identified scrotal abnormalities and abnormal findings among infertile men. Advancements in diagnostic techniques indicate that the incidence of varicoceles is significantly greater than previously reported. Most (90%) occur on the left side because of discrepancies in venous drainage, and they may be painful or tender. Varicocele occurs in 10% to 15% of males and is seen most often after puberty.6,7 Because most develop in adolescence, physiologic changes in testosterone level may contribute to increasing blood flow to the testicle, causing venous dilation. Unilateral right-sided varicoceles are rare and result from compression or obstruction of the inferior vena cava by a tumor or thrombus. Varicoceles may be less likely to be diagnosed among obese men.

FIGURE 36.5

Varicocele. Dilation of veins within the spermatic cord. (From Ball JW et al: Seidel's guide to physical examination, ed 8, St Louis, 2015, Mosby.)

The cause of varicocele is poorly understood. Blood pools in the veins rather than flowing into the venous system. Varicocele decreases blood flow through the testis, interfering with spermatogenesis and causing infertility. Varicoceles can alter testosterone and follicle-stimulating hormone levels, cause oxidative stress, decrease sperm count, and

1986

affect sperm quality. Varicocele surgical repair is generally done when the male has a grade II or III varicocele and an abnormal semen analysis and the female has no known cause of infertility. If the varicocele is mild and fertility is not an issue, a scrotal support is usually sufficient to relieve symptoms of scrotal heaviness or “dragging.” Color Doppler ultrasonography is used to confirm the diagnosis. A hydrocele is a collection of fluid between the layers of the tunica vaginalis (Fig. 36.6). It is the most common cause of scrotal swelling. Hydroceles occur in 6% of male newborns and are congenital malformations that often resolve spontaneously in the first year of life.8 In North America, common infectious causes include epididymitis and viruses. Worldwide, however, filariasis is a major cause. especially with recent travel to tropical countries. Other causes include trauma, torsion of the testicle or testicular appendage, and recent scrotal surgery. A man presenting with a hydrocele in his third or fourth decade needs careful evaluation for testicular cancer.

FIGURE 36.6

Hydrocele. Accumulation of clear fluid between the visceral (inner) and parietal (outer) layers of the tunica vaginalis.

Hydroceles vary in size, and most are asymptomatic. The most important feature on physical examination is a tense, smooth scrotal mass that easily transilluminates. Transillumination, or holding a light behind the scrotum, can help distinguish a hydrocele from a hernia or a solid mass. Treatment includes watchful waiting in infants and for those older than 1 year; 75% of hydroceles resolve within 6 months.8 Symptomatic or communicating hydroceles need definitive treatment. Treatment includes surgical resection, aspiration, and sclerotherapy (injection of a sclerosing agent into the scrotal sac [cystic dilation]) to excise the tunica vaginalis. Spermatoceles (epididymal cysts) are benign cystic collections of fluid of the epididymis located between the head of the epididymis and the testis. Spermatoceles are filled with a

1987

milky fluid containing sperm and are usually painless (Fig. 36.7). Spermatoceles that cause significant pain or discomfort are excised. Both spermatoceles and epididymal cysts present clinically as discrete, firm, freely mobile masses distinct from the testis that may be transilluminated. Usually, however, spermatoceles are asymptomatic or produce mild discomfort that is relieved by scrotal support. Neither hydroceles nor spermatoceles are associated with infertility.

FIGURE 36.7 Spermatocele. Retention cyst of the head of the epididymis or of an aberrant tubule or tubules of the rete testis. The spermatocele lies outside the tunica vaginalis; therefore, on palpation it can be readily distinguished and separated from the testis. (From Lloyd-Davies RW et al: Color atlas of urology, ed 2, London, 1994, Wolfe Medical.)

Cryptorchidism and Ectopy Cryptorchidism is a group of abnormalities in which the testis fails to descend completely; an ectopic testis has strayed from the normal pathway of descent. Ectopy may be caused by an abnormal connection at the distal end of the gubernaculum testis that leads the gonad to an abnormal position, usually at the superficial inguinal site. In cryptorchidism, the descent of one or both testes is arrested, with unilateral arrest occurring more often than bilateral arrest. The testes may remain in the abdomen, or testicular descent may be arrested in the inguinal canal or the puboscrotal junction. Cryptorchidism is a common congenital anomaly, with an incidence of approximately 3% in full-term infants. However, this rate increases significantly with low birth weight.9,10 The incidence of cryptorchidism in adults is 0.7% to 0.8%.11 Cryptorchidism is commonly associated with vasal or epididymal abnormalities. These congenital anomalies affect about 33% to 66% of newborns with cryptorchidism. Other structural anomalies include posterior urethral valves (less than 5%), upper genital tract abnormalities (less than 5%), and hypospadias. The presence of both hypospadias and cryptorchidism raises the suspicion of mixed gonadal dysgenesis (intersex infant). It has been hypothesized that cryptorchidism may result from an absence or abnormality of the gubernaculum—a cordlike structure that extends from the lower pole of the testis to the scrotum; a congenital gonadal or dysgenetic defect that makes the testis insensitive to gonadotropins (a likely explanation for unilateral cryptorchidism); or lack of maternal gonadotropins (a likely explanation for bilateral cryptorchidism of prematurity).11

1988

Mechanical possibilities include a short spermatic cord, fibrous bands or adhesions in the normal path of the testes, or a narrowed inguinal canal. Chromosomal studies do not support a genetic component. Physiologic cryptorchidism, also called retractile or migratory testis, is an involuntary retraction of the testes out of the scrotum that occurs with excitement, physical activity, or exposure to cold and is caused by the small mass of prepubertal testis and the strength of the cremaster muscle. This is a common phenomenon that is self-limiting (descent occurs at puberty). Physical examination discloses the absence of one or both testes in the scrotum and an atrophic scrotum on the affected side. If the undescended testis is in a vulnerable position, over the pubic bone for example, an individual may complain of severe pain secondary to trauma. The adult male with bilateral cryptorchidism may be infertile. Testicular cancer also is a well-established complication of cryptorchidism. In men with a history of unilateral cryptorchidism, neoplasms also develop more commonly in the contralateral testis. This finding suggests cryptorchidism affects the testes and is a process more significant than simply the position of the testis in childhood. The risk of testicular cancer is 35 to 50 times greater for men with cryptorchidism or a history of cryptorchidism than for the general male population. Because definite histologic change occurs in the cryptorchid testis by 1 year of age, surgical correction is recommended around that age.10 Treatment often begins with administration of gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG), hormones that may initiate descent and make surgery unnecessary. If hormonal therapy is not successful (success rates range from 6% to 75%), the testis is located and moved surgically (orchiopexy) in young children or removed (orchiectomy) in adults and children more than 10 years of age.11 The testis that is properly placed in the scrotum provides adequate hormonal function and gives the scrotum a normal appearance. A successful operation does not ensure fertility if the testis is congenitally defective. Approximately 20% of males with unilateral undescended testis remain infertile even though orchiopexy is performed by age 1 year; most individuals with treated or untreated bilateral testicular maldescent have poor fertility.

Torsion of the Testis and Testicular Appendages In torsion of the testis, the testis rotates on its vascular pedicle, interrupting its blood supply (Fig. 36.8). Torsion of the testis is one of several conditions that cause an acute scrotum, which is testicular pain and swelling. Testicular appendages include the appendix testis (a remnant of the müllerian duct) and the appendix epididymis (a remnant of the wolffian duct). Torsion of the appendages can also cause acute scrotum and be confused with testicular torsion, a urologic emergency.

1989

FIGURE 36.8 Torsion of the Testis. The testes appear dark red and partially necrotic as a result of hemorrhagic infarction. (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)

Torsion of the testis can occur at any age but is most common among neonates and adolescents, particularly at puberty.8 The onset may be spontaneous or may follow physical exertion or trauma. Torsion twists the arteries and veins in the spermatic cord, reducing or stopping circulation to the testis. Vascular engorgement and ischemia develop, causing scrotal swelling and pain not relieved by rest or scrotal support. Diagnostic testing includes urinalysis (to determine infection) and color Doppler ultrasonography.11 Torsion of the testis is a surgical emergency. If it cannot be reduced manually (scrotal elevation), surgery must be performed within 6 hours after the onset of symptoms to preserve normal testicular function.

Orchitis Orchitis is an acute inflammation of the testes (Fig. 36.9). It is uncommon except as a complication of systemic infection or as an extension of an associated epididymitis (see the section Epididymitis). Infectious organisms may reach the testes through the blood or the lymphatics or, most commonly, by ascent through the urethra, vas deferens, and epididymis. Most cases of orchitis are actually cases of epididymo-orchitis (inflammation of both the epididymis and testis). Occasionally in middle-aged men, a nonspecific, apparently noninfectious, inflammatory process (called granulomatous orchitis) can occur, presumably a granulomatous response to spermatozoa.

1990

FIGURE 36.9

Orchitis. (From Ball JW et al: Seidel's guide to physical examination, ed 8, St Louis, 2015, Mosby.)

Mumps, the most common infectious cause of orchitis, usually affects postpubertal males. The onset is sudden, occurring 3 to 4 days after the onset of parotitis. Signs and symptoms include high fever, reaching 40° C (104° F), marked prostration, bilateral or unilateral erythema, edema and tenderness of the scrotum, and leukocytosis. An acute hydrocele may develop. Urinary signs and symptoms, which accompany epididymitis, are absent. Atrophy with irreversible damage to spermatogenesis may result in 30% of affected testes. Bilateral orchitis does not affect hormonal function but may cause permanent sterility. Treatment is supportive and includes bed rest, scrotal support, elevation of the scrotum, hot or cold compresses, and analgesic agents for relief of pain. If an acute hydrocele develops, it is aspirated. Testicular abscess usually requires orchiectomy (removal of the testis). Appropriate antimicrobial drugs should be used for bacterial orchitis, and corticosteroids are indicated in proven cases of nonspecific granulomatous orchitis.

Cancer of the Testis Testicular cancer is a highly treatable, usually curable cancer that most often develops in young and middle-aged men. For men with seminoma (all stages combined), the cure rate exceeds 90%. For men with low-stage seminoma or nonseminoma, the cure rate approaches 100%.12 Overall, testicular cancers are uncommon, accounting for approximately 1% of all male cancers; yet they are the most common solid tumor of young adult men, and their incidence has risen over the past two decades in Western countries.12,13 Cancer of the testis occurs most commonly in men between the ages of 15 and 35 years. In the United States, the lifetime probability of developing testicular cancer is 0.3% for white men, an incidence that is 4.5 times higher than that found in black men. Testicular tumors are slightly more

1991

common on the right side than on the left, a pattern that parallels the occurrence of cryptorchidism, and they are bilateral in 1% to 3% of cases (Fig. 36.10). Risk factors for testicular cancer include an undescended testicle, abnormal development of the testicles, a personal history of testicular cancer, a family history of testicular cancer (especially in father or brother), and being white.14

FIGURE 36.10

Testicular Tumor. (From Wolfe J: 400 self-assessment picture tests in clinical medicine, London, 1984, Wolfe Medical.)

Pathophysiology Ninety percent of testicular cancers are germ cell tumors, arising from the male gametes. Germ cell tumors include seminomas (most common), embryonal carcinomas, teratomas, yolk sac tumors, and choriocarcinomas. Testicular tumors also can arise from specialized cells of the gonadal stroma (Leydig, Sertoli, granulosa, theca cells). The cause of testicular neoplasms is unknown. A genetic predisposition is suggested by the fact that the incidence is higher among brothers, identical twins, and other close male relatives. Genetic predisposition is supported statistically, showing that the disease is relatively rare among Africans, African Americans, Asians, and native New Zealanders. Clinical Manifestations Painless testicular enlargement commonly is the first sign of testicular cancer. Occurring gradually, it may be accompanied by a sensation of testicular heaviness or a dull ache in the lower abdomen. Occasionally, acute pain occurs because of rapid growth resulting in hemorrhage and necrosis. Ten percent of affected men have epididymitis, 10% have

1992

hydroceles, and 5% have breast enlargement (gynecomastia). The testicular mass is usually discovered by the individual or by his sexual partner. At the time of initial diagnosis, approximately 10% of individuals already have symptoms related to metastases. Lumbar pain also may be present and usually is caused by retroperitoneal node metastasis. Signs of metastasis to the lungs include cough, dyspnea, and bloody sputum (hemoptysis). Supraclavicular node involvement may cause difficulty swallowing (dysphagia) and neck swelling. With metastasis to the central nervous system (CNS), alterations in vision or mental status, papilledema, and seizures may be experienced. Evaluation and Treatment An incorrect diagnosis at the initial examination occurs in as many as 25% of men with testicular cancer. Epididymitis and epididymo-orchitis are the most common misdiagnoses; others include hydrocele and spermatocele. Evaluation begins with careful physical examination, including palpation of the scrotal contents with the individual in the standing and supine positions. Signs of testicular cancer include abnormal consistency, induration, nodularity, or irregularity of the testis. The abdomen and lymph nodes are palpated to seek evidence of metastasis, and CT scanning is an important aspect of staging and treatment planning.14 Although testicular self-examination has not been studied enough to be recommended by the American Cancer Society, many physicians recommend monthly examinations after puberty. Testicular biopsy is not recommended because it may cause dissemination of the tumor and increase the risk of local recurrence. Primary testicular cancer can be assessed rapidly and accurately by scrotal ultrasonography. Tumor markers are higher than normal in the presence of a tumor and may help detect a tumor that is too small to be palpated during the physical examination or to be visualized on imaging. Serum tumor markers include alpha-fetoprotein (AFP), betahuman chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH) and are important for staging and monitoring germ cell tumors. Radiologic imaging and measurement of serum markers are used in clinical staging of the disease. Besides surgery, treatment involves radiation and chemotherapy singly or in combination. Radiation therapy, chemotherapy, and retroperitoneal lymph node dissection can all cause infertility problems so banking sperm may be recommended before undergoing any treatment. An increased risk of leukemia has been associated with platinum-based chemotherapy and radiation therapy.14 Factors influencing the prognosis include histologic studies of the tumor stage of the disease and selection of appropriate treatment. Most individuals treated for cancer of the testis can expect a normal life span; some have persistent paresthesias, Raynaud phenomenon, or infertility. Approximately 10% of men treated for testicular cancer will experience a relapse; if the relapse is discovered early and treated, 99% can be cured. Orchiectomy does not affect sexual function.

Epididymitis Epididymitis, or inflammation of the epididymis, generally occurs in sexually active young males (younger than 35 years) and is rare before puberty (Fig. 36.11). In young men, the usual cause is a sexually transmitted microorganism, such as N. gonorrhoeae or C. trachomatis. Coliform bacteria are the common pathogens in other age groups. Men who practice unprotected anal intercourse may acquire sexually transmitted epididymitis that results from infection with Escherichia coli, Haemophilus influenzae, tuberculosis, or

1993

Cryptococcus or Brucella species. In men older than 35 years, Enterobacteriaceae (intestinal bacteria) and Pseudomonas aeruginosa associated with urinary tract infections and prostatitis also may cause epididymitis. Epididymitis also may result from a chemical inflammation caused by the reflux of sterile urine into the ejaculatory ducts, which is then called chemical epididymitis. It is associated with urethral strictures, congenital posterior valves, and excessive physical straining in which increased abdominal pressure is transmitted to the bladder. Chemical epididymitis is usually self-limiting and does not require evaluation or intervention unless it persists.

FIGURE 36.11 Epididymitis Secondary to Gonorrhea or Nongonococcal Urethritis. This infection has spread to the testes, and rupture through the scrotal wall is threatened. (From Taylor PK: Diagnostic picture tests in sexually transmitted disease, London, 1995, Mosby.)

Pathophysiology The pathogenic microorganism usually reaches the epididymis by ascending the vasa deferentia from an already infected urethra or bladder. The resulting inflammatory response causes symptoms of bacterial epididymitis. Epididymitis caused by heavy lifting or straining results from the reflux of urine from the bladder into the vas deferens and epididymis. Urine is extremely irritating to the epididymis and initiates the inflammatory response called chemical epididymitis. Clinical Manifestations The main symptom of epididymitis is scrotal or inguinal pain caused by inflammation of the epididymis and surrounding tissues. The pain is usually acute and severe. Flank pain may occur if, as the urethra passes over the spermatic cord, edematous swelling of the cord obstructs the urethra. The individual may have pyuria, bacteriuria, and a history of urinary symptoms, including urethral discharge. The scrotum on the involved side is red and edematous. The tail of the epididymis near the lower pole of the testis usually swells first; swelling then ascends to the head of the epididymis. The spermatic cord also may be swollen and tender.

1994

Complications include abscess formation, infarction of the testis, recurrent infection, and infertility. Infarction is probably caused by thrombosis (obstruction by blood clots) of the prostatic vessels secondary to severe inflammation. Recurrent epididymitis may result from inadequate initial treatment or failure to identify or treat predisposing factors. Chronic epididymitis can cause scarring of the epididymal endothelium and infertility. Once scarring has occurred, treatment with antibiotics is ineffective because adequate antibiotic levels cannot be achieved within the epididymis. Evaluation and Treatment A history of recent urinary tract infection or urethral discharge suggests the diagnosis of epididymitis. Common physical findings include a swollen, tender epididymis or testis located in the normal anatomic position with an intact same-side cremasteric reflex. The relief of pain when the inflamed testis and epididymis are elevated (Prehn sign) also is diagnostic. The definitive diagnosis is based on culture or Gram stain of a urethral swab. Epididymal aspiration may be necessary to obtain a specimen, especially if the individual has been taking antibiotics and has sterile urine. Treatment includes antibiotic therapy for the infection itself. Analgesics, ice, and scrotal elevation can provide symptomatic relief. If the individual does not steadily improve, he should be reevaluated for possible complications, such as abscess formation, sepsis, or continued infection. Complete resolution of swelling and pain may take several weeks to months. The individual's sexual partner should be treated with antibiotics if the causative microorganism is a sexually transmitted pathogen.

Quick Check 36.3 1. Why is a genetic predisposition suggested for testicular cancer? 2. Why is epididymitis rare in prepubescent males? 3. Why is testicular torsion considered a urologic emergency?

Disorders of the Prostate Gland Benign Prostatic Hyperplasia Benign prostatic hyperplasia (BPH), also called benign prostatic hypertrophy, is the enlargement of the prostate gland (Fig. 36.12). (Because the major prostatic changes are caused by hyperplasia, not hypertrophy, benign prostatic hyperplasia is the preferred term.) This condition becomes problematic when prostatic tissue compresses the urethra where it passes through the prostate, resulting in frequency of lower urinary tract symptoms. Similar to prostate cancer, BPH occurs more often in Westernized countries (e.g., United States, United Kingdom, and Canada). Overall, no clear patterns have emerged with risk of BPH and race.15 In the United States studies of black men have observed an increased prostate transition zone and total volume compared with white men.15 Being overweight or obese with central fat distribution (i.e., around the abdomen) increases the risk of developing BPH. Autopsy studies observe a histological prevalence of 8%, 50%, and 80% in the 4th, 6th, and 9th decades of life, respectively.15 BPH is common and involves a complex

1995

pathophysiology with several endocrine and local factors and a remodeled microenvironment. Its relationship to aging is well documented. At birth the prostate is pea sized, and growth of the gland is gradual until puberty. At that time, there is a period of rapid development that continues until the third decade of life, when the prostate reaches adult size (see Chapter 34). Around age 40 to 45, benign hyperplasia begins and continues slowly until death. Although androgens, such as dihydrotestosterone (DHT), are necessary for normal prostatic development, their role in BPH remains unclear.

FIGURE 36.12 Prostate Zones, Benign Prostatic Hyperplasia, and Prostate Cancer Locations. Benign prostatic hyperplasia (BPH) occurs in the peripheral zone of the prostate gland that can enlarge (not shown). BPH nodules and atrophy are associated with inflammation in the transition zone. Most cancer lesions occur in the peripheral zone. Carcinoma can involve the central zone but rarely occurs in isolation, suggesting that prostatic intraepithelial neoplasia (PIN) lesions do not easily progress to carcinoma in this region. (Adapted from De Marzo AM et al: Nat Rev Cancer 7:256-269, 2007.)

Pathophysiology Current causative theories for BPH focus on aging and the levels and ratios of endocrine

1996

factors (e.g., androgens and estrogens [androgen/estrogen ratio]), the role of chronic inflammation, and the effects of autocrine/paracrine growth-stimulating and growthinhibiting factors. Recent data shows that human prostate stromal cells can actively contribute to the inflammatory process from the induction of inflammatory cytokines and chemokines (see the section Cancer of the Prostate). With aging, circulating androgens are associated with BPH and enlargement. Other effects related to estrogens include apoptosis, aromatase expression, and paracrine regulation that may be important for stimulating inflammation. BPH is a multifactorial disease, and not all men respond well to currently available treatments, which suggests that factors are involved other than androgens. The prostate is an estrogen target tissue, and estrogens directly and indirectly affect growth and differentiation of the prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators have been shown to promote or inhibit prostate proliferation, signifying potential roles in BPH. Taken together, these interactions lead to an increase in prostate volume. The remodeled stroma promotes local inflammation with altered cytokine, reactive oxygen/nitrogen species, and chemoattractants. The resultant increased oxygen demands of proliferating cells cause a local hypoxia that induces angiogenesis and changes to fibroblasts. BPH begins in the periurethral glands, which are the inner glands or layers of the prostate. The prostate enlarges as nodules form and grow (nodular hyperplasia) and glandular cells enlarge (hypertrophy). The development of BPH occurs over a prolonged period, and changes within the urinary tract are slow and insidious. Clinical Manifestations As nodular hyperplasia and cellular hypertrophy progress, tissues that surround the prostatic urethra compress it, usually, but not always, causing bladder outflow obstruction. These symptoms are sometimes called the spectrum of lower urinary tract symptoms (LUTS). Symptoms include the urge to urinate often, some delay in starting urination, and decreased force of the urinary stream. As the obstruction progresses, often over several years, the bladder cannot empty all the urine, and the increasing volume leads to long-term urine retention. The volume of urine retained may be great enough to produce uncontrolled “overflow incontinence” with any increase in intra-abdominal pressure. At this stage, the force of the urinary stream is significantly reduced, and much more time is required to initiate and complete voiding. Hematuria, bladder or kidney infection, bladder calculi, acute urinary retention hydroureter, hydronephrosis, and renal insufficiency are common complications. Progressive bladder distention causes diverticular outpouchings of the bladder wall. The ureters may be obstructed where they pass through the hypertrophied detrusor muscle, potentially causing hydroureter, hydronephrosis, and bladder or kidney infection. Evaluation and Treatment The diagnosis is made from a medical history, physical examination, and laboratory tests, including urinalysis. Careful review of symptoms is necessary. A digital rectal examination (DRE) and measurement of the PSA level are conducted to determine hyperplasia. However, the PSA level alone cannot confirm symptoms attributable to BPH because the PSA level is elevated in both BPH and prostate cancer. Annual DREs are used to screen

1997

men older than 40 years for BPH, sooner in high-risk men.16 If marked enlargement, moderate to severe symptoms, or complications are present, transrectal ultrasound (TRUS) is used to determine bladder and prostate volume and residual urine. Urinalysis, serum creatinine and blood urea nitrogen levels, uroflowmetry, postvoid residual (PVR) urine, a pressure-flow study, cystometry, and cystourethroscopy are used to determine kidney and bladder function. BPH has been treated successfully with drugs. α1-Adrenergic blockers (prazosin and tamsulosin) are used to relax the smooth muscle of the bladder and prostate. Antiandrogen agents, such as finasteride (Proscar), selectively block androgens at the prostate cellular level and cause the prostate gland to shrink. By shrinking the prostate, these drugs have been shown to improve BPH-related symptoms and reduce the risk of future urinary retention and BPH-related surgery. α1-Adrenergic blockers do not affect PSA and have no effect on the prostate cancer risk; however, antiandrogen agents lower the PSA level by 50% after 6 months of therapy.17,18 Newer, minimally invasive treatments include interstitial laser treatment, transurethral radiofrequency procedures (e.g., transurethral needle ablation [TUNA]), and Cooled ThermoTherapy.

Prostatitis Prostatitis is an inflammation of the prostate. The incidence and prevalence of prostatitis are not known. Inflammation is usually limited to a few of the gland's excretory ducts. Prostatitis syndromes have been classified by the National Institutes of Health as (1) acute bacterial prostatitis (ABP), (2) chronic bacterial prostatitis (CBP), (3) chronic pelvic pain syndrome (CPPS), and (4) asymptomatic inflammatory prostatitis (Box 36.4). ABP and CBP are mostly caused by gram-negative Enterobacteriaceae and Enterococci species that originate in the gastrointestinal flora. The most common organism is Escherichia coli, which is identified in the majority of infections. Klebsiella species, Pseudomonas aeruginosa, and Serratia species are common gram-negative cultured microorganisms. Nonbacterial prostatitis (CP/CPPS) syndromes are caused by a cascade of inflammatory, immunologic, neuroendocrine, and neuropathic mechanisms, such that the initiating cause is unknown.

Box 36.4

National Institutes of Health Classification of Prostatitis Syndrome This system, developed for clinical research purposes, can be simplified for use in primary care practice (see text). Category I, or acute bacterial prostatitis (ABP), is an acute infection of the prostate and is manifested by systemic signs of infection and a positive urine culture result. Category II, or chronic bacterial prostatitis (CBP), is a chronic bacterial infection in which bacteria are received in significant numbers from a purulent prostatic fluid. These bacteria are thought to be the most common cause of recurrent urinary tract infection in men. Category III, or chronic pelvic pain syndrome (CPPS), is diagnosed when no pathologic bacteria can be localized to the prostate (culture of expressed prostatic

1998

fluid or postprostatic massage urine specimen) and is further divided into IIIa and IIIb. Category IIIa is inflammatory CPPS, in which a significant number of white blood cells (WBCs) are localized to the prostate; category IIIb is noninflammatory. Category IV is asymptomatic inflammatory prostatitis in which bacteria or WBCs are localized to the prostate, but individuals are asymptomatic. Bacterial prostatitis. Acute bacterial prostatitis (ABP, category I) is an ascending infection of the urinary tract that tends to occur in men between the ages of 30 and 50 years, but it is also associated with BPH in older men. Infection stimulates an inflammatory response in which the prostate becomes enlarged, tender, firm, or boggy. The onset of prostatitis may be acute and unrelated to previous illnesses, or it may follow catheterization or cystoscopy. Clinical manifestations of acute bacterial prostatitis are those of urinary tract infection or pyelonephritis. A sudden onset of malaise, low back and perineal pain, high fever (up to 40° C [104° F]), and chills is common, as are dysuria, inability to empty the bladder, nocturia, and urinary retention. The individual also may have symptoms of lower urinary tract obstruction, such as a slow, small, “narrowed” urinary stream, which may be a medical emergency. Acute inflammatory prostatic edema can compress the urethra, causing urinary obstruction. Systemic signs of infection include sudden onset of a high fever, fatigue, arthralgia, and myalgia. Prostatic pain may occur, especially when the individual is in an upright position, because the pelvic floor muscles tighten with standing and compression of the prostate gland occurs. Some individuals experience low back pain, painful ejaculation, and rectal or perineal pain. Palpation discloses an enlarged, extremely tender and swollen prostate that is firm, indurated, and warm to the touch. Because acute bacterial prostatitis is usually associated with a bladder infection caused by the same microorganism, urine cultures disclose its identity. Prostatic massage may express enough secretions from the urethra for direct bacterial examination, but massage may be painful and increases the risk that the infection will ascend to adjacent structures or enter the bloodstream and cause septicemia. To resolve the infection and control its spread, individuals may require antibiotics. In severe cases, the individual is hospitalized and treated with intravenous antibiotics, followed by oral antibiotics. Analgesics, antipyretics, bed rest, and adequate hydration are also therapeutic. Complications include urinary retention that resolves with antibiotic therapy; prostatic abscess that may rupture into the urethra, rectum, or perineum; epididymitis; bacteremia; and septic shock. Urinary retention requiring drainage is best managed with a suprapubic catheter; Foley catheterization is contraindicated during acute infection. Chronic bacterial prostatitis (CBP, category II) is characterized by recurrent urinary tract symptoms and persistence of pathogenic bacteria (usually gram negative) in urine or prostatic fluid. This form of prostatitis is the most common recurrent urinary tract infection in men. Symptoms may be similar to those of an acute bladder infection: frequency, urgency, dysuria, perineal discomfort, low back pain, myalgia, arthralgia, and sexual dysfunction. The prostate may be only slightly enlarged or boggy, but it may be fibrotic because repeated infections can cause it to be firm and irregular in shape. When the initial urine sample is bacteria free, prostatic massage is used to express secretions. Subsequently, the first 10 ml of voided urine is collected and examined microscopically. Prostatic secretions showing more than 10 white blood cells (WBCs) per

1999

high-power field (hpf) and macrophages containing fat are indicative of bacterial infection; the diagnosis is confirmed by culture. A pelvic x-ray or transurethral ultrasound (TUUS may show prostatic calculi. Treatment of CBP is difficult because it is often caused by prostatic calculi. Calculi are silent and are found in up to 50% of men with prostatitis. Infected calculi can serve as a source of bacterial persistence and relapsing urinary tract infection. Calculi harbor pathogens within the stone and, consequently, pathogens cannot be eradicated from the urinary tract. A permanent cure is achieved by surgical intervention. Chronic prostatitis/chronic pelvic pain syndrome. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, category III) is diagnosed when no pathogenic bacteria can be localized to the prostate. It is further subdivided into categories IIIa and IIIb (see Box 36.4). Category IIIa refers to inflammatory CPPS in which the WBC count is elevated and localized to the prostate. Compared with category III, symptoms tend to be milder but are persistent and annoying. Presumably, noninfectious prostatitis or pain is caused by reflux of sterile urine into the ejaculatory ducts because of high-pressure voiding. Reflux may be triggered by spasms of the external or internal sphincters. Category IIIb is noninflammatory. Category IV exists when individuals are asymptomatic but have an increase in bacteria and WBCs localized to the prostate. Microorganisms suspected of causing CP/CPPS include E. Enterobacter organisms, P. aeruginosa, and Helicobacter pylori. Men with nonbacterial prostatitis may complain of pain or a dull ache that is continuous or spasmodic in the suprapubic, infrapubic, scrotal, penile, or inguinal area. Other symptoms are pain on ejaculation and urinary symptoms, such as frequency of urination. The prostate gland generally feels normal on palpation. Nonbacterial prostatitis is a diagnosis of exclusion. Digital examination of the prostate, bacterial cultures of the urogenital tract, microscopic examination of expressed prostatic fluid, urethroscopy, and urodynamic studies are used to verify the diagnosis of nonbacterial prostatitis. There is no generally accepted treatment for nonbacterial prostatitis. Hot sitz baths, bed rest, and pharmacologic therapies, including antiinflammatory drugs, can relieve symptoms.

Cancer of the Prostate Prostate cancer is the most commonly diagnosed, non–skin cancer in men in the United States; the lifetime risk for this diagnosis currently is estimated at 15.9%.19 The incidence varies greatly worldwide (Fig. 36.13), but prostate cancer is considered the third leading cause of cancer death globally, accounting for 7.1% of all cancer deaths. In the U.S., the lifetime risk of being diagnosed with prostate cancer is approximately 11%, with a 2.5% lifetime risk of dying from it.19,20 An estimated 1.1 million cases of prostate cancer were diagnosed worldwide in 2012, accounting for 15% of the cancers diagnosed in men. Almost 70% of diagnosed cases of prostate cancer (759,000) were found to occur in more developed regions.21 Importantly, incidence rates vary by more than 25-fold worldwide, with the highest rates recorded mostly in developed countries, such as Oceania, Europe, and North America, largely because of wide use or overuse of PSA testing. Screening with PSA can amplify the incidence of prostate cancer by allowing detection of prostate lesions that,

2000

although meeting the pathologic criteria for malignancy, may have low potential (e.g., latent, indolent, preclinical) for growth and metastasis. In countries with higher use of PSA testing, such as the United States, Canada, Australia, and the Nordic countries, trends in incidence rates follow similar patterns.

FIGURE 36.13

Selected World Population Age-Standardized (to the World Population) Incidence Rates of Prostate Cancer. (From Jemal A et al: Biomark Prev 19:1893, 2010.)

Unlike in Western countries, the incidence and death rates are rising in several Asian and Central and Eastern European countries, including Japan. Death rates have been decreasing in several countries, including Australia, Canada, the United Kingdom, the United States, Italy, and Norway, in part because of improved treatment. Males of African descent in the Caribbean region have the highest mortality from prostate cancer in the world. Most cases of prostate cancer have a good prognosis even without treatment, but some cases are aggressive. Prostate cancer is rare before age 50 years, and very few men die from this cancer before 60 years of age. Indeed, more than 75% of all prostate cancer is diagnosed in men older than 65.19 With aging, most of the androgen-metabolizing enzymes undergo significant alteration and older age, race (black), and family history remain the wellestablished risk factors. Dietary factors. Although evidence exists for a dietary role in prostate cancer, the epidemiologic evidence is inconsistent. The problem has been confounded by the lack of biomarkers for certain nutrients, difficulties in measuring and quantifying diet, and a limitation of clinical trials to study diet over time. An important factor is the effects of diet on signaling pathways,

2001

hormones, oxidative stress, and reactive oxygen species (ROS). The nutrients in the epidemiology of prostate cancer that have received the most attention include carotenoids, fat, vitamin E, vitamin D/calcium, and selenium. Less studied are isoflavones, curcumin, lycopene, green tea, omega-3 polyunsaturated fats, and sulforaphane (Box 36.5).

Box 36.5

Summary of Diet for Prostate Cancer • Lower rates of prostate cancer are found in countries whose residents consume a lowfat and high-vegetable diet. When men from a low-risk country move to the United States and eat a Western diet, their rates of prostate cancer increase significantly. Inconclusive are the exact culprits that increase this risk, including fat and sugar intake. • Obesity is linked to advanced and aggressive prostate cancer. • High body mass index (BMI) is associated with more aggressive disease and a worse outcome. • A calorie-dense or an excessive carbohydrate intake and obesity, independent of dietary fat intake, may increase the risk of developing prostate cancer. • Dietary fat may increase levels of androgens, increase oxidative stress, and increase reactive oxygen species (ROS). • Monounsaturated fats may decrease the risk of prostate cancer. • High levels of linoleic acid (found in corn oil) act as a proinflammatory eicosanoid, which is implicated in promotion of cell proliferation and angiogenesis, as well as inhibition of apoptosis. • The Western diet has increased omega-6–to–omega-3 ratios and therefore is proinflammatory. Carcinogenic nitrosamines are formed after consumption of processed meat that contains nitrites and from heme iron present in large quantities of red meat. • Even given this knowledge, it is important to realize that studies showing an association between meat intake and prostate cancers have been largely inconclusive. Some studies indicated that red meat is positively associated with an increased prostate cancer risk with an association with more aggressive disease states. Despite some studies showing a 43% elevation in prostate cancer risk with a diet excessively high in red meat, others show no association with prostate cancer risk. • Although the role of red meat in prostate and breast cancer remains inconclusive, one explanation for the possible associations reported is the accumulation of carcinogens during the cooking process. Cooking meat at high temperatures produces heterocyclic amines and aromatic hydrocarbons that are carcinogenic. • Vitamin E has long been considered a candidate for prostate cancer prevention from in vitro and in vivo animal studies. Vitamin E belongs to the family of tocopherols and tocotrienols that exist as α, β, γ, and δ isoforms. Among these, δ-tocopherol is the major dietary isoform, whereas supplements contain α-tocopherol. Vitamin E is a fatsoluble vitamin obtained from vegetable oils, nuts, and egg yolk. It is a potent

2002

intracellular antioxidant known to inhibit peroxidation and deoxyribonucleic acid (DNA) damage. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) showed that supplementation with vitamin E could reduce the incidence of prostate cancer among men who smoked. In vitro studies demonstrate that αtocopherol succinate induces cell cycle arrest in human prostate cancer cells (i.e., induces apoptosis) and inhibits the androgen receptor. Mouse studies show vitamin E can inhibit the growth-promoting effects of a high-fat diet; however, vitamin E in combination with selenium does not reduce the incidence of prostate cancer in Lady mice models. A prospective large clinical trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), showed no reduction in prostate cancer period prevalence but an increased risk of prostate cancer with vitamin E alone. • Selenium is a trace mineral and exists in food as selenomethionine and selenocysteine. It is essential for the functioning of many antioxidant enzymes and proteins in the body. Humans receive selenium in their diet through plant (dependent on soil concentrations) and animal products. The SELECT trial showed that neither selenium nor vitamin E, taken alone or together, helped to prevent prostate cancer. • Vitamin D may play an important role in prostate cancer prevention. • Soy's anticancer properties include inhibition of cell proliferation and angiogenesis and a reduction in prostate-specific antigen (PSA) and androgen receptor levels. Countries whose residents have a high intake of soy have much lower rates of prostate cancer. • Tomatoes or tomato products ingested daily seem to reduce prostate cancer risk. In vitro studies show that the lycopene found in tomatoes inhibits DNA strand breaks. Unresolved is whether lycopene itself or a metabolic product is responsible for its biologic effect. In clinical studies tomato paste, which is high in lycopene, reduced plasma PSA levels in men with benign prostatic hyperplasia. Lycopene administration is associated with cell cycle arrest (apoptosis) and growth factor signaling. In 2007 the U.S. Food and Drug Administration (FDA) evaluated 13 available studies and found the relationship between lycopene and a reduced risk of prostate cancer inadequate. • Vegetables such as broccoli, cabbage, cauliflower, brussels sprouts, Chinese cabbage, and turnips (all crucifers) may be protective (several epidemiologic studies) against prostate cancer. In particular, a diet high in broccoli reduced cancer risk. By contrast, four studies revealed no cancer preventive effects. Cruciforms have anticancer properties mediated by the phytochemicals phenethyl isothiocyanate, sulforaphane, and indole-3-carbinol. Sulforaphane is a naturally occurring isothiocyanate that was first isolated in broccoli. It protects against carcinogen-induced cancer in many rodents. Mice given 240 mg of broccoli sprouts per day showed a significant reduction in growth of prostate cancer cells. Sulforaphane treatment lowered androgen receptor protein and gene expression. • Green tea contains polyphenols, including epigallocatechin gallate (EGCG). Green tea consumption has been associated with a reduced incidence of several cancers, including prostate cancer. Green tea consumed within a balanced, controlled diet in humans improved overall antioxidant potential. The anticancer effect potential of green tea from in vitro and experimental studies shows that these compounds bind directly to carcinogens and induce phase II enzymes that inhibit heterocyclic amines.

2003

EGCG administration decreased NF-κB activity. Green tea was shown to inhibit insulin-like growth factor 1 (IGF-1) and increase insulin-like growth factor binding protein 3 (IGFBP3), leading to inhibition of prostate cancer development and progression. Yet, in two small randomized studies in individuals with high-grade prostatic neoplasia, green tea showed no effects. However, treatment with a mixture of bioactive compounds that share molecular anticarcinogenic targets may enhance the effect on these targets at low concentrations of individual compounds. • Epidemiologic studies have consistently shown that regular consumption of fruits and vegetables is strongly associated with a reduced risk of developing chronic diseases, such as cancer. It is now accepted that the actions of any specific phytonutrient alone do not explain the observed health benefits of diets rich in fruits and vegetables; also, clinical trials demonstrated that consumption of phytonutrients did not show consistent preventive effects. Synergistic inhibition of prostate cancer cell growth has been evident with the use of combinations of low concentrations of various carotenoids or carotenoids with retinoic acid and the active metabolite of vitamin D. Combinations of several carotenoids (e.g., lycopene, phytoene, and phytofluene) or carotenoids and polyphenols (e.g., carnosic acid and curcumin) and/or other compounds (e.g., vitamin E) synergistically inhibit the androgen receptor activity and activate the electrophile/antioxidant response element (EpRE/ARE) transcription system. The activation of EpRE/ARE is up to fourfold higher than the sum of activities of single ingredients. • Examples of important potential processes that can be targeted in the regulation of tumorigenesis include cholesterol synthesis and metabolites, ROS and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, and endoglin and Janus kinase signaling. • Curcumin has anticarcinogenic potential, with well-characterized antiinflammatory, antiangiogenic, and antioxidant properties. Recent studies report that curcumin modulates the Wingless signaling pathway (Wnt) that supports its antiproliferative potential. Curcumin is characteristic of regulating multiple targets, a desirable feature in current drug design and drug development. Together with its potential for treating castration-resistant prostate cancer and its safety profile, this feature enables curcumin to serve as an ideal compound for the design and syntheses of agents with improved potential for enhancing clinical therapies used to treat prostate cancer. • Overall, multiple signaling pathways are involved in prostate cancer development and progression, many of which are affected by dietary and lifestyle factors.

2004

References Alexander DD, et al. A review and meta-analysis of prospective studies of red and processed meat intake and prostate cancer. Nutr J. 2010;9:50. Astorg P. Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence. Cancer Causes Control. 2004;15:367– 386. Beier R, et al. Induction of cyclin E-cdk2 kinase activity, E2Fdependent transcription and cell growth by Myc are genetically separable events. EMBO J. 2000;19(21):5813–5823. Casey SC, et al. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol. 2015;35(Suppl):S199–S223. Chen QH. Curcumin-based anti-prostate cancer agents. Anticancer Agents Med Chem. 2015;15(2):138–156. Dagnelie PC, et al. Diet, anthropometric measures and prostate cancer risk: a review of prospective cohort and intervention studies. BJ Int. 2004;93(8):1139–1150. Demark-Wahnefried W, Moyad MA. Dietary intervention in the management of prostate cancer. Curr Opin Urol. 2007;17:168– 174 [737-743, 2001]. Freedland SJ, Aronson WJ. Obesity and prostate cancer. Urology. 2005;65:433–439. Giovannucci E, et al. Risk factors for prostate cancer incidence and progression in the health professionals follow-up study. Int J Cancer. 2007;121:1571–1578. Greenwald P. Clinical trials in cancer prevention: current results and perspectives for the future. J Nutr. 2004;134(12 Suppl):3507S–3512S. Hill P, et al. Diet and urinary steroids in black and white North American men and black South African men. Cancer Res. 1979;39:5101–5105. Kim DJ, et al. Premorbid diet in relation to survival from 2005

prostate cancer (Canada). Cancer Causes Control. 2000;11:65– 77. Kobayashi N, et al. Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase-2, and prostaglandin E2. Clin Cancer Res. 2006;12(15):4660–4670. Kolonel LN. Fat, meat, and prostate cancer. Epidemiol Rev. 2001;23:72–81. Kristal AR, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008;167:925– 934. Linnewiel-Hermoni K, et al. The anti-cancer effects of carotenoids and other phytonutrients resides in their combined activity. Arch Biochem Biophys. 2015;572:28–35. Lloyd JC, et al. Effect of isocaloric low fat diet on prostate cancer xenograft progression in a hormone deprivation model. J Urol. 2010;183:1619–1624. Matsumara K, et al. Involvement of the estrogen receptor beta in genistein-induced expression of p21 (waf1/cip1) in PC-3 prostate cancer cells. Anticancer Res. 2008;28:709–714. Ngo TH, et al. Effect of diet and exercise on serum insulin, IGF1, and IGFBP-1 levels and growth of LNCaP cells in vitro (United States). Cancer Causes Control. 2002;13:929–935. Ngo TH, et al. Effect of isocaloric low-fat diet on human LAPC-4 prostate cancer xenografts in severe combined immunodeficient mice and the insulin-like growth factor axis. Clin Cancer Res. 2003;9:2734–2743. Ni J, Yeh S. The roles of alpha-vitamin E and its analogues in prostate cancer. Vitam Horm. 2007;76:493–518. Punnen S, et al. Impact of meat consumption, preparation, and mutagens on aggressive prostate cancer. PLoS ONE. 2011;6:e27711. Rodriguez C, et al. Body mass index, weight change, and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev. 2007;16:63–69. 2006

Salem S, et al. Major dietary factors and prostate cancer risk: a prospective multicenter case-control study. Nutr Cancer. 2011;63:21–27 [2011]. Sinha R, et al. Meat and meat-related compounds and risk of prostate cancer in a large prospective cohort study in the United States. Am J Epidemiol. 2009;170:1165–1177. Teiten M, et al. Anti-proliferative potential of curcumin in androgen dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway. Int J Oncol. 2011;38:603–611. Wang P, et al. Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells. RSC Adv. 2014;4(66):35242–35250. Wright JL, et al. AMACR polymorphisms, dietary intake of red meat and dairy and prostate cancer risk. Prostate. 2011;71:498– 506. Zhou DY, et al. Curcumin analogues with high activity for inhibiting human prostate cancer cell growth and androgen receptor activation. Mol Med Rep. 2014;10(3):1315–1322. Associations between obesity and prostate cancer are not clear because there are some inconsistencies, but obesity seems to be negatively associated with more indolent prostate cancer and positively associated with more aggressive disease and a worse outcome. Because adipose tissue is increasingly being regarded as hormonally active tissue, high body fat and obesity need in-depth exploration to understand the associated risk of prostate problems. Adipose tissue is now known to affect circulating levels of several bioactive messengers and therefore could affect the risk of developing prostate problems in addition to several other well-recognized health problems. High-energy intake (consumption of excess calories) indicates that this may indeed increase insulin levels and levels of insulinlike growth factor 1 (IGF-1), a powerful carcinogenic agent. Hormones. Prostate cancer develops in an androgen-dependent epithelium and is usually androgen sensitive. Androgens are synthesized not only in the testis, accounting for 50% to 60% of the total testosterone in the prostate, but also in the prostate gland itself. In a process called intraprostatic conversion, the hormone dehydroepiandrosterone (DHEA) produced by the adrenal glands is converted to testosterone and then into DHT in the prostate (Fig. 36.14). Additionally, prostate cancer cells have been reported to make androgens from cholesterol (i.e., de novo). However, these overall relative contributions from intratumoral sources remain to be determined. Population studies have not yet provided clear and convincing patterns involving associations between circulating hormone concentrations (i.e., not tissue

2007

concentrations) and the risk for prostate cancer. Thus, there is universal agreement that androgens are important for prostatic growth, development, and maintenance of tissue balance; but their role in cancer is controversial. In men younger than 50 years, circulating levels of androgens and estrogens appear to be higher in men of African descent than in European-American men.

FIGURE 36.14 Sources of Androgens and Aromatase and Estrogen Signaling in the Prostate. A, Body sources of androgens in the prostate gland. Hypothalamic gonadotropin-releasing hormone (GnRH) causes the release of luteinizing hormone (LH) from the anterior pituitary gland. LH stimulates the testes to produce testosterone, which accumulates in the blood. Pituitary adrenocorticotropic hormone (ACTH) release stimulates the adrenal glands, which secrete the androgen precursor dehydroepiandrosterone (DHEA) into the blood. DHEA is converted into testosterone and then into dihydrotestosterone (DHT) in the prostate. B, Aromatase and estrogen signaling in the prostate. In normal and benign tissue, aromatase is expressed within the stroma and regulated by promoter PII. Estrogen then exerts its effects in an autocrine fashion through the stromal ER-α receptor and also in a paracrine fashion through both ER-α and ER-β receptors. With prostate cancer, aromatase is now expressed within the tumor cells and in stromal cells and is regulated by aromatase promoters 1.3, 1.4, and PII. Thus estrogen exerts its effects in an autocrine way through stromal and epithelial ER-α and ER-β. Consequently, the increased levels of estrogen and abnormal ER-α signaling promote inflammation, which increases aromatase expression and the development of a positive feedback cycle. Inflammation drives aromatase expression, thus increasing estrogen, which in turn promotes further inflammation. ACTH, Adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone. (A adapted from Labrie F: Nat Rev Urol 8:73-80, 2011. B from Ellem SJ, Risbridger GP: J Steroid Biochem Mol Biol 118[4-5]:246-251, 2010.)

Despite the well-documented importance of androgens, their pathophysiologic process in prostate diseases is incomplete. Androgens also are metabolized to estrogens (see Fig. 36.14, B) through the action of the enzyme aromatase, and a growing body of evidence implicates estrogens in the etiology of prostate disease (see the Pathogenesis section). Vasectomy. Vasectomy has been identified as a possible risk factor for prostate cancer in both casecontrolled studies and cohort studies. Three mechanisms by which vasectomy could increase the risk are (1) elevation of circulating androgens; (2) activation of immunologic

2008

mechanisms involving antisperm antibodies; and (3) reduction of seminal fluid levels of 5αdihydrotestosterone, the active metabolite of testosterone in the prostate, in vasectomized men. These results suggest an elevation of circulating free testosterone level after vasectomy. However, with these combined mechanisms, it is unlikely that vasectomy plays a causal role. Chronic inflammation. Certain metabolic comorbidities, including obesity, diabetes, sleep apnea, and erectile dysfunction, may be linked both to BPH and to inflammation. The causes of chronic inflammation are emerging (possible causes are shown in Fig. 36.15). Thus, chronic inflammation may be an important risk factor for prostatic adenocarcinoma. Chronic inflammation involves autocrine/paracrine growth-stimulating and growth-inhibiting factors. These factors include insulin-like growth factors (IGFs), epidermal growth factors, fibroblast factors, and transforming growth factor-beta (TGF-β), as well as several others. Recent data show that human prostate stromal cells can actively contribute to the inflammatory process from the induction of inflammatory cytokines and chemokines. Importantly, continuous input from TGF-β and IGF in the tumor microenvironment or stroma results in cancer progression. Understanding these events can help in the prevention, diagnosis, and therapy of prostate cancer (Fig. 36.16).

2009

FIGURE 36.15 Possible Causes of Prostate Inflammation. A, Infection, including viruses, bacteria, fungi, and parasites. B, Hormones, for example, estrogen at key times during development. C, Physical trauma, any type of blunt physical injury. D, Urine reflex. E, Certain dietary factors (see text).

2010

FIGURE 36.16 Working Model of Stromal-Epithelial Interaction in Prostate Cancer Development and Progression. Normally, signaling events between tumor growth factor β (TGF-β) and insulin-like growth factor (IGF) are tightly regulated, keeping the epithelial cells under homeostatic balance. TGF-β binds to co-receptors on the cell surface known as betaglycan receptor type I (TbR-I) and betaglycan receptor type II (TbR-II). A reduction in TbRs in the stromal cells results in an increase in IGF production. The increase in IGF has a proliferative effect on the prostate epithelial cells (which have already undergone a cancer initiation process as a result of the hormones testosterone and estradiol). TGF-β and IGF in the stromal cells adjacent to prostate epithelial cells perpetuate a vicious cycle to promote cancer progression. (Adapted from Lee C et al: Biomed Res 2014:502093, 2014.)

Genetic and epigenetic factors. Other possible causes are those of genetic predisposition (familial and hereditary forms). Genetic studies suggest that a strong familial predisposition may be responsible for 5% to 10% of prostate cancers.5 Compared with men with no family history, those with one firstdegree relative with prostate cancer have twice the risk and those with two first-degree relatives have five times the risk.22 Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men age 65 or older). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. Men with BRCA2 (tumor suppressor) germline mutations have a 20-fold increase in the risk of prostate cancer.23 A common type of somatic mutation that develops into chromosomal rearrangements is the ETS gene. The most common epigenetic alteration in prostate cancer is hypermethylation of the glutathione S-transferase (GSTP1) gene located on chromosome 11. More than 30 independent, peer-reviewed studies have reported a consistently high sensitivity and specificity of GSTP1 hypermethylation in prostatectomy or biopsy tissue. There is no clear evidence of a causal link between BPH and prostate cancer, even though

2011

they may often occur together. Variations in several other genes related to inflammatory pathways might affect the probability of developing prostate cancer. Pathophysiology More than 95% of prostatic neoplasms are adenocarcinomas, and most occur in the periphery of the prostate (see Fig. 36.12 and Fig. 36.17). Prostatic adenocarcinoma is a heterogeneous group of tumors with a diverse spectrum of molecular and pathologic characteristics and, therefore, diverse clinical behaviors and challenges. The biologic aggressiveness of the neoplasm appears to be related to the degree of differentiation rather than the size of the tumor (Box 36.6). Several genetic alterations have been found for prostate carcinoma, including acquired genomic structural changes, somatic mutations, and epigenetic alterations.

FIGURE 36.17 Photomicrograph of Prostate Cancer Cells. Pink ruffled cells are prostate cancer cells. (From Cancer Research UK, London Research Institute, Electron Microscopy Unit.)

Box 36.6

Determining the Grade of Prostate Cancer With the Gleason Score Grade 1. The cancer cells closely resemble normal cells. They are small, uniform in shape, evenly spaced, and well differentiated (i.e., they remain separate from one another). Grade 2. The cancer cells are still well differentiated, but they are arranged more loosely and are irregular in shape and size. Some of the cancer cells have invaded the neighboring prostate tissue.

2012

Grade 3. This is the most common grade. The cells are less well differentiated (some have fused into clumps) and are more variable in shape. Grade 4. The cells are poorly differentiated and highly irregular in shape. Invasion of the neighboring prostate tissue has progressed further. Grade 5. The cells are undifferentiated. They have merged into large masses that no longer resemble normal prostate cells. Invasion of the surrounding tissue is extensive. Hormonal factors. Just as the testicles are the male equivalent of the female ovaries, the prostate is the male equivalent of the female uterus; in both situations they originate from the same embryonic cells. This may be important in understanding the role of the associated hormones testosterone (T), DHT, and estrogens in prostate cancer development. Testicular T synthesis and serum T levels fall as men age, but the levels of estradiol do not decline, remaining unchanged or increasing with age. The relationship between hormones and the pathophysiology of prostate carcinogenesis is incomplete and controversial. The main issues and controversies include (1) sources of androgen production outside of the testes, or extratesticular sources (e.g., from adrenal DHEA and from prostate tissue cholesterol [de novo] itself); (2) the role of prostatic androgen receptor; (3) the role of estrogens, aromatase enzyme, and the estrogen receptors ERα and ERβ; and (4) the role of the surrounding microenvironment or stroma. Prostate cancer is considered a hormone-dependent disease; cell growth and survival of early stage prostate cancer can respond to androgens and this is the background evidence for androgen-deprivation therapy (ADT). However, evidence thus far is lacking to associate plasma androgens with prostate cancer progression. Prostatic tissue has the ability to produce its own steroids, including androgens and estrogens. Therefore, the local tissue levels of sex steroids have become a major focus of intraprostatic hormonal profiles. Prostate tissue contains many metabolizing enzymes for the local production of active androgens and estrogens. Carcinogenesis can alter these intraprostatic enzymes and alter the normal balance. The androgenic hormone responses in the normal prostate and prostate cancer are mediated by androgen receptor (AR) signaling. Exactly how AR drives the growth of prostate cancer cells is not fully known. Testicular T provides the main source of androgens in the prostate (see Fig. 36.14) and is the major circulating androgen, whereas DHT predominates in prostate tissue and binds to the AR with greater affinity than does T. The adrenal cortex contributes the far less potent DHEA, which promotes the synthesis of androgens in the prostate. In the target tissues and, to a lesser extent, in the testes themselves, T is converted to DHT by the enzyme 5α-reductase (Fig. 36.18). Thus, DHT is the most potent intraprostatic androgen.

2013

FIGURE 36.18

Testosterone and Conversion to Dihydrotestosterone.

Normally, a small amount of estrogen (i.e., estrone and estradiol) is produced daily by the aromatization of androstenedione and T, respectively. This reaction is catalyzed by the enzyme aromatase. A small quantity of estradiol is released by the testes (see Fig. 36.18); the rest of the estrogens in males are produced by adipose tissue, liver, skin, brain, and other nonendocrine tissue. Thus, T is a precursor of two hormones, DHT and estradiol. Accumulating evidence shows that estrogens participate in the pathogenesis and development of BPH and prostate cancer by activating estrogen receptor α (ER-α). In contrast, estrogen receptor β (ER-β) is involved in the differentiation and maturation of prostatic epithelial cells and thus exerts antitumor effects in prostate cancer. The effect of estrogen is determined by the two receptors ER-α and ER-β. ER-α leads to abnormal proliferation, inflammation, and the development of premalignant lesions. In contrast, ER-β leads to antiproliferative, antiinflammatory, and potentially anticarcinogenic effects that act in concert or balance the actions of ER-α and androgens. Increased expression of ER-α has been found to be associated with prostate cancer progression, metastasis, and the so-called castration-resistant (i.e., medical treatment that suppresses androgens) phenotype. A specific oncogene is regulated by ERs, and hormones that stimulate the ER-α receptor–like (i.e., agonists) endogenous estrogens can stimulate oncogene expression. Most of the androgen-metabolizing enzymes undergo a significant age-dependent alteration. In epithelium, both the blood levels of 5α-reductase activity and the DHT level decrease with age, whereas in stroma (prostate), not only the 5α-reductase activity but also the stromal DHT level is rather constant over the lifetime. In contrast to the relatively unaltered DHT level over time, the estrogen concentration follows an age-dependent increase. Thus the age-dependent decrease of the DHT accumulation in epithelium and the concomitant increase of the estrogen accumulation in stroma lead to a tremendous increase with age of the estrogen/androgen ratio in the human prostate. In animal studies, chronic exposure to T plus estradiol is strongly carcinogenic, whereas T alone is weakly carcinogenic. In mice studies, elevated T levels in the absence of estrogen leads to the development of hypertrophy and hyperplasia but not malignancy. High estrogen and low T levels have been shown to lead to inflammation with aging and the emergence of precancerous lesions. The mechanism is not clearly understood and may involve estrogengenerated oxidative stress and deoxyribonucleic acid (DNA) toxicity, and it requires androgen-mediated and estrogen receptor–mediated processes, such as changes in sex steroid metabolism and receptor status. In addition, there are changes in the balance between autocrine/paracrine growth-stimulatory and growth-inhibitory factors, such as the IGFs. Investigators have summarized these key findings on hormones and prostate cancer: (1) androgens are clearly involved in the progression of prostate cancer; (2) it is only with the addition of estrogen to T in rats that cancer can be reliably induced; (3) in vivo and in vitro

2014

studies have identified multiple mechanisms involving hormonal involvement with genotoxicity, epigenetic toxicity, hyperprolactinemia, chronic inflammation, and estrogen receptor–mediated changes. Prostate epithelial neoplasia. A precursor lesion, prostatic epithelial neoplasia (PIN), has been described. PIN may be more concentrated in prostates containing cancer and is noted in proximity to cancer. However, the final fate of PIN is unknown, including the possibilities of latency, invasion, and even regression. The current working model of prostate carcinogenesis suggests that repeated cycles of injury and cell death occur to the prostate epithelium as a result of damage (i.e., from oxidative stress) from inflammatory responses. The direct injury is hypothesized as a response to infections; autoimmune disease; circulating carcinogens or toxins, or both, from the diet; or urine that has refluxed into the prostate (see Fig. 36.15). The resultant manifestation of this injury is focal atrophy or prostate intraepithelial atrophy (PIA). Biologic responses cause an increase in proliferation and a massive increase in epithelial cells that have a phenotype intermediate between basal cells and mature luminal cells (Fig. 36.19). In a small subset of cells, some may contain “stem cell” or tumor-initiating properties and telomere shortening (see Chapter 11). A subset of PIN cells may activate telomerase enzyme, causing the cells to become immortal. Molecular genetic and epigenetic changes can increase genetic instability that might progress to high-grade PIN and early prostate cancer formation. This model of prostate carcinogenesis needs much more research.

FIGURE 36.19 Cellular and Molecular Model of Early Prostate Neoplasia Progression. A, This stage includes infiltration of lymphocytes, macrophages, and neutrophils caused by repeated infections, dietary factors, urine reflux, injury, onset of autoimmunity (which triggers inflammation), and wound healing. B, Epigenetic alterations mediate telomere shortening. C, Genetic instability and accumulation of genetic alterations. D, Continued proliferation of genetically unstable cells, leading to cancer progression. PIN, Prostatic intraepithelial neoplasia.

Stromal environment. The prostate gland is composed of secretory luminal epithelium, basal epithelium, neuroendocrine cells, and various cell types comprising supportive tissue or stroma. Stroma, or tissue microenvironment, produces autocrine/paracrine factors as well as structural supporting molecules that help regulate normal cell behavior and organ homeostasis. Stromal components in the tumor microenvironment are important contributions to tumor progression and metastasis. Reciprocal interactions between tumor

2015

cells and stromal components influence the metastatic, dormancy-related, and stem cell– like potential of tumor cells. The stromal compartment of the tumor is complex and includes inflammatory/immune cells, vascular endothelial cells, pericytes, fibroblasts, adipocytes, and components of the extracellular matrix. Tumor-infiltrating inflammatory cells release a host of growth factors, chemokines, cytokines, and proinvasive matrixdegrading enzymes to promote tumor growth and progression. Angiogenesis occurs in response to factors secreted from tumor cells, resulting in continued growth and progression. Adipocytes in the tumor microenvironment produce adipokines, which are important for tumor growth. Fibroblasts in the tumor microenvironment provide the structural framework of the stroma; they remain quiet or dormant, but proliferate during wound healing, inflammation, and cancer. Tumor cells release paracrine factors that activate fibroblasts to become “cancer-associated fibroblasts” (CAFs). CAFs secrete factors that modulate tumor growth and modify the stroma to enhance metastasis and dampen responses to anticancer therapies. These findings suggest that alteration in the prostate microenvironment with therapeutic agents and approaches—in particular, natural products such as berberine, resveratrol, onionin A, EGCG, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone—warrants further investigation to target the tumor microenvironment for the treatment and prevention of cancer. Epithelial-mesenchymal transition (EMT) was first described in embryonic development, and is observed in a number of solid tumors (see Chapter 11). Cells that undergo EMT become more migratory and invasive and gain access to vascular vessels. Numerous studies have shown that these transition states (EMT and mesenchymal-epithelial transition [MET]) are a consequence of tumor-stromal interactions. Prostate cancer is known to be diverse and composed of multiple genetically distinct cancer cell clones. However, recent studies indicate that most metastatic cancers arise from a single precursor cancer cell. From all these observations, a multifactorial general hypothesis of prostate carcinogenesis emerges: (1) androgens act as strong tumor promoters through androgen receptor–mediated mechanisms to enhance the carcinogenic activity of strong endogenous DNA toxic carcinogens, including reactive estrogen metabolites and estrogen, and prostategenerated reactive oxygen species; (2) reciprocal interactions between tumor cells and the stromal microenvironment promote prostate cancer pathogenesis; and (3) possibly unknown environmental and lifestyle carcinogens may contribute to prostate cancer. All these factors are modulated by diet and genetic determinants, such as hereditary susceptibility genes and polymorphic genes, which encode receptors and enzymes involved in the metabolism and action of steroid hormones. The most common sites of distant metastasis are the lymph nodes, bones, lungs, liver, and adrenals. The pelvis, lumbar spine, femur, thoracic spine, and ribs are the most common sites of bone metastasis. Local extension is usually posterior, although late in the disease the tumor may invade the rectum or encroach on the prostatic urethra and cause bladder outlet obstruction (Fig. 36.20). The spread of cancer through blood vessels is illustrated in Fig. 36.21.

2016

FIGURE 36.20 Carcinoma of the Prostate. A, Schematic of carcinoma of the prostate. B, Carcinoma of the prostate extending into the rectum and urinary bladder. (B from Damjanov I, Linder J, editors: Pathology: a color atlas, St Louis, 2000, Mosby.)

2017

FIGURE 36.21 Distribution of Hematogenous Metastases in Prostate Cancer. The results are from a study of 556 men with metastatic prostate cancer. (Adapted from Budendorf L et al: Hum Pathol 31:578, 2000.)

Clinical Manifestations Prostatic cancer often causes no symptoms until it is far advanced. The first manifestations of disease are those of bladder outlet obstruction: slow urinary stream, hesitancy, incomplete emptying, frequency, nocturia, and dysuria. Unlike the symptoms of obstruction caused by BPH, the symptoms of obstruction caused by prostatic cancer are progressive and do not remit. Local extension of prostatic cancer can obstruct the upper urinary tract ureters as well. Rectal obstruction also may occur, causing the individual to experience large bowel obstruction or difficulty in defecation. Symptoms of late disease include bone pain at sites of bone metastasis, edema of the lower extremities, enlargement of lymph nodes, liver enlargement, pathologic bone fractures, and mental confusion associated with brain metastases. Prostatic cancer and its treatment can affect sexual functioning. Evaluation and Treatment Screening for prostatic cancer includes DRE and also PSA blood tests. However, evidence is lacking on whether PSA screening or DRE reduces the mortality from prostate cancer.24 It is unclear if the detection of prostate cancer at an early stage leads to any change in the natural history or outcome. Observational studies in some countries show a trend toward lower mortality, but the relationship between the intensity and trends of screening is not clear, and the associations with screening are inconsistent. Strong evidence shows implementation of PSA or DRE detects some prostate cancers that would never have caused significant clinical problems. These screening tests lead to some degree of overtreatment. The screening tests can harm patients, including radical prostatectomy and radiation therapy that lead to irreversible side effects in many men. The most common side effects are erectile dysfunction and urinary incontinence. The screening process can cause considerable anxiety, especially in men who have a prostate biopsy but no identified prostate cancer. Screening can lead to biopsies, which are associated with complications, including fever, pain, hematuria, hematospermia, positive urine cultures for bacteria, and,

2018

rarely, sepsis. About 20% to 70% of men who had no problems before radical prostatectomy or external beam radiation therapy will have reduced sexual function or urinary problems, or both. Prostate cancer usually grows very slowly and is predominantly a tumor of older men; the median age at diagnosis is 72 years.25 Until recently, many physicians and organizations encouraged yearly PSA screening for men beginning at age 50; however, as the benefits and detriments have become more clearly understood, a number of organizations now caution men against routine population screening (Fig. 36.22). For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit to reduce the chance of death from prostate cancer in some men.19

2019

FIGURE 36.22 Benefits and Harms of Prostate-Specific Antigen (PSA) Screening for Prostate Cancer. The U.S. Preventive Services Task Force (USPSTF) recommends against PSA-based screenings for prostate cancer (grade D recommendation). (Adapted from USPSTF Recommendation Statement, Annals of Internal Medicine, 2012.)

The sum of the current evidence suggests that PSA screening may reduce the prostate cancer mortality risk but is associated with false positive results, biopsy complications, and overdiagnosis. Compared with conservative approaches (e.g., watchful waiting), active treatments for screen-detected prostate cancer have unclear effects on long-term survival but are associated with sexual and urinary difficulties.26 Supporting this evidence is the

2020

knowledge that some tumors found through PSA screening do not cause symptoms, grow slowly, and are unlikely to threaten a man's life. Across age ranges, black men and men with a family history of prostate cancer have an increased risk of developing and dying of prostate cancer. Black men are approximately twice as likely to die of prostate cancer compared with men of other races in the United States, and the reason for this disparity is unknown. Black men represent a very small minority of participants in randomized clinical trials of screening, and thus no firm conclusions can be made about the balance of benefits and harms of PSA-based screening in this population. As such, it is questionable practice to selectively recommend PSA-based screening for black men in the absence of data that support a more favorable balance of risks and benefits. Because of this “overtreatment” phenomenon, active surveillance with delayed intervention is gaining traction as a viable management approach in contemporary practice. Individuals and clinicians are increasingly considering the balance of benefits and harms of prostate cancer screening on the basis of family history, race/ethnicity, comorbid medical conditions, and other health needs. The current US Preventive Services Task Force (USPSTF) recommendation statement19 has added an opinion that clinicians should not screen men who do not express a preference for screening, and it also recommends against PSA-based screening for prostate cancer in any man 70 years or older. Treatment of prostatic cancer depends on the stage of the neoplasm, the anticipated effects of treatment, and the age, general health, and life expectancy of the individual. Options include no treatment; surgical treatments, such as total prostatectomy, transurethral resection of the prostate (TURP), or cryotherapy; nonsurgical treatments, such as radiation therapy, hormone therapy, or chemotherapy; watchful waiting; and any combination of these treatment modalities. In addition, new approaches are using immunotherapy. Palliative treatment is aimed at relieving urinary, bladder outlet, or colon obstruction; spinal cord compression; and pain. Box 36.7 shows the staging for prostate cancer. Prognosis and survival rates have improved steadily over the past 50 years. Over the past 25 years, the 5-year relative survival rate for all stages combined has increased from 68% to almost 100%. According to the most recent data, the 10-year relative survival rate is 98% for all stages combined (local, regional, and distant).5

Box 36.7

Staging for Prostate Cancer Stage I

2021

In stage I, cancer is found in the prostate only. In addition: • The cancer is found by performing a needle biopsy (done for a high prostate-specific antigen [PSA] level) or by examining a small amount of tissue during surgery for other reasons (e.g., benign prostatic hyperplasia). The PSA level is lower than 10, and the Gleason score is 6 or lower; or • The cancer is found on half or less of one lobe of the prostate. The PSA level is lower than 10, and the Gleason score is 6 or lower; or • The cancer cannot be felt during a digital rectal exam and cannot be seen in imaging tests. Cancer is found in half or less of one lobe of the prostate. The PSA level and the Gleason score are not known.

Stage II In stage II, cancer is more advanced than in stage I but has not spread outside the prostate. Stage II is divided into stages IIA and IIB.

Stage IIA • The cancer is found by performing a needle biopsy (done for a high PSA level) or by examining a small amount of tissue during surgery for other reasons (e.g., benign prostatic hyperplasia). The PSA level is lower than 20, and the Gleason score is 7; or • The cancer is found by performing a needle biopsy (done for a high PSA level) or by examining a small amount of tissue during surgery for other reasons (e.g., benign prostatic hyperplasia). The PSA level is at least 10 but lower than 20, and the Gleason score is 6 or lower; or • The cancer is found in half or less of one lobe of the prostate. The PSA level is at least 10 but lower than 20, and the Gleason score is 6 or lower; or • The cancer is found in half or less of one lobe of the prostate. The PSA level is lower than 20, and the Gleason score is 7; or • The cancer is found in more than half of one lobe of the prostate.

2022

Stage IIB • The cancer is found on opposite sides of the prostate. The PSA can be any level, and the Gleason score can range from 2 to 10; or • The cancer cannot be felt during a digital rectal examination and cannot be seen in imaging tests. The PSA level is 20 or higher, and the Gleason score can range from 2 to 10; or • The cancer cannot be felt during a digital rectal examination and cannot be seen in imaging tests. The PSA can be any level, and the Gleason score is 8 or higher.

Stage III • In stage III, the cancer has spread beyond the outer layer of the prostate and may have spread to the seminal vesicles. The PSA can be any level, and the Gleason score can range from 2 to 10.

Stage IV In stage IV, the PSA can be any level and the Gleason score can range from 2 to 10. Also: • The cancer has spread beyond the seminal vesicles to nearby tissue or organs, such as the rectum, bladder, or pelvic wall; or • The cancer may have spread to the seminal vesicles or to nearby tissue or organs, such as the rectum, bladder, or pelvic wall. The cancer has spread to nearby lymph nodes; or • The cancer has spread to distant parts of the body, which may include lymph nodes or bones. Prostate

2023

cancer often spreads to the bones.

Data from National Cancer Institute: PDQ prostate cancer treatment, Bethesda, Md, 2015, Author. Updated April 16, 2015. Available at http://cancer.gov/cancertopics/pdq/treatment/prostate/Patient. Figures copyright Terese Winslow. Stress incontinence can occur after surgery and mild urge incontinence can occur after radiation therapy. Prostate cancer and its treatment can affect sexual functioning. The sensation of orgasm is not usually affected, but smaller amounts of ejaculate will be produced or men may experience a “dry” ejaculate because of retrograde ejaculation.

Sexual Dysfunction In males, the normal sexual response involves erection, emission, and ejaculation. Sexual dysfunction is the impairment of any or all of these processes and can be caused by various physiologic, psychological, and emotional factors. Until the late 1970s, most cases of male sexual dysfunction were considered psychogenic. Now there is evidence that 89% to 90% of cases involve organic factors and include (1) vascular, endocrine, and neurologic disorders; (2) chronic disease, including renal failure and diabetes; (3) penile diseases and penile trauma; and (4) iatrogenic factors, such as surgery and pharmacologic therapies. Most of these disorders cause erectile dysfunction (ED). Pathophysiology Sexual dysfunction can have a specific physiologic cause, can be associated with many chronic diseases and their treatment, or may be related to low energy levels, stress, or depression. For example, vascular disease may cause impotence, and endocrine disorders or conditions that cause decreased T levels or testicular atrophy can diminish sexual functioning or libido. In addition, neurologic disorders and spinal cord injuries can interfere with sympathetic, parasympathetic, and CNS mechanisms required for erection, emission, and ejaculation. Drug-induced sexual dysfunction consists of decreased desire, decreased erectile ability, or decreased ejaculatory ability. Alcohol and other CNS depressants, antihypertensives,

2024

antidepressants, antihistamines, and hormonal preparations are commonly used drugs that affect sexual functioning. Other pharmacologic agents may diminish the quality or quantity of sperm or cause priapism. Clinical Manifestations, Evlauation, and Treatment Evaluation of sexual dysfunction includes a thorough history and physical examination. Particular attention is given to the drug history and examination of the genitalia, prostate, and nervous system. Basic laboratory tests are used to identify the presence of endocrinopathies or other underlying disorders that can cause dysfunction. Psychological evaluation is indicated for younger men with a sudden onset of sexual dysfunction or for men of any age who can achieve but not maintain an erection. If no physiologic cause is found and the condition does not improve with psychotherapy, the man is referred for further investigation of organic causes. Treatments for organic sexual dysfunction include both medical and surgical approaches. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionized the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function. The original PDE5i, Viagra (sildenafil), has created much enthusiasm over its ability to help a man maintain an erection. For a small percentage of men (1%), however, this improvement in sexual function is accompanied by heart attacks and death. Whether these effects are the result of sexual performance or Viagra has been controversial. Research has shown that Viagra increases blood concentrations of the enzyme cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG), which increases blood flow to the penis. PKG, however, plays a dual role: first, it increases platelet aggregation; and then, minutes later, it decreases clot size. The initial clot could cause some men with heart disease to experience cardiac arrest. Currently available PDE5i medications in the United States include sildenafil, vardenafil, tadalafil, and avanafil, each of which has a unique side effects profile. For instance, sildenafil is associated with (in addition to the previously mentioned cardiac issues) an increased rate of visual changes, vardenafil with QT prolongation, and tadalafil with lower back pain. Nonsurgical approaches include correction of underlying disorders, particularly drug-induced dysfunction and endocrinopathy-related dysfunction (e.g., reduced T level associated with chronic renal failure). Use of vasodilators and cessation of smoking can benefit individuals with vasculogenic erectile dysfunction. Surgical approaches include penile implants, penile revascularization, and correction of other anatomic defects contributing to sexual dysfunction.

Impairment of Sperm Production and Quality Spermatogenesis requires adequate secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary and sufficient secretion of T by the testes. Inadequate secretion of gonadotropins may be caused by numerous alterations (e.g., hypothyroidism, hyperadrenocortisolism, hyperprolactinemia, or hypogonadotropic hypogonadism). In the absence of adequate gonadotropin levels, the Leydig cells are not stimulated to secrete T, and sperm maturation is not promoted in the Sertoli cells. Spermatogenesis also depends on an appropriate response by the testes. Defects in testicular response to the gonadotropins result in decreased secretion of T and inhibin B and occur as a result of normal feedback mechanisms and high levels of circulating

2025

gonadotropins. In the absence of adequate T levels, spermatogenesis is impaired. Newer studies demonstrate the importance of inhibin B as a valuable marker of the competence of Sertoli cells and spermatogenesis. Impaired spermatogenesis also can be caused by testicular trauma, infection, atrophy of the testes, systemic illness involving high fever, ingestion of various drugs, exposure to environmental toxins, and cryptorchidism. Fertility is adversely affected if spermatogenesis is normal but the sperm are chromosomally or morphologically abnormal or are produced in insufficient quantities. Chromosomal abnormalities are caused by genetic factors and by external variables, such as exposure to radiation or toxic substances. Because the Y chromosome plays a key role in testis determination and control of spermatogenesis, understanding how the genes interact can elucidate exact causes of infertility. Research related to mapping the critical genes and gene pathways is the current focus of male infertility. Common mechanisms may be involved in infertility and testicular cancer. In utero environmental exposure to endocrine disruptors modulates the genetic makeup of the gonad and may result in both infertility and testicular cancer. Sperm motility also may affect fertility. Motility appears to be affected by the characteristics of the semen. Dysfunction of the prostate, excessive viscosity of the semen, presence of drugs or toxins in the semen, and presence of antisperm antibodies are associated with impaired sperm motility. However, new data show that motile density may not be a good indicator of infertility. Approximately 17% of infertile males have antisperm antibodies in their semen. These antibodies may be (1) cytotoxic antibodies, which attack sperm and reduce their number in the semen; or (2) sperm-immobilizing antibodies, which impair sperm motility and reduce their ability to traverse the endocervical canal. Male infertility has a variety of causes, and many of the causes can be corrected. Hormonal disorders, such as thyroid disturbances or low T levels, can be diagnosed and corrected. During sperm creation and maturation, the testes must be kept cooler than body temperature. Temperature elevations caused by illness, abnormal testes placement, or exposure to high temperatures in hot tubs or saunas may kill or disable sperm. Male infertility is also linked to abnormalities of the seminal tract and sexual dysfunction that disrupts ejaculation. The most common test for male infertility is semen analysis. A fresh semen sample is evaluated for volume and concentration, morphology, and motility of sperm. More advanced analysis may examine the function of the sperm, including ability to bind to and penetrate eggs. In addition, the sperm's DNA also may be analyzed for number and ability to merge with the egg's DNA. Treatment for impaired spermatogenesis involves correcting any underlying disorders, avoiding radiation and possibly electromagnetic radiation (hypothesis from cell phones) and toxins, and using hormones to enhance spermatogenesis. In addition, semen can be modified to improve sperm motility; modifications are followed by artificial insemination.

Quick Check 36.4 1. What is the current understanding of hormones in the pathophysiology of prostate cancer? 2. Why is the worldwide variation of prostate cancer incidence important?

2026

3. Describe what is meant by prostate cancer cell and stromal interactions for carcinogenesis. 4. What causes impaired spermatogenesis?

2027

Disorders of the Male Breast Gynecomastia Gynecomastia is the overdevelopment of breast tissue in a male. Gynecomastia accounts for approximately 85% of all masses that develop in the male breast and affects 32% to 40% of the male population. If only one breast is involved, it is typically the left. The incidence is greatest among adolescents and men older than 50 years. Gynecomastia results from hormonal alterations, which may be idiopathic or caused by systemic disorders, drugs, or neoplasms. Gynecomastia usually involves an imbalance of the estrogen/T ratio. The normal estrogen/T ratio can be altered in one of two ways. First, estrogen levels may be excessively high, although T levels are normal. This is the case in drug-induced and tumor-induced hyperestrogenism. Second, T levels may be extremely low, although estrogen levels are normal, as is the case in hypergonadism. Gynecomastia also can be caused by alterations in breast tissue responsiveness to hormonal stimulation. Breast tissue may have increased responsiveness to estrogen or decreased responsiveness to androgen. Alterations of responsiveness may cause many cases of idiopathic gynecomastia. Besides puberty and aging, estrogen/T imbalances are associated with hypogonadism, Klinefelter syndrome, and testicular neoplasms. Hormone-induced gynecomastia is usually bilateral. Pubertal gynecomastia is a self-limiting phenomenon that usually disappears within 4 to 6 months. Senescent gynecomastia usually regresses spontaneously within 6 to 12 months. Systemic disorders associated with gynecomastia include cirrhosis of the liver, infectious hepatitis, chronic renal failure, chronic obstructive lung disease, hyperthyroidism, tuberculosis, and chronic malnutrition. It may be that these disorders ultimately alter the estrogen/T ratio, initiating the gynecomastia. Gynecomastia is often seen in males receiving estrogen therapy, either in preparation for a sex-change operation or in the treatment of prostatic carcinoma. Other drugs that can cause gynecomastia include digitalis, cimetidine, spironolactone, reserpine, thiazide, isoniazid, ergotamine, tricyclic antidepressants, amphetamines, vincristine, and busulfan. Gynecomastia is usually unilateral in these instances. Malignancies of the testes, adrenals, or liver can cause gynecomastia if they alter the estrogen/testosterone ratio. Pituitary adenomas and lung cancer also are associated with gynecomastia. Pathophysiology The enlargement of the breast consists of hyperplastic stroma and ductal tissue. Hyperplasia results in a firm, palpable mass that is at least 2 cm in diameter and located beneath the areola. Evaluation and Treatment The diagnosis of gynecomastia is based on physical examination. Identification and treatment of the cause are likely to be followed by resolution of the gynecomastia. The man should be taught to perform breast self-examination and is reexamined at 6- and 12-month intervals if the gynecomastia persists.

2028

Carcinoma Male breast cancer (MBC) accounts for 0.26% of all male cancers and 1.1% of all breast cancers. About 2550 new cases of breast cancer in men were estimated in 2018.5 Global incidence rates were generally less than 1 per 100,000 man-years, in contrast to much higher rates in females.27 It is seen most commonly after the age of 60 years, with the peak incidence between 60 and 69 years (men tend to be diagnosed at an older age than women). However, it has been reported in males as young as 6 years old and in adolescents. Klinefelter syndrome is the strongest risk factor for developing male breast carcinoma. Other risk factors include germline mutation in BRCA1 or BRCA2, but familial cases usually have BRCA2 rather than BRCA1 mutations.28 Obesity increases the risk of MBC. Testicular disorders, including cryptorchidism, mumps, orchitis, and orchiectomy, are related to risk. The relationship between these factors and the risk of disease is not clearly defined. Recent data on the most frequent molecular subtypes of MBC appears to be different from those for female breast cancers. Luminal A and luminal B are most common; and basal-like, unclassifiable triple-negative, and HER2-driven male breast cancers are rare.28 Male breast tumors often resemble carcinoma of the breast in women (see Breast Cancer in Chapter 35). The majority of MBCs express estrogen and progesterone receptors. The malignant male breast lesion is usually a unilateral solid mass located near the nipple. Because the nipple is commonly involved, crusting and nipple discharge are typical clinical manifestations. Other findings include skin retraction, ulceration of the skin over the tumor, and axillary node involvement. Patterns of metastasis are similar to those in females. The diagnosis of cancer is confirmed by biopsy. Because of delays in seeking treatment, MBC tends to be advanced at the time of diagnosis and therefore is likely to have a poor prognosis. Treatment protocols are similar to those for female breast cancer, but endocrine therapy is used more often for males because a higher percentage of male tumors are hormone dependent. The mainstay of treatment is modified mastectomy with axillary node dissection to assess the stage and prognosis. Because 90% of tumors are hormonal receptor positive, tamoxifen is standard adjuvant therapy. Orchiectomy is performed to treat metastatic disease. For metastatic disease, hormonal therapy is the main treatment but chemotherapy also can provide palliation.

2029

Sexually Transmitted Infections Sexually transmitted infections (STIs) are a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity. Sexually contracted infections affected approximately 2.5 million Americans in 2017.29 Young women ages 15 to 24 account for about one half of the reported cases in the United States, and they face the most severe consequences of an undiagnosed infection29 (Table 36.1). STIs can lead to severe reproductive health problems (e.g., infertility and ectopic pregnancy). Untreated or undertreated chlamydial infections are the primary cause of preventable infertility and ectopic pregnancy. In addition to ectopic pregnancy and infertility, other complications of STIs include pelvic inflammatory disease (PID), chronic pelvic pain, neonatal morbidity and mortality, genital cancer, and epidemiologic synergy with HIV transmission (Table 36.2). Long-term sequelae of untreated or undertreated STIs may be disastrous and can affect a person's physical, emotional, and financial well-being. Treatment guidelines for STIs can be found on the CDC website (http://www.cdc.gov/std/treatment/default.htm). TABLE 36.1 Currently Recognized Sexually Transmitted Infections Causal Microorganism Bacteria Campylobacter Calymmatobacterium granulomatis Chlamydia trachomatis

Infection Campylobacter enteritis Granuloma inguinale Urogenital infections; lymphogranuloma venereum

Polymicrobial Gardnerella vaginalis interaction with anaerobes (Bacteroides and Mobiluncus spp.) and genital mycoplasmas Haemophilus ducreyi Mycoplasma Neisseria gonorrhoeae Shigella Treponema pallidum Viruses Cytomegalovirus Hepatitis B virus (HBV) Hepatitis C virus (HCV) Herpes simplex virus (HSV) Human immunodeficiency virus (HIV) Human papillomavirus (HPV) Molluscum contagiosum virus Zika virus Protozoa Entamoeba histolytica Giardia lamblia Trichomonas vaginalis Ectoparasites Phthirus pubis

Bacterial vaginosis Chancroid Mycoplasmosis Gonorrhea Shigellosis Syphilis Cytomegalic inclusion disease Hepatitis Hepatitis Genital herpes Acquired immunodeficiency syndrome (AIDS) Condylomata acuminata, cervical dysplasia, and cervical cancer Molluscum contagiosum Zika virus disease Amebiasis; amebic dysentery Giardiasis Trichomoniasis Pediculosis pubis

2030

Sarcoptes scabiei Fungus Candida albicans

Scabies Candidiasis

TABLE 36.2 Photographs of STIs and Their Precursors Bacterial Sources Gonococcal Infections Symptomatic gonococcal urethritisa

Endocervical gonorrheaa

Skin lesions of disseminated gonococcal infectiona

Bacterial Vaginosis Vaginal examination showing mild bacterial vaginosisa

2031

Syphilis Erythematous penile plaques of secondary syphilisb

Multiple primary syphilitic chancres of the labia and perineum

(Courtesy Barbara Romanowski, MD.)a

Papular secondary syphilisa

2032

Lymphogranuloma “Groove sign” in man with lymphogranuloma venereum (LV)b

Chlamydial Infections Beefy red mucosa in chlamydial infectiona

Chlamydial epididymitis

2033

(Courtesy Richard E. Berger.)a

Chlamydial ophthalmia: erythematous conjunctiva in an infanta

Viral Sources Genital Herpes Early lesions of primary genital herpesa

Primary vulvar herpes

2034

(Courtesy Barbara Romanowski, MD.)a

Generalized herpes simplex in patient with atopic dermatitis.

(Courtesy David Mandeville and Peter Lane, MD.)a

Human papillomavirus (HPV) Human papillomavirus (HPV) infection of the cervixb

Exophytic (outward-growing) condyloma, subclinical human papillomavirus (HPV) infection, and high-grade cervical intraepithelial neoplasia (CIN)b

Condylomata Acuminata

2035

Condylomata acuminata: vulvar and perineala

Condylomata acuminata: perianala

Condylomata acuminata: penilea

Parasite Sources Trichomonisasis “Strawberry cervix” seen with trichomoniasisa

2036

Scabies Nodular lesions of scabies on male genitaliab

Scabies of the palm with secondary pyoderma in an infanta

Pediculosis pubis (Phthirus pubis [crab louse]) Phthirus pubis feeding on its hosta

Pubic hair with multiple nitsa

2037

aFrom

Morse SA, Ballard RC, Holmes KK, et al: Atlas of sexually transmitted diseases and AIDS, ed 4, London, 2010, Elsevier. bFrom

Morse SA, Moreland AA, Holmes KK: Atlas of sexually transmitted diseases and AIDS, ed 2, London, 1996, Elsevier.

Anyone can become infected with an STI, but young people and gay and bisexual men are at greatest risk. Young people between the ages of 15 to 24 years continue to have the highest reported rates of chlamydia and gonorrhea compared with other groups. Both young men and women are heavily affected by STIs, but young women have the most serious long-term health consequences. Undiagnosed STIs cause 20,000 women to become infertile each year.29 Men who have sex with men (MSM) account for about 75% of all primary and secondary syphilis cases. Primary and secondary syphilis are the most infectious stages of the disease and, if not treated adequately, can lead to visual impairment and stroke. Syphilis infection raises the risk of acquiring and transmitting HIV infection. Half of MSM with syphilis also are infected with HIV. Individual risk behaviors, such as higher numbers of lifetime sex partners and environmental, social, and cultural factors, contribute to health disparities of MSM (e.g., difficulty accessing health care). Homophobia and stigma also can make it difficult for gay and bisexual men to find culturally sensitive and appropriate care and treatment. STIs screening is critical. It is recommended that women who are sexually active and younger than 25 years of age or have multiple sex partners be tested annually for chlamydia and gonorrhea. Pregnant women should request syphilis, HIV, chlamydia, and hepatitis B testing early in the pregnancy. These tests also should be requested if a woman has a new or multiple sex partners. Recommended tests include syphilis, chlamydia, gonorrhea, and HIV once a year for gay, bisexual, or other men who have sex with men. More frequent testing is recommended for men at high risk.

Quick Check 36.5 1. What is the cause of male gynecomastia? 2. What are the risk factors for male breast cancer? 3. What factors increase the incidence of STIs? 4. What are the serious long-term health consequences of STIs for young women? 5. What are the long-term health consequences for MSM who acquire syphilis?

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Summary Review Alterations of Sexual Maturation 1. Sexual maturation, or puberty, is marked by the development of secondary sex characteristics, rapid growth and ultimately, the ability to reproduce. Puberty begins later in boys than in girls, typically around 14 to 14.5 years. 2. Delayed puberty in boys is the onset of sexual maturation after 14 to 14.5 years and seldom requires treatment. Precocious puberty is the onset before these ages, and treatment depends on the cause.

Disorders of the Male Reproductive System 1. Disorders of the urethra include urethritis (infection of the urethra) and urethral strictures (narrowing or obstruction of the urethral lumen caused by scarring). 2. Most cases of urethritis result from sexually transmitted pathogens. Urologic instrumentation, foreign body insertion, trauma, or an anatomic abnormality can cause urethral inflammation with or without infection. 3. Urethritis causes urinary symptoms, including a burning sensation during urination (dysuria), frequency, urgency, urethral tingling or itching, and a clear or purulent discharge. 4. The scarring that causes urethral stricture can be attributed to trauma or severe untreated urethritis. 5. Manifestations of urethral stricture include those of bladder outlet obstruction: urinary frequency and hesitancy, mild dysuria, double urinary stream or spraying, and dribbling after voiding. 6. Phimosis and paraphimosis are penile disorders involving the foreskin (prepuce). In phimosis, the foreskin cannot be retracted over the glans. In paraphimosis, the foreskin is retracted and cannot be reduced (returned to its normal anatomic position over the glans). Phimosis is caused by poor hygiene and chronic infection and can lead to paraphimosis. Paraphimosis can constrict the penile blood vessels, preventing circulation to the glans. 7. Peyronie disease consists of fibrosis affecting the corpora cavernosa, which prevents engorgement on the affected side, causing a lateral curvature during erection. Peyronie disease can cause painful erection, painful intercourse for both partners, and poor erection distal to the involved area. 8. Priapism is a prolonged, painful erection that is not stimulated by sexual arousal. Priapism is idiopathic in the majority of cases but can be associated with spinal cord trauma, sickle cell disease, leukemia, pelvic tumors, infections, or penile trauma. 9. Balanitis is an inflammation of the glans penis, and it usually occurs in conjunction with posthitis, an inflammation of the prepuce. It is associated with phimosis, inadequate cleansing under the foreskin, skin disorders, and pathogens (e.g., Candida albicans). 10. Cancer of the penis is rare. Condyloma acuminatum is a benign tumor caused by

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HPV. Penile carcinoma in situ tends to involve the glans; invasive carcinoma of the penis involves the shaft as well. 11. Varicocele, hydrocele, and spermatocele are common disorders of the scrotum. 12. A varicocele is an abnormal dilation of the veins within the spermatic cord and is classically described as a “bag of worms.” Varicoceles are one of the most commonly identified scrotal abnormalities and abnormal findings among infertile men. 13. A hydrocele is a collection of fluid between the testicular and scrotal layers of the tunica vaginalis. Hydroceles can be idiopathic or can be caused by trauma or infection of the testes. 14. A spermatocele is a cyst located between the testis and epididymis that is filled with fluid and sperm. 15. Cryptorchidism is a congenital condition in which one or both testes fail to descend into the scrotum completely, whereas an ectopic testis has strayed from the normal pathway of descent. Uncorrected cryptorchidism is associated with infertility and a significantly increased risk of testicular cancer. 16. Torsion of the testis is the rotation of a testis, which twists blood vessels in the spermatic cord. This interrupts the blood supply to the testis, resulting in edema and ischemia. Torsion of the testis is a surgical emergency and must be corrected within 6 hours to preserve normal testicular function. 17. Orchitis is an acute infection of the testes. Complications of orchitis include hydrocele and abscess formation. 18. Testicular cancer is uncommon but most often affects males 15 to 35 years of age. Although its cause is unknown, risk factors include genetic predisposition, history of cryptorchidism, abnormal testicular development, HIV and AIDS, Klinefelter syndrome, and a history of testicular cancer. 19. Epididymitis, an inflammation of the epididymis, is usually caused by a sexually transmitted pathogen that ascends through the vasa deferentia from an already infected urethra or bladder. 20. BPH, also called benign prostatic hypertrophy, is the enlargement of the prostate gland. This condition becomes symptomatic as the enlarging prostate compresses the urethra, causing symptoms of bladder outlet obstruction and urine retention. 21. Prostatitis is inflammation of the prostate. Prostatitis syndromes have been classified by the National Institutes of Health as (1) acute bacterial prostatitis (ABP), (2) chronic bacterial prostatitis (CBP), (3) chronic pelvic pain syndrome (CPPS), and (4) asymptomatic inflammatory prostatitis. 22. Prostate cancer is the most commonly diagnosed, non–skin cancer in American males, and the incidence varies greatly worldwide. Possible risk factors include genetic and epigenetic factors, environmental and dietary factors, inflammation, vasectomy, and alterations in levels of hormones (testosterone, dihydrotestosterone, and estradiol) and growth factors. Incidence is greatest in developed countries because of wide use or overuse of screening, which can amplify the incidence. 23. Most cancers of the prostate are adenocarcinomas that develop at the periphery of the gland. 24. Sexual dysfunction in males can be caused by any physical or psychological factor that impairs erection, emission, or ejaculation.

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25. Spermatogenesis (sperm production by the testes) can be impaired by disruptions that reduce testosterone secretion and by testicular trauma, infection, atrophy from any cause, systemic illness involving high fever, ingestion of various drugs, exposure to environmental toxins, and cryptorchidism.

Disorders of the Male Breast 1. Gynecomastia is the overdevelopment (hyperplasia) of breast tissue in a male; it affects 32% to 40% of the male population. The incidence is greatest among adolescents and men older than 50 years of age. It is first seen as a firm, palpable mass at least 2 cm in diameter and is located in the subareolar area. 2. Gynecomastia is caused by hormonal or breast tissue alterations that cause estrogen to dominate. These alterations can result from systemic disorders, drugs, neoplasms, or idiopathic causes. 3. Breast cancer is relatively uncommon in males, but it has a poor prognosis because men tend to delay seeking treatment until the disease is advanced. The incidence is greatest in men in their sixties.

Sexually Transmitted Infections 1. STIs are contracted by intimate, as well as sexual, contact. STIs can lead to severe reproductive health problems, such as infertility, ectopic pregnancy, chronic pelvic pain, neonatal morbidity and mortality, and genital cancer. They include systemic infections, such as tuberculosis and hepatitis, which can spread to a sexual partner. 2. The etiology of an STI may be bacterial, viral, protozoan, parasitic, or fungal.

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Key Terms Acute bacterial prostatitis (ABP, category I), 840 Androgen receptor (AR) signaling, 846 Balanitis, 833 Benign prostatic hyperplasia (BPH, benign prostatic hypertrophy), 838, 838 Bladder outflow obstruction, 839 Chemical epididymitis, 838 Chronic bacterial prostatitis (CBP, category II), 840 Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, category III), 841 Complete precocious puberty, 831 Condyloma acuminatum, 833 Cryptorchidism, 835 Delayed puberty, 830 Ectopic testis, 835 Epididymitis, 838 Fibroblast, 847 Gynecomastia, 852 Hydrocele, 835 Intraprostatic conversion, 842 Nonbacterial prostatitis, 841 Orchitis, 836 Paraphimosis, 832 Peyronie disease (“bent nail syndrome”), 832 Phimosis, 831 Precocious puberty, 830 Priapism, 833 Prostatic epithelial neoplasia (PIN), 847 Prostatitis, 840 Sexual dysfunction, 849 Sexually transmitted infection (STI), 853 Spermatocele (epididymal cyst), 835 Stroma, 847 Testicular appendage, 836 Torsion of the testis, 836 Urethral stricture, 831 Urethritis, 831 Varicocele, 834

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References 1. Jospe N. Disorders of pubertal development. Osborn LM, et al. Pediatrics. Mosby: Philadelphia; 2005. 2. Whittemore BJ, et al. Endocrine and metabolic disorders. Burns CE, et al. Pediatric primary care. Saunders: St Louis; 2012. 3. Euling SY, et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics. 2008;12(Suppl 3):S172–S191. 4. Centers for Disease Control and Prevention (CDC). How many cancers are linked with HPV each year?. Author: Atlanta; 2014. 5. American Cancer Society (ACS). Cancer facts & figures 2019. Author: Atlanta; 2019. 6. Chen SS. Differences in the clinical characteristics between young and elderly men with varicocele. Int J Androl. 2012;35(5):695–699. 7. Hart RJ, et al. Testicular function in a birth cohort of young men. Hum Reprod. 2015;30(12):2713–2724. 8. Günther P, Rübben I. The acute scrotum in childhood and adolescence. Dtsch Arztebl Int. 2012;109(25):449–457. 9. Jensen MS, et al. Cryptorchidism and hypospadias in a cohort of 934,538 Danish boys: the role of birth weight, gestational age, body dimensions, and fetal growth. Am J Epidemiol. 2012;175(9):917–925. 10. John Radcliffe Hospital Cryptorchidism Study Group. Cryptorchidism: a prospective study of 7500 consecutive male births, 1984–8. Arch Dis Child. 1992;67:892–899. 11. Walsh TJ, Smith JF. Male infertility. McAninch JW, Lue TF. Smith and Tanagho's general urology. ed 18. McGraw Hill Lange: Norwalk, Conn; 2012. 12. National Cancer Institute (NCI). Testicular cancer incidence and mortality. [Available at] www.cancer.gov/cancertopics/pdq/treatment/testicular; 2014. 13. Cheng L, et al. Testicular cancer. Nat Rev Dis Primers. 2043

2018;4(1):29. 14. PDQ Adult Treatment Editorial Board. PDQ® testicular cancer treatment. National Cancer Institute: Bethesda, MD; 2019 [Available at] https://www.cancer.gov/types/testicular/patient/testiculartreatment-pdq [PMID] 26389286 [Updated ]. 15. Lim KB. Epidemiology of clinical benign prostatic hyperplasia. Asian J Urol. 2017;4(3):148–151. 16. Pearson R, Williams PM. Common questions about the diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2014;90(11):769–774. 17. Jiwrajka M, et al. Review and update of benign prostatic hyperplasia in general practice. Aust J Gen Pract. 2018;47:471– 475. 18. Kapoor A. Benign prostatic hyperplasia (BPH) management in the primary care setting. Can J Urol. 2012;19(5 Suppl 1):10–17. 19. U. S. Preventive Services Task Force (US PSTF). Screening for prostate cancer: U. S. Preventive Services Task Force recommendation statement. J Am Med Assoc. 2018;319:1901– 1913. 20. Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. 21. Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–E386. 22. Albright F, et al. Significant evidence for a heritable contribution to cancer predisposition: a review of cancer familiality by site. BMC Cancer. 2012;12:138. 23. Leongamornlert D, et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012;106(10):1697–1701. 24. PDQ Screening and Prevention Editorial Board. PDQ® prostate cancer screening. National Cancer Institute.: Bethesda, Md; 2019 [Available at] https://www.cancer.gov/types/prostate/hp/prostatescreening-pdq [Updated ]. 2044

25. National Cancer Institute (NCI). PDQ® prostate cancer treatment. Author: Bethesda, Md; 2015 [Available at] www.cancer.gov/types/prostate/hp/prostate-treatmentpdq [Date last modified April 2, 2015]. 26. Fenton JJ, et al. Prostate-specific antigen-based screening for prostate cancer: evidence report and systematic review for the US Preventive Services Task Force. J Am Med Assoc. 2018;319:1914–1931. 27. Ferzoco RM, Ruddy KJL. The epidemiology of male breast cancer. Curr Oncol Rep. 2016;18(1):1. 28. Deb S, et al. The cancer genetics and pathology of male breast cancer. Histopathology. 2016;68(1):110–118. 29. Centers for Disease Control and Prevention (CDC). Fact sheet reported STDs in the United States 2017 national data for chlamydia, gonorrhea, and syphilis. Author: Atlanta, Ga; 2017.

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U N I T 11

The Digestive System OUTLINE 37 Structure and Function of the Digestive System 38 Alterations of Digestive Function 39 Alterations of Digestive Function in Children

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37

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Structure and Function of the Digestive System Sue E. Huether

CHAPTER OUTLINE The Gastrointestinal Tract, 858 Mouth and Esophagus, 858 Stomach, 861 Small Intestine, 864 Large Intestine, 867 The Gastrointestinal Tract and Immunity, 869 Intestinal Microbiome, 869 Splanchnic Blood Flow, 869 Exocrine Pancreas, 874 Accessory Organs of Digestion, 869 Liver, 869 Gallbladder, 873 Exocrine Pancreas, 874 GERIATRIC CONSIDERATIONS: Aging & the Digestive System, 876

The digestive system includes the gastrointestinal (GI) tract and accessory organs of digestion: the liver, gallbladder, and exocrine pancreas (Fig. 37.1). The digestive system breaks down ingested food, prepares it for uptake by the body's cells, absorbs fluid, and eliminates wastes. The GI tract and gut microbiome also provide important immune and protective functions. Except for chewing, swallowing, and defecation of solid wastes, the movements of the digestive system (peristalsis) are all controlled by hormones and the autonomic nervous system.

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FIGURE 37.1

Structures of the Digestive System. (From Patton KT, Thibodeau GA: The human body in health & disease, ed 7, St Louis, 2018, Elsevier.)

Food breakdown begins in the mouth with chewing and continues in the stomach, where food is churned and mixed with acid, mucus, and enzymes. From the stomach, the fluid and partially digested food pass into the small intestine, where bile and enzymes secreted by the intestinal cells, liver, gallbladder, and exocrine pancreas break it down into absorbable components of proteins, carbohydrates, and fats. These nutrients pass through the walls of the small intestine into blood and lymphatic vessels, which carry them to the liver for storage or further processing. Ingested substances and secretions not absorbed in the small intestine pass into the large intestine, where fluid continues to be absorbed. Fluid wastes travel to the kidneys and are eliminated in the urine. Solid wastes pass into the rectum and are eliminated from the body through the anus. Aging can alter the structure and function of the gastrointestinal tract (see Geriatric Considerations: Aging & the Digestive System).

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The Gastrointestinal Tract The gastrointestinal tract (alimentary canal) is a single, hollow tube that consists of the mouth, esophagus, stomach, small intestine, large intestine, rectum, and anus (see Fig. 37.1). It carries out these digestive processes: 1. Ingestion of food 2. Propulsion of food and wastes from the mouth to the anus 3. Secretion of mucus, water, and enzymes 4. Mechanical digestion of food particles 5. Chemical digestion of food particles 6. Absorption of digested food 7. Elimination of waste products by defecation 8. Immune and microbial protection against infection Histologically, the GI tract consists of four layers. From the inside out they are the mucosa, submucosa, muscularis, and serosa or adventitia (Fig. 37.2). These concentric layers vary in thickness, and each layer has sublayers. A network of intrinsic nerves that controls mobility, secretion, sensation, and blood flow is located solely within the GI tract and controlled by local and autonomic nervous system stimuli through the enteric (intramural) plexus located in different layers of the gastrointestinal walls (see Fig. 37.2).

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FIGURE 37.2 Wall of the Gastrointestinal Tract. The wall of the gastrointestinal tract is made up of four layers with a network of nerves between the layers. This generalized diagram shows a segment of the gastrointestinal tract. Note that the serosa is continuous with a fold of serous membrane called the mesentery. Note also that digestive glands may empty their products into the lumen of the gastrointestinal tract by way of ducts. (From Patton KT: Anatomy & physiology, ed 10, St Louis, 2019, Elsevier.)

Mouth and Esophagus The mouth is the site for mastication (chewing) and mixing of food with saliva. There are 32 permanent teeth in the adult mouth, and they are important for speech and mastication. As food particles become smaller and move around in the mouth, taste buds are continuously stimulated, adding to the satisfaction of eating. The tongue's surface and soft palate have thousands of taste buds that contain taste receptors. These can distinguish salty, sour, bitter, sweet, and savory (umami) tastes. Tastes and food odors, which stimulate the olfactory nerve, help to initiate salivation and the secretion of gastric juice in the stomach.

Salivation The three pairs of salivary glands—the submandibular, sublingual, and parotid glands (Fig. 37.3)—secrete about 1 L of saliva per day. Saliva consists mostly of water with mucus, sodium, bicarbonate, chloride, potassium, and salivary α-amylase (ptyalin), an enzyme that initiates carbohydrate digestion in the mouth and stomach.

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FIGURE 37.3

Salivary Glands. (From Patton KT, Thibodeau GA: The human body in health & disease, ed 7, St Louis, 2018, Elsevier.)

The composition of saliva and other gastric juices depends on the rate of secretion (Fig. 37.4, A). Aldosterone can increase the epithelial exchange of sodium for potassium, increasing sodium conservation and potassium excretion. The bicarbonate concentration of saliva sustains a pH of about 7.4, which neutralizes bacterial acids and prevents tooth decay. Saliva also contains mucin, immunoglobulin A (IgA), and other antimicrobial substances, which help prevent infection. Mucin provides lubrication. Exogenous fluoride (e.g., fluoride in drinking water) is also secreted in the saliva, providing additional protection against tooth decay.

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FIGURE 37.4

Electrolyte Concentrations and Flow Rate. A, Saliva. Changes in the concentrations of

sodium (Na+), potassium (K+), chloride (Cl−), and bicarbonate (

) increase the flow rate of saliva. At

low rates of salivary flow (e.g., between meals), Na+, Cl−, and are reabsorbed in the collecting ducts of the salivary glands and the saliva contains fewer of these electrolytes (i.e., is more hypotonic). At higher flow rates (e.g., when stimulated by food), reabsorption decreases and saliva is hypertonic. By this mechanism, Na+, Cl−, and

are recycled until they are released to help with digestion and absorption. B, Gastric juice. The Na+ concentration is lower in the gastric juice than in the plasma, whereas the hydrogen (H+), potassium (K+), and Cl− concentrations are higher.

Both the sympathetic and parasympathetic divisions of the autonomic nervous system control salivation. Cholinergic parasympathetic fibers stimulate the salivary glands, and atropine (an anticholinergic agent) inhibits salivation and makes the mouth dry. βAdrenergic stimulation from sympathetic fibers also increases salivary secretion. Salivary gland secretion is not regulated by hormones.

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Swallowing The esophagus is a hollow, muscular tube approximately 25 cm long that conducts substances from the oropharynx to the stomach (see Fig. 37.1). Swallowed food is moved to the stomach by peristalsis, the coordinated, sequential contraction and relaxation of outer longitudinal and inner circular layers of muscles. The pharynx and upper third of the esophagus contain striated muscle (voluntary) that is directly innervated by skeletal motor neurons that control swallowing. The lower two thirds contain smooth muscle (involuntary) that is innervated by preganglionic cholinergic fibers from the vagus nerve. The fibers are activated in a downward sequence and coordinated by the swallowing center in the medulla. Peristalsis is stimulated when afferent fibers distributed along the length of the esophagus sense changes in wall tension caused by stretching as food passes. The greater the tension, the greater the intensity of esophageal contraction. Occasionally, intense contractions cause pain similar to “heartburn” or angina. Each end of the esophagus is opened and closed by a sphincter. The upper esophageal sphincter prevents air from entering the esophagus during respiration. The lower esophageal sphincter (cardiac sphincter) prevents regurgitation from the stomach and caustic injury to the esophagus. Swallowing is coordinated primarily by the swallowing center in the medulla. During the oropharyngeal (voluntary) phase, which takes place in less than 1 second, the following steps occur: 1. Food is segmented into a bolus by the tongue and forced posteriorly toward the pharynx. 2. The superior constrictor muscle of the pharynx contracts so the food cannot move into the nasopharynx. 3. Respiration is inhibited, and the epiglottis slides down to prevent the food from entering the larynx and trachea. The esophageal (involuntary) phase takes 5 to 10 seconds and proceeds as follows: 1. The bolus of food enters the esophagus. 2. Waves of relaxation travel the esophagus, preparing for the movement of the bolus. 3. Peristalsis, the sequential waves of muscular contractions that travel down the esophagus, transports the food to the lower esophageal sphincter, which is relaxed at that point. The bolus moves at 2 to 6 cm/sec. 4. The bolus enters the stomach, and the sphincter muscles return to their resting tone. Peristalsis that immediately follows the oropharyngeal phase of swallowing is called primary peristalsis. If a bolus of food becomes stuck in the esophageal lumen, secondary peristalsis—a wave of contraction and relaxation independent of voluntary swallowing— occurs. This is in response to stretch receptors stimulated by increased wall tension, which activate impulses from the swallowing center of the brain. The muscle tone of the lower esophageal sphincter changes with neural and hormonal stimulation and relaxes with swallowing. Cholinergic vagal input and the digestive hormone gastrin increase sphincter tone. Nonadrenergic, noncholinergic vagal impulses

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relax the lower esophageal sphincter, as do the hormones progesterone, secretin, and glucagon.1

Quick Check 37.1 1. What are the functions of saliva? 2. What are the phases of swallowing and how are they controlled?

Stomach The stomach is a hollow, muscular organ just below the diaphragm (Fig. 37.5) that stores food during eating, secretes digestive juices, mixes food with these juices, and propels partially digested food, called chyme, into the duodenum of the small intestine. Functional areas are the fundus (upper portion), body (middle portion), and antrum (lower portion). Its major anatomic boundaries are:

FIGURE 37.5 The Stomach. A portion of the anterior wall has been excised to reveal the muscle layers of the stomach wall. Note that the mucosa lining the stomach forms folds called rugae. The dashed lines distinguish the fundus, body, and antrum of the stomach. (Modified from Patton KT, Thibodeau GA: The human body in health & disease, ed 7, St Louis, 2018, Elsevier.)

• The lower esophageal sphincter, where food passes through the cardiac orifice at the gastroesophageal junction into the stomach. • The pyloric sphincter, which relaxes as food is propelled through the pylorus (gastroduodenal junction) into the duodenum.

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The stomach has three layers of smooth muscle: an outer, longitudinal layer; a middle, circular layer; and an inner, oblique layer (the most prominent) (see Fig. 37.5). These layers become progressively thicker in the body and antrum where food is mixed and pushed into the duodenum. The interior of the stomach is lined with mucosa. When the stomach is empty, this mucosal layer sits in folds called rugae. Few substances are absorbed in the stomach. The stomach mucosa is impermeable to water but can absorb alcohol and aspirin because they are lipid soluble. The stomach's blood supply comes from a branch of the celiac artery (Fig. 37.6) and is so abundant that nearly all arterial vessels would need to be blocked before ischemic changes occur in the stomach wall. A series of small veins drain blood from the stomach toward the hepatic portal vein.

FIGURE 37.6 Major Blood Vessels and Organs Supplied With Blood in the Splanchnic Circulation. Numbers in parentheses reflect approximate blood flow values (ml/min) for each major vessel in an 80-kg (176 lb) normal, resting, adult human. Arrows indicate the direction of blood flow. (Modified from Johnson LR: Gastrointestinal pathophysiology, St Louis, 2001, Mosby.)

The sympathetic and parasympathetic divisions of the autonomic nervous system innervate the stomach. Some of the autonomic fibers are extrinsic—that is, they originate outside the stomach and are controlled by nerve centers in the brain. The vagus nerve provides parasympathetic innervation and branches of the celiac plexus innervate the stomach sympathetically. The myenteric (Auerbach) plexus and submucosal (Meissner) plexus are intrinsic and part of the enteric (intramural) nervous system. They originate within the stomach and respond to local stimuli.

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In its resting state, the stomach is small and contains about 50 ml of fluid. There is minimal wall tension, and the muscle layers in the fundus contract very little. Swallowing causes the fundus to relax (receptive relaxation) to receive a bolus of food from the esophagus. Relaxation is coordinated by efferent, nonadrenergic, noncholinergic vagal fibers and is facilitated by two polypeptide hormones secreted by the gastrointestinal mucosa—gastrin and cholecystokinin. (The actions of digestive hormones are summarized in Table 37.1.) Food is stored in vertical or oblique layers as it arrives in the fundus, whereas fluids flow relatively quickly down to the antrum. TABLE 37.1 Selected Hormones* and Neurotransmitters of the Digestive System Hormone/Neuro Transmitter Mucosa Gastrin of the stomach Histamine Somatostatin Source

Stimulus for Secretion

Action

Presence of partially digested proteins in the stomach

Stimulates gastric glands to secrete hydrochloric acid, pepsinogen, and histamine; growth of gastric mucosa Gastrin Stimulates acid secretion Acid in stomach Inhibits acid, pepsinogen, and histamine secretion and release of gastrin Acetylcholine Vagus and local nerves in stomach Stimulates release of pepsinogen and acid secretion Gastrin-releasing Vagus and local nerves in stomach Stimulates gastrin and release of pepsinogen peptide (bombesin) and acid secretion Ghrelin High during fasting Stimulates growth hormone secretion and hypothalamus to increase appetite Mucosa Motilin Presence of acid and fat in the duodenum Increases gastrointestinal motility of the Secretin Presence of chyme (acid, partially digested Stimulates pancreas to secrete alkaline small proteins, fats) in duodenum pancreatic juice and liver to secrete bile; intestine decreases gastrointestinal motility; inhibits gastrin and gastric acid secretion Serotonin (5Intestinal distention; vagal stimulation; Stimulates intestinal secretion, motility and hydroxytryptamine) presence of acids, amino acids, or sensation (i.e., pain and nausea), hypertonic fluids; released from vasodilation; activates gut immune enterochromaffin cells throughout responses intestine Cholecystokinin Presence of chyme (acid, partially digested Stimulates gallbladder to eject bile and proteins, fats) in duodenum pancreas to secrete alkaline fluid; decreases gastric motility; constricts pyloric sphincter; inhibits gastrin Enteroglucagon Intraluminal fats and carbohydrates Weakly inhibits gastric and pancreatic secretion and enhances insulin release, lipolysis, ketogenesis, and glycogenolysis Gastric inhibitory Fat and glucose in the small intestine Inhibits gastric secretion and emptying; peptide (GIP) stimulates insulin release Peptide YY Intraluminal fat and bile acids Inhibits postprandial gastric acid and pancreatic secretion and delays gastric and small bowel emptying Pancreatic Protein, fat, and glucose in the small Decreases pancreatic bicarbonate and polypeptide intestine enzyme secretion Vasoactive Intestinal mucosa and muscle Relaxes intestinal smooth muscle intestinal peptide *The

digestive hormones are not secreted into the gastrointestinal lumen, but rather into the bloodstream, where they travel to target tissues. Multiple peptide hormone genes and more than 100 hormonally active peptides are expressed in the gastrointestinal tract. Modified from Johnson LR: Gastrointestinal physiology, ed 8, St Louis, 2014, Mosby. Data from Feldman M et al:

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Sleisenger and Fordtran's gastrointestinal and liver disease, ed 10, Philadelphia, 2015, Saunders.

Gastric (stomach) motility increases with the initiation of peristaltic waves, which sweep over the body of the stomach toward the antrum. The rate of peristaltic contractions is approximately three per minute and is influenced by neural and hormonal activity. Gastrin, motilin (an intestinal hormone), and the vagus nerve increase the rate of contraction by lowering the threshold potential of muscle fibers. (The neural and biochemical mechanisms of muscle contraction are described in Chapter 40.) Sympathetic activity and secretin (another intestinal hormone) are inhibitory and raise the threshold potential. The rate of peristalsis is mediated by pacemaker cells that initiate a wave of depolarization (basic electrical rhythm), which moves from the upper part of the stomach to the pylorus. Gastric mixing and emptying of chyme from the stomach take several hours. Mixing occurs as food is propelled toward the antrum. As food approaches the pylorus, the velocity of the peristaltic wave increases. This forces the contents back toward the body of the stomach. This retropulsion effectively mixes food with digestive juices, and the oscillating motion breaks down large food particles. With each peristaltic wave, a small portion of the chyme passes through the pylorus and into the duodenum. The pyloric sphincter is about 1.5 cm long and is always open about 2 mm. It opens wider during contraction of the antrum. Normally there is no regurgitation from the duodenum into the antrum. The rate of gastric emptying (movement of chyme into the duodenum) depends on the volume, osmotic pressure, and chemical composition of the gastric contents. Larger volumes of food increase gastric pressure, peristalsis, and rate of emptying. Solids, fats, and nonisotonic solutions (i.e., hypertonic or hypotonic gastric tube feedings) delay gastric emptying. (Osmotic pressure and tonicity are described in Chapters 1 and 5.) Products of fat digestion, which are formed in the duodenum by the action of bile from the liver and enzymes from the pancreas, stimulate the secretion of cholecystokinin. This hormone inhibits food intake, reduces gastric motility, and decreases gastric emptying so that fats are not emptied into the duodenum at a rate that exceeds the rate of bile and enzyme secretion. Osmoreceptors in the wall of the duodenum are sensitive to the osmotic pressure of duodenal contents. The arrival of hypertonic or hypotonic gastric contents activates the osmoreceptors, which delay gastric emptying to facilitate formation of an isosmotic duodenal environment. The rate at which acid enters the duodenum also influences gastric emptying. Secretions from the pancreas, liver, and duodenal mucosa neutralize gastric hydrochloric acid in the duodenum. The rate of emptying is adjusted to the duodenum's ability to neutralize the incoming acidity.2

Gastric Secretion The stomach secretes large volumes of gastric juices or gastric secretions, including acid, pepsinogen, mucus, enzymes, hormones, intrinsic factor, and gastroferrin. Intrinsic factor is necessary for the intestinal absorption of vitamin B12, and gastroferrin facilitates the absorption of iron in the small intestine. The hormones are secreted into the blood and travel to target tissues. The other gastric secretions are released directly into the stomach lumen.3 Gastric secretion is stimulated by the process of eating (gastric distention), by the actions of the hormone gastrin and paracrine pathways (e.g., histamine, ghrelin, somatostatin), and by the effects of the neurotransmitter acetylcholine and other chemicals (e.g., ethanol,

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coffee, protein). The secretion of gastric juice is influenced by numerous stimuli that together facilitate the process of digestion. There are three phases of gastric secretion, all of which promote the secretion of acid by the stomach:

• Cephalic phase—stimulated by the thought, smell, and taste of food • Gastric phase—stimulated by distention of the stomach • Intestinal phase—stimulated by histamine and digested protein In the fundus and body of the stomach, the gastric glands of the mucosa are the primary secretory units (Fig. 37.7). The composition of gastric juice depends on volume and flow rate (see Fig. 37.4, B). The potassium level remains relatively constant, but its concentration is greater in gastric juice than in plasma. The rate of secretion varies with the time of day. Generally, the rate and volume of secretion are lowest in the morning and highest in the afternoon and evening. Loss of gastric juices through vomiting, drainage, or suction may decrease body stores of sodium and potassium and result in fluid, electrolyte (e.g., hyponatremia, hypokalemia, dehydration), and acid-base imbalances (e.g., metabolic alkalosis)4 (see Chapter 5).

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FIGURE 37.7 Gastric Pits and Gastric Glands. Gastric pits are depressions in the epithelial lining of the stomach. At the bottom of each pit are one or more tubular gastric glands. Chief cells produce pepsinogen, which is converted to pepsin (a proteolytic enzyme); parietal cells secrete hydrochloric acid and intrinsic factor; G cells produce gastrin; endocrine cells (enterochromaffin-like cells and D cells) secrete histamine and somatostatin. (From Patton KT, et al: Essentials of anatomy & physiology, St Louis, 2012, Mosby.)

Gastric secretion is inhibited by somatostatin, by unpleasant odors and tastes, and by rage, fear, or pain. A discharge of sympathetic impulses inhibits parasympathetic impulses. Increased secretions are associated with aggression or hostility and may contribute to some forms of gastric pathology. Acid. The major functions of gastric hydrochloric acid are to dissolve food fibers, act as a bactericide against swallowed microorganisms, and convert pepsinogen to pepsin. The production of acid by the parietal cells requires the transport of hydrogen and chloride from the parietal cells to the stomach lumen. Acid is formed in the parietal cells, primarily through the hydrolysis of water (Fig. 37.8). At a high rate of gastric secretion, bicarbonate moves into the plasma, producing an “alkaline tide” in the venous blood, which also may result in a more alkaline urine.4

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FIGURE 37.8

Hydrochloric Acid Secretion by Parietal Cell.

Acid secretion is stimulated by the vagus nerve, which releases acetylcholine and stimulates the secretion of gastrin; gastrin then stimulates the release of histamine from enterochromaffin cells (mast cells; see Chapter 6) in the gastric mucosa. Histamine stimulates acid secretion by activating histamine receptors (H2 receptors) on acid-secreting parietal cells. Caffeine, calcium, and ghrelin also stimulate acid secretion. Acid secretion is inhibited by somatostatin, secretin, and other intestinal hormones.3 Pepsin. Acetylcholine, gastrin, and secretin stimulate the chief cells to release pepsinogen during eating. Pepsinogen is quickly converted to pepsin in the acidic gastric environment (optimum pH for pepsin activation = 2). Pepsin is a proteolytic enzyme—that is, it breaks down protein and forms polypeptides in the stomach. Once chyme has entered the duodenum, the alkaline environment of the duodenum inactivates pepsin. Mucus. The gastric mucosa is protected from the digestive actions of acid and pepsin by intercellular tight junctions, a coating of mucus called the mucosal barrier, and gastric mucosal blood flow. Prostaglandins protect the mucosal barrier by stimulating the secretion of mucus and bicarbonate and by inhibiting the secretion of acid. A break in the protective barrier may occur from ischemia or by exposure to Helicobacter pylori, aspirin, nonsteroidal antiinflammatory drugs (inhibit prostaglandin synthesis), ethanol, or regurgitated bile. Breaks cause inflammation and ulceration.

Quick Check 37.2 1. Why are there three layers of stomach muscle? 2. What hormones stimulate gastric motility? 3. What are the phases of gastric secretion?

Small Intestine The small intestine is coiled within the peritoneal cavity and is about 5 to 6 meters long.

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Functionally, it is divided into three segments: the duodenum, jejunum, and ileum (Fig. 37.9, A). The duodenum begins at the pylorus and ends where it joins the jejunum at a suspensory ligament called the Treitz ligament. The end of the jejunum and the beginning of the ileum are not distinguished by an anatomic marker. These structures are not grossly different, but the jejunum has a slightly larger lumen than the ileum. The ileocecal valve, or sphincter, controls the flow of digested material from the ileum into the large intestine and prevents reflux into the small intestine.

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FIGURE 37.9 The Small Intestine. A, Segments of the small intestine. Inserts show longitudinal sections of the duodenum, jejunum, and ileum. B, Anatomy of a villus. Arrows show migration and then shedding of epithelial cells.

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The duodenum lies behind the peritoneum, or retroperitoneally, and is attached to the posterior abdominal wall. The peritoneum is the serous membrane surrounding the organs of the abdomen and pelvic cavity. It is analogous to the pericardium around the heart and the pleura around the lungs. The visceral peritoneum lies on the surface of the organs, and the parietal peritoneum lines the wall of the body cavity. The space between these two layers is called the peritoneal cavity and normally contains just enough fluid to lubricate the two layers and prevent friction during organ movement. The ileum and jejunum are suspended in loose folds from the posterior abdominal wall by a peritoneal membrane called the mesentery. The mesentery facilitates intestinal motility and supports blood vessels, nerves, and lymphatics. The arterial supply to the duodenum arises primarily from the gastroduodenal artery, a branch of the celiac artery. The jejunum and ileum are supplied by branches of the superior mesenteric artery (see Fig. 37.6). The superior mesenteric vein drains blood from the entire small intestine and empties into the hepatic portal circulation. The regional lymph nodes and lymphatics drain into the thoracic duct, which empties into the subclavian vein. Enteric nerves from both divisions of the autonomic nervous system innervate the small intestine.5 Secretion, motility, pain sensation, and intestinal reflexes (e.g., relaxation of the lower esophageal sphincter) are mediated parasympathetically by the vagus nerve. Sympathetic activity inhibits motility and produces vasoconstriction. Intrinsic reflexive activity is mediated by the myenteric (Auerbach) plexus and the submucosal (Meissner) plexus of the enteric nervous system. The smooth muscles of the small intestine are arranged in two layers: a longitudinal outer layer and a thicker inner circular layer (see Figs. 37.2 and 37.9, A). Circular folds of the small intestine slow the passage of food, thereby providing more time for digestion and absorption. The folds are most numerous and prominent in the jejunum and proximal ileum (see Fig. 37.9, A). Absorption occurs through villi (sing., villus), which cover the circular folds and are the functional units of the intestine. A villus is composed of absorptive columnar cells (enterocytes) and mucus-secreting goblet cells of the mucosal epithelium (see Fig. 37.9, B). Each villus secretes some of the enzymes necessary for digestion and absorbs nutrients. Near the surface, columnar cells closely adhere to each other at sites called tight junctions. Water and electrolytes are absorbed through these intercellular spaces. The surface of each columnar epithelial cell on the villus contains tiny projections called microvilli (sing., microvillus). Together the microvilli create a mucosal surface known as the brush border. The villi and microvilli greatly increase the surface area available for absorption. Coating the brush border is an “unstirred” layer of water that is important for the absorption of water-soluble substances including emulsified micelles of fat. The lamina propria (a connective tissue layer of the mucous membrane) lies beneath the epithelial cells of the villi and contains lymphocytes and plasma cells, which produce immunoglobulins (see The Gastrointestinal Tract and Immunity section). Central arterioles ascend within each villus and branch into a capillary array that extends around the base of the columnar cells and cascades down to the venules that lead to the hepatic portal circulation. A central lacteal, or lymphatic capillary, also is contained within each villus and is important for the absorption and transport of fat molecules (see Fig. 37.9, B). The contents of the lacteals flow to regional nodes and channels that eventually drain into the thoracic duct. Between the bases of the villi are the crypts of Lieberkühn, which extend to the

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submucosal layer. Undifferentiated cells arise from stem cells at the base of the crypt and move toward the tip of the villus, maturing to become columnar epithelial secretory cells (water, electrolytes, and enzymes) and goblet cells (mucus). After completing their migration to the tip of the villus, they function for a few days and then are shed into the intestinal lumen and digested. Discarded epithelial cells are an important source of endogenous protein. The entire epithelial population is replaced about every 4 to 7 days. Many factors can influence this process of cellular proliferation. Starvation, vitamin B12 deficiency, and cytotoxic drugs or irradiation suppress cell division and shorten the villi. Decreased absorption across the epithelial membrane can cause diarrhea and malnutrition. Nutrient intake and intestinal resection stimulate cell production.

Intestinal Digestion and Absorption The process of digestion is initiated in the stomach by the actions of gastric hydrochloric acid and pepsin. The chyme that passes into the duodenum is a liquid with small particles of undigested food. Digestion of food components continues in the proximal portion of the small intestine by the action of pancreatic enzymes, intestinal enzymes, and bile salts. As seen in Fig. 37.10, in the proximal small intestine:

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FIGURE 37.10

Digestion and Absorption of Food.

• carbohydrates are broken down to monosaccharides and disaccharides, • proteins are degraded further to amino acids and peptides, and • fats are emulsified and reduced to fatty acids (Box 37.1) and monoglycerides. Box 37.1

Dietary Fat Saturated Fatty Acid (Palmitic Acid [C16H32O2]) Each carbon atom in the chain is linked by single bonds to adjacent carbon and hydrogen atoms; atoms are solid at room temperature and found in animal fat and tropical oils (coconut and palm oils); they increase the blood levels of low-density lipoprotein (LDL) cholesterol (“bad” cholesterol) and also the risk of coronary artery disease.

Unsaturated Fatty Acid Unsaturated fatty acids are soft or liquid at room temperature; omega-6 fatty acids are found in plants and vegetables (olive, canola, and peanut oils), and omega-3 fatty acids are found in fish and shellfish. • Monounsaturated fatty acids (e.g., oleic acid [C18H34O2]): Contain one double bond in the carbon chain and are found in plants and animals; may be beneficial in reducing blood cholesterol, glucose levels, and systolic blood pressure; do not lower high-density lipoprotein (HDL) cholesterol (“good” cholesterol) level; low HDL levels have been associated with coronary heart disease. • Polyunsaturated fatty acids (e.g., linoleic acid [C18H32O2]): Contain two or more double bonds in the carbon chain and are found in plants and fish oils; omega-6 fatty acids lower total and LDL cholesterol blood levels; high levels of polyunsaturated fatty acids may lower the LDL level; omega-3 fatty acids lower blood triglyceride levels, reduce platelet aggregation and blood-clotting tendencies, are necessary for growth and development, and may prevent coronary artery disease, hypertension, cancer, and inflammatory and immune disorders. These nutrients, along with water, vitamins, and electrolytes, are absorbed across the intestinal mucosa by active transport, diffusion, or facilitated diffusion. Products of carbohydrate and protein breakdown move into villus capillaries and then to the liver through the hepatic portal vein. Digested fats move into the lacteals and reach the liver

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through the portal and systemic circulation. These components are metabolized within the liver (see the Metabolism of Nutrients section). Intestinal motility exposes nutrients to a large mucosal surface area by mixing chyme and moving it through the lumen. Different segments of the GI tract absorb different nutrients. Digestion and absorption of all major nutrients and many drugs occur in the small intestine. Sites of absorption are shown in Fig. 37.11. Box 37.2 outlines the major nutrients involved in this process.

FIGURE 37.11

Sites of Absorption of Major Nutrients. (Modified from Patton KT: Anatomy & physiology, ed 10, St Louis, 2019, Elsevier.)

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Box 37.2

Major Nutrients Absorbed in the Small Intestine Water and Electrolytes • Approximately 85% to 90% of the water that enters the gastrointestinal tract is absorbed in the small intestine. • Sodium passes through tight junctions and is actively transported across cell membranes; it is exchanged for bicarbonate to maintain electroneutrality in the ileum; sodium absorption is enhanced by cotransport with glucose. • Potassium moves passively across tight junctions with changes in the electrochemical gradient.

Carbohydrates • Only monosaccharides are absorbed by the intestinal mucosa; therefore complex carbohydrates must be hydrolyzed to the simplest form. • Salivary and pancreatic amylases break down starches to oligosaccharides (lactose, maltose, sucrose) in the stomach and duodenum; brush-border enzymes hydrolyze them in the small intestine so they can pass through the unstirred water layer by diffusion. • Fructose diffuses into the bloodstream; glucose and galactose diffuse or are actively transported. • Cellulose remains undigested and stimulates large intestine motility.

Proteins • From 90% to 95% of protein is absorbed; major hydrolysis is accomplished in the small intestine by the pancreatic enzymes trypsin, chymotrypsin, and carboxypeptidase. • Brush-border enzymes break down proteins into smaller peptides that can cross cell membranes. In the cytosol, they are metabolized into amino acids, specifically neutral amino acids, basic amino acids, and proline and hydroxyproline.

Fats Digestion and absorption occur in four phases: • Phase 1—Emulsification and lipolysis: Emulsifying agents (bile salts) cover small fat particles and prevent them from reforming into fat droplets; then lipolysis with pancreatic lipases divides them into monoglycerides and free fatty acids. • Phase 2—Micelle formation: A spherical formation of lipid products that are water soluble. • Phase 3—Fat absorption: Fat products move from micelles to the absorbing surface of

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the intestinal epithelium and enter enterocytes. • Phase 4—Triglycerides are resynthesized and, along with cholesterol, fat-soluble vitamins and phospholipids, combine with proteins to form chylomicrons (lipoproteins). Chylomicrons leave the enterocyte, enter the lymphatics, and travel to the portal circulation.

Minerals • Calcium—absorbed by passive diffusion and transported actively across cell membranes bound to a carrier protein; absorption primarily in the ileum. • Magnesium—50% absorbed by active transport or passive diffusion in the jejunum and ileum. • Phosphate—absorbed by passive diffusion and active transport in the small intestine. • Iron—absorbed by epithelial cells of the duodenum and jejunum; vitamin C facilitates.

Vitamins • Absorbed mainly by sodium-dependent active transport, with vitamin B12 bound to intrinsic factor and absorbed in the terminal ileum.

Intestinal Motility The movements of the small intestine facilitate digestion and absorption.5 Chyme leaving the stomach and entering the duodenum stimulates intestinal movements that help blend secretions from the liver, gallbladder, pancreas, and intestinal glands. A churning motion brings the luminal contents into contact with the absorbing cells of the villi. Propulsive movements then advance the chyme toward the large intestine. Intestinal motility is affected by the following two movements:

• Segmentation. Localized rhythmic contractions of circular smooth muscles divide and mix the chyme, enabling it to have contact with digestive enzymes and the absorbent mucosal surface, and then propel it toward the large intestine. • Peristalsis. Waves of contraction along short segments of longitudinal smooth muscle allow time for digestion and absorption. The intestinal villi move with contractions of the muscularis mucosae, a thin layer of muscle separating the mucosa and submucosa, with absorption promoted by the swaying of the villi in the luminal contents. Neural reflexes along the length of the small intestine facilitate motility, digestion, and

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absorption. The ileogastric reflex inhibits gastric motility when the ileum becomes distended. This prevents the continued movement of chyme into an already distended intestine. The intestinointestinal reflex inhibits intestinal motility when one part of the intestine is overdistended. Both of these reflexes require extrinsic innervation. The gastroileal reflex, which is activated by an increase in gastric motility and secretion, stimulates an increase in ileal motility and relaxation of the ileocecal valve. This empties the ileum and prepares it to receive more chyme. The gastroileal reflex is probably regulated by the hormones gastrin and cholecystokinin. During prolonged fasting or between meals, particularly overnight, slow waves sweep along the entire length of the intestinal tract from the stomach to the terminal ileum. This interdigestive myoelectric complex appears to propel residual gastric and intestinal contents into the colon. The ileocecal valve (sphincter) marks the junction between the terminal ileum and the large intestine. This valve is intrinsically regulated and is normally closed. The arrival of peristaltic waves from the last few centimeters of the ileum causes the ileocecal valve to open, allowing a small amount of chyme to pass. Distention of the upper large intestine causes the sphincter to constrict, preventing further distention or retrograde flow of intestinal contents.

Quick Check 37.3 1. What cells arise from the crypts of Lieberkühn? 2. How are fats absorbed from the small intestine? 3. Which reflexes inhibit intestinal motility? Which promote it?

Large Intestine The large intestine is approximately 1.5 meters long and consists of the cecum, appendix, colon, rectum, and anal canal (Fig. 37.12, A). The cecum is a pouch that receives chyme from the ileum. Attached to it is the vermiform appendix, an appendage having limited physiologic function. However, recent studies suggest it may have an important protective role in gut immunity.6 From the cecum, chyme enters the colon, which loops upward, traverses the abdominal cavity, and descends to the anal canal. The four parts of the colon are the ascending colon, transverse colon, descending colon, and sigmoid colon. Two sphincters control the flow of intestinal contents through the cecum and colon: the ileocecal valve, which admits chyme from the ileum to the cecum; and the rectosigmoid canal, which controls the movement of wastes from the sigmoid colon into the rectum. A thick (2.5 to 3 cm) portion of smooth muscle surrounds the anal canal, forming the internal anal sphincter. Overlapping it distally is the striated skeletal muscle of the external anal sphincter (anus).

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FIGURE 37.12 The Large Intestine. A, Structure of the large intestine. B, Microscopic cross section illustrating cellular structures of the large intestine. The wall of the large intestine is lined with columnar epithelium, in contrast to the villi characteristics of the small intestine. The longitudinal layer of muscularis is reduced to become the teniae coli. (A modified from Patton KT, Thibodeau GA: The human body in health & disease, ed 7, St Louis, 2018, Mosby; B from Gartner LP, Hiatt JL: Color textbook of histology, ed 3, Philadelphia, 2007, Saunders.)

In the cecum and colon, the longitudinal muscle layer consists of three longitudinal bands called teniae coli (see Fig. 37.12, B). They are shorter than the colon and give it a gathered appearance. The circular muscles of the colon separate the gathers into outpouchings called haustra (sing., haustrum). The haustra become more or less prominent with the contractions and relaxations of the circular muscles. The mucosal surface of the colon has rugae (folds), particularly between the haustra, and crypts of Lieberkühn but no villi. Columnar epithelial cells and mucus-secreting goblet cells form the mucosa throughout the large intestine. The columnar epithelium absorbs fluid and electrolytes, and the mucus-secreting cells lubricate the mucosa. In the large intestine, extrinsic parasympathetic innervation occurs through the vagus nerve. Vagal stimulation increases rhythmic contraction of the proximal colon from the cecum to the first part of the transverse colon. Vagal fibers reach the distal colon through the sacral parasympathetic splanchnic nerves. The internal anal sphincter is usually contracted, and its reflex response is to relax when the rectum is distended. The intrinsic myenteric plexus provides the major innervation of the internal anal sphincter, but responds to sympathetic stimulation to maintain contraction and parasympathetic stimulation that facilitates relaxation when the rectum is full. Sympathetic innervation of this sphincter arises from the celiac and superior mesenteric ganglia and the sphincter nerve. The external anal sphincter is innervated by the pudendal nerve arising from sacral levels of the spinal cord. Sympathetic activity in the entire large intestine modulates intestinal reflexes, conveys somatic sensations of fullness and pain, participates in the defecation reflex, and constricts blood vessels. The blood supply of the large intestine and rectum is derived primarily from branches of the superior and inferior mesenteric arteries7 (see Figs. 37.6 and 37.12, A) and venous blood drains through the inferior mesenteric vein. The primary type of colonic movement is segmental. The circular muscles contract and relax at different sites, shuttling the intestinal contents back and forth between the haustra,

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most commonly during fasting. The movements massage the intestinal contents, called the fecal mass at that point, and facilitate the absorption of water. Propulsive movement occurs with the proximal-to-distal contraction of several haustral units. Peristaltic movements also occur and promote the emptying of the colon. The gastrocolic reflex initiates propulsion in the entire colon, usually during or immediately after eating, when chyme enters from the ileum. The gastrocolic reflex causes the fecal mass to pass rapidly into the sigmoid colon and rectum, stimulating defecation. Gastrin may participate in stimulating this reflex. Epinephrine inhibits contractile activity, as do exogenous opioids. Approximately 500 to 700 ml of chyme flows from the ileum to the cecum per day. Most of the water is absorbed in the colon by diffusion and active transport. Aldosterone increases membrane permeability to sodium, thereby increasing both the diffusion of sodium into the cell and the active transport of sodium to the interstitial fluid. (See Chapters 5 and 20 for a discussion of aldosterone secretion.) The colon does not absorb monosaccharides and amino acids, but some short-chain free fatty acids, which are produced by fermentation, are absorbed. Absorption and epithelial transport occur in the cecum, ascending colon, transverse colon, and descending colon. By the time the fecal mass enters the sigmoid colon, the mass consists entirely of wastes, called the feces, and is composed of food residue, unabsorbed GI secretions, shed epithelial cells, and bacteria. The movement of feces into the sigmoid colon and rectum stimulates the defecation reflex (rectosphincteric reflex). The rectal wall stretches, and the tonically constricted internal anal sphincter (smooth muscle with autonomic nervous system control) relaxes, creating the urge to defecate. The defecation reflex can be overridden voluntarily by contraction of the external anal sphincter and muscles of the pelvic floor. The rectal wall gradually relaxes, reducing tension, and the urge to defecate passes. Retrograde contraction of the rectum may displace the feces out of the rectal vault until a more convenient time for evacuation. Pain or fear of pain associated with defecation (e.g., rectal fissures or hemorrhoids) can inhibit the defecation reflex. Squatting and sitting facilitate defecation because these positions straighten the angle between the rectum and anal canal and increase the efficiency of straining (increasing intraabdominal pressure). Intra-abdominal pressure is increased by initiating the Valsalva maneuver—that is, inhaling and forcing the diaphragm and chest muscles against the closed glottis to increase both intrathoracic and intra-abdominal pressure, which is transmitted to the rectum.

The Gastrointestinal Tract and Immunity The GI tract's gut-associated lymphoid tissue (GALT) plays a major role in immune defenses by killing many pathogenetic microorganisms and preventing reaction to foreign proteins (dietary antigens) ingested in the diet.8 The mucosa of the intestine covers a large surface area, and mucosal secretions produce antibodies, particularly IgA, and enzymes that provide defenses against microorganisms. Small intestinal Paneth cells, located near the base of the crypts of Lieberkühn (see Fig. 37.9, B), produce defensins and other antimicrobial peptides and lysozymes important to mucosal immunity. Small intestinal Peyer patches (lymph nodules containing collections of lymphocytes, plasma cells, and macrophages) are most numerous in the ileum and produce antimicrobial peptides and IgA as a component of GALT in the small intestine (see Figs. 37.2 and 7.3). Peyer patches are

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important for antigen processing and immune defense (see Chapter 7).

Intestinal Microbiome The type and number of bacterial flora vary greatly throughout the normal GI tract and among individuals. There are an increasing number of bacteria from the proximal to the distal GI tract, with the highest number in the colon. Genetics, diet, environmental pollution, personal hygiene, vaccination, infection, antibiotics and other drugs, and radiation affect the normal composition of bacterial flora. The intestinal bacteria do not have major digestive or absorptive functions, but they do play a role in the metabolism of bile salts, estrogens, androgens, lipids, carbohydrates, various nitrogenous substances, and drugs. They produce antimicrobial peptides, hormones, neurotransmitters, antiinflammatory metabolites, and vitamins; destroy toxins; prevent pathogen colonization; and alert the immune system to protect against infection. They are important to overall health and, when altered (dysbiosis) or translocated, they cause disease.9 The intestinal tract is sterile at birth but becomes colonized within a few hours. Within 3 to 4 weeks after birth, the normal flora are established. The number and diversity of bacteria decrease with aging, increasing the risk for infection. The normal flora do not have the virulence factors associated with pathogenic microorganisms, thus permitting immune tolerances. Bacteria in the stomach are relatively sparse because of the secretion of acid that kills ingested pathogens or inhibits bacterial growth (with the exception of H. pylori). Bile acid secretion, intestinal motility, and antibody production suppress bacterial growth in the duodenum. In the duodenum and jejunum, there is a low concentration of aerobes, primarily streptococci, lactobacilli, staphylococci, and other enteric bacteria. Anaerobes are found distal to the ileocecal valve but not proximal to the ileum. They constitute about 95% of the fecal flora in the colon and contribute one third of the solid bulk of feces. Bacteroides (gram negative) and Firmicutes (gram positive) are the most common colon bacteria.

Splanchnic Blood Flow The splanchnic (visceral) blood flow provides blood to the esophagus, stomach, small and large intestines, liver, gallbladder, pancreas, and spleen (see Fig. 37.6). Blood flow is regulated by cardiac output and blood volume, the autonomic nervous system, hormones, and local autoregulatory blood flow mechanisms. The GI circulation serves as an important reservoir of blood volume to maintain circulation to the heart and lungs when needed.

Quick Check 37.4 1. What is the major arterial blood supply to the large intestine? 2. What is the Valsalva maneuver? 3. What roles do bacterial flora play in the GI tract?

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Accessory Organs of Digestion The liver, gallbladder, and exocrine pancreas all secrete substances necessary for the digestion of chyme. These secretions are delivered to the duodenum through the sphincter of Oddi at the major duodenal papilla (of Vater) (Fig. 37.13). The liver produces bile, which contains salts necessary for fat digestion and absorption. Between meals, bile is stored in the gallbladder. The exocrine pancreas produces (1) enzymes needed for the complete digestion of carbohydrates, proteins, and fats; and (2) an alkaline fluid that neutralizes chyme, creating a duodenal pH that supports enzymatic action.

FIGURE 37.13

Accessory Organs of Digestion. Location of the liver, gallbladder, and exocrine pancreas.

The liver also receives nutrients absorbed by the small intestine and metabolizes or synthesizes them into forms that can be absorbed by the body's cells. It then releases the nutrients into the bloodstream or stores them for later use.

Liver The liver weighs 1200 to 1600 g. It is located under the right diaphragm and is divided into right and left lobes (Fig. 37.14). The larger, right lobe is divided further into the caudate and quadrate lobes. The falciform ligament separates the right and left lobes and attaches the liver to the anterior abdominal wall. The round ligament (ligamentum teres) extends along the free edge of the falciform ligament, extending from the umbilicus to the inferior surface of the

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liver. The coronary ligament branches from the falciform ligament and extends over the superior surface of the right and left lobes, binding the liver to the inferior surface of the diaphragm. The liver is covered by the Glisson capsule, which contains blood vessels, lymphatics, and nerves. When the liver is diseased or swollen, distention of the capsule causes pain because it is innervated by sensory neurons.

FIGURE 37.14 Gross Structure of the Liver. A, Anterior surface. B, Visceral surface. (From Applegate E: The anatomy and physiology learning system, ed 4, St Louis, 2011, Saunders.)

The metabolic functions of the liver require a large amount of blood. The liver receives blood from both arterial and venous sources. The hepatic artery is formed by the merging of superior mesenteric and splenic veins and receives blood from the inferior mesenteric, gastric, and cystic veins. It provides arterial oxygenated blood at the rate of about 400 to 500 ml/min or about 5% to 7% of the cardiac output (see Fig. 37.6). The hepatic portal vein receives deoxygenated blood from the inferior and superior mesenteric veins, the splenic vein, and the gastric and esophageal veins, and delivers about 1000 to 1500 ml/min to the liver. The hepatic portal vein, which carries 70% of the blood to the liver, is rich in nutrients that have been absorbed from the intestinal tract (Fig. 37.15).

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FIGURE 37.15 Hepatic Portal Circulation. In this unusual circulatory route, a vein is located between two capillary beds. The hepatic portal vein collects blood from capillaries in visceral structures located in the abdomen and empties into the liver. Hepatic veins return blood to the inferior vena cava. (From Herlihy B: The human body in health and illness, ed 5, St Louis, 2015, Saunders.)

Within the liver lobes are approximately 100,000 tiny anatomic units called liver lobules (Fig. 37.16). They are formed of cords or plates of hepatocytes, which are the functional cells of the liver. These cells can regenerate; therefore damaged or resected liver tissue can regrow. Small capillaries, or sinusoids, are located between the plates of hepatocytes. They receive a mixture of venous and arterial blood from branches of the hepatic artery and portal vein. Blood from the sinusoids drains to a central vein in the middle of each liver lobule. Venous blood from all the lobules then flows into the hepatic vein, which empties into the inferior vena cava. The sinusoids of the liver lobules are lined with highly permeable endothelium. This permeability enhances the transport of nutrients from the sinusoids into the hepatocytes, where they are metabolized.

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FIGURE 37.16 Schematic of the Liver Lobule. A cross section of a single liver lobule shows that, in whole, it is shaped like a hexagonal cylinder. The cut away area shows the central vein in the center of the lobule, separated by cords of hepatocytes forming sinusoids from six portal areas at the periphery. The portal areas contain a portal vein, hepatic artery, and bile duct. Blood flows toward the center of the lobule, whereas bile flows toward the portal triads at the margins. Note the hepatic artery providing oxygenated blood to the hepatic sinusoids. (From Polin RA, et al: Fetal and neonatal physiology, ed 4, St Louis, 2011, Saunders.)

The immune functions of the liver are carried out by various cells, including sinusoidal endothelial cells, Kupffer, stellate, and natural killer cells. Sinusoidal cells line the sinusoidal capillaries and, in addition to their barrier function, have immune functions including endocytosis, antigen presentation, and leukocyte recruitment. The sinusoids also are lined with phagocytic Kupffer cells (tissue macrophages) and are part of the mononuclear phagocyte system. Kupffer cells are important for healing injury to the liver, are bactericidal, and are important for bilirubin production and lipid metabolism. Stellate cells contain retinoids (vitamin A), are contractile in liver injury, regulate sinusoidal blood flow, may proliferate into myofibroblasts, participate in liver fibrosis, produce erythropoietin, can act as antigen-presenting cells, remove foreign substances from the blood, and trap bacteria. Natural killer cells (pit cells) also are found in the sinusoidal lumen; they produce interferon-γ and are important in tumor defense. Between the endothelial lining of the sinusoid and the hepatocyte is the Disse space, which drains interstitial fluid into the hepatic lymph system.

Secretion of Bile The liver assists intestinal digestion by secreting 700 to 1200 ml of bile per day. Bile is an

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alkaline, bitter-tasting, yellowish green fluid that contains bile salts (conjugated bile acids), cholesterol, bilirubin (a pigment), electrolytes, and water. It is formed by hepatocytes and secreted into the bile canaliculi. Bile canaliculi are small channels that conduct bile outward to bile ducts and eventually drain into the common bile duct (see Figs. 37.13 and 37.16). This duct empties bile into the ampulla of Vater, and then into the duodenum through an opening called the major duodenal papilla (sphincter of Oddi). Bile salts are required for the intestinal emulsification and absorption of fats, including fat-soluble vitamins. Having facilitated fat emulsification and absorption, most bile salts are actively absorbed in the terminal ileum and returned to the liver through the portal circulation for resecretion. The pathway for recycling of bile salts is termed the enterohepatic circulation (Fig. 37.17).

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FIGURE 37.17

Enterohepatic Circulation of Bile Salts.

Bile has two fractional components: the acid-dependent fraction and the acidindependent fraction. Hepatocytes secrete the bile acid–dependent fraction, which consists of bile acids, cholesterol, lecithin (a phospholipid), and bilirubin. The bile acid– independent fraction, which is secreted by the hepatocytes and epithelial cells of the bile canaliculi, is a bicarbonate-rich aqueous fluid that gives bile its alkaline pH and facilitates buffering of chyme entering the duodenum from the stomach. Bile salts are conjugated in the liver from primary and secondary bile acids. The primary bile acids are cholic acid and chenodeoxycholic (chenic) acid. These acids are synthesized from cholesterol by the hepatocytes. The secondary bile acids are deoxycholic and

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lithocholic acid. These acids are formed in the small intestine by intestinal bacteria, after which they are absorbed and flow to the liver (see Fig. 37.17). Both forms of bile acids are conjugated with amino acids (glycine or taurine) in the liver to form bile salts. Conjugation makes the bile acids more water soluble, thus restricting their diffusion from the duodenum and ileum. The primary and secondary bile acids together form the bile acid pool. Some bile salts are deconjugated by intestinal bacteria to secondary bile acids. These acids diffuse passively into the portal blood from both small and large intestines. An increase in the plasma concentration of bile acids accelerates the uptake and resecretion of bile acids and salts by the hepatocytes. The cycle of hepatic secretion, intestinal absorption, and hepatic resecretion of bile acids completes the enterohepatic circulation. Bile secretion is called choleresis. A choleretic agent stimulates the liver to secrete bile. One strong stimulus is a high concentration of bile salts. Other choleretics include cholecystokinin, vagal stimulation, and secretin, which increase the rate of bile flow by promoting contraction of the gallbladder and the secretion of bicarbonate from canaliculi and other intrahepatic bile ducts.

Metabolism of Bilirubin Bilirubin is a byproduct of the destruction of aged red blood cells. It gives bile a greenish black color and produces the yellow tinge of jaundice. Aged red blood cells are absorbed and destroyed by macrophages (Kupffer cells) of the mononuclear phagocyte system, primarily in the spleen and liver. Within these cells, hemoglobin is separated into its component parts: heme and globin (Fig. 37.18). The globin component is further degraded into its constituent amino acids, which go into the amino acid pool to form new protein. The heme component is converted to biliverdin by the enzymatic cleavage of iron. The iron attaches to transferrin in the plasma and can be stored in the liver or used by the bone marrow to make new red blood cells. The biliverdin is enzymatically converted to bilirubin in the Kupffer cell and then is released into the plasma where it binds to albumin and is known as unconjugated bilirubin, or free bilirubin, which is lipid soluble. Bilirubin also has a role as an antioxidant and provides cytoprotection.

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FIGURE 37.18

Bilirubin Metabolism. See text for further explanation.

In the liver, unconjugated bilirubin moves from plasma in the sinusoids into the hepatocyte. Within hepatocytes, unconjugated bilirubin joins with glucuronic acid to form

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conjugated bilirubin, which is water soluble and is secreted in the bile. When conjugated bilirubin reaches the distal ileum and colon, it is deconjugated by bacteria and converted to urobilinogen. Urobilinogen is then reabsorbed in the intestines and excreted in the urine as urobilin. A small amount is eliminated in feces, as stercobilin (an end-product of heme metabolism), which contributes to the stool's brown pigmentation. The elimination of bilirubin also is an important route for the elimination of cholesterol.

Vascular and Hematologic Functions Because of its extensive vascular network, the liver can store a large volume of blood. The liver can release blood to maintain systemic circulatory volume in the event of hemorrhage. The liver also has hemostatic functions; it synthesizes most clotting factors (see Chapter 22). Vitamin K, a fat-soluble vitamin, is essential for the synthesis of the clotting factors. Because bile salts are needed for reabsorption of fats, vitamin K absorption depends on adequate bile production in the liver.

Metabolism of Nutrients Carbohydrates. The liver contributes to the stability of blood glucose levels by releasing glucose during hypoglycemia (low blood glucose level), absorbing glucose during hyperglycemia (high blood glucose level), and storing it as glycogen (glycogenesis) or converting it to fat. When all glycogen stores have been used, the liver can convert amino acids and glycerol to glucose (gluconeogenesis). Proteins. Protein synthesis requires the presence of all the essential amino acids (obtained only from food), as well as nonessential amino acids. Proteins perform many important functions in the body; these are summarized in Table 37.2. TABLE 37.2 Importance of Proteins in the Body Function Contraction Energy Fluid balance Protection Regulation Structure

Example Actin and myosin enable muscle contraction. Proteins can be metabolized for energy. Albumin is a major source of plasma oncotic pressure.

Antibodies, complement, and C-reactive protein protect against infection and foreign substances. Enzymes control chemical reactions; hormones regulate many physiologic processes. Collagen fibers provide structural support to many parts of the body; keratin strengthens skin, hair, and nails. Transport Hemoglobin transports oxygen and carbon dioxide in the blood; plasma proteins serve as transport molecules; proteins in cell membranes control movement of materials into and out of cells. Coagulation Hemostasis is regulated by clotting factors and proteins that balance coagulation and anticoagulation.

Within hepatocytes, amino acids are converted to carbohydrates (keto acids) by the removal of ammonia (NH3), a process known as deamination. The ammonia is converted to urea by the liver and passes into the blood to be excreted by the kidneys. Depending on

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the nutritional status of the body, the keto acids either are converted to fatty acids for fat synthesis and storage or are oxidized by the Krebs tricarboxylic acid cycle (see Chapter 1) to provide energy for the liver cells. The plasma proteins, including albumins and globulins (with the exception of gamma globulin, which is formed in lymph nodes and lymphoid tissue), are synthesized by the liver. They play an important role in preserving blood volume and pressure by maintaining plasma oncotic pressure. The liver also synthesizes several nonessential amino acids and serum enzymes, including aspartate aminotransferase (AST; previously SGOT), alanine aminotransferase (ALT; previously SGPT), lactate dehydrogenase (LDH), and alkaline phosphatase. Fats. Ingested fat absorbed by lacteals in the intestinal villi enters the liver circulation through the lymphatics, primarily as triglycerides. In the liver, the triglycerides can be hydrolyzed to glycerol and free fatty acids and used to produce metabolic energy called adenosine triphosphate (ATP), or they can be released into the bloodstream bound to proteins (lipoproteins). The lipoproteins are carried by the blood to adipose cells for storage. The liver also synthesizes phospholipids and cholesterol, which are needed for the hepatic production of bile salts, steroid hormones, components of plasma membranes, and other special molecules.

Metabolic Detoxification The liver alters exogenous and endogenous chemicals (e.g., drugs), foreign molecules, and hormones to make them less toxic or less biologically active. This process, called metabolic detoxification or biotransformation, diminishes intestinal or renal tubular reabsorption of potentially toxic substances and facilitates their intestinal and renal excretion. In this way alcohol, barbiturates, amphetamines, steroids, and hormones (including estrogens, aldosterone, antidiuretic hormone, and testosterone) are metabolized or detoxified, preventing excessive accumulation and adverse effects. Although metabolic detoxification is usually protective, the end products of metabolic detoxification sometimes become toxins (Did You Know? Paracetamol [Acetaminophen] and Acute Liver Failure) or active metabolites (see Chapter 4). Toxins of alcohol metabolism, for example, are acetaldehyde and hydrogen, which can damage the liver's ability to function.

Did You Know? Paracetamol (Acetaminophen) and Acute Liver Failure Paracetamol (acetaminophen) toxicity from chronic use or overdose is the leading cause of acute liver failure in the developed world. Hepatoxicity should be suspected when doses exceed 4 to 10 grams per day. The onset is sudden and unpredictable, with abdominal pain and nausea developing between 12 and 24 hours, followed by coagulopathy and encephalopathy within 72 to 96 hours. Elevated serum aminotransferase levels (possibly up to 400 times normal), accompanied by hypoprothrombinemia, lactic acidosis, and renal

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failure, support a diagnosis of acute liver failure caused by acetaminophen. Complications of cerebral edema and infection are difficult to diagnose and treat and may lead to multiorgan failure, irreversible brain damage, and death. Early treatment (within 8 hours of overdose) with correct dosing with N-acetylcysteine provides a good chance of recovery. The survival rate at 1 year after liver transplantation for liver failure is 70%. Data from Chiew AL et al: Cochrane Database Syst Rev 2:CD003328, 2018; Ramachandran A, Jaeschke H: Gene Expr 18(1):19-30, 2018.

Storage of Minerals and Vitamins The liver stores certain vitamins and minerals, including iron and copper, in times of excessive intake and releases them in times of need. The liver can store vitamins B12 and D for several months and vitamin A for several years. The liver also stores vitamins E and K. Iron is stored in the liver as ferritin, an iron-protein complex, and is released as needed for red blood cell production. Common tests of liver function are listed in Table 37.3. TABLE 37.3 Common Tests of Liver Function Test Serum Enzymes Alkaline phosphatase

Normal Value

Interpretation

35-150 units/L

Increases with biliary obstruction and cholestatic hepatitis Increases with biliary obstruction and cholestatic hepatitis

Gamma-glutamyl transpeptidase

Male: 12-38 units/L Female: 9-31 units/L Aspartate aminotransferase (previously serum Male: 8-40 glutamate-oxaloacetate transaminase) units/L Female: 6-34 units/L Alanine aminotransferase (previously serum Male: 10-40 glutamate-pyruvate transaminase) units/L Female: 9-32 units/L Lactate dehydrogenase 110-220 units/L 5′-Nucleotidase Bilirubin Metabolism Serum bilirubin Unconjugated (indirect) Conjugated (direct)

2-11 units/L

Increases with hepatocellular injury and injury in other tissues (e.g., skeletal and cardiac muscle) Increases with hepatocellular injury and necrosis

Isoenzyme LD5 is elevated with hypoxic and primary liver injury Increases with increase in alkaline phosphatase and cholestatic disorders

0.1-1 mg/dL 0.1-0.4 mg/dL 10 mEq/L/30 sec 2-5 g/24 hr >200 µg/g of stool

Decreased volume with pancreatic disease as secretin stimulates pancreatic secretion

Measures fatty acids; decreased pancreatic lipase increases stool fat (malabsorption) Decreased in pancreatic insufficiency

Quick Check 37.6 1. What is the function of the gallbladder? 2. How does the endocrine pancreas differ from the exocrine pancreas?

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Geriatric Considerations Aging & the Digestive System Age-related changes in digestive function vary among individuals and within organ systems. The following are some of the changes that can occur.

Oral Cavity and Esophagus • Tooth enamel and dentin deteriorate, so cavities are more likely. • Teeth are lost as a result of periodontal disease and brittle roots that break easily. • Taste buds decline in number. • Sense of smell diminishes. • Salivary secretion decreases. These changes may make eating less pleasurable, reduce the appetite, and result in food not being sufficiently chewed or lubricated; therefore swallowing is difficult (dysphagia).

Stomach • Gastric motility, blood flow, and the volume and acid content of gastric juice may be reduced, particularly with gastric atrophy, and gastric emptying may be delayed. • The protective mucosal barrier declines.

Intestines • Changes in the composition of the intestinal microbiota result in increased susceptibility to disease. • The size of Peyer patches and degree of mucosal immunity decline, resulting in an increased risk for infection and inflammation. • The brain-gut axis (bidirectional neuroendocrine communication) may be disrupted, and enteric neurons may degenerate, with changes in GI motility, secretion, and absorption, as well as the elder person's appetite and overall nutritional status. • Intestinal villi may become shorter and more convoluted, with diminished reparative capacity. • Intestinal absorption, motility, and blood flow may decrease, prolonging transit time and altering nutrient and drug absorption. • Rectal muscle mass decreases, and the anal sphincter weakens. • Constipation, fecal impaction, and fecal incontinence may develop; these are related to immobility, a low-fiber diet, and changes in the enteric nervous system's structure and functions.

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Liver • Decreased hepatic regeneration leads to a decrease in the size and weight of the liver. • The ability to detoxify drugs decreases. • Blood flow decreases, influencing the efficiency of drug metabolism.

Pancreas and Gallbladder • Fibrosis, fatty acid deposits, and pancreatic atrophy occur. • Secretion of digestive enzymes, particularly proteolytic enzymes, decreases. • No changes occur in the gallbladder and bile ducts, but the prevalence of gallstones and cholecystitis is increased. Data from Soenen S et al: Curr Opin Clin Nutr Metab Care, 19(1):12-18, 2016; Tan JL et al: Drugs Aging 32(12):999-1008, 2015.

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Summary Review The Gastrointestinal Tract 1. The major functions of the GI tract are the mechanical and chemical breakdown of food and the absorption of digested nutrients. 2. Except for swallowing and defecation, which are controlled voluntarily, the functions of the GI tract are controlled by extrinsic and intrinsic autonomic nerves and intestinal hormones. 3. The GI tract is a hollow tube that extends from the mouth to the anus. 4. The walls of the GI tract have four layers. From the inside out they are the mucosa, submucosa, muscularis, and serosa. 5. Digestion begins in the mouth, with chewing and salivation. The digestive component of saliva is α-amylase, which initiates carbohydrate digestion. 6. The esophagus is a muscular tube that transports food from the mouth to the stomach. The tunica muscularis in the upper part of the esophagus is striated muscle, and that in the lower part is smooth muscle. 7. Food is propelled through the esophagus by peristalsis (waves of sequential relaxations and contractions of the layers of muscles). 8. Swallowing is controlled by the swallowing center in the medulla of the brain. The two phases of swallowing are the oropharyngeal phase (voluntary swallowing) and the esophageal phase (involuntary swallowing). 9. The lower esophageal sphincter opens to admit swallowed food into the stomach and then closes to prevent regurgitation of food back into the esophagus. 10. The stomach is a baglike structure that secretes digestive juices, mixes and stores food, and propels partially digested food (chyme) through the pylorus into the duodenum. 11. The vagus nerve stimulates gastric (stomach) secretion and motility. 12. The hormones gastrin and motilin stimulate gastric emptying; the hormones secretin and cholecystokinin delay gastric emptying. 13. The stomach secretes large volumes of gastric secretions, including acid, pepsinogen, mucus, enzymes, hormones, intrinsic factor (needed for vitamin B12 absorption), and gastroferrin (facilitates absorption of iron). 14. The three phases of gastric secretion by the stomach are the cephalic phase (anticipation and swallowing), the gastric phase (food in the stomach), and the intestinal phase (chyme in the intestine). 15. Parietal cells produce hydrochloric acid, which dissolves food fibers, kills microorganisms, and activates the enzyme pepsin. Acid secretion is stimulated by the vagus nerve, gastrin, and histamine and is inhibited by sympathetic stimulation and intestinal hormones. 16. Chief cells in the stomach secrete pepsinogen, which is converted to pepsin in the acidic environment created by hydrochloric acid. Pepsin breaks down proteins and forms polypeptides. 17. Mucus is secreted throughout the stomach and protects the stomach wall from acid and digestive enzymes.

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18. The small intestine is 5 meters long and has three segments: the duodenum, jejunum, and ileum. 19. The peritoneum is a double layer of membranous tissue. The visceral layer covers the abdominal organs, and the parietal layer extends along the abdominal wall. The peritoneal cavity is the space between the two layers. The duodenum lies behind the peritoneum (retroperitoneal). 20. The ileocecal valve connects the small and large intestines and prevents reflux into the small intestine. 21. Villi are small fingerlike projections that extend from the small intestinal mucosa and increase its absorptive surface area. 22. Enzymes secreted by the small intestine (maltase, sucrase, lactase), pancreatic enzymes, and bile salts act in the small intestine to digest proteins, carbohydrates, and fats. 23. Digested substances are absorbed across the intestinal wall and then transported to the liver, where they are metabolized further. Carbohydrate and protein components move into villus capillaries and to the liver through the hepatic portal vein. 24. Bile salts emulsify and hydrolyze fats and incorporate them into water-soluble micelles. The fat content of the micelles diffuses through the epithelium into lacteals (lymphatic ducts) in the villi. From there, fats flow into lymphatics and into the systemic circulation, which delivers them to the liver. 25. Minerals and water-soluble vitamins are absorbed by both active and passive transport throughout the small intestine. 26. Contractions of the circular muscles (segmentation) mix the chyme, and peristaltic movements created by longitudinal muscles propel the chyme along the intestinal tract. 27. The ileogastric reflex inhibits gastric motility when the ileum is distended. The intestinointestinal reflex inhibits intestinal motility when one intestinal segment is overdistended. The gastroileal reflex increases intestinal motility when gastric motility increases. 28. The large intestine consists of the cecum, appendix, colon (ascending, transverse, descending, and sigmoid), rectum, and anal canal. 29. The teniae coli are three bands of longitudinal muscle that extend the length of the colon and give it a gathered appearance. Haustra are pouches of colon formed with alternating contraction and relaxation of the circular muscles. 30. The mucosa of the large intestine contains mucus-secreting cells and mucosal folds, but no villi. 31. The large intestine massages the fecal mass and absorbs water and electrolytes. 32. Distention of the ileum with chyme causes the gastrocolic reflex, or the mass propulsion of feces to the rectum. 33. Defecation is stimulated when the rectum is distended with feces. The tonically contracted internal anal sphincter relaxes, and if the voluntarily regulated external sphincter relaxes, defecation occurs. 34. The immune system of the GI tract consists of Paneth cells, which produce defensins and other antimicrobial peptides and lysozymes; and the lymph nodes of Peyer patches, which contain lymphocytes, plasma cells, and macrophages. 35. The largest number of intestinal bacteria (intestinal microbiome) is in the colon.

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The most numerous anaerobes are Bacteroides and Firmicutes. Intestinal bacteria are important for metabolism of bile salts, metabolism of selected drugs and hormones, destruction of pathogens, and prevention of pathogen colonization. 36. The intestinal tract is sterile at birth and becomes totally colonized within 3 to 4 weeks. 37. The splanchnic blood flow provides blood to the esophagus, stomach, small and large intestines, gallbladder, pancreas, and spleen.

Accessory Organs of Digestion 1. The liver, gallbladder, and exocrine pancreas secrete substances necessary for digestion. These secretions flow through an opening guarded by the sphincter of Oddi. 2. The liver sits under the diaphragm. It has digestive, metabolic, hematologic, vascular, and immunologic functions. 3. The liver is divided into the right and left lobes and is supported by the falciform, round, and coronary ligaments. 4. Plates of hepatocytes, which are the functional cells of the liver, together form anatomic units called liver lobules. 5. Hepatocytes synthesize bile and secrete it into the bile canaliculi, which are small channels between the hepatocytes. The bile canaliculi drain bile into the common bile duct and then into the duodenum through an opening called the major duodenal papilla (sphincter of Oddi). 6. Sinusoids are capillaries located between the plates of hepatocytes. Blood from the portal vein and hepatic artery flows through the sinusoids to a central vein in each lobule and then to the hepatic vein and inferior vena cava. 7. Kupffer cells, which are part of the mononuclear phagocyte system, line the sinusoids and destroy microorganisms in sinusoidal blood; they are important in bilirubin production and lipid metabolism. 8. The liver produces 700 to 1200 mL of bile per day. Bile is made up of bile salts, cholesterol, bilirubin, electrolytes, and water. 9. The primary bile acids are synthesized from cholesterol by the hepatocytes. The primary acids are then conjugated to form bile salts. The secondary bile acids are the product of bile salt deconjugation by bacteria in the intestinal lumen. 10. Most bile salts and acids are recycled. The absorption of bile salts and acids from the terminal ileum and their return to the liver are known as the enterohepatic circulation of bile. 11. Bilirubin is a pigment liberated by the lysis of aged red blood cells in the liver and spleen. Unconjugated bilirubin is fat soluble and can cross cell membranes. Unconjugated bilirubin is converted to water-soluble, conjugated bilirubin by hepatocytes and is secreted with bile. 12. The liver produces clotting factors and can store a large volume of blood. 13. The liver plays a major role in the metabolism of carbohydrates, proteins, and fats and stores minerals, vitamin B12, and fat-soluble vitamins. 14. The liver metabolically transforms or detoxifies hormones, toxic substances, and drugs to less active substances. This process is known as metabolic detoxification.

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15. The gallbladder is a saclike organ located on the inferior surface of the liver. The gallbladder stores bile between meals and ejects it when chyme enters the duodenum. 16. Stimulated by cholecystokinin, the gallbladder contracts and forces bile through the cystic duct and into the common bile duct. The sphincter of Oddi relaxes, enabling bile to flow through the major duodenal papilla into the duodenum. 17. The pancreas is a gland located behind the stomach. The endocrine pancreas produces hormones (glucagon, insulin) that facilitate the formation and cellular uptake of glucose. The exocrine pancreas secretes an alkaline solution and the enzymes (trypsin, chymotrypsin, carboxypeptidase, α-amylase, lipase) that digest proteins, carbohydrates, and fats. 18. Secretin stimulates pancreatic secretion of alkaline fluid, and cholecystokinin and acetylcholine stimulate secretion of enzymes. Pancreatic secretions originate in acini and ducts of the pancreas and empty into the duodenum through the common bile duct or an accessory duct that opens directly into the duodenum.

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Key Terms Acini, 874 Ampulla of Vater, 874 Antrum, 861 Ascending colon, 867 Bile, 871 Bile acid pool, 872 Bile acid–dependent fraction, 871 Bile acid–independent fraction, 871 Bile canaliculi, 871 Bile salt, 871 Bilirubin, 872 Body, 861 Brush border, 865 Cardiac orifice, 861 Cecum, 867 Chief cell, 864 Cholecystokinin, 862 Choleresis, 872 Choleretic agent, 872 Chyme, 861 Colon, 867 Common bile duct, 871 Conjugated bilirubin, 872 Crypts of Lieberkühn, 865 Cystic duct, 873 Deamination, 873 Defecation reflex (rectosphincteric reflex), 869 Descending colon, 867 Disse space, 871 Duodenum, 864 Enteric (intramural) plexus, 858 Enterocyte, 865 Enterohepatic circulation, 871 Enterokinase, 875 Esophageal (involuntary) phase, 860 Esophagus, 859 Exocrine pancreas, 874 External anal sphincter (anus), 867 Fecal mass, 867 Feces, 869 Fundus, 861 Gallbladder, 873 Gastric emptying, 863

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Gastric gland, 863 Gastrin, 862 Gastrocolic reflex, 867 Gastroileal reflex, 867 Gastrointestinal tract (alimentary canal), 858 Glisson capsule, 869 Gut-associated lymphoid tissue (GALT), 869 Haustrum (pl., haustra), 867 Hepatic artery, 870 Hepatic portal vein, 870 Hepatic vein, 871 Hepatocyte, 870 Ileocecal valve (sphincter), 864 Ileogastric reflex, 865 Ileum, 864 Internal anal sphincter, 867 Intestinointestinal reflex, 865 Intrinsic factor, 863 Jejunum, 864 Kupffer cell (tissue macrophage), 871 Lacteal, 865 Lamina propria, 865 Large intestine, 867 Liver, 869 Liver lobule, 870 Lower esophageal sphincter (cardiac sphincter), 860 Major duodenal papilla (sphincter of Oddi), 871 Mastication (chewing), 858 Mesentery, 864 Metabolic detoxification (biotransformation), 873 Microvillus (pl., microvilli), 865 Motilin, 862 Mouth, 858 Mucosal barrier, 864 Myenteric (Auerbach) plexus, 861 Natural killer cell (pit cell), 871 Oropharyngeal (voluntary) phase, 860 Pancreas, 874 Pancreatic duct (Wirsung duct), 874 Paneth cell, 869 Pepsin, 864 Parietal cell, 863 Peristalsis, 865 Peritoneal cavity, 864 Peritoneum, 864 Peyer patch, 869 Primary bile acid, 872

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Primary peristalsis, 860 Pyloric sphincter, 861 Pylorus (gastroduodenal junction), 861 Rectosigmoid canal, 867 Rectum, 869 Retropulsion, 862 Rugae, 861 S cell, 875 Saliva, 859 Salivary α-amylase (ptyalin), 859 Salivary gland, 859 Secondary bile acid, 872 Secondary peristalsis, 860 Secretin, 862 Segmentation, 865 Sigmoid colon, 867 Sinusoid, 870 Small intestine, 864 Splanchnic (visceral) blood flow, 869 Stellate cell, 871 Stomach, 861 Submucosal (Meissner) plexus, 861 Swallowing, 860 Teniae coli, 867 Transverse colon, 867 Trypsin inhibitor, 875 Unconjugated bilirubin, 872 Upper esophageal sphincter, 860 Urobilinogen, 872 Valsalva maneuver, 869 Vermiform appendix, 867 Villus (pl., villi), 865

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References 1. Woodland P, et al. The neurophysiology of the esophagus. Ann N Y Acad Sci. 2013;1300:53–70. 2. Hellström PM, et al. The physiology of gastric emptying. Best Pract Res Clin Anaesthesiol. 2006;20(3):397–407. 3. Chu S, Schuberft ML. Gastric secretion. Curr Opin Gastroenterol. 2012;28(6):587–593. 4. Niv Y, Fraser GM. The alkaline tide phenomenon. J Clin Gastroenterol. 2002;35(1):5–8. 5. Kumral D, Zfass AM. Gut movements: a review of the physiology of gastrointestinal transit. Dig Dis Sci. 2018;63(10):2500–2506. 6. Kooij IA, et al. The immunology of the vermiform appendix: a review of the literature. Clin Exp Immunol. 2016;186(1):1–9. 7. Bobadilla JL. Mesenteric ischemia. Surg Clin North Am. 2013;93(4):925–940 [ix]. 8. Ahluwalia B, Magnusson MK, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand J Gastroenterol. 2017;52(11):1185–1193. 9. Cani PD. Human gut microbiome: hopes, threats and promises. Gut. 2018;67(9):1716–1725. 10. Housset C, et al. Functions of the gallbladder. Compr Physiol. 2016;6(3):1549–1577.

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Alterations of Digestive Function Sue E. Huether

CHAPTER OUTLINE Disorders of the Gastrointestinal Tract, 879 Clinical Manifestations of Gastrointestinal Dysfunction, 879 Disorders of Motility, 883 Gastritis, 887 Peptic Ulcer Disease, 888 Malabsorption Syndromes, 891 Inflammatory Bowel Disease, 893 Diverticular Disease of the Colon, 895 Appendicitis, 896 Mesenteric Vascular Insufficiency, 896 Disorders of the Accessory Organs of Digestion, 896 Common Complications of Liver Disorders, 897 Disorders of the Liver, 901 Disorders of the Gallbladder, 904 Disorders of the Pancreas, 905 Cancer of the Digestive System, 906 Cancer of the Gastrointestinal Tract, 906 Cancer of the Accessory Organs of Digestion, 910

Disorders of the gastrointestinal (GI) tract disrupt one or more of its structures and functions. The GI tract is a continuous, hollow organ that extends from the mouth to the anus. It includes the esophagus, stomach, small intestine, large intestine, and rectum. The accessory organs of digestion include the salivary glands, liver, gallbladder, and pancreas. Structural and neural abnormalities can slow, obstruct, or accelerate the movement of intestinal contents at any level of the GI tract. Inflammatory and ulcerative conditions of the GI wall disrupt secretion, motility, and absorption. Inflammation or obstruction of the liver, pancreas, or gallbladder can alter metabolism and result in local and systemic symptoms. Many clinical manifestations of GI tract disorders are nonspecific and can be caused by a

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variety of impairments.

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Disorders of the Gastrointestinal Tract Clinical Manifestations of Gastrointestinal Dysfunction Anorexia Anorexia is the lack of a desire to eat despite physiologic stimuli that would normally produce hunger. This nonspecific symptom is often associated with nausea, abdominal pain, diarrhea, psychological stress, and weight loss. Side effects of drugs, cancer, heart disease, renal disease, and liver disease are often accompanied by anorexia.

Vomiting Vomiting (emesis) is the forceful emptying of stomach and intestinal contents (chyme) through the mouth. The vomiting center lies in the medulla oblongata. Stimuli initiating the vomiting reflex include severe pain; distention of the stomach or duodenum; the presence of ipecac or copper salts in the duodenum; stimulation of the vestibular system through the eighth cranial nerve (motion sickness); side effects of many drugs; torsion or trauma affecting the ovaries, testes, uterus, bladder, or kidney; motion; and activation of the in the medulla (e.g., morphine). Nausea and retching (dry heaves) are distinct events that usually precede vomiting. Nausea is a subjective experience associated with various conditions, including abnormal pain and labyrinthine stimulation (i.e., spinning movement). Specific neural pathways have not been identified, but hypersalivation and tachycardia are common associated symptoms. Retching is the muscular event of vomiting without the expulsion of vomitus. Vomiting begins with deep inspiration. The glottis closes, the intrathoracic pressure falls, and the esophagus becomes distended. Simultaneously, the abdominal muscles contract, creating a pressure gradient from abdomen to thorax. The lower esophageal sphincter (LES) and body of the stomach relax. The duodenum and antrum of the stomach produce reverse peristalsis, and the pressure gradient forces chyme from the stomach and duodenum up into the esophagus. Because the upper esophageal sphincter is closed, chyme does not enter the mouth. When the stomach is full of gastric contents, the diaphragm is forced high into the thoracic cavity by strong contractions of the abdominal muscles. The higher intrathoracic pressure forces the upper esophageal sphincter to open, and chyme is expelled from the mouth. Then the stomach relaxes, and the upper part of the esophagus contracts, forcing the remaining chyme back into the stomach. The lower esophageal sphincter then closes. The cycle is repeated if there is a volume of chyme remaining in the stomach. A diffuse sympathetic discharge causes the tachycardia, tachypnea, and diaphoresis that accompany retching and vomiting. The parasympathetic system mediates copious salivation, increased gastric motility, and relaxation of the upper and lower esophageal sphincters. Spontaneous vomiting not preceded by nausea or retching is called projectile vomiting. It is caused by direct stimulation of the vomiting center by neurologic lesions (e.g., increased intracranial pressure, tumors, or aneurysms) involving the brainstem, or it can be a symptom of GI obstruction (pyloric stenosis). The metabolic consequences of vomiting are fluid, electrolyte, and acid-base disturbances including hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis (see Chapter 5).

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Constipation Constipation is difficult or infrequent defecation. It is a common problem, particularly among the elderly, and usually means a decrease in the number of bowel movements per week, hard stools, and difficult evacuation. The definition must be individually determined because normal bowel habits range from one to three evacuations per day to one per week. Constipation is not significant until it causes health risks or impairs the individual's quality of life. Pathophysiology Constipation can occur as a primary or secondary condition. Primary constipation is generally classified into three categories. Normal transit (functional) constipation involves a normal rate of stool passage but difficulty with stool evacuation. Functional constipation is associated with a sedentary lifestyle, low-residue diet (habitual consumption of highly refined foods), or a low fluid intake. Slow-transit constipation involves impaired colonic motor activity, with infrequent bowel movements, straining to defecate, mild abdominal distention, and palpable stool in the sigmoid colon. Secondary constipation can be caused by diet, medications, or neurogenic disorders (e.g., stroke, Parkinson disease, spinal cord lesions, multiple sclerosis, Hirschsprung disease) in which neural pathways or neurotransmitters are altered and colon transit time is delayed. Rectal fissures, strictures, or hemorrhoids also may cause constipation. Antacids containing calcium carbonate or aluminum hydroxide, anticholinergics, iron, and bismuth tend to inhibit bowel motility. Opioid-induced constipation is caused by drugs that activate µ-opioid receptors in the gut and slow transit time. Endocrine or metabolic disorders associated with constipation include hypothyroidism, diabetes mellitus, hypokalemia, and hypercalcemia. Pelvic hiatal hernia (herniation of the bowel through the floor of the pelvis), diverticula, irritable bowel syndrome (constipation predominant), and pregnancy are associated with constipation. Aging may result in decreased mobility, changes in neuromuscular function, use of medications, and comorbid medical conditions causing constipation. Constipation as a notable change in bowel habits can be an indication of colorectal cancer. Clinical Manifestations Indicators of constipation include two of the following for at least 3 months: (1) straining with defecation at least 25% of the time; (2) lumpy or hard stools at least 25% of the time; (3) sensation of incomplete emptying at least 25% of the time; (4) manual maneuvers to facilitate stool evacuation for at least 25% of defecations; and (5) fewer than three bowel movements per week.1 Changes in bowel evacuation patterns, such as less frequent defecation, smaller stool volume, hard stools, difficulty passing stools (straining), or a feeling of bowel fullness and discomfort, require investigation. Fecal impaction (hard, dry stool retained in the rectum) is associated with rectal bleeding, abdominal or cramping pain, nausea and vomiting, weight loss, and episodes of diarrhea. Straining to evacuate stool may cause engorgement of the hemorrhoidal veins and hemorrhoidal disease or thrombosis with rectal pain, bleeding, and itching. Passage of hard stools can cause painful anal fissures. Evaluation and Treatment The history, current use of medications, physical examination, and stool diaries provide

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precise clues regarding the nature of constipation. The individual's description of frequency, stool consistency, associated pain, and presence of blood or whether evacuation was stimulated by enemas or cathartics (laxatives) is important. Palpation may disclose colonic distention, masses, and tenderness. Digital examination of the rectum and anorectal manometry are performed to assess sphincter tone and detect anal lesions. Colonic transit time and imaging techniques can assist in identifying the cause of constipation. Colonoscopy is used to visualize the lumen directly. The treatment for constipation is to manage the underlying cause or disease for each individual. Management of constipation usually consists of bowel retraining, in which the individual establishes a satisfactory bowel evacuation routine without becoming preoccupied with bowel movements. The individual also may need to engage in moderate exercise, drink more fluids, and increase fiber intake. Fiber supplements, stool softeners, and laxative agents are useful for some individuals. Enemas can be used to establish a bowel routine, but they should not be used habitually. Biofeedback may be beneficial in some instances for forming new bowel evacuation habits. When there is failure to respond to dietary or medical therapies, surgery (colectomy) is considered as a last resort.

Diarrhea Diarrhea is the presence of loose, watery stools. Acute diarrhea is more than three loose stools developing within 24 hours and lasting less than 14 days. Persistent diarrhea lasts longer than 14 to 30 days, and chronic diarrhea lasts longer than 4 weeks. Diarrhea can have high rates of morbidity and mortality in children younger than 5 years of age, particularly in developing countries (see Chapter 39) and in the elderly. Many factors determine stool volume, including water content of the colon, diet, the presence of nonabsorbed food, nonabsorbable material, and intestinal secretions. Stool volume in the normal adult averages less than 200 g/day. Stool volume in children depends on age and size. An infant may pass up to 100 g/day. The adult intestine processes approximately 9 L of luminal contents per day: 2 L are ingested. and the remaining 7 L consist of intestinal secretions. Of this volume, most of the fluid is absorbed: (7 to 8 L) in the small intestine and a smaller amount (1 to 2 L) in the colon. Normally, approximately 150 ml of water is excreted daily in the stool. Pathophysiology Diarrhea in which the volume of feces is increased is called large-volume diarrhea. It generally is caused by excessive amounts of water or secretions or both in the intestines. Small-volume diarrhea, in which the volume of feces is not increased, usually results from excessive intestinal motility and may be caused by an inflammatory disorder of the intestine, such as ulcerative colitis, Crohn disease, or microscopic colitis, but also can result from colon cancer or fecal impaction. The three major mechanisms of diarrhea are osmotic, secretory, and motile. 1. Osmotic diarrhea. A nonabsorbable substance in the intestine draws excess water into the intestine and increases stool weight and volume, producing large-volume diarrhea. Causes include lactase and pancreatic enzyme deficiency; excessive ingestion of synthetic, nonabsorbable sugars; full-strength tube-feeding formulas; or dumping

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syndrome associated with gastric resection (see the Postgastrectomy Syndromes section). 2. Secretory diarrhea. Excessive mucosal secretion of fluid and electrolytes produces large-volume diarrhea. Infectious causes include viruses (e.g., rotavirus), bacterial enterotoxins (e.g., Escherichia coli and Vibrio cholerae), exotoxins from overgrowth of Clostridium difficile after antibiotic therapy, or small bowel bacterial overgrowth. 3. Motility diarrhea is caused by resection of the small intestine (short bowel syndrome), surgical bypass of an area of the intestine, fistula formation between loops of intestine, irritable bowel syndrome– diarrhea predominant, diabetic neuropathy, hyperthyroidism, and laxative abuse. Excessive motility decreases transit time and the opportunity for fluid absorption, resulting in diarrhea. Clinical Manifestations Diarrhea can be acute or chronic, depending on its cause. Systemic effects of prolonged diarrhea are dehydration, electrolyte imbalance (hyponatremia, hypokalemia), and weight loss. Manifestations of acute bacterial or viral infection include fever, with or without vomiting or cramping pain. Most infectious diarrhea usually lasts less than 2 weeks. The exceptions are Clostridium difficile, Aeromonas, or Yersinia enterocolitica.2 Fever, cramping pain, and bloody stools accompany chronic diarrhea caused by inflammatory bowel disease or dysentery. Anal and perineal skin irritation can occur. Evaluation and Treatment A thorough history is taken to document the onset, frequency, volume of stools, duration of diarrhea, and presence of blood in the stools. Malabsorption syndromes usually manifest steatorrhea (fat in the stool), bloating, and diarrhea. Exposure to contaminated food or water is indicated if the individual has traveled in foreign countries or areas where drinking water might be contaminated. Iatrogenic diarrhea is suggested if the individual has undergone abdominal radiation therapy, intestinal resection, or treatment with selected drugs (e.g., antibiotics, diuretics, antihypertensives, laxatives, anticoagulants or chemotherapy). Physical examination helps identify underlying systemic disease. Stool studies, abdominal imaging, endoscopy, and intestinal biopsies provide more specific data, particularly for persistent diarrhea. Treatment for diarrhea includes restoration of fluid and electrolyte balance, administration of antimotility (e.g., loperamide) and/or water-absorbent (e.g., attapulgite and polycarbophil) medications, and treatment of causal factors. Natural bran and commercial preparations of psyllium are inexpensive and effective treatments for mild diarrhea. Probiotics can be useful for preventing and treating Clostridium difficile–associated diarrhea as an approach to restoring normal microflora in addition to antibiotic therapy. Fecal transplantation can be used for cases that are resistant to conventional therapies, particularly Clostridium difficile–associated diarrhea. Nutritional deficiencies need to be corrected in cases of chronic diarrhea or malabsorption.3

Abdominal Pain Abdominal pain is the presenting symptom of a number of GI diseases and can be acute or

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chronic. The causal mechanisms of abdominal pain are mechanical, inflammatory, or ischemic. Generally, the abdominal organs are not sensitive to mechanical stimuli, such as cutting, tearing, or crushing. However, these organs are sensitive to stretching and distention, which activate nerve endings in both hollow and solid structures. Pain accompanies rapid distention rather than gradual distention. Traction on the peritoneum caused by adhesions, distention of the common bile duct, or forceful peristalsis resulting from intestinal obstruction causes pain because of increased tension. Capsules that surround solid organs, such as the liver and gallbladder, contain pain fibers that are stimulated by stretching if these organs swell. Abdominal pain may be generalized to the abdomen or localized to a particular abdominal quadrant. The nature of the pain is often described as sharp, dull, or colicky. Abdominal pain is usually associated with tissue injury and inflammation. Biochemical mediators of the inflammatory response, such as histamine, bradykinin, and serotonin, stimulate organic nerve endings and produce abdominal pain. The edema and vascular congestion that accompany chemical, bacterial, or viral inflammation also cause painful stretching. Hindrance of blood flow from the distention of bowel obstruction or mesenteric vessel thrombosis produces the pain of ischemia, and increased concentrations of tissue metabolites stimulate pain receptors. Abdominal pain can be parietal (somatic), visceral, or referred. Parietal pain, from the parietal peritoneum, is more localized and intense than visceral pain, which arises from the organs themselves. Parietal pain lateralizes because, at any particular point, the parietal peritoneum is innervated from only one side of the nervous system. Visceral pain arises from a stimulus (distention, inflammation, ischemia) acting on an abdominal organ. Inflammatory mediators associated with chronic low-grade inflammation can cause pain hypersensitivity. The pain is usually poorly localized, diffuse, or vague with a radiating pattern because nerve endings in abdominal organs are sparse and multisegmented. Pain arising from the stomach, for example, is experienced as a sensation of fullness, cramping, or gnawing in the midepigastric area. Referred pain is visceral pain felt at some distance from a diseased or affected organ. It is usually well localized and is felt in the skin dermatomes or deeper tissues that share a central afferent pathway with the affected organ. For example, acute cholecystitis may have pain referred to the right shoulder or scapula.

Gastrointestinal Bleeding Upper gastrointestinal bleeding is bleeding in the esophagus, stomach, or duodenum and is characterized by frank, bright red bleeding or dark, grainy digested blood (“coffee grounds”) that has been affected by stomach acids (Table 38.1). Upper GI bleeding is commonly caused by bleeding varices (varicose veins) in the esophagus, peptic ulcers, arteriovenous malformations, or a Mallory-Weiss tear at the esophageal-gastric junction caused by severe retching. Lower gastrointestinal bleeding, or bleeding from the jejunum, ileum, colon, or rectum, can be caused by polyps, diverticulitis, inflammatory disease, cancer, or hemorrhoids. Occult bleeding is usually caused by slow, chronic blood loss that is not obvious and results in iron deficiency anemia as iron stores in the bone marrow are slowly depleted. Acute, severe GI bleeding is life-threatening, depending on the volume and rate of blood loss, associated diseases and the age of the individual, and the effectiveness of treatment.

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TABLE 38.1 Presentations of Gastrointestinal Bleeding Presentations Definition Acute Bleeding Hematemesis Bloody vomitus; either fresh, bright red blood or dark grainy digested blood with “coffee grounds” appearance Melena Black, sticky, tarry, foul-smelling stools caused by digestion of blood in gastrointestinal tract; should be distinguished from black stools caused by dietary iron supplements, blackberries, or bismuth (e.g., Pepto-Bismol) Hematochezia Fresh, bright red blood passed from rectum Occult Trace amounts of blood in normal-appearing stools or gastric secretions; detectable only with positive Bleeding fecal occult blood test (guaiac test)

Physiologic response to GI bleeding depends on the amount and rate of the loss (Fig. 38.1). Changes in blood pressure and heart rate are the best indicators of massive blood loss in the GI tract. During the early stages of blood volume depletion, the peripheral arteries and arterioles constrict to shunt blood to vital organs, including the brain. Signs of largevolume blood loss are postural hypotension (a drop in blood pressure that occurs with a change from the recumbent position to a sitting or upright position), lightheadedness, and loss of vision. Tachycardia develops as a compensatory response to maintain cardiac output and tissue perfusion. If blood loss continues, hypovolemic shock develops (see Chapter 26). Diminished blood flow to the kidneys causes decreased urine output and may lead to oliguria (low urine output), tubular necrosis, and renal failure. Ultimately, insufficient cerebral and coronary blood flow causes irreversible anoxia and death.

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FIGURE 38.1

Pathophysiology of Gastrointestinal Bleeding.

The presentations of GI bleeding are summarized in Table 38.1. The accumulation of blood in the GI tract is irritating and increases peristalsis, causing vomiting or diarrhea, or both. If bleeding is from the lower GI tract, the diarrhea is frankly bloody. Bleeding from the upper GI tract also can be rapid enough to produce hematochezia (bright red stools), but generally some digestion of the blood components will have occurred, producing melena—black or tarry stools that are sticky and have a characteristic foul odor. The digestion of blood proteins originating from massive upper GI bleeding is reflected by an

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increase in blood urea nitrogen (BUN) levels (see Fig. 38.1). The hematocrit and hemoglobin values are not the best indicators of acute GI bleeding because plasma volume and red cell volume are lost proportionately. As the plasma volume is replaced, the hematocrit and hemoglobin values begin to reflect the extent of blood loss. The interpretation of these values is modified to account for exogenous replacement of fluids and the hydration status of the tissues.

Quick Check 38.1 1. How is visceral pain “referred”? 2. How does osmotic diarrhea differ from secretory diarrhea? 3. What are the best clinical indicators of acute GI bleeding blood loss?

Disorders of Motility Dysphagia Pathophysiology Dysphagia is difficulty swallowing. It can result from mechanical obstruction of the esophagus or from a functional disorder that impairs esophageal motility. Intrinsic obstructions originate in the wall of the esophageal lumen (esophageal dysphagia) and include tumors, strictures, and diverticular herniations (outpouchings). Extrinsic mechanical obstructions originate outside the esophageal lumen and narrow the esophagus by pressing inward on the esophageal wall. The most common cause of extrinsic mechanical obstruction is tumor. Functional dysphagia is caused by neural or muscular disorders that interfere with voluntary swallowing or peristalsis. Disorders that affect the striated muscles of the hypopharyngeal area and upper esophagus interfere with the oropharyngeal (voluntary) phase of swallowing (oropharyngeal dysphagia). Typical causes are dermatomyositis (a muscle disease) and neurologic impairments caused by cerebrovascular accidents, Parkinson disease, multiple sclerosis, muscular dystrophy, or achalasia. Achalasia is a rare form of dysphagia related to loss of inhibitory neurons in the myenteric plexus with smooth muscle atrophy in the middle and lower portions of the esophagus. The myenteric neurons are attacked by a cell-mediated and antibody-mediated immune response against an unknown antigen. This leads to altered esophageal peristalsis and failure of the lower esophageal sphincter (LES) to relax, causing functional obstruction of the lower esophagus with varying severity. Food accumulates above the obstruction, distends the esophagus, and causes dysphagia. Cough and aspiration can occur. As hydrostatic pressure increases, food is slowly forced past the obstruction into the stomach. Chronic esophageal distention requires dilation or surgical myotomy of the LES. Clinical Manifestations Distention and spasm of the esophageal muscles during eating or drinking may cause a mild or severe stabbing pain at the level of obstruction. Discomfort occurring 2 to 4 seconds after swallowing is associated with upper esophageal obstruction. Discomfort occurring 10

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to 15 seconds after swallowing is more common in obstructions of the lower esophagus. If obstruction results from a growing tumor, dysphagia begins with difficulty swallowing solids and advances to difficulty swallowing semisolids and liquids. If motor function is impaired, both solids and liquids are difficult to swallow. Regurgitation of undigested food, an unpleasant taste sensation, vomiting, aspiration, and weight loss are common manifestations of all types of dysphagia. Aspiration of esophageal contents can lead to cough and pneumonia. Evaluation and Treatment Knowledge of the person's history and clinical manifestations contributes significantly to a diagnosis of dysphagia. Imaging is used to visualize the contours of the esophagus and identify structural defects. Esophageal motility testing documents abnormal pressure changes associated with obstruction or loss of neural regulation. Esophageal endoscopy is performed to examine the esophageal mucosa and obtain biopsy specimens. The individual is taught to manage symptoms by eating small meals slowly, taking fluid with meals, and sleeping with the head elevated to prevent regurgitation and aspiration. Food and medications may need to be formulated so they can be swallowed Anticholinergic drugs (e.g., botulinum toxin) may relieve symptoms of dysphagia. Mechanical dilation of the esophageal sphincter and surgical separation of the lower esophageal muscles with a longitudinal incision (myotomy) are the most effective treatments for achalasia.

Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) is the reflux of acid and pepsin or bile salts from the stomach into the esophagus, causing esophagitis. The prevalence of GERD is estimated at 18% to 27% in North America.4 Risk factors for GERD include older age, obesity, hiatal hernia, and drugs or chemicals that relax the LES (anticholinergics, nitrates, calcium channel blockers, nicotine). GERD may be a trigger for asthma or chronic cough. Gastroesophageal reflux that does not cause symptoms is known as physiologic reflux. In nonerosive reflux disease (NERD), individuals have symptoms of reflux disease but no visible or minimal esophageal mucosal injury (functional heartburn). Pathophysiology Abnormalities in LES function, esophageal motility, and gastric motility or emptying can cause GERD. The resting tone of the LES tends to be lower than normal from either transient relaxation or weakness of the sphincter. Vomiting, coughing, lifting, bending, obesity, or pregnancy increases abdominal pressure, contributing to the development of reflux esophagitis. A hiatal hernia can weaken the LES. Delayed gastric emptying can contribute to reflux esophagitis by (1) lengthening the period during which reflux is possible and (2) increasing gastric acid content. Disorders that delay emptying include gastroparesis; gastric or duodenal ulcers, which can cause pyloric edema; and strictures that narrow the pylorus.5 The severity of the esophagitis depends on the composition of the gastric contents and the esophageal mucosa exposure time. If the gastric content is highly acidic or contains bile salts and pancreatic or intestinal enzymes, reflux esophagitis can be severe. The refluxate causes mucosal injury and inflammation, with hyperemia, increased capillary permeability,

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edema, tissue fragility, and erosion. Fibrosis and thickening may develop. Precancerous lesions (Barrett esophagus; see the Esophageal Cancer section) can be a long-term consequence. Precancerous lesions can progress to adenocarcinoma. Clinical Manifestations The clinical manifestations of erosive reflux esophagitis are heartburn (pyrosis), acid regurgitation, dysphagia, chronic cough, asthma attacks (see Chapter 29), laryngitis, hoarseness, and upper abdominal pain within 1 hour of eating. The symptoms worsen if the individual lies down or if intra-abdominal pressure increases (e.g., as a result of coughing, vomiting, or straining at stool). Edema, strictures, esophageal spasm, or decreased esophageal motility may result in dysphagia with weight loss. Alcohol or acidcontaining foods, such as citrus fruits, can cause discomfort during swallowing. Evaluation and Treatment The diagnosis of GERD is based on the history and clinical manifestations. Esophageal endoscopy shows hyperemia, edema, erosion, and strictures. Dysplastic changes (Barrett esophagus) can be identified by tissue biopsy. Impedance/pH monitoring measures the movement of stomach contents upward into the esophagus and the acidity of the refluxate. Because heartburn also may be experienced as chest pain, cardiac ischemia must be ruled out. Proton pump inhibitors are the agents of choice for controlling symptoms and healing esophagitis. Other therapies include histamine 2 (H2)-receptor antagonists or prokinetics and antacids. Weight reduction, smoking cessation, elevation of the head of the bed 6 inches, and avoiding tight clothing also help to alleviate symptoms. Laparoscopic fundoplication is the most common surgical intervention when medical treatment fails.6 Eosinophilic esophagitis is an idiopathic chronic inflammatory disease of the esophagus characterized by infiltration of eosinophils associated with atopic disease, including asthma and food allergies. It occurs in adults and children. Dysphagia, food impaction, vomiting, and weight loss are common symptoms. Endoscopy with biopsy identifies the eosinophilic infiltration and differentiates this condition from GERD. Treatment is symptomatic and includes acid inhibitors, elimination diets, and swallowed steroids.

Hiatal Hernia Pathophysiology Hiatal hernia is a type of diaphragmatic hernia with protrusion (herniation) of the upper part of the stomach through the diaphragm and into the thorax7 (Fig. 38.2). In sliding hiatal hernia (type 1) (the most common type), the proximal portion of the stomach moves into the thoracic cavity through the esophageal hiatus, an opening in the diaphragm for the esophagus and vagus nerves. A congenitally short esophagus, fibrosis or excessive vagal nerve stimulation, or weakening of the diaphragmatic muscles at the gastroesophageal junction contributes to the hernia. GERD is associated with this type of herniation. Coughing, bending, tight clothing, ascites, obesity, and pregnancy accentuate the hernia.

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FIGURE 38.2 Three Types of Hiatal Hernia. A, Type I—sliding hernia. The visceral peritoneum remains intact and restrains the size of the hernia in sliding hiatal hernia. B, Type II—paraesophageal or rolling hernia. The membrane becomes thinner or defective in a paraesophageal hernia, allowing a true peritoneal sac to protrude into the posterior mediastinum, where negative intrathoracic pressure causes it to enlarge. C, Type III—mixed hernia. GE, Gastroesophageal. NOTE: Type IV—complex paraesophageal hernia is not shown. (From Townsend CM et al: Sabiston textbook of surgery, ed 19, Philadelphia, 2012, Saunders.)

Paraesophageal hiatal hernia (type 2) is the herniation of the greater curvature of the stomach through a secondary opening in the diaphragm alongside the esophagus. The position of a portion of the stomach above the diaphragm causes congestion of mucosal blood flow, leading to gastritis and ulcer formation. Strangulation of the hernia is a major complication. It can present with vomiting and epigastric and retrosternal epigastric pain and is a surgical emergency. Mixed hiatal hernia (type 3), less common, is a combination of sliding and paraesophageal hiatal hernias. It tends to occur in conjunction with several other diseases, including reflux esophagitis, peptic ulcer, cholecystitis (gallbladder inflammation), cholelithiasis (gallstones), chronic pancreatitis, and diverticulosis. Clinical Manifestations Hiatal hernias are often asymptomatic. Generally, a wide variety of symptoms develop later in life and are associated with other GI disorders, including GERD. Symptoms include heartburn, regurgitation, dysphagia, and epigastric pain. Ischemia from hernia strangulation causes acute, severe chest or epigastric pain, nausea, vomiting, and GI bleeding.

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Evaluation and Treatment Diagnostic procedures include radiology with barium swallow, endoscopy, and highresolution manometry. A chest x-ray film often will show the protrusion of the stomach into the thorax, indicating paraesophageal hiatal hernia. Treatment for a sliding hiatal hernia is usually conservative. The individual can diminish reflux by eating small, frequent meals and avoiding the recumbent position after eating. Abdominal supports and tight clothing should be avoided, and weight control is recommended for obese individuals. Antacids alleviate reflux esophagitis. Individuals who are uncomfortable at night benefit from sleeping with the head of the bed elevated 6 inches. Surgery is performed if medical management fails to control symptoms. Gastroparesis is delayed gastric emptying in the absence of a mechanical gastric outlet obstruction. It is most commonly associated with diabetes mellitus, surgical vagotomy, or fundoplication. It can be idiopathic. The pathophysiology is not well understood but involves abnormalities of the autonomic nervous system, smooth muscle cells, enteric neurons, and GI hormones. Diabetic gastroparesis represents a form of neuropathy involving the vagus nerve. Symptoms include nausea, vomiting, abdominal pain, and postprandial fullness or bloating. Treatment options include dietary management; prokinetic drugs; and, in some cases, gastric electrical stimulation; or surgical venting gastrostomy.8

Pyloric Obstruction Pathophysiology Pyloric obstruction (gastric outlet obstruction) is the narrowing or blocking of the opening between the stomach and the duodenum. This condition can be congenital (e.g., infantile hypertrophic pyloric stenosis; see Chapter 39) or acquired. Acquired obstruction is caused by peptic ulcer disease or carcinoma near the pylorus. Duodenal ulcers are more likely than gastric ulcers to obstruct the pylorus. Ulceration causes obstruction resulting from inflammation, edema, spasm, fibrosis, or scarring. Tumors cause obstruction by growing into the pylorus. Clinical Manifestations Early in the course of pyloric obstruction, the individual experiences vague epigastric fullness, which becomes more distressing after eating and at the end of the day. Nausea and epigastric pain may occur as the muscles of the stomach contract in attempts to force chyme past the obstruction. These symptoms disappear when the chyme finally moves into the duodenum. As obstruction progresses, anorexia develops sometimes accompanied by weight loss. Severe obstruction causes gastric distention and atony (lack of muscle tone and gastric motility). Gastric distention stimulates gastric secretion, which increases the feeling of fullness. Rolling or jarring of the abdomen produces a sloshing sound called the succussion splash. At this stage, vomiting is a cardinal sign of obstruction. It is usually copious and occurs several hours after eating. The vomitus contains undigested food but no bile. Prolonged vomiting leads to dehydration, which is accompanied by a hypokalemic and hypochloremic metabolic alkalosis caused by loss of gastric potassium and acid, respectively. Because food does not enter the intestine, stools are infrequent and small. Prolonged pyloric obstruction causes severe malnutrition, dehydration, and extreme

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debilitation. Evaluation and Treatment The diagnosis is based on clinical manifestations, a history of ulcer disease, and examination of residual gastric contents. Endoscopy is performed if gastric carcinoma is the suggested cause of pyloric obstruction. Obstructions resulting from ulceration often resolve with conservative management. A large-bore nasogastric tube is used to aspirate stomach contents and relieve distention. Then nasogastric suction is maintained for 2 to 3 days to decompress the stomach and restore normal motility. Gastric secretions that contribute to inflammation and edema can be suppressed with proton pump inhibitors or H2-receptor antagonists. Fluids and electrolytes (saline and potassium) are given intravenously to promote rehydration and correct hypokalemia and alkalosis (see Chapter 5). Severely malnourished individuals may require parenteral hyperalimentation (intravenous nutrition). Surgery or the placement of pyloric stents may be required to treat gastric carcinoma or persistent obstruction caused by fibrosis and scarring.9

Intestinal Obstruction and Paralytic Ileus Intestinal obstruction can be caused by any condition that prevents the normal flow of chyme through the intestinal lumen (Table 38.2). Obstructions can occur in either the small or the large intestine (Table 38.3). The small intestine is more commonly obstructed because of its narrower lumen. Classifications of intestinal obstruction are summarized in Table 38.4. Intestinal obstruction is classified by cause as simple or functional. Simple obstruction is mechanical blockage of the lumen by a lesion and it is the most common type of intestinal obstruction. Paralytic ileus, or functional obstruction, is a failure of intestinal motility often occurring after intestinal or abdominal surgery, acute pancreatitis, or hypokalemia. Acute obstructions usually have mechanical causes, such as adhesions or hernias (Fig. 38.3). Chronic or partial obstructions are more often associated with tumors or inflammatory disorders, particularly of the large intestine. TABLE 38.2 Common Causes of Intestinal Obstruction Cause Pathophysiology Hernia Protrusion of intestine through weakness in abdominal muscles or through inguinal ring Intussusception Telescoping of one part of intestine into another; this usually causes strangulation of the blood supply; more common in infants 10-15 months of age than in adults (see Fig. 38.3, D) Torsion Twisting of the intestine on its mesenteric pedicle, with occlusion of the blood supply; often associated (volvulus) with fibrous adhesions; occurs most often in middle-aged and elderly men Diverticulosis Inflamed saccular herniations (diverticula) of mucosa and submucosa through tunica muscularis of the colon; diverticula are interspersed between thick, circular, fibrous bands; most common in obese individuals older than 60 years (see Fig. 38.8) Tumor Tumor growth into intestinal lumen; adenocarcinoma of the colon and the rectum is the most common tumoral obstruction; most common in individuals older than 60 years Paralytic Loss of peristaltic motor activity in intestine; associated with abdominal surgery, peritonitis, (adynamic) hypokalemia, ischemic bowel, spinal trauma, or pneumonia ileus Fibrous Peritoneal irritation from surgery, trauma, or Crohn disease leads to the formation of fibrin and adhesions adhesions that attach to intestine, omentum, or peritoneum and can cause obstruction; most common in

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small intestine

TABLE 38.3 Large and Small Bowel Obstruction Type of Obstruction Small bowel obstruction

Large bowel obstruction

Cause Adhesions: secondary to previous abdominal surgeries—75% Hernia: inguinal, ventral, or femoral—10% Tumors: may be associated with intussusception—10% Mesenteric ischemia—3%-5% Crohn disease—24 to 48 hours) of meconium and intestinal dilation. Plugs of meconium are found in the distal ileum and proximal colon, resulting in obstruction of passage of meconium from the rectum. Radiocontrast enema aids with both diagnosis and treatment. Distal intestinal obstruction syndrome (DIOS), formerly called meconium ileus equivalent, is seen in a small number of children and adults with cystic fibrosis. It is characterized by partial or complete intestinal obstruction by abnormally viscous intestinal contents in the terminal ileum and proximal colon. Pathophysiology The terminal ileum is plugged with thick, sticky meconium resulting from the formation of abnormal mucus. The segment of the ileum proximal to the obstruction is distended with liquid contents, and its walls may be hypertrophied. The segment distal to the obstruction is collapsed and filled with small pellets of pale-colored stool. Meconium in the obstructed segment has the consistency of thick syrup or glue. Peristalsis fails to propel this sticky material through the ileum, so it becomes impacted. Volvulus, atresia, or perforation of the bowel occurs in complicated MI. Clinical Manifestations Abdominal distention usually develops during the first few days after birth. The distention increases as air is swallowed. The infant does not pass meconium and begins to vomit bilestained material within hours or days of birth. Infants with cystic fibrosis may have signs of pulmonary involvement, such as tachypnea, intercostal retractions, and grunting respirations. The distended abdomen shows patterns of dilated intestinal loops that feel doughlike when palpated. Some of the loops contain scattered, firm, movable masses. Despite hyperactive peristalsis, the rectal ampulla is empty. Evaluation and Treatment Radiologic examination confirms the presence of meconium in the ileum or ileocecum. The sweat test, which measures the amount of chloride in the sweat, is performed to detect or rule out cystic fibrosis and is accurate in 90% of infants. In cases not complicated by volvulus or perforation, the obstruction is relieved by intestinal lavage and administration of oral laxatives. If this is not possible, the meconium is removed surgically. Survival of infants with simple meconium ileus is improving, with rates approaching 100%. Mortality of infants increases if the obstruction is complicated by peritonitis. DIOS is treated with hydration and stool softeners.

Large Intestine, Rectum, and Anus Hirschsprung Disease Hirschsprung disease, or congenital aganglionic megacolon, is a functional obstruction of the colon. It is rare but the most common cause of colon obstruction, and it accounts for about one third of all GI obstructions in infants. The incidence is higher in males, siblings of children with Hirschsprung disease, and children with Down syndrome or other congenital

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malformations.16. Pathophysiology The cause of Hirschsprung disease is unknown, but it is associated with genetic mutations in some cases. Hirschsprung disease is characterized by the absence of parasympathetic nervous system intrinsic ganglion cells in the submucosal and myenteric plexuses along variable lengths of the colon (see Fig. 37.2 for normal colon structure). Lacking neural stimulation, muscle layers fail to propel feces through the colon, leading to functional obstruction. This causes the proximal colon to become distended, hence the term megacolon (Fig. 39.3). In most cases, the aganglionic segment is limited to the rectal end of the sigmoid colon. In rare cases, the entire colon lacks ganglion cells and the ileum may be involved.

FIGURE 39.3

Hirschsprung Disease.

Clinical Manifestations The infant typically becomes symptomatic during the first 24 to 72 hours after birth with delayed passage of meconium. Mild to severe constipation is the usual manifestation of Hirschsprung disease, with poor feeding, poor weight gain, and progressive abdominal distention. However, diarrhea may be the first sign because only water can travel around the impacted feces. The most serious complication in the neonatal period is enterocolitis related to fecal impaction. Bowel dilation stretches and partly occludes the encircling blood and lymphatic vessels, causing edema, ischemia, infarction of the mucosa, and significant outflow of fluid into the bowel lumen. Copious liquid stools result. Infarction and destruction of the mucosa enable enteric microorganisms to penetrate the bowel wall and gram-negative sepsis can occur accompanied by fever and vomiting. Severe and rapid fluid and electrolyte changes

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may take place, causing hypovolemic or septic shock or death. Evaluation and Treatment Radiocontrast enema and anorectal manometry are screening tools for the diagnosis of Hirschsprung disease. The definitive diagnosis is made by rectal biopsy, showing an absence of ganglion cells in the submucosa of the colon. Surgery is the definitive treatment in all cases of Hirschsprung disease. In general, the prognosis of congenital megacolon is satisfactory for children who undergo surgical treatment. Bowel training may be prolonged; most children achieve bowel continence before puberty but some have longterm constipation or fecal incontinence.17

Anorectal Malformations Anorectal malformations (ARMs) represent a spectrum of rare anomalies of the anus and rectum (Fig. 39.4). ARMs include anorectal stenosis, imperforate anus, anorectal atresia, and rectal atresia. Persistent cloaca (an embryonic component of the hind gut) is the most severe type of anorectal malformation and occurs exclusively in girls. The rectum, urethra, and vagina fail to develop separately; instead, they drain through a single, common channel onto the perineum. Infants with anorectal malformations may have other developmental anomalies (i.e., Down syndrome, Hirschsprung disease, duodenal atresia, neurogenic bladder, and spinal malformations).

FIGURE 39.4

Anorectal Stenosis and Imperforate Anus. Except for the rectovaginal fistula, all of the malformations shown occur in both males and females.

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Most ARMs are identified in routine physical examination during the neonatal period. Types of imperforate anus include an anal opening that is narrow or misplaced; a membrane (covering) may be present over the anal opening; the rectum may not connect to the anus; the rectum may connect to part of the urinary tract or to the reproductive system through a fistula; or the anal opening is not present. Treatment recommendations depend on the type of imperforate anus, the presence and type of associated abnormalities, and the child's overall health status. Anal stenosis can be treated by dilations. Infants with an imperforate anus and other anorectal malformations require surgical correction. Lower lesions have better functional outcomes than higher lesions. Continuing care is required to maintain bowel, bladder, and reproductive function.18

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Acquired Impairment of Motility in the Gastrointestinal Tract Gastroesophageal Reflux (GER) and Gastroesophageal Reflux Disease (GERD) Gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus independent of swallowing. GER is normal and nonpathologic in healthy infants and may be asymptomatic or exhibited by regurgitation and vomiting. The frequency of GER is highest in premature infants and declines during the first 6 to 12 months of life. Infants usually outgrow their reflux and do not require treatment.19 Gastroesophageal reflux disease (GERD) is different from GER. It occurs when it is the cause of troublesome symptoms or complications, or both, described as esophageal or extraesophageal in nature. Children at greatest risk for complicated GERD are those with prematurity, neurologic impairment, EA, obesity, hiatal hernia, achalasia, chronic lung diseases, and certain genetic disorders, including cystic fibrosis. Pathophysiology GERD is influenced by genetic, environmental, anatomic, hormonal, and neurogenic factors. Although transient lower esophageal sphincter relaxations (TLESRs) are the most common pathophysiologic cause of GERD, inadequate adaptation of sphincter tone to changes in abdominal pressure also may be implicated. Factors that maintain lower esophageal sphincter integrity in children include the location of the gastroesophageal junction in a high-pressure zone within the abdomen, mucosal gathering within the sphincter, and the angle at which the esophagus is inserted into the stomach. Reflux persists if any one of these pressure-maintaining factors is altered. Other mediators of GERD are esophageal peristalsis or clearance, mucosal resistance that mediates the noxiousness of the refluxate, and delayed gastric emptying. Reflux of acidic gastric contents results in inflammation of the esophageal epithelium (esophagitis) and stimulation of the vomiting reflex. Esophageal inflammation resulting from GERD is differentiated from eosinophilic esophagitis (EoE), which can occur in children. EoE is thought to be an allergic esophageal disease involving both immediate and delayed hypersensitivity reactions to food ingestion. An eosinophilic infiltrate is associated with inflammation of the entire esophagus that is nonresponsive to acid-suppression therapy. The hallmark symptoms of EoE are dysphagia, food refusal or impaction, and throat and chest pain. Treatment involves elimination of problem foods from the diet and oral steroids. Clinical Manifestations The clinical manifestations of GERD include excessive regurgitation or vomiting; food refusal/anorexia; unexplained crying, choking, or gagging; sleep disturbance; dysphagia; and abdominal or epigastric pain, or both. Esophageal complications of GERD can be significant, such as esophagitis, hemorrhage, stricture, Barrett esophagus (metaplasia) (see Chapter 38), and, rarely, adenocarcinoma. Extraesophageal symptoms include cough and wheezing, laryngitis, pharyngitis, dental erosions, sinusitis, recurrent otitis media, and

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Sandifer syndrome (a neurologic disorder). This constellation of symptoms is often indistinguishable from those of cow's milk protein allergy, which may coexist with or overlap GERD. Evaluation and Treatment The clinical manifestations are often adequate to confirm a diagnosis of GERD. Esophageal pH monitoring with a probe for 24 hours and endoscopy with biopsy are routinely used for diagnosis. In breast-fed babies, maternal elimination of cow's milk protein is recommended, whereas formula-fed infants may require feeding volume and frequency adjustments using extensively hydrolyzed protein or amino acid–based formulas. Using thickened feedings has been shown to improve symptoms of GERD. Prone positioning is recommended only for infants older than 1 year of age because of the risk of sudden infant death syndrome. Lifestyle changes for children and adolescents include weight loss, smoking cessation, sleeping position changes, and avoidance of caffeine, chocolate, alcohol, and spicy foods. Medications are used to buffer or reduce gastric acid secretion, increase motility, or increase lower esophageal sphincter pressure to treat GERD. If no improvement is seen with medical management or the child has life-threatening events with reflux, an antireflux surgical procedure, including gastropexy and fundoplication, is performed.20

Intussusception Intussusception is the telescoping of a proximal segment of intestine into a distal segment, causing an obstruction. It is rare but the most common cause of small bowel obstruction in children in the United States.21 Most cases occur between 5 and 7 months of age. Intussusception is more common in males and can occur in children with polyps or tumors (lead points), cystic fibrosis, Meckel diverticulum, intestinal adhesions, or immediately after abdominal surgery. There is a small risk of intussusception associated with rotavirus vaccination, but the health benefits of the vaccine far exceed the risk of intussusception.22 Pathophysiology In intussusception, the ileum commonly telescopes into the cecum and part of the ascending colon by collapsing through the ileocecal valve, although intussusception can occur anywhere from the duodenum to the rectum. The proximal portion of the intestine (the intussusceptum) telescopes into the distal portion (the intussuscipiens) in the direction of peristaltic flow (Fig. 39.5). The intussusceptum then drags its mesentery into the enveloping lumen, causing an intussusception. Initially, the mesentery is constricted, obstructing venous return. Compression of the mesenteric vessels between the two layers of intestinal wall and at the U-shaped angle at either end of the intussusceptum leads within hours to venous stasis, engorgement, edema, exudation, and further vascular compression. Edema and compression obstruct the flow of chyme through the intestine. Unless the intussusception is treated, bleeding, necrosis, and bowel perforation ensue.

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FIGURE 39.5

Ileocolic Intussusception. Dotted outline indicates normal anatomy.

Clinical Manifestations The classic symptoms of intussusception include colicky abdominal pain, irritability, knees drawn to the chest, abdominal mass, vomiting, and bloody (currant jelly) stools. All of these symptoms may not occur. Intussusception has been discovered incidentally by computed tomography (CT) or magnetic resonance imaging (MRI) scan for other indications. Abdominal tenderness and distention develop as intestinal obstruction becomes more acute. Evaluation and Treatment The diagnosis is based on clinical manifestations, the onset of symptoms, and ultrasonographic or radiologic imaging studies. An enema reduction is usually effective for large bowel intussusception and avoids the progression to ischemia and perforation. Laparotomy remains the treatment of choice for small bowel intussusception. Untreated intussusception in infants is nearly always fatal. Most infants recover if the intussusception is reduced within 24 hours.23

Appendicitis Appendicitis is common in children between the ages of 10 and 11 years. The mechanisms of disease, symptoms, and treatment are similar to those for adults and can be reviewed in Chapter 38.

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Quick Check 39.2 1. Describe the pathologic defect in meconium ileus. 2. Why is there poor bowel motility with Hirschsprung disease? 3. Describe the defect in intussusception.

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Impairment of Digestion, Absorption, and Nutrition Cystic Fibrosis Cystic fibrosis (CF) is an autosomal recessive disease of the exocrine glands that involves multiple organ systems but mostly the GI and respiratory systems. CF leads to death at a younger age; the prognosis is determined mainly by the degree of pulmonary involvement. This section focuses on GI complications of CF. (Chapter 30 discusses the epidemiology and pulmonary involvement.) Pathophysiology The GI presentation of CF is caused by a dysfunction of the CF transmembrane regulator (CFTR) protein, which is located on epithelial membranes and regulates chloride and sodium ion channels. It is found throughout the airways, sweat glands, digestive tract, pancreas, hepatobiliary system, and reproductive system. The hallmark pathophysiologic triad of CF is obstruction, infection, and inflammation that are evident throughout the GI tract and within the airways. The full spectrum of involvement is summarized in Table 39.1. TABLE 39.1 Cystic Fibrosis—Pathophysiology, Clinical Manifestations, and Complications Organ Secretory Dysfunction Involved Sweat Elevated concentrations of sodium and Glands chloride in sweat Digestive System Esophagus None Intestine Newborn Viscid meconium Older child and adult Pancreas (enzyme deficiency)

Liver

Inspissated (dried out) mucofecal masses (intestinal sludging)

Inspissation and precipitation of pancreatic secretions, causing obstruction of pancreatic ducts Insulin deficiency

Clinical Manifestations

Complications

Hyponatremia; hypochloremia

Heat prostration; shock

Gastroesophageal reflux

Risk for aspiration events

Meconium ileus with intestinal obstruction Partial intestinal obstruction with severe cramping pains

Meconium peritonitis

Absence of pancreatic enzymes, causing malabsorption of food; fatty, bulky stools Decreased vitamins A, D, E, and K absorption Growth failure Glucose intolerance

Inspissation and precipitation of bile in Focal biliary cirrhosis; biliary system shrunken, “hobnail” liver

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Gastroesophageal reflux Volvulus (obstruction), intussusception (prolapse) Distal intestinal obstruction syndrome Hypoproteinemia; iron deficiency anemia; malnutrition Recurrent pancreatitis, pancreatic cysts Vitamins A, D, E, and K deficiency and rectal prolapse Decreased bone density and risk of fractures in adolescents and adults Diabetes mellitus Portal hypertension with esophageal varices, hematemesis and hypersplenism Hepatic steatosis

Salivary glands

Inspissation and precipitation of secretions in small ducts of submaxillary and sublingual salivary glands Respiratory System Paranasal Viscid mucus structures Nose Lungs

Nasal polyps Viscid mucus in bronchioles and bronchi

Reproductive System Male Viscid genital tract secretions during embryologic development, causing failure of formation of normal vas deferens Female Distention of endocervical epithelial cells with cytoplasmic mucin

Focal biliary cirrhosis Steatorrhea from lack of bile salts Mild patchy fibrosis of salivary None glands

Retention of mucus; clouding seen on sinus roentgenograms Obstruction of nasal airflow Obstruction of bronchioles causing bronchiolectasis, bronchiectasis, and chronic lung infection

Mucopyoceles (pus accumulations) with nasal deformity or orbital cavity extension None Hemoptysis; pneumothorax; cor pulmonale; atelectasis; chronic bacterial infection; respiratory failure

Delayed puberty Sterility

None

Delayed puberty Decreased fertility

Polypoid cervicitis (cervical inflammation) while taking oral contraceptives

Data from Assis DN, Freedman SD: Clin Chest Med 37(1):109–118, 2016; Lavelle LP et al: Radiographics 35(3):680–695, 2015; Leeuwen L, Fitzgerald DA, Gaskin KJ: Paediatr Respir Rev 15(1):69–74, 2014; Marcdante KJ, Kliegman RM, editors: Nelson essentials of pediatrics, ed 7, Philadephia, 2014, Saunders; Stalvey MS, Clines GA: Curr Opin Endocrinol Diabetes Obes 20(6):547–552, 2013.

Dysfunction of the CFTR protein results in altered sodium, chloride, and potassium resorption, all of which remain external to the surface of the epithelial membrane, with reduced clearance from tubular structures lined by affected epithelia. Maldigestion of proteins, carbohydrates, fats, and fat-soluble vitamins occurs because mucus obstruction of the pancreatic ducts blocks the flow of pancreatic enzymes, causing intestinal malabsorption and degenerative and fibrotic changes in the pancreas and GI tract. Diabetes mellitus commonly develops from damage to insulin-producing beta cells and insulin resistance. Clinical Manifestations Clinical manifestations are summarized in Table 39.1. Gastrointestinal symptoms often precede pulmonary manifestations. Most of those with CF present early in life with pancreatic insufficiency (PI). PI is the cause of nutrient malabsorption and failure to thrive in children with CF. Steatorrhea (fatty stools) and abdominal distention are common symptoms with potential sequelae that include DIOS, fibrotic colonopathy, intussusception, or focal biliary cirrhosis. Children who are pancreatic sufficient (PS) are at greater risk of developing pancreatitis. Evaluation and Treatment All states in the United States screen newborns for cystic fibrosis using a blood test to detect immunoreactive trypsinogen. Genetic screening and the sweat test are required for diagnosis. Evaluation of pancreatic sufficiency also is essential. The extent of pancreatic function is determined by 72-hour fecal fat measurements, which are not easily obtained. Therefore, the most common measurement of fat malabsorption is fecal elastase. A serum

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test for trypsinogen also can be used to detect pancreatic insufficiency in children older than 8 years of age. The goal of treatment for PI is to reduce malabsorption of nutrients and improve growth. Most children with CF take pancreatic enzyme replacement therapy (PERT) for the rest of their lives. PERT is administered before or with every meal, snack, or enteral feeding supplementation. High doses of PERT are associated with DIOS; therefore, minimal effective doses are indicated. High-caloric, high-protein diets with frequent snacks and vitamin supplements are used to treat malnutrition. Nutritional status and growth should be carefully monitored, and growth hormone may be included with nutritional supplements.24

Celiac Disease Celiac disease (CD), also known as celiac sprue or gluten-sensitive enteropathy, is an autoimmune disease that damages small intestinal villous epithelium when gluten (gliadin), the protein component of cereal grains, is ingested. CD is a common multiorgan disease with a strong genetic predisposition. It is associated with certain human leukocyte antigens (HLAs) and autoantibodies.25 Nonceliac gluten sensitivity (GS) occurs in individuals who do not have celiac disease or wheat allergy, however, they do have intestinal symptoms or extraintestinal symptoms, or both, when they ingest foods that contain gluten. Symptoms improve on withdrawal of gluten.26 The pathogenesis of CD is complex and involves genetic and immunologic factors. Environmental factors include early infections, gut microbiota in infants, feeding patterns, and the timing and amount of gluten. CD presents with greater frequency in children with type 1 diabetes mellitus, autoimmune thyroid or liver disease, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin A (IgA) deficiency, and Addison disease, and in those with first-degree relatives with CD. Pathophysiology The major pathophysiologic characteristic of celiac disease is autoimmune injury to the small intestinal epithelial cells of genetically susceptible individuals. There are increased numbers of intraepithelial lymphocytes, atrophy and flattening of villi, crypt hyperplasia in the upper small intestine, and malabsorption of most nutrients in the presence of cereal gluten, particularly wheat, rye, and barley (Fig. 39.6).

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FIGURE 39.6

Pathophysiology of Celiac Disease.

Damage to the mucosa of the duodenum and jejunum exacerbates malabsorption. The secretion of intestinal hormones, such as secretin and cholecystokinin, may be diminished. Consequently, secretion of pancreatic enzymes and expulsion of bile from the gallbladder are reduced, contributing to malabsorption. Destruction of mucosal cells causes inflammation, and water and electrolytes are secreted, leading to watery diarrhea. Potassium loss leads to muscle weakness. Magnesium and calcium malabsorption can cause seizures or tetany. Unabsorbed fatty acids combine with calcium, and secondary hyperparathyroidism increases phosphorus excretion, resulting in bone reabsorption. Calcium is no longer able to bind oxalate in the intestine and is absorbed, which causes hyperoxaluria. Gallbladder function may be abnormal, and bile salt conjugation may decrease. Fat malabsorption in the jejunum is the major cause of steatorrhea. Deficiencies of fatsoluble vitamins are common in children with CD. Vitamin K malabsorption leads to hypoprothrombinemia. There can be iron and folic acid malabsorption manifested as cheilosis; anemia; and a smooth, red tongue. Vitamin B12 absorption is impaired in those with extensive ileal disease, and folate and iron deficiencies are common. Clinical Manifestations The onset of clinical manifestations of celiac disease depends on the age of the infant when gluten-containing substances are added to the diet. It is not uncommon for a person to be diagnosed later in life. The severity of the symptoms can vary tremendously; many untreated children older than 3 years of age present with nongastrointestinal symptoms related to malabsorption and malnutrition, and the effect of autoantibodies on nonintestinal

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tissues. GI and extraintestinal symptoms of CD are listed in Box 39.1.

Box 39.1

Symptoms of Celiac Disease Gastrointestinal Symptoms Diarrhea Abdominal pain and distension Vomiting Anorexia Constipation

Extraintestinal Symptoms Fatigue Iron deficiency anemia Weight loss, growth failure Delayed puberty Infertility Dermatitis herpetiformis Dental enamel hypoplasia, aphthous stomatitis Arthritis Osteoporosis Fractures Neurologic manifestations: ataxia, neuropathy, seizures Data from Jericho H, Guandalini S: Nutrients 10(6), 2018; Leonard MM et al: JAMA 318(7):647-656, 2017. An unusual complication of celiac disease in infancy is celiac crisis. Celiac crisis is characterized by severe diarrhea, dehydration, and hypoproteinemia as a result of malabsorption and protein deficiency. Evaluation and Treatment The diagnosis includes confirmation with serologic autoantibody measurement against tissue transglutaminase IgA (most sensitive and specific), antiendomysium IgA, or deaminated gliadin peptides, which are more sensitive in children younger than 2 years of age. A negative genetic screening for HLA haplotypes rules out CD. If an autoantibody or genetic screen is positive, a small duodenal biopsy sample may be obtained to check for the classic mucosal changes caused by CD. A wide variety of screening tests for malabsorption also may be useful. Even though very useful screening tools are available to diagnose CD, many children remain undiagnosed. Treatment consists of lifelong adherence to a gluten-free diet (GFD), which includes the

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elimination of wheat, rye, barley, and malt. Lactose (milk sugar) intolerance also may be present from damage to villi; therefore, lactose also may be excluded from the diet but should be resumed after treatment. Infants are routinely given fat-soluble vitamins, iron, and folic acid supplements to treat deficiencies. Bone mineral density (BMD) screening is required. For most children the long-term prognosis is excellent. Refractory CD, which is resistant to a GFD treatment, is rare and may require steroids or immunosuppressants.

Malnutrition Pediatric malnutrition is an imbalance between nutrient requirements (energy expenditure) and intake that results in energy, protein, and micronutrient deficits that impair growth and development. Malnutrition may involve impaired absorption, altered nutrient utilization, increased nutrient losses, or increased nutrient requirements (hypermetabolism). Severe or moderate acute or chronic illnesses can contribute to the development of malnutrition, including surgery, trauma, burns, and chronic diseases (e.g., cystic fibrosis, tuberculosis, chronic kidney disease, malignancies, congenital heart disease [CHD], GI diseases, and neuromuscular diseases). Malnutrition unrelated to illness develops from a lack of access to nutrients as a result of environmental factors (i.e., political/socioeconomic, inadequate food supplies, or food contaminated with parasites) or behavioral factors (e.g., anorexia nervosa). Malnutrition may be acute (less than 3 months’ duration) or chronic (more than 3 months’ duration). Kwashiorkor (a deficiency of dietary protein) and marasmus (all forms of inadequate nutrient intake) are terms that have been used to describe types of malnutrition in children, particularly in developing countries. Collectively they are known as protein-energy malnutrition (PEM). PEM describes the effects of malnutrition but not the etiology or interactions that contribute to nutrient depletion. A definition of pediatric malnutrition that includes the etiology (illness or environmental), identification of pathogenesis and chronicity, associations with inflammation, and resulting impact on functional status is more directive for defining the risk of malnutrition, planning interventions, and assessing outcomes.27 States of long-term starvation are often the result of widespread nutritional deficiencies among children in developing countries and economically destitute populations, particularly when associated with human immunodeficiency virus (HIV) infection.28 Malnutrition can occur in infants or children from 1 to 4 years of age who have been weaned from breast milk to a high-starch, protein-deficient diet or switched to overdiluted commercial formulas that lack adequate protein and carbohydrates. Hospitalized children are at risk for malnutrition. Acute illness, trauma, surgery, or preexisting chronic diseases contribute to malnutrition and requires assessment and intervention. Acute and chronic inflammatory states also increase nutrient requirements. Treatments, including radiation therapy, chemotherapy, and longer times on mechanical ventilation, also can contribute to malnutrition with increased hospital length of stay, and increased morbidity and mortality rates.29 Pathophysiology The pathogenesis of PEM (kwashiorkor) is uncertain but includes inadequate dietary protein, leaky gut syndrome (compromised gut barrier), and intestinal inflammation. The lack of sufficient plasma proteins results in hypoproteinemia and generalized edema with a

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substantial loss of potassium. The liver swells with stored fat because no hepatic proteins are synthesized to form and release lipoproteins. Pancreatic atrophy and fibrosis may be present. There is reduced bone density and impaired renal function. If the condition is not reversed, the prognosis is very poor and growth is severely retarded. Lack of all nutrients (proteins, carbohydrates, fats, and micronutrients [marasmus]) is more common in infants and leads to dehydration, weight loss, and growth restriction. There is wasting of muscle and fat but not the edema associated with PEM. Alterations in gut microbiota also are involved in the pathophysiology of malnutrition.30 Children with malnutrition show stunting of gut microbiota maturation, which may delay normal development of the gut, depress intestinal immune function, and promote inflammation and infection. Healthy gut bacteria also produces short-chain fatty acids, B vitamins, and vitamin K, and promotes the absorption of minerals important for maintaining the intestinal epithelium.31 Clinical Manifestations Children with PEM have marked generalized edema, dermatoses, hypopigmented hair, a distended abdomen, hepatomegaly, and almost normal weight for age (because of edema). Children with malnutrition related to inadequate proteins, carbohydrates, fats, and micronutrients demonstrate greater wasting of protein and fat stores characterized by muscle wasting, diarrhea, dermatosis, low hemoglobin level, and infection. There is loss of subcutaneous fat and an absence of edema. Both conditions lead to delays in physical, behavioral, and cognitive development and academic performance. Lastly, micronutrient deficiencies, especially with zinc, selenium, iron, and antioxidant vitamins, can lead to immune deficiency and infections. Severe vitamin A deficiency commonly results in blindness.32 Evaluation and Treatment Evaluation of malnutrition is based on the nutritional history and clinical manifestations, including anthropometric measurements and use of appropriate growth charts. Laboratory monitoring is used to assess for macronutrient and micronutrient deficiencies, aminotransaminase alterations, the presence of inflammation, and response to refeeding. Treatment of underlying disease and provision of deficient nutrients will resolve clinical symptoms in 4 to 6 weeks.33 Developmental sequelae of malnutrition may be irreversible; therefore early intervention is recommended. Nutritional rehabilitation with appropriate environmental stimulation for infants and young children has been shown to resolve or improve cerebral shrinkage, physical growth, and psychomotor development.

Faltering Growth (Failure to Thrive) Faltering growth (previously known as failure to thrive [FTT]) is not a diagnosis but a physical sign demonstrating that a child has a slower rate of weight gain in childhood than expected for age and sex. It is manifested as a deceleration in weight gain, a low weight/height or body mass index (BMI) ratio, or a low weight/height/head circumference ratio. Faltering growth is a common problem and can present at any time in childhood but is usually present before 18 months of age.34 Pathophysiology

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Faltering growth is considered a multifactorial condition that includes biologic, psychosocial, and environmental contributions that may or may not be related to illness (Box 39.2). In more than 80% of cases, an underlying medical condition is never found. Categories of faltering growth include inadequate caloric intake, inadequate caloric absorption, or excessive caloric expenditure. Infants and children are at risk if their parents or primary caregivers are unable to provide nurturance.

Box 39.2

Factors Associated With Faltering Growth Poverty (food insecurity related to lack of money) Premature birth; low birth weight Inadequate caloric intake or caloric absorption (infant feeding problems, underlying chronic disease or malabsorption syndromes) Incorrect preparation of formula (too diluted, too concentrated) Mechanical feeding difficulties (oromotor dysfunction, congenital anomalies, central nervous system disorders) Unsuitable feeding habits (food fads, excessive juice) Behavior problems affecting eating Disturbed parent-child relationship; parental stress, parental lack of knowledge; child neglect Data from Krishna A et al: Glob Health Action 8:26523, 2015; National Guideline Alliance (UK): Faltering growth–recognition and management, London, 2017, National Institute for Health and Care Excellence (UK); available from https://www.ncbi.nlm.nih.gov/books/NBK458459/. Clinical Manifestations Clinical manifestations of faltering growth are delayed growth accompanied by manifestations of malnutrition or an underlying disease (e.g., diarrhea or infectious disease, or both). Infants who present with faltering growth frequently have feeding problems. Symptoms include pallid or dry, cracked skin; sparse hair; poorly developed musculature; decreased subcutaneous fat; swollen abdomen with malabsorption, diarrhea, or anorexia; and signs of vitamin deficiencies, such as rickets. Social or emotional manifestations include reduced energy level, reduced responsiveness and interaction with the environment, social isolation, spasticity and rigidity when held or touched, inability to make eye contact or smile, refusal to eat, and rejection of foods. There may be long-term adverse effects on cognitive, behavioral, and academic performance. Evaluation and Treatment Faltering growth is suggested if a child falls below the 3rd percentile for weight, or shows stagnation in length or weight on appropriate growth charts. Underlying medical conditions are evaluated. If illness is ruled out, a thorough review of psychosocial, emotional, and environmental components of care is necessary. Screening tools are

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available to assist with evaluation of nutrition status and to guide therapy, particularly in hospitalized children. Treatment for faltering growth includes treating an underlying illness if found, increasing volume or caloric density of formula, increasing frequency of breast-feeding (if found to be insufficient), structuring meals and snacks, and adding high-calorie foods and additives. Eliminating fruit juice, soda, or excessive milk also will improve appetite and absorption of nutrients. Medications are used to stimulate appetite. Nutrient deficiencies are supplemented. If the child is unable to gain weight, an oral enteral supplement may be added to the diet or a nasogastric or gastrostomy tube can be used to supplement oral intake. If the cause is not medical, management involves the immediate total care of the child and measures to address (1) the psychosocial and emotional problems of the caregivers and (2) parent-child interactions. Counseling, parental modeling, and long-term family support are sometimes required. Hospital admission and evaluation are recommended if the diagnosis is unclear or the child is in nutritional or emotional jeopardy. Eating patterns, food preferences, caloric intake, and family interactions can be assessed and treatment plans implemented during the hospital stay.

Necrotizing Enterocolitis Necrotizing enterocolitis (NEC) is an ischemic, inflammatory condition that causes bowel necrosis and perforation. NEC is not a specific diagnosis but a constellation of signs and symptoms with several proposed etiologies. It is the most common severe neonatal GI emergency that predominantly affects the smallest and most premature infants. Approximately 5% to 10% of infants born weighing less than 1500 g will develop NEC; of those, about 40% will not survive.35 Pathophysiology The exact etiology of NEC is unclear.36 Factors contributing to the development of NEC include infections, abnormal bacterial colonization, intestinal ischemia, immature immune responses, exaggerated inflammatory responses, immature intestinal motility, altered microcirculatory blood flow and barrier function, perinatal stress, effects of medications and feeding practices, and genetic predisposition. The immature mucosal barrier delays digestion and motility is slower, allowing for the accumulation of noxious substances that damage the intestine, increase permeability, and increase the risk for infection. Translocation of intestinal bacteria and other substances contributes to injury, with inflammation, vasoconstriction of mesenteric blood flow, development of systemic inflammatory disease, multiple organ failure and death. Immature intestinal innate immunity and an unfavorable balance between normal and pathogenic bacteria promote intestinal inflammation and release of proinflammatory cytokines. Accumulation of gas in the intestine can cause pressure that decreases blood flow, and an imbalance between vasodilator and vasoconstrictor inputs in the immature gut may lead to vasoconstriction promoting ischemia and oxidative stress, reperfusion injury, and necrosis. Clinical Manifestations Manifestations of NEC usually appear suddenly and within weeks of premature birth, and

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sooner for term neonates. Signs and symptoms of “classic” NEC include feeding intolerance, abdominal distention and bloody stools after 8 to 10 days of age, septicemia with an elevated white blood cell count, and falling platelet levels. An unstable temperature, bradycardia, and apnea are nonspecific signs. In late preterm or term infants, NEC is more likely to be associated with other predisposing factors, such as low Apgar scores, chorioamnionitis, exchange transfusions, prolonged rupture of membranes, congenital heart defects, or neural tube defects. Evaluation and Treatment The diagnosis is based on the clinical manifestations, laboratory results, and plain films of the abdomen. Symptoms usually progress rapidly, often within hours, from subtle signs to abdominal discoloration, intestinal perforation, and peritonitis or even death. Abdominal radiographs show pneumoperitoneum, pneumatosis intestinalis (gas in the bowel wall), or unchanging “rigid” loops of small bowel. Systemic hypotension requires intensive medical support or bowel resection, or both. Efforts are in progress to identify predictive biologic markers for early diagnosis. Preventive strategies include encouragement of breast milk feeding, preferential feeding of human milk, judicious fluid management to prevent vascular fluid overload, and confirmation of patent ductus arteriosus (see Chapter 27). Additional treatments include administration of amino acids (i.e., arginine and glutamine supplements) to support intestinal epithelial cell growth, and enteral probiotics to support normal gut bacteria. The rapid onset of symptoms makes primary prevention difficult. Treatments include cessation of feeding, implementation of gastric suction to decompress the intestines, maintenance of fluid and electrolyte balance, and administration of antibiotics to control sepsis. Surgical resection is the treatment of choice for perforation, and peritoneal drainage may be used as an adjunct to laparotomy. Overall mortality is high, particularly for infants who have surgery.

Quick Check 39.3 1. Why do individuals with cystic fibrosis have pancreatic insufficiency? 2. Why does loss of villi occur with celiac disease? 3. Compare kwashiorkor and marasmus.

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Diarrhea Diarrhea is an increase in the water content, volume, or frequency of stools and can be acute or chronic. Diarrhea is usually defined as three or more watery or loose stools in 24 hours. Children with acute gastroenteritis often remain mildly symptomatic for up to 4 weeks, therefore, diarrhea that persists longer than 4 weeks is considered chronic. Diarrhea is a common GI problem during infancy and early childhood and is the leading cause of death in young children, particularly among preterm infants and children in developing countries.37 Severe, acute infectious diarrhea occurs one to three times during the first 3 years of life. Most episodes are self-limiting and resolve within 72 hours. The pathophysiologic mechanisms of diarrhea in children are similar to those described for adults—osmotic, secretory, intestinal dysmotility, or inflammatory (see Chapter 38). Prolonged diarrhea is more dangerous in infants and children, however, because they have much smaller fluid reserves and more rapid peristalsis and metabolism than adults. Therefore dehydration in children can develop rapidly if any disturbance: • increases fluid secretion into the GI lumen (secretory diarrhea). • draws fluid into the lumen by osmosis (osmotic diarrhea). • reduces intestinal transit time with luminal fluid retention (intestinal dysmotility). • causes inflammation that results in malabsorption and an increased luminal osmotic load from nutrients, fluid, and blood, which may increase gut motility (inflammatory diarrhea).

Acute Infectious Diarrhea Diarrhea in infants and young children has numerous causes, including bacterial and systemic infections, malabsorption syndromes, autoimmune disorders, congenital malformations, and genetic disorders. Acute infection is the most common cause of childhood diarrhea worldwide.37 Acute infectious diarrhea in infants and young children is usually associated with viral or bacterial gastroenteritis. Viruses include rotaviruses, noroviruses, and adenoviruses. Rotavirus is a common cause in young children and is associated with a higher death rate in low-income countries. Rotavirus vaccination is an effective preventive strategy. Numerous bacteria or parasites can contaminate food or water and cause diarrhea. Bacterial causes of diarrhea have geographic variation, and specific bacteria can be identified using molecular analysis or stool culture. Clostridium difficile is often associated with previous antibiotic therapy. Infectious diarrhea has a rapid onset, with watery stools sometimes mixed with blood, abdominal cramping, fever, vomiting, and weight loss. Severe dehydration, acidosis, and shock can occur quickly from diarrhea and vomiting. Hemolytic uremic syndrome and renal failure can develop when diarrhea is associated with Shigella toxin and Escherichia coli infection (see Chapter 33). Other causes of acute diarrhea in the older child include antibiotic therapy, appendicitis, chemotherapy, inflammatory bowel disease, parasitic infestation, parenteral infections, and ingestion of toxic substances.

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Treatment of diarrhea requires evaluation of the cause through the history, stool testing for common pathogens, and laboratory analysis. Treatment of underlying illness is warranted when identified. Other treatments include hydration, electrolyte replacement, nutrition maintenance, and antibiotics if a pathogen is found. Antispasmodics may relieve abdominal cramping, and selected probiotics can reduce the duration and improve morbidity and mortality.38 Intravenous solutions are used only when oral solutions are not tolerated. Prevention includes clean water, environmental sanitation, and good hygiene.

Primary Lactose Intolerance Lactose malabsorption and lactose intolerance, the inability to digest lactose, are caused by inadequate production or impaired activity of the enzyme lactase. It is a common cause of diarrhea, particularly in children under the age of 7 years. The malabsorption of lactose results in osmotic diarrhea accompanied by abdominal pain, bloating, and flatulence. Systemic manifestations include skin disease, rheumatologic complaints, chronic fatigue, and failure to thrive. Intolerance to other forms of carbohydrates and deficient enzymes can cause symptoms similar to lactose intolerance.39 The diagnosis can be made through elimination of dietary lactose or by performing a hydrogen lactose breath test or an oral lactose tolerance test. Treatment consists of reducing milk consumption or supplementing the diet with oral lactase. Some children can tolerate lactose in fermented forms, such as cheese and yogurt, or by adding soy food. A diet low in fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAPs) or administration of probiotics to alter intestinal flora has been found to be effective in children with lactose intolerance and IBS who have persistent symptoms.

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Disorders of the Liver Disorders of Biliary Metabolism and Transport Neonatal Jaundice Jaundice (icterus) is a yellow pigmentation of the skin caused by an increased level of bilirubin in the bloodstream (i.e., a total serum bilirubin [TSB] level that exceeds the 95th percentile for the infant's age in hours or greater than 20 mg/dl, except in the low birth weight population). Jaundice usually becomes clinically apparent when the serum bilirubin concentration is greater than 2 mg/dl (34 µmol/L). Physiologic jaundice (hyperbilirubinemia) of the newborn is a frequently encountered problem in otherwise healthy newborns caused by lack of maturity of bilirubin uptake and conjugation. Poor caloric intake or dehydration, or both, associated with inadequate breast-feeding also may contribute to the high levels of bilirubin. High bilirubin levels in the newborn period can be associated with hemolytic disease, metabolic and endocrine disorders, anatomic abnormalities of the liver, and infections. For older infants and children, the most common causes of unconjugated hyperbilirubinemia are hemolytic processes resulting in bilirubin overproduction. Pathologic jaundice is a bilirubin concentration greater than 20 mg/dl in the newborn period associated with a severe illness, or a total serum bilirubin level that rises by more than 5 mg/dl during the newborn period. Risk factors for development of pathologic jaundice include fetal-maternal blood type incompatibility (ABO and Rh incompatibility, hemolytic disease in the newborn), premature birth, exclusive breast-feeding in some infants, maternal age greater than or equal to 25 years, male sex, delayed meconium passage, glucose-6-phosphate dehydrogenase deficiency, and excessive birth trauma, such as bruising or cephalohematomas.40 Pathophysiology Pathologic jaundice results from the complex interaction of factors that cause (1) increased bilirubin production (e.g., hemolysis), (2) impaired hepatic uptake or excretion of unconjugated bilirubin, or (3) delayed maturation of liver bilirubin conjugating mechanisms. The most common cause is hemolytic disease of the newborn and all pregnant women should be tested for ABO and Rh incompatibility (see Chapters 8 and 24). Unconjugated bilirubin (indirect bilirubin) is lipid soluble and bound to albumin in the blood, and in the free form it readily crosses the blood-brain barrier in infants. Chronic bilirubin encephalopathy (kernicterus) is caused by the deposition of toxic, unconjugated bilirubin in brain cells and usually does not occur in healthy, full-term infants. The mechanism of injury is not clearly known. An elevated level of conjugated bilirubin is a sign of underlying disease. Clinical Manifestations Physiologic jaundice develops during the second or third day after birth and usually subsides in 1 to 2 weeks in full-term infants and in 2 to 4 weeks in premature infants. After this, increasing bilirubin values and persistent jaundice indicate pathologic hyperbilirubinemia. Manifestations include yellowing of the skin, dark urine, light-colored

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stools, and weight loss. Premature infants with respiratory distress, acidosis, or sepsis are at greater risk for kernicterus and the development of bilirubin-induced neurologic dysfunction (BIND) (e.g., neuromotor signs, hyperexcitable neonatal reflexes, and speech and hearing impairment).41 Evaluation and Treatment Jaundice is detected by clinical assessment. Both total and direct (conjugated) bilirubin levels are monitored. Other causes of jaundice must be eliminated to confirm physiologic jaundice. Treatment depends on the degree of hyperbilirubinemia. Physiologic jaundice is commonly treated by phototherapy and several techniques are available. Pathologic jaundice requires an exchange transfusion and treatment of the underlying disorder.

Biliary Atresia Biliary atresia (BA) is a rare congenital malformation characterized by the absence or obstruction of extrahepatic bile ducts resulting in neonatal cholestasis. The etiology of duct injury is not clear but is thought to be related to an embryonic (or congenital) abnormality or an acquired anomaly (e.g., perinatal viral-induced progressive inflammation with innate autoimmune destruction). The disease expression is a continuum in which the principal process is one of bile duct destruction. The atresia of the bile ducts is associated with inflammation, fibrosis, loss of epithelial cells, and obstruction of the bile canaliculi. Progressive obstruction leads to secondary biliary cirrhosis (see Chapter 38), portal hypertension, or liver failure. Jaundice is the primary clinical manifestation of BA, along with hepatomegaly and acholic (clay-colored) stools. Fat absorption is impaired because of the lack of bile salts. Abdominal distention caused by hepatomegaly and ascites may cause anorexia and faltering growth. Fat-soluble vitamin deficiencies (A, D, E, K) require supplementation. Manifestations of cirrhosis and liver failure include ascites, hypoalbuminemia, hypercoagulation, pruritus, esophageal varices, and gastrointestinal bleeding that may lead to death. Early diagnosis of BA is essential; the best outcome is achieved when the infant is diagnosed and treated in the first 30 to 45 days of life. BA that is diagnosed late does not respond well to current surgical treatment. The diagnosis of BA is based on the clinical manifestations, abnormal liver function test results, liver biopsy results, and an intraoperative cholangiogram. Serum aminotransaminase and alkaline phosphatase levels are elevated, and conjugated (direct) serum bilirubin levels rise progressively. BA can be relieved by hepatoportoenterostomy (HPE, or the Kasai procedure), in which a segment of the small intestine is used to create a bile duct. Even with initial restoration of bile flow, however, obliteration of intrahepatic bile ducts can continue and cirrhosis results. Liver transplantation is performed for 80% of children with BA and is the only long-term therapeutic option.42

Inflammatory Disorders Hepatitis Details related to viral hepatitis are presented in Chapter 38, including differentiation of the types of viruses (see Table 38.8).

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Hepatitis A virus. HAV is transmitted through contact with the feces of people infected with HAV. Approximately 30% to 50% of the reported cases of hepatitis A virus (HAV) occur in children, particularly children of nursery school age. Outbreaks tend to occur in day-care centers with large numbers of children who are not toilet trained and with staff members who practice poor handwashing techniques.43 Vertical transmission from mother to newborn or from a transfusion is rare. HAV in children is usually mild and asymptomatic, but it may involve nausea, vomiting, and diarrhea. Jaundice appears in more than 70% of older children. Almost all children recover from hepatitis A without residual liver damage, although relapse may occur. After HAV infection, the body produces antibodies that prevent reinfection. Vaccination programs have successfully reduced the incidence of HAV in the United States by 95%.44 Hepatitis B virus. Risk factors for hepatitis B virus (HBV) include infants of mothers who are chronic hepatitis B surface antigen (HBsAg) carriers, children from families that immigrated to the United States or are adopted from endemic areas, infection from HBsAg-positive household contacts, and children who abuse parenteral drugs or engage in unprotected sex. Maternalfetal transmission (vertical transmission) is the most common route of HBV transmission in children. About 25% to 50% of children between the ages of 1 and 5 years of age who are acutely infected will develop chronic infection. Chronic hepatitis may develop more often in young children because their immune system is immature. The most serious consequence of HBV infection is fulminant hepatitis, which occurs in 1% of cases. Hepatitis D virus (HDV) infection depends on active infection with HBV. Exacerbation of HBV is more common in children with an HDV superinfection. There is evidence that the risk of fulminant hepatitis is higher in individuals with combined infection with HBV, HDV, HCV, or HIV than in those with HBV infection alone. There also is a higher risk of hepatocellular carcinoma and increased mortality in this group. Aggressive HBV vaccination programs have reduced the incidence of HBV; HDV reduction has mirrored this response. To prevent perinatal transmission of HBV, immunoprophylaxis and HBV vaccination within the first 12 hours of birth are recommended, with close follow-up visits. Treatment is conservative, and antivirals are used for chronic disease. Children ages 2 to 17 years who are HBsAg seropositive for more than 6 months with elevated serum alanine transaminase (ALT) and HBV deoxyribonucleic acid (DNA) levels for more than 3 months respond to treatment with antivirals. Maternal antiviral therapy during pregnancy and lactation reduces the HBV mother-to-child transmission rate.45,46 Hepatitis C virus. Hepatitis C virus (HCV) in children is most commonly transmitted vertically and is enhanced by maternal coinfection with HIV. Risk factors for vertical transmission include internal fetal monitoring, prolonged rupture of membranes, and fetal anoxia. HCV transmission also can occur through exposure to infected blood or contaminated materials (as in injection drug use or tattooing and body piercing) and, less commonly, after sexual encounters with partners infected with HCV. Transmission from blood transfusions has become a negligible risk with universal HCV screening of blood. With vertical transmission, spontaneous resolution of HCV is high; otherwise, the disease is usually mild

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in children and cirrhosis is rare. Because of adverse drug events, only children with persistently elevated serum aminotransferases or those with progressive liver disease are treated with antiviral drugs.47 Chronic hepatitis. HBV and HCV are the main causes of chronic hepatitis in children. Manifestations of chronic hepatitis include malaise, anorexia, fever, GI bleeding, hepatomegaly, edema, and transient joint pain. Often there are no symptoms. Serum alanine aminotransferase and bilirubin levels are elevated. There may be evidence of impairment of synthetic functions of the liver: prolonged prothrombin time, thrombocytopenia, and hypoalbuminemia. The diagnosis is based on the clinical manifestations and liver biopsy results. There is no curative therapy for chronic HBV or chronic HCV. Children are treated with antiviral drugs and should continue to be monitored. Liver transplant may ultimately be required for chronic hepatitis. There is an autoimmune form of chronic hepatitis, known as autoimmune hepatitis (AIH) or autoimmune primary sclerosing cholangitis (PSC), which has an unknown etiology. The pathogenic mechanism is thought to be immunologic with loss of tolerance to hepatocytespecific autoantigens, environmental, or genetic in nature. These diseases present with elevations in the levels of aminotransferases, autoantibodies, and immunoglobulin G (IgG). AIH is more common in female children. Both females and males are treated with immunosuppressive therapy; about 50% to 80% will achieve remission and long-term survival.48

Cirrhosis Cirrhosis is fibrotic scarring of the liver, in response to inflammation and tissue damage, that results in obstruction to the flow of blood and bile. Most forms of chronic liver diseases in children can progress to cirrhosis, but they seldom do so. The complications of cirrhosis in children are the same as those in adults: portal hypertension, the opening of collateral vessels between the portal and systemic veins, and varices. In addition, children with cirrhosis experience growth failure caused by nutritional deficits, as well as developmental delay, particularly in gross motor function because of ascites and weakness. The cause of cirrhosis may influence its severity and course (i.e., biliary atresia and hepatitis). Some types of cirrhosis can be stabilized if the cause is identified and treated early.49 The risk of cirrhosis is increasing in obese children with nonalcoholic fatty liver disease (see Did You Know? Childhood Obesity and Nonalcoholic Fatty Liver Disease).

Did You Know? Childhood Obesity and Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. It is associated with obesity, insulin resistance, genetic predisposition, ethnicity, the gut microbiome, and environmental factors (diet and lack of exercise). NAFLD is associated with dyslipidemia, hypertension, and early cardiac dysfunction in

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children and can progress to cirrhosis and cardiometabolic syndrome within a few years if not treated. The rise in childhood obesity worldwide is contributing to the increasing prevalence of NAFLD. The disease usually presents in prepubertal children and is predominant in males and in children of Hispanic origin. The diagnosis is made by exclusion of other causes of the disease, usually by 12 to 13 years of age. Liver biopsy is required for definitive diagnosis of nonalcoholic steatohepatitis (NASH). Compared to adults, there are differences in the extent of fat, inflammation, and fibrosis in children, and there is no standard scoring system. There also is no consensus regarding treatment. Exercise and slow, consistent weight loss with a low glycemic index diet have been shown to be more effective than a low-fat diet in lowering body weight. Pharmacologic agents are being evaluated to control insulin resistance and prevent the progression of liver disease and cirrhosis. Omega-3 fatty acids, probiotics, and vitamin E may delay disease progression. Research is in progress to define the pathophysiology, noninvasive diagnostic procedures, and prevention measures. Data from Fang YL et al: World J Gastroenterol 24(27):2974-2983, 2018; Goyal NP, Schwimmer JB: Clin Liver Dis 22(1):59-71, 2018; Selvakumar PKC et al: Pediatr Clin North Am 64(3):659-675, 2017.

Metabolic Disorders More than 5000 genetically determined metabolic pathways have been identified in liver tissue. The earliest possible identification of metabolic disorders is essential because (1) early treatment may prevent permanent damage to vital organs, such as the liver or brain; (2) precise genetic counseling may be possible with prenatal diagnosis; and (3) complications can be minimized, even if cure is not possible. More common inborn errors of metabolism include galactosemia, fructosemia, and Wilson disease, which have treatable hepatic clinical manifestations. The mechanisms of disease, clinical manifestations, and evaluation and treatment of these disorders are reviewed in Table 39.2. TABLE 39.2 Galactosemia, Fructosemia, and Wilson Disease Galactosemia Fructosemia Deficiency of Deficiency of fructose-1galactose-1-phosphate phosphate aldolase uridylyltransferase Autosomal recessive trait Autosomal recessive Cannot metabolize fructose, trait sucrose, or honey; occurs when Cannot convert breast milk is replaced with galactose to glucose cow's milk Toxic accumulation of Toxic accumulation of fructose galactose in body in body tissues tissues, liver, and brain Clinical High levels of blood High levels of blood fructose manifestation galactose Vomiting Vomiting Hypoglycemia Hypoglycemia May have failure to thrive May have failure to Hepatomegaly thrive Jaundice Symptoms of cirrhosis Seizures Mechanism of disease

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Wilson Disease Defect in copper excretion by liver Autosomal recessive: defect on chromosome 13 (ATP 7B) Impaired transport of copper into bile/blood caused by diminished transport protein (ceruloplasmin) Toxic accumulations of copper in liver, brain, kidney, corneas Intention tremors Indistinct speech Dystonia Greenish yellow rings in cornea Hepatomegaly Jaundice Anorexia

Evaluation

Treatment

at 2-6 months— jaundice Intellectual disabilities if not treated Cataracts if not treated Newborn screening Presence of reducing substances in urine when infant is receiving lactose Galactose-free diet

Renal tubular defects

Detailed dietary history Liver or intestinal mucosa biopsy Fructose-, sucrose-, honey-free diet Vitamin C supplementation

Low plasma ceruloplasmin level

Chelation therapy to remove copper from body Decreased dietary intake of copper Liver transplantation

Quick Check 39.4 1. Why is diarrhea such a serious disorder in infants and children? 2. What is biliary atresia? 3. What are the three most common metabolic disorders that cause liver damage in children?

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Summary Review Congenital Impairment of Motility in the Gastrointestinal Tract 1. Alterations of digestive function in children include congenital or acquired disorders of the intestinal tract; disorders of digestion, absorption, or nutrition; or liver disease. 2. CL and CP (failure of the bony palate to fuse in the midline) may occur separately or together. The fissure may affect the uvula, soft palate, hard palate, nostril, and maxillary alveolar ridge, with difficulty sucking and swallowing. 3. EA, a condition in which the esophagus ends in a blind pouch, may occur with or without a TEF. As the infant swallows oral secretions or ingests milk, the pouch fills, causing either drooling, regurgitation, or aspiration into the lungs. 4. IHPS is an obstruction of the pyloric outlet caused by hypertrophy of circular muscles in the pyloric sphincter. 5. In intestinal malrotation, the small intestine lacks a normal posterior attachment during fetal development, causing volvulus (twisting of the bowel on itself) that may partly or completely occlude the GI tract and its blood vessels. 6. Meckel diverticulum is a congenital malformation of the GI tract involving all layers of the small intestinal wall; it usually occurs in the ileum. 7. Meconium ileus is a newborn condition in which intestinal secretions and amniotic waste products produce a thick, sticky plug that obstructs the intestine; it occurs in up to 20% of newborns with cystic fibrosis. 8. Hirschsprung disease (congenital aganglionic megacolon) is caused by a malformation of the parasympathetic nervous system in a segment of the colon needed for peristalsis, resulting in colon obstruction. 9. Malformations of the anus and rectum range from mild congenital stenosis of the anus to complex deformities.

Acquired Impairment of Motility in the Gastrointestinal Tract 1. GERD is the presence of symptoms related to the return of stomach contents into the esophagus. This is caused by relaxation or incompetence of the lower esophageal sphincter that results from immaturity of the gastroesophageal sphincter. 2. Intussusception is the telescoping of a proximal segment of intestine into a distal segment, causing an obstruction. 3. Appendicitis is common in children 10 to 11 years of age, and the mechanisms of disease, symptoms, and treatment are similar to those for adults.

Impairment of Digestion, Absorption, and Nutrition 1. CF is an inherited fibrocystic disease that involves mucosal chloride and sodium

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ion channels in many organs, including the GI tract and pancreas; CF causes pancreatic enzyme deficiency with maldigestion. 2. CD is caused by hypersensitivity to gluten protein, with autoimmune injury and loss of the villous epithelium. It results in malabsorption and growth failure. 3. Pediatric malnutrition is an imbalance between nutrient requirements and intake that results in energy, protein, and micronutrient deficits, which impair growth and development. 4. Kwashiorkor is a severe protein deficiency. Marasmus is a deficiency of all dietary nutrients, including carbohydrates. 5. Faltering growth, or FTT, is a multifactorial condition that includes biologic, psychosocial, and environmental contributions. It may or may not be related to illness, and it results in inadequate physical growth and development of a child. 6. NEC is an ischemic, inflammatory disorder in neonates, particularly premature infants, thought to result from immaturity, infection, stress, and anoxia of the bowel wall.

Diarrhea 1. Diarrhea in infants and children is three or more watery or loose stools in 24 hours. It may last up to 4 weeks in acute cases, or longer in chronic cases. It is commonly caused by viral or bacterial enterocolitis. 2. Primary lactose intolerance is the inability to digest milk sugar because of a lack of the enzyme lactase, resulting in osmotic diarrhea.

Disorders of the Liver 1. Physiologic jaundice of the newborn is caused by mild hyperbilirubinemia that subsides in 1 or 2 weeks. Pathologic jaundice is caused by severe hyperbilirubinemia and can cause brain damage (kernicterus). 2. Biliary atresia is a congenital malformation of the bile ducts that obstructs bile flow and causes jaundice, cirrhosis, and liver failure. 3. Acute hepatitis is usually caused by a virus, and hepatitis A is the most common form of childhood hepatitis. Chronic hepatitis B or C usually occurs by maternal transmission. 4. Cirrhosis is fibrotic scarring of the liver and is rare in children, but it can develop from most forms of chronic liver disease. 5. The most common metabolic disorders or inborn errors of metabolism that cause liver damage in children are galactosemia, fructosemia, and Wilson disease. All three are inherited as genetic traits and allow toxins to accumulate in the liver and other body tissues.

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Key Terms Anorectal malformation (ARM), 920 Atresia, 917 Biliary atresia (BA), 928 Celiac crisis, 924 Celiac disease (CD), 923 Cirrhosis, 929 Cleft lip (CL), 916 Cleft palate (CP), 916 Cystic fibrosis (CF), 922 Diarrhea, 927 Distal intestinal obstruction syndrome (DIOS), 919 Eosinophilic esophagitis (EoE), 921 Esophageal atresia (EA), 917 Faltering growth, 926 Fructosemia, 929 Galactosemia, 929 Gastroesophageal reflux (GER), 920 Gastroesophageal reflux disease (GERD), 920 Hepatitis A virus (HAV), 928 Hepatitis B virus (HBV), 928 Hepatitis C virus (HCV), 929 Hepatitis D virus (HDV), 928 Hirschsprung disease, 920 Infantile hypertrophic pyloric stenosis (IHPS), 918 Intestinal malrotation, 919 Intussusception, 921 Jaundice (icterus), 927 Kernicterus, 928 Kwashiorkor, 925 Lactose intolerance, 927 Lactose malabsorption, 927 Marasmus, 925 Meckel diverticulum, 919 Meconium, 919 Meconium ileus (MI), 919 Meconium plug syndrome (MPS), 919 Necrotizing enterocolitis (NEC), 926 Nonceliac gluten sensitivity (GS), 924 Nonsyndromic (isolated) CP, 916 Pathologic jaundice, 928 Physiologic jaundice (hyperbilirubinemia) of the newborn, 927 Protein-energy malnutrition (PEM), 925 Rotavirus, 927

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Syndromic CLP, 916 Tracheoesophageal fistula (TEF), 917 Wilson disease, 929

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1. Arosarena OA. Cleft lip and palate. Otolaryngol Clin North Am. 2007;40(1):27–60. 2. National Institute of Dental and Craniofacial Research (NIDCR). Prevalence (number of cases) of cleft lip and palate. [updated October 13, 2011; Available at] www.nidcr.nih.gov/DataStatistics/FindDataByTopic/CraniofacialBirthD [Last reviewed July 2018]. 3. Dixon MJ, et al. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011;12(3):167– 178. 4. Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet. 2013;163C(4):246–258. 5. Molina-Solana R, et al. Current concepts on the effect of environmental factors on cleft lip and palate. Int J Oral Maxillofac Surg. 2013;42(2):177–184. 6. Mossey PA, et al. Cleft lip and palate. Lancet. 2009;374(9703):1773–1785. 7. Farronato G, et al. How various surgical protocols of the unilateral cleft lip and palate influence the facial growth and possible orthodontic problems? Which is the best timing of lip, palate and alveolus repair? Literature review. Stomatologija. 2014;16(2):53–60. 8. Jayaram R, Huppa C. Surgical correction of cleft lip and palate. Front Oral Biol. 2012;16:101–110. 9. Shaye D. Update on outcomes research for cleft lip and palate. Curr Opin Otolaryngol Head Neck Surg. 2014;22(4):255–259. 10. Lee S. Basic knowledge of tracheoesophageal fistula and esophageal atresia. Adv Neonatal Care. 2018;18(1):14–21. 11. van der Zee DC, Tytgat SHA, van Herwaarden MYA. Esophageal atresia and tracheo-esophageal fistula. Semin Pediatr Surg. 2017;26(2):67–71. 12. El-Gohary Y, et al. Pyloric stenosis: an enigma more than a century after the first successful treatment. Pediatr Surg Int. 2229

2018;34(1):21–27. 13. Langer JC. Intestinal rotation abnormalities and midgut volvulus. Surg Clin North Am. 2017;97(1):147–159. 14. Lin XK, et al. Clinical characteristics of Meckel diverticulum in children: a retrospective review of a 15-year single-center experience. Medicine (Baltimore). 2017;96(32):e7760. 15. Sathe M, Houwen R. Meconium ileus in Cystic Fibrosis. J Cyst Fibros. 2017;16(Suppl 2):S32–S39. 16. Butler Tjaden NE, Trainor PA. The developmental etiology and pathogenesis of Hirschsprung disease. Transl Res. 2013;162(1):1–15. 17. Wester T, Granström AL. Hirschsprung disease—bowel function beyond childhood. Semin Pediatr Surg. 2017;26(5):322–327. 18. Cairo SB, et al. Challenges in transition of care for patients with anorectal malformations: a systematic review and recommendations for comprehensive care. Dis Colon Rectum. 2018;61(3):390–399. 19. Mousa H, Hassan M. Gastroesophageal reflux disease. Pediatr Clin North Am. 2017;64(3):487–505. 20. Adamiak T, Plati KF. Pediatric esophageal disorders: diagnosis and treatment of reflux and eosinophilic esophagitis. Pediatr Rev. 2018;39(8):392–402. 21. Applegate KE. Intussusception in children: evidence-based diagnosis and treatment. Pediatr Radiol. 2009;39(Suppl 2):S140–S143. 22. Tate JE, et al. Intussusception rates before and after the introduction of rotavirus vaccine. Pediatrics. 2016;138(3). 23. Gray MP, et al. Recurrence rates after intussusception enema reduction: a meta-analysis. Pediatrics. 2014;134(1):110–119. 24. Sathe MN, Freeman AJ. Gastrointestinal, pancreatic, and hepatobiliary manifestations of cystic fibrosis. Pediatr Clin North Am. 2016;63(4):679–698. 25. Leonard MM, et al. Celiac disease and nonceliac gluten sensitivity: a review. JAMA. 2017;318(7):647–656. 26. Barbaro MR, et al. Recent advances in understanding non2230

celiac gluten sensitivity. F1000Res. 2018;7 [Faculty Rev-1631]. 27. Beer SS, et al. Pediatric malnutrition: putting the new definition and standards into practice. Nutr Clin Pract. 2015;30(5):609–624. 28. Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg. 2009;103(6):541–548. 29. Prieto MB, Cid JL. Malnutrition in the critically ill child: the importance of enteral nutrition. Int J Environ Res Public Health. 2011;8(11):4353–4366. 30. Million M, Diallo A, Raoult D. Gut microbiota and malnutrition. Microb Pathog. 2017;106:127–138. 31. Kane AV, Dinh DM, Ward HD. Childhood malnutrition and the intestinal microbiome malnutrition and the microbiome. Pediatr Res. 2015;77(0):256–262. 32. Maida JM, et al. Pediatric ophthalmology in the developing world. Curr Opin Ophthalmol. 2008;19(5):403–408. 33. Kismul H, et al. Diet and kwashiorkor: a prospective study from rural DR Congo. PeerJ. 2014;2:e350. 34. Homan GJ. Failure to thrive: a practical guide. Am Fam Physician. 2016;94(4):295–299. 35. Müller MJ, Paul T, Seeliger S. Necrotizing enterocolitis in premature infants and newborns. J Neonatal Perinatal Med. 2016;9(3):233–242. 36. Hackam D, Caplan M. Necrotizing enterocolitis: pathophysiology from a historical context. Semin Pediatr Surg. 2018;27(1):11–18. 37. Scharf RJ, Deboer MD, Guerrant RL. Recent advances in understanding the long-term sequelae of childhood infectious diarrhea. Curr Infect Dis Rep. 2014;16(6):408. 38. Hojsak I. Probiotics in Children: what is the evidence? Pediatr Gastroenterol Hepatol Nutr. 2017;20(3):139–146. 39. Berni Canani R, et al. Diagnosing and treating intolerance to carbohydrates in children. Nutrients. 2016;8(3):157. 40. Muchowski KE. Evaluation and treatment of neonatal 2231

hyperbilirubinemia. Am Fam Physician. 2014;89(11):873–878. 41. Bhutani VK, Wong RJ, Stevenson DK. Hyperbilirubinemia in preterm neonates. Clin Perinatol. 2016;43(2):215–232. 42. Zagory JA, Nguyen MV, Wang KS. Recent advances in the pathogenesis and management of biliary atresia. Curr Opin Pediatr. 2015;27(3):389–394. 43. Klevens RM, et al. The evolving epidemiology of hepatitis A in the United States: incidence and molecular epidemiology from population-based surveillance, 2005-2007. Arch Intern Med. 2010;170(20):1811–1818. 44. Centers for Disease Control and Prevention (CDC). Viral hepatitis–hepatitis A information, overview and statistics. [Available at] https://www.cdc.gov/hepatitis/hav/havfaq.htm#vaccine [Page last reviewed May 8, 2019]. 45. Karnsakul W, Schwarz KB. Hepatitis B and C. Pediatr Clin North Am. 2017;64(3):641–658. 46. Komatsu H, Inui A. Hepatitis B virus infection in children. Expert Rev Anti Infect Ther. 2015;13(4):427–450. 47. El-Guindi MA. Hepatitis C viral infection in children: updated review. Pediatr Gastroenterol Hepatol Nutr. 2016;19(2):83–95. 48. Moy L, Levine J. Autoimmune hepatitis: a classic autoimmune liver disease. Curr Probl Pediatr Adolesc Health Care. 2014;44(11):341–346. 49. Cordova J, Jericho H, Azzam RK. An overview of cirrhosis in children. Pediatr Ann. 2016;45(12):e427–e432.

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UNIT 12

The Musculoskeletal and Integumentary Systems OUTLINE 40 Structure and Function of the Musculoskeletal System 41 Alterations of Musculoskeletal Function 42 Alterations of Musculoskeletal Function in Children 43 Structure, Function, and Disorders of the Integument 44 Alterations of the Integument in Children

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Structure and Function of the Musculoskeletal System Geri C. Reeves

CHAPTER OUTLINE Structure and Function of Bones, 933 Elements of Bone Tissue, 933 Types of Bone Tissue, 937 Characteristics of Bone, 938 Maintenance of Bone Integrity, 939 Structure and Function of Joints, 940 Fibrous Joints, 940 Cartilaginous Joints, 940 Synovial Joints, 943 Structure and Function of Skeletal Muscles, 943 Whole Muscle, 943 Components of Muscle Function, 947 Tendons and Ligaments, 951 Aging & the Musculoskeletal System, 952 Aging of Bones, 952 Aging of Joints, 952 Aging of Muscles, 952

The way an individual functions in daily life, moves about, or manipulates objects physically depends on the integrity of the musculoskeletal system. The musculoskeletal system is actually two systems: (1) the skeleton composed of bones and joints and (2) soft tissues (skeletal muscles, tendons, and ligaments). Each system contributes to mobility. The skeleton supports the body and provides leverage to the skeletal muscles so that movement of various parts of the body is possible. Contraction of the skeletal muscles and bending or rotation at the joints facilitate movements of the various body parts.

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Structure and Function of Bones Bones give form to the body, support tissues, and permit movement by providing points of attachment for muscles. Many bones meet in movable joints that determine the type and extent of movement possible. Bones also protect many of the body's vital organs. For example, the bones of the skull, thorax, and pelvis are hard exterior shields that protect the brain, heart and lungs, and reproductive and urinary organs, respectively. Within certain bones, the marrow cavities serve as storage sites for the hematopoietic stem cells that form both blood and immune cells. In adults, blood cells originate exclusively in the marrow cavities of the skull, vertebrae, ribs, sternum, shoulders, and pelvis. The development of blood cells is discussed in Chapter 22. Bones also have a crucial role in mineral homeostasis (storing minerals [i.e., calcium, phosphate, carbonate, magnesium] that are essential for the proper performance of many delicate cellular mechanisms), have a role in hormone homeostasis, and assist in maintaining normal immunologic function.

Elements of Bone Tissue Mature bone is a rigid connective tissue consisting of cells; fibers; a homogenous, gelatinous medium termed ground substance; and large amounts of crystallized minerals, mainly calcium, that give bone its rigidity. Ground substance consists of proteoglycans and hyaluronic acid secreted by chondroblasts. The structural elements of bone are summarized in Table 40.1. TABLE 40.1 Structural Elements of Bone Structural Elements Bone Cells Osteoblasts Osteoclasts Osteocytes Bone Matrix Bone morphogenic proteins (BMPs) BMP-1 BMP-2 BMP-3 (osteogenin) BMP-4 BMP-6 BMP-7

Function Synthesize collagen and proteoglycans, mineralize osteoid matrix; produce receptor activator of nuclear factor-κB ligand (RANKL), which in turn stimulates osteoclast resorption of bone; also produce osteoprotegerin (OPG), which inhibits osteoclast formation by binding to RANKL Resorb bone; major role in bone homeostasis Transform osteoblasts trapped in osteoid; signal both osteoblasts and osteoclasts; maintain bone matrix; mechanosensory receptors to reduce or augment bone mass; produce sclerostin (SOST), which inhibits bone growth Subfamily of transforming growth factor-β (TGF-β) cytokine growth factors; induce and regulate bone and cartilage formation; affect all other organ systems Unrelated to other BMPs (is a metalloprotease); key role in extracellular matrix (ECM) formation Promotes chondrogenesis, bone formation; clinically used to enhance bone formation in spine surgery Inhibits bone formation Osteoblast differentiation; involved in cartilage repair, endochondral bone formation; enhances chondrogenesis Found in human plasma; promotes osteoblast differentiation from mesenchymal stem cells (MSCs) Osteogenic cell formation from MSCs; enhances bone formation in spine surgery; induces formation of brown fat

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BMP-9 BMP-13 Collagen fibers Proteoglycans Glycoproteins Albumin αGlycoproteins Laminin Osteocalcin Osteonectin Sialoprotein Minerals Calcium Phosphate Alkaline phosphatase Vitamins Vitamin D Vitamin K

Promotes osteoblast formation from MSCs Inhibits bone formation by reducing calcium mineralization Lend support and tensile strength Control transport of ionized materials through matrix Transports essential elements to matrix; maintains osmotic pressure of bone fluid Promote calcification Stabilizes basement membranes in bones Vitamin K–dependent protein present in bone; inhibits calcium phosphate precipitation (attracts calcium ions to incorporate into hydroxyapatite crystals); serum osteocalcin is a sensitive marker of bone formation Binds calcium in bone; necessary for normal bone formation Promotes calcification, osteoblast formation Crystallizes, providing bone rigidity and compressive strength Balance of organic and inorganic phosphate required for proper bone mineralization; regulates vitamin D, promoting mineralization Promotes mineralization

Assists with differentiation, mineralization of osteoblasts Increases bone calcification; reduces serum osteocalcin

Bone cells enable bone to grow, repair itself, change shape, and continuously synthesize new bone tissue and resorb (dissolve or digest) old tissue. The fibers in bone are made of collagen, which gives bone its tensile strength (the ability to hold itself together). Ground substance acts as a medium for the diffusion of nutrients, oxygen, metabolic wastes, biochemicals, and minerals between bone tissue and blood vessels. Bone formation begins during embryonic development when mesenchymal stem cells begin differentiating into either chondrocytes or preosteoblasts. In mature bone, the formation of new tissue begins with the production of an organic matrix by the bone cells. This bone matrix consists of ground substance, collagen, and other proteins (see Table 40.1) that take part in bone formation and maintenance. The next step in bone formation is calcification, in which minerals are deposited and then crystallize. Minerals bind tightly to collagen fibers, producing tensile and compressional strength in bone and allowing it to withstand pressure and weightbearing.

Bone Cells Bone contains three types of cells: osteoblasts, osteocytes, and osteoclasts (Fig. 40.1). Both osteoblasts and osteocytes originate from osteoprogenitor cells found in the mesenchymal stem cell lineage. Osteoclasts originate from hematopoietic stem cells. Osteoblasts are the bone-forming cells. Osteocytes, the most numerous cells within bone, are osteoblasts that have become imprisoned within the mineralized bone matrix. They have multiple important duties in maintaining bone homeostasis, including synthesizing new bone matrix molecules and initiating osteoclast function. Osteoclasts primarily resorb (remove) bone during processes of growth and repair.

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FIGURE 40.1 Bone Cells. A, Osteoblasts are responsible for the production of collagenous and noncollagenous proteins that compose osteoid. Active osteoblasts are aligned on the osteoid. Note the eccentrically located nuclei. B, Electron photomicrograph of an osteocyte. Osteocytes reside within the lacunae of compact bone. C, Osteoclasts actively resorb mineralized tissue. The scalloped surface in which the multinucleated osteoclasts rest is termed Howship lacuna. (A and C from Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby; B from Wikimedia Commons, courtesy Robert M. Hunt.)

Osteoblasts. Originating from mesenchymal stem cells (MSCs), osteoblasts are the primary boneproducing cells, and are involved in many functions related to the skeletal system (see Table 40.1). Osteoblasts are responsive to parathyroid hormone (PTH) and produce osteocalcin when stimulated by 1,25-dihydroxy-vitamin D3. Osteoblasts are active on the outer surfaces of bones, where they form a single layer of cells. Osteoblasts initiate new bone formation by their synthesis of osteoid (nonmineralized bone matrix). Osteoblasts also mineralize newly formed bone matrix. Stimulation of new bone formation and orderly mineralization of bone matrix occur by concentrating some of the plasma proteins (growth factors) found in the bone matrix and by facilitating the deposit and exchange of calcium and other ions at the site. Enzymes, signaling proteins, and growth factors, including bone morphogenic proteins (BMPs) and other members of the transforming growth factor-beta (TGF-β) superfamily, are critical components of bone formation, maintenance, and remodeling (Table 40.2). TABLE 40.2 Selected Factors Affecting Bone Formation, Maintenance, and Remodeling Factor Function Transforming growth Superfamily of polypeptides; regulates bone formation, many other cellular processes factor-beta (TGF-β) through signaling Platelet-derived growth Increases number of osteoblasts factor (PDGF) Fibroblast growth factor FGF-2 increases osteoblast population, but not function; inhibits alkaline phosphatase (FGF) activity, osteocalcin, type I collagen, and osteopontin Insulin-Like Growth Factor (IGF) IGF-1 Increases peak bone mass during adolescence; decreases osteoblast apoptosis; maintains bone matrix IGF-2 Increases BMP-9–induced endochondral ossification Smad proteins Mediate signaling cascade of TGF-β, especially in embryonic bone development; play role in crosstalk between BMP/TGF-β and Wnt signaling pathways

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Bone morphogenic proteins Members of TGF-β superfamily of polypeptides; have many functions outside skeletal (BMPs) system; stimulate endochondral bone and cartilage formation and function, promote osteoblast maturation; augment bone remodeling by affecting both osteoblasts and osteoclasts Tumor necrosis factors Superfamily of cytokines; play major role in regulating bone metabolism, especially (TNFs) osteoclast function Osteoprotegerin (OPG) Inhibits bone remodeling/resorption; produced by several cells, including osteoblasts; is a decoy receptor for RANKL (binds to RANKL, inhibiting RANK/RANKL interactions, suppressing osteoclast formation and bone resorption); also may directly interfere with ability of osteoclasts’ podosomes to attach to bone matrix Receptor activator of Stimulates differentiation of osteoclast precursors; activates mature osteoclasts nuclear factor-κB (RANK) Receptor activator of Promotes osteoclast differentiation/activation; inhibits osteoclast apoptosis nuclear factor-κB ligand (RANKL) BMP antagonists Prevent BMP signaling Noggin Binds BMP-2 and -4, reducing osteoblast function Gremlin Multiple effects in and out of skeletal system, but also binds BMP-2, -4, and -7, thus reducing BMP signaling; may play role in development of osteoporosis Twisted gastrulation Acts as either a BMP agonist or a BMP antagonist Activin (a BMP-related Affects both osteoblasts and osteoclasts; may promote bone formation and fracture healing; protein) expressed by both osteoblasts and chondrocytes; helps regulate bone mass Annexins Class of calcium-binding proteins; help mineralize matrix vesicles; may influence bone formation Inhibin Dominant over activin and BMPs; helps regulate bone mass and strength by affecting formation of osteoblasts and osteoclasts Leptin Plays role in bone formation and resorption Wnt Antagonists Dickkopf family (Dkk) Disrupt Wnt signaling, leading to reduced bone mass Sclerostin A protein secreted by osteocytes, osteoblasts, and osteoclasts; binds to BMP-6 and BMP-7; interferes with Wnt signaling pathway, inhibiting bone formation by osteoblasts Transcription Factors β-Catenin pathway Protein with multiple functions; one of most important is activation of genetic transcription factors; balance between Wnt/β-catenin signaling promotes normal bone formation/resorption Wnts (complex signaling Important in differentiating osteoblasts, bone formation; has overlapping effects with pathway) BMPs, helps regulate bone formation and remodeling; crosstalks with other signaling pathways Nuclear factor of activated Affects embryonic osteoclastogenesis; plays role in certain osteoclast, osteoblast, and B cells (NF-κB) chondroblast functions Matrix Metalloproteinases (MMPs) Family of endopeptidases Help maintain equilibrium of extracellular matrix (ECM); breakdown almost all (enzymes) that includes components of ECM collagenases, gelatinases, stromelysins, matrilysins A disintegrin and Proteolytic enzymes; also have cell-signaling functions, usually linked to cell membrane metalloproteinase (ADAM) A disintegrin and Similar to ADAMs but are secreted into circulation, are found around cells; various metalloproteinase with subgroups affect multiple tissues thrombospondin motifs (ADAMTs) Cysteine protease Cathepsin K expressed by osteoclasts; assists in bone remodeling by cleaving proteins, such as collagen type I, collagen type II, and osteonectin Mmp Inhibitors Tetracyclines (especially Block enzymatic function of MMPs doxycycline), bisphosphonates Tissue inhibitors of Balance effect of MMPs in maintaining ECM equilibrium metalloproteinases (TIMPs)

From Boyce BF et al: Ann N Y Acad Sci 1192:367-375, 2010; Genetos DC et al: PLoS One 9(9):e107482, 2015; Kim Y-S et al: J Korean Med Sci 25:985-991, 2010; Norrie JL et al: Dev Biol 393 (2):270-281, 2014; Stewart A et

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al: J Cell Physiol 223(3):658-666, 2010; Wang RN et al: Genes Dis 1(1):87-105, 2014; Zhao H et al: Cytokine 71(2):199-206, 2014.

Osteoblasts use intercellular calcium signaling to include osteoclastic activity. One of the most important discoveries linking osteoblast and osteoclast function is the cytokine receptor activator nuclear factor κ-B ligand, or RANKL (discussed later). RANKL is expressed by osteoblasts and osteocytes and is necessary for forming osteoclasts1-3 (see the Osteoclasts section). Thus, the cells of the osteoblastic lineage (osteoblasts, osteocytes) form a network of cells in bone that sense the shape and structure of bone and determine where it is appropriate that bone be formed or resorbed, according to the Wolff law (bone is shaped according to its function). Osteoblasts synthesize and secrete osteoid when active, and in the resting state they are termed satellite cells. If appropriately stimulated, however, the resting osteoblasts are capable of resuming activity. Osteocytes. Osteocytes, the most abundant cells in bone, are transformed osteoblasts trapped or surrounded in osteoid as it hardens because of minerals that enter during calcification (see Fig. 40.1, B). The osteocyte is within a space in the hardened bone matrix called a lacuna. Osteocytes are the most abundant cells found in bone and have numerous functions, including acting as mechanoreceptors and synthesizing certain matrix molecules, playing a major role in controlling osteoblast differentiation and production of growth factors, and maintaining bone homeostasis. As the major source of sclerostin, RANKL, and osteoprotegerin, osteocytes are thought to be key regulators of both bone formation and bone resorption.4-6 They also help concentrate nutrients in the matrix. Osteocytes obtain nutrients from capillaries in the canaliculi, which contain nutrient-rich fluids. Through exchanges among these cells, hormone catalysts, and minerals, optimal levels of calcium, phosphorus, and other minerals are maintained in blood plasma. One of the osteocyte's primary functions is to act as a mechanoreceptor, responding to changes in weight bearing or other stressors (“loading”) on bone. Lying within the lacunae are the osteocyte's primary cilia, which are likely the primary mechanoreceptors in bone. Once changes in bone, such as mechanical stress, hormonal imbalance, loading, or unloading, are detected by the osteocyte's mechanoreceptors, multiple molecular signals are produced and the process of bone remodeling begins. Remodeling is described in the Maintenance of Bone Integrity section. Osteoclasts. Osteoclasts are large (typically 20 to 100 µm in diameter), multinucleated cells that develop from the hematopoietic monocyte-macrophage lineage. Osteoclasts are the major resorptive cells of bone. They migrate over bone surfaces to resorption areas that have been prepared and stripped of osteoid by enzymes, such as collagenases produced by osteoblasts in the presence of PTH, which is necessary for the resorptive process. Osteoclasts travel over the prepared bone surfaces, creating irregular, scalloped cavities known as Howship lacunae or resorption bays, as they resorb bone areas and then acidify hydroxyapatite to dissolve it. A specific area of the cell membrane forms adjacent to the bone surface and develops multiple infoldings to permit intimate contact with the resorption bay. These infoldings,

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known as the ruffled border, greatly increase the surface areas of cells under their scalloped or ruffled borders. Osteoclasts resorb bone by secretion of hydrochloric acid, acid proteases (such as cathepsin K), and matrix metalloproteinases (MMPs) that help digest collagen, along with the action of cytokines (see Table 40.2). Osteoclasts also resorb bone through the action of lysosomes (digestive vacuoles) filled with hydrolytic enzymes in their mitochondria. Osteoclasts bind to the bone surfaces through attachments called podosomes, which are footlike structures that cluster together along a sealing membrane that forms a “belt” containing multiple proteins, enzymes, and integrin receptors. Once resorption is complete, the osteoclasts retract and loosen from the bone surface under the ruffled border through the action of calcitonin. Calcitonin binds to receptor areas of the osteoclasts’ cell membranes to effectively loosen the osteoclasts from the bone surfaces. Once resorption is completed, osteoclasts disappear by the process of degeneration, either by reverting to the form of their parent cells or by undergoing cell movements away from the site, in which the osteoclast becomes an inactive or a resting osteoclast. In addition to resorption of bone, osteoclasts assist the endocrine and renal systems in maintaining appropriate serum calcium and phosphorus levels. Osteoclasts also appear to have a role in the body's immune response.

OPG/RANKL/RANK System Osteoprotegerin (OPG), a glycoprotein belonging to the tumor necrosis factor superfamily, inhibits bone remodeling and resorption, inhibiting osteoclast formation. Numerous cells, including osteoblasts and osteocytes, produce it. OPG is the key to the interaction between osteoblasts and osteoclasts. Osteoblasts and osteoclasts cooperate (a process called coupling) to maintain normal bone homeostasis. RANKL is an essential cytokine needed for the formation and activation of osteoclasts. Like an automobile's accelerator, RANKL increases bone loss. OPG, similar to an automobile's brakes, reduces bone loss because when it is activated, it promotes bone formation. When RANKL binds to its receptor (i.e., receptor activator nuclear factor κ-B [RANK]) on osteoclast precursor cells, it triggers their proliferation and increases bone resorption. OPG is secreted by osteoblasts and B lymphocytes and serves as a decoy by binding to RANK, preventing RANKL from binding to RANK and thus preventing bone resorption. Therefore, the overall balance between RANKL and OPG determines the amount of bone loss. The balance between RANKL and OPG is regulated by cytokines and hormones. Alterations of the RANKL/RANK/OPG system can lead to dysregulation and pathologic conditions, including primary osteoporosis, immune-mediated bone diseases, malignant bone disorders, and inherited skeletal diseases (see Fig. 40.5).

Bone Matrix Bone matrix is made of the extracellular elements of bone tissue, specifically collagen fibers, structural proteins (e.g., proteoglycans and certain glycoproteins), carbohydrate-protein complexes, ground substance, and minerals. Collagen fibers. Collagen fibers make up the bulk of bone matrix. They are formed in this way:

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1. Osteoblasts synthesize and secrete type I collagen and osteocalcin. 2. Collagen molecules assemble into three thin chains (alpha chains) to form fibrils. 3. Fibrils organize into the staggered pattern, with each fibril overlapping its nearest neighbor by about one fourth its length. This creates gaps into which mineral crystals are deposited. 4. After mineral deposition, fibrils interlink and twist to form ropelike fibers. 5. The fibers join to form the framework that gives bone its tensile and supportive strength. Proteoglycans. Proteoglycans are large complexes of numerous polysaccharides attached to a common protein core. They strengthen bone by forming compression-resistant networks between the collagen fibers. Proteoglycans also control the transport and distribution of electrically charged particles (ions), particularly calcium, through the bone matrix, thereby playing a role in bone calcium deposition and calcification. Proteoglycans are important constituents of ground substance. Glycoproteins. Glycoproteins are carbohydrate-protein complexes that control the collagen interactions that lead to fibril formation. They also may function in calcification. Four glycoproteins are present in bone: sialoprotein, which binds easily with calcium; osteocalcin, which binds preferentially to crystallized calcium; bone albumin, which is identical to serum albumin and possibly transports essential nutrients to and from bone cells and maintains the osmotic pressure of bone fluid; and alpha-glycoprotein (α-glycoprotein), which probably plays a significant role in calcification and also may facilitate bone resorption by activating osteoclasts (see Table 40.1).

Bone Minerals After collagen synthesis and fiber formation, the final step in bone formation is mineralization. Mineralization has two distinct phases: (1) formation of the initial mineral deposit (initiation) and (2) proliferation or accretion of additional mineral crystals on the initial mineral deposits (growth). The majority of the minerals in the body are an analog of the naturally occurring mineral hydroxyapatite (HAP). The HAP crystals then penetrate the matrix vesicle membrane and enter into the extracellular space. As the calcium and phosphorus concentrations increase in the bone matrix, the first precipitate to form is dicalcium phosphate dihydrate (DCPD). Once DCPD precipitation begins, the remaining phases of bone crystal formation proceed until insoluble HAP is produced, with approximately 80% to 90% of the HAP incorporated into the collagen fibers. Amorphous calcium phosphate is distributed throughout the bone matrix.

Types of Bone Tissue Bone is composed of two types of bony (osseous) tissue: compact bone (cortical bone) and spongy bone (cancellous bone) (Fig. 40.2). Cortical bone is about 85% of the skeleton; cancellous bone makes up the remaining 15%. Both types of bone tissue contain the same structural elements, with a few exceptions. In addition, both compact tissue and spongy

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tissue are present in every bone. The major difference between the two types of tissue is the organization of the elements.

FIGURE 40.2 Anatomy of the Bone. A, External anatomy of a long bone. B, Internal structure of a long bone showing spongy (cancellous) and compact bone. (From Solomon E: Introduction to human anatomy and physiology, ed 4, St Louis, 2016, Saunders.)

Compact bone is highly organized, solid, and extremely strong. The basic structural unit in compact bone is the haversian system (Fig. 40.3). Each haversian system consists of:

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FIGURE 40.3 Structure of Compact and Cancellous Bone. A, Magnified view of compact bone. B, Longitudinal section of a long bone showing both cancellous and compact bone. C, Section of a flat bone. Outer layers of compact bone surround cancellous bone. Fine structure of compact and cancellous bone is shown in the electron photomicrograph. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Mosby. Photo courtesy Dennis Strete.)

• A central canal, called the haversian canal • Concentric layers of bone matrix, called lamellae (sing., lamella) • Tiny spaces (lacunae) between the lamellae • Bone cells (osteocytes) within the lacunae • Small channels or canals, called canaliculi (sing., canaliculus) Spongy bone is less complex and lacks haversian systems. In spongy bone, the lamellae are not arranged in concentric layers but in plates or bars termed trabeculae (sing., trabecula) that branch and unite with one another to form an irregular meshwork. The pattern of the meshwork is determined by the direction of stress on the particular bone. The spaces between the trabeculae are filled with red bone marrow. The osteocyte-containing lacunae are distributed between the trabeculae and interconnected by canaliculi. Capillaries

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pass through the marrow to nourish the osteocytes. All bones are covered with a double-layered connective tissue called the periosteum. The outer layer of the periosteum contains blood vessels and nerves, some of which penetrate to the inner structures of the bone through channels called Volkmann canals (Fig. 40.3). The inner layer of the periosteum is anchored to the bone by collagenous fibers (Sharpey fibers) that penetrate the bone. Sharpey fibers also help hold or attach tendons and ligaments to the periosteum of bones.

Characteristics of Bone The human skeleton consists of 206 bones that constitute the axial skeleton and the appendicular skeleton. The axial skeleton consists of 80 bones that make up the skull, vertebral column, and thorax. The appendicular skeleton consists of 126 bones that make up the upper and lower extremities, the shoulder girdle (pectoral girdle), and the pelvic girdle (os coxae) (Fig. 40.4). The skeleton contributes approximately 14% of an adult's body weight.

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FIGURE 40.4

Anterior View of the Skeleton. (From Drake R, et al: Gray's atlas of anatomy, ed 2, Philadelphia, 2015, Churchill Livingstone.)

Bones can be classified by shape as long, flat, short (cuboidal), or irregular. Long bones are longer than they are wide and consist of a narrow tubular midportion (diaphysis) that merges into a broader neck (metaphysis) and a broad end (epiphysis) (see Fig. 40.2). The diaphysis consists of a shaft of thick, rigid compact bone that is able to tolerate bending forces. Contained within the diaphysis is the elongated marrow (medullary) cavity. The marrow cavity of the diaphysis contains primarily fatty tissue, which is referred to as yellow marrow. The yellow marrow assists red bone marrow in hematopoiesis only

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during times of stress. The yellow marrow cavity of the diaphysis is continuous with marrow cavities in the spongy bone of the metaphysis and diaphysis. The marrow contained within the epiphysis is red because it contains primarily blood-forming tissue (see Chapter 22). A layer of connective tissue, the endosteum, lines the outer surfaces of both types of marrow cavity. The broadness of the epiphysis allows weight bearing to be distributed over a wide area. The epiphysis is made up of spongy bone covered by a thin layer of compact bone. In a child, the epiphysis is separated from the metaphysis by a cartilaginous growth plate (epiphyseal plate). After puberty, the epiphyseal plate calcifies and the epiphysis and metaphysis merge. By adulthood, the line of demarcation between the epiphysis and metaphysis is undetectable. In flat bones, such as the ribs and scapulae, two plates of compact bone are nearly parallel to each other. Between the compact bone plates is a layer of spongy bone. Short bones, such as the bones of the wrist or ankle, are often cuboidal. They consist of spongy bone covered by a thin layer of compact bone. Irregular bones, such as the vertebrae, mandibles, or other facial bones, have various shapes that include thin and thick segments. The thin part of an irregular bone consists of two plates of compact bone surrounding spongy bone. The thick part consists of spongy bone surrounded by a layer of compact bone.

Maintenance of Bone Integrity Remodeling The internal structure of bone is maintained by remodeling, a three-phase process in which existing bone is resorbed and new bone is laid down to replace it. Clusters of bone cells, termed basic multicellular units, implement remodeling. The basic multicellular units are made up of bone precursor cells that differentiate into osteoclasts and osteoblasts. Precursor cells are located on the free surfaces of bones and along the vascular channels (especially the marrow cavities). In phase 1 (activation) of the remodeling cycle, a stimulus (e.g., hormone, drug, vitamin, physical stressor) activates the cytokine system, particularly the tumor necrosis factor (TNF) superfamily, to form osteoclasts. Osteoclasts attach to the bone matrix by actin microfilaments and multiple other proteins that form footlike structures called podosomes. Once attached, the osteoclasts’ integrin receptors anchor its microfilaments to the extracellular matrix, thus providing receptor pathways between the osteocyte and bone matrix. Lysosomal enzymes produced by osteoclasts “digest” bone; the osteoclasts then release the degraded bone products into the vascular system. After bone is resorbed, the osteoclast leaves behind an elongated cavity termed a resorption cavity. The resorption cavity in compact bone follows the longitudinal axis of the haversian system, whereas the resorption cavity in spongy bone parallels the surface of the trabeculae. New bone formation begins as osteoblasts lining the walls of the resorption cavity express osteoid and alkaline phosphatase, forming sites for calcium and phosphorus deposition. As the osteoid mineralizes, new bone is formed. Successive layers (lamellae) in compact bone are laid down, until the resorption cavity is reduced to a narrow haversian canal around a blood vessel. In this way, old haversian systems are destroyed and new haversian systems are formed. New trabeculae are formed in spongy bone. The formation phase takes 4 to 6 months in humans.

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Repair The remodeling process can repair microscopic bone injuries, but gross injuries, such as fractures and surgical wounds (osteotomies), heal by the same stages as soft tissue injuries, except that new bone, instead of scar tissue, is the final result (see Chapter 6). The stages of bone healing are listed here and shown in Fig. 40.5:

FIGURE 40.5 Bone Remodeling. All bone cells participate in bone remodeling. In the remodeling sequence, bone sections are removed by bone-resorbing cells (osteoclasts) and replaced with a new section laid down by bone-forming cells (osteoblasts). Bone remodeling is necessary because it allows the skeleton to respond to mechanical loading, maintains quality control (repair and prevent microdamage), and allows the skeleton to release growth factors and minerals (calcium and phosphate) stored in bone matrix to the circulation. The cells work in response to signals generated in the environment (see F). Only the osteoclastic cells mediate the first phase of remodeling. They are activated, scoop out bone (A), and resorb it; then the work of the osteoblasts begins (B). They form new bone that replaces bone removed by the resorption process (C). The sequence takes 4 to 6 months. D, Micrograph of active bone remodeling seen in the settings of primary or secondary hyperparathyroidism. Note the active osteoblasts surmounted on red-stained osteoid. Marrow fibrosis is present. E, Bone remodeling cycle in normal bone with (F). Numerous signaling factors are necessary for remodeling. Factors most important for resorption include granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-1 (IL-1) and IL-6, receptor activator for nuclear factor-κB ligand (RANKL), prostaglandin E2 (PGE2), and tumor necrosis factor-alpha (TNF-α). Important factors for bone formation include osteoprotegerin (OPG), transforming growth factor-beta (TGF-β), and estrogen. (Adapted from Nucleus Medical Art. D from Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)

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1. Hematoma formation 2. Procallus formation 3. Callus formation 4. Replacement (basic multicellular units of the callus are replaced with lamellar or trabecular bone) 5. Remodeling (periosteal and endosteal surfaces of the bone are remodeled to the size and shape of the bone before injury) The speed with which bone heals depends on the severity of the bone disruption; the type and amount of bone tissue that need to be replaced (spongy bone heals faster); the blood and oxygen supply available at the site; the presence of growth and thyroid hormones, insulin, vitamins, and other nutrients; the existence of systemic disease; the effects of aging (see the Osteoporosis section in Chapter 41); and the availability of effective treatment, including immobilization and the prevention of complications such as infection. In general, however, hematoma formation occurs within hours of fracture or surgery, formation of procallus by osteoblasts within days, callus formation within weeks, and replacement and contour modeling within years—up to 4 years in some cases.

Quick Check 40.1 1. Name the different types of bone cells. 2. What are the major cells involved in bone resorption? 3. What are the stages of bone wound healing? 4. Briefly describe the process of remodeling.

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Structure and Function of Joints The site where two or more bones are attached is called a joint, or an articulation (Fig. 40.6). The primary function of joints is to provide stability and mobility to the skeleton. A joint's function depends on both its location and its structure. Generally, joints that stabilize the skeleton have a simpler structure than those that enable the skeleton to move. Most joints provide both stability and mobility to some degree.

FIGURE 40.6 Various Kinds of Joints. Fibrous: A, Syndesmosis (tibiofibular); B, suture (skull). Cartilaginous: C, Symphysis (vertebral bodies); D, synchondrosis (first rib and sternum). Synovial: E, Condyloid (wrist); F, gliding (radioulnar); G, hinge or ginglymus (elbow); H, ball and socket (hip); I, saddle (carpometacarpal of thumb); J, pivot (atlantoaxial). (From Dorland: Dorland's medical illustrated dictionary, ed 32, St Louis, 2012, Saunders.)

Joints are classified based on the degree of movement they permit or on the connecting tissues that hold them together. Based on movement, a joint is classified as a synarthrosis (immovable joint), an amphiarthrosis (slightly movable joint), or a diarthrosis (freely movable joint). From connective structures, joints are classified broadly as fibrous, cartilaginous, or synovial. Each of these three structural classifications can be subdivided according to the shape and contour of the articulating surfaces (ends) of the bones and the type of motion the joint permits.

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A joint in which bone is united directly to bone by fibrous connective tissue is called a fibrous joint. These joints have no joint cavity and allow little, if any, movement. Fibrous joints are further subdivided into three types: sutures, syndesmoses, and gomphoses. A suture has a thin layer of dense fibrous tissue that binds together interlocking flat bones in the skulls of young children. Sutures form an extremely tight union that permits no motion. By adulthood, the fibrous tissue has been replaced by bone. A syndesmosis is a joint in which the two bony surfaces are united by a ligament or membrane. The fibers of ligaments are flexible and stretch, permitting a limited amount of movement. The paired bones of the lower arm (radius and ulna) and the lower leg (tibia and fibula) and their ligaments are syndesmotic joints. A gomphosis is a special type of fibrous joint in which a conical projection fits into a complementary socket and is held in place by a ligament. The teeth held in the maxilla or mandible are gomphosis joints.

Cartilaginous Joints There are two types of cartilaginous joints: symphyses and synchondroses. A symphysis is a cartilaginous joint in which bones are united by a pad or disk of fibrocartilage. A thin layer of hyaline cartilage usually covers the articulating surfaces of these two bones, and the thick pad of fibrocartilage acts as a shock absorber and stabilizer. Examples of symphyses are the symphysis pubis, which joins the two pubic bones, and the intervertebral disks, which join the bodies of the vertebrae. A synchondrosis is a joint in which hyaline cartilage, rather than fibrocartilage, connects the two bones. The joints between the ribs and the sternum are synchondroses. The hyaline cartilage of these joints is called costal cartilage. Slight movement at the synchondroses between the ribs and the sternum allows the chest to move outward and upward during breathing.

Joint (Articular) Capsule The joint (articular) capsule is fibrous connective tissue that covers the ends of bones where they meet in a joint; Sharpey fibers firmly attach the proximal and distal capsule to the periosteum, and ligaments and tendons also may reinforce the capsule. It is composed of parallel, interlacing bundles of dense, white fibrous tissue richly supplied with nerves, blood vessels, and lymphatic vessels. Nerves in and around the joint capsule are sensitive to rate and direction of motion, compression, tension, vibration, and pain.

Synovial Membrane The synovial membrane is a smooth, delicate inner lining of joint capsule found in the nonarticular portion of the synovial joint and any ligaments or tendons that traverse this cavity. It is composed of two layers: the vascular subintima and the thin cellular intima. The vascular subintima merges with the fibrous joint capsule and is composed of loose fibrous connective tissue, elastin fibers, fat cells, fibroblasts, macrophages, and mast cells; the cellular intima consists of rows of synovial cells embedded in fiber-free intercellular matrix and contains two types of cells—A and B. A cells (macrophages) ingest and remove (phagocytose) bacteria and particles of debris in the joint cavity; B cells (fibroblasts) are the most numerous and secrete hyaluronate, which gives synovial fluid its viscous quality. The synovial membrane is richly supplied with blood and lymphatic vessels and is capable of rapid repair and regeneration.

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Joint (Synovial) Cavity The joint (synovial) cavity is an enclosed, fluid-filled space between articulating surfaces of two bones, also called joint space. It enables two bones to move “against” one another and is surrounded by synovial membrane and filled with synovial fluid.

Synovial Fluid Synovial fluid is superfiltrated plasma from blood vessels that lubricates the joint surfaces, nourishes the pad of the articular cartilage, and covers the ends of the bones. Hyaluronic acid in the synovial fluid gives it important biomechanical properties. It also contains freefloating synovial cells and various leukocytes that phagocytose joint debris and microorganisms.

Articular Cartilage Articular cartilage is a layer of hyaline cartilage that covers the end of each bone; it may be thick or thin, depending on the size of the joint, the fit of the two bone ends, and the amount of weight and shearing force the joint normally withstands. The function of articular cartilage is to reduce friction in the joint and to distribute the forces of weightbearing. Articular cartilage is composed of chondrocytes (cartilage cells) (about 2% of the tissue) and an intercellular matrix consisting of type II collagen (about 10% to 30% of weight), proteoglycans (about 5% to 10% of weight), and water. The water content ranges from 60% to almost 80% of the net weight of the cartilage. At the surface of articular cartilage, the collagen fibers run parallel to the joint surface and are closely compacted into a dense, protective mat. In the middle layer (the proliferative zone) of the cartilage, the fibers are arranged tangential to the surface, which allows them to deform and absorb some of the weight-bearing (Fig. 40.7). In the bottom layer (the hypertrophic zone) of the cartilage, the fibers are perpendicular to the joint surface, allowing them to resist shear forces, and are embedded in a calcified layer of cartilage called the tidemark. The tidemark anchors the collagen fibers to the underlying (subchondral) bone. Collagen fibers are important components of the cartilage matrix because they account for approximately 60% of the dry weight and because they (1) anchor the cartilage securely to underlying bone, (2) provide a taut framework for the cartilage, (3) control the loss of fluid from the cartilage, and (4) prevent the escape of protein polysaccharides (proteoglycans) from the cartilage. The proteoglycans give articular cartilage its stiff quality and regulate the movement of synovial fluid through the cartilage. The proteoglycans are macromolecules consisting of proteins, carbohydrates (glycosaminoglycans), and hyaluronic acid.

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FIGURE 40.7 Collagen Zones. The three collagen zones (reserve, proliferative, and hypertrophic) are distinctly shown in a growth plate. (From Hjorten R et al: Bone 41[4]:535, 2007.)

Synovial Joints Structure of Synovial Joints Synovial joints (diarthroses) are the most movable and the most complex joints in the body (Fig. 40.8).

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FIGURE 40.8

Knee Joint (Synovial Joint). A, Frontal view. B, Lateral view.

Movement of Synovial Joints Synovial joints are described as uniaxial, biaxial, or multiaxial according to the shapes of the bone ends and the type of movement occurring at the joint (Fig. 40.9). Usually, one of the bones is stable and serves as an axis for the motion of the other bone. The body movements made possible by various synovial joints are either circular or angular (Fig. 40.10).

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FIGURE 40.9

Movements of Synovial (Diarthrodial) Joints.

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FIGURE 40.10

Body Movements Made Possible by Synovial (Diarthrodial) Joints.

Quick Check 40.2 1. How do these joints differ from each other: synarthrosis, amphiarthrosis, and diarthrosis? 2. Name at least two characteristics of each of the joints in the previous question that either facilitate or hinder movement. 3. Name three functions of articular cartilage.

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Structure and Function of Skeletal Muscles Skeletal muscles arise from mesodermal precursor cells that then form myoblasts, or embryonic cells, which become muscle cells. The millions of individual fibers of skeletal muscle contract and relax to perform the work necessary to move the body (Fig. 40.11). Muscle constitutes 40% of an adult's body weight and 50% of a child's weight. Muscle is 75% water, 20% protein, and 5% organic and inorganic compounds. Thirty-two percent of all protein stores for energy and metabolism are contained in muscle. Between the ages of 30 and 60, muscle mass decreases by about 0.5 pound of muscle each year. For each 0.5 pound of muscle lost, almost 1 pound of fat typically is gained.

FIGURE 40.11

Skeletal Muscles of the Body. A, Anterior view. B, Posterior view.

Whole Muscle There are more than 350 named muscles in the body. The body's muscles vary dramatically in size and shape. They range from 2 to 60 cm in length and are shaped according to function. Fusiform muscles are elongated muscles shaped like straps that can run from one joint to another. The biceps brachii and psoas major are examples of fusiform muscles. Pennate muscles are broad, flat, and slightly fan shaped, with fibers running obliquely to the muscle's long axis. The multipennate deltoid muscle, which flexes and extends the arm, is a good example of a muscle shaped according to its function.

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Each skeletal muscle is a separate organ, encased in a three-part connective tissue framework called fascia. The layers of connective tissue protect the muscle fibers, attach the muscle to bony prominences, and provide a structure for a network of nerve fibers, blood vessels, and lymphatic channels. The layers are: 1. The outermost layer, the epimysium, which is located on the surface of the muscle and tapers at each end to form the tendon (Fig. 40.12; also see the Tendons and Ligaments section for a discussion of tendons). Tendons allow short muscles to exert power on a distant joint, whereas a thick muscle would interfere with the joint's mobility.

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FIGURE 40.12 Levels of Organization Within a Skeletal Muscle Showing Muscle Fibers and Their Coverings. (From Standring S: Gray's anatomy, ed 40, Edinburgh, 2008, Churchill Livingstone.)

2. The perimysium, which further subdivides the muscle fibers into bundles of connective tissue, or fascicles.

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3. The endomysium, which surrounds the muscle. It is the smallest unit of muscle visible without a microscope. The ligaments, tendons, and fascia are made up of connective tissue that also buffers the limbs from the effects of sudden strains or changes in speed. The rapid recovery necessary for strenuous exercise is supported by the elastic property of muscle and its connective tissue. Skeletal muscle has been designated as voluntary (controlled directly by the nervous system), striated (has a striped pattern when viewed under a light microscope), or extrafusal (to distinguish from other contractile fibers in the sensory organ of the muscle). Components that are visible on gross inspection of the whole muscle include the motor and sensory nerve fibers. These function together with the muscle, innervating portions of it and providing the electrical impulses needed for motor function.

Motor Unit From the anterior horn cell of the spinal cord, the axons of motor nerves branch to innervate a specific group of muscle fibers. Each anterior horn cell, its axon (part of the lower motor neuron; see Chapter 14), and the muscle fibers innervated by it are called a motor unit (Fig. 40.13). The motor units are composed of lower motor neurons, which extend to skeletal muscles. Often termed the functional unit of the neuromuscular system, the motor unit behaves as a single entity and contracts as a whole when it receives an electrical impulse.

FIGURE 40.13

Motor Units of a Muscle. Each motor unit consists of a motor neuron and all the muscle fibers (cells) supplied by the neuron and its axon branches.

The whole muscle may be controlled by several motor nerve axons. These branch to innervate many motor units within the muscle. The whole muscle then may be made up of many motor units. The number of motor units per individual muscle varies greatly. In the calf, for example, 1 motor axon innervates approximately 2000 muscle fibers, out of a total of 1.2 million muscle fibers. This is a high innervation ratio of muscle fibers to axons, and it contrasts markedly with the low innervation ratio found in laryngeal muscles, where two to three muscle fibers constitute each motor unit and the innervation ratio can be of great functional significance. The greater the innervation ratio of a particular organ, the greater its endurance. Higher innervation ratios prevent fatigue, whereas lower innervation ratios

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allow for precision of movement. Sensory receptors. Although muscles function as effector organs, they also contain sensory receptors and are involved in sending different signals to the central nervous system. Among these are the muscle spindles and Golgi tendon organs. Spindles are mechanoreceptors that lie parallel to muscle fibers and respond to muscle stretching. Golgi tendon organs are dendrites that terminate and branch to tendons near the neuromuscular junction. The muscle spindles, Golgi tendon organs, and free nerve endings provide a means of reporting changes in length, tension, velocity, and tone in the muscle. This system of afferent signals is responsible for the muscle stretch response and maintenance of normal muscle tone. Muscle fibers. Each muscle fiber is a single muscle cell that is cylindrical in structure and surrounded by a membrane capable of excitation and impulse propagation. The muscle fiber contains bundles of myofibrils, the fiber's functional subunits, in a parallel arrangement along the longitudinal axis of the muscle (Fig. 40.14). At birth, the muscle fibers have completed development from precursor cells called myoblasts. All voluntary muscles are derived from the mesodermal layer of the embryo. Genetic transcription factors, most notably MyoD, induce skeletal muscle differentiation. Myoblasts are the main cells responsible for muscle growth and regeneration. Myoblasts are termed satellite cells when in a dormant state. Satellite cells are crucial in muscle growth, maintenance, repair, and regeneration. Once muscle is injured, satellite cells become activated and increase the number of transcriptional factors necessary to form myoblasts and assist in repair.

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FIGURE 40.14 Myofibrils of a Skeletal Muscle Fiber (Cell) and Overall Organization of Skeletal Muscle. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Mosby.)

The type of peripheral nerve influences the muscle fiber and motor unit considerably. Whether motor nerves are fast or slow determines the type of muscle fibers in the motor unit. White muscle (type II fibers [white fast-twitch fibers]) is innervated by relatively large type II alpha motor neurons with fast conduction velocities. These fibers rely on a short-term anaerobic glycolytic system for rapid energy transfer. Red muscle (type I fibers [slow-twitch fibers]) depends on aerobic oxidative metabolism. Table 40.3 describes the specific characteristics of type I and type II fibers. TABLE 40.3 Characteristics of Human Skeletal Muscle Fibers Characteristics

Type I (Red) (Oxidative Fibers [OFs])

Anatomic location Fiber diameter Motor neuron size Contraction speed Motor neuron type

Deep axial portion of muscle Small Small Slow Type I, α

Glycogen content (at rest) Oxidative capacity Myosin-ATPase activity

Low

Type II (White) Type II-1A (Fast Oxidative Glycolic Fibers [FOGs]) Surface portion of muscle Large Large Fast Type II-A, II-B, II-X, and II-D II-A: fatigue resistant; II-B: fast fatigable; II-X and II-D: intermediate fatigability High

High Low

High (for short periods) High

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Metabolism Used for Aerobic metabolic capacity Fatigue resistance Myoglobin content Capillary supply Mitochondria Intensity of contraction Example (most muscles are mixed) Satellite cell content

Oxidative (also most effective in removing Some oxidative pathways, mostly glycolysis glucose from bloodstream) Maintaining body posture, skeletal support, Short, intense activity (e.g., sprinting) aerobic activity High Low High High Profuse Many Low

Intermediate to low Low Intermediate to low Few High

Soleus muscle

Laryngeal

High

Low

From Schiaffino S, Reggiani C: Physiol Rev 91:1447-1531, 2011; Verdijk LB et al: Age 36(2):545-547, 2014.

The overlap of muscle fibers that appears with staining gives a checkerboard appearance to muscle biopsy specimens. This overlap provides an equal distribution of fiber types throughout the muscle and also helps to compensate for muscle fiber loss and fatigue of individual motor units during activity. Despite this, some muscles contain proportionally more of one fiber type than another. Postural muscles have more type I fibers, allowing them the high resistance to fatigue that is necessary to maintain the same position for extended periods. The ocular muscles have more type II muscle fibers, allowing them to respond rapidly to visual changes. The number of muscle fibers varies according to location. Large muscles, such as the gastrocnemius, have more fibers (1.2 million) than smaller muscles, such as the lumbrical muscles in the hand (10,000). The diameter of muscle fibers also varies. The closely packed polygons are small (10 to 20 µm) until puberty, when they attain the normal adult diameter of 40 to 80 µm. Women usually have smaller diameter fibers than men. Small muscles, such as the ocular muscles, are 15 µm in diameter; larger, more proximal muscles are 40 µm in diameter. Fiber size can have functional significance, such as the association of larger fiber diameter with the generation of greater forces. The major components of the muscle fiber include the muscle membrane, sarcoplasm, mitochondria, sarcotubular system, and myofibrils (see Fig. 40.14). The muscle membrane is a two-part membrane. It includes the sarcolemma, which contains the plasma membrane of the muscle cell, and the cell's basement membrane. The sarcolemma is 7.5 µm thick and is capable of propagating electrical impulses to initiate contraction. At the motor nerve end plate, where the nerve impulse is transmitted, the sarcolemma forms the highly convoluted synaptic cleft. The sarcolemma is made up of lipid molecules and protein systems. The protein systems perform special functions, such as transport of nutrients and protein synthesis. They also provide the sodium-potassium pump and include the cell's cholinergic receptor. The basement membrane is 50 µm thick and is composed primarily of proteins and polysaccharides. It also serves as the cell's microskeleton and maintains the shape of the muscle cell. The basement membrane also may function to restrict further diffusion of electrolytes once they have crossed the sarcolemma. The sarcoplasm is the cytoplasm of the muscle cell and contains myoglobin plus the intracellular components that are common to all cells (see Chapter 1). Myoglobin is a protein found primarily in skeletal and heart muscle. Related to hemoglobin in the blood, myoglobin stores oxygen and iron in the muscle. The sarcoplasm is an aqueous substance that provides a matrix that surrounds the myofibrils. It contains numerous enzymes and

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proteins that are responsible for the cell's energy production, protein synthesis, and oxygen storage. The mitochondria house enzyme systems for energy production, particularly those that regulate processes such as the citric acid cycle and adenosine triphosphate (ATP) formation. Many other structures are present in the sarcoplasm. The ribosomes are composed of primarily ribonucleic acid (RNA) and participate in protein synthesis. The cell nucleus, satellite cells, glycogen granules, and lipid droplets are suspended in the sarcoplasmic matrix. Blood vessels, nerve endings, muscle spindles, and Golgi tendon organs are also directly located within this structure. Unique to the muscle is the sarcotubular system, a network that includes the transverse tubules and the sarcoplasmic reticulum, which crosses the interior of the cell. The sarcoplasmic reticulum is constructed like the endoplasmic reticulum in other cells. The sarcoplasmic reticulum is composed of tubules that run parallel to the myofibrils. The longitudinal tubules are termed sarcotubules. In muscle cells, the sarcoplasmic reticulum contains a network of intracellular receptors known as ryanodine receptors (RyRs). In response to a nerve impulse, RyR1 (found in skeletal muscle cells) releases intracellular calcium and initiates muscle contraction at the sarcomere, a portion of the myofibril. The transverse tubules, which also contain calcium release channels and are closely associated with the sarcotubules, run across the sarcoplasm and communicate with the extracellular space. Together, the tubules of this membrane system allow for uptake and regulation of intracellular calcium, release of calcium during muscle contraction, and storage of calcium during muscle relaxation. Myofibrils. Myofibrils, the most abundant subcellular muscle component (85% to 90% of the total volume), are the functional units of muscle contraction. Each myofibril contains sarcomeres, which appear at intervals (see Fig. 40.14). Sarcomeres are composed of several proteins. The two most abundant are actin and myosin, but three other giant, muscle-specific proteins (titin, nebulin, and obscurin) play important roles in myofibril formation and function (see Table 40.4). TABLE 40.4 Contractile Proteins of Skeletal Muscle Sarcomere Protein Actinin

Location Z disk

Actin

I band (thin filaments) Z disk Z disk A band (thick filament) Half of sarcomere (from Z disk to M band)

α-Actin β-Actin Myosin Titin*(largest and third most abundant muscle protein) Nebulin* Obscurin*

I band (with αactin) Surrounds

Function Attaches actin to Z disks; helps coordinate sarcomere contraction; cross-links thin filaments in adjacent sarcomeres Contraction; activates myosin-ATPase; interacts with myosin Main ligand of titin; links and controls filament length Regulatory and structural function; links filaments, controls filament length Contraction force; two distinct types: myosin heavy chain (MyHC) and myosin light chain (MyLC); hydrolyzes ATP and develops tension Coordinates assembly of proteins that comprise sarcomere; regulates resting length of sarcomere; important for myofibril assembly, stabilization, and maintenance Interacts with myosin to produce contraction; binding site for actin, desmin, titin, other proteins; stabilizes and regulates length of actin filaments; plays role in assembly, structure, and maintenance of Z disks May mediate interaction of sarcoplasmic reticulum and myofibrils; plays role

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sarcomere (mainly in muscle response to injury; has role in formation and stabilization of M at Z disk and M bands and A band band) *Also

may function as molecular scaffolds for myofibril formation.

ATP, Adenosine triphosphate; ATPase, adenosinetriphosphatase. Data from Herzog JA et al: Mol Cell Biomech 11(1):1-17, 2014; Luther PK: J Muscle Res Cell Motil 30:171-185, 2009; Pappas CT et al: J Cell Biol 189(5):858-870, 2010; Schiaffino S, Reggiani C: Physiol Rev 91:1447-1531, 2011.

On cross section, they are seen to be irregular polygons with a mean diameter of less than 1 µm. Each myofibril is composed of serially repeating sarcomeres, separated by Z bands, which give the muscle its striped, cross-striated appearance. Each sarcomere has a dark A band and is flanked by two light I bands (Fig. 40.15). The A band is 1.5 to 1.6 µm long and contains the thick myosin filaments. Included in the A band is a lighter zone called the H band, and in the center of the H band is the dark M band, or M line. The I band, which contains actin, is divided at the midpoint of each sarcomere by the Z band. Its length varies with the start of muscle contraction. The Z disk (made up of different layers of Z bands, depending on muscle type) marks the boundaries of the sarcomere.

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FIGURE 40.15 Muscle Fibers. A, The Z disks define the end of an individual sarcomere. The M line (which lies within the H band) is made of cross-connecting elements of the cytoskeleton. B, Actin is the primary protein of the I band (thin filament). Nebulin also extends along the I band and contains binding sites for actin and myosin. Myosin (thick filament) extends through the A band. Titin extends from the Z disk to the M band, binding with myosin; strong titin anchoring within the I band is necessary for proper muscle function. During contraction, the I bands and H bands shorten, moving the Z disks closer together. C, Electron photomicrograph of human muscle tissue corresponding to schematics in A and B. (A modified from Thompson JM et al: Mosby's clinical nursing, ed 5, St Louis, 2002, Mosby; C courtesy Louisa Howard.)

Myofibrils are composed of myofilaments. Each myofilament is structured in a closely packed hexagonal arrangement, with two thin filaments for every thick filament. The thick filament, along with C protein and M line protein, is made up of myosin. Myosin has two subunits—heavy and light meromyosin, which resemble twisted golf club shafts. The thin filaments are twisted double strands consisting of actin, troponin, and tropomyosin (see Chapter 25 and Fig. 25.11). Muscle proteins. A multitude of muscle proteins have been identified and their functions are still being discovered. Table 40.4 summarizes the location and function of some of the important muscle proteins. Nonprotein constituents of muscle. Nitrogen, creatine, creatinine, phosphocreatine, purines, uric acid, and amino acids all serve in the complex process of muscle metabolism. Energy is provided by glycogen and its derivatives. Creatine metabolism and creatinine metabolism have been used to measure muscle mass. Plasma creatine is taken up by muscle and converted into the high-energy phosphate compound phosphocreatine by the enzyme creatine kinase. Creatinine is formed in muscle from creatine at a constant rate of 2% per day. Creatine excretion is increased in muscle wasting. This change reflects the reduction in total body creatine stores and the loss of muscle mass. Inorganic compounds, anions (phosphate, chloride), and cations (calcium, magnesium, sodium, potassium) are important in the regulation of protein synthesis, muscle contraction, and enzyme systems, as well as in the stabilization of cell membranes. The total body potassium (TBK) level, measured by the K40 method, has been used to measure muscle mass, also called lean body mass. TBK levels reflect changes in muscle mass seen during growth, malnutrition, and muscle wasting.

Components of Muscle Function The ultimate function of muscle is to accomplish work. Although variously expressed in such measures as foot-pounds or kilogram-meters, work usually refers to the amount of energy liberated or force exerted over a distance (Work = Force × Distance). Muscles usually contract or tense while doing work. Muscle contraction occurs on the molecular level and leads to the observable phenomenon of muscle movement.

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The four steps of muscle contraction are (1) excitation, (2) coupling, (3) contraction, and (4) relaxation. The process involves the electrical properties of all cells and the movement of ions across the plasma membrane (see Chapter 1). The muscle fiber is an excitable tissue. At rest, an electrical charge of −90 mV is continually maintained across the sarcolemma. This resting potential, generated by the separation of positive and negative charges on either side of the membrane, creates an electrochemical equilibrium caused by the selective permeability of the sarcolemma to electrolytes in the intracellular and extracellular fluids, particularly potassium and sodium. Excitation, the first step of muscle contraction, begins with the spread of an action potential from the nerve terminal to the neuromuscular junction. The rapid depolarization of the membrane initiates an electrical impulse in the muscle fiber membrane called the muscle fiber action potential. As the action potential advances along the sarcolemmal membrane, it spreads to the transverse tubules. A receptor on the transverse tubule opens, allowing calcium to enter the cell. The second stage, coupling, follows the depolarization of the transverse tubules. This triggers the release of calcium ions from the sarcoplasmic reticulum through RyR1 channels into the sarcoplasm. The calcium then binds to a protein on the actin filament. (Calcium affects troponin and tropomyosin, muscle proteins that bind with actin when the muscle is at rest.) In the presence of calcium, however, both these proteins are attracted to calcium ions, leaving the actin free to bind with myosin. The release of intracellular calcium ions is the critical link between a nerve impulse (electrical excitation) and muscle contraction. Contraction begins as the calcium ions combine with troponin, a reaction that overcomes the inhibitory function of the troponin-tropomyosin system. Myosin binds to actin, forming cross-bridges. The myosin heads attach to the exposed actin-binding sites, pulling actin (the thin filament) inward. The thin filament, actin, then slides toward the thick filament, myosin. The two ends of the myofibril shorten after contraction when the myosin heads attach to the actin molecules, forming a cross-bridge that constitutes an actin-myosin complex. ATP, located on the actin-myosin complex, is released when the cross-bridges attach. Contraction was first described by A.F. Huxley in the 1950s. It is commonly known as the cross-bridge theory because the actin and myosin proteins form cross-bridges as they contract. The useful distance of contraction of a skeletal muscle is approximately 25% to 35% of the muscle's length. The last step, relaxation, begins as calcium ions are actively transported back into the sarcoplasmic reticulum, removing ions from interaction with troponin. The cross-bridges detach, and the sarcomere lengthens. (The cross-bridge theory of muscle contraction is discussed in Chapter 25.)

Muscle Metabolism Skeletal muscle requires a constant supply of ATP and phosphocreatine. These substances are necessary to fuel the complex processes of muscle contraction, driving the cross-bridges of actin and myosin together and transporting calcium from the sarcoplasmic reticulum to the myofibril. Other internal processes of the muscular system that require ATP include protein synthesis, which replenishes muscle constituents and accommodates growth and repair. The rate of protein synthesis is related to hormone levels (particularly insulin), the presence of amino acid substrates, and overall nutritional status. At rest, the rate of ATP formation by oxidation of glucose or acetoacetate is sufficient to maintain internal

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processes, given normal nutritional status. During activity, the need for ATP increases 100fold. The metabolic pathways for muscle activity in Table 40.5 show reactions to the immediate need for increased ATP caused by contraction. Activity lasting longer than 5 seconds expends the available stored ATP and phosphocreatine. TABLE 40.5 Energy Sources for Muscular Activity Sources Short-term (anaerobic) sources Long-term (aerobic) sources

Reactions ATP → ADP + Pi + Energy Phosphocreatine + ADP ⇌ Creatine + ATP Glycogen/glucose + Pi + ADP → Lactate + ATP Glycogen/glucose + ADP + Pi + O2 → H2O + CO2 + ATP Free fatty acids + ADP + Pi + O2 → H2O + CO2 + ATP Creatine kinase catalyzes reversible reaction of ATP to ADP: Creatine phosphate + ATP Creatine + ATP

ADP, Adenosine diphosphate; ATP, adenosine triphosphate; CO2, carbon dioxide; H2O, water; O2, oxygen; Pi, inorganic phosphate From Spence AP, Mason EE: Human anatomy and physiology, ed 4, St Paul, Minn, 1992, West Publishing.

Stored glycogen and blood glucose are converted anaerobically to sustain brief activity without increasing the demand for oxygen. Anaerobic glycolysis is much less efficient than aerobic glycolysis, using six to eight times more glycogen to produce the same amount of ATP. With increased activity, such as intense exercise, or with ischemia, an increase in the amount of lactic acid occurs because of the breakdown of glycogen, thus causing a shift in muscle pH (see Table 40.5). This short-term mechanism buys time by allowing ATP formation in spite of inadequate energy stores or oxygen supply. When the anaerobic threshold is reached and more oxygen is required, physiologic changes occur, including an increase in lactic acid level and increases in oxygen consumption, heart rate, respiratory rate, and muscle blood flow. Strenuous exercise requires oxygen, which activates the aerobic glycogen pathway for ATP formation. During maximal exercise, free fatty acid mobilization and the aerobic glycogen pathways provide ATP over an extended time. These pathways require oxygen both to maintain maximal activity and to return the muscle to the resting state. Maximal exercise increases oxygen uptake by 15 to 20 times over the resting state. When this system becomes exhausted or inadequate to respond to the need for ATP, fatigue and weakness finally force the muscle to reduce activity, with a resultant buildup of lactic acid in muscle fibers. Sustaining maximal muscular activity accumulates an oxygen debt, which is the amount of oxygen needed to oxidize the residual lactic acid, convert it back to glycogen, and replenish ATP and phosphocreatine stores. For example, after running at maximal speed for 10 seconds, the average person has consumed 1 L of oxygen. At rest, oxygen consumption for the same period is approximately 40 ml. As the person recovers, the measured oxygen debt is 4 L greater than the amount used during activity. Oxygen consumption is measured to calculate the metabolic cost of activity in normal and diseased muscle. It is an indirect measure of energy expenditure, along with timed tests of activity, heart rate, and respiratory quotient (ratio of carbon dioxide to expired

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oxygen consumed). Energy expenditure is measured directly by heat production, because heat is released whenever work is accomplished. Another factor that changes energy requirements is muscle fiber type. Type II fibers rely on anaerobic glycolytic metabolism and fatigue readily. Type I fibers can resist fatigue for longer periods because of their capacity for oxidative metabolism.

Muscle Mechanics Muscle contraction cannot be viewed in isolation. Several factors determine how force is transmitted from the cross-bridges on individual muscle fibers to accomplish whole-muscle contraction. First, when a motor unit responds to a single nerve stimulus, it develops a phasic contraction, also called a twitch. Because the motor unit contracts in an all-or-nothing manner, the contraction that is generated will be a maximal contraction. The central nervous system smoothly grades the force generated by recruiting additional motor units and varying the discharge frequency of each active motor unit. This adding of motor units within the muscle is called repetitive discharge. Recruitment and repetitive discharge of motor units allow the muscle to activate the number of motor units needed to generate the desired force. The total force developed is the sum of the force generated by each motor unit. If the motor units are stimulated again and the muscle unit has not been able to relax between stimulation and the next contraction, the second contraction will fuse with the first, causing physiologic tetanus (not to be confused with the disease tetanus). Other variables, such as fiber type, innervation ratio, muscle temperature, and muscle shape, influence the efficiency of muscular contraction. The two muscle fiber types differ in their responses to electrical activity. Tetanus and duration of phasic contractions, which take microseconds to accomplish, are achieved more rapidly in type II (white fast-twitch) than in type I (red slow-twitch) muscle fibers. Low innervation ratios promote control and coordination, whereas high ratios promote strength and endurance. Muscles work best at normal body temperature, or 37° C (98.6° F). Finally, muscles with a large cross-sectional area, such as the fan-shaped pennate muscles, develop greater contractile forces than smaller diameter muscles. The initial length of a muscle and the range of shortening that occur when the muscle contracts also determine the force it can generate. The long fusiform muscles have a greater range of shortening and can contract up to 57% of their resting length. A certain amount of elongation is necessary to generate sufficient tension and muscular force. The elongation that occurs during the swing of a golf club or tennis racket is an example of how stretch improves contractile force.

Types of Muscle Contraction During isometric (or static) contraction, the muscle maintains constant length as tension is increased (Fig. 40.16). Isometric contraction occurs, for example, when the arm or leg is pushed against an immovable object. The muscle contracts, but the limb does not move. Isometric contraction is also called static (holding) contraction.

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FIGURE 40.16 Isotonic and Isometric Contraction. A, In isotonic contraction, the muscle shortens, producing movement. B, In isometric contraction, the muscle pulls forcefully against a load but does not shorten. (From Patton KT, Thibodeau GA: Structure & function of the body, ed 15, St Louis, 2016, Mosby.)

During dynamic (formerly known as isotonic) contraction, the muscle maintains a constant tension as it moves. Isotonic contractions can be eccentric (lengthening) or concentric (shortening). Positive work is accomplished during concentric contraction, and energy is released to exert force or lift a weight. In contrast, during an eccentric contraction the muscle lengthens and absorbs energy (e.g., extending the elbow while lowering a weight). Eccentric contraction requires less energy to accomplish and has been said to result in the development of pain and stiffness after unaccustomed exercise.

Movement of Muscle Groups Muscles do not act alone but in groups, often under automatic control. When a muscle contracts and acts as a prime mover, or agonist, its reciprocal muscle, or antagonist, relaxes. To illustrate this, hold the right arm in the horizontal position in front of the body and bend the elbow; use the other hand to feel the biceps on the top and the triceps on the bottom of the arm. When the elbow is bent, the biceps are firm, and the triceps are soft. As the arm is extended, the muscles change. When the elbow is completely extended, the biceps is soft and the triceps firm. Completing this movement causes the agonist and antagonist to change automatically; only the movement is commanded, not the alternate contraction and relaxation of the specific muscle groups. Other associated actions occur with walking; as the foot leaves the ground, the

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paravertebral and gluteal muscles on the opposite sides of the body contract to maintain balance. Paralysis offsets this process and decreases balance.

Tendons and Ligaments Tendons are important musculoskeletal structures that attach muscle to bone at a site called an enthesis. Ligaments attach bone to bone, helping to form joints, as well as stabilizing them against excessive movement. Both tendons and ligaments are primarily composed of types III, IV, V, and VI collagen and fibroblasts (called tenocytes in tendons). The fibroblasts in tendons are arranged in parallel rows; fibroblasts appear less organized in ligaments. Collagen fibers and fibroblasts form fascicles, with multiple fascicles then forming a whole tendon or ligament. In the proteoglycan matrix of tendons, collagen oligomeric matrix protein (COMP) assists in providing gliding and viscoelastic properties. Compared with tendons, ligament fibers typically contain a greater proportion of elastin. Two main functions of tendons are (1) transferring forces from muscle to bone and (2) as a type of biologic spring for muscles to enable additional stability during movement. Ligaments stabilize joints by restricting movement. Although both tendons and ligaments can withstand significant distraction (stretching) force, they tend to buckle when compressive force is applied. Both tendons and ligaments have complex structures at the attachment site of two dissimilar tissues. These complex structures and differences in mechanical and structural characteristics (either tendon and bone or ligament and bone) make healing and repair of damaged tissue complicated (see Did You Know? Tendon and Ligament Repair).

Did You Know? Tendon and Ligament Repair Injury of tendons and ligaments is one of the greatest challenges in musculoskeletal rehabilitation. When these types of structures are damaged, attempts to engineer suitable tissue replacements have proved disappointing. The structures and intricate protein composition of tendons and ligaments are the basis for their complex biomechanical properties. One reason for a poor clinical outcome in synthetic tendon structures has been the inability to replicate any material that can bear the high mechanical stresses that occur at the interface between two dissimilar materials (i.e., either tendon and bone or ligament and bone). One promising area of investigation is finding or engineering a biodegradable material, or “scaffold,” implanted with specific cells that would regenerate into normal tendon or ligament. The scaffold must be strong enough to withstand the forces at the tissue/bone interface and then gradually break down as it is completely replaced by new cells. Currently, investigators are using synthetic polymers, silk, and collagen as scaffolds, with tendon or ligament fibroblasts and mesenchymal stem cells as the implanted cells. Once these biochemical hurdles have been overcome, the repair of damaged tendons and ligaments will be revolutionized. Data from Jahr H et al: Curr Rheumatol Rep 17(3):22, 2015.

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Aging & the Musculoskeletal System Aging of Bones Aging is accompanied by the loss of bone tissue. Bones become less dense, less strong, and more brittle with aging. The bone remodeling cycle takes longer to complete, and the rate of mineralization also decelerates. With aging, women experience loss of bone density, accelerated by rapid bone loss during early menopause from increased osteoclastic bone resorption, fewer osteocytes, and decreased numbers of osteoblasts. By age 70 years, susceptible women have, on average, lost 50% of their peripheral cortical bone mass (see Chapter 41). Bone mass losses can lead to deformity, pain, stiffness, and high risk for fractures. Men also experience bone mass loss but at later ages and much slower rates than women. Also, initial bone mass in men is approximately 30% higher than in women; therefore bone loss in men causes less risk of disability than that found in women. Men's peak bone mass is related to race, heredity, hormonal factors, physical activity, and calcium intake during childhood. Bone loss in both sexes is related to smoking, calcium deficiency, alcohol intake, and physical inactivity. Bone mass can be gained in healthy young women up to the third decade through participation in physical activity, intake of dietary calcium and other minerals, and use of oral contraceptives. Height is also lost with aging because of intervertebral disk degeneration and, sometimes, osteoporotic spinal fractures. Stem cells in the bone marrow perform less efficiently with aging, predisposing older persons to acute and chronic illnesses. Such illnesses cause weakness and confusion in older persons and may increase the risk of injury or falling.

Aging of Joints With aging, cartilage becomes more rigid, fragile, and susceptible to fraying because of increased cross-linking of collagen and elastin, decreased water content in the cartilage ground substance, and reduced concentrations of glycosaminoglycans. Decreased range of motion of the joint is related to the changes in ligaments and muscles. Bones in joints develop evidence of osteoporosis, with fewer trabeculae and thinner, less dense bones, making them prone to fractures. Intervertebral disk spaces decrease in height. The rate of loss of height accelerates at age 70 years and beyond. Tendons shrink and harden.

Aging of Muscles The function of skeletal muscle depends on many influences that are affected by cellular factors, such as reduced mitochondrial volume associated with aging. Other influences include the nervous, vascular, and endocrine systems. In the young child, the development of muscle tissue depends greatly on continuing neurodevelopmental maturation. Muscle loss begins at about age 50; however, muscle function remains trainable even into advanced age. Maintaining musculoskeletal fitness at any age can improve overall health. Age-related loss in skeletal muscle is referred to as sarcopenia and is a direct cause of the age-related decrease in muscle strength. As the body ages, muscle mass and strength decline slowly; thus, strength is maintained through the fifth decade, with a slow decline in dynamic and isometric strength evident after age 70. The amount of type II fibers also

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decreases. There is reduced synthesis of RNA, loss of mitochondrial function, and reduction in the size of motor units. The regenerative function of muscle tissue remains normal in aging persons. As much as 30% to 40% of skeletal muscle mass and strength may be lost from the third to ninth decades. Muscle fatigue also may contribute to loss of function with aging. Sarcopenia is thought to be secondary to progressive neuromuscular changes and diminishing levels of anabolic hormones. There is an age-related decline in the synthesis of mixed proteins, myosin heavy chains, and mitochondrial protein. Changes in these muscle proteins are related to reduced levels of insulin-like growth factor-1 (IGF-1), testosterone, and dehydroepiandrosterone (DHEA) sulfate. Maximal oxygen intake declines with age. The basal metabolic rate is reduced, and lean body mass decreases in the aged population.

Quick Check 40.3 1. Name three differences between slow-twitch and fast-twitch muscle fibers. 2. Why is adenosine triphosphate (ATP) used for muscle contraction? 3. Define the differences between tendons and ligaments. 4. Describe significant changes that occur in the musculoskeletal system with aging.

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Summary Review Structure and Function of Bones 1. Bones provide support and protection for the body's tissues and organs and are important sources of minerals and blood cells. Bones permit movement by providing points of attachment for muscles. 2. Mature bone is a rigid connective tissue consisting of cells (growth, repair, synthesis, and resorption of old tissue); collagen fibers (tensile strength); a homogenous gelatinous medium called ground substance (diffusion); and large amounts of crystallized minerals, mainly calcium (rigidity). 3. Bone formation begins with the production of an organic matrix by bone cells. Bone minerals crystallize in and around collagen fibers in the matrix, called calcification, giving bone its characteristic hardness and strength. 4. Bone contains three types of cells: osteoblasts, osteocytes, and osteoclasts. These allow bone tissue to be continuously synthesized, remodeled, and resorbed. 5. Osteoblasts are cells derived from osteogenic mesenchymal stem cells; they are the primary bone-producing cells and are involved in many functions related to the skeletal system. Osteoblasts initiate new bone formation by their synthesis of osteoid (nonmineralized bone matrix). 6. Osteocytes are transformed osteoblasts that are trapped or surrounded in osteoid as it hardens. They are the most numerous cells in bone. Though imbedded in the bone matrix, osteocytes have important functions in directing bone remodeling. 7. Osteoclasts are large, multinucleated cells that develop from the hematopoietic monocyte-macrophage lineage. Osteoclasts are the major resorptive cells of bone. 8. Bone matrix is made of the extracellular elements of bone tissue, specifically collagen fibers, structural proteins (e.g., proteoglycans and certain glycoproteins), carbohydrate-protein complexes, ground substance, and minerals. 9. Bones in the body are made up of compact (cortical) bone tissue and spongy (cancellous) bone tissue. 10. Compact bone is highly organized, solid, and extremely strong. The basic structural units are the haversian systems that consist of concentric layers of crystallized matrix called lamellae, surrounding a central canal that contains blood vessels and nerves. Dispersed throughout the concentric layers of crystallized matrix are small spaces, called lacunae, containing osteocytes. Smaller canals, called canaliculi, interconnect the osteocyte-containing spaces. 11. The crystallized matrix in spongy bone is arranged in bars or plates called trabeculae. Spaces containing osteocytes are dispersed between the bars or plates and interconnected by canaliculi. 12. There are 206 bones in the body, divided into the axial skeleton and the appendicular skeleton. Bones are classified by shape as long, short, flat, or irregular. Long bones have a broad end (epiphysis), broad neck (metaphysis), and narrow midportion (diaphysis) that contains the medullary cavity. 13. The internal structure of bone is maintained by remodeling, a process in which existing bone is resorbed and new bone is laid down to replace it. Clusters of bone

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precursor cells, called basic multicellular units, implement remodeling. 14. Bone injuries are repaired in stages: (1) hematoma formation occurs within hours of fracture or surgery, (2) procallus formation by osteoblasts occurs within days, (3) callus formation occurs within weeks, and (4) replacement and (5) remodeling occur within years. Remodeling restores the original shape and size to the injured bone.

Structure and Function of Joints 1. A joint, or articulation, is the site where two or more bones attach. Joints provide stability and mobility to the skeleton. Joints help move bones and muscle. 2. Joints are classified as synarthroses (immovable), amphiarthroses (slightly moveable), or diarthroses (freely movable), depending on the degree of movement they allow. 3. Joints are also classified by the type of connecting tissue holding them together. Fibrous joints are connected by dense fibrous tissue, ligaments, or membranes. Cartilaginous joints are connected by fibrocartilage or hyaline cartilage. Synovial joints are connected by a fibrous joint capsule that contains a small fluid-filled space. The fluid in the space nourishes the articular cartilage that covers the ends of the bones meeting in the synovial joint. 4. Articular cartilage is a highly organized system of collagen fibers and proteoglycans. The fibers firmly anchor the cartilage to the bone, and the proteoglycans control the loss of fluid from the cartilage.

Structure and Function of Skeletal Muscles 1. Myoblasts are precursor cells that become muscle cells. 2. Whole muscles vary in size (2 to 60 cm) and shape (fusiform, pennate). They are encased in a three-part connective tissue framework, called fascia, that protects the muscle fibers, attaches the muscle to bone, and provides a structure for a network of nerve fibers, blood vessels, and lymphatic channels. 3. The fundamental concept of muscle function is the motor unit, defined as the muscle fibers innervated by a single motor nerve, its axon, and anterior horn cell. 4. Satellite cells are dormant myoblasts; however, when activated, they can regenerate muscle. 5. Skeletal muscle is made up of millions of individual muscle fibers, each of which is a single, cylindrical muscle cell. Muscle fibers contain bundles of myofibrils arranged in parallel along the longitudinal axis and include the muscle membrane, myofibrils, sarcotubular system, sarcoplasm, and mitochondria. 6. There are two types of muscle fibers, type I and type II, determined by motor nerve innervation. 7. Myofibrils and myofilaments contain the major muscle proteins actin and myosin, which interact to form cross-bridges during muscle contraction. The nonprotein muscle constituents provide an energy source for contraction and regulate protein synthesis and enzyme systems, as well as stabilize cell membranes. 8. Muscle contraction includes (1) excitation, (2) coupling, (3) contraction, and (4)

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relaxation. 9. Skeletal muscle requires a constant supply of ATP and phosphocreatine to fuel muscle contraction and for growth and repair. ATP and phosphocreatine can be generated aerobically or anaerobically. 10. Motor units contract in an all-or-nothing manner, so the contraction generated will be the maximal contraction. Efficiency of muscle contraction is affected by muscle fiber type, innervation ratio, temperature, and muscle shape. 11. There are two types of muscle contraction. In isometric (static) contraction, the muscle maintains a constant length as tension is increased. In dynamic (formerly called isotonic) contraction, the muscle maintains a constant tension as it moves, either lengthening (eccentric contraction) or shortening (concentric contraction). 12. Muscles act in groups. When a muscle contracts and acts as a prime mover, or agonist, its reciprocal muscle, or antagonist, relaxes. 13. Tendons attach muscle to bone at sites called entheses. Ligaments attach bone to bone, helping to form joints and stabilizing them against excessive movement. Both tendons and ligaments are mostly composed of types III, IV, V, and VI collagen and fibroblasts (called tenocytes in tendons).

Aging & the Musculoskeletal System 1. Bones become less dense, less strong, and more brittle with aging. The bone remodeling cycle takes longer to complete, and the rate of mineralization also decelerates. 2. With aging, cartilage becomes more rigid, fragile, and susceptible to fraying. Decreased range of motion of the joint is related to the changes in ligaments and muscles. 3. The regenerative function of muscle tissue and the trainability of muscle function remains normal in elderly persons. 4. Sarcopenia, or age-related loss of skeletal muscle, is a direct cause of decrease in muscle strength. A slow decline in dynamic and isometric strength is evident after age 70 years. 5. As much as 30% to 40% of skeletal muscle mass and strength may be lost from the third to ninth decades. Muscle fatigue also may contribute to loss of function with aging. A reduced basal metabolic rate and decreased lean body mass are also noted in the elderly population.

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Key Terms A cell (macrophage), 940 Agonist, 951 Alpha-glycoprotein (α-glycoprotein), 937 Amphiarthrosis (slightly movable joint), 940 Antagonist, 951 Appendicular skeleton, 938 Articular cartilage, 942 Axial skeleton, 938 B cell (fibroblast), 940 Basement membrane, 946 Basic multicellular unit, 939 Bone albumin, 937 Bone fluid, 937 Bone matrix, 933 Calcification, 933 Canaliculus (pl., canaliculi), 937 Chondrocyte, 942 Collagen fiber, 937 Compact bone (cortical bone), 937 Concentric (shortening) contraction, 951 Contraction, 950 Coupling, 948 Cross-bridge theory, 950 Diaphysis, 938 Diarthrosis (freely movable joint), 940 Dynamic (isotonic) contraction, 951 Eccentric (lengthening) contraction, 951 Endomysium, 943 Endosteum, 939 Enthesis, 951 Epimysium, 943 Epiphysis, 938 Excitation, 948 Fascia, 943 Fascicle, 943 Fibril, 937 Fibrous joint, 940 Flat bone, 939 Fusiform muscle, 943 Glycoprotein, 937 Golgi tendon organ, 944 Gomphosis, 940 Ground substance, 933

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Growth plate (epiphyseal plate), 939 Haversian canal, 937 Haversian system, 937 Hydroxyapatite (HAP), 937 Integrin, 935 Irregular bone, 939 Isometric (static) contraction, 951 Joint (articular) capsule, 940 Joint (articulation), 940 Joint (synovial) cavity, 941 Lacuna, 935 Lamella (pl., lamellae), 937 Ligament, 951 Long bone, 938 Metaphysis, 938 Mineralization, 937 Motor unit, 944 Muscle fiber (muscle cell), 944 Muscle fiber action potential, 948 Muscle membrane, 946 Myoblast, 000, 943 Myofibril, 944, 946 Myoglobin, 946 Osteoblast, 934 Osteocalcin, 937 Osteoclast, 935 Osteocyte, 935 Osteoid, 934 Osteoprotegerin (OPG), 935 Oxygen debt, 950 Pennate muscle, 943 Perimysium, 943 Periosteum, 938 Physiologic tetanus, 950 Podosome, 935 Proteoglycan, 937 Receptor activator nuclear factor kappa-B ligand (RANKL), 935 Red muscle (type I fiber [slow-twitch fiber]), 945 Relaxation, 950 Remodeling, 939 Repetitive discharge, 950 Resorb, 933 Ruffled border, 935 Sarcolemma, 946 Sarcomere, 946 Sarcopenia, 952 Sarcoplasm, 946

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Sarcoplasmic reticulum, 946 Sarcotubular system, 946 Sarcotubule, 946 Satellite cell, 944 Short bone, 939 Sialoprotein, 937 Skeletal muscle (voluntary, striated, or extrafusal muscle), 944 Spindle, 944 Spongy bone (cancellous bone), 937 Static (holding) contraction, 951 Suture, 940 Symphysis, 940 Synarthrosis (immovable joint), 940 Synchondrosis, 940 Syndesmosis, 940 Synovial fluid, 941 Synovial joint, 943 Synovial membrane, 940 Tendon, 951 Tidemark, 942 Trabecula (pl., trabeculae), 938 Transverse tubule, 946 Voluntary muscle, 944 White muscle (type II fiber [white fast-twitch fiber]), 945

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References 1. Jimi E, Fukushima H. NF-κB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-κB. Clin Calcium. 2016;26(2):298–304. 2. Atkins GJ, Findlay DM. Osteocyte regulation of bone mineral: a little give and take. Osteoporos Int. 2012;23(8):2067–2079. 3. Honma M, et al. Regulatory mechanisms of RANKL presentation to osteoclast precursors. Curr Osteoporos Rep. 2014;12(1):115–120. 4. Bellido T. Osteocyte-driven bone remodeling. Calcif Tissue Int. 2014;94:25–34. 5. Komori T. Functions of the osteocyte network in the regulation of bone mass. Cell Tissue Res. 2013;352:191–198. 6. Sapir-Koren R, Livshits G. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? Osteoprors Int. 2014;25:2685–2700.

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41

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Alterations of Musculoskeletal Function Benjamin A. Smallheer

CHAPTER OUTLINE Musculoskeletal Injuries, 955 Skeletal Trauma, 955 Support Structures, 959 Disorders of Bones, 964 Metabolic Bone Diseases, 964 Infectious Bone Disease: Osteomyelitis, 971 Disorders of Joints, 973 Osteoarthritis, 973 Classic Inflammatory Joint Disease, 976 Disorders of Skeletal Muscle, 984 Secondary Muscular Dysfunction, 984 Fibromyalgia, 984 Chronic Fatigue Syndrome, 985 Metabolic Muscle Diseases, 987 Inflammatory Muscle Diseases: Myositis, 988 Toxic Myopathies, 989 Musculoskeletal Tumors, 990 Bone Tumors, 990 Muscle Tumors, 994

Musculoskeletal injuries include fractures, dislocations, sprains, and strains. Metabolic disorders, infections, inflammatory or noninflammatory diseases, or tumors may cause alterations in bones, joints, and muscles. The most common disease affecting bone is osteoporosis; much attention and debate has been focused on its risk factors and pathophysiology. Soft tissue disorders—including muscle, tendon, and ligament injuries; tumors; and metabolic derangements—also affect the musculoskeletal system.

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Musculoskeletal Injuries Trauma is referred to as the “neglected disease.” It is the leading cause of death in people ages 1 to 44 years of all races and socioeconomic levels. Each year, more than 120,000 persons in the United States die from unintentional injuries.1 Musculoskeletal injuries have a major impact on the affected individuals, families, and society in general because of the physical and psychological effects of limitation on mobility and daily activities, pain, and decreased quality of life. In addition, there are direct costs of diagnosis and treatments, and indirect economic costs related to loss of employment and decreased productivity.

Skeletal Trauma Fractures A fracture is a break in the continuity of a bone. A break occurs when force is applied that exceeds the tensile or compressive strength of the bone. The incidence of fractures varies for individual bones according to age and sex with the highest incidence of fractures in young males (between the ages of 15 and 24 years) and older persons (65 years of age or older). Fractures of healthy bones, particularly the tibia, clavicle, and lower humerus, tend to occur in young persons as the result of trauma. Fractures of the hands and feet are often caused by accidents in the workplace. The incidence of fractures of the upper femur, upper humerus, vertebrae, and pelvis is highest in older adults and often is associated with osteoporosis (see the Osteoporosis section). Hip fractures, the most serious outcome of osteoporosis, have a wide variation in geographic occurrence. Classification of fractures. There are numerous classification systems for various types of fractures, but the simplest systems describe the basic features of the broken bone. Fractures can be classified as complete or incomplete and as open or closed (Fig. 41.1). In a complete fracture the bone is broken entirely, whereas in an incomplete fracture the bone is damaged but is still in one piece. Complete and incomplete fractures also can be called open (formerly referred to as compound) if the skin is open and closed (formerly called simple or incomplete) if it is not. A fracture in which a bone breaks into more than two fragments is termed a comminuted fracture. Fractures are also classified according to the direction of the fracture line. A linear fracture runs parallel to the long axis of the bone. An oblique fracture occurs at a slanted angle to the shaft of the bone. A spiral fracture encircles the bone, and a transverse fracture occurs straight across the bone.

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FIGURE 41.1 Examples of Types of Bone Fractures. A, Oblique: Fracture at oblique angle across both cortices. Cause: Direct or indirect energy, with angulation and some compression. B, Occult: Fracture that is hidden or not readily discernible. Cause: Minor force or energy. C, Open: Skin broken over fracture; possible soft tissue trauma. Cause: Moderate to severe energy that is continuous and exceeds tissue tolerance. D, Pathologic: Transverse, oblique, or spiral fracture of bone weakened by tumor pressure or presence. Cause: Minor energy or force, which may be direct or indirect. E, Segmented: Fracture with two or more pieces or segments. Cause: Direct or indirect moderate to severe force. F, Spiral: Fracture that curves around cortices and may become displaced by twist. Cause: Direct or indirect twisting energy or force with distal part held or unable to move. G, Transverse: Horizontal break through bone. Cause: Direct or indirect energy toward bone. H, Greenstick: Break in only one cortex of bone. Cause: Minor direct or indirect energy. I, Impacted: Fracture with one end wedged into opposite end of inside fractured fragment. Cause: Compressive axial energy or force directly to distal fragment. (Redrawn from Mourad L: Musculoskeletal system. In Thompson JM et al, editors: Mosby's clinical nursing, ed 7, St Louis, 2002, Mosby.)

Incomplete fractures tend to occur in the more flexible, growing bones of children. The three main types of incomplete fractures are greenstick, torus, and bowing fractures. A greenstick fracture perforates one cortex and splinters the spongy bone. The name is derived from the damage sustained by a young tree branch (a green stick) when it is bent sharply. The outer surface is disrupted, but the inner surface remains intact. Greenstick fractures typically occur in the metaphysis or diaphysis of the tibia, radius, and ulna. In a torus fracture, the cortex buckles but does not break. Bowing fractures usually occur when

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longitudinal force is applied to bone. This type of fracture is common in children and usually involves the paired radius-ulna or the fibula-tibia. A complete diaphyseal fracture occurs in one of the bones of the pair, which disperses the stress sufficiently to prevent a complete fracture of the second bone, which bows rather than breaks. A bowing fracture resists correction (reduction) because the force necessary to reduce it must be equal to the force that bowed it. Treatment of bowing fractures is also difficult because the bowed bone interferes with reduction of the fractured bone. Types of fractures are summarized in Table 41.1. TABLE 41.1 Types of Fractures Type of Definition Fracture Typical Complete Fractures Closed Noncommunicating wound between bone and skin Open Communicating wound between bone and skin Comminuted Multiple bone fragments Linear Fracture line parallel to long axis of bone Oblique Fracture line at an angle to long axis of bone Spiral Fracture line encircling bone (as a spiral staircase) Transverse Fracture line perpendicular to long axis of bone Impacted Fracture fragments pushed into each other Pathologic Fracture at a point where bone has been weakened by disease, for example, by tumors or osteoporosis Avulsion Fragment of bone connected to a ligament or tendon detaches from main bone Compression Fracture wedged or squeezed together on one side of bone Displaced Fracture with one, both, or all fragments out of normal alignment Extracapsular Fragment close to joint but remains outside joint capsule Intracapsular Fragment within joint capsule Typical Incomplete Fractures Greenstick Break in one cortex of bone with splintering of inner bone surface; commonly occurs in children and elderly persons Torus Buckling of cortex Bowing Bending of bone Stress Microfracture Transchondral Separation of cartilaginous joint surface (articular cartilage) from main shaft of bone

Fractures may be further classified by cause as pathologic, stress, or transchondral fractures. A pathologic (also known as insufficiency or fragility) fracture is a break at the site of a preexisting abnormality, resulting from force that would not fracture a normal bone. In any bone that lacks normal ability to deform and recover, these fractures can occur with normal weight bearing or activity. Rheumatoid arthritis, osteoporosis, Paget disease, osteomalacia, rickets, hyperparathyroidism, and radiation therapy all cause bone to lose its normal ability to deform and recover. Pathologic fractures are generally a result of bone weakness caused by another disease, such as cancer, metabolic bone disorders, or infection. Although usually considered insufficiency fractures, breaks in the bone attributable to osteoporosis can also be referred to as pathologic fractures. Any disease process that weakens a bone (especially the cortex) predisposes the bone to pathologic fracture. During activities that subject a bone to repeated strain, such as certain types of sports, a stress fracture can occur in normal or abnormal bone. The forces placed on the bone are cumulative, eventually causing a fracture. A fatigue fracture is caused by repetitive, sometimes abnormal stress or torque applied to a bone with a normal ability to deform and

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recover. Fatigue fractures usually occur in individuals who engage in a new or different activity that is both strenuous and repetitive (e.g., joggers, skaters, dancers, military recruits). Because gains in muscle strength occur more rapidly than gains in bone strength, the newly developed muscles place exaggerated stress on the bones that are not yet ready for the additional stress. The imbalance between muscle and bone development causes microfractures to develop in the cortex. If the activity is controlled and increased gradually, new bone formation catches up to the increased demands and microfractures do not occur. A transchondral fracture consists of fragmentation and separation of a portion of the articular cartilage. (Joint structures are defined in Chapter 40.) Single or multiple sites may be fractured, and the fragments may consist of cartilage alone or cartilage and bone. Typical sites of transchondral fracture are the distal femur, the ankle, the patella, the elbow, and the wrist. Transchondral fractures are most prevalent in adolescents. Pathophysiology Fracture healing is a complex process that occurs primarily in one of two ways: direct or indirect healing.2 Both types of healing require integration of cells, signaling pathways, and various molecules. In direct (or primary) healing, intramembranous bone formation occurs when adjacent bone cortices are in contact with one another, such as when surgical fixation devices are used. No callus formation occurs with direct bone healing. Indirect (or secondary) healing involves both intramembranous and endochondral bone formation, development of callus, and eventual remodeling of solid bone. Bone formation that begins with an underlying cartilage scaffold is termed endochondral bone formation. A hallmark of indirect fracture healing is the formation of callus. Indirect fracture healing is most often observed when a fracture is treated with a cast. When a bone is broken, the periosteum and blood vessels in the cortex, marrow, and surrounding soft tissues are disrupted. Bleeding occurs from the damaged ends of the bone and from the neighboring soft tissue. A clot (hematoma) forms within the medullary canal, between the fractured ends of the bone, and beneath the periosteum (Fig. 41.2). Bone tissue immediately adjacent to the fracture dies. This dead tissue (along with any debris in the fracture area) stimulates vasodilation, exudation of plasma and leukocytes, and infiltration by inflammatory leukocytes, growth factors, and mast cells that simultaneously decalcify the fractured bone ends. Within 48 hours after injury, vascular tissue from surrounding soft tissue and the marrow cavity invades the fracture area, and blood flow to the entire bone increases. Boneforming cells in the periosteum, endosteum, and marrow are activated to produce subperiosteal procallus along the outer surface of the shaft and over the broken ends of the bone (Fig. 41.2). Osteoblasts within the procallus synthesize collagen and matrix, which becomes mineralized to form callus. As the repair process continues, remodeling occurs, during which unnecessary callus is resorbed and trabeculae are formed along lines of stress as the repair tissues align with the tissue cells of the host (Fig. 41.3).

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FIGURE 41.2 Schematic of Bone Healing. A, Bleeding at broken ends of the bone with subsequent hematoma formation. B, Organization of hematoma into fibrous network. C, Invasion of osteoblasts, lengthening of collagen strands, and deposition of calcium. D, Callus formation; new bone is built while osteoclasts destroy dead bone. E, Remodeling is accomplished while excess callus is reabsorbed and trabecular bone is deposited. (From Monahan FD et al: Phipps’ medical-surgical nursing: health and illness perspectives, ed 8, St Louis, 2007, Mosby.)

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FIGURE 41.3

Exuberant Callus Formation After Fracture. (From Rosai J: Ackerman's surgical pathology, ed 8, St Louis, 1996, Mosby.)

Clinical Manifestations The signs and symptoms of a fracture include unnatural alignment (deformity), swelling, muscle spasm, tenderness, pain and impaired sensation, and decreased mobility. The position of the broken bone segments is determined by the pull of attached muscles, gravity, and the direction and magnitude of the force that caused the fracture. Immediately after a bone is fractured, there often is numbness at the fracture site because of trauma to the nerve or nerves at the injury site. The numbness may last several minutes, during which time the injured person can continue to use the fractured bone. However, once the numbness dissipates, the subsequent pain is quite severe and may be incapacitating until relieved with medication and treatment of the fracture. Pain can be caused by muscle spasms at the fracture site, overriding of the fracture segments, or damage to adjacent soft tissues. Pathologic fractures can cause angular deformity, painless swelling, or generalized bone pain. Stress fractures are painful because of accelerated remodeling; initially, pain occurs during activity and is usually relieved by rest. Stress fractures also cause local tenderness and soft tissue swelling. Transchondral fractures may be entirely asymptomatic or may be painful during movement. Range of motion in the joint is limited, and movement may evoke audible clicking sounds (crepitus). Evaluation and Treatment Adequate immobilization with a splint or cast is often all that is required for healing of fractures that are not misaligned. Treatment of a displaced fracture involves realigning the bone fragments (reduction) close to their normal or anatomic position and holding the fragments in place (immobilization) so that bone union can occur. Several methods are

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available to reduce a fracture: closed manipulation, traction, and open reduction. Many displaced fractures can be reduced by closed manipulation and reduction. The bone is moved or manipulated into place without opening the skin. Closed reduction is used when the contour of the bone is in fair anatomic alignment and can be manually placed into normal alignment, and then maintained with immobilization. Splints and casts are used to immobilize and hold a closed reduction in place. Traction may be used to accomplish or maintain reduction. When bone fragments are displaced (not in their anatomic position), weights may be used to apply firm, steady traction (pull) and countertraction to the long axis of the bone. Traction stretches and fatigues muscles that have pulled the bone fragments out of place, more readily allowing the distal fragment to align with the proximal fragment. Traction can be applied to the skin (skin traction) or directly to the involved bone (skeletal traction). Skin traction is used when only a few pounds of pulling force are needed to realign the fragments or when the traction will be used only for a brief time, such as before surgery or, for children with femoral fractures, for 3 to 7 days before a cast is applied. In skeletal traction, a pin or wire is drilled through the bone distal to the fracture site, and a traction bow, rope, and weights are attached to the pin or wire to apply tension and to provide the pulling force required to overcome the muscle spasm and help realign the fracture fragments. More often, surgical repair (open reduction and internal fixation) or external fixation devices are used to realign displaced fractures. Open reduction is a surgical procedure that exposes the fracture site; the fragments are then manipulated into alignment under direct visualization. Some form of hardware, such as a screw, plate, nail, or wire, is used to maintain the reduction (internal fixation). External fixation, a procedure in which pins or rods are surgically placed into uninjured bone near the fracture site and then stabilized with an external frame of bars, is another method used to treat fractures that would not be adequately stabilized with a cast. Bone grafts—using donor bone from the individual (autograft), a cadaver (allograft), or bone substitutes (ceramic composites, bioactive cement)—can fill voids in the bone. Improper reduction or immobilization of a fractured bone may result in nonunion, delayed union, or malunion. Nonunion is failure of the bone ends to grow together. The gap between the broken ends of the bone fills with dense fibrous and fibrocartilaginous tissue instead of new bone. Occasionally, the fibrous tissue contains a fluid-filled space that resembles a joint and is termed a false joint, or pseudoarthrosis. Delayed union is union that does not occur until approximately 8 to 9 months after a fracture. Malunion is the healing of a bone in an incorrect anatomic position.

Dislocation and Subluxation Dislocation and subluxation are usually caused by trauma. Dislocation is the displacement of one or more bones in a joint in which the opposing joint surfaces entirely lose contact with one another. If contact between the opposing joint surfaces is only partially lost (partial dislocation), the injury is called a subluxation. Dislocation and subluxation are most common in persons younger than 20 years of age and are generally associated with fractures. However, they also may be the result of congenital or acquired disorders that cause (1) muscular imbalance, seen with congenital dislocation of the hip; (2) incongruities in the articulating surfaces of the bones, as occur with rheumatoid arthritis (see the Rheumatoid Arthritis section); or (3) joint instability.

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The joints most often dislocated or subluxated are the joints of the shoulder, elbow, wrist, finger, hip, and knee. The shoulder joint most often injured is the glenohumeral joint. Finger dislocations are common injuries in contact sports such as basketball, football, and rugby. Traumatic dislocation of the elbow joint is common in the immature skeleton (“nursemaid's elbow”). In adults, an elbow dislocation is usually associated with a fracture of the ulna or head of the radius. Traumatic dislocation of the wrist usually involves the distal ulna and carpal bones. Any one of the eight carpal bones can be dislocated after an injury. Dislocation in the hand usually involves the metacarpophalangeal and interphalangeal joints. Considerable trauma is needed to dislocate the hip. Anterior hip dislocation is rare in healthy persons; it is caused by forced abduction; for example, when an individual lands on his or her feet after falling from an elevated height. Posterior dislocation of the hip can occur as a result of an automobile accident in which the flexed knee strikes the dashboard, causing the head of the femur to be pushed posteriorly from the hip joint. The knee is an unstable weight-bearing joint that depends heavily on the soft tissue structures around it for support. It is exposed to many different types of motion (flexion, extension, rotation) and is one of the most commonly injured joints. A knee dislocation can be anterior, posterior, lateral, medial, or rotary. It is often the result of an injury that occurs during contact sports activities, such as soccer, lacrosse, or football. Pathophysiology Dislocations and subluxations are often accompanied by fracture because stress is placed on areas of bone not usually subjected to stress. In addition, as the joint loses its normal congruity, there may be bruising or tearing of adjacent nerves, blood vessels, ligaments, supporting structures, and soft tissue. Dislocations of the shoulder may damage the shoulder capsule and the axillary nerve. Damage to axillary nerves can cause anesthesia or dysesthesia in the sensory distribution of the nerve and paralysis of the deltoid muscle. Dislocations also may disrupt circulation, leading to ischemia and possibly even permanent disability of the affected extremity tissues. Clinical Manifestations Signs and symptoms of dislocations or subluxations include pain, swelling, limitation of motion, and joint deformity. Pain may be caused by effusion of inflammatory exudate into the joint or by associated tendon and ligament injury. Joint deformity is typically caused by muscle contractions that exert pull on the dislocated or subluxated joint. Limitation of motion results from effusion into the joint or the displacement of bones. Evaluation and Treatment Evaluation of dislocations and subluxations is based on clinical manifestations and radiographic evaluation. Treatment consists of reduction and immobilization for 2 to 6 weeks to allow healing of damaged structures, followed by exercises to restore normal range of motion in the joint. Depending on the joint and severity of injury, complete healing can take months to sometimes years.

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Sprains and Strains of Tendons and Ligaments Tendons and ligaments support the bones and joints and either facilitate or limit motion, respectively. Either structure can be completely separated from bone at its points of attachment, torn, lacerated, or ruptured. Tendon and ligament injuries often accompany fractures and dislocations. A tendon is fibrous connective tissue that attaches skeletal muscle to either bone or another structure; the area of attachment on a bone is called an enthesis. Functionally, muscles and tendons work together as a single, integrated unit allowing motion. A ligament is a band of fibrous connective tissue that connects bones where they meet in a joint. The structural composition of tendons and ligaments are similar. The primary difference between tendons and ligaments is their anatomic function and location. Tearing or stretching of a muscle or tendon is commonly known as a strain. Major trauma can tear or rupture a tendon at any site in the body. The tendons most commonly injured are those of the hands and feet, the knee (patellar), the upper arm (biceps and triceps), the thigh (hamstring), the ankle, and the heel (Achilles). Ligament tears are commonly known as sprains. Ligament tears and ruptures can occur at any joint but are most common in the wrist, ankle, elbow, and knee joints. A complete separation of a tendon or ligament from its bony attachment site is known as an avulsion and is commonly seen in young athletes, especially sprinters, hurdlers, and distance runners. Strains and sprains are classified as first degree (mild), second degree (moderate), and third degree (severe). In first-degree injuries, the fibers are stretched but the muscle (strain) or joint (sprain) remains stable. In second-degree strains or sprains, there is more tearing of the tendon or ligament fibers, resulting in muscle weakness or some joint instability and incomplete tearing of fibers. Third-degree strains and sprains result in a full tearing of fibers, creating an inability to contract the muscle normally (strain) or cause significant joint instability (sprain). Pathophysiology When a tendon or ligament is torn, an inflammatory exudate develops between the torn ends. Within 4 to 5 days after the injury, collagen formation begins. As the collagen fibers interweave and connect with preexisting tendon fibers, they become organized parallel to the lines of the musculotendinous unit. Eventually vascular fibrous tissue fuses the new and surrounding tissues into a single mass. Collagen fibers reconnect the tendon and bone, forming a new enthesis. It may take more than 3 months for the new enthesis to achieve mechanical stability of a joint. If powerful muscle contractions occur during healing, the tendon or ligament ends may separate again, which causes the tendon or ligament to heal in a lengthened shape or with an excessive amount of scar tissue, resulting in poor tendon or ligament function. Clinical Manifestations Tendon and ligament injuries are painful and are usually accompanied by soft tissue swelling, changes in tendon or ligament contour, and dislocation or subluxation of bones. Pain is generally sharp and localized, and tenderness persists over the distribution of the tendon or ligament. Movement or weight bearing increases pain. Even with prompt treatment, depending on the tendon or ligament involved, significant injuries may result in

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decreased mobility, instability, and weakness of the affected joints. Evaluation and Treatment Evaluation is based on the mechanism of injury and the clinical manifestations. Stress radiography, arthroscopy, or arthrography also may be considered. Initial treatment consists of protection, rest, ice, compression, and elevation (PRICE) for the first 48 to 72 hours. Once swelling and acute pain subside, in most cases support of the affected tendon or ligament with a compression dressing or brace will provide appropriate reinforcement while the tissues heal. Rehabilitation is crucial to regaining a good functional outcome. In severe (third-degree) injuries, treatment may include surgical intervention to suture the tendon or ligament ends in close approximation with one another or the enthesis. If this is not feasible because of the extent of damage, tendon or ligament grafting may be necessary. Prolonged, functional rehabilitation programs help ensure return of near-normal functioning, but recovery may be complicated by posttraumatic arthritis.

Tendinopathy, Epicondylopathy, and Bursitis Trauma also can cause painful inflammation of tendons (tendinopathy [tendonitis]) and bursae (bursitis). Other causes of damage to tendons include reduced tissue perfusion, mechanical irritation, crystal deposits, postural misalignment, and hypermobility of a joint. Thus, tendinopathy is a more accurate term than tendonitis in most cases. Microvascular and increased nerve growth often occur to these areas which increases the body's transmission of pain sensations. The histopathology of common conditions, such as lateral epicondylopathy (“tennis elbow”) or medial epicondylopathy (“golfer's elbow”), is a degenerative process3 (Fig. 41.4). A bony prominence at the end of a bone where tendons or ligaments attach is termed an epicondyle. When force is sufficient to cause microscopic tears (microtears) in tissue, the result is known as tendinopathy or epicondylopathy. Microtears in the tendon, the presence of disorganized collagen fibers, and neovascularization indicate incomplete tissue repair. Initial inflammatory changes cause thickening of the tendon sheath, limited movements, and pain. Microtears cause bleeding, edema, and pain in the involved tendon or tendons.

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FIGURE 41.4 Epicondylopathy and Tendinopathy. A, Lateral and medial epicondyles of the distal humerus, sites of tennis elbow (lateral) and golfer's elbow (medial). B, Achilles tendon, common site of tendinopathy.

Lateral epicondylopathy (tennis elbow) is caused by irritation and overstretching of the extensor carpi radialis brevis (ECRB) tendon and forearm extensor muscles, resulting in tissue degradation, loss of grip strength, and pain. Medial epicondylopathy (golfer's elbow) is the result of similar forces affecting the forearm muscles responsible for forearm flexion and pronation (see Fig. 41.4). Repetitive load-bearing activities or acute injuries that involve flexion, extension, pronation, or supination of the elbow and forearm can lead to either lateral or medial elbow symptoms. Clinical manifestations of epicondylopathy are usually localized to one side of the joint. In general, there is local tenderness and more pain with active motion than with passive motion. With tendinopathy or tendonitis, the pain is localized over the involved tendon. Stressing the tendon with simple activities, such as lifting even a few pounds of weight, can increase pain. Pain and sometimes weakness limit joint movement. Bursae are small sacs lined with synovial membrane and filled with synovial fluid that

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are located between bony prominences and soft tissues such as tendons, muscles, and ligaments (Fig. 41.5). Bursae can be either “constant” (those formed during embryologic development) or “adventitious” (bursae that develop as a result of chronic friction and degeneration of fibrous tissue between adjacent structures). The primary function of a bursa is to separate, lubricate, and cushion these structures. When irritated or injured, these sacs become inflamed and swell. Because most bursae lie outside joints, joint movement is rarely compromised with bursitis. Acute bursitis occurs primarily during middle age and is caused by trauma. Chronic bursitis can result from repeated trauma. Septic bursitis is caused by wound infection or bacterial infection of the skin overlying the bursae. Bursitis commonly occurs in the shoulder, hip, knee, and elbow but also can affect the spine, wrist, foot, and ankle.

FIGURE 41.5 Olecranon Bursitis. Note swelling at the point of the elbow (olecranon). A smaller, rheumatoid nodule also is present. (From Hochberg MC et al: Rheumatology, ed 6, Philadelphia, 2015, Elsevier.)

Pathophysiology Bursitis usually is an inflammation that is reactive to overuse or excessive pressure but also can be caused by infection, autoimmune diseases, crystal deposition, or acute trauma. The inflamed bursal sac becomes engorged, and the inflammation can spread to adjacent tissues. The inflammation may decrease with rest, ice, and aspiration of the fluid. (Inflammation is discussed in Chapter 6.) Clinical Manifestations Joint motion is rarely limited in bursitis, except by pain. Shoulder pain may impair arm abduction. Bursitis in the knee produces pain when climbing stairs, and crossing the legs is painful in bursitis of the hip. Lying on the side of the inflamed trochanteric bursa is also very painful. Signs of infectious bursitis may include the presence of pain, warmth and erythema, severe inflammation, or an adjacent source of infection, such as from total joint replacement surgery. Prior corticosteroid injections or evidence of a puncture site at the joint increases the potential for infectious bursitis.

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Evaluation and Treatment The diagnosis of tendinopathy, epicondylopathy, and bursitis is primarily based on the clinical history and physical examination. Other imaging techniques, such as ultrasound or magnetic resonance imaging (MRI), may be used to evaluate the severity of the problem. Treatment may include temporary immobilization of the joint with a sling, splint, or cast; administration of systemic analgesics; application of ice or heat; or local injection of an anesthetic, a corticosteroid, platelet-rich plasma (PRP), or a combination local anesthetic/corticosteroid. Physical therapy to prevent loss of function begins after acute inflammation subsides (Did You Know? Managing Tendinopathy).

Did You Know? Managing Tendinopathy Tennis and golfer's elbow, Achilles tendinopathy, and other tendon problems account for a large percentage of sports-related overuse injuries. Successful treatment of these conditions is challenging because of the mechanisms of tendon healing, as well as inconsistent results, with many interventions still not completely understood. Chronic pain is common and may be the result of ingrowth of nerves that accompanies ingrowth of new blood vessels during the healing process. Recent studies suggest that the traditional approach of corticosteroid injections is helpful only for the short term. Other therapies that show promise include the following: Prolotherapy: An irritant such as glucose or lidocaine is injected into the affected tendon, inducing an inflammatory response, thereby stimulating the growth of new tendon fibers. Eccentric exercises: The tendon is “prestretched,” increasing its resting length and resulting in less strain during movement. The load on the tendon is gradually increased, causing the tendon itself to strengthen. Extracorporeal shockwave therapy (SWT): External acoustic or sonic waves are focused on the affected area. The shockwaves stimulate soft tissue healing and inhibit pain receptors. Needling: This treatment involves multiple insertions of a sterile needle into affected tissue. It is thought the pain sensation is reduced by stimulating A-nerve fibers. This technique is often referred to as “dry needling” since no fluid is introduced. Platelet-rich plasma: This autologous source of concentrated platelets is obtained by centrifugation of plasma. The resulting solution contains high concentrations of cytokines and growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β), which are thought to promote the growth of new, healthy tissue. Autologous tenocyte injections: Autologous injection of tenocytes at the site of tendinopathy is thought to provide necessary mediators of tissue healing. From Andarawis-Puri N et al: J Orthop Res 33(6):780-784, 2015; Krey D et al: Phys Sportsmed 43(1):80-86, 2015; Langer PR: Clin Podiatr Med Surg 32(2):183-193, 2015; Mautner K, Kneer L:

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Phys Med Rehabil Clin North Am 25(4):865-880, 2014; Wang A et al: Am J Sports Med 43(7):1775-1783, 2015.

Muscle Strains Muscle strain is a general term for local muscle damage. Mild injury, such as muscle strain, is usually seen after traumatic or sports injuries. It is often the result of sudden, forced motion causing the muscle to become stretched beyond normal capacity. Strains often involve the tendon as well. Penetrating injuries, such as knife and gunshot wounds, can cause traumatic rupture (see Chapter 4). The incidence of muscle rupture is greater in young people. However, tendon rupture occurs with greater frequency in the older population. Muscle strain may be chronic when the muscle is repeatedly stretched beyond its usual capacity. Tissue biopsy of a muscle experiencing chronic strain reveals evidence of tissue disruption with subsequent signs of muscle regeneration and connective tissue repair. Hemorrhage into the surrounding tissue and signs of inflammation also may be present. Muscle healing occurs in three phases: 1. Destruction, in which the myofibers of the damaged muscle contract and necrose, beginning an inflammatory reaction. The gap between torn fibers is filled by a hematoma. 2. Repair, which begins with monocytes phagocytizing the dead tissue and activating satellite cells, which become myoblasts. The myoblasts infiltrate the scar tissue, and new capillary formation begins at the site of injury. The first two phases occur within a week of injury. 3. Remodeling occurs as the myofibers mature, form contractile tissue, and attach to the ends of scar tissue. Regeneration may take up to 6 weeks, and the affected muscle should be protected during that time. Degrees of acute muscle strain, together with their manifestations and treatment, are summarized in Table 41.2. TABLE 41.2 Muscle Strain Type First degree (example: bench press in untrained athlete)

Manifestations Muscle overstretched, pain but no muscle deformity

Treatment Ice should be applied 5 or 6 times in first 24-48 hr; gradual resumption of full weight bearing after initial rest for up to 2 weeks Exercises individualized to specific injury Treatment similar to that for first-degree strains

Second degree (example: any muscle strain with bruising and pain) Third degree (example: traumatic injury)

Muscle intact with some tearing of fibers, swelling, pain Caused by tearing of Surgery to approximate ruptured edges; immobilization fascia, marked weakness, and non–weight bearing status for 6 weeks deformity

A late complication of some muscle injuries is myositis ossificans, also known as heterotopic ossification (HO). Although it is not completely understood, evidence suggests

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the pathophysiology of HO is related to the inability of mesenchymal cells to differentiate into osteoblastic stem cells, resulting in an inappropriate differentiation of fibroblasts into bone-forming cells. Though uncommon, HO also may be associated with burns, joint surgery, and trauma to the musculoskeletal system or central nervous system. HO may involve the muscle or tendons, ligaments, or bones near the muscle, causing stiffness or deformity of an extremity. Radiographic evidence of HO may be seen as soft tissue calcification on plain radiographs.

Rhabdomyolysis Once used interchangeably with the term myoglobinuria, rhabdomyolysis is the rapid breakdown of muscle that causes the release of intracellular contents, including the protein pigment myoglobin, into the extracellular space and bloodstream. Physical interruptions in the sarcolemma membrane, called delta lesions, are the route by which muscle constituents are released. (The sarcolemma membrane, the plasma membrane of the muscle cell, is described in Chapter 40.) Myoglobinuria refers to the presence of the muscle protein myoglobin in the urine. Pathophysiology The term rhabdomyolysis is sometimes incorrectly used interchangeably with crush injury (a description of injuries resulting from crushing of a body part), compartment syndrome (the consequences of increased intracompartmental pressures of a muscle), or crush syndrome (the systemic pathophysiologic events caused by rhabdomyolysis, primarily involving the kidneys and coagulation syndrome).4 Rhabdomyolysis has many causes (Box 41.1) and can result in serious complications, including acute renal failure and electrolyte imbalances from the release of intracellular contents into the circulation (e.g., hyperkalemia and hyperphosphatemia), compounded by renal impairment, acid-base derangement, and cardiac dysrhythmias. The most clinically significant complication is acute renal failure, because myoglobin precipitates in the tubules, obstructing flow of ultrafiltrate through the nephron and producing injury).5 Other complications include disseminated intravascular coagulation (DIC), likely caused by activation of the clotting cascade by sarcolemma damage and the release of intracellular components from the damaged muscles.

Box 41.1

Selected Causes of Rhabdomyolysis Direct Trauma Blunt trauma or crush injury (motor vehicle crashes, collapsed buildings) Burns (thermal) Electrical injury Excessive compression (from immobility attributable to stroke, alcohol or drug intoxication)

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Drugs Alcohol Amphetamines Anesthetic and paralytic agents (halothane, propofol, succinylcholine—malignant hyperthermia syndrome) Antihistamines (diphenhydramine, doxylamine) Antihyperlipidemic agents (statins, clofibrate, bezafibrate) Antipsychotics and antidepressants (amitriptyline, doxepin, fluoxetine, haloperidol, lithium, protriptyline, perphenazine, promethazine, chlorpromazine, trifluoperazine, venlafaxine) Caffeine Cocaine Corticosteroids Fibrinates (antilipid agents: bezafibrate, ciprofibrate, clozfibrate, clofibrate, ezetimibe, gemfibrozil) Heroin HIV integrase inhibitor (raltegravir) Hypnotics and sedatives (benzodiazepines, barbiturates) LSD (lysergic acid diethylamide) Methadone Methamphetamine Methylenedioxymethamphetamine (MDMA; “ecstasy”) Miscellaneous medications (amphotericin B, azathioprine, ε-aminocaproic acid, quinidine, penicillamine, salicylates, theophylline, terbutaline, thiazides, vasopressin) Phencyclidine Protease inhibitors Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) Miscellaneous drugs (amphotericin B, arsenic, azathioprine, halothane, naltrexone, quinidine, penicillamine, propofol, salicylates, succinylcholine, theophylline, terbutaline, thiazides, vasopressin)

Excessive Muscular Contraction Status epilepticus Delirium tremens Acute psychosis Severe dystonia Sporadic strenuous exercise (e.g., marathons, squats) Tetanus

Infectious Agents Bacteria (group B streptococci, Streptococcus pneumoniae, Staphylococcus epidermidis,

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Borrelia burgdorferi, Escherichia coli, Clostridium perfringens, Clostridium tetani, Streptococcus viridans; Bacillus, Brucella, Legionella, Listeria, Leptospira, Mycoplasma, Plasmodium, Rickettsia, Salmonella, and Vibrio species) Fungal organisms (Aspergillus, Candida species) Viruses (influenza types A and B, coxsackievirus, dengue, Epstein-Barr, HIV, cytomegalovirus, parainfluenza, varicella-zoster, West Nile)

Toxins Carbon monoxide Envenomation (black widow spider, Africanized honey bees, vipers) Hemlock Methanol Toluene

Hereditary Enzyme Disorders (Rare) McArdle disease (myophosphorylase deficiency) Tarui disease (type VII glycogen storage disease) Phosphoglycerate mutase deficiency (glycogen storage disease type X) Carnitine palmitoyltransferase deficiency (CPT1 deficiency)

Miscellaneous Causes Diabetic ketoacidosis Endocrinopathy Heatstroke Hypothermia Nonketotic hyperosmolar coma Polymyositis Severe electrolyte disorders (near-drowning or water intoxication, severe vomiting or diarrhea) Data from Cervellin G et al: Clin Chem Lab Med 48(6):749-756, 2010; Croche F et al: Int J STD AIDS 21(11):783-785, 2010; Halpern P et al: Hum Exp Toxicol 30(4):259-266, 2011; Keltz E et al: Muscles Ligaments Tendons J 3(4):303-312, 2014; Torres PA et al: Ochsner J 15(1):58-69, 2015; Zutt R et al: Neuromuscul Disord 24(8):651-659, 2014. Clinical Manifestations A classic triad of muscle pain, weakness, and dark urine is considered typical of rhabdomyolysis. Abnormally dark urine caused by myoglobinuria may be the first and only symptom; however, the presence of myoglobin in urine alone is not a reliable test to diagnose rhabdomyolysis. The renal threshold for myoglobin is low (approximately 0.5 mg/dl of urine); therefore, only 200 g of muscle need to be damaged to cause visible changes in the urine. Myoglobin is rapidly cleared, and levels may return to normal within

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24 hours of injury. Along with the release of myoglobin, creatine kinase (CK) and other serum enzymes are released in massive quantities (normal CK levels are 5 to 25 international units/L for women and 5 to 35 international units/L for men). The efflux of intracellular proteins and enzymes includes loss of potassium, phosphate, nucleotides, creatinine, and creatine. Serum hypocalcemia is seen early in the course of myoglobinuria and is followed by late hypercalcemia. The risk of renal failure increases proportionately to the increase in the levels of serum CK, potassium, and phosphorus. Evaluation and Treatment The most important and clinically useful measurement in rhabdomyolysis is the serum CK level. A level 5 to 10 times the upper limit of normal (about 1000 units/L) is used to identify rhabdomyolysis.5 Once CK levels exceed 15,000 units/L, acute renal failure is likely. Other laboratory tests may include hyperkalemia, which can cause life-threatening cardiac arrhythmias, and a decreased blood urea nitrogen to creatinine ratio, caused by a release of creatine from damaged muscle being converted to creatinine. Additional laboratory tests— such as measurement of the hemoglobin, hematocrit, and platelet levels and determination of the activated partial thromboplastin time—may be indicated in the presence of other trauma or suspected bleeding. A recent study evaluated the ultrasonographic appearance of rhabdomyolysis in damaged muscle from earthquake victims and found abnormalities in muscle texture and subcutaneous tissue, as well as liquid collections in the damaged tissue.6 Maintaining adequate urinary flow and prevention of kidney failure are goals of treatment. Rapid intravenous hydration maintains adequate kidney perfusion. Other complications, such as hyperkalemia, may require temporary hemodialysis. Treatments such as using mannitol to cause an osmotic diuresis or bicarbonate to alkalinize the urine have not been shown to consistently improve outcomes.

Compartment Syndrome Compartment syndrome is the result of increased pressure within a muscle compartment. Several layers of fibrous fascia surround skeletal muscles. These compartments are not able to expand. Increased pressure within these compartments creates increased pressure on the muscle tissue, leading to diminished capillary blood flow which results in local tissue hypoxia and necrosis. Causes of compartment syndrome include conditions that increase the contents of the compartment (such as bleeding or interstitial edema after an injury), a decrease in the compartment's volume (e.g., a tight bandage or cast), or a combination of these two conditions that results in a disturbance of the muscle's microvasculature7-9 (Box 41.2). Any condition that disrupts the vascular supply to an extremity (such as severe burns, bleeding disorders, crush injury, snake or insect bites, extremely tight bandages, or casts) can cause increased pressure within the muscle compartments.

Box 41.2

Factors Affecting the Development of Compartment Syndrome 2301

Increased Intracompartmental Pressure Fracture (open or closed) Traction Crush syndrome Vigorous exercise or nonroutine activity/overuse in nonathletes High-energy soft tissue injury (blast injuries, blunt force trauma) Fluid infusion Arterial puncture Ruptured abdominal aortic aneurysm Ruptured ganglion/other cyst Envenomation (venomous snakes, black widow spiders) Nephrotic syndrome Viral myositis Acute hematogenous osteomyelitis Orthopedic procedures (e.g., osteotomy, joint replacement) Seizures Tetany

Reduced Compartment Volume Burns Repair of muscle herniation Circumferential dressings Casts that are too tight

Conditions That Disturb Microcirculation Diabetes Hypothyroidism Bleeding disorders (hemophilia, von Willebrand disease, leukemia, vitamin K deficiency, viral hemorrhagic fevers [dengue]) Excessive anticoagulation Malignancies Data from Raza H, Mahapatra A: Adv Orthop 2015:543412, 2015; Shadgan B et al: Can J Surg 53(5):329-334, 2010. Pathophysiology The weight of a limb extremity can generate enough pressure to produce muscle ischemia (Figs. 41.6 and 41.7). This causes edema, rising compartment pressure, and tamponade that lead to muscle infarction and neural injury and eventually result in cell loss.

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FIGURE 41.6

Pathogenesis of Compartment Syndrome and Crush Syndrome Caused by Prolonged Muscle Compression. ECF, Extracellular fluid.

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FIGURE 41.7

Muscle Compartments of the Lower Leg. (From Mohahan FD et al: Phipps’ medical-surgical nursing: health and illness perspectives, ed 8, St Louis, 2007, Mosby.)

Clinical Manifestations Compartments often affected are the anterior and deep posterior tibial compartments in the leg, the forearm, the gluteal compartments in the buttocks, and the abdominal wall. Diagnosis is initiated by the clinical examination. The “6 Ps” of compartment syndrome are pain (out of proportion to the injury), pressure (swelling and rigidity of the affected area), pallor (pale appearance), paresthesia (impaired or altered sensations to the area, or both), paresis (impaired function of the involved extremity), and pulselessness (loss of a pulse to the area). None of these signs is truly dependable, although pain with passive extension of the fingers or toes in the affected extremity and paresthesia tend to be most suggestive of compartment syndrome.7,10 A condition known as Volkmann ischemic contracture can develop when compartment syndrome goes unrecognized or is not adequately treated. Irreversible neurovascular damage can occur. Contracture deformities of the fingers, hand, and wrist can lead to partial or complete disability of the affected limb. Evaluation and Treatment Direct measurement of intracompartmental pressure, using a manometer or an electronic transducer, is beneficial to confirm the diagnosis. However, the individual's history and physical examination findings alone can provide significant information to make the diagnosis of compartment syndrome. Laboratory tests, ultrasonography, and imaging studies may help exclude other conditions but generally are not helpful in diagnosing compartment syndrome. Once a diagnosis of compartment syndrome has been made or intracompartmental pressures reach 30 mm Hg, surgical intervention is warranted to relieve pressure within the compartment.

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Surgical intervention consists of performing a fasciotomy of the affected area to decompress the compartment and allow the return of a normal blood supply. Skin grafts are often required to close the resultant opening, but vacuum-assisted wound closure devices also have been used successfully in accelerating wound closure.

Malignant Hyperthermia Malignant hyperthermia (MH) is an autosomal dominant inherited muscle disorder characterized by a hypermetabolic reaction to certain volatile anesthetics or certain depolarizing muscle relaxants (e.g., succinylcholine) that activate a prolonged release of intracellular calcium from the sarcoplasmic reticulum. Researchers have described at least six forms of malignant hyperthermia susceptibility, which are caused by mutations in different genes.11 Variations of the calcium voltage-gated channel subunit alpha 1 S (CACNA1S) and ryanodine receptor of skeletal muscle (RYR1) genes increase the risk of developing malignant hyperthermia.11 These mutations result in a release of uncontrolled amounts of calcium from the sarcoplasmic reticulum into the cytoplasm, causing continuous muscle contraction. This process also causes hypermetabolism, with extremely high body temperature, muscle rigidity, rhabdomyolysis, and death if not quickly treated with an infusion of the skeletal muscle relaxant dantrolene.12 Though reported in all countries, ages, and sexes, young males tend to be more susceptible to MH. Common signs and symptoms are respiratory acidosis (with an elevated end tidal carbon dioxide), tachycardia, masseter muscle and skeletal muscle spasm, and elevated body temperature. Evaluation and Treatment Careful and thorough preoperative assessment should alert the anesthesiologist to the possibility of an individual being susceptible to malignant hyperthermia. A family history of anesthetic problems and previous untoward anesthetic experiences (muscle cramping, unexplained fevers, dark urine) are criteria that require further clarification before administration of a volatile anesthetic, such as halothane, or the muscle relaxant succinylcholine. The caffeine halothane muscle contracture test is considered the most sensitive and definitive predictor of an individual developing MH. A muscle biopsy is obtained from the individual and then separately exposed to standardized amounts of halothane and caffeine. If the muscle bundles exhibit a contracture at specified limits, the individual is considered susceptible to MH. Priorities in the treatment of MH include identifying and treating the underlying disorder and preventing life-threatening renal failure. MH and myoglobinuria can be treated by infusing dantrolene sodium (Dantrium). Secondary problems include electrolyte imbalance, volume depletion, acidosis, hyperuricemia, hyperkalemia, and calcium imbalance; these need specific treatment. Short-term dialysis also may be necessary.

Quick Check 41.1 1. How are fractures classified? 2. What is the primary pathology of epicondylopathy?

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3. What are some causes of compartment syndrome? 4. Why is myoglobinuria a dangerous complication of rhabdomyolysis?

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Disorders of Bones Metabolic Bone Diseases Metabolic bone disease is characterized by abnormal bone strength caused by abnormalities of minerals, vitamin D, bone mass, or bone structures. Individuals of all ages may be affected by this disease. Causes of these conditions are attributed to genetics, poor diet, or hormone influence leading to altered or inadequate biochemical reactions.

Osteoporosis Osteoporosis, or porous bone, is generally described as decreased bone mineral density (BMD) and an increased risk of fractures because of alterations in bone microarchitecture. It is a complex, multifactorial, chronic disease that often progresses silently for decades until fractures occur. It is the most common disease that affects bone but is not a consequence of the aging process. The World Health Organization (WHO) has defined osteoporosis as “a systematic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility.”13 Old bone is removed (resorption) and new bone is added (formation) to the skeleton throughout an individual's lifetime. In osteoporosis, old bone is being resorbed faster than new bone is being formed, causing the bones to lose density, becoming thinner and more porous. A progressive loss of bone mass may continue until the skeleton is no longer strong enough to support itself. Eventually, bones can fracture spontaneously. As bone becomes more fragile, falls or bumps that would not have caused a fracture previously now cause bone to break, referred to as a fragility fracture. The most common sites for osteoporosisrelated fractures are the spine, femoral neck, and wrist.14 Bone tissue can be normally mineralized in osteoporosis, but the density of bone is decreased and the structural integrity of trabecular bone is impaired. Cortical bone becomes more porous and thinner, making bone weaker and prone to fractures (Figs. 41.8 and 41.9).

FIGURE 41.8 Vertebral Body. Osteoporotic vertebral body (right) shortened by compression fractures compared with a normal vertebral body. Note that the osteoporotic vertebra has a characteristic loss of horizontal trabeculae and thickened vertical trabeculae. (From Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

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FIGURE 41.9 Electron Microscopic Comparison of Normal and Osteoporotic Bone. A, Normal trabecular structure. B, Osteoporotic bone; note the loss of supporting trabeculae. (From Golob AL, Laya MB: Med Clin North Am 99[3]:587-606, 2015.)

Skeletal homeostasis depends on a narrow range of plasma calcium and phosphate concentrations, which are maintained by the endocrine system. Therefore, endocrine dysfunction ultimately can cause metabolic bone disease. Hormones most commonly associated with osteoporosis are parathyroid hormone, cortisol, thyroid hormone, and growth hormone. (Endocrine function is discussed in Chapters 19 and 20.) Other factors that can adversely affect normal bone homeostasis include multiple medications (e.g., glucocorticoids, proton pump inhibitors, thiazolidinediones, antiseizure medications, aromatase inhibitors, selective serotonin reuptake inhibitors [SSRIs], and anticoagulants), vitamin D deficiency, underlying diseases (rheumatoid disease, Paget disease, cancer, diabetes), low physical activity, and abnormal body mass index.15-19 During childhood and the teenage years, new bone is added faster than old bone is removed. Consequently, bones become larger, heavier, and denser. Bone formation continues at a pace faster than resorption until peak bone mass, or maximum bone density and strength, is reached, around age 30. Up to 90% of peak bone mass is obtained by age 20. After age 30, bone resorption slowly exceeds bone formation. In women, bone loss is most rapid in the first years after menopause but persists throughout the postmenopausal years. In 2011, the U.S. Preventive Services Task Force (USPSTF) issued a new recommendation that women age 65 or older be routinely screened for osteoporosis.20 The major complications for persons with osteoporosis are fractures (Did You Know? Osteoporosis Facts and Figures at a Glance). Fractures are the major complication of osteoporosis. It is estimated that over 90% of all fractures occur as a result of falls.21 Hip fractures, in particular, can have devastating effects on an individual's life. In addition to direct medical costs, studies have shown decreased quality of life, as well as excess loss of life-years for those experiencing hip or osteoporotic fractures.22,23

Did You Know? Osteoporosis Facts and Figures at a Glance • Osteoporosis is the most common bone disease of adults and the foremost cause of

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fractures in the elderly. • Nearly 10 million Americans have osteoporosis (T-score ≥ 2.5 SD below normal peak bone mass) and nearly 43.1 million have low bone density (T-score 1.5 to 2.5 SD below normal peak bone mass). • The National Osteoporosis Foundation (NOF) estimates that only about 40% of individuals with a hip fracture return to their prefracture level of functioning. • Hip fractures account for only 14% of fractures in osteoporosis but are responsible for 72% of fracture costs. • Osteoporosis-related fractures result in approximately 180,000 nursing home admissions, more than 432,000 hospital admissions, and nearly 2.5 million medical office visits annually. • By 2025, fractures are estimated to increase to 3 million annually, with medical costs escalated to $25.3 billion. • It is estimated that 1 in 2 white women and 1 in 5 white men will experience a hip, spine, or wrist fracture sometime in their lives. See discussion below for other ethnic groups see discussion below. • By 2025, Hispanics are predicted to account for 20% of fractures in Arizona and California, with Asians and other nonwhite ethnic groups sustaining 27% of fractures in New York. Data from National Osteoporosis Foundation: Clinician's guide to prevention and treatment of osteoporosis, Washington, DC, 2014, Author. Vertebral fractures tend to occur in the later years of life; however, they are more difficult to ascertain because people may be unaware of the fracture. The degree of compression necessary to define a vertebral fracture is not standardized, although attempts have been made to standardize the definition and diagnosis of vertebral fractures. Thus, the true prevalence is unknown but fractures do increase in frequency by the sixth and seventh decades. Approximately 1 in 6 women and 1 in 12 men will sustain a vertebral fracture.24 Age-related loss of bone density and osteoporosis is most common in white women but affects all races. Asian and black women have only about half the fracture rate of whites, but that percentage is expected to increase with improved life expectancy.25 In spite of a lower incidence, mortality in black women after a hip fracture is higher than among white women. Other factors may include a lower calcium intake, a high percentage of lactose intolerance, and increased prevalence of diseases such as sickle cell disease and lupus that increase the risk of developing osteoporosis.26 Both black women and black men have generally been undertreated for osteoporosis. Fracture prevention is a primary goal of osteoporosis treatment. Measuring the BMD by using dual x-ray absorptiometry (DXA) to calculate an individual's T-score continues to be the most common method of evaluating bone health and predicting fracture risk. Unfortunately, the technology to perform DXA scans is not available in all areas of the world. As a result, several tools that do not require BMD testing have been developed and validated to predict future fracture risk. These tools are summarized in Table 41.3. When BMD measurement is not available, fracture prediction using the Internet-based FRAX tool is similar to the use of other tools, such as the Osteoporosis Self-assessment Tool, or OST.27

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TABLE 41.3 Comparison of Fracture Risk Assessment Tools Not Using Bone Mineral Density Risk Factor Age Weight Previous low-energy fracture Estrogen therapy Rheumatoid arthritis Height Parental hip fracture Smoking Alcohol Glucocorticoid therapy Secondary osteoporosis Sex Ethnicity

FRAX X X X X X X X X X X X

SCORE X X X X X

OSIRIS X X X X

ORAI X X

OST X X

X

X

FRAX, World Health Organization's “Fracture Risk Assessment Tool”; ORAI, osteoporosis risk assessment instrument; OSIRIS, osteoporosis index of risk; OST, osteoporosis self-assessment tool; SCORE, simple calculated osteoporosis risk estimation. Chart from Rubin KH et al: Bone 56:18, 2013.

Bone quality is not defined by bone mass alone (as measured by BMD) but also by the microarchitecture of the bone. Thus, other variables include crystal size and shape, brittleness, vitality of bone cells, structure of the bone proteins, integrity of the trabecular network, and the ability to repair tiny cracks. Because bone density relates to the quantity of bone, the quality of bone is not accurately identified by bone density testing alone. As a result, bone density testing may not accurately identify those who will eventually be susceptible to fractures. Postmenopausal osteoporosis is bone loss that occurs in middle-aged and older women. It can occur because of estrogen deficiency, as well as from estrogen-independent agerelated mechanisms (e.g., secondary causes such as hyperparathyroidism and decreased mechanical stimulation). Estrogen deficiency can also increase with stress, excessive exercise, and low body weight. Postmenopausal changes result in a substantial increase in bone turnover—that is, a remodeling imbalance between the activity of osteoclasts (bone destroyers) and osteoblasts (bone formers). Increased formation and activity of osteoclasts causes removal or resorption of bone and results in a cascade of proinflammatory cytokines. In addition, estrogen helps osteoclast apoptosis (programmed cell death) so a decrease in estrogen levels is associated with survival of the bone-removing osteoclasts. Biologically, these processes involve the receptor activator nuclear factor κB ligand, osteoprotegerin signaling pathways, and insulin-like growth factor (IGF) (see Fig. 41.10; also see Chapter 40 and Fig. 40.5). Other causes may include a combination of inadequate dietary calcium intake and lack of vitamin D (and possibly decreased magnesium), lack of exercise, low body mass, and family history. IGF is known to help in fracture healing and collagen synthesis and improves conditions for bone mineralization. IGF levels significantly decline by age 60. Excessive phosphorus intake, chiefly through the intake of highly processed foods, hampers the calcium/phosphorus balance by interfering with parathyroid hormone and fibroblast growth factor 23 (FGF-23).28,29

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FIGURE 41.10 OPG/RANKL/RANK System. Expression of RANKL, a cytokine and part of the TNF family, and OPG, a glycoprotein receptor antagonist, is modulated by various cytokines, hormones, drugs, and mechanical strains (see inserts). In bone RANKL is expressed by both stromal cells and osteoblasts. RANKL stimulates the receptor RANK on osteoclast precursor cells and mature osteoclasts and activates intracellular signaling pathways to promote osteoclast differentiation and activation, as well as cytoskeletal reorganization and survival (PKB/Akt pathway), which increase resorption and bone loss. OPG, secreted by stromal cells and osteoblasts, acts as a “decoy” receptor and blocks RANKL binding to and activation of RANK. BMP, Bone morphogenic protein; IL, interleukin; OPG, osteoprotegerin; PTH, parathyroid hormone; RANK, receptor activator nuclear factor κB; RANKL, receptor activator nuclear factor κB ligand; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha. (Adapted from Hofbauer LC, Schoppet M: JAMA 292[4]:490-495, 2004.)

Sex hormones, particularly estradiol (estrogen), are major determinants of bone density in both females and males. Androgens (i.e., testosterone and dihydrotestosterone) have long been recognized as stimulants of bone formation. Increasing age in both men and women is associated with declining levels of estradiol and androgen, leading to losses in BMD. Other factors, such as inadequate dietary calcium intake, decreases in weight-bearing exercise, and sarcopenia, also are associated with osteoporosis. Other risk factors are identified in Risk Factors: Osteoporosis.

Risk Factors Osteoporosis Genetic Family history of osteoporosis White race Greater age Female sex

Anthropometric 2311

Small stature Fair or pale skinned Thin build Low bone mineral density

Hormonal and Metabolic Early menopause (natural or surgical) Late menarche Nulliparity Obesity Hypogonadism Gaucher disease Cushing syndrome Weight below healthy range Acidosis

Dietary Low dietary calcium and vitamin D Low endogenous magnesium Excessive protein* Excessive sodium intake Anorexia Malabsorption

Lifestyle Sedentary Smoker Alcohol consumption (excessive) Low-impact fractures as an adult Inability to rise from a chair without using one's arms

Concurrent Hyperparathyroidism

Illness and Trauma Renal insufficiency, hypocalciuria Rheumatoid arthritis Spinal cord injury Systemic lupus erythematosus

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Liver Disease Marrow disease (myeloma, mastocytosis, thalassemia)

Drugs Corticosteroids Dilantin Gonadotropin-releasing hormone agonists Loop diuretics Methotrexate Thyroid medications Heparin Cyclosporin Medroxyprogesterone acetate (Depo-Provera) Retinoids

*Low

levels of protein intake also have been reported.

Insufficient intake or malabsorption of dietary minerals is a factor in the development of osteoporosis. Calcium absorption from the intestine decreases with age, and studies of individuals with osteoporosis show that their calcium intake is lower than that of agematched controls. Other mineral deficiencies, including magnesium, also may be important. Vitamin deficiencies, particularly vitamin D, as well as either deficiencies or excesses of protein also contribute to bone loss. Decreased serum levels of trace elements (zinc, copper, iron, magnesium, and manganese) have been associated not only with lower peak bone mass in developing bone, but also with later development of osteoporosis.30-32 Excessive intake of caffeine, phosphorus, alcohol, and nicotine, along with low body fat (weight less than 125 pounds [56.7 kg]) has been shown to lower bone mineral density.33-35 Secondary osteoporosis is osteoporosis caused by other conditions, including hormonal imbalances (endocrine disease, diabetes, hyperparathyroidism, hyperthyroidism), medications (e.g., heparin, corticosteroids, phenytoin, barbiturates, lithium), and other substances (e.g., tobacco, ethanol). Other conditions, including rheumatoid disease, human immunodeficiency virus (HIV), malignancies, malabsorption syndrome, and liver or kidney disease, also increase the risk for developing osteoporosis36 (see Risk Factors: Osteoporosis). Secondary osteoporosis sometimes develops temporarily in individuals receiving large doses of heparin by reducing osteoblast formation and increasing bone resorption by reducing OPG and, thus, increasing osteoclast formation.19 Osteoporosis caused by heparin therapy usually resolves when therapy stops. Other medications that increase the risk of osteoporosis include glucocorticoids, proton pump inhibitors, aromatase inhibitors, lithium, methotrexate, anticonvulsants, cyclophosphamide, thiazolidinediones, and cyclosporine. Regional osteoporosis—osteoporosis confined to a segment of the appendicular skeleton —often has no known cause. Classic regional osteoporosis is associated with disuse or

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immobilization of a limb because of fractures or bone or joint inflammation. A negative calcium balance develops early and continues throughout the period of immobilization. After 8 weeks of immobilization, significant osteoporosis is present. One result of weightlessness has been a uniform distribution of osteoporosis observed in astronauts and in individuals treated with air suspension therapy. Transient regional osteoporosis has no known etiology and is characterized by bone marrow edema and, sometimes, severe pain. Transient regional osteoporosis is usually self-limiting and tends to occur in middle-aged men, as well as in women during their late second or third trimester of pregnancy.37 Bone marrow edema can be seen on magnetic resonance imaging (MRI) and areas of localized bone demineralization are seen in plain radiographs. The lower extremity is most often affected but other areas also can be involved. Treatment is primarily symptomatic, and the condition usually resolves spontaneously over 3 to 6 months, with no long-term adverse effects. Pathophysiology Osteoporosis develops when the remodeling cycle (coupling)—bone resorption and bone formation—is disrupted, leading to an imbalance in the coupling process. Osteoclasts are differentiated cells that function to resorb bone. The explosion of new information in the field of bone biology has led to new understanding of osteoclast biology and bone pathophysiology. Of primary importance is the osteoclast differentiation pathway, which is dependent on various processes, including proliferation, maturation, fusion, and activation. These processes, in turn, are dependent on the availability of stem cells to allow differentiation to occur and are controlled by hormones, cytokines, and paracrine stromal cell interactions. Thus, proper intracellular communication within bone among its molecular regulators is necessary for normal bone homeostasis. Numerous interleukins, tumor necrosis factor (TNF), TGF-β, prostaglandin E2, and hormones interact to control osteoclasts (Fig. 41.10). Staggering in its importance to understanding osteoclast biology is the cytokine receptor activator of nuclear factor κB ligand (RANKL); its receptor activator nuclear factor κB (RANK); and its decoy receptor osteoprotegerin (OPG), a glycoprotein (see Chapter 40 and Fig. 40.5). Glucocorticoid-induced osteoporosis (e.g., prednisone, cortisone) is the most common type of secondary osteoporosis. Glucocorticoids have a direct impact on bone quality by improving osteoclast survival, inhibiting osteoblast formation and function, and increasing osteocyte apoptosis.38,39 Glucocorticoids increase RANKL expression and inhibit OPG production by osteoblasts. Overall, these alterations result in decreased thickness of the bone cortex and fewer, thinner, and more widely spaced trabeculae in the marrow. Age-related bone loss begins in the third to fourth decade. The cause remains unclear, but it is known that decreased serum growth hormone (GH) and IGF-1 levels, along with increased binding of RANKL and decreased OPG production, affect osteoblast and osteoclast function. Loss of trabecular bone in men proceeds in a linear fashion with thinning of trabecular bone rather than complete loss, as is noted in women (Fig. 41.11). Men have approximately 30% greater bone mass than women, which may be a factor in their later involvement with osteoporosis (Fig. 41.12). In addition, men have a more gradual decrease in the levels of testosterone and estradiol (and possibly progesterone), thereby maintaining their bone mass longer than women. Reduced physical activity in older persons is also a likely factor.

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FIGURE 41.11 Mechanism of Loss of Trabecular Bone in Women and Trabecular Thinning in Men. Bone thinning predominates in men because of reduced bone formation. Loss of connectivity and complete trabeculae predominates in women.

FIGURE 41.12 Bone Loss in Men and Women. With aging, the absolute amount of bone resorbed on the inner bone surface and formed on the outer bone surface is greater in men than in women.

Clinical Manifestations The specific clinical manifestations of osteoporosis depend on the bones involved. The most common manifestations, however, are pain and bone deformity because of fracture. These manifestations more often occur in an advanced disease state. Fractures are likely to occur because the trabeculae of spongy bone become thin and sparse, and compact bone becomes porous. As the bones lose volume, they become brittle and weak and may collapse or become misshapen. Vertebral collapse causes kyphosis (hunchback) and diminishes height (Fig. 41.13). Fractures of the long bones (particularly the femur), distal radius, ribs, and vertebrae are most common. Fracture of the neck of the femur tends to occur in older women with osteoporosis. Fatal complications of fractures include fat or pulmonary embolism, pneumonia, hemorrhage, and shock. Approximately 20% of persons may die as a result of surgical complications. Osteoporosis in men, as in women, also may be related to hypogonadism, with estradiol levels being more clinically important than testosterone levels in both sexes. Adequate dietary intake of calcium, vitamin D, magnesium, and other

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trace minerals (Did You Know? Calcium, Vitamin D, and Bone Health); adherence to a regular regimen of weight-bearing exercise; and avoidance of alcoholism, tobacco, and glucocorticoids help to prevent primary osteoporosis.

FIGURE 41.13 Kyphosis. This elderly woman's condition was caused by a combination of spinal osteoporotic vertebral collapse and chronic degenerative changes in the vertebral column. (From Kamal A, Brocklehurst JC: Color atlas of geriatric medicine, ed 2, St Louis, 1992, Mosby.)

Did You Know? Calcium, Vitamin D, and Bone Health An adequate calcium intake is essential for developing and maintaining normal bone structure, but one question remains a topic of discussion and research: “What is an adequate calcium intake?” Calcium is the most abundant mineral in the body and plays a role in maintaining muscle function, hormonal secretion, neurotransmission, and vascular health. Recent conflicting evidence about the effect of calcium on heart disease, for example, has been hotly debated in the medical literature. The conflicting reports about extraskeletal health benefits of vitamin D also were reviewed by the Institute of Medicine (IOM) and were found to lack enough evidence to be considered reliable. The role of vitamin D in bone health is unquestioned; the clinical effects of inadequate vitamin D (osteomalacia, rickets) have been well known for many years. Vitamin D is essential for absorbing and maintaining calcium homeostasis in the body. Recently,

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vitamin D has been postulated to be involved in many extraskeletal functions, such as reducing cancer risk, improving cognitive function in the elderly, preventing autoimmune diseases, improving resistance to infection, providing cardiovascular support, stabilizing posture, and inhibiting metabolic syndrome. Some of these potentially beneficial effects are from data gleaned from the National Health and Nutrition Examination Survey III (NHANES III), whereas other descriptions are based on observational or small studies. Vitamin D levels are evaluated by measuring serum 1,25-dihydroxy-vitamin D levels. There is still disagreement about what constitutes an “optimal” vitamin D level, but many sources indicate it should be at least 30 to 32 ng/ml. Based on these levels, it has been estimated that nearly 75% of the adult population in the United States have low vitamin D levels. The IOM evaluated and summarized clinical evidence and literature reviews regarding the roles of calcium and vitamin D in disease reduction and other health outcomes in North America. Review of these findings resulted in updates of the recommended daily intake of both nutrients. In general, daily calcium intakes of 500 mg for ages 1 through 3, 800 mg for ages 4 through 8, 1100 to 1300 mg for ages 9 to 13, and 800 to 1000 mg for ages 14 through adulthood are adequate for maintaining proper bone health. Recommended dietary allowances for vitamin D vary from 400 to 600 international units (IU) a day for all ages. Additionally, the IOM found that once calcium intake exceeds more than 2000 mg a day or vitamin D intake is more than 4000 IU per day, there is increased risk for harm. Data from Adams JS, Hewison M: J Clin Endocrinol Metab 95(2):471-478, 2010; Annweiler C et al: J Neuroeng Rehabil 7:50, 2010; Binkley N et al: Endocrinol Metab Clin North Am 39(2):287301, 2010; Bolland MJ et al: BMJ 341:3691, 2010; Dawson-Hughes B: BMJ 341:4993, 2010; Grove ML, Book D: BMJ 342:5003, 2010; Heiss G et al: BMJ 342:4995, 2010; National Institutes of Health (NIH) Office of Dietary Supplements (no authors listed): Vitamin D fact sheet for health professionals, November 2014; Newberry SJ et al: Vitamin D and calcium: a systematic review of health outcomes (update), evidence report/technology assessment no. 217, prepared by the Southern California Evidence-based Practice Center under contract no. 2902012-00006-1, AHQR Publication No. 14-E004-EF, Rockville, Md, 2014, Agency for Healthcare Research and Quality. Evaluation and Treatment In general, osteoporosis is detected radiographically as increased radiolucency of bone. By the time abnormalities are detected by radiologic examination, up to 25% to 30% of bone tissue may have been lost. Dual x-ray absorptiometry (DXA) is the current gold standard for detecting and monitoring osteoporosis; however, bone density is not necessarily indicative of bone quality. The utility of DXA in predicting fracture risk has recently been enhanced by the development of a trabecular bone score (TBS). The TBS evaluates pixel variations in the gray-level areas of lumbar spine images from DXA scans and has been shown to correlate with high-resolution peripheral quantitative computed tomography (HRpQCT) and be a reliable predictor of fractures.40-42 High-resolution imaging techniques, such as quantitative computed tomography (QCT) scans and HRpQCT imaging, show changes in the trabecular and cortical microarchitecture. Newer MRI techniques also show promise for providing more detailed information about cortical and trabecular bone and have the added safety of

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no radiation exposure.43 Other evaluation procedures include measurement of serum and urinary biochemical markers to monitor bone turnover (Box 41.3).

Box 41.3

Biochemical Markers of Bone Turnover Biochemical markers of bone turnover are useful in monitoring osteoporosis treatment. Markers of resorption include urinary N-telopeptide (NTx), C-telopeptide (CTx), and deoxypyridinoline. Markers of bone formation include bone-specific alkaline phosphatase (BSAP) and osteocalcin. However, these tests have diurnal variability within the same individual, so there must be significant changes in levels to indicate a difference in bone turnover. The goals of osteoporosis treatment are risk reduction and the prevention of fractures. Bisphosphonates are first-line medications for treating osteoporosis; they primarily work by inhibiting hydroxyapatite breakdown, reducing bone resorption. New medications formulated to prevent or treat osteoporosis are currently being prescribed and evaluated. There are new treatments that help rebuild the skeleton (Did You Know? New Treatments for Osteoporosis). Selective steroid agents (e.g., raloxifene) also may be prescribed. Regular, moderate weight-bearing exercise can slow the rate of bone loss and, in some cases, reverse demineralization because the mechanical stress of exercise stimulates bone formation. An exercise program to enhance strength and balance has the added benefits of reducing the risk of falls and promoting bone quality.

Did You Know? New Treatments for Osteoporosis Although bisphosphonates remain the first line of osteoporosis therapy, not all individuals are able to tolerate them, and side effects can include bisphosphonate-related osteonecrosis of the jaw (BRONJ), atrial fibrillation, and fractures. Zoledronic acid, a third-generation bisphosphonate, is given as an annual intravenous infusion and has demonstrated efficacy in treating glucocorticoid-associated osteoporosis, in addition to reducing vertebral and nonvertebral fractures in women and men. However, it can cause an acute phase response in recipients and still carries some risk of BRONJ. Several new treatment options promise progress in treating osteoporosis and may be better tolerated than bisphosphonates. Denosumab is a commercially available human monoclonal antibody for the treatment of osteoporosis. It binds to the receptor activator nuclear factor κB ligand (RANKL) (see Chapter 40) preventing activation of osteoclasts. By reducing osteoclast activity, bone density is increased and bone resorption is reduced, thus lessening the incidence of fractures. Because denosumab is not cleared by the kidneys (as are bisphosphonates), it has the potential to be useful in those with chronic kidney disease. It is given every 6 months as a 60-mg subcutaneous injection. Raloxifene, a selective estrogen receptor modulator (SERM), has been in use for several

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years to treat postmenopausal osteoporosis. It has been effective in reducing vertebral fractures but not hip or other nonspinal fractures. Newer SERMs, including lasofoxifene (which is not approved for use in the United States), have been shown to reduce both vertebral and nonvertebral fractures. Bazedoxifene, in combination with estrogen, has been designated as a tissue-selective estrogen complex (TSEC), and is approved for use in Japan and Europe. It has been shown to reduce both vertebral and nonvertebral fractures in postmenopausal women. Neither of these agents, given as daily oral doses, stimulates endometrial or breast tissue. Other biologic agents for treating osteoporosis include odanacatib, a cathepsin K inhibitor. By affecting this enzyme (produced by osteoclasts), bone density is increased. It is given as a once weekly oral agent. Agents directed at signaling pathways of bone formation and homeostasis are another target of osteoporosis intervention. One of the main signaling targets is the Wingless/Integrated (Wnt) pathway. Wnt stimulates osteoblast function and bone formation but is blocked by sclerostin (which is produced by the osteocyte gene SOST). Parathyroid hormone (PTH) inhibits sclerostin expression, which may result in increased numbers of osteoblasts. The development of monoclonal antibodies to sclerostin may provide another means to increase bone formation and density. Data from Bone HG et al: Osteoporosis Int 26(2):699-712, 2015; Choi HJ: J Menopausal Med 21(1):1-11, 2015; Reid IR: Nat Rev Endocrinol 11(7):418-428, 2015; Reyes C et al: J Cell Biochem 117(1):20-28, 2016; Suresh E, Abrahamsen B: Cleve Clin J Med 82(2):105-114, 2015. The anabolic or bone-building drug parathyroid hormone (PTH) has been widely studied and is a major regulator of calcium homeostasis. PTH acts directly on osteocytes, stimulates bone formation, and promotes migration of progenitor bone cells from the marrow into the bloodstream, increasing the production of osteoblasts when intermittently administered (see Did You Know? New Treatments for Osteoporosis).

Osteomalacia Osteomalacia is a metabolic disease characterized by inadequate and delayed mineralization of osteoid in mature compact and spongy bone. In osteomalacia, the remodeling cycle proceeds normally through osteoid formation, but mineral calcification and deposition do not occur. Bone volume remains unchanged, but the replaced bone consists of soft osteoid instead of rigid bone. Rickets is similar to osteomalacia in pathogenesis, but it occurs in the growing bones of children, whereas osteomalacia occurs in adult bone. (Rickets is described in Chapter 42.) Both osteomalacia and rickets are relatively rare in the United States and Western Europe but are significant health problems in Great Britain, Ethiopia, Pakistan, Iran, and India. Concomitant diseases, such as HIV, chronic kidney or liver disease, certain cancers, and impaired nutrient absorption from bariatric surgery, can result in vitamin D deficiency and secondary osteomalacia.44 In the United States, other causes include prematurity with very low birth weight and adherence to a rigid macrobiotic vegetarian diet. Breast-fed black infants who do not receive vitamin D supplementation have been shown to be at risk for developing nutritional rickets.45,46 Many factors contribute to the development of osteomalacia, but the most important is a

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deficiency of vitamin D. The major risk factors in vitamin D deficiency are diets deficient in vitamin D, decreased endogenous production of vitamin D, intestinal malabsorption of vitamin D, renal tubular diseases, certain types of tumors (particularly of mesenchymal origin), and anticonvulsant therapy. Classic vitamin D deficiency is rare in the United States because of the addition of synthetic vitamin D to dairy products and bread. Disorders of the small bowel, hepatobiliary system, and pancreas are causes of vitamin D deficiency in the United States. In malabsorptive disease of the small bowel, both vitamin D and calcium absorption are decreased, so vitamin D is lost in feces. Liver disease interferes with the metabolism of vitamin D to its more active form, and diseases of the pancreas and biliary system cause a deficiency of bile salts, which are necessary for normal intestinal absorption of vitamin D. Pathophysiology Crystallization of minerals in osteoid requires adequate concentrations of calcium and phosphate. When the concentrations are too low, crystallization (and hence ossification) does not proceed normally. Vitamin D deficiency disrupts mineralization because vitamin D normally regulates and enhances the absorption of calcium ions from the intestine. A lack of vitamin D causes the plasma calcium concentrations to fall. Low plasma calcium levels stimulate increased synthesis and secretion of PTH. Although the increase in circulating PTH level raises the plasma calcium concentration, it also stimulates increased renal clearance of phosphate. When the concentration of phosphate in the bone decreases below a critical level, mineralization cannot proceed normally. Newer research has identified a complex interplay of matrix proteins, hormones, metallopeptidases, and certain proteins as also being involved in the development of osteomalacia. Abnormalities occur in both spongy and compact bone. Trabeculae in spongy bone become thinner and fewer, whereas haversian systems in compact bone develop large channels and become irregular. Because osteoid continues to be produced but not mineralized, abnormal quantities of osteoid accumulate, coating the trabeculae and the linings of the haversian canals. Excessive osteoid also can accumulate in areas beneath the periosteum. The excess of osteoid leads to gross deformities of the long bones, spine, pelvis, and skull. Clinical Manifestations Osteomalacia causes varying degrees of diffuse muscular and skeletal pain and tenderness. Pain is noted particularly in the hips, and the individual may be hesitant to walk. Muscular weakness is common and may contribute to a waddling gait. Facial deformities and bowed legs or “knock-knees” may be present. Bone fractures and vertebral collapse occur with minimal trauma. Low back pain may be an early complaint, but pain may also involve ribs, feet, other areas of the vertebral column, and other sites. Fragility fractures may occur. Uremia may be present in renal osteodystrophy. Evaluation and Treatment Laboratory data may include elevated blood urea nitrogen (BUN) and creatinine levels, normal or low serum calcium levels, and a serum inorganic phosphate level that is usually more than 5.5 mg. Alkaline phosphatase and PTH levels are usually elevated. Radiographic findings may show symmetric bowing deformities and fractures with callus formation,

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particularly in the lower extremities. These types of fractures, known as pseudofractures, along with radiolucent bands perpendicular to the surface of involved bones can help differentiate osteomalacia from fragility fractures that are seen in osteoporosis. A bone biopsy is used to obtain information on bone structure and remodeling and evaluate the presence of subclinical renal osteodystrophy to determine bone architecture, turnover, and even aluminum deposits. Treatment of osteomalacia may vary, depending on its etiology, but these general principles are followed:

• Adjustment of serum calcium and phosphorus levels to normal • Suppression of secondary hyperthyroidism • Chelation of bone aluminum if needed • Administration of calcium carbonate to reduce hyperphosphatemia • Administration of vitamin D supplements (oral or infusion) • Administration of bisphosphonate • Implementation of renal dialysis, if indicated Paget Disease Paget disease of bone (PDB, or osteitis deformans), the second most common bone disease after osteoporosis, is a state of increased metabolic activity in bone characterized by localized abnormal and excessive bone remodeling. Chronic accelerated remodeling eventually enlarges and softens the affected bones, causing bowing deformity, fracture, or neurologic problems. This process can occur in any bone but most often affects the vertebrae, skull, sacrum, sternum, pelvis, and femur. The disease process may occur in one or more bones without causing significant clinical manifestations. Paget disease occurs with equal frequency in men more than 55 years of age and women older than 40 years of age. It is often symptomless and the diagnosis is often suspected when an elevated serum alkaline phosphatase level or abnormal x-ray film is noted. Radioisotope bone scan, x-rays, and CT are used to confirm the diagnosis. Serum plasma procollagen-1 N-peptide (PINP) is another serum marker that may provide a more accurate diagnosis.47 Autopsy data from England and Germany indicate that approximately 3% to 4% of the population older than 40 years of age has Paget disease. It is most prevalent in Australia, Great Britain, New Zealand, and the United States. Paget disease affects several members of the same family in 5% to 25% of individuals. The cause of PDB is not yet fully known, but studies have implicated both genetic and environmental factors. Implicated environmental factors include viruses, particularly the paramyxovirus family (that includes mumps, parainfluenza, and measles viruses), but no definitive microorganism has yet been identified.48 Researchers have identified variations in three genes associated with PDB: SQSTM1, TNFRSF11A, and TNFRSF11B.49 Interaction between genetic and environmental factors appears to increase osteoclast activity in PDB. Pathophysiology

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Paget disease begins with excessive resorption of spongy bone and deposition of disorganized bone. The trabeculae diminish, and bone marrow is replaced by extremely vascular fibrous tissue. The resorption phase of Paget disease is followed by the formation of abnormal new bone at an accelerated rate. The collagen fibers are disorganized, and glycoprotein levels in the matrix decrease. Mineralization may extend into the bone marrow. Bone formation is excessive around partially resorbed trabeculae, causing them to thicken and enlarge. The net result of this accelerated remodeling process is increased bone fragility and an increased risk for bone tumors. Clinical Manifestations In the skull, abnormal remodeling is first evident in the frontal or occipital regions; then it encroaches on the outer and inner surfaces of the entire skull. The skull thickens and assumes an asymmetric shape. Thickened segments of the skull may compress areas of the brain, producing altered mentation and dementia. Impingement of new bone on cranial nerves can cause sensory abnormalities, impaired motor function, deafness from compression of the auditory nerve, atrophy of the optic nerve, and obstruction of the lacrimal duct. Headache also is commonly noted. Extensive alterations of the facial bones are rare except in the jaw, where sclerosis and thickening of the maxilla and mandible displace teeth and produce malocclusion. In long bones, resorption begins in the subchondral regions of the epiphysis and extends into the metaphysis and diaphysis. Occasionally, Paget disease affects both ends of a tubular bone. In the femur, Paget disease produces an exaggerated lateral curvature. In the tibia, anterior curvature is also exaggerated. Stress fractures are common in the lower extremities. Clinical manifestations of Paget disease in the vertebral column depend on the level of involvement and are caused by compression of adjacent structures. In the cervical spine, cord compression can lead to spastic quadriplegia. Approximately 1% of persons with Paget disease develop osteogenic sarcoma. Evaluation and Treatment Evaluation of Paget disease is made on the basis of radiographic findings of irregular bone trabeculae with a thickened and disorganized pattern. Early disease is detected by bone scanning that shows increased uptake of bone radionuclides. Plasma alkaline phosphatase and urinary hydroxyproline levels are elevated. Many individuals require no treatment if the disease is localized and does not cause symptoms. Treatment during active disease is for relief of pain and prevention of deformity or fracture. Bisphosphonates are the treatment of choice; a one-time infusion of zoledronic acid can provide long-term reduction of biochemical markers and even remission. Several new agents have been approved for the treatment of PDB.

Infectious Bone Disease: Osteomyelitis Osteomyelitis is a bone infection most often caused by bacteria; however, fungi, parasites, and viruses also can cause bone infection (Fig. 41.14). Multiple classification systems have been used to describe osteomyelitis; the simplest refers to the mode of infection. A bone infection caused by pathogens carried through the bloodstream is called hematogenous osteomyelitis. Acute hematogenous osteomyelitis is more often seen in children and is characterized by fever, pain, and voluntary immobility of the affected limb. (Osteomyelitis

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in children is discussed in Chapter 42.) Contiguous osteomyelitis occurs when infection spreads to an adjacent bone and is often caused by open fractures, penetrating wounds, or surgical procedures. Other causes of osteomyelitis include metabolic and vascular diseases (diabetes, peripheral vascular disease), lifestyle risks (smoking, alcohol or drug abuse), and advanced age. In infants, incidence rates among males and females are approximately equal. In children and older adults, however, males are most commonly affected. A new category of autoimmune, noninfectious osteomyelitis, known as chronic nonbacterial osteomyelitis (CNO), has recently been identified as a cause of chronic bone pain in children.50

FIGURE 41.14

Osteomyelitis Showing Sequestration and Involucrum.

Staphylococcus aureus remains the primary microorganism responsible for osteomyelitis. Other microorganisms include group B streptococcus, Haemophilus influenzae, Salmonella, and gram-negative bacteria. Group B streptococcus and H. influenzae tend to infect young children; Salmonella infection is associated with sickle cell anemia; and gram-negative infections are most common in older adults and immunocompromised individuals with impaired immunity. Mycobacterial, viral, and fungal infections occur in immunocompromised individuals. Cutaneous, sinus, ear, and dental infections are the primary sources of bacteria in hematogenous bone infections. Soft tissue infections, disorders of the gastrointestinal tract, infections of the genitourinary system, and respiratory tract infections are also sources of bacterial contamination. In addition, infections that occur after total joint replacement procedures are sometimes the cause. The vulnerability of specific bone depends on the anatomy of its vascular supply. In adults, hematogenous osteomyelitis is more common in the spine, pelvis, and small bones. Microorganisms reach the vertebrae through arteries, veins, or lymphatic vessels. The spread of infection from pelvic organs to the vertebrae is well documented. Vaginal, uterine, ovarian, bladder, and intestinal infections can lead to iliac or sacral osteomyelitis. Superficial animal or human bites inoculate local soft tissue with bacteria that later spread to underlying bone. Deep bites can introduce microorganisms directly onto bone. The most common infecting organism in human bites is Staphylococcus aureus. In animal bites, the most common infecting organism is Pasteurella multocida, which is part of the normal mouth flora of cats and dogs.

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Direct contamination of bones with bacteria can also occur in open fractures or dislocations with an overlying skin wound. Intervertebral disk surgery and operative procedures involving implantation of large foreign objects, such as metallic plates or artificial joints, are associated with contiguous osteomyelitis. Osteomyelitis of the arm and hand bones tends to occur in persons who abuse drugs. In general, persons who are chronically ill, have diabetes or alcoholism, or are receiving large doses of steroids or immunosuppressive drugs are particularly susceptible to chronic osteomyelitis or recurring episodes of this disease. Pathophysiology Regardless of the source of the pathogen, the pathologic features of bone infection are similar to those in any other body tissue (see Chapter 6). First, the invading pathogen provokes an intense inflammatory response. S. aureus, in addition to producing toxins that destroy neutrophils, also forms colonies of microorganisms, called biofilms, that adhere to surfaces (such as implants) and increase antibiotic resistance. Biofilms also can reduce the duration of osteoblast activity while enhancing osteoclast activity and promoting inflammation (also see Chapter 9). Primarily through activation of the cytokine pathway, the biofilm and inflammation alter the normal balance between osteoblast and osteoclast activity.51 Once inflammation is initiated, the small terminal vessels thrombose and exudate seals the bone's canaliculi. Inflammatory exudate extends into the metaphysis and the marrow cavity and through small metaphyseal openings into the cortex. In children, exudate that reaches the outer surface of the cortex forms abscesses that lift the periosteum of underlying bone. Lifting of the periosteum disrupts blood vessels that enter bone through the periosteum, which deprives underlying bone of its blood supply. This leads to necrosis and death of the area of bone infected, producing sequestrum, an area of devitalized bone. Lifting of the periosteum also stimulates an intense osteoblastic response. Osteoblasts lay down new bone that can partially or completely surround the infected bone. This layer of new bone surrounding the infected bone is called an involucrum (Fig. 41.15). Openings in the involucrum allow the exudate to escape into surrounding soft tissue and ultimately through the skin by way of sinus tracts.

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FIGURE 41.15 Resected Femur in a Person With Draining Osteomyelitis. The drainage tract in the subperiosteal shell of viable new bone (involucrum) reveals the inner native necrotic cortex (sequestrum). (From Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

In adults, this complication is rare because the periosteum is firmly attached to the cortex and resists displacement. Instead, infection disrupts and weakens the cortex, which predisposes the bone to pathologic fracture. Clinical Manifestations Clinical manifestations of osteomyelitis vary with the age of the individual, the site of involvement, the initiating event, the infecting organism, and the type of infection—acute, subacute, or chronic. Osteomyelitis is generally considered acute if diagnosed within 2 weeks after symptom onset and is associated with an abrupt onset of inflammation (see Fig. 41.15). Subacute osteomyelitis is disease that has been present for 1 to several months, and chronic disease is that which has been present for many months to even years.52 If an acute infection is not completely eliminated, the disease may become subacute or chronic. In subacute osteomyelitis, signs and symptoms are usually vague. In the chronic stage, infection is silent between exacerbations. The microorganisms persist in small abscesses or fragments of necrotic bone and produce occasional exacerbations of acute osteomyelitis. The progression from acute to subacute osteomyelitis may be the result of inadequate or inappropriate therapy, or the development of drug-resistant microorganisms. In the adult, hematogenous osteomyelitis has an insidious onset. The symptoms are usually vague and include fever, malaise, anorexia, weight loss, and pain in and around the infected areas. Edema may or may not be evident. Recent infection (urinary, respiratory, cutaneous) or instrumentation (catheterization, cystoscopy, myelography, diskography) usually precedes onset of symptoms. Single or multiple abscesses (Brodie abscesses) characterize subacute or chronic osteomyelitis. Brodie abscesses are circumscribed lesions 1 to 4 cm in diameter that are found usually in the ends of long bones and surrounded by dense ossified bone matrix. The abscesses are thought to develop when the infectious microorganism has become less virulent or the individual's immune system is resisting the infection somewhat successfully.

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In contiguous osteomyelitis, signs and symptoms of soft tissue infection predominate. Inflammatory exudate in the soft tissues disrupts muscles and supporting structures and forms abscesses. Low-grade fever, lymphadenopathy, local pain, and swelling usually occur within days of contamination by a puncture wound. Evaluation and Treatment Laboratory data show an elevated white cell count and an elevated level of noncardiac Creactive protein (CRP). Radiographic studies include radionuclide bone scanning, CT, functional imaging using a combination of radionuclide scanning (using fluorodeoxyglucose [FDG]) and single photon emission computed tomography (SPECT), positron emission tomography (PET), and MRI. MRI scanning with gadolinium contrast shows both bone and soft tissue, providing more accurate assessment of infection. MRI also shows early changes of bone marrow edema. FDG-SPECT imaging is highly sensitive for evaluating osteomyelitis of the extremities.53 Treatment of osteomyelitis includes bone biopsy to identify the causative organism, use of antimicrobial agents, and débridement of infected bone. Biodegradable antibioticimpregnated bioabsorbable beads have also benefited many individuals; newer therapies include the promise of injectable scaffolds impregnated with antibiotics and other antimicrobial substances.54 Chronic conditions may require surgical removal of the inflammatory exudate followed by continuous wound irrigation with antibiotic solutions in addition to systemic treatment with antibiotics. The optimal antibiotic regimen for treating osteomyelitis is still unclear. Hyperbaric oxygen therapy of 100% oxygen may stimulate healing by suppressing proinflammatory cytokines and prostaglandins. Implants for total joint replacements may need to be removed to treat the infected joint more thoroughly.

Quick Check 41.2 1. What are the causes associated with osteoporosis in women and men? 2. How does osteoporosis differ from osteomalacia? Name three differences. 3. What are the risk factors for osteomyelitis?

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Disorders of Joints The American College of Rheumatology (ACR) recognizes several groups of joint disease (arthropathies). Most of these disorders can be placed into two major categories: noninflammatory joint disease and inflammatory joint disease. With the improvement in detection methods, however, inflammatory pathways are now being identified in conditions previously classified as noninflammatory, such as osteoarthritis.

Osteoarthritis Osteoarthritis (OA) is the most common, age-related disorder of synovial joints. Affecting the entire joint, OA is characterized by local areas of loss and damage of articular cartilage, inflammation, new bone formation of joint margins (osteophytosis), subchondral bone changes, variable degrees of mild synovitis, and thickening of the joint capsule (Fig. 41.16). Pathology centers on load-bearing areas. Advancing disease shows narrowing of the joint space, attributable to cartilage loss, bone spurs (osteophytes), and sometimes changes in the subchondral bone. OA can arise in any synovial joint but is commonly found in the knees, hips, hands, and spine. It is less common in people younger than 40 years of age, and its prevalence increases with age. Although the exact causes of OA are unclear, obesity and trauma are well-known risk factors. Recent research has identified specific microRNAs that affect gene expression in chondrocytes, and that may play a role in the development of OA. OA involves a complex interaction of transcription factors, cytokines, growth factors, matrix molecules, the immune system, mechanical stresses on joints, and enzymes (see the Pathophysiology section). Emerging understanding of synovitis and inflammation in OA has led to the recognition of the role played by the body's immune system in OA.

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FIGURE 41.16 Osteoarthritis (OA). A, Cartilage and degeneration of the hip joint from osteoarthritis. B, Heberden nodes and Bouchard nodes. C, Severe osteoarthritis with small islands of residual articular cartilage next to exposed subchondral bone. (C from Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)

Although incidence rates are quite similar in men and women, after age 50, women typically are more severely affected. OA usually occurs in those persons who put exceptional stress (or joint loading) on joints (e.g., obese persons, gymnasts, long-distance runners or marathoners); persons participating in such sports as basketball, soccer, or football have been shown to develop osteoarthritis at earlier ages than usual. Obesity itself is an independent risk factor for developing OA of the knee. A previously torn anterior cruciate ligament or meniscectomy increases the risk for accelerated osteoarthritis of the knee.

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Pathophysiology The primary defect in OA is loss of articular cartilage. The chondrocytes of the articular cartilage become damaged early in the disease process because of atypical load bearing, as well as both genetic/epigenetic and biochemical factors (Fig. 41.17).

FIGURE 41.17 Working Model Epigenetic Changes in the Pathophysiology of Oa. From the proposed effects of risk factors, chondrocytes experience epigenetic events of deoxyribonucleic acid (DNA) methylation and histone modifications that occur in the nucleus and microRNAs (miRNAs) which function in the cytoplasm. Overall, these factors result in aberrant expression of transcription factors (TFs), cytokines, collagen, aggrecan, and matrix proteinases. Altered expression of these factors may disrupt the fine balance of anabolic and catabolic activity and affect cartilage homeostasis, resulting in articular cartilage degradation and the development of OA. (Adapted from Zhang M, Wang J: Genes Dis 2[1]:69-75, 2015.)

Early in the disease process, the articular cartilage loses its glistening appearance, becoming yellow-gray or brownish gray. As the disease progresses, surface areas of the articular cartilage flake off and deeper layers develop longitudinal fissures (fibrillation). The cartilage becomes thin and may be absent over some areas, leaving the underlying bone (subchondral bone) unprotected. Consequently, the unprotected subchondral bone

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becomes sclerotic (dense and hard). Cysts sometimes develop within the subchondral bone and communicate with the longitudinal fissures in the cartilage. Pressure builds in the cysts until the cystic contents are forced into the synovial cavity, breaking through the articular cartilage on the way. As the articular cartilage erodes, cartilage-coated osteophytes grow outward from the underlying bone and alter the bone contours and joint anatomy. These spurlike bony projections enlarge until small pieces, called joint mice, break off into the synovial cavity. If osteophyte fragments irritate the synovial membrane, synovitis and joint effusion result. Joint pain, however, may be more related to inflammation of the synovium than subsequent cartilage damage or the radiographic extent of arthritis.55,56 The joint capsule also becomes thickened and at times adheres to the deformed underlying bone, which may contribute to the limited range of motion of the joint (see Fig. 41.16). Articular cartilage is lost through a cascade of signaling, cytokine, and anabolic growth factor pathways. Enzymatic processes (including matrix metalloproteinases) assist in breaking the macromolecules of proteoglycans, glycosaminoglycans, and collagen into large, diffusible fragments. Then the fragments are taken up by the cartilage cells (chondrocytes) and digested by the cell's own lysosomal enzymes. (Processes of cellular uptake and lysosomal digestion are described in Chapter 1.) Enzymatic destruction of articular cartilage begins in the matrix, with destruction of proteoglycans and collagen fibers. Enzymes, particularly stromelysin and acid metalloproteinases, affect proteoglycans by interfering with assembly of the proteoglycan subunit or the proteoglycan aggregate (see Chapter 40). Changes in the conformation of proteoglycans disrupt the pumping action that regulates movement of water and synovial fluid into and out of the cartilage. Cartilage imbibes too much fluid and becomes less able to withstand the stresses of weightbearing. With aging, the proteoglycan content is decreased, and water content in cartilage can be increased by as much as 8%, affecting the strength of the cartilage. Disruptions in cellular signaling pathways, particularly the TGF-β superfamily, play a significant role in the development of OA. Other studies indicate that cytokines, such as interleukin-1 (IL-1) and TNF (see Chapter 6 for discussion of cytokines), play a major role in cartilage degradation57 as a result of release and activation of proteolytic and collagenolytic enzymes associated with an imbalance of cell responses to growth factor activity.58,59 Cell-signaling proteins, particularly adipokines, such as adiponectin and collagenases (enzymes that degrade collagen), contribute to collagen breakdown in cartilage.60 Collagen breakdown destroys the fibrils that give articular cartilage its tensile strength and exposes the chondrocytes to mechanical stress and enzyme attack. The osteochondral junction formed by cartilage and its underlying subchondral bone allows alterations in one tissue to affect the adjacent one (biomechanical coupling). When articular cartilage is damaged, abnormal subchondral bone remodeling occurs. Thus, a cycle of destruction begins that involves all the components of a joint: cartilage, bone, and the synovium. Clinical Manifestations Clinical manifestations of OA typically appear during the fifth or sixth decade of life; although often asymptomatic, articular surface changes are common after the age of 40 years. Pain in one or more joints—usually with weight bearing, use of the joint, or load bearing—is the first and most predominant symptom of the disease. Resting the joint often relieves pain. If present, nocturnal pain is usually not relieved by rest and may be

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accompanied by paresthesias (numbness, tingling, or prickling sensations). Sometimes pain is referred to another part of the body, such as severe pain in the back of the thigh along the course of the sciatic nerve. OA in the lower cervical spine may cause brachial neuralgia (pain in the arm) and is aggravated by movement of the neck. Osteoarthritic conditions in the hip cause pain that may be referred to the lower thigh and knee area. Sleep deprivation adds to the stress of the chronic pain of OA. Physical examination of the person with OA usually shows general involvement of both peripheral and central joints. Peripheral joints most often involved are in the hands, wrists, knees, and feet. Central joints most often afflicted are in the lower cervical spine, lumbosacral spine, shoulders, and hips. Joint structures are capable of generating a limited number of signs and symptoms. The primary signs and symptoms of osteoarthritic joint disease are pain, stiffness, enlargement or swelling, tenderness, limited range of motion, muscle wasting, partial dislocation, and deformity (Risk Factors: Osteoarthritis).

Risk Factors Osteoarthritis • Trauma, sprains, strains, joint dislocations, and fractures • Long-term mechanical stress—athletics, ballet dancing, repetitive physical tasks, and obesity • Inflammation in joint structures • Joint instability from damage to supporting structures • Neurologic disorders (e.g., diabetic neuropathy, Charcot neuropathic joint) in which pain and proprioceptive reflexes are diminished or lost • Congenital or acquired skeletal deformities • Hematologic or endocrine disorders, such as hemophilia, which causes chronic bleeding into the joints, or hyperparathyroidism, which causes bone to lose calcium • Drugs (e.g., colchicine, indomethacin, steroids) that stimulate the collagen-digesting enzymes in the synovial membrane The origin of joint stiffness is unknown. Joint stiffness is generally defined as difficulty initiating joint movement, immobility, or a loss of range of motion. The stiffness usually occurs as joint movement begins, and it dissipates rapidly after a few minutes. Stiffness lasting longer than 30 minutes is uncommon in OA. Enlargement and bulging of bone contour, commonly described as swelling, may be caused by bone enlargement or the proliferation of osteophytes around the margins of the joint. In the hands, these areas are called Heberden and Bouchard nodes, where they are typical features of OA (see Fig. 41.16). Inflammation of the joint lining, known as synovitis, is thought to be initiated by the release of cartilage extracellular matrix into the joint, which then activates the body's complement system. Swelling also occurs if inflammatory exudate or blood enters the joint cavity, thereby increasing the volume of synovial fluid. This condition, termed joint effusion, is caused by (1) the presence of osteophyte fragments in the synovial cavity, (2)

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drainage of cysts from diseased subchondral bone, or (3) acute trauma to joint structures, resulting in hemorrhage and inflammatory exudation into the synovial cavity (see Fig. 41.16, C). Range of motion is limited to some degree, depending on the extent of cartilage degeneration. Frequently, joint motion is accompanied by sounds of crepitus, creaking, or grating. Abnormal knee alignment (either varus or valgus) has been shown to be a risk factor for and can increase progression of the disease.61,62 As OA of the lower extremity progresses, the person may begin to noticeably limp (Fig. 41.18). Having a limp is distressing because it affects the person's independence and ability to perform usual activities of daily living. The affected joint is also more symptomatic after use, such as at the end of a period of strenuous activity.

FIGURE 41.18

Typical Varus Deformity of Knee Osteoarthritis. (From Doherty M: Color atlas and text of osteoarthritis, London, 1994, Wolfe.)

Evaluation and Treatment Evaluation consists primarily of clinical assessment and radiologic studies. More expensive studies, including CT scan, arthroscopy, and MRI, are rarely needed. Newer imaging technologies, such as compositional MRI, are showing promise in identifying structural changes in cartilage; improvements in technology may also allow better monitoring of OA treatment. Treatment is either conservative or surgical. Conservative treatment includes both pharmacologic and nonpharmacologic therapies. Both exercise and weight loss have been

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shown to be two of the most important nonpharmacologic treatments in improving knee OA symptoms. Exercise can reduce pain and improve physical function in people with knee OA.63,64 Exercises to improve muscle tone, range of motion, and balance; stretch the joint capsule; and reduce the fear of falling also have shown promise in reducing OA symptoms. Braces and foot orthoses may help correct biomechanical abnormalities, thereby reducing pain and improving mobility. Dietary and nutritional supplements can sometimes also improve symptoms. Nutraceuticals, such as chondroitin and glucosamine, have shown success in relieving OA pain in some individuals.65 Other nonsurgical therapies include analgesic and antiinflammatory drug therapy to reduce swelling and pain. Acetaminophen was once considered first-line treatment, but it has been shown to be less effective than nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen. However, prolonged use significantly increases the risk of serious associated side effects that are common.66 Intra-articular injection of corticosteroids and high-molecular-weight viscose supplements, such as hyaluronic acid, also decreases knee pain with OA.67 Recently, because of its high concentration of growth factors, PRP also has been injected into osteoarthritic knee joints with some success in reducing pain and markers of inflammation.68 Current evidence does not support low-level laser therapy for knee osteoarthritis.69 Newer agents, including inhibitors of cytokines, matrix metalloproteinases (MMPs), and leptin, are under investigation and may prove more effective in treating OA. Surgery is used to improve joint movement, correct deformity or malalignment, or create a new joint with artificial implants. However, emerging evidence, based on systematic reviews,70 cautions against the use of arthroscopy in nearly all persons with degenerative knee disease (Did You Know? Evidence Against the Use of Arthroscopy for Nearly All Patients with Degenerative Knee Disease).

Did You Know? Evidence Against the Use of Arthroscopy for Nearly All Patients With Degenerative Knee Disease An international expert panel provided recommendations on the role of arthroscopic surgery in degenerative disease. These recommendations were based on a recent randomized trial of patients with a degenerative medial meniscus tear; the panel found that knee arthroscopy was no better than exercise therapy alone for these patients.1 This study adds to the growing evidence that the benefits of arthroscopy may not outweigh the burdens and risks.2,3 The panel made a strong recommendation against arthroscopy for degenerative knee disease.4 This recommendation applies to patients with or without imaging evidence of osteoarthritis, mechanical symptoms, or sudden symptom onset. Here, the term degenerative knee disease included patients with knee pain, particularly if they are greater than 35 years old, with or without imaging evidence of osteoarthritis, meniscal tears, locking, clicking, or other mechanical symptoms. However, degenerative knee disease did not include patients with persistent locked knee, patients with acute or subacute onset of symptoms, or patients with major knee trauma and acute onset of joint swelling (e.g., hemarthrosis).4 The international panel included orthopedic surgeons, a rheumatologist, physiotherapists, a general practitioner, general internists,

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epidemiologists, methodologists, and patients who had experienced degenerative knee disease. Characteristics of patients and trials included in this systemic review were as follows: 13 trials were examined; 12 of 13 trials were free of industry funding; 1668 patients were followed (median age 54.8 years); symptom duration was 3 months (12 months median, 52 months maximum); percent of women studied was 49.2; mean BMI was 27; no patients were involved in designing or conducting trials. In addition, 12 observational studies for complications (>1.8 million patients) were reviewed. In general, it takes 2 to 6 weeks to recover from arthroscopy. Patients may experience pain, swelling, and limited function. Most patients cannot bear full weight on the leg (i.e., they may need crutches) in the first week after surgery, and physical activity and driving are limited during the recovery period. Degenerative knee disease is a chronic condition and symptoms fluctuate. Pain, on average, tends to improve with time after the patient sees a physician,5,6 and delaying knee replacement is encouraged when possible.7

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References 1. Kise NJ, et al. Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two-year followup. BMJ. 2016;354:i3740. 2. Khan M, et al. Arthroscopic surgery for degenerative tears of the meniscus: a systematic review and meta-analysis. CMAJ. 2014;186(14):1057–1064. 3. Thorlund JB, et al. Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ. 2015;350:h2747. 4. Siemieniuk RAC, et al. Arthroscopic surgery for degenerative knee arthritis and meniscal tear: a clinical guideline. BJM. 2017;357:j1982. 5. Brignardello-Peterson R, et al. Knee arthroscopy versus conservative management in patients with degenerative knee disease: a systematic review. BMJ Open. 2017;7(5):e016114. 6. de Roolij M, et al. Prognosis of pain and physical functioning in patients with knee osteoarthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2016;68(4):481–492. 7. McGrory B, et al. American Academy of Orthopaedic Surgeons evidence-based clinical practice guideline on surgical management of osteoarthritis. J Bone Joint Surg Am. 2016;98(8):688–692. Sihvonen R, et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Eng J Med. 2013;369:2515–2524. Howard DH. Trends in the use of knee arthroscopy in adults. J Am Med Assoc Intern Med. 2018;178(11):1557–1558. Some researchers have estimated that 1 in 4 individuals has a lifetime risk of developing symptomatic OA of the hip.71 More than 280,000 total hip and more than 600,000 total knee replacement surgeries are performed yearly in the United States, most of which are related to OA.72

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Classic Inflammatory Joint Disease Inflammatory joint disease is commonly called arthritis. Inflammatory joint disease is characterized by inflammatory damage or destruction in the synovial membrane or articular cartilage and by systemic signs of inflammation (fever, leukocytosis, malaise, anorexia, hyperfibrinogenemia). Inflammatory joint disease can be infectious or noninfectious. Infectious inflammatory joint disease is caused by invasion of the joint by bacteria, mycoplasmas, viruses, fungi, or protozoa. These agents can invade the joint through a traumatic wound, surgical incision, or contaminated needle, or they can be delivered by the bloodstream from sites of infection elsewhere in the body—typically bones, heart valves, or blood vessels. Noninfectious inflammatory joint disease, the most common form, is caused by immune reactions or the deposition of crystals of monosodium urate in and around the joint. Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis are noninfectious inflammatory diseases caused by immune reactions and possibly hypersensitivity reactions; gouty arthritis is a noninfectious inflammatory disease caused by crystal deposition.

Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease distinguished by joint swelling and tenderness and destruction of synovial joints leading to disability. (Autoimmune disease is described in Chapter 8.) RA can cause inflammation of several other tissues. The first joint tissue to be affected is the synovial membrane, which lines the joint cavity (see Chapter 40, Fig. 40.9). The two primary types of synovial cells are fibroblast-like synovial cells and macrophage-like synovial cells. Though the initiating mechanism of RA is still unknown, its pathology is fairly well understood. Some factor activates the synovial fibroblasts (SFs) that line the joint cavity.73,74 The SFs undergo significant changes and develop an exaggerated immune response. Once activated, both types of SF abnormally proliferate and produce proinflammatory cytokines, enzymes, and prostaglandins that perpetuate the inflammatory process and thicken the synovial tissue.75 This thickened synovial tissue, called “pannus,” invades the bone and acts like a localized tumor, where other factors (including increased osteoclast activity) cause bone destruction. Some of the most significant synovial changes involve altered signaling pathways for immune reactions, where SFs attach to articular cartilage and attack it, causing more inflammation; the release of enzymes, such as MMPs, inflammatory chemokines, and cytokines (interleukins and TNF); and ingrowth of blood vessels. Increased blood vessel formation improves the opportunity for activated SFs to enter the bloodstream and affect other joints.76 Eventually, inflammation spreads to the fibrous joint capsule and surrounding ligaments and tendons, causing pain, joint deformity, and loss of function (Fig. 41.19). The joints most commonly affected are in the fingers, feet, wrists, elbows, ankles, and knees, but the shoulders, hips, and cervical spine also may be involved, as well as the tissues of the lungs, heart, kidneys, and skin.

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FIGURE 41.19 Rheumatoid Arthritis of the Hand. Note the swelling from chronic synovitis of metacarpophalangeal joints, marked ulnar drift, subcutaneous nodules, and subluxation of metacarpophalangeal joints with extension of proximal interphalangeal joints and flexion of distal joints. Note also deformed position of thumb. Hand has wasted appearance. (From Mourad LA: Orthopedic disorders, St Louis, 1991, Mosby.)

The incidence and prevalence of RA have decreased over the past five decades; RA now affects about 1% of the adult population in developed countries.77 The frequency of RA increases with age. Besides inflammation and destruction of the joints, RA can cause fever, malaise, rash, lymph node or spleen enlargement, and Raynaud phenomenon (transient lack of circulation to the fingertips and toes). Despite intensive research, the exact cause of RA remains obscure. It is likely a combination of genetic factors interacting with inflammatory mediators. There is a strong genetic predisposition to developing RA. The chronic inflammation characteristics of RA result from an intricate interplay of chemokines that are powerful mediators of inflammation. Chemokines attract T cells and produce inflammatory changes.1 A key genetic element has been localized to the human leukocyte antigen (HLA) areas of the major histocompatibility complex in all ethnic groups. Recent research reveals the possibility of specific amino acid malpositions in the HLA molecule as a major factor in developing rheumatic diseases.78 A surprising new discovery is the presence of T-cell abnormalities in individuals with RA. With long-term or intensive exposure to the antigen, normal antibodies (immunoglobulins [Igs]) become autoantibodies—antibodies that attack host tissues (self-antigens). Because they are usually present in individuals with RA, the altered antibodies are termed rheumatoid factors (RFs). The RFs usually consist of two

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classes of immunoglobulin antibodies (antibodies for IgM and IgG) but occasionally involve antibodies for IgA. Their main antigenic targets are portions of the immunoglobulin molecules. RFs bind with their target self-antigens in blood and synovial membrane, forming immune complexes (antigen-antibody complexes). (See Chapter 7 for a discussion about antigen-antibody binding in the immune response.) Environmental factors, including geographic area of birth, diet, socioeconomic status, and especially smoking, have been identified as risk factors for developing and having higher disease activity of RA. RA and other autoimmune diseases have a higher prevalence among women. Additionally, because disease symptoms lessen during pregnancy and are increased again in the postpartal period, researchers are including hormonal involvement in their studies. Pathophysiology Although no specific events (e.g., trauma, illness, or environmental conditions) have been identified that would cause immune abnormalities to develop into localized tissue and joint inflammation, the pathology of RA is fairly well understood. During inflammation, arginine (an α-amino acid) can be enzymatically modified into another α-amino acid, citrulline. The citrullinated proteins can be seen as antigens by the body's immune system. Thus both T and B cells play a role in the autoimmune response. T cells express RANKL, which promotes osteoclast formation and causes bony erosion. Cartilage damage in RA is the result of at least three processes: (1) neutrophils and other cells in the synovial fluid become activated, degrading the surface layer of articular cartilage; (2) inflammatory cytokines induce enzymatic (metalloproteinase) breakdown of cartilage and bone; and (3) T cells also interact with synovial fibroblasts, converting synovium into a thick, abnormal layer of granulation tissue known as pannus (see Chapter 7). Macrophages, components of pannus (Fig. 41.20), stimulate the release of IL-1, PDGF, and fibronectin. The B lymphocytes are stimulated to produce more RFs. The newly targeted self-antigens (immunoglobulins) are in relatively constant supply and can thus perpetuate inflammation and the formation of immune complexes indefinitely (Fig. 41.21).

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FIGURE 41.20

Synovitis. Inflamed synovium showing typical arrangements of macrophages and fibroblastic cells.

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FIGURE 41.21 Emerging Model of Pathogenesis of Rheumatoid Arthritis. Rheumatoid arthritis is an autoimmune disease of a genetically susceptible host triggered by an unknown antigenic agent. A chronic autoimmune reaction with activation of CD4+ helper T cells and possibly other lymphocytes and the local release of inflammatory cytokines and mediators eventually destroy the joint. T cells stimulate cells in the joint to produce cytokines that are key mediators of synovial damage. Apparently, immune complex deposition also plays a role. Tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as some other cytokines, stimulate synovial cells to proliferate and produce other mediators of inflammation, such as prostaglandin E2 (PGE2), matrix metalloproteinases, and enzymes that all contribute to destruction of cartilage. Activated T cells and synovial fibroblasts also produce receptor activator of nuclear factor κB ligand (RANKL), which activates the osteoclasts and promotes bone destruction. Pannus is a mass of synovium and synovial stroma with inflammatory cells, granulation tissue, and fibroblasts that grows over the articular surface and causes its destruction.

Inflammatory and immune processes have several damaging effects on the synovial membrane. Along with the swelling caused by leukocyte infiltration, the synovial membrane undergoes hyperplastic thickening as its cells proliferate and abnormally enlarge. As synovial inflammation progresses to involve its blood vessels, small venules become occluded by hypertrophied endothelial cells, fibrin, platelets, and inflammatory cells, which decrease vascular flow to the synovial tissue. Compromised circulation,

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coupled with increased metabolic needs as a result of hypertrophy and hyperplasia, causes hypoxia and metabolic acidosis. Acidosis stimulates the release of hydrolytic enzymes from synovial cells into the surrounding tissue, initiating erosion of the articular cartilage and inflammation in the supporting ligaments and tendons. Pannus formation does not lead to synovial or articular regeneration but rather to formation of scar tissue that immobilizes the joint. Clinical Manifestations The onset of RA is usually insidious, although as many as 15% of cases have an acute onset. RA begins with general systemic manifestations of inflammation, including fever, fatigue, weakness, anorexia, weight loss, and generalized aching and stiffness. Local manifestations also appear gradually over a period of weeks or months. Typically, the joints become painful, tender, and stiff. Pain early in the disease is caused by pressure from swelling. Later in the disease, pain is caused by sclerosis of subchondral bone and new bone formation. Pain and inability to perform normal functions are the main reasons people seek medical help. Stiffness usually lasts for about 1 hour after rising in the morning and is thought to be related to synovitis. Initially the joints most commonly involved are the metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and wrists, with later involvement of larger weightbearing joints. Widespread, symmetric joint swelling is caused by increasing amounts of inflammatory exudate (leukocytes, plasma, plasma proteins) in the synovial membrane, hyperplasia of inflamed tissues, and formation of new bone. On palpation, the swollen joint feels warm and the synovial membrane feels boggy. The skin over the joint may have a ruddy, cyanotic hue and may look thin and shiny. An inflamed joint may lose some of its mobility. Even mild synovitis can lead to reduced range of motion, which becomes evident after inflammation subsides. Extension becomes limited and is eventually lost if flexion contractures develop. Limited range of motion can progress to permanent deformities of the fingers, toes, and limbs, including ulnar deviation of the hands, boutonnière and swan neck deformities of the finger joints, plantar subluxation of the metatarsal heads of the foot, and hallux valgus (angulation of the great toe toward the other toes). Flexion contractures of the knees and hips are also common. Joint deformities cause the physical limitations experienced by persons with RA (see Fig. 41.19). Loss of joint motion is quickly followed by secondary atrophy of the surrounding muscles. With secondary muscle atrophy, the joint becomes unstable, which further aggravates joint pathology. Two complications of chronic RA are caused by excessive amounts of inflammatory exudate in the synovial cavity. One complication is the formation of cysts in the articular cartilage or subchondral bone. Occasionally, these cysts communicate with the skin surface (such as in the sole of the foot) and can drain through passages called fistulae. The second complication is rupture of a cyst or of the synovial joint itself, usually caused by strenuous physical activity that places excessive pressure on the joint. Rupture releases inflammatory exudate into adjacent tissues, thereby spreading inflammation. Extrasynovial rheumatoid nodules, seen in up to 30% of individuals with RA, are the most common extra-articular manifestations. Each nodule is a collection of inflammatory cells surrounding a central core of fibrinoid and cellular debris. Nodules are most often found in subcutaneous tissue over the extensor surfaces of elbows and fingers. Less common sites are the scalp, back, feet, hands, buttocks, and knees.

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Rheumatoid nodules also may invade the skin, cardiac valves, pericardium, pleura, lung parenchyma, and spleen. These nodules are identical to those encountered in some individuals with rheumatic fever and are characterized by central tissue necrosis surrounded by proliferating connective tissue. Also noted are large numbers of lymphocytes and occasional plasma cells. Acute glaucoma may result with nodules forming on the sclera. Pulmonary involvement may result in diffuse pleuritis or multiple intraparenchymal nodules. Together, the occurrence of pulmonary nodules and pneumoconiosis (chronic inflammation of the lungs from inhalation of dust) creates the syndrome called Caplan syndrome. Diffuse pulmonary fibrosis may occur because of immunologically mediated immune complex deposition. Rheumatoid nodules within the heart may cause valvular deformities, particularly of the aortic valve leaflets, and pericarditis. Lymphadenopathy of the nodes close to the affected joints may develop. Rheumatoid nodules within the spleen result in splenomegaly. Changes in skeletal muscle are often noted in the form of nonspecific atrophy secondary to joint dysfunction. Involvement of blood vessels results in an acute necrotizing vasculitis, characteristic of that noted in other immunologic/inflammatory states. Thromboses of such involved vessels may lead to myocardial infarctions, cerebrovascular occlusions, mesenteric infarction, kidney damage, and vascular insufficiency in the hands and fingers (Raynaud phenomenon). Fortunately, the development of vascular changes (particularly systemic vasculitis) is decreasing in frequency as more effective RA treatments are becoming available. Evaluation and Treatment The diagnosis of RA relies on clinical evaluation of joint swelling; however, limitation of movement and control of pain often prevent identification of individuals who would benefit from treatment in early stages of the disease. Early treatment can be effective in preventing the systemic and joint abnormalities of chronic disease. Autoantibodies, RF, and anticitrullinated protein antibody (ACPA) can be present for years to decades before synovial or radiographic involvement becomes apparent.79 Compared with RF, ACPA is a much more specific serum marker for RA. The ACR and the European League Against Rheumatism (EULAR) revised their RA classification criteria in 2010 to better identify the early stage of RA.80 These new criteria are shown in Table 41.4. The clinical examination and history are the mainstays of RA diagnosis, but new imaging techniques show promise for earlier diagnosis, leading to earlier treatment, with a better chance for avoiding disability and joint destruction. TABLE 41.4 The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis Target population to be tested: 1. Persons who have at least one joint with definite clinical synovitis (swelling)a 2. Persons who have synovitis not better explained by another diseaseb Classification criteria for rheumatoid arthritis (RA) (score-based algorithm): Add scores of categories A to D; a score of ≥6/10 is needed for positive RA diagnosis)c Clinical Finding Score A. Joint involvementd

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1 large jointe 2-10 large joints 1-3 small joints (with or without involvement of large joints)f 4-10 small joints (with or without involvement of large joints) >10 joints (at least 1 small joint)g B. Serology (at least 1 test result is needed for classification)h Negative RF and negative ACPA Low-positive RF or low-positive ACPA High-positive RF or high-positive ACPA C. Acute-phase reactants (at least 1 test result is needed for classification)i Normal CRP and normal ESR Abnormal CRP or abnormal ESR D. Duration of symptomsj 50% of the diameter of the bone or >3 or 4 cm) is noted radiographically.

Malignant Bone Tumors Malignant bone tumors are uncommon tumors in childhood, accounting for fewer than 5% of childhood malignancies and occurring mostly during adolescence. The two most common malignant bone tumors are osteosarcoma and Ewing sarcoma.

Osteosarcoma Osteosarcoma is the most common malignant bone tumor found during childhood and originates in bone-producing mesenchymal cells. It accounts for 60% of all malignant bone tumors and generally strikes between the ages of 10 and 18. Osteosarcoma may develop as a result of rapid local growth, which increases the likelihood of mutation. It can be induced by ionizing radiation, even with relatively low doses, and can be a tragic consequence of therapeutic radiation for other forms of cancer. There also has been a link to individuals with retinoblastoma (a hereditary eye tumor). Osteosarcoma has not been linked to chemical carcinogens or viruses. No DNA or ribonucleic acid (RNA) virus has been isolated. Molecular analysis has demonstrated deletion of genetic material on the long arm of chromosome 13, which led to the identification of a tumor-suppressor gene as being part of the mechanism for tumor development. The oncogene src also has been associated with osteosarcoma. Pathophysiology Osteosarcoma occurs mainly in the metaphyses of long bones near sites of active physeal growth. The tumor most commonly occurs at the distal femur, proximal tibia, or proximal humerus. As a tumor of mesenchymal cells, osteosarcoma makes osteoid tissue. Osteosarcoma is a bulky tumor that extends beyond the bone into a soft tissue mass. It may encircle the bone and destroy the trabeculae of the diseased area. Osteosarcoma disseminates through the bloodstream, usually to the lung. As many as 25% of children diagnosed with osteosarcoma exhibit lung metastases at diagnosis. Other sites of metastatic spread include other bones and visceral organs. Clinical Manifestations

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The most common presenting complaint is pain. Night pain, awakening a child from sleep, is a particularly foreboding sign. There may be swelling, warmth, and redness caused by the vascularity of the tumor. Symptoms also may include cough, dyspnea, and chest pain if lung metastasis is present. If a lower extremity is involved, a child may limp or suffer a pathologic fracture. Although osteosarcoma is not the result of trauma, trauma may call attention to a preexisting tumor. Evaluation and Treatment Although needle biopsy is often sufficient to establish the diagnosis, tissue biopsy confirms it. The five histologic types of osteosarcoma are determined by the predominant cell type. The tumor is graded according to degree of malignancy; the higher the grade, the worse the prognosis. Surgery and chemotherapy are the primary treatments for osteosarcoma. If surgical excision is impossible, radiation therapy may allow local tumor control. Traditionally, surgery includes amputation at the joint above the involved bone; however, more recent limb salvage procedures have gained acceptance, and amputation may be avoided in many children. Chemotherapy is an important component of treatment. Children routinely receive chemotherapy preoperatively; then the disease is restaged with MRI and surgical biopsy to determine rate of “tumor kill.” If more than 90% of tumor cells are killed by chemotherapy, the prognosis is markedly improved. Chemotherapy is then used after surgery for any additional cell spill during surgery. The use of chemotherapy with surgery has increased the 5-year survival rate to 60% or more.11 A number of approaches have been used to treat pulmonary metastases. Because pulmonary metastases are generally solitary, thoracotomy with wedge resection has proven to be the most effective treatment.

Ewing Sarcoma Ewing sarcoma is a malignant round cell tumor of bone and soft tissue and is the second most common and most lethal malignant bone tumor that occurs during childhood. The most common period of diagnosis is between 5 and 15 years of age; it is rare after age 30 years. Ewing sarcoma is slightly more common in males than females and is linked with periods of rapid bone growth. Pathophysiology Ewing sarcoma is most commonly located in the midshaft of long bones or in flat bones. The most common sites include the femur, pelvis, and humerus. Arising from bone marrow, Ewing sarcoma can penetrate the cortex of the bone to form a soft tissue mass (Fig. 42.14). Unlike osteosarcoma, Ewing sarcoma does not make bone and radiographically appears as a permeative, destructive lesion. Ewing sarcoma metastasizes to nearly every organ. Metastasis occurs early and is usually apparent at diagnosis or within 1 year. The most common sites are the lung, other bones, lymph nodes, bone marrow, liver, spleen, and central nervous system.

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FIGURE 42.14 Ewing Sarcoma of the Distal Radius. Radiograph of an 8-year-old boy showing a permeative lesion of the distal radius. Note the loss of bone cortex on the ulnar border, suggesting an aggressive process. Bone biopsy revealed Ewing sarcoma.

Clinical Manifestations As with osteosarcoma, the most common complaint is pain that increases in severity. A soft tissue mass is often present. Additional symptoms may include fever, malaise, and anorexia. The radiographic appearance is similar to that of infection, and diagnosis is confirmed only with biopsy. Evaluation and Treatment Evaluation is done with genetic testing, elevated sedimentation rate, and lactate dehydrogenase (LDH) levels. Biopsy is used to conclusively establish the diagnosis of a small round cell tumor. Treatment includes radiation, chemotherapy, and, if possible, surgical débridement. Chemotherapy is continued for 12 to 18 months after resection. Present 5-year survival with this tritherapeutic approach is 65% to 75%;12 however, tumors in the trunk or pelvis have a markedly worse prognosis. Metastasis at diagnosis is another poor prognostic indicator, with 5-year survival rate dropping to less than 40%.

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Nonaccidental Trauma It is estimated that more than 1.5 million children are abused per year in the United States. Maltreatment may be psychologic, sexual, or physical.13 Skeletal trauma is present in a significant number of abused children14-16 (Fig. 42.15). Thirty percent of children who have been physically abused are seen by an orthopedist. Accurate and appropriate referrals to child protection agencies not only are legally mandated but also are essential for the wellbeing of the child. An abused child who is returned to the same situation without intervention has a 10% to 15% chance of subsequent mortality.

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FIGURE 42.15 Rib and Metaphyseal Fractures. Rib fractures are very common and highly specific for abuse. In 31 children who died as a result of abuse, there was an extremely high incidence of rib and metaphyseal fractures. The red arrows indicate common sites of fracture related to abuse. (Data from Radiology Assistant Radiology Assistant Educational Site, Radiological Society of the Netherlands. Available from .)

Fractures in Nonaccidental Trauma Children who are not yet ambulatory and present with a long bone fracture have more than a 75% chance of that fracture being caused by nonaccidental trauma (NAT).17 “Corner”

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metaphyseal fractures are nearly always from abuse but occur only 25% of the time (Fig. 42.16). Fractures at multiple stages of healing also suggest abuse; however, osteogenesis imperfecta or other causes of systemic osteomalacia must be ruled out. The most common presentation is a transverse tibia fracture. After walking age, only 2% of long bone fractures are the result of NAT.18

FIGURE 42.16 Corner Fracture. Bilateral knee radiograph showing healing corner fractures of bilateral proximal tibias and distal femurs. Note the varying amount of callus formation signifying fractures at different stages of healing.

Evaluation and Treatment NAT necessitates early consultation with child protective services. The child should undergo skeletal survey (especially if younger than 2 years of age) and have a complete physical examination to evaluate for pattern bruising, burns, or multiple soft tissue injuries. A thorough history must be obtained for all identified injuries. It is important to remember that social isolation can lead to an increased likelihood of abuse, but no social status is immune. When the cause of injury is unclear, bone scan can be helpful in diagnosing subtle injuries, especially rib fractures. Posterior rib fractures are especially likely to be the result of abuse. MRI/computed tomography (CT) of the brain to check for subdural hematoma and retinal examination to look for hemorrhages are essential. The treating health care provider must have a nonjudgmental attitude. The child and family involved in NAT are emotionally delicate and require not only physical but also emotional care. Social workers need to be involved early to ensure that the child receives appropriate medical care. Fortunately, fractures tend to heal quickly for those in this age

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group. Neurologic injury and social disease, however, are much more difficult to cure.

Quick Check 42.3 1. What are the most common benign bone tumors of children? 2. How does osteosarcoma affect the respiratory system? 3. What is the most lethal bone tumor in children? 4. What is the most common orthopedic injury in NAT?

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Summary Review Congenital Defects 1. Clubfoot is a common deformity in which the foot is turned out of its normal shape or position. Clubfoot can be positional, idiopathic, or teratologic. Positional is correctable passively, however, idiopathic and teratologic may require casting, bracing, or surgery. 2. Developmental dysplasia of the hip (DDH) is an abnormality in the development of the femoral head, acetabulum, or both. DDH can be idiopathic or teratologic. It is a serious and disabling condition in children if not diagnosed and treated early, with best outcomes when treated before walking age. 3. Osteogenesis imperfecta (brittle bone disease) is an inherited disorder of collagen that affects primarily bones and results in serious fractures of many bones.

Bone and Joint Infection 1. Osteomyelitis is a local or generalized bacterial or granulomatous infection of bone and bone marrow. Bacteria are usually introduced by direct extension from a nearby infection, through the bloodstream, or by trauma. Infection starts in the metaphysis, then ruptures out to spread into the diaphysis. 2. Septic arthritis is a bacterial or granulomatous infection of the joint space and is a surgical emergency. It can occur on its own, or secondary to osteomyelitis in very young children in which the metaphysis is still located within the joint capsule of certain joints.

Juvenile Idiopathic Arthritis 1. Juvenile idiopathic arthritis is an inflammatory joint disorder characterized by pain and swelling. Large joints are most commonly affected.

Osteochondroses 1. Avascular diseases of the bone are collectively referred to as osteochondroses and are caused by an insufficient blood supply to growing bones. 2. Legg-Calvé-Perthes disease is characterized by the death of the epiphysis of the femoral head and degeneration of the head of the femur, followed by regeneration or recalcification. Children older than age 6 years at onset have a worse prognosis. 3. Osgood-Schlatter disease is characterized by tendonitis of the anterior patellar tendon and inflammation or partial separation of the tibial tubercle caused by chronic irritation, usually as a result of overuse of the quadriceps muscles. The condition is seen primarily in muscular, athletic adolescent males.

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Scoliosis 1. Scoliosis is a rotational curvature of the spine most obvious in the anteroposterior plane and can be classified as nonstructural or structural. Nonstructural scoliosis results from a cause other than the spine itself, such as posture, leg length discrepancy, or splinting from pain. Structural scoliosis is a curvature of the spine associated with vertebral rotation.

Neuromuscular Disorders 1. The neuromuscular disorders are a group of genetically transmitted diseases characterized by progressive atrophy of skeletal muscles leading to weakness. They cause significant disability in children resulting in lifelong neurologic, orthopedic, and pulmonary complications. 2. Duchenne muscular dystrophy is characterized by the absence of the membranestabilizing protein dystropin in muscle cells. Weakness leads to abnormal gait, frequent falls, and eventual loss of ambulation. Respiratory, cardiac, and neurologic problems are also present, requiring a multidisciplinary approach to care. 3. Spinal muscular atrophy is characterized by degeneration of motor neurons in the spinal cord leading to progressive muscle atrophy. Children have progressive muscle weakness and lack of motor skills. 4. Facioscapulohumeral muscular dystrophy involves asymmetric muscle weakness, starting in the face and then progressing to the shoulders and legs. 5. Myotonic muscular dystrophy classically presents with myotonia, or a difficulty relaxing muscles. It also can affect the brain, eyes, heart, and endocrine system.

Musculoskeletal Tumors 1. Musculoskeletal tumors may be benign (osteochondroma and nonossifying fibroma) or malignant (osteosarcoma and Ewing sarcoma). 2. Osteochondroma appears as a solitary bony protuberance near active growth plates of the proximal humerus, distal femur, or proximal tibia. Hereditary multiple exostoses is characterized by multiple bony protuberances throughout the skeleton. 3. Nonossifying fibromas are lesions in which fibrocytes have replaced normal bone. Treatment may be required if the lesions grow so large that they compromise the strength of the bone. 4. Osteosarcoma, the most common malignant childhood bone tumor, originates in bone-producing mesenchymal cells and is most often located near active growth plates, such as the distal femur, proximal tibia, or proximal humerus. It is a bulky tumor that creates osteoid tissue. Pain, especially night pain, is the most common presenting symptom. It commonly causes lung metastases. The primary treatments for osteosarcoma are surgery and chemotherapy. 5. Ewing sarcoma originates from cells within the bone marrow space and is most

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often located in the midshaft of long bones or in flat bones. The most common sites include the femur, pelvis, and humerus, and the most common presenting symptom is pain that increases in severity. Ewing sarcoma metastasizes to nearly every organ. The primary treatment for Ewing sarcoma is a combination of chemotherapy, radiation, and surgery.

Nonaccidental Trauma 1. Child abuse by nonaccidental trauma must be considered with any long bone injury in a child who is not yet walking. The health care provider is legally responsible to report suspected nonaccidental trauma. 2. The presence of soft tissue injury, corner fractures, and multiple fractures at different stages of healing is extremely helpful for making a diagnosis of nonaccidental trauma. 3. When nonaccidental trauma is suspected, a child must be evaluated radiographically for other fractures, burns, multiple soft tissue injuries, and retinal hemorrhage.

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Key Terms Acetabular dysplasia, 1000 Acute hematogenous osteomyelitis, 1002 Antalgic (painful) abductor lurch, 1005 Clubfoot, 999 Developmental dysplasia of the hip (DDH), 999 Dislocated hip, 1000 Duchenne muscular dystrophy (DMD), 1007 Dystrophin, 1007 Ewing sarcoma, 1010 Facioscapulohumeral (FSH) muscular dystrophy, 1008 Hereditary multiple exostoses (HME), 1009 Involucrum, 1002 Juvenile idiopathic arthritis (JIA), 1003 Legg-Calvé-Perthes (LCP) disease, 1004 Malignant bone tumor, 1009 Myotonic muscular dystrophy (MMD), 1008 Neuromuscular disorder, 1006 Nonossifying fibroma, 1009 Nonstructural scoliosis, 1006 Oligoarthritis, 1003 Osgood-Schlatter disease, 1005 Osteochondroma, 1009 Osteochondrosis, 1003 Osteogenesis imperfecta (OI; brittle bone disease), 1000 Osteomyelitis, 1001 Osteosarcoma, 1009 Polyarthritis, 1003 Scoliosis, 1006 Septic arthritis, 1003 Sever disease, 1006 Spinal muscular atrophy (SMA), 1008 Still disease, 1003 Structural scoliosis, 1006 Subluxated hip, 1000 Talipes equinovarus, 999

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References 1. Morcuende JA, et al. Plaster cast treatment of clubfoot: the Ponseti method of manipulation and casting. J Pediatr Orthop. 1994;3(2):161–167. 2. Jari S, et al. Unilateral limitation of abduction of the hip: a valuable clinical sign for DDH? J Bone Joint Surg Br. 2002;84(1):104–107. 3. Patel RM, et al. A cross-sectional multicenter study of osteogenesis imperfecta in North America—results from the Linked Clinical Research Centers. Clin Genet. 2015;87(2):133– 140. 4. Principi N, et al. Kingella kingae infections in children. BMC Infect Dis. 2015;15:260. 5. Vaderhave KL, et al. Community-associated methicillinresistant Staphylococcus aureus in acute musculoskeletal infection in children: a game changer. J Pediatr Orthop. 2009;29(8):927–931. 6. Mata SG, et al. Legg-Calvé-Perthes disease and passive smoking. J Pediatr Orthop. 2000;20(3):326–330. 7. Cassas KJ, Cassettari-Wayhs A. Childhood and adolescent sports-related overuse injuries. Am Fam Physician. 2006;73(6):1014–1022. 8. Katz DE, et al. Brace wear control of curve progression in adolescent idiopathic scoliosis. J Bone Joint Surg Am. 2010;92:1343–1352. 9. Stuart L, et al. Effects of bracing in adolescents with idiopathic scoliosis. N Engl J Med. 2013;369:1512–1521. 10. Cummings JR, et al. Congenital clubfoot. Instr Course Lect. 2002;51:385–400. 11. Heyden JB, Hoang BH. Osteosarcoma: basic science and clinical implications. Orthop Clin North Am. 2006;37(1):1–7. 12. Ruyman FB, Grovas AC. Progress in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas. Cancer Invest. 2000;18(3):223. 2434

13. Administration for Children and Families Children's Bureau. Child maltreatment 2009. U.S. Department of Health and Human Services: Washington, DC; 2010 [Available at] http://www.acf.hhs.gov/programs/cb/stats_research/index.htm#can 14. Lane WG, et al. Racial differences in the evaluation of pediatric fractures for physical abuse. J Am Med Assoc. 2002;288(13):1603–1609. 15. Swoboda SL, et al. Skeletal trauma in child abuse. Pediatr Ann. 2013;42(11):e245–e252. 16. Wood JN, et al. Evaluation for occult fractures in injured children. Pediatrics. 2015;136(2):232–240. 17. Rex C, Kay PR. Features of femoral fractures in nonaccidental injury. J Pediatr Orthop. 2000;20(3):411–413. 18. Thomas SA, et al. Long-bone fractures in young children: distinguishing accident injuries from child abuse. Pediatrics. 1991;88(3):471–476.

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Structure, Function, and Disorders of the Integument Sue Ann McCann, Sue E. Huether

CHAPTER OUTLINE Structure and Function of the Skin, 1014 Layers of the Skin, 1014 Clinical Manifestations of Skin Dysfunction, 1016 Disorders of the Skin, 1022 Inflammatory Disorders, 1022 Papulosquamous Disorders, 1023 Vesiculobullous Diseases, 1026 Infections, 1027 Vascular Disorders, 1030 Benign Tumors, 1031 Skin Cancer, 1032 Burns, 1035 Cold Injury, 1038 Disorders of the Hair, 1039 Alopecia, 1039 Hirsutism, 1039 Disorders of the Nail, 1039 Paronychia, 1039 Onychomycosis, 1039 GERIATRIC CONSIDERATIONS: Aging & Changes in Skin Integrity, 1040

The skin is the largest organ of the body, accounting for about 20% of body weight. Combined with the accessory structures of hair, nails, and glands, it forms the integumentary system. The skin's primary function is environmental protection by serving as a barrier against microorganisms, ultraviolet radiation, loss of body fluids, and the stress of mechanical forces. The skin regulates body temperature and is involved in immune

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surveillance and the activation of vitamin D. Touch and pressure receptors provide important protective functions and pleasurable sensations. The microbiome of the skin protects against pathologic bacteria.

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Structure and Function of the Skin Layers of the Skin The skin is formed of two major layers: (1) a superficial, or outer, layer of epidermis and (2) a deeper layer of dermis (the true skin) (Fig. 43.1). The subcutaneous layer (hypodermis) is the lowest lying layer of connective tissue that contains macrophages, fibroblasts, fat cells, nerves, fine muscles, blood vessels, lymphatics, and hair follicle roots. Each skin layer contains cells that represent progressive stages of skin cell differentiation and function. These are summarized in Table 43.1.

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FIGURE 43.1 Structure of the Skin. A, Cross section showing major skin structures. B, Layers of the epidermis. (A from Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders; B from Gawkrodger D, Ardern-Jones M: Dermatology, ed 5, Philadelphia, 2012, Churchill Livingstone.)

TABLE 43.1 Layers of the Skin Structure Epidermis

Cell Types Characteristics Keratinocytes Most important layer of skin; normally very thin (0.12 mm) but can thicken and form corns or calluses with constant pressure or friction; includes rete pegs that extend into

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Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum basale (germinativum)

Dermis Papillary layer (thin) Reticular layer (thick) Subcutaneous Layer (Hypodermis)

papillary layer of dermis Langerhans Antigen presenting cells and immune functions (dendritic) cells Keratinocytes Tough superficial layer covering the body Keratinocytes Clear layers of cells containing eleidin, which becomes keratin as cells move up to corneum layer Keratinocytes Keratohyalin gives granular appearance to this layer Melanocytes New Polygonal shaped with spinous processes projecting between adjacent keratinocytes keratinocytes Keratinocytes Basal layer where keratinocytes divide and move upward to replace cells shed from surface Melanocytes Melanocytes synthesize pigment melanin Merkel cells Mechanoreceptors for light touch Macrophages Irregular connective tissue layer with rich blood, lymphatic, and nerve supply; contains sensory receptors and sweat glands (apocrine, eccrine, sebaceous), macrophages Mast cells (phagocytic and important for wound healing), and mast cells (release histamine and have immune functions) (see Chapter 6) Histiocytes Wandering macrophages that collect pigments and inflammatory debris Subcutaneous tissue or superficial fascia of varying thickness that connects overlying dermis to underlying muscle; contains macrophages, fibroblasts, fat cells, nerves, blood vessels, lymphatics, and hair follicle roots

Dermal Appendages The dermal appendages include the nails, hair, sebaceous glands, and the eccrine and apocrine sweat glands. The fingernails and toenails are protective keratinized plates. They are composed of (1) the proximal nail fold, (2) the eponychium (cuticle), (3) the matrix from which the nail grows and its nail root, (4) the hyponychium (nail bed), (5) the nail plate, and (6) the paronychium (lateral nail fold) (Fig. 43.2). Nail growth continues throughout life at 1 mm or less per day.

FIGURE 43.2

Structures of the Nail. (Redrawn from Thompson JM et al: Mosby's clinical nursing, ed 5, St Louis, 2002, Mosby.)

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Hair color, density, grain, and pattern of distribution vary among people and depend on age, sex, and race. Hair follicles arise from the matrix (or bulb) located deep in the dermis. They extend from the dermis at an angle and have an erector pili muscle attached near the mid-dermis that straightens the follicle when contracted, causing the hair to stand up. Hair growth begins in the bulb, with cellular differentiation occurring as the hair progresses up the follicle. Hair is fully hardened, or cornified, by the time it emerges at the skin surface. Hair color is determined by melanin-secreting follicular melanocytes. Hair growth is cyclic, with periods of growth and rest that vary over different body surfaces. The sebaceous glands open onto the surface of the skin through a canal. They are found in greatest numbers on the face, chest, and back, with modified glands on the eyelids, lips, nipples, glans penis, and prepuce. Sebaceous glands secrete sebum, composed primarily of lipids, which oils the skin and hair and prevents drying. Androgens stimulate the growth of sebaceous glands, and their enlargement is an early sign of puberty. The eccrine sweat glands are distributed over the body, with the greatest numbers in the palms of the hands, soles of the feet, and forehead. They are important in thermoregulation and cooling of the body through evaporation. The apocrine sweat glands are fewer in number but produce significantly more sweat than the eccrine glands. They are located near the bulb of hair follicles in the axillae, scalp, face, abdomen, and genital area. Their ducts open into the hair follicle. The interaction of sweat with commensal (normal) flora bacteria contributes to the odor of perspiration.

Blood Supply and Innervation The blood supply to the skin is limited to the papillary capillaries, or plexus, of the dermis. These capillary loops are supplied by a deeper arterial plexus. Branches from the deep plexus also supply hair follicles and sweat glands. A subpapillary network of veins drains the capillary loops. Arteriovenous anastomoses in the dermis facilitate the regulation of body temperature. Heat loss is regulated by (1) variations in skin blood flow through the opening and closing of arteriovenous anastomoses and (2) the evaporative heat loss of sweat. The sympathetic nervous system regulates both vasoconstriction and vasodilation through α-adrenergic receptors in the skin. The lymphatic vessels of the skin arise in the papillary dermis and drain into larger subcutaneous trunks, removing cells, proteins, and immunologic mediators. The structure and function of the skin change with advancing age. A summary of aging changes is included in the box Geriatric Considerations: Aging and Changes in Skin Integrity.

Quick Check 43.1 1. Describe the two layers of the skin. 2. How do the skin blood vessels and sweat glands regulate body temperature? 3. What are some changes that occur in the skin with aging?

Clinical Manifestations of Skin Dysfunction Lesions 2442

Identification of the morphologic structure of the skin, including differentiation between primary and secondary lesions, and assessment of the appearance of the skin in combination with obtaining a health history, are essential to identify underlying pathophysiology. Tables 43.2 and 43.3 describe and illustrate lesions of the skin. Clinical manifestations of select skin lesions are described in Table 43.4. TABLE 43.2 Primary Skin Lesions Macule A flat, circumscribed area that is a change in the color of the skin; less than 1 cm in diameter Examples: Freckles, flat moles (nevi), petechiae, measles, scarlet fever

Maculesa Papule An elevated, firm, circumscribed area less than 1 cm in diameter Examples: Wart (verruca), elevated moles, lichen planus, fibroma, insect bite

Lichen Planusb Patch A flat, nonpalpable, irregular-shaped macule more than 1 cm in diameter Examples: Vitiligo, port-wine stains, mongolian spots, café au lait spots

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Plaque Elevated, firm, and rough lesion with flat top surface greater than 1 cm in diameter Examples: Psoriasis, seborrheic and actinic keratoses

Plaqued Wheal Elevated, irregularly shaped area of cutaneous edema; solid, transient; variable diameter Examples: Insect bites, urticaria, allergic reaction

Wheale Nodule Elevated, firm, circumscribed lesion; deeper in dermis than a papule; 1-2 cm in diameter Examples: Erythema nodosum, lipomas

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Lipomaf Tumor Elevated, solid lesion; may be clearly demarcated; deeper in dermis; more than 2 cm in diameter Examples: Neoplasms, benign tumor, lipoma, neurofibroma, hemangioma

Neurofibromaf Vesicle Elevated, circumscribed, superficial; does not extend into dermis; filled with serous fluid; less than 1 cm in diameter Examples: Varicella (chickenpox), herpes zoster (shingles), herpes simplex

Vesiclesg Vesicle more than 1 cm in diameter Examples: Blister, pemphigus vulgaris

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Bullah Pustule Elevated, superficial lesion; similar to a vesicle but filled with purulent fluid Examples: Impetigo, acne

Acnec Cyst Elevated, circumscribed, encapsulated lesion; in dermis or subcutaneous layer; filled with liquid or semisolid material Examples: Sebaceous cyst, cystic acne

Sebaceous Cystc Telangiectasia Fine (0.5-1 mm), irregular red lines produced by capillary dilation; can be associated with acne rosacea (face), venous hypertension (spider veins in legs), systemic sclerosis, or developmental abnormalities (port wine birthmarks) Example: Telangiectasia in rosacea

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Telangiectasiae aFarrar

WE et al: Infectious diseases, ed 2, London, 1992, Gower.

bJames

WD et al: Andrews’ diseases of the skin, ed 11, Philadelphia, 2011, Saunders.

cWeston dHabif

WL, Lane AT: Color textbook of pediatric dermatology, ed 3, Philadelphia, 2002, Mosby.

TP: Clinical dermatology: a color guide to diagnosis and therapy, ed 5, Philadelphia, 2010, Mosby.

eBolognia fWeston gBlack

JL et al: Dermatology, ed 3, Philadelphia, 2012, Saunders.

WL et al: Color textbook of pediatric dermatology, ed 4, Philadelphia, 2007, Mosby.

MM et al: Obstetric and gynecologic dermatology, ed 3, Philadelphia, 2008, Mosby.

hMarks

JG, Miller JJ: Lookingbill & Marks’ principles of dermatology, ed 4, London, 2006, Saunders.

TABLE 43.3 Secondary Skin Lesions Scale Heaped-up, keratinized cells; flaky skin; irregular shape; thick or thin; dry or oily; variation in size Examples: Flaking of skin with seborrheic dermatitis after scarlet fever, or flaking of skin after a drug reaction; dry skin

Fine Scalinga Lichenification Rough, thickened epidermis secondary to persistent rubbing, itching, or skin irritation; often involves flexor surface of extremity Example: Chronic dermatitis

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Atopic Dermatitis of Armb Keloid Irregularly shaped, elevated, progressively enlarging scar; grows beyond boundaries of wound; caused by excessive collagen formation during healing Examples: Keloid formation after surgery

Keloidc Scar Thin to thick fibrous tissue that replaces normal skin after injury or laceration to the dermis Examples: Healed wound or surgical incision

Hypertrophic Scard Excoriation Loss of epidermis; linear, hollowed-out, crusted area Examples: Abrasion or scratch, scabies

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Scabiesc Fissure Linear crack or break from the epidermis to the dermis; may be moist or dry Examples: Athlete's foot, cracks at the corner of mouth, anal fissure, dermatitis

Fissures From Infected Dermatitisc Erosion Loss of part of the epidermis; depressed, moist, glistening; follows rupture of a vesicle or bulla or chemical injury Example: Chemical injury

Erosion on Lege Ulcer Loss of epidermis and dermis; concave; varies in size Examples: Pressure ulcer, stasis ulcers

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Pressure Ulcer on Heelf Atrophy Thinning of skin surface and loss of skin markings; skin appears translucent and paperlike Examples: Aged skin, striae

Aged Sking aBaran

R et al: Color atlas of the hair, scalp, and nails, St Louis, 1991, Mosby.

bJames

WD et al: Andrews’ diseases of the skin, ed 11, Philadelphia, 2011, Saunders.

cWeston dNouri

WL et al: Color textbook of pediatric dermatology, ed 4, St Louis, 2007, Mosby.

K, Leal-Khouri S: Techniques in dermatologic surgery, Philadelphia, 2003, Mosby.

eBolognia

JL et al: Dermatology, ed 3, Philadelphia, 2012, Saunders.

fRobinson

JK et al: Surgery of the skin, ed 3, Philadelphia, 2015, Saunders.

gSeidel

HM et al: Seidel's guide to physical examination, ed 8, St Louis, 2015, Mosby.

TABLE 43.4 Clinical Manifestations of Select Skin Lesions Type Comedone

Clinical Manifestation Plug of sebaceous and keratin material lodged in opening of hair follicle; open comedone has dilated orifice (blackhead) and closed comedone has narrow opening (whitehead) Burrow Narrow, raised, irregular channel caused by parasite Petechiae Circumscribed area of blood less than 0.5 cm in diameter Purpura Circumscribed area of blood greater than 0.5 cm in diameter Telangiectasia Dilated, superficial blood vessels

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Pressure injury. Pressure injury is localized damage to the skin that results from unrelieved pressure, shearing forces, friction, and moisture. Pressure that consistently interrupts normal blood flow to and from the skin or underlying tissues is the most common cause. The risks for pressure injury are summarized in the box Risk Factors: Pressure Injury.

Risk Factors Pressure Injury External Factors • Prolonged pressure or immobilization • Prolonged moisture exposure • Neurologic disorders (coma, spinal cord injuries, cognitive impairment, or cerebrovascular disease) • Fractures or contractures • Debilitation • Pain • Sedation • Use of vasopressors • Friction and shearing forces • Coarse bed sheets used for turning by dragging, which produces friction and a shearing force • Prolonged head of bed elevation greater than 30 degrees. • Inadequate caretaking staff • Lack of communication/education regarding pressure injury care

Disease/Tissue Factors • Impaired mobility or sensation • Impaired perfusion; low blood pressure, ischemia • Fecal or urinary incontinence; prolonged exposure to moisture • Malnutrition, dehydration • Chronic diseases accompanied by anemia, edema, renal failure, malnutrition, peripheral vascular disease, or sepsis • Previous history of pressure injury • Thin skin associated with aging or prolonged use of steroids Data from Cox J, Roche S, Murphy V: Adv Skin Wound Care 31(7):328-334, 2018; Raetz JG,

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Wick KH: Am Fam Physician 92(10):888-894, 2015. Pressure injuries usually develop over bony prominences, such as the sacrum, heels, ischia, and greater trochanters. Continuous pressure on tissue between the bony prominence and a resistant outside surface distorts capillaries and occludes the blood supply. Pressure injury also can occur in soft tissues from unrelieved pressure, for example, from nasal cannulas or endotracheal tubes. If the pressure is relieved within a few hours, a brief period of reactive hyperemia (redness) occurs and there may be no lasting tissue damage. If the pressure continues unrelieved, the endothelial cells lining the capillaries become disrupted with platelet aggregation, forming microthrombi that block blood flow and cause anoxic necrosis of surrounding tissues. Shearing and friction are mechanical forces moving parallel to the skin (dragging) and can extend to the bony skeleton, causing detachment and injury of tissues. Pressure injuries are staged or graded (Fig. 43.3). One classification scheme is available from the National Pressure Advisory Panel at https://npuap.org/page/PressureInjuryStages.

FIGURE 43.3 Stages of Pressure Ulcers. Stage 1—nonblanchable intact dermis. Stage 2—partial thickness skin loss into the dermis. Stage 3—full thickness skin loss through the dermis with visible adipose tissue. Stage 4—full thickness with exposure of muscle and bone. (From Buck's Step-by-Step Medical Coding, 2020 Edition, ed 1, St. Louis, 2020, Elsevier.)

Superficial damage results in a layer of dead tissue that forms as an abrasion, blister, erosion, or nonblanchable red/darkened skin or as a reddish blue discoloration when there is deeper tissue damage. Superficial lesions are more common on the sacrum as a result of shearing or friction forces (forces parallel to the skin). Deep lesions develop closer to the bone as a result of tissue distortion and vascular occlusion from pressure perpendicular to the tissue (over the heels, trochanter, and ischia). Bacteria colonize the dead tissue, and infection is usually localized and self-limiting. Proteolytic enzymes from bacteria and macrophages dissolve necrotic tissues and cause a foul-smelling discharge that resembles, but is not, pus. The necrotic tissue initiates an inflammatory response with potential pain,

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fever, and leukocytosis. If the lesion is large, toxicity and pain lead to a host of possible complications, including loss of appetite, debility, local/systemic infections, and renal insufficiency. The primary goals for those at risk for pressure injury are prevention and early detection. Preventive techniques include frequent assessment of the skin, with repositioning and turning of the individual; promotion of movement; implementation of pressure reduction (type of positioning and use of specialty beds), pressure removal (positioning interval), and pressure distribution devices (positioning aids); and elimination of excessive moisture and drainage. Adequate nutrition, oxygenation, and fluid balance must be maintained. Superficial lesions should be covered with flat, moisture-retaining but not wet dressings that cannot wrinkle and cause increased pressure or friction. Successful healing requires continued adequate relief of pressure, débridement of necrotic tissue, opening of deep pockets for drainage, and repair of damaged tissue by construction of skin flaps for large, deep ulcers. Infection requires treatment with antibiotics, and pain should be controlled.1

Keloids and Hypertrophic Scars Keloids are rounded, firm elevated scars with irregular clawlike margins that extend beyond the original site of injury (Fig. 43.4). They are most common in darkly pigmented skin types and generally appear weeks to months after a stable scar has formed. Hypertrophic scars are elevated erythematous fibrous lesions that do not extend beyond the border of injury. Hypertrophic scars appear within 3 to 4 months after injury and usually regress within 1 year. Both lesions are caused by abnormal wound healing with excessive fibroblast activity and collagen formation, and loss of control of normal tissue repair and regeneration. Genetic susceptibility is likely.

FIGURE 43.4

Keloid. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Excessive or poorly aligned tension on a wound, introduction of foreign material into the skin, infection, and certain types of trauma (e.g., burns) are all provocative factors. Those parts of the body at risk include shoulders, back, chin, ears, and lower legs. Various treatments are available for the management of keloids and hypertrophic scars.2

Pruritus 2453

Pruritus, or itching, is a symptom associated with many primary skin disorders, such as eczema, psoriasis, or insect infestations, or it can be a manifestation of systemic disease (e.g., chronic renal failure, cholestatic liver disease, thyroid disorders, iron deficiency, neuropathies, or malignancy) or the use of opiate drugs. It may be acute or chronic (neuropathic itch), localized or generalized, and migratory (moves from one location to another). Multiple stimuli can produce itching, and there is interaction between itch and pain sensations. There are many itch mediators, including histamine, serotonin, prostaglandins, bradykinins, neuropeptides, acetylcholine, interleukin-2 (IL-2), and IL-31. Small unmyelinated type C nerve fibers transmit itch sensations, and specific spinal pathways carry itch sensations to the brain. Management of pruritus is challenging and depends on the cause; the primary condition must be treated. Both topical and systemic therapies are used.3

Quick Check 43.2 1. What areas are at greatest risk of pressure injury? 2. How does a keloid differ from a normal scar? 3. What stimulates pruritus?

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Disorders of the Skin Disorders of the skin may be precipitated by trauma, abnormal cellular function, infection, immune responses and inflammation, and systemic diseases.

Inflammatory Disorders The most common inflammatory disorders of the skin are eczema and dermatitis. Eczema and dermatitis are general terms that describe a particular type of inflammatory response in the skin and can be used interchangeably. Eczematous disorders are generally characterized by pruritus, lesions with indistinct borders, and epidermal changes. These lesions can appear as erythema, papules, or scales; they can present in an acute, subacute, or chronic phase. Edema, serous discharge, and crusting occur with continued irritation and scratching. In chronic eczema, the skin becomes thickened, leathery, and hyperpigmented from recurrent irritation and scratching. Eczematous inflammations need to be differentiated from other epidermal rashes and dermatoses, particularly psoriasis.

Allergic Contact Dermatitis Allergic contact dermatitis is a common form of T-cell–mediated or delayed hypersensitivity (see Chapter 8 for different types of allergic responses). The response is an interaction of skin barrier function, reaction to irritants, and neuronal responses, such as pruritus. Genetic susceptibility involves several genes including loss of function mutations in the gene encoding the epidermal protein filaggrin which binds keratin filaments and provides a skin barrier. Various allergens (e.g., microorganisms, chemicals, foreign proteins, latex, drugs, metals) can form the sensitizing antigen. Contact with poison ivy is a common example (Fig. 43.5). When the allergen contacts the skin, it is bound to a carrier protein, forming a sensitizing antigen. The Langerhans cells (antigen-presenting dendritic cells) process the antigen and present it to T cells. T cells then become sensitized to the antigen, inducing the release of inflammatory cytokines, resulting in the symptoms of dermatitis. In latex allergy there is either a type IV hypersensitivity reaction to chemicals used in latex rubber processing or a type I immediate hypersensitivity reaction with immunoglobulin E (IgE) antibodies formed in response to latex rubber protein.4

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FIGURE 43.5 Poison Ivy. A, Poison ivy on knee. B, Poison ivy dermatitis. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

In delayed hypersensitivity (type IV), several hours pass before an immunologic response is apparent. The T cells play an important role because they differentiate and secrete lymphokines that affect macrophage (Langerhans cells) movement and aggregation, coagulation, and other inflammatory responses (see Chapter 8). Sensitization usually develops with the first exposure to the antigen, and symptoms of dermatitis occur with reexposure. The manifestations of allergic contact dermatitis include erythema and swelling with pruritic (itching) vesicular lesions in the areas of allergen contact. The pattern of distribution provides clues to the source of the antigen (e.g., hands exposed to chemical solutions or boundaries from rings and bracelets). The antigen must be removed for the inflammatory response to resolve and tissue repair to begin. Treatment may require topical or systemic steroids.

Irritant Contact Dermatitis Irritant contact dermatitis is a nonspecific inflammatory dermatitis caused by activation of the innate immune system by proinflammatory properties of chemicals. The severity of the inflammation is related to the concentration of the irritant, length of exposure, and disruption of the skin barrier. Chemical irritation from acids and prolonged exposure to soaps, detergents, and various agents used in industry can cause inflammatory lesions. The skin lesions resemble allergic contact dermatitis. Removing the source of irritation and using topical agents provide effective treatment.

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Atopic Dermatitis Atopic dermatitis (allergic dermatitis) is common in individuals with a history of hay fever or asthma and is associated with IgE antibodies. It is more common in infancy and childhood, but some individuals are affected throughout life. Specific details of this disorder are presented in Chapter 44.

Stasis Dermatitis Stasis dermatitis usually occurs on the lower legs as a result of chronic venous stasis and edema and is associated with varicosities, phlebitis, and vascular trauma. Pooling of venous blood traps neutrophils that may release oxidants and proteolytic enzymes. Increased venous pressure widens interendothelial pores, with deposition of red blood cells, fibrin, and other macromolecules, making them unavailable for repair while promoting inflammation. Erythema and pruritus develop initially, followed by scaling, petechiae, and hyperpigmentation. Progressive lesions become ulcerated, particularly around the ankles and pretibial surface (Fig. 43.6).

FIGURE 43.6

Stasis Ulcer. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Treatment includes elevating the legs as often as possible, not wearing tight clothes around the legs, and not standing for long periods. Defined infections are treated with antibiotics. Chronic lesions with ulceration are treated with moist dressings, external compression/dressings, and vein ablation surgery.5

Seborrheic Dermatitis Seborrheic dermatitis is a common chronic inflammation of the skin involving the scalp, eyebrows, eyelids, ear canals, nasolabial folds, axillae, chest, and back (Fig. 43.7). In infants it is known as cradle cap. The cause is unknown. Proposed theories include genetic predisposition, Malassezia yeast infection, immunosuppression, and epidermal hyperproliferation.6

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FIGURE 43.7

Seborrheic Dermatitis. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

The lesions develop from infancy to old age with periods of remission and exacerbation. They appear as scaly, white or yellowish inflammatory plaques with mild pruritus. Topical therapy includes antifungal shampoos, calcineurin inhibitors (immunomodulating agents that reduce inflammation), and low-dose steroids for acute flares. Corticosteroids should not be used for maintenance therapy.

Papulosquamous Disorders Psoriasis, pityriasis rosea, lichen planus, acne vulgaris, acne rosacea, and lupus erythematosus are characterized by papules, scales, plaques, and erythema. Collectively they are described as papulosquamous disorders.

Psoriasis Psoriasis is a chronic, relapsing, proliferative, inflammatory disorder that involves the skin, scalp, and nails and can occur at any age. The onset is generally established by 40 years of age, but it can occur in children. A family history of psoriasis is common, and the genetic mechanisms are complex. The onset of psoriasis later in life is less familial and more secondary to comorbidities, such as obesity, smoking, hypertension, and diabetes.7 The inflammatory cascade of psoriasis involves the complex interactions between macrophages, fibroblasts, dendritic cells, natural killer cells, T-helper cells, and regulatory T cells. These immune cells lead to the secretion of numerous inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), and other cytokines, including IL-17 and IL-23, that promote the lesions of psoriasis. These inflammatory markers are the target for several therapeutic drugs known as biologic agents.8 Both the dermis and the epidermis are thickened because of cellular hyperproliferation, altered keratinocyte differentiation, and expanded dermal vasculature. Epidermal shedding time escalates to 3 to 4 days from the normal of 14 to 20 days. Cell maturation and keratinization are bypassed, and the epidermis thickens and plaques form. The loosely cohesive keratin gives the lesion a silvery appearance. Capillary dilation and increased vascularization occurs to accommodate the increased cell metabolism and causes erythema. The disease can be mild, moderate, or severe, depending on the size, distribution, and inflammation of the lesions. Psoriasis is marked by remissions and exacerbations.

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The types of psoriasis include plaque (psoriasis vulgaris), inverse, guttate, pustular, and erythrodermic. Plaque psoriasis is the most common. The typical plaque psoriatic lesion is a well-demarcated, thick, silvery, scaly, erythematous plaque surrounded by normal skin (Fig. 43.8). Small, erythematous papules enlarge and coalesce into larger inflammatory lesions on the face, scalp, elbows, and knees and at sites of trauma (Koebner phenomenon).

FIGURE 43.8 Psoriasis. Typical oval plaque with well-defined borders and silvery scale. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Inverse psoriasis is rare and involves lesions that develop in skin folds (i.e., the axilla or groin). In guttate psoriasis, small papules appear suddenly on the trunk and extremities (Fig. 43.9) a few weeks after a streptococcal respiratory tract infection. Guttate psoriasis may resolve spontaneously in weeks or months. Pustular psoriasis appears as blisters of noninfectious pus (collections of neutrophils), and erythrodermic (exfoliative) psoriasis is often accompanied by pruritus or pain with widespread red, scaling lesions that cover a large area of the body.

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FIGURE 43.9 Guttate Psoriasis After Streptococcal Infection. Numerous uniformly small lesions may abruptly occur after streptococcal pharyngitis. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Psoriatic arthritis of the hands, feet, knees, and ankle joints develops in 5% to 30% of cases. Psoriatic nail disease can occur in all psoriasis subtypes with pitting, onycholysis, subungual hyperkeratosis, and nail plate dystrophy. A number of comorbidities are associated with the inflammatory mechanisms of psoriasis (Did You Know? Psoriasis and Comorbidities).

Did You Know? Psoriasis and Comorbidities In addition to skin and joint manifestations, severe psoriasis is associated with inflammatory bowel disease and metabolic syndrome, which includes hypertension, insulin resistance, dyslipidemias, abdominal obesity, and nonalcoholic fatty liver disease. There is an increased risk for atherosclerosis, myocardial infarction, and stroke that is independent of traditional risk factors for these diseases. The underlying mechanisms are thought to be related to increased levels of systemic proinflammatory mediators and chemokines, which are central to the chronic inflammation, oxidative stress, and angiogenesis of psoriasis. The increased prevalence of cancer, particularly lymphoma, may be related to the pathogenesis of psoriasis or may be a consequence of immune modulation therapies. Crohn disease also is associated with psoriasis, and these two diseases have a genetic overlap. The psychosocial effects of psoriasis include depression, suicidal ideation, anxiety, and an overall reduced quality of life. Treatment considerations need to include screening, monitoring, and managing of comorbidities and assuring support systems to maintain quality of life. Data from Hu SC, Lan CE: Int J Mol Sci 18(10):E2211, 2017; Pietrzak D et al: Arch Dermatol Res 309(9):679-693, 2017; Takeshita J et al: J Am Acad Dermatol 76(3):393-403, 2017.

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Treatment is individualized and related to maintaining skin moisture, reducing epidermal cell turnover and pruritus, and promoting immunomodulation. Mild psoriasis is treated with skin-directed therapy, such as medium- to high-strength topical corticosteroids, vitamin D analogues, emollients, and keratolytic agents (e.g., salicylic acid), and ultraviolet light therapy. Systemic therapy is indicated for moderate to severe disease or in the presence of psoriatic arthritis. Medications currently approved by the U.S. Food and Drug Administration include methotrexate, acitretin, and cyclosporine (short term). Newer FDA-approved biologics target TNF-α, IL-17, and IL-23.9,10

Pityriasis Rosea Pityriasis rosea is a self-limiting inflammatory disorder that occurs more often in young adults. The cause is thought to be a herpeslike virus (e.g., human herpesvirus 6 [HHV6roseola] and HHV7).11 Pityriasis rosea begins as a single lesion (herald patch) that is circular, demarcated, and salmon-pink, approximately 3 to 10 cm in diameter, and usually located on the trunk. Early lesions are macular and papular. Secondary lesions develop within 14 to 21 days and extend over the trunk and upper part of the extremities (Fig. 43.10), although rarely on the face. The small, erythematous, rose-colored papules expand into characteristic oval lesions that are bilateral, symmetrically distributed, and have raised, scaly borders. The pattern of distribution on the back follows the skin lines around the trunk and resembles a drooping pine tree. The scales are sloughed from the margin of the lesions, forming a collarette pattern. Itching is the most common symptom. Occasionally headache, fatigue, or sore throat precedes the development of the lesions.

FIGURE 43.10 Pityriasis Rosea Herald Patch. A collarette pattern has formed around the margins (arrows). (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

The diagnosis of pityriasis rosea follows the clinical appearance of the lesion. Secondary syphilis, psoriasis, drug eruption, nummular eczema, and seborrheic dermatitis are among the differential diagnosis considerations. The disorder is usually self-limiting and resolves in a few months with symptomatic treatment for pruritus or cosmetic concerns. Ultraviolet light (with some risk for hyperpigmentation) or systemic corticosteroids have been used to control pruritus. Acyclovir and erythromycin also may be used for treatment.12

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Lichen Planus Lichen planus (LP) is a benign autoimmune inflammatory disorder of the skin and mucous membranes. The age of onset is usually between 30 and 70 years. The cause is unknown, but T cells, adhesion molecules, inflammatory cytokines, perforin, and antigen-presenting cells are involved. LP also is linked to numerous drugs and to the hepatitis C virus. The disorder begins with nonscaling, purple-colored, flat-topped, polygonal pruritic papules 2 to 4 mm in size, usually located symmetrically on the wrists, ankles, lower legs, and genitalia (Fig. 43.11). New lesions are pale pink and evolve into a dark violet color. Persistent lesions may be thickened and red, forming hypertrophic lichen planus. Oral lesions (oral lichen planus) appear as lacy white rings that must be differentiated from leukoplakia or oral candidiasis. Usually, oral lesions do not ulcerate, but localized or extensive painful ulcerations can occur, and, rarely, there may be an increased risk for oral cancer. Thinning and splitting of nails are common, and part of or the entire nail may be shed.

FIGURE 43.11

Hypertrophic Lichen Planus on Arms. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Pruritus is the most distressing symptom. The lesions are self-limiting and may last for months or years, with an average duration of 6 to 18 months. Postinflammatory hyperpigmentation is a common consequence of the lesion. Some individuals have a recurrence. The diagnosis is made by the clinical appearance and the histopathology of the lesion. Treatment is individualized and includes topical, intralesional, or systemic corticosteroids (second line for resistant LP), and systemic acitretin, with or without adjuvant light therapy. Antihistamines are given for itching, and topical or systemic corticosteroids may be used short term to control inflammation. Mucous membrane lesions are treated with topical steroids, topical retinoids or immunomodulators (or both), and systemic glucocorticoids.13

Quick Check 43.3

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1. Why does inflammation occur with contact dermatitis? 2. What factors are associated with atopic dermatitis? 3. What lesions are associated with papulosquamous disorders? 4. Give three examples of papulosquamous disorders.

Acne Vulgaris Acne vulgaris is an inflammatory disorder of the pilosebaceous follicle (the sebaceous gland contiguous with a hair follicle) that usually occurs during adolescence. Acne vulgaris is discussed in Chapter 44.

Hydradenitis Suppurativa (Inverse Acne) Hydradenitis suppurativa (inverse acne) is an inflammatory disease involving the deep sections of apocrine (sweat) glands complicated by fibrosis and draining sinus tracts. Occurring more commonly in women, the incidence and cause is unknown but may be related to genetic predisposition, altered structure of the pilosebaceous unit with bacterial infection, and an altered immune response. Aggravating factors include smoking, tight clothing, heat, perspiration, shaving of prone areas, obesity, and stress. The lesions present as deep, firm painful subcutaneous nodules, often with sinus tracts, and rupture horizontally under the skin. Sites of involvement include apocrine gland–rich areas (e.g., the axillae, groin, perianal region, and perineum). Other areas include the neck, adjacent scalp, back, buttocks, scrotum or labia, and inframammary or mammary region in women. Lesions may be minimal or severe, with multiple draining fistulas. Treatment includes topical therapy, systemic medication, and incision and drainage of nodules. Complete, spontaneous resolution is rare.

Acne Rosacea Acne rosacea is a chronic inflammation of the skin that develops in middle-aged adults and occurs more commonly in women. There are four subtypes of lesions, and they may occur in combination: erythematotelangiectatic, papulopustular, phymatous (nodular), and ocular (eyelids and ocular surface). The exact cause is unknown. Genetic factors, immune dysregulation, and neurovascular dysregulation are involved. Factors that trigger altered immune responses include sun exposure and damage; consumption of alcohol or hot beverages; hormonal fluctuations; and microorganisms, such as Demodex folliculorum [mites].14 The most common lesions are erythema, papules, pustules, and telangiectasia. They occur in the middle third of the face, including the forehead, nose, cheeks, and chin (Fig. 43.12). Neurovascular dysregulation is associated with chronic, inappropriate vasodilation, resulting in flushing, a burning sensation, and sun sensitivity. Sebaceous hypertrophy, fibrosis, and telangiectasia may be severe enough to produce an irreversible bulbous appearance of the nose (rhinophyma). Disorders of the eye often accompany rosacea, particularly conjunctivitis and keratitis, which can result in visual impairment. Facial application of fluorinated topical steroids may increase the severity of telangiectasias.

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FIGURE 43.12 Granulomatous Rosacea. Pustules and erythema occur on the forehead, cheeks, and nose. (From Habif TP: Clinical dermatology, ed 6, Philadelphia, 2016, Saunders.)

Photoprotection (sunscreen, wide-brimmed hat) is essential, along with avoidance of other triggers. Both topical drugs (metronidazole, azelaic acid) and oral drugs (tetracyclines and doxycycline) may be effective. Surgical excision of excessive tissue may be required for rhinophyma.

Lupus Erythematosus Lupus erythematosus is a systemic inflammatory, autoimmune disease with cutaneous manifestations (see Chapter 8). Discoid (or cutaneous) lupus erythematosus (DLE) is limited to the skin but can progress to systemic lupus erythematosus. Discoid (cutaneous) lupus erythematosus. Discoid (cutaneous) lupus erythematosus (DLE) usually occurs in genetically susceptible adults, particularly women in their late thirties or early forties, but people of any age can be affected. Differentiation of acute, subacute, intermittent, or chronic subtypes is by physical examination, laboratory studies, histologic (skin biopsy) analysis, and antibody serology direct immunofluorescence. The lesions may be single or multiple and vary in size. Often the lesions are located on light-exposed areas of the skin, and photosensitivity is common. The face is the most common site of lesion involvement, with a butterfly pattern of distribution found over the nose and cheeks. The cause is unknown but is related to genetic and environmental factors and an altered

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immune response to an unknown antigen or to ultraviolet B wavelengths. There is development of self-reactive T and B cells, a decreased number of regulatory T cells, and increased levels of proinflammatory cytokines. Autoantibodies and immune complexes cause tissue damage and inflammation (Fig. 43.13). On skin biopsy with immunofluorescent observation, there are lumpy deposits of immunoglobulins, especially IgM (lupus band test).15,16

FIGURE 43.13 Subacute Cutaneous Lupus (Discoid Lupus Erythematosus). (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

The early lesion is asymmetric, a 1- to 2-cm raised red plaque with a brownish scale. The scale penetrates the hair follicle and leaves a visible follicle opening (carpet-tack appearance) when removed. The lesions persist for months and then resolve spontaneously or atrophy, causing a depressed scar. Healed lesions may have residual telangiectasia and hypopigmented scarring. Treatment options include sun protection and use of topical steroids, calcineurin inhibitors, antimalarial drugs (e.g., hydroxychloroquine sulfate), and immunosuppressants. These medications must be used with caution to prevent serious side effects.

Vesiculobullous Diseases Vesiculobullous skin diseases share a common characteristic of vesicle, or blister, formation. Two such diseases are pemphigus and erythema multiforme.

Pemphigus Pemphigus (meaning to blister or bubble) is a group of rare autoimmune blistering diseases

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of the skin and oral mucous membranes. Pemphigus vulgaris is the most common form and is caused by circulating autoantibodies directed against desmosome adhesion molecules in the epidermis. Loss of adhesion causes fluid accumulation, resulting in blister formation (Fig. 43.14). There are often painful, superficial erosions prone to infection. Pemphigus can occur in all age groups but is more prevalent in persons between 40 and 50 years of age. There is a genetic predisposition, as well as environmental (viral infections, drug-induced, dietary intake, or physical effects, such as radiation or surgery) and endogenous (emotional or hormonal stressors) influences.

FIGURE 43.14 Bullous Pemphigoid. Generalized eruption with blisters arising from an edematous, erythematous annular base. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

The diagnosis of pemphigus is made from the clinical and histologic findings of antibodies at the site of blister formation. The clinical course of the disease may range from rapidly fatal to relatively benign. The primary treatment for pemphigus is systemic corticosteroids in combination with adjuvant immunosuppressants.17

Erythema Multiforme Erythema multiforme is a syndrome characterized by inflammation of the skin and mucous membranes caused by an immunologic reaction to a drug or microorganisms (e.g., herpes simplex virus) that targets small blood vessels in the skin or mucosa.18 Bullous erythema multiforme involves the mucous membranes. It is relatively rare and occurs more often during the second to fourth decade of life; however, it can occur at any age. Edema develops in the superficial dermis, forming vesicles and bullae. The lesions vary in clinical presentation, involving the skin or mucous membranes, or both. Characteristically, a “bull's-eye” or “target” lesion develops on the skin surface with a central erythematous region surrounded by concentric rings of alternating edema and inflammation. The lesions usually occur suddenly in groups over a period of 2 to 3 weeks. However, urticarial plaques, 1 to 2 cm in diameter, can develop without the target lesion. A vesiculobullous form is characterized by mucous membrane lesions and erythematous plaques on the extensor surfaces of the extremities. Single or multiple vesicles or bullae may arise on a part of the plaque, accompanied by pruritus and burning. The lesions heal within 3 to 4 weeks.

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Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Stevens-Johnson syndrome (SJS) (severe mucocutaneous bullous form involving 10% of body surface area) and toxic epidermal necrolysis (TEN) (severe mucocutaneous bullous form involving more than 30% of body surface area) are the same disease with a continuum of symptoms based on clinical presentation and severity. Both of these diseases are type IV hypersensitivity reactions to drugs and are medical emergencies18 (see Chapter 44 for pediatric considerations). Prodromal symptoms of SJS/TEN, which include fever, headache, malaise, sore throat, and cough, develop in approximately one third of the cases. The bullous lesions form erosions and crusts when they rupture. With mucosal involvement, the mouth, air passages, esophagus, urethra, and conjunctiva may be affected. Blindness can result from corneal ulcerations. Difficulty eating, breathing, and urinating may develop, with severe consequences. The disease can involve the kidneys and extend from the upper respiratory passages into the lungs. Severe forms of the disease can be fatal. Recognizing the person's medication history that preceded the target lesion and performing a skin biopsy are required to establish the diagnosis. Any ongoing drug therapy should be withdrawn and reevaluated, and underlying infections should be treated. The fluid and electrolyte balance should be monitored in severe forms of the disease, and mucous membranes should be carefully managed with a bland diet, warm saline eyewashes, topical anesthetics, or corticosteroids to maintain comfort and prevent infection. IgG and cyclosporin A are commonly used for immunosuppression, but there is lack of consensus regarding this treatment.19 Individuals with TENS are commonly referred to a burn unit for care or receive wound care dressings comparable to burn care. Ophthalmic, kidney, and lung involvement require special care. Resolution occurs in 8 to 10 days, usually without scarring. Mucosal lesions may take 6 weeks to heal.

Quick Check 43.4 1. Describe the inflammatory lesion associated with lupus erythematosus. 2. Compare the three forms of pemphigus. 3. What is the characteristic lesion of erythema multiforme?

Infections Cutaneous infections are common forms of skin disease. They generally remain localized, although serious complications can develop with systemic involvement that can be lifethreatening. The types of skin infection include bacterial, viral, and fungal. The microbiome of the skin consists of aerobes, yeast, and anaerobes and often provides protection against pathogens that cause skin infections, including Staphylococcus and Streptococcus.

Bacterial Infections Most acute bacterial skin and skin-structure infections are caused by local invasion of pathogens. Coagulase-positive Staphylococcus aureus and, less often, beta-hemolytic streptococci are the common causative microorganisms. Community-acquired methicillin-

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resistant Staphylococcus aureus (CA-MRSA [see Chapter 9]) also is a cause of serious skin infection, particularly skin abscesses. Folliculitis. Folliculitis is an infection of the hair follicle. It can be caused by bacteria, viruses, or fungi, although S. aureus is the common culprit. The infection develops from proliferation of the microorganism around the opening and inside the follicle. Inflammation is caused by released enzymes from the bacteria. The lesions appear as pustules with a surrounding area of erythema. They are most prominent on the scalp and extremities and rarely cause systemic symptoms. Prolonged skin moisture, skin trauma (e.g., shaving hair), occlusive clothing, topical agents, and poor hygiene are associated contributing factors. Cleaning with soap and water and topical application of antibiotics are effective treatments. Furuncles and carbuncles. Furuncles, or “boils,” are abscesses of hair follicles (Fig. 43.15). They may develop after folliculitis spreads into the surrounding dermis. The invading microorganism is usually S. aureus, including CA-MSRA (see Chapter 9). The infecting strain may spread to the skin from the anterior nares. The initial lesion is a deep, firm, red, painful nodule 1 to 5 cm in diameter. Within a few days, the erythematous nodules change to a large, fluctuant, and tender cystic nodule accompanied by cellulitis. No systemic symptoms are present, and the lesion may drain large amounts of pus and necrotic tissue.

FIGURE 43.15

Furuncle of the Forearm. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Carbuncles are a collection of furuncles and usually occur on the back of the neck, the upper back, and the lateral thighs. The lesion begins in the subcutaneous tissue and lower dermis as a firm mass that evolves into an erythematous, painful, swollen abscess that drains through many openings. Chills, fever, and malaise can occur during the early stages of lesion development. Furuncles and carbuncles are treated with warm compresses to provide comfort and promote localization and spontaneous drainage. Abscess formation, recurrent infections, extensive lesions, or lesions associated with cellulitis or systemic symptoms require incision

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and drainage and are treated with systemic antibiotics.20 Cellulitis. Cellulitis is an infection of the dermis and subcutaneous tissue usually caused by S. aureus, CA-MRSA, or group B streptococci. Cellulitis can occur as an extension of a skin wound, as an ulcer, or from furuncles or carbuncles. The infected area is warm, erythematous, swollen, and painful. The infection is usually in the lower extremities and responds to systemic antibiotics. Cellulitis also can be associated with other diseases, including chronic venous insufficiency and stasis dermatitis. Cellulitis must be differentiated from necrotizing fasciitis. Necrotizing fasciitis is a rare, rapidly spreading infection. It is commonly caused by Streptococcus pyogenes, starting in the fascia, muscles, and subcutaneous fat, with subsequent necrosis. Treatment requires antibiotics and often surgical débridement to prevent toxic shock syndrome. Erysipelas. Erysipelas is an acute superficial infection of the upper dermis most often caused by S. pyogenes, beta-hemolytic streptococci, and S. aureus. The face, ears, and lower legs are involved. Chills, fever, and malaise precede the onset of lesions by 4 hours to 20 days. The initial lesions appear as firm, red spots that enlarge and coalesce to form a clearly circumscribed, advancing, bright red, hot lesion with a raised border. Vesicles may appear over the lesion and at the border. Pruritus, burning, and tenderness are present. Cold compresses provide symptomatic relief, and systemic antibiotics are required to arrest the infection.21 Impetigo. Impetigo is a superficial infection of the skin that is caused by coagulase-positive Staphylococcus or beta-hemolytic streptococci. The disease occurs in adults but is more common in children (see Chapter 44). Lyme disease. Lyme disease is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi. It is transmitted by the bite of the Ixodes tick, and it is the most frequently reported vector-borne illness. The highest incidence of Lyme disease is among children. The microorganism is difficult to culture, escapes immunodefenses, and hides in tissue. It spreads to other tissues by entering capillary beds. Symptoms of the disease occur in three stages, although about half of infected individuals are symptom free.22 Localized infection (stage 1 occurs soon after the bite (within 3 to 32 days) with erythema migrans (bull's-eye rash), a T-cell–mediated response, usually with fever. Within days to weeks after the onset of the illness, there is disseminated infection, with secondary erythema migrans, usually with myalgias, arthralgias, and more rarely, meningitis, neuritis, or carditis (stage 2). Post-Lyme disease syndrome, or chronic Lyme disease, can continue for years with arthritis, encephalopathy, polyneuropathy, or heart failure (stage 3). The diagnosis of Lyme disease is based on the clinical presentation and history of the tick bite, if known. Serologic tests are used to confirm the diagnosis, although there is a delayed antibody response and the test may be negative during the first 3 weeks after infection. Antibiotics (e.g., doxycycline [not used in children younger than 8 years or

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in pregnant or breast-feeding women] or amoxicillin) are used for treatment. Reinfection can occur. There is currently no vaccine for Lyme disease.

Viral Infections Herpes simplex virus. Skin infections with herpes simplex virus (HSV) are commonly caused by two types of HSV: HSV-1 and HSV-2. Either type can occur in different parts of the body, including oral and genital locations. Their differences are distinguished by laboratory tests. HSV-1, transmitted by contact with infected saliva, is generally associated with oral infections (cold sore or fever blister) or infection of the cornea (herpes keratitis), mouth (gingivostomatitis), and orolabia (lips/labialis), but it can also cause genital herpes. With initial (primary) infection, the virus is imbedded in sensory nerve endings and it moves by retrograde axonal transport to the dorsal root ganglion, where the virus develops lifelong latency.23 During the secondary phase, the lesions occur at the same site from reactivation of the virus. The virus travels down the peripheral nerve to the site of the original infection, where it is shed. Exposure to ultraviolet light, skin irritation, fever, fatigue, or stress may cause reactivation. The lesions for HSV-1 appear as clusters of inflamed and painful vesicles on an erythematous base (e.g., within the mouth, over the tongue, on the lips, around the nose) (Fig. 43.16). Increased sensitivity, paresthesias, pruritus, and mild burning may occur before the onset of the lesions. The vesicles rupture, forming a crust. Lesions may last 2 to 6 weeks but usually resolve within 2 weeks. Treatment is symptomatic and includes topical or oral antiviral agents.

FIGURE 43.16

Herpes Simplex of the Lips (Labialis). Typical presentation with tense

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vesicles appearing on the lips and extending onto the skin. (From Habif TP: Clinical dermatology: a color guide to diagnosis and therapy, ed 4, St Louis, 2004, Mosby.)

Genital infections are more commonly caused by HSV-2.24 The virus is spread by skin-toskin mucous membrane contact during viral shedding. Risk of infection is high in immunosuppressed persons or in persons who have sexual contact with infected individuals. Vertical transmission from mother to neonate is associated with significant neonatal neurologic morbidity and mortality. The initial infection is asymptomatic. With recurrent exposure, the lesions begin as small vesicles that progress to ulceration within 3 to 4 days with pain, itching, and weeping. Treatment is symptomatic and includes topical or oral antiviral agents. Long-term suppression of HSV-1 and HSV-2 may be attempted with daily antiviral dosing. Currently there is no vaccine to prevent HSV infection. Herpes zoster and varicella. Herpes zoster (shingles) and varicella (chickenpox) are caused by the same herpesvirus— varicella-zoster virus (VZV). VZV occurs as a primary infection, followed years later by activation of the virus to cause herpes zoster. During this time, the virus remains latent in trigeminal and dorsal root ganglia. Herpes zoster has initial symptoms of pain and paresthesia localized to the affected dermatome (the cutaneous area innervated by a single spinal nerve; see Chapter 14), followed by vesicular eruptions that follow a facial, cervical, or thoracic lumbar dermatome (Fig. 43.17). Local symptoms are alleviated with compresses, calamine lotion, or baking soda. Approximately 15% to 20% of individuals experience postherpetic neuralgia (pain) with reactivation of the virus. Antiviral drugs, tricyclic antidepressants, and analgesics are helpful treatments. The varicella vaccine is safe and effective in children and adults to prevent chicken pox. The herpes zoster vaccine is given to adults 60 years and older to prevent shingles.25

FIGURE 43.17 Herpes Zoster. Diffuse involvement of a dermatome. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

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Warts. Warts (verrucae) are benign lesions of the skin caused by the many different types of human papillomavirus (HPV) that infect the stratified epithelium of skin and mucous membranes. The lesions can occur anywhere and are flat, round, or fusiform and elevated with a rough, grayish surface. Warts are transmitted by touch. Common warts (verruca vulgaris) occur most often in children and are usually on the fingers (Fig. 43.18). Plantar warts are usually located at pressure points on the bottom of the feet. Warts are commonly removed with cryotherapy, electrocautery, topical salicylic acid, or other topical or intralesional agents.

FIGURE 43.18

Verruca Vulgaris (Near Toes). (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Condylomata acuminata (venereal warts) are caused by HPV. These warts are sexually transmitted and highly contagious. The cauliflower-like lesions occur in moist areas, along the glans of the penis, vulva, and anus. Oncogenic types of HPV are a primary cause of cervical and other types of cancer and are preventable by prophylactic vaccination26 (see Chapter 35).

Fungal Infections Dermatophytes are the fungi that cause superficial skin infections. These fungi thrive on keratin (stratum corneum, hair, nails). Fungal disorders are known as mycoses; when caused by dermatophytes, the mycoses are termed tinea (dermatophytosis or ringworm). Tinea infections. Tinea infections are classified according to their location on the body. Fig. 43.19 shows the location and extension of tinea pedis. The most common sites are summarized in Table 43.5.

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FIGURE 43.19 Tinea Pedis. Inflammation has extended from the web area onto the dorsum of the foot. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

TABLE 43.5 Common Sites of Tinea Infections Site Tinea capitis (scalp) Tinea corporis (skin areas, excluding scalp, face, hands, feet, groin) Tinea cruris (groin, also known as “jock itch”) Tinea pedis (foot; also known as “athlete's foot”) Tinea manus (hand) Tinea unguium or onychomycosis (nails)

Clinical Manifestations Scaly, pruritic scalp with bald areas; hair breaks easily Circular, clearly circumscribed, mildly erythematous scaly patches with slightly elevated ringlike border; some forms are dry and macular, and other forms are moist and vesicular Small, erythematous, and scaling vesicular patches with well-defined borders that spread over inner and upper surfaces of thighs; occurs with heat and high humidity Occurs between toes and may spread to soles of feet, nails, and skin or toes; slight scaling; macerated, painful skin, occasionally with fissures and vesiculation Dry, scaly, erythematous lesions, or moist, vesicular lesions that begin with clusters of intensely pruritic, clear vesicles; often associated with fungal infection of feet Superficial or deep inflammation of nail that develops yellow-brown accumulations of brittle keratin over all or portions of nail

Tinea is diagnosed by culture, microscopic examination of skin scrapings prepared with potassium hydroxide wet mount, or observation of the skin with an ultraviolet light (Wood lamp). Cultures establish the diagnosis for a particular type of fungus. Fungi have characteristic spores and filaments, known as hyphae, that are more prominent when prepared in potassium hydroxide. The spores fluoresce blue-green when exposed to ultraviolet light. Treatment is related to the type of fungi and includes both topical and systemic antifungal medication. Candidiasis. Candidiasis is caused by the yeastlike fungus Candida albicans and normally can be found on mucous membranes, on the skin, in the gastrointestinal tract, and in the vagina. C. albicans can change from a normal microorganism to a pathogen, particularly in the

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critically ill and those who are immunosuppressed. Under normal circumstances, the resident bacteria on the skin, mainly cocci, inhibit proliferation of C. albicans. Factors that predispose to C. albicans infection include (1) local environment of moisture, warmth, maceration, or occlusion; (2) systemic administration of antibiotics; (3) pregnancy; (4) diabetes mellitus; (5) Cushing disease; (6) debilitated states; (7) infants younger than 6 months of age (as a result of decreased immune reactivity); (8) immunosuppressed persons; and (9) certain neoplastic diseases of the blood and monocyte/macrophage system. Candidiasis affects only the outer layers of mucous membranes and skin and occurs in the mouth, vagina, uncircumcised penis, nail folds, interdigital areas, and large skin folds. Table 43.6 lists the points of differentiation of various sites of candidiasis habitation. TABLE 43.6 Sites of Candidiasis Site Risk Factors Vagina Heat, moisture, occlusive (vulvovaginitis) clothing Pregnancy Systemic antibiotic therapy Diabetes mellitus Sexual intercourse with infected male Penis (balanitis) Uncircumcised Sexual intercourse with infected female Mouth Diabetes mellitus Immunosuppressive therapy Inhaled steroid therapy

Clinical Manifestations Vaginal itching; white, watery, or creamy discharge Red, swollen vaginal and labial membranes with erosions Lesions may spread to anus and groin

Treatment Miconazole cream Clotrimazole tablets or cream Nystatin tablets Ketoconazole cream Loose cotton clothing

Pinpoint, red, tender papules and pustules on glans and shaft of penis

Any of creams listed above Topical steroids for severe inflammation Nystatin oral suspension Clotrimazole troches Ketoconazole

Red, swollen, painful tongue and oral mucous membranes Localized erosions and plaques appear with chronic infection

The initial lesion is a thin-walled pustule that extends under the stratum corneum with an inflammatory base that may burn or itch. The accumulation of inflammatory cells and scale produces a whitish yellow, curdlike substance over the infected area. The lesion ceases to spread when it reaches dry skin. Topical antifungal agents are commonly used for treatment.27

Vascular Disorders Vascular abnormalities are commonly associated with skin diseases; they may be congenital or may involve vascular responses to local or systemic vasoactive substances. Blood vessels may increase in number, dilate, constrict, or become obliterated by disease processes.

Cutaneous Vasculitis Vasculitis (angiitis) is an inflammation of the blood vessel wall that can result in bleeding aneurysm formation, or occlusion with ischemia or infection of surrounding tissue. The extensive vascular bed in the skin results in vasculitic syndromes that may be localized and self-limiting or generalized with multiorgan involvement. The initiating site may be the blood, the vessel wall, or the adjacent tissue. Small vessels are usually affected.

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Cutaneous vasculitis develops from the deposit of immune complexes in small blood vessels as a toxic response to drugs (phenothiazines, barbiturates, sulfonamides), allergens, or streptococcal or viral infection, or as a component of systemic vasculitic syndromes. The deposits activate complement, which is chemotactic for polymorphonuclear leukocytes (neutrophils), and proinflammatory cytokines. The disorder is also known as cutaneous leukocytoclastic angiitis (from the presence of leukocytes [i.e., neutrophils] in and around vessel walls). A systemic form (cutaneous systemic vasculitis) can involve other organs, including the kidneys, lungs, and gastrointestinal tract. The pattern of skin involvement includes palpable purpura in the lower legs and feet (from the leakage of blood from damaged vessels) that may progress to hemorrhagic bullae with necrosis and ulceration from occlusion of the vessel. Lesions appear in clusters and persist for 1 to 4 weeks. The disease may be self-limiting and occur as a single episode. Biopsy confirms the diagnosis. Identifying and removing the antigen (chemical, drug, or source of infection) is the first step of treatment. Corticosteroids and immunosuppressants may be used when symptoms are severe.28

Urticaria Urticaria (hives) is a circumscribed area of raised erythema and edema of the superficial dermis. Urticarial lesions are most commonly associated with type I hypersensitivity reactions to drugs (penicillin, aspirin), certain foods (strawberries, shellfish, food dyes), environmental exposure (pollen, animal dander, insect bites), systemic diseases (intestinal parasites, lupus erythematosus), or physical agents (heat or cold) (see Chapter 8). The lesions are mediated by histamine release from sensitized mast cells or basophils, or both, which causes the endothelial cells of skin blood vessels to contract. The leakage of fluid from the vessel appears as wheals, welts, or hives, and there may be few or many that may be distributed over the entire body. Most lesions resolve spontaneously within 24 hours, but new lesions may appear. All possible causes of the reaction should be removed. Antihistamines usually reduce hives and provide relief of itching. Corticosteroids and βadrenergic agonists (e.g., epinephrine) may be required for severe attacks. Chronic urticaria (recurrent wheals for more than 6 weeks) is either induced by an external trigger or develops spontaneously from an endogenous mechanism. Both types involve inappropriate activation of mast cells.29 Angioedema (welts or swelling deeper within the skin or mucous membranes) is associated with both groups and more commonly affects the eyes and mouth.

Scleroderma Localized scleroderma (morphea) means sclerosis of the skin and underlying tissue. The disease is rare, more common in females, and the cause is unknown but thought to be related to an autoimmune reaction to endothelial cells and fibroblasts.30 Genetic predisposition and an immune reaction to a toxic substance are possible initiating mechanisms of the disease. Autoantibodies are often recovered from the skin and serum of individuals with scleroderma. Impaired regulation of collagen gene expression by fibroblasts probably underlies the persistent fibrosis. There are subtypes of localized scleroderma but all involve thickening of the skin. The lesions appear as shiny patches of

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hardened or tightened skin or streaks on the skin. Localized scleroderma is differentiated from the systemic form of the disease by the absence of sclerodactyly (thickening and tightness of the skin of the fingers or toes) Raynaud phenomenon, or abnormalities of the nail bed capillaries. The disease is usually self-limiting, but there may be recurring lesions. Systemic scleroderma involves the connective tissues of the skin and internal organs, including the kidneys, gastrointestinal tract, and lungs. There are massive deposits of collagen (the collagen that makes scar tissue) with progressive fibrosis accompanied by inflammatory reactions. There are vascular changes in the capillary network, with a decrease in the number of capillary loops, dilation of the remaining capillaries, formation of perivascular infiltrates, and the development of occlusion and ischemia.31 The clinical features of systemic scleroderma can be summarized using the CREST syndrome as a guide: Calcinosis—calcium deposits in the subcutaneous tissue that cause pain Raynaud phenomenon—episodes of arteriolar vasoconstriction or spasm in response to cold or stress Esophageal changes—swallowing difficulty related to acid reflux and increased esophageal fibrosis Sclerodactyly—tightening of skin over the fingers and toes leading to tapering of the digits with scarring and tissue atrophy Telangiectasias—dilation of capillaries causing small (0.5 cm), weblike red marks on the skin surface The cutaneous lesions are most often on the face and hands, the neck, and the upper chest, although the entire skin can be involved. The skin is hard, hypopigmented, taut, shiny, and tightly connected to the underlying tissue. The tightness of the facial skin projects an immobile, masklike appearance, and the mouth may not open completely. The nose may assume a beaklike appearance. The hands are shiny and sometimes red and edematous (Fig. 43.20). Progression to internal organs may occur, and death is caused by subsequent respiratory failure, renal failure, cardiac dysrhythmias, or esophageal or intestinal obstruction or perforation.

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FIGURE 43.20 Scleroderma. Note inflammation and shiny skin resulting from a combination of Raynaud phenomenon and scleroderma affecting the fingers (acrosclerosis). (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Suitable clothing and a warm environment are essential for protecting the hands. Trauma and smoking should be avoided. Treatment is individualized and based on the severity and progression of the disease.

Quick Check 43.5 1. Name two bacterial skin infections, and describe the typical lesions. 2. Compare herpes zoster and varicella. 3. What features distinguish urticarial lesions?

Benign Tumors Most benign tumors of the skin are associated with aging. Benign tumors include seborrheic keratosis, keratoacanthoma, actinic keratosis, and moles. Lipomas (moveable fatty tumors) and ganglion cysts (fluid-filled sacs near tendons or joints) are nodular lesions that are palpable under the skin.32

Seborrheic Keratosis Seborrheic keratosis is a benign proliferation of cutaneous basal cells that produces flat or slightly elevated lesions that may be smooth or warty in appearance. The pathogenesis is unknown. These benign tumors are usually seen in older people and occur as multiple lesions on the chest, back, and face. The color varies from tan to waxy yellow, flesh colored, or dark brown-black. Lesion size varies from a few millimeters to several centimeters, and they are often oval and greasy appearing with a hyperkeratotic scale (Fig. 43.21). Cryotherapy with liquid nitrogen and laser therapy are effective treatments.

FIGURE 43.21 Seborrheic Keratosis. Typical lesion is broad and flat with a comparatively smooth surface. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

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Keratoacanthoma A keratoacanthoma is a benign, self-limiting tumor of squamous cell differentiation arising from hair follicles. It usually occurs on sun-damaged skin of elderly individuals. The incidence is highest among smokers and males. The most commonly affected sites are the face, back of the hands, forearms, neck, and legs. The lesion develops in stages (proliferative, mature, and involution) over a period of 1 to 2 months with a histologic pattern resembling that of squamous cell carcinoma. Although the lesions will resolve spontaneously, they can be removed by curettage or excision to improve the cosmetic appearance and reduce the risk of evolution to squamous cell carcinoma (SCC). A biopsy is performed to rule out SCC.

Actinic Keratosis Actinic keratosis is a premalignant lesion composed of aberrant proliferations of epidermal keratinocytes caused by prolonged exposure to ultraviolet radiation. The prevalence is highest in individuals with unprotected, light-colored skin and rare in those with darkcolored skin. The lesions appear as rough, poorly defined papules, which may be felt more than seen. Surrounding areas may have telangiectasias. Treatment options include cryoablation, photodynamic therapy, laser surgery, and topical therapies. Excision and biopsy may be performed. Any existing lesions should continue to be evaluated for progression to squamous cell carcinoma. Sun protection clothing and sunblocking agents are required to prevent lesions from developing elsewhere.

Nevi (Moles) Nevi (sing., nevus) (also known as moles or birthmarks) are benign pigmented or nonpigmented lesions. Melanocytic nevi, formed from melanocytes, may be congenital or acquired and small (less than 1 cm) or large (greater than 20 cm). Congenital melanocytic nevi are monitored and may be removed to reduce the risk of cutaneous malignant melanoma. During the early stages of nevi development, the cells accumulate at the junction of the dermis and epidermis and are macular lesions. Over time, the cells move deeper into the dermis, and the nevi become nodular and symmetric without irregular borders. Nevi may appear on any part of the skin, may vary in size, may occur singly or in groups, and may undergo transition to malignant melanoma (see Fig. 43.25). The classification of nevi is summarized in Table 43.7. Nevi irritated by clothing or trauma or large lesions may be excised. Multiple and changing moles require regular evaluation.33 TABLE 43.7 Classification of Nevi Type Junctional nevus Compound nevus Intradermal nevus

Common Characteristics Flat, well-circumscribed; vary in size up to 2 cm; dark-colored hairs may be present; originate in basal layer of epidermis and can eventually reach cutaneous surface; most likely to develop into melanoma Most common in adolescents; majority of pigmented lesions in children; usually 1 cm in size; hairs may be present; surface is elevated and smooth; rarely develops into melanoma; Small, less than 1 cm, with regular edges and bristlelike hairs; color ranges from fair skin tone to light brown; slight likelihood of developing into melanoma

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Quick Check 43.6 1. List two diseases caused by insect bites. 2. Compare keratoacanthoma and actinic keratosis.

Skin Cancer Skin cancer is the most common cancer in the world. Nonmelanoma skin cancers include basal cell carcinoma and squamous cell carcinoma. Malignant melanoma is the most serious type of skin cancer and the most common cause of death from skin cancer.34 Important trends related to skin cancer are described in Box 43.1.

Box 43.1

Important Trends in Skin Cancer Incidence • Skin cancer is the most commonly diagnosed cancer in the United States. An estimated 5.4. million cases of squamous and basal cell carcinoma were diagnosed among 3.3 million people in 2012 • Malignant melanoma is the most serious form of skin cancer; it is not as common as the other forms of skin cancer; an estimated 91,270 new cases were predicted in 2018

Mortality • Total estimated deaths from skin cancer in 2018 (excluding basal cell and squamous cell carcinomas*) were 13,460; 9320 deaths were from malignant melanoma, and 4140 were from other nonepithelial skin cancers

Risk Factors • Excessive exposure to ultraviolet radiation from the sun or tanning salons • Fair complexion • Occupational exposure to coal tar, pitch, creosote, arsenic compounds, and radium • In people of color, skin cancer is less common, is diagnosed at a more advanced stage, and has a higher morbidity and mortality than in people with light-colored skin; it is often found on the palms and soles. • Immunosuppression

Warning Signs 2479

• Any unusual skin condition, especially a change in the size, borders, or color of a mole or other darkly pigmented growth or spot

Prevention and Early Detection • Avoid the sun when ultraviolet light is strongest (e.g., 10 a.m. to 3 p.m.), avoid sun tanning beds, seek shade, use sunscreen preparations, especially those containing ingredients such as para-aminobenzoic acid (PABA), and wear protective clothing • Basal cell and squamous cell skin cancers often form a pale, waxlike pearly nodule or a red, scaly, sharply outlined patch • Melanomas usually have a dark brown or black pigmentation; they start as small, molelike growths that increase in size, change color, become ulcerated, and bleed easily from slight injury

Treatment • Options for treatment include surgery, electrodesiccation (tissue destruction by heat), radiation therapy, cryosurgery (tissue destruction by freezing) • Malignant melanomas require wide and often deep excisions and removal of nearby lymph nodes; selective lymphadenectomy, immunotherapy; vaccines; oncolytic viruses; and targeted small molecules.

Survival • For basal cell and squamous cell cancers, cure is virtually ensured with early detection and treatment; malignant melanoma, however, metastasizes quickly and accounts for a lower 5-year survival rate.

*There

are no accurate estimates for basal cell and squamous cell carcinomas.

Data from American Cancer Society: Cancer facts & figures 2018, Atlanta, 2018, Author. Chronic exposure to ultraviolet (UV) radiation causes most skin cancers. Lesions are most common on the face, neck, hands, and other areas subject to intense, repetitive sunlight exposure. Protection from the sun and avoidance of tanning beds, particularly during childhood, significantly reduce the risk of skin cancer in later years. Genetic mutations in oncogenes and tumor-suppressor genes (see Chapter 11) are associated with skin cancers. Dark-skinned persons and those who avoid sunlight are significantly less likely to develop these malignant tumors. In dark-skinned persons, basal cells contain more of the pigment melanin, a protective factor against sun exposure.

Basal Cell Carcinoma Basal cell carcinoma (BCC) of the skin is the most common cancer in the world. BCC is

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thought to be caused by UV radiation exposure and also is associated with arsenic in food or water. BCCs have numerous subtypes, including superficial, nodular, pigmented, morpheaform, and combinations of these; thus, they can have very different clinical presentations—from superficial erythematous papules; to thick, pigmented nodules resembling melanomas; to erosive, necrotic, and ulcerating lesions (Fig. 43.22). As the tumor grows, it usually has a depressed center, a rolled border, and small blood vessels on the surface (telangiectasias). Early tumors are so small they are not clinically apparent. The lesion grows slowly, often ulcerates, develops crusts, and is firm to the touch. If left untreated, basal cell lesions invade surrounding tissues and, over months or years, can destroy a nose, eyelid, or ear (for treatment, see Box 43.1). Metastasis is rare because these tumors do not invade blood or lymph vessels.

FIGURE 43.22 Types of Basal Cell Carcinoma. A, Superficial. B, Nodular. C, Pigmented. D, Morpheaform —recurrent tumor. (A and D from Bolognia JL et al: Dermatology, ed 3, Philadelphia, 2012, Saunders. B and C from James WD et al: Andrews’ diseases of the skin: clinical dermatology, ed 11, Philadelphia, 2009, Saunders.)

Squamous Cell Carcinoma Squamous cell carcinoma (SCC) of the skin is a tumor of the epidermis and is the second most common human cancer. Two types are characterized: in situ and invasive. Ultraviolet radiation exposure causes SCC, and actinic keratosis is a precursor lesion. Other risk factors include arsenic at a higher level in drinking water, exposure to x-rays and gamma rays, immunosuppression, and light-colored skin.

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Premalignant lesions include actinic keratosis, leukoplakia (whitish discolored areas), scars, radiation-induced keratosis, tar and oil keratosis, and chronic ulcers. In situ SCC is usually confined to the epidermis (intraepidermal) but may extend into the dermis. Bowen disease is a dysplastic epidermal lesion often found on unexposed areas of the body such as the penis and demonstrated by flat, reddish, scaly patches. These lesions rarely invade surrounding tissue and, although they rarely metastasize, they do so more often than BCCs. Other components of the skin (e.g., sweat glands, hair follicles) can develop into skin cancer, but this is relatively uncommon. SCC is the most common cause of lip cancer and is more prevalent in older white men. The lower lip is the most common site. Long-term environmental exposure results in dryness, chapping, hyperkeratosis, and predisposition to malignancy. Immunosuppression, pipe smoking, and chronic alcoholism increase the risk for lip cancer. The most common lesion is termed exophytic and usually develops in the outer part of the lip along the vermilion border. The lip becomes thickened and evolves to an ulcerated center with a raised border (Fig. 43.23). These lesions have an irregular surface, follow cracks in the lip, and tend to extend toward the inner surface.

FIGURE 43.23 Lip Cancer. Biopsy confirmed squamous cell carcinoma. Lip vermilion shows diffuse actinic keratosis. (From Bagheri SC et al: Current therapy in oral and maxillofacial surgery, Philadelphia, 2012, Saunders.)

Invasive SCC can arise from premalignant lesions of the skin. It rarely develops from normal-appearing skin and is usually confined to the epidermis (intraepidermal), but it may extend into the reticular layer of the dermis (see Table 43.1). Invasive SCCs grow more rapidly than BCCs and can spread to regional lymph nodes. These tumors are firm and increase in both elevation and diameter. The surface may be granular and bleed easily (Fig. 43.24). Treatment includes surgical excision, radiotherapy, chemical destruction, immunotherapy, and adjuvant therapy.35

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FIGURE 43.24 Squamous Cell Carcinoma. The sun-exposed ear is a common site for squamous cell carcinoma. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Cutaneous Melanoma Cutaneous melanoma is a malignant tumor of the skin originating from melanocytes, cells that synthesize the pigment melanin and are located in the basal layer of the skin. The incidence is increasing worldwide. Risk factors include a personal or family history, or both, UV radiation exposure (including sun bed use before age 30 years), immunosuppression, fair hair, light skin with repeated sunburns, freckles, younger females and older males, geographic location, past pesticide exposure, and three or more clinically atypical (dysplastic) nevi. The risk of melanoma is lower in nonwhite people. However, they have more advanced disease and a higher death rate when diagnosed. Cutaneous melanomas arise as a result of malignant degeneration of melanocytes located either along the basal layer of the epidermis (see Fig. 43.1) or in a benign melanocytic nevus. The clinical varieties of cutaneous melanoma include superficial spreading melanoma (SSM), the most common; lentigo malignant melanoma (LMM) (Fig. 43.25), frequently found in the elderly and confused with age spots; primary nodular melanoma (PNM), an aggressive tumor. Acral lentiginous melanoma (ALM) is rare and aggressive and occurs on non–hairbearing surfaces (i.e., palms of the hands and soles of the feet) and mucous membranes in African-American people. Amelanotic (lack of pigment) and desmoplastic (fibrous or connective tissue) melanomas are similar rare forms of melanoma and may be aggressive and difficult to diagnose. Melanoma also can arise in the uvea of the eye and on mucous membranes, where they are less visible.

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FIGURE 43.25 Types of Melanoma. A, Superficial spreading melanoma. B, Nodular melanoma. C, Lentigo malignant melanoma. D, Acral lentiginous melanoma on plantar surface of foot. (From Bolognia JL et al: Dermatology essentials, Philadelphia, 2014, Saunders.)

The pathogenesis of malignant melanoma is complex. Most familial melanomas are associated with tumor-suppressor genes and proto-oncogenes. Melanomas have a high mutation rate stimulated by UV radiation. Four major genomic subtypes (BRAF mutant, RAS mutant, NF1 mutant, and Triple wild-type) have been identified, providing guidance for targeted therapy. The relationship between nevi and melanoma makes it important for the clinician to understand the various forms of nevi (see Table 43.7). Most nevi never become suspicious, but suspicious pigmented nevi need to be evaluated and removed. Indications for biopsy include any color change, size change, irregular notched margin, itching, bleeding or oozing, nodularity, scab formation, and ulceration or an unusual pattern of presentation. The ABCDE rule is used as a guide: Asymmetry, Border irregularity, Color variation, Diameter larger than 6 mm, and Elevation or Evolving, which includes raised appearance or rapid enlargement. Staging is determined by vertical lesion thickness (depth of tumor), lymph node involvement, and presence of metastasis (TNM staging). Treatment of melanoma with no evidence of metastatic disease involves a wide surgical excision of the primary lesion site. A lymph node biopsy of the peripherally draining lymph node (sentinel node) is warranted for lesions greater than 1 mm deep. Lesions on the extremities have the best surgical prognosis. Radiation therapy, chemotherapy, and immunotherapy (checkpoint inhibitors that block proteins to stop the immune system from attacking cancer cells and signal transduction), oncolytic viruses, and targeted molecular therapy that inhibits gene mutations, in addition to vaccines, are used to treat metastatic disease and have demonstrated long-term improvement in disease outcome.36 Early detection is critical to reducing mortality from metastatic disease.

Kaposi Sarcoma Kaposi sarcoma (KS) is a vascular malignancy associated with immunodeficiency states and occurs among transplant recipients taking immunosuppressive drugs. Genetic and environmental cofactors determine disease progression. Four forms of the disease have

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been described: classic (more benign), epidemic (rapidly progressive and associated with acquired immunodeficiency syndrome [AIDS]), African endemic (associated with HPV), and iatrogenic (associated with immunosuppressant treatment, including organ transplant).37 The endothelial cell is thought to be the progenitor of KS. The lesions emerge as red, purple, or brown macules and develop into plaques and nodules. They tend to be multifocal rather than spreading by metastasis. The lesions initially appear over the lower extremities in the classic form (Fig. 43.26). The rapidly progressive form associated with AIDS tends to spread symmetrically over the upper body, particularly the face and oral mucosa. The lesions are often pruritic and painful. Most individuals with epidemic KS have involvement of lymph nodes, particularly in the gastrointestinal tract and lungs. Organ involvement is much less common in the classic form than in the epidemic form. The rapidly progressive form has a poor prognosis and shorter survival rates than the classic form. (See Chapter 8 for a further discussion of AIDS.)

FIGURE 43.26

Kaposi Sarcoma. The purple lesion commonly seen on the skin. (Courtesy Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.)

Diagnosis is by medical history, physical examination, and skin biopsy, with a high index of suspicion for those with immunodeficiency. Chest x-ray reveals lesions in the lungs. Local lesions can be excised. Multiple disseminated lesions may be treated with a combination of α-interferon, radiotherapy, and cytotoxic drugs. Antiangiogenic agents are being tested. Individuals receiving highly active antiretroviral therapy (HAART) have a markedly reduced incidence of KS.

Primary Cutaneous Lymphomas Primary cutaneous lymphomas are cutaneous T-cell and B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis (see Chapter 22 for classification and general pathophysiology of lymphomas). Cutaneous lymphomas are rare but are the second most common site of extranodal non-Hodgkin lymphoma. Cutaneous lymphomas present with skin lesions and are more common in men, usually in the fifth and sixth decades. Cutaneous lymphomas develop from clonal expansion of B cells, T-helper cells, and rarely T-suppressor cells. The most common is cutaneous T-cell lymphoma and mycosis

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fungoides is the most prominent subtype. Mycosis fungoides can present as focal or widespread erythematous patches or plaques, follicular papules, comedone-like lesions, and tumors. There may be patches of alopecia. The lesions progress over a period of months or years. The differential diagnosis of the different types of cutaneous lymphomas is based on clinical manifestations, histologic, immunologic and cytogenetic features, and response to appropriate treatment. Treatment is based on the clinical presentation and staging of the disease and includes topical therapy, immunotherapy, chemotherapy, radiation therapy, and phototherapy.38

Quick Check 43.7 1. What is the most common skin cancer? 2. What malignancy can arise from melanocytes? 3. How is Kaposi sarcoma related to AIDS?

Burns The incidence of burn injuries has declined in the past several years. Most burns occur in the home, with the highest percentage occurring in men.39 Burns may be caused by thermal or nonthermal sources, including chemical, electrical, or radioactive sources. Thermal injuries result from thermal contact, scalds, or radiation. Direct contact, inhalation, and ingestion of acids, alkalis, or blistering agents cause chemical burns. Electrical burns occur with the passage of electrical current through the body to the ground or electrical flames or flashes. In addition to cutaneous injury, burns can be associated with smoke inhalation and other traumatic injuries that exacerbate local and systemic responses. Ventilatory support is often needed with inhalation injury.

Burn Wound Depth The depth of injury identifies the level of tissue destruction; the extent of injury determines clinical management, healing, and mortality. The depth of the burn is divided into four categories, summarized in Table 43.8. TABLE 43.8 Depth of Burn Injury SECOND DEGREE First Characteristic Superficial Degree Partial Thickness Morphology Destruction Destruction of of epidermis and epidermis some dermis only; local pain and

THIRD DEGREE

FOURTH DEGREE

Deep Partial Thickness

Full Thickness

Destruction of epidermis and dermis, leaving only skin appendages

Destruction of epidermis, dermis, and underlying subcutaneous tissue

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Full Thickness and Deeper Tissue Destruction of epidermis, dermis, and underlying subcutaneous tissue, tendons, muscle, and

Skin function Tactile and pain sensors Blisters

erythema Intact Intact

Absent Intact

Absent Intact but diminished

Absent Absent

Present within minutes; thin walled and fluid filled

May or may not appear as fluid-filled blisters; often is layer of flat, dehydrated tissue paper–like skin that lifts off in sheets Mottled with areas of waxy, white, dry surface

Healing time

Usually none or present after first 24 hr Skin peels at 24-48 hr; normal or slightly red underneath 3-5 days

21-28 days

30 days to many months

Blisters rare; usually a layer of flat, dehydrated tissue paper–like skin that lifts off easily White, cherry red, or black; may contain visible thrombosed veins; dry, hard, leathery surface Will not heal; may close from edges as secondary healing if wound is small

Scarring

None

May be present; low incidence influenced by genetic predisposition

Highest incidence because of slow healing rate promoting scar tissue development; also influenced by genetic predisposition

Appearance of wound after initial débridement

Red to pale ivory, moist surface

bone Absent Absent None

Black and charred appearing wound

Will not heal; requires skin grafting; may require amputation and/or reconstructive surgery Skin graft; scarring Degree of scarring minimized by early associated with excision and grafting; reconstruction and influenced by genetic grafting success predisposition

First-degree burns require no treatment unless the person is elderly or an infant, in which case severe nausea and vomiting may lead to inadequate fluid intake and dehydration. Fluid therapy may be required in these cases. First-degree burns heal in 3 to 5 days without scarring. Second-degree burns involve thin-walled, fluid-filled blisters that develop within just a few minutes after injury (Fig. 43.27). Tactile and pain sensors remain intact throughout the healing process, and wound care can cause extreme pain. Wounds heal in 3 to 4 weeks with adequate nutrition and no wound complications. Scar formation is unusual and is genetically determined.

FIGURE 43.27 Superficial Partial-Thickness Burn. Scald injury after débridement of overlying blister and nonadherent epithelium. (Courtesy Intermountain Burn Center, University of Utah, Salt Lake City, Utah.)

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Deep partial-thickness burns (Fig. 43.28) look waxy white and take weeks to heal. Necrotic tissue is surgically removed, and then the person's own unburned skin from another body area (autograft) is applied. Healing commonly results in hypertrophic scarring with poor functional and cosmetic results (Fig. 43.29).

FIGURE 43.28

Deep Partial-Thickness Burn. Note pale appearance and minimal exudates. (Courtesy Intermountain Burn Center, University of Utah, Salt Lake City, Utah.)

FIGURE 43.29 Axillary Burn Scar Contracture. Note the blanching of the anterior axillary fold and small ulceration from a deep partial-thickness burn, both indicating the diminished range of motion. (Courtesy Intermountain Burn Center, University of Utah, Salt Lake City, Utah.)

Third-degree burns, or full-thickness burns, have a dry, leathery appearance from loss of dermal elasticity (Fig. 43.30). In areas of circumferential burns, distal circulation may be

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compromised from pressure caused by edema. Escharotomies (tissue decompression by cutting through burned skin) are performed to release pressure and prevent compartment syndrome (the compression of blood vessels, veins, muscles, or abdominal organs resulting in ischemia, necrosis, and irreversible injury). Full-thickness burns are painless because all nerve endings have been destroyed by the injury.

FIGURE 43.30

Full-Thickness Burn. The wound is dry and insensate. (Courtesy Intermountain Burn Center, University of Utah, Salt Lake City, Utah.)

Fourth-degree burns require skin grafting or reconstructive surgery. The extent of total body surface area (TBSA) burned is estimated using either the “Rule of Nines” (Fig. 43.31) or the modified Lund-Browder chart.40 The severity of burn injury also considers many factors, including age, medical history, extent and depth of injury, and body area involved. The American Burn Association has defined criteria to assist health care professionals in identifying who should be referred to a specialized multidisciplinary burn center (https://ameriburn.org/public-resources/burn-center-referral-criteria/).

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FIGURE 43.31 Estimation of Burn Injury: Rule of Nines. A commonly used assessment tool with estimates of the percentages (in multiples of 9) of the total body surface area burned. A, Adults (anterior view). B, Adults (posterior view).

Pathophysiology and Clinical Manifestations Burn injury results in dramatic changes in many physiologic functions of the body within the first few minutes after the event.41 Burns exceeding 20% of TBSA in most adults are considered to be major burn injuries and are associated with massive evaporative water losses and fluctuations of large amounts of fluids, electrolytes, and plasma proteins into the body tissues, manifested as generalized massive edema, circulatory hypovolemia, and hypotension. The immediate (acute) systemic physiologic consequences of a major burn injury focus on the profound, life-threatening hypovolemic shock that occurs in conjunction with cellular and immunologic disruption within a few minutes of injury (Fig. 43.32). Burn shock is a condition consisting of a hypovolemic cardiovascular component and a cellular component.

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FIGURE 43.32

Immediate Cellular and Immunologic Alterations of Burn Shock.

Hypovolemia associated with burn shock results from massive fluid losses and shifts to the interstitial space from the circulating blood volume. The losses are caused by an increase in capillary permeability that occurs immediately and persists for approximately 24 hours after burn injury. There is decreased cardiac contractility and decreased blood volume. Blood is shunted away from the liver, kidney, and gut—known as the “ebb phase” of the burn response. This phase persists during the first 24 to 72 hours after the burn injury and is associated with a hypometabolic state with hypodynamic circulation, decreased oxygen consumption, and hyperglycemia. Most organ systems are affected. Decreased perfusion of the viscera can diminish gut barrier function and result in translocation of bacteria and endotoxemia with sepsis. Intravenous fluid resuscitation, often with lactated Ringer solution, is critical to restore the circulating blood volume. The rate of fluid replacement must be carefully monitored to prevent complications associated with fluid overload. Formulas are available (i.e., the Parkland formula or the modified Brooke formula) to guide calculation of the fluid volume replacement.42 Cellular metabolism is disrupted with the onset of the burn wound, resulting in altered cell membrane permeability and loss of normal electrolyte homeostasis. Many cytokines and inflammatory mediators in burn serum play a role in these cellular processes. Acute kidney injury is associated with hypovolemia, decreased cardiac output, the inflammatory response, and the effects of angiotensin, vasopressin, and aldosterone.

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Cardiovascular and Systemic Response to Burn Injury The clinical manifestations of burn shock are the result of multiple physiologic alterations related to burn injury and the release of inflammatory cytokines, in addition to the loss of fluid. The hallmark of burn shock is decreased cardiac contractility and diminished cardiac output with inadequate capillary perfusion in most tissues. Decreased cardiac output is related to myocardial depressant factor, as well as reduced intravascular volume. Fluid and protein movement out of the vascular compartment results in an elevated hematocrit level and white blood cell count, and hypoproteinemia. If these are not treated immediately, profound hypovolemic shock and inadequate perfusion lead to irreversible shock and death within a few hours. Restoration of capillary integrity and renewal of a functional lymphatic system are required for resolution of the edema. Usually this occurs within 24 hours, but in extensive burns, it may take days or weeks. After the individual has reached the endpoint of burn shock, the term used to describe the person's condition is capillary seal. The liver, with its metabolic, inflammatory, immune, and acute phase functions, plays a pivotal role in burn injury survival and recovery by modulating multiple metabolic pathways. Hepatic changes are common after a major burn, including fatty changes and hepatomegaly, which can influence burn wound recovery.43 The hepatic response also alters clotting factors and contributes to a hypercoagulable state, and it can increase the risk for disseminated intravascular coagulation (systemic formation of microthrombi and abnormal bleeding).44

Metabolic Response to Burn Injury A major burn injury (greater than 30% of the TBSA) initiates a systemic hypermetabolic response with an increase in the metabolic rate and a hyperdynamic circulation that begins about 48 hours after the ebb phase. This phase is known as the “flow phase” and can persist for a year or longer after a burn.45 Metabolic responses involve the sympathetic nervous system and other homeostatic regulators. Levels of catecholamines, cortisol, glucagon, and insulin (insulin resistance) are elevated, with a corresponding increase in energy expenditure and increased gluconeogenesis, glycogenolysis, lipolysis, proteolysis, and lactic acidosis. Myocardial oxygen consumption is elevated, and there is catabolic loss of muscle mass. Hyperglycemia and insulin resistance can be prolonged in severe burns and require management with intensive insulin therapy to improve postburn morbidity and mortality. Burn injury initiates an inflammatory response, with local activation and recruitment of inflammatory cells, such as leukocytes and monocytes, at the site of injury. These cells release inflammatory cytokines that contribute to the hypermetabolic state. The metabolic rate increases in proportion to the burn size and compensates for the profound water and heat loss associated with the burn. The inflammatory response and the release of cytokines at the wound level are magnified into a generalized systemic inflammatory response syndrome that can lead to multiple organ dysfunction. Hypermetabolism also increases the thermal regulatory set point and core and skin temperatures. There is persistent tachycardia, hypercapnia, and body wasting. Wound healing may be impaired, contributing to increased risk for infection and sepsis. Increasing the ambient temperature and early excision and grafting can decrease resting energy

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expenditure and improve mortality after major burns. Inflammatory mediators circulating to the lung result in pulmonary edema that can be life-threatening.

Immunologic Response to Burn Injury The immunologic/inflammatory response to burn injury is immediate, prolonged, and severe. The result in individuals surviving burn shock is immunosuppression with increased susceptibility to potentially fatal systemic burn wound sepsis. White blood cells are altered at a time when their need to inhibit sepsis is vital. Macrophages, neutrophils, lymphocytes, and platelets release large amounts of inflammatory cytokines and antibodies; their levels remain elevated for weeks after burn injury. Phagocytosis is impaired, and cellular and humoral immunity is abnormal. Individuals with altered immunocompetence or chronic disease before burn injury are at additional risk for complications, including wound sepsis.

Evaporative Water Loss With major burn injury, there is loss of the skin's barrier function and ability to regulate evaporative water loss. Normally, the skin is the major source of insensible water loss (75%), and the lungs are minor sources (25%), with a total loss of about 600 to 800 ml/day. This increases dramatically with burns because both the skin and the lungs have increased loss of water as a result of skin injury, hypermetabolism, and hyperventilation, especially in an intubated individual. Total evaporative losses exceed many liters per day in an adult with large burn wounds. Replacement of the loss is mandatory to prevent volume deficit and shock. Evaluation and Treatment Burn recovery is complex and prolonged, and complications are the rule rather than the exception. The severity of inhalation injury is also a significant morbidity and mortality factor. The goal of burn management is wound débridement and closure in a manner that promotes survival. Scar formation with contractures is often a consequence of healing in deep partial-thickness and third-degree burns (Fig. 43.33).

FIGURE 43.33

Hypertrophic Scarring. Deep partial-thickness thermal injury can result in extensive

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hypertrophic scarring. (Courtesy Intermountain Burn Center, University of Utah, Salt Lake City, Utah.)

The essential elements of survival of major burn injury are (1) provision of adequate fluids and nutrition, (2) meticulous management of wounds with early surgical excision and grafting (Fig. 43.34), (3) aggressive treatment of infection or sepsis, and (4) promotion of thermoregulation. Several drugs are used for the management of severe burns, including β-adrenergic antagonists, β-adrenergic agonists, recombinant human growth hormone, insulin, androgenic steroids, and antibiotics. Burn pain is almost always acute and severe, and treatment strategies are aggressive. The risk of developing stress ulcers (Curling ulcers) is reduced with antacids or histamine H2-receptor antagonists.

FIGURE 43.34 Application of Cultured Epithelial Autografts. Thin sheets of keratinocytes are attached to a gauze backing to allow application onto the clean, excised thigh. (Courtesy Intermountain Burn Center, University of Utah, Salt Lake City, Utah.)

Nutritional therapy focuses on early enteral therapy to reduce gut-mediated sepsis and to reduce the catabolic state. Advancements in skin replacement procedures promote wound closure and healing. Reconstructive surgery reduces complications associated with scarring and contractures.

Cold Injury Exposure to extreme cold includes a spectrum of injuries46:

• Frostnip—mild and completely reversible injury characterized by skin pallor and numbness • Chilblains—more serious than frostnip; violaceous skin color with plaques or nodules, pain, and pruritus, but no ice crystal formation; chronic vasculitis can develop and is usually located on the face, anterior lower leg, hands, and feet • Frostbite—tissues freeze and form ice crystals at temperatures 2494

below −2° C (28° F); progresses from distal to proximal and potentially reversible • Flash freeze—rapid cooling with intracellular ice crystals associated with contact with cold metals or volatile liquids The most common areas affected are fingers, toes, ears, nose, and cheeks. Mild frostbite (frostnip) is cold exposure without tissue freezing. It causes pallor and pain, followed by redness and discomfort during rewarming, with no tissue damage. Frostbite occurs when tissues freeze slowly with ice crystal formation. Frozen skin becomes white or yellowish and has a waxy texture. There is numbness and no sensation of pain. Frostbite injury is related to direct cold injury to cells, indirect injury from ice crystal formation, and endothelial cell damage. During rewarming, there is progressive microvascular thrombosis followed by reperfusion injury with the release of inflammatory mediators (including thromboxanes, prostaglandins, bradykinins, and histamines) and with impaired circulation and anoxia to the exposed area. Cyanosis and mottling develop, followed by redness, edema, and burning pain on rewarming in more severe cases. Edema can cause capillary compression and vascular stasis. Within 24 to 48 hours, vesicles and bullae appear that resolve into crusts that eventually slough, leaving thin, newly formed skin. Frostbite may be classified by depth of injury: superficial includes partial skin freezing (first degree) and full-thickness skin freezing (second degree); deep includes full-thickness and subcutaneous freezing (third degree) and deep tissue freezing (fourth degree). Third-degree and fourthdegree frostbite result in gangrene with loss of tissue. Immediate treatment of frostbite is to cover affected areas with other body surfaces and warm clothing. The area should not be rubbed or massaged. Rewarming for severe frostbite should occur after emergency transport. Immersion in a warm water bath (40° to 42° C [104° to 107.6° F]) until frozen tissue is thawed is the best treatment. Pain is severe and should be treated with potent analgesics. Antibiotics may be given. Vasodilators, thrombolytics, hyperbaric oxygen, and sympathectomy may improve healing responses. Débridement or amputation of necrotic tissue occurs when there is a clear line of demarcation.

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Disorders of the Hair Alopecia Alopecia means loss of hair from the head or body. Hair loss occurs when there is disruption in the growth phase of the hair follicle. Hair loss can be associated with systemic disorders such as hypothyroidism and iron deficiency, chemotherapy for cancer, malnutrition, compulsive hair pulling (trichotillomania), traction on hair from braiding and ponytails, use of hair treatment chemicals, hormonal alterations, and immune reactions.

Androgenic Alopecia Androgenic alopecia, or localized hair loss, occurs in about 80% of men. It is not a disease but a genetically predisposed response to androgens that clusters in families. Within the distribution of hair over the scalp, androgen-sensitive hair follicles are on top and androgen-insensitive follicles are on the sides and back. In genetically predisposed men, the androgen-sensitive follicles are transformed into vellus follicles that grow short, thin hair. Male-pattern baldness begins with frontotemporal recession and progresses to loss of hair over the top of the scalp. Minoxidil may be used to stimulate hair growth and finasteride (a 5α-reductase inhibitor) may reduce the effect of androgens on hair follicles.

Female-Pattern Alopecia Some genetically susceptible women in their twenties and thirties experience progressive thinning and loss of hair over the central part of the scalp, and the prevalence increases with advancing age. Contrary to male-pattern baldness, there is usually no loss of hair along the frontal hairline but the hairs are shorter and thinner (follicular miniaturization). The mechanism of hair loss is unknown but related to genetic and hormonal changes.

Alopecia Areata Alopecia areata is an autoimmune T-cell–mediated chronic inflammatory disease directed against hair follicles and results in hair loss.47 There is a rapid onset of hair loss in multiple areas of the scalp, usually in round patches. The eyebrows, eyelashes, beard, and other areas of body hair are rarely involved. Stressful events, cell-mediated immune cytokines, genetic susceptibility, and metabolic disorders (e.g., Addison disease, thyroid disease, and lupus erythematosus) are associated with alopecia areata. The affected areas of skin are smooth or may have short shafts of poorly developed hair that breaks at the surface (“exclamation mark” hair). Regrowth occurs within 1 to 3 months, but hair loss may recur at the same site. Permanent regrowth of hair usually occurs. The diagnosis is made by observation of the pattern of hair loss. Biopsy may show a lymphocytic infiltrate around the follicle. There are several treatments for alopecia areata, including corticosteroids and topical immunotherapy.

Hirsutism Hirsutism occurs in women and is the abnormal growth and distribution of hair on the

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face, body, and pubic area in a male pattern. There is also frontotemporal hair recession. These areas of hair growth are androgen sensitive. Variations of hair growth in women are great, and a male pattern may be normal. Women who develop hirsutism may be secreting hormones associated with polycystic ovarian syndrome, adrenal hyperplasia, or adrenal tumors; and these disorders require treatment. If no hormonal pathologic conditions exist, treatment may include cosmetic removal of hair, suppression of excessive androgen production, or blockage of peripheral androgen receptors.

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Disorders of the Nail Paronychia Paronychia is an acute or chronic infection of the cuticle. One or more fingers or toes may be involved. Individuals whose hands are frequently exposed to moisture are at greatest risk. The most common causative microorganisms are staphylococci and streptococci. Occasionally Candida will be present. Acute paronychia is manifested by the rapid onset of painful inflammation of the cuticle, usually after minor trauma. An abscess may develop requiring incision and drainage for relief of pain. The skin around the nail becomes more edematous and painful with progressive infection. Pus may be expressed from the proximal nail fold, and an abscess may develop. The nail plate is usually not affected, although it can become discolored with ridges. Chronic paronychia develops slowly, with tenderness and swelling around the proximal or lateral nail folds, and tends to affect more than one nail. Treatment includes prevention by keeping the hands dry. Oral antifungals are not effective because they do not penetrate the affected tissues. Therapy includes topical application of antiinflammatory agents and antifungals, steroids, or calcineurin inhibitors.48

Onychomycosis Onychomycosis (tinea unguium) is a fungal or dermatophyte infection of the nail unit. The most common pattern is a nail plate that turns yellow or white and becomes elevated with the accumulation of hyperkeratotic debris within the plate. Fungal infections of the nail are differentiated from psoriasis, lichen planus, and trauma by culture and microscopy and the absence of pitting on the nail surface, which is characteristic of psoriasis. Treatment is difficult because topical or systemic antifungal agents do not penetrate the nail plate readily. Systemic antifungal drugs are effective and topical drugs are available; when used in combination the potential for success improves. Rarely, surgical excision of the nail may be required. Education is essential to preventing recurrence.49

Quick Check 43.8 1. Describe the three degrees of burn injury. 2. What dangers accompany frostbite? 3. What is alopecia? Compare the different types. 4. What disorders of the nail are seen?

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Geriatric Considerations Aging & Changes in Skin Integrity • Skin becomes thinner, dryer, and more wrinkled. These changes are accelerated by exposure to sunlight and air pollution. • DNA repair of damaged skin decreases. • Epidermal cells contain less moisture and change shape. • The dermis thins, producing translucent, paper-thin quality that is more susceptible to tearing. • The dermis becomes more permeable and less able to clear substances, so they accumulate and cause irritation. • A loss of epidermal rete pegs occurs, which weakens the connection to the dermis and gives skin a smooth, shiny, and wrinkled appearance with an increased likelihood of tearing from shearing forces. • There is a loss of elastin, contributing to wrinkling. • There is a loss of flexibility of collagen fibers, so skin cannot stretch and regain shape as readily. • The barrier function of the stratum corneum is diminished, increasing the risk for injury and infection. • A significantly decreased number of Langerhans cells reduces the skin's immune response. • The dermoepidermal border flattens, shortening and reducing the number of capillary loops.

Other Skin Changes With Aging • Wound healing declines as a result of decreased estrogen in both men and women, decreased blood flow, and a slower rate of basal cell and fibroblast turnover. • There are fewer melanocytes; pigmentation becomes irregular, giving decreased protection from ultraviolet radiation and leading to graying of hair. • Atrophy of eccrine, apocrine, and sebaceous glands causes dry skin. • Pressure and touch receptors and free nerve endings decrease in number, causing reduced sensory perception. • With compromised temperature regulation, loss of cutaneous vasomotion, and decreased eccrine sweat production, there is an increased risk of heat stroke and hypothermia. • The nail plate thins, and nails are more brittle. Data from Chang AL: J Invest Dermatol 136(5):897-899, 2016; Newton VL et al: G Ital

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Dermatol Venereol 150(6):665-674, 2015.

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Summary Review Structure and Function of the Skin 1. Skin is the largest organ of the body and equals 20% of body weight. Its major functions are to provide a protective barrier and to regulate body temperature. 2. The skin has two layers—the epidermis (outermost layer) and dermis. The underlying hypodermis (subcutaneous layer) contains connective tissue, fat cells, fibroblasts, and macrophages. 3. The epidermis contains basal and spinous layers with melanocytes, keratinocytes, Langerhans cells, and Merkel cells. 4. The dermis is composed of connective tissue elements, hair follicles, sweat glands, sebaceous glands, blood vessels, nerves, and lymphatic vessels. 5. The dermal appendages include the nails, hair, sebaceous glands, and eccrine and apocrine sweat glands. 6. The papillary capillaries provide the major blood supply to the skin, arising from deeper arterial plexuses. 7. Heat loss and heat conservation are regulated by arteriovenous anastomoses that lead to the papillary capillaries in the dermis and evaporative loss of sweat. 8. Clinical manifestations of skin dysfunction include lesions, keloids and hypertropic scars, and pruritus. 9. Pressure injury is localized damage to the skin that results from unrelieved pressure and shearing forces that occlude capillary blood flow, with resulting ischemia and necrosis. Areas at greatest risk are pressure points over bony prominences, such as the greater trochanters, sacrum, ischia, and heels. 10. Keloids are sharply elevated scars that extend beyond the border of traumatized skin. Hypertrophic scars are elevated fibrous lesions that do not extend beyond the border of injury. Both are caused by excess fibroblast activity and abnormal wound healing. 11. Pruritus, or itching, is associated with many skin disorders. Itch mediators stimulate small unmyelinated type C nerve fibers to transmit itch sensation.

Disorders of the Skin 1. The most common inflammatory disorders of the skin are eczema and dermatitis. Eczema is characterized by pruritus, lesions with indistinct borders, and epidermal changes. There are multiple types of dermatitis. 2. Allergic contact dermatitis is a form of delayed hypersensitivity that develops with sensitization to allergens, such as metal, chemicals, or poison ivy. 3. Irritant contact dermatitis develops from prolonged exposure to chemicals, such as acids or soaps, with disruption of the skin barrier. Removing the source of irritation and using topical agents provide effective treatment. 4. Atopic or allergic dermatitis is associated with a family history of asthma or hay fever and is associated with elevated IgE levels. It is more common in infancy and childhood.

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5. Stasis dermatitis occurs on the legs and results from chronic venous stasis and edema. Progressive lesions become ulcerated. Elevating the legs, not wearing tight clothes, and not standing for long periods are used with treatment. 6. Seborrheic dermatitis involves scaly, yellowish, inflammatory plaques of the scalp, eyebrows, eyelids, ear canals, chest, axillae, and back. The cause is unknown but a genetic predisposition, Malassezia yeast infection, immunosuppression, and epidermal hyperproliferation have been implicated. 7. Papulosquamous disorders are characterized by papules, scales, plaques, and erythema and include psoriasis, pityriasis rosea, lichen planus, acne vulgaris, acne rosacea, and lupus erythematosus. 8. Psoriasis is a chronic inflammatory skin disease associated with a complex inflammatory cascade involving multiple immune cells resulting in cellular proliferation of both the epidermis and the dermis; it is characterized by scaly, erythematous, pruritic plaques. 9. Pityriasis rosea is a self-limiting inflammatory disease characterized by oval lesions with scales around the edges; it is located along skin lines of the trunk and may be caused by a herpeslike virus. 10. Lichen planus is an autoimmune papular, violet-colored inflammatory lesion of unknown origin manifested by severe pruritus. 11. Acne vulgaris is an inflammation of the pilosebaceous follicle. 12. Hydradenitis suppurativa (inverse acne) is an inflammatory disease involving the deep sections of apocrine glands. The lesions present in apocrine-gland rich areas as deep, firm painful subcutaneous nodules, often with sinus tracts, and rupture horizontally under the skin. 13. Acne rosacea develops on the middle third of the face with hypertrophy and inflammation of the sebaceous glands and is associated with altered innate immune responses. 14. Discoid (cutaneous) lupus erythematosus is an autoimmune disease that can affect only the skin. The systemic form also presents cutaneous lesions. The cutaneous inflammatory lesions usually occur in sun-exposed areas with a butterfly distribution over the nose and cheeks. 15. Pemphigus is a chronic, autoimmune, blistering disease that begins in the mouth or on the scalp and spreads to other parts of the body, often with a fatal outcome. 16. Erythema multiforme is an acute inflammation of the skin and mucous membranes (bullous form) with lesions that appear targetlike, with alternating rings of edema and inflammation; it is often associated with immunologic reactions to drugs. 17. Stevens-Johnson syndrome (severe mucocutaneous bullous form involving 10% of the body surface area) and toxic epidermal necrolysis (severe mucocutaneous bullous form involving more than 30% of the body surface area) are the same disease with a continuum of symptoms. Both are type IV hypersensitivity reactions to drugs and are medical emergencies. 18. Cutaneous infections generally remain localized and can be bacterial, viral, and fungal in origin. 19. Bacterial infections include (1) folliculitis, infection of the hair follicle; (2) furuncle, abscess of the hair follicle that extends to the surrounding tissue; (3) carbuncle, collection of furuncles that forms a draining abscess; (4) cellulitis, diffuse infection of the dermis and subcutaneous tissue; (5) erysipelas, superficial streptococcal

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infection of the skin commonly affecting the face, ears, and lower legs; (6) impetigo, a superficial infection caused by Staphylococcus or Streptococcus; and (7) Lyme disease. 20. Lyme disease is an immune response caused by the spirochete Borrelia burgdorferi. It is transmitted by tick bites and often shows migrating erythematous bull's eye lesions that can progress to myalgias, arthralgias, and neurologic manifestations. 21. Viral skin infections include HSV, herpes zoster and varicella, and warts. 22. HSV-1 causes cold sores but can infect the cornea, mouth, and labia. HSV-2 commonly causes genital lesions and is usually spread by sexual contact. 23. Herpes zoster (shingles) and varicella (chickenpox) are both caused by the varicella-zoster virus and can be prevented by vaccination. 24. Warts are benign, rough, elevated lesions caused by human papillomavirus. Condylomata acuminata, or venereal warts, are spread by sexual contact. 25. Tinea infections (fungal infections) can occur anywhere on the body and are classified by location (i.e., tinea pedis, tinea corporis, tinea capitis). 26. Candidiasis is a yeastlike fungal infection (Candida albicans) that occurs on the skin and mucous membranes and in the gastrointestinal tract and vagina. 27. Vascular abnormalities are commonly associated with skin diseases. 28. Cutaneous vasculitis is an inflammation of skin blood vessels related to immune complex deposition, with purpura, ischemia, and necrosis resulting from vessel necrosis. 29. Urticarial lesions are commonly associated with type I hypersensitivity responses and appear as wheals, welts, or hives. 30. Localized scleroderma is an autoimmune-mediated fibrosis that primarily affects the skin. 31. Systemic scleroderma is an autoimmune-mediated sclerosis of the skin that may also affect systemic organs and cause renal failure, bowel obstruction, or cardiac dysrhythmias. 32. Most benign tumors of the skin are associated with aging. 33. Seborrheic keratosis is a benign proliferation of basal cells that produces elevated, smooth, or warty lesions of varying size. It is most common among the elderly population. 34. Keratoacanthoma arises from hair follicles on sun-exposed areas. Three stages of development over a period of 1 to 2 months characterize the lesion. Lesions resolve spontaneously or can be removed. 35. Actinic keratosis is a rough, poorly defined papule that develops in sun-exposed individuals with fair skin. The lesion may become malignant in the form of a squamous cell carcinoma. 36. Nevi (moles) arise from melanocytes and may be pigmented or nonpigmented. They occur singly or in groups and may undergo transition to malignant melanoma. 37. Skin cancer is usually caused by chronic exposure to ultraviolet radiation and is the most common cancer in the world. 38. Basal cell carcinoma is the most common skin cancer and occurs most often on ultraviolet-exposed areas of the skin. 39. Squamous cell carcinoma is a tumor of the epidermis and can be localized (in situ) or invasive.

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40. Cutaneous melanoma is a malignant tumor that arises from melanocytes. If it is not excised early, metastasis occurs through the lymph nodes. 41. Kaposi sarcoma is a vascular malignancy associated with immunodeficiency. 42. Primary cutaneous lymphomas are clonal expansions of T-cell and B-cell lymphocytes. Mycosis fungoides is the most common T-cell lymphoma. 43. Burns are classified according to depth and extent of injury as first-, second-, third-, or fourth-degree burns. 44. Severe burns cause profound edema and burn shock related to an inflammatory response throughout the cardiovascular system, with loss of capillary seal. Fluid resuscitation is critical to prevent shock and death. 45. Burns cause a hypermetabolic response, with increased cortisol, glucagon, and insulin levels (insulin resistance) and gluconeogenesis. 46. Immune suppression associated with inflammatory cytokine release from burned tissue increases the risk for infection and can delay wound healing. 47. Cold injury usually occurs on the face and digits, with direct injury to cells and impaired circulation.

Disorders of the Hair 1. Alopecia is loss of hair from the head or body. 2. Androgenic alopecia is an inherited form of baldness with hair loss in the central scalp and recession of the frontotemporal hairline. 3. Female-pattern alopecia is a thinning of the central hair of the scalp beginning in women at 20 to 30 years of age. 4. Alopecia areata is an autoimmune-mediated loss of hair and may be associated with stress or metabolic diseases; it is usually reversible. 5. Hirsutism is a male pattern of hair growth in women that may be normal or the result of excessive secretion of androgenic hormones.

Disorders of the Nail 1. Paronychia is an inflammation of the cuticle that can be acute or chronic. It is usually caused by staphylococci, streptococci, or fungi. 2. Onychomycosis is a fungal infection of the nail plate.

Aging & Changes in Skin Integrity 1. Skin becomes thinner, drier, and more wrinkled. 2. Wound healing decreases. 3. Fewer melanocytes means pigmentation becomes irregular, providing less protection from ultraviolet light.

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Key Terms Acne rosacea, 1025 Acne vulgaris, 1025 Actinic keratosis, 1031 Allergic contact dermatitis, 1022 Alopecia, 1039 Alopecia areata, 1039 Androgenic alopecia, 1039 Apocrine sweat gland, 1014 Atopic dermatitis (allergic dermatitis), 1022 Basal cell carcinoma (BCC), 1032 Bullous erythema multiforme, 1026 Burn shock, 1036 Candidiasis, 1029 Capillary seal, 1037 Carbuncle, 1027 Cellulitis, 1027 Chronic urticaria, 1030 Condylomata acuminata (venereal warts), 1029 Cutaneous melanoma, 1033 Cutaneous vasculitis, 1030 Deep partial-thickness burn, 1036 Dermal appendage, 1014 Dermatitis, 1022 Dermis, 1014 Discoid (cutaneous) lupus erythematosus (DLE), 1025 Eccrine sweat gland, 1014 Eczema, 1022 Epidermis, 1014 Erysipelas, 1027 Erythema multiforme, 1026 Erythrodermic (exfoliative) psoriasis, 1023 Escharotomy, 1036 First-degree burn, 1035 Folliculitis, 1027 Fourth-degree burn, 1036 Frostbite injury, 1038 Furuncle, 1027 Guttate psoriasis, 1023 Herald patch, 1024 Herpes simplex virus (HSV), 1028 Herpes zoster (shingles), 1028 Hirsutism, 1039 Human papillomavirus (HPV), 1028

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Hydradenitis suppurativa (inverse acne), 1025 Hypertrophic scar, 1021 Impetigo, 1027 Inverse psoriasis, 1023 Irritant contact dermatitis, 1022 Kaposi sarcoma (KS), 1034 Keloid, 1021 Keratoacanthoma, 1031 Lichen planus (LP), 1024 Lip cancer, 1033 Localized scleroderma (morphea), 1030 Lupus erythematosus, 1025 Lyme disease, 1027 Mycosis fungoides, 1035 Necrotizing fasciitis, 1027 Nevus (pl., nevi), 1031 Onychomycosis (tinea unguium), 1039 Papillary capillary, 1015 Papulosquamous disorder, 1023 Paronychia, 1039 Pemphigus, 1026 Pityriasis rosea, 1024 Plaque psoriasis, 1023 Pressure injury, 1016 Primary cutaneous lymphoma, 1034 Psoriasis, 1023 Psoriatic arthritis, 1023 Psoriatic nail disease, 1023 Pustular psoriasis, 1023 Sebaceous gland, 1014 Seborrheic dermatitis, 1023 Seborrheic keratosis, 1031 Second-degree burn, 1035 Squamous cell carcinoma (SCC), 1032 Stasis dermatitis, 1022 Stevens-Johnson syndrome (SJS), 1026 Subcutaneous layer (hypodermis), 1014 Systemic scleroderma, 1030 Third-degree burn (full-thickness burn), 1036 Tinea infection, 1029 Total body surface area (TBSA), 1036 Toxic epidermal necrolysis (TEN), 1026 Urticaria (hives), 1030 Urticarial lesion, 1030 Varicella (chickenpox), 1028 Wart (verrucae), 1028

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References 1. Westby MJ, et al. Dressings and topical agents for treating pressure ulcers. Cochrane Database Syst Rev. 2017;(6) [CD011947]. 2. Lee HJ, Jang YJ. Recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids. Int J Mol Sci. 2018;19(3):E711. 3. Nowak D, Yeung J. Diagnosis and treatment of pruritus. Can Fam Physician. 2017;63(12):918–924 [Review: Erratum in: Can Fam Physician 64(2):92, 2018]. 4. Burkhart C, Schloemer J, Zirwas M. Differentiation of latex allergy from irritant contact dermatitis. Cutis. 2015;96(6):369– 371 [401]. 5. Sundaresan S, Migden MR, Silapunt S. Stasis dermatitis: pathophysiology, evaluation, and management. Am J Clin Dermatol. 2017;18(3):383–390. 6. Dessinioti C, Katsambas A. Seborrheic dermatitis: etiology, risk factors, and treatments: facts and controversies. Clin Dermatol. 2013;31(4):343–351. 7. Conrad C, Gilliet M. Psoriasis: from pathogenesis to targeted rherapies. Clin Rev Allergy Immunol. 2018;54(1):102–113. 8. Woo YR, Cho DH, Park HJ. Molecular mechanisms and management of a cutaneous inflammatory disorder: psoriasis. Int J Mol Sci. 2017;18(12):E2684. 9. Liau MM, Oon HH. Therapeutic drug monitoring of biologics in psoriasis. Biologics.2019;13:127–132. 10. Ogawa E, et al. Pathogenesis of psoriasis and development of treatment. J Dermatol. 2018;45(3):264–272. 11. Drago F, et al. Pityriasis rosea: a comprehensive classification. Dermatology. 2016;232(4):431–437. 12. Mahajan K, et al. Pityriasis rosea: an update on etiopathogenesis and management of difficult aspects. Indian J Dermatol. 2016;61(4):375–384. 13. Arnold DL, Krishnamurthy K. Lichen, planus, StatPearls 2507

[Internet]. StatPearls Publishing: Treasure Island FL; 2018 [Available from] http://www.ncbi.nlm.nih.gov/books/NBK526126/ [Last update March 21, 2019]. 14. Ahn CS, Huang WW. Rosacea pathogenesis. Dermatol Clin. 2018;36(2):81–86. 15. Ribero S, et al. The cutaneous spectrum of lupus erythematosus. Clin Rev Allergy Immunol. 2017;53(3):291–305. 16. Zhang YP, et al. Pathogenesis of cutaneous lupus erythema associated with and without systemic lupus erythema. Autoimmun Rev. 2017;16(7):735–742. 17. Kasperkiewicz M, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026. 18. Lerch M, et al. Current perspectives on erythema multiforme. Clin Rev Allergy Immunol. 2018;54(1):177–184. 19. Schneider JA, Cohen PR. Stevens-Johnson syndrome and toxic epidermal necrolysis: a concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther. 2017;34(6):1235–1244. 20. Russo A, et al. Current and future trends in antibiotic therapy of acute bacterial skin and skin-structure infections. Clin Microbiol Infect. 2016;22(Suppl 2):S27–S36. 21. Michael Y, Shaukat NM. Erysipelas, StatPearls [Internet]. StatPearls Publishing: Treasure Island FL; 2019 [Available from] http://www.ncbi.nlm.nih.gov/books/NBK532247/ [Last update February 3, 2019]. 22. Steere AC, et al. Lyme borreliosis. Nat Rev Dis Primers. 2016;2:16090. 23. Miranda-Saksena M, et al. Infection and transport of herpes simplex virus type 1 in neurons: role of the cytoskeleton. Viruses. 2018;10(2):E92. 24. Garland SM, Steben M. Genital herpes. Best Pract Res Clin Obstet Gynaecol. 2014;28(7):1098–1110. 25. James SF, et al. Shingrix: the new adjuvanted recombinant herpes zoster vaccine. Ann Pharmacother. 2018;52(7):673–680. 26. Hancock G, Hellner K, Dorrell L. Therapeutic HPV vaccines. 2508

Best Pract Res Clin Obstet Gynaecol. 2018;47:59–72. 27. Dadar M, et al. Candida albicans—biology, molecular characterization, pathogenicity, and advances in diagnosis and control—an update. Microb Pathog. 2018;117:128–138. 28. Marzano AV, et al. Skin involvement in cutaneous and systemic vasculitis. Autoimmun Rev. 2013;12(4):467–476. 29. Moolani Y, Lynde C, Sussman G. Advances in understanding and managing chronic urticaria. F1000Res. 2016;5. 30. Raker V, et al. Early inflammatory players in cutaneous fibrosis. J Dermatol Sci. 2017;87(3):228–235. 31. Asano Y. Systemic sclerosis. J Dermatol. 2018;45(2):128–138. 32. Higgins JC, Maher MH, Douglas MS. Diagnosing common benign skin tumors. Am Fam Physician. 2015;92(7):601–607. 33. Puig S, Malvehy J. Monitoring patients with multiple nevi. Dermatol Clin. 2013;31(4):565–577. 34. Linares MA, Zakaria A, Nizran P. Skin cancer. Prim Care. 2015;42(4):645–659. 35. Dl Stefani A, et al. Practical indications for the management of non-melanoma skin cancer patients. G Ital Dermatol Venereol. 2017;152(3):286–294. 36. Leonardi GC, et al. Cutaneous melanoma: from pathogenesis to therapy (review). Int J Oncol. 2018;52(4):1071–1080. 37. PDQ® Adult Treatment Editorial Board. PDQ Kaposi sarcoma treatment. [Bethesda, MD: National Cancer Institute; Available at] https://www.cancer.gov/types/soft-tissuesarcoma/hp/kaposi-treatment-pdq [Last updated July 27, 2018]. 38. Dabaja B. Renaissance of low-dose radiotherapy concepts for cutaneous lymphomas. Oncol Res Treat. 2017;40(5):255–260. 39. American Burn Association. Burn incidence and treatment in the United States: 2016 fact sheet. [Available at] http://ameriburn.org/resources_factsheet.php. 40. Yu CY, et al. Human body surface area database and estimation formula. Burns. 2010;36(5):616–629. 41. Kaddoura I, et al. Burn injury: review of pathophysiology and therapeutic modalities in major burns. Ann Burns Fire 2509

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Alterations of the Integument in Children Noreen Heer Nicol, Sue E. Huether

CHAPTER OUTLINE Acne Vulgaris, 1044 Dermatitis, 1045 Atopic Dermatitis, 1045 Diaper Dermatitis, 1045 Infections of the Skin, 1046 Bacterial Infections, 1046 Fungal Infections, 1047 Viral Infections, 1048 Insect Bites and Parasites, 1051 Scabies, 1051 Pediculosis (Lice Infestation), 1051 Fleas, 1051 Bedbugs, 1051 Cutaneous Hemangiomas and Vascular Malformations, 1052 Cutaneous Hemangiomas, 1052 Cutaneous Vascular Malformations, 1053 Other Skin Disorders, 1053 Miliaria, 1053 Erythema Toxicum Neonatorum, 1053

Children frequently develop alterations of the skin, which may be minor or severe and localized or generalized. Skin diseases in children may have different causative mechanisms and different patterns of distribution than those found in adults, although there may be similarities. Some skin diseases resolve spontaneously and require no treatment. Diagnosis is commonly made from the history, appearance, and distribution of the lesion or lesions. Common skin diseases of childhood are presented here.

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Acne Vulgaris Acne vulgaris is the most common skin disease and occurs primarily between the ages of 12 and 25 years. Acne tends to occur in families, and genetic susceptibility may determine the severity of the disease. Acne develops at distinctive pilosebaceous units known as sebaceous follicles. Located primarily on the face and upper parts of the chest and back, these follicles have many large sebaceous glands, a small vellus hair (very short, nonpigmented, and very thin hair), and a dilated follicular canal that is visible as a pore on the skin surface. Acne lesions may be noninflammatory or inflammatory (cystic) (Fig. 44.1). In noninflammatory acne, the comedones are open (blackheads) and closed (whiteheads), with the accumulated material causing distention of the follicle and thinning of follicular canal walls. Inflammatory (cystic) acne develops in closed comedones when the follicular wall ruptures, expelling sebum into the surrounding dermis and initiating inflammation. Pustules form when the inflammation is close to the surface; papules and cystic nodules can develop when the inflammation is deeper, causing mild to severe scarring. Both types of lesions may exist in the same individual.

FIGURE 44.1 Acne. A, Inflammatory papules and pustules. B, Severe nodular cystic acne. (From Kliegman RM et al, editors: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.)

The pathophysiology includes (1) hyperkeratinization of the follicular epithelium; (2) excessive sebum production; (3) follicular proliferation of anaerobic Cutibacterium acnes (C. acnes, previously known as Propionibacterium acnes); and (4) inflammation and rupture of a follicle from accumulated debris and bacteria (see Fig. 44.1). C. acnes shifts from being symbiotic to a pathogenic strain of bacteria and from being noninflammatory to inflammatory The causal mechanism is not completely understood. Androgens (dehydroepiandrosterone sulfate and testosterone), synthesized in increasing amounts during puberty, increase the size and productivity of the sebaceous glands, which promotes proliferation of inflammatory C. acnes strains in susceptible individuals A diet high in simple carbohydrates and high glycemic dairy products may be associated with acne by increasing insulin/insulin-like growth factor 1 (IGF-1) that enhances signaling of androgens and overstimulates the nutrient and growth factor-sensitive kinase mechanistic target of rapamycin complex (1mTORC) in pilosebaceous units.1,2 The result is an alteration of the skin barrier, hyperkeratinization, plugging of the pilosebaceous unit, inflammation, edema, pus formation, and breakdown of the follicle wall.3 The treatment of acne should be individualized according to severity. Combinations of a

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topical retinoid, benzoyl peroxide, and antimicrobial agents are preferred. Retinoids are anticomedogenic and comedolytic, have antiinflammatory effects, and target multiple pathogenic microorganisms associated with acne. Benzoyl peroxide is antimicrobial with some keratolytic effects. Antibiotics have antiinflammatory and antimicrobial effects, although stronger recommendations to limit oral antibiotic usage in acne are being made worldwide to avoid development of antibiotic resistance and to promote future effectiveness of the drugs. Use of systemic therapies, including oral antibiotics, sex hormones, corticosteroids, and isotretinoin (requires pregnancy prevention), may be limited by side effects. New drugs are available including immune modulators and inhibitors of proinflammatory cytokines.1 Acne surgery, including comedo extraction, intralesional steroids, and cryosurgery, is useful in selected individuals. Severe scarring may be treated with dermabrasion, lasers, and resurfacing techniques. Diets should avoid high glycemic index foods. Psychologic support is important because acne negatively affects quality of life, self-esteem, and mood in adolescents and is associated with an increased risk of anxiety, depression, and suicidal ideation. Special consideration must be given to treatment for those with darker skin because they have greater risk for hyperpigmentation and keloidal scarring. Research is continuing on the development of vaccines to prevent acne.4 Acne conglobata is a highly inflammatory form of acne with communicating cysts and abscesses beneath the skin that can cause scarring. Remissions tend to occur during the summer, perhaps from more exposure to sunlight. This type of acne requires the use of systemic and combination therapies to prevent drug resistance.

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Dermatitis Atopic Dermatitis Atopic dermatitis (AD), also known as atopic eczema, is the most common cause of eczema in children. Individuals with AD may develop asthma and allergies later in life. Onset is usually from 2 to 6 months of age, and most cases develop within the first 5 years of life. The cause of this chronic relapsing form of pruritic eczema involves an interplay of genetic predisposition; altered skin barrier function associated with filaggrin gene mutations and filaggrin deficiency (proteins that bind keratin in the epidermis); reduced ceramide (a stratum corneum lipid) levels; decreased antimicrobial peptides; altered innate immunity; and altered immune responses to allergens, irritants, and microbes. Filaggrin gene mutations also are associated with increased risk for asthma in AD and ichthyosis vulgaris (dry, scaly skin) (Fig. 44.2). There is an altered skin microbiome with formation of biofilm by Staphylococcus aureus that may act as super-antigens causing exacerbations of eczema.5 Although AD is predominantly associated with type 2 immune responses, activation of T-cell cytokine pathways have been reported, resulting in new therapeutic targets using novel biologic therapy, including treatment of adults.6

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FIGURE 44.2 Atopic Dermatitis. Characteristic lesions with crusting from irritation and scratching over knees and around ankles. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

AD has a constellation of clinical features that include severe pruritus and a characteristic eczematoid appearance with redness, edema, and scaling. The skin becomes increasingly dry, itchy, sensitive, and easily irritated because the barrier function of the skin is impaired. Itching is the hallmark of atopic dermatitis and rubbing and scratching to relieve the itch are responsible for many of the clinical skin changes of AD. In young children, a rash appears primarily on the face, scalp, trunk, and extensor surfaces of the arms and legs (see Fig. 44.2). In older children and adults, the rash tends to be found on the neck, antecubital and popliteal fossae, and hands and feet. Individuals with AD also tend to develop viral, bacterial, and fungal skin infections in the eczematous areas. There are no specific laboratory features of AD that can be used for diagnostic and treatment purposes. Most affected individuals show increased serum levels of immunoglobulin E (IgE) level, eosinophils (eosinophilia), and positive skin test results to a variety of common food and inhalant allergens. Management of individuals with AD includes accurate diagnosis and comprehensive evaluation of triggers and response to treatment; management of confounding factors, including sleep disruption; and education of individuals and caregivers. Avoidance of triggers and promotion of skin hydration, including soaking baths and consistent use of an

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emollient moisturizer, are key to good therapy.7 Antiinflammatory agents, such as topical corticosteroids and calcineurin inhibitors, are necessary during active flare-ups of eczema. Immunomodulator therapy and wet wrap therapy8 are used for severe eczema. Systemic therapy for moderate to severe eczema includes the use of sedating antihistamines, antibiotics, and new biologic agents.8

Diaper Dermatitis Diaper dermatitis (diaper rash) is a form of irritant contact dermatitis initiated by a combination of factors including prolonged exposure to and irritation by urine wetness and feces as well as maceration by wet diapers or airtight plastic diaper covers. Disposable diaper designs have decreased the incidence of diaper dermatitis in infants. Diapers with a meshlike, aperture topsheet may represent a better way to mitigate known causes of diaper dermatitis through their superior ability to absorb fecal matter.9 Often, diaper dermatitis is secondarily infected with Candida albicans. The resulting inflammation affects the lower aspect of the abdomen, genitalia, buttock, and upper portion of the thigh. The lesions vary from mild erythema to erythematous papular lesions and can affect overall infant health. Candidal (monilial) diaper dermatitis is usually very erythematous, with sharp margination and pustulovesicular satellite lesions (Fig. 44.3).

FIGURE 44.3

Diaper Dermatitis. A, Diaper dermatitis with erosions. B, Diaper dermatitis with Candida

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albicans secondary infection. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Treatment involves frequent diaper changes to keep the affected area clean and dry or regular exposure of the perineal area to air, use of superabsorbent diapers, and topical protection with a product containing petrolatum or zinc oxide, or both. Topical antifungal medication is used to treat C. albicans when present.10

Quick Check 44.1 1. What causes the inflammation of acne vulgaris? 2. What lesions are typical of atopic dermatitis in children? 3. What causes diaper dermatitis?

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Infections of the Skin Infectious diseases caused by bacteria, viruses, and fungi constitute the major forms of skin disease. Breaks in the skin integrity, particularly those that inoculate pathogens into the dermis and epidermis, may cause or exacerbate infections. Most infections tend to occur superficially; however, systemic signs and symptoms develop occasionally and can be lifethreatening in immunosuppressed children.

Bacterial Infections Impetigo Contagiosum Impetigo is the most common bacterial skin infection in children 2 to 5 years of age and is highly contagious. S. aureus and, less commonly, Streptococcus pyogenes cause impetigo. The mode of transmission is by both direct and indirect contact. The disease is more common in midsummer to late summer, with a higher incidence in hot, humid climates. Impetigo is particularly infectious among people living in crowded conditions with poor sanitary facilities or in settings such as day-care facilities. It affects children in good health, but conditions such as anemia and malnutrition are predisposing factors. Bacterial invasion occurs through minor breaks in the cutaneous surface or as a secondary infection of a preexisting dermatosis or infestation. The staphylococci produce bacterial toxins called exfoliative toxins (ETs) that cause a disruption in the skin barrier with blister formation. There are two types of impetigo: nonbullous and, more rarely, bullous (caused only by S. aureus), in which blisters enlarge or coalesce to form bullae. Both forms of impetigo begin as vesicles that rupture to form a honey-colored crust (Fig. 44.4). The lesions are often located on the face, around the nose and mouth, but the hands and other exposed areas also are involved. Impetigo is clinically characterized by crusted erosions or ulcers that may arise as a primary infection or as a secondary infection of a preexisting dermatosis or infestation.

FIGURE 44.4 Impetigo. Multiple crusted and oozing lesions of impetigo. (From Kliegman RM et al, editors: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.)

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The treatment of choice for both types of impetigo is topical antibiotics (e.g., mupirocin or fusidic acid) for uncomplicated lesions. For extensive or complicated impetigo, systemic antibiotics may be warranted but β-lactam antibiotics should be avoided if methicillinresistant Staphylococcus aureus (MRSA) is suspected. Prompt treatment avoids complications, such as glomerulonephritis, necrotizing fasciitis, and septic shock syndrome. Lesions usually resolve in 2 to 3 weeks without scarring. Using good handwashing techniques and isolating the infected child's washcloth, towels, drinking glass, and linen are important for prevention.11

Staphylococcal Scalded-Skin Syndrome Staphylococcal scalded-skin syndrome (SSSS), also known as Ritter disease, is considered a pediatric emergency. It is the most serious staphylococcal infection that affects the skin and usually occurs in infants within 48 hours after birth and children younger than 5 years of age. SSSS is caused by virulent group II strains of staphylococci that produce an exfoliative toxin. The toxin attacks desmoglein and keratinocyte adhesion molecules and causes a separation of the skin just below the granular layer of the epidermis with blister formation12 (see Fig. 43.1). The toxin is usually produced at body sites other than the skin and arrives at the epidermis through the circulatory system. Staphylococci typically are not found in the skin lesions themselves. Adults have circulating antistaphylococcal antibodies and are better able to metabolize and excrete the toxin. Neonates are at the highest risk because of their lack of immunity with no prior exposure to the toxin. The clinical symptoms begin with fever, malaise, rhinorrhea, and irritability followed by generalized erythema with exquisite tenderness of the skin. There may be an associated impetigo, but the infection often begins in the throat or chest. The erythema spreads from the face and trunk to cover the entire body except for the palms, soles, and mucous membranes. The diagnosis is mainly clinical, based on the findings of tender erythroderma, bullae, and desquamation with a scalded appearance, especially in friction zones, periorificial scabs/crusting, positive Nikolsky sign, and absence of mucosal involvement. Within 48 hours, blisters and bullae may form, giving the child the appearance of being scalded. The pain is severe (Fig. 44.5). Fluid loss from ruptured blisters and water evaporation from denuded areas may cause dehydration. Perioral and nasolabial crusting and fissures develop. In severe cases, the skin of the entire body may slough. When secondary infection can be prevented, healing of the involved skin occurs in 10 to 14 days, usually without scarring.

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FIGURE 44.5 Staphylococcal Scalded-Skin Syndrome (SSSS). The skin lesions, showing desquamation and wrinkling of the skin margins, appeared 1 day after drainage of a staphylococcal abscess. (From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, St Louis, 2011, Saunders.)

Before medical intervention is initiated, culture and histologic or exfoliative cytologic studies must be performed to differentiate SSSS from erythema multiforme and toxic epidermal necrolysis (TEN), both of which are usually caused by an immune reaction to drugs (see Chapter 43). When SSSS infection is confirmed, treatment with oral or intravenous antibiotics begins. The skin should be treated in the same manner as a severe burn, with meticulous aseptic technique. Special care is required when there is involvement of the lips and eyelids. Infection control practices are important for prevention.13

Fungal Infections Tinea Capitis Tinea capitis, a fungal infection of the scalp (scalp ringworm), is the most common fungal infection of childhood. It rarely affects infants and is seen in children between 2 and 10 years of age. The primary microorganism responsible for this disease in North America is Trichophyton tonsurans. There is direct human transmission of T. tonsurans in crowded areas, the most prevalent environment of the fungus, and also from contact with infected cats and dogs. The lesions are often circular and manifested by broken hairs 1 to 3 mm above the scalp, leaving a partial area of alopecia from 1 to 5 cm in diameter (Fig. 44.6). A slight erythema and scaling with raised borders can be observed.

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FIGURE 44.6

Tinea Capitis. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Diagnosis is best confirmed by potassium hydroxide (KOH) examination, and fungal culture and dermoscopy can be helpful. Tinea capitis always requires systemic treatment because topical antifungal agents do not penetrate the hair follicle. Several oral antifungal agents are available for treatment.14

Tinea Corporis Tinea corporis (ringworm) is a common superficial dermatophyte infection in children. The organisms most commonly responsible for this disease are Microsporum canis and Trichophyton mentagrophytes. As in tinea capitis, contact with kittens and puppies is a common source of the disorder. Tinea corporis preferentially affects the nonhairy parts of the face, trunk, and limbs. Lesions are often erythematous, round or oval scaling patches that spread peripherally with clearing in the center, creating the ring appearance, which is why this disease is commonly referred to as ringworm. The lesions are distributed asymmetrically, and multiple lesions, when present, overlap. Transmission occurs by direct contact with an infected lesion and through indirect contact with personal items used by the infected person. KOH examination of the scale from the border of the lesions confirms the diagnosis. Most lesions respond well to applications of appropriate topical antifungal medications.

Thrush Thrush is the term used to describe the presence of C. albicans in the mucous membranes of the mouths of infants. It occurs less commonly in adults, and infected adults are usually immunocompromised. C. albicans penetrates the epidermal barrier more easily than other microorganisms because of its keratolytic proteases and other enzymes. Thrush is characterized by the formation of white plaques or spots in the mouth that lead to shallow ulcers caused by keratolytic proteases from the microorganism. The tongue may have a dense, white covering. The underlying mucous membrane is red and tender and may bleed when the plaques are removed. The disease is often accompanied by fever and gastrointestinal irritation. The infection commonly spreads to the groin, buttocks, and other parts of the body. Treatment may be difficult and includes oral antifungal washes, such as

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nystatin oral suspension. Simultaneous treatment of a Candida nipple infection or vaginitis in the mother is helpful in reducing the C. albicans surface colonization of the infant. Feeding bottles and nipples should be sterilized to prevent reinfection. The diaper area should be kept clean and dry.

Viral Infections Viral infections of the skin in children are caused by poxvirus, papovavirus, and herpesvirus.

Molluscum Contagiosum Molluscum contagiosum is a common, highly contagious viral infection of the skin and, occasionally, conjunctiva that affects school-aged children, sexually active young adults, and immunocompromised individuals. The incidence is higher among children who swim or have eczema; however, the mechanism of disease is not clear.15 The disease is transmitted by skin-to-skin contact or from autoinoculation. Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and the causative agent of molluscum contagiosum. The poxvirus proliferates within the follicular epithelium and induces epidermal cell proliferation. The epidermis grows down into the dermis to form saccules containing clusters of virus. The characteristic molluscum body is composed of mature, immature, and incomplete viruses and cellular debris.16 The lesions of molluscum are discrete, slightly umbilicated, dome-shaped papules 1 to 5 mm in diameter that appear anywhere on the skin or conjunctiva. The lesions are mainly on the trunk, face, and extremities in children (Fig. 44.7). There is usually no inflammation surrounding molluscum lesions unless they are traumatized or secondary infection occurs. Scarring may occur with healing.

FIGURE 44.7 Molluscum Contagiosum. Waxy pink globules with umbilicated centers. (From Habif TP: Clinical dermatology: a color guide to diagnosis and therapy, ed 4, St Louis, 2004, Mosby.)

The three best diagnostic procedures are (1) staining smears of the expressed molluscum

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body, (2) examining a biopsy specimen, or (3) inoculating a molluscum suspension into cell cultures to demonstrate the cytotoxic reactions. Most lesions are self-limiting and clear in 6 to 9 months if not manipulated. Treatment options include immunomodulatory and antiviral therapy and destructive procedures (cryotherapy, curettage, or laser ablation); however, no treatment is universally effective. KOH solution applications can be safe, effective, and inexpensive. Treatment is recommended for genital molluscum to prevent sexual transmission and autoinoculation. Measures to prevent spread of infection must be taken. Recurrences are common.17

Rubella (German or 3-Day Measles) Rubella is a common communicable disease of children and young adults caused by a ribonucleic acid (RNA) virus that enters the bloodstream through the respiratory route. This disease is mild in most children. The incubation period ranges from 14 to 21 days. Prodromal symptoms include enlarged cervical and postauricular lymph nodes, low-grade fever, headache, sore throat, rhinorrhea, and cough. A faint-pink to red coalescing maculopapular rash develops on the face with spread to the trunk and extremities 1 to 4 days after the onset of initial symptoms (Fig. 44.8). The rash is thought to be the result of virus dissemination to the skin. The rash subsides after 2 to 3 days, usually without complication. Children are usually not contagious after development of the rash (Table 44.1).

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FIGURE 44.8 Rubella (3-Day Measles). A, Typical distribution of full-blown maculopapular rash with tendency to coalesce. B, Rash of rubella. (From Centers for Disease Control and Prevention: Image Bank, Figure #712. Available from , accessed October 11, 2015.)

TABLE 44.1 Differential Presentation of Viral Diseases Producing Rashes Viral Disease Rubella (German measles; rubivirus)

Rubeola (measles; paramyxovirus)

Roseola (exanthema subitum; human herpesvirus 6 and 7) Varicella (chickenpox; herpes

Prodromal Symptoms 14-21 days 1-2 days Mild fever Malaise Respiratory symptoms 7-12 days 2-5 days Fever Cough Respiratory symptoms

Incubation

5-15 days

2-5 days High fever

11-20 days

1-2 days Low-grade

Duration/Characteristics 1-3 days Pink-red maculopapular rash Face and trunk 3-5 days Purple-red to brown maculopapular papules Face, trunk, extremities

1-3 days Pink-red macular papules Neck and trunk Red papules, vesicles, pustules in clusters

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Clinical Symptoms Enlarged and tender occipital and periauricular lymph nodes Koplik spots*1-3 days before rash Rash develops when fever subsides

Eruption of new lesions

zoster virus)

Hand, foot, and mouth disease (coxsackie A virus)

*Koplic

fever Cough May be asymptomatic 4-6 days

Fever, sore throat, anorexia

3-7 days Gray thick-walled vesicles 3-6 mm in diameter with a red or noninflamed base, commonly on palms, soles and sides of feet, and mouth mucosa

for 4-5 days Occasional ulcerative lesion in mouth None or fever, diarrhea, sore throat

spots: clusters of white lesions on the lower buccal mucosa.

Vaccination for rubella is usually combined with vaccines for mumps and measles (rubeola) (MMR). Measles is known to occur in previously immunized children. The Centers for Disease Control and Prevention vaccine recommendations are available at https://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html. Rubella has almost been eliminated in the United States because of vaccination campaigns. However, challenges to maintain elimination include large outbreaks of measles in highly traveled developed countries, frequent international travel, and clusters of U.S. residents who remain unvaccinated because of personal belief exemptions. Although MMR vaccine may rarely be associated with adverse neurologic events, studies conclude that MMR immunization does not cause autism. Lack of vaccination, however, leads to loss of herd immunity and significant morbidity and mortality with pneumonia, croup, and encephalitis being causes of death worldwide. Women of childbearing age are immunized if their rubella hemagglutination-inhibition titer is low. Pregnancy should be avoided for 3 months after vaccination because the attenuated virus in the vaccine may remain viable for this period. Pregnant women who have rubella early in the first trimester may have a fetus who develops congenital defects. There is no specific treatment for rubella. Recovery is spontaneous, although lymph nodes may remain enlarged for weeks. Supportive therapy includes rest, fluids, and use of a vaporizer. In rare cases, a mild encephalitis or peripheral neuritis may follow rubella.18

Rubeola (Red Measles) Rubeola is a highly contagious, acute viral disease of childhood. Transmitted by direct contact with droplets from infected persons, rubeola is caused by an RNA-containing paramyxovirus with an incubation period of 7 to 12 days, during which there are no symptoms. The virus enters the respiratory tract and attaches to alveolar macrophages, amplifies in local lymphatic tissue, and progresses to systemic disease. Prodromal symptoms include high fever (up to 40.5° C [104.9° F]), malaise, enlarged lymph nodes, rhinorrhea, conjunctivitis, and barking cough. Within 3 to 4 days, an erythematous maculopapular rash develops over the head and spreads distally over the trunk, extremities, hands, and feet. Early lesions blanch with pressure, followed by a brownish hue that does not blanch as the rash fades. Characteristic pinpoint white spots surrounded by an erythematous ring develop over the buccal mucosa and are known as Koplik spots. These spots precede the rash by 1 to 2 days. The rash then subsides within 3 to 5 days. Complications associated with measles may be caused by the primary infection or by a secondary bacterial infection. Measles encephalitis occurs rarely, and most children recover completely; only a small minority of children develop permanent brain damage or die. Bacterial complications include otitis media and pneumonia, usually caused by group A

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hemolytic Streptococcus, Haemophilus influenzae, or S. aureus infection. Measles is prevented by vaccination. As discussed in the Rubella section, immunization is key to prevention. There is no specific treatment for measles, and supportive therapy is the same as that recommended for rubella. Antibiotic therapy is initiated if secondary bacterial infections develop.

Roseola (Exanthema Subitum) Roseola is a human herpesviruses 6 or 7 infection of children between 6 months and 2 years of age and can be seen in children up to 4 years of age. The incubation period is 5 to 15 days, followed by the sudden onset of fever (38.9° to 40.5° C [102° to 104.9° F]) that lasts 3 to 5 days. After the fever, an erythematous macular rash that lasts about 24 hours develops primarily over the trunk and neck. Children usually feel well, eat normally, and have few other symptoms. There is usually no treatment.

Small Pox Smallpox (variola) was a highly contagious and deadly, but also preventable, disease caused by poxvirus variolae. Smallpox was eradicated worldwide in 1977. Routine vaccination in the United States was discontinued in 1972, and a new vaccine, ACAM2000, has been produced for the U.S. Strategic National Stockpile. Information is available from the U.S. Food and Drug Administration at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/QuestionsaboutVaccines/ucm078041.htm (last updated: 03/23/2018).

Chickenpox Chickenpox (varicella) is a disease of early childhood, with 90% of unvaccinated children contracting the disease during the first decade of life. Being a highly contagious virus, chickenpox is spread by close person-to-person contact and by airborne droplets. Introduction of an infected person into a household results in a 90% possibility of susceptible persons developing the disease within the incubation period, usually 14 days. Vesicular lesions occur in the epidermis as infection occurs within keratinocytes. An inflammatory infiltrate is often present. Vesicles eventually rupture, followed by crust formation or the development of transient ulcers on mucous membranes. Children are contagious for at least 1 day before development of the lesions. Transmission of the virus may occur until approximately 5 to 6 days after the onset of the first skin lesions in healthy children. In immunocompromised children, the virus is recoverable for a longer period, but infected children must be considered contagious for at least 7 to 10 days. Normally, children who develop chickenpox have no prodromal symptoms. The first sign of illness may be pruritus or the appearance of vesicles, usually on the trunk, scalp, or face. The rash later spreads to the extremities. Characteristically, lesions can be seen in various stages of maturation with macules, papules, and vesicles present in a particular area at the same time (Fig. 44.9). The vesicular lesions are superficial and rupture easily. New lesions will erupt for 4 to 5 days, until there are approximately 100 to 300 in different stages of development. The vesicles become crusted, and over time only the crust remains, although there may be an occasional vesicle on the palm later in the disease. Although uncommon, ulcerative lesions are sometimes seen in the mouth and, less commonly, on the

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conjunctiva and pharynx. Fever usually lasts 2 to 3 days, with body temperature ranging from 38.5° to 40° C (101.3° to 104° F).

FIGURE 44.9 Chickenpox. A, Pattern of generalized, polymorphous eruption. B, Chickenpox lesions. (From Centers for Disease Control and Prevention: Image Bank, Figure #6121. Available from , accessed October 11, 2018.)

Complications are rare in children but more common in adults. They can include transient hematuria (from rupture of vesicles in the bladder), epistaxis, laryngeal edema, and varicella pneumonia. One case of chickenpox produces almost complete immunity against a second attack. Rarely, the fetus may be malformed (congenital varicella syndrome) if chickenpox develops in the first half of pregnancy. Infants whose mothers have chickenpox at any stage of pregnancy have a higher risk of developing herpes zoster during the first few years of life.19 Varicella-zoster immunoglobulin should be administered to neonates whenever the onset of maternal disease is between 5 days before and 2 days after delivery. Uncomplicated chickenpox requires no specific therapy. Baths, wet dressings, and oral antihistamines occasionally help relieve pruritus and prevent secondary infection from developing as a result of scratching. Oral antibiotics should be given if secondary bacterial infection is present. Zoster immune globulin may be administered to immunodeficient individuals if given within 72 hours after exposure to chickenpox. Oral acyclovir may be valuable in immunosuppressed or other select groups of children. The varicella vaccine protects against varicella.20 Herpes zoster is a vesicular eruption from a recurrence of the

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latent varicella virus, along the distribution of a dorsal root ganglion (see Chapter 43).

Hand, Foot, and Mouth Disease Hand, foot, and mouth disease (HFMD) is a contagious viral disease primarily of infants and young children. It is commonly caused by coxsackievirus and enterovirus. The infection manifests as fever; vesicular ulcerous lesions in the mouth; and vesicular rashes on the hands, feet, and buttocks. A small number of children may experience severe complications, such as meningitis, encephalitis, acute flaccid paralysis, and neurorespiratory syndrome. The disease is self-limiting with supportive care. Research is in progress to develop a preventive vaccine.21

Erythema Infectiosum (Fifth Disease) Erythema infectiosum (fifth disease) is cause by infection with B19 parvovirus. The infection is characterized by a mild fever, headache, sore throat, pruritus, and arthralgia followed by a blotchy, maculopopular, lacy rash on the cheeks (slapped-cheek), which spreads to the trunk and limbs and may last for up to 6 weeks. Symptoms are usually selflimiting. Diagnosis is related to symptoms and can include immunologic assays or a polymerase chain reaction test to identify the virus.22 Treatment is symptomatic and includes nonsteroidal antiinflammatory drugs for arthralgias and antihistamines for pruritus. Infection in women less than 20 weeks pregnant can lead to miscarriage and requires special care.

Quick Check 44.2 1. Compare the cause and presentation of impetigo and staphylococcal scalded-skin syndrome. 2. Describe rubella and rubeola. 3. How are chickenpox and herpes zoster related?

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Insect Bites and Parasites Insect bites and infestations are common causes of skin disorders in children and adults. Skin damage occurs by various mechanisms, including trauma of bites and stings, allergic reactions, transmission of disease, injection of substances that cause local or systemic reactions, and inflammatory reactions resulting from embedded and retained insect mouth parts and scratching of the skin.

Scabies Scabies is a contagious disease caused by the itch mite Sarcoptes scabiei (Fig. 44.10, A), which can colonize the human epidermis. It is transmitted by close personal contact and by infected clothing and bedding. Scabies is often epidemic in areas of overcrowded housing, with poor sanitation, and in children. Immunocompromised individuals are at greater risk. Scabies can facilitate S. pyogenes and S. aureus skin coinfections with systemic complications. The scabies mite has adapted mechanisms to overcome host defenses. Infestation is initiated by a female mite that tunnels into the skin, depositing eggs, and creating a burrow several millimeters to 1 cm long. Over a 3-week period, the eggs mature into adult mites, which sometimes are recognized as tiny dots at the ends of intact burrows.

FIGURE 44.10

Scabies. A, Scabies mite, as seen clinically when removed from its burrow. B,

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Characteristic scabies bites. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Symptoms appear 3 to 5 weeks after infestation. The primary lesions are burrows, papules, and vesicular lesions, with intense pruritus that worsens at night. Pruritus is thought to be related to immune and inflammatory responses. In older children and adults, the lesions occur in the webs of fingers; in the axillae; in the creases of the arms and wrists; along the belt line; and around the nipples, genitalia, and lower buttocks. Infants and young children have a different pattern of distribution, with involvement of the palms, soles, head, neck, and face (see Fig. 44.10, B). Secondary infections and crusting develop as a result of scratching and eczematous changes. Diagnosis of scabies is made by observation of the tunnels and burrows and by microscopic examination of scrapings of the skin to identify the mite or its eggs or feces. Treatment involves the application of a scabicide, which is curative. All clothing and linens should be washed and dried in hot cycles or dry-cleaned. Development of a protective vaccine is in progress.23

Pediculosis (Lice Infestation) The three known types of human lice are (1) the head louse (Pediculus capitis), (2) the body louse (Pediculus corporis), and (3) the crab or pubic louse (Phthirus pubis). They are parasites and survive by sucking blood. The female louse reproduces every 2 weeks, producing hundreds of nits as newly hatched lice mate with older lice. The mouthparts are shaped for piercing and sucking and are attached to the skin of the host while the louse is feeding. When piercing the skin, the louse secretes toxic saliva, and the mechanical trauma and toxin produce a pruritic dermatitis. Head and body lice are acquired directly by personal contact or indirectly by sharing of combs, brushes, or towels or contact with infested clothes, toys, furniture, carpets, or bedding. Crab lice are spread by close body contact, usually with an infected adult. Other common sources of transmission include sharing clothing or headphones. Pruritus is the major symptom of lice infestation. With head lice, the ova attach to hairs above the ears and in the occipital region. The primary lesion caused by the body louse is a pinpoint red macule, papule, or wheal with a hemorrhagic puncture site. The primary lesion often is not seen, because it is masked by excoriations, wheals, and crusts. The crab louse is found on pubic hairs but also may be found in other body hair, such as eyelashes, mustache, beard, and underarm hair. Young children in particular may become infected with crab lice on their eyebrows or eyelashes. The live louse, 2 to 3 mm long, is rarely observed. The ova, or nits, can be observed as oval, yellowish, pinpoint specks fastened to a hair shaft. The ova fluoresce under an ultraviolet light (Wood's lamp) and are observed best with a microscope. Nits are removed with a nit comb, and pediculicides, such as lindane shampoo or lotion, are the most effective treatment. Success or failure of therapy for ectoparasitic infestation depends on education related to the use of the topical preparation than on the type of scabicide or pediculicide used.24 All clothes, towels, bedding, combs, and brushes should be washed and dried in hot air or instead washed in boiling water, or clothes can be ironed to rid them of lice. Individuals who have close personal contact with the infected person also should be treated.

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Fleas Young children are very susceptible to fleabites. Bites occur in clusters along the arms and legs or where clothing is tight fitting, such as near elastic bands that circle the thigh or waist. The bite produces an urticarial wheal with a central hemorrhagic puncture (Fig. 44.11). Itching can be controlled with antihistamines.25 Treatment includes spraying carpets, crevices, and furniture with malathion or lindane powder. Infected animals should be treated, and clothes and bedding should be washed in hot water.

FIGURE 44.11

Fleabites. Fleabite producing a urticarial wheal with central puncture.

Bedbugs Bedbugs (Cimex lectularius) are blood-sucking parasites that live in the crevices and cracks of floors, walls, and furniture and in bedding or furniture stuffing. They are 3 to 5 mm long and reddish brown. Bedbugs are nocturnal, emerging to feed in darkness by attaching to the skin to suck blood, and are attracted by warmth and carbon dioxide. Feeding occurs for 5 to 15 minutes, and the bedbug then leaves and can survive for a year from one feeding. It will move long distances to search for food and can travel from house to house. Immunologic reactions to bedbug saliva vary, but bites typically yield erythematous and

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pruritic papules. The face and distal extremities, areas uncovered by sleeping clothes or blankets, are preferentially involved. If the host has not been previously sensitized, the only symptom is a red macule that develops into a nodule, lasting up to 14 days. In sensitized children and adults, pruritic wheals, papules, and vesicles may form. Most lesions respond to oral antihistamines or topical corticosteroids, or both. Secondary infections require antibiotic treatment. Bedbugs are eliminated by inspecting and cleaning or disposing of bedding, mattresses, furniture, and other contaminated items and by using applications of approved insecticides, usually by a professional.26

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Cutaneous Hemangiomas and Vascular Malformations Cutaneous vascular anomalies are frequent tumors of early infancy and are categorized as either hemangiomas or vascular malformations.

Cutaneous Hemangiomas Cutaneous hemangiomas are benign tumors that form from the rapid growth of vascular endothelial cells, which results in formation of extra blood vessels. Hemangiomas can be superficial or deep. The etiology may be related to embolization of fetal placental endothelial cells with placental trauma or loss of placental angiogenic inhibitor of placental and maternal origin. Superficial hemangiomas (previously known as infantile hemangiomas) are associated with expression of endothelial glucose transporter 1 (GLUT1), an erythrocyte-type glucose transporter protein. Infiltration of fat cells, fibrosis, and the rich vascular network give the lesions a firm, rubbery feel. Female children are affected more often than male children. Some superficial hemangiomas are apparent at birth, but usually emerge 3 to 5 weeks after birth. They grow rapidly during the first few years of life and become bright red and elevated with minute capillary projections that give them a strawberry appearance. Only one lesion is usually present and is located on the head and neck area or trunk (Fig. 44.12). After the initial growth, the lesion grows at the same rate as the child and then starts to involute at 12 to 16 months of age. Most superficial hemangiomas involute by 5 to 9 years of age, usually without scarring and require no treatment. Hemangiomas located over the eye, ear, nose, mouth, urethra, or anus may require treatment because they interfere with function and have a higher risk for infection or injury.27

FIGURE 44.12

Superficial (Capillary) Hemangioma. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Deep hemangiomas (previously known as cavernous hemangiomas) are a rare variant of

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superficial hemangiomas and located deeper in the dermis or subcutaneous tissue (Fig. 44.13). They are present and fully grown at birth and are usually solitary lesions on the head or limbs that appear as a spongy purplish mass of tissue. They have larger and more mature vessels within the lesion. There are two groups of deep hemangiomas: rapidly involuting and noninvoluting. Rapidly involuting deep hemangiomas disappear by 12 months to 14 months of age, leaving an area of thin skin. Noninvoluting cavernous hemangiomas do not undergo involution.

FIGURE 44.13

Deep Hemangioma. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Rapidly progressing hemangiomas are treated with a beta blocker (e.g., propranolol), with regression occurring within 2 weeks, and should be considered a first-line agent. Other therapies include systemic or intralesional steroids and ablative procedures. Interferons, vincristine, cyclophosphamide, and radiotherapy can suppress angiogenesis.

Cutaneous Vascular Malformations Cutaneous vascular malformations are rare congenital malformations present at birth but may not be apparent for several years.28 They grow proportionately with the child and never regress. Occasionally they expand rapidly, particularly during the hormonal changes of puberty or pregnancy and in association with trauma. Vascular malformations are classified as low flow or high flow. Low-flow malformations involve capillaries, veins, and lymphatics. High-flow malformations involve arteries. The most common capillary malformations are nevus flammeus (port-wine stains) and salmon patches (stork bite, angel kiss). Port-wine (nevus flammeus) stains are congenital malformations of the dermal capillaries. The lesions are flat, and their color ranges from pink to dark reddish purple. They are present at birth or within a few days after birth and do not fade with age.

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Involvement of the face and other body surfaces is common, and the lesions may be large (Fig. 44.14). Overgrowth of underlying structures (i.e., legs, arms, facial bones) also can occur. The pulsed dye laser is the treatment of choice to successfully lighten the color and flatten the more nodular and cavernous lesions. Waterproof cosmetics may be used to cover the lesions.

FIGURE 44.14 Port-Wine Hemangioma. Port-wine hemangioma in a child. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Salmon patches (nevus simplex) are macular pink lesions present at birth and located on the nape of the neck, forehead, upper eyelids, or nasolabial fold region. They are a variant of port-wine stains, more superficial, and one of the most common congenital malformations in the skin. The pink color results from distended dermal capillaries, and most of the patches fade by 1 year of age. Those located at the nape of the neck may persist for a lifetime. They generally do not present a cosmetic problem.

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Other Skin Disorders Miliaria Miliaria is a dermatosis commonly seen in infants that is characterized by a vesicular eruption after prolonged exposure to perspiration with subsequent obstruction of the eccrine ducts. There are two forms of miliaria: miliaria crystallina and miliaria rubra. In miliaria crystallina, ductal rupture occurs within the stratum corneum and appears as 1- to 2-mm clear vesicles without erythema. They rupture within 24 to 48 hours and leave a white scale. In miliaria rubra (prickly heat), the ductal rupture occurs in the lower epidermis with inflammatory cells attracted to the site of the rupture. Miliaria rubra is characterized by 2- to 4-mm discrete erythematous papules or papulovesicles (Fig. 44.15). Both forms may become secondarily infected, requiring systemic antibiotics. The key to management is avoidance of excessive heat and humidity, which cause sweating. Light clothing, cool baths, and air conditioning assist in keeping the skin surface dry and cool.

FIGURE 44.15 Miliaria Rubra. Note discrete erythematous papules or papulovesicles. (Courtesy Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah.)

Erythema Toxicum Neonatorum Erythema toxicum neonatorum (toxic erythema of the newborn) is a benign, erythematous accumulation of macules, papules, or pustules that appears at birth or 3 to 4 days after birth. The lesions first appear as a blotchy, macular erythematous rash. The macules vary from 1 mm to 1 cm in diameter. When papules or pustules develop, they are light yellow or white and 1 to 3 mm in diameter. There may be a few or several hundred lesions, and any body surface can be affected, with the exception of the palms and soles, where there are no pilosebaceous follicles. The cause of the lesion is unknown but may be related to an innate immune response to the first commensal microflora with release of inflammatory mediators. It is self-limiting and resolves spontaneously within a few weeks after birth. No treatment is required.

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Quick Check 44.3 1. Give two examples of insect bites or parasites that affect children. What features are observed in each? 2. Compare a superficial hemangioma with a vascular malformation.

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Summary Review Acne Vulgaris 1. Acne vulgaris is a common disorder related to obstruction of pilosebaceous follicles and proliferation of Cutibacterium acnes, with follicular occlusion and inflammation primarily of the face, neck, and upper trunk. It is characterized by both noninflammatory and inflammatory lesions. Treatment is dependent on severity.

Dermatitis 1. Atopic dermatitis is an alteration in the skin barrier. It occurs as red, scaly lesions on the face, cheeks, and flexor surfaces of the extremities in infants and young children. Atopic dermatitis is associated with inflammatory cytokines. Individuals may develop asthma and allergies later in life. 2. Diaper dermatitis, or diaper rash, is a type of irritant contact dermatitis that develops from prolonged exposure to urine and feces and often becomes secondarily infected with Candida albicans.

Infections of the Skin 1. Impetigo is a contagious bacterial disease occurring in two forms: bullous and vesicular. The toxins from the bacteria produce a weeping lesion with a honeycolored crust. 2. Staphylococcal scalded-skin syndrome (Ritter disease) is a staphylococcal skin infection that produces an exfoliative toxin with painful blisters and bullae formation over large areas of the skin, requiring emergency care and systemic antibiotic treatment. 3. Tinea capitis (scalp ringworm) and tinea corporis (ringworm) are fungal infections of the scalp and body caused by dermatophytes. 4. Thrush is a fungal infection of the mouth caused by Candida albicans. 5. Molluscum contagiosum is a poxvirus infection of the skin that produces pale papular lesions filled with viral and cellular debris. 6. Rubella (German or 3-day measles) is a communicable viral disease characterized by fever, sore throat, enlarged cervical and postauricular lymph nodes, and a generalized maculopapular rash that lasts 1 to 4 days. 7. Rubeola (red measles) is a viral contagious disease with symptoms of high fever, enlarged lymph nodes, conjunctivitis, and a red rash that begins on the head, spreads to the trunk and extremities, and lasts 3 to 5 days. Both bacterial and viral complications may accompany rubeola. 8. Roseola (exanthema subitum) is a benign disease of infants with a sudden onset of fever that lasts 3 to 5 days, followed by a rash that lasts 24 hours. 9. Smallpox (variola) was a highly contagious, deadly viral disease that has been eradicated worldwide by vaccination.

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10. Chickenpox (varicella) is a highly contagious disease caused by the varicella-zoster virus. Vesicular lesions occur on the skin and mucous membranes. Individuals are contagious from 1 day before the development of the rash until about 5 to 6 days after the rash develops. 11. Hand, foot, and mouth disease is a contagious viral disease commonly caused by coxsackievirus and enterovirus that manifests with fever, vesicular ulcerous lesions in the mouth, and vesicular rashes on the hands, feet, and buttocks. 12. Erythema infectiousum (fifth disease) is an infection caused by B19 parvovirus that usually causes mild symptoms of fever, headache, pruritus, and arthralgias followed by a rash on the cheeks spreading to the trunk and limbs.

Insect Bites and Parasites 1. Scabies is a pruritic lesion caused by the itch mite, which burrows into the skin and forms papules and vesicles. The mite is very contagious and is transmitted by direct contact. 2. Pediculosis (lice infestation) is caused by blood-sucking parasites that secrete toxic saliva and damage the skin to produce pruritic dermatitis. Lice are spread by direct contact and are recognized by the ova or nits that attach to the shafts of body hairs. 3. Fleabites produce a pruritic wheal with a central puncture site and occur as clusters in areas of tight-fitting clothing. 4. Bedbugs are blood-sucking parasites that live in cracks of floors, furniture, or bedding and feed at night. They produce pruritic wheals and nodules.

Cutaneous Hemangiomas and Vascular Malformations 1. Cutaneous hemangiomas are benign tumors that form from the rapid growth of vascular endothelial cells and result in formation of extra blood vessels that can be superficial or deep. 2. Superficial hemangiomas involve infiltration of fat cells, fibrosis, and the rich vascular network, giving the lesions a firm, rubbery feel. Most superficial hemangiomas involute by 5 to 9 years of age. 3. Deep hemangiomas are present at birth, with larger vessels than a superficial hemangioma, and are purplish. Rapidly involuting deep hemangiomas disappear by 12 to 14 months of age, leaving an area of thin skin. 4. Cutaneous vascular malformations are rare congenital anomalies of blood vessels present at birth. 5. Port-wine stains are congenital malformations of dermal capillaries that do not fade with age. 6. Salmon patches are macular pink lesions with dilated capillaries that usually resolve by 1 year of age. They are a variant of port-wine stains.

Other Skin Disorders 1. Miliaria is characterized by a vesicular eruption that results from obstruction of the

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sweat duct opening in infants. In miliaria crystallina, ductal rupture occurs within the stratum corneum and appears as 1- to 2-mm clear vesicles without erythema. In miliaria rubra (prickly heat), the ductal rupture occurs in the lower epidermis, attracts inflammatory cells, and appears as 2- to 4-mm discrete erythematous papules or papulovesicles 2. Erythema toxicum neonatorum is a benign accumulation of macules, papules, and pustules that spontaneously resolves within a few weeks after birth.

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Key Terms Acne conglobata, 1045 Acne vulgaris, 1044 Atopic dermatitis (AD), 1045 Bedbug, 1051 Chickenpox (varicella), 1049 Cutaneous hemangioma, 1052 Cutaneous vascular malformation, 1053 Deep hemangioma, 1052 Diaper dermatitis (diaper rash), 1045 Erythema infectiosum (fifth disease), 1050 Erythema toxicum neonatorum, 1053 Fleabite, 1051 Hand, foot, and mouth disease (HFMD), 1050 Herpes zoster, 1050 Impetigo, 1046 Inflammatory (cystic) acne, 1044 Miliaria, 1053 Miliaria crystallina, 1053 Miliaria rubra (prickly heat), 1053 Molluscum contagiosum, 1048 Molluscum contagiosum virus (MCS), 1048 Noninflammatory acne, 1044 Roseola, 1049 Rubella, 1048 Rubeola, 1049 Scabies, 1051 Smallpox (variola), 1049 Staphylococcal scalded-skin syndrome (SSSS; Ritter disease), 1046 Superficial hemangioma, 1052 Thrush, 1047 Tinea capitis, 1047 Tinea corporis (ringworm), 1047

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References 1. Bhat YJ, Latief I, Hassan I. Update on etiopathogenesis and treatment of acne. Indian J Dermatol Venereol Leprol. 2017;83(3):298–306. 2. Melnik BC. Acne vulgaris: the metabolic syndrome of the pilosebaceous follicle. Clin Dermatol. 2018;36(1):29–40. 3. Dréno B. What is new in the pathophysiology of acne, an overview. J Eur Acad Dermatol Venereol. 2017;31(Suppl 5):8–12. 4. Wang Y, et al. The anti-inflammatory activities of Propionibacterium acnes CAMP factor-targeted acne vaccines. J Invest Dermatol. 2018;138(11):2355–2364. 5. Malik K, Heitmiller KD, Czarnowicki T. An update on the pathophysiology of atopic dermatitis. Dermatol Clin. 2017;35(3):317–326. 6. Deleanu D, Nedelea I. Biological therapies for atopic dermatitis: an update. Exp Ther Med. 2019;17(2):1061–1067. 7. Fleischer DM, et al. Atopic dermatitis: skin care and topical therapies. Semin Cutan Med Surg. 2017;36(3):104–110. 8. Nicol NH, Boguniewicz M. Wet wrap therapy in moderate to severe atopic dermatitis. Immunol Allergy Clin North Am. 2017;37(1):123–139. 9. Gustin J, et al. The impact of diaper design on mitigating known causes of diaper dermatitis. Pediatr Dermatol. 2018;35(6):792–795. 10. Fölster-Holst R. Differential diagnoses of diaper dermatitis. Pediatr Dermatol. 2018;35(Suppl 1):s10–s18. 11. Nardi NM, Schaefer TJ. Impetigo, StatPearls [Internet]. StatPearls Publishing: Treasure Island FL; 2017 [Available at] http://www.ncbi.nlm.nih.gov/books/NBK430974/. 12. Ross A, Shoff HW. Staphylococcal scalded skin syndrome, StatPearls [Internet]. StatPearls Publishing: Treasure Island FL; 2019 [Available at] http://www.ncbi.nlm.nih.gov/books/NBK448135/ [last updated June 10, 2019]. 2543

13. Leung AKC, Barankin B, Leong KF. Staphylococcal-scalded skin syndrome: evaluation, diagnosis, and management. World J Pediatr. 2018;14(2):116–120. 14. Gupta AK, et al. Tinea capitis in children: a systematic review of management. J Eur Acad Dermatol Venereol. 2018;32:2264– 2274. 15. Olsen JR, et al. Epidemiology of molluscum contagiosum in children: a systematic review. Fam Pract. 2014;31(2):130–136. 16. Zorec TM, et al. New insights into the evolutionary and genomic landscape of molluscum contagiosum virus (MCV) based on nine MCV1 and six MCV2 complete genome sequences. Viruses. 2018;10(11). 17. Forbat E, Al-Niaimi F, Ali FR. Molluscum contagiosum: review and update on management. Pediatr Dermatol. 2017;34(5):504–515. 18. Spencer JP, Trondsen Pawlowski RH, Thomas S. Vaccine adverse events: separating myth from reality. Am Fam Physician. 2017;95(12):786–794. 19. Smith CK, Arvin AM. Varicella in the fetus and newborn. Semin Fetal Neonatal Med. 2009;14(4):209–217. 20. Lo Presti C, et al. Chickenpox: an update. Med Mal Infect. 2019;49(1):1–8. 21. Esposito S, Principi N. Hand, foot and mouth disease: current knowledge on clinical manifestations, epidemiology, aetiology and prevention. Eur J Clin Microbiol Infect Dis. 2018;37(3):391–398. 22. Allmon A, Deane K, Martin KL. Common skin rashes in children. Am Fam Physician. 2015;92(3):211–216. 23. Arlian LG, Morgan MS. A review of Sarcoptes scabiei: past, present and future. Parasit Vectors. 2017;10(1):297. 24. Bragg BN, Simon LV. Pediculosis humanis (lice, capitis, pubis), StatPearls [Internet]. StatPearls Publishing: Treasure Island FL; 2018 [Available at] http://www.ncbi.nlm.nih.gov/books/NBK470343/. 25. Juckett G. Arthropod bites. Am Fam Physician. 2013;88(12):841– 847. 2544

26. Ibrahim O, Syed UM, Tomecki KJ. Bedbugs: helping your patient through an infestation. Cleve Clin J Med. 2017;84(3):207–211. 27. Smith CJF, et al. Infantile hemangiomas: an updated review on risk factors, pathogenesis, and treatment. Birth Defects Res. 2017;109(11):809–815. 28. Slaughter KA, Chen T, Williams E 3rd. Vascular lesions. Facial Plast Surg Clin North Am. 2016;24(4):559–571.

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Index Page numbers followed by “f” indicate figures, “t” indicate tables, and “b” indicate boxes. A A band, 572–573, 573f, 947 A disintegrin and metalloproteinase (ADAM), 936t A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), 936t Abbreviations, pulmonary, 665t ABCDE rule, 1034 Abdominal distention caused by hepatomegaly, 928 in meconium syndromes, 919

Abdominal pain, 881, 906 Abducens nerve, 319t Aberrant conduction, 626t–627t A-beta (Aβ) fibers, 330 Abnormal uterine bleeding, 784–785, 785f, 785t, 787b ABO blood group, 184 ABO blood types, 184–185, 184f ABO incompatibility, 550 Abscess, 146 brain, 403 Brodie, 972 cavitation of, 688 definition of, 688 peritonsillar, 699 respiratory tract, 688 spinal cord, 403 tonsillar, 699

Absolute polycythemia, 514

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Absolute refractory period, 26 Absorption, impairment of, 922–927 Absorption atelectasis, 677 Abuse, childhood, 1010 Acanthamoeba keratitis, 342 Acanthosis nigricans, 248t Accelerated junctional rhythm, 625t–626t Accelerated ventricular rhythm, 625t–626t Acceleration/deceleration axonal shearing, 386f Accessory muscles, 662 Accessory organs of digestion anatomy of, 869–875, 870f cancer of, 910–911 disorders of, 896–906

Accidental hyperthermia, 335 Accidental hypothermia, 336b Accommodation, 338, 340 ACD, Anemia of chronic disease Acetabular dysplasia, 999–1000 Acetylcholine, 304t, 322, 862t, 875 Acetylcholine receptor (AChR), 405 Achalasia, 883 Achilles tenotomy, 999 AChR, Acetylcholine receptor Acid carbonic, 123–124 potential, 127–128 renal excretion of, 127f strong, 123–124 volatile, 123–124 weak, 123–124

Acid-base balance, 123–130 buffer systems in, 125–127, 125t hydrogen ion in, 123–125 pH in, 123–125

Acid-base imbalances, 127–130, 127f, 130b

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changes, primary and compensatory, 128f metabolic acidosis, 129, 129t metabolic alkalosis, 129 respiratory acidosis, 129–130 respiratory alkalosis, 130

Acid maltase deficiency, 987–988 Acidemia, 127, 659 Acidosis, 127 metabolic, 129, 129t oxyhemoglobin curve affected by, 667 respiratory, 129–130

Acini (acinus), 656, 770 Acne conglobata, 1045 Acne rosacea, 1025, 1025f Acne vulgaris, 1025, 1044–1045, 1045f, 1046b Acoustic nerve, 319t Acquired hypercoagulability, 543–544 Acquired immunodeficiency syndrome (AIDS), 189–190 in children, 295 clinical manifestations of, 190–193 clinical symptoms of, 193f defining opportunistic infections, 190b neurologic complications of, 403 pathogenesis of, 189–190 pediatric, central nervous system involvement and, 193–194, 194b treatment and prevention of, 191–193, 192b typical progression from, 192f

Acral lentiginous melanoma (ALM), 1033–1034 Acrocephaly, 419f Acromegaly, 451, 451f ACSs, Acute confusional states ACT, Adoptive cell therapy ACTH, Adrenocorticotropic hormone Actin, 572, 573f Actinic keratosis, 1031, 1032b Actinin, 948t

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Action potentials, 26 cardiac, 568 propagation of, 570

Active immunity, 157 Active immunization, 207–208 Active transport, 19, 19f, 22f Activin, 761t, 770, 936t Acute alcohol intoxication, 89 Acute alcoholic myopathy, 989 Acute alcoholism, 87 Acute aortic syndromes, 597 Acute bacterial conjunctivitis, 342, 342f Acute bacterial meningitis, 422 Acute bacterial prostatitis, 840, 840b Acute bronchitis, 686 Acute colonic pseudo-obstruction, 886 Acute confusional states (ACSs), 360, 360b Acute coronary syndromes description of, 602 pathophysiology of, 606–611, 606f unstable angina, 606–607, 607b, 608f unstable atherosclerotic plaque, 606, 607f

Acute cough, 671 Acute epiglottitis, 698t, 699 Acute gastritis, 887–888 Acute gouty arthritis, 982, 983f Acute hematogenous osteomyelitis, 1002–1003 Acute hydrocephalus, 370 Acute idiopathic TTP, 537 Acute infectious diarrhea, in children, 927 Acute inflammation, 146–147 Acute inflammatory response, 136f, 243 Acute kidney injury classification of, 742t clinical manifestations of, 743–744

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definition of, 742 evaluation of, 744 intrarenal, 742t, 743, 744t mechanisms of, 743f oliguria, 743, 743f pathophysiology of, 742–743 postrenal, 743 prerenal, 742–743, 742t, 744t progression of, to chronic kidney disease, 744 RIFLE criteria for, 742, 742t treatment of, 744

Acute liver failure, 901 Acute lymphocytic leukemia in children, 558 description of, 294, 521, 521t, 522f, 523

Acute mesenteric arterial insufficiency, 896 Acute monoblastic leukemia, 559f Acute myelogenous leukemia in children, 558 description of, 521, 521t, 522f, 523

Acute myeloid leukemia, in children, 558 Acute nonlymphocytic leukemia (ANL), 523 Acute orthostatic hypotension, 596 Acute otitis media (AOM), 344 Acute pain, 330 Acute pancreatitis, 905–906, 906f Acute-phase reactants, 147 Acute poststreptococcal glomerulonephritis, 754 Acute pyelonephritis, 735–737, 756 Acute rejection, 186 Acute respiratory distress syndrome, 679–680, 680f Acute rheumatic fever, 616–618, 617f Acute tubular necrosis, 743 Acyanotic heart defects, 639 Acyclovir, 1050 ADAM, Adisintegrin and metalloproteinase

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ADAMTs, Adisintegrin and metalloproteinase with thrombospondin motifs ADAMTS13, 537 Adaptation, 73 cellular, Cellular adaptation potassium, 121

Adaptation stage diseases of, 210 of general, adaptation syndrome, 210 of stress, 210

Adaptive immunity, 133, 156–173 inflammation and, 156 overview, 156–157

ADCC, Antibody-dependent cellular cytotoxicity Addison disease, 467f, 469 A-delta (Aδ) fibers, 328, 333 Adenine, 40 Adenocarcinomas, 228 colorectal, 908 ductal, 911 gastric, 908 lung, 691–693, 692f, 692t prostate, 845

Adenomas growth hormone-secreting, 451 pituitary, 450

Adenomyosis, 796 Adenosarcoma, 794–795 Adenosine deaminase (ADA deficiency), 187 Adenosine diphosphate, 496–497 Adenosine monophosphate deaminase deficiency, 988 Adenosine triphosphate cardiomyocyte use of, 572 description of, 494 skeletal muscle use of, 950

ADH, Antidiuretic hormone ADHD, Attention-deficit/hyperactivity disorder Adipocytes, 4, 474

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cancer associated, 272

Adipokines, 460, 475 coronary artery disease risks, 603 obesity effects on, 477–478, 594 secreted by adipose tissue, 475b

Adiponectin, 460, 478, 818–819 Adipose tissue, 33t–35t, 474–476, 901 as endocrine organ, 475

Adjuvant chemotherapy, 253 ADM, Adrenomedullin Adolescence, 761 Adolescents, cancer in, 291–297 Adoptive cell therapy (ACT), 253 Adrenal cortex disorders of, 467–470 Addison disease, 469 Cushing syndrome, 467–468, 467f–468f hyperaldosteronism, 468–469

hormones produced by, 441–442, 442f hypercortical function of, 467–468 hypofunction of, 467, 469–470

Adrenal glands aging effects on, 444b aldosterone secretion by, 442 anatomy of, 441–444, 442f androgens secreted by, 469 estrogens and androgens secreted by, 442 estrogens secreted by, 469 glucocorticoids produced by, 442f mineralocorticoids produced by, 442

Adrenal medulla hormones produced by, 442–444, 444f, 444b tumors of, 470, 470b

Adrenarche, 762 Adrenergic receptors α, 216, 322, 322t–323t β, 216, 322, 322t–323t

Adrenergic transmission, 322

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Adrenocorticotropic hormone (ACTH) Cushing syndrome caused by excessive secretion of, 467 deficiency of, 449–450 description of, 213–214 functions of, 434, 437t secretion of, 442

Adrenomedullin (ADM), 584 Aerobic glycolysis, 240 Affective-motivational system, 328–329 Afferent arteriole, 716 Afferent loop obstruction, 891 Afferent lymphatic vessels, 587 Afferent neuron, 309–310 Afferent pathways, 298, 327 Aflatoxins, 910 Afterload, 575–576, 620, 622f Agammaglobulinemia, 187 Age-related macular degeneration (AMD), 340 Ageusia, 345 Agglutination, 166–167 Aging aortic valve degeneration caused by, 615 benign prostatic hyperplasia caused by, 839 of bone, 952 breast changes secondary to, 813 cellular and tissue biology and, 104–106 chest wall affected by, 668b degenerative extracellular changes with, 105t endocrine glands affected by, 444b exercise affected by, 668b eye changes secondary to, 339t female reproductive system changes secondary to, 776–777, 777b gas exchange affected by, 668b gastrointestinal system affected by, 876b growth hormone affected by, 435b, 444b hearing changes secondary to, 344b insulin-like growth factor in, 435b

2553

of joints, 952 lung immunity, 668b male reproductive system changes secondary to, 777, 777b of muscle, 952 negative effects of stress, 221 nervous system and, 324b olfaction changes secondary to, 345b pituitary gland changes, 435b pulmonary system affected by, 668b renal function affected by, 725b skin changes caused by, 1040b taste changes secondary to, 345b thyroid gland changes, 435b

Agitated delirium, 360 Agnosia, 359 Agonal gasps, 354t Agonal rhythm, 625t–626t Agonist, 951 Agranulocytes, 486–487 AGT, Angiotensinogen AI, Anemia of inflammation AIDS, Acquired immunodeficiency syndrome AIH, Autoimmune hepatitis Air pollution, 83–85 cancer caused by, 274–276 coronary artery disease risks, 603

Air trapping, 685, 685f Airway(s) conducting, 655–656, 657f gas-exchange, 656–657, 656f–658f, 657b

Airway obstruction in children, 697–700, 698f, 700b description of, 681

Airway remodeling, 681 Airway resistance, 664 Akathisia, 373t Akinesia, 374

2554

Alarm reaction, 211, 211f Alarm stage, of general adaptation syndrome, 210, 211f Albinism, 97 Albumin, 934t description of, 484 plasma, 113

Alcohol breast cancer risks and, 818 consumption, cancer and, 272–274, 273t death and, 86 immune defects of, 89 nutrition and, 86–87

Alcohol-related neurodevelopmental disorder, 414b Alcoholic cirrhosis, 901–902 Alcoholic fatty liver, 901 Alcoholic hepatitis, 90f, 901 Alcoholic liver disease, 89, 901–903 Alcoholic steatohepatitis, 901 Aldosterone blood pressure affected by, 583 nephron function affected by, 722 secretion of, 442 sodium concentration and, 115

Algor mortis, 106 Alkalemia, 127 Alkaline phosphatase, 934t Alkaline (bile) reflux gastritis, 891 Alkalosis, 127 metabolic, 129 hypochloremic, 129

respiratory, 130

Alleles, 51 Allergens, 181 desensitization to, 182

Allergic alveolitis, 678 Allergic conjunctivitis, 342

2555

Allergic contact dermatitis, 180, 1022, 1022f development of, 181, 181f, 181b

Allergic disease, 181–182 Allergy, 181–182 definition of, 174 food, 895

Alloantigens (isoantigens), 183–186 Allodynia, 331–332 Alloimmunity, 183–186 description of, 174

Allostasis, 211 Allostatic overload, 211 ALM, Acral lentiginous melanoma Alopecia, 247b, 256, 1039 Alopecia areata, 1039 Alpha cells, 439–440 Alpha globulins, 484–485 Alpha granules, 497 Alpha rigidity, 370, 371t Alpha trait, 555 Alpha1-antitrypsin (α1-antitrypsin), 146 Alpha1 antitrypsin deficiency, 146, 685 Alpha-glycoprotein, 937 Alpha-thalassemia, 555 major, 555 minor, 555

ALS, Amyotrophic lateral sclerosis Alternative pathway, 137 Alveolar dead space, 673–674 Alveolar ducts, 656, 659f Alveolar hypoventilation, 672 Alveolar hypoxia, chronic, 659 Alveolar macrophages, 657, 658f Alveolar minute volume, 672–673

2556

Alveolar pressure, 665, 666f Alveolar rhabdomyosarcoma, 994 Alveolar sac, 659f Alveolar surface tension, 662–663 Alveolar ventilation, 660 Alveoli (alveolus) anatomy of, 656, 659f gas pressure in, 665

Alveolocapillary membrane anatomy of, 658, 659f damage to, 678 diffusion across, 666 edema effects on, 674 oxygen diffusion across, 666

Alzheimer disease, 362–365, 363t–364t, 364f Amalgam, dental, 85–86 Amblyopia, 340t Ambulatory blood pressure monitoring, 652 AMD, Age-related macular degeneration Amelanotic melanoma, 1033–1034 Amenorrhea, 784f American Joint Committee on Cancer (AJCC) staging system, 992 Amino acid metabolism defects, 421 Amino acids, 41 in proteins, 7

Ammonia, 627 Ammonia buffer, 126 Amnesia, 357, 358t Amniotic fluid embolism, 598t Amphiarthrosis, 940 Amphipathic, 4–6 Ampulla of Vater, 874 α−Amylase, 859 Amylin, 440, 457 Amyloidosis, 532

2557

Amyotrophic lateral sclerosis (ALS), 377–378 Anabolism, 17 Anaerobic glycolysis, 18 Anaerobic metabolism, 624 Anal agenesis, 921f Anal cancer, 260t–264t Anal membrane atresia, 921f Anal sphincter, 867 Anaphase, 28 Anaphylactic shock, 629–630, 631f Anaphylatoxins, 137 Anaphylaxis, 629 of hypersensitivity reactions, 174–175

Anaplasia, 227–228 Anaplastic rhabdomyosarcoma, 994 Androgen(s) description of, 762, 775 functions of, 776 in prostate cancer, 842–844, 842f pubertal functions of, 768 synthesis of, 842–844

Androgen insensitivity syndrome, 780, 783 Androgen receptor, signaling by, 846 Androgenic alopecia, 1039 Androgens adrenal cortex secretion of, 442 hypersecretion of, 469

Andropause, 777 Anemia, 247b, 505–514, 891 aplastic, 506t, 514, 514t of blood loss, 507 acute, 507, 507b chronic, 507

cancer and, 248t in children, 548, 549t, 549b of chronic inflammation, 506t classification of, 505–507, 506t, 509t

2558

clinical manifestations of, 505–507, 506f compensatory mechanisms for, 507 Cooley, 555 definition of, 505 of diminished erythropoiesis, 507–514 folate deficiency, 506t, 511 hemolytic in children, 548, 553–554 description of, 506t, 514t

hypochromic-microcytic, 510f hypoplastic, 514 hypoxemia associated with, 507 in leukemia, 525t macrocytic-normochromic, 506t, 510f megaloblastic, 507–511 microcytic-hypochromic, 506t, 511–512 nervous system manifestations of, 507 normocytic-normochromic, 506t, 514t pernicious, 506t, 510f posthemorrhagic, 506t progression of, 506f sickle cell, 506t, 551–552 sideroblastic, 506t

Anemia of chronic disease (ACD), 512–514, 512t, 514b clinical manifestations of, 513 evaluation of, 513–514 pathophysiology of, 513, 513f treatment of, 513–514

Anemia of inflammation (AI), 512 Anencephaly, 416 Aneuploid cell, 44–45 Aneuploidy, 44–47 Aneurysms aortic, 597 berry, 398, 398f cerebral, 597 clinical manifestations of, 597 definition of, 596–597 diagnosis of, 597 false, 596

2559

fusiform, 398, 398f, 596, 597f illustration of, 597f intracranial, 398, 398f saccular, 596, 597f true, 596 types of, 597f

Angelman syndrome, 54, 66–67, 66f Angina pectoris microvascular, 605b Prinzmetal, 605 stable, 604–606 treatment of, 605 unstable, 606–607, 607b, 608f

Angioedema, 1030 Angiogenesis, 149, 239 definition of, 568 endothelium's role in, 581t inducing, 239 tumor-induced, 240f

Angiogenic factors, 239 Angiogenic inhibitors, 239 Angiotensin 1-7, 594b Angiotensin I, 115 Angiotensin II, 115, 593, 745 Angiotensin-converting enzyme, 115 Angiotensinogen (AGT), 478 Angle-closure glaucoma, 339 ANH, Atrial natriuretic hormone Anhidrotic ectodermal dysplasia, 64 Anion gap, 129 Anions, 20 Anisocytosis, 505 Ankylosing spondylitis, 979–981, 981f ANL, Acute nonlymphocytic leukemia Annexins, 936t Anoikis, 245

2560

Anomic aphasia, 361t Anorectal malformations, in children, 920 Anorectal stenosis, 920, 921f Anorexia, 879 Anorexia nervosa, 480 Anorexia of aging, 480–481, 481b Anorexigenic brain pathways, 249 Anorexigenic neurons, 475–476 Anorexins, 475–476 Anorgasmia, 806 Anosmia, 344 Anoxia, 78 ANS, Autonomic nervous system Antagonist, 951 Antalgic (painful) abductor lurch, 1005 Anterior cerebral artery, 315t, 316f Anterior columns, 309 Anterior fontanelle, 415, 415f Anterior fossa, 311 Anterior horn, 308–309 Anterior pituitary anatomy of, 433–436 chromophils, 433 chromophobes, 433 development of, 761 disease of acromegaly, 451, 451f hyperpituitarism, 450, 450b hypopituitarism, 449–450, 450f pituitary adenoma, 450 prolactinoma, 451–452

progesterone secretion by, 768 regions of, 433 tropic hormones, 434, 437t

Anterior spinal artery, 315, 317f Anterior spinothalamic tracts, 311 Anterograde amnesia, 357, 358t

2561

Antibiotic resistance, 206, 207f Antibiotics bactericidal, 206 bacteriostatic, 206

Antibody, 137, 163–168 anti-Rh, 550 classes of, 163–166 clinical use of, 159t colostral, 168 functions of, 166–168, 167f heterophilic, 521 maternal, 550 molecular structure of, 166, 166f monoclonal, 168b, 253 in newborn, 171b plasma cell production of, 485 properties of, 164t

Antibody-dependent cell-mediated cytotoxicity, 178 Antibody-dependent cellular cytotoxicity (ADCC), 170 Antibody-mediated hemorrhagic disease, 557–558 Antibody screen test, 500t–501t Anticipatory responses, 211 Anticipatory stress response, 211 Anticitrullinated protein antibody, 979 Anticoagulants, 500t–501t pulmonary embolism treated with, 689 venous thrombosis treated with, 543

Anticodon, 43 Antidiuretic hormone (ADH), 115, 116f, 436–437, 437b diabetes insipidus and, 449 ectopic production of, 448 homeostatic function of, 436 secretion of, 436 syndrome of inappropriate antidiuretic hormone secretion, 448, 449t synthesis of, 433 in urine regulation, 718f

Antigen-antibody binding, 166, 166f Antigen-binding fragments (Fab), 166

2562

Antigen-binding site, 166 Antigen-presenting cells (APCs), 161 Antigen receptors, cell surface, 156–157 Antigenic determinant, 166 Antigenic drift, 202–203 Antigenic shifts, 202–203, 204f Antigenic variation, 202–203 Antigens, 137, 202–203 clinical use of, 159t definition of, 156–157, 157b endogenous, 161 exogenous, 161 processing and presentation, 161, 162f–163f T-cell-independent, 163, 165f tumor-associated, 243

Antigravity posture, 378 Antihistamines, 142–143 Antiinflammatory cytokines, 142 Antimetabolites, 253 Antimicrobial peptides, 135 Antimicrobials infection treated with, 206–207, 207t mechanism of action, 207t

Antioxidants, 83 Antiphospholipid syndrome, 543–544 Antiport, 20 Antiretroviral therapy (ART), 191–192 Anti-Rh antibodies, 550 Antithrombin III, 498, 540–541 Antitoxins, 167, 199 Anus congenital impairment of, 920 imperforate, 920, 921f

AOM, Acute otitis media Aorta, 565, 566f aneurysms of, 596–597

2563

coarctation of, 643, 643f

Aortic semilunar valve, 566 Aortic valve age-related degeneration of, 615 commissurotomy of, 644 regurgitation, 616 stenosis of, 615, 615f, 643–644, 644f

APCs, Antigen-presenting cells Aplastic anemia, 506t, 514t Aplastic crisis, 554 Apneusis, 354t Apocrine sweat glands, 1014–1015 Apoferritin, 495 Apoptosis, 15, 102–103, 102f cancer cell resistance to, 241 cell injury culminating in, 100f dysregulated, 102–103 extrinsic pathway of, 241 features of, 101t intrinsic pathway of, 241 mechanisms of, 103f

Apotransferrin, 495 Appendicitis, 896, 922, 922b Appendicular skeleton, 938 Appendix epididymis, 836 Appendix testis, 836 Apraxia, 379 Aprosody, 379 Aquagenic pruritus, 515 Aquaporins, 113 Aqueduct of Sylvius, 308, 420 Aqueous humor, 338 Arachnoid layer, 309f, 311–312 Arachnoid villi, 313–314, 313f Arcuate arteries, 716

2564

Areflexia, 377 Areola, 771 Areolar tissue, connective, 33t–35t Arnold-Chiari malformation, 416, 418f, Chiari II malformation Aromatase, 842f, 846 Arousals alterations in, 351–357 brain death secondary to, 355, 355b breathing patterns in, 352, 354f, 354t cerebral death secondary to, 355–357 clinical manifestations and evaluation of, 352–353, 352t–353t, 355b infratentorial disorders as cause of, 352 metabolic disorders as cause of, 352, 352t motor response assessments in, 353, 356f oculomotor responses in, 353, 356f outcomes of, 355–357 psychogenic (unresponsiveness), 352 pupillary changes associated with, 352 structural, 351 supratentorial disorders as cause of, 352

mediation of, 351

Arrhythmia, 623–624 Arsenic inorganic, 285–286 toxic effects of, 85, 89t

ART, Antiretroviral therapy Arterial blood pressure, 581–582 Arterial chemoreceptors, 583 Arterial pressure, of carbon dioxide, 665 Arterial switch procedure, 647 Arterial thromboembolism, 598t Arterial thrombosis formation of, 543 in thrombocythemia, 538–539

Arteries collateral, 568 coronary, 567–568, 569f diseases of, 592–611, 598b aneurysm, 596–597, 597f coronary artery disease, Coronary artery disease embolism, 598

2565

hypertension, Hypertension hypertension-related complications of, 594–595, 595t myocardial ischemia, Myocardial ischemia orthostatic hypotension, 596 peripheral artery disease, 601–602 peripheral vascular disease, 598–599, 599b thrombus formation, 597–598

disorders involving, function of, 563 elastic, 577 muscular, 577

Arteriogenesis, definition of, 568 Arteriolar remodeling, 593 Arterioles, 577, 580f Arteriosclerosis, 599 Arteriovenous anastomoses, 1015–1016 Arteriovenous malformation (AVM), 399 Arthritis acute gouty, 982, 983f juvenile idiopathic, 1003, 1004t osteoarthritis, Osteoarthritis psoriatic, 1023 rheumatoid, Rheumatoid arthritis septic, 1003, 1003f

Arthropathies, 973 Arthus reaction, 178 Articular capsule, 940 Articular cartilage, 942–943, 974 Asbestos, 285 Ascending pathways, 298 Aschoff bodies, 617f, 618 Ascites, 897–898, 898f ASD, Atrial septal defect Aseptic meningitis, 402, 422 Ask-Upmark kidney, 751 Aspartate, 304t Asphyxiation, 91–93 Aspiration chronic pulmonary, 706

2566

description of, 676 of foreign bodies, 699–700

Aspiration pneumonitis, 706 Assisted reproductive technology, 807 Association fibers, 305 Associational neurons, 299 Asterixis, 373t Asthma bronchial, 683f in children, 706–707, 707b clinical manifestations of, 681 definition of, 680, 706 evaluation of, 681–682, 706–707 hygiene hypothesis of, 680–681, 706 immunotherapy for, 682 microbiome and, 681b pathophysiology of, 681, 682f–683f, 706 prevalence of, 706 risk factors for, 680 status asthmaticus, 681 treatment of, 681–682, 706–707

Asthma predictive index, 706–707 Astigmatism, 340, 340f Astrocytes, 300, 301f, 301t Astrocytoma, 407–408, 408t, 424t Asymptomatic hyperuricemia, 982 Asystole, 625t–626t Ataxic breathing, 354t Ataxic cerebral palsy, 421 Ataxic gait, 379 Atelectasis, 676–677, 700–701 Atherosclerosis, 96, 543, 596–597, 599–601, 600f–601f Athetosis, 373t Atopic, allergy, 176 Atopic dermatitis, 854t–855t, 1022, 1045, 1045f Atopy, Allergy

2567

Atresia biliary, 928 definition of, 917 esophageal, 917, 918f

Atria, 565, 566f Atrial fibrillation, 625t–626t Atrial flutter, 625t–626t Atrial natriuretic hormone (ANH), 115 Atrial natriuretic peptide, 594, 722 Atrial receptors, 576 Atrial septal defect (ASD), 641–642 Atrial septostomy, 645–646 Atrial tachycardia, 625t–626t Atrioventricular canal (AVC) defect, 642–643, 642f Atrioventricular dissociation, 626t–627t Atrioventricular node automaticity, 570 in cardiac conduction system, 569

Atrioventricular valves, 565–566, 566f Atrophy, 74–75, 74f, 1019t–1020t, 1020f Attention-deficit/hyperactivity disorder (ADHD), 359b Atypical ductal hyperplasia, 808–809, 809f Atypical hyperplasia, 76 Atypical lobular hyperplasia, 808–809, 809f Atypical pneumonia, 705 Auditory dysfunction, 343 Auerbach plexus, 861, 864 Aura, 367 Autocrine signaling, 14–15 Autocrine stimulation, 232–234 Autoimmune diseases, 182 examples of, 182, 183t systemic lupus erythematosus, 182–183 transfusion reactions, 184–185, 185–186

Autoimmune gastritis, 510

2568

Autoimmune hepatitis (AIH), 929 Autoimmune primary sclerosing cholangitis (PSC), 929 Autoimmune type 1 diabetes mellitus, 457 Autoimmunity, 174, 182–183 Autolysis, 100 Automatic cells, 570 Autonomic hyperreflexia (dysreflexia), 391, 391f–392f Autonomic nervous system (ANS), 216–217 components of, 318 functions of, 322, 322b lung innervation, 659 neuroreceptors of, 322, 322t–323t neurotransmitters of, 322, 322t–323t parasympathetic nervous system, 320f, 321 postganglionic neurons, 318–319, 321f preganglionic neurons, 318–319, 321f in salivation, 859 stimulation of, 330 sympathetic nervous system, 319–321, 320f

Autonomic neuropathy, 464t Autophagic vacuoles, 74–75 Autophagy, 74–75 Autoregulation, 368 description of, 585 of intrarenal blood flow, 717, 717f

Autosomal aneuploidy, 46 Autosomal dominant inheritance, 52–54 delayed age of onset of, 53 epigenetics and, 54 expressivity, 53–54 genomic imprinting and, 54, 55f pedigree, 52, 52f–53f penetrance, 53–54 recurrence risks, 52

Autosomal dominant polycystic kidney disease, 751–752 Autosomal recessive inheritance, 54–56 consanguinity, 56

2569

pedigree, 54, 55f recurrence risks of, 54–56, 55f

Autosomal recessive polycystic kidney disease, 751–752 Autosomes, 44 AVM, Arteriovenous malformation Avulsion, 959 Awareness alterations in, 357–359 amnesia in, 357 clinical manifestations of, 358t, 359 evaluation and treatment of, 359, 359b pathophysiology of, 358–359

definition of, 357 mediation of, 357

Axial skeleton, 938 Axon hillock, 299, 300f Axonal shearing, 386f Axons, 299 5-Azacytidine, 70–71, 70f Azotemia, 742 B B cells bone marrow and, 157–158 clonal selection, 162–163, 165f description of, 156–157, 489 development of, 158–160

Bacilli, 199 Bacteremia, 199–201 Bacteria, 197t antibiotic resistance of, 206–207 definition of, 197t infection, 199–201 pyrogenic, 199 secreted by, 167 structure of, 199f

Bacterial embolism, 598t Bacterial endocarditis, 619f

2570

Bacterial infections examples of, 200t–201t of skin, 1027–1028, 1027f

Bacterial meningitis, 401–402 in children, 422

Bacterial pneumonia, 705 Bacterial prostatitis, 840–841, 840b Bacterial tracheitis, 699 Bactericidal, antibiotics, 206 Bacteriostatic antibiotics, 206 Bainbridge reflex, 576 Balanitis, 833, 833f Ballism, 373t Balloon angioplasty, for coarctation of the aorta, 643 Bare lymphocyte syndrome, 187 Bariatric surgery, outcomes of, 479b Barlow sign, 999–1000 Barometric pressure, 664 Baroreceptor, 583, 584f Baroreceptor reflexes, 576 Baroreceptors, 116–117 Barr bodies, 56 Barrel chest, 706 Barrett esophagus, 69–70, 907 Bartholin glands, 763–764, 791f Bartholinitis, 791–792 Basal body temperature, 770 Basal cell carcinoma (BCC), 280, 1032, 1033f Basal ganglia, 305–306, 307f Basal ganglia motor syndromes, 379–380 Basal ganglion gait, 379 Basal ganglion posture, 378–379 Basal lamina, 12 Basal nuclei system, 305–306

2571

Base pair substitution, 41, 42f–43f Basement membrane, 12, 13f, 946 Bases, 40 Basic fibroblast growth factor (bFGF), 239 Basilar artery, 314, 316f Basis pedunculi, 308 Basopenia, 518, 519t Basophil count, 500t–501t Basophilia, 518, 519t Basophils, 144 description of, 485f, 486, 487t disorders involving, 519t

BBB, Blood-brain barrier BCC, Basal cell carcinoma B-cell neoplasms, 529 B-cell receptor, 158, 160f Bcl-2, 244 BCR-ABL gene, 294 BCR-ABL protein, 253–254, 523, 523f Becker muscular dystrophy, 1006t Beckwith-Wiedemann syndrome, 54, 67 Bedbugs, 1051–1052 Bee sting allergy, 181–182 Beige adipocytes, 475 Bell palsy, 378b Bence Jones protein, 532 Benign breast disease, 808–810, 809f Benign nerve sheath tumors, 408 Benign prostatic hyperplasia, 75–76, 838–840, 839f, 846–847 Benign tumors, 1032t description of, 227, 228f of skin, 1031, 1031f

Benzol, 285–286 Benzoyl peroxide, 1044–1045

2572

Beriberi, 623 Berry aneurysms, 398, 398f Beta cells, 439–440, 457 Beta globulins, 484–485 Beta-hemolytic streptococci, 1027 Beta-thalassemia, 555, 556f major, 555 minor, 555

Bevacizumab, 254t bFGF, Basic fibroblast growth factor Biallelic, 66 Bicarbonate, 720–721 chloride and, 115 in saliva, 859

Bicornuate uterus, 781f Bile, 871–872 Bile acid-dependent fraction, 871–872 Bile acid-independent fraction, 871–872 Bile canaliculi, 871 Bile duct cancer, 260t–264t Bile salts deficiency of, 892–893 description of, 871, 871f

Biliary atresia, 928 Biliary metabolism and transport, transport of, 927–928 Bilirubin, 97, 495f conjugated, 872, 900 metabolism of, 872, 872f, 900t unconjugated, 872, 928

Binding sites, 10 Binge drinking, 89 Biofilms, 198, 972 Biotransformation, 83, 873 Bipolar neurons, 299 Bisphenol A, 67–68, 819

2573

Bisphosphonates, 936t osteogenesis imperfecta treated with, 1001 osteoporosis treated with, 968–969, 969b Paget disease of bone treated with, 971

Bites human, 971 insect, 1051–1052, 1051f–1052f

Black gallstones, 904–905 Bladder anatomy of, 716–717, 716f cancer of, 285–286, 734 distention of, 839–840 exstrophy of, 753–754, 753f innervation of, 717 neurogenic, 732–733, 732t, 737t overactive bladder syndrome, 731–732, 758t trigone of, 716, 716f uroepithelium of, 716

Bladder outflow obstruction, 839 Bladder outlet obstruction in children, 754 description of, 731

Bladder tumors, 734 Blalock-Taussig shunt, 645 Blast cell, 521, 559 Blastocyst, 490–491, 766 Blebs, 685 Bleeding abnormal uterine, 784–785, 785f, 785t, 787b gastrointestinal, 881–883, 881t, 882f in leukemia, 524, 525t in stress-related mucosal disease, 890 time, 499b, 500t–501t traumatic, 508b types of, 496t

Blepharitis, 341 Blood aging and, 499–502

2574

carbon dioxide transport in, 667, 667b composition of, 484–488, 485f erythrocytes, 485–486 plasma, 484–485, 486t plasma proteins, 484–485 platelets, 485f, 487t, 488

functions of, 484 oxygen transport in, 666–667

Blood-brain barrier, 315, 317f Blood cells, 485–488, 487t development of, 490–496 hematopoiesis, 491–496 platelets, 485f, 488, 488f

Blood clot, 137, 498 lysis of, 498–499 mechanism, 498f retraction of, 498–499

Blood flow in cardiac cycle, 567, 567f–568f coronary, 585 factors affecting, 577–581, 581b laminar, 581, 582f pressure effects on, 578–580 resistance effects on, 578–580 through heart, 563, 564f turbulent, 581, 582f velocity effects on, 581, 582f

Blood group antigens, 184 Blood lead levels, 85 Blood plasma, 111 Blood pressure ambulatory monitoring of, 652 arterial, 581–582 baroreceptors effect on, 583, 584f cardiac output effects on, 582 chemoreceptor reflex control of, 584f in children, 650t classification of, 593t diastolic, 581–582 hormone effects on, 583

2575

regulation of, 581–585, 583f, 585b systolic, 581–582 total peripheral resistance effects on, 582–583 venous, 585

Blood supply to brain, 314–315, 315f–316f, 316b to spinal cord, 315, 317f

Blood urea nitrogen, 723–724, 724t Blood velocity, 581, 582f Blood vessels arterioles, 577, 580f endothelial injury to, 543 endothelium of, 577, 580f factors affecting, 577–581 in hemostasis, 496–497 layers of, 577, 580f lumen of, 577 metarterioles, 577, 580f stiffness of, 581 structure of, 577, 580f vascular compliance of, 581

Blood volume, description of, 484 Bloom syndrome, 238, 293 Blunt-force injuries, 91f, 91t–92t BMI, Body mass index BMPs, Bone morphogenic proteins BNP, B-type natriuretic peptide Body fluids, Total body water distribution of, 111–113, 112t geriatric considerations in, 130 pediatric considerations in, 130b

hydrogen ions in, 123

Body heat loss of, 333, 334t production of, 333

Body mass index (BMI), 271–272 epigenetics and, 68b

Body temperature

2576

basal, 770 in menstrual cycle, 770 normal range of, 333

Bohr effect, 667 Bombesin, 862t Bone, 33t–35t age-related loss of, 965 aging of, 952 anatomy of, 933–940, 934t, 935f, 937f calcification of, 933 calcium and, 969b cancellous, 937, 938f cells of, 933–935, 935f, 936t characteristics of, 938–939 compact, 937, 938f cortical, 937, 938f, 964–965 flat, 939 formation of, 936t function of, 933–940 healing of, 940 homeostasis of, 965 integrity of, 939–940 irregular, 939 long, 938, 971 maintenance of, 936t marrow cavities in, 933 minerals of, 937 osteoblasts of, 490, 934–935, 934t, 935f osteoclasts of, 438, 490, 934t, 935, 935f, 939–940 osteocytes of, 934t, 935, 935f quality of, 966 remodeling of, 936t, 939–940, 941f repair of, 940 spongy, 937, 938f structural elements of, 934t, 935f structure of, 933–940, 940b trabecular, 965f, 968f vitamin D and, 969b

Bone albumin, 937 Bone and mineral disorders, 891

2577

Bone cancer, 260t–264t Bone density, 965, 965b loss, 247b

Bone disorders osteomalacia, 970 osteomyelitis, 971–972, 971f–972f osteoporosis, Osteoporosis Paget disease, 820t, 970–971

Bone-forming tumors, 992 Bone infections osteomyelitis, 971–972, 971f–972f, 1001–1003, 1002f, 1002b septic arthritis, 1003, 1003f

Bone loss age-related, 967 in men, 968f in women, 968f

Bone marrow B cells from, 157–158 hematopoiesis in, 490 lymphoid stem cells in, 157–158 myeloma cells in, 531–532 stem cell in, 952

Bone mass, 952 gender differences in, 967–968 peak, 965

Bone matrix, 933, 937 Bone mineral density, 964 Bone morphogenic proteins (BMPs), 934t, 936t Bone tumors benign, 990, 994b bone destruction caused by, patterns of, 990–992, 992t chondrogenic, 990, 993, 993f chondrosarcoma, 993, 993f classification of, 990, 991t collagenic, 993–994 diagnosis of, 991–992 epidemiology of, 990 fibrosarcoma, 993–994

2578

giant cell tumor, 994 malignant, 990, 992t myelogenic, 994 origination of, 990, 991f osteogenic, 992–993, 993f osteosarcoma, 992–993, 993f pathologic features of, 990–991 staging of, 992, 992t

Bone turnover, 966, 969b Bony labyrinth, 342–343 Botulism, 405

2579

Bouchard nodes, 973f, 975 Bowing fracture, 956, 956t Bowman capsule, 713, 715f, 719 Brachial neuralgia, 974–975 Brachial plexus, 317 Brachycephaly, 419f Brachytherapy, 252–253 Bradykinesia, 374 Bradykinin, 137–138 Brain anatomy of, 418f Arnold-Chiari malformation of, 416, 418f blood supply to, 314–315, 315f–316f, 316b cardiovascular control centers in, 576 cerebellum, 308 cerebral arteries of, 315t, 316f cerebral hemispheres of, 304, 306f in children, 414 description of, 303 development of, 414 malformations of, 419–420, 420b

diencephalon, 308 divisions of, 303, 306f, 308b edema of, 369, 369f forebrain, 304–308, 304t hindbrain, 304t, 306f, 308, 312f hypothalamus, 308, 308b midbrain, 304f, 304t, 308 myelencephalon, 308 pons, 308 postnatal growth of, 414 telencephalon, 304–306, 306f thalamus, 308 venous drainage of, 314–315, 316f

Brain abscesses, 403 Brain cancer, 260t–264t Brain death, 355, 355b Brain herniation syndromes, 368f, 369b

2580

Brain injuries classification of, 385t closed, 384–385 concussion, 388 contusions, 384–385 diffuse axonal injury, 385t, 387–388 epidural (extradural) hematoma, 385, 385t, 387f intracerebral hematomas, 387, 387f secondary, 388 subarachnoid hemorrhage, 385t subdural hematoma, 385t, 386–387, 387f

Brain natriuretic peptide, 722 Brain networks, 303, 305f, 305b Brain tumors, 291 astrocytoma, 407–408, 408t, 424t brainstem glioma, 424t in children, 423, 424f, 424t, 425b ependymoma, 408, 424t gliomas, 407 intracerebral, 407–408 intracranial, 407 location of, 424f medulloblastoma, 424t meningioma, 408 metastatic, 406, 409 neuroblastoma, 423–425 neurofibromas, 408 primary, 406 retinoblastoma, 425, 425f–426f, 425b sites of, 406, 407f

Brainstem anatomy of, 303, 305f respiratory center in, 660, 661f reticular formation, 303, 305f

Brainstem glioma, 424t Branching morphogenesis, 810–813 BRCA1, 819, 852–853 mutations, 238

BRCA2, 819, 844–845, 852–853

2581

mutations, 238

Breast(s) age-related changes in, 776 aging effects on, 813 anatomy of, 770–772, 771f, 772b density, 816–817, 817f description of, 770 development of, 781–782, 813–815, 815f estrogen effects on, 772 function of, 772 involution of, 813 lobular involution of, 813 lymphatic drainage of, 770–771, 771f male carcinoma of, 852–853 description of, 772 gynecomastia of, 772, 852

postlactational involution of, 813 structure of, 770–772 terminal duct lobular units, 813

Breast cancer, 825b alcohol consumption and, 818 breast density effects on diagnosis of, 816–817 clinical manifestations of, 824, 825t description of, 260t–264t diet and, 818 ductal carcinoma in situ, 810, 811f, 811b, 821–825, 823f environmental causes of, 817–819 environmental chemicals and, 819 evaluation of, 824–825 genetic heterogeneity, 819 global mortality rates for, 812f growth hormone and, 816 hereditary influences, 819 hormonal factors, 813–815, 814f incidence of, 810, 812f inherited syndromes, 819–821 insulin-like growth factors and, 816 ionizing radiation exposure as cause of, 817–818 lobular carcinoma in situ, 820t, 821–825 lobular involution and, 813 male, 852–853

2582

mammographic screening of, 811f, 811b, 816–817 menopausal hormone therapy and, 815–816 metastasis of, 245, 821, 823f mortality rates for, 812f obesity and, 818–819, 852–853 oral contraceptives and, 816 physical activity and, 274 pregnancy and, 810–813 prolactin and, 815 radiation exposure as cause of, 817–818 reproductive factors involved in, 810–813 risk factors for, 810t screening of, 811f, 811b treatment of, 824–825 types of, 820t

Breast disorders atypical ductal hyperplasia, 808–809, 809f benign breast disease, 808–810, 809f fibrocystic changes, 808 galactorrhea, 807–808 gynecomastia, 772

Breast lesions atypical ductal hyperplasia, 808–809, 809f nonproliferative, 808 proliferative, 808, 809f

Breathing airway resistance, 664 alveolar surface tension in, 662–663 chemical control of, 662b labored, 671 mechanics of, 662–664 patterns abnormalities of, in pulmonary disease, 671 in arousal alterations, 352, 354t

restricted, 671 work of, 664, 671

Brittle bone disease, 1000 Broad-spectrum antibiotics, 135 Broca aphasia, 361t–362t Broca speech area, 305, 306f, 359–360

2583

Brodie abscess, 972 Brodmann area, 305 Bronchi (bronchus), 655–656, 656f Bronchial circulation, 657–659, 660b Bronchiectasis, 677 Bronchioles, 658, 659f Bronchiolitis, 677, 703–704, 706b Bronchiolitis obliterans, 677 Bronchiolitis obliterans organizing pneumonia, 677 Bronchioloalveolar cell carcinoma, 693 Bronchitis acute, 686 chronic, 682–685, 683f–684f

Bronchoconstriction, exercise-induced, 707b Bronchodilation, 664 Bronchogenic carcinomas, 691–693 Bronchopulmonary dysplasia, 702–703, 703t, 703b, 704f Brown adipocytes, 474 Brown fat thermogenesis, 333 Brudzinski sign, 399, 422 Brush border, 865 Bruton agammaglobulinemia (X-linked agammaglobulinemia), 187 B-type natriuretic peptide (BNP), 115 in heart failure diagnosis, 649 in hypertension, 594

“Buffalo hump,”, 467, 467f–468f Buffering carbonic acid-bicarbonate, 125 protein, 125–126 renal, 126–127

Bulbar palsy, progressive, 377 Bulbourethral glands, 775 Bulla, 685, 1017t–1018t, 1018f Bullous emphysema, 685f Bullous erythema multiforme, 1026

2584

Bullous impetigo, 1046 Bundle branches, 569–570 Bundle of His, 569–570 Burkitt lymphomas in children, 560 description of, 520, 530–531, 531f

Burns, 1035–1038, 1039b cardiovascular responses to, 1037 cellular response to, 1037f clinical manifestations of, 1036–1037 cultured epithelial autografts for, 1038f deep-partial thickness, 1035t, 1036, 1036f depth of, 1035–1037, 1035t, 1036f evaporative water loss secondary to, 1038 first degree, 1035, 1035t fluid resuscitation for, 1036–1037 fourth degree, 1035t, 1036 full thickness, 1035t, 1036, 1036f hypermetabolism secondary to, 1038 immunologic response to, 1038 immunosuppression secondary to, 1038 incidence of, 1035 metabolic response to, 1037–1038 pathophysiology of, 1036–1037 rule of nines for, 1036, 1037f scarring caused by, 1038f second degree, 1035, 1035t, 1036f shock caused by, 1036 survival from, 1038 systemic responses to, 1037 third degree, 1035t, 1036 total body surface area (TBSA) estimations, 1036, 1037f

Bursae, 960 Bursitis, 959–960, 960f Buschke-Löwenstein patches, 833–834 Bystander effects, 278f, 279 C C1, 137

2585

C3, 137 deficiency, 188

C5, 137 C cells, 438 C fibers, 328, 330–331, 333 Cabergoline, 452 CABG, Coronary artery bypass graft Cachexia, 247b, 250f, 480 molecular mechanism of, 247–249

CAD, Coronary artery disease Cadherins, 11b Cadmium, toxic effects of, 85, 89t Caffeine, 863–864 CAFs, Cancer-associated fibroblasts CAKUT, Congenital abnormalities of the kidney and urinary tract Calcaneovalgus, 1000t Calcaneovarus, 1000t Calcaneus, 1000t Calcification, 933 Calcitonin, 438, 935 Calcitonin gene-related peptide (CGRP), 219t Calcium alterations in, 124t bone and, 934t, 969b in cellular accumulations, 97–99, 98f–99f contractile strength affected by influx of, 571 cytosolic, 98f parathyroid hormone in homeostasis of, 969 small intestine absorption of, 868b

Calcium-calmodulin complex, 432 Calcium stones, 729–730 Calcium-troponin complex, 574 California viral encephalitis, 402 Callus, 75 Calor, 136

2586

Caloric ice water test, 356f Calyces, renal, 712, 713f cAMP, Cyclic adenosine monophosphate CA-MRSA, Community-acquired methicillin-resistant Staphylococcus aureus CAMs, Cell adhesion molecules Canal of Schlemm, 338–339 Canaliculi, 937 Cancer in adolescents, Adolescents, cancer in apoptosis resistance by, 242f biology, 227–257 of bladder, 285–286, 734 bone, 260t–264t brain, 260t–264t causes of, 259f cell surface antigens expressed by, 243 cellular differentiation during, 229f chemotherapy for, 253 in children, Childhood cancers classification of, 260t–264t clinical manifestations of, 247–249 anemia, 247b cachexia, 247–249, 250f, 256

colorectal, 260t–264t, 264, 907t, 908–910, 908b–909b, 909f definition of, 227 development of, 258 diagnosis of, 249–252, 249t DNA methylation and, 69–70, 230–231, 267, 270f early life conditions, 264–265 environmental-lifestyle factors, 265–286 air pollution, 274–276 alcohol consumption, 272–274, 273t chemicals, 283–286, 286b diet, 267, 268f–269f electromagnetic radiation, 282, 282b infection, 282–283 ionizing radiation, 274f, 276–280, 276t microorganisms, 283 nutrition, 267–271, 270f obesity, 271–272, 271f, 272t occupational hazards, 283–286, 286b physical activity, 274 reproductive behavior, 282–283

2587

sexual behavior, 282–283 tobacco use, 265–267 ultraviolet radiation, 280–282 viruses, 283

epidemiology of, 258–290 epigenetic screening for, 70 epigenetics and, 69–71, 70f, 258–264, 258b, 259f exomes in, 279f familial, 238t genetics of, 231f, 258–264, 258b, 259f global burden of, 264f, 265b glucose requirement in, 242f growth factor signaling pathways in, 234f hallmarks of, 227–228, 230f heterogeneity, 231–232 immune destruction evasion by, 243–244 immunotherapy, 243 incidence of, 264, 264f laryngeal, 260t–264t, 690–691, 691f leukopenia, 247b malignant transformation, 230–231 in men, 265 microenvironment of, 233f, 258 molecular-era drugs, 254t mortality in, 264 nasopharyngeal, 260t–264t neovascularization of, 245 obtaining tissue, biopsy, 250t ocular, 260t–264t oral cavity, 260t–264t pain, 332t paraneoplastic syndromes, 248t precursor lesions for, 854t–855t prevention of, 267 progression, 272f–273f proliferative signaling by, 232–235 radiation-induced, 277–279 radiation therapy for, 252–253 sites of, 260t–264t skin, 238 staging of, 249–252, 249t surgery for, 252

2588

targeted disruption of, 253–254, 254b terminology of, 227–228 thrombocytopenia, 247b tissue, 258–264, 258b treatment of, 252–254 tumor markers for, 250–252, 251t tumor-specific antigens expressed, 233f in utero conditions, 264–265 vaginal, 260t–264t in women, 265 wound healing and, 231–232

Cancer associated adipocytes, 272 Cancer-associated fibroblasts (CAFs), 243, 847 Cancer cells apoptosis resistance by, 241 biology of, 228–247, 232b dormancy of, 245–247 energy metabolism, reprogramming by, 241 epithelial-mesenchymal transition, 245, 246f genomic instability of, 238 growth suppressor evasion by, 235–238 heterogeneity of, 231–232 immune destruction evasion by, 243–244, 244f metastasis of, 244–247, 247b proliferative signaling by, 232–235 replication immortality of, 238–239, 239b

Cancer genes, 235t Cancer heterogeneity, 231–232 Candida albicans, 135, 196, 205f, 790, 1029, 1045–1046 Candidiasis, 204, 1029, 1030t Cannabinoid receptor, 330 Cannabinoids, 330 abuse of, 83t

Cannabis, 330 Capillaries fenestrations in, 577 function of, 563 lymphatic, 585–586, 586f papillary, 1015–1016

2589

permeability of, inflammation and, 113 systemic circulation, 577

Capillary bed, 580f Capillary hydrostatic pressure, 112–113 Capillary (plasma) oncotic pressure, 112 Capillary seal, 1037 Caplan syndrome, 979 Capsules, 199 Caput medusae, 897 CAR T cells, 253, 254f Carbohydrates as cellular accumulations, 95–96 metabolism of in chronic kidney disease, 746 by liver, 872

small intestine absorption of, 868b

Carbon dioxide (CO2), 314, 493–494 from cellular metabolism, 660 diffusion gradient for, 667 transport, 667, 667b

Carbon monoxide (CO), 93, 493–494 poisoning, 106, 671–672

Carbon tetrachloride, chemical injury of liver cells induced by, 85f Carbonic acid (H2CO3), 123–124, 660, 720–721 Carbonic acid-bicarbonate buffering, 125 Carbonic anhydrase, 123–124, 126–127 Carboxypeptidase, 138–139 Carbuncles, 1027 Carcinogenesis, 283 Carcinogens chemicals as, 283–286, 286b definition of, 258 dietary sources of, 267 occupational hazards as, 283–286, 286b

Carcinoid syndrome, 248t Carcinoma, 228

2590

basal cell, 280, 1032, 1033f thyroid, 455, 455b

Carcinoma in situ (CIS), 228, 228b Carcinomatous meningitis, 409 Cardiac and pulmonary damage, 247b Cardiac cells, skeletal muscle versus, 571 Cardiac conduction system, 569–570, 570f, 570b Cardiac cycle, blood flow in, 567, 567f–568f Cardiac muscle, 35t–36t hypertrophy of, 75

Cardiac orifice, 861 Cardiac output afterload, 575–576, 620, 622f calculation of, 574 in elderly adults, 575t factors that affect, 574–576, 575f, 577b heart rate effects on, 576 myocardial contractility, 576 preload, 574–575

Cardiac tamponade, 612 Cardiac veins, 567 Cardiogenic shock, 628, 629f Cardiomyocytes, description of, 564, 571 Cardiomyopathies, 613–614, 613f Cardiovascular control centers, 576 Cardiovascular disorders acute rheumatic fever, 616–618, 617f aortic regurgitation, 616 aortic stenosis, 615, 615f atherosclerosis, 543, 596–597, 599–601, 600f–601f cardiomyopathies, 613–614, 613f in children acquired heart diseases, 650 Kawasaki disease, 650, 650b obesity and, 651b systemic hypertension, 650–652, 650t–651t, 652b

chronic venous insufficiency, 591 coronary artery disease, Coronary artery disease

2591

deep venous thrombosis, 591–592 in diabetes mellitus, 465–466 embolism, 598 hypertension, Hypertension infective endocarditis, 618–620, 618b, 619f mitral regurgitation, 616 mitral stenosis, 615–616, 616f mitral valve prolapse syndrome, 616, 617f orthostatic hypotension, 596 pericardial effusion, 612, 612f peripheral artery disease, 601–602 peripheral vascular disease, 598–599, 599b Raynaud phenomenon, 598–599 renin-angiotensin-aldosterone system in, 594b rheumatic heart disease, 616–618, 617f superior vena cava syndrome, 592 thromboangiitis obliterans, 598 thrombus formation, 597–598 tricuspid regurgitation, 616 valvular dysfunction, 614–616, 614t, 615f varicose veins, 591, 592f

Cardiovascular function, 591–638 Cardiovascular vasomotor control center, 576 Caretaker genes, 237–238 Carina, 655–656, 656f Carnitine palmitoyltransferase, 988 deficiency of, 989t

Carrier detection tests, 56 Carriers, 51 heterozygous, 54 obligate, 53

Cartilage elastic, 33t–35t fibrous, 33t–35t hyaline, 33t–35t rheumatoid arthritis-induced damage to, 977

Cartilage-forming tumors, 993 Cartilaginous joints, 940–943 CAs, Catecholamines

2592

Cascade, 137 Caseation necrosis, 688 Caseous necrosis, 101, 147 Caspases, 103, 241 Catabolism, 17, 17f protein, 214

Catalase, 146 Cataract, 339, 340t Catecholamines (CAs) in Cushing syndrome, 467–468 description of, 216 excess, 470 neuroreceptors and, 322 pathophysiologic effects of, 216–217 physiologic effects of, 217t proinflammatory cytokine production affected by, 216–217 synthesis of, 444f

β-Catenin pathway, 936t Cations, 20 Cauda equina, 308 Cauda equina syndrome, 393, 733 Caudate nucleus, 305–306 Caveolae, 4 Cavernous hemangiomas, 1052–1053, 1052f Cavernous sinus, 314 Cavitation, 688 Cavus, 1000t CBC, Complete blood count CCD, Central core disease CCK, Cholecystokinin CD, Crohn disease CD3, 161 CD4, 161 CD8, 161 CDR, Complementary determining region

2593

Cecum, 867 Celiac crisis, 924 Celiac disease, in children, 923–925, 924f, 925b Celiac ganglia, 319–321, 320f Celiac sprue, 923–924 Cell adhesion molecules (CAMs), 9, 141 Cell cortex, 9 Cell cycle, 27–28, 27f, 29b arrest, 28, 29f cytokinesis, 27–28 meiosis, 44, 46f mitosis, 27–28, 44 regulation of, 270f

Cell division control of, 28 DNA damage response in, 28

Cell junction, 12–13 Cell-mediated hypersensitivity reactions, type IV, 178–181 mechanism of, 178–180, 180f

Cell-mediated immunity, 168–171 Cell polarity, 4 Cell surface antigen receptors, 156–157 Cell surface receptors, 140 Cells burn injury response by, 1037f components, 2–10 cytoplasmic organelles, 3–4 nucleus, 3, 3f plasma membrane, Plasma membrane structure and function of, 2–10

conductivity of, 2 eukaryotes, 1, 2f extracellular matrix, 12, 12f functions of, 1–2 junction, specialized, 12–13 membrane transport in, 18–26, 19f, 22b, 27b active, 19, 19f, 22f in mammalian cells, 23t mediated, 18–19, 20f

2594

passive, 19–22

metabolic absorption, 2 myocardial, 571–573, 572f of nervous system, 298–301, 300f–302f, 301t, 301b prokaryotes, 1 reproduction, 27–28 respiration of, 2

Cell-to-cell adhesions, 11–13 Cellular accumulations, 94–95 calcium, 97–99, 98f–99f carbohydrates in, 95–96 glycogen, 96 hemoproteins, 97 lipids in, 95–96 mechanisms of, 95f melanin, 97 pigments, 97 protein in, 96–97 substances can produce, 94–95 urate, 99 water in, 95

Cellular adaptation, 74–77, 74f accumulations of, 94–95 atrophy, 74–75, 74f dysplasia, 76, 76f hyperplasia, 75–76, 76f hypertrophy, 75, 75f metaplasia, 76–77, 76f stages of, 77f

Cellular biology, 1–39 Cellular communication, 2, 13–15, 15f gap junctions in, 13, 15f need for, 13–14

Cellular death, 99–104, 104b apoptosis, Apoptosis autophagy, 103–104, 103b, 104f necrosis, Necrosis

Cellular dormancy, 245–247 Cellular injury, 77–94, 78b chemical or toxic injury, 82–90

2595

drugs and, 83 ethanol and, 86–90 irreversible, 77 lead and, 85, 88f, 88b, 90b manifestations of, 94–99 mechanisms of, 77, 94t mercury and, 85–86 reactive oxygen species in, 81f reversible, 77 systemic manifestations of, 99, 99t themes in, 78t toxins and, 83–85 types of, 77t

Cellular mediators and products, 140–142 Cellular metabolism, 17–18 adenosine triphosphate in, 17 carbon dioxide produced by, 660 food of, 17–18 impairment of, in shock, 624–627, 628f oxidative phosphorylation, 18 production of, 17–18 thiamine deficiency effects on, 623

Cellular receptors, 10, 11f of adaptive immune system, 140

Cellular respiration, 41 Cellular swelling, 95 Cellulitis, 1027 Centigray, 276 Central and peripheral nervous systems, disorders of, 248t Central canal, 308–309 Central chemoreceptors, 661 Central core disease (CCD), 987 Central cyanosis, 671 Central diabetes insipidus, 449 Central fever, 335 Central herniation, 368f, 369b Central (secondary) hyperthyroidism, 452

2596

Central (secondary) hypothyroidism, 454 Central nervous system (CNS) blood supply to, 314–315, 315f–316f, 315t, 316b blood-brain barrier of, 315, 317f brain, Brain cancer of, 260t–264t components of, 298 divisions of, 304t infections of, 422 malformations of, 415–420 neural tube defects, 416–417, 416t, 417f–418f

metabolic disorders of, 421–422 motor pathways, 307f, 310f, 311, 312f protective structures of, 311–314 cerebrospinal fluid, 313–314, 313f, 314t cranium, 311 meninges, 311–313, 313f vertebral column, 314, 314f–315f

spinal cord, Spinal cord vomiting associated with injuries of, 353

Central nervous system disorders, 384–404 AIDS-related neurologic complications, 403 brain or spinal cord abscess, 403 cerebrovascular accidents (stroke syndromes), 395–399, 396b degenerative spinal disorders degenerative joint disease, 394 herniated intervertebral disk, 394–395, 394f–395f low back pain, 392–394

demyelinating disorders, 403–404 encephalitis, 402–403, 402b Guillain-Barré syndrome, 404, 404b headache, 400–401, 400t infection and inflammation, 401–403, 402f meningitis, 401–402, 402f multiple sclerosis, 403–404, 404f, 405t subarachnoid hemorrhage, 398–399, 399t vascular malformation, 399

Central nervous system tumors, 406–409 Central neurogenic hyperventilation, 354t Central neuropathic pain, 332 Central retinal artery, 338

2597

Central sensitization, 332 Central sulcus, 305, 306f Central (secondary) thyroid disorders, 452 Central venous pressure, 574 Centromere, 28 Cerebellar (ataxic) gait, 379 Cerebellar motor syndromes, 379–380 Cerebellar tonsillar herniation, 368f, 369b Cerebellar tremor, 373t Cerebellum, 306f, 308 Cerebral aneurysms, 597 Cerebral aqueduct, 308 Cerebral artery, 315t, 316f Cerebral artery vasospasm, 399 Cerebral blood flow alterations in, 367 definition of, 367b

Cerebral blood oxygenation, 367b Cerebral blood volume, 367b Cerebral cortex, 304 Cerebral death, 355–357 Cerebral edema, 369, 369f, 397 Cerebral hemispheres, 304, 306f Cerebral hemodynamics, alterations in, 367–370, 367b brain herniation syndromes, 368f, 369b cerebral edema, 369, 369f hydrocephalus, 369–370, 370t increased intracranial pressure, 367–369, 368f

Cerebral hypoxia, 93 Cerebral infarction, 397 Cerebral ischemia, delayed, 399 Cerebral palsy, 421, 806t Cerebral peduncles, 308 Cerebral perfusion pressure (CPP), 367, 367b

2598

Cerebral thromboses, 396 Cerebral veins, 314–315, 316f Cerebrospinal fluid (CSF) description of, 313–314, 313f, 314t hydrocephalus caused by blockage of, 419–420 pH of, 661 pressure, 313–314

Cerebrovascular accidents (CVAs), 395–399, 396b, 806t Cerebrovascular disease (CVD), 395–399, 423 Cerebrum anatomy of, 303 venous drainage of, 314–315, 316f

Ceruloplasmin, 485 Cervical cancer, 260t–264t, 807b cervical intraepithelial neoplasia, 797, 799f description of, 238–239 Papanicolaou test screenings for, 797 precursor lesions for, 798t primary prevention, 800b progression of, 799f screening for, 797, 800t, 800b staging of, 798t

Cervical carcinoma in situ, 797 Cervical intraepithelial neoplasia (CIN), 283, 797, 799f Cervicitis, 790–791 Cervix aging effects on, 776 anatomy of, 765, 766f, 798f epithelial cells of, 798f functions of, 765 mucosa of, 768t mucus of, 770 neoplasm progression in, 230f

CGD, Chronic granulomatous disease cGMP, Cyclic guanosine monophosphate CGRP, Calcitonin gene-related peptide Chalazion, 341

2599

Channel, 18–19 Chaperones, 9 CHD, Congenital heart disease Checkpoint inhibitors, immune, 253 Chemical asphyxiants, 93 Chemical carcinogenesis, 283–286, 286b Chemical epididymitis, 838 Chemical liver injury, 84f Chemical synapses, 14–15 Chemokine ligand 2 (CCL2), 243 Chemokine receptor inhibitors, 191–192 Chemokines, 141 Chemoreceptors central, 661–662, 662b peripheral, 662

Chemotactic factor, 137 Chemotaxis, 143 Chemotherapy adjuvant, 253 for cancer, 253 induction, 253 leukemia treated with, 525 neoadjuvant, 253

Chest muscle retraction, 697–698, 699f Chest pain, 686 Chest wall aging effects on, 668b anatomy of, 659–660, 659f disorders, 674, 675f elastic properties of, 663–664, 668b pain in, 672 restriction of, 674, 675f

Cheyne-Stokes respirations, 354t, 671 Chiari II malformation (Arnold-Chiari malformation), 416 Chickenpox, 1049–1050, 1049t, 1050f Chief cells, 863f, 864

2600

Chilblains, 1038 Childhood cancers, 291–297 brain tumors, 291 childhood exposures associated with, 295, 296b chromosomal abnormalities associated with, 294 congenital factors associated with, 294t death rates for, 291 embryonic tumors, 291 environmental factors, 295, 295b Epstein-Barr virus and, 295 etiology of, 291–295 genetic factors, 293–295 genomic factors, 293–295 incidence of, 291–295, 292f, 292t, 294t lymphomas in, 291 magnetic fields and, 296b mesodermal germ layer, 291, 293f multiple causation model of, 293 prenatal exposure as cause of, 295, 295t prognosis for, 296–297, 297b survival rates for, 296 types of, 291–295, 292f

Children abuse of, 1010 acquired immunodeficiency syndrome in, 295 airway obstruction in, 697–700, 698f, 700b amino acid metabolism defects, 421 anencephaly, 416 Arnold-Chiari malformation, 416, 418f blood pressure in, 650t brain growth and development in, 414 cardiovascular disorders in acquired, 650 Kawasaki disease, 650, 650b obesity and, 651b systemic hypertension, 650–652, 650t–651t

central nervous system infections in, 422 central nervous system malformations, 415–420 cerebral palsy, 421 cerebrovascular disease, 423 coagulation disorders in, 557–558, 558b computed tomography in, 296b

2601

cortical dysplasias, 419 craniosynostosis, 417–419, 419f digestive function alterations in, 916–932 anorectal malformations as, 920 appendicitis as, 922, 922b celiac disease as, 923–925, 924f, 925b cleft lip as, 916–917, 917f cleft palate as, 916–917, 917f cystic fibrosis as, 922–923, 923t diarrhea as, 927 duodenal obstruction as, 918–919 esophageal atresia as, 917, 918f esophageal malformation as, 917–918 failure to thrive as, 926, 926b faltering growth as, 926, 926b gastroesophageal reflux (GER) as, 920–921 gastroesophageal reflux disease (GERD) as, 920–921 Hirschsprung disease as, 920, 920f ileum obstruction as, 918–919 infantile hypertrophic pyloric stenosis (IHPS) as, 918 intestinal malrotation as, 919 intussusception as, 921–922, 922f jejunum obstruction as, 918–919 malnutrition as, 925 Meckel diverticulum as, 919, 919b meconium syndromes as, 919–920 necrotizing enterocolitis as, 926–927, 927b primary lactose intolerance as, 927

encephalitis, 422 encephalocele, 416 encephalopathies, 420–422 epilepsy and seizure, 423 erythrocyte disorders in, 548–556, 556b anemia, 548, 549t, 549b iron deficiency anemia, 548–550 sickle cell disease, 551–555, 552f–554f, 553t thalassemias, 555–556

fever in, 335b glucose-6-phosphate dehydrogenase deficiency in, 548 growth hormone deficiency in, 450 hematologic function in, 548–562 hydrocephalus, 419–420, 420f immune thrombocytopenic purpura in, 557–558 insect bites in, 1051–1052, 1051f–1052f integument in, alterations of, 1044–1055 acne vulgaris, 1044–1045, 1045f, 1046b atopic dermatitis, 1045, 1045f cutaneous hemangiomas, 1052–1053, 1052f, 1053b

2602

cutaneous vascular malformations, 1053, 1053f dermatitis, 1045–1046, 1045f–1046f diaper dermatitis, 1045–1046, 1046f erythema toxicum neonatorum, 1053 impetigo contagiosum, 1046–1047, 1046f miliaria, 1053, 1053f staphylococcal scalded-skin syndrome (SSSS), 1046–1047, 1047f, 1050b

lead exposure in, 422 lead in, 85, 88f, 88b liver disorders in, 927–929 biliary atresia as, 928 cirrhosis as, 929 hepatitis as, 928–929 inflammatory disorders and, 928–929 metabolic disorders and, 929, 929t–930t, 929b neonatal jaundice as, 927–928

lymphomas in, 559–560, 560f, 560b meningitis, 422 meningocele, 416, 418f metabolic disorders of central nervous system, 421–422 microcephaly, 419, 419f Moyamoya disease, 423 musculoskeletal function in, alterations of, 999–1013 bone infection, 1001–1003, 1002f, 1002b clubfoot, 999, 1000f, 1000t developmental dysplasia of the hip, 999–1000, 1001f Duchenne muscular dystrophy, 1006t, 1007–1008, 1007f–1008f Ewing sarcoma, 1010, 1010f fascioscapulohumeral muscular dystrophy, 1006t, 1008 joint infection, 1001–1003, 1002f, 1002b juvenile idiopathic arthritis, 1003, 1004t Legg-Calvé-Perthes disease, 1004–1005, 1005f musculoskeletal tumors, 1009–1010, 1009f–1010f, 1011b myotonic muscular dystrophy, 1006t, 1008–1009 neuromuscular disorders, 1006–1009 nonaccidental trauma, 1010–1011, 1011f nonossifying fibroma, 1009, 1009f Osgood-Schlatter disease, 1005 osteochondroma, 1009, 1009f osteochondroses, 1003–1006, 1005f, 1009b osteogenesis imperfecta, 1000–1001, 1002f osteomyelitis, 1001–1003, 1002f, 1002b osteosarcoma, 1009–1010 scoliosis, 1006, 1006f septic arthritis, 1003, 1003f sever disease, 1006 spinal muscular atrophy, 1008

myelodysplasia, 416 myelomeningocele, 416, 416t, 418f

2603

neoplastic disorders in leukemia, 558–559, 559f lymphomas, 559–560, 560f, 560b

nervous system in, 414–415, 415b neural tube defects, 416–417, 416t, 417f–418f night terrors in, 337 obesity in, 651b, 929b pain perception in, 329t parasite infestations in pediculosis, 854t–855t scabies, 854t–855t

parasites in bedbugs, 1051–1052 fleas, 1051, 1052f pediculosis, 1051 scabies, 1051, 1051f

peanut allergy in, 175b perinatal stroke, 423 phenylketonuria, 421, 421f pulmonary disease and disorders in, 697–711 acute epiglottitis, 698t, 699 acute respiratory distress syndrome, 707 aspiration pneumonitis, 706 asthma, 706–707, 707b bronchiolitis, 703–704, 706b bronchopulmonary dysplasia, 702–703, 703t, 703b, 704f croup, 697–699, 698f cystic fibrosis, 707–709, 708f foreign body aspiration, 699–700 obstructive sleep apnea syndrome, 700 pneumonia, 704–706, 705t respiratory distress syndrome of the newborn, 700–702, 700b, 701f–702f respiratory tract infections, 703–704 sudden infant death syndrome, 709, 709b tonsillar infections, 699

renal disorders in, 751–759 acute poststreptococcal glomerulonephritis, 754 glomerular disorders, 754–755 hemolytic uremic syndrome, 755 hypoplastic kidney, 751 immunoglobulin A nephropathy, 754 nephroblastoma, 755–756, 756t, 756b nephrotic syndrome, 754–755, 755f polycystic kidney disease, 751–752 renal agenesis, 752

skin infections in bacterial, 1046–1047, 1046f–1047f chickenpox, 1049–1050, 1049t, 1050f erythema infectiosum, 1050

2604

fungal, 1047–1048 hand, foot, and mouth disease (HFMD), 1049t, 1050 herpes zoster, 1049t, 1050 molluscum contagiosum, 1048, 1048f roseola, 1049, 1049t rubella, 1048–1049, 1048f, 1049t rubeola, 1049, 1049t small pox, 1049 thrush, 1047–1048 tinea capitis, 1047, 1047f tinea corporis, 1047 varicella, 1049–1050, 1049t, 1050f viral, 1048–1050, 1048f, 1049t, 1050f

somnambulism in, 337 spina bifida, 416, 418f spina bifida occulta, 416–417 storage diseases, 421–422 strabismus in, 338 stroke, 423 sudden infant death syndrome in, 709, 709b urinary system disorders in, 751–759 bladder exstrophy, 753–754, 753f bladder outlet obstruction, 754 enuresis, 757, 758t epispadias, 753–754 hypospadias, 753, 753f, 835–836 ureterocele, 752–753 ureteropelvic junction obstruction, 752–753 urinary incontinence, 757–758, 758t, 758b urinary tract infections, 756, 756b vesicoureteral reflux, 757, 757f

Chlamydia trachomatis, 342, 831, 853t Chlamydial ophthalmia, 854t–855t Chlamydophilal pneumonia, 705, 705t Chloride balance of, 115–117 transport of, 115

Cholangiocellular carcinoma, 910 Cholecalciferol, 722–723 Cholecystitis, 905 Cholecystokinin (CCK), 476b, 478, 862–863, 862t Cholelithiasis, 494, 904–905, 905f Cholesterol, 602 Cholesterol gallstones, 904–905

2605

Cholinergic crisis, 406 Cholinergic transmission, 322 Cholinesterase inhibitors, 365 Chondrocytes, 490, 942 Chondrogenic tumors, 990, 993, 993f Chondrosarcoma, 993, 993f Chordae tendineae, 565–566 Chordee, 753, 753f Chorea, 372–374, 373t Choroid, 338, 338f Choroid plexuses, 312 Chromaffin cells, 442–444 Chromatids, 28, 47f Chromatin, 28, 64 Chromophils, 433 Chromophobes, 433 Chromosomal mosaics, 46 Chromosome aberrations, 44–51 aneuploidy, 44 Down syndrome, 46, 48f incidence of, 44 Klinefelter syndrome, 47, 50f polyploidy, 44 tetraploidy, 44 translocation, 51f triploidy, 44 Turner syndrome, 47, 50f

Chromosome bands, 44, 47f Chromosome breakage, 48 Chromosome translocations, 230–231 Chromosomes, 40, 44–51 aberrations and associated diseases, 44–51 homologous, 44, 47f instability of, 238 karyotype of, 44, 47f sex, 44

2606

aneuploidy of, 46–47

structure of, 47f abnormalities of, 48–51, 49t, 50f

translocations, oncogene activation by, 231f

Chronic active hepatitis, 904 Chronic alcoholism, 89 Chronic bacterial prostatitis, 840, 840b Chronic bilirubin encephalopathy, 928 Chronic bronchitis, 682–685, 683f–684f Chronic conjunctivitis, 342 Chronic cough, 671 Chronic fatigue syndrome, 985 Chronic gastritis, 888 Chronic granulomatous disease (CGD), 187 Chronic hepatitis, 929 Chronic immune (fundal) gastritis, 888 Chronic inflammation, 146–147, 147b, 148f anemia of, 506t description of, 242

Chronic kidney disease acute kidney injury progression to, 744 carbohydrate metabolism in, 746 cardiovascular disease in, 746 clinical manifestations of, 745–746 creatinine clearance in, 746 definition of, 744 dyslipidemia in, 746 electrolyte balance in, 746 endocrine system in, 748 evaluation of, 748 fluid balance in, 746 gastrointestinal system in, 747t, 748 hematologic system in, 747t, 748 immune system in, 747t, 748 integumentary system in, 747t, 748 neurologic system in, 747t, 748 pathophysiology of, 744–745 progression of, 744, 745t, 746f

2607

protein metabolism in, 746 pulmonary system in, 746–748, 747t reproductive system in, 747t, 748 stages of, 745t systemic effects of, 747t, 748b treatment of, 748 urea clearance in, 746

Chronic lymphocytic leukemia, 521, 521t, 525–526 Chronic mesenteric ischemia, 896 Chronic mucocutaneous candidiasis, 188 Chronic myelogenous leukemia in children, 558 description of, 521, 521t, 522f, 525–526, 526f tyrosine kinase inhibitors for, 559

Chronic myeloid leukemia, 231f Chronic nonimmune (antral) gastritis, 888 Chronic obstructive pulmonary disease air trapping in, 685, 685f characteristics of, 682, 684t chronic bronchitis, 682–685, 683f–684f clinical manifestations of, 684t emphysema, 685–686, 685f

Chronic orthostatic hypotension, 596 Chronic pain, 331, 332t Chronic pancreatitis, 906 Chronic pelvic pain syndrome, 841 Chronic prostatitis, 841 Chronic pulmonary aspiration, 706 Chronic pyelonephritis, 737, 756 Chronic rejection, 186, 186b Chronic relapsing TTP, 537 Chronic tension-type headache (CTTH), 401 Chronic traumatic encephalopathy (CTE), 388 Chronic venous insufficiency (CVI), 591 Chronotropic effect, 216 Chylomicrons, 602

2608

Chylothorax, 676t Chyme, 861, 865, 867 Cigarette smoking cancer and, 265 coronary artery disease risks, 603 environmental tobacco smoke, 265 lung cancer risks, 691

Ciliated simple columnar epithelium, 31t–32t Cimex lectularius, 1051 CIN, Cervical intraepithelial neoplasia Cingulate gyrus herniation, 368f, 369b Circadian rhythms, 335 disorders involving, 337

Circle of Willis, 314, 316f Circulating tumor cells, 821 Circulation bronchial, 657–659, 660b collateral, 568 coronary, 567–568, 569f pulmonary anatomy of, 564f, 657–659, 660b control of, 659 description of, 563 perfusion distribution in, 665

splanchnic, 861f, 869

Circulatory system anatomy of, 578f–579f blood vessels, Blood vessels description of, 563, 567b functions of, 563

Circumflex artery, 567–568 Circumlocution, 359–360 Cirrhosis, 901–903, 903b alcoholic liver disease as cause of, 901 ascites caused by, 897, 898f causes of, 901, 901b in children, 929 clinical manifestations of, 902, 902f definition of, 901

2609

evaluation of, 902–903 in hereditary hemochromatosis, 516 treatment of, 902–903

CIS, Carcinoma in situ Citric acid cycle, 17–18 Citrulline, 977 Clara cell, 658f Class switch, 165–166 Classical pathway, 137 Clastogens, 48 Clear cell tumors, 733 Cleft lip, 916–917, 917f Cleft palate, 916–917, 917f Clinical allergic reactions, selected causes of, 178t Clitoris, 763, 764f–765f Cloaca, persistent, 920 Cloacal exstrophy, 754 Clonal deletion, 160 Clonal diversity, 157–161, 158f, 161b Clonal expansion, 230–231 Clonal proliferation, 230–231, 232f Clonal selection B cell, 162–163, 165f clonal diversity versus, 160t description of, 157, 161–163 illustration of, 158f T-cytotoxic cell, 165f

Clonic phase, of epilepsy, 365–367 Closed brain injuries, 384–385, 385t Clostridioides difficile, 135 Clostridium botulinum, 199 Clostridium difficile acute infectious diarrhea caused by, 927 diarrhea caused by, 881

Clot retraction test, 500t–501t

2610

Clotting factors description of, 557t fibrinogen, 485 function of, 498 laboratory tests for, 500t–501t

Clotting systems, 137, 498 CLRs, C-type lectin receptors Clubbing, 672, 672f, 706 Clubfoot, 999, 1000f, 1000t Cluster breathing, 354t Cluster headache, 401 Cluster of differentiation, 161 Coagulation disorders in children, 557–558, 558b consumptive thrombohemorrhagic disorders, 540–542 description of, 539–544 disseminated intravascular coagulation, Disseminated intravascular coagulation hemophilias, 557, 557t thromboembolic disorders, 543–544, 543f

Coagulation system, 137 Coagulative necrosis, 100 Coarctation of the aorta, 643, 643f Coated vesicles, 23 Cobalamin, 510–511 Cocaine, 86t Cocci, 199 Cochlea, 342–343, 343f Codons, 41 stop, 41

Cognitive-evaluative system, 328–329 Cognitive function alterations in, seizure disorders, 365–367, 365t neural systems involved in, 351

Cognitive systems, alterations in, 351–367 Cogwheel rigidity, 370, 371t

2611

Cold injury, 1038–1039 Collagen, 150 Collagen fibers, 934t, 937, 942–943, 942f Collagen-forming tumors, 993 Collagenic tumors, 993–994 Collagenous colitis, 894 Collagens, 12 Collateral arteries, 568 Collateral circulation, 568 Collecting duct, 713f–714f, 714–716 Collectins, 135, 663 Colloid, 438, 438f Colon anatomy of, 867 diverticular disease of, 895–896, 895f

Colonization, 197–198 Colony stimulating factor-1, 243 Color blindness, 341 Color vision, 340–341 Colorectal cancer, 260t–264t, 264, 907t, 908–910, 908b–909b, 909f Colorectal polyps, 908 Colostral antibodies, 168 Coma malignant hyperthermia versus, 335 metabolically induced, 353

Combined deficiencies, 187 Commensal relationship, 135 Comminuted fracture, 955, 956t Commissural fibers, 305 Communicability, 198 Communicating hydrocephalus, 370, 370t Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), 1027 Community-acquired pneumonia, 686–687, 704 Compact bone, 937, 938f

2612

Compartment I disorders, 783 Compartment II disorders, 783 Compartment III disorders, 783 Compartment IV disorders, 783 Compartment syndrome, 961–963, 963b, 964f Compensation, 127–128 Compensatory antiinflammatory syndrome, sepsis and, 632b Compensatory hyperplasia, 75, 148–149 Compensatory hypertrophy, 729 Complement, in septic shock, 632b Complement cascade, 137 Complement deficiencies, 188 Complement receptors, 140, 140t Complement system, 137, 139b activation of, 137 alternative pathway of, 137 classical pathway of, 137 lectin pathway of, 137

Complementary base pairing, 41 Complementary determining region (CDR), 166 Complete blood count (CBC), 147 Complete fracture, 955, 956t Complete precocious puberty, 782, 831 Compliance, of lung, 663–664 Complicated plaque, 599 Compound fracture, 955, 956t Compound nevus, 1032t Compound skull fracture, 385t, 387 Compression atelectasis, 676 Compressional asphyxiation, 92 Compressive syndrome, 409 Computed tomography pediatric, 296b radiation dose from, 278f, 278t, 278b

2613

Concentration gradient, 20 Concussion brain, 388 spinal cord, 389t

Conditioned pain modulation, 330 Conducting airways, 655–656, 657f Conduction, of heat, 334t Conduction system, 568 Conductive aphasia, 359–360 Conductive dysphasia, 361t Conductive hearing loss, 343–344 Condylomata acuminata, 833–834, 854t–855t, 1029 Cones, 338 Confusion, 362t Congenital abnormalities of the kidney and urinary tract (CAKUT), 751, 752f, 754b Congenital adrenal hyperplasia, 468 Congenital anal stenosis, 921f Congenital closure glaucoma, 339 Congenital heart disease (CHD), 639–649 acyanotic heart defects, 639 aortic stenosis, 643–644, 644f atrial septal defect, 641–642 atrioventricular canal defect, 642–643, 642f categories of, 639, 640f coarctation of aorta, 643, 643f cyanotic heart defects, 639 endocarditis risk, 644b environmental factors associated with, 639, 640t genetic factors in, 639, 640t heart failure caused by, 649, 649t, 649b hypoplastic left heart syndrome, 648–649, 648f, 649b incidence of, 639 naming of, 640 patent ductus arteriosus, 640–641 pulmonic stenosis, 644, 645f shunt, 639, 641f Tetralogy of Fallot, 639, 645–646, 646f

2614

total anomalous pulmonary venous connection, 647–648, 647f transposition of the great arteries, 646–647, 647f tricuspid atresia, 645–646, 646f truncus arteriosus, 648, 648f

Congenital hydrocephalus, 370, 419–420 Congenital hypothyroidism, 455 Congenital nephrotic syndrome, 755 Congenital talipes equinovarus, 999, 1000t Congestive heart failure, 466 Congestive splenomegaly, 534 Conjugated bilirubin, 872, 900 Conjunctivitis, 341 Conjunctivitis-otitis syndrome, 342 Conn syndrome, 468 Connective tissues, 33t–35t fibroblast in, 13f

Connexons, 13 Consanguinity, 56 Consciousness, 351 loss of, 387

Constipation, 880 Constrictive pericarditis, 612–613, 612f Consumptive thrombohemorrhagic disorders, 540–542 Contact activation (intrinsic) pathway, 137 Contact dermatitis allergic, 180, 1022, 1022f irritant, 1022

Contact-dependent signaling, 14–15 Contiguous osteomyelitis, 971 Continuous positive airway pressure for bronchopulmonary dysplasia, 703 for obstructive sleep apnea syndrome, 700 for respiratory distress syndrome of the newborn, 702

Contractility, myocardial, 573, 620 Contractures, 984

2615

Contralateral control, 308 Contrecoup injury, 385t Contusions, 384–385 spinal cord, 389t

Conus medullaris, 308 Convection, of heat, 334t Convergence, 302–303 Convulsion, 365 Cooley anemia, 555 Cooper ligaments, 770, 771f Coping, 221–224 Cor pulmonale, 674, 690, 690f Cornea, 339t “Corner” metaphyseal fractures, 1010, 1011f Cornification, 770 Coronary arteries, anatomy of, 567–568, 569f Coronary artery bypass graft (CABG), 606 Coronary artery disease (CAD), 465–466, 602–611, 606b adipokines and, 603 atherogenic diet and, 603 atherosclerosis as cause of, 602 chronic kidney disease and, 603 cigarette smoking and, 603 development of, 602–603 in diabetes mellitus, 603 dietary factors, 602 dyslipidemia and, 602–603, 602t, 603b highly-sensitive C-reactive protein and, 603 hypertension and, 603 inflammation markers and, 603 ischemia and, 603 medications for, 603 obesity and, 603 risk factors for, 603 sedentary lifestyle and, 603 troponin I and, 603

Coronary blood flow, 585

2616

Coronary capillaries, 568 Coronary circulation arteries of, 567–568, 569f autonomic regulation of, 585 autoregulation of, 585 capillaries, 568 regulation of, 585 veins, 568, 569f

Coronary ligament, 869–870 Coronary ostia, 567 Coronary perfusion pressure, 585 Coronary sinus, 567, 569f Corpora cavernosa, 774, 774f Corpora quadrigemina, 308 Corpus callosum, 305 Corpus luteum, 767 Corpus luteum cysts, 794 Corpus spongiosum, 774 Corrigan pulse, 616 Cortical bone, 937, 938f, 964–965 Cortical dysplasias, 419 Cortical nephrons, 712 Cortical spreading depression (CSD), 400 Corticobulbar tract axons of, 311 description of, 305

Corticospinal tracts, 305, 311 Corticosteroids, 685–686 Corticotropin-releasing hormone (CRH), 213–214, 436t, 442 Cortisol, 442 chronic, pathophysiologic effects of, 214–216 physiologic effects of, 214, 216t stress-related secretion of, 216

Costal cartilage, 940 Costochondritis, 672

2617

Cough, 670–671 Cough reflex, 660 Coup injury, 385t Coupling, 948–950 Cowper glands, 775 Cow's milk allergy, 548 COX, Cyclooxygenase COX-1, 143 COX-2, 143 CpG dinucleotide, 64 CpG island, 54 CPP, Cerebral perfusion pressure Crack, 86t “Cracked pot” sign, 420 Cranial nerves description of, 318, 318f list of, 319t palsy of, 377

Cranial vault, 311 Craniosacral division, 321 Craniostenosis, 419f Craniosynostosis, 417–419, 419f Cranium, 311 Creatinine clearance, 723, 746 metabolism of, 947 plasma concentration of, 723

CREST syndrome, 1030–1031 Creutzfeldt-Jakob disease, 363t CRH, Corticotropin-releasing hormone Cri du chat syndrome, 48–49, 640t Cricoid cartilage, 697 Crista ampullaris, 343 Critical region, 66–67

2618

Crohn disease (CD), 893t, 894 Cross-bridge, 573 Cross-bridge theory, 573, 574f, 950 Crossover, 58, 58f Crush syndrome, 961 Cryoglobulins, 178 Cryptorchidism, 835–836 Crypts of Lieberkühn, 864f, 865, 869, 893–894 Crystalline fragment, 166 Crystallization, 730 CSD, Cortical spreading depression CSF, Cerebrospinal fluid CTE, Chronic traumatic encephalopathy CTTH, Chronic tension-type headache C-type lectin receptors (CLRs), 140, 140t C-type natriuretic peptide, 722 Cul-de-sac, 764, 765f Cultured epithelial autografts, 1038f Curcumin, 269, 843b–844b Curling ulcers, 890, 1038 Cushing diseases, 467–468, 467f Cushing-like syndrome, 467 Cushing syndrome, 248t, 518 Cushing ulcers, 890 Cushing's syndrome, 467–468, 467f Cutaneous hemangiomas, 1052–1053, 1052f, 1053b Cutaneous leukocytoclastic angiitis, 1030 Cutaneous lymphomas, 1034–1035 Cutaneous melanoma, 1032t, 1033–1034, 1034f Cutaneous vascular malformations, 1053, 1053f Cutaneous vasculitis, 1030 Cutibacterium acnes, 1044 CVAs, Cerebrovascular accidents

2619

CVD, Cerebrovascular disease CVI, Chronic venous insufficiency Cyanide, 93 Cyanosis central, 671 definition of, 639, 671 peripheral, 671 in pulmonary disease, 671–672

Cyanotic heart defects, 639 Cyclic adenosine monophosphate (cAMP), 432 hormones associated with, 432t protein kinase activation by, 432

Cyclic guanosine monophosphate (cGMP), 432, 432t Cyclooxygenase (COX), 143 Cyclooxygenase-2, 908 Cyclopia, 416 Cyst(s) breast, 808 corpus luteum, 794 dermoid, 794 follicular, 794 ovarian, 793–794, 793f, 794b skin, 1017t–1018t, 1018f

Cystatin C, 723, 724t, 744 Cysteine protease, 936t Cystic acne, 1044 Cystic duct, 873 Cystic fibrosis, 54, 55f, 707–709, 708f, 922–923, 923t Cystic fibrosis transmembrane conductance regulator gene, 707 Cystic fibrosis transmembrane conductance regulator protein, 708 Cystic fibrosis transmembrane regulator (CFTR) protein, 922 Cystitis, 734–735, 756 gangrenous, 735 hemorrhagic, 734 interstitial, 735 mild, 734 suppurative, 734

2620

ulcerative, 735

Cystocele, 731, 792, 793f Cystometric test, 732b Cystosarcoma phyllodes, 820t Cysts, 146 Cytochromes, 18, 97 Cytokines, 140–141, 146b proinflammatory, 141–142

Cytokinesis, 27, 44 phases of, 27–28

Cytopenia, 530 Cytoplasmic matrix, 3–4 Cytoplasms, 2–3 organelles of, 2f, 3–4

Cytosine, 40 Cytoskeleton, 4t–6t Cytosol, 3–4 Cytosolic calcium, 98f Cytotoxic edema, 369 D Damage-associated molecular patterns (DAMPs), 140 DAMPs, Damage-associated molecular patterns Dandy-Walker malformation (DWM), 420 Dark adaptation disorder, 340t Data processing deficits, 359–365 acute confusional states, 360, 360b agnosia, 359 aphasia, 359–360, 359f, 361t–362t

Daughter cells, 28 Daytime incontinence, 757 DCIS, Ductal carcinoma in situ DDD, Degenerative disk disease D-dimer, 542 de Quervain thyroiditis, 455

2621

Dead space ventilation, 660 Deafferentation pain, 332t Deamination, 873 Decerebrate posture/response, 356f, 378 Decomposition, 106 Decornification, 770 Decorticate posture/response, 356f, 378 Deep hemangiomas, 1052–1053, 1052f Deep-partial thickness, 1035t, 1036, 1036f Deep venous thrombosis prevention of, 592 in thrombocythemia, 538–539 treatment of, 591–592

Defecation reflex, 869 Defensins, 135 Degenerative disk disease (DDD), 394 Degenerative joint disease, 394 Degranulation, 142–143 Dehiscence, 151–152 Dehydration, 118 signs and symptoms of, 118b

Dehydroepiandrosterone (DHEA), 842–844, 846 Dehydroepiandrosterone sulfate, 761t, 786 Delayed age of onset, 53 Delayed cerebral ischemia, 399 Delayed gastric emptying, 883 Delayed hypersensitivity, 1022 reactions, 174 skin test, 180

Delayed puberty, 781–782, 782t, 830, 831b Delayed repolarization, 121 Deletion, of chromosome, 48–49 Delipidation, 272f–273f Delirium conditions that cause, 360b

2622

dementia versus, 363t evaluation and treatment of, 360, 360b excited delirium syndrome, 360 pathophysiology and clinical manifestations of, 360

Delta cells, 439–440 Delta lesions, 961 Dementia Alzheimer disease, 362–365, 363t–364t, 364f of Alzheimer type, 362 definition of, 362 delirium versus, 363t frontotemporal, 363t, 365 Lewy body, 363t, 374 neurodegenerative, 364b vascular, 363t

Demyelinating disorders, 403–404 Dendrites, 299, 300f Dendritic cells, 139–140, 144, 253 Dense, regular (white fibrous) tissue, 33t–35t Dense bodies, 497 Dense irregular tissue, 33t–35t Dental amalgam, 85–86 Deoxyhemoglobin, 493 Deoxyribonucleic acid (DNA), 1 in chromatin, 40 composition of, 40, 51b double-helix model of, 40, 42f as genetic code, 41 mutations of, 41 replication of, 41, 42f structure of, 40, 41f

Depolarization, 26, 570 Dermal appendages, 1014–1015, 1015f Dermatitis allergic contact, 1022, 1022f atopic, 854t–855t, 1022, 1045, 1045f in children, 1045–1046, 1045f–1046f diaper, 1045–1046, 1046f

2623

irritant contact, 1022 seborrheic, 1023, 1023f stasis, 1022, 1023f

Dermatomes, 318, 318f, 396f Dermatomyositis, 248t, 989, 989f Dermatophytes, 204, 1029 Dermis, 1014, 1015f, 1016t Dermoid cysts, 794 Dermopathy, Graves, 453–454 DES, Diethylstilbestrol Descending inhibitory pathways, 330, 330f Descending pathways, 298, 299f Desensitization, 182 Desmoglein, 1046–1047 Desmoplastic melanoma, 1033–1034 Desmosomes, 13 Detrusor areflexia, 733 Detrusor hyperreflexia, 732–733 Detrusor sphincter dyssynergia, 732–733, 733f Developmental dysplasia of the hip, 999–1000, 1001f, 1003b Developmental plasticity, 264–265 DHEA, Dehydroepiandrosterone Diabetes mellitus categories of, 457 complications of acute, 461–464, 463t cardiovascular disease, 465–466 chronic, 464–466, 464t congestive heart failure, 466 coronary artery disease, 465–466 diabetic ketoacidosis, 462–464, 463f, 463t diabetic nephropathy, 464–465, 464t, 465f diabetic neuropathies, 464t, 465, 466f diabetic retinopathy, 464, 464t, 465f foot amputation, 465, 466f hyperosmolar hyperglycemic nonketotic syndrome, 463f, 463t, 464 hypoglycemia, 461–462, 463t infection, 466 macrovascular, 464t, 465–466 microvascular, 464–465, 464t

2624

peripheral vascular disease, 466 stroke, 466

complications of, coronary artery disease, 568 diagnostic criteria for, 457, 457b epidemiology of, 458t etiology of, 458t gestational, 461 glycosylated hemoglobin, 457 heart failure and, 621b maturity-onset diabetes of youth, 461 type 1, 457–459, 458f, 458b, 459t type 2, 460–461, 460f, 461b, 462f

Diabetic glomerulopathy, 740f Diabetic ketoacidosis (DKA), 462–464, 463f, 463t Diabetic nephropathy, 464–465, 464t, 465f description of, 740 end-stage renal failure caused by, 748

Diabetic retinopathy, 464, 464t, 465f Diameter, 578–579 Diapedesis, 144 Diaper dermatitis, 1045–1046, 1046f Diaphoresis, 118 Diaphragm, 662, 662f Diaphysis, 937f, 938 Diarrhea, 880–881, 883b in children, 927 clinical manifestations of, 881 Clostridium difficile-associated, 881 definition of, 880, 927 evaluation of, 881 and hypokalemia, 121 in infants, 927 large-volume, 880 motility, 881 osmotic, 880–881 pathophysiologic mechanisms of, 927 pathophysiology of, 880–881 postgastrectomy, 891 secretory, 881

2625

small-volume, 880 treatment of, 881

Diarthrosis, 940 Diastole, 567, 577 Diastolic blood pressure, 581–582 Diastolic depolarization, 570 Diastolic dysfunction, 622 DIC, Disseminated intravascular coagulation Dicalcium phosphate dihydrate, 937 Dickkopf family (Dkk), 936t Diencephalon, 308 Diet breast cancer and, 818 cancer and, 267, 268f–269f fats in, 865b gluten-free, 924–925 prostate cancer and, 841–842, 843b–844b type 2 diabetes mellitus and, 460

Dietary potassium, 121 Diethylstilbestrol (DES), 265, 295 Differential count, 147 Differential white cell count, 500t–501t Diffuse axonal injury, 385t, 387–388 Diffuse large B-cell lymphoma, 526 Diffuse noxious inhibitory control (DNIC), 330 Diffuse papillomatosis, 808 Diffusion, 20–22 DiGeorge syndrome (22q11.2 deletion syndrome), 187 facial anomalies associated with, 187f

Digestion accessory organs of, 869–875, 870f impairment of, 922–927 in small intestine, 865, 866f

Digestive function, alterations of, in children, 916–932 Digestive system, Gastrointestinal tract exocrine pancreas, 874–875

2626

gallbladder, 873 liver, Liver mouth and esophagus, 858–860 overview of, 858 structures of, 858, 859f

Digestive tract, cancer of, 260t–264t Dihydrotestosterone, 838, 845, 846f 5α−Dihydrotestosterone, 844 1,25-Dihydroxy-vitamin D3, 439 Dilated cardiomyopathy, 613, 613f Dilutional hyponatremia, 119 Dimorphic fungi, 204 DIOS, Distal intestinal obstruction syndrome Dipeptidyl peptidase IV (DPP-IV), 460 2,3-Diphosphoglycerate, 667 Diplegia, 376b Diploid cells, 44 Diplopia, 338 Dipsogenic polydipsia, 449 Direct antiglobulin test, 500t–501t Direct transmission/contact, 196–197 Directional transport, 4 Disease-modifying antirheumatic drugs (DMARDs), 979 Diseases of adaptation, 210 Diskogenic pain, 392–393 Dislocation, 958–959 Disse space, 871 Disseminated intravascular coagulation (DIC), 540–542 clinical course of, 540 clinical manifestations of, 542 conditions associated with, 541b D-dimer tests for, 542 definition of, 540 diagnosis of, 540 evaluation of, 542 pathophysiology of, 540–542, 541f

2627

plasmin in, 540 thrombosis in, 542 tissue factor in, 539 treatment of, 542

Dissemination/spread of infections, 198 Distal convoluted tubule, 713f–715f, 714–716, 719f, 721–722 Distal intestinal obstruction syndrome (DIOS), 919 Disuse atrophy, 74, 985–987 Diuretics, urine flow affected by, 722 Divergence, 302–303 Diverticula, 895 Diverticular disease of the colon, 895–896, 895f Diverticulitis, 895 Diverticulosis, 885t, 895 DKA, Diabetic ketoacidosis Dkk, Dickkopf family DMARDs, Disease-modifying antirheumatic drugs DNA, Deoxyribonucleic acid DNA-binding proteins, 3 DNA damage response, 28, 29f DNA methylation, 54, 64, 65b cancer and, 69–70, 230–231, 267

DNA methyltransferase, 270f DNA polymerase, 41 DNA sequencing, 58 DNIC, Diffuse noxious inhibitory control Dolichocephaly, 419f Doll eyes phenomenon, 356f Dolor, 136 Dominance, 51 Dominant, 51 Dopamine in movement disorders, 372 properties of, 304t substantia nigra synthesis of, 305–306

2628

Dormancy, of cancer cells, 245–247 Dorsal column, 309, 311 Dorsal respiratory group (DRG), 660 Dorsal root ganglion, 308–309 Dosage compensation, 56 Dose rate ionizing radiation, 280 “Double bubble” sign, 918 Double-helix model, 40, 42f Double-strand break (DSB), 277–278 Down syndrome, 46, 48f atrioventricular canal defect in, 642 congenital heart disease in, 639, 640t leukemia risks, 294 maternal age and, 46, 48f

Down-regulation, 431, 431f DPP-IV, Dipeptidyl peptidase IV DRG, Dorsal respiratory group Driver mutations, 230–231 Drowning, 93 Drug, encephalopathies caused by, 422 Drusen, 340 Dry-lung drowning, 93 DSB, Double-strand break Dual x-ray absorptiometry (DXA), 965–966, 968 Duchenne muscular dystrophy, 57, 1006t, 1007–1008, 1007f–1008f Ductal adenocarcinomas, 911 Ductal carcinoma in situ (DCIS), 228, 810, 811f, 811b, 821–825, 823f Ductus arteriosus definition of, 640 patent, 640–641, 641f

Dumping syndrome, 891 Duodenal ulcers, 889, 890f, 891t Duodenum anatomy of, 864 arterial supply to, 864

2629

obstruction of, 918–919 osmoreceptors in, 863

Dupuytren contracture, 832 Dura mater, 311 Dutch Famine Birth Cohort, 264–265 Dwarfism, 450, 450f DWM, Dandy-Walker malformation DXA, Dual x-ray absorptiometry Dynorphins, 329 Dysarthria, 359–360 Dysbiosis, 895 Dysfunctional equilibrium, 378–379 Dysfunctional righting, 378–379 Dysfunctional uterine bleeding, 75–76 Dysfunctional voiding, 758t Dysfunctional wound healing, 150–152, 152b Dysgeusia, 345 Dyslipidemia in chronic kidney disease, 746 coronary artery disease and, 602–603, 602t, 603b

Dyslipoproteinemia, 602 Dysmenorrhea, 783 Dyspareunia, 806 Dysphagia, 883, 907 Dysphasia, 359, 361t Dysplasia, 76, 76f Dyspnea, 670 Dyspraxia, 379 Dysrhythmias, 623–624, 625t–626t, 626t–627t Dyssomnias, 336–337 Dyssynergia, 732–733 Dystonia, 371f, 372, 378 Dystonic (dyskinetic) cerebral palsy, 421 Dystonic movements, 378

2630

Dystonic postures, 378 Dystrophic calcification, 98 Dystrophin, 57, 1007 E Ear anatomy of, 342–343, 342f–343f external, 342, 342f infections, 344 inner, 342–343, 343f mastoid air cells of, 342 middle, 342, 342f

Eastern equine encephalitis, 402 EBV, Epstein-Barr virus E-cadherin, 824 Eccentric contraction, 951 Ecchymosis, 496t Eccrine sweat glands of, 1014–1015 ECD, Endocardial cushion defect ECM, Extracellular matrix Ectodermal dysplasia, 64 Ectopic testis, 835–836 Eczema, in children, 1045 Edema, 113–115, 115b alveolocapillary membrane affected by, 674 brain, 369, 369f cerebral, 369, 369f, 397 clinical manifestations of, 113–115 dependent, 113–114 evaluation of, 115 formation of, 114f generalized, 113–114 interstitial, 633 localized, 113–114 in nephrotic syndrome, 741t pathophysiology of, 113 pitting, 113–114, 114f

2631

pulmonary, 678–679, 679f treatment for, 115

EDRF, Endothelium-derived relaxing factor EEG, Electroencephalogram Effective osmolality, 21 Effective ventilation, 660 Effector cells, 161 Effector organs, 298 Efferent arteriole, 716 Efferent lymphatic vessels, 587 Efferent neurons, 309–310 Efferent pathways, 298, 327 Efferent tubules, 772 EGF, Epidermal growth factor Eisenmenger syndrome, 642 Ejaculation, 774 Ejaculatory duct, 774–775 Ejection fraction description of, 574 heart failure with preserved, 623t heart failure with reduced, 620, 622f, 623t

Elastic arteries, 577 Elastic cartilage, 33t–35t Elastic recoil, 663 Elastic tissue, 33t–35t Elastin, 12 Elderly fever in, 335b pain perception in, 329t proprioception loss in, 346 self-defense mechanisms in, 171b sleep characteristics in, 337b thermoregulation in, 333

Elderly adults cardiac output in, 575t cardiovascular function in, 575t

2632

Electrical impulses, movement of, 26, 26f Electrocardiogram constrictive pericarditis findings, 612 description of, 570, 571f left ventricular hypertrophy findings, 622 myocardial infarction diagnosis using, 609, 611f myocardial ischemia diagnosis using, 605, 605f

Electroencephalogram (EEG), 335 Electrolytes, 9 distribution of, 111–113, 112t polarity of, 20 in saliva, 860f as solute, 20–22

Electromagnetic fields (EMFs), 282 Electromagnetic radiation (EMR), 282, 282b Electromechanical dissociation, 625t–626t Electromyography, 732b Electronic cigarettes (e-cigarettes), 267 Electron-transport chain, 18 Embolic stroke, 396–397 Embolism, 598, 598t Embolus, 543, 598, 598t Embryonal rhabdomyosarcoma, 994 Embryonal tumors, 291 Embryonic development, 417f Embryonic stem cells, 65–66 Embryonic tumors, 291 Emesis, 879–880, 886 EMFs, Electromagnetic fields Emphysema, 685–686, 685f Empirical risks, 59–60 Empyemas, 403, 675–676, 676t EMR, Electromagnetic radiation EMT, Epithelial-mesenchymal transition Encephalitis, 402–403, 402b, 422

2633

Encephalocele, 416 Encephalopathies acute, 422 drug-induced, 422 lead poisoning as cause of, 422 static (nonprogressive), 420–421

Encounter, contact with microorganism, 196 End-diastolic volume, 574 Endemic diseases, 198 Endocannabinoids, 330, 478 Endocardial cushion defect (ECD), 642 Endocardial disorders, 614–620, 618b, 00026##b0095 acute rheumatic fever, 616–618, 617f aortic regurgitation, 616 aortic stenosis, 615, 615f infective endocarditis, 618–620, 618b, 619f mitral regurgitation, 616 mitral stenosis, 615–616, 616f mitral valve prolapse syndrome, 616, 617f rheumatic heart disease, 616–618, 617f tricuspid regurgitation, 616 valvular dysfunction, 614–616, 614t, 615f

Endocarditis, 644b Endocardium, anatomy of, 564, 565f Endocervical canal, 765, 766f Endocervical gonorrhea, 854t–855t Endochondral bone formation, 957 Endocrine disorders, 987 Endocrine glands aging effects on, 444b anatomy of, 429, 430f pineal gland, 437 structure of, 433–444 thyroid and parathyroid glands, 437–439, 437f

Endocrine pancreas, 439–441 Endocrine system aging effects on, 444b

2634

anatomy of, 429, 430f chronic kidney disease effects on, 748 dysfunction of, 447 functions of, 429

Endocytic matrix, 24b Endocytosis, 23–24, 24f, 146 Endogenous antigens, 161 Endogenous antioxidants, 83 Endogenous microorganisms, 196 Endogenous opioids, 329 Endogenous pyrogens, 140–141, 147, 333–334 Endolarynx, 655 Endolymphatic hydrops, Ménière disease Endometrial cancer, 260t–264t, 801–802, 801f, 802t Endometrial polyps, 794–795, 795f Endometriosis, 796–797, 796f Endometrium anatomy of, 765, 766f hormonal effects on, 768t hyperplasia of, 75–76, 801–802

Endomorphins, 329 Endomysium, 943 Endoplasmic reticulum, 4t–6t Endoplasmic reticulum stress, 102 Endorphins as endogenous opioids, 329 properties of, 304t

β Endorphins, 437t description of, 329 in stress response, 219t

Endosome, 23 Endosteal layer, 311 Endosteum, 938–939 Endothelial cells, 4, 143, 577, 580f Endothelial injury, 599

2635

Endothelins, 584 Endothelium, 260t–264t, 577 functions of, 581t inflammation of, 597–598 vascular, 563, 580f, 581t

Endothelium-derived relaxing factor (EDRF), 584 Endotoxin, 199, 201t End-stage renal failure, 748 Energy balance, regulation of, 475–476, 476b Energy metabolism diseases of, 987–988 reprogramming, 239–241, 241f

Engulfment, 146 Enkephalins as endogenous opioids, 329 properties of, 304t

Enneking staging system, 992, 992t Enteric plexus, 858 Enterocele, 793 Enteroglucagon, 862t Enterohepatic circulation, 871, 871f Enterokinase, 875 Enthesis, 951, 959 Entropion, 341 Enuresis, 757, 758t Environmental chemicals, 819 Environmental tobacco smoke (ETS), 265–267, 276 Enzymes, 199 EoE, Eosinophilic esophagitis Eosinopenia, 518, 519t Eosinophil, description of, 485f, 486, 487t Eosinophil chemotactic factor of anaphylaxis (ECF-A), 143 Eosinophil count, 500t–501t Eosinophilia, 518, 519t Eosinophilic chemotaxic factor of anaphylaxis, 518

2636

Eosinophilic esophagitis (EoE), 921 Eosinophils, 144 disorders involving, 519t

Ependymal cells, 300, 301t Ependymoma, 408, 424t Epicardium, 564, 565f Epicondyle, 959–960 Epicondylopathy, 959–960, 959f Epicritic information, 311 Epidemic diseases, 198 Epidermal growth factor (EGF), 29t, 232 Epidermis, 1014, 1015f, 1016t Epididymal cysts, 835, 835f Epididymis anatomy of, 773, 773f appendix, 836 disorders of, 834–838

Epididymitis, 838, 838f Epidural (extradural) hematoma, 313, 385, 385t, 387f Epidural space, 313 Epigallocatechin gallate, 843b–844b Epigenetic disease molecular approaches to understand, 68–69, 69b treatment of, 70–71

Epigenetic silencing, 238 Epigenetics, 54, 55f, 64–72, 65f, 67b cancer and, 69–71, 70f, 258–264, 258b, 259f, 267b and ethanol exposure in utero, 68 future directions on, 71 and genetic abnormalities, 68, 69f in genomic imprinting, 66–67 human development, 65–66 and maternal care, 68 mechanisms of, 64–65 DNA methylation, 54, 64, 65b histone modification in, 64–65

modification, twin studies on, 68, 70f

2637

nutrition and, 67–68 prostate cancer, 844–845

Epiglottitis, acute, 698t Epilepsy, 365, 423, Posttraumatic seizures Epileptogenic focus, 365–367 Epimysium, 943 Epinephrine, 216, 322, 583 Epiphyseal plate, 939 Epiphysis, 937f, 938 Epispadias, 753–754 Epithalamus, 308 Epithelial cells, chemicals from, 135 Epithelial tissues, 31t–32t Epithelialization, 150 Epithelial-mesenchymal transition (EMT), 245, 246f, 820, 847 Epithelioid cells, 147 Epitope, 166 EPSPs, Excitatory postsynaptic potentials Epstein-Barr virus (EBV) childhood cancer and, 295 description of, 243, 282–283 Hodgkin lymphoma and, 527–528 infectious mononucleosis caused by, 518–519 outcomes of, 520f transmission of, 520

Equatorial plate, 28 Equilibrium receptors, 343 Equinovalgus, 1000t Equinovarus, 999, 1000f, 1000t Equinus, 1000t Erectile reflex, 774 Erection, 774 Erlotinib, 254t Erosion, 1019t–1020t, 1020f ERRs, Excess relative risks

2638

Eryptosis, 507–509 Erysipelas, 1027 Erythema, 180 Erythema multiforme, 1026, 1047 Erythema toxicum neonatorum, 1053 Erythroblastosis fetalis, 550 Erythrocyte osmotic fragility test, 500t–501t Erythrocyte sedimentation rate, 147 Erythrocytes, 140 characteristics of, 487t, 488b development of, 491–495 differentiation, 493f disorders involving absolute polycythemia, 514, 516 hereditary hemochromatosis, 516–517, 517f iron overload, 516–517 myeloproliferative, 514–517 polycythemia vera, 514–516, 515t relative polycythemia, 514

disorders involving, in children, 548–556, 556b fetal, 548 functions of, 485–486 illustration of, 487f properties of, 485–486 senescent, 494–495 sickled, 553, 553f size and shape of, 485–486 in vascular relaxation, 494

Erythrocytosis, 515 Erythrodermic (exfoliative) psoriasis, 1023 Erythromyalgia, 538 Erythropoiesis diminished, anemia of, 507–514 nutritional requirements for, 494, 494t

Erythropoietin, 491, 493f, 723 effects of, 723b

Escharotomies, 1036 Escherichia coli, 838 infection, acute infectious diarrhea caused by, 927

2639

Esophageal atresia, in children, 917, 918f Esophageal malformation, 917–918 Esophageal varices, 897 Esophagus aging effects on, 876b anatomy of, 858–860, 859f Barrett, 907 cancer of, 260t–264t, 906–908, 907t, 907b congenital impairment of, 916–918

Essential thrombocythemia, 538 Essential tremor, 373t Estradiol, 767–768, 802f Estrogen adrenal hypersecretion of, 469 biologic effects of, 767–768 biosynthesis of, 816f breast development affected by, 771 functions of, 761t, 767, 768t nonreproductive effects of, 768b in sexual differentiation, 760–761 in stress response, 219t

Estrogen receptor-α, 846 Estrogen receptor-β, 846 Estrogens, adrenal cortex secretion of, 442 Estrone, 767 Ethanol, 86–90 cellular injury and, 86–90

ETS, Environmental tobacco smoke Eukaryotes, 1, 2f organelles of, 1

Euploid cells, 44 Eupnea, 671 Eustachian (pharyngotympanic) tube, 342 Evaporation, 334t Ewing sarcoma, 1010, 1010f Exanthema subitum, 1049, 1049t

2640

Excess relative risks (ERRs), 276–277 Excessive fibrin, 151 Excitation, 948 Excitation-contraction coupling, 573–574 Excitatory neurotransmitters, 329 Excitatory postsynaptic potentials (EPSPs), 302 Excited delirium syndrome (ExDS), 360 Excoriation, 1019f, 1019t–1020t ExDS, Excited delirium syndrome Executive attention, deficits of, 357–358, 358t Exercise, effects of, 223 Exercise-induced bronchoconstriction, 707b Exfoliative toxins, 1046 Exhaustion stage, of general adaptation syndrome, 210 Exocrine pancreas anatomy of, 870f, 874–875, 875f, 875b insufficiency, 892

Exocytosis, 23–24, 24f Exogenous antigens, 161 Exogenous microorganisms, 196 Exogenous pyrogens, 147, 333–334 Exomes, in cancer, 279f Exons, 43 Exophthalmos, 453f Exosomes, 23, 25f Exotoxins, 199, 201t Expectancy-related cortical activation, 330 Expiration forces during, 663f muscles of, 662, 668f physiology of, 675f

Expiratory reserve volume, 664f Expression disorders, 379 Expressive aphasia, 359–360, 361t

2641

Expressive aprosody, 379 Expressivity, 53–54 Exstrophy of bladder, 753–754, 753f External auditory canal, 342 External intercostal muscles, 662 External urethral sphincter, 716–717, 716f Extinction, 358–359 Extracellular fluid, 111 potassium concentration, 120 potassium in, 121 sodium in, 115 water movement in, 112–113, 113f

Extracellular matrix (ECM), 12, 12f, 815f injury to, 77

Extracorporeal membrane oxygenation, 707 Extradural brain abscesses, 403 Extradural space, 313 Extrafusal muscle, 944 Extrahepatic obstructive jaundice, 900 Extraocular muscles anatomy, 338f paralysis of, 338–339

Extrapyramidal motor syndromes, 379–380, 379t, 380b Extrapyramidal/nonspastic cerebral palsy, 421 Extrapyramidal system, 306 Extrinsic pathway, of clotting system, 498 Exudate fibrous, 146 of inflammation, 146 purulent, 146 serous, 146

Eye aging-related changes in, 339t anatomy of, 338, 338f choroid of, 338, 338f external structure of, 341–342

2642

extrinsic muscles of, 339f infections of, 200t–201t iris of, 338, 338f lacrimal apparatus of, 341, 341f layers of, 338, 338f movement-related alteration of, 338–339 retina of, 338 sclera of, 338, 338f

Eyelid, 338–339 F F (or PP) cells, 439–440 Facial nerve, 319t Facilitation, 302–303 Facilitatory pathways, 330 Facioscapulohumeral muscular dystrophy, 69f Factor V Leiden, 543 Factor VIII deficiency, 557 Factor X, 137 Failure to thrive, 926, 926b Falciform ligament, 869–870 Fallopian tubes ampulla of, 766, 766f anatomy of, 766, 766f hormone effects on, 768t

False aneurysm, 596 False joint, 958 False vocal cords, 655, 657f Faltering growth, 926, 926b Falx cerebri, 311–312 Familial adenomatous polyposis, 252, 908 Familial essential thrombocythemia, 538 Familial polycythemia, 515t Fanconi anemia, 293 Fascia, 943

2643

Fascicles, 317, 318f, 943 Fasciculations, 377 Fasciculus cuneatus, 311 Fasciculus gracilis, 311 Fascioscapulohumeral muscular dystrophy (FSHMD), 68, 1006t, 1008 FASDs, Fetal alcohol spectrum disorders Fast-twitch fibers, 945 Fat(s) liver metabolism of, 873 small intestine absorption of, 868b

Fat embolism, 598t Fatigue, 247b Fatigue fracture, 957 Fatty liver, 96f alcoholic, 96, 96f

Fatty necrosis, 101 Fatty streak, 599 FDG, 18F-Fluorodeoxyglucose Fecal mass, 867 Feedback systems, 429–430, 431f Female-pattern alopecia, 1039 Female reproductive system, 760–779, 767b, 770b aging effects on, 776–777, 777b clitoris, 763, 764f–765f development of, 760–762, 762b external genitalia of, 763–764, 763f–764f fallopian tubes, 766, 766f function of, 762 hormones of, 761t internal genitalia of, 762f, 764–767, 765f labia majora, 763, 764f–765f labia minora, 763, 764f–765f mons pubis, 763, 764f ovaries, 766–767, 766f perineum, 764, 764f puberty, 761–762 sex hormones of, 767–768

2644

uterus, 764–765, 765f–767f vestibule, 762f, 763–764, 764f

2645

Female reproductive system disorders, 780–829 abnormal uterine bleeding, 784–785, 785f, 785t, 787b adenomyosis, 796 amenorrhea, 783–784, 784f bartholinitis, 791–792 cervicitis, 790–791 cystocele, 731, 792, 793f delayed puberty, 781, 782t dysmenorrhea, 783 endometrial cancer, 801–802, 801f, 802t endometrial polyps, 794–795, 795f endometriosis, 796–797, 796f enterocele, 793 infections, 788–792 infertility, 807 inflammation, 788–792 leiomyomas, 795–796, 795f ovarian cysts, 793–794, 793f, 794b pelvic inflammatory disease, 788–790, 788f, 790b pelvic organ prolapse, 792–793, 792f, 792b, 794t, 794b polycystic ovary syndrome, 785–786, 786f, 787b precocious puberty, 782, 782b–783b premenstrual disorders syndrome, 786–787 rectocele, 793, 793f reproductive tract abnormalities, 780–781 salpingitis, 788–789, 789f sexual dysfunction, 806, 806t sexual maturation alterations, 781–782, 782t vaginal cancer, 800–801 vaginitis, 790 vulvar cancer, 801 vulvodynia, 791

Female reproductive tract abnormalities, 780–781 Feminization, 469 Fentanyl, 86t FEP, Free erythrocyte protoporphyrin Ferritin, 97, 495, 873 serum, 500t–501t

Ferrous iron, 493

2646

Fertility, 852 Fetal alcohol spectrum disorders (FASDs), 89 Fetal alcohol syndrome, 89, 90f Fetal hemoglobin, 493 Fetus, vulnerability of, to environments, 265f Fever antipyrogenic medications for, 335 benefits of, 334–335 central, 335 in children, 335b description of, 327 in elderly, 335b inflammation and, 147 pathogenesis of, 333–334, 334f of unknown origin, 334

FFAs, Free fatty acids FGF, Fibroblast growth factor FGF-2, Fibroblast growth factor-2 Fibrillation, 377, 974 Fibrin, 137 in bacterial endocarditis, 618

Fibrin clot, 137, 485 Fibrin degradation products, 499, 540–541 Fibrin-fibrinogen degradation, 500t–501t Fibrin split products, 540–541 Fibrinogen, 485, 497 Fibrinogen assay, 500t–501t Fibrinolysis, 755 Fibrinolytic system, 138–139, 499, 499f Fibrinopeptides (FPs), 137 Fibrins, 137 Fibroadenomas, 808 Fibroblast(s) cancer-associated, 243 in connective tissue, 13f synovial, 977

2647

Fibroblast growth factor (FGF), 29t, 936t Fibroblast growth factor-2 (FGF-2), 243 Fibroblasts, 12 cancer-associated, 847 in prostate cancer, 847

Fibromyalgia, 984–985, 985t, 985b, 986f Fibronectin, 12, 540–541 Fibrosarcoma, 820t, 993–994 Fibrous adhesions, 151, 151f, 885t Fibrous cartilage, 33t–35t Fibrous exudate, 146 Fibrous joints, 940 Fibrous pericardium, 565f Fibrous plaque, 599 Fifth disease, 1050 Fight or flight response, 210, 319–321, 444 Filaggrin, 1045 Filtration, 20 Filtration fraction, 717 Filtration slits, 713 Filum terminale, 308, 309f Fimbriae, 766, 766f First-degree block, 626t–627t First degree burns, 1035, 1035t First messenger, 15, 17f, 432, 432f Fissure, 1019f, 1019t–1020t Fissure of Rolando, 305, 306f Fistulae, 979 Flaccid paresis/paralysis, 377 Flaccidity, 371t Flagella, 199 Flail chest, 674, 675f Flash freeze, 1038 Flat bones, 939

2648

Fleas, 1051, 1052f Fluent aphasia, 362t 18

F-Fluorodeoxyglucose (FDG), 241

FMR1, 68 Foam cells, 599, 601f, 1009 Focal brain injury, 384–387, 385t Focal segmental glomerulosclerosis (FSGS), 755 Folate (folic acid), 494, 511 Folate deficiency anemia, 506t Folic acid deficiency, 86–87 Follicles, 438, 438f ovarian, 767, 767f

Follicle-stimulating hormone (FSH), 434, 437t deficiency of, 450 functions of, 761, 761t granulosa cell growth affected by, 770 in menstrual cycle, 770

Follicular cysts, 794 Folliculitis, 1027 Fontanelles, 415, 415f Food allergy, 895 Food intake, regulation of, 475–476, 476b Food intolerance, 895 Food poisoning, 200t–201t Foot amputation, 465, 466f Foramen of Luschka, 313–314 Foramen of Magendie, 313–314 Foramen of Monro, 313–314 Foramen ovale definition of, 565, 641–642 patent, 641–642, 645

Forebrain, 304–308, 304t Foreign body aspiration, 699–700 Fossilization, 106

2649

Fovea centralis, 338 Fraction of inspired oxygen (FIO2), 664 Fractures, 955–958, 964b avulsion, 956t bowing, 956, 956t callus formation after, 957, 957f in children, 1010, 1011f classification of, 955–958, 956f, 956t clinical manifestations of, 957–958 closed, 955, 956t comminuted, 955, 956t complete, 955, 956t compound, 955, 956t compression, 956t “corner” metaphyseal, 1010, 1011f definition of, 955 delayed union of, 958 direct healing of, 957 displaced, 956t evaluation of, 958 external fixation of, 958 extracapsular, 956t fatigue, 957 greenstick, 956, 956f, 956t healing of, 957, 957f hip, 965, 965b immobilization of, 958 impacted, 956f, 956t incidence of, 955 incomplete, 956, 956t indirect healing of, 957 internal fixation of, 958 intracapsular, 956t linear, 955, 956t malunion of, 958 nonaccidental, 1010–1011, 1011f nonunion of, 958 oblique, 955, 956f, 956t open, 955, 956f, 956t open reduction of, 958 osteoporotic, 965, 965b, 966t

2650

pathologic, 956, 956f, 956t pathophysiology of, 957 skull, 313 spiral, 955, 956f, 956t stress, 956t, 957 torus, 956, 956t traction for, 958 transchondral, 956t, 957 transverse, 955, 956f, 956t treatment of, 958 vertebrae, 389, 390t vertebral, 965

Fragile sites, 51 Fragile X-associated primary ovarian insufficiency, 68 Fragile X syndrome, 68 Fragile X tremor ataxia syndrome, 68 Fragility fracture, 956, 964 Frailty, 105–106, 106f Frailty syndrome, 105 Frameshift mutation, 41, 43f Frank-Starling law, 574–575, 575f, 620 Free erythrocyte protoporphyrin (FEP), 512 Free fatty acids (FFAs), 460 Free radicals, 79–82, 277, 277f biologically relevant, 81t generation of, 79–80 inactivation of, 82t oxygen-derived, 82b termination of, 82t

Fresh frozen plasma, 540 Friction rub, 611 Frontal lobe, 305, 306f Frontal lobe ataxic gait, 379 Frontotemporal dementia, 363t, 365 Frostbite, 1038 Frostnip, 1038

2651

Fructosemia, 929, 929t–930t FSGS, Focal segmental glomerulosclerosis FSH, Follicle-stimulating hormone FSHMD, Fascioscapulohumeral muscular dystrophy Full-field digital mammography, 817 Full thickness, 1035t, 1036, 1036f Functio laesa (loss of function), 136 Functional confusion, 362t Functional dysphagia, 883 Functional hearing loss, 344 Functional immaturity of the colon, 919 Functional incontinence, 731t Fungal infections in children, 1047–1048, 1047f description of, 204, 205f of nails, 1039 of skin, 1029, 1029f, 1029t

Fungal meningitis, 402 Fungi, 197t, 204, 205f Furuncles, 1027, 1027f Fusidic acid, for impetigo, 1046 Fusiform aneurysms, 398, 398f, 596, 597f Fusiform muscles, 943 G G1 phase, 27 G2 phase, 27 GABA, Gamma-aminobutyric acid Gait disorders, 379 Galactorrhea, 807–808 Galactosemia, 929, 929t–930t Galea aponeurotica, 311 Galeazzi sign, 999–1000 Gallbladder

2652

aging effects on, 876b anatomy of, 870f, 873, 875f cancer of, 260t–264t, 907t, 910–911 disorders of, 904–905 functions of, 873

Gallstones, 904–905, 905f Gametes, 44 Gamma-aminobutyric acid (GABA), 436 properties of, 304t

Gamma globulins, 484–485 Gamma rigidity, 370, 371t Ganglia basal, 305–306, 307f collateral, 319–321 definition of, 299 paravertebral, 319–321 sympathetic, 319–321

Gangrenous cystitis, 735 Gangrenous necrosis, 101–102 Gap junctions, 13, 571–572 in cellular communication, 13, 15f

GAS, General adaptation syndrome Gas exchange, 668b Gas-exchange airways, 656–657, 656f–658f, 657b Gas gangrene, 102 Gas pressure, 665f measurement of, 664

Gas transport, 664–667 Gasping breathing pattern, 354t Gastrectomy description of, 891 postgastrectomy syndromes, 891

Gastric acid, 863–864 Gastric adenocarcinoma, 908 Gastric distention, 884–885 Gastric emptying, 863

2653

Gastric glands, 863, 863f Gastric inflammation, 242–243 Gastric inhibitory peptide (GIP), 862t Gastric motility, 862–863, 862t Gastric mucosal atrophy, 510 Gastric outlet obstruction, 884 Gastric pits, 863f Gastric secretions, 863–864, 863f Gastric ulcers, 889–890, 891t, 892f Gastrin, 441, 862–864, 862t, 867 Gastrin-releasing peptide, 862t Gastritis, 887–888, 891 Gastrocolic reflex, 867 Gastroduodenal artery, 864 Gastroduodenal junction, 861 Gastroesophageal reflux (GER), 920–921 Gastroesophageal reflux disease (GERD), 883–884, 907, 920–921 Gastroferrin, 863 Gastroileal reflex, 865–867 Gastrointestinal allergy, 175 Gastrointestinal bleeding, 881–883, 881t, 882f Gastrointestinal hormones, obesity and, 476b, 478 Gastrointestinal infections, 200t–201t Gastrointestinal system aging effects on, 876b chronic kidney disease effects on, 747t, 748

Gastrointestinal tract, 247b cancer manifestations of, 256 description of, 879 digestive processes in, 858 esophagus, 858–860, 859f immunity and, 869 large intestine, 867–869, 868f layers of, 858 motility of

2654

acquired impairment of, 920–922 congenital impairment of, 916–920

mouth, Mouth small intestine, Small intestine splanchnic blood flow, 869, 869b stomach, Stomach wall of, 859f

Gastrointestinal tract cancers, 906–910 colorectal cancer, 907t, 908–910, 908b–909b, 909f esophageal cancer, 906–908, 907t, 907b gallbladder cancer, 907t, 910–911 liver cancer, 907t, 910, 910b pancreatic cancer, 907t, 911, 911b stomach cancer, 907t, 908, 908b

Gastrointestinal tract disorders abdominal pain, 881 achalasia, 883 anorexia, 879 appendicitis, 896 bile salt deficiency, 892–893 constipation, 880 Crohn disease, 893t, 894 diarrhea, 880–881, 883b diverticular disease of the colon, 895–896, 895f duodenal ulcers, 889, 890f, 891t dysphagia, 883 gastric ulcers, 889–890, 891t, 892f gastritis, 887–888, 891 gastroesophageal reflux disease (GERD), 883–884 gastrointestinal bleeding, 881–883, 881t, 882f hiatal hernia, 884 inflammatory bowel disease, 893–895, 893t intestinal obstruction, 885–887, 886f–887f, 886t, 887b irritable bowel syndrome (IBS), 894–895, 895b lactase deficiency, 892 lactose intolerance, 892 malabsorption syndromes, 891–893 mesenteric vascular insufficiency, 896 microscopic colitis, 894 motility-related, 883–887, 884f, 885t–886t, 886f–887f, 887b peptic ulcer disease, Peptic ulcer disease

2655

postgastrectomy syndromes, 891 pyloric obstruction, 884 ulcerative colitis (UC), 893–894, 893t vomiting, 879–880, 886

Gastroparesis, 884 Gating, 13 GBM, Glioblastoma multiforme GCS, Glasgow Coma Scale GDM, Gestational diabetes mellitus Gene amplification, 230–231 Gene expression, 230–231 Gene mapping, 58, 59f Gene splicing, 43 Gene therapy, 58b General adaptation syndrome (GAS), 210 Generalized edema, 113–114 Generalized lymphadenopathy, 527 Generalized tonic-clonic seizure, preictal phase of, 367 Genes, 40 Genetic abnormalities, epigenetics and, 68, 69f Genetic conflict hypothesis, 66 Genetic diseases autosomal dominant inheritance, 52–54 delayed age of onset of, 53 epigenetics and, 54 expressivity, 53–54 genomic imprinting and, 54, 55f pedigree, 52, 52f–53f penetrance, 53–54 recurrence risks, 52

autosomal recessive inheritance, 54–56 consanguinity, 56 pedigree, 54, 55f recurrence risks of, 54–56, 55f

transmission of, 51–58

Genetic heterogeneity, 819 Genetics, 40 Genital herpes, 854t–855t

2656

Genome, 237f Genomic imprinting, 54, 55f, 66–67 Genomic instability, 238, 279 Genotype, 51 GER, Gastroesophageal reflux GERD, Gastroesophageal reflux disease Germ cell mutation, 238 somatic cell and, 265t

German measles, Rubella Gestational diabetes insipidus, 449 Gestational diabetes mellitus (GDM), 461 GFD, Gluten-free diet GH, Growth hormone Ghrelin, 441, 460, 476b, 478, 862t GHRH, Growth hormone-releasing hormone Giant cell tumor, 994 Giantism, 450f, 451 Gibbs-Donnan equilibrium, 21–22 GIP, Gastric inhibitory peptide Glans penis, 773f, 774, 833 Glasgow Coma Scale (GCS), 384, 385t, 388 Glaucomas, 339, 340t Gleason score, 845b Gliadin, 923–924 Glioblastoma multiforme (GBM), 408 Gliomas, 407 Glisson capsule, 869–870 Global amnesia, 357 Global aphasia, 359–360 Globulins, 484–485 Globus pallidus, 305–306 Glomerular capillaries, 716 Glomerular filtration

2657

capillary pressures that affect, 719, 720f definition of, 719 in proximal convoluted tubule, 720–721

Glomerular filtration membrane, 713 Glomerular filtration rate, 717, 720, 723, 724b, 746 Glomerular injury chronic, 740 mechanisms of, 736f

Glomerular lesions, 738t Glomerulonephritis acute, 737 acute poststreptococcal, 754 chronic, 740 clinical manifestations of, 738 description of, 754 evaluation of, 738 immunoglobulin A nephropathy, 754 immunologic pathogenesis of, 739t pathophysiology of, 736f, 737–738 treatment of, 738 types of, 738–740, 739t

Glomerulosclerosis, focal segmental, 755 Glomerulotubular balance, 721 Glomerulus anatomy of, 713, 715f disorders involving, 754

Glossitis, 512f Glossopharyngeal nerve, 319t GLP-1, Glucagon-like peptide 1 Glucagon, 441, 457 in type 2 diabetes mellitus, 460

Glucagon-like peptide 1 (GLP-1), 460, 461b, 476b, 478 Glucocorticoid receptor (GR), 214 Glucocorticoids, 441–442 croup treated with, 699 osteoporosis induced by, 967 physiologic effects of, 442, 443f secretion of, 211f

2658

synthesis and secretion of, 443f

Glucose, 624–627 Glucose-6-phosphate dehydrogenase deficiency in children, 548 test for, 500t–501t

Glucose transporters, 440, 1052 Glutamate, 304t Glutathione S-transferase (GSTP1) gene, 844–845 Glutathione-S-transferases, 270–271 Gluten-free diet (GFD), 924–925 Gluten-sensitive enteropathy, 923–924 Glycerophospholipid, 6 Glycine, 304t Glycocalyx, 10 Glycogen, 96 Glycogen storage diseases, 96, 988 Glycolipids, 4 Glycolysis, 17, 18f aerobic, 240 description of, 239

Glycoprotein IIb/IIIa, 497 Glycoproteins, 4, 9, 934t, 937 Glycosylated hemoglobin, 457 GM-CSF, Granulocyte-macrophage colony-stimulating factor GnRH, Gonadotropin-releasing hormone Goblet cells, 656, 708 Goiter, 452–453 toxic multinodular, 454

Golfer's elbow, 959–960 Golgi complex, 4t–6t Golgi tendon organs, 944 Gomphosis, 940 Gonadarche, 762 Gonadotropin-releasing hormone (GnRH), 436t, 761, 761t, 770, 836

2659

Gonadotropins, 761, 761t Gonads aging effects on, 444b description of, 760 in sexual maturation, 762

Gonorrhea, 838f, 854t–855t Gout, 99, 981–984, 982f–983f, 982t Gouty arthritis, 981–982, 983f Gower sign, 1007 GR, Glucocorticoid receptor Graft-versus-host disease (GVHD), 188 Granulation tissue, 150 Granulocyte colony-stimulating factor, 525 Granulocyte-macrophage colony-stimulating factor (GM-CSF), 253, 525 Granulocytes, 486, 496 disorders involving, 518

Granulocytopenia, 518 Granulocytosis, 518, 519t Granuloma, 147, 148f Granulomatous orchitis, 836 Granulosa cells, 767, 770 Grasp reflex, 356f Graves disease, 452–454, 453f–454f Gravity, 666f Gray matter, 304 Great cardiac veins, 568, 569f Great vessels, 564–565 Green tea, 843b–844b Greenstick fracture, 956, 956f, 956t Gremlin, 936t Ground substance, 933 Group A beta-hemolytic Streptococcus, 699 Growth factor-regulated kinases, 235–237 Growth factors, 28

2660

signaling pathways, in cancer, 234f

Growth hormone (GH) aging and, 435b, 444b breast cancer and, 816 deficiency of, 450 functions of, 437t hypersecretion of, 451, 451f secretion of, 434 in stress response, 219t

Growth hormone-releasing hormone (GHRH), 436t Growth plate, 939 Guanine, 40 Gubernaculum, 835–836 Guillain-Barré syndrome, 299, 404, 404b Gunshot wounds, 91t–92t, 92f Gut microbiome, obesity and, 478–479, 478b–479b Guttate psoriasis, 1023, 1024f GVHD, Graft-versus-host disease Gynecomastia, 772, 852 Gyri, 304, 306f H H band, 572–573, 573f, 947, 949f H1N1 virus, 202–203 H2 blockers, 143 Haemophilus influenzae, 401–402 type B, 699

Hageman factor (factor XII), 137, 498 Hair cancer manifestations of, 256 description of, 1014 disorders of, 1039

Hair cells, 343, 343f Haldane effect, 667 Hallucinogens, abuse of, 83t HAND, Human immunodeficiency virus-associated neurocognitive disorder

2661

Hanging strangulation, 92 Haploid cells, 44 Haptens, 157 Hashimoto disease, 455, 455f Haustra, 867 Haversian system, 937, 938f Hayflick limit, 238–239 HCV, Hepatitis C virus HD, Huntington disease Headache, 400–401, 400t Health care-associated pneumonia, 686 Hearing, 342–343 Hearing loss, 343 Heart action, control, 568–574, 570b, 574b action potentials of, 570 adenosine triphosphate, 572 automaticity of, 570 blood flow through, 564, 565f chambers of, 565, 565f conduction system, 569–570, 570f, 570b epicardium, 564, 565f fibrous skeleton of, 566, 566f Frank-Starling law of, 574–575, 575f functions of, 563–564 great vessels of, 564–565, 565f hypertension-related complications of, 594–595, 595t innervation of, 570–571, 572f intracardiac pressures, 567, 567t left, 563 pericardium of, 564, 565f rhythmicity of, 570 right, 563 structures of, 564–567 sudden cardiac death, 609 valves of, 565–566 weight of, 563–564

Heart disease

2662

acquired, in children, 650 dysrhythmias, 623–624, 625t–626t, 626t–627t manifestations of, 620–624, 624b rheumatic heart disease, 616–618, 617f

Heart failure (HF) afterload in, 620, 622f clinical manifestations of, 649b congenital heart disease as cause of, 649, 649t, 649b definition of, 620–623 diabetes and, 621b high-output, 623, 624f left clinical manifestations of, 620 description of, 620–623 in infants, 649 management of, 622

with preserved ejection fraction, 622, 623t with reduced ejection fraction, 620, 622f right, 623, 623f risk factor for, 620 systolic, 620

Heart rate atrial receptors that affect, 576 biochemicals that affect, 576 cardiac output affected by, 576 definition of, 571 determinants of, 576 hormones that affect, 576 neural reflexes that affect, 576 normal, 576

Heart wall anatomy of, 564, 565f disorders of, 611–620 cardiomyopathies, 613–614, 613f pericardial effusion, 612, 612f

Heat, body loss of, 333, 334t production of, 333, 334t

Heat cramps, 335 Heat exhaustion, 335 Heat stroke, 335

2663

Heberden nodes, 973f, 975 Heel cord contractures, 984 HeLa cells, 238–239 Helicobacter pylori acute gastritis associated with, 887–888 description of, 242–243 duodenal ulcers caused by, 889 iron deficiency anemia caused by, 549 pathologic characteristics of, 888b pernicious anemia and, 510

Helminths, 197t, 206t Helper T cells, 681 Hemagglutinin protein, 202–203 Hemangiomas, cutaneous, 1052–1053, 1052f, 1053b Hematemesis, 881t Hematochezia, 881t, 882–883 Hematocrit, 579 determination, 500t–501t

Hematogenous osteomyelitis, 971 Hematologic differential counts, 502t Hematologic function, alterations of, 505–547 Hematologic system blood tests, 500t–501t chronic kidney disease effects on, 747t lymphoid organs, 488–490 lymph nodes, 489–490, 490f mononuclear phagocyte system, 488t spleen, 489, 489f, 490b

Hematoma epidural (extradural), 385, 385t, 387f intracerebral, 387, 387f subdural, 385t, 386–387, 387f

Hematopoiesis, 491–496, 491b, 492f in bone marrow, 490 cellular differentiation, 490–491, 492f medullary, 491

Hematopoietic cells, 492f

2664

Hematopoietic growth factors, 491 Hematopoietic stem cells, 490 Heme, 493, 495, 495f Hemiagnosia, 332t Hemianopia, 341 Hemifacial spasm, 371f Hemiparesis, 376b Hemiplegia, 376b Hemiplegic posture, 378 Hemizygous, 56 Hemochromatosis, 97 Hemodynamic stroke, 397 Hemoglobin, 125–126 fetal, 493 laboratory tests for, 500t–501t molecular structure of, 493f oxygen transport by, 666 postnatal fall in, 499 sickle cell, 551, 552f synthesis of, 491–494

Hemoglobin desaturation, 667 Hemoglobin determination, 500t–501t Hemoglobin electrophoresis, 500t–501t Hemoglobin H disease, 555 Hemoglobin S, 551 Hemolysis definition of, 507 hemolytic jaundice caused by, 900

Hemolytic anemia in children, 548, 553–554 description of, 506t, 514t

Hemolytic disease of the fetus and newborn, 550–551 ABO incompatibility, 550 clinical manifestations of, 550 description of, 548 evaluation of, 551

2665

pathophysiology of, 550, 551f Rh incompatibility, 550 treatment of, 551

Hemolytic jaundice, 97, 900, 900t Hemolytic uremic syndrome, 755 acute infectious diarrhea caused by, 927

Hemophilia, 557, 557t Hemophilia A, 557 Hemophilia B, 557 Hemoproteins, 97 Hemoptysis, 671 Hemorrhage, 535 intracranial, 398 rapidly expanding, 496t subarachnoid, 398–399, 399t

Hemorrhagic cystitis, 734 Hemorrhagic disorders antibody-mediated, 557–558 classification of, 535t platelet disorders, 536–539

Hemorrhagic exudate, 146 Hemorrhagic stroke, 397–398, 423 Hemosiderin, 495 accumulation of, 97, 98f

Hemosiderosis, 97, 98f Hemostasis, 149 blood clotting, 498f blood vessels in, 496–497 components of, 496 definition of, 496 function of, 505 liver's role in, 872 mechanisms of, 496–499 platelets in, 497 spontaneous activation of, 498

Hemostatic plug, 496 Hemothorax, 676t

2666

Henoch-Schönlein purpura nephritis, 754 Heparin, 543 Heparin-binding protein, 497 Heparin-induced thrombocytopenia, 536 Hepatic artery, 870 Hepatic encephalopathy, 898–899, 901 Hepatic portal vein, 870, 870f Hepatic vein, 870–871 Hepatitis, in children, 928–929 Hepatitis A virus, 903–904, 903t, 928 Hepatitis B virus, 243, 903–904, 903t, 928 Hepatitis C virus, 282–283, 903–904, 903t Hepatitis D virus, 903–904, 903t, 928 Hepatitis E virus, 903–904, 903t Hepatocellular carcinoma, 910 Hepatocellular jaundice, 900t Hepatocytes, 870–871, 873 Hepatomegaly in biliary atresia, 928 in pernicious anemia, 510

Hepatoportoenterostomy, 928 Hepatopulmonary syndrome, 897, 901 Hepatorenal syndrome, 900–901 Hepcidin, 495, 516–517 Herald patch, 1024, 1024f Hereditary angioedema, 139 Hereditary hemochromatosis, 516–517, 517f Hereditary multiple exostoses (HME), 1009 Hereditary nonpolyposis colorectal cancer, 54, 238, 908 Hereditary thrombophilias, 543 Heredity, at molecular level, 40–44 Hernia, 885t hiatal, 884

Herniated intervertebral disk, 394–395, 394f–395f

2667

Heroin, 86t Herpes simplex virus, 1028, 1028f Herpes zoster in adults, 1028, 1028f in children, 1049t, 1050

Herpesviruses description of, 202 HHV8, 243

Heterophilic antibodies, 521 Heterosegmental pain inhibition, 330 Heterotopic ossification, 960–961 Heterozygous, defined, 51 Heterozygous carriers, 54 Hexosaminidase A (HexA), 421–422 HF, Heart failure HHNKS, Hyperosmolar hyperglycemic nonketotic syndrome Hiatal hernia, 884 Hibernating myocardium, 608 Hiccups, 353 Hidradenitis suppurativa, 1025 HIF-1α, Hypoxia-inducible factor-1α High-density lipoproteins, 602 High-grade squamous intraepithelial lesions, 798 High-output failure, 623, 624f High-resolution peripheral quantitative computed tomography, 968 Hilum (hila), 655–656 Hindbrain, 304t, 306f, 308, 312f Hip developmental dysplasia of, 999–1000, 1001f fractures of, 965, 965b

Hirschsprung disease, 920, 920f Hirsutism, 1039 Histaminase, 138–139 Histamine, 304t, 862t

2668

Histamine receptors, 142–143 Histamines, 137 effects of, 143f

Histocompatibility leukocyte antigen (HLA), 457 Histone deacetylase inhibitors, 71, 71b Histones, 1 modification of, 64–65

HIV, Human immunodeficiency virus HIV fusion inhibitors, 191–192 HIV integrase, 190 HIV integrase inhibitors, 191–192 HIV protease, 190 HIV protease inhibitors, 191–192 HIV reverse transcriptase, 190 Hives, 176, 1030 HLA, Histocompatibility leukocyte antigen HLAs, Human leukocyte antigens HLHS, Hypoplastic left heart syndrome HME, Hereditary multiple exostoses Hodgkin disease, 295 Hodgkin lymphoma in children, 560 description of, 527–529, 528f, 529t, 560 lymphadenopathy in, 560, 560f treatment of, 560

Homeostasis, 73, 210 impairments in, 539–540 liver disease-related impairments in, 539–540 platelets in, 535

Homologous chromosomes, 44, 47f Homozygote, 51 Homozygous, defined, 51 Homunculus, 305, 307f Hordeolum (stye), 341 Hormonal hyperplasia, 75

2669

Hormonal signaling, 14–15 Hormone receptors, 430–432 down-regulation, 431 location of, 431–432, 432b regulation of, 431, 431f up-regulation, 431, 431f

Hormone replacement therapy endometrial cancer risks, 801 hypothyroidism treated with, 454

Hormones alterations of, 447, 448t blood pressure affected by, 583 breast cancer and, 813–815, 814f characteristics of, 429 ectopic sources of, 447 feedback systems, 429–430, 431f first messenger, 432, 432f heart rate affected by, 576 hypothalamic, 436t, 448f lipid-soluble, 430, 430t, 432 in menstrual cycle, 769f, 771 nephron function affected by, 722, 723b pancreatic, 439–441 parathyroid glands, 439, 439b pituitary, 433, 434f anterior, 433, 437t posterior, 436

in prostate cancer, 842–847, 846f protein, 430 regulation of, 429–432 release of, 429–430 second messenger, 432, 432f, 432t, 447 secretion of, 429 somatotropic, 437t steroid, 429, 433f stress response affected by, 219t structural categories of, 429, 430t target cells for, 430, 431f–432f, 447 thyroid gland, 438–439, 438f transport, 430 vasoconstrictor, 583, 585f

2670

water-soluble, 430, 430t, 432

Horseshoe kidney, 751 Host cell, stages of, 202f Housekeeping genes, 65–66 Howship lacunae, 935 HPA, Hypothalamic-pituitary-adrenal axis HPV, Human papillomavirus Human bites, 971 Human chorionic gonadotropin functions of, 761t secretion of, 770

Human defense mechanisms, 133 overview of, 134t

Human epidermal growth factor receptor 2 (HER2), 232–234 Human immunodeficiency virus (HIV), 189 Human immunodeficiency virus (HIV)-1 life cycle and sites of drug intervention, 191f structure of, 190, 190f typical progression from, 192f

Human immunodeficiency virus-associated neurocognitive disorder (HAND), 403 Human leukocyte antigen (HLA-B27), 979–980 Human leukocyte antigens (HLAs), 161, 185, 185f inheritance of, 185–186, 185f

Human papillomavirus (HPV) cancers associated with, 282–283 cervical cancer caused by, 797, 854t–855t condyloma acuminatum caused by, 833–834 description of, 243 oropharyngeal cancers associated with, 283 vaccine, 285b vulvar cancer and, 801 warts caused by, 1028–1029, 1029f

Human T-cell lymphotropic virus, type 1, 243–244, 283 Humoral immunity, 157, 163–168 Hunchback, 968 Hunner ulcers, 735

2671

Huntington disease (HD), 53, 372–374, 379–380 Hyaline cartilage, 33t–35t Hydrocele, 835, 835f Hydrocephalus, 369–370, 370t cause of, 308 in children, 416, 419–420, 420f congenital, 419–420 myelomeningocele and, 416

Hydrochloric acid, 863, 863f Hydrogen ions in body fluids, 123–124 renal buffering of, 126–127

Hydrogen sulfide, 93 Hydronephrosis, 728–729 Hydropic degeneration, 95 Hydrops fetalis, 550, 556 Hydrostatic pressure, 20, 21f capillary, 112–113 interstitial, 112

Hydrothorax, 676t Hydroureter, 728–729 Hydroxyapatite, 937 21-Hydroxylase deficiency, 468 5-hydroxytryptamine, 862t Hydroxyurea myelosuppression treated with, 516 sickle cell disease treated with, 555 thrombocythemia treated with, 539

Hygiene hypothesis, 680–681, 706 Hyperactive confusional state, 360 Hyperactivity, 373t Hyperacute rejection, 186 Hyperaldosteronism, 129, 468–469 primary, 121

Hyperalgesia, 332t Hyperbaric oxygen therapy, 972

2672

Hyperbilirubinemia, 550, 899–900 of newborn, 927–928

Hypercalcemia, 124t, 248t, 456, 532 Hypercalciuria, 456 Hypercapnia, 129, 672, 673f causes of, 672 definition of, 672 oxyhemoglobin curve affected by, 667

Hyperchloremia, 118 Hypercholesterolemia, 601f Hypercoagulability, 535–536 acquired, 543–544

Hypercorticoadrenalism, 468 Hypercortisolism, 467 Hypercyanotic spells, 645 Hyperglycemia, 458, 460f, 1037 Hypergonadotropic hypogonadism, 782t, 831b Hyperhemolytic crisis, 554 Hyperinsulinemia, 460, 786f Hyperkalemia, 122–123 clinical manifestations of, 122t, 123 evaluation of, 123 hypoxia and, 122 neuromuscular effects of, 123 pathophysiology of, 122–123 symptoms of, 123 treatment of, 123

Hyperkalemic periodic paralysis, 987 Hyperkinesia, 372, 373t Hyperlipidemia, 741t Hypermagnesemia, 124t Hypermenorrhea, 785t Hypermimesis, 379 Hypernatremia, 118 clinical manifestations of, 118 evaluation of, 118

2673

pathophysiology of, 118 treatment of, 118

Hyperopia, 340 Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS), 463t, 464 Hyperparathyroidism, 456, 746 Hyperphosphatemia, 124t Hyperpituitarism, 450, 450b Hyperplasia, 75–76, 76f Hyperplastic polyps, 794–795 Hyperpnea, 671 Hyperpolarization, 570, 571f Hyperpolarized state, 26 Hyperprolactinemia, 452, 807 Hypersensitivity pneumonitis, 678 Hypersensitivity reactions, 174 examples of, 175t immunologic mechanisms of, 174–186, 175t mechanisms of, 175–181 type I, 175, 177f type II, 177 type III, 178 type IV, 178

Hypersomnia, 337 Hypersplenism, 534 Hypertension, 596b acromegaly-associated, 451 ambulatory blood pressure monitoring in, 652 atrial natriuretic peptide in, 594 B-type natriuretic peptide in, 594 cardiovascular complications of, 594–595 causes of, 652t in children, 650–652, 650t–651t classification of, 650 clinical manifestations of, 596 complicated, 594–596 coronary artery disease and, 603 definition of, 592–593

2674

dietary modifications for, 596 evaluation of, 596 inflammation in, 594 insulin resistance in, 594 laboratory tests for, 652t obesity as risk factor for, 594, 594b pathophysiology of, 593, 595f portal, 897, 897f pressure-natriuresis relationship, 593, 593f prevalence of, 592–593 primary, 593–594, 593b, 595t, 650 pulmonary arterial, 690, 690f race and, 593 renin-angiotensin-aldosterone system in, 593, 594b secondary, 593–594, 650, 651b treatment of, 596

Hypertensive crisis, 596 Hypertensive hypertrophic cardiomyopathy, 613–614 Hyperthermia, 335 malignant, 963

Hyperthyroidism, 452–454, 453f, 623 Hypertonia, 370–372, 371t Hypertonic alterations, 118 Hypertrophic cardiomyopathy, 613–614, 613f Hypertrophic obstructive cardiomyopathy, 613–614 Hypertrophic osteoarthropathy, 248t Hypertrophic scar/scarring, 151, 152f, 1021, 1038f Hypertrophy, 75, 75f Hyperuricemia, in chronic leukemias, 526 Hyperventilation, 671 Hypervolemic hypernatremia, 118 Hypervolemic hyponatremia, 119 Hyphae, 1029 Hypoactive confusional state, 360 Hypoactive delirium, 360 Hypoactive sexual desire, 806

2675

Hypoalbuminemia, 741t, 754 Hypocalcemia, 746 Hypocapnia, 130, 671 Hypochloremia, 119 Hypochloremic metabolic alkalosis, 129 Hypochromic-microcytic anemia, 510f Hypocortisolism, 469 Hypocretins, 335 Hypodermis, 1014, 1015f, 1016t Hypogammaglobulinemia, 187 Hypogeusia, 345 Hypoglossal nerve, 319t Hypoglycemia, 248t, 461–462, 463t Hypogonadotropic hypogonadism, 782t, 831b Hypokalemia, 121–122 cardiac effects of, 121 clinical manifestations of, 121, 122f, 122t diarrhea and, 121 evaluation of, 121–122 pathophysiology of, 121 predisposing factors of, 121 treatment of, 121–122

Hypokalemic periodic paralysis, 987 Hypokinesia, 374 Hypomagnesemia, 456 Hypomethylation, 69 Hypomimesis, 379 Hyponatremia, 119–120 clinical manifestations of, 119–120 evaluation of, 120 pathophysiology of, 119 treatment of, 120

Hypoparathyroidism, 456–457, 457b Hypoperfusion, 397 Hypophosphatemia, 456

2676

Hypophysial portal system, 435f Hypopituitarism, 449–450, 450f Hypoplastic left heart syndrome (HLHS), 648–649, 648f, 649b Hypopolarized state, 26 Hyporeflexia, 377 Hyposmia, 344 Hypospadias, 753, 753f, 835–836 Hypotension, orthostatic, 596 Hypothalamic-pituitary system, 433–437 alterations of, 447–452 hormones of, 433, 434f

Hypothalamic-pituitary-adrenal axis (HPA), 214 feedback mechanisms of, 214–216 regulation of, 213–216 schematic diagram of, 214f

Hypothalamic-pituitary-gonadal axis, 762, 763f, 782 Hypothalamohypophysial tract, 433, 436f Hypothalamus anatomy of, 433 body heat conservation and, 333 description of, 308, 308b gonadotropin-releasing hormone production by, 761 hormones produced by, 436t, 448f neurosecretory cells of, 433 in sleep, 335

Hypothermia, 335, 336b Hypothyroidism, 453f, 454–455, 455f Hypotonia, 370, 371t Hypotonic alterations, 119–120 Hypoventilation, 671 Hypovolemia, 905–906, 1036–1037 Hypovolemic hypernatremia, 118 Hypovolemic hyponatremia, 119 Hypovolemic shock, 118, 628–629, 630f Hypoxemia in anemia, 507

2677

causes of, 672 clubbing of fingers caused by, 672, 672f definition of, 672 pulmonary disease as cause of, 672–674, 673f

Hypoxia, 466 cerebral, 93 chronic alveolar, 659 definition of, 672 and hyperkalemia, 122 inflammation and, 77–78, 80f ischemia and, 77–78, 79f progressive, 78 tissue, 507, 672

Hypoxia-inducible factor-1α (HIF-1α), 239 Hypoxic injury, 77–78 Hypoxic pulmonary vasoconstriction, 659 I I band, 572–573, 573f IARC, International Agency for Research on Cancer Iatrogenic hypothyroidism, 455 IBS, Irritable bowel syndrome Icterus, 899–900, 927–928, Jaundice Icterus gravis neonatorum, 550 Icterus neonatorum, 550 Ictus, 367 Idiojunctional rhythm, 625t–626t Idiopathic Addison disease (organ-specific autoimmune adrenalitis), 469 Idiopathic inflammatory myopathies, 989 Idiopathic pulmonary fibrosis, 678 Idioventricular rhythm, 625t–626t IF, Intrinsic factor IgE-mediated hypersensitivity reactions, type I, 175–177 evaluation and treatment of, 176–177 mechanisms of, 175–176, 176f

IGFBPs, Insulin-like growth factor-binding proteins

2678

IHPS, Infantile hypertrophic pyloric stenosis IICP, Increased intracranial pressure Ileal pouch anal anastomosis, 894 Ileocecal valve, 864, 867 Ileocolic intussusception, 922f Ileogastric reflex, 865–867 Ileum intussusception of, 922 obstruction of, 918–919

Image processing, 357, 358t Imatinib, 254t Imatinib mesylate, 527 Immediate hypersensitivity reactions, 174 Immortality, 238–239 Immune complex disease, 178 Immune complex-mediated hypersensitivity reactions, type III, mechanism of, 178, 180f Immune responses cellular interaction in, 161–163, 163b overview of, 158f primary, 168, 168b, 170f secondary, 168, 168b, 170f from vaccination, 207–208

Immune surveillance hypothesis, 243

2679

Immune system burn injury response by, 1038 cancer cell evasion from, 244f chronic kidney disease effects on, 747t, 748 effects of acute and chronic stress on, 217–218 microorganisms defenses against, 197t role of, 217–218, 218f secretory, 168, 169f

Immune thrombocytopenia purpura in children, 557–558 description of, 536–537

Immunity, 133–155 active, 157 alterations in, 174–195 cell-mediated, 168–171 deficiencies in, 186–188 facial anomalies associated with DiGeorge syndrome, 187f initial clinical presentation of, 186 primary (congenital), 186–188 secondary (acquired), 188–194

gastrointestinal tract's role in, 869 humoral, 157, 163–168 innate, Innate immunity passive, 157

Immunization, active, 207–208 Immunocompetent, 157 Immunogenicity, 198 Immunogens, 157, 157b Immunoglobulin, G, 550 Immunoglobulin A (IgA), 165 nephropathy, 754

Immunoglobulin D (IgD), 165 Immunoglobulin E (IgE), 165, 167, 168f Immunoglobulin G (IgG), 163 Immunoglobulin M (IgM), 163 Immunoglobulin superfamily CAMs, 11b Immunoglobulins classes of, 163–166

2680

structures of, 166f

Immunologic injury, 94 Immunomodulators, for Crohn disease, 894 Immunoreactive cells, 142–144 Immunotherapy asthma exacerbations managed with, 682 for cancer, 253 type 1 diabetes mellitus prevention using, 459b

Imperforate anus, 920, 921f Impetigo in adults, 1027 in children, 1046–1047, 1046f

Impetigo contagiosum, 1046–1047, 1046f Inbreeding, 56 Inclusion body myositis, 989 Incomplete fracture, 956, 956t Incomplete penetrance, 53 Incontinence, 731t Increased intracranial pressure (IICP), 367–369, 368f Increased vascular permeability, 136 Incretins, 460 Incus (anvil), 342, 342f Indirect (secondary) healing, of fractures, 957 Indirect transmission, 197 Indomethacin, 641 Induction chemotherapy, 253 Induration, clear hard center, 180 Infantile hypertrophic pyloric stenosis (IHPS), 918 Infants diarrhea in, 927 hemangiomas in, 1052 hemoglobin values in, 499 hypothyroidism in, 454 pain perception in, 329t reflexes of, 415, 415t skull of, 415

2681

sleep characteristics in, 337b thermoregulation in, 333

Infarct, 100–101 Infarction, 598 Infections, 196–209, 247b antimicrobials for, 206–207, 207t cancer and, 256, 282–283 central nervous system, 401–403, 402f classes of, 197t in diabetes mellitus, 466, 467b dissemination or spread of, 198 ear, 344 of eye, 200t–201t female reproductive system, 788–792 gastrointestinal, 200t–201t nosocomial, 200t–201t otitis media, 200t–201t parasitic, 204–206 pathogenic, 197–198, 197t process of, 196–198 sexually transmitted, 200t–201t skin, 200t–201t, 1027–1029, 1027f–1029f, 1029t–1030t, 1031b stages of, 198–199, 199b Staphylococcus aureus, 202b transmission of, 196–197 wound, 200t–201t zoonotic, 200t–201t, 201–202

Infectious diarrhea, acute, 927 Infectious disease, 199–206 Infectious injury, 93 Infectious microorganisms, active immunization against, 207–208 Infectious mononucleosis, 520–521, 521b clinical manifestations of, 520–521 evaluation of, 521 pathophysiology of, 520 treatment of, 521

Infective endocarditis, 618–620, 618b, 619f Infectivity, 198 Inferior colliculi, 308

2682

Inferior mesenteric ganglia, 319–321, 320f Inferior vena cava, 564–565 Infertility, 247b endometriosis and, 797 female, 807

Infiltrations, 94–95 Infiltrative splenomegaly, 534 Inflammasomes, 981 Inflammation, 135–139 activation of, 135 acute, 146–147 local manifestations of, 146 systemic manifestations of, 146–147

acute-phase reactants, 147 adaptive immunity and, 156 cellular components of, 139–146, 139f cellular products of, 140–142 central nervous system, 401–403 chronic, 146–147, 147b, 148f, 242, 242t, 258 endothelium, 581t exudate of, 146 female reproductive system, 788–792 fever in, 147 gastric, 242–243 healing and, 146f in hypertension, 594 hypoxia and, 77–78, 80f leukocytosis in, 147 markers of, 603 mediators of, 140–142, 141f, 632, 632b in multiple organ dysfunction syndrome, 633 obesity and, 478 permeability of, capillaries and, 113 plasma protein systems and, 137–139, 138f, 147 platelets in, 144 prostate cancer and, 844, 845f–846f resolution of, 147–148 tumor-promoting, 242–243, 242t of vascular tissues and cells, 139–140, 139f in wound healing, 149

2683

Inflammatory acne, 1044, 1045f Inflammatory bowel disease, 893–895, 893t Inflammatory cytokines, 140 Inflammatory disorders, liver disorders and, in children, 928–929 Inflammatory gastrointestinal infections, 200t–201t Inflammatory injury, 94 Inflammatory joint disease, 984b ankylosing spondylitis, 979–981, 981f characteristics of, 976 gout, 981–984, 982f–983f, 982t infectious, 976 noninfectious, 976 rheumatoid arthritis, Rheumatoid arthritis

Inflammatory response, 133 acute, 243 myocardial infarction as cause of, 609

Influenza, antigenic shifts in, 202–203 Infratentorial disorders, 352 Infratentorial herniation, 369b Infundibulum, 766, 766f Inguinal canal, 772 Inhalation disorders, 678 Inheritance autosomal dominant, 52–54 delayed age of onset of, 53 epigenetics and, 54 expressivity, 53–54 genomic imprinting and, 54, 55f pedigree, 52, 52f–53f penetrance, 53–54 recurrence risks, 52

autosomal recessive, 54–56 consanguinity, 56 pedigree, 54, 55f recurrence risks of, 54–56, 55f

mode of, 51–52 multifactorial, 59–60, 60f, 60b X-linked, 56–58 pedigrees of, 57 recurrence risks of, 57 sex determination, 56–57

2684

sex-influenced traits, 57–58 sex-limited, 57–58 X-inactivation, 56

Inhibin, 761t, 851–852, 936t Inhibitory neurotransmitters, 329 Inhibitory postsynaptic potentials (IPSPs), 302 Injuries asphyxial, 91 immunologic, 93 infectious, 93 inflammatory, 93 intentional, 90–93, 91t–92t, 93b unintentional, 90–93, 91t–92t, 93b

Innate barriers, 133 Innate immunity, 133–146, 134t, 135b, 137b adaptive immunity and, 156 cell-derived chemicals, 135 defects in, 188 in the elderly, 153b glucocorticoids effects on, 442 inflammation, 135–139 microbiome, 135 in the newborn child, 152b physical barriers in, 133–135, 134f

Inner dura, 311 Inositol triphosphate (IP3), 432, 432t Inotropic agents definition of, 576 negative, 576 positive, 576

Inotropic effect, 216 Insect bites, 1051–1052, 1051f–1052f Insomnia, 336 Inspiration forces during, 663f muscles of, 662 physiology of, 675f

Inspiratory reserve volume, 664f, 668f

2685

Insufficiency fracture, 956 Insula, 305 Insular lobe, 305 Insulin actions of, 441f glucose uptake affected by, 440 potassium and, 121 secretion of, 429, 440

Insulin-like growth factor, 435b aging effects on, 444b in bone formation, 936t breast cancer and, 816

Insulin-like growth factor 1 (IGF-1), 29t, 434, 576 Insulin-like growth factor 2 (IGF-2), 29t, 434 Insulin-like growth factor-binding proteins (IGFBPs), 434 Insulin receptor, 440 Insulin resistance, 460, 478 in burn injury, 1037 coronary artery disease risks, 603 in hypertension, 594 in polycystic ovary syndrome, 786 in uremia, 748

Insulin shock, 461–462 Integral membrane proteins, 9 Integrin αIIbβ3, 497 Integrin receptors, 935 Integrins, 11b Integumentary system, chronic kidney disease effects on, 747t, 748 Intention tremor, 373t Intentional injuries, 90–93, 91t–92t, 93b Interbrain, 308 Intercalated cells, 714–716 Intercalated disks, 571–572 Intercostal muscles, 662 Interferon, 142 Interferon-γ (IFN-γ), 171

2686

Interleukin 1 (IL-1), 142, 162, 199–201, 687 Interleukin-1β, 632b Interleukin 2 (IL-2), 29t, 162 Interleukin 6 (IL-6), 142, 199–201, 632b Interleukin 7 (IL-7), 172 Interleukin 10 (IL-10), 142, 244 Interleukins (ILs), 141 Interlobar arteries, 716 Intermittent claudication, 601–602 Intermittent positive-pressure ventilation, 703 Internal anal sphincter, 867 Internal capsule, 306 Internal carotid arteries, 314, 315f Internal hydrocephalus, 370 Internal urethral sphincter, 716–717, 716f International Agency for Research on Cancer (IARC), 258, 272 Interneurons, 299, 309–310, 328 Interphase, 27, 28f Interspinous bursae, 392–393 Interstitial cells, 775f Interstitial edema, 633 Interstitial fluids, 111 water movement in, 112–113, 113f

Interstitial/hydrocephalic edema, 369 Interstitial hydrostatic pressure, 112 Interstitial oncotic pressure, 112 Intervention strategies, 221–224 Interventricular foramen, 313–314 Intervertebral disk, 314, 315f Intervertebral disk herniation, 394–395, 394f–395f Intestinal malrotation, 919 Intestinal obstruction, 885–887, 886f–887f, 886t, 887b Intestine microbiome of, 869

2687

obstruction of, 885–887, 886f–887f, 886t, 887b torsion of, 885t

Intestinointestinal reflex, 865–867 Intracardiac pressures, 567, 567t Intracellular fluid, 111 water movement in, 113

Intracerebral hematomas, 387, 387f Intracranial aneurysm, 398, 398f Intracranial hemorrhage, 398 Intracranial hypertension, 367–368, 368f Intracranial pressure, normal, 367b Intradermal nevus, 1032t Intraductal papillomas, 808 Intrahepatic obstructive jaundice, 900 Intraprostatic conversion, 842–844 Intrarenal acute kidney injury, 742t, 743, 744t Intrarenal blood flow, 717 Intraventricular hydrocephalus, 370 Intrinsic factor (IF), 507, 863 Intrinsic pathway, 498 Introns, 43 Intussusception in adults, 885t, 886f in children, 921–922, 922f

Invasion, of carcinoma cells, 823f Invasion/local spread, for metastasis, 245 Invasion pathogens, 198 Invasive gastrointestinal infections, 200t–201t Inverse acne, 1025 Inverse psoriasis, 1023 Involucrum, 972, 972f, 1002–1003 Iodide, 438 Iodine deficiency, 818 Ionizing radiation

2688

acute effects of, 280 biologic responses to, 279b breast cancer caused by, 817–818 Bystander effects of, 278f, 279 cancer and, 274f, 276–280, 276t, 817–818 computed tomography, 278f, 278t, 278b dose rate, 280 excess relative risks, 276–277 exposure to, 274f, 277 genomic instability caused by, 279 latent effects of, 280 low-dose, 280, 281f, 281b low-level, 280 microenvironment effects of, 280 nontargeted effects of, 278f, 279 responses to, 279b

Ions, 9 IPSPs, Inhibitory postsynaptic potentials Iris, 338, 338f Iron cycle, 494–495, 495f dietary sources of, 495, 548 homeostasis of, 495 liver storage of, 873 small intestine absorption of, 868b

Iron deficiency anemia, 507, 511–512 in children, 548–550 clinical manifestations of, 512, 512f, 549–550 evaluation of, 512, 550 pathophysiology of, 506t, 511, 549 treatment of, 512, 550

Iron overload, 516–517 Irregular bone, 939 Irreversible coma, 355–357 Irreversible injury, 77 Irritable bowel syndrome (IBS), 894–895, 895b Irritant contact dermatitis, 1022 Irritant receptors, 660

2689

Irritative syndrome, 409 Ischemia, hypoxia and, 77–78, 79f Ischemia-reperfusion injury, 78 Ischemic injury, 77–78 Ischemic penumbra, 397 Ischemic (occlusive) stroke, 395–397, 423 Ischemic ulcers, 890 Islets of Langerhans, 439–440 Isoflavones, 818 Isohemagglutinins, 184 Isoimmunity, 174 Isometric contraction, 951, 951f Isothiocyanates, 270 Isotonic alterations, 118 Isotonic contraction, 951, 951f Isotonic fluid excess, 118 Isotonic fluid loss, 118 Isovolemic (euvolemic) hypernatremia, 118 Isovolemic hyponatremia, 119 Isthmus, 438 J Janus family of tyrosine kinases, 432 Janus kinase 2 gene (JAK2 gene), 514–515 Jaundice, 899–900, 899f, 900t neonatal, 927–928 pathologic, 928 physiologic, 927–928

Jejunum fat malabsorption in, 924 obstruction of, 918–919

Jerk nystagmus, 338 Jet-lag syndrome, 337 Joint capsule, 940

2690

Joint cavity, 941 Joint disorders description of, 973–974 inflammatory diseases, Inflammatory joint disease osteoarthritis, Osteoarthritis

Joint infection, 1001–1003, 1002f, 1002b Joint mice, 974 Joints aging of, 952 cartilaginous, 940–943 definition of, 940 effusion of, 973f, 975 fibrous, 940 function of, 940–943 stiffness of, 975 structure of, 940–943, 943b synovial, 943, 943f–945f types of, 942f

J-receptors, 660 Junctional bradycardia, 625t–626t Junctional complex, 13, 14f Junctional nevus, 1032t Junctional tachycardia, 625t–626t Juvenile idiopathic arthritis, 1003, 1004t Juxtaglomerular apparatus, 713, 715f Juxtaglomerular cells, 713, 715f Juxtamedullary nephrons, 713, 715f K Kallikrein, 137–138 Kaposi sarcoma, 243, 260t–264t, 283, 295, 1034, 1034f Karyogram, 44, 47f Karyolysis, 100 Karyorrhexis, 100 Karyotype, 44, 47f Kasai procedure, 928

2691

Kawasaki disease (KD), 650, 650b KD, Kawasaki disease Kegel exercises, 792 Keloid scar, 151, 152f Keloids, 1019f, 1019t–1020t, 1021, 1021f Keratitis, 342 Keratoacanthoma, 1031 Kernicterus, 550, 928 Kernig sign, 399, 422 Ketosis, 885–886 Kidney(s) acid-base buffering by, 126 agenesis of, 752 anatomy of, 712, 713f–715f aplasia of, 751 arteries of, 716 blood vessels of, 716–717 cancer of, 260t–264t congenital anomalies of, 752f description of, 712 dysfunction of, 742, 742t dysplastic, 751 ectopic, 751 function of, 712 horseshoe, 751 hydronephrosis of, 729f hypertension-related complications of, 594–595, 595t hypoplastic, 751 lobe of, 712 structure of, 712–716, 713f–715f, 716b veins of, 716

Kidney disorders glomerular disorders, 754–755 hemolytic uremic syndrome, 755 hypoplastic kidney, 751 immunoglobulin A nephropathy, 754 nephroblastoma, 755–756, 756t, 756b nephrotic syndrome, 754–755, 755f

2692

polycystic kidney disease, 751–752 renal agenesis, 752

Kidney stones, 729–730, 737t Kinin cascade, 137 Kinin system, 137–138 Kininase, 138–139 Kininogen, 137–138 Klinefelter syndrome, 47, 50f, 56, 640t, 852 Kocher criteria, 1003 Koilonychia, 512, 512f Koplik spots, 1049 Krebs cycle, 17–18 Kupffer cells, 494, 871, 901–902 Kussmaul respiration, 129, 671, 746–748 Kwashiorkor, 480, 925 Kyphoscoliosis, 674 Kyphosis, 968, 968f L Labia majora, 763, 764f–765f Labia minora, 763, 764f–765f Labored breathing, 671 Lactase deficiency, 892 Lacteal, 873 Lactobacillus sp. description of, 204 L. acidophilus, 764

Lactose intolerance, 892 in children, 924–925, 927

Lactose malabsorption, in children, 927 Lacuna, 935 Lacunar infarcts, 397 Lacunar strokes, 397 Lamellae, 937

2693

Lamina propria, 865 Laminar blood flow, 581, 582f Laminin, 934t Landau reflex, 415t Laparotomy, 911 Laplace law, 574–575, 596, 663, 895–896 Large cell carcinoma, 692t, 693 Large intestine aging effects on, 876b anatomy of, 867–869, 868f, 869b congenital impairment of, 920 microbiome of, 869 obstruction of, 885t, 886

Large-volume diarrhea, 880 Laryngeal box, 655 Laryngoscopy, 691 Larynx anatomy of, 655, 657f, 697, 698f cancer of, 260t–264t, 690–691, 691f

Latent tuberculosis infection, 688 Lateral apertures, 313–314 Lateral columns, 309 Lateral corticospinal tract, 311 Lateral epicondylopathy, 959f, 960 Lateral fissure, 305 Lateral horn, 308–309 Lateral spinothalamic tracts, 311 Lateral sulcus, 305, 306f LBP, Low back pain LCA, Left coronary artery Lead blood levels of, 85 cellular injury and, 85 in children, 85, 88f, 88b children exposed to, 422 encephalopathy caused by, 422

2694

sources of overexposure, 85

Lead poisoning, 422 Lead-pipe rigidity, 370, 371t Left anterior descending (LAD) artery, 567–568 Left atrium, 565, 566f Left bundle branch, 569–570 Left coronary artery (LCA), 567–568, 569f Left heart failure clinical manifestations of, 620 description of, 620–623 in infants, 649 management of, 622

Left-to-right shunting, 639–640, 642 Left ventricle, 565, 566f afterload of, 575–576

Left ventricular end-diastolic volume, 620 Left ventricular hypertrophy, 75 Legg-Calvé-Perthes disease, 1004–1005, 1005f Leiomyomas, 227, 228f, 795–796, 795f Lens, 338 Lentiform nucleus, 305–306 Lentigo malignant melanoma (LMM), 1033–1034, 1034f Leptin, 336–337, 460, 477, 603, 818–819, 936t resistance, 477

“Let-down” reflex, 437, 772 Leukemia, 228, 260t–264t, 521–527 acute, 521, 523–525 acute lymphocytic, description of, 521, 521t, 522f, 523 acute monoblastic, 559f acute myelogenous, description of, 521, 521t, 522f, 523 acute myeloid, 558 anemia in, 525t bleeding associated with, 524, 525t chemotherapy for, 525 in children, 291, 558–559, 559f chronic, 521, 525–527, 527b chronic lymphocytic, 521, 521t, 525–526

2695

chronic myelogenous in children, 558 description of, 521, 521t, 522f, 525–526 tyrosine kinase inhibitors for, 559

classification of, 521 clinical manifestations of, 524, 525t, 558–559 definition of, 521, 558 Down syndrome and, 294 epidemiology of, 521–522, 521t evaluation of, 525, 559 genetic factors, 293 imatinib mesylate for, 527 incidence of, 521–522, 521t neurologic manifestations of, 524 pathophysiology of, 523f, 524, 558 Philadelphia chromosome in, 523, 523f, 525 risk factor for, 522 stem-like cancer cells, 523, 524f survival rates for, 522 treatment of, 525, 559

Leukemic blasts, 523 Leukemic cells, 558–559 Leukemoid reaction, 518 Leukocoria, 425 Leukocytes, 140 agranulocytes, 486–487 basophils, 486, 487t, 488f disorders involving, 519t

development of, 496 disorders involving agranulocytosis, 518 basopenia, 518, 519t basophilia, 518, 519t eosinopenia, 518, 519t eosinophilia, 518, 519t granulocytopenia, 518 infectious mononucleosis, 520–521 leukocytosis, 517 leukopenia, 517 lymphocytopenia, 519–520, 519t lymphocytosis, 518–519, 519t neutropenia, 518, 519t quantitative alterations of, 517–527

eosinophils, 486, 487t, 492f

2696

disorders involving, 519t

function of, 486–487 granulocytes, 486, 496 disorders involving, 518

lymphocytes, 487, 487t disorders involving, 518–520, 519t

macrophages, 487, 487t monocytes, 487, 487t, 496 disorders involving, 518, 519t

natural killer cells, 487, 487t neutrophils, 486, 487t, 488f disorders involving, 518, 519t

Leukocytosis, 489, 517 in inflammation, 147

Leukopenia, 247b, 517 Leukoplakia, 1033 Leukotrienes, 143 Level of consciousness, 352 alterations in, 353t pupillary changes based on, 352, 355f

Levonorgestrel intrauterine device, 785, 796 Levothyroxine, for hypothyroidism, 454 Lewy body dementia, 363t, 374 Leydig cells, 772 LFS, Li-Fraumeni syndrome LH, Luteinizing hormone Libido, 775–776, 806 Lice, 1051 Lichen planus, 1024–1025, 1025f Lichenification, 1019f, 1019t–1020t Life expectancy, 105 across the United States, 105b

Li-Fraumeni syndrome (LFS), 238, 293–294 Ligaments definition of, 959 description of, 951 repair, 951b sprains of, 959

2697

strains of, 959

Ligands, 10 Ligature strangulation, 92–93 Limbic system, 306 Linear fracture, 955, 956t Linkage, 58 analysis, 58, 58f, 60b

Linoleic acid, 843b–844b Lip(s) cancer of, 260t–264t, 1033, 1033f cleft, 916–917, 917f

Lipid bilayer, of plasma membrane, 4, 8f proteins and, 9

Lipid metabolism defects, 421–422, 422b Lipid peroxidation, 80 Lipid rafts, 6 Lipids as cellular accumulations, 95–96 deficiency of, 988

Lipid-soluble hormones, 430, 430t, 432 Lipiduria, 741t Lipofuscin, 74–75, 340 Lipoid nephrosis, 754 Lipolysis, 478 Lipoma, 227 Lipopolysaccharide (LPS), 199 Lipoprotein(a), 603 Lipoprotein(s), 484–485 definition of, 602 high-density, 602 low-density, 602 very-low-density, 602

Lipotoxicity, 478 β-Lipotropin, 437t Liquefactive necrosis, 100–101

2698

Liquid biopsy, 249b Literal paraphasia, 362t Liver aging effects on, 876b alcoholic disease of, 901–903 anatomy of, 869–873, 870f–871f, 873b bile secretion by, 871–872 bilirubin metabolism, 872, 872f burn injury responses by, 1037 cancer of, 260t–264t, 907t, 910, 910b disorders of, 901–904 hematologic functions of, 872 lobules of, 870–871, 871f metabolic detoxification by, 873 metabolic functions of, 870 mineral storage in, 873 nutrient metabolism in, 872–873 vascular functions of, 872 vitamin storage in, 873

Liver cells, 96 Liver disorders acute liver failure, 901 in children, 927–929 biliary atresia as, 928 cirrhosis as, 929 hepatitis as, 928–929 inflammatory disorders and, 928–929 metabolic disorders and, 929, 929t–930t, 929b neonatal jaundice as, 927–928

cirrhosis, Cirrhosis complications of, 897–901, 901b ascites, 897–898, 898f hepatic encephalopathy, 898–899 hepatorenal syndrome, 900–901 jaundice, 899–900, 899f, 900t portal hypertension, 897, 897f

hemostatic impairments caused by, 539–540 viral hepatitis, 903–904, 903t, 904b

Liver function tests, 874t Liver injury, chemical, 84f Livor mortis, 106 LMM, Lentigo malignant melanoma

2699

Lobular carcinoma in situ, 820t, 821–825 Lobular involution, 813 Localized edema, 113–114 Localized lymphadenopathy, 527 Locked-in syndrome, 357 Locus, 51 Long bones, 938, 971 Longitudinal fissure, 304 Long-term memory, 357 Long-term starvation, 480 Loop of Henle, 713f–715f, 714, 719f Loose tissue, connective, 33t–35t Loss of consciousness, 387 Lou Gehrig disease, 377–378 Low back pain (LBP), 332t, 392–394 Low bladder wall compliance, 732 Low-density lipoproteins coronary artery disease and, 602 description of, 602 function of, 602 oxidation of, 599, 601f

Low-dose ionizing radiation, 280, 281f, 281b Lower esophageal sphincter, 860, 879–880, 883 Lower extremity ischemia, 601–602 Lower gastrointestinal bleeding, 881–882 Lower motor neurons, 310 structure of, 377f syndromes, 376–377

Lower respiratory tract infection, 200t–201t Lower urinary tract symptoms, 839 Low-level ionizing radiation, 280 Lown-Ganong-Levine syndrome, 626t–627t LPS, Lipopolysaccharide Lumen, 577

2700

Lung(s) acinus of, 656 alveolar pressure in, 666f alveoli of, 656, 659f autonomic nervous system, 659 bronchi of, 655–656, 656f cancer of, 260t–264t carbon dioxide diffusion gradient in, 667 defense mechanisms of, 655, 656t elastic properties of, 663–664, 664b epithelial cells of, 656 gravity effects on, 665 hilum of, 655–656 lobes of, 655 oxygen transport in, 666–667 vasculature of, 658–659

Lung cancer, 693b adenocarcinoma, 691–693, 692t cigarette smoking and, 691 clinical manifestations of, 692t, 693 definition of, 691 description of, 260t–264t evaluation of, 693 large cell carcinoma, 692t, 693 molecular therapies for, 693b neuroendocrine tumors, 692t, 693 non-small cell, 691–693, 692t pathology of, 692f pathophysiology of, 693 risk factors for, 691 small cell carcinoma, 692t, 693 squamous cell carcinoma, 692f, 692t TNM staging classification of, 693 treatment of, 693, 693b types of, 691–693, 692t

Lung receptors, 660–661 Lung volumes, 664f Lupus erythematosus, 1025–1026 systemic, 806t

Lupus nephritis, 740

2701

Luteinizing hormone (LH), 434 deficiency of, 450 functions of, 761, 761t in menstrual cycle, 770

Lycopene, 843b–844b Lyme disease, 1027–1028 Lymph composition of, 586 description of, 563 immune system cells in, 586

Lymph nodes, 489–490, 490f anatomy of, 586f, 587 in Hodgkin lymphoma, 528, 528f

Lymphadenitis, 136 Lymphadenopathy, 527, 527f, 560 Lymphangitis, 136 Lymphatic system anatomy of, 585–587, 586f, 587b of breast, 770–771, 771f capillaries of, 586f definition of, 585–586 disorders involving, lymphadenopathy, 527, 527f fluid balance function of, 586f veins of, 586 venules of, 586

Lymphatic vessels, 568 Lymphedema, 113, 114f, 247b Lymphoblastic lymphoma, 531 Lymphoblasts, 558 Lymphocyte count, 500t–501t Lymphocytes, 140, 144, 487, 487t description of, 156–157, 157f disorders involving, 518–520, 519t tumor-infiltrating, 244

Lymphocytic colitis, 894 Lymphocytopenia, 519–520, 519t Lymphocytosis

2702

description of, 518–519, 519t monoclonal B-cell, 526

Lymphogranuloma venereum, 854t–855t Lymphoid function, alterations of, 527–534, 534b Lymphoid organs primary, 160–161 secondary, 157, 159f

Lymphoid progenitor cells, 496 Lymphoid stem cells, 157–158 Lymphoid tissues of secretory immune system, 168 as sites of B-cell and T-cell differentiation, 159f

Lymphokines, 141 T cells secreting, 171

Lymphomas, 228, 260t–264t Burkitt in children, 560 description of, 520, 530–531, 531f

in children, 291, 559–560, 560f, 560b cutaneous, 1034–1035 definition of, 559 diffuse large B-cell, 526 Hodgkin in children, 560 description of, 527–529, 528f, 529t, 560 lymphadenopathy in, 560, 560f treatment of, 560

lymphoblastic, 531 malignant, 527–531, 528f, 529t, 530f–531f mucosa-associated lymphoid tissue, 242–243 multiple myeloma, 531–534, 531f–532f, 534b non-Hodgkin, 529–531, 530t in children, 559–560

pathophysiology of, 523, 523f primary cutaneous, 1034–1035 REAL/WHO classification of, 527

Lynch syndrome, 908 Lyon hypothesis, 56 Lysosomal storage diseases, 421–422 Lysosomes, 2, 4t–6t

2703

Lysozyme, 135 Lytic lesions, 532, 532f M M band, 947, 949f M line, 572–573, 573f M phase, 27 M protein, 531, 533f, 615 MAC, Membrane attack complex Macewen sign, 420 Macroadenomas, 450 Macrocytic-normochromic anemias, 506t, 507 Macromolecule, 12 Macrophage colony stimulating factors, 243 Macrophages, 33t–35t, 144, 487, 487t alveolar, 657, 658f in atherogenesis, 599 in pannus, 977, 977f tumor-associated, 243, 246f

Macula densa, 713, 715f, 717 Macula lutea, 338 Macular edema, 464 Macule, 343, 1017f, 1017t–1018t Magnesium alterations in, 124t parathyroid hormone secretion affected by, 439 small intestine absorption of, 868b

Magnetic fields, 296b Major duodenal papilla, 871 Major histocompatibility complex (MHC), 161, 185 class I, 161 class II, 161

Major muscles, 662 Malabsorption syndromes description of, 891–893

2704

lactase deficiency, 892 lactose intolerance, 892 pancreatic exocrine insufficiency, 892

Maladaptive coping, 221–222 Malaria, 204–206 Maldigestion, 891 Male-pattern baldness, 57–58 Male reproductive system, 760–779, 776b aging effects on, 777, 777b development of, 760–762, 762b epididymis, 773, 773f external genitalia of, 763f, 772–774, 772f, 774f hormones of, 761t internal genitalia of, 762f, 774–775 puberty, 761–762 scrotum, 773–774, 773f sex hormones of, 775–776 spermatogenesis, 775, 775f

Male reproductive system disorders, 831–852 balanitis, 833, 833f benign prostatic hyperplasia, 838–840, 839f, 846–847 cryptorchidism, 835–836 ectopic testis, 835–836 epididymitis, 838, 838f gynecomastia, 852 hydrocele, 835, 835f orchitis, 836–837, 836f paraphimosis, 831–832, 832f Peyronie disease, 832, 833f phimosis, 831–832, 832f priapism, 833, 833f prostate cancer, Prostate cancer scrotal disorders, 834–835 sexually transmitted infections, 853–856, 853t–855t spermatocele, 835, 835f testicular cancer, Testicular cancer testicular torsion, 836, 836f urethral strictures, 831 urethritis, 831, 838f varicocele, 834, 835f

2705

Malignant hyperthermia, 335, 963 Malignant melanoma, 97 Malignant tumors, 227–228 Malleus (hammer), 342, 342f Mallory-Weiss tear, 881–882 Malnutrition, 480 atrophy and, 74–75 in children, 925 protein-energy, 925

Malrotation, intestinal, 919 Maltase, 987–988 Mammary adenocarcinoma, 228 Mammary stem cells, 820–821 Mammography, 811f, 811b, 816–817 Mannose-binding lectin, 137 Mannose-binding lectin (MBL) deficiency, 188 Manual strangulation, 92–93 MAP, Mean arterial pressure Marasmus, 480, 925 Marginating storage pool, 496 Margination, 144 Marijuana, 86t Mast cells, 139–140, 142–143, 142f, 167, 629 Mastoid air cells, 342 Mastoid process, 342 Maternal-fetal transmission, of hepatitis B virus, 928 Matrix metalloproteinases, description of, 239, 935 Maturity-onset diabetes of youth (MODY), 461 McArdle disease, 988 MCP-1, Monocyte chemotactic protein-1 MCS, Minimally conscious state MCV, Molluscum contagiosum virus Mean arterial pressure (MAP), 581–582 Mean corpuscle hemoglobin, 500t–501t

2706

Mean corpuscle volume, 500t–501t Mean corpuscular hemoglobin concentration, 500t–501t Mean pulmonary artery pressure, 565 Measles, mumps, rubella vaccine, 1048 Meckel diverticulum, in children, 919, 919b Meconium, 919 Meconium ileus (MI), 919 Meconium ileus equivalent, 919 Meconium plug syndrome (MPS), 919 Meconium syndromes, 919–920 Medial epicondylopathy, 959f, 960 Median aperture, 313–314 Median eminence, 436 Mediastinum, 563–564, 655 Mediated transport, 18–19, 20f Mediators, synthesis of, 143 Mediterranean diet, 603b, 818 Medroxyprogesterone, 785 Medullary hematopoiesis, 491 Medulloblastoma, 424t Megakaryocytes, 144, 488 Megaloblastic anemia, 507–511, 518 Meibomian gland, 341 Meiosis, 44, 46f Meissner plexus, 861, 864 Melanin, 97 Melanocyte-stimulating hormone, 434, 437t Melanoma, 280, 1032t, 1033–1034, 1034f Melatonin, 219t, 437, 816 Melena, 881t, 882–883 Membrane attack complex (MAC), 137 Membrane potentials, 570 Membrane proteins, 9

2707

Membrane transport proteins, 18–19 Membranous urethra, 716–717 Memory alterations in, 358t amnesia, 357 definition of, 357 working, 358t

Memory cells, 157, 163 Menarche, 768–769, 781 Ménière disease (endolymphatic hydrops), 344 Meningeal layer, 311 Meninges, 311–313, 313f Meningioma, 408 Meningitis, 401–402 aseptic, 402 bacterial, 401–402 in children, 422 definition of, 401 fungal, 402 pneumococcal, 401 viral, 402

Meningocele, 416, 418f Menometrorrhagia, 785t Menopausal hormone therapy, 815–816 Menopause, 768–769, 776–777 Menorrhagia, 785t Menorrhea, 785t Menstrual blood flow, 770 Menstrual cycle age of onset, 768–769 basal body temperature in, 770 duration of, 769, 769f follicle-stimulating hormone in, 770 luteinizing hormone in, 770 phases of, 769f, 770

Menstrual disorders abnormal uterine bleeding, 784–785, 785f, 785t, 787b

2708

amenorrhea, 783–784, 784f dysmenorrhea, 783

Menstruation, description of, 765, 770 Mental stress-induced myocardial ischemia, 605 Mercury, cellular injury and, 85–86 Merkel disks, 345–346 Mesangial cells, 713 Mesencephalon, 308 Mesenchymal cells, 77 Mesenchymal stem cells (MSCs), 188, 490 Mesenteric arterial insufficiency, 896 Mesenteric vascular insufficiency, 896 Mesenteric venous thrombosis, 896 Mesoderm, 990 Mesodermal germ layer, 291, 293f Mesothelium, 260t–264t Messenger ribonucleic acid, 41 Metabolic acidosis, 129, 129t causes of, 746 description of, 623 ketosis and, 885–886 signs and symptoms of, 129

Metabolic alkalosis, 129 hypochloremic, 129

Metabolic bone diseases osteomalacia, 970 osteoporosis, Osteoporosis Paget disease, 820t, 970–971

Metabolic detoxification, 873 Metabolic disorders, liver disorders and, in children, 929, 929t–930t, 929b Metabolic pathway, 17 Metabolic syndrome, 458, 458b Metabolically healthy obesity, 479, 479b Metabolism, 17 burn injury response, 1037–1038

2709

cellular, 17–18 adenosine triphosphate in, 17 carbon dioxide produced by, 660 food of, 17–18 impairment of, in shock, 624–627, 628f oxidative phosphorylation, 18 production of, 17–18 thiamine deficiency effects on, 623

muscle description of, 950 diseases affecting, 987–988

protein in chronic kidney disease, 746 cortisol effects on, 214

Metaphase spread, 44, 47f Metaphysis, 938 Metaplasia, 76–77, 76f Metarterioles, 577, 580f Metastasis/metastases, 227–228 brain tumors, 406, 409 breast cancer, 245, 821, 823f cancer cell, 244–247, 246f, 247b prostate cancer, 848, 848f spinal cord tumors, 409 of testicular cancer, 837

Metastatic calcification, 98–99 Metencephalon, 308 Metformin, 461 Methamphetamine, 86t Methane, 93 Methemoglobin, 493, 495 Methicillin-resistant Staphylococcus aureus (MRSA), 206–207, 699, 1001–1002, 1046 community acquired, 1027

Methotrexate, 979 Metrorrhagia, 785t MG, Myasthenia gravis MGUS, Monoclonal gammopathy of undetermined significance MHC, Major histocompatibility complex MI, Meconium ileus

2710

Microadenomas, 450 Microalbuminuria, 465, 594–595 Microbiome, 135, 603, 604b Microcephaly, 419, 419f Microcirculation, 580f Microcytic-hypochromic anemias iron deficiency anemia, 506t, 511–512, 512f sideroblastic anemia, 506t

Microdomains, 4 Microfilaments, 299 Microglia, 300, 301t β2-microglobulin, 161, 533 Microorganisms antibiotic-resistant, 206 antibiotics that destroy, 207t classes of, 197t description of, 196–199, 197b opportunistic, 196 parasitic, 204–206 pathogenic, 197–198, 197t pneumonia caused by, 686, 686t, 686b tissue damage caused by, 198, 198t

MicroRNAs, 238, 973 Microscopic colitis, 894 Microsporum canis, 1047 Microtubules, 299 Microvascular angina, 605b Microvasculature thrombosis, 538 Micturition, 716 Micturition reflex, 717 Midbrain, 304f, 304t, 308 Midcortical nephrons, 712 Middle cerebral artery, 315t, 316f Middle ear, 342, 342f Middle fossa, 311

2711

Migraine, 400–401, 400t Migratory testis, 836 Mild concussion, 388 Mild cystitis, 734 Mild traumatic brain injury, 388 Miliaria, 1053, 1053f Miliaria crystallina, 1053 Miliaria rubra, 1053, 1053f Millimeters of mercury, 578 Mindfulness therapy, for stress, 223–224, 224b Mineralization, of bone, 937 Mineralocorticoids, 442 Minimal change nephropathy, 754 Minimally conscious state (MCS, minimally preserved consciousness), 357 Minute ventilation (V̇), 660 Minute volume, 660 Mirror focus, 367 Missense mutations, 41 Mitochondria, 4t–6t in cellular injury, 78 and reactive oxygen species, 81

Mitogen, 28, 29t Mitogen-activated protein kinase (MAPK) pathway, 232 Mitosis, 27, 44, 46f phases of, 27–28

Mitotic cells, 227 Mitral complex, 565–566 Mitral valve anatomy of, 565–566 bacterial endocarditis of, 619f regurgitation, 616 stenosis, 615–616, 616f

Mitral valve prolapse syndrome, 616, 617f Mixed gonadal dysgenesis, 835–836 Mixed hearing loss, 344

2712

Mixed hiatal hernia, 884 Mixed incontinence, 731t Mixed nerves, 317 Mixed precocious puberty, 783b, 831b MLH1, 69–70 Mmp inhibitors, 936t Mobitz I block, 626t–627t Mobitz II block, 626t–627t Moderate traumatic brain injury (moderate concussion), 388 MODY, Maturity-onset diabetes of youth Moles, 1031 Molluscum contagiosum, 1048, 1048f Molluscum contagiosum virus (MCV), 1048 Monoallelic expression, 66 Monoblasts, 559f Monoclonal antibodies, 168b, 253 Monoclonal B-cell lymphocytosis, 526 Monoclonal gammopathy of undetermined significance (MGUS), 533 Monocyte chemotactic protein-1 (MCP-1), 243 Monocyte count, 500t–501t Monocyte-derived macrophages, 144 Monocytes, 144, 487, 487t disorders involving, 518, 519t

Monocytopenia, 518, 519t Monocytosis, 519t Monokines, 141 Mononuclear phagocyte system, 487, 488t Monosodium urate crystals, 981 Monounsaturated fatty acids, 865b Mons pubis, 763, 764f Montgomery glands, 771 Moro reflex, 415t Morphine, 329

2713

Morphine sulfate, 645 Moschcowitz disease, 537 Motilin, 862t Motility diarrhea, 881 Motor aphasia, 361t Motor function syndromes, 376f Motor neuron, 309–310 Motor neuron diseases, 377, 378b Motor neurons, 377 Motor pathways, 307f, 310f, 311, 312f Motor performance alterations, 378–379 expression disorders, 379 gait disorders, 379 postural disorders, 378–379

Motor responses abnormal, 357t in arousal alterations, 353, 356f

Motor units, 310, 944–947, 947f Mouth anatomy of, 858–860, 861b congenital impairment of, 916–918 salivation in, 859, 860f

Moyamoya disease, 423 MPS, Meconium plug syndrome MRSA, Methicillin-resistant Staphylococcus aureus MS, Multiple sclerosis MSCs, Mesenchymal stem cells Mu receptors, 329 Mucopolysaccharidoses, 95–96 Mucopurulent cervicitis, 791 Mucosa-associated lymphoid tissue (MALT) lymphoma, 242–243 Mucous gland cells, 2 Müllerian ducts, 760, 780 Müllerian inhibitory hormone, 760 Multichannel urodynamic testing, 732b

2714

Multigenerational phenotype, 265t Multiple-antibiotic resistance, 206 Multiple causation model, 293 Multiple myeloma, 531–534, 531f–532f, 534b clinical manifestations of, 532–533 evaluation and treatment of, 533–534 pathophysiology of, 532

Multiple organ dysfunction syndrome, 634b clinical manifestations of, 633 definition of, 624 evaluation of, 633–634 gastrointestinal system in, 633 hypermetabolism in, 633 myocardial depression in, 633 pathogenesis of, 633, 634f pathophysiology of, 633 supply-dependent oxygen consumption, 633 treatment of, 633–634

Multiple organ failure, 199–201 Multiple sclerosis (MS), 403–404, 404f, 405t, 806t Multipolar neurons, 299 Mupirocin, for impetigo, 1046 Muscle aging of, 952 agonist of, 951 antagonist of, 951 energy sources for, 950t healing of, 960 mechanics of, 950–951 nonprotein constituents of, 947 structure of, 948f–949f

Muscle contraction cross-bridge theory of, 573 excitation-contraction coupling in, 573–574 isometric, 951, 951f isotonic, 951, 951f steps of, 948–950 types of, 951, 951f

2715

Muscle fibers, 944–946, 945t Muscle function, 947–951 Muscle membrane description of, 946 diseases of, 987

Muscle metabolism description of, 950 diseases affecting, 987–988

Muscle movement alterations, 372–375 Huntington disease, 372–374, 379–380 hyperkinesia, 372, 373t hypokinesia, 374 Parkinson disease, 374–375, 374f–375f

Muscle pump, 577, 581f Muscle strain, 960–961, 961t Muscle tension, stress-induced, 984 Muscle tissues, 35t–36t Muscle tone alterations, 370–372, 371t Muscle tumors, 994 Muscle wasting in cachexia, 250f in Cushing syndrome, 467

Muscular arteries, 577 Muscular dysfunction, secondary, 984 Muscular ventricular septal defects, 642 Musculoskeletal disorders, Paget disease, 820t Musculoskeletal injuries bursitis, 959–960, 960f compartment syndrome, 961–963, 963b, 964f dislocation, 958–959 epicondylopathy, 959–960, 959f fractures, Fractures joints, Joint disorders malignant hyperthermia, 963 muscle tumors, 994 osteoarthritis, Osteoarthritis osteomalacia, 970

2716

osteomyelitis, 971–972, 971f–972f osteoporosis, Osteoporosis Paget disease, 970–971 rhabdomyolysis, 961–962, 962b rheumatoid arthritis, Rheumatoid arthritis skeletal muscle, Skeletal muscle disorders subluxation, 958–959 tendinopathy, 959–960, 959f, 961b

Musculoskeletal system, structure and function of, 933–954 Musculoskeletal tumors, in children, 1009–1010, 1009f–1010f, 1011b Mutagens, 41 Mutation, 41 Mutational hot spots, 41 Mutations, 230–231 Mutualistic relationship, 135 Myalgic encephalomyelitis, 985 Myasthenia, 248t Myasthenia gravis (MG), 405–406, 406b Myasthenic crisis, 406 MYC, Myelocytomatosis viral oncogene homolog MYC gene, 559 MYC protein, 234 MYC proto-oncogene, 234 Mycobacterium smegmatis, 833 Mycobacterium tuberculosis, 688 Mycoplasmal pneumonia, 705t, 706 Mycoses, 204 Mycosis fungoides, 1035 Myelencephalon, 308 Myelin, 299 Myelin sheath, 299 Myelinated neurons, 318–319 Myelocytomatosis viral oncogene homolog (MYC), 232 Myelodysplasia, 416 Myelogenic tumors, 994

2717

Myeloid malignancies, 516b Myeloid tissue, 490 Myeloma, 994 Myelomeningocele, 416, 416t, 418f Myeloproliferative neoplasms, 516b, 538 Myenteric plexus, 861, 864 Myoblasts, 944–945 Myocardial infarction, 78 cardiac troponin I in, 609 chest pain associated with, 609 clinical manifestations of, 609 complications of, 610t creatine phosphokinase MB release after, 608 definition of, 610b description of, 607–611, 611b diagnosis of, 609–611 electrocardiogram of, 609, 611f evaluation of, 609–611 functional changes caused by, 608, 609f functional impairment caused by, 608–609 hospitalization admission for, 606–607 inflammatory response caused by, 609 non-ST elevation, 606–607, 608f pathophysiology of, 608–609, 609f percutaneous coronary intervention for, 606–607 reperfusion injury and, 608 sexual dysfunction secondary to, 806t ST elevation, 606, 608f sudden cardiac death caused by, 609 transmural, 607–608 treatment of, 609–611 ventricular end-diastolic volume affected by, 609

Myocardial ischemia, 602–611, 606b clinical manifestations of, 604–605 coronary artery disease as cause of, 602 electrocardiogram of, 605, 605f evaluation of, 605–606 mental stress-induced, 605 pathophysiology of, 604, 604f

2718

percutaneous coronary intervention for, 606 silent, 605 transient, 604–606 treatment of, 605–606

Myocardial oxygen consumption, 573 Myocardial remodeling, 608 Myocardial stunning, 608 Myocarditis, 618 Myocardium anatomy of, 564, 565f cardiomyopathies of, 613–614, 613f cells of, 571–572, 572f conduction system of, 569 contractility of, 573–574, 620 disorders of, 613–614, 613f hibernating, 608 hypertrophy, 594–595 metabolism, 573 oxygen supply, 576 relaxation of, 574

Myoclonus, 373t Myofascial pain syndromes, 332t Myofibrils, 571, 572f, 947 Myofilaments, 947 Myoglobin, 585, 946 Myokines, 274, 274b–275b, 275f Myometrium, 765, 766f Myoneural junction, 299 Myopathy, 989, 990b Myophosphorylase, 988 Myopia, 340 Myosin, 572, 573f, 948t Myositis, 988–989, 989f Myositis ossificans, 960–961 Myotonia, 987 Myotonic channelopathies, 987

2719

Myotonic muscular dystrophy, 1006t, 1008–1009 Myxedema coma, 454 in hypothyroidism, 454, 455f pretibial, 453–454, 453f

N NA, Neuraminidase NAFLD, Nonalcoholic fatty liver disease Nails definition of, 1014 disorders of, 1039 onychomycosis, 1039 paronychia, 1039 psoriatic disease of, 1023

Naloxone, 329 Narcolepsy, 337 Nasal cavity cancer, 260t–264t NASH, Nonalcoholic steatohepatitis Nasopharynx anatomy of, 655, 656f cancer of, 260t–264t

National Council on Radiation Protection and Measurements (NCRP), 277 Natriuretic hormones sodium excretion regulated b, 594 types of, 594

Natriuretic peptides (NPs), 115, 116f, 583 atrial, 594, 722 brain, 722 C-type, 722 description of, 718 nephron function affected by, 722

Natural killer (NK) cells, 144, 170, 233f, 487, 487t, 871 Nausea, 879 NCF, Neutrophil chemotactic factor NCRP, National Council on Radiation Protection and Measurements Nebulin, 948t

2720

Neck righting reflex, 415t Necrosis cell injury culminating in, 100f features of, 101t types of, 101f

Necrotizing enterocolitis, 926–927, 927b Necrotizing fasciitis, 1027 Negative feedback, 429–430 Negative inotropic agents, 576 Neglect syndrome, 358–359 Neisseria gonorrhoeae, 166–167, 196–197, 831 Neisseria meningitidis, 401, 422 Neoadjuvant chemotherapy, 253 Neologism, 362t Neonatal cholestasis, 928 Neonatal jaundice, 550, 927–928 Neoplasms, 227 clonal proliferation model of, 232f infectious agents associated with, 242t inflammatory conditions associated with, 242t progression of, in cervix, 230f

Neoplastic disorders, 558–560, 560b Neoplastic polyps, 908, 909f Neovascularization, 239, 245 Nephritic syndrome, 739t, 740–741, 742b Nephroblastoma, 755–756, 756t, 756b Nephrogenic diabetes insipidus, 449 Nephron aldosterone effects on, 722 antidiuretic hormone effects on, 722 blood vessels of, 714f, 716 components of, 712, 713f cortical, 712 description of, 712 distal tubule of, 713f–715f, 714–716, 719f, 721–722 function of, 719–722

2721

glomerular filtration membrane of, 713 hormones that affect, 722, 723b juxtamedullary, 713, 715f Loop of Henle, 713f–715f, 714, 719f midcortical, 712 natriuretic peptide effects on, 722 proximal convoluted tubule of, 714, 714f–715f, 719f tubules of, 712, 713f–715f types of, 712

Nephrotic syndrome in children, 754–755, 755f description of, 248t, 739t, 740–741, 741t, 742b pathophysiology of, 741f

Nerve(s) injury to, 300–301, 302f parasympathetic, 321 regeneration of, 300–301, 302f

Nerve growth factor (NGF), 29t Nerve impulse, 301–303, 303f, 303b Nervous system aging and, 324b anemia effects on, 507 autonomic, Autonomic nervous system cells of, 298–301, 300f–302f, 301t, 301b central, Central nervous system in children, 414–415, 415b development of, 414, 415f nerve impulse, 301–303, 303f, 303b nerve injury and regeneration, 300–301, 302f neuroglia, 300 neurons, Neurons organization of, 298, 299f overview of, 298 peripheral, 298, 317–318 satellite cells of, 298 Schwann cells of, 298 somatic, 298

Net filtration, 112, 117b Net filtration pressure, 719

2722

Neural tube defects (NTDs), 416–417, 416t, 417f–418f Neuraminidase (NA), 202–203 Neuritic plaques, 362–363 Neuroblastoma, 423–425 Neurodegenerative dementia, 364b Neuroendocrine tumors, of lung, 692t, 693 Neurofibrillary tangles, 97, 362–363, 364f Neurofibrils, 299 Neurofibromas, 408 Neurofibromatosis, 53, 54f Neurofibromatosis type 1 (NF1), 409 Neurofibromatosis type 2 (NF2), 409 Neurogenic bladder, 732–733, 732t, 737t Neurogenic diabetes insipidus, 449 Neurogenic shock, 390, 629, 630f Neuroglia, 300 Neuroglial cells, 298 Neurohormonal signaling, 14–15 Neurohypophysis, 436 Neurologic system, Nervous system chronic kidney disease effects on, 747t, 748

Neuromodulators, 302, 304t Neuromotor function alterations, 370–378, 370b amyotrophic lateral sclerosis, 377–378 hypertonia, 370–372, 371t hypotonia, 370, 371t lower motor neuron syndromes, 376–377, 377f, 377t motor neuron diseases, 377, 378b muscle movement, 372–375 Huntington disease, 372–374 hyperkinesia, 372, 373t hypokinesia, 374 Parkinson disease, 374–375, 374f–375f

muscle tone alterations, 370–372, 371t upper motor neuron syndromes, 375–376, 375f–376f, 376b, 377t

Neuromuscular junction description of, 299, 311f

2723

disorders of, 405–406

Neurons associational, 299 bipolar, 299 classification of, 299 components of, 299, 302f description of, 299, 300f efferent, 299 epileptogenic, 365–367 interneurons, 299, 309–310, 328 multipolar, 299 orexigenic, 475–476 postganglionic, 318–319, 321f postsynaptic, 302 preganglionic, 318–319, 321f presynaptic, 302 pseudounipolar, 299 sensory, 299 synapse between, 302, 303f transmission by, 303f types of, 299 unipolar, 299

Neuropathic pain, 329, 331–332 Neuropathies, diabetic, 464t, 465, 466f Neuropeptides, 217 Neuropeptides Y, 219t Neuroplasticity, 302, 302b Neuroreceptors, 322, 322t–323t Neurotransmitters, 14–15 autonomic nervous system, 322, 322t–323t definition of, 302 inhibitory, 329 pain modulation, 329–330 types of, 304t

Neutralization, 166–167 Neutropenia, 518, 519t Neutrophil(s), in cystic fibrosis, 708 Neutrophil chemotactic factor (NCF), 143

2724

Neutrophil count, 499, 500t–501t Neutrophilia, 518, 519t Neutrophils, 144 congenital defects in, 518 description of, 486, 487t disorders involving, 518, 519t

Nevi, 1031, 1032t Newborn(s) cholestasis in, 928 in cystic fibrosis, 709b respiratory distress syndrome of, 700–702, 700b, 701f–702f self-defense mechanisms in, 171b

NF1, Neurofibromatosis type 1 NF2, Neurofibromatosis type 2 NGF, Nerve growth factor Nicotine, 603 Night terrors, 337 Nipple anatomy of, 771, 771f retraction of, 824f

Nissl substances, 299 Nitric oxide (NO), 78, 496–497 in septic shock, 631 vascular function roles of, 584

Nitrogenous bases, 40 NK-cell neoplasms, 529 NLRs, Nucleotide-binding-like receptors N-MYC oncogene, 235, 235f Nociceptin/orphanin FQ, 329 Nociception description of, 327–328 phases of, 327–328

Nociceptive pain, 327–328, 330, 331b Nociceptors definition of, 327–328 stimuli that activate, 327–328

2725

Nodes of Ranvier, 299 Nodule, 1017f, 1017t–1018t Noggin, 936t Nonalcoholic fatty liver disease (NAFLD), 903, 929b Nonalcoholic steatohepatitis (NASH), 903 Nonbacterial prostatitis, 841 Nonbacterial thrombotic endocarditis, 248t, 618 Noncardiogenic pulmonary edema, 679 Nonceliac gluten sensitivity (GS), 923–924 Non-coding RNA, 230–231 Noncommunicating hydrocephalus, 370, 370t Nondisjunction, 45–46, 48f Nonerosive reflux disease, 883 Nonfluent aphasia, 361t Nongonococcal urethritis, 831, 838f Non-Hodgkin lymphomas in children, 559–560 description of, 295, 529–531, 530t, 1034

Nonhomologous end joining (NHEJ) pathway, 277–278 Noninflammatory acne, 1044 Nonmyelinating Schwann cells, 300, 301t Nonoliguric kidney failure, 744 Nonossifying fibroma, 1009, 1009f Nonpuerperal hyperprolactinemia, 807 Non-REM sleep, 336 Nonshivering thermogenesis, 474 Non-small cell lung cancer, 691–693, 692t Non-ST elevation MI (non-STEMI), 606, 608f Nonstructural scoliosis, 1006 Nonsyndromic (isolated) cleft lip/palate, 916 Nontargeted effects, of ionizing radiation, 278f, 279 Nonunion, 958 Nonvolatile acids, 123–124 Norepinephrine

2726

heart rate affected by, 576 as neurotransmitter, 583 in pain inhibition, 329 properties of, 304t

Normal flora, 135 Normal microbiome, 135 Normal-pressure hydrocephalus, 370 Normal-weight obesity (NWO), 479 Normocytic-normochromic anemias, 506t, 514t Nosocomial infections, 200t–201t, 247b NPs, Natriuretic peptides NTDs, Neural tube defects Nuclear envelope, 3 Nuclear factor of activated B cells (NF-κΒ), 936t Nuclear factor-kappa B (NF-κβ), 141–142, 560, 936t Nuclear pores, 3 Nucleolus, 3 Nucleotide, 40 Nucleotide-binding-like receptors (NLRs), 140 Nucleotide oligomerization domain-like (NOD-like) receptor, 140, 140t Nucleus, 3, 3f Nucleus pulposus, 314 “Nursemaid's elbow,”, 958 Nutrients liver metabolism of, 872–873 small intestine absorption of, 867f, 868b

Nutrigenomics, 267 Nutrition alcohol intake and, 86–87 cancer, 267–271, 269f endometrial cancer and, 801f epigenetics and, 67–68 impairment of, 922–927 regulation, 270f

Nystagmus, 338, 346

2727

O Obesity, 476–479, 477f breast cancer risks, 818–819, 852–853 cancer and, 271–272, 271f, 272t cardiovascular disease and, 651b in children, 651b, 929b coronary artery disease risks, 603 hypertension risks associated with, 594, 594b insulin resistance caused by, 460 leptin and, 336–337, 460, 477, 818–819 metabolic changes of, 272f–273f metabolically healthy, 479, 479b peripheral, 479 pubertal onset affected by, 781 respiratory failure risks, 674

Obesity hypoventilation syndrome, 336–337 Obesogens, 476b Obligate carriers, 53 Oblique fracture, 955, 956f, 956t Obscurin, 948t Obstructive jaundice, 900 Obstructive lung diseases characteristics of, 680 chronic obstructive pulmonary disease, 682, 684t

Obstructive sleep apnea syndrome (OSAS), 336–337 in children, 700

Obstructive uropathy, 728 Occipital lobe, 305, 306f Occult bleeding, 881–882, 881t Occupational hazards, as carcinogens, 283–286, 286b Ocular cancer, 260t–264t Ocular movements, alterations in, 338–339 Ocular myasthenia, 405 Oculocephalic reflex, 356f Oculomotor nerve, 319t Oculovestibular reflex, 356f

2728

Odynophagia, 907 Ogilvie syndrome, 886 OGTT, Oral glucose tolerance testing Olecranon bursitis, 960f Olfaction (smell), 344, 345f, 345b Olfactory cells, 344 Olfactory hallucinations, 344 Olfactory nerve, 319t Oligoarthritis, 1003 Oligodendrocytes, 300, 301t Oligodendroglia, 300, 301t Oligodendroglioma, 408 Oligohydramnios, 752 Oligomenorrhea, 785t Oliguria, 123, 743, 743f OME, Otitis media with effusion OnabotulinumtoxinA, 735 Oncogenes activation mechanisms of, 231f definition of, 232–234 gene amplification of, 235 genetic events that activate, 234 mutations in, 239 N-MYC, 235, 235f signal cascade activation by, 234 translocations effect on, 234f

Oncomirs, 238 Oncosis, 95, 96f Oncotic pressure, 484 capillary (plasma), 112 interstitial, 112

Onychomycosis, 1039 OPCs, Oropharyngeal cancer Open angle glaucoma, 339 Open fracture, 955, 956f, 956t

2729

Open pneumothorax, 675 OPG, Osteoprotegerin Ophthalmopathy, 453, 453f Opioid receptors, 329 Opioids abuse of, 83t endogenous, 329, 330f

Opisthorchis viverrini, 283 Opportunistic, pathogens, 135 Opportunistic infections, 204 Opportunistic pathogens, 135 Opsonins, 137, 144, 167 Opsonization, 144 Optic chiasm, 338 Optic disc, 338 Optic nerve, 338 description of, 319t

Optic neuritis, 404 Opt-out screening, 191 Oral candidiasis, 1030t Oral cavity aging effects on, 876b cancer of, 260t–264t

Oral contraceptives, 816 Oral glucose tolerance testing (OGTT), 461 Orchiopexy, 836 Orexigenic brain pathways, 249 Orexigenic neurons, 475–476 Orexins, 475–476 Organ of Corti, 343, 343f Organelles, 1 cytoplasmic, 3–4, 4t–6t, 4b

Organic confusion, 362t Organ-specific autoimmune adrenalitis, Idiopathic Addison disease

2730

Oropharyngeal cancer (OPCs), 283 Oropharyngeal secretions, 687 Oropharynx, 655 Orthopnea, 670 Orthostatic hypotension, 596 Ortolani sign, 999–1000 OSAS, Obstructive sleep apnea syndrome Osgood-Schlatter disease, 1005 OSHA-relevant carcinogenic factors, overview of, 283t–285t Osmolality, 21 plasma, 115

Osmolarity, 21 Osmoreceptors, 115 Osmosis, 20–22 Osmotic diarrhea, 880–881 Osmotic pressure, 21 Ossicles, 342 Osteitis deformans, 970 Osteoarthritis characteristics of, 973, 973f clinical manifestations of, 974–975 evaluation of, 975–976 pathology of, 973 pathophysiology of, 974, 974f risk factors for, 975b treatment of, 975–976, 976b varus deformity associated with, 975, 975f

Osteoblasts, 490, 934–935, 934t, 935f, 957 Osteocalcin, 934t, 937 Osteochondroma, 1009, 1009f Osteochondroses, 1003–1006, 1005f, 1009b Osteoclasts, 438, 490, 934t, 935, 935f, 939–940 Osteocytes, 934t, 935, 935f Osteogenic tumors, 992–993, 993f Osteoid, 934

2731

Osteomalacia, 970 Osteomyelitis in adults, 971–972, 971f–972f, 972b in children, 1001–1003, 1002f, 1002b

Osteonectin, 934t Osteophytes, 973 Osteophytosis, 973 Osteoporosis clinical manifestations of, 968 definition of, 964 description of, 964 electron microscopy of, 965f evaluation of, 968–969, 969b facts about, 965b fractures caused by, 965, 965b, 966t glucocorticoid-induced, 967 heparin as cause of, 967 kyphosis secondary to, 968, 968f pathophysiology of, 967–968 postmenopausal, 966 regional, 967 risk factors for, 967b secondary, 967 treatment of, 968–969, 969b in vertebral body, 965f

Osteoprotegerin (OPG), 935–937, 936t, 966f, 967 Osteosarcoma in adults, 992–993, 993f in children, 1009–1010

Ostium primum atrial septal defect, 641 Ostium secundum atrial septal defect, 641 Otitis externa, 344 Otitis media, 200t–201t, 344, 345f Otitis media with effusion (OME), 344 Otoliths, 343 Oval window, 342, 343f Ovarian cancer, 260t–264t

2732

biology of, 805–806 clinical manifestations of, 803–805 epithelial, 803 evaluation of, 805–806 incidence of, 802 metastasis of, 805, 805f pathophysiology of, 802–803 risk factors for, 804t staging of, 806t treatment of, 805–806

Ovarian cycle, 767, 770 Ovarian cysts, 793–794, 793f, 794b Ovarian follicles, 767, 767f Ovarian tumors, 802–803, 803f, 805f Ovaries age-related changes in, 776 anatomy of, 766–767, 766f torsion of, 794

Overactive bladder syndrome, 731–732, 758t Overflow incontinence, 731t, 839 Ovulation definition of, 770 ovarian cancer and, 803

Ovum, 760, 762 Oxidation, 17 Oxidative phosphorylation, mitochondrial (OXPHOS), 239–240 Oxidative stress, 77–79 in chronic alcoholism, 89

Oxycephaly, 419f Oxygen cell absorption of, 2 deprivation of, in myocardial infarction, 608 diffusion of, 673–674 exercise requirements for, 950 hemoglobin transport of, 666

Oxygen consumption, 950 Oxygen debt, 950

2733

Oxygen saturation (SaO2), 666 Oxygen supplementation, 699 Oxygen toxicity, 678 Oxygen transport, 666–667 Oxygenation arterial, 666 hypoxemia caused by, 672

Oxyhemoglobin, 667 Oxyhemoglobin dissociation curve, 667, 667f Oxytocin, 772 function of, 437 in stress response, 219t synthesis of, 433

Ozone, 85 P P wave, 570, 571f p53, 237f Pacemakers, 568 Pacinian corpuscles, 345–346 PAF, Platelet-activating factor Paget disease of bone, 820t, 970–971 Pain, 247b abdominal, 881, 906 acute, 330 cancer-associated, 332t chest wall, 672 chronic, 331, 332t clinical descriptions of, 330–333, 331b, 333b deafferentation, 332t definition of, 327–333 fibromyalgia-related, 984 low back, 332t, 392–394 myofascial, 332t neuroanatomy of, 327–329 neuropathic, 329, 331–332 nociceptive, 327–328, 330, 331b

2734

perception of, 328–329, 328t persistent, 331 phantom limb, 332t referred, 330–331, 331f somatic, 330–331 transduction, 328 transmission of, 328, 328f visceral, 330–331

Pain inhibition, segmental, 330 Pain modulation descending pathways of, 330, 330f description of, 329–330 neurotransmitters of, 329–330 pathways of, 330

Pain threshold, 329, 329t Pain tolerance, 329 Painful bladder syndrome/interstitial cystitis, 735 Palate, cleft, 916–917, 917f Pallor mortis, 106 Palmar grasp reflex, 415t Palmomental reflex, 356f PAMPs, Pathogen-associated molecular patterns Pancreas acinar cells of, 874, 875f aging effects on, 444b, 876b anatomy of, 439–440, 440f cancer of, 260t–264t, 907t, 911, 911b disorders of, 905–906, 911 endocrine, hormones secreted by, 439–441 enzymes produced by, 875 exocrine anatomy of, 870f, 874–875, 875f, 875b insufficiency, 892

innervation of, 874 secretions by, 874

Pancreatic duct, 874 Pancreatic enzyme replacement therapy (PERT), in cystic fibrosis, 923 Pancreatic exocrine insufficiency, 892

2735

Pancreatic function, tests of, 876t Pancreatic insufficiency (PI), 892 in cystic fibrosis, 922

Pancreatic polypeptide, 441, 862t, 875 Pancreatitis, 905, 906f Pancytopenia, 514, 523 Pandemic diseases, 198 Paneth cells, 869 Panhypopituitarism, 449 Pannus, 977, 977f Papanicolaou test, 797 Papillary capillaries, 1015–1016 Papillary muscles, 565–566 Papilledema, 340t Papule, 1017f, 1017t–1018t Para-aminohippurate, 721, 724 Paracetamol, 873, 873b Parachute reaction reflex, 415t Paracrine signaling, 14–15 Paradoxical sleep, 336 Paraesophageal hiatal hernia, 884, 884f Parafollicular cells, 438 Paragangliomas, 470 Paralysis agitans, 374 Paralytic ileus, 885–887, 886t, 905–906 Paranasal sinus cancer, 260t–264t Paraneoplastic syndromes, 247, 248t, 693 Paraparesis, 376b Paraphimosis, 831–832, 832f Paraplegia, 376b Paraprotein, 532 Parasitic disease, 206t Parasitic infection, 204–206

2736

Parasitic microorganisms, 204–206 Parasomnias, 337 Parasympathetic nerves, 321 Parasympathetic nervous system, 320f–321f, 321 in stress response, 216

Parathyroid glands alterations of, 456–457 hormones produced by, 437–439, 437f hyperparathyroidism of, 456 hypoparathyroidism of, 456–457

Parathyroid hormone (PTH), 439, 439f, 456, 722–723, 969 Parathyroid hormone-related protein, 247–249 Paratonia (gegenhalten), 370, 371t Paratope, 166 Paravertebral ganglia, 319–321 Parenting, 68 Parietal cells, 863, 863f Parietal lobe, 305, 306f Parietal pain, 881 Parietal pleura, 659–660, 659f Parietooccipital sulcus, 305, 306f Parkinson disease (PD), 374–375 clinical manifestations of, 374–375, 375f definition of, 374 pathophysiology of, 374, 374f tardive dyskinesia in, 372

Parkinsonian tremor, 373t Parkinsonism, 374 Paronychia, 1039 Parosmia, 344 Paroxysmal dyskinesias, 372 Paroxysmal nocturnal dyspnea, 670 Pars distalis, 433 Pars intermedia, 433 Pars nervosa, 436

2737

Pars tuberalis, 433 Partial precocious puberty, 831b Partial pressure of carbon dioxide, 665f, 667f Partial pressure of oxygen (PO2), 664, 667f Partial thromboplastin time, 500t–501t Partial trisomy, 46 Particulate matter (PM), 85, 87f, 274–276 Passenger mutations, 230–231 Passive diffusion, 21f Passive immunity, 157 Passive immunotherapy, 208, 208b Passive transport, 19–22 diffusion, 20–22 filtration, 20 osmosis, 20–22

Patch (skin lesion), 1017f, 1017t–1018t Patched 1 tumor-suppressor gene, 279 Patent ductus arteriosus (PDA), 640–641, 641f Patent foramen ovale (PFO), 641–642, 645 Pathogen-associated molecular patterns (PAMPs), 140, 631 Pathogenic fungi, 205t Pathogenic microorganisms, 196 Pathogens, opportunistic, 135 Pathologic atrophy, 74 Pathologic contracture, 984 Pathologic fracture, 956, 956f, 956t Pathologic fungi, 204 Pathologic hormonal hyperplasia, 75–76 Pathologic hyperplasia, 75–76 Pathologic hypertrophy, 75 Pathologic jaundice, 928 Pattern recognition receptors, 140, 140t, 486 Pavlik harness, 1000, 1001f PCI, Percutaneous coronary intervention

2738

PD, Parkinson disease PDA, Patent ductus arteriosus PDGF, Platelet-derived growth factor Peak bone mass, 965 Pediatric, and renal function, 725b Pediculosis, 854t–855t, 1051 Pedigree, 52, 52f analysis of, 58 for autosomal dominant inheritance, 52, 52f–53f for autosomal recessive inheritance, 54, 55f for cystic fibrosis, 54, 55f for retinoblastoma, 53f symbols used in, 52f of X-linked inheritance, 57

Pelvic inflammatory disease, 788–790, 788f, 790b Pelvic organ prolapse, 731, 792–793, 792f, 792b, 794t, 794b Pelvic splanchnic nerve, 321 PEM, Protein-energy malnutrition Pendular nystagmus, 338 Penetrance, 53–54 Penetration pathogens, 198 Penile disorders, 831–834 paraphimosis, 831–832, 832f Peyronie disease, 832, 833f phimosis, 831–832, 832f priapism, 833, 833f

Penis anatomy of, 773f–774f, 774 cancer of, 260t–264t, 833–834, 834b candidiasis of, 1030t erectile reflex of, 774 functions of, 774 hypospadias, 753, 753f, 835–836 torsion of, 753 tumors of, 833

Pennate muscles, 943 Penumbra, 397

2739

Pepsin, 864 Peptic ulcer disease, 888–891, 891b description of, 888, 888b, 889f duodenal ulcers, 889, 890f, 891t gastric ulcers, 889–890, 891t, 892f lesions caused by, 889f postgastrectomy syndromes, 891 risk factors for, 888b stress-related mucosal disease, 890

Peptide YY (PYY), 476b, 478, 862t Perception, of pain, 328–329, 328t Perceptual dominance, 329 Percutaneous coronary intervention (PCI) myocardial infarction treated with, 606–607 myocardial ischemia treated with, 606 stable angina treated with, 606

Perfusion, 582, 665 Periaqueductal gray, 330 Pericardial cavity, 564 Pericardial effusion, 612, 612f Pericardial fluid, 564 Pericardial membranes, 611 Pericardial sac, 564 Pericardial space, 565f Pericarditis, 746 acute, 611, 611f constrictive, 612–613, 612f

Pericardium anatomy of, 564, 565f disorders of, 611–613, 611f–612f, 614b

Perilymph, 342–343 Perimembranous ventricular septal defects, 642 Perimenopausal hormone transition, 776f Perimenopause, 776 Perimetrium, 765, 766f Perimysium, 943

2740

Perinatal stroke, 423 Perineal body, 764 Perineum, 764, 764f Periodic paralysis, 987 Periorbital edema, 989f Periosteum, 311, 938 Peripheral artery disease, 601–602 Peripheral chemoreceptors, 662 Peripheral cyanosis, 671 Peripheral membrane proteins, 9 Peripheral nerve regeneration, 302f Peripheral nervous system autonomic division of, Autonomic nervous system components of, 298 cranial nerves, 318, 318f description of, 317 disorders of, 405, 406t divisions of, 298 somatic division of, 298 spinal nerves, 309f, 317

Peripheral neuropathic pain, 331–332 Peripheral neuropathies, 346 Peripheral obesity, 479 Peripheral sensitization, 331–332 Peripheral tolerance, 160, 171 Peripheral vascular disease diabetes mellitus and, 466 Raynaud phenomenon, 598–599 thromboangiitis obliterans, 598

Peripheral vascular system, 577 Peristalsis, 860, 865 Peritoneal cavity, 864 Peritoneum, 864 Peritonsillar abscess, 699 Peritubular capillaries, 716, 720f

2741

Periurethral glands, 839 Permeable membrane, 20 Pernicious anemia, 506t, 509–511, 510f clinical manifestations of, 510 evaluation of, 510–511 pathophysiology of, 510 treatment of, 510–511

Peroxisomes, 4t–6t Persistent cloaca, 920 Persistent pain, 331 Persistent vegetative state, 357 Personalized medicine, 252 PERT, Pancreatic enzyme replacement therapy Pes, 1000t Pessary, 792 Petechial hemorrhage, 496t Peyer patches, 869 Peyronie disease, 832, 833f PFO, Patent foramen ovale pH, 123–125 of body fluids, 125t of cerebrospinal fluid (CSF), 661 maintenance of, 124–125 of vagina, 765

Phagocyte, 136 Phagocyte defects, 187 Phagocytic vacuole, 146 Phagocytosis, 23, 144–146, 145f Phagolysosome, 146 Phagosome, 146 Phantom limb pain, 332t Pharyngeal cancer, 260t–264t Pharynx, cancer of, 260t–264t Phencyclidine-like drugs, abuse of, 83t Phenotype, 51, 57b

2742

Phenylalanine, 421 Phenylalanine hydroxylase (PAH) gene, 421 Phenylketonuria (PKU), 421, 421f Pheochromocytomas (chromaffin cell tumors), 470 Philadelphia chromosome, 235, 523, 523f, 525 Phimosis, 831–832, 832f Phlebotomy, for hereditary hemochromatosis, 517 Phokines, 141 Phosphate alterations in, 124t in bone, 934t parathyroid hormone secretion affected by, 439 small intestine absorption of, 868b

Phosphate buffer, 126 Phosphatidylinositol-3-kinase (PI3K) pathway, 232 Phosphodiesterase E4 inhibitors, 685–686 Phosphodiesterase E5 inhibitors, 851 Phospholipids, 6 Phthirus pubis, 854t–855t Physical activity cancer and, 269f, 274 endometrial cancer and, 801f

Physiologic atrophy, 74 Physiologic hypertrophy, 75 Physiologic jaundice, 927–928 Physiologic muscle contracture, 984 Physiologic stress, 210–211 Physiologic tetanus, 950 PI, Pancreatic insufficiency Pia mater, 312 Pica, 422, 550 Pick disease, 365 PIF, Prolactin-inhibiting factor Pigmented brown gallstones, 904–905

2743

Pigmented nevi, 97 Pigments, as cellular accumulations, 97 Pili (fimbria), 199 Pineal gland, 437 Pinkeye, 342 Pinna, 342 Pinocytosis, 23 Pipe smokers, 267 Pitting edema, 113–114, 114f Pituitary adenoma, 450 Pituitary gland aging effects on, 444b anatomy of, 435f hormones produced by, 433 location of, 433 posterior, 447–449 diabetes insipidus, 449, 449t hormones of, 436–437 syndrome of inappropriate antidiuretic hormone secretion, 448, 449t

tumors of, 451

Pituitary stalk, 436 Pityriasis rosea, 1024, 1024f PKU, Phenylketonuria Placebo effect, 330 Plagiocephaly, 417–419 Plantar grasp reflex, 415t Plantar warts, 1028–1029 Planus, 1000t Plaque (skin lesion), 1017f, 1017t–1018t atherosclerotic description of, 599, 601f unstable, 606, 607f

Plaque psoriasis, 1023, 1023f Plasma, 33t–35t, 138–139 composition of, 484–485, 486t inorganic ions in, 485 serum and, 484

2744

water movements in, 112–113, 113f

Plasma albumin, 113 Plasma cell count, 500t–501t Plasma cells, 157, 162 antibody production by, 484 in asthma, 681 description of, 490 malignant, 532

Plasma creatinine concentration, 723 Plasma membrane, 4–10, 7f components of, 4–10 functions, 7f, 7t lipid bilayer of, description of, 4 outer surface of, 4

Plasma membrane receptors, 10 classes of, 16t

Plasma osmolality, 115 Plasma protein, synthesis of, 147 Plasma protein systems, 137–139, 138f clotting system, 137 complement system, 137 control and interaction of, 138–139 kinin system, 137–138

Plasma proteins, 484–485 albumin, 484 fibrinogen, 485 globulins, 484–485 regulatory, 485 transport, 485

Plasma volume, 718f Plasmalemma, 2–3 Plasmin, 138–139, 499, 540–541 Plasminogen, 138–139 Plasminogen activator inhibitor-1, 540–541 Plasmodium falciparum, 204–206 Plastic rigidity, 370, 371t Plasticity, developmental, 264–265

2745

Platelet-activating factor (PAF), 143, 632b Platelet count, 500t–501t Platelet-derived growth factor (PDGF), 29t, 936t Platelet-rich plasma, 961b Platelets, 137, 140, 144, 487t, 488 activation of, 497 adhesion studies, 500t–501t aggregation of, 500t–501t alpha granules of, 497 dense bodies of, 497 development of, 496 disorders involving, 535–544 in chronic kidney disease, 748 thrombocythemia, 538–539 thrombocytopenia, 536–538

function of, 497 alterations of, 539, 544b

laboratory tests for, 500t–501t micrograph of, 488f normal concentration of, 488 syndrome, sticky, 497b thromboxane A2 production by, 497

Pleomorphic cells, 227–228 Pleura abnormalities of, 674–676, 675f, 676t, 676b anatomy of, 659–660, 659f

Pleural cavity, 659–660, 659f Pleural effusion, 113–114, 675, 676t Pleural friction rub, 672 Pleural space, 659f Plexuses brachial, 317 definition of, 299, 317 spinal nerves, 317

2746

PM, Particulate matter PMR, Posteromedial release Pneumococcal meningitis, 401 Pneumococcal pneumonia, 705, 705t Pneumococcus, 687 Pneumoconiosis, 678 Pneumonia atypical, 705 bacterial, 705 in children, 704–706, 705t chlamydophilal, 705, 705t clinical manifestations of, 688 community-acquired, 686–687, 704 definition of, 686 evaluation of, 688, 705–706 health care-associated, 686 microorganisms that cause, 686, 686t, 686b mycoplasmal, 705t, 706 pathophysiology of, 687, 687f, 705 pneumococcal, 705, 705t prevention of, 688 risk factors for, 686 staphylococcal, 705, 705t streptococcal, 705, 705t treatment of, 688, 705–706 ventilator-associated, 686, 686b viral, 688, 705–706, 705t

Pneumothorax, 674–675, 675f PNM, Primary nodular melanoma Podagra, 982–983 Podocytes, 713 Podosomes, 935 Poikilocytosis, 505 Poikilothermia, 389–390 Point mutations, 230–231 Poiseuille law, 578 Poison ivy, 1022, 1022f

2747

Pollutants, 87f heavy metals as, 85–90

Pollution air cancer caused by, 274–276 coronary artery disease risks, 603

indoor, 276

Polyarthritis, 1003 Polycystic kidney disease, 751–752 Polycystic ovary syndrome, 785–786, 786f, 787b Polycythemia, 248t absolute, 514 familial, 515t relative, 514 secondary, 514, 515t

Polycythemia vera, 514–516, 515t clinical manifestations of, 515 pathophysiology of, 515

Polydipsia primary, 449 in type 1 diabetes mellitus, 459t

Polygenic traits, 59 Polymenorrhea, 785t Polymorphism, 51 Polymorphonuclear neutrophil, 144 Polymyositis, 989 Polypeptides, 7, 41 Polyphagia, in type 1 diabetes mellitus, 459t Polyploidy, 44 Polyps, endometrial, 794–795, 795f Polysomnography, 337 Polyunsaturated fatty acids, 865b Polyuria, 459t Pompe disease, 988 Pons, 308 Ponseti casting, for clubfoot, 999

2748

Pores of Kohn, 657, 658f, 677, 677f Porous bone, 964 Porphyrin analysis, 500t–501t Portal hypertension, 897, 897f cirrhosis and, 929

Portopulmonary hypertension, 897 Port-wine hemangioma, 1053, 1053f Position effect, 49 Positive feedback, 429–430 Positive inotropic agents, 576 Postcentral gyrus, 305, 306f Postconcussion syndrome, 388 Posterior cerebral artery, 315t, 316f Posterior column, 309, 311 Posterior fontanelle, 415, 415f Posterior fossa, 311 Posterior horn, 308–309 Posterior pituitary gland, 447–449 diabetes insipidus, 449, 449t hormones of, 436–437 syndrome of inappropriate antidiuretic hormone secretion, 448, 449t

Posterior spinal artery, 315, 317f Posteromedial release (PMR), 999 Postganglionic neurons, 318–319, 321f Postgastrectomy syndromes, 891 Posthemorrhagic anemia, 506t, 507 Posthyperventilation apnea, 354t Postictal state, 367 Postmenopausal osteoporosis, 966 Postobstructive diuresis, 729 Postpartum thyroiditis, 455 Postsynaptic neurons, 302 Posttranslational modification, 7 Posttraumatic seizures (epilepsy), 388

2749

Posttraumatic stress disorder (PTSD), 216 Postural disorders, 378–379 Postural hypotension, 596 Postural tremor, 373t Postvoid residual urine, 732b Potassium (K+) active transport of, 22, 22f alterations in, 120–123, 120b, 123b hypokalemia, Hypokalemia

dietary, 121 in distal tubular cells, 120 insulin and, 120–121 total body, 120

Potassium adaptation, 121 Potential acid, 127–128 Potter syndrome, 752 Pouchitis, 894 PR interval, 570, 571f Prader-Willi syndrome, 54, 66–67, 66f–67f Precapillary sphincter, 577 Precentral gyrus, 305 Precipitation, 166–167 Precocious puberty, 782, 782b–783b, 830–831, 831b Precursor cells, 29 Predominantly antibody deficiencies, 187 Preganglionic neurons, 318–319, 321f Pregnancy breast cancer and, 810–813 gestational diabetes mellitus in, 461 progesterone's effects in, 768

Prehn sign, 838 Prekallikrein, 137–138 Prekallikrein activator, 137–138 Preload, 574–575, 620, 622 Premature atrial contractions, 625t–626t

2750

Premature atrial tachycardia, 625t–626t Premature infants, 701 Premature junctional contractions, 625t–626t Premature ventricular contractions, 625t–626t Premenstrual disorder syndrome, 786–787 Premenstrual dysphoric disorder, 786–787, 788b Premenstrual syndrome, 786–787 Premotor area, 305, 306f Prepuce, 774 Prerenal acute kidney injury, 742–743, 742t, 744t Presbycusis, 343 Presbyopia, 340 Presenilin, 362 Pressure, blood flow affected by, 578–580 Pressure injury, 1016–1021, 1019t–1020t, 1020f–1021f, 1020b Pressure-natriuresis relationship, 593, 593f Presynaptic neurons, 302 Pretibial myxedema, 453–454, 453f PRF, Prolactin-releasing factor Priapism, 833, 833f Prickly heat, 1053, 1053f Primary adrenal insufficiency, 469 Primary aldosteronism, 468 Primary amenorrhea, 783 Primary biliary cholangitis, 903 Primary cutaneous lymphomas, 1034–1035 Primary dysmenorrhea, 783 Primary gout, 982 Primary healing, of fractures, 957 Primary hyperaldosteronism, 121, 468 Primary hyperparathyroidism, 456 Primary hypertension, 593–594, 593b, 595t Primary hypothyroidism, 454

2751

Primary (congenital) immune deficiency, 186–188 evaluation and care of, 188 replacement therapies for, 188

Primary immune responses, 168, 168b, 170f Primary intention, wound healing, 148 Primary lymphoid organs, 160–161 Primary motor area, 305, 309f Primary nephrotic syndrome, 754 Primary nodular melanoma (PNM), 1033–1034 Primary peristalsis, 860 Primary pneumothorax, 675 Primary polydipsia, 449 Primary progressive multiple sclerosis, 405t Primary sclerosing cholangitis (PSC), 910 autoimmune, 929

Primary thyroid disorders, 452 Primary voluntary motor area, 305 Primitive reflexes, 353, 356f Principal cells, 714–716 Prinzmetal angina, 605 Proband, 52 Prodroma, 367 Proerythroblasts, 491 Progesterone biologic effects of, 768, 768t in endometrial cancer, 802f functions of, 761t

Programmed cell death, 15 Progressive bulbar palsy, 377 Progressive hypoxia, 78 Progressive relapsing multiple sclerosis, 405t Progressive relaxation training, 984 Proinflammatory cytokines, 141–142 Prokaryocytes, 199

2752

Prokaryotes, 1 Prolactin, 772 breast cancer and, 815 function of, 436, 437t secretion of, 434, 451 serum levels of, 808 in stress response, 219t

Prolactin-inhibiting factor (PIF), 436t, 807 Prolactin-releasing factor (PRF), 436t Prolactinomas, 451–452, 807 Prolapse, 565–566 Proliferative phase, of wound healing, 149 Promoter site, 41 Prophase, 28 Prophet of pituitary transcription factor (PROP-1) gene, 449 Propionibacterium acnes, 1044 Proprioception, 346, 346b Prostacyclin, 584 Prostaglandins, 143 E2, 333–334 F2α, 783

Prostate cancer adenocarcinoma, 845 in Africans, 841 carcinogenesis of, 847 cells of, 846f chronic inflammation and, 844, 845f–846f clinical manifestations of, 848, 848f description of, 260t–264t dietary factors, 841–842, 843b–844b epigenetic factors, 844–845 evaluation of, 848–849 genetic factors, 844–845 Gleason score for, 845b hormonal factors, 842–847, 846f incidence of, 841, 841f inflammation and, 844, 845f–846f

2753

metastatic, 253, 848, 848f prostate-specific antigen screening for, 841, 848, 849f screening for, 841, 848, 849f staging for, 850b–851b stromal environment of, 847–849 stromal-epithelial interaction in, 846f treatment of, 848–849 vasectomy and, 844

Prostate epithelial neoplasia, 847, 847f Prostate gland anatomy of, 774f, 775 enlargement of, 731 inflammation of, 845f stroma of, 847 zones of, 839f

Prostate gland disorders benign prostatic hyperplasia, 838–840, 839f, 846–847 prostatitis, 840–841, 840b

Prostate-specific antigen, 841, 848, 849f Prostatic urethra, 716–717, 716f Prostatitis, 840–841, 840b Protamines, 65 Protease inhibitors, 138–139 Proteases, 216–217 Protein buffering, 125–126 Protein C, 498, 543 Protein-energy malnutrition (PEM), 925 Protein folding, in endoplasmic reticulum, 10f, 10b Protein hormones, 430 Protein kinases, 432 Protein metabolism in chronic kidney disease, 746 cortisol effects on, 214

Protein wasting, 467 Proteins, 7–9 accumulation of, 96–97 amino acids in, 7, 41

2754

catabolism of, 214 functions of, 873t genes to, 41–44 homeostasis of, 9, 11f integral membrane, 9 membrane, 9 metabolism of, by liver, 872–873 peripheral membrane, 9 in plasma membrane, 9f posttranslational modification, 7 regulation of, in cells, 9, 11f small intestine absorption of, 868b synthesis of, 45f transmembrane, 9, 9f

Proteinuria in multiple myeloma, 532 in nephrotic syndrome, 741t tubulointerstitial injury caused by, 745

Proteoglycans, 934t, 937 Proteome, 7 Proteomics, 7 Proteostasis, 11f Prothrombin time, 500t–501t Prothrombinase complex, 498 Proton pump inhibitors, 884 Proto-oncogenes definition of, 232–234 MYC, 234

Protopathic, 311 Protoporphyrin, 493 Protozoa, 197t Protozoan parasites, 206, 206t Proximal convoluted tubule anatomy of, 714, 714f–715f, 719f glomerular filtration in, 720–721 sodium reabsorption in, 720

Pruritus, 1021, 1022b, 1051

2755

PS, Pulmonic stenosis Psammoma bodies, 98 PSC, Primary sclerosing cholangitis Pseudoarthrosis, 958 Pseudocysts, 905 Pseudomonas aeruginosa, 135, 838 Pseudoparalysis, 1003 Pseudostratified ciliated columnar epithelium, 31t–32t Pseudothrombocytopenia, 536 Pseudounipolar neurons, 299 Psoriasis, 1023–1024, 1023f–1024f, 1024b Psoriatic arthritis, 1023 Psoriatic nail disease, 1023 Psychological stressors, 211 Psychomotor stimulants, abuse of, 83t PTH, Parathyroid hormone Ptosis, 338–339 PTSD, Posttraumatic stress disorder Ptyalin, 859 Puberty, 783b age of onset, 781 alterations of, 781–782, 782t delayed, 781–782, 782t, 830, 831b description of, 761 precocious, 782, 782b–783b, 830–831, 831b

Puerperal infections, 788–792 Pulmonary arterial hypertension, 690, 690f Pulmonary artery anatomy of, 657–658 constriction of, 659 description of, 564–565, 657–658

Pulmonary artery pressure, 657–658 Pulmonary atresia, 644 Pulmonary blood flow congenital heart defects that affect, 640–643

2756

gravity effects on, 666f

Pulmonary circulation anatomy of, 564f, 657–659, 660b control of, 659 description of, 563

Pulmonary diseases and disorders, 670–696 acute epiglottitis, 698t, 699 acute respiratory distress syndrome, 679–680, 680f, 707 atelectasis, 676–677 bronchiectasis, 677 bronchiolitis, 677, 703–704, 706b bronchopulmonary dysplasia, 702–703, 703t, 703b, 704f chronic bronchitis, 682–685, 683f–684f conditions caused by, 674b hypercapnia, 672, 673f hypoxemia, 672, 673f respiratory failure, 674

cor pulmonale, 674, 690, 690f croup, 697–699, 698f emphysema, 685–686, 685f epiglottitis, 698t, 699 foreign body aspiration, 699–700 hypersensitivity pneumonitis, 678 inhalation disorders, 678 lower airway, 700–709, 703b obstructive lung diseases, 680–686, 681b, 682f–685f, 684t, 686b pneumoconiosis, 678 pulmonary arterial hypertension, 690, 690f pulmonary embolism, 689, 689f pulmonary fibrosis, 677–678 pulmonary vascular disease, 689–690, 690b respiratory tract infections, 686–688, 686t, 686b, 687f, 689b restrictive lung diseases, 676–680, 680b signs and symptoms of breathing pattern abnormalities, 671 clubbing, 672, 672f, 706 cough, 670–671 cyanosis, 671–672 dyspnea, 670 hemoptysis, 671 hyperventilation, 671 hypoventilation, 671 pain, 672 sputum abnormalities, 671

2757

toxic gas exposure, 678

Pulmonary edema, 678–679, 679f Pulmonary embolism, 689, 689f Pulmonary fibrosis, 677–678 Pulmonary semilunar valve, 566 Pulmonary system aging effects on, 668b bronchial circulation, 657–659, 660b chest wall, 659–660, 659f chronic kidney disease effects on, 746–748, 747t conducting airways of, 655–656, 657f–658f defense mechanisms of, 655, 656t function of, 660–667, 660f breathing, 662–664 description of, 655 gas transport, 664–667 ventilation, 660

gas-exchange airways, 656–657, 656f–658f, 657b larynx, 655, 657f lower airway, 658f pleura, 659–660, 659f structures of, 655–660, 656f trachea, 655–656, 658f upper airway, 655, 657f

Pulmonary veins, 565, 658 Pulmonary ventilation, 664f Pulmonic stenosis (PS), 644, 645f Pulse pressure, 582 Pulsus paradoxus, 612, 681 Pupils, 338, 338f arousal alterations and, 352, 355f drugs that affect, 352–353 level of consciousness and, 352, 355f

Purkinje fibers, 570 Purpura fulminans, 401 Purpuric disorders, 535–536 Purulent exudate, 146 Pustular psoriasis, 1023

2758

Pustule, 1017t–1018t, 1018f Putamen, 305–306 Putrefaction, 106 Pyelonephritis acute, 735–737, 756 causes of, 737t chronic, 737, 756

Pyelonephritis-associated fimbriae, 735 Pyknosis, 100 Pyloric obstruction, 884 Pyloric sphincter, 861 Pyloric stenosis infantile hypertrophic, 918 threshold of liability, 60f

Pylorus, 861 Pyosalpinx, 789f Pyramidal lobe, 438 Pyramidal motor syndrome, 379t Pyramidal/spastic cerebral palsy, 421 Pyramidal system, 305 Pyrimidines, 40 Pyrogenic bacteria, 199 Pyrogens, 147 Pyruvate, 18f PYY, Peptide YY Q QRS complex, 570, 571f QT interval, 570, 571f Quadriparesis, 376b Quadriplegia, 376b Qualitative leukocyte disorders, 517 Quantitative leukocyte disorders, 517

2759

R Radial scar, 808 Radiation electromagnetic, 282, 282b of heat, 334t

Radiation-induced cancer, 277–279 Radiation therapy for cancer, 252–253 secondary malignancies caused by, 817–818

Radicular arteries, 315, 317f Radicular syndrome, 409 Radiculopathy, 395, 396f Radiofrequency electromagnetic radiation (RF-EMR), 282 Radiolysis, 277 Radius, 578–579 Radon, 276 RANK, Receptor activator nuclear factor κB RANK system, 935–937, 936t RANKL, Receptor activator nuclear factor κB ligand RANKL system, 935–937, 936t Rapid eye movement (REM) sleep, 336 Rapidly progressing hemangiomas, 1053 RAS, 232 Raynaud phenomenon, 178, 598–599 Reactive oxygen species, 79 in cellular injury, 81f mitochondria and, 81, 82b

Reactive physiologic response, 211 Receptive aphasia, 359–360, 361t Receptive aprosody, 379 Receptive fluent aphasia, 361t Receptor activator nuclear factor κB (RANK), 935–937, 936t, 966–967, 966f, 978f Receptor activator nuclear factor κB ligand (RANKL), 934–935, 936t, 966–967, 966f, 978f Receptor-mediated endocytosis, 24–26, 24f

2760

Receptor protein, 15 Receptor tyrosine kinase, 234 Recessive, 51 Recessiveness, 51 Reciprocal translocation, 49 Recombinant human erythropoietin, 491 Recombination, 58 Rectal atresia, 921f Rectal carcinomas, 909 Rectocele, 793, 793f Rectosigmoid canal, 867 Rectosphincteric reflex, 869 Rectovaginal fistula, 921f Rectum, congenital impairment of, 920 Recurrence risks of autosomal dominant inheritance, 52 of autosomal recessive inheritance, 54–56, 55f of X-linked inheritance, 57

Red cell count, 500t–501t Red measles, 1049, 1049t Red nucleus, 308 Reduced oxygen-carrying capacity, 505 Reduction-oxidative reactions, 79–80 Reed-Sternberg (RS) cells, 527–528, 528f, 560, 560f Refeeding syndrome, 480, 480b Referred pain, 330–331, 331f, 881 Reflex arcs, 309–310, 310f Reflexes in infants, 415, 415t primitive, 353, 356f

Refraction alteration, 340, 340f Refractory period, 570 Regeneration, in wound healing, 147–148 Regional osteoporosis, 967

2761

Relapsing-remitting multiple sclerosis, 405t Relative polycythemia, 514 Relative refractory period, 26 Relaxation, myocardial, 574 Relaxin, 761t Remodeling, of bone, 936t, 939–940, 941f Renal adenomas, 733 Renal aplasia, 751 Renal arteries, 716 Renal blood flow, 717, 724 Renal buffering, 126f Renal capsule, 712, 713f Renal cell adenocarcinoma, 733, 733f Renal cell carcinoma, 734f Renal columns, 712, 713f Renal corpuscle, 713, 713f Renal cortex, 712, 713f–714f Renal disorders glomerular disorders, 754–755 hemolytic uremic syndrome, 755 hypoplastic kidney, 751 immunoglobulin A nephropathy, 754 nephroblastoma, 755–756, 756t, 756b nephrotic syndrome, 754–755, 755f polycystic kidney disease, 751–752 renal agenesis, 752

Renal failure acute infectious diarrhea caused by, 927 definition of, 742 end-stage, 748

Renal fascia, 712 Renal function aging effects on, 725b antidiuretic hormone effects on, 722 description of, 719–723 distal convoluted tubule, 721–722

2762

glomerular filtration, 719–722 hormones that affect, 722, 723b loop of Henle, 721–722 pediatrics and, 725 proximal convoluted tubule, 720–721 specific gravity of, 724t tests of, 723–724, 724t

Renal insufficiency, 742 Renal medulla, 712, 713f Renal papillae, 716 Renal pelvis, cancer of, 260t–264t Renal plasma flow, 717 Renal stones, 984 Renal transitional cell carcinoma, 733 Renal tubules anatomy of, 712, 713f–715f substances transported by, 721, 721t, 721b

Renal tumors, 733–734, 733f–734f Renalase, 717 Renin, 115, 594b Renin-angiotensin system, 442 Renin-angiotensin-aldosterone system, 115, 116f in cardiovascular disease, 594b in hypertension, 593, 594b physiologic effects of, 717–718 renal blood flow regulation by, 717–718 renal perfusion affected by, 620

Repair, in wound healing, 148 Reperfusion injury, 78, 81f, 608 Repetitive discharge, 950 Replication, of DNA, 41 Repolarization, 26, 570 delayed, 121

Reproductive behavior, cancer and, 282–283 Reproductive system, 760–779 chronic kidney disease effects on, 747t, 748

2763

development of, 760–762, 762b maturation of, 761–762, 763f puberty, 761–762 sexual differentiation in utero, 760–761

Residual volume, 668f Resistance, blood flow affected by, 578–580 Resistance stage, of stress, 210 Resolution, in wound healing, 147–148 Respiration(s) brainstem control of, 660 cellular, 2 Cheyne-Stokes, 671 Kussmaul, 671, 746–748 neurochemical control of ventilation, 660–662, 661f physiology of, 675f

Respiratory acidosis, 129–130 Respiratory alkalosis, 130, 674 Respiratory bronchioles, 656, 658f Respiratory center, 660 Respiratory distress syndrome of the newborn, 700–702, 700b, 701f–702f Respiratory failure, 674 “Respiratory rate,”, 660 Respiratory syncytial virus, bronchiolitis caused by, 703 Respiratory tract, malignancies of, 260t–264t, 690–693, 691f–692f, 692t Respiratory tract infections, 200t–201t abscess, 688 acute bronchitis, 686 in children, 703–704 description of, 686 tuberculosis, 688

Resting membrane potential, 26, 301–302 Restless legs syndrome (RLS), 337–338, 338b Restricted breathing, 671 Restrictive cardiomyopathy, 614 Restrictive lung diseases acute respiratory distress syndrome, 679–680, 680f

2764

aspiration, 676 atelectasis, 676–677 bronchiectasis, 677 bronchiolitis, 677 characteristics of, 676

Retching, 879 Reticular activating system, 303, 305f Reticular formation, 303, 305f, 335 Reticulocyte, 491, 496b count, 500t–501t

Reticulospinal tract, 311 Retina, 338 aging-related changes in, 339t

Retinal detachment, 340t Retinoblastoma, 425, 425f–426f, 425b familial form of, 238 gene for, 53, 293 pedigree of, 53f

Retinoblastoma (RB) gene, 235–237 Retinoids, for acne, 1044–1045 Retinol-binding protein 4, 478 Retrograde amnesia, 357, 358t Retroviruses, 189–190 Reverse transcriptase inhibitors, 191–192 Reverse Warburg effect, 240–241 Reversible injury, 77 Reye syndrome, 520–521 RF-EMR, Radiofrequency electromagnetic radiation Rh blood group, 184 Rh incompatibility, 550 Rhabdomyolysis, 961–962, 962b Rhabdomyoma, 994 Rhabdomyosarcomas, 291–292, 994 Rheumatic heart disease, 616–618, 617f Rheumatoid arthritis

2765

cartilage damage in, 977 clinical manifestations of, 978–979 complications of, 979 criteria for, 980t definition of, 976 disease-modifying antirheumatic drugs for, 979 evaluation of, 979 of hand, 977f incidence of, 976–977 methotrexate for, 979 pathology of, 976 pathophysiology of, 977–978, 978f prevalence of, 976–977 treatment of, 979

Rheumatoid factor, 977 Rheumatoid nodules, 979 Rhinovirus, 706 Ribonucleic acid, 41 messenger, 41 ribosomal, 43 transcription of, 41, 44f transfer, 43 translation, 43

Ribonucleic acid-protein complexes, 1 Ribosomal ribonucleic acid, 43 Ribosomes, 4t–6t, 9 protein synthesis in, 43

Rickets, 970 Rifaximin, 899 Right atrium, 565, 566f Right bundle branch, 569–570 Right coronary artery, 567–568, 569f Right heart failure, 623, 623f Right lymphatic duct, 586 Right-to-left shunting, 639 Right ventricle, anatomy of, 565, 566f Rigidity, 370, 371t

2766

Rigor mortis, 106 Ringworm, 1047 Rituximab, 254t RLS, Restless legs syndrome RNA, 3 RNA polymerase, 41 Robertsonian translocation, 49 Rods, 338 Rome IV criteria, for irritable bowel syndrome, 895, 895b Rooting reflex, 415t Roseola, 1049, 1049t Rostral ventromedial medulla (RVM), 330 Rotavirus, acute infectious diarrhea caused by, 927 Rotter nodes, 824 Round ligament, 869–870 Rubella, 1048–1049, 1048f, 1049t Rubeola, 1049, 1049t Rubor, 136 Rubral tremor, 373t Rubrospinal tract, 311 Ruffini endings, 345–346 Rugae, of vagina, 764 Rule of nines, 1036, 1037f Russell bodies, 97 Russell-Silver syndrome, 67 RVM, Rostral ventromedial medulla Ryanodine receptors, 946, 987 S S cells, 875 S phase, 27 Saccular aneurysms, 398, 398f, 596, 597f Sacroiliitis, 981

2767

Saliva, 859 Salivary glands anatomy of, 859, 860f cancer of, 260t–264t

Salivation, 859, 860f Salmon patches, 1053 Salpingitis, 788–789, 789f Saltatory conduction, 299 Saphenous veins, 591 Sarcolemma, 946 Sarcoma, 228 in children, 291 chondrosarcoma, 993, 993f Ewing, 1010, 1010f fibrosarcoma, 820t, 993–994 Kaposi, 260t–264t, 283, 295, 1034 osteosarcoma in adults, 992–993, 993f in children, 1009–1010

rhabdomyosarcomas, 994

Sarcomeres, 572–573, 573f, 948t Sarcopenia, 952, 985–987 Sarcoplasm, 946 Sarcoptes scabiei, 1051 Sarcotubular system, 946 Sarcotubules, 946 Satellite cells, 298, 301t, 935, 944–945 Saturated fatty acids, 865b Scabies, 854t–855t, 1051, 1051f Scale (skin), 1019f, 1019t–1020t Scaphocephaly, 417–419 Scar, 151, 1019f, 1019t–1020t, 1038f burn-related, 1035t contracture, 152 hypertrophic, 151, 152f, 1021 keloid, 151, 152f, 1019t–1020t, 1021, 1021f

2768

Scar tissue, 148 Scavenger receptors, 140, 140t SCC, Squamous cell carcinoma Schistosoma haematobium, 283 Schistosomiasis, 735 Schwann cells, 298, 301t Schwannomas, 409 Sciatica, 393 SCIDs, Severe combined immunodeficiencies Sclera, 338, 338f Scleroderma, 1030–1031, 1031f Sclerosing adenosis, 808 Sclerostin, 936t SCN, Suprachiasmatic nucleus Scoliosis, 1006, 1006f Scotoma, 340t Scrotum anatomy of, 773–774, 773f disorders of, 834–838

Seaweed, 818 Sebaceous follicles, 1044 Sebaceous glands, 1014 Seborrheic dermatitis, 341, 1023, 1023f Seborrheic keratosis, 1031, 1031f Second degree burns, 1035, 1035t, 1036f Second messenger, 15, 17f, 432, 432f, 432t, 447 Secondary amenorrhea, 784, 784f Secondary brain injury, 388 Secondary dysmenorrhea, 783 Secondary gout, 982 Secondary hyperaldosteronism, 468 Secondary hyperparathyroidism, 456 Secondary hypocortisolism, 469–470 Secondary hypothyroidism, 454

2769

Secondary (acquired) immune deficiency, 186 acquired immunodeficiency syndrome, 189–190 immunosuppressive treatments, 189 malignancies, 188 some conditions known to be associated, 188–194, 189b

Secondary immune responses, 168, 168b, 170f Secondary intention, of wound healing, 148 Secondary lymphoid organs, 157, 159f Secondary nephrotic syndrome, 754 Secondary osteoporosis, 967 Secondary parkinsonism, 374 Secondary peristalsis, 860 Secondary pneumothorax, 675 Secondary polycythemia, 514, 515t Secondary progressive multiple sclerosis, 405t Secondary thrombocythemia, 538 Second-degree block, 626t–627t Secretin, 862, 862t Secretory diarrhea, 881 Secretory IgA, 165, 168 Secretory immune system, 168, 169f Secretory immunoglobulin, 168 Sedative-hypnotics, abuse of, 83t Sedentary lifestyle, 603 Segmental pain inhibition, 330 Seizure/seizure disorders, 365–367, 367t causes of, 365t in children, 423 clinical manifestations of, 367 conditions associated with, 365 epilepsy, 365, 365f evaluation and treatment of, 367, 367b generalized tonic-clonic seizure, 367 in myelodysplasia, 416 posttraumatic, 388 in subarachnoid hemorrhage, 399

2770

types of, 365–367, 366t

Selectins, 11b Selective attention deficits of, 357, 358t definition of, 357

Selective auditory attention, 357 Selective COX-2 inhibitors, 143 Selective IgA deficiency, 187 Selective visual attention, 357 Selenium, 843b–844b Sella turcica, 433 Selye, Hans, 210 Semen, 775 Semicircular canals, 342–343, 342f Semilunar valves, 566 Seminal vesicles, 774–775 Seminiferous tubules, 772, 773f, 775f Senescence, 104 Senile disease complex, 362 Sensorimotor syndrome, 409 Sensorineural hearing loss, 343 Sensory aphasia, 361t Sensory-discriminative system, 328–329 Sensory function, alterations in, 327 Sensory inattentiveness, 358–359 Sensory neurons, 299, 309–310 Sensory pathways, 310f, 311, 312f Sensory speech area, 305 Sepsis description of, 199–201 disseminated intravascular coagulation associated with, 540 guidelines, 633b mortality rates for, 633b

Septic arthritis, 1003, 1003f

2771

Septic shock, 199–201, 630–632, 631f, 631t, 632b–633b Septicemia, 623 description of, 199–201

Septum primum, 565 Sequestration crisis, 554 Sequestrum, 971f, 972 Serotonin, 497 digestive system actions of, 862t in pain inhibition, 329 properties of, 304t

Serous cell, 658f Serous exudate, 146 Serous pericardium, 565f Sertoli cells, 775 Serum, 484 Serum ferritin, 500t–501t Serum sickness, 178 Sever disease, 1006 Severe combined immunodeficiencies (SCIDs), 187 Severe congenital neutropenia, 187 Severe traumatic brain injury (severe concussion), 388 Sex chromosome aneuploidy, 46–47 Sex cord-stromal tumors, 803 Sex determination, 56–57 Sex hormone-binding globulin, 786 Sex hormones bone density affected by, 966–967 definition of, 760 female, 767–768 male, 775–776 secretion of, 767 summary of, 761t

Sex-influenced traits, 57–58 Sex-limited traits, 57–58 Sexual arousal, 764

2772

Sexual behavior, cancer and, 282–283 Sexual differentiation, 760–761 Sexual dysfunction drug-induced, 851 female, 806, 806t male, 849–852

Sexual maturation alterations of, 781–782, 782t, 830–831, 831b description of, 761–762, 763f

Sexual trauma, 806 Sexually transmitted infections/diseases, 200t–201t, 853–856, 853t–855t Sharpey fibers, 938 Sharp-force injuries, 91f, 91t–92t Shear stress, 568 Sheehan syndrome, 449 Shift work sleep disorder, 337 Shift-to-the-left, 518 Shift-to-the-right, 518 Shigella toxin, acute infectious diarrhea caused by, 927 Shingles, 1028 Shock, 624–634, 630b anaphylactic, 629–630, 631f burn-induced, 1036 cardiogenic, 628, 629f cellular metabolism impairment in, 624 clinical manifestations of, 627–628 description of, 624 glucose impairment in, 624–627 hypovolemic, 628–629, 630f, 1036–1037 neurogenic, 629, 630f oxygen use impairment in, 624 septic, 630–632, 631f, 631t, 632b–633b treatment of, 628 types of, 628–632

Short-term starvation, 480 Shunt, 639, 673f Shunting

2773

illustration of, 673f left-to-right, 639–640, 642 right-to-left, 639 ventilation-perfusion mismatch caused by, 673–674

SIADH, Syndrome of inappropriate antidiuretic hormone Sialoprotein, 934t, 937 Sickle cell anemia, 506t, 551–552 Sickle cell disease, 551–555, 552f–554f, 553t clinical manifestations of, 553–554 evaluation of, 554–555 pathophysiology of, 553 treatment of, 554–555

Sickle cell-Hb C disease, 551–552 Sickle cell test, 500t–501t, 555f Sickle cell-thalassemia, 551–552, 554 Sickle cell trait, 551–552 Sickled erythrocytes, 553, 553f Sideroblastic anemias, 506t Signal transduction, 13–15, 15f Signal transduction pathways, 15, 16f Signaling cell, 15 Sildenafil, 851 Silencing, 238 Silent ischemia, 605 Silent mutations, 41 Simple columnar epithelium, 31t–32t Simple cuboidal epithelium, 31t–32t Simple squamous epithelium, 31t–32t Single gene defects, 186 Sinoatrial node, 569 Sinus block, 626t–627t Sinus bradycardia, 625t–626t Sinus dysrhythmias, 625t–626t Sinus tachycardia, 625t–626t Sinus venosus atrial septal defect, 641

2774

Sinusoids, 870–871 Sipuleucel-T, 253 Sister chromatids, 28, 45–46, 47f Skeletal (striated) muscle, 35t–36t adenosine triphosphate use by, 950 aging of, 952 anatomy of, 946f cardiac muscle versus, 571 contractile proteins of, 946–947, 948t energy sources for, 950t fast-twitch fibers, 945 fibers of, 944–946, 945t function of, 943–951 fusiform, 943 mechanics of, 950–951 metabolism of, 950 motor unit of, 944–947, 947f myofibrils of, 946–947 pennate, 943 sarcomere of, 948t sensory receptors of, 944 slow-twitch fibers, 945 structure of, 943–951, 947f as voluntary muscle, 944–945 wasting of, 251f

Skeletal muscle disorders acid maltase deficiency, 987–988 adenosine monophosphate deaminase deficiency, 988 channelopathies, 987 chronic fatigue syndrome, 985 contractures, 984 dermatomyositis, 989, 989f disuse atrophy, 985–987 fibromyalgia, 984–985, 985t, 985b, 986f glycogen storage disease type V, 988 inclusion body myositis, 989 lipid deficiencies, 988 McArdle disease, 988 metabolic muscle diseases, 987–988 muscle membrane abnormalities, 987

2775

myositis, 988–989, 989f myotonia, 987 periodic paralysis, 987 polymyositis, 989 Pompe disease, 988 stress-induced muscle tension, 984 toxic myopathies, 989–990, 990b

Skeletal trauma dislocation, 958–959 fractures, Fractures subluxation, 958–959

Skeleton appendicular, 938 axial, 938

Skeletonization, 106 Skene glands, 763–764 Skin aging effects on, 1040b apocrine sweat glands of, 1014–1015 blood supply of, 1015–1016 cancer manifestations of, 256 cancer of, 1032–1035 chronic kidney disease effects on, 747t, 748 dermal appendages, 1014–1015, 1015f dermatomes of, 318, 318f, 396f dermis, 1014, 1015f, 1016t eccrine sweat glands of, 1014–1015 epidermis, 1014, 1015f, 1016t innervation of, 1015–1016 layers of, 1014–1016, 1015f, 1016t, 1016b papillary capillaries of, 1015–1016 sebaceous glands of, 1014 structure and function of, 1014–1021, 1015f, 1016t subcutaneous layer of, 1014, 1015f, 1016t

Skin cancer, 260t–264t, 1035b basal cell carcinoma, 280, 1032, 1033f carcinogenesis of, 280f cutaneous lymphomas, 1034–1035 cutaneous melanoma, 1032t, 1033–1034, 1034f description of, 260t–264t

2776

Kaposi sarcoma, 243, 260t–264t, 283, 295, 1034, 1034f melanoma, 280 occupational factors, 281 primary cutaneous lymphomas, 1034–1035 risk factors for, 282b squamous cell carcinoma, 280, 1032–1033, 1033f sun exposure and, 281 trends in, 1032b types of, 280 ultraviolet radiation as cause of, 1032–1033

Skin disorders acne rosacea, 1025, 1025f acne vulgaris, 1025, 1044–1045, 1045f, 1046b actinic keratosis, 1031 allergic contact dermatitis, 1022, 1022f atopic dermatitis, 1022 bacterial infections, 1027–1028, 1027f benign tumors, 1031, 1031f burns, Burns cancer, Skin cancer candidiasis, 1029, 1030t carbuncles, 1027 cellulitis, 1027 cold injury, 1038–1039 condylomata acuminata, 1029 cutaneous vasculitis, 1030 discoid lupus erythematosus, 1025–1026, 1026f eczema, 1022 erysipelas, 1027 erythema multiforme, 1026 folliculitis, 1027 fungal infections, 1029, 1029f, 1029t furuncles, 1027, 1027f herpes simplex virus, 1028, 1028f herpes zoster, 1028, 1028f impetigo, 1027 infections, 1027–1029, 1027f–1029f, 1029t–1030t inflammatory, 1022–1023, 1022f–1023f, 1027b irritant contact dermatitis, 1022 keratoacanthoma, 1031 lichen planus, 1024–1025, 1025f

2777

lupus erythematosus, 1025–1026 Lyme disease, 1027–1028 necrotizing fasciitis, 1027 nevi, 1031, 1032t papulosquamous, 1023–1026, 1023f–1026f, 1024b–1025b pemphigus, 1026, 1026f pityriasis rosea, 1024, 1024f pruritus, 1021 psoriasis, 1023–1024, 1023f–1024f, 1024b scleroderma, 1030–1031, 1031f seborrheic dermatitis, 1023, 1023f seborrheic keratosis, 1031, 1031f shingles, 1028, 1028f urticaria, 1030 varicella-zoster virus, 1028 vascular, 1030–1031 vesicobullous, 1026–1027 warts, 1028–1029, 1029f

Skin infections bacterial, 1027–1028, 1027f, 1046–1047, 1046f–1047f description of, 200t–201t fungal, 1029, 1029f, 1029t–1030t, 1047–1048, 1047f pressure injury, 1016–1021, 1019t–1020t, 1020f–1021f, 1020b viral, 1028–1029, 1028f–1029f, 1048–1050, 1048f, 1049t, 1050f

Skin lesions, 1016–1021 clinical manifestations of, 1021t pressure injury, 1016–1021, 1019t–1020t, 1020f–1021f, 1020b primary, 1017t–1018t secondary, 1019t–1020t

Skull fontanelles of, 415, 415f of infants, 415 sutures of, 415, 415f

Skull fracture cause of, 313 compound, 387

SLE, Systemic lupus erythematosus Sleep, 335–338 breathing control during, 662b deprivation of, 337

2778

hypothalamus’ role in, 335 in infants, 337b non-REM, 336 paradoxical, 336 phases of, 335 REM, 336

Sleep apnea, 336–337 Sleep deprivation, 213 Sleep disorders, 336–338 Sleepwalking, 337 Sliding hiatal hernia, 884, 884f SLL, Small lymphocytic lymphoma Slow-reacting substances of anaphylaxis, 143 Slow-twitch fibers, 945 SMA, Spinal muscular atrophy Small cell carcinoma, of lung, 692t, 693 Small intestine absorption in, 865, 865b, 866f–867f aging effects on, 876b anatomy of, 864–867, 864f, 867b carcinoma of, 908 congenital impairment of, 918–920 digestion in, 865, 866f duodenum, 864 innervation of, 864 microvilli of, 865 motility in, 865–867, 867b nutrients absorbed in, 868b obstruction of, 885–886, 885t segments of, 864 smooth muscle of, 864 villi of, 864f, 865

Small lymphocytic lymphoma (SLL), 525–526 Small pox, 1049 Small vessel disease, 397 Small-volume diarrhea, 880 Smoking

2779

cancer and, 265 chronic bronchitis in, 671 coronary artery disease risks, 603 environmental tobacco smoke, 265–267

Smoldering myeloma, 533, 534b Smooth (visceral) muscle, 35t–36t Snout reflex, 356f Social drugs, 86t, 90 Social support, 222 Sodium (Na+) active transport of, 22, 22f aldosterone effects on, 593 concentration of, aldosterone and, 115 in ECF, 115

Sodium balance alterations in, 117–120, 117f hypernatremia, 118 hyponatremia, 119–120 isotonic, 118

maintenance of, 115 signs and symptoms of, 119t

Sodium bicarbonate, 129, 720–721 Sodium-glucose cotransporter 2 inhibitors, 461b Sodium-potassium pump, 946

2780

Sodium reabsorption, 720 Soft tissue, 260t–264t Solitary papillomas, 808 Soluble immune-complex glomerulonephritis, 739t Solute, 18–19 Somatic cell mutation, 238 Somatic cells, 44, 45f germ cell and, 265t

Somatic death, 106–107, 107b Somatic motor pathways, 312f Somatic nervous system, 298 Somatic pain, 330–331 Somatic recombination, 158–160 Somatic sensory pathways, 312f Somatosensory function, 345–346 Somatostatin (SOM), 219t, 436t, 441, 862t, 863 Somatotropic hormones, 437t Somnambulism, 337 Spaces, 111 Spasmodic croup, 697 Spasmodic torticollis, 372f Spastic cerebral palsy, 421 Spastic paresis/paralysis, 375–376 Spasticity, 370, 371t, 376 Spatial summation, 302–303 Sperm, 772, 851–852 Spermatic cord, 773–774 Spermatocele, 835, 835f Spermatocytes, 775, 775f Spermatogenesis, 772, 775, 775f, 851–852 Spermatogonia, 775, 775f Spermatozoon, 760, 775f Sphincter of Oddi, 905

2781

Sphingolipids, 6 Spina bifida (split spine), 416, 418f Spina bifida occulta, 416–417 Spinal accessory nerve, 319t Spinal cord abscess of, 403 anatomy of, 308, 309f–310f arteries of, 315, 317f blood supply to, 315, 317f central canal of, 308–309 coverings of, 309f cross section of, 308–309, 310f reflex arcs, 309–310, 310f tracts of, 310f tumors of, 409, 409b

Spinal cord injuries clinical manifestations of, 389–391 evaluation and treatment of, 391–392 pathophysiology of, 389 primary, 389 secondary, 389 sexual dysfunction secondary to, 806t types of, 389t

Spinal muscular atrophy (SMA), 377 Spinal nerves, 309f, 317 Spinal shock, 376, 389–390, 393t Spinal stenosis, 394 Spinal tracts, 309, 314b Spindle fibers, 28 Spindles, 944 Spine compression injuries of, 390f degenerative disorders of degenerative joint disease, 394 herniated intervertebral disk, 394–395, 394f–395f low back pain, 392–394

flexion injury of, 390f flexion-rotation injuries of, 390f, 390t hyperextension injuries of, 390f, 390t

2782

Spinnbarkeit mucus, 765 Spinothalamic tracts, 309 Spiral fracture, 955, 956f, 956t Spirochetes, 199 Splanchnic blood flow, 869 Splanchnic circulation, 861f Splanchnic nerves, 319–321 Spleen absence of, 489 anatomy of, 489, 489f erythrocytes in, 489f functions of, 489 in Hodgkin lymphoma, 529

Splenectomy, 535 Splenic function, alterations of, 534–535, 535b Splenic pooling, 535 Splenic sinusoids, 485–486 Splenomegaly in chronic leukemias, 526 congestive, 534 definition of, 897 diseases related to, 534, 535b in infectious mononucleosis, 520–521 infiltrative, 534 pathophysiology of, 534

Spondyloarthropathies, 979 Spondylolisthesis, 394 Spondylolysis, 394 Spongy bone, 937, 938f Spontaneous mutations, 41 Sporadic motor neuron disease, 377–378 Sporadic motor system disease, 377–378 Sprains, 959 Sputum, 671 Squamous cell carcinoma (SCC) description of, 280

2783

esophageal, 907 lung cancer caused by, 692f, 692t penile cancer caused by, 834 of skin, 1032–1033, 1033f

Squamous-columnar junction, 765 SRY gene, 56–57, 57f, 760 SSM, Superficial spreading melanoma SSSS, Staphylococcal scalded-skin syndrome ST elevation MI (STEMI), 606, 608f Stable angina, 604–606 Stable angina pectoris, 604–605 Staghorn calculus, 729–730 Stapes, 342, 342f Staphylococcal pneumonia, 705, 705t Staphylococcal scalded-skin syndrome (SSSS), 1046–1047, 1047f, 1050b Staphylococcus aureus, 196–197, 988 impetigo contagiosum caused by, 1046 methicillin-resistant, 206–207, 1027, 1046 septic arthritis caused by, 1003

Staphylococcus dermatitis, 341 Starling forces, 112 Starvation, 480 Stasis dermatitis, 1022, 1023f Static contraction, 951, 951f Status asthmaticus, 681 Status epilepticus, 367 Steatorrhea, 881, 892, 922, 924 Steatosis, 96, 901 Stellate cells, 871 Stem cells, 29, 30f, 269 in bone marrow, 952 disorder, 514–515 hematopoietic, 490 mammary, 820–821 mesenchymal, 490

2784

Stem-like cancer cells, 523, 524f Stenosis aortic, 615, 615f, 643–644, 644f definition of, 568 mitral, 615–616, 616f pulmonic, 644, 645f valvular, 614, 615f

Stepping reflex, 415t Stercobilin, 872 Sterols, 6 Stevens-Johnson syndrome, 1026–1027 Sticky platelet syndromes, 497b Still disease, 1003 Stomach aging effects on, 876b anatomy of, 861–864, 861f, 864b blood supply to, 861, 861f cancer of, 260t–264t, 907t, 908, 908b congenital impairment of, 918 emptying of, 863 gastric secretions in, 863–864, 863f hydrochloric acid secretion in, 863f innervation of, 861 layers of, 861 motility in, 862–863, 862t mucus of, 864 retropulsion in, 862–863 ulcers of, 889–890, 891t, 892f

Storage diseases, 96 Strabismus, 338 Strains ligaments, 959 muscle, 960–961, 961t stress and, 210 tendons, 959

Strangulation, 92–93 Stratified columnar epithelium, 31t–32t Stratified squamous epithelium, 31t–32t

2785

Strawberry hemangioma, 1052 Street drugs, 86t, 90 Streptococcal pneumonia, 705, 705t Streptococcus pneumoniae, 206–207, 687 Streptococcus pyogenes, 1027 impetigo contagiosum caused by, 1046

Streptolysin O, 618 Stress acute, 214 background and general concepts of, 210–211 catecholamine release secondary to, 444 chronic, 218–221 coping with, 221–224 cortisol secretion during, 220 cytokine secretion affected by, 216–217 definition of, 210 disease and, 210–226 conditions associated with, 211, 211b, 213t

early life alters brain development, 220b glucocorticoid secretion during, 215b good side of, 221–223, 222f immune system's role in, 217–218, 218f modern overview of, 211 muscle tension caused by, 984 myocardial ischemia caused by, 605 physiologic, 210, 212f strain and, 210 traditional overview of, 210–211

Stress fracture, 956t, 957 Stress hormone, 211 Stress incontinence, 731t, 758t, 849 Stress-related mucosal disease, 890 Stress response anticipatory, 211 behavioral, 211, 212f definition of, 211 hormones that affect, 219t parasympathetic nervous system in, 216 physiologic, 211, 212f

2786

schematic diagram of, 212f sympathetic nervous system in, 216

Stress systems, 211–218 adaptive roles of, 213, 213f

Stress ulcer, 890 Stressors definition of, 210 psychologic, 211

Stretch receptors, 660 Striated muscle, 944 Striatum, 305–306 Stroke, 78 childhood, 423 diabetes mellitus and, 466 embolic, 396–397 hemodynamic, 397 hemorrhagic, 397–398, 423 ischemic, 395–397, 423 lacunar, 397 perinatal, 423 risk factors for, 395, 396b signs and symptoms of, 397t thrombotic, 396

Stroke volume, 574 Stroma, 231–232, 233f Stromal cells, 231–232 Strong acid, 123–124 Structural scoliosis, 1006 Struvite stones, 729–730 Subacute thyroiditis, 455 Subarachnoid hemorrhage, 398–399, 399t Subarachnoid space, 312 Subclinical hypothyroidism, 454 Subcortical nuclei, 305–306 Subcutaneous layer, 1014, 1015f, 1016t Subdural brain abscesses, 403

2787

Subdural hematoma, 385t, 386–387, 387f Subdural space, 312 Subendothelial connective tissue matrix, 143 Subgaleal space, 311 Subluxated hip, 999–1000, 1001f Subluxation, 958–959 Submucosal plexus, 861, 864 Substance P (SP), 436t properties of, 304t in stress response, 219t

Substantia gelatinosa, 308–309 Substantia nigra, 305–306 Substrate phosphorylation, 18 Substrates, 17 Subthalamus, 308 Subvalvular aortic stenosis, 644 Suck reflex, 356f Sucking reflex, 415t Sudden cardiac death, 609 Sudden infant death syndrome, 709, 709b Suffocation, 91–92 Sulci, 304 Summation, 302–303 Sun exposure, skin cancer and, 281 Sunburn, 281 Superantigens, 162, 165f Superficial hemangiomas, 1052, 1052f Superficial mycoses, 204 Superficial spreading melanoma (SSM), 1033–1034 Superior colliculi, 308 Superior mesenteric ganglia, 319–321, 320f Superior vena cava, 564–565 Superior vena cava syndrome, 592 Supersaturation, 730

2788

Suppurative cystitis, 734 Suprachiasmatic nucleus (SCN), 338 Supratentorial disorders, 352 Supratentorial herniation, 369b Supravalvular aortic stenosis, 644 Surface tension, 662 Surfactant description of, 658f, 663 impairment of, 677 respiratory distress syndrome of the newborn caused by deficiency of, 700–702, 700b, 701f–702f

Surgery, 252 Sutures cranial, 415, 415f definition of, 940 illustration of, 942f

SVR, Systemic vascular resistance Swallowing, 859–860 Sweat glands, 1014–1015 Sylvian fissure, 305, 306f Sympathetic ganglia, 319–321 Sympathetic nervous system description of, 319–321, 320f functions of, 324f in hypertension, 593 in stress response, 216 venous compliance controlled by, 585

Sympathetic paragangliomas, 470 Symphysis definition of, 940 illustration of, 942f

Symport, 20 Synapses, 302, 303f Synaptic bouton, 302 Synaptic cleft, 302, 303f Synarthrosis, 940 Synchondrosis, 940, 942f

2789

Syndesmophyte, 980 Syndesmosis, 940 Syndrome of inappropriate antidiuretic hormone (SIADH), 448, 449t secretion, 119, 248t

Syndromic cleft lip/palate, 916 Synovial cavity, 941 Synovial fibroblasts, 977 Synovial fluid, 941 Synovial joints, 943, 943f–945f Synovial membrane, 940–941, 977–978 Synovitis, 975, 977f α-Synuclein, 374 Syphilis, 853, 854t–855t Systemic circulation, 577–585 anatomy of, 564f arteries of, 577 arterioles, 577 bronchial circulation, 658 capillaries of, 577 description of, 563 venules, 577

Systemic inflammatory response syndrome, 632 Systemic lupus erythematosus (SLE), 182–183, 806t Systemic scleroderma, 1030 Systemic vascular resistance (SVR), 575–576 Systole, 567 Systolic blood pressure, 581–582 Systolic compressive effect, 585 Systolic heart failure, 620 T T-cell neoplasms, 529 T-cell receptors (TCRs), 160–161, 160f T-cell-independent antigens, 163, 165f T cells

2790

in asthma, 681 helper, 681 regulatory, 244

T-cytotoxic (Tc) lymphocytes, 157 clonal selection, 165f function of, 169–170, 170f in immune response, 162

T lymphocytes, 144 description of, 156–157 development of, 160–161 function of, 169–171 lymphokine-secreting, 171

T tubules, 571 T wave, 570, 571f TA, Truncus arteriosus Tactile dysfunction, 346 Taenia solium, 988 Talipes, 999, 1000t Tamm-Horsfall protein, 734 Tamponade, 612 TAPVC, Total anomalous pulmonary venous connection Tardive dyskinesia, 372 Target cells, 15 for hormones, 430, 431f–432f, 447

Taste, 344, 345b Taste buds, 344 Tay-Sachs disease (GM2 gangliosidosis), 421–422 TBG, Thyroxine-binding globulin TBI, Traumatic brain injury TCRs, T-cell receptors TEF, Tracheoesophageal fistula Tegmentum, 308 TEL-AML1 gene, 294 Telangiectasia, 1017t–1018t, 1018f, 1021t Telencephalon, 304–306, 306f

2791

Telomerase, 238–239, 239f Telomeres, 238–239, 239f length, negative effects of stress on, 221

Telophase, 28 Template, 41 Temporal fossa, 311, 385 Temporal lobe, 305 Temporal summation, 302–303 TEN, Toxic epidermal necrolysis Tender points, 984 Tendinopathy, 959–960, 959f, 961b Tendons anatomy of, 943 definition of, 959 functions of, 951 repair of, 951b sprains of, 959 strains of, 959

Teniae coli, 867, 868f, 895–896 Tennis elbow, 960 Tenocytes, 951 Tension pneumothorax, 675 Tension-type headache (TTH), 401 Tentorium cerebelli, 311–312 Terminal duct lobular units, 813 Termination sequence, 41–43 Tertiary hyperparathyroidism, 456 Testes aging effects on, 777 anatomy of, 772, 772f–773f appendix, 836 disorders of, 834–838 ectopic, 835–836 migratory, 836 orchitis, 836–837, 836f torsion of, 836, 836f

2792

tumors of, 837, 837f

Testes-determining factor, 760 Testicular appendages, 836 Testicular cancer, 837 clinical manifestations of, 837 cryptorchidism and, 836 description of, 260t–264t, 265 evaluation of, 837 metastasis of, 837 pathophysiology of, 837 treatment of, 837

Testosterone functions of, 761, 761t, 775–776 in sexual differentiation, 760–761 in stress response, 219t

“Tet” spells, 645 Tetany, 456 Tethered cord syndrome, 416–417 Tetracyclines, 936t Tetralogy of Fallot (TOF), 639, 645, 646f Tetraploidy, 44 TGA, Transposition of the great arteries TGF-β, Transforming growth factor-beta Th1 cells, 162, 486 Th2 cells, 162, 486 Th17 cells, 162, 171 Thalamus, 308 Thalassemia alpha-, 555 beta-, 555 in children, 555–556 pathophysiology of, 506t sickle cell, 554

Theca cells, 767 Thelarche, 761, 772, 782 T-helper lymphocytes, 157, 161–162, 164f

2793

Therapeutic hyperthermia, 335 Therapeutic hypothermia, 336b Thermoreceptors, 333 Thermoregulation disorders of, 335 in infants and elderly, 333 mechanisms of, 333 trauma effects on, 335, 335b

Thiamine deficiency, 623 Third-degree block, 626t–627t Third degree burns, 1035t, 1036 Third-order neuron, 311 Thoracentesis, 675 Thoracic cavity, 659–660, 659f Thoracic duct, 586, 586f Thoracolumbar division, 319–321, 320f Threshold of liability, 59 Threshold potential, 26 Thrombin, 498 Thrombin time, 500t–501t Thromboangiitis obliterans, 598 Thrombocythemia, 538–539 Thrombocytopenia, 497 definition of, 536 description of, 247b heparin-induced, 536 immune thrombocytopenia purpura, 536–537 pathophysiology of, 536 pseudo-, 536 thrombotic thrombocytopenia purpura, 537–538, 538f

Thrombocytosis, 538 Thromboembolic disease/disorders, 535–536, 543–544, 543f, 598t Thromboembolus, 591–592 Thrombomodulin, 498 Thrombophilia, 535–536

2794

Thrombopoiesis, 496 Thrombopoietin, 496, 538 Thrombosis, 535–536 in disseminated intravascular coagulation, 541

Thrombospondin-1 (TSP-1), 239 Thrombotic crisis, 553 Thrombotic strokes, 396 Thrombotic thrombocytopenia purpura, 535, 537–538, 538f Thromboxane A2, 497 Thrombus arterial, 598 description of, 543, 543f venous, 591–592

Thrush, 1047–1048 Thymine, 40 Thymus, 157–158 Thyroglobulin, 438 Thyroid cancer, 260t–264t Thyroid glands aging effects on, 444b alterations in, 452–455, 452f carcinoma, 455, 455b Graves disease, 452–454, 453f–454f hypothyroidism, 453f, 454–455 nodular, 454 thyrotoxic crisis, 454 thyrotoxicosis/hyperthyroidism, 452–454, 453f

anatomy of, 437–439, 437f–438f dysgenesis of, 455 hormones produced by, 438–439, 438f

Thyroid hormone actions of, 438–439 muscle protein synthesis regulation by, 987 secretion of, 438 synthesis of, 438

Thyroid storm, 454 Thyroid-stimulating hormone (TSH), 333, 429–430, 437t, 438 deficiency of, 450

2795

description of, 807

Thyroid-stimulating immunoglobulins, 452–453 Thyrotoxic crisis, 454 Thyrotoxicosis, 452–454, 453f Thyrotropin-releasing hormone (TRH), 333, 436t, 438 Thyroxine (T4), 333, 429–430, 452, 808 Thyroxine-binding globulin (TBG), 438 TIAs, Transient ischemic attacks Tidal volume, 668f, 671 Tidemark, 942–943 Tight junctions, 13, 865 TILs, Tumor-infiltrating lymphocytes TIMPs, Tissue inhibitors of metalloproteinases Tinea, 1029, 1029f, 1029t, 1047, 1047f Tinea capitis, 1047, 1047f Tinea corporis, 1047 Tinnitus, 343 Tissue, 28–29 formation and differentiation, 29, 30f

Tissue damage, microorganisms that cause, 198, 198t Tissue factor, 137 description of, 540 in disseminated intravascular coagulation pathophysiology, 539

Tissue factor (extrinsic) pathway, 137 Tissue factor pathway inhibitor, 498 Tissue hypoxia, 507 Tissue inhibitors of metalloproteinases (TIMPs), 936t Tissue plasminogen activator, 499, 543 Tissue-specific antigens, 177 Tissue-specific hypersensitivity reactions, type II, 177–178 mechanism of, 177–178, 179f

Tissue thromboplastin, 137 Tissue transglutamine IgA, 924 Tissue-type plasminogen activator (tPA), 397

2796

Titer, 168 Titin, 572, 948t TLRs, Toll-like receptors TNF-α, Tumor necrosis factor-alpha TNM staging, 693, 1034 TNM system, tumor staging by, 251f Tobacco health consequences, 266f use, 265–267

TOF, Tetralogy of Fallot Tolerance, breakdown of, 182 Toll-like receptors (TLRs), 140, 140t, 631, 631f Tonic neck reflex, 415t Tonic phase, of epilepsy, 365–367 Tonicity, 22, 22f Tonsil cancer, 260t–264t Tonsillar abscess, 699 Tonsillar infections, 699 Tonsillitis, 699 Tophaceous gout, 982 Tophi, 981 Torsion of ovaries, 794 of penis, 753 of testis, 836, 836f

Torticollis, spasmodic, 372f Torus fracture, 956, 956t Total abdominal hysterectomy, 788f Total anomalous pulmonary venous connection (TAPVC), 647–648, 647f Total body potassium, 120, 947 Total body surface area (TBSA) estimations, of burn injury, 1036, 1037f Total body water distribution of, 111–113, 112t isotonic alterations in, 118

Total brain death, 355

2797

Total iron-binding capacity, 500t–501t Total lung capacity, 668f Total peripheral resistance (TPR), 575–576, 582–583 Total resistance, 579–580 Touch sensation, 345–346 Tourette syndrome, 372b Toxic adenoma, 454 Toxic epidermal necrolysis (TEN), 1026–1027, 1047 Toxic gas exposure, 678 Toxic multinodular goiter, 454 Toxic myopathies, 989–990, 990b Toxigenicity, 198 Toxins, 167, 199 Toxoplasma gondii, 403 tPA, Tissue-type plasminogen activator TPR, Total peripheral resistance Trabeculae, 938 Trabecular bone, 965f, 968f Trachea anatomy of, 655–656, 658f, 698f subglottic, 697, 698f

Tracheitis, 672, 698t, 699 Tracheobronchitis, 672 Tracheoesophageal fistula (TEF), 917, 918f Trachoma, 342 Trafficking, 9 Transcalvarial herniation, 368f, 369b Transcellular fluids, 111 Transchondral fracture, 956t, 957 Transcortical aphasias, 359–360 Transcortical motor aphasia, 361t Transcription, 41–43, 44f Transcription factors, 936t Transfer reactions, 18

2798

Transfer ribonucleic acid, 43 Transferrin, 97, 485, 495 saturation, 500t–501t

Transformation, malignant, 230–231 Transforming growth factor-beta (TGF-β), 29t, 142, 936t, 961, 966f, 974 Transfusion reactions, autoimmune diseases, 184–185, 185–186 Transgenerational phenotype, 265t Transient ischemic attacks (TIAs), 396 Transient lower esophageal sphincter relaxations, 920–921 Transient regional osteoporosis, 967 Transitional cell carcinoma, 733 Transitional epithelium, 31t–32t Transjugular intrahepatic portosystemic shunt, 897 Translation, 43–44, 45f Translocations, chromosome, 230–231 oncogene activation by, 231f, 234, 234f

Transmembrane proteins, 9, 9f Transmission, of microorganisms, 196–197 Transmural myocardial infarction, 607–608 Transport maximum, 720 Transporter, 18–19 Transposition of the great arteries (TGA), 646–647, 647f Transvaginal ultrasound, 802, 805 Transverse fibers, 305 Transverse fracture, 955, 956f, 956t Transverse tubules, 946 Trastuzumab, 254t Trauma anemia, 507 effects on future generations, 221b skeletal dislocation, 958–959 fractures, Fractures subluxation, 958–959

thermoregulation affected by, 335

2799

Traumatic brain injury (TBI), 384–388 classification of, 384 closed, 384–385, 385t, 386f complications of, 388, 388b definition of, 384 diffuse axonal injury, 385t, 387–388 focal brain injury, 384–387, 385t hypopituitarism caused by, 449 open, 387 primary, 384–388 secondary, 388

Traumatic coagulopathy, 508f, 508b Traumatic injury, 508b Tregs cells, T-regulatory cells T-regulatory cells (Tregs cells), 157, 162, 171, 171b Treitz ligament, 864, 864f Tremor intention, 373t Parkinsonian, 373t postural, 373t at rest, 373t

Trendelenburg gait, 1005 TRH, Thyrotropin-releasing hormone Tricarboxylic acid cycle, 17–18 Trichinella larvae, 988 Trichomoniasis, 854t–855t Trichophyton mentagrophytes, 1047 Trichophyton tonsurans, 1047 Tricuspid complex, 565–566 Tricuspid valve anatomy of, 565–566 atresia of, 645–646, 646f murmur of, 690 regurgitation, 616

Trigeminal nerve, 319t Trigone, 716, 716f Triiodothyronine (T3), 429–430, 438, 452

2800

Triploidy, 44 Trisomy, 44–45 Trisomy 13, 640t Trisomy 16, 46 Trisomy X, 47 Trochlear nerve, 319t Tropomyosin, 572, 573f Tropomyosin molecule, 572 Troponin, 572 Troponin I cardiac, in myocardial infarction, 609 description of, 603

Trousseau phenomenon, 248t Truncus arteriosus (TA), 648, 648f Trypanosoma brucei, 206 Trypanosoma cruzi, 206 Trypsin inhibitor, 875 Trypsinogen, 875 TSH, Thyroid-stimulating hormone TSP-1, Thrombospondin-1 TTH, Tension-type headache Tubercle, 688 Tuberculin skin test, 688 Tuberculosis, 688 Tuberculous granuloma, 148f Tubuloglomerular feedback, 717 Tubulointerstitial fibrosis, 728–729 Tubulus rectus, 772 Tumor-associated antigen, 243 Tumor-associated macrophage, 243, 246f Tumor-infiltrating lymphocytes (TILs), 244 Tumor initiation, 228–230 Tumor markers, 250–252 Tumor necrosis factor-alpha (TNF-α), 141–142, 687

2801

Tumor necrosis factors, 936t Tumor protein p53 (TP53), 237–238 Tumor-suppressor genes, 53 childhood cancers secondary to, 293–294, 295t familial cancer syndromes caused by, 238t functions of, 235 p53, 236f–237f silencing, 236f

Tumors, 136, 227, 885t of adrenal medulla, 470, 470b angiogenesis induced, 240f benign, 227, 228f, 1031, 1031f, 1032t bladder, 734 classification of, 227–228, 252 inflammation promotion by, 242–243, 242t initiation of, 228–230 malignant, 227–228, 228f microenvironment of, 821f–822f muscle, 994 nomenclature for, 227–228 penile, 833 progression of, 228–230 promotion of, 228–230 renal, 733–734, 733f–734f skin, 1017t–1018t, 1018f, 1031, 1031f, 1032t spinal cord, 409, 409b testicular, 837, 837f

Tunica albuginea, 772, 773f Tunica dartos, 773–774 Tunica externa, 577, 580f Tunica intima, 577, 580f Tunica media, 577, 580f Tunica vaginalis, 772, 773f Turbulent blood flow, 581, 582f Turner syndrome, 47, 50f, 56, 640t 22q11.2 deletion syndrome, DiGeorge syndrome Twisted gastrulation, 936t “Two-hit” hypothesis, 425

2802

Tympanic cavity, 342 Tympanic membrane, 342 Type-1 fimbriae, 735 Type I hypersensitivity reactions, 175, 177f Type II hypersensitivity reactions, 177 Type III hypersensitivity reactions, 178 Type IV hypersensitivity reactions, 178 Tyrosine kinase inhibitors, chronic myelogenous leukemia treated with, 559 Tyrosine kinases, 432, 432t U UC, Ulcerative colitis Ulcerative colitis (UC), 893–894, 893t Ulcerative cystitis, 735 Ulcers Curling, 890, 1038 Cushing, 890 duodenal, 889, 890f, 891t gastric, 889–890, 891t, 892f ischemic, 890 pressure, 1016–1021, 1020b, 1021f skin, 1019t–1020t, 1020f stasis, 1023f surgical treatment of, 890–891 venous stasis, 591, 592f

Ultraviolet (UV) radiation cancer caused by, 280–282 gene mutations caused by, 281 melanoma caused by, 280 skin cancer caused by, 280

Umbilical cord blood, 171b Uncal herniation, 368f, 369b Unconjugated bilirubin, 872, 928 Unfolded-protein response, 10f, 10b Unicornuate uterus, 781f Unilateral neglect syndrome, 358–359

2803

Unintentional injuries, 90–93, 91t–92t, 93b Uniparental disomy, 67 Unipolar neurons, 299 Uniport, 20 Universal donors, 184 Universal recipients, 184 Unmyelinated neurons, 318–319 Unstable angina, 606–607, 607b, 608f Upper airway anatomy of, 655, 657f infections of, 697–699, 698f, 698t

Upper esophageal sphincter, 860 Upper gastrointestinal bleeding, 881–882 Upper motor neuron paresis (weakness) or paralysis, 375–376 Upper motor neurons, 310 gait associated with disorders of, 379 structure of, 377f syndromes involving, 375–376, 375f–376f, 376b

Upper respiratory tract infections, 200t–201t Up-regulation, 431, 431f Urate, 982, 982t Urea, 722, 746 Uremia, 742 Uremic frost, 748 Uremic syndrome, 742 Ureter(s) anatomy of, 716, 716f cancer of, 260t–264t ureterovesical, 757f

Ureterocele, 752–753 Ureterohydronephrosis, 728–729, 729f Ureteropelvic junction obstruction, 752–753 Ureterovesical junction, 734 Urethra anatomy of, 716–717, 716f

2804

disorders of, 831, 834–838 hypospadias, 753, 753f, 835–836 polyps of, 754

Urethral strictures, 731, 831 Urethral valve, 754 Urge incontinence, 731t, 758t Uric acid, 982, 983f Uric acid stones, 729–730 Urinalysis, 724 Urinary bladder, cancer of, 260t–264t Urinary calculi, 729 Urinary incontinence, 731t, 757–758, 758t, 758b Urinary meatus, 763–764 Urinary system bladder, 716–717, 716f organs of, 713f ureters, 716, 716f, 718b urethra, 716–717, 716f

Urinary tract infection, in children, 756, 756b Urinary tract obstruction, 728–750, 737b antibiotic resistance and, 737b causes of, 734 complicated, 734 cystitis, 734–735 definition of, 734 incontinence, 731t kidney stones, 729–730, 737t lower, 730–733, 731t–732t, 734b mechanism of, 735f neurogenic bladder, 732–733, 732t overactive bladder syndrome, 731–732 sites of, 729f uncomplicated, 734, 737b upper, 728–730, 730b

Urine color of, 722 composition of, 722 concentration

2805

countercurrent mechanism for, 721, 721f description of, 721

dilution of, 721, 721f diuretics effect on flow of, 722 formation of, 712, 720f obstruction of, 720 postvoid residual, 732b

Urobilinogen, 494, 872 Urodilatin, 115, 718, 722 Uroepithelium, 716, 716f Uroflowmetry, 732b Urokinase-like plasminogen activator, 499 Urticaria, 176, 1030 Urushiol, 157 Usual ductal hyperplasia, 808 Uterine cancer, 260t–264t Uterine fibroids, 795, 795f Uterus abnormal uterine bleeding, 784–785, 785f, 785t, 787b abnormalities, 781 age-related changes, 776 anatomy of, 764–765, 765f bicornuate, 781f corpus of, 765, 767f double, 781f malformations of, 781f muscle of, 768t positions of, 765, 766f prolapse, 792, 792f unicornuate, 781f wall of, 765

V Vaccinations definition of, 207–208 Haemophilus influenzae, 401–402 immune response from, 207–208 for oncogenic viruses, 243

2806

purpose of, 207–208

Vacuolar degeneration, 95 Vacuolation, 95 Vagina anatomy of, 764, 765f cancer of, 260t–264t, 800–801 candidiasis of, 1030t fornix of, 764 menstrual cycle response by, 770 mucosa of, 768t pH of, 765 self-cleansing action of, 764

Vaginal intraepithelial neoplasia, 800–801 Vaginal mesh, for pelvic organ prolapse, 792b Vaginismus, 806 Vaginitis, 790 Vaginosis, 790, 854t–855t Vagus nerve, 319t, 863–864 Valgus, 1000t Valsalva maneuver, 869 Valvular aortic stenosis, 643 Valvular hypertrophic cardiomyopathy, 613–614 Valvular regurgitation, 615 Valvular stenosis, 614, 615f Variable region, 166 Varicella-zoster virus in adults, 1028 in children, 1049–1050, 1049t, 1050f

Varices, 897, 897f Varicocele, 834, 835f Varicose veins, 591, 592f Variola, 1049 Varus, 1000t Vas deferens, 773, 773f Vasa recta, 716, 721

2807

Vasa vasorum, 577 Vascular dementia, 363t, 365 Vascular endothelial growth factor (VEGF), 239 Vascular endothelium, 563, 580f, 581t Vascular malformation, 399, 400b Vascular mediators, 144 Vascular permeability, 136 Vascular response, to inflammation, 135–137 Vasculitis cutaneous, 1030 definition of, 539

Vasectomy, 844 Vasoactive amines, 142–143 Vasoactive intestinal peptide (VIP), 219t, 304t, 862t Vasoactive intestinal polypeptide, 425 Vasoconstriction description of, 577 hormones that cause, 583, 585f

Vasodilation, 136, 334t, 577 hormones that cause, 583 mediators of, 583–584

Vasogenic edema, 369 Vasogenic shock, 390, 629 Vasomotor flushes, 776 Vasomotor tone, 322, 324f Vasoocclusive crisis, 553 Vasopressin, 115, 583 Vegetables, 843b–844b Vegetative state, 357 VEGF, Vascular endothelial growth factor Veins anatomy of, 577, 581, 581f chronic venous insufficiency of, 591 coronary, 568, 569f diseases of, 591–592, 592b

2808

distention of, 591 lymphatic, 586 saphenous, 591 thrombosis formation in, 591–592, Venous thrombosis types of, 578f–579f valves in, 577, 581f

Venous sinuses, 489 Venous stasis ulcers, 591, 592f Venous thromboembolism, 598t Venous thrombosis, 248t anticoagulant therapy for, 543 deep description of, 591–592 in thrombocythemia, 538–539

description of, 591–592 formation of, 543 heparin for, 543 mesenteric, 896 risk factors for, 591–592

Ventilation alveolar, 660 chemoreceptors in, 661–662, 662b definition of, 660 distribution of, 665 lung receptors in, 660–661 muscles of, 662f neurochemical control of, 660–662, 661f during sleep, 662b symbols associated with, 665t

Ventilation-perfusion mismatch, 673–674, 683–684 Ventilation-perfusion ratio (V̇/Q̇), 665, 673–674, 673f Ventilator-associated pneumonia, 686, 686b Ventilatory rate, 660 Ventral horn, 308–309 Ventricles, of brain, 313 Ventricular block, 626t–627t Ventricular bradycardia, 625t–626t Ventricular end-diastolic pressure, 574

2809

Ventricular end-diastolic volume, 574, 609 Ventricular fibrillation, 625t–626t Ventricular remodeling, 620, 621f Ventricular septal defect (VSD), 642 Ventricular standstill, 625t–626t Ventricular system, 313–314 Ventricular tachycardia, 625t–626t Venules description of, 577 function of, 563

Vermiform appendix, 867 Vermis, 308 Verrucae, 1028–1029 Vertebrae fracture, 389, 390t Vertebral, anal, cardiovascular, tracheoesophageal, renal, and limb anomalies (VACTERL), 917 Vertebral arteries, 314, 315f Vertebral body osteoporosis, 965f Vertebral column anatomy of, 314, 314f fractures of, 965 spinal cord in, 308, 309f

Vertebral injuries, 389 Vertical transmission, of hepatitis B virus, 928 Vertigo, 346 Very-low-density lipoproteins, 602 Vesicle, 1017t–1018t, 1018f Vesicosphincter dyssynergia, 732–733 Vesicoureteral reflux, 737t, 757, 757f Vestibular nystagmus, 346 Vestibule, 342–343, 342f, 762f, 763–764, 764f Vestibulocochlear nerve, 319t Vestibulospinal tract, 311 Video-urodynamic recording, 732b

2810

Vigilance, 358t Viral conjunctivitis, 342 Viral diseases, description of, 201 Viral encephalitis, 422 Viral hepatitis, 903–904, 903t, 904b Viral meningitis, 402, 422 Viral pneumonia, 705–706, 705t Virchow triad, 543, 591–592 Virilization, 469, 469f Virulence, 198 Viruses, 197t, 201 cancer and, 283 human diseases caused by, 203t life cycle of, 201–202 pathogenicity of, 198 stages of, 202f

Visceral obesity, 479 Visceral pain, 330–331, 881 Visceral peritoneum, 864 Visceral pleura, 659–660, 659f Viscosity, 579 Vision, 338–342 color, 340–341 dysfunction involving, 338–341 pathways of, 341f

Visual acuity alterations, 339–340, 340t Vital capacity, 668f Vitamin(s), small intestine absorption of, 868b Vitamin B12, 494, 510–511 Vitamin D, 934t in bone health, 969b deficiency of, 746, 970 description of, 722–723 functions of, 439b

Vitamin E, 843b–844b

2811

Vitamin K, 934t Vitamin K deficiency, 539 Vitreous humor, 338 Vocal cords carcinoma of, 691 false, 655, 657f true, 655

Volatile acids, 123–124 Volkmann canals, 938, 938f Volkmann ischemic contracture, 963 Volume-sensitive receptors, 116–117 Volvulus, 885t, 886f Vomiting, 353, 879–880, 886 von Recklinghausen disease, 53 von Willebrand factor, 497, 537 VSD, Ventricular septal defect Vulvar cancer, 260t–264t, 801 Vulvodynia, 791 W Wallerian degeneration, 300 Wandering, 373t Warburg effect, 240 Warts, 1028–1029, 1029f WAS, Wiskott-Aldrich syndrome WAT, White adipose tissue Water movements of alterations in, 113–115, 117t between plasma and interstitial fluid, 112–113, 113f water movement between ICF and ECF, 113

reabsorption of, 115

Water balance, 115–117 ADH and, 115 alterations in, 117–120, 120b

Water intoxication, 119

2812

Water-soluble hormones, 430, 430t, 432 Weak acid, 123–124 Weight gain, in Cushing syndrome, 467 Weight loss cachexia-related, 247–249 in Crohn disease, 894 postgastrectomy, 891

Wernicke aphasia, 361t Wernicke area, 305, 359–360 West Nile virus (WNV), 402b Westley croup score, 699 Wheal, 1017f, 1017t–1018t Wheal and flare reaction, 176 White adipocytes, 474 White adipose tissue (WAT), 247–249 White blood cell adhesion, 136 White matter, 304 Whole blood clotting time, 500t–501t Willis Ekbom disease, 337–338 Wilms tumor, 294 Wilson disease, 929, 929t–930t Wind-up, 332 Wirsung duct, 874 Wiskott-Aldrich syndrome (WAS), 187 WNV, West Nile virus Wolffian ducts, 760 Wolff-Parkinson-White syndrome, 626t–627t Women bone loss in, 968f microvascular angina in, 605b

Work of breathing, 664, 671 Working memory (short-term memory), 357, 358t Wound contracture of, 152 dehiscence of, 151–152

2813

disruption of, 151–152 infection of, 200t–201t

Wound healing, 147–152 cancer and, 231–232 dysfunctional, 150–152, 152b epithelialization, 150 fibroblasts, 150 granulation tissue, 150 inflammation and, 149 maturation in, 150 new tissue formation and, 149–150 phases of, 150f primary intention, 149f proliferative phase of, 149–150 remodeling in, 150 secondary intention, 149f

X X chromosomes, 64 X inactivation, 56, 56f X-linked inheritance, 56–58 pedigrees of, 57 process of, 56f recurrence risks of, 57 sex determination, 56–57 sex-influenced traits, 57–58 sex-limited, 57–58 X-inactivation, 56

X-linked SCID, 187 Xenobiotics, 82–83, 82f, 270 Xenoestrogens, 819 Xeroderma pigmentosum, 238 Y Yawning, 353 Yellow marrow, 938–939 Z

2814

Z bands, 947, 949f Z line, 572–573, 573f Zollinger-Ellison syndrome, 888–889 Zona fasciculata, 441 Zona glomerulosa, 441 Zona reticularis, 441 Zoonotic infections, 196–197, 200t–201t

2815

Prefixes and Suffixes Used in Medical Terminology Prefix aacanthoafananteantiautobiblastcircumco-, concontracrinedediadipldysectoefem-, enendoepieuex-, exoextrahaplhem-, hemathemihom(e)ohyperhypoinfrainterintraisojuxtamacromegamesmetamicromillimononecroneonon-

Meaning Without, not Spiny, thorny Toward Without, not Before Against; resisting Self Two; double Immature cell, embryonic Around With; together Against Secrete, separate Down from, undoing Across; through Twofold, double Bad; disordered; difficult Displaced, outside Away from In, into Within Upon, above Good Out of, out from Outside of Single Blood Half Same; equal Over; above Under; below Below, beneath Between Within Same, equal Near Large Large; million(th) Middle Beyond, change, after Small; millionth Thousandth One (single) Death New Not

2816

oligoorthoparaperperipolypostpreproquadrireretrosemisubsuper-, supratranstriSuffix -al, -ac -algia -aps, -apt -arche -ase -blast -centesis -cide -clast -crine -cytosis -ectomy -emesis -emia -flux -gen -genesis -gram -graph(y) -hydrate -ia, -sia -iasis -ic, -ac -in -ism -itis -lemma -lepsy -lith -logy -lunar -malacia -megaly -metric, -metry -oid -oma -opia -oscopy -ose -osis -ostomy -otomy

Few, scanty Straight; correct, normal By the side of; near Through Around; surrounding Many After Before First; promoting Four Back again Behind Half Under Over, above, excessive Across; through Three; triple Meaning Pertaining to Pain Fit; fasten Beginning; origin Signifies an enzyme Sprout; make A piercing To kill Break; destroy Release; secrete Increase in number A cutting out Vomiting Refers to blood condition Flow Creates; forms Creation, production Something written To write, draw Containing H2O (water) Condition; process Abnormal condition Pertaining to Signifies a protein Signifies “condition of” Signifies “inflammation of” Sheath, covering Seizure Stone; rock Study of Moon; moonlike Softening Enlargement Measurement, length Like; in the shape of Tumor Vision, vision condition Viewing Pertaining to, sugar Condition, process Formation of an opening Cut

2817

-penia -philic -phobic -phragm -plasia -plasm -plasty -plegia -pnea -(r)rhage, -(r)rhagia -(r)rhaphy -(r)rhea -some -tensin, -tension -tonic -tripsy -ule -uria

Lack Loving Fearing Partition Growth, formation Substance, matter Shape; make Paralysis Breath, breathing Breaking out, discharge Sew, suture Flow Body Pressure Pressure, tension Crushing Small, little Refers to urine condition

2818

Word Roots Commonly Used in Medical Terminology Root acroadenalveolangiarthrasthenbarbilibrachibradybronchcalccapncarcincardcephalcervchemcholchondrchromcorpcorticocranicryptcuspcut(an)cyancystcytdactyldendrdentdermdiastoldipsejaculelectrentereryth(r) esthefebregastrgestgingivglomer-

Meaning Extremity Gland Small hollow; cavity Vessel Joint Weakness Pressure Bile Arm Slow Air passage Calcium; limestone Smoke Cancer Heart Head, brain Neck Chemical Bile Cartilage Color Body Pertaining to cortex Skull Hidden Point Skin Blue Bladder Cell Fingers, toes (digits) Tree; branched Tooth Skin Relax; stand apart Thirst To throw out Electrical Intestine Red Sensation Fever Stomach To bear, carry Gums Ball

2819

glossglucglutinglychepathisthydrohysteriatrkalkarykeratkinlactlaparleukligliplysmalmelanmen-, mens-, (menstru-) metrmutamy-, myomycmyelmyxnatnatrnephrneurnoct-, nyctoculodontoncoophthalmorchidosteootoov-, oooxypathpedphagpharmphlebphotophysiopinoplexpneumopneumonpodpoiepolprandialpresbyproctpseud-

Tongue Glucose, sugar Glue Sugar (carbohydrate); glucose Liver Tissue Water Uterus Treatment Potassium Nucleus Cornea To move; divide Milk; milk production Abdomen White To tie; bind Lipid (fat) Break apart Bad Black Month (monthly) Uterus Change Muscle Fungus Marrow Mucus Birth Sodium Nephron, kidney Nerve Night Eye Tooth Cancer Eye Testis Bone Ear Egg Oxygen Disease Children Eat Drug Vein Light Nature (function) of Drink Twisted; woven Air, breath Lung Foot Make; produce Axis, having poles Meal Old Rectum False

2820

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Mind Pelvis Pus Heat; fever Kidney Nose Stiffness Flesh; muscle Hard Seed; sperm Contamination Greek sigma or Roman S Cavity; recess Sound Breathe A standing, stopping Together Contract; stand together Fast Heat Clot A cut; a slice Poison Grow; nourish Drum Enlarged vessel Vessel, duct Bladder; blister Volume

2821