Porth's pathophysiology concepts of altered health states [9. ed.] 9781451146004, 1451146000

Table of contents :
Cover
Half Title Page
Title: Porth’s Pathophysiology: Concepts of Altered Health States, Ninth Edition
ISBN 9781451146004
Contributors
Reviewers
Preface
To the Reader
Acknowledgments
Contents
UNIT I: Concepts of Health and Disease
CHAPTER 1: Concepts of Health and Disease
CONCEPTS OF HEALTH AND DISEASE
Health
Disease
HEALTH AND DISEASE IN POPULATIONS
Epidemiology and Patterns of Disease
Determination of Risk Factors
Natural History
Preventing Disease
Evidence-Based Practice and Practice Guidelines
References
CHAPTER 2: Concepts of Altered Health in Children
GROWTH AND DEVELOPMENT
Prenatal Growth and Development
Birth Weight and Gestational Age
INFANCY
Growth and Development
Health Problems of the Neonate
Health Problems of the Infant
EARLY CHILDHOOD
Growth and Development
MIDDLE TO LATE CHILDHOOD
Growth and Development
Common Health Problems
ADOLESCENCE
Growth and Development
Common Health Problems
REVIEW EXERCISES
References
CHAPTER 3: Concepts of Altered Health in Older Adults
THE OLDER ADULT AND THEORIES OF AGING
Who Are Older Adults?
Theories of Aging
PHYSIOLOGIC CHANGES OF AGING
Integumentary Changes
Stature and Musculoskeletal Function
Cardiovascular Function
Respiratory Function
Neurologic Function
Special Sensory Function
Immune Function
Gastrointestinal Function
Renal Function
Genitourinary Function
FUNCTIONAL PROBLEMS ASSOCIATED WITH AGING
Functional Assessment
Urinary Incontinence
Instability and Falls
Sensory Impairment
Depression
Dementia
Delirium
DRUG THERAPY IN THE OLDER ADULT
Factors Contributing to Adverse Drug Reactions
Strategies to Enhance Therapeutic Effects and Prevent Harm
REVIEW EXERCISES
References
UNIT II: Cell Function and Growth
CHAPTER 4: Cell and Tissue Characteristics
FUNCTIONAL COMPONENTS OF THE CELL
Protoplasm
The Nucleus
The Cytoplasm and Its Organelles
The Cytoskeleton
The Cell (Plasma) Membrane
INTEGRATION OF CELL FUNCTION AND REPLICATION
Cell Communication
Cell Receptors
The Cell Cycle and Cell Division
Cell Metabolism and Energy Sources
MOVEMENT ACROSS THE CELL MEMBRANE AND MEMBRANE POTENTIALS
Movement of Substances across the Cell Membrane
Membrane Potentials
BODY TISUES
Cell Differentiation
Embryonic Origin of Tissue Types
Epithelial Tissue
Connective or Supportive Tissue
Muscle Tissue
Nervous Tissue
Extracellular Tissue Components
REVIEW EXERCISES
References
CHAPTER 5: Cellular Adaptation, Injury, and Death
CELLULAR ADAPTATION
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Intracellular Accumulations
Pathologic Calcifications
CELL INJURY AND DEATH
Causes of Cell Injury
Mechanisms of Cell Injury
Reversible Cell Injury and Cell Death
Cellular Aging
REVIEW EXERCISES
References
CHAPTER 6: Genetic Control of Cell Function and Inheritance
GENETIC CONTROL OF CELL FUNCTION
DNA Structure and Function
From Genes to Proteins
CHROMOSOMES
Cell Division
Chromosome Structure
PATTERNS OF INHERITANCE
Definitions
Genetic Imprinting
Mendel’s Laws
Pedigree
GENE TECHNOLOGY
Genetic Mapping
Recombinant DNA Technology
RNA Interference Technology
REVIEW EXERCISES
References
CHAPTER 7: Genetic and Congenital Disorders
GENETIC AND CHROMOSOMAL DISORDERS
Single-Gene Disorders
Multifactorial Inheritance Disorders
Chromosomal Disorders
Mitochondrial Gene Disorders
DISORDERS DUE TO ENVIRONMENTAL INFLUENCES
Period of Vulnerability
Teratogenic Agents
Folic Acid Deficiency
DIAGNOSIS AND COUNSELING
Genetic Assessment
Prenatal Screening and Diagnosis
REVIEW EXERCISES
References
CHAPTER 8: Neoplasia
CONCEPTS OF CELL DIFFERENTIATION AND GROWTH
The Cell Cycle
Cell Proliferation
Cell Differentiation
CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS
Terminology
Benign Neoplasms
Malignant Neoplasms
ETIOLOGY OF CANCER
Genetic and Molecular Basis of Cancer
Host and Environmental Factors
CLINICAL MANIFESTATIONS
Tissue Integrity
Systemic Manifestations
Paraneoplastic Syndromes
SCREENING, DIAGNOSIS, AND TREATMENT
Screening
Diagnostic Methods
Cancer Treatment
CHILDHOOD CANCERS
Incidence and Types
Biology of Childhood Cancers
Diagnosis and Treatment
REVIEW EXERCISES
References
UNIT III: Disorders of Integrative Function
CHAPTER 9: Stress and Adaptation
HOMEOSTASIS
Constancy of the Internal Environment
Control Systems
Feedback Systems
STRESS AND ADAPTATION
The Stress Response
Coping and Adaptation to Stress
DISORDERS OF THE STRESS RESPONSE
Effects of Acute Stress
Effects of Chronic Stress
Posttraumatic Stress Disorder
Treatment and Research of Stress Disorders
REVIEW EXERCISES
References
CHAPTER 10: Alterations in Temperature Regulation
BODY TEMPERATURE REGULATION
Mechanisms of Heat Production
Mechanisms of Heat Loss
INCREASED BODY TEMPERATURE
Fever
Hyperthermia
DECREASED BODY TEMPERATURE
Hypothermia
REVIEW EXERCISES
References
CHAPTER 11: Activity Tolerance and Fatigue
EXERCISE AND ACTIVITY TOLERANCE
Types of Exercise
Physiologic and Psychological Responses of Exercise
Assessment of Activity and Exercise Tolerance
Exercise and Activity Tolerance in Older Adults
ACTIVITY INTOLERANCE AND FATIGUE
Mechanisms of Fatigue
Acute Physical Fatigue
Chronic Fatigue
BED REST AND IMMOBILITY
Physiologic Effects of Bed Rest
Time Course of Physiologic Responses
Psychosocial Responses
Management of People Who Are Immobile or on Bed Rest
REVIEW EXERCISES
References
UNIT IV: Infection, Inflammation, and Immunity
CHAPTER 12: Mechanisms of Infectious Disease
INFECTIOUS DISEASES
Terminology
Agents of Infectious Disease
MECHANISMS OF INFECTION
Epidemiology of Infectious Diseases
Portal of Entry
Source
Symptomatology
Disease Course
Site of Infection
Virulence Factors
DIAGNOSIS AND TREATMENT OF INFECTIOUS DISEASES
Diagnosis
Treatment
BIOTERRORISM AND EMERGING GLOBAL INFECTIOUS DISEASES
Bioterrorism
Global Infectious Diseases
REVIEW EXERCISES
References
CHAPTER 13: Innate and Adaptive Immunity
THE IMMUNE RESPONSE
Cytokines and Their Role in Immunity
INNATE IMMUNITY
Epithelial Barriers
Cells of Innate Immunity
Pathogen Recognition
Soluble Mediators of Innate Immunity
The Complement System
ADAPTIVE IMMUNITY
Antigens
Cells of Adaptive Immunity
B Lymphocytes and Humoral Immunity
T Lymphocytes and Cellular Immunity
Lymphoid Organs
Active versus Passive Immunity
Regulation of the Adaptive Immune Response
DEVELOPMENTAL ASPECTS OF THE IMMUNE SYSTEM
Transfer of Immunity from Mother to Infant
Immune Response in the Older Adult
References
CHAPTER 14: Inflammation, Tissue Repair, and Wound Healing
THE INFLAMMATORY RESPONSE
Acute Inflammation
Chronic Inflammation
Systemic Manifestations of Inflammation
TISSUE REPAIR AND WOUND HEALING
Tissue Repair
Wound Healing
REVIEW EXERCISES
References
CHAPTER 15: Disorders of the Immune Response
IMMUNODEFICIENCY DISORDERS
Humoral (B Cell) Immunodeficiencies
Cell-Mediated (T Cell) Immunodeficiencies
Combined T-Cell and B-Cell Immunodeficiencies
Disorders of the Complement System
Disorders of Phagocytosis
Stem Cell Transplantation
HYPERSENSITIVITY DISORDERS
Type I, Immediate Hypersensitivity Disorders
Type II, Antibody-Mediated Disorders
Type III, Immune Complex–Mediated Disorders
Type IV, Cell-Mediated Hypersensitivity Disorders
Latex Allergy
TRANSPLANTATION IMMUNOPATHOLOGY
Mechanisms Involved in Transplant Rejection
AUTOIMMUNE DISEASE
Immunologic Tolerance
Mechanisms of Autoimmune Disease
Diagnosis and Treatment of Autoimmune Disease
REVIEW EXERCISES
References
CHAPTER 16: Acquired Immunodeficiency Syndrome
THE AIDS EPIDEMIC AND TRANSMISSION OF HIV INFECTION
Emergence of AIDS
Transmission of HIV Infection
PATHOPHYSIOLOGY AND CLINICAL COURSE
Molecular and Biologic Features of HIV
Classification and Phases of HIV Infection
Clinical Course
PREVENTION, DIAGNOSIS, AND TREATMENT
Prevention
Diagnostic Methods
Treatment
HIV INFECTION IN PREGNANCY AND IN INFANTS AND CHILDREN
Preventing Perinatal HIV Transmission
Diagnosis of HIV Infection in Children
Clinical Presentation of HIV Infection in Children
REVIEW EXERCISES
References
UNIT V: Disorders of Neural
Function
CHAPTER 17: Organization and Control of Neural Function
NERVOUS TISSUE CELLS
Neurons
Neuroglial Cells
Metabolic Requirements of Nervous Tissue
NEUROPHYSIOLOGY
Action Potentials
Synaptic Transmission
Messenger Molecules
DEVELOPMENTAL ORGANIZATION OF THE NERVOUS SYSTEM
Embryonic Development
Segmental Organization
STRUCTURE AND FUNCTION OF THE SPINAL CORD AND BRAIN
Spinal Cord
The Brain
THE AUTONOMIC NERVOUS SYSTEM
Autonomic Efferent Pathways
Sympathetic Nervous System
Parasympathetic Nervous System
Central Integrative Pathways
Autonomic Neurotransmission
REVIEW EXERCISES
References
CHAPTER 18: Somatosensory Function, Pain, and Headache
ORGANIZATION AND CONTROL OF SOMATOSENSORY FUNCTION
Sensory Systems
Sensory Modalities
Clinical Assessment of Somatosensory Function
PAIN
Pain Theories
Pain Mechanisms and Pathways
Pain Threshold and Tolerance
Types of Pain
Assessment of Pain
Management of Pain
ALTERATIONS IN PAIN SENSITIVITY AND SPECIAL TYPES OF PAIN
Alterations in Pain Sensitivity
Special Types of Pain
HEADACHE AND ASSOCIATED PAIN
Headache
Migraine Headache
Cluster Headache
Tension-Type Headache
Chronic Daily Headache
Temporomandibular Joint Pain
PAIN IN CHILDREN AND OLDER ADULTS
Pain in Children
Pain in Older Adults
REVIEW EXERCISES
References
CHAPTER 19: Disorders of Motor Function
ORGANIZATION AND CONTROL OF MOTOR FUNCTION
Organization of Movement
The Motor Unit
Spinal Reflexes
Motor Pathways
Assessment of Motor Function
DISORDERS OF THE MOTOR UNIT
Skeletal Muscle Disorders
Disorders of the Neuromuscular Junction
Lower Motor Neuron Disorders
Peripheral Nerve Disorders
DISORDERS OF THE CEREBELLUM AND BASAL GANGLIA
Disorders of the Cerebellum
Disorders of the Basal Ganglia
UPPER MOTOR NEURON DISORDERS
Amyotrophic Lateral Sclerosis
Multiple Sclerosis
Vertebral and Spinal Cord Injury
REVIEW EXERCISES
References
CHAPTER 20: Disorders of Brain Function
MANIFESTATIONS AND MECHANISMS OF BRAIN INJURY
Manifestations of Brain Injury
Mechanisms of Brain Injury
TRAUMATIC BRAIN INJURY
Primary and Secondary Brain Injuries
Hematomas
CEREBROVASCULAR DISEASE
Cerebral Circulation
Stroke (Brain Attack)
INFECTIONS AND NEOPLASMS
Infections
Brain Tumors
SEIZURE DISORDERS
Etiology
Classification
Diagnosis and Treatment
Status Epilepticus
Nonconvulsive Seizures
REVIEW EXERCISES
References
CHAPTER 21: Sleep and Sleep Disorders
NEUROBIOLOGY OF SLEEP
Neural Structures and Pathways
The Sleep–Wake Cycle
Circadian Rhythms
Melatonin
SLEEP DISORDERS
Diagnostic Methods
Circadian Rhythm Disorders
Insomnia
Narcolepsy
Sleep-Related Movement Disorders
Sleep-Related Breathing Disorders
Parasomnias
SLEEP AND SLEEP DISORDERS IN CHILDREN AND OLDER ADULTS
Sleep and Sleep Disorders in Children
Sleep and Sleep Disorders in Older Adults
REVIEW EXERCISES
References
CHAPTER 22: Disorders of Thought, Emotion, and Memory
PSYCHIATRIC DISORDERS
Incidence and Prevalence
The Diagnosis of Psychiatric Disorders
Understanding Psychiatric Disorders
TYPES OF PSYCHIATRIC DISORDERS
Schizophrenia
Mood Disorders
Anxiety Disorders
Substance Use Disorders
DISORDERS OF MEMORY AND COGNITION
Normal Cognitive Aging
Dementia
REVIEW EXERCISES
References
UNIT VI: Disorders of Special Sensory Function
CHAPTER 23: Disorders of Visual Function
DISORDERS OF THE ACCESSORY STRUCTURES OF THE EYE
Disorders of the Eyelids
Disorders of the Lacrimal System
DISORDERS OF THE CONJUNCTIVA, CORNEA, AND UVEAL TRACT
Disorders of the Conjunctiva
Disorders of the Cornea
Disorders of the Uveal Tract
The Pupil and Pupillary Reflexes
INTRAOCULAR PRESSURE AND GLAUCOMA
Control of Intraocular Pressure
Glaucoma
DISORDERS OF THE LENS AND LENS FUNCTION
Disorders of Refraction and Accommodation
Cataracts
DISORDERS OF THE VITREOUS AND RETINA
Disorders of the Vitreous
Disorders of the Retina
DISORDERS OF NEURAL PATHWAYS AND CORTICAL CENTERS
Optic Pathways
Visual Cortex
Visual Fields
DISORDERS OF EYE MOVEMENT
Extraocular Eye Muscles and Their Innervation
Strabismus
Amblyopia
Eye Examination in Infants and Children
REVIEW EXERCISES
References
CHAPTER 24: Disorders of Hearing and Vestibular Function
DISORDERS OF THE AUDITORY SYSTEM
Disorders of the External Ear
Disorders of the Middle Ear and Eustachian Tube
Disorders of the Inner Ear
Disorders of the Central Auditory Pathways
Hearing Loss
DISORDERS OF VESTIBULAR FUNCTION
The Vestibular System and Vestibular Reflexes
Vertigo
Motion Sickness
Disorders of Peripheral Vestibular Function
Disorders of Central Vestibular Function
Diagnosis and Treatment of Vestibular Disorders
REVIEW EXERCISES
References
UNIT VII: Disorders of the Hematopoietic System
CHAPTER 25: Blood Cells and the Hematopoietic System
COMPOSITION OF BLOOD AND FORMATION OF BLOOD CELLS
Plasma
Blood Cells
Formation of Blood Cells (Hematopoiesis)
DIAGNOSTIC TESTS
Blood Count
Erythrocyte Sedimentation Rate
Bone Marrow Aspiration and Biopsy
REVIEW EXERCISES
References
CHAPTER 26: Disorders of Hemostasis
MECHANISMS OF HEMOSTASIS
Vascular Constriction
Formation of the Platelet Plug
Blood Coagulation
Clot Retraction
Clot Dissolution
HYPERCOAGULABILITY STATES
Hypercoagulability Associated with Increased Platelet Function
Hypercoagulability Associated with Increased Clotting Activity
BLEEDING DISORDERS
Bleeding Associated with Platelet Disorders
Bleeding Associated with Coagulation Factor Deficiencies
Bleeding Associated with Vascular Disorders
Disseminated Intravascular Coagulation
REVIEW EXERCISES
References
CHAPTER 27: Disorders of Red Blood Cells
THE RED BLOOD CELL
Hemoglobin Synthesis
Red Cell Production
Red Cell Destruction
Red Cell Metabolism and Hemoglobin Oxidation
Laboratory Tests
BLOOD TYPES AND TRANSFUSION THERAPY
ABO Blood Groups
Rh Types
Blood Transfusion Reactions
ANEMIA
Blood Loss Anemia
Hemolytic Anemias
Anemias of Deficient Red Cell Production
POLYCYTHEMIA
Absolute Polycythemia—Primary
Absolute Polycythemia—Secondary
AGE-RELATED CHANGES IN RED BLOOD CELLS
Red Cell Changes in the Neonate
Red Cell Changes With Aging
REVIEW EXERCISES
References
CHAPTER 28: Disorders of White Blood Cells and Lymphoid Tissues
HEMATOPOIETIC AND LYMPHOID TISSUES
Leukocytes (White Blood Cells)
Bone Marrow and Hematopoiesis
Lymphoid Tissues
NONNEOPLASTIC DISORDERS OF WHITE BLOOD CELLS
Neutropenia (Agranulocytosis)
Infectious Mononucleosis
NEOPLASTIC DISORDERS OF LYMPHOID AND HEMATOPOIETIC ORIGIN
Malignant Lymphomas
Leukemias
Plasma Cell Dyscrasias
REVIEW EXERCISES
References
UNIT VIII: Disorders of Cardiovascular Function
CHAPTER 29: Structure and Function of the Cardiovascular System
ORGANIZATION OF THE CIRCULATORY SYSTEM
Pulmonary and Systemic Circulations
Volume and Pressure Distribution
PRINCIPLES OF BLOOD FLOW
Relationships between Blood Flow, Pressure, and Resistance
Wall Tension, Radius, and Pressure
Distention and Compliance
THE HEART AS A PUMP
Functional Anatomy of the Heart
Cardiac Cycle
Regulation of Cardiac Performance
THE SYSTEMIC CIRCULATION AND CONTROL OF BLOOD FLOW
Blood Vessels
Arterial System
Venous System
Local and Humoral Control of Blood Flow
THE MICROCIRCULATION AND LYMPHATIC SYSTEM
Structure and Function of the Microcirculation
Capillary–Interstitial Fluid Exchange
The Lymphatic System
NEURAL CONTROL OF CIRCULATORY FUNCTION
Autonomic Nervous System Regulation
Central Nervous System Responses
REVIEW EXERCISES
References
CHAPTER 30: Disorders of Blood Flow in the Systemic Circulation
BLOOD VESSEL STRUCTURE AND FUNCTION
Endothelial Cells
Vascular Smooth Muscle Cells
DISORDERS OF THE ARTERIAL CIRCULATION
Hyperlipidemia
Atherosclerosis
Vasculitis
Polyarteritis Nodosa
Giant Cell Temporal Arteritis
Arterial Disease of the Extremities
Acute Arterial Occlusion
Atherosclerotic Occlusive Disease
Thromboangiitis Obliterans
Raynaud Disease and Phenomenon
Aneurysms
Aortic Aneurysms
Aortic Dissection
DISORDERS OF THE VENOUS CIRCULATION
Varicose Veins
Chronic Venous Insufficiency
Venous Thrombosis
REVIEW EXERCISES
References
CHAPTER 31: Disorders of Blood Pressure Regulation
THE ARTERIAL BLOOD PRESSURE
Mechanisms of Blood Pressure Regulation
Blood Pressure Measurement
HYPERTENSION
Primary (Essential) Hypertension
Systolic Hypertension
Secondary Hypertension
Malignant Hypertension
High Blood Pressure in Pregnancy
High Blood Pressure in Children and Adolescents
High Blood Pressure in Older Adults
ORTHOSTATIC HYPOTENSION
Pathogenesis
Etiology
Diagnosis
Treatment
REVIEW EXERCISES
References
CHAPTER 32: Disorders of Cardiac Function
DISORDERS OF THE PERICARDIUM
Acute Pericarditis
Pericardial Effusion and Cardiac Tamponade
Constrictive Pericarditis
CORONARY ARTERY DISEASE
Coronary Circulation
Acute Coronary Syndrome
Chronic Ischemic Heart Disease
CARDIOMYOPATHIES
Primary Cardiomyopathies
Secondary Cardiomyopathies
INFECTIOUS AND IMMUNOLOGIC DISORDERS
Infective Endocarditis
Rheumatic Heart Disease
VALVULAR HEART DISEASE
Hemodynamic Derangements
Mitral Valve Disorders
Aortic Valve Disorders
HEART DISEASE IN INFANTS AND CHILDREN
Embryonic Development of the Heart
Fetal and Perinatal Circulation
Congenital Heart Defects
Kawasaki Disease
REVIEW EXERCISES
References
CHAPTER 33: Disorders of Cardiac Conduction and Rhythm
CARDIAC CONDUCTION SYSTEM
Action Potentials
Electrocardiography
DISORDERS OF CARDIAC RHYTHM AND CONDUCTION
Mechanisms of Arrhythmias and Conduction Disorders
Types of Arrhythmias and Conduction Disorders
Diagnostic Methods
Treatment
REVIEW EXERCISES
References
CHAPTER 34: Heart Failure and Circulatory Shock
HEART FAILURE
Pathophysiology of Heart Failure
Acute Heart Failure Syndromes
Clinical Manifestations of Heart Failure
Diagnosis and Treatment
CIRCULATORY FAILURE (SHOCK)
Pathophysiology of Circulatory Shock
Cardiogenic Shock
Hypovolemic Shock
Distributive Shock
Obstructive Shock
Complications of Shock
HEART FAILURE IN CHILDREN AND OLDER ADULTS
Heart Failure in Infants and Children
Heart Failure in Older Adults
REVIEW EXERCISES
References
UNIT IX: Disorders of Respiratory Function
CHAPTER 35: Structure and Function of the Respiratory System
STRUCTURAL ORGANIZATION OF THE RESPIRATORY SYSTEM
Conducting Airways
Lungs and Respiratory Airways
Pulmonary Vasculature and Lymphatic Supply
Innervation
Pleura
EXCHANGE OF GASES BETWEEN THE ATMOSPHERE AND THE LUNGS
Basic Properties of Gases
Ventilation and the Mechanics of Breathing
Lung Volumes
Pulmonary Function Studies
Efficiency and the Work of Breathing
EXCHANGE AND TRANSPORT OF GASES
Ventilation
Perfusion
Mismatching of Ventilation and Perfusion
Diffusion
Oxygen and Carbon Dioxide Transport
CONTROL OF BREATHING
Respiratory Center
Regulation of Breathing
Cough Reflex
Dyspnea
REVIEW EXERCISES
References
CHAPTER 36: Respiratory Tract Infections, Neoplasms, and Childhood Disorders
RESPIRATORY TRACT INFECTIONS
The Common Cold
Rhinosinusitis
Influenza
Pneumonias
Tuberculosis
Fungal Infections
CANCER OF THE LUNG
Histologic Subtypes and Pathogenesis
Clinical Manifestations
Diagnosis and Treatment
RESPIRATORY DISORDERS IN CHILDREN
Lung Development
Manifestations of Respiratory Disorders or Infection in the Infant or Small Child
Respiratory Disorders in the Neonate
Respiratory Infections in Children
REVIEW EXERCISES
References
CHAPTER 37: Disorders of Ventilation and Gas Exchange
PHYSIOLOGIC EFFECTS OF VENTILATION AND DIFFUSION DISORDERS
Hypoxemia
Hypercapnia
DISORDERS OF LUNG INFLATION
Disorders of the Pleura
Atelectasis
OBSTRUCTIVE AIRWAY DISORDERS
Physiology of Airway Disease
Asthma
Chronic Obstructive Pulmonary Disease
Bronchiectasis
Cystic Fibrosis
CHRONIC INTERSTITIAL (RESTRICTIVE) LUNG DISEASES
Etiology and Pathogenesis of Interstitial Lung Diseases
Clinical Manifestations
Diagnosis and Treatment
Occupational and Environmental Interstitial Lung Diseases
Sarcoidosis
DISORDERS OF THE PULMONARY CIRCULATION
Pulmonary Embolism
Pulmonary Hypertension
Cor Pulmonale
ACUTE RESPIRATORY DISORDERS
Acute Lung Injury/Acute Respiratory Distress Syndrome
Acute Respiratory Failure
REVIEW EXERCISES
References
UNIT X: Disorders of Renal Function and Fluids and Electrolytes
CHAPTER 38: Structure and Function of the Kidney
KIDNEY STRUCTURE AND FUNCTION
Gross Structure and Location
Renal Blood Supply
The Nephron
Urine Formation
Regulation of Renal Blood Flow
Elimination Functions of the Kidney
Endocrine Functions of the Kidney
Action of Diuretics
TESTS OF RENAL FUNCTION
Urine Tests
Glomerular Filtration Rate
Blood Tests
Cystoscopy
Ultrasonography
Radiologic and Other Imaging Studies
REVIEW EXERCISES
References
CHAPTER 39: Disorders of Fluid and Electrolyte Balance
COMPOSITION AND COMPARTMENTAL DISTRIBUTION OF BODY FLUIDS
Dissociation of Electrolytes
Diffusion and Osmosis
Compartmental Distribution of Body Fluids
Capillary–Interstitial Fluid Exchange
SODIUM AND WATER BALANCE
Body Water Balance
Sodium Balance
Mechanisms of Regulation
Thirst and Antidiuretic Hormone
Disorders of Sodium and Water Balance
POTASSIUM BALANCE
Regulation of Potassium Balance
Disorders of Potassium Balance
CALCIUM, PHOSPHORUS, AND MAGNESIUM BALANCE
Mechanisms Regulating Calcium, Phosphorus, and Magnesium Balance
Disorders of Calcium Balance
Disorders of Phosphorus Balance
Disorders of Magnesium Balance
REVIEW EXERCISES
References
CHAPTER 40: Disorders of Acid–Base Balance
MECHANISMS OF ACID–BASE BALANCE
Acid–Base Chemistry
Metabolic Acid and Bicarbonate Production
Calculation of pH
Regulation of pH
Laboratory Tests
DISORDERS OF ACID–BASE BALANCE
Metabolic Versus Respiratory Acid–Base Disorders
Compensatory Mechanisms
Metabolic Acidosis
Metabolic Alkalosis
Respiratory Acidosis
Respiratory Alkalosis
REVIEW EXERCISES
References
CHAPTER 41: Disorders of Renal Function
CONGENITAL AND INHERITED DISORDERS OF THE KIDNEYS
Congenital Disorders of the Kidneys
Inherited Cystic Kidney Diseases
Simple and Acquired Renal Cysts
OBSTRUCTIVE DISORDERS
Mechanisms of Renal Damage
Renal Calculi
URINARY TRACT INFECTIONS
Etiology and Pathogenesis
Clinical Manifestations
Diagnosis and Treatment
Infections in Special Populations
DISORDERS OF GLOMERULAR FUNCTION
Etiology and Pathogenesis of Glomerular Injury
Types of Glomerular Disease
Glomerular Lesions Associated with Systemic Disease
TUBULOINTERSTITIAL DISORDERS
Renal Tubular Acidosis
Pyelonephritis
Drug-Related Nephropathies
MALIGNANT TUMORS OF THE KIDNEY
Wilms Tumor
Renal Cell Carcinoma
REVIEW EXERCISES
References
CHAPTER 42: Acute Renal Injury and Chronic Kidney Disease
ACUTE RENAL INJURY
Types of Acute Renal Injury
Diagnosis and Treatment
CHRONIC KIDNEY DISEASE
Definition and Classification
Assessment of Glomerular Filtration Rate and Other Indicators of Renal Function
Clinical Manifestations
Treatment
CHRONIC KIDNEY DISEASE IN CHILDREN AND OLDER ADULTS
Chronic Kidney Disease in Children
Chronic Kidney Disease in Older Adults
REVIEW EXERCISES
References
CHAPTER 43: Disorders of the Bladder and Lower Urinary Tract
CONTROL OF URINE ELIMINATION
Bladder Structure
Neural Control of Bladder Function
Diagnostic Methods of Evaluating Bladder Structure and Function
ALTERATIONS IN BLADDER FUNCTION
Lower Urinary Tract Obstruction and Stasis
Neurogenic Bladder Disorders
Urinary Incontinence
CANCER OF THE BLADDER
Etiology and Pathophysiology
Clinical Manifestations
Diagnosis and Treatment
REVIEW EXERCISES
References
UNIT XI: Disorders of Gastrointestinal Function
CHAPTER 44: Structure and Function of the Gastrointestinal System
STRUCTURE AND ORGANIZATION OF THE GASTROINTESTINAL TRACT
Upper Gastrointestinal Tract
Middle Gastrointestinal Tract
Lower Gastrointestinal Tract
Gastrointestinal Wall Structure
MOTILITY
Control of Gastrointestinal Motility
Swallowing and Esophageal Motility
Gastric Motility
Small Intestinal Motility
Colonic Motility and Defecation
HORMONAL, SECRETORY, AND DIGESTIVE FUNCTIONS
Gastrointestinal Hormones
Gastrointestinal Secretions
Intestinal Flora
DIGESTION AND ABSORPTION
Carbohydrate Absorption
Fat Absorption
Protein Absorption
REVIEW EXERCISES
References
CHAPTER 45: Disorders of Gastrointestinal Function
COMMON MANIFESTATIONS OF GI DISORDERS ANOREXIA, NAUSEA, AND VOMITING
Anorexia
Nausea
Retching and Vomiting
DISORDERS OF THE ESOPHAGUS
Congenital Anomalies
Dysphagia
Esophageal Diverticulum
Tears (Mallory-Weiss Syndrome)
Hiatal Hernia
Gastroesophageal Reflux
Cancer of the Esophagus
DISORDERS OF THE STOMACH
Gastric Mucosal Barrier
Gastritis
Peptic Ulcer Disease
Cancer of the Stomach
DISORDERS OF THE SMALL AND LARGE INTESTINES
Irritable Bowel Syndrome
Inflammatory Bowel Disease
Infectious Enterocolitis
Diverticular Disease
Appendicitis
Alterations in Intestinal Motility
Alterations in Intestinal Absorption
Neoplasms
REVIEW EXERCISES
References
CHAPTER 46: Disorders of Hepatobiliary and Exocrine Pancreas Function
THE LIVER AND HEPATOBILIARY SYSTEM
Metabolic Functions of the Liver
Bile Production and Cholestasis
Bilirubin Elimination and Jaundice
Tests of Hepatobiliary Function
DISORDERS OF HEPATIC AND BILIARY FUNCTION
Hepatotoxic Disorders
Viral Hepatitis
Autoimmune Hepatitis
Intrahepatic Biliary Disorders
Alcohol-Induced Liver Disease
Cirrhosis, Portal Hypertension, and Liver Failure
Cancer of the Liver
DISORDERS OF THE GALLBLADDER AND EXOCRINE PANCREAS
Disorders of the Gallbladder and Extrahepatic Bile Ducts
Disorders of the Exocrine Pancreas
REVIEW EXERCISES
References
CHAPTER 47: Alterations in Nutritional Status
NUTRITIONAL STATUS
Energy Metabolism
Energy Storage
Energy Expenditure
NUTRITIONAL NEEDS
Dietary Reference Intakes
Nutritional Needs
Regulation of Food Intake and Energy Storage
OVERWEIGHT AND OBESITY
Body Mass Index
Causes of Obesity
Types of Obesity
Health Risks Associated with Obesity
Prevention and Treatment of Obesity
UNDERNUTRITION AND EATING DISORDERS
Malnutrition and Starvation
Eating Disorders
REVIEW EXERCISES
References
UNIT XII: Disorders of Endocrine Function
CHAPTER 48: Mechanisms of Endocrine Control
THE ENDOCRINE SYSTEM
Hormones
Control of Hormone Levels
Diagnostic Tests
REVIEW EXERCISES
References
CHAPTER 49: Disorders of Endocrine Control of Growth and Metabolism
GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION
Hypofunction and Hyperfunction
Primary, Secondary, and Tertiary Disorders
PITUITARY AND GROWTH DISORDERS
Assessment of Hypothalamic–Pituitary Function
Pituitary Tumors
Hypopituitarism
Growth and Growth Hormone Disorders
Isosexual Precocious Puberty
THYROID DISORDERS
Control of Thyroid Function
Hypothyroidism
Hyperthyroidism
DISORDERS OF ADRENAL CORTICAL FUNCTION
Control of Adrenal Cortical Function
Congenital Adrenal Hyperplasia
Adrenal Cortical Insufficiency
Glucocorticoid Hormone Excess (Cushing Syndrome)
Incidental Adrenal Mass
REVIEW EXERCISES
References
CHAPTER 50: Diabetes Mellitus and the Metabolic Syndrome
HORMONAL CONTROL OF GLUCOSE, FAT, AND PROTEIN METABOLISM
Glucose, Fat, and Protein Metabolism
Glucose-Regulating Hormones
DIABETES MELLITUS
Classification and Etiology
Clinical Manifestations of Diabetes Mellitus
Diagnostic Tests
Treatment
Acute Complications of Diabetes
Counter-Regulatory Mechanisms and the Somogyi Effect and Dawn Phenomenon
Chronic Complications
Infections
REVIEW EXERCISES
References
UNIT XIII: Disorders of Genitourinary and Reproductive Function
CHAPTER 51: Structure and Function of the Male Genitourinary System
STRUCTURE OF THE MALE REPRODUCTIVE SYSTEM
Embryonic Development
Testes and Scrotum
Genital Duct System
Accessory Organs
Penis
SPERMATOGENESIS AND HORMONAL CONTROL OF MALE REPRODUCTIVE FUNCTION
Spermatogenesis
Hormonal Control of Male Reproductive Function
NEURAL CONTROL OF SEXUAL FUNCTION AND CHANGES WITH AGING
Neural Control
Changes with Aging
REVIEW EXERCISES
References
CHAPTER 52: Disorders of the Male Genitourinary System
DISORDERS OF THE PENIS
Congenital and Acquired Disorders
Disorders of Erectile Function
Cancer of the Penis
DISORDERS OF THE SCROTUM AND TESTES
Congenital and Acquired Disorders
Infection and Inflammation
Neoplasms
DISORDERS OF THE PROSTATE
Infection and Inflammation
Hyperplasia and Neoplasms
REVIEW EXERCISES
References
CHAPTER 53: Structure and Function of the Female Reproductive System
REPRODUCTIVE STRUCTURES
External Genitalia
Internal Genitalia
MENSTRUAL CYCLE
Hormonal Control of the Menstrual Cycle
Ovarian Follicle Development and Ovulation
Endometrial Changes
Cervical Mucus Changes
Menopause
BREASTS
Structure and Function
Changes During Pregnancy and Lactation
REVIEW EXERCISES
REFERENCES
CHAPTER 54: Disorders of the Female Reproductive System
DISORDERS OF THE EXTERNAL GENITALIA AND VAGINA
Disorders of the External Genitalia
Disorders of the Vagina
DISORDERS OF THE CERVIX AND UTERUS
Disorders of the Uterine Cervix
Disorders of the Uterus
DISORDERS OF THE FALLOPIAN TUBES AND OVARIES
Pelvic Inflammatory Disease
Ectopic Pregnancy
Cancer of the Fallopian Tube
Ovarian Cysts and Tumors
DISORDERS OF PELVIC SUPPORT AND UTERINE POSITION
Disorders of Pelvic Support
Variations in Uterine Position
MENSTRUAL DISORDERS
Dysfunctional Menstrual Cycles
Amenorrhea
Dysmenorrhea
Premenstrual Symptom Disorders
DISORDERS OF THE BREAST
Galactorrhea
Mastitis
Ductal Disorders
Fibroadenoma and Fibrocystic Changes
Breast Cancer
INFERTILITY
Male Factors
Female Factors
Assisted Reproductive Technologies
REVIEW EXERCISES
References
CHAPTER 55: Sexually Transmitted Infections
INFECTIONS OF THE EXTERNAL GENITALIA
Condylomata Acuminata (Genital Warts)
Genital Herpes
Molluscum Contagiosum
Chancroid
Granuloma Inguinale
Lymphogranuloma Venereum
VAGINAL INFECTIONS
Candidiasis
Trichomoniasis
Bacterial Vaginosis
VAGINAL–UROGENITAL–SYSTEMIC INFECTIONS
Chlamydial Infections
Gonorrhea
Syphilis
REVIEW EXERCISES
References
UNIT XIV: Disorders of Musculoskeletal Function
CHAPTER 56: Structure and Function of the Musculoskeletal System
BONY STRUCTURES OF THE SKELETAL SYSTEM
Bone Structures
Bone Tissue
Cartilage
Hormonal Control of Bone Formation and Metabolism
ARTICULATIONS AND JOINTS
Tendons and Ligaments
Types of Joints
REVIEW EXERCISES
References
CHAPTER 57: Disorders of Musculoskeletal Function: Trauma, Infection, Neoplasms
INJURY AND TRAUMA OF MUSCULOSKELETAL STRUCTURES
Athletic Injuries
Soft Tissue Injuries
Joint (Musculotendinous) Injuries
Fractures
Complications of Fractures and Other Musculoskeletal Injuries
BONE INFECTIONS
Osteomyelitis
Tuberculosis of the Bone or Joint
OSTEONECROSIS
Etiology and Pathogenesis
Clinical Manifestations, Diagnosis, and Treatment
NEOPLASMS
Characteristics of Bone Tumors
Benign Neoplasms
Malignant Bone Tumors
Metastatic Bone Disease
REVIEW EXERCISES
References
CHAPTER 58: Disorders of Musculoskeletal Function: Developmental and Metabolic Disorders
ALTERATIONS IN SKELETAL GROWTH AND DEVELOPMENT
Bone Growth and Remodeling
Alterations during Normal Growth Periods
Hereditary and Congenital Deformities
Juvenile Osteochondroses
Scoliosis
METABOLIC BONE DISEASE
Osteopenia
Osteoporosis
Osteomalacia and Rickets
Paget Disease
REVIEW EXERCISES
References
CHAPTER 59: Disorders of Musculoskeletal Function: Rheumatic Disorders
SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Systemic Sclerosis/Scleroderma
Polymyositis and Dermatomyositis
SERONEGATIVE SPONDYLOARTHROPATHIES
Ankylosing Spondylitis
Reactive Arthropathies
Psoriatic Arthritis
Enteropathic Arthritis
OSTEOARTHRITIS SYNDROME
Epidemiology and Risk Factors
Pathogenesis
Clinical Manifestations
Diagnosis and Treatment
CRYSTAL-INDUCED ARTHROPATHIES
Gout
RHEUMATIC DISEASES IN CHILDREN AND OLDER ADULTS
Rheumatic Diseases in Children
Rheumatic Diseases in Older Adults
REVIEW EXERCISES
References
UNIT XV: Disorders of Integumentary Function
CHAPTER 60: Structure and Function of the Skin
STRUCTURE AND FUNCTION OF THE SKIN
Skin Structures
Skin Appendages
Functions of the Skin
MANIFESTATIONS OF SKIN DISORDERS
Lesions and Rashes
Pruritus
Dry Skin
Skin Variations in Dark-Skinned People
REVIEW EXERCISES
References
CHAPTER 61: Disorders of Skin Integrity and Function
PRIMARY DISORDERS OF THE SKIN
Pigmentary Skin Disorders
Infectious Processes
Acne and Rosacea
Allergic and Hypersensitivity Dermatoses
Papulosquamous Dermatoses
Arthropod Infestations
ULTRAVIOLET RADIATION, THERMAL, AND PRESSURE INJURY
Skin Damage Caused by Ultraviolet Radiation
Thermal Injury
Pressure Ulcers
NEVI AND SKIN CANCERS
Nevi
Skin Cancer
AGE-RELATED SKIN MANIFESTATIONS
Skin Manifestations of Infancy and Childhood
Skin Manifestations and Disorders in Older Adults
REVIEW EXERCISES
References
Appendix: Lab Values
Glossary
Index

Citation preview

PORTH’S PATHOPHYSIOLOGY Concepts of Altered Health States

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PORTH’S PATHOPHYSIOLOGY Concepts of Altered Health States NINTH EDITION

Sheila C. Grossman, PhD, APRN, FNP-BC, FAAN Professor & FNP Track Coordinator Fairfield University School of Nursing Fairfield, Connecticut

Carol Mattson Porth, RN, MSN, PhD (Physiology) Professor Emeritus College of Nursing University of Wisconsin – Milwaukee Milwaukee, Wisconsin

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Acquisitions Editor: David Troy Product Manager: Katherine Burland Editorial Assistant: Latisha Oglesby Production Project Manager: Cynthia Rudy Design Coordinator: Joan Wendt Manufacturing Coordinator: Karin Duffield Prepress Vendor: SPi Global 9th edition Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Copyright © 2009 by Wolters Kluwer Health | Lippincott Williams & Wilkins. Copyright © 2005, 2002 by Lippincott Williams & Wilkins. Copyright © 1998 by Lippincott-Raven Publishers. Copyright © 1994 by J.B. Lippincott Company. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Lippincott Williams & Wilkins at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in China Cataloging-in-Publication Data available on request from the Publisher. ISBN: 978-1-4511-4600-4  Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of this information in a particular situation remains the professional responsibility of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in his or her clinical practice. LWW.com

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Contributors Cynthia Bautista, PhD, RN, CNRN, CCNS, ACNS-BC Neuroscience Clinical Nurse Specialist Yale New Haven Hospital New Haven, Connecticut (Chapters 17, 18, 19, 20)

Christine Kurtz, DNP, PMHCNS-BC

Jaclyn Conelius, PhD, APRN, FNP-BC Assistant Professor Fairfield University School of Nursing Fairfield, Connecticut (Chapters 29, 30, 31, 32, 33, 34)

Jessie Moore, MS, APRN

Sally O. Gerard, DNP, RN, CDE Assistant Professor of Nursing and Coordinator, Nursing Leadership Track Fairfield University School of Nursing Fairfield, Connecticut (Chapters 48, 50)

Nancy Moriber, PhD, CRNA, APRN

Lisa Grossman, MD, MPH

Martha Burke O’Brien, MS, ANP-BC, APRN Director of Student Health Services Trinity College Hartford, Connecticut (Chapter 23)

Administrative Chief Resident Obstetrics/Gynecology Columbia University Medical Center New York, New York (Chapters 6, 7, 53, 54, 55)

Theresa Kessler, PhD, RN, ACNS-BC, CNE Professor Valparaiso University Valparaiso, Indiana (Chapters 21, 40)

Melissa Kramps, DNP, APRN Nurse Practitioner Memory Disorders Center New York, New York (Chapter 3)

Adjunct Assistant Professor Valparaiso University College of Nursing Valparaiso, Indiana (Chapter 21) Program Coordinator, Weight Loss Surgery Yale New Haven Hospital – Saint Raphael Campus New Haven, Connecticut (Chapter 47) Visiting Assistant Professor and Director, Nurse Anesthesia Track Fairfield University School of Nursing Fairfield, Connecticut (Chapters 13, 15)

Eileen O’Shea, DNP, RN Assistant Professor Fairfield University School of Nursing Fairfield, Connecticut (Chapter 2) Kathleen Wheeler, PhD, APRN, PMHNP-BC, FAAN Professor Fairfield University School of Nursing Fairfield, Connecticut (Chapter 22)

Zachary Krom, MSN, RN, CCRN Service Line Educator: Adult Surgery Yale New Haven Hospital New Haven, Connecticut (Chapters 44, 45, 46)

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Reviewers Mary Fisler Aebi, RN, MSN

Brian H. Kipp, PhD

Associate Professor Mt. Hood Community College Yachats, Oregon

Associate Professor Grand Valley State University Allendale, Michigan

Beverly Anderson, MSN, RN

Lori Knight, CHIM

Associate Professor of Nursing Salt Lake Community College West Jordon, Utah

Instructor Health Information Management Program SIAST, Wascana Campus Regina, Canada

Lou Anne Baldree, MD Clinical Associate Professor of Nursing College of Nursing East Carolina University Greenville, North Carolina

Kay Luft, MN, CNE, CCRN Associate Professor St. Luke’s College of Health Sciences Kansas City, Missouri

Karen Chandra, RN, MSN, MBA

Dr. Nicholas Lutfi, DPM, MS Associate Professor of Anatomy Nova Southeastern University Ft. Lauderdale-Davie, Florida

Assistant Professor Harper College Palatine, Illinois

Dale E. Collins, MS, RT(R)(M)(QM), RDMS, RVT

Barbara McGeever, BSN, MSN, PhD

Clinical Coordinator University of Arkansas for Medical Sciences Massachusetts General Hospital Imaging Associates of Providence Little Rock, Arkansas

Assistant Professor Neumann University Aston, Pennsylvania

Kent Davis, MD Professor of Biology Brigham Young University – Idaho Rexburg, Idaho

Jack Pennington, PhD Assistant Professor Goldfarb School of Nursing Barnes Jewish College St. Louis, Missouri Kathy Sheppard, PhD

Wendy Dusek, BS, DC Natural Science Instructor Wisconsin Indianhead Technical College New Richmond, Wisconsin

Kelly L. Fisher, RN, PhD Dean and Associate Professor of Nursing Endicott College Beverly, Massachusetts

Chair ADN Program Associate Professor University of Mobile Mobile, Alabama

Paula S. Steiert, MS Instructor of Biology St. John’s College of Nursing Southwest Baptist University Springfield, Missouri

Catherine Jennings, DNP, MSN, APN-C Assistant Professor Graduate Nursing Felician College Newton, New Jersey

vi

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Preface Over the last 30 years, Carol M. Porth’s text, Pathophysiology: Concepts of Altered Health States, has become widely known as a seminal text in pathophysiology for nursing and health profession students. It is a testament to her extensive knowledge, skills, and commitment that she succeeded in creating such a student-friendly and, at the same time, state-of-the-art book. It is a great honor to carry forward this tradition as the new author of the ninth edition of Porth’s Pathophysiology. The goal for this edition has been to retain the text’s solid foundation while updating and incorporating new advances in science and technology. Once again, talented clinicians, researchers, and scholars have contributed their expertise and knowledge to the book. The major emphasis continues to be on relating normal body functioning to the physiologic changes that occur as a result of disease, as well as on the body’s ability to compensate for these changes through mechanisms of healing and those that work to prevent and resist disease. Although primarily designed as a textbook, the book also serves as a reference that students will find useful throughout their educational program and, eventually, in practice.

Features that were proven to be effective in previous editions have been retained, and appropriate updates to content have been made. The sequencing of units has been updated to continue to enhance students’ ability to master basic concepts and then advance to more complex material. Case studies have been created for each unit and integrated into relevant chapters. Reference lists for each chapter have been updated, and selected clinical application content has been incorporated throughout the text to enhance students’ understanding of the pathophysiology of frequently seen conditions. Attention has been given to the incorporation of the most recent advances from the fields of genetics, immunity, microbiology, and molecular biology. Advances in health care technology are presented through the inclusion of international studies, WHO guidelines, and the health variants of diverse populations. I am pleased to present this new edition and to play a role in continuing the legacy of this valuable resource for students, instructors, and health professionals.

This edition marks the 30th anniversary of Pathophysiology: Concepts of Altered Health States. From its first edition published in 1982, it has grown to become a trusted and definitive resource for students, instructors, and health care professionals. The goal for each edition has been to develop a text that is current, accurate, and presented in a logical manner. While its vision and objectives have remained the same throughout the editions, the methods used to gather, analyze, present, and deliver the information have changed. Myriad cultural, political, and technological factors have helped to shape the text, and it is now a reflection of the global community. Technology has allowed me to work with contributors from around the world, to harvest information from a seemingly unlimited reservoir, and to deliver the information to an ever-growing audience. With each edition, the task at hand was to create a learning environment that would, in the words of Chinese scholars, “open the gates of knowledge” to the reader. The art of opening up a subject and generating enthusiasm for that subject is what produces autonomy and ultimately, an independent learner. While other physiology-based texts take a “how-to” or heavily application-oriented approach, that was not the intent here. Rather, this text focuses on the scientific basis upon which the practice components of the health professions are based, fostering a practitioner with the knowledge and skills to develop creative solutions within a dynamic profession. A holistic conceptual framework uses body systems as an organizing framework and demonstrates how the systems

are interrelated. Selection of content was based on common health problems across the lifespan, and recent advances in the fields of genetics, immunology, microbiology, and molecular biology are included. Concepts are presented in a manner that is logical and understandable for students, building from basic to more complex. The chapters are arranged so that common accompaniments to disease states, such as inflammation and repair, genetic control of cell function and inheritance, and immunologic processes, appear in the early chapters before the specific discussions of particular disease states. Proven strengths of the text include the expanded chapters on health and disease; nutrition; sleep and sleep disorders; pediatrics; gerontology; and thought, emotion, and mood disorders. Advances in health care are presented through the inclusion of international studies, World Health Organization guidelines, and the health variants of diverse populations. Many “trademark” features and learning aids have been developed over the years that inspire students’ enthusiasm and facilitate learning, including more than 700 detailed, full-color illustrations depicting the clinical manifestations of selected disease states and other important visuals. Learning objectives are listed at the beginning of each major section in a chapter, and summary statements appear at the end. Organizing the content in this manner encourages students to pause and review important points. Key points boxes within each chapter help students develop true understanding by incorporating information within a larger conceptual unit, versus merely asking

Sheila C. Grossman

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viii   Preface

them to memorize ­miscellaneous facts. The Understanding features that appear in some chapters break physiologic processes and phenomena into their sequential parts, providing insight into the many opportunities for disease to disrupt the processes. Review exercises are included to provide practice in using the c­ onceptual approach in solving problems related to patient scenarios. Other helpful tools include a glossary and a table of normal laboratory values. In developing content for the previous editions, my perspective as a nurse–physiologist led to an approach based on relating normal body functioning to the physiologic changes that participate in disease production and that occur as a result of disease. I also focused on the body’s remarkable ability to compensate for these changes. The beauty of physiology is that it integrates all of the aspects of human genetics, molecular and cellular biology, and anatomy and physiology into a functional whole that can be used to explain both the physical

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and psychological aspects of altered health. In its very essence, each edition has reflected my desire to share the beauty of the human body and to emphasize that in disease as in health, there is more “going right” in the body than is “going wrong.” Throughout its 30 years, authoring the book has been a meaningful endeavor. The preparation of each edition has been a challenging and humbling task. I have experienced great joy and satisfaction in engaging the reader and sharing the excitement and wonder that I have for the physiologic basis of life and altered health. With this ninth ­edition, we welcome a new voice and vision to the enterprise as Dr. Sheila Grossman leads the publishing effort for this new edition and shares in the experience of “opening the gates of knowledge.” Carol Mattson Porth

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To the Reader This book was written with the intent of making the subject of pathophysiology an exciting exploration that relates normal body functioning to the physiologic changes that occur as a result of disease, as well as the body’s remarkable ability to compensate for these changes. Indeed, it is these changes that represent the signs and symptoms of disease. Using a book such as this can be simplified by taking time out to find what is in the book and how to locate information when it is needed. The table of contents at the beginning of the book provides an overall view of the organization and content of the book. It also provides clues as to the relationships among areas of content. For example, the location of the chapter on neoplasia within the unit on cell function and growth indicates that neoplasms are products of altered cell growth. The index, which appears at the end of the book, can be viewed as a road map for locating content. It can be used to quickly locate related content in different chapters of the book or to answer questions that come up in other courses.

ORGANIZATION The book is organized into units and chapters. The units identify broad areas of content, such as alterations in the circulatory system. Many of the units have an introductory chapter that contains essential information about the structure and function of the body systems that are being discussed in the unit. These chapters provide the foundation for understanding the pathophysiology content presented in the subsequent chapters. The chapters focus on specific areas of content, such as heart failure and circulatory shock. The chapter outline that appears at the beginning of each chapter provides an overall view of the chapter content and organization.

It is essential for any professional to use and understand the vocabulary of his or her profession. Throughout the text, you will encounter terms in italics. This is a signal that a word and the ideas associated with it are important to learn. In addition, a glossary is provided to help you expand your vocabulary and improve your comprehension of what you are reading.The glossary contains concise definitions of frequently encountered terms. If you are unsure of the meaning of a term you encounter in your reading, check the glossary in the back of the book before proceeding.

BOXES Boxes are used throughout the text to summarize and highlight key information. You will frequently encounter two types of boxes: Key Points boxes and Summary boxes. One of the ways to approach learning is to focus on the major ideas or concepts rather than trying to memorize a list of related and unrelated bits of information. As you have probably already discovered, it is impossible to memorize everything that is in a particular section or chapter of the book. Not only does your brain have a difficult time trying to figure out where to store all the different bits of information, your brain does not know how to retrieve the information when you need it. Most important of all, memorized lists of content can seldom, if ever, be applied directly to an actual clinical situation. The Key Points boxes guide you in identifying the major ideas or concepts that form the foundation for truly understanding the major areas of content. When you understand the concepts in the Key Points boxes, you will have a framework for remembering and using the facts given in the text.

READING AND LEARNING AIDS In an ever-expanding world of information, you will not be able to read, let alone remember, everything that is in this book, or in any book, for that matter. With this in mind, we have developed a number of special features that will help you focus on and master the essential content for your current as well as future needs. The objectives that appear at the beginning of each major area of content provide a focus for your study. After you have finished each of these areas of content, you may want to go back and make sure that you have met each of the objectives.

The Summary boxes at the end of each section provide a review and a reinforcement of the main content that has been covered. Use the summaries to assure that you have covered and understood what you have read. ix

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x   To the Reader

ILLUSTRATIONS AND PHOTOS The full-color illustrations will help you to build your own mental image of the content that is being presented. Each drawing has been developed to fully support and build upon the ideas in the text. Some illustrations are used to help you picture the complex interactions of the multiple phenomena that are involved in the development of a particular disease; others can help you to visualize normal function or understand the mechanisms whereby the disease processes exert their effects. In addition, photographs of pathologic processes and lesions provide a realistic view of selected pathologic processes and lesions.

TABLES AND CHARTS Tables and charts are designed to present complex information in a format that makes it more meaningful and easier to remember. Tables have two or more columns, and are often used for the purpose of comparing or contrasting information. Charts have one column and are used to summarize information.

UNDERSTANDING PHYSIOLOGIC PROCESSES Understanding boxes focus on the physiologic processes and phenomena that form the basis for understanding disorders presented in the text. This feature breaks a process or phenomenon down into its component parts and presents it in a sequential manner, providing an insight into the many opportunities for disease processes to disrupt the sequence.

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To the Reader    xi

MATERIAL FOR REVIEW An important feature has been built into the text to help you verify your understanding of the material presented. After you have finished reading and studying the chapter, work on answering the review exercises at the end of the chapter. They are designed to help you integrate and synthesize material. If  you are unable to answer a question, reread the relevant section in the chapter.

CASE STUDIES New to this edition, each unit opens with a case study introducing a patient’s case history and symptoms. Throughout the unit chapters, more information is added to the case as it relates to the information being presented, showing students an example of a real-life application of the content.

APPENDIX The appendix, Lab Values, provides rapid access to normal ­values for many laboratory tests, as well as a description of the prefixes, symbols, and factors (e.g., micro, m, 10−6) used for describing these values. Knowledge of normal values can help you to put abnormal values in context. We hope that this guide has given you a clear picture of how to use this book. Good luck and enjoy the journey!

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xii   To the Reader

INSTRUCTOR RESOURCES This ninth edition comes with a collection of ancillary materials designed to help you plan learning activities and evaluate students’ learning. The Instructor Resources are available online at —http://thepoint.lww.com—and include information and activities that will help you engage your students throughout the semester, including the following: •• Guided Lecture Notes that walk you through the chapter learning objective by learning objective with integrated references to the PowerPoint presentations •• Image Bank •• Test Generator •• Prelecture Quizzes •• Discussion Topics •• Assignments •• Case Studies with critical-thinking/discussion questions •• Online eBook •• Journal Articles

STUDENT RESOURCES Students can also visit ing tools:

to access the following learn-

•• Animations of selected pathophysiologic processes •• Links to relevant journal articles •• Student Review Questions for every chapter

STUDY GUIDE Study Guide for Porth’s Pathophysiology: Concepts of Altered Health States reinforces and complements the text by helping you assess and apply your knowledge through case studies and a variety of question styles, including multiple choice, fill-in-the-blank, matching, short answer, and figure-labeling exercises that will help you practice for the NCLEX.

Practice makes perfect. And this is the perfect practice PrepU is an adaptive learning system designed to improve students’ competency mastery and provide instructors with realtime analysis of their students’ knowledge at both a class and individual student level. PrepU demonstrates formative assessment—it ­determines what students know as they are learning, and focuses them on what they are struggling with, so they do not spend time on what they already know. Feedback is immediate and remediates students back to this specific text, so they know where to go back to the text, read, and help understand a concept. Adaptive and personalized No student has the same experience—PrepU recognizes when a student has reached “mastery” of a concept before moving them on to higher levels of learning. This will be a different experience for each student based on the number of questions they answer and whether they answer them correctly. Each question is also “normed” by all students in PrepU around the country—how every student answers a specific question generates the difficulty level of each question in the system. This adaptive experience allows students to practice at their own pace and to study much more effectively. Personalized reports Students get individual feedback about their performance, and instructors can track class statistics to gauge the level of understanding. Both get a window into performance to help identify areas for remediation. Instructors can access the average mastery level of the class, students’ strengths and weaknesses, and how often students use PrepU. Students can see their own progress charges and strengths and weaknesses—so they can continue quizzing in areas where they are weaker. Mobile optimized Students can study anytime, anywhere with PrepU, as it is mobile optimized. More convenience equals more quizzing and more practice for students! There is a PrepU resource available with this book! For more information, visit http://thepoint.lww.com/PrepU

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Acknowledgments With the first edition of Pathophysiology: Concepts of Altered Health States, an exciting and challenging journey began. My companions on this journey were many. Each of the many persons who participated in the creation of this long-standing work made a unique contribution. The contributing authors are deserving of special recognition as the ninth edition bears the indelible imprint of their skill and expertise. Many of them have been with the book since its early editions, and the text and figures they created endure as much of what they authored appears in this revision. Given my sincere appreciation for their work, I would be remiss in not recognizing and acknowledging their authorship. Those I would like to acknowledge and thank include the following: •• Judith Aberg, MD, Associate Professor, New York University School of Medicine, Principal Investigator, AIDS Clinical Trial Unit and Director HIV, Bellevue Hospital Center. Chapter 16, Acquired Immunodeficiency Syndrome. •• Toni Ballestrieri, RN, BSN, CCNS, Milwaukee, Wisconsin. Chapter 32, Disorders of Cardiac Function. •• Anna Barkman, RN, MSN, CCNS, Faculty School of Nursing, Mount Royal College, Calgary, Alberta, Canada. Chapter 34, Heart Failure and Circulatory Shock. •• Diane Book, MD, Assistant Professor, Department of Neurology, Medical College of Wisconsin. Chapter 20, Disorders of Brain Function. •• Edward W. Carroll, PhD (Deceased), Clinical Assistant Professor, Department of Biomedical Sciences, Marquette University. Chapter 4, Cell and Tissue Characteristics; Chapter 6, Genetic Control of Cell Function and Inheritance; Chapter 17, Organization and Control of Neural Function; Chapter 23, Disorders of Visual Function. •• Robin Curtis, PhD, Retired Professor, Department of Cellular Biology, Neurobiology and Anatomy, Medical College of Wisconsin. Chapter 17, Organization and Control of Neural Function; Chapter 23, Disorders of Visual Function. •• W. Michael Dunn Jr, PhD, Professor of Pathology and Immunology, Washington University School of Medicine. Chapter 12, Mechanisms of Infectious Disease. •• Jason Faulhaber, MD, Fellow, Division of Infectious Diseases and Immunology, New York University School of Medicine. Chapter 16, Acquired Immunodeficiency Syndrome. •• Suzanne Fontana, RN, PhD, APRN-BC, Associate Professor and Family Nurse Practitioner, College of Nursing, University of Wisconsin – Milwaukee. Chapter 24, Disorders of Hearing and Vestibular Function. •• Kathryn Gaspard, PhD, Clinical Associate Professor Emerita, College of Nursing, University of Wisconsin – Milwaukee. Chapter 25, Blood Cells and the Hematopoietic System; Chapter 26, Disorders of Hemostasis; Chapter 27, Disorders of Red Blood Cells.

•• Kathleen Gunta, RN, MS, OCNS-C, Clinical Nurse Specialist, Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin. Chapter 57, Disorders of Musculoskeletal Function: Trauma, Infection, Neoplasms; Chapter 58, Disorders of Musculoskeletal Function: Developmental and Metabolic Disorders. •• Safak Guven, MD, MBA, FACE, FACP, Las Vegas, Nevada. Chapter 50, Diabetes Mellitus and the Metabolic Syndrome, with Glenn Matfin and Julie Kuenzi. •• Surena Hung, MD, Assistant Professor, Department of Neurology, Medical College of Wisconsin. Chapter 19, Disorders of Motor Function. •• Scott A. Jens, OD, FAAO, Director Optometry, Isthmus Eye Care, Middleton, Wisconsin. Chapter 23, Disorders of Visual Function. •• Mary Kay Jiricka, RN, MSN, CCRN, APN-BC, Cardiac Intensive Care Unit, Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin. Chapter 11, Activity Tolerance and Fatigue. •• Mary Pat Kunert, RN, PhD (Deceased), Associate Professor, College of Nursing, University of Wisconsin – Milwaukee. Chapter 9, Stress and Adaptation; Chapter 10, Alterations in Temperature Regulation. •• Nathan A. Ledeboer, PhD, Assistant Professor of Pathology, Medical College of Wisconsin. Chapter 12, Mechanisms of Infectious Disease. •• Kim Litwack, RN, PhD, FAAN, APNP, Chapter 18, Somatosensory Function, Pain, and Headache; Chapter 35, Structure and Function of the Respiratory System; Chapter 40, Disorders of Acid–Base Balance. •• Judy Wright Lott, RN, PhD, DSN, FAAN, Dean and Professor of Nursing, Louise Herrington School of Nursing, Baylor University, Waco, Texas. Chapter 2, Concepts of Altered Health in Children. •• Patricia McCowen Mehring, RN, MSN, WHNP, Nurse Practitioner of OB-GYN, Medical College of Wisconsin. Chapter 53, Structure and Function of the Female Reproductive System; Chapter 54, Disorders of the Female Reproductive System; Chapter 55, Sexually Transmitted Infections. •• Carrie J. Merkle, RN, PhD, FAAN, Associate Professor, College of Nursing, University of Arizona, Tucson, Arizona. Chapter 5, Cellular Adaptation, Injury, and Death; Chapter 8, Neoplasia. •• Kathleen Mussato, RN, PhD, Research Manager, Henna Heart Center, Children’s Hospital of Wisconsin. Chapter 32, Disorders of Cardiac Function (Heart Disorders in Children). •• Janice Kuiper Pikna, RN, MSN, CS, Clinical Nurse Specialist—Gerontology Froedtert Hospital, Milwaukee, Wisconsin. Chapter 3, Concepts of Altered Health in Older Adults. xiii

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•• Sandra Kawczynski Pasch, RN, MS, MA, Assistant Professor, Columbia College of Nursing, Milwaukee, Wisconsin. Chapter 22, Disorders of Thought, Mood, and Memory. •• Joan Pleus, RD, MS, CDE, Program Manager/Biomedical Core, Clinical Research Center, Medical College of Wisconsin. Chapter 47, Alterations in Nutritional Status. •• Charlotte Pooler, RN, BScN, MN, PhD (Nursing), CNCC (C), CNC (C), Director, Baccalaureate Nursing Program, Grant MacEwan College, Edmonton, Alberta, Canada. Chapter 37, Disorders of Ventilation and Gas Exchange. •• Debra Bancroft Rizzo, RN, MSN, FNP-C, Nurse Practitioner, Rheumatic Disease Center, Glendale, Wisconsin. Chapter 59, Disorders of Musculoskeletal Function: Rheumatic Disorders. •• Gladys Simandl, RN, PhD, Professor Columbia College of Nursing, Glendale, Wisconsin. Chapter 60, Structure and Function of the Skin; Chapter 61, Disorders of Skin Integrity and Function. •• Cynthia Sommer, PhD, MT (ASCP), Associate Professor Emerita, Department of Biological Sciences, University of Wisconsin. Chapter 13, Innate and Adaptive Immunity; Chapter 14, Inflammation, Tissue Repair, and Wound Healing. •• Jill Winters, RN, PhD, Associate Professor and Director of Research and Scholarship, Marquette University, Milwaukee, Wisconsin. Chapter 33, Disorders of Cardiac Conduction and Rhythm. And for the chapters we contributed as author and coauthor Carol M. Porth, RN, MSN, PhD (physiology), FAHA. Chapter 1, Concepts of Health and Disease; Chapter 7, Genetic and Congenital Disorders; Chapter 15, Disorders of the Immune Response; Chapter 21, Sleep and Sleep Disorders; Chapter 28, Disorders of White Blood Cells and Lymphoid Tissues; Chapter 29, Structure and Function of the Cardiovascular System; Chapter 31, Disorders of Blood Pressure Regulation; Chapter 36, Respiratory Tract Infections, Neoplasms, and Childhood Disorders; Chapter 38, Structure and Function of the Kidney; Chapter 40, Disorders of Acid–Base Balance, with Kim Litwack; Chapter 41, Disorders of Renal Function; Chapter 42, Acute Renal Failure and Chronic Kidney Disease; Chapter 43, Disorders of the Bladder and Lower Urinary Tract; Chapter 44, Structure and Function of the Gastrointestinal System; Chapter 45, Disorders  of Gastrointestinal Function; Chapter 46, Disorders of  Hepatobiliary and Exocrine Pancreas Function; Chapter 56, Structure and Function of the Musculoskeletal System.

Electrolyte Balance; Chapter 48, Mechanisms of Endocrine Control; Chapter 49, Disorders of Endocrine Control of Growth and Metabolism; Chapter 50, Diabetes Mellitus and the Metabolic Syndrome; Chapter 51, Structure and Function of the Male Genitourinary System; Chapter 52, Disorders of the Male Genitourinary System. Other people who deserve recognition Dr. Kathryn Gaspard also deserves recognition. Dr. Gaspard has been with the book since its early editions, providing consultation and insight into the development of the book’s content and illustrations. Georgianne Heymann, who has also been with the book since its early editions, assisted in editing the manuscript and provided encouragement and support when the tasks associated with manuscript preparation became most frustrating. It is often said that a picture is worth a thousand words. This is particularly true in a book such as this, where illustrations form the basis for understanding difficult concepts. Illustrations in this book owe their origin to Carole Hilmer, who developed illustrations for the first five editions of the book, as well as Jennifer Smith, Anne Rains, and Wendy Jackelow, who continued the work of developing many new illustrations and modifying the old illustrations. To those at Lippincott Williams & Wilkins (formerly J.B. Lippincott), who first offered me this opportunity, I thank you for your support and confidence in me through the publishing process. The editorial and production staff along with reviewers and consultants offered advice and guidance that were invaluable in preparing the work. Without the students in the classes I have taught over the years, there would be no book. They deserve a special salute, for they are the inspiration upon which this book was founded. Within the ever-changing field of health care, it was through my students’ eyes that I was able to see their “real world” of patient care. They provided the questions, suggestions, and contact that directed the organization and selection of content for the book. And last, but certainly not least, I would like to acknowledge my family and my friends for what seemed to be unlimited patience, understanding, and encouragement throughout the journey. I have been very fortunate in this collective experience to have been surrounded by people that I would deem kindred spirits. Thank you all. Carol Mattson Porth

Glenn Matfin, BSc (Hons), MB, ChB, DCM, FPPM, FACE, FACP, FRCP. Chapter 30, Disorders of Blood Flow in the Systemic Circulation; Chapter 39, Disorders of Fluid and

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Contents Unit I Concepts of Health and Disease  1 1 Concepts of Health and Disease  2 CONCEPTS OF HEALTH AND DISEASE  2 Health 3 Disease 3 HEALTH AND DISEASE IN POPULATIONS  7 Epidemiology and Patterns of Disease  7 Determination of Risk Factors  8 Natural History  8 Preventing Disease  9 Evidence-Based Practice and Practice Guidelines 9

2 Concepts of Altered Health in Children  12 GROWTH AND DEVELOPMENT  13 Prenatal Growth and Development  14 Birth Weight and Gestational Age  15 INFANCY 17 Growth and Development  17 Health Problems of the Neonate  21 Health Problems of the Infant  27 EARLY CHILDHOOD  29 Growth and Development  29 Common Health Problems  30 MIDDLE TO LATE CHILDHOOD  30 Growth and Development  30 Common Health Problems  31 ADOLESCENCE 33 Growth and Development  33 Common Health Problems  35

3 Concepts of Altered Health in Older Adults 40 THE OLDER ADULT AND THEORIES OF AGING  40 Who Are Older Adults?  40 Theories of Aging  42 PHYSIOLOGIC CHANGES OF AGING  43 Integumentary Changes  43 Stature and Musculoskeletal Function  45 Cardiovascular Function  45 Respiratory Function  46 Neurologic Function  46 Special Sensory Function  46 Immune Function  47 Gastrointestinal Function  48 Renal Function  48 Genitourinary Function  49 FUNCTIONAL PROBLEMS ASSOCIATED WITH AGING 49 Functional Assessment  50 Urinary Incontinence  51 Instability and Falls  52 Sensory Impairment  53 Depression 53 Dementia 55 Delirium 56 DRUG THERAPY IN THE OLDER ADULT  57 Factors Contributing to Adverse Drug Reactions 58 Strategies to Enhance Therapeutic Effects and Prevent Harm  58

Unit II Cell Function and Growth  63 4 Cell and Tissue Characteristics  64 FUNCTIONAL COMPONENTS OF THE CELL  64 Protoplasm 65 The Nucleus  66 The Cytoplasm and Its Organelles  66 The Cytoskeleton  70 The Cell (Plasma) Membrane  72 INTEGRATION OF CELL FUNCTION AND REPLICATION 73 Cell Communication  73 Cell Receptors  74 The Cell Cycle and Cell Division  76 Cell Metabolism and Energy Sources  77 MOVEMENT ACROSS THE CELL MEMBRANE AND MEMBRANE POTENTIALS  81 Movement of Substances across the Cell Membrane 81 Membrane Potentials  83 body Tissues  87 Cell Differentiation  88 Embryonic Origin of Tissue Types  88 Epithelial Tissue  88 Connective or Supportive Tissue  93 Muscle Tissue  94 Nervous Tissue  97 Extracellular Tissue Components  98

5 Cellular Adaptation, Injur  y, and Death 101 CELLULAR ADAPTATION  101 Atrophy 102 Hypertrophy 103 Hyperplasia 103 Metaplasia 104 Dysplasia 104 Intracellular Accumulations  104 Pathologic Calcifications  105 Cell Injury and Death  106 Causes of Cell Injury  107 Mechanisms of Cell Injury  110 Reversible Cell Injury and Cell Death  112 Cellular Aging  115

6 Genetic Control of Cell Function and Inheritance 118 GENETIC CONTROL OF CELL FUNCTION  119 DNA Structure and Function  119 From Genes to Proteins  122 CHROMOSOMES 127 Cell Division  127 Chromosome Structure  128 PATTERNS OF INHERITANCE  130 Definitions 130 Genetic Imprinting  131 Mendel’s Laws  132 Pedigree 132 GENE TECHNOLOGY  133 Genetic Mapping  133 Recombinant DNA Technology  134 RNA Interference Technology  136

xv

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7 Genetic and Congenital Disorders  138 GENETIC AND CHROMOSOMAL DISORDERS 138 Single-Gene Disorders  139 Multifactorial Inheritance Disorders  144 Chromosomal Disorders  145 Mitochondrial Gene Disorders  150 DISORDERS DUE TO ENVIRONMENTAL INFLUENCES 151 Period of Vulnerability  151 Teratogenic Agents  151 Folic Acid Deficiency  154 DIAGNOSIS AND COUNSELING  155 Genetic Assessment  155 Prenatal Screening and Diagnosis  155

8 Neoplasia  160 CONCEPTS OF CELL DIFFERENTIATION AND GROWTH 161 The Cell Cycle  161 Cell Proliferation  162 Cell Differentiation  164 CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS  166 Terminology 166 Benign Neoplasms  168 Malignant Neoplasms  168 ETIOLOGY OF CANCER  174 Genetic and Molecular Basis of Cancer  174 Host and Environmental Factors  179 CLINICAL MANIFESTATIONS  183 Tissue Integrity  183 Systemic Manifestations  183 Paraneoplastic Syndromes  185 SCREENING, DIAGNOSIS, AND TREATMENT 186 Screening 186 Diagnostic Methods  187 Cancer Treatment  189 CHILDHOOD CANCERS  195 Incidence and Types  195 Biology of Childhood Cancers  196 Diagnosis and Treatment  196

Unit III Disorders of Integrative Function 201 9 Stress and Adaptation  202 HOMEOSTASIS 203 Constancy of the Internal Environment  203 Control Systems  203 Feedback Systems  204 STRESS AND ADAPTATION  204 The Stress Response  205 Coping and Adaptation to Stress  209 DISORDERS OF THE STRESS RESPONSE  212 Effects of Acute Stress  212 Effects of Chronic Stress  212 Posttraumatic Stress Disorder  212 Treatment and Research of Stress Disorders 213

10 Alterations in Temperature Regulation 216 BODY TEMPERATURE REGULATION  216 Mechanisms of Heat Production  219 Mechanisms of Heat Loss  219 INCREASED BODY TEMPERATURE  220 Fever 220 Hyperthermia 224

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DECREASED BODY TEMPERATURE  226 Hypothermia 227

11 Activity T ­ olerance and Fatigue  230 EXERCISE AND ACTIVITY TOLERANCE  230 Types of Exercise  231 Physiologic and Psychological Responses of Exercise 232 Assessment of Activity and Exercise Tolerance 236 Exercise and Activity Tolerance in Older Adults 237 ACTIVITY INTOLERANCE AND FATIGUE  238 Mechanisms of Fatigue  238 Acute Physical Fatigue  239 Chronic Fatigue  239 BED REST AND IMMOBILITY  243 Physiologic Effects of Bed Rest  243 Time Course of Physiologic Responses  247 Psychosocial Responses  247 Management of People Who Are Immobile or on Bed Rest  247

Unit IV Infection, Inflammation, and Immunity 251 12 Mechanisms of Infectious Disease  252 INFECTIOUS DISEASES  252 Terminology 252 Agents of Infectious Disease  254 MECHANISMS OF INFECTION  261 Epidemiology of Infectious Diseases  262 Portal of Entry  262 Source 263 Symptomatology 263 Disease Course  263 Site of Infection  264 Virulence Factors  265 DIAGNOSIS AND TREATMENT OF INFECTIOUS DISEASES 267 Diagnosis 267 Treatment 270 BIOTERRORISM AND EMERGING GLOBAL INFECTIOUS DISEASES  273 Bioterrorism 273 Global Infectious Diseases  274

13 Innate and Adaptive Immunity  276 THE IMMUNE RESPONSE  276 Cytokines and Their Role in Immunity  277 INNATE IMMUNITY  282 Epithelial Barriers  282 Cells of Innate Immunity  283 Pathogen Recognition  284 Soluble Mediators of Innate Immunity  286 The Complement System  287 ADAPTIVE IMMUNITY  288 Antigens 288 Cells of Adaptive Immunity  291 B Lymphocytes and Humoral Immunity  294 T Lymphocytes and Cellular Immunity  297 Lymphoid Organs  300 Active versus Passive Immunity  302 Regulation of the Adaptive Immune Response 302 DEVELOPMENTAL ASPECTS OF THE IMMUNE SYSTEM 303 Transfer of Immunity from Mother to Infant 303 Immune Response in the Older Adult  304

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Contents   xvii

14 Inflammation, Tissue Repair, and Wound Healing  306 THE INFLAMMATORY RESPONSE  306 Acute Inflammation  307 Chronic Inflammation  317 Systemic Manifestations of Inflammation  317 TISSUE REPAIR AND WOUND HEALING  319 Tissue Repair  319 Wound Healing  322

15 Disorders of the Immune Response 329 IMMUNODEFICIENCY DISORDERS  329 Humoral (B Cell) Immunodeficiencies  332 Cell-Mediated (T Cell) Immunodeficiencies  334 Combined T-Cell and B-Cell Immunodeficiencies 336 Disorders of the Complement System  337 Disorders of Phagocytosis  338 Stem Cell Transplantation  340 HYPERSENSITIVITY DISORDERS  341 Type I, Immediate Hypersensitivity Disorders 341 Type II, Antibody-Mediated Disorders  345 Type III, Immune Complex–Mediated Disorders 346 Type IV, Cell-Mediated Hypersensitivity Disorders 347 Latex Allergy  349 TRANSPLANTATION IMMUNOPATHOLOGY 350 Mechanisms Involved in Transplant Rejection 351 AUTOIMMUNE DISEASE  353 Immunologic Tolerance  353 Mechanisms of Autoimmune Disease  355 Diagnosis and Treatment of Autoimmune Disease 356

16 Acquired Immunodeficiency Syndrome 361 THE AIDS EPIDEMIC AND TRANSMISSION OF HIV INFECTION  361 Emergence of AIDS  362 Transmission of HIV Infection  362 PATHOPHYSIOLOGY AND CLINICAL COURSE 363 Molecular and Biologic Features of HIV  363 Classification and Phases of HIV Infection  366 Clinical Course  367 PREVENTION, DIAGNOSIS, AND TREATMENT 373 Prevention 374 Diagnostic Methods  374 Treatment 375 HIV INFECTION IN PREGNANCY AND IN INFANTS AND CHILDREN  376 Preventing Perinatal HIV Transmission  377 Diagnosis of HIV Infection in Children  377 Clinical Presentation of HIV Infection in Children 377

Unit V Disorders of Neural Function 381 17 Organization and Control of Neural Function 382 NERVOUS TISSUE CELLS  382 Neurons 383

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Neuroglial Cells  384 Metabolic Requirements of Nervous Tissue  386 NEUROPHYSIOLOGY 387 Action Potentials  387 Synaptic Transmission  388 Messenger Molecules  390 DEVELOPMENTAL ORGANIZATION OF THE NERVOUS SYSTEM  391 Embryonic Development  392 Segmental Organization  394 STRUCTURE AND FUNCTION OF THE SPINAL CORD AND BRAIN  400 Spinal Cord  400 The Brain  403 THE AUTONOMIC NERVOUS SYSTEM  413 Autonomic Efferent Pathways  414 Sympathetic Nervous System  414 Parasympathetic Nervous System  416 Central Integrative Pathways  417 Autonomic Neurotransmission  417

18 Somatosensor y Function, Pain, and Headache 422 ORGANIZATION AND CONTROL OF SOMATOSENSORY FUNCTION  423 Sensory Systems  423 Sensory Modalities  427 Clinical Assessment of Somatosensory Function 429 pain 430 Pain Theories  431 Pain Mechanisms and Pathways  431 Pain Threshold and Tolerance  435 Types of Pain  435 Assessment of Pain  438 Management of Pain  439 ALTERATIONS IN PAIN SENSITIVITY AND SPECIAL TYPES OF PAIN  442 Alterations in Pain Sensitivity  442 Special Types of Pain  443 HEADACHE AND ASSOCIATED PAIN  445 Headache 445 Migraine Headache  445 Cluster Headache  446 Tension-Type Headache  447 Chronic Daily Headache  447 Temporomandibular Joint Pain  448 PAIN IN CHILDREN AND OLDER ADULTS  448 Pain in Children  448 Pain in Older Adults  449

19 Disorders of Motor Function  452 ORGANIZATION AND CONTROL OF MOTOR FUNCTION 453 Organization of Movement  453 The Motor Unit  455 Spinal Reflexes  455 Motor Pathways  457 Assessment of Motor Function  457 DISORDERS OF THE MOTOR UNIT  461 Skeletal Muscle Disorders  461 Disorders of the Neuromuscular Junction  463 Lower Motor Neuron Disorders  465 Peripheral Nerve Disorders  465 DISORDERS OF THE CEREBELLUM AND BASAL GANGLIA 470 Disorders of the Cerebellum  470 Disorders of the Basal Ganglia  471 UPPER MOTOR NEURON DISORDERS  475 Amyotrophic Lateral Sclerosis  476 Multiple Sclerosis  476 Vertebral and Spinal Cord Injury  479

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20 Disorders of Brain Function  489 MANIFESTATIONS AND MECHANISMS OF BRAIN INJURY  489 Manifestations of Brain Injury  490 Mechanisms of Brain Injury  493 TRAUMATIC BRAIN INJURY  502 Primary and Secondary Brain Injuries  502 Hematomas 503 CEREBROVASCULAR DISEASE  506 Cerebral Circulation  506 Stroke (Brain Attack)  507 INFECTIONS AND NEOPLASMS  515 Infections 515 Brain Tumors  516 SEIZURE DISORDERS  519 Etiology 519 Classification 520 Diagnosis and Treatment  521 Status Epilepticus  522 Nonconvulsive Seizures  523

21 Sleep and Sleep Disorders  525 NEUROBIOLOGY OF SLEEP  525 Neural Structures and Pathways  526 The Sleep–Wake Cycle  526 Circadian Rhythms  529 Melatonin 530 SLEEP DISORDERS  531 Diagnostic Methods  531 Circadian Rhythm Disorders  532 Insomnia 533 Narcolepsy 535 Sleep-Related Movement Disorders  536 Sleep-Related Breathing Disorders  537 Parasomnias 539 SLEEP AND SLEEP DISORDERS IN CHILDREN AND OLDER ADULTS  540 Sleep and Sleep Disorders in Children  540 Sleep and Sleep Disorders in Older Adults  541

22 Disorders of Thought, Emotion, and Memory 544 PSYCHIATRIC DISORDERS  544 Incidence and Prevalence  544 The Diagnosis of Psychiatric Disorders  545 Understanding Psychiatric Disorders  545 TYPES OF PSYCHIATRIC DISORDERS  553 Schizophrenia 553 Mood Disorders  556 Anxiety Disorders  559 Substance Use Disorders  561 DISORDERS OF MEMORY AND COGNITION 562 Normal Cognitive Aging  562 Dementia 563

Unit VI Disorders of Special Sensory Function 573 23 Disorders of Visual Function  574 DISORDERS OF THE ACCESSORY STRUCTURES OF THE EYE  575 Disorders of the Eyelids  575 Disorders of the Lacrimal System  577 DISORDERS OF THE CONJUNCTIVA, CORNEA, AND UVEAL TRACT  578 Disorders of the Conjunctiva  578 Disorders of the Cornea  581 Disorders of the Uveal Tract  583 The Pupil and Pupillary Reflexes  584

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INTRAOCULAR PRESSURE AND GLAUCOMA 585 Control of Intraocular Pressure  585 Glaucoma 586 DISORDERS OF THE LENS AND LENS FUNCTION 589 Disorders of Refraction and Accommodation 589 Cataracts 590 DISORDERS OF THE VITREOUS AND RETINA 592 Disorders of the Vitreous  592 Disorders of the Retina  592 DISORDERS OF NEURAL PATHWAYS AND CORTICAL CENTERS  603 Optic Pathways  603 Visual Cortex  604 Visual Fields  604 DISORDERS OF EYE MOVEMENT  606 Extraocular Eye Muscles and Their Innervation 606 Strabismus 608 Amblyopia 610 Eye Examination in Infants and Children  610

24 Disorders of Hearing and Vestibular Function 613 DISORDERS OF THE AUDITORY SYSTEM  613 Disorders of the External Ear  613 Disorders of the Middle Ear and Eustachian Tube 615 Disorders of the Inner Ear  620 Disorders of the Central Auditory Pathways 623 Hearing Loss  623 DISORDERS OF VESTIBULAR FUNCTION  628 The Vestibular System and Vestibular Reflexes 628 Vertigo 630 Motion Sickness  631 Disorders of Peripheral Vestibular Function 631 Disorders of Central Vestibular Function  633 Diagnosis and Treatment of Vestibular Disorders 633

Unit VII Disorders of the Hematopoietic System 637 25 Blood Cells and the ­Hematopoietic System 638 COMPOSITION OF BLOOD AND FORMATION OF BLOOD CELLS  638 Plasma 639 Blood Cells  640 Formation of Blood Cells (Hematopoiesis) 643 DIAGNOSTIC TESTS  646 Blood Count  646 Erythrocyte Sedimentation Rate  646 Bone Marrow Aspiration and Biopsy  647

26 Disorders of Hemostasis  648 MECHANISMS OF HEMOSTASIS  648 Vascular Constriction  649 Formation of the Platelet Plug  649 Blood Coagulation  651 Clot Retraction  652 Clot Dissolution  652

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Contents   xix HYPERCOAGULABILITY STATES  655 Hypercoagulability Associated with Increased Platelet Function  655 Hypercoagulability Associated with Increased Clotting Activity  656 BLEEDING DISORDERS  657 Bleeding Associated with Platelet Disorders 658 Bleeding Associated with Coagulation Factor Deficiencies 660 Bleeding Associated with Vascular Disorders 661 Disseminated Intravascular Coagulation  661

27 Disorders of Red Blood Cells  665 THE RED BLOOD CELL  665 Hemoglobin Synthesis  666 Red Cell Production  667 Red Cell Destruction  668 Red Cell Metabolism and Hemoglobin Oxidation 669 Laboratory Tests  669 BLOOD TYPES AND TRANSFUSION THERAPY 671 ABO Blood Groups  671 Rh Types  671 Blood Transfusion Reactions  673 ANEMIA 673 Blood Loss Anemia  674 Hemolytic Anemias  674 Anemias of Deficient Red Cell Production 678 POLYCYTHEMIA 682 Absolute Polycythemia—Primary  682 Absolute Polycythemia—Secondary  682 AGE-RELATED CHANGES IN RED BLOOD CELLS 683 Red Cell Changes in the Neonate  683 Red Cell Changes With Aging  685

28 Disorders of White Blood Cells and Lymphoid Tissues  688 HEMATOPOIETIC AND LYMPHOID TISSUES 688 Leukocytes (White Blood Cells)  689 Bone Marrow and Hematopoiesis  689 Lymphoid Tissues  692 NONNEOPLASTIC DISORDERS OF WHITE BLOOD CELLS  693 Neutropenia (Agranulocytosis)  693 Infectious Mononucleosis  696 NEOPLASTIC DISORDERS OF LYMPHOID AND HEMATOPOIETIC ORIGIN  697 Malignant Lymphomas  697 Leukemias 701 Plasma Cell Dyscrasias  706

Unit VIII Disorders of Cardiovascular Function 711 29 Structure and Function of the Cardiovascular System  712 ORGANIZATION OF THE CIRCULATORY SYSTEM 712 Pulmonary and Systemic Circulations  713 Volume and Pressure Distribution  714 PRINCIPLES OF BLOOD FLOW  715 Relationships between Blood Flow, Pressure, and Resistance  715

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Wall Tension, Radius, and Pressure  718 Distention and Compliance  718 THE HEART AS A PUMP  719 Functional Anatomy of the Heart  719 Cardiac Cycle  723 Regulation of Cardiac Performance  725 THE SYSTEMIC CIRCULATION AND CONTROL OF BLOOD FLOW  727 Blood Vessels  727 Arterial System  728 Venous System  729 Local and Humoral Control of Blood Flow 730 THE MICROCIRCULATION AND LYMPHATIC SYSTEM 732 Structure and Function of the Microcirculation 732 Capillary–Interstitial Fluid Exchange  733 The Lymphatic System  735 NEURAL CONTROL OF CIRCULATORY FUNCTION 735 Autonomic Nervous System Regulation  736 Central Nervous System Responses  737

30 Disorders of Blood Flow in the Systemic Circulation  739 BLOOD VESSEL STRUCTURE AND FUNCTION 740 Endothelial Cells  740 Vascular Smooth Muscle Cells  741 DISORDERS OF THE ARTERIAL CIRCULATION 742 Hyperlipidemia 742 Atherosclerosis 747 Vasculitis 752 Polyarteritis Nodosa  752 Giant Cell Temporal Arteritis  753 Arterial Disease of the Extremities  753 Acute Arterial Occlusion  754 Atherosclerotic Occlusive Disease  754 Thromboangiitis Obliterans  755 Raynaud Disease and Phenomenon  755 Aneurysms 756 Aortic Aneurysms  757 Aortic Dissection  758 DISORDERS OF THE VENOUS CIRCULATION 760 Varicose Veins  761 Chronic Venous Insufficiency  762 Venous Thrombosis  762

31 Disorders of Blood Pressure Regulation 766 THE ARTERIAL BLOOD PRESSURE  766 Mechanisms of Blood Pressure Regulation 767 Blood Pressure Measurement  772 HYPERTENSION 773 Primary (Essential) Hypertension  773 Systolic Hypertension  780 Secondary Hypertension  780 Malignant Hypertension  782 High Blood Pressure in Pregnancy  782 High Blood Pressure in Children and Adolescents  784 High Blood Pressure in Older Adults  786 ORTHOSTATIC HYPOTENSION  787 Pathogenesis 787 Etiology 788 Diagnosis 789 Treatment 789

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32 Disorders of Cardiac Function  792 DISORDERS OF THE PERICARDIUM  793 Acute Pericarditis  794 Pericardial Effusion and Cardiac Tamponade 795 Constrictive Pericarditis  796 CORONARY ARTERY DISEASE  797 Coronary Circulation  797 Acute Coronary Syndrome  804 Chronic Ischemic Heart Disease  812 CARDIOMYOPATHIES 814 Primary Cardiomyopathies  814 Secondary Cardiomyopathies  818 INFECTIOUS AND IMMUNOLOGIC DISORDERS 819 Infective Endocarditis  819 Rheumatic Heart Disease  821 VALVULAR HEART DISEASE  824 Hemodynamic Derangements  824 Mitral Valve Disorders  824 Aortic Valve Disorders  827 Heart Disease in Infants and Children 829 Embryonic Development of the Heart  830 Fetal and Perinatal Circulation  831 Congenital Heart Defects  832 Kawasaki Disease  840

33 Disorders of Cardiac Conduction and Rhythm 845 CARDIAC CONDUCTION SYSTEM  845 Action Potentials  847 Electrocardiography 850 DISORDERS OF CARDIAC RHYTHM AND CONDUCTION 852 Mechanisms of Arrhythmias and Conduction Disorders 852 Types of Arrhythmias and Conduction Disorders 853 Diagnostic Methods  860 Treatment 861

34 Heart Failure and Circulatory Shock 867 HEART FAILURE  867 Pathophysiology of Heart Failure  868 Acute Heart Failure Syndromes  876 Clinical Manifestations of Heart Failure  876 Diagnosis and Treatment  878 CIRCULATORY FAILURE (SHOCK)  881 Pathophysiology of Circulatory Shock  882 Cardiogenic Shock  883 Hypovolemic Shock  885 Distributive Shock  887 Obstructive Shock  889 Complications of Shock  890 HEART FAILURE IN CHILDREN AND OLDER ADULTS 891 Heart Failure in Infants and Children  891 Heart Failure in Older Adults  893

Unit IX Disorders of Respiratory Function 897 35 Structure and Function of the Respiratory System  898 STRUCTURAL ORGANIZATION OF THE RESPIRATORY SYSTEM  898 Conducting Airways  900

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Lungs and Respiratory Airways  904 Pulmonary Vasculature and Lymphatic Supply 905 Innervation 906 Pleura 906 EXCHANGE OF GASES BETWEEN THE ATMOSPHERE AND THE LUNGS  908 Basic Properties of Gases  908 Ventilation and the Mechanics of Breathing  908 Lung Volumes  913 Pulmonary Function Studies  914 Efficiency and the Work of Breathing  915 EXCHANGE AND TRANSPORT OF GASES 916 Ventilation 916 Perfusion 917 Mismatching of Ventilation and Perfusion 918 Diffusion 919 Oxygen and Carbon Dioxide Transport  919 CONTROL OF BREATHING  924 Respiratory Center  924 Regulation of Breathing  924 Cough Reflex  926 Dyspnea 926

36 Respiratory Tract Infections, Neoplasms, and Childhood Disorders 928 RESPIRATORY TRACT INFECTIONS  929 The Common Cold  929 Rhinosinusitis 930 Influenza 932 Pneumonias 934 Tuberculosis 939 Fungal Infections  942 cancer of the lung  945 Histologic Subtypes and Pathogenesis  945 Clinical Manifestations  947 Diagnosis and Treatment  947 RESPIRATORY DISORDERS IN CHILDREN 948 Lung Development  948 Manifestations of Respiratory Disorders or Infection in the Infant or Small Child  951 Respiratory Disorders in the Neonate  951 Respiratory Infections in Children  952

37 Disorders of Ventilation and Gas Exchange 958 PHYSIOLOGIC EFFECTS OF VENTILATION AND DIFFUSION DISORDERS  959 Hypoxemia 959 Hypercapnia 962 DISORDERS OF LUNG INFLATION  963 Disorders of the Pleura  963 Atelectasis 967 OBSTRUCTIVE AIRWAY DISORDERS  968 Physiology of Airway Disease  968 Asthma 969 Chronic Obstructive Pulmonary Disease  973 Bronchiectasis 977 Cystic Fibrosis  978 CHRONIC INTERSTITIAL (RESTRICTIVE) LUNG DISEASES 981 Etiology and Pathogenesis of Interstitial Lung Diseases 981 Clinical Manifestations  981 Diagnosis and Treatment  982

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Contents   xxi Occupational and Environmental Interstitial Lung Diseases  982 Sarcoidosis 983 DISORDERS OF THE PULMONARY CIRCULATION 984 Pulmonary Embolism  984 Pulmonary Hypertension  986 Cor Pulmonale  988 ACUTE RESPIRATORY DISORDERS  988 Acute Lung Injury/Acute Respiratory Distress Syndrome 989 Acute Respiratory Failure  991

Unit X Disorders of Renal Function and Fluids and Electrolytes 997 38 Structure and Function of the Kidney 998 KIDNEY STRUCTURE AND FUNCTION  998 Gross Structure and Location  998 Renal Blood Supply  1000 The Nephron  1000 Urine Formation  1003 Regulation of Renal Blood Flow  1008 Elimination Functions of the Kidney  1010 Endocrine Functions of the Kidney  1012 Action of Diuretics  1013 TESTS OF RENAL FUNCTION  1015 Urine Tests  1015 Glomerular Filtration Rate  1016 Blood Tests  1016 Cystoscopy 1017 Ultrasonography 1017 Radiologic and Other Imaging Studies  1017

39 Disorders of Fluid and Electrolyte Balance 1019 COMPOSITION AND COMPARTMENTAL DISTRIBUTION OF BODY FLUIDS  1019 Dissociation of Electrolytes  1020 Diffusion and Osmosis  1020 Compartmental Distribution of Body Fluids 1022 Capillary–Interstitial Fluid Exchange  1023 SODIUM AND WATER BALANCE  1028 Body Water Balance  1028 Sodium Balance  1029 Mechanisms of Regulation  1030 Thirst and Antidiuretic Hormone  1030 Disorders of Sodium and Water Balance  1033 POTASSIUM BALANCE  1041 Regulation of Potassium Balance  1041 Disorders of Potassium Balance  1042 CALCIUM, PHOSPHORUS, AND MAGNESIUM BALANCE 1047 Mechanisms Regulating Calcium, Phosphorus, and Magnesium Balance  1047 Disorders of Calcium Balance  1050 Disorders of Phosphorus Balance  1054 Disorders of Magnesium Balance  1056

40 Disorders of Acid–Base Balance 1062 MECHANISMS OF ACID–BASE BALANCE  1062 Acid–Base Chemistry  1062 Metabolic Acid and Bicarbonate Production 1063 Calculation of pH  1065

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Regulation of pH  1065 Laboratory Tests  1069 DISORDERS OF ACID–BASE BALANCE  1070 Metabolic Versus Respiratory Acid–Base Disorders 1071 Compensatory Mechanisms  1071 Metabolic Acidosis  1072 Metabolic Alkalosis  1076 Respiratory Acidosis  1078 Respiratory Alkalosis  1079

41 Disorders of Renal Function  1083 CONGENITAL AND INHERITED DISORDERS OF THE KIDNEYS  1084 Congenital Disorders of the Kidneys  1084 Inherited Cystic Kidney Diseases  1084 Simple and Acquired Renal Cysts  1087 OBSTRUCTIVE DISORDERS  1088 Mechanisms of Renal Damage  1089 Renal Calculi  1090 URINARY TRACT INFECTIONS  1093 Etiology and Pathogenesis  1094 Clinical Manifestations  1095 Diagnosis and Treatment  1096 Infections in Special Populations  1096 DISORDERS OF GLOMERULAR FUNCTION 1098 Etiology and Pathogenesis of Glomerular Injury 1098 Types of Glomerular Disease  1100 Glomerular Lesions Associated with Systemic Disease 1104 TUBULOINTERSTITIAL DISORDERS  1105 Renal Tubular Acidosis  1105 Pyelonephritis 1106 Drug-Related Nephropathies  1107 MALIGNANT TUMORS OF THE KIDNEY  1108 Wilms Tumor  1108 Renal Cell Carcinoma  1109

42 Acute Renal Injury and Chronic Kidney Disease 1112 ACUTE RENAL INJURY  1112 Types of Acute Renal Injury  1113 Diagnosis and Treatment  1116 Chronic kidney disease  1117 Definition and Classification  1117 Assessment of Glomerular Filtration Rate and Other Indicators of Renal Function  1118 Clinical Manifestations  1119 Treatment 1124 CHRONIC KIDNEY DISEASE IN CHILDREN AND OLDER ADULTS  1128 Chronic Kidney Disease in Children  1128 Chronic Kidney Disease in Older Adults  1128

43 Disorders of the Bladder and Lower Urinary Tract  1132 CONTROL OF URINE ELIMINATION  1132 Bladder Structure  1132 Neural Control of Bladder Function  1133 Diagnostic Methods of Evaluating Bladder Structure and Function  1136 ALTERATIONS IN BLADDER FUNCTION  1137 Lower Urinary Tract Obstruction and Stasis 1138 Neurogenic Bladder Disorders  1139 Urinary Incontinence  1142 Cancer of the bladder  1146 Etiology and Pathophysiology  1147 Clinical Manifestations  1147 Diagnosis and Treatment  1147

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xxii   Contents

Unit XI Disorders of Gastrointestinal Function 1149 44 Structure and Function of the Gastrointestinal System  1150 STRUCTURE AND ORGANIZATION OF THE GASTROINTESTINAL TRACT  1150 Upper Gastrointestinal Tract  1151 Middle Gastrointestinal Tract  1152 Lower Gastrointestinal Tract  1152 Gastrointestinal Wall Structure  1152 MOTILITY 1155 Control of Gastrointestinal Motility  1155 Swallowing and Esophageal Motility  1156 Gastric Motility  1158 Small Intestinal Motility  1159 Colonic Motility and Defecation  1160 HORMONAL, SECRETORY, AND DIGESTIVE FUNCTIONS 1161 Gastrointestinal Hormones  1161 Gastrointestinal Secretions  1162 Intestinal Flora  1165 DIGESTION AND ABSORPTION  1165 Carbohydrate Absorption  1166 Fat Absorption  1167 Protein Absorption  1168

45 Disorders of Gastrointestinal Function 1170 COMMON MANIFESTATIONS OF GI DISORDERS ANOREXIA, NAUSEA, AND VOMITING 1171 Anorexia 1171 Nausea 1171 Retching and Vomiting  1171 DISORDERS OF THE ESOPHAGUS  1172 Congenital Anomalies  1173 Dysphagia 1173 Esophageal Diverticulum  1174 Tears (Mallory-Weiss Syndrome)  1174 Hiatal Hernia  1174 Gastroesophageal Reflux  1174 Cancer of the Esophagus  1176 DISORDERS OF THE STOMACH  1177 Gastric Mucosal Barrier  1177 Gastritis 1178 Peptic Ulcer Disease  1180 Cancer of the Stomach  1182 DISORDERS OF THE SMALL AND LARGE INTESTINES 1183 Irritable Bowel Syndrome  1184 Inflammatory Bowel Disease  1184 Infectious Enterocolitis  1190 Diverticular Disease  1192 Appendicitis 1193 Alterations in Intestinal Motility  1193 Alterations in Intestinal Absorption  1199 Neoplasms 1201

46 Disorders of Hepatobiliary and Exocrine Pancreas Function  1209 THE LIVER AND HEPATOBILIARY SYSTEM  1209 Metabolic Functions of the Liver  1212 Bile Production and Cholestasis  1214 Bilirubin Elimination and Jaundice  1215 Tests of Hepatobiliary Function  1217 DISORDERS OF HEPATIC AND BILIARY FUNCTION 1218 Hepatotoxic Disorders  1218

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Viral Hepatitis  1220 Autoimmune Hepatitis  1225 Intrahepatic Biliary Disorders  1225 Alcohol-Induced Liver Disease  1226 Cirrhosis, Portal Hypertension, and Liver Failure 1228 Cancer of the Liver  1233 DISORDERS OF THE GALLBLADDER AND EXOCRINE PANCREAS  1234 Disorders of the Gallbladder and Extrahepatic Bile Ducts  1234 Disorders of the Exocrine Pancreas  1237

47 Alterations in Nutritional Status  1244 nutritional status  1244 Energy Metabolism  1245 Energy Storage  1245 Energy Expenditure  1246 nutritional needs  1247 Dietary Reference Intakes  1247 Nutritional Needs  1248 Regulation of Food Intake and Energy Storage 1251 OVERWEIGHT AND OBESITY  1252 Body Mass Index  1252 Causes of Obesity  1252 Types of Obesity  1253 Health Risks Associated with Obesity  1253 Prevention and Treatment of Obesity  1254 UNDERNUTRITION AND EATING DISORDERS 1256 Malnutrition and Starvation  1257 Eating Disorders  1259

Unit XII Disorders of Endocrine Function 1263 48 Mechanisms of Endocrine Control 1264 THE ENDOCRINE SYSTEM  1264 Hormones 1264 Control of Hormone Levels  1268 Diagnostic Tests  1272

49 Disorders of Endocrine Control of Growth and Metabolism  1277 GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION 1277 Hypofunction and Hyperfunction  1278 Primary, Secondary, and Tertiary Disorders 1278 PITUITARY AND GROWTH DISORDERS  1278 Assessment of Hypothalamic–Pituitary Function 1278 Pituitary Tumors  1279 Hypopituitarism 1279 Growth and Growth Hormone Disorders 1280 Isosexual Precocious Puberty  1285 THYROID DISORDERS  1285 Control of Thyroid Function  1286 Hypothyroidism 1288 Hyperthyroidism 1291 DISORDERS OF ADRENAL CORTICAL FUNCTION 1293 Control of Adrenal Cortical Function 1293 Congenital Adrenal Hyperplasia  1296 Adrenal Cortical Insufficiency  1297

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Contents   xxiii Glucocorticoid Hormone Excess (Cushing Syndrome) 1299 Incidental Adrenal Mass  1300

50 Diabetes Mellitus and the Metabolic Syndrome 1303 HORMONAL CONTROL OF GLUCOSE, FAT, AND PROTEIN METABOLISM 1303 Glucose, Fat, and Protein Metabolism  1304 Glucose-Regulating Hormones  1305 DIABETES MELLITUS  1308 Classification and Etiology  1309 Clinical Manifestations of Diabetes Mellitus  1314 Diagnostic Tests  1314 Treatment 1316 Acute Complications of Diabetes  1323 Counter-Regulatory Mechanisms and the Somogyi Effect and Dawn Phenomenon 1325 Chronic Complications  1326 Infections 1330

Unit XIII Disorders of Genitourinary and Reproductive Function 1333 51 Structure and Function of the Male Genitourinary System  1334 STRUCTURE OF THE MALE REPRODUCTIVE SYSTEM 1334 Embryonic Development  1334 Testes and Scrotum  1335 Genital Duct System  1336 Accessory Organs  1336 Penis 1337 SPERMATOGENESIS AND HORMONAL CONTROL OF MALE REPRODUCTIVE FUNCTION 1338 Spermatogenesis 1338 Hormonal Control of Male Reproductive Function 1339 NEURAL CONTROL OF SEXUAL FUNCTION AND CHANGES WITH AGING  1343 Neural Control  1343 Changes with Aging  1343

52 Disorders of the Male Genitourinary System 1346 DISORDERS OF THE PENIS  1346 Congenital and Acquired Disorders  1346 Disorders of Erectile Function  1348 Cancer of the Penis  1351 DISORDERS OF THE SCROTUM AND TESTES 1351 Congenital and Acquired Disorders  1351 Infection and Inflammation  1354 Neoplasms 1355 DISORDERS OF THE PROSTATE  1356 Infection and Inflammation  1357 Hyperplasia and Neoplasms  1358

53 Structure and Function of the Female Reproductive System  1365 REPRODUCTIVE STRUCTURES  1365 External Genitalia  1365

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Internal Genitalia  1367 MENSTRUAL CYCLE  1369 Hormonal Control of the Menstrual Cycle 1370 Ovarian Follicle Development and Ovulation 1373 Endometrial Changes  1375 Cervical Mucus Changes  1375 Menopause 1375 BREASTS 1379 Structure and Function  1379 Changes During Pregnancy and Lactation 1380

54 Disorders of the Female Reproductive System 1382 DISORDERS OF THE EXTERNAL GENITALIA AND VAGINA  1383 Disorders of the External Genitalia  1383 Disorders of the Vagina  1385 DISORDERS OF THE CERVIX AND UTERUS 1386 Disorders of the Uterine Cervix  1386 Disorders of the Uterus  1389 DISORDERS OF THE FALLOPIAN TUBES AND OVARIES 1394 Pelvic Inflammatory Disease  1394 Ectopic Pregnancy  1395 Cancer of the Fallopian Tube  1396 Ovarian Cysts and Tumors  1396 DISORDERS OF PELVIC SUPPORT AND UTERINE POSITION  1400 Disorders of Pelvic Support  1400 Variations in Uterine Position  1402 MENSTRUAL DISORDERS  1403 Dysfunctional Menstrual Cycles  1403 Amenorrhea 1404 Dysmenorrhea 1404 Premenstrual Symptom Disorders  1405 DISORDERS OF THE BREAST  1406 Galactorrhea 1407 Mastitis 1407 Ductal Disorders  1407 Fibroadenoma and Fibrocystic Changes 1407 Breast Cancer  1408 INFERTILITY 1410 Male Factors  1411 Female Factors  1411 Assisted Reproductive Technologies  1412

55 Sexually Transmitted Infections  1416 INFECTIONS OF THE EXTERNAL GENITALIA 1417 Condylomata Acuminata (Genital Warts) 1417 Genital Herpes  1418 Molluscum Contagiosum  1420 Chancroid 1420 Granuloma Inguinale  1421 Lymphogranuloma Venereum  1421 VAGINAL INFECTIONS  1422 Candidiasis 1422 Trichomoniasis 1422 Bacterial Vaginosis  1423 VAGINAL–UROGENITAL–SYSTEMIC INFECTIONS 1424 Chlamydial Infections  1424 Gonorrhea 1425 Syphilis 1427

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xxiv   Contents

Unit XIV Disorders of Musculoskeletal Function 1431 56 Structure and Function of the Musculoskeletal System  1432 BONY STRUCTURES OF THE SKELETAL SYSTEM 1432 Bone Structures  1433 Bone Tissue  1435 Cartilage 1437 Hormonal Control of Bone Formation and Metabolism 1437 ARTICULATIONS AND JOINTS  1440 Tendons and Ligaments  1440 Types of Joints  1440

57 Disorders of Musculoskeletal Function: Trauma, Infection, Neoplasms 1444 INJURY AND TRAUMA OF MUSCULOSKELETAL STRUCTURES  1444 Athletic Injuries  1445 Soft Tissue Injuries  1445 Joint (Musculotendinous) Injuries  1445 Fractures 1451 Complications of Fractures and Other Musculoskeletal Injuries  1455 BONE INFECTIONS  1460 Osteomyelitis 1461 Tuberculosis of the Bone or Joint  1463 OSTEONECROSIS 1464 Etiology and Pathogenesis  1464 Clinical Manifestations, Diagnosis, and Treatment 1465 NEOPLASMS 1465 Characteristics of Bone Tumors  1465 Benign Neoplasms  1466 Malignant Bone Tumors  1466 Metastatic Bone Disease  1469

58 Disorders of Musculoskeletal Function: Developmental and Metabolic Disorders  1472 ALTERATIONS IN SKELETAL GROWTH AND DEVELOPMENT 1472 Bone Growth and Remodeling  1473 Alterations during Normal Growth Periods 1473 Hereditary and Congenital Deformities 1481 Juvenile Osteochondroses  1484 Scoliosis 1486 METABOLIC BONE DISEASE  1488 Osteopenia 1489 Osteoporosis 1489 Osteomalacia and Rickets  1493 Paget Disease  1495

59 Disorders of Musculoskeletal Function: Rheumatic Disorders  1499 SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES 1500 Rheumatoid Arthritis  1500 Systemic Lupus Erythematosus  1505 Systemic Sclerosis/Scleroderma  1508 Polymyositis and Dermatomyositis  1509

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SERONEGATIVE SPONDYLOARTHROPATHIES 1509 Ankylosing Spondylitis  1510 Reactive Arthropathies  1511 Psoriatic Arthritis  1512 Enteropathic Arthritis  1512 OSTEOARTHRITIS SYNDROME  1513 Epidemiology and Risk Factors  1513 Pathogenesis 1513 Clinical Manifestations  1516 Diagnosis and Treatment  1517 CRYSTAL-INDUCED ARTHROPATHIES  1518 Gout 1518 RHEUMATIC DISEASES IN CHILDREN AND OLDER ADULTS  1520 Rheumatic Diseases in Children  1520 Rheumatic Diseases in Older Adults  1521

Unit XV Disorders of Integumentary Function 1525 60 Structure and Function of the Skin 1526 STRUCTURE AND FUNCTION OF THE SKIN 1526 Skin Structures  1527 Skin Appendages  1533 Functions of the Skin  1534 MANIFESTATIONS OF SKIN DISORDERS 1535 Lesions and Rashes  1535 Pruritus 1535 Dry Skin  1539 Skin Variations in Dark-Skinned People  1540

61 Disorders of Skin Integrity and Function 1541 PRIMARY DISORDERS OF THE SKIN  1541 Pigmentary Skin Disorders  1542 Infectious Processes  1543 Acne and Rosacea  1549 Allergic and Hypersensitivity Dermatoses 1555 Papulosquamous Dermatoses  1559 Arthropod Infestations  1562 ULTRAVIOLET RADIATION, THERMAL, AND PRESSURE INJURY  1565 Skin Damage Caused by Ultraviolet Radiation 1566 Thermal Injury  1567 Pressure Ulcers  1571 NEVI AND SKIN CANCERS  1574 Nevi 1574 Skin Cancer  1574 AGE-RELATED SKIN MANIFESTATIONS  1578 Skin Manifestations of Infancy and Childhood  1578 Skin Manifestations and Disorders in Older Adults  1581

Appendix: Lab Values  1585 Glossary 1587 Index 1599

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Unit 1

Concepts of Health and Disease Mrs. Sora, 85 years old, was born during the Great Depression. She is a widow who has recently moved in with her daughter since her social security income was not enough to allow her to keep her own home. She presents with soreness and back pain, describing “a tingling and burning feeling on the left side of my back just above my waist.” The discomfort started about 2 days ago, and she thought it would go away. However, it has increased in intensity, and this morning she noticed a rash over the painful region. Her daughter suspects that her mother’s vision has declined, because she has had a few recent falls in the evenings. The daughter is also concerned about her mother’s loss of hearing acuity and appetite and her growing fatigue. The daughter adds that her mom was hospitalized for ­pneumonia about 4 months ago, and became very confused during the course of the illness. Mrs. Sora’s vital signs are all within normal limits (blood pressure = 122/68 mm Hg, pulse = 77, respiratory rate = 14/minute, and temperature = 98.8°F). Physical examination of the rash on Mrs. Sora’s back reveals grouped vesicular papules over the T7 left side dermatome. Discomfort is felt with light palpation. Upon further questioning Mrs. Sora says, “Yes, I had chicken pox when I was in first grade.” The rash is diagnosed as varicella-zoster virus (VZV). Mrs. Sora’s case is discussed further in Chapter 3 along with her daughter’s other concerns.

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Concepts of Health and Disease CONCEPTS OF HEALTH AND DISEASE Health Disease Etiology Pathogenesis Morphology and Histology Clinical Manifestations Diagnosis Clinical Course

HEALTH AND DISEASE IN POPULATIONS

Epidemiology and Patterns of Disease Incidence and Prevalence Morbidity and Mortality Determination of Risk Factors Cross-Sectional and Case–Control Studies Cohort Studies Natural History Preventing Disease Evidence-Based Practice and Practice Guidelines

1 Sheila C. Grossman

The term pathophysiology, which is the focus of this book, may be defined as the physiology of altered health. The term combines the words pathology and physiology. Pathology (from the Greek pathos, meaning “disease”) deals with the study of the structural and functional changes in cells, t­ issues, and organs of the body that cause or are caused by disease. Physiology deals with the functions of the human body. Thus, pathophysiology deals not only with the cellular and organ changes that occur with disease but with the effects that these changes have on total body function (Fig. 1.1). Examples of atrophy of the brain (Fig. 1.1A) and ­hypertrophy of the myocardium (Fig. 1.1B) illustrate pathophysiological changes from a cerebrovascular accident to long-standing ­unmanaged hypertension and how this impacts the myocardium. Pathophysiology also focuses on the mechanisms of the underlying disease and provides information to assist with planning preventive as well as therapeutic health care measures and practices such as following a healthy diet, exercising, and being compliant with prescribed medications. This chapter is intended to orient the reader to the concepts of health and disease, various terms that are used throughout the book, the sources of data and what they mean, and the broader aspects of pathophysiology in terms of the health and ­well-being of populations.

CONCEPTS OF HEALTH AND DISEASE After completing this section of the chapter, you should be able to meet the following objectives: •• State the World Health Organization definition of health. •• Define pathophysiology. •• Explain the meaning of reliability, validity, sensitivity, specificity, and predictive value as it relates to ­observations and tests used in the diagnosis of disease.

2

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Chapter 1  Concepts of Health and Disease    3

A

B

FIGURE 1.1  • (A) Atrophy of the frontal lobe of the brain. The gyri are thin and the sulci are extremely wide. (B) Myocardial hypertrophy. This cross section of the heart illustrates left ventricular hypertrophy due to long-standing hypertension. (From Rubin R., Strayer D. S. (2012). ­Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., pp. 2 and 4). Philadelphia, PA: Lippincott Williams & Wilkins.)

What constitutes health and disease often is difficult to ­determine because of the way different people view the topic. What is defined as health is determined by many factors, including genetics, age, gender, cultural, and ethnic differences, as well as individual, group, and governmental expectations.

Health In 1948, the Preamble to the Constitution of the World Health Organization (WHO) defined health as a “state of complete physical, mental, and social well-being and not merely the absence of disease and infirmity,” a definition that has not been amended since that time.1 Although ideal for many people, this was an unrealistic goal. The U.S. Department of Health and Human Services in Healthy People 2020 describes the determinants of health as 1. Attain lives free of preventable disease, disability, injury, and premature death 2. Achieve health equity and eliminate disparities 3. Promote good health for all 4. Promote healthy behaviors across the life span2 Every decade, the U.S. Department of Health and Human Services spearheads initiatives to facilitate the goals of the new decade in their report such as the current Healthy People 2020. These consensus reports are developed to specifically assist in preventing some health problems and to offer advice to promote health as defined by the WHO.

Disease A disease is considered an acute or chronic illness that one acquires or is born with that causes physiological dysfunction in one or more body system. Each disease generally has specific signs and symptoms that characterize its pathology and identifiable etiology. The aspects of the disease process

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include etiology, pathogenesis, morphologic changes, clinical manifestations, diagnosis, and clinical course. Etiology The causes of disease are known as etiologic factors. Among the recognized etiologic agents are biologic agents (e.g., bacteria, viruses), physical forces (e.g., trauma, burns, radiation), chemical agents (e.g., poisons, alcohol), one’s genetic inheritance, and nutritional excesses or deficits. Most disease-causing agents are nonspecific, and many different agents can cause disease of a single organ. On the other hand, a single agent or traumatic event can lead to disease of a number of organs or systems. For example, in cystic fibrosis, sickle cell anemia, and familial hypercholesterolemia, a single amino acid, transporter molecule, or receptor protein produces widespread pathology. Although a disease agent can affect more than a single organ and a number of disease agents can affect the same organ, most disease states do not have a single cause. Instead, the majority of diseases are multifactorial in origin. This is particularly true of diseases such as cancer, heart disease, and diabetes. This is illustrated in Figure 1.2, which traces the five causes of cancer and the pathophysiology that evolves from the disease mechanisms triggered by the causes. The multiple factors that predispose to a particular disease often are referred to as risk factors. One way to view the factors that cause disease is to group them into categories according to whether they were present at birth or acquired later in life. Congenital conditions are defects that are present at birth, although they may not be evident until later in life or may never manifest. Congenital conditions may be caused by genetic influences, environmental factors (e.g., viral infections in the mother, maternal drug use, irradiation, or gestational position in utero), or a combination of genetic and environmental factors. Acquired defects are those that are caused by events that occur after birth. These include injury,

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4   UNIT I  Concepts of Health and Disease Viruses Chemicals Radiation Physical agents Inherited mutations in DNA repair enzymes

Mutations

Inactivation of tumor suppressor genes Activation of oncogenes Increased sensitivity to apoptosis Aberrant DNA and histone methylation Malignant transformation

Clonal expansion

Tumor heterogeneity

Invasion

Metastasis FIGURE 1.2  •  Summary of the general mechanisms of cancer. (From Rubin R., Strayer D. S. (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 204). Philadelphia, PA: Lippincott Williams & Wilkins.)

exposure to infectious agents, inadequate nutrition, lack of oxygen, inappropriate immune responses, and neoplasia. Many diseases are thought to be the result of a genetic predisposition and an environmental event or events that serve as a trigger to initiate disease development. There are 35,000 genes in the human genome, 1 to 10 million proteins, and 2 to 3000 metabolites of the human metabolome.3 Huge advances in molecular biology and the wide variability of people have led to evolution in systems biology and ­personalized ­medicine.

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This will assist in identifying etiology of disease and in the development of individualized interventions.3 Pathogenesis While etiology describes what sets the disease process in motion, pathogenesis explains how the disease process evolves. In other words, pathogenesis is the sequence of cellular and tissue events that take place from the time of initial contact with an etiologic agent until the ultimate expression of a disease. Although etiology and pathogenesis are two terms often used interchangeably, their meanings are quite different. For example, atherosclerosis often is cited as the etiology (or cause) of coronary artery disease. In reality, the progression of the inflammatory process from a fatty streak to the occlusive vessel lesion seen in people with coronary artery disease represents the pathogenesis of the disorder. The true etiology of atherosclerosis remains largely uncertain. Morphology and Histology Morphology refers to the fundamental structure or form of cells or tissues. Morphologic changes are concerned with both the gross anatomic and microscopic changes that are characteristic of a disease. Histology deals with the study of the cells and extracellular matrix of body tissues. The most common method used in the study of tissues is the preparation of histologic ­sections— thin, translucent sections of human tissues and organs—that can be examined with the aid of a microscope. Histologic sections play an important role in the diagnosis of many types of cancer. A lesion represents a pathologic or traumatic discontinuity of a body organ or tissue. Descriptions of lesion size and characteristics often can be obtained through the use of radiographs, ultrasonography, and other imaging methods. Lesions also may be sampled by biopsy and the tissue samples subjected to histologic study. Diagnostic pathology has evolved greatly in the last few years to include immunologic and molecular biological tools for studying disease states4 (Fig. 1.3). Clinical Manifestations Diseases can manifest in a number of ways. Sometimes the condition produces manifestations, such as fever, that make it evident that the person is sick. In other cases, the condition is silent at the onset and is detected during examination for other purposes or after the disease is far advanced. Signs and symptoms are terms used to describe the structural and functional changes that accompany a disease. A symptom is a subjective complaint that is noted by the person with a disorder, whereas a sign is a manifestation that is noted by an observer. Pain, difficulty in breathing, and dizziness are symptoms of a disease. An elevated temperature, a swollen extremity, and changes in pupil size are objective signs that can be observed by someone other than the person with the disease. Signs and symptoms may be related to the primary disorder or they may represent the body’s attempt to compensate for the altered function caused by the pathologic condition. Many pathologic states are not observed directly. For example, one cannot see that a person is hemorrhaging or that he or she

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Chapter 1  Concepts of Health and Disease    5 plasma cells fibroblast

collagen

endothelial cell mast cell

elastic fiber

macrophage

B

A

eosinophil

adipose cell

lymphocytes

FIGURE 1.3 • Loose connective tissue. (A) Photomicrograph of a mesentery spread stained with ­ erhoeff’s hematoxylin to show nuclei and elastic fibers. The elastic fibers appear as blue-black, thin, V long, and branching threads without discernible beginnings or endings. Collagen fibers appear as orangestained, long, straight profiles and are considerably thicker than the elastic fibers. Nuclei of other cell types (e.g., lymphocytes, plasma cells, and macrophages) are also present but not easily identifiable. (B) Schematic diagram illustrating the components of loose connective tissue. Note the association of different cell types with the surrounding extracellular matrix, which contains blood vessels and different types of fibers. (From Ross M. H., Pawlina W. (2011). Histology: A text and atlas with correlated cell and molecular biology (6th ed., p. 159). Philadelphia, PA: Lippincott Williams & Wilkins.)

has decreased ­pulmonary gas exchange. Instead, what can be observed is the body’s attempt to compensate for changes in function brought about by the disease, such as the tachycardia that accompanies blood loss or the increased respiratory rate that occurs with pneumonia. A syndrome is a compilation of signs and symptoms (e.g., chronic fatigue syndrome) that are characteristic of a specific disease state. Complications are possible adverse extensions of a disease or outcomes from treatment. Sequelae are lesions or impairments that follow or are caused by a disease. Diagnosis A diagnosis is the designation as to the nature or cause of a health problem (e.g., bacterial pneumonia or hemorrhagic stroke). The diagnostic process requires a careful history, physical examination (PE), and diagnostic tests. The history is used to obtain a person’s account of his or her symptoms and their progression, and the factors that contribute to a ­diagnosis. The PE is done to observe for signs of altered body structure or function. The diagnostic tests are ordered to validate what is thought to be the problem. They are also performed to determine other possible health problems that were not obtained from the history and PE, but may be present given the signs and symptoms identified. The development of a diagnosis involves weighing competing possibilities and selecting the most likely one from among the conditions that might be responsible for the p­ erson’s

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clinical presentation. The clinical probability of a given disease in a person of a given age, gender, race, lifestyle, genetic background, and locality often is influential in arrival at a presumptive diagnosis. Laboratory tests and imaging are used to confirm a diagnosis. An important factor when interpreting diagnostic test results is the determination of whether they are normal or abnormal. Is a blood count above normal, within the normal range, or below normal? What is termed a normal value for a laboratory test is established statistically from test results obtained from a selected sample of people. A normal value represents the test results that fall within the bell curve or the 95% distribution. Thus, the normal levels for serum sodium (136 to 145 mEq/L) represent the mean serum level for the reference population ±2 standard deviations. The normal values for some laboratory tests are adjusted for gender, other comorbidities, or age. For example, the normal hemoglobin range for women is 12.0 to 16.0 g/dL, and for men, 14.0 to 17.4 g/dL.5 Serum creatinine level often is adjusted for age in the elderly, and normal values for serum phosphate differ between adults and children. Laboratory parameters are interpreted based on the reliability, validity, sensitivity, and specificity of the measurement.5,6 Validity refers to the extent to which a measurement tool measures what it is intended to measure. For example, the validity of blood pressure measurements obtained by a sphygmomanometer might be compared with those obtained

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6   UNIT I  Concepts of Health and Disease

by intra-arterial findings, which are measurements obtained from invasive arterial catheters inserted into radial arteries of acutely ill people. Reliability refers to the extent to which an observation, if repeated, gives the same result. A poorly calibrated blood pressure machine may give inconsistent measurements of blood pressure, particularly of pressures in either the high or low range. Reliability also depends on the person’s skill in taking the measurements. For example, blood pressure measurements may vary from one person to another because of the technique that is used (e.g., different observers may deflate the cuff at a different rate, thus obtaining different values), the way the numbers on the manometer are read, or differences in hearing acuity. In the field of clinical laboratory measurements, standardization is aimed at increasing the trueness and reliability of measured values. Standardization relies on the use of written standards, reference measurement procedures, and reference materials.7 In the United States, the Food and Drug Administration (FDA) regulates in vitro diagnostic devices, including clinical laboratory instruments, test kits, and reagents. Manufacturers who propose to market new diagnostic devices must submit information on their instrument, test kit, or reagent to the FDA, as required by existing statutes and regulations. The FDA reviews this information to decide whether the product may be marketed in the United States. Measures of sensitivity and specificity are concerned with determining how likely or how well the test or observation will identify people with the disease and people without the disease5,6 (Fig. 1.4). Sensitivity refers to the proportion of people with a disease who are positive for that disease on a given test or observation (called a true-positive result). If the result of a very sensitive test is negative, it tells us the person does not have the ­disease and the disease has been excluded or “ruled out.” Specificity refers to the proportion of people without the disease who are negative on a given test or observation (called a true-negative result). Specificity can be calculated only from among people who do

DISEASE

Positive

Present

Absent

True positive

False positive

TEST Negative

False negative

a

b

c

d True negative

FIGURE 1.4  •  The relationship between a diagnostic test result and the occurrence of disease. There are two possibilities for the test result to be correct (true positive and true negative) and two possibilities for the result to be incorrect (false positive and false negative). (From Fletcher R. H., Fletcher S. W. (2005). Clinical epidemiology: The essentials (4th ed., p. 36). Philadelphia, PA: Lippincott Williams & Wilkins.)

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not have the disease. A test that is 95% specific correctly identifies 95 of 100 normal people. The other 5% are false-­positive results. A false-positive test result can be unduly stressful for the person being tested, whereas a false-negative test result can delay ­diagnosis and jeopardize the outcome of treatment. Predictive value is the extent to which an observation or test result is able to predict the presence of a given disease or condition.8 A positive predictive value refers to the proportion of true-positive results that occurs in a given population. In a group of women found to have “suspect breast nodules” in a cancer screening program, the proportion later determined to have breast cancer would constitute the positive predictive value. A negative predictive value refers to the true-negative observations in a population. In a screening test for breast cancer, the negative predictive value represents the proportion of women without suspect nodules who do not have breast cancer. Although predictive values rely in part on sensitivity and specificity, they depend more heavily on the prevalence of the condition in the population. Despite unchanging sensitivity and specificity, the positive predictive value of an observation rises with prevalence, whereas the negative predictive value falls. Clinical Course The clinical course describes the evolution of a disease. A ­disease can have an acute, subacute, or chronic course. An acute disorder is one that is relatively severe, but self-limiting. Chronic disease implies a continuous, long-term process. A chronic disease can run a continuous course or can present with exacerbations (aggravation of symptoms and severity of the disease) and remissions (a period during which there is a decrease in severity and symptoms). Subacute disease is intermediate or between acute and chronic. It is not as severe as an acute disease and not as prolonged as a chronic disease. The spectrum of disease severity for infectious diseases, such as hepatitis B, can range from preclinical to persistent chronic infection. During the preclinical stage, the disease is not clinically evident but is destined to progress to clinical disease. As with hepatitis B, it is possible to transmit a virus during the preclinical stage. Subclinical disease is not clinically apparent and is not destined to become clinically apparent. It is diagnosed with antibody or culture tests. Most cases of tuberculosis are not clinically apparent, and evidence of their presence is established by skin tests. Clinical disease is manifested by signs and symptoms. A persistent chronic infectious disease persists for years, sometimes for life. Carrier status refers to a person who harbors an organism but is not infected, as evidenced by antibody response or clinical manifestations. This person still can infect others. Carrier status may be of limited duration or it may be chronic, lasting for months or years.

IN SUMMARY The term pathophysiology, which is the focus of this book, may be defined as the physiology of altered health. A disease has been defined as any deviation from or interruption of the

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Chapter 1  Concepts of Health and Disease    7

normal structure or function of any part, organ, or system of the body that is manifested by a characteristic set of symptoms or signs and whose etiology, pathology, and prognosis may be known or unknown. The causes of disease are known as etiologic factors. Pathogenesis describes how the disease process evolves. Morphology refers to the structure or form of cells or tissues; morphologic changes are changes in structure or form that are characteristic of a disease. A disease can manifest in a number of ways. A symptom is a subjective complaint, such as pain or dizziness, whereas a sign is an observable manifestation, such as an elevated temperature or a reddened, sore throat. A syndrome is a compilation of signs and symptoms that are characteristic of a specific disease state. A diagnosis is the designation as to the nature and cause of a health problem. Health care providers need to perform comprehensive histories and PEs and validate their findings with diagnostic tests, including laboratory tests, imaging studies (e.g., CT scans), and other tests. The value of many diagnostic tests is based on their reliability and validity, as well as their sensitivity and specificity. Having a comprehensive understanding of pathophysiology will assist the health care provider to best identify problems during the history and PE and to use laboratory data as further validation.7 The clinical course of a disease describes its evolution. It can be acute (relatively severe, but self-limiting), chronic (continuous or episodic, but taking place over a long period), or subacute (not as severe as acute or as prolonged as chronic). Within the disease spectrum, a disease can be designated preclinical, or not clinically evident; subclinical, not clinically apparent and not destined to become clinically apparent; or clinical, characterized by signs and symptoms.

HEALTH AND DISEASE IN POPULATIONS After completing this section of the chapter, you should be able to meet the following objectives: •• Define the term epidemiology. •• Compare the meaning of the terms incidence and prevalence as they relate to measures of disease frequency. •• Differentiate primary, secondary, and tertiary levels of prevention.

The health of people is closely linked to the health of the community and to the population it encompasses. The ability to traverse continents in a matter of hours has opened the world to issues of populations at a global level. Diseases that once were confined to local areas of the world now pose a threat to populations throughout the world. As we move through the 21st century, we are continually reminded that the health care system and the services it delivers are targeted to particular populations. Managed care systems

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are focused on a population-based approach to planning, delivering, providing, and evaluating health care. The focus of health care also has begun to emerge as a partnership in which people are asked to assume greater responsibility for their own health.

Epidemiology and Patterns of Disease Epidemiology is the study of disease occurrence in human populations.8 It was initially developed to explain the spread of infectious diseases during epidemics and has emerged as a science to study risk factors for multifactorial diseases, such as heart disease and cancer. Epidemiology looks for patterns of people affected with a particular disorder, such as age, race, dietary habits, lifestyle, or geographic location. In contrast to biomedical researchers who study the mechanisms of disease production, epidemiologists are more concerned with whether something happens than how it happens. For example, the ­epidemiologist is more concerned with whether smoking itself is related to cardiovascular disease and whether the risk of heart disease decreases when smoking ceases. On the other hand, the biomedical researcher is more concerned about the causative agent in cigarette smoke and the pathway by which it contributes to heart disease. Much of our knowledge about disease comes from epidemiologic studies. Epidemiologic methods are used to determine how a disease is spread, how to control it, how to prevent it, and how to eliminate it. Epidemiologic methods also are used to study the natural history of disease, to evaluate new preventive and treatment strategies, to explore the impact of different patterns of health care delivery, and to predict future health care needs. As such, epidemiologic studies serve as a basis for clinical decision making, allocation of health care dollars, and development of policies related to public health issues. Incidence and Prevalence Measures of disease frequency are an important aspect of epidemiology. They establish a means for predicting what diseases are present in a population and provide an indication of the rate at which they are increasing or decreasing. A disease case can be either an existing case or the number of new episodes of a particular illness that is diagnosed within a given period. Incidence reflects the number of new cases arising in a population at risk during a specified time. The population at risk is considered to be people without the disease but who are at risk for developing it. It is determined by dividing the number of new cases of a disease by the population at risk for development of the disease during the same period (e.g., new cases per 1000 or 100,000 people in the population who are at risk). The cumulative incidence estimates the risk of developing the disease during that period of time. Prevalence is a measure of existing disease in a population at a given point in time (e.g., number of existing cases divided by the current population).8 The prevalence is not an estimate of risk of developing a disease because it is a function of both new cases and how long the cases remain in the population. Incidence and prevalence are always reported as rates (e.g., cases per 100 or cases per 100,000).

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8   UNIT I  Concepts of Health and Disease

Morbidity and Mortality Morbidity and mortality statistics provide information about the functional effects (morbidity) and death-producing (mortality) characteristics of a disease. These statistics are useful in terms of anticipating health care needs, planning of public education programs, directing health research efforts, and allocating health care dollars. Morbidity describes the effects an illness has on a person’s life. Many diseases, such as arthritis, have low death rates but a significant impact on a person’s life. Morbidity is concerned not only with the occurrence or incidence of a ­disease but with persistence and the long-term consequences of the disease. Mortality statistics provide information about the causes of death in a given population. In most countries, people are legally required to record certain facts such as age, gender, and cause of death on a death certificate. Internationally agreed on classification procedures (the International Classification of ­ Diseases [ICD] by the WHO) are used for coding the cause of death, and the data are expressed as death rates.1 Crude mortality rates (i.e., number of deaths in a given period) do not account for age, gender, race, socioeconomic status, and other factors. For this reason, mortality often is expressed as death rates for a specific population, such as the infant mortality rate. Mortality also can be described in terms of the leading causes of death according to age, gender, race, and ethnicity. For example, among all people 65 years of age and older, the five leading causes of death in the United States are heart disease, cerebrovascular disease, malignant disease, chronic lower respiratory disease, and accidents.9

Determination of Risk Factors Conditions suspected of contributing to the development of a disease are called risk factors. They may be inherent to the person (high blood pressure or overweight) or external (smoking or drinking alcohol). There are different types of studies used to determine risk factors, including cross-sectional studies, case–control studies, and cohort studies. Cross-Sectional and Case–Control Studies Cross-sectional studies use the simultaneous collection of information necessary for classification of exposure and outcome status. They can be used to compare the prevalence of a disease in those with the factor (or exposure) with the prevalence of a disease in those who are unexposed to the factor, for example, by comparing the prevalence of coronary heart disease in smokers and nonsmokers. Case–control studies are designed to compare people known to have the outcome of interest (cases) and those known not to have the outcome of interest (controls).8 Information on exposures or characteristics of interest is then collected from people in both groups. For example, the characteristics of maternal alcohol consumption in infants born with fetal alcohol syndrome (cases) can be compared with those in infants born without the syndrome (controls). Cohort Studies A cohort is a group of people who were born at approximately the same time or share some characteristics of interest.8 People

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enrolled in a cohort study (also called a longitudinal study) are followed over a period of time to observe a specific health outcome. A cohort may consist of a single group of people chosen because they have or have not been exposed to suspected risk factors. For example, two groups specifically selected because one has been exposed and the other has not or a single exposed group in which the results are compared with the general population. Framingham Study. One of the best-known examples of a cohort study is the Framingham Study, which was carried out in Framingham, Massachusetts.10 Framingham was selected because of the size of the population, the relative ease with which the people could be contacted, and the stability of the population in terms of moving into and out of the area. This longitudinal study, which began in 1950, was set up by the U.S. Public Health Service to study the characteristics of people who would later develop coronary heart disease. The study consisted of 5000 persons, between 30 and 59 years of age, selected at random and followed for an initial period of 20 years. During this time it was predicted that 1500 of them would develop coronary heart disease. The advantage of such a study is that it can explore a number of risk factors at the same time and determine the relative importance of each. Another advantage is that the risk factors can be related later to other diseases such as stroke. Nurses’ Health Study. Another well-known cohort study is the Nurses’ Health Study, which was developed by Harvard University and Brigham and Women’s Hospital. The study began in 1976 with a cohort of 121,700 female nurses, 30 to 55  years of age, living in the United States.11 The study expanded in 1989 to include a group of 238,000 female nurse participants.11 Initially designed to explore the relationship between oral contraceptives and breast cancer, nurses in the study have provided answers to detailed questions about their menstrual cycle, smoking habits, diet, weight and waist measurements, activity patterns, health problems, and medication use. They have collected urine and blood samples and even provided researchers with their toenail clippings. In selecting the cohort, it was reasoned that nurses would be well organized, accurate, and observant in their responses and that physiologically they would be no different from other groups of women. It also was anticipated that their childbearing, eating, and smoking patterns would be similar to those of other working women.

Natural History The natural history of a disease refers to the progression and projected outcome of the disease without medical intervention. By studying the patterns of a disease over time in populations, epidemiologists can better understand its natural history. Knowledge of the natural history can be used to determine disease outcome, establish priorities for health care services, determine the effects of screening and early detection programs on disease outcome, and compare the results of new treatments with the expected outcome without treatment. There are some diseases for which there are no effective treatment methods available, or the current treatment measures

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Chapter 1  Concepts of Health and Disease    9

are effective only in certain people. In this case, the natural history of the disease can be used as a predictor of outcome. For example, the natural history of hepatitis C indicates that 80% of people who become infected with the virus fail to clear the virus and progress to chronic infection.12 Information about the natural history of a disease and the availability of effective treatment methods provides directions for preventive measures. In the case of hepatitis C, careful screening of blood donations and education of intravenous drug abusers can be used to prevent transfer of the virus. At the same time, scientists are striving to develop a vaccine that will prevent infection in people exposed to the virus. The development of vaccines to prevent the spread of infectious diseases such as polio and hepatitis B undoubtedly has been motivated by knowledge about the natural history of these diseases and the lack of effective intervention measures. With other diseases, such as breast ­cancer, early detection through use of breast self-examination and mammography increases the chances for a cure. Prognosis refers to the probable outcome and prospect of recovery from a disease. It can be designated as chances for full recovery, possibility of complications, or anticipated survival time. Prognosis often is presented in relation to treatment options, that is, the expected outcomes or chances for survival with or without a certain type of treatment. The prognosis associated with a given type of treatment usually is ­presented along with the risk associated with the treatment.

Preventing Disease Basically, leading a healthy life contributes to the prevention of disease. There are three fundamental types of prevention— primary prevention, secondary prevention, and tertiary prevention8 (Fig. 1.5). It is important to note that all three levels are aimed at prevention. Primary prevention is directed at keeping disease from occurring by removing all risk factors. Examples of primary prevention include the administration of folic acid to pregnant women and women who may become pregnant to prevent fetal neural tube defects, giving immunizations to children to prevent communicable disease, and counseling people to adopt healthy lifestyles as a means of preventing heart disease.8 Primary prevention is often accomplished outside the health care system at the community level. Some primary prevention measures are Clinical diagnosis

Onset

NO DISEASE

ASYMPTOMATIC DISEASE

CLINICAL COURSE

Primary

Secondary

Tertiary

Remove risk factors

Early detection and treatment

Reduce complications

FIGURE 1.5 • Levels of prevention. Primary prevention prevents ­disease from occurring. Secondary prevention detects and cures disease in the asymptomatic phase. Tertiary prevention reduces complications of disease. (From Fletcher R. H., Fletcher S. W. (2005). Clinical epidemiology: The essentials (4th ed., p. 149). Philadelphia, PA: Lippincott Williams & Wilkins.)

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mandated by law (e.g., wearing seat belts in automobiles and helmet use on motorcycles). Other primary prevention activities (e.g., use of earplugs or dust masks) occur in specific occupations. Secondary prevention detects disease early when it is still asymptomatic and treatment measures can effect a cure or stop the disease from progressing. The use of a Papanicolaou (Pap) smear for early detection of cervical cancer is an ­example of secondary prevention. Screening also includes history taking (asking if a person smokes), PE (blood pressure measurement), laboratory tests (cholesterol level determination), and other procedures (colonoscopy) that can be “applied ­reasonably rapidly to asymptomatic people.”8 Most secondary prevention is done in clinical settings. All types of health care professionals (e.g., physicians, nurses, dentists, audiologists, optometrists) participate in secondary prevention. Tertiary prevention is directed at clinical interventions that prevent further deterioration or reduce the complications of a disease once it has been diagnosed. An example is the use of β-adrenergic drugs to reduce the risk of death in people who have had a heart attack. The boundaries of tertiary prevention go beyond treating the problem with which the person presents. In people with diabetes, for example, tertiary prevention requires more than good glucose control. It also includes provision for regular ophthalmologic examinations for early detection of retinopathy, education for good foot care, and treatment for other cardiovascular risk factors such as hyperlipidemia.8 Tertiary prevention measures also include measures to limit physical impairment and the social consequences of an illness. Most tertiary prevention programs are located within health care systems and involve the services of a number of different types of health care professionals.

Evidence-Based Practice and Practice Guidelines Evidence-based practice and evidence-based practice guidelines have gained popularity with clinicians, public health practitioners, health care organizations, and the public as a means of improving the quality and efficiency of health care.13 Their development has been prompted, at least in part, by the enormous amount of published information about diagnostic and treatment measures for various disease conditions as well as demands for better and more cost-effective health care. Evidence-based practice refers to making decisions in health care based on scientific data that has shown a specific way of managing a disease, patient symptoms, and complaints. Using evidence-based practice mandates that health care providers cannot practice according to only “their” way or according to “how it has always been done before.” Evidence-based practice is based on the integration of the individual clinical expertise of the practitioner with the best external clinical evidence from systematic research.13 The term clinical expertise implies the proficiency and judgment that individual clinicians gain through clinical experience and clinical practice. The best external clinical evidence relies on the identification of clinically relevant research, often from the basic sciences, but especially from patient-centered

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10   UNIT I  Concepts of Health and Disease

clinical studies that focus on the accuracy and precision of diagnostic tests and methods, the power of prognostic indicators, and the effectiveness and safety of therapeutic, rehabilitative, and preventive regimens. Clinical practice guidelines are systematically developed statements intended to inform practitioners and people in making decisions about health care for specific clinical circumstances.6,13 Providers not only should review but must weigh various outcomes, both positive and negative, and make recommendations. Guidelines are different from systematic reviews. They can take the form of algorithms, which are ­step-by-step methods for solving a problem, written directives for care, or a combination thereof. The development of evidence-based practice guidelines often uses methods such as meta-analysis to combine evidence from different studies to produce a more precise estimate of the accuracy of a diagnostic method or the effects of an intervention method.14 Development of evidence-based practice guidelines requires review. Those who should review the guidelines include practitioners with expertise in clinical content, who can verify the completeness of the literature review and ensure clinical sensibility; experts in guideline development who can examine the method by which the guideline was developed; and potential users of the guideline.13 Once developed, practice guidelines must be continually reviewed and changed to keep pace with new research findings and new diagnostic and treatment methods. For example, both the Guidelines for the Prevention, Evaluation, and Treatment of High Blood Pressure,7 first developed in 1972 by the Joint National Committee, and the Guidelines for the Diagnosis and Management of Asthma,15 first developed in 1991 by the Expert Panel, have undergone multiple revisions as new evidence from research has evolved. Evidence-based practice guidelines, which are intended to direct patient care, are also important in directing research into the best methods of diagnosing and treating specific health problems. For example, health care providers use the same c­ riteria for diagnosing the extent and severity of a particular condition such as hypertension with the proven guidelines for hypertension (The 7th Report of the Joint National Committee on Prevention, Detection, and Evaluation, and Treatment of High Blood Pressure [JNC 7]). Providers also use the same protocols for treatment with their hypertension patients until new data supports a change such as the use of new pharmacological agents.

IN SUMMARY Epidemiology refers to the study of disease in populations. It looks for patterns such as age, race, and dietary habits of people who are affected with a particular disorder. These patterns are used to determine under what circumstances the particular disorder will occur. Incidence is the number of new cases arising in a given population during a specified time. Prevalence is the number of people in a ­population

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who have a particular disease at a given point in time or period. Incidence and prevalence are reported as proportions or rates (e.g., cases per 100 or 100,000 population). Morbidity describes the effects an illness has on a person’s life. It is concerned with the incidence of disease as well as its persistence and long-term consequences. Mortality, or death, statistics provide information about the causes of death in a given population. Conditions suspected of contributing to the development of a disease are called risk factors. Studies used to determine risk factors include cross-sectional studies, case–­control studies, and cohort studies. The natural history refers to the p­ rogression and projected outcome of a disease without m ­ edical intervention. Prognosis is the term used to designate the probable outcome and prospect of recovery from a disease. The three fundamental types of prevention are primary prevention, secondary prevention, and tertiary prevention. Primary prevention, such as immunizations, is directed at removing risk factors so disease does not occur. Secondary prevention, such as a Pap smear, detects disease when it still is asymptomatic and curable with treatment. Tertiary prevention, such as use of β-adrenergic drugs to reduce the risk of death in persons who have had a heart attack, focuses on clinical interventions that prevent further deterioration or reduce the complications of a disease. Evidence-based practice and evidence-based practice guidelines are mechanisms that use the current best evidence to make decisions about the health care of people. They are based on the expertise of the individual practitioner integrated with the best clinical evidence from systematic review of credible research studies. Practice guidelines may take the form of algorithms, which are step-by-step methods for solving a problem, written directives, or a combination thereof. References 1. World Health Organization. (2003). About WHO: Definition of health; disease eradication/elimination goals. [Online]. Available: www.who.int/ about/definition/en/. Accessed January 12, 2011. 2. U. S. Department of Health and Human Services. (2010). Healthy People 2020—The mission, vision, and goals of 2020. [Online]. Available: http:// www.healthypeople.gov/2020/TopicsObjectives2020/pdfs/HP2020_brochure.pdf. Accessed January 22, 2011. 3. Naylor S., Chen J. (2010). Unraveling human complexity and disease with systems biology and personalized medicine. Personalized Medicine 7(3), 275–289. 4. Kumar V., Abbas A., Fausto N. (2005). Robbins and Cotran pathologic basis of disease (7th ed., p. 4). Philadelphia, PA: Elsevier Saunders. 5. Fischbach F., Dunning M. B. (2009). A manual of laboratory and ­diagnostic tests (8th ed., pp. 12–13, 96). Philadelphia, PA: Lippincott Williams & Wilkins. 6. Andreoli T. E., Benjamin I. J., Griggs R. C., et al. (2010). Andreoli and Carpenter’s Cecil essentials of medicine (8th ed., pp. 16–18). Philadelphia, PA: Elsevier Saunders. 7. Wians F. H. (2009). Clinical laboratory tests: Which, why and what do the results mean? Lab Medicine 40(2), 105–113. 8. Fletcher R. H., Fletcher S. W. (2005). Clinical epidemiology: The essentials (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 9. Centers for Disease Control and Prevention. (2009). FastStats. Death, percent of deaths, and death rates for 15 leading causes of death in selected

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Chapter 1  Concepts of Health and Disease    11 age groups by race and sex: United States 2009. [Online]. Available: http://www.cdc.gov/nchs/fastats/lcod.htm C. Accessed January 26, 2011. 10. Framingham Heart Study. (2001). Framingham Heart Study: Design, rationale, objectives, and research milestones. [Online]. Available: www. nhlbi.nih.gov/about/framingham/design.htm. Accessed January 6, 2011. 11. Channing Laboratory. (2008). The Nurse’s Health Study. [Online]. Available: http://www.channing.harvard.edu/nhs/. Accessed January 29, 2011. 12. Dillon J. (2007). Clinical update: Management of Hepatitis C. Primary Health Care 17(5), 25–29. 13. Panesar S. S., Philippon M. J., Bhandari M. (2010). Principles of evidencebased medicine. Orthopedic Clinics of North America 41(2), 131–138.

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14. Nestoriuc Y., Kriston L., Rief W. (2010). Meta analysis as the core of evidence based behavioral medicine: Tools and pitfalls of a statistical approach. Current Opinion in Psychiatry 23(2), 145–150. 15. National Asthma Education and Prevention Program. (2007). Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. [Online]. Available: http://www.aanma.org/advocacy/guidelines-for-the-diagnosisand-management-of-asthma/#Guidelines. Accessed May 22, 2013.

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Concepts of Altered Health in Children GROWTH AND DEVELOPMENT

Prenatal Growth and Development Embryonic Development Fetal Development Birth Weight and Gestational Age Abnormal Intrauterine Growth Assessing Gestational Age

INFANCY

Growth and Development Length and Head and Chest Circumference Organ Systems Health Problems of the Neonate Distress at Birth and the Apgar Score Neonatal Hypoglycemia Neonatal Jaundice/Hyperbilirubinemia Birth Injuries Health Problems of the Premature Infant Health Problems of the Infant Nutritional Disturbances Irritable Infant Syndrome or Colic Failure to Thrive Sudden Unexpected Infant Death/Sudden Infant Death Syndrome Injuries Infectious Diseases

EARLY CHILDHOOD

Growth and Development Common Health Problems Injury Infectious Diseases Child Maltreatment

MIDDLE TO LATE CHILDHOOD Growth and Development Common Health Problems Tooth Decay Injury and Illness Overweight and Obesity

ADOLESCENCE

Growth and Development Common Health Problems Injury Suicide Cancer Risky Sexual Behavior and Adolescent Pregnancy Substance Abuse

2 Eileen R. O’Shea

Children are not miniature adults. Physical and p­ sychological maturation and development strongly influence the type of illnesses children experience and their responses to these illnesses. Although many signs and symptoms are the same in persons of all ages, some diseases and complications are more likely to occur in the child. This chapter provides an overview of the developmental stages of childhood and the related health care needs of children. Specific diseases are presented in the different chapters throughout the book. In the late 19th century, the infant mortality rate was 200  deaths per 1000 live births.1 Infectious diseases were rampant, and children, with their immature and inexperienced immune systems and their frequent exposure to other infected children, were especially vulnerable. To date, infant mortality rates in the United States have decreased significantly as the result of several factors, including •• Introduction of antimicrobial agents •• Infectious disease control •• Nutritional and technologic advances •• Collaborative prevention initiatives sponsored by federal and state programs, local health departments, the private sector, and the community2 However, the US record low of 6.4 infant deaths per 1000 live births in 2009 was higher than that of many other industrialized countries in the world.3,4 Also of concern is the difference in mortality rates for white and nonwhite infants. NonHispanic black and American Indian/Alaska Native infants have consistently had a higher mortality rate than those of other racial or ethnic groups.4 The greatest disparity exists for non-Hispanic black infants. In 2006, the infant death rate for non-Hispanic black infants averaged 13.4 per 1000 live births in contrast to non-Hispanic white infants whose death rate averaged 5.6 per 1000.3 One of the more perplexing causes of infant mortality is the incidence of preterm birth and low birth weight (LBW) infants among women of all races and classes. Reasons for the disparities and incidence of preterm and LBW newborns are related to the lack of prenatal care among non-Hispanic

12

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Chapter 2  Concepts of Altered Health in Children    13

black women and due to the number of twin, triplet, and h­ igher-order multiple births among white women.2,5

GROWTH AND DEVELOPMENT After completing this section of the chapter, you should be able to meet the following objectives: •• Characterize the use of percentiles to describe growth and development during infancy and childhood. •• Describe the major events that occur during prenatal development from fertilization to birth. •• Define the terms low birth weight, small for gestational age, and large for gestational age. The terms growth and development describe an ongoing dynamic process that begins with a fertilized ovum and continues throughout the infant, childhood, and adolescent periods until adulthood is achieved. Growth describes physical changes in body size as a whole or in its individual parts. Development, on the other hand, embraces other aspects of growth, such as changes in capabilities, acquisitions of skills, and psychosocial behaviors. Skill acquisition occurs in a standard fashion— from simple to complex and from general to the specific.6 In addition, pediatric development progresses in a predictable sequence—from head to toe (cephalocaudal) and from midline to the periphery (proximodistal)6 (Fig. 2.1). Each phase of development builds upon previous successes in order to achieve a higher-level skill. For example, the infant must first learn to roll over before he or she is able to sit up. Likewise, the toddler must learn to stand before he or she can walk. Growth and development encompass a complex interaction between genetic and environmental influences, such as nutrition and sensory stimulation.6,7 The experience of each child is unique, and the patterns of growth and development may be profoundly different for individual children within the context of what is considered normal. Because of the wide variability, these norms often can be expressed only in statistical terms. Evaluation of growth and development requires comparison of a child’s growth and development with a standard. Statistics are calculations derived from measurements that are used to describe the sample measured or to make predictions about the rest of the population represented by the sample. Because all children grow and develop at different rates, the standard must somehow take this individual variation into account. The standard typically is derived from measurements made on a sample of children deemed representative of the total population. When multiple measurements of biologic variables such as height, weight, head circumference, and blood pressure are made, most values fall around the center or middle of all the values. Plotting the data on a graph yields a bell-shaped curve, which depicts the normal distribution of these continuously variable values. The mean and standard

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FIGURE 2.1 • The child’s pattern of growth is in a head-to-toe ­ irection, or cephalocaudal, and in an inward-to-outward pattern called d proximodistal. (From Bowden V. R., Greenberg C. S. (2010). Children and their families: The continuum of care (2nd ed., p. 77). Philadelphia, PA: Lippincott Williams & Wilkins.)

deviation are common statistics used in describing the characteristics of a population. The mean represents the average of the measurements. It is the sum of the values divided by the number of values. A normal bell-shaped curve is symmetric, with the mean falling in the center of the curve and one half of the values falling on either side of the mean. The standard deviation determines how far a value varies or deviates from the mean. The points one standard deviation above and below the mean include 68% of all values, two standard deviations 95% of all values, and three standard deviations 99.7% of all values.7 If a child’s height is within one standard deviation of the mean, he or she is as tall as 68% of children in the population. If a child’s height is greater than three standard deviations above the mean, he or she is taller than 99.7% of children in the population. The bell-shaped curve can also be marked by percentiles, which are useful for comparison of an individual’s values with other values. When quantitative data are arranged in ascending and descending order, a middle value called the median can be described, with one half (50%) of the values falling on either side. The values can be further divided into percentiles. A percentile is a number that indicates the percentage of values for the population that are equal to or below the number. Percentiles are used most often to compare an i­ndividual’s

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14   UNIT I  Concepts of Health and Disease

value with a set of norms. They are used e­xtensively to develop and interpret physical growth charts and measurements of ability and intelligence. Utilizing standardized growth charts can provide health professionals with a means to measure what is a normal growth trajectory of children or alert them to what is an atypical pattern.8 Currently, the United States uses two different growth charts based on the child’s age. The Centers for Disease Control and Prevention (CDC) recommends that the World Health Organization (WHO) (2006) growth chart be used to measure children ages 0 to 2 years and the 2000 CDC growth chart be utilized for all children older than 2.8 The WHO (2006) charts differ from previously used CDC growth charts in that the WHO charts were developed as the outcome of a rigorous longitudinal study, in which an international sample of children from diverse ethnic groups was sampled.8–12 Because the WHO charts were developed based on a global sample of children, they can be applied to children regardless of ethnicity, socioeconomic status, and type of feeding.12 Findings from recent studies support that the WHO growth charts provide a more sensitive indicator, which allows for earlier intervention in the very young age groups.13–15 Growth charts for children can be accessed via the CDC Web site: http://www.cdc.gov/growthcharts/data_tables.htm.

Prenatal Growth and Development Human development is considered to begin with f­ ertilization, the union of sperm and ovum resulting in a zygote (Fig. 2.2). The process begins with the intermingling of a haploid number of paternal (23, X or Y) and maternal (23, X) chromosomes in the ampulla of the oviduct that fuse to form a zygote.16,17 Within 24 hours, the unicellular organism becomes a two-cell organism and, within 72 hours, a 16-cell organism called a morula. This series of mitotic divisions is called cleavage. During cleavage, the rapidly developing cell mass travels down the oviduct to the uterus by a series of peristaltic Fertilization

Cleavage

Gastrulation

Organogenesis

Implantation

FIGURE 2.2  •  Milestones in embryonic development.

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movements. Shortly after entering the uterus (about 4 days after fertilization), the morula is separated into two parts by fluid from the uterus. The outer layer gives rise to the placenta (trophoblast), and the inner layer gives rise to the embryo (embryoblast). The structure is now called a blastocyst. By the 6th day, the blastocyst attaches to the endometrium. This is the beginning of implantation, and it is completed during the 2nd week of development.16,18 Prenatal development is divided into two main periods. The first, or embryonic, period begins during the 2nd week and continues through the 8th week after fertilization.17,18 During the embryonic period, the main organ systems are developed, and many function at a minimal level. The second, or fetal period, begins during the 9th week. During the fetal period, the growth and differentiation of the body and organ systems occur. Embryonic Development Embryonic development progresses through three stages.16 During the first stage, growth occurs through an increase in cell numbers and the elaboration of cell products. The second stage is one of morphogenesis (development of form), which includes massive cell movement. During this stage, the movement of cells allows them to interact with each other in the formation of tissues and organs. The third stage is the stage of differentiation or maturation of physiologic processes. Completion of differentiation results in organs that are capable of performing specialized functions. Embryonic development begins during the 2nd week of gestation with implantation of the blastocyst. As implantation of the blastocyst progresses, a small space appears in the embryoblast, which is the primordium of the amniotic cavity. Concurrently, morphologic changes occur in the embryoblast that result in formation of a flat, almost circular bilaminar plate of cells called the embryonic disk. The embryonic disk, which forms the embryo proper, gives rise to all three germ layers of the embryo (i.e., ectoderm, mesoderm, endoderm). The 3rd week is a period of rapid development, noted for the conversion of the bilaminar embryonic disk into a trilaminar embryonic disk through a process called gastrulation.16–18 The ectoderm differentiates into the epidermis and nervous system, and the endoderm gives rise to the epithelial linings of the respiratory passages, digestive tract, and glandular cells of organs such as the liver and pancreas. The mesoderm becomes smooth muscle tissue, connective tissue, blood vessels, blood cells, bone marrow, skeletal tissue, striated muscle tissue, and reproductive and excretory organs. The notochord, which is the primitive axis about which the axial skeleton forms, is also formed during the 3rd week. The neurologic system begins its development during this period. Neurulation, a process that involves formation of the neural plate, neural folds, and their closure, is completed by the 4th week.16,17 Disturbances during this period can result in brain and spinal defects such as spina bifida. The cardiovascular system is the first functional organ system to develop. The primitive heart, which beats and circulates blood, ­develops

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Chapter 2  Concepts of Altered Health in Children    15

during this period. This is also a time period in which congenital heart defects may occur.6 By the 4th week, the neural tube is formed. The embryo begins to curve and fold into a characteristic “C”-shaped structure. The limb buds are visible, as are the otic pits (i.e., primordia of the internal ears) and the lens placodes (primordia of the crystalline lenses). The 5th week is notable for the rapid growth of the head secondary to brain growth. During the 6th week, the upper limbs are formed by fusion of the swellings around the branchial groove. In the 7th week, there is the beginning of the digits, and the intestines enter the umbilical cord (umbilical herniation). By the 8th week, the embryo is human-like in appearance—eyes are open, and eyelids and ear auricles are easily identified. Fetal Development The fetal period extends from the 9th week to birth.16–18 Between the 9th and 12th weeks, fetal head growth slows, whereas body length growth is greatly accelerated. By the 11th week, the intestines in the proximal portion of the cord have returned to the abdomen. The primary ossification centers are present in the skull and long bones, and maturation of the fetal external genitalia is established by the 12th week. During the fetal period, the liver is the major site of red blood cell formation (i.e., erythropoiesis). At 12 weeks, this activity has decreased and erythropoiesis begins in the spleen. The kidney becomes functional around the 12th week, at which time urine is passed into the amniotic fluid.18 The 13th through 16th weeks are notable for ossification of the skeleton, scalp hair patterning, and differentiation of the ovaries in female fetuses.16 By the 17th through 20th week, growth has slowed. The fetal skin is covered with a fine hair called lanugo and a white, cheeselike material called vernix caseosa. Eyebrows and head hair are visible. In male fetuses, the testes begin to descend, and in female fetuses, the uterus is formed. Brown fat, which is a specialized type of adipose tissue that produces heat by oxidizing fatty acids, also forms during this period.16 It is found near the heart and blood vessels that supply the brain and kidneys and is thought to play a role in maintaining the temperature of these organs during exposure to environmental changes that occur after birth. During the 21st through 25th weeks, significant fetal weight gain occurs. At 21 weeks, rapid eye movements begin, and blink–startle reflexes have been reported at 22 to 23 weeks after application of a vibroacoustic noise source to the mother’s abdomen.16 The type II alveolar cells of the lung begin to secrete surfactant. The pulmonary system becomes more mature and able to support respiration during the 26th through 29th weeks. Breathing movements are present as a result of central nervous system (CNS) maturation. At this age, a fetus can survive if born prematurely and given expert postnatal care. There is substantial weight gain during this time. Although still somewhat lean, the fetus is better proportioned. The 30th through 34th weeks are significant for an increasing amount of white fat (8% of body weight),

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which gives the fetal limbs an almost chubby appearance.16 During the 35th week, grasp and the pupillary light reflex are ­present. If a normal-weight fetus is born during this period, it is premature by “date” as opposed to premature by “weight.”17 Expected time of birth is 266 days, or 38 weeks after fertilization, or 40 weeks after the last menstrual period (LMP).16 At this time, the neurologic, cardiovascular, and pulmonary systems are developed enough for the infant to make the transition to extrauterine life. The survival of the newborn depends on this adaptation after the placenta is removed.

Birth Weight and Gestational Age Development during the fetal period is primarily concerned with rapid growth and differentiation of tissues, organs, and systems. Fetal weight gain is linear from 20 weeks’ gestation through 38 weeks’ gestation. In the last half of pregnancy, the fetus gains 85% of his or her birth weight. After 38 weeks’ gestation, the rate of growth declines, probably related to the constraint of uterine size and decreased placental function.16 After birth, weight gain resumes at a rate similar to intrauterine rates. At birth, the average weight of the full-term newborn is 3000 to 4000 g. Infants weighing 2500 g or less at birth are classified as LBW. LBW is further broken down into very low birth weight (VLBW) and extremely low birth weight (ELBW). VLBW is defined as a birth weight less than 1500 g and ELBW as a birth weight less than 1000 g.19 An infant is considered term when born between the beginning of the 38th week and completion of the 41st week. An infant is considered premature when born before the end of the 37th week and postmature when born after the end of the 41st week. The lowest mortality rates occur among newborns with weights between 3000 and 4000 g and gestational ages of 38 to 42 weeks.20 Abnormal Intrauterine Growth Growth of the fetus in the uterus depends on a multitude of intrinsic and extrinsic factors. Optimal fetal growth depends on efficient placental function, adequate provision of energy and growth substrates, appropriate hormonal environment, and adequate room in the uterus. Birth weight variability in a population is primarily determined by genetic factors, fetal sex, maternal health and nutrition, parity, intrinsic fetal growth potential, as well as other physiologic and environmental factors.21 Abnormal growth, which can occur at any time during fetal development, can have immediate and longterm consequences. Lubchenco and Battaglia established standards for birth weight, gestational age, and intrauterine growth in the United States in the 1960s.22,23 With these standards, gestational age can be assessed and normal and abnormal growth can be identified. The Colorado Growth Curve places newborns into percentiles.22 The 10th through 90th percentiles of intrauterine growth encompass 80% of births.24 Growth is considered

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16   UNIT I  Concepts of Health and Disease

abnormal when a newborn falls above or below the 90th and 10th percentiles, respectively. Small for Gestational Age.  Small for gestational age (SGA) is a term that denotes fetal undergrowth. SGA is defined as a birth weight less than 2 standard deviations below the mean for gestational age or below the 10th percentile. The terms small for gestational age and intrauterine growth retardation (IUGR) are used interchangeably, but are not synonymous.16,21,25 IUGR refers to a process that causes a reduction in an expected pattern of growth. However, SGA refers to an infant with a birth weight lower than the predetermined cutoff point.25 IUGR can occur at any time during fetal development. Depending on the time of insult, the infant can have symmetric or proportional growth retardation or asymmetric or disproportional growth retardation.19 Impaired growth that occurs early in pregnancy during the hyperplastic phase of growth results in a symmetric growth retardation, and there is a proportionate decrease in length, weight, and head size for gestational age.19,25 This is irreversible postnatally. Causes of IUGR include chromosomal abnormalities, congenital infections, and exposure to environmental toxins.16,19,25 Impaired growth that occurs later in pregnancy during the hypertrophic phase of growth results in asymmetric growth retardation.19 Infants with IUGR due to intrauterine malnutrition often have weight reduction out of proportion to length or head circumference but are spared impairment of head and brain growth. Tissues and organs are small because of decreased cell size, not decreased cell numbers. Postnatally, the impairment may be partially corrected with good nutrition. Gestational growth can be affected by maternal, placental, and fetal factors. The maternal environment can have a significant effect on birth weight and size.25 Underweight mothers are more likely to give birth to small-weight infants.25 Maternal nutrition and weight gain are influenced by many factors. Women at risk for poor nutrition and poor fetal growth include adolescents, women of low economic status, women with short interpregnancy intervals, women with unusual or stringent diet restrictions, and women who do heavy physical work during pregnancy.25 Various maternal diseases have been associated with restricted fetal growth, including prepregnancy hypertension, diabetes mellitus, and chronic maternal illnesses and infections.25 Growth retardation in the fetus may also be related to maternal exposure to environmental agents such as recreational drugs (drugs of abuse), therapeutic drugs, and environmental hazards. Tobacco in the form of cigarette smoking during pregnancy reduces birth weight. The reduction in birth weight is related to the number of cigarettes smoked.16,25 Occupational exposure to agents such as industrial solvents used as thinners in paint, glue, and varnishes can pose a threat to the pregnant mother and fetus.25 Other factors that may decrease fetal growth include impairment of the uteroplacental and fetoplacental circulation.16 A broad range of pathologic processes can lead to a reduction in either uterine blood

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flow or circulation to the fetus; both conditions can result in IUGR.16 Fetal factors associated with IUGR include numeric and structural chromosomal aberrations and gene abnormalities.16 Additionally, multiple births cause a progressive decrease in placental and fetal weight as the number of fetuses increases. Infants of twin and triplet gestations tend to weigh less than those of singlet gestations.25 Mortality rates among infants with IUGR are 10 to 20 times greater than infants whose size and weight are appropriate for gestational age.25 The causes of this mortality are primarily due to hypoxia and congenital anomalies, although other complications include polycythemia, hyperbilirubinemia, and hypoglycemia.25 SGA infants have increased plasma volume and circulating red cell mass, which is most likely the result of fetal hypoxia and subsequent erythropoietin production.25 Many of the SGA infants also experience fasting hypoglycemia during the first days of life, probably as the result of depleted hepatic glycogen stores.25 The long-term effects of growth retardation depend on the timing and severity of the insult. Many of these infants have developmental disabilities on follow-up examination, especially if the growth retardation is symmetric.19 If the insult occurred later because of placental insufficiency or uterine restraint, good nutrition may lead to catch-up growth allowing the infant to attain appropriate growth goals. Large for Gestational Age.  Large for gestational age (LGA) is a term that denotes fetal overgrowth and a birth weight above the 90th percentile.20,25 The excessive growth may result from maternal or fetal factors. Maternal factors include maternal obesity and diabetes. Fetal factors consist mainly of genetic and chromosomal abnormalties.25 Size of the biologic mother has been recognized as a factor that influences birth weight. Heavy women tend to have LGA infants.25 Women with diabetes also tend to have LGA infants, especially if the diabetes was poorly controlled during pregnancy.25 Complications when an infant is LGA include birth asphyxia and trauma due to mechanical difficulties during the birth process, hypoglycemia, polycythemia, and hyperbilirubinemia.25 Maternal hyperglycemia exposes the fetus to increased levels of glucose, which stimulate fetal pancreatic islet hyperplasia and increased insulin secretion. Insulin increases fat deposition and the result is a macrosomic (large body size) infant. Infants with macrosomia have enlarged viscera and are large and plump because of an increase in body fat. Fetal hyperinsulinemia is associated with fetal hypoxia and erythropoietin-induced polycythemia. The presence of polycythemia places the infant at risk for hyperbilirubinemia.25 LGA infants and infants of diabetic mothers (IDMs) are also at risk for hypoglycemia (to be discussed). Other potential long-term effects of LGA include insulin resistance, metabolic syndrome, overweight or obesity, diabetes, and early cardiovascular disease. In addition, there is increasing evidence that links high birth weight with overall leukemia risk.26

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Chapter 2  Concepts of Altered Health in Children    17

Assessing Gestational Age Gestational age assessment can be divided into two categories: prenatal assessment and postnatal assessment. Prenatal assessment of gestational age most commonly includes careful menstrual history, physical milestones during pregnancy (e.g., ­ ovements), and uterine size, detection of fetal heart rate, and m prenatal tests for maturity (e.g., ultrasonography, amniotic fluid studies). The Nägele rule uses the first day of the LMP to calculate the day of labor by adding 7 days to the LMP and counting back 3 months.16,27 This method may be inaccurate if the mother is not a good historian or has a history of irregular menses, which interferes with identification of a normal cycle. Postnatal assessment of gestational age is done by examination of external physical and neuromuscular characteristics alone or in combination. Assessment of gestational age should be a part of every initial newborn examination. Accurate assessment of gestational age facilitates risk assessment and identification of abnormalities and allows for earlier interventions. Dubowitz and Ballard developed the most common methods used in nurseries today. The Dubowitz method is comprehensive and includes 21 criteria using external physical (11) and neuromuscular (10) signs.28 The estimate of gestational age is best done within 12 hours of birth and is accurate within 1 week’ gestational age. The method is less accurate for infants born at less than 30 weeks’ gestational age. The Ballard method is an abbreviated Dubowitz method that includes 12 criteria, using 6 external physical and 6 neuromuscular signs.27 The New Ballard Score (NBS) was updated and modified to include newborns at gestational ages of 20 to 44 weeks and is the most commonly used method.20,24

IN SUMMARY Growth and development begin with union of ovum and sperm and are ongoing throughout a child’s life to adulthood. Abnormalities during this process can have profound effects on the individual. Prenatal development is composed of two periods, the embryonic period and the fetal period. During these periods, the zygote becomes the newborn with the organ maturity to make the adjustments necessary for extrauterine life. An infant is considered term when born between the beginning of the 38th week and completion of the 41st week. An infant is considered premature when born before the end of the 37th week and postmature when born after the end of the 41st week. At birth, the average weight of the full-term newborn is 3000 to 4000 g. Infants weighing 2500 g or less at birth are classified as being LBW. LBW is further broken down into VLBW (6 feet). Because of their large size, DNA molecules are combined with several types of protein and small amounts of RNA into a coiled structure known as chromatin. The organization

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Semiconservative Model

Conservative Model

original strand of DNA newly synthesized strand of DNA FIGURE 6.2 • Semiconservative versus conservative models of DNA replication as proposed by Meselson and Stahl in 1958. In semiconservative DNA replication, the two original strands of DNA unwind and a complementary strand is formed along each original strand.

of DNA into chromatin is essential for controlling transcription and for packaging the molecule. Some DNA-associated proteins form binding sites for repressor molecules and hormones that regulate genetic transcription; others may block genetic transcription by preventing access of nucleotides to the surface of the DNA molecule.2 A specific group of proteins called histones is thought to control the folding of the DNA strands.2 Each double-stranded DNA molecule periodically coils around histones, which keeps the DNA organized.3 With cells that do not divide the DNA strands are in a less compact form called chromatin. Figure 6.3 illustrates how both the chromosomes and chromatin, which consist of chromosomal DNA, are coiled around histones. Although solving the structural problem of how to fit a huge amount of DNA into the nucleus, the chromatin fiber, when complexed with histones and folded into various levels of compaction, makes the DNA inaccessible during the processes of replication and gene expression. To accommodate these processes, chromatin must be induced to change its structure, a process called chromatin remodeling.4 Several chemical interactions are now known to affect this process. One of these involves the acetylation of a histone amino acids group that is linked to the opening of the chromatin fiber and gene activation. Another important chemical modification involves the methylation of histone amino acids, which is correlated with gene inactivation. Genetic Code Four bases—guanine, adenine, cytosine, and thymine (uracil is substituted for thymine in RNA)—make up the alphabet of the genetic code. A sequence of three of these bases forms the

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Chapter 6  Genetic Control of Cell Function and Inheritance    121 Dividing cell

Nondividing cell

Nucleoplasm

Chromatin

Chromatin

Chromosome

Histones Chromosomal DNA

Double helix FIGURE 6.3  •  DNA strand organization. The DNA strands are shown in chromosomes for dividing cells and in chromatin for nondividing cells and are coiled around histones. (From McConnell T. H., Hull K. L. (2011). Human form human function: Essentials of anatomy & physiology (p. 71, Figure 3.5). Philadelphia, PA: Lippincott Williams & Wilkins.)

fundamental triplet code used in transmitting the genetic information needed for protein synthesis. This triplet code is called a codon (Table 6.1). An example is the nucleotide sequence UGG (uracil, guanine, guanine), which is the triplet RNA code for the amino acid tryptophan. The genetic code is a universal language used by most living cells (i.e., the code for the amino acid tryptophan is the same in a bacterium, a plant, and a human being). Stop codons, which signal the end of a protein molecule, are also present.5 Mathematically, the four bases can be arranged in 64 different combinations. Sixty-one of the triplets correspond to particular amino acids, and three are stop signals. Only 20 amino acids are used in protein synthesis in humans. Several triplets code for the same amino acid; therefore, the genetic code is said to be redundant or degenerate. For example, AUG is a part of the initiation or start signal as well as the codon for the amino acid methionine. Codons that specify the same amino acid are called ­synonyms. Synonyms usually have the same first two bases but differ in the third base.

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DNA Repair Rarely, accidental errors in duplication of DNA occur. These errors are called mutations. Mutations result from the substitution of one base pair for another, the loss or addition of one or more base pairs, or rearrangements of base pairs. Many of these mutations occur spontaneously, whereas others occur because of environmental agents, chemicals, and radiation. Mutations may arise in somatic cells or in germ cells. Only those DNA changes that occur in germ cells can be inherited. Considering the millions of base pairs that must be duplicated in each cell division, it is not surprising that random changes in replication occur. Most of these defects are corrected by DNA repair mechanisms. Several repair mechanisms exist, and each depends on specific enzymes called endonucleases that recognize local distortions of the DNA helix, cleave the abnormal chain, and remove the distorted region.6 The gap is then filled when the correct deoxyribonucleotides, created by a DNA polymerase using the intact complementary strand as a template, are added to the cleaved DNA. The newly synthesized end of the segment is then joined to the remainder of the DNA strand by a DNA ligase. The normal regulation of these gene repair mechanisms is under the control of DNA repair genes. Loss of these gene functions renders the DNA susceptible to accumulation of mutations. When these affect protooncogenes or tumor suppressor genes, cancer may result. Genetic Variability As the Human Genome Project was progressing, it became evident that the human genome sequence is almost exactly (99.9%) the same in all people. It is the small variation (0.01%) in gene sequence (termed a haplotype) that is thought to account for the individual differences in physical traits, behaviors, and disease susceptibility. These variations are sometimes referred to as polymorphisms (from the existence of more than one morphologic or body form in a population). An international effort has been organized to develop a map (HapMap) of these variations with the intent of providing a link between genetic variations and common complex diseases such as cancer, heart disease, diabetes, and some forms of mental disease.7 Mitochondrial DNA In addition to nuclear DNA, part of the DNA of a cell resides in the mitochondria. Mitochondrial DNA is inherited from the mother by her offspring (i.e., matrilineal inheritance). It is a double-stranded closed circle, containing 37 genes, 24 of which are needed for mitochondrial DNA translation and 13 of which encode enzymes needed for oxidative metabolism.8 Replication of mitochondrial DNA depends on enzymes encoded by nuclear DNA. Thus, the proteinsynthesizing apparatus and molecular components for ­oxidative metabolism are jointly derived from nuclear and mitochondrial genes. Genetic disorders of mitochondrial ­ DNA, although rare, commonly affect tissues such as those of the neuromuscular system that have a high requirement for oxidative metabolism.

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122   UNIT II  Cell Function and Growth

TABLE 6.1 TRIPLET CODES FOR AMINO ACIDS AMINO ACID

RNA CODONS

Alanine Arginine Asparagine Aspartic acid Cysteine Glutamic acid Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine Start (CI) Stop (CT)

GCU CGU AAU GAU UGU GAA CAA GGU CAU AUU CUU AAA AUG UUU CCU UCU ACU UGG UAU GUU AUG UAA

GCC CGC AAC GAC UGC GAG CAG GGC CAC AUC CUC AAG

GCA CGA

GCG CGG

GGA

GGG

AUA CUA

UUC CCC UCC ACC

AGA

AGG

CUG

UUA

UUG

CCA UCA ACA

CCG UCG ACG

AGC

AGU

UAC GUC

GUA

GUG

UAG

UGA

From Genes to Proteins Although DNA determines the type of biochemical product needed by the cell and directs its synthesis, it is RNA through the process of translation, which is responsible for the actual assembly of the products. RNA Structure and Function RNA, like DNA, is a large molecule made up of a long string of nucleotides. However, it differs from DNA in three aspects of its structure. First, RNA is a single-stranded rather than a double-stranded molecule. Second, the sugar in each nucleotide of RNA is ribose instead of deoxyribose. Third, the pyrimidine base thymine in DNA is replaced by uracil in RNA. Cells contain three types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA).9 All three types of RNA are synthesized in the nucleus by RNA polymerase enzymes and then moved into the cytoplasm, where protein synthesis takes place. Messenger RNA carries the instructions for protein synthesis, obtained from the DNA molecule, into the cytoplasm. Transfer RNA reads the instructions and delivers the appropriate amino acids to the ribosome, where ribosomal RNA translates the instructions and provides the machinery needed for protein synthesis. Messenger RNA.  Messenger RNA is the template for protein synthesis. It is a long molecule containing several hundred to several thousand nucleotides. Each group of three nucleotides forms a codon that is exactly complementary to a nucleotide

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triplet of the DNA molecule. Messenger RNA is formed by a process called transcription.9 In this process, the weak hydrogen bonds of DNA are broken so that free RNA nucleotides can pair with their exposed DNA counterparts on the meaningful strand of the DNA molecule (see Fig. 6.4). As with the base pairing of the DNA strands, complementary RNA bases pair with the DNA bases. In RNA, uracil (U) replaces thymine and pairs with adenine. As with DNA, guanine pairs with cytosine. Ribosomal RNA.  The ribosome is the physical structure in the cytoplasm where protein synthesis takes place. Ribosomal RNA forms 60% of the ribosome, with the remainder of the ribosome composed of the structural proteins and enzymes needed for protein synthesis.9 As with the other types of RNA, rRNA is synthesized in the nucleus. Unlike the two other types of RNA, rRNA is produced in a specialized nuclear structure called the nucleolus. The formed rRNA combines with ribosomal proteins in the nucleus to produce the ribosome, which is then transported into the cytoplasm. On reaching the cytoplasm, most ribosomes become attached to the endoplasmic reticulum and begin the task of protein synthesis. Transfer RNA.  Transfer RNA is a clover-shaped molecule containing only 80 nucleotides, making it the smallest RNA molecule.9 Its function is to deliver the activated form of an amino acid to the protein that is being synthesized in the ribosomes. At least 20 different types of tRNA are known, each of which recognizes and binds to only one type of amino acid. Each tRNA molecule has two recognition sites: the first is complementary for the mRNA codon and the second for the amino

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Chapter 6  Genetic Control of Cell Function and Inheritance    123

TRANSCRIPTION

T C

G G C C

A U

A U

G C

G C

G C

C G

C G

A

RNA

G

DNA template RNA polymerase creates strand RNA from the DNA template C strand by matching with T U/T and G with C. G C A A C G

G

Free ribonucleotide

T

G

G

A

C

A

C

T

T

C

C

C

G

G

G

NUCLEUS DNA sense strand CYTOPLASM

FIGURE 6.4  •  The DNA helix and transcription of messenger RNA (mRNA). The DNA helix unwinds and a new mRNA strand is built on the template strand of the DNA. The mRNA contains the same base sequence as the DNA strand except that T bases are replaced with U bases. The mRNA leaves the ­nucleus through pores in the nuclear envelope. (From McConnell T., Hull K. (2011). Human form human function: Essentials of anatomy & physiology (p. 83). Philadelphia, PA: Lippincott Williams & Wilkins.)

acid itself. Each type of tRNA carries its own specific amino acid to the ribosomes, where protein synthesis is taking place; there it recognizes the appropriate codon on the mRNA and delivers the amino acid to the newly forming protein molecule. Transcription Transcription occurs in the cell nucleus and involves the synthesis of RNA from a DNA template (Fig. 6.4).9 Genes are transcribed by enzymes called RNA polymerases that generate a single-stranded RNA identical in sequence (with the exception of U in place of T) to one of the strands of DNA. It is initiated by the assembly of a transcription complex composed of RNA polymerase and other associated factors. This complex binds to the double-stranded DNA at a specific site called the promoter region. Within the promoter region, the so-called TATA box is located. The TATA box contains the crucial thymine–adenine–thymine–adenine (TATA) nucleotide sequence that RNA polymerase recognizes and binds to. This binding also requires transcription factors, a ­transcription initiation site, and other proteins. Transcription continues to copy the meaningful strand into a single strand of RNA as it travels along the length of the gene, stopping only when it reaches a termination site with a stop codon. On reaching the stop signal, the RNA polymerase enzyme leaves the gene and releases the RNA strand. The RNA strand then is processed. Processing involves the addition of certain nucleic acids at the ends of the RNA strand and cutting and splicing of certain internal sequences. Splicing involves the removal of stretches of RNA. Because of the splicing process, the final mRNA sequence is different from the original DNA template. The retained protein-coding regions of the mRNA sequences are called exons and the regions between exons are called introns.10 The functions of the introns are unknown. They are

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thought to be involved in the activation or deactivation of genes during various stages of development. Splicing permits a cell to produce a variety of mRNA molecules from a single gene. By varying the splicing segments of the initial mRNA, different mRNA molecules are formed. For example, in a muscle cell, the original tropomyosin mRNA is spliced in as many as 10 different ways, yielding distinctly different protein products. This permits different proteins to be expressed from a single gene and reduces how much DNA must be contained in the genome. Translation Translation occurs in the cytoplasm of the cell and involves the synthesis of a protein using its mRNA template.9 Proteins are made from a standard set of amino acids, which are joined end to end to form the long polypeptide chains of protein molecules. Each polypeptide chain may have as many as 100 to more than 300 amino acids in it. Besides rRNA, translation requires the coordinated actions of mRNA and tRNA (Fig. 6.5). Each of the 20 different tRNA molecules transports its specific amino acid to the ribosome for incorporation into the developing protein molecule. Messenger RNA provides the information needed for placing the amino acids in their proper order for each specific type of protein. During protein synthesis, mRNA contacts and passes through the ribosome, during which it “reads” the directions for protein synthesis. As mRNA passes through the ribosome, tRNA delivers the ­appropriate amino acids for attachment to the growing polypeptide chain. The long mRNA molecule usually travels through and directs protein synthesis in more than one ribosome at a time. After the first part of the mRNA is read by the first ribosome, it moves onto a second and a third. As a result, ribosomes that are actively involved in protein synthesis are often found in clusters called polyribosomes.

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124   UNIT II  Cell Function and Growth Forming protein Amino acid

Peptide bond

U

A

Transfer RNA "head" bearing anticodon

U

Ribosome

A A

G C G G

U C G A C C A U U C G A U U U C G C C A U A G U C C U U G G C C Direction of messenger RNA advance

Messenger RNA

Codon

The process of translation is not over when the genetic code has been used to create the sequence of amino acids that constitute a protein. To be useful to a cell, this new polypeptide chain must fold up into its unique three-­dimensional conformation. The folding of many proteins is made more efficient by special classes of proteins called molecular chaperones.11 Typically the function of a chaperone is to assist a newly synthesized polypeptide chain to attain a functional conformation as a new protein and then to assist the protein’s arrival at the site in the cell where the protein carries out its function. Molecular chaperones also assist in preventing the misfolding of existing proteins. Disruption of chaperoning mechanisms causes intracellular molecules to become denatured and insoluble. These denatured proteins tend to stick to one another, precipitate, and form inclusion bodies. The development of inclusion bodies is a common pathologic process in Parkinson, Alzheimer, and Huntington diseases. A newly synthesized polypeptide chain may also need to combine with one or more polypeptide chains from the same or an adjacent chromosome, bind small cofactors for its activity, or undergo appropriate enzyme modification. During the posttranslation process, two or more peptide chains may combine to form a single product. For example, two α-globin chains and two β-globin chains combine to form the α2β2hemoglobin molecule. The protein products may also be modified chemically by the addition of various types of functional groups. For example, fatty acids may be added, providing hydrophobic regions for attachment to cell membranes. Other modifications may involve cleavage of the protein, either to

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U U

FIGURE 6.5 • Protein synthesis. A messenger RNA (mRNA) strand is shown moving along a small ribosomal subunit in the cytoplasm. As the mRNA codon passes along the ribosome, a new amino acid is added to the growing peptide chain by the transfer RNA (tRNA) bearing the anticodon for the mRNA-designated amino acid. As each amino acid is bound to the next by a peptide bond, its tRNA is released.

remove a specific amino acid sequence or to split the m ­ olecule into smaller chains. As an example, the two chains that make up the circulating active insulin molecule, one containing 21 and the other 30 amino acids, were originally part of an 82-amino-acid proinsulin molecule. Regulation of Gene Expression Only about 2% of the genome encodes instructions for synthesis of proteins; the remainder consists of noncoding regions that serve to determine where, when, and in what quantity proteins are made. The degree to which a gene or particular group of genes is active is called gene expression. A phenomenon termed induction is an important process by which gene expression is increased. Gene repression is a process by which a regulatory gene acts to reduce or prevent gene expression. Activator and repressor sites commonly monitor levels of the synthesized product and regulate gene transcription through a negative feedback mechanism. Whenever product levels decrease, gene transcription is increased, and when levels increase, it is repressed. Although control of gene expression can occur in multiple steps, many regulatory events occur at the transcription level. The initiation and regulation of transcription require the collaboration of a battery of proteins, collectively termed transcription factors.9 Transcription factors are a class of proteins that bind to their own specific DNA region and function to increase or decrease transcriptional activity of the genes. The role of transcription factors in gene expression explains why neurons and liver cells have completely different structures and functions although all the

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Chapter 6  Genetic Control of Cell Function and Inheritance    125

Understanding

DNA-Directed Protein Synthesis

Deoxyribonucleic acid (DNA) directs the synthesis of the many thousands of proteins that are contained in the different cells of the body. Although some of the proteins are structural proteins, the majority are enzymes that catalyze the different chemical reactions in the cell. Because DNA is located in the cell’s nucleus and protein synthesis takes place in the cytoplasm, a second type of nucleic acid—ribonucleic acid (RNA)—participates in the actual assembly of the proteins. There are three types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA) that participate in (1) the transcription of the DNA instructions for protein synthesis and (2) the translation of those instructions into the assembly of the polypeptides that make up the various proteins. The genetic code is a triplet of four bases (adenine [A], thymine [T], guanine [G], and cytosine [C], with thymine in DNA being replaced with uracil [U] in RNA) that control the sequence of amino acids in a protein molecule that is being synthesized. The triplet RNA code is called a codon.

Transcription Transcription involves copying the genetic code containing the instructions for protein synthesis from DNA to a complementary strand of mRNA. Transcription is initiated by an enzyme called RNA polymerase, which binds to a promoter site on DNA. Many other proteins, including transcription factors, function to increase or decrease transcriptional activity of the genes. After mRNA has been transcribed, it detaches from DNA and is processed by cutting, removing introns, and splicing the exon RNA sequences to produce a variety of mRNA molecules from a single gene. Once mRNA has been processed, it diffuses through the nuclear pores into the cytoplasm, where it controls protein synthesis.

Nuclear envelope

Transcription

RNA processing

DNA

Pre-mRNA

mRNA

Continued

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126   UNIT II  Cell Function and Growth

Understanding

DNA-Directed Protein Synthesis (Continued)

Translation The process of translation involves taking the instructions transcribed from DNA to mRNA and transferring them to the rRNA of ribosomes located in the cytoplasm. When the mRNA carrying the instructions for a particular p­ rotein comes in contact with a ribosome, it binds to a small subunit of the rRNA. It then travels through the ribosome where the transcribed instructions are communicated to the tRNA, which delivers and transfers the correct amino acid to its proper position on the growing peptide chain. There are 20 types of tRNA, one for each of the 20 different types of amino acid. Each type of tRNA carries an anticodon complementary to the mRNA codon calling for the amino acid carried by the tRNA, and it is the recognition of the mRNA codon by the tRNA anticodon that ensures the proper sequence of amino acids in a synthesized protein. In order to be functional, the newly synthesized protein must be folded into its functional form, modified further, and then routed to its final position in the cell.

Peptide bond Amino acid

Forming protein

Transfer RNA Ribosomal RNA C GG CU U AGC U AGC C U AGCC UA Codon

Messenger RNA

nucleated cells in a person contain the same DNA and thus the same genetic information. Some, referred to as general transcription factors, are required for transcription of all structural genes. Others, termed specific transcription factors, have more specialized roles, activating genes only at specific stages of development. For example, the PAX family of transcription factors is involved in the development of such embryonic tissues as the eye and portions of the nervous system. Genetic Mediators of Embryonic Development Regulation of gene expression also plays an essential role in the developing embryo. During embryonic development, many thousands of genes are expressed to control axial specification (i.e., ventral/dorsal, anterior/posterior/medial/ lateral, left/right), pattern formation (spatial arrangement of ­differentiated cells in body tissues and organs), and organogenesis (­ development of the different body organs). Many of these genes code transcription factors that produce signaling molecules. Two examples are sonic hedgehog and fibroblast

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growth factor.12 Signaling molecules bind to cells and are transported to the nucleus, where they initiate changes in gene expression. Depending on the embryonic tissue, these transcription factors and signaling molecules are produced temporally at various times during embryonic development. Sonic hedgehog signaling is involved in many key developmental events at multiple times during embryogenesis.12 It participates in such diverse developmental steps as establishment of the left-to-right axis responsible for the rostral–­ caudal orientation of the nervous system, the separation of the brain into two cerebral hemispheres, right and left eye orientation, and the separation and development of the correct number of fingers and toes. Fibroblast growth factors participate in a wide variety of developmental processes, including cell migration, growth, and differentiation. They are widely expressed in developing bone, and many autosomal dominant disorders of bone growth are mutations of fibroblast growth factor receptor genes. The most prevalent of these is a condition called achondroplasia, which is characterized by short stature with limbs that are disproportionately shorter than the trunk and macrocephaly (large head).

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Chapter 6  Genetic Control of Cell Function and Inheritance    127

IN SUMMARY Genes are the fundamental unit of information storage in the cell. They determine the types of proteins and enzymes made by the cell and therefore control inheritance and dayto-day cell function. Genetic information is stored in a stable macromolecule called DNA. Genes transmit information contained in the DNA molecule as a triplet code. The genetic code is determined by the arrangement of the nitrogenous bases of the four nucleotides (i.e., adenine, guanine, thymine [or uracil in RNA], and cytosine). Gene mutations represent accidental errors in duplication, rearrangement, or deletion of parts of the genetic code. Fortunately, most mutations are corrected by DNA repair mechanisms in the cell. The transfer of stored information from DNA into production of cell products is accomplished through a second type of nucleotide called RNA. Messenger RNA transcribes the instructions for product synthesis from the DNA molecule, undergoes splicing where the introns are removed, and moves to the cell’s cytoplasm, where ribosomal RNA uses the information to direct protein synthesis through the process known as translation. Transcription is initiated by RNA polymerase and other associated factors that bind to the double-stranded DNA at a specific site called the promoter region. Transfer RNA acts as a carrier system for delivering the appropriate amino acids to the ribosomes. The degree to which a gene or particular group of genes is active is called gene expression. Gene expression involves a set of complex interrelationships among different levels of control, including RNA transcription and posttranslational processing. The initiation and regulation of RNA transcription are controlled by transcription factors that bind to specific DNA regions and function to regulate gene expression of the many different types of cells in the body. Posttranslational processing involves the proper folding of the newly synthesized polypeptide chain into its unique three-dimensional conformation. Special classes of proteins called molecular chaperones make the folding of many proteins more efficient. Posttranslational processing may also involve the combination of polypeptide chains from the same or an adjacent chromosome, the binding of small cofactors, or enzyme modification.

CHROMOSOMES After completing this section of the chapter, you should be able to meet the following objectives: •• Define the terms autosomes, chromatin, meiosis, and mitosis. •• List the steps in constructing a karyotype using cytogenetic studies. •• Explain the significance of the Barr body.

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Most genetic information of a cell is organized, stored, and retrieved in small intracellular structures called chromosomes. Although the chromosomes are visible only in dividing cells, they retain their integrity between cell divisions. The chromosomes are arranged in pairs; one member of the pair is inherited from the father, the other from the mother. Each species has a characteristic number of chromosomes. In the human, 46 single or 23 pairs of chromosomes are present. Of the 23 pairs of human chromosomes, 22 are called autosomes and are alike in both males and females. Each of the 22 pairs of autosomes has the same appearance in all people, and each has been given a numeric designation for classification p­ urposes (Fig. 6.6). In the diploid cell, each of the 22 autosomal chromosomes has a homolog. Homologous chromosomes contain a similar series of genes; that is, they have similar sequences. They are not identical, however, because one homolog comes from the haploid sperm of the father and one from the haploid ovum of the mother. The sex chromosomes, which make up the 23rd pair of chromosomes, determine the sex of a person. All males have an X and Y chromosome (i.e., an X chromosome from the mother and a Y chromosome from the father); all females have two X chromosomes (i.e., one from each parent). The much smaller Y chromosome contains the male-specific region (MSY) that determines sex.13 This region comprises more than 95% of the length of the Y chromosome. Only one X chromosome in the female is active in controlling the expression of genetic traits; however, both X chromosomes are activated during gametogenesis. In the female, the active X chromosome is invisible, but the inactive X chromosome can be visualized with appropriate nuclear staining. Inactivation is thought to involve the addition of a methyl group to the X chromosome. This inactive chromatin mass is seen as the Barr body in epithelial cells or as the drumstick body in the chromatin of neutrophils.14 The genetic sex of a child can be determined by microscopic study of cell or tissue samples. The total number of X chromosomes is equal to the number of Barr bodies plus one (i.e., an inactive plus an active X chromosome). For example, the cells of a normal female have one Barr body and therefore a total of two X chromosomes. A normal male has no Barr bodies. Males with Klinefelter syndrome, who have one Y and two X chromosomes (one active and one inactive), exhibit one Barr body. In the female, whether the active X chromosome is derived from the mother or father is determined within a few days after conception, the selection being random for each postmitotic cell line. Thus, the tissues of normal women have on average 50% maternally derived and 50% paternally derived active X chromosomes. This is known as the Lyon principle.14

Cell Division Two types of cell division occur in humans and many other animals: mitosis and meiosis. Mitosis involves duplication of somatic cells in the body and is represented by the cell cycle (Fig. 6.7). Meiosis is limited to replicating germ cells and takes place only once in a cell line. It results in the formation of gametes or reproductive cells (i.e., ovum and sperm), each

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128   UNIT II  Cell Function and Growth

FIGURE 6.6 • Karyotype of human chromosomes. (From Rubin R., Strayer D. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 221). Philadelphia, PA: Lippincott Williams & Wilkins.)

of which has only a single set of 23 chromosomes. Meiosis is typically divided into two distinct phases, meiosis I and meiosis II. Similar to mitosis, cells about to undergo the first meiotic division replicate their DNA during interphase. During metaphase I homologous autosomal chromosomes pair up, forming a synapsis or tetrad (two chromatids per chromosome). They are sometimes called bivalents. They do, however, pair up in several regions. The X and Y chromosomes are not homologs and do not form bivalents. While in metaphase I, an interchange of chromatid segments can occur. This process is called crossing-over (Fig. 6.8). Crossing-over allows for new combinations of genes, increasing genetic variability. After telophase I, each of the two daughter cells contains one member of each homologous pair of chromosomes and a sex chromosome (23 double-stranded chromosomes). No DNA synthesis occurs before meiotic division II. During anaphase II, the 23 double-stranded chromosomes (two chromatids) of each of the two daughter cells from meiosis I divide at their centromeres. Each subsequent daughter cell receives 23 single-stranded chromatids. Thus, a meiotic division of one cell forms a total of four daughter cells. Meiosis, occurring only in the gamete-producing cells found in the testes or ovaries, has a different outcome in males and females. In males, meiosis (spermatogenesis) results in four viable daughter cells called spermatids that differentiate into sperm cells. In females, gamete formation or oogenesis is quite different. After the first meiotic division of a primary oocyte, a secondary oocyte and another structure called a polar body are formed. This small polar body contains little cytoplasm, but it may undergo a second meiotic division, resulting in two polar bodies. The secondary oocyte undergoes its second meiotic division, producing one mature oocyte and another polar body. Four viable sperm cells are produced during spermatogenesis, but only one ovum is produced by oogenesis.

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Key Points CHROMOSOMES •  The DNA that stores genetic material is organized into 23 pairs of chromosomes. There are 22 pairs of autosomes, which are alike for males and females, and one pair of sex chromosomes, with XX pairing in females and XY pairing in males. •  Cell division involves the duplication of the chromosomes. Duplication of chromosomes in somatic cell lines involves mitosis, in which each daughter cell receives a pair of 23 chromosomes. Meiosis is limited to replicating germ cells and results in formation of a single set of 23 chromosomes.

Chromosome Structure Cytogenetics is the study of the structure and numeric char­ acteristics of the cell’s chromosomes. Chromosome studies can be done on any tissue or cell that grows and divides in culture. Lymphocytes from venous blood are frequently used for this purpose. After the cells have been cultured, a drug called colchicine is used to arrest mitosis in metaphase. A chromosome spread is prepared by fixing and spreading the chromosomes on a slide. Subsequently, appropriate staining techniques show the chromosomal banding patterns so they can be identified. The chromosomes are photographed, and the photomicrographs of each of the chromosomes are cut out and arranged in pairs according to a standard classification system (see Fig.  6.6). The completed picture is called a ­karyotype, and the procedure for preparing the picture is called karyotyping. A uniform system of chromosome

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Chapter 6  Genetic Control of Cell Function and Inheritance    129

INTERPHASE

S Phase

G1 Phase

se ha op Pr e phas Meta Anap hase Te l o ph as e

Cy to ke

G2 Phase

ne sis

MITOS

IS (1-3h)

Chromosome

Centrioles (centrosomes) Chromosome Spindle fibers

Nuclear membrane Centromere

Chromatid

Cleavage furrow

TELOPHASE

ANAPHASE

METAPHASE

PROPHASE

FIGURE 6.7  •  Mitosis. Mitosis consists of division of the nucleus and is made up of four steps: telophase, anaphase, metaphase, and prophase. (From McConnell T. H., Hull K. L. (2011). Human form human function: Essentials of anatomy & physiology (p. 79, Figure 3.12). Philadelphia, PA: Lippincott Williams & Wilkins.)

FIGURE 6.8  •  Crossing-over of DNA at the time of meiosis.

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c­lassification was o­riginally formulated at the 1971 Paris Chromosome Conference and was later revised to describe the chromosomes as seen in more elongated prophase and prometaphase preparations. In the metaphase spread, each chromosome takes the form of chromatids to form an “X” or “wishbone” pattern. Human chromosomes are divided into three types according to the position of the centromere. If the centromere is in the center and the arms are of approximately the same length, the chromosome is said to be metacentric; if it is not centered and the arms are of clearly different lengths, it is submetacentric; and if it is near one end, it is acrocentric. The short arm of the chromosome is designated as “p” for “petite,” and the long arm is designated as “q” for no other reason than it is the next

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130   UNIT II  Cell Function and Growth

p

2

22 21

1 11 1

Ocular albinism Hypophosphatemia, hereditary Duchenne/Becker muscular dystrophy Chronic granulomatous disease Retinitis pigmentosa Wiskott-Aldrich syndrome

It is prepared by special laboratory techniques in which body cells are cultured, fixed, and then stained to display identifiable banding patterns. A photomicrograph is then made. Often the photomicrographs of individual chromosomes are cut out and regrouped according to chromosome number.

SCID, X-linked 13 21

q

Agammaglobulinemia Fabry disease

2 25

28

Hemophilia B Fragile X syndrome Color blindness Diabetes insipidus, nephrogenic G6PD deficiency Hemophilia A

FIGURE 6.9  •  The localization of inherited diseases as represented on the banded karyotype of the X chromosome. Notice the nomenclature of arms (p, q), regions (1, 2), and bands (e.g., 22 [region 2, band 2]). (From Rubin R., Strayer D. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 251). Philadelphia, PA: Lippincott Williams & Wilkins.)

letter of the alphabet.14 The arms of the chromosome are indicated by the chromosome number followed by the p or q designation (e.g., 15p). Chromosomes 13, 14, 15, 21, and 22 have small masses of chromatin called satellites attached to their short arms by narrow stalks. At the ends of each chromosome are special DNA sequences called telomeres. Telomeres allow the end of the DNA molecule to be replicated completely. The banding patterns of a chromosome are used in describing the position of a gene on a chromosome. Each arm of a chromosome is divided into regions, which are numbered from the centromere outward (e.g., 1, 2). The regions are further divided into bands, which are also numbered (Fig. 6.9). These numbers are used in designating the position of a gene on a chromosome. For example, Xp22 refers to band 2, region 2 of the short arm (p) of the X chromosome.

IN SUMMARY The genetic information in a cell is organized, stored, and retrieved as small cellular structures called chromosomes. Forty-six chromosomes arranged in 23 pairs are present in the human being. Twenty-two of these pairs are autosomes. The 23rd pair is the sex chromosomes, which determine the person’s sex. Two types of cell division occur, meiosis and mitosis. Mitotic division occurs in somatic cells and results in the formation of 23 pairs of chromosomes. Meiosis is limited to replicating germ cells and results in the formation of gametes or reproductive cells (ovum and sperm), each of which has only a single set of 23 chromosomes. A karyotype is a photograph of a person’s ­chromosomes.

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Jennifer’s karyotype revealed an additional chromosome 21. This additional chromosome resulted from an act of nondisjunction. This event has been found to occur more frequently as a woman ages. Therefore, women 35 years of age and older are particularly encouraged to undergo prenatal screening as will be described in Chapter 7.

PATTERNS OF INHERITANCE After completing this section of the chapter, you should be able to meet the following objectives: •• Construct a hypothetical pedigree for a recessive and dominant trait according to Mendel’s laws. •• Contrast genotype and phenotype. •• Define the terms allele, locus, expressivity, and penetrance.

The characteristics inherited from a person’s parents are inscribed in gene pairs found along the length of the chromosomes. Alternate forms of the same gene are possible (i.e., one inherited from the mother and the other from the father), and each may produce a different aspect of a trait.

Definitions Genetics has its own set of definitions. The genotype of a person is the genetic information stored in the base sequence triplet code. The phenotype refers to the recognizable traits, physical or biochemical, associated with a specific genotype. Often, the genotype is not evident by available detection methods. More than one genotype may have the same phenotype. Some brown-eyed people are carriers of the code for blue eyes, and other brown-eyed people are not. Phenotypically, these two types of brown-eyed people are the same, but genotypically they are different. With regard to a genetic disorder, not all people with a mutant gene are affected to the same extent. Expressivity refers to the manner in which the gene is expressed in the phenotype, which can range from mild to severe. Penetrance ­represents the ability of a gene to express its function. Seventy-five percent penetrance means 75% of people of a particular genotype present with a recognizable phenotype. Syndactyly and blue sclera are genetic mutations that often do not exhibit 100% penetrance.

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Chapter 6  Genetic Control of Cell Function and Inheritance    131

The position of a gene on a chromosome is called its locus, and alternate forms of a gene at the same locus are called alleles. When only one pair of genes is involved in the transmission of information, the term single-gene trait is used. Single-gene traits follow the mendelian laws of inheritance. Polygenic inheritance involves multiple genes at different loci, with each gene exerting a small additive effect in determining a trait. Multiple pairs of genes, many with alternate codes, determine most human traits, accounting for some dissimilar forms that occur with certain genetic disorders. Polygenic traits are predictable, but with less reliability than single-gene traits. Multifactorial inheritance is similar to polygenic inheritance in that multiple alleles at different loci affect the outcome; the difference is that multifactorial inheritance includes environmental effects on the genes. Many other gene–gene interactions are known. These include epistasis, in which one gene masks the phenotypic effects of another nonallelic gene; multiple alleles, in which more than one allele affects the same trait (e.g., ABO blood types); complementary genes, in which each gene is mutually dependent on the other; and collaborative genes, in which two different genes influencing the same trait interact to produce a phenotype neither gene alone could produce.

Genetic Imprinting Besides autosomal and sex-linked genes and mitochondrial inheritance, it was found that certain genes exhibit a “parent of origin” type of transmission in which the parental genomes do not always contribute equally in the development of a person (Fig. 6.10). The transmission of this phenomenon is called genetic imprinting. Although rare, it is

estimated that approximately 100 genes exhibit genetic imprinting. Evidence ­suggests a genetic conflict occurs in the developing embryo: the male genome attempts to establish larger offspring, whereas the female prefers smaller offspring to conserve her energy for the current and subsequent pregnancies. It was the pathologic analysis of ovarian teratomas (tumors made up of various cell types derived from an undifferentiated germ cell) and hydatidiform moles (gestational tumors made up of trophoblastic tissue) that yielded the first evidence of genetic imprinting. All ovarian teratomas were found to have a 46,XX karyotype. The results of detailed chromosomal polymorphism analysis confirmed that these tumors developed without the paternally derived genome. Conversely, analysis of hydatidiform moles suggested that they were tumors of paternal origin. Well-known examples of genomic imprinting are the transmission of the mutations in Prader-Willi and Angelman syndromes.15 Both syndromes exhibit mental retardation as a common feature. It was also found that both disorders had the same deletion in chromosome 15. When the deletion is inherited from the mother, the infant presents with Angelman (“happy puppet”) syndrome. When the same deletion is inherited from the father, Prader-Willi syndrome results. A related chromosomal disorder is uniparental disomy. This occurs when two chromosomes of the same number are inherited from one parent. Normally, this is not a problem except in cases where a chromosome has been imprinted by a parent. If imprinting inactivates an allele, the offspring will have only one working copy of the chromosome, resulting in possible problems.

A

Generation I

C

Generation II

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B

+

+

+ FIGURE 6.10 • Pedigree of genetic imprinting. In generation I, male A has inherited a mutant allele from his affected mother (not shown); the gene is “turned off” during spermatogenesis, and therefore, none of his offspring (generation II) will express the mutant allele, regardless of whether they are carriers. However, the gene will be “turned on” again during oogenesis in any of his daughters (B) who inherit the allele. All offspring (generation III) who inherit the mutant allele will be affected. All offspring of normal children (C) will produce normal offspring. Children of female D will all express the mutation if they inherit the allele.

+

Generation III

+

+

+

+ D

+ +

Affected individuals

+

Have the mutant allele but are not affected

+

Do not have the mutant allele and are not affected

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132   UNIT II  Cell Function and Growth

Key Points

Female

Male

Dd

Dd

TRANSMISSION OF GENETIC INFORMATION •  The transmission of information from one generation to the next is vested in genetic material transferred from each parent at the time of conception. •  Mendelian, or single-gene, patterns of inheritance include autosomal dominant and recessive traits that are transmitted from parents to their offspring in a predictable manner. Polygenic inheritance, which involves multiple genes, and multifactorial inheritance, which involves multiple genes as well as environmental factors, are less predictable.

D

d

Mendel’s Laws A main feature of inheritance is predictability: given certain conditions, the likelihood of the occurrence or recurrence of a specific trait is remarkably predictable. The units of inheritance are the genes, and the pattern of single-gene expression can often be predicted using Mendel’s laws of genetic transmission. Techniques and discoveries since Gregor Mendel’s original work was published in 1865 have led to some modification of the original laws. Mendel discovered the basic pattern of inheritance by conducting carefully planned experiments with simple garden peas. Experimenting with several phenotypic traits in peas, Mendel proposed that inherited traits are transmitted from parents to offspring by means of independently inherited factors—now known as genes—and that these factors are ­transmitted as recessive and dominant traits. Mendel labeled dominant factors (his round peas) “A” and recessive factors (his wrinkled peas) “a.” Geneticists continue to use capital letters to designate dominant traits and lowercase letters to identify recessive traits. The possible combinations that can occur with transmission of single-gene dominant and recessive traits can be described by constructing a figure called a Punnett square using capital and lowercase letters (Fig. 6.11). The observable traits of single-gene inheritance are inherited by the offspring from the parents. During maturation, the primordial germ cells (i.e., sperm and ovum) of both parents undergo meiosis, or reduction division, in which the number of chromosomes is divided in half (from 46 to 23). At this time, the two alleles from a gene locus separate so that each germ cell receives only one allele from each pair (i.e., Mendel’s first law). According to Mendel’s second law, the alleles from the different gene loci segregate independently and recombine randomly in the zygote. People in whom the two alleles of a given pair are the same (AA or aa) are called homozygotes. Heterozygotes have different alleles (Aa) at a gene locus. A recessive trait is one expressed only in a homozygous pairing; a dominant trait is one expressed in either a homozygous or a heterozygous pairing. All people with a dominant allele (depending on the penetrance of the genes) manifest that trait. A carrier is a person who is heterozygous

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D

d

DD

Dd

1/4

1/4

Dd

dd

1/4

1/4

DD=1/4 Dd=1/2 dd=1/4

FIGURE 6.11 • The Punnett square showing all possible combinations for transmission of a single-gene trait (dimpled cheeks). The example shown is when both parents are heterozygous (Dd) for the trait. The alleles carried by the mother are on the left, and those carried by the f­ather are on the top. The D allele is dominant, and the d allele is recessive. The DD and Dd offspring have dimples, and the dd offspring does not.

for a recessive trait and does not manifest the trait. For example, the genes for blond hair are recessive and those for brown hair are dominant. Therefore, only people with a genotype having two alleles for blond hair would be blond; people with either one or two brown alleles would have brown hair.

Pedigree A pedigree is a graphic method (see Figs. 6.10 and 6.11) for portraying a family history of an inherited trait. It is constructed from a carefully obtained family history and is useful for tracing the pattern of inheritance for a particular trait.

IN SUMMARY Inheritance represents the likelihood of the occurrence or recurrence of a specific genetic trait. The genotype refers to information stored in the genetic code of a person, whereas the phenotype represents the recognizable traits, physical and biochemical, associated with the genotype. Expressivity refers to the expression of a gene in the phenotype, and penetrance is the ability of a gene to express its function. The point on the DNA molecule that controls the inheritance of a particular trait is called a gene locus. Alternate forms of a gene at a gene locus are called alleles. The alleles at a gene locus may carry recessive or dominant traits. A recessive trait is one expressed only when two copies (homozygous) of the recessive allele are present. Dominant traits are expressed with either homozygous or heterozygous pairing of the alleles. A pedigree is a graphic method for portraying a family history of an inherited trait.

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GENE TECHNOLOGY After completing this section of the chapter, you should be able to meet the following objectives: •• Briefly describe the methods used in linkage studies, dosage studies, and hybridization studies. •• Describe the process of recombinant DNA technology. •• Characterize the process of RNA interference.

The past several decades have seen phenomenal advances in the field of genetics. These advances have included the assembly of physical and genetic maps through the Human Genome Project, the establishment of the International HapMap Project to map the haplotypes of the many closely related single nucleotide polymorphisms in the human genome, and the development of methods for applying the technology of these projects to the diagnosis and treatment of disease. Many health care professions also have established clinical competencies for their specific professions regarding genomics and genetics since the application of genetics is becoming more evident in all areas of disease screening and management. There are multiple new genetic diagnostics being used that are able to assess patients for various genetic alterations. Information obtained from these technologies greatly assists in planning the care and specifically pharmacological management of many types of diseases. Health care professionals need to be able to answer questions and explain to patients and families genetic information and how this knowledge may or may not influence the course of one’s health.

Genetic Mapping Genetic mapping is the assignment of genes to specific chromosomes or parts of the chromosome. Another type of mapping strategy, the haplotype map, focuses on identifying the slight variations in the human genome that affect an individual’s susceptibility to disease and responses to environmental factors such as microbes, toxins, and drugs. There are two types of gene maps: genetic maps and physical maps. Genetic maps are like highway maps. They use linkage studies (e.g., dosage, hybridization) to estimate the distances between chromosomal landmarks (i.e., gene markers). Physical maps are similar to a surveyor’s map. They make use of cytogenetic and molecular techniques to determine the actual, physical locations of genes on chromosomes. Genetic maps and physical maps have been refined over the decades. The earliest mapping efforts localized genes on the X chromosome. The initial assignment of a gene to a particular chromosome was made in 1911 for the color blindness gene inherited from the mother (i.e., following the X-linked pattern of inheritance). In 1968, the specific location of the Duffy blood group on the long arm of chromosome 1 was determined.

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The Human Genome Project The Human Genome Project, initiated in 1990 and completed in 2003, sought to identify all the genes in the human genome. The international project was charged with developing genetic and physical maps that allowed the precise location of genes and with exploring technologies that would enable the sequencing of large amounts of DNA with high accuracy and low cost. Some of what was discovered was quite unexpected, including the revelation that humans have a mere 30,000 genes, rather than the predicted 100,000. Another surprising finding was that, on an average, any two people share 99.9% of their DNA sequence, indicating that the remarkable diversity among people is vested in about 0.1% of our DNA.1,2 To date, the locations of more than 25,000 genes have been mapped to a specific chromosome, and most of them to a specific region on the chromosome.16 However, genetic mapping is continuing so rapidly that these numbers are constantly being updated. An excellent source of articles regarding specific chromosome sequencing in humans is the National Center for Biotechnology Information (NCBI) (www.ncbi. nlm.nih.gov/index.html).16 Another source is the Genome Data Base, a central database for mapped genes and an international repository for most mapping information.17 Genetic Mapping Methods Many methods have been used for developing genetic maps. The most important ones are family linkage studies, gene dosage methods, and hybridization studies. Often, the specific assignment of a gene is made using information from several mapping techniques. Linkage Studies.  Linkage studies assume that genes occur in a linear array along the chromosomes. During meiosis, the paired chromosomes of the diploid germ cell exchange genetic material because of the crossing-over phenomenon (see Fig. 6.8). This exchange usually involves more than one gene; large blocks of genes (representing large portions of the chromosome) are usually exchanged. Although the point at which one block separates from another occurs randomly, the closer together two genes are on the same chromosome, the greater the chance is that they will be passed on together to the offspring. When two inherited traits occur together at a rate greater than would occur by chance alone, they are said to be linked. Several methods take advantage of the crossing-over and recombination of genes to map a particular gene. In one method, any gene that is already assigned to a chromosome can be used as a marker to assign other linked genes. For example, it was found that an extra long chromosome 1 and the Duffy blood group were inherited as a dominant trait, placing the position of the blood group gene close to the extra material on chromosome 1. Color blindness has been linked to classic hemophilia A (i.e., lack of factor VIII) in some pedigrees; hemophilia A has been linked to glucose-6-phosphate dehydrogenase deficiency in others; and color blindness has

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been linked to glucose-6-phosphate dehydrogenase deficiency in still others. Because the gene for color blindness is found on the X chromosome, all three genes must be found in a small section of the X chromosome. Linkage analysis can be used clinically to identify affected persons in a family with a known genetic defect. Males, because they have one X and one Y chromosome, are said to be hemizygous for sex-linked traits. Females can be homozygous or heterozygous for sexlinked traits. Heterozygous females are known as carriers for X-linked defects. One autosomal recessive disorder that has been successfully diagnosed prenatally by linkage studies using amniocentesis is congenital adrenal hyperplasia (due to 21-hydroxylase deficiency), which is linked to an immune response gene (human leukocyte antigen [HLA]) type.18 Postnatal linkage studies have been used in diagnosing hemochromatosis, which is closely linked to another HLA type.19 People with this disorder are unable to metabolize iron, and it accumulates in the liver and other organs. It cannot be diagnosed by conventional means until irreversible damage has been done. Given a family history of the disorder, HLA typing can determine if the gene is present, and if it is present, dietary restriction of iron intake may be used to prevent organ damage. Gene Dosage Studies. Dosage studies involve measuring enzyme activity. Autosomal genes are normally arranged in pairs, and normally both are expressed. If both alleles are present and both are expressed, the activity of the enzyme should be 100%. If one member of the gene pair is missing, only 50% of the enzyme activity is present, reflecting the activity of the remaining normal allele. Hybridization Studies.  A recent biologic discovery revealed that two somatic cells from different species, when grown together in the same culture, occasionally fuse to form a new hybrid cell. Two types of hybridization methods are used in genomic studies: somatic cell hybridization and in situ hybridization. Somatic cell hybridization involves the fusion of human somatic cells with those of a different species (typically, the mouse) to yield a cell containing the chromosomes of both species. Because these hybrid cells are unstable, they begin to lose chromosomes of both species during subsequent cell divisions. This makes it possible to obtain cells with different partial combinations of human chromosomes. The enzymes of these cells are then studied with the understanding that for an enzyme to be produced, a certain chromosome must be present and, therefore, the coding for the enzyme must be located on that chromosome. In situ hybridization involves the use of specific sequences of DNA or RNA to locate genes that do not express themselves in cell culture. DNA and RNA can be chemically tagged with radioactive or fluorescent markers. These chemically tagged DNA or RNA sequences are used as probes to detect gene location. The probe is added to a chromosome

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spread after the DNA strands have been separated. If the probe matches the complementary DNA of a chromosome segment, it hybridizes and remains at the precise location (therefore the term in situ) on a chromosome. Radioactive or fluorescent markers are used to find the location of the probe. Haplotype Mapping As work on the Human Genome Project progressed, many researchers reasoned that identifying the common patterns of DNA sequence variations in the human genome would be possible. An international project, known as the International HapMap Project, was organized with the intent of developing a haplotype map of these variations.7 One of the findings of the Human Genome Project was that the genome sequence was 99.9% identical for all people. It is anticipated that the 0.1% variation may greatly affect a person’s response to drugs, toxins, and predisposition to various diseases. Sites in the DNA sequence where people differ at a single DNA base are called single nucleotide polymorphisms (SNPs, pronounced “snips”). A haplotype consists of the many closely linked SNPs on a single chromosome that generally are passed as a block from one generation to another in a particular population. One of the motivating factors behind the HapMap Project was the realization that the identification of a few SNPs was enough to uniquely identify the haplotypes in a block. The specific SNPs that identify the haplotypes are called tag SNPs. A HapMap is a map of these haplotype blocks and their tag SNPs. This approach reduces the number of SNPs required to examine an entire genome and make genome scanning methods much more efficient in finding regions with genes that contribute to disease development. Much attention has focused on the use of SNPs to decide whether a genetic variant is associated with a higher risk of disease susceptibility in one population versus another. Pharmacogenetics addresses the variability of drug response due to inherited characteristics in people, allowing identification of people who can be expected to respond favorably to a drug and those who can be expected to experience adverse reactions. This results in safer, more effective, and more cost-efficient use of medications.

Recombinant DNA Technology The term recombinant DNA refers to a combination of DNA molecules that are not found together in nature. Recombinant DNA technology makes it possible to identify the DNA sequence in a gene and produce the protein product encoded by a gene. The specific nucleotide sequence of a DNA fragment can often be identified by analyzing the amino acid sequence and mRNA codon of its protein product. Short sequences of base pairs can be synthesized, radioactively labeled, and subsequently used to identify their complementary sequence. In this way, identifying normal and abnormal gene structures is possible. Tests of DNA sequences are particularly useful in identifying polymorphisms, including the previously discussed SNPs, that are associated with various diseases. Because

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genetic variations are so distinctive, DNA fingerprinting (analysis of DNA sequence differences) can be used to determine family relationships or help identify persons involved in criminal acts. The methods of recombinant DNA technology can also be used in the treatment of disease. For example, recombinant DNA technology is used in the manufacture of human insulin that is used to treat diabetes mellitus. Gene Isolation and Cloning The gene isolation and cloning methods used in recombinant DNA technology rely on the fact that the genes of all organisms, from bacteria through mammals, are based on a similar molecular organization. Gene cloning requires cutting a DNA molecule apart, modifying and reassembling its fragments, and producing copies of the modified DNA, its mRNA, and its gene product. The DNA molecule is cut apart by using a bacterial enzyme, called a restriction enzyme, that binds to DNA wherever a particular short sequence of base pairs is found and cleaves the molecule at a specific nucleotide site. In this way, a long DNA molecule can be broken down into smaller, discrete fragments, one of which presumably contains the gene of interest. Many restriction enzymes are commercially available that cut DNA at different recognition sites. The restrictive fragments of DNA can often be replicated through insertion into a unicellular organism, such as a bacterium. To do this, a cloning vector such as a bacterial virus or a small DNA circle that is found in most bacteria, called a plasmid, is used. Viral and plasmid vectors replicate autonomously in the host bacterial cell. During gene cloning, a bacterial vector and the DNA fragment are mixed and joined by a special enzyme called a DNA ligase. The recombinant vectors formed are then introduced into a suitable culture of bacteria, and the bacteria are allowed to replicate and express the recombinant vector gene. Sometimes, mRNA taken from a tissue that expresses a high level of the gene is used to produce a complementary DNA molecule that can be used in the cloning process. Because the fragments of the entire DNA molecule are used in the cloning process, additional steps are taken to identify and separate the clone that contains the gene of interest. Pharmaceutical Applications Recombinant DNA technology has also made it possible to produce proteins that have therapeutic properties. One of the first products to be produced was human insulin. Recombinant DNA corresponding to the A chain of human insulin was isolated and inserted into plasmids that were in turn used to transform Escherichia coli. The bacteria then synthesized the insulin chain. A similar method was used to obtain the B chains. The A and B chains were then mixed and allowed to fold and form disulfide bonds, producing active insulin molecules. Human growth hormone has also been produced in E. coli. More complex proteins are produced in mammalian cell culture using recombinant DNA techniques. These include erythropoietin, which is used to stimulate red blood cell production; factor VIII, which is used to treat hemophilia;

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and tissue plasminogen activator (tPA), which is frequently administered after a heart attack to dissolve thrombi. DNA Fingerprinting The technique of DNA fingerprinting is based in part on those techniques used in recombinant DNA technology and on those originally used in medical genetics to detect slight variations in the genomes of different individuals.20 Using restriction enzymes, DNA is cleaved at specific regions (Fig. 6.12). The DNA fragments are separated according to size by electrophoresis and denatured (by heating or treating chemically) so that all the DNA is single stranded. The single-stranded DNA is then transferred to nitrocellulose paper, baked to attach the DNA to the paper, and treated with series of radioactive probes. After the radioactive probes have been allowed to bond with the denatured DNA, radiography is used to reveal the labeled DNA fragments. When used in forensic pathology, this procedure is applied to specimens from the suspect and the forensic specimen. Banding patterns are then analyzed to see if they match. With conventional methods of analysis of blood and serum enzymes, a 1 in 100 to 1000 chance exists that the two specimens match because of chance. With DNA fingerprinting, these odds are 1 in 100,000 to 1 million. When necessary, the polymerase chain reaction (PCR) can be used to amplify specific segments of DNA. It is particularly suited for amplifying regions of DNA for clinical and forensic testing procedures because only a small sample of DNA is required as the starting material. Regions of DNA can be amplified from a single hair or drop of blood or saliva. Gene Therapy Although quite different from inserting genetic material into a unicellular organism such as bacteria, techniques are available for inserting genes into the genome of intact multicellular plants and animals. Promising delivery vehicles for these genes are the adenoviruses. These viruses are ideal vehicles because their DNA does not become integrated into the host genome. However, repeated inoculations are often needed because the body’s immune system usually targets cells expressing adenovirus proteins. Sterically stable liposomes also show promise as DNA delivery mechanisms.21 This type of therapy is one of the more promising methods for the treatment of genetic disorders such as cystic fibrosis, certain cancers, and many infectious diseases. Two main approaches are used in gene therapy: transferred genes can replace defective genes or they can selectively inhibit deleterious genes. Cloned DNA sequences are usually the compounds used in gene therapy. However, the introduction of the cloned gene into the multicellular organism can influence only the few cells that get the gene. An answer to this problem would be the insertion of the gene into a sperm or ovum; after fertilization, the gene would be replicated in all of the differentiating cell types. Even so, techniques for cell insertion are limited. Not only are moral and ethical issues involved, but these techniques cannot direct the inserted DNA

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Chromosomal DNA

Digest with restriction endonucleases

RNA Interference Technology

DNA fragments

Su sp ec t1 Su sp ec t2 Su sp ec t3

ct im Vi

Ev id en ce

Separate fragments by gel electrophoresis

Gel

Denature and transfer DNA to nitrocellulose paper

t3 ec sp

FIGURE 6.12 • DNA fingerprinting. Restrictive enzymes are used to break chromosomal DNA into fragments, which are then separated by gel electrophoresis, denatured, and transferred to nitrocellulose paper; the DNA bands are labeled with a radioactive probe and observed using autoradiography. (Modified from Smith C., Marks A. D., Lieberman M. (2005). Marks’ basic medical biochemistry (2nd ed., p. 309). ­Philadelphia, PA: Lippincott Williams & Wilkins.)

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One approach of gene therapy focuses on the previously described replacement of missing or defective genes. However, several genetic disorders are due not to missing genes but to faulty gene activity. With this in mind, some scientists are approaching the problem by using RNA interference (RNAi) to stop genes from making unwanted disease proteins.22 RNAi is a naturally occurring process in which small pieces of double-stranded RNA (small interfering RNA [siRNA]) suppress gene expression. Scientists believe that RNAi may have originated as a defense against viral infections and potentially harmful genomic invaders. In viral infections, RNAi would serve to control the infection by preventing the synthesis of viral proteins. With the continued refinement of techniques to silence genes, RNAi has already had a major impact on molecular biology. For example, it has given scientists the ability to practice reverse genomics, in which a gene’s function can be inferred through silencing its expression. Increasingly, pharmaceutical companies are using RNAi to identify d­ isease-related drug targets. There also is considerable interest in harnessing RNAi for therapeutic purposes, including the treatment of human immunodeficiency virus (HIV) infection and hepatitis C. Before this can occur, however, the therapeutic methods must be shown to be safe and effective, and obstacles to delivering the RNAi into targeted cells must be overcome. It is difficult for RNA to cross the cell membrane, and enzymes in the blood quickly break it down.

IN SUMMARY

Su

Su

sp

ec

t1 ec sp Su

Vi

ct

im

ce en Ev id

t2

Incubate with probe, wash and perform autoradiography to observe labeled DNA bands

Radioactive DNA probe

to attach to a particular chromosome or supplant an existing gene by knocking it out of its place. To date, gene therapy has been used successfully to treat children with severe combined immunodeficiency disease, and in a suicide gene transfer to facilitate treatment of graftversus-host disease after donor lymphocyte infusion.

The genome is the gene complement of an organism. Genomic mapping is a method used to assign genes to particular chromosomes or parts of a chromosome. The most important ones used are family linkage studies, gene dosage methods, and hybridization studies. Often the specific assignment of a gene is determined by using information from several mapping techniques. Linkage studies assign a chromosome location to genes based on their close association with other genes of known location. Recombinant DNA studies involve the extraction of specific types of mRNA used in synthesis of complementary DNA strands. The complementary DNA strands, labeled with a radioisotope, bind with the genes for which they are complementary and are used as gene probes. A haplotype consists of the many closely linked SNPs on a single chromosome that generally are passed as a block from one generation

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to another in a particular population. The International HapMap Project has been developed to map the SNPs on the human genome with the anticipation that it may be useful in the prediction and management of disease. Genetic engineering has provided the methods for manipulating nucleic acids and recombining genes (recombinant DNA) into hybrid molecules that can be inserted into unicellular organisms and reproduced many times over. As a result, proteins that formerly were available only in small amounts can now be made in large quantities once their respective genes have been isolated. DNA fingerprinting, which relies on recombinant DNA technologies and those of genetic mapping, is often used in forensic investigations. A newer strategy for management of genetic disorders focuses on gene silencing by using RNAi to stop genes from making unwanted disease proteins.

REVIEW EXERCISES 1. The Human Genome Project has revealed that humans have only 30,000 to 35,000 genes. Only about 2% of the genome encodes instructions for protein synthesis, whereas 50% consists of repeat sequences that do not code proteins. A. Use this information to explain how this small number of protein-encoding genes is able to produce the vast array of proteins needed for organ and structural development in the embryo, as well as those needed for normal function of the body in postnatal life. 2. A child about to undergo surgery is typed for possible blood transfusions. His parents are told that he is type O positive. Both his mother and father are type A positive. A. How would you explain this variation in blood type to the parents? 3. More than 100,000 people die of adverse drug reactions each year; another 2.2 million experience serious reactions, whereas others fail to respond at all to the therapeutic actions of drugs. A. Explain how the use of information about single nucleotide polymorphisms (SNPs) might be used to map individual variations in drug responses. 4. Human insulin, prepared by recombinant DNA technology, is used for the treatment of diabetes mellitus. A. Explain the techniques used for the production of a human hormone with this technology.

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References 1. Holmes F. L. (2001). Meselson, Stahl, and the replication of DNA: A history of “the most beautiful experiment in biology.” New Haven, CT: Yale University Press. 2. McConnell T. H., Hull K. L. (2011). Human form human function: Essentials of anatomy & physiology. Philadelphia, PA: Lippincott Williams & Wilkins. 3. Gahan P. B. (2011). Circulating nucleic acids in plasma and serum. New York: Springer. 4. Wie C. (2004). Methods in enzymology: Chromatin and chromatin remodeling enzymes, Part A. St. Louis, MO: Elsevier. 5. Sund J., Ander M., Aqvist J. (2010). Principles of stop-codon reading on the ribosome. Nature 465, 947–950. 6. Jogland S. N. (2009). Gene biotechnology. New Delhi, India: Himalaya Publishing House. 7. Chung D. C., Haber D. A. (2010). Principles of clinical cancer genetics: A handbook from the Massachusetts General Hospital. New York: Springer. 8. Ahmad S. (2010). Diseases of DNA repair. New York: Springer. 9. Hall J. E. (2011). Guyton and Hall textbook of medical physiology (12th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 10. Primrose S. B., Twyman R. (2003). Principles of genome analysis and genomics (3rd ed.). Malden, MA: Wiley-Blackwell. 11. Wyttenbach A., O’Connor V. (Eds.) (2011). Folding for the synapse. New York: Springer. 12. Stanton B. Z., Peng L. F. (2010). Small molecule modulators of the Sonic Hedgehog signaling pathway. Molecular Biosynthesis 6(1), 44–54. 13. Skaletsky H., Kuroda-Kawaguchi T., Minx P. J., et al. (2003). The malespecific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423(6942), 825–837. 14. Rubin R., Strayer D. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine. Philadelphia, PA: Lippincott Williams & Wilkins. 15. Gurrieri F., Accadia M. (2009). Genetic imprinting: The paradigm of Prader-Willi and Angelman syndromes. Endocrine Development 14, 20–28. 16. National Center for Biotechnology Information. (2009). Human genome and  maps. [Online]. Available: www.ncbi.nlm.nih.gov/index.html. Re­trieved November 25, 2011. 17. National Center for Biotechnology Information. (2009). Genome database. [Online]. Available: http://www.ncbi.nlm.nih.gov/sites/genome. Retrieved November 25, 2011. 18. Nimkarn S., Lin-Su K., New M. I. (2011). Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia. Pediatric Clinics of North America 58(5), 1281–1300. 19. McElroy V. (2009). Hemochromatosis: A literature review. Journal of Diagnostic Medical Sonography 25(6), 325–330. 20. Laino C. (2008). Genetic fingerprinting is changing clinical practice. Oncology Times 30(15), 5–6. 21. Gregoriadis G. (2006). Liposome technology. Volume 1: Liposome preparation and related techniques. London, UK: Informa Healthcare. 22. Petrocca F., Lieberman J. (2011). Promise and challenge of RNA interference-based therapy for cancer. Journal of Clinical Oncology ­ 29(6), 747–754.

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Genetic and Congenital Disorders GENETIC AND CHROMOSOMAL DISORDERS

Single-Gene Disorders Autosomal Dominant Disorders Autosomal Recessive Disorders X-Linked Recessive Disorders Fragile X Syndrome Multifactorial Inheritance Disorders Cleft Lip and Cleft Palate Chromosomal Disorders Structural Chromosomal Abnormalities Numeric Disorders Involving Autosomes Numeric Disorders Involving Sex Chromosomes Mitochondrial Gene Disorders

DISORDERS DUE TO ENVIRONMENTAL INFLUENCES Period of Vulnerability Teratogenic Agents Radiation Chemicals and Drugs Infectious Agents Folic Acid Deficiency

DIAGNOSIS AND COUNSELING

Genetic Assessment Prenatal Screening and Diagnosis Ultrasonography Maternal Serum Markers Amniocentesis Chorionic Villus Sampling Percutaneous Umbilical Cord Blood Sampling Cytogenetic and Biochemical Analyses

7 Lisa C. Grossman

Congenital defects, sometimes called birth defects, are abnormalities of a body structure, function, or metabolism that are present at birth. They affect more than 185,000 infants discharged from the hospital in the United States each year and are the leading cause of infant death.1 Birth defects may be caused by genetic factors (i.e., single-gene or multifactorial inheritance or chromosomal aberrations) or environmental factors that are active during embryonic or fetal development (e.g., maternal disease, infections, or drugs taken during pregnancy). Although congenital defects are present at birth, genetic disorders may make their appearance later in life. This chapter provides an overview of genetic and congenital disorders and is divided into three parts: 1. Genetic and chromosomal disorders 2. Disorders due to environmental agents 3. Diagnosis and counseling

GENETIC AND CHROMOSOMAL DISORDERS After completing this section of the chapter, you should be able to meet the following objectives: •• Describe three types of single-gene disorders and their patterns of inheritance. •• Contrast disorders due to multifactorial inheritance with those caused by single-gene inheritance. •• Describe three patterns of chromosomal breakage and rearrangement. A genetic disorder can be described as a discrete event that affects gene expression in a group of cells related to each other by gene linkage. Most genetic disorders are caused by changes in the deoxyribonucleic acid (DNA) sequence that alters the synthesis of a single gene product. Others are a result of chromosomal aberrations that trigger deletion or duplication errors.2 Some genetic disorders are a result of an abnormal number of chromosomes.2

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The genes on each chromosome are arranged in pairs and in strict order, with each gene occupying a specific location or locus. The two members of a gene pair, one inherited from the mother and the other from the father, are called alleles. If the members of a gene pair are identical (i.e., code the exact same gene product), the person is homozygous, and if the two members are different, the person is heterozygous. The genetic composition of a person is called a genotype, whereas the phenotype is the observable expression of a genotype in terms of morphologic, biochemical, or molecular traits. If the trait is expressed in the heterozygote (one member of the gene pair codes for the trait), it is said to be dominant. If it is expressed only in the homozygote (both members of the gene pair code for the trait), it is recessive. Although gene expression usually follows a dominant or recessive pattern, it is possible for both alleles of a gene pair to be fully expressed in the heterozygote, a condition called codominance. Many genes have only one normal version, which geneticists call the wild-type allele. Other genes have more than one normal allele (alternate forms) at the same locus. This is called polymorphism. Blood group inheritance (e.g., AO, BO, AB) is an example of codominance and polymorphism. A gene mutation is a biochemical event such as nucleotide change, deletion, or insertion that produces a new allele. A single mutant gene may be expressed in many different parts of the body. Marfan syndrome, for example, is a defect in a connective tissue protein that has widespread effects involving skeletal, eye, and cardiovascular structures. In other single-gene disorders, the same defect can be caused by mutations at several different loci. Childhood deafness can result from many different types of autosomal recessive mutations. Genetic disorders can involve a single-gene trait, a multifactorial inheritance, a chromosomal abnormality, or a mitochondrial gene disorder. The disorder may be inherited as a family trait or arise as a sporadic case due to a new mutation.

Single-Gene Disorders Single-gene disorders are caused by a defective or mutant allele at a single gene locus and follow mendelian patterns of inheritance. Single-gene disorders are primarily disorders of the pediatric age group. Less than 10% manifest after puberty and only 1% after the reproductive years.3 Single-gene disorders are characterized by their patterns of transmission, which usually are obtained through a family genetic history. The patterns of inheritance depend on whether the phenotype is dominant or recessive and whether the gene is located on an autosomal or sex chromosome. In addition to disorders caused by mutations of genes located on the chromosomes located within the nucleus, another class of disorders with a maternal pattern of inheritance involves the mitochondrial genome. Virtually all single-gene disorders lead to formation of an abnormal protein or decreased production of a gene product. The disorder can result in a defective enzyme or decreased amounts of an enzyme, defects in receptor proteins and their

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function, alterations in nonenzyme proteins, or mutations resulting in unusual reactions to drugs. Table 7.1 lists some of the common single-gene disorders and their manifestations. Autosomal Dominant Disorders In autosomal dominant disorders, a single mutant allele from an affected parent is transmitted to an offspring regardless of sex. The affected parent has a 50% chance of transmitting the disorder to each offspring (Fig. 7.1). The unaffected relatives of the parent or unaffected siblings of the offspring do not transmit the disorder. In many conditions, the age of onset is delayed, and the signs and symptoms of the disorder do not appear until later in life, as in Huntington chorea. Autosomal dominant disorders also may manifest as a new mutation. Whether the mutation is passed on to the next generation depends on the affected person’s reproductive capacity. Many autosomal dominant mutations are accompanied by reduced reproductive capacity; therefore, the defect is not perpetuated in future generations. If an autosomal defect is accompanied by a total inability to reproduce, essentially all new cases of the disorder will be due to new mutations. If the defect does not affect reproductive capacity, it is more likely to be inherited. Although there is a 50% chance of inheriting a dominant genetic disorder from an affected parent, there can be wide variation in gene penetration and expression. When a person inherits a dominant mutant gene but fails to express it, the trait is described as having reduced penetrance. Penetrance is expressed in mathematical terms: a 50% penetrance indicates that a person who inherits the defective gene has a 50% chance of expressing the disorder. The person who has a mutant gene but does not express it is an important exception to the rule that unaffected persons do not transmit an autosomal dominant trait. These people can transmit the gene to their descendants and so produce a skipped generation. Autosomal dominant disorders also can display variable expressivity, meaning that they can be expressed differently among people. Polydactyly or supernumerary digits, for example, may be expressed in either the fingers or the toes. The gene products of autosomal dominant disorders usually are regulatory proteins involved in rate-limiting components of complex metabolic pathways or key components of structural proteins such as collagen.4 Two disorders of autosomal inheritance, Marfan syndrome and neurofibromatosis (NF), are described in this chapter. Marfan Syndrome.  Marfan syndrome is an autosomal dominant disorder of the connective tissue, which gives shape and structure to other tissues in the body and holds them in place. The basic biochemical abnormality in Marfan syndrome affects fibrillin I, a major component of microfibrils found in the extracellular matrix.5 These microfibrils form the scaffolding for the deposition of elastin and are considered integral components of elastic fibers. Fibrillin I is coded by the FBNI gene, which maps to chromosome 15q21. Over 100 mutations in the FBNI gene have been found, making genetic diagnosis

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TABLE 7.1 SOME DISORDERS OF MENDELIAN OR SINGLE-GENE INHERITANCE AND THEIR ­SIGNIFICANCE DISORDER

SIGNIFICANCE

Autosomal Dominant Achondroplasia Adult polycystic kidney disease Huntington chorea Familial hypercholesterolemia Marfan syndrome Neurofibromatosis (NF) Osteogenesis imperfecta Spherocytosis von Willebrand disease

Short-limb dwarfism Chronic kidney disease Neurodegenerative disorder Premature atherosclerosis Connective tissue disorder with abnormalities in the skeletal, ocular, cardiovascular systems Neurogenic tumors: fibromatous skin tumors, pigmented skin lesions, and ocular nodules in NF-1; bilateral acoustic neuromas in NF-2 Brittle bone disease due to defects in collagen synthesis Disorder of red blood cells Bleeding disorder

Autosomal Recessive Cystic fibrosis Glycogen storage diseases Oculocutaneous albinism Phenylketonuria (PKU) Sickle cell disease Tay-Sachs disease

Disorder of membrane transport of chloride ions in exocrine glands causing lung and pancreatic disease Excess accumulation of glycogen in the liver and hypoglycemia (von Gierke disease); glycogen accumulation in striated muscle in myopathic forms Hypopigmentation of skin, hair, eyes as a result of inability to synthesize melanin Lack of phenylalanine hydroxylase with hyperphenylalaninemia and impaired brain development Red blood cell defect Deficiency of hexosaminidase A; severe mental and physical deterioration beginning in infancy

X-Linked Recessive Bruton-type hypogammaglobulinemia Hemophilia A Duchenne dystrophy Fragile X syndrome

Immunodeficiency Bleeding disorder Muscular dystrophy Intellectual disability

unfeasible. The prevalence of Marfan syndrome is estimated to be 1 per 5000. Approximately 70% to 80% of cases are familial and the remainder are sporadic, arising from new mutations in the germ cells of the parents.5 Marfan syndrome affects several organ systems, including the eyes; the cardiovascular system, specifically correlated highly with aortic aneurysms; and the skeletal system (bones and joints).5–8 There is a wide range of variation in the ­expression

FIGURE 7.1 •  Simple pedigree for inheritance of an autosomal dominant trait. The colored circle or square represents an affected parent with a mutant gene. An affected parent with an autosomal dominant trait has a 50% chance of passing the mutant gene on to each child regardless of sex.

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of the disorder. People may have abnormalities of one, two, or more systems. The skeletal deformities, which are the most obvious features of the disorder, include a long, thin body with exceptionally long extremities and long, tapering fingers, sometimes called arachnodactyly or spider fingers; hyperextensible joints; and a variety of spinal deformities, including kyphosis and scoliosis (Fig. 7.2). Chest deformities, pectus excavatum (i.e., deeply depressed sternum) or pigeon chest deformity, often are present and may require surgery. The most common eye disorder is bilateral dislocation of the lens due to weakness of the suspensory ligaments. Myopia and predisposition to retinal detachment also are common, the result of increased optic globe length due to altered connective tissue support of ocular structures. However, the most life-threatening aspects of the disorder are the cardiovascular defects, which include mitral valve prolapse, progressive dilation of the aortic valve ring, and weakness of the aorta and other arteries. Dissection and rupture of the aorta may lead to premature death. In women, the risk of aortic dissection is increased in pregnancy. The diagnosis of Marfan syndrome is based on major and minor diagnostic criteria that include skeletal, cardiovascular, and ocular deformities. There is no cure for Marfan syndrome. Treatment plans include echocardiograms and ­electrocardiograms

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of people with NF-1, cutaneous and subcutaneous neurofibromas develop in late childhood or adolescence.4 The cutaneous neurofibromas, which vary in number from a few to many hundreds, manifest as soft, pedunculated lesions that project from the skin. They are the most common type of lesion, often are not apparent until puberty, and are present in greatest density over the trunk (Fig. 7.3). The subcutaneous lesions grow just below the skin. They are firm and round and may be painful. Plexiform neurofibromas involve the larger peripheral nerves. They tend to form large tumors that cause severe disfigurement of the face, overgrowth of an extremity, or skeletal deformities such as scoliosis. Pigmented nodules of the iris (Lisch nodules), which are specific for NF-1, usually are present after 6 years of age.11 They do not present any clinical problem but are useful in establishing a diagnosis. If a person presents with sudden visual loss and no radiological findings or increased intracranial pressure, it is a warning of possible increased tumor growth in the central nervous system (CNS).9 A second major component of NF-1 is the presence of large (usually ≥15 mm in diameter), flat cutaneous pigmentations, known as café au lait spots.4 They are usually a u­ niform light brown in whites and darker brown in people of color, with sharply demarcated edges. Although small single lesions may be found in normal children, larger lesions or six or more spots larger than 1.5 cm in diameter suggest NF-1. A Wood lamp, which uses ultraviolet light, can be used to detect lighter spots.

EYE Lens dislocation, myopia SKELETAL DEFORMITY Pectus carinatum (pigeon chest), pectus excavatum (funnel chest) Vertebral deformity (kyphosis, scoliosis) Long arms, arm span exceeds height

CARDIOVASCULAR Aortic aneurysm, floppy valves

Dissecting aortic aneurysm with exsanguination Joint hypermobility, especially fingers, wrists, and knees FIGURE 7.2  •  Clinical features of Marfan syndrome.

to assess the status of the cardiovascular system, periodic eye examinations, and evaluation of the skeletal system, especially in children and adolescents. The risks associated with participation in sports depend on which organ systems are involved. Neurofibromatosis. Neurofibromatosis is a condition that causes tumors to develop from the Schwann cells of the neurological system.4 There are at least two genetically and clinically distinct forms of the disorder: 1. Type 1 NF (NF-1), also known as von Recklinghausen disease 2. Type 2 bilateral acoustic NF (NF-2)4,9 Both of these disorders result from a genetic defect in a tumor suppressor gene that regulates cell differentiation and growth. The gene for NF-1 has been mapped to the long arm of chromosome 17 and the gene for NF-2 to chromosome 22.4 Type 1 NF is a common disorder, with a frequency of 1 in 4000 that affects people of all races.4,10 In more than 90%

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FIGURE 7.3  •  Neurofibromatosis type 1. Multiple cutaneous neurofibromas are noted on the face and trunk. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 238). Philadelphia, PA: Lippincott Williams & Wilkins.)

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The skin pigmentations become more evident with age as the melanosomes in the epidermal cells accumulate melanin. Children with NF-1 are also susceptible to neurologic complications. There is an increased incidence of learning disabilities, attention deficit disorders, and abnormalities of speech among affected children. Complex partial and generalized tonic–clonic seizures are a frequent complication. Malignant neoplasms are also a significant problem in people with NF-1. One of the major complications of NF-1, occurring in 3% to 5% of people, is the appearance of a neurofibrosarcoma in a neurofibroma, usually a larger plexiform ­neurofibroma.4 NF-1 is also associated with increased incidence of other neurogenic tumors, including meningiomas, optic gliomas, and pheochromocytomas. Type 2 NF is characterized by tumors of the acoustic nerve. Most often, the disorder is asymptomatic through the first 15 years of life. This type of NF occurs less frequently at a rate of 1 in 50,000 people.4 The most frequent symptoms are headaches, hearing loss, and tinnitus. There may be associated intracranial and spinal meningiomas.4 The condition is often made worse by pregnancy, and oral contraceptives may increase the growth and symptoms of the tumors because many neurofibromas express progesterone receptors.4 People with the disorder should be warned that severe disorientation may occur during diving or swimming underwater, and drowning may result. Surgery may be indicated for debulking or removal of the tumors. Autosomal Recessive Disorders Autosomal recessive disorders are manifested only when both members of the gene pair are affected. In this case, both parents may be unaffected but are carriers of the defective gene. Autosomal recessive disorders affect both sexes. The occurrence risks in each pregnancy are one in four for an affected child, two in four for a carrier child, and one in four for a normal (noncarrier, unaffected), homozygous child (Fig. 7.4). Consanguineous mating (mating of two related people), or inbreeding, increases the chance that two people who mate will be carriers of an autosomal recessive disorder.3

FIGURE 7.4 • Simple pedigree for inheritance of an autosomal recessive trait. The half-colored circle and square represent a mutant gene. When both parents are carriers of a mutant gene, there is a 25% chance of having an affected child (full-colored circle or square), a 50% chance of a carrier child, and a 25% chance of a nonaffected or noncarrier child, regardless of sex. All children (100%) of an affected parent are carriers.

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With autosomal recessive disorders, the age of onset is frequently early in life. In addition, the symptomatology tends to be more uniform than with autosomal dominant disorders. Furthermore, autosomal disorders are characteristically caused by loss-of-function mutations, many of which impair or eliminate the function of an enzyme. In the case of a heterozygous carrier, the presence of a mutant gene usually does not produce symptoms because equal amounts of normal and defective enzymes are synthesized. This “margin of safety” ensures that cells with half their usual amount of enzyme function normally. By contrast, the inactivation of both alleles in a homozygote results in complete loss of enzyme activity. Autosomal recessive disorders include almost all inborn errors of metabolism. Enzyme disorders that impair catabolic pathways result in an accumulation of dietary substances (e.g., phenylketonuria [PKU]) or cellular constituents (e.g., lysosomal storage diseases). Other disorders result from a defect in the enzyme-mediated synthesis of an essential protein (e.g., the cystic fibrosis transmembrane conductance regulator in cystic fibrosis). Two examples of autosomal recessive disorders that are not covered elsewhere in this book are PKU and Tay-Sachs disease. Phenylketonuria.  PKU is a rare autosomal recessive metabolic disorder that affects approximately 1 in every 10,000 to 15,000 infants in the United States. The disorder is caused by a deficiency of the liver enzyme phenylalanine hydroxylase, which allows toxic levels of the amino acid, phenylalanine, to accumulate in tissues and the blood.12 If untreated, the disorder results in mental retardation, microcephaly, delayed speech, and other signs of impaired neurologic development. Because the symptoms of PKU develop gradually and would be difficult to assess, policies have been developed to screen all infants for abnormal levels of serum phenylalanine.12,13 It is important that blood samples for PKU screening be obtained at least 24 hours after birth to ensure accuracy.12 Infants with the disorder are treated with a special diet that restricts phenylalanine intake. The results of dietary therapy of children with PKU have been impressive. The diet can prevent mental retardation as well as other neurodegenerative effects of untreated PKU. However, dietary treatment must be started early in neonatal life to prevent brain damage. Infants with elevated phenylalanine levels (>10 mg/dL) should begin treatment by 7 to 10 days of age, indicating the need for early diagnosis. Evidence suggests that high levels of phenylalanine even during the first 2 weeks of life can be very harmful to the infant.13 Recent research regarding trials of sapropterin dihydrochloride in managing mild-tomoderate PKU shows potential promise, but more outcome data are needed.14 Tay-Sachs Disease.  Tay-Sachs disease is a variant of a class of lysosomal storage diseases, known as the gangliosidoses, in which there is failure to break down the GM2 gangliosides of cell membranes.15 Tay-Sachs disease is inherited as

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an  ­autosomal recessive trait and occurs ten times more frequently in offspring of Eastern European (Ashkenazi) Jews compared to the general population.16 The GM2 ganglioside accumulates in the lysosomes of all organs in Tay-Sachs disease, but is most prominent in the brain neurons and retina.4 Microscopic examination reveals neurons ballooned with cytoplasmic vacuoles, each of which constitutes a markedly distended lysosome filled with gangliosides. In time, there is progressive destruction of neurons within the brain substance, including the cerebellum, basal ganglia, brain stem, spinal cord, and autonomic nervous system. Involvement of the retina is detected by ophthalmoscopy as a cherry-red spot on the macula. Infants with Tay-Sachs disease appear normal at birth but begin to manifest progressive weakness, muscle flaccidity, and decreased attentiveness at approximately 6 to 10 months of age. This is followed by rapid deterioration of motor and mental function, often with development of generalized seizures. Retinal involvement leads to visual impairment and eventual blindness. Death usually occurs before 4 to 5 years of age. Analysis of the blood serum for the lysosomal enzyme, hexosaminidase A, which is deficient in Tay-Sachs disease, allows for accurate identification of genetic carriers for the disease. Although there is no cure for the disease, evidence suggests that the development of recombinant human lysosomal (beta)hexosaminidase A may be helpful in assisting some people with Tay-Sachs disease to have a higher quality of life.16 X-Linked Recessive Disorders Sex-linked disorders are almost always associated with the X, or female, chromosome, and the inheritance pattern is predominantly recessive. Because of the presence of a normal paired gene, female heterozygotes rarely experience the effects of a defective gene, whereas all males who receive the gene are typically affected. The common pattern of inheritance is one in which an unaffected mother carries one normal and one mutant allele on the X chromosome. This means that she has a 50% chance of transmitting the defective gene to her sons, and her daughters have a 50% chance of being carriers of the mutant gene (Fig. 7.5). When the affected son procreates, he transmits the defective gene to all of his daughters, who become carriers of the mutant gene. Because the genes of the Y chromosome are unaffected, the affected male does not transmit the defect to any of his sons, and they will not be carriers or transmit the disorder to their children. X-linked recessive disorders include glucose-6-phosphate dehydrogenase deficiency, hemophilia A, and X-linked agammaglobulinemia. Fragile X Syndrome Fragile X syndrome is a single-gene disorder that causes intellectual disability.4 The mutation occurs at the Xq27 on the fragile site and is characterized by amplification of a CGG repeat.4 The disorder, which affects approximately 1 in 1250 males and 1 in 2500 females, is the most common form of inherited intellectual disability.4 As with other X-linked disorders, fragile X syndrome affects boys more often than girls.

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FIGURE 7.5  •  Simple pedigree for inheritance of an X-linked recessive trait. X-linked recessive traits are expressed phenotypically in the male offspring. A small colored circle represents the X chromosome with the defective gene and the larger colored square, the affected male. The affected male passes the mutant gene to all of his daughters, who become carriers of the trait and have a 50% chance of passing the gene; her sons and her daughters have a 50% chance of being carriers of the gene (remember that their father has a normal X).

Pathogenesis. The fragile X gene has been mapped to the long arm of the X chromosome, designated the FMR1 (fragile X mental retardation 1) site.17 The gene product, the fragile X mental retardation protein (FMRP), is a widely expressed cytoplasmic protein. It is most abundant in the brain and testis, the organs most affected by the disorder. Each gene contains an introduction or promoter region and an instruction region that carries the directions for protein synthesis. The promoter region of the FMR1 gene contains repeats of a specific CGG (cytosine, guanine, guanine) triplet code that, when normal, controls gene activity. The mechanism by which the normal FMR1 gene is converted to an altered, or mutant, gene capable of producing disease symptoms involves an increase in the number of CGG repeats in the promoter region of the gene. Once the repeat exceeds a threshold length, no FMRP is produced, resulting in the fragile X phenotype. People without fragile X syndrome have between 6 and 40 repeats. A gene with 55 to 200 repeats is generally considered a permutation and one with more than 200 repeats, a full mutation.17 The inheritance of the FMR1 gene follows the pattern of X-linked traits, with the father passing the gene on to all his daughters but not his sons. Approximately 20% of males who have been shown to carry the fragile X mutation are c­ linically and cytogenetically normal.17 Because these male carriers transmit the trait through all their daughters (who are phenotypically normal) to affected grandchildren, they are called transmitting males. Clinical Manifestations and Diagnosis. Affected boys are intellectually disabled and share a common physical phenotype that includes a long face with large mandible and large, everted ears. Hyperextensible joints, a high-arched palate, and mitral valve prolapse, which are observed in some cases, mimic a connective tissue disorder. Some physical abnormalities may be subtle or absent. Because girls have two

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X ­chromosomes, they are more likely to have relatively normal cognitive development, or they may show a learning disability in a particular area, such as mathematics. Diagnosis of fragile X syndrome is based on mental and physical characteristics. DNA molecular tests can be done to confirm the presence of an abnormal FMR1 gene. Because the manifestations of fragile X syndrome may resemble those of other learning disorders, it is recommended that people with intellectual disability of unknown cause, developmental delay, learning disabilities, autism, or autism-like behaviors be evaluated for the disorder.17 Fragile X screening is now often offered along with routine prenatal screening to determine if the woman is a carrier.

Key Points GENETIC AND CHROMOSOMAL DISORDERS •  Genetic disorders are inherited as autosomal dominant disorders, in which each child has a 50% chance of inheriting the disorder, or as autosomal recessive disorders, in which each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected. •  Sex-linked disorders almost always are associated with the X chromosome and are predominantly recessive. •  Chromosomal disorders reflect events that occur at the time of meiosis and result from defective movement of an entire chromosome or from breakage of a chromosome with loss or translocation of genetic material.

Multifactorial Inheritance Disorders Multifactorial inheritance disorders are caused by multiple genes and, in many cases, environmental factors.4 The exact number of genes contributing to multifactorial traits is not known, and these traits do not follow the same clear-cut pattern of inheritance as do single-gene disorders. Disorders of multifactorial inheritance can be expressed during fetal life and be present at birth, or they may be expressed later in life. Congenital disorders that are thought to arise through multifactorial inheritance include cleft lip or palate, clubfoot, congenital dislocation of the hip, congenital heart disease, pyloric stenosis, and urinary tract malformation. Environmental factors are thought to play a greater role in disorders of multifactorial inheritance that develop in adult life, such as coronary artery disease, diabetes mellitus, hypertension, and cancer. Although multifactorial traits cannot be predicted with the same degree of accuracy as mendelian single-gene mutations, characteristic patterns exist. First, multifactorial ­congenital malformations tend to involve a single organ or tissue derived from the same embryonic developmental field. Second, the risk of recurrence in future pregnancies is for the same or a similar defect. This means that parents of a child with

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a cleft palate defect have an increased risk of having another child with a cleft palate, but not with spina bifida. Third, the increased risk (compared with the general population) among first-degree relatives of the affected person is 2% to 7%, and among second-degree relatives, it is approximately one half that amount.4 The risk increases with increasing incidence of the defect among relatives. This means that the risk is greatly increased when a second child with the defect is born to a couple. The risk also increases with severity of the disorder and when the defect occurs in the sex not usually affected by the disorder. Cleft Lip and Cleft Palate Cleft lip with or without cleft palate is one of the most common birth defects, occurring in about 0.1% of all pregnancies.4 It is also one of the more conspicuous birth defects, resulting in an abnormal facial appearance and defective speech. Cleft lip with or without cleft palate is more frequent among boys, whereas isolated cleft palate is twice as common among girls.4 The incidence of cleft palate is approximately 1 in 2500.4 Developmentally, the defect has its origin at about the 35th day of gestation when the frontal prominences of the craniofacial structures fuse with the maxillary process to form the upper lip.4 This process is under the control of many genes, and disturbances in gene expression (hereditary or environmental) at this time may result in cleft lip with or without cleft palate (Fig. 7.6). The defect may also be caused by teratogens (e.g., rubella, anticonvulsant drugs) and is often encountered in children with chromosomal abnormalities. Cleft lip and palate defects may vary from a small notch in the vermilion border of the upper lip to complete separation involving the palate and extending into the floor of the nose. The clefts may be unilateral or bilateral and may involve the alveolar ridge. The condition may be accompanied

Unilateral

Bilateral

FIGURE 7.6  •  Cleft lip and cleft palate.

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by  deformed, supernumerary, or absent teeth. Isolated cleft palate occurs in the midline and may involve only the uvula or may extend into or through the soft and hard palates. A child with cleft lip or palate may require years of special treatment by medical and dental specialists, including a plastic surgeon, pediatric dentist, orthodontist, speech therapist, and nurse specialist. The immediate problem in an infant with cleft palate is feeding. Nursing at the breast or nipple depends on suction developed by pressing the nipple against the hard palate with the tongue. Although infants with cleft lip usually have no problems with feeding, those with cleft palate usually require specially constructed, soft artificial nipples with large openings and a squeezable bottle. Major advances in the care of children born with cleft lip and palate have occurred within the last quarter of the 20th century.18 Surgical closure of the lip is usually performed by 3 months of age, with closure of the palate usually done before 1 year of age. Depending on the extent of the defect, additional surgery may be required as the child grows. In some situations, the palate is repaired prior to the cleft lip, and results indicate that the palate surgery is easier when done prior to the cleft lip repair.19 Also the time between surgeries when cleft palate is repaired prior to lip repair is shorter.19 Displacement of the maxillary arches and malposition of the teeth usually require orthodontic correction. Cleft lip and palate can also cause speech defects. The muscles of the soft palate and the lateral and posterior walls of the nasopharynx constitute a valve that separates the nasopharynx from the oropharynx during swallowing and in the production of certain sounds.

Chromosomal Disorders Chromosomal disorders form a major category of genetic disease, accounting for a large proportion of reproductive wastage (early gestational abortions), congenital malformations, and intellectual disability. Cytogenetics is the term given to chromosome disorders, and they are classified using the International System for Human Cytogenetic Nomenclature.4 During cell division in non–germ cells, the chromosomes replicate so that each cell receives a full diploid number. In germ cells, a different form of division called meiosis takes place. During meiosis, the double sets of 22 autosomes and the 2 sex chromosomes (normal diploid number) are reduced to single sets (haploid number) in each gamete. At the time of conception, the haploid number in the ovum and that in the sperm join and restore the diploid number of chromosomes. Chromosomal abnormalities are commonly described according to the shorthand description of the karyotype. In this system, the total number of chromosomes is given first, followed by the sex chromosome complement, and then the description of any abnormality. For example, a male with trisomy 21 is designated 47,XY,+21. The aberrations underlying chromosomal disorders may take the form of alterations in the structure of one or more chromosomes or an abnormal number of chromosomes.

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Occasionally, mitotic errors in early development give rise to two or more cell lines characterized by distinctive karyotypes, a condition referred to as mosaicism. Mosaicism can result from mitotic errors during cleavage of the fertilized ovum or in somatic cells. Sometimes, mosaicism consists of an abnormal karyotype and a normal one, in which case the physical deformities caused by the abnormal cell line usually are less severe. Structural Chromosomal Abnormalities Structural changes in chromosomes usually result from breakage in one or more of the chromosomes followed by rearrangement or deletion of the chromosome parts. Among the factors believed to cause chromosome breakage are exposure to radiation sources, such as x-rays; influence of certain chemicals; extreme changes in the cellular environment; and viral infections. Several patterns of chromosome breakage and rearrangement can occur (Fig. 7.7). There can be a deletion of the broken portion of the chromosome. When one chromosome is involved, the broken parts may be inverted. Isochromosome formation occurs when the centromere, or central portion, of the chromosome separates horizontally instead of vertically. Ring formation results when deletion is followed by uniting of the chromatids to form a ring. Translocation occurs when there are simultaneous breaks in two chromosomes from different pairs, with exchange of chromosome parts. With a balanced reciprocal translocation, no genetic information is lost; therefore, persons with translocations usually are normal. However, these people are translocation carriers and may have normal or abnormal children. A special form of translocation called a centric fusion or robertsonian translocation involves two acrocentric chromosomes in which the centromere is near the end, most commonly chromosomes 13 and 14 or 14 and 21. Typically, the break occurs near the centromere affecting the short arm in one chromosome and the long arm in the other. Transfer of the chromosome fragments leads to one long and one extremely short fragment. The short fragment is usually lost during subsequent divisions. In this case, the person has only 45 chromosomes, but the amount of genetic material that is lost is so small that it often goes unnoticed. Difficulty, however, arises during meiosis; the result is gametes with an unbalanced number of chromosomes. The chief clinical importance of this type of translocation is that carriers of a robertsonian translocation involving chromosome 21 are at risk for producing a child with Down syndrome. The manifestations of aberrations in chromosome structure depend to a great extent on the amount of genetic material that is lost or displaced. Many cells sustaining unrestored breaks are eliminated within the next few mitoses because of deficiencies that may in themselves be fatal. This is beneficial because it prevents the damaged cells from becoming a permanent part of the organism or, if it occurs in the gametes, from giving rise to grossly defective zygotes. Some altered chromosomes, such as those that occur with translocations, are passed on to the next generation.

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A

Deletion Lost

B

Balanced translocation

C

Inversion

Pericentric

D

Numeric Disorders Involving Autosomes Having an abnormal number of chromosomes is referred to as aneuploidy. Among the causes of aneuploidy is a failure of the chromosomes to separate during oogenesis or spermatogenesis. This can occur in either the autosomes or the sex chromosomes and is called nondisjunction (Fig. 7.8). Nondisjunction gives rise to germ cells that have an even number of chromosomes (22 or 24). The products of conception formed from this even number of chromosomes have an uneven number of chromosomes, 45 or 47. Monosomy refers to the presence of only one member of a chromosome pair. The defects associated with monosomy of the autosomes are severe and usually cause abortion. Monosomy of the X chromosome (45,X), or Turner syndrome, causes less severe defects. Polysomy, or the presence of more than two chromosomes to a set, occurs when a germ cell containing more than 23 chromosomes is involved in conception. Trisomy 18

Paracentric

Lost

MEIOSIS I

Robertsonian translocation

Normal

MEIOSIS II Isochromosomal translocation

E

A

F

Normal

Normal

Ring formation Normal

Nondisjunction Fragments FIGURE 7.7 •  Structural abnormalities in the human chromosome. (A) Deletion of part of a chromosome leads to loss of genetic material and shortening of the chromosome. (B) A reciprocal translocation involves two nonhomologous chromosomes, with exchange of the acentric segment. (C) Inversion requires two breaks in a single chromosome, with inversion to the opposite side of the centromere (pericentric) or with the fragment inverting but remaining on the same arm (paracentric). (D) In robertsonian translocation, two nonhomologous acrocentric chromosomes break near their centromeres, after which the long arms fuse to form one large metacentric chromosome. (E) Isochromosomes arise from faulty centromere division, which leads to duplication of the long arm and deletion of the short arm, or the reverse. (F) A ring chromosome forms with breaks in both telomeric portions of a chromosome, deletion of the acentric fragments, and fusion of the remaining centric portion. (From Rubin R, Strayer D. S., (Eds.), (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 223). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Normal

B

Nondisjunction

C

FIGURE 7.8 • Nondisjunction as a cause of disorders of chromosomal numbers. (A) Normal distribution of chromosomes during meiosis I and II. (B) If nondisjunction occurs at meiosis I, the gametes contain either a pair of chromosomes or a lack of chromosomes. (C) If nondisjunction occurs at meiosis II, the affected gametes contain two of copies of one parenteral chromosome or a lack of chromosomes.

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(Edwards syndrome) and trisomy 13 (Patau syndrome) share several karyotypic and clinical features with trisomy 21  (Down syndrome). In contrast to Down syndrome, however, the malformations are much more severe and wide-ranging. As a result, these infants rarely survive beyond the first years of life.5 Down Syndrome.  First described in 1866 by John Langdon Down, trisomy 21, or Down syndrome, causes a combination of birth defects including some degree of intellectual disability, characteristic facial features, and other health problems. It is the most common chromosomal disorder. Approximately 95% of cases of Down syndrome are caused by nondisjunction or an error in cell division during meiosis, resulting in a trisomy of chromosome 21. A rare form of Down syndrome can occur in the offspring of people in whom there has been a robertsonian translocation (see Fig. 7.7) involving the long arm of chromosome 21q and the long arm of one of the acrocentric chromosomes (most often 14 or 22). The translocation adds to the normal long arm of chromosome 21. Therefore, the person with this type of Down syndrome has 46 chromosomes, but essentially a trisomy of 21q.4–6 The risk of having a child with Down syndrome increases with maternal age.4,20 The reason for the correlation between maternal age and nondisjunction is unknown, but is thought to reflect some aspect of aging of the oocyte. Although men continue to produce sperm throughout their reproductive life, women are born with all the oocytes they ever will have. These oocytes may change as a result of the aging process. With increasing age, there is a greater chance of a woman having been exposed to damaging environmental agents such as drugs, chemicals, and radiation. Unlike trisomy 21, Down syndrome due to a chromosome (21;14) translocation shows no relation to maternal age but has a relatively high recurrence risk in families when a parent, particularly the mother, is a carrier. A child with Down syndrome has specific physical characteristics that are classically evident at birth.4,20 These features include a small and rather square head. There is a flat facial profile, with a small nose and somewhat depressed nasal bridge; small folds on the inner corners of the eyes (epicanthal folds) and upward slanting of the eyes; small, low-set, and malformed ears; a fat pad at the back of the neck; an open mouth; and a large, protruding tongue (Fig. 7.9). The child’s hands usually are short and stubby, with fingers that curl inward, and there usually is only a single palmar (i.e., simian) crease. There is excessive space between the large and second toes. Hypotonia and joint laxity also are present in infants and young children. There often are accompanying congenital heart defects and an increased risk of gastrointestinal malformations. Approximately 1% of people with trisomy 21 Down syndrome have mosaicism (i.e., cell populations with the normal chromosome number and trisomy 21). These people may be less severely affected. There is a high correlation of the development of acute leukemia, both myeloid and lymphoblastic, among children with Down syndrome.21 In addition, there is an increased risk of Alzheimer disease among older

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Epicanthal folds, slanted eyes, and flat facial profile Malformed ears

Congenital heart disease

Acute lymphoblastic leukemia

Growth failure Mental retardation Flat occiput Big, protruding, wrinkled tongue

Intestinal malformations

Short, broad hands with simian crease

Wide gap between 1st and 2nd toes

FIGURE 7.9  •  Clinical features of a child with Down syndrome.

people with Down syndrome, and many of these children have a higher chance of acquiring cardiovascular disease. There are several prenatal screening tests that can be done to determine the risk of having a child with Down syndrome.18 The most commonly used are blood tests that measure maternal serum levels of α-fetoprotein (AFP), human chorionic gonadotropin (hCG), unconjugated estriol, inhibin A, and pregnancy-associated plasma protein A (PAPP-A) (see section on Diagnosis and Counseling). The results of three or four of these tests, together with the woman’s age, often are used to determine the probability of a pregnant woman having a child with Down syndrome. Nuchal translucency (sonolucent space on the back of the fetal neck) is another test that can be done to assess this aspect of the fetus by uses ­ultrasonography and can be performed between 10 and 13 weeks’ gestation.18 The fetus with Down syndrome tends to have a greater area of translucency compared with a chromosomally normal infant. The nuchal transparency test is usually used in combination with other screening tests. The only way to accurately determine the presence of Down syndrome in the fetus is through chromosome analysis using chorionic villus sampling, amniocentesis, or percutaneous umbilical blood sampling, which is discussed later in this chapter.

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Remember Jennifer, the newborn born with Down syndrome in the unit opener case study? Her disorder could have been diagnosed prenatally. Her mother was 46, which is considered advanced maternal age and associated with increased risk of aneuploidy, such as trisomy 21. The mother was offered first trimester screening at her first sonogram at 12 weeks and accepted. An increased nuchal translucency was seen on sonogram, and her trisomy 21 risk calculated from her first trimester screen indicated a 1:20 risk for trisomy 21. She declined invasive testing, such as amniocentesis, because she stated that positive results from further testing would not change her decision to continue with the pregnancy. On her anatomy sonogram and follow-up sonograms, the fetus was noted to have an absent nasal bone, echogenic bowel, short long bones, and an echogenic focus in the heart, which are all markers for possible Down syndrome. Women with abnormal first trimester screens, abnormal second trimester screens, abnormal sonogram findings, personal or family history of genetic conditions, or who are of advanced maternal age should be referred to a genetic counselor during their pregnancy for further discussion and management. Numeric Disorders Involving Sex Chromosomes Chromosomal disorders associated with the sex chromosomes are much more common than those related to the autosomes, except for trisomy 21. Furthermore, imbalances (excess or deletions) are much better tolerated than those involving the autosomes. This is related in a large part to two factors that are peculiar to the sex chromosomes: 1. The inactivation of all but one X chromosome 2. The modest amount of genetic material that is carried on the Y chromosome Although girls normally receive both a paternal and a maternal X chromosome, the clinical manifestations of X chromosome abnormalities can be quite variable because of the process of X inactivation (previously discussed in Chapter 6). In somatic cells of females, only one X chromosome is transcriptionally active. The other chromosome is inactive. The process of X  inactivation, which is random, occurs early in embryonic life and is usually complete at about the end of the first week of development. After one X chromosome has become inactivated in a cell, all cells descended from that cell have the same inactivated X chromosome. Although much of one X chromosome is inactivated in females, several regions contain genes that escape inactivation and continue to be expressed by both X chromosomes. These genes may explain some of the variations in clinical symptoms seen in cases of numeric abnormalities of the X chromosome, such as Turner syndrome. It is well known that the Y chromosome determines the male sex. The gene that dictates testicular development (Sry: sex-determining region Y gene) has been located on its distal short arm.5 Recent studies of the Y chromosome have yielded additional information about gene families in the so-called

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“male-specific Y” or MSY region. All of these are believed to be involved in spermatogenesis. A few additional genes with homologs on the X chromosome have been mapped to the Y chromosome, but to date, no disorders resulting from mutations in these genes have been described. Turner Syndrome.  Turner syndrome describes an absence of all (45,X/0) or part of the X chromosome.22 Some women with Turner syndrome may have part of the X chromosome, and some may display a mosaicism with one or more additional cells lines. This disorder affects approximately 1 of every 2500 live births and is the most frequent occurring genetic disorder in women.22 Characteristically, the girl with Turner syndrome is short in stature, but her body proportions are normal (Fig. 7.10). Females with Tuner syndrome lose the majority of their oocytes by the age of 2 years. Therefore, they do not menstruate and shows no signs of secondary sex characteristics. There are variations in the syndrome, with abnormalities ranging from essentially none to cardiac abnormalities such as bicuspid aortic valve and coarctation of the aorta, problems with hearing and vision, a small size mandible, a horseshoe kidney, and a small webbed neck.4 Women with Turner syndrome have been found to develop autoimmune disorders associated with male predominance, such as type 1 diabetes mellitus and Hashimoto thyroiditis.23 Small stature

Low posterior hairline and webbed neck Broad chest with widely spaced nipples

Coarctation of aorta and bicuspid aortic valve

Poor breast development Ovarian dysgenesis with primary amenorrhea, estrogen and progesterone deficiencies, and infertility

Multiple pigmented nevi

Wide carrying angle of arms

Retardation of bone age

Lymphedema of hands and feet at birth and later

FIGURE 7.10  •  Clinical features of Turner syndrome.

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Although most women with Turner syndrome have normal intelligence, they may have problems with visuospatial organization (e.g., difficulty in driving, nonverbal problemsolving tasks such as mathematics, and psychomotor skills) and attention deficit disorders.24 The diagnosis of Turner syndrome often is delayed until late childhood or early adolescence in girls who do not present with the classic features of the syndrome. Only about 20%  to 33% of affected girls receive a diagnosis as a newborn because of puffy hands and feet or redundant nuchal skin. Another 33% are diagnosed in mid-childhood because of short stature. The remainder of the girls are mainly diagnosed in adolescence when they fail to enter puberty.24 It is important to diagnose girls with Turner syndrome as early as possible so treatment plans could be implemented and managed throughout their lives. The management of Turner syndrome begins during childhood and requires ongoing assessment and treatment. Growth hormone therapy generally can result in a gain of 6 to 10 cm in final height. Estrogen therapy, which is instituted around the normal age of puberty, is used to promote development and maintenance of secondary sexual characteristics.24 Klinefelter Syndrome.  Klinefelter syndrome is a condition of testicular dysgenesis accompanied by the presence of one or more extra X chromosomes in excess of the normal male XY complement.4,25 Most males with Klinefelter syndrome have one extra X chromosome (47,XXY). In rare cases, there may be more than one extra X chromosome (48,XXXY). The presence of the extra X chromosome in the 47,XXY male results from nondisjunction during meiotic division in one of the parents. The extra X chromosome is usually of maternal origin, but approximately 1/3 of the time, it is of paternal origin. The cause of the nondisjunction is unknown. Advanced maternal age increases the risk, but only slightly. Klinefelter syndrome occurs in approximately 1 per 1000 newborn male infants. Although the presence of the extra chromosome is fairly common, the syndrome with its accompanying signs and symptoms that may result from the extra chromosome is uncommon. Many men live their lives without being aware that they have an additional chromosome. For this reason, it has been suggested that the term Klinefelter syndrome be replaced with 47,XXY male.26 Klinefelter syndrome is characterized by enlarged breasts, sparse facial and body hair, small testes, and the inability to produce sperm25,27 (Fig. 7.11). Regardless of the number of X chromosomes present, the male phenotype is retained. The condition often goes undetected at birth. The infant usually has normal male genitalia, with a small penis and small, firm testicles. At puberty, the intrinsically abnormal testes do not respond to stimulation from the gonadotropins and undergo degeneration. This leads to a tall stature with abnormal body proportions in which the lower part of the body is longer than the upper part. Later in life, the body build may become heavy, with a female distribution of subcutaneous fat and variable

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Tall stature

Lack of facial hair Narrow shoulders

Gynecomastia Long arms and legs Wide hips

Decreased pubic hair

Testicular atrophy Infertility Barr body

XXY

FIGURE 7.11  •  Clinical features of Klinefelter syndrome.

degrees of breast enlargement. There may be deficient secondary male sex characteristics, such as a voice that remains feminine in pitch and sparse beard and pubic hair. Although the intellect usually is normal, most 47,XXY males have some degree of language impairment. Adequate management of Klinefelter syndrome requires a comprehensive neurodevelopmental evaluation. In infancy and early childhood, this often includes a multidisciplinary approach to determine appropriate treatments such as physical therapy, infant stimulation programs, and speech therapy.25 Men with Klinefelter syndrome have congenital hypogonadism, which results in an inability to produce normal amounts of testosterone accompanied by an increase in hypothalamic gonadotrophic hormones. Androgen therapy is usually initiated when there is evidence of a testosterone deficit. Infertility is common in men with Klinefelter syndrome because of a decreased sperm count. If sperm are present, cryopreservation

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TABLE 7.2 SOME DISORDERS OF ORGAN SYSTEMS ASSOCIATED WITH MITOCHONDRIAL DNA MUTATIONS DISORDER

MANIFESTATIONS

Chronic progressive external ophthalmoplegia Deafness

Progressive weakness of the extraocular muscles Progressive sensorineural deafness, often associated with aminoglycoside antibiotics Progressive weakness of the extraocular muscles of early onset with heart block, retinal pigmentation Painless, subacute, bilateral visual loss, with central blind spots (scotomas) and abnormal color vision Proximal muscle weakness, sensory neuropathy, developmental delay, ataxia, seizures, dementia, and visual impairment due to retinal pigment degeneration Mitochondrial encephalomyopathy (cerebral structural changes), lactic acidosis, and strokelike syndrome, seizures, and other clinical and ­laboratory abnormalities; may manifest only as diabetes mellitus Myoclonic epilepsy, ragged red fibers in muscle, ataxia, sensorineural deafness Myoclonic seizures, cerebellar ataxia, mitochondrial myopathy (muscle weakness, fatigue)

Kearns-Sayre syndrome Leber hereditary optic neuropathy Leigh disease

MELAS

MERRF Myoclonic epilepsy with ragged red fibers

may be useful for future family planning. However, genetic counseling is advised because of the increased risk of autosomal and sex chromosomal abnormalities. Men with Klinefelter syndrome also experience increased risk for osteoporosis and need to be educated on prevention management.28

Mitochondrial Gene Disorders The mitochondria contain their own DNA, which is distinct from the DNA contained in the cell nucleus. There are multiple disease-affected rearrangements and point mutations. Mitochondrial DNA (mtDNA) is packaged in a doublestranded circular chromosome located inside the mitochondria.29 Mitochondrial DNA contains 37 genes: 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and 13  structural genes encoding subunits of the mitochondrial respiratory chain enzymes, which participate in oxidative phosphorylation and generation of adenosine triphosphate.4 In contrast to the mendelian pattern of inheritance of nuclear DNA, disorders of mtDNA are inherited on the maternal line. This can be explained by the fact that ova contain numerous mitochondria in their abundant cytoplasm, whereas spermatozoa contain few, if any, mitochondria. Thus, the mtDNA in the zygote is derived solely from the mother. The zygote and its daughter cells have many mitochondria, each of which contains multiple copies of the maternally derived mtDNA. During growth of the fetus or later, it is likely that some cells will contain only normal or mutant mtDNA (a situation called homoplasmy), whereas others receive a mixture of normal and mutant DNA (heteroplasmy). In turn, the clinical expression of a disease produced by a given mutation of mtDNA depends on the total content of mitochondrial genes and the proportion that is mutant. The fraction of mutant

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mtDNA must exceed a critical value for a mitochondrial ­disease to become symptomatic. This threshold varies in different organs and is presumably related to the energy requirements of the cells. Mitochondrial DNA mutations generally affect tissues that are dependent on oxidative phosphorylation to meet their high needs for metabolic energy. Thus, mtDNA mutations frequently affect the neuromuscular system and produce disorders such as encephalopathies, myopathies, retinal degeneration, loss of extraocular muscle function, and deafness.29,30 The range of mitochondrial diseases is broad, however, and may include liver dysfunction, bone marrow failure, and pancreatic islet cell dysfunction and diabetes, among other disorders. Table 7.2 describes representative examples of disorders due to mutations in mtDNA.

IN SUMMARY Genetic disorders can affect a single gene (mendelian inheritance) or several genes (polygenic inheritance). Single-gene disorders may be present on an autosome or on the X chromosome, and they may be expressed as a dominant or recessive trait. In autosomal dominant disorders, a single mutant allele from an affected parent is transmitted to an offspring regardless of sex. The affected parent has a 50% chance of transmitting the disorder to each offspring. Autosomal recessive disorders are manifested only when both members of the gene pair are affected. Usually, both parents are unaffected but are carriers of the defective gene. Their chances of having an affected child are one in four; of having a carrier child, two in four; and of having a noncarrier, unaffected child, one in four. Sex-linked

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d­ isorders, which are associated with the X chromosome, are those in which an unaffected mother carries one normal and one mutant allele on the X chromosome. She has a 50% chance of transmitting the defective gene to her sons, who are affected, and her daughters have a 50% chance of being carriers of the mutant gene. Because of a normal paired gene, female heterozygotes rarely experience the effects of a defective gene. The fragile X syndrome is an inherited form of mental retardation that results from a repeating sequence of three nucleotides on a single gene in the X chromosome. Multifactorial inheritance disorders are caused by multiple genes and, in many cases, environmental factors. Chromosomal disorders result from a change in chromosome number or structure. A change in chromosome number is called aneuploidy. Monosomy involves the presence of only one member of a chromosome pair; it is seen in Turner syndrome, in which there is monosomy of the X chromosome. Polysomy refers to the presence of more than two chromosomes in a set. Klinefelter syndrome involves polysomy of the X chromosome. Trisomy 21 (i.e., Down syndrome) is the most common form of chromosome disorder. Alterations in chromosome structure involve deletion or addition of genetic material, which may involve a translocation of genetic material from one chromosome pair to another. The mitochondria contain their own DNA, which is distinct from nuclear DNA. This DNA, which is inherited maternally, is subject to mutations at a higher rate than nuclear DNA, and it has no repair mechanisms. Disorders of mitochondrial genes interfere with oxidative phosphorylation and the production of cellular energy. The range of mitochondrial gene disorders is diverse, with neuromuscular disorders predominating.

DISORDERS DUE TO ENVIRONMENTAL INFLUENCES After completing this section of the chapter, you should be able to meet the following objectives: •• Cite the most susceptible period of intrauterine life for development of defects due to environmental agents. •• State the cautions that should be observed when considering use of drugs during pregnancy, including the possible effects of alcohol abuse, vitamin A derivatives, and folic acid deficiency on fetal development.

The developing embryo is subject to many nongenetic influences. After conception, development is influenced by the environmental factors that the embryo shares with the mother. The physiologic status of the mother—her hormone ­balance,

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her general state of health, her nutritional status, and the drugs she takes—undoubtedly influences the development of the unborn child. For example, maternal diabetes mellitus is associated with increased risk of congenital anomalies in the infant. Maternal smoking is associated with lowerthan-­ normal neonatal weight. Maternal use of alcohol, in the context of chronic alcoholism, is known to cause fetal abnormalities. Some agents cause early abortion. Measles and other infectious agents cause congenital malformations. Other agents, such as radiation, can cause chromosomal and genetic defects and produce developmental disorders.

Period of Vulnerability The embryo’s development is most easily disturbed during the period when differentiation and development of the organs are taking place. This time interval, which is often referred to as the period of organogenesis, extends from day 15 to day 60 after conception. Environmental influences during the first 2 weeks after fertilization may interfere with implantation and result in abortion or early resorption of the products of conception. Each organ has a critical period during which it is highly susceptible to environmental derangements4 (Fig. 7.12). Often, the effect is expressed at the biochemical level just before the organ begins to develop. The same agent may affect different organ systems that are developing at the same time.

Teratogenic Agents A teratogenic agent is a chemical, physical, or biologic agent that produces abnormalities during embryonic or fetal development. Maternal disease or altered metabolic state also can affect the development of the embryo or fetus. Theoretically, teratogenic agents can cause birth defects in three ways: 1. By direct exposure of the pregnant woman and the embryo or fetus to the agent 2. Through exposure of the soon-to-be-pregnant woman to an agent that has a slow clearance rate, such that a teratogenic dose is retained during early pregnancy 3. As a result of mutagenic effects of an environmental agent that occur before pregnancy, causing permanent damage to a woman’s (or a man’s) reproductive cells For discussion purposes, teratogenic agents have been divided into three groups: radiation, drugs and chemical substances, and infectious agents. Chart 7.1 lists commonly identified agents in each of these groups. Radiation Heavy doses of ionizing radiation are teratogenic and mutagenic and have the capacity to effect inheritable changes in genetic materials. Specifically, excessive levels of radiation have been shown to cause microcephaly, skeletal malformations, and mental retardation. There is no evidence that diagnostic levels of radiation (e.g., from a chest x-ray) cause congenital abnormalities. Additionally all efforts to shield the fetus are taken when possible. In situations where a study is

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152   UNIT II  Cell Function and Growth Weeks 2

4

6

8

16

38

Central nervous system Heart Extremities Eyes External genitalia

Prenatal Death

Maximal Sensitivity to Development of Morphologic Abnormalities

FIGURE 7.12  •  Sensitivity of specific organs to teratogenic agents at critical periods in embryogenesis. Exposure to adverse influences in the preimplantation and early postimplantation stages of development (far left) leads to prenatal death. Periods of maximal sensitivity to teratogens (horizontal bars) vary for different organ systems, but overall are limited to the first 8 weeks of pregnancy. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 216). Philadelphia, PA: Lippincott Williams & Wilkins.)

Chart 7.1

TERATOGENIC AGENTS*

Radiation Drugs and Chemical Substances Alcohol Anticoagulants Warfarin Antibiotics Quinolones Tetracycline Antiepileptics Anti-HTN Ace inhibitors, angiotensin II receptor blockers Antipsychotics Lithium Cancer drugs Aminopterin

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Methotrexate 6-Mercaptopurine Isotretinoin (Accutane) Thalidomide Infectious Agents Viruses Cytomegalovirus Herpes simplex virus Measles (rubella) Mumps Varicella–zoster virus (chickenpox) Nonviral factors Syphilis Toxoplasmosis *

Not inclusive.

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Chapter 7  Genetic and Congenital Disorders    153

necessary for the woman’s health, the benefits to her of having proper diagnostic imaging outweigh potential theoretical risks to the fetus. Administration of therapeutic doses of radioactive iodine (131I) during the 13th week of gestation, the time when the fetal thyroid is beginning to concentrate iodine, has been shown to interfere with thyroid development. Chemicals and Drugs Environmental chemicals and drugs can cross the placenta and cause damage to the developing embryo and fetus. It has been estimated that only 2% to 3% of developmental defects have a known drug or environmental origin. Some of the bestdocumented environmental teratogens are the organic mercurials, which cause neurologic deficits and blindness. Certain fish and water sources may be contaminated by mercury. The precise mechanisms by which chemicals and drugs exert their teratogenic effects are largely unknown. They may produce cytotoxic (cell-killing), antimetabolic, or growth-inhibiting effects to the embryonic and fetal development. Drugs top the list of chemical teratogens, probably because they are regularly used at elevated doses. Many drugs can cross the placenta and expose the fetus to both the pharmacologic and teratogenic effects. Factors that affect placental drug transfer and drug effects on the fetus include the rate at which the drug crosses the placenta, the duration of exposure, and the stage of placental and fetal development at the time of exposure.26 Lipid-soluble drugs tend to cross the placenta more readily and enter the fetal circulation. The molecular weight of a drug also influences the rate and amount of drug transferred across the placenta. Drugs with a molecular weight of less than 500 can cross the placenta easily, depending on lipid solubility and degree of ionization; those with a molecular weight of 500 to 1000 cross the placenta with more difficulty; and those with molecular weights of more than 1000 cross very poorly.26 Several medications have been considered teratogenic. However, perhaps the best known of these drugs is thalidomide, which has been shown to give rise to a full range of ­malformations, including phocomelia (i.e., short, flipper-like appendages) of all four extremities. Other drugs known to cause fetal abnormalities are the antimetabolites used in the treatment of cancer, the anticoagulant drug warfarin, several of the anticonvulsant drugs, ethyl alcohol, and cocaine. Some drugs affect a single developing structure; for example, propylthiouracil can impair thyroid development and tetracycline can interfere with the mineralization phase of tooth development. More recently, vitamin A and its derivatives (the retinoids) have been targeted for concern because of their teratogenic potential. Concern over the teratogenic effects of vitamin A derivatives arose with the introduction of the acne drug isotretinoin (Accutane). In 1983, the U.S. Food and Drug Administration established a system for classifying drugs according to probable risks to the fetus. According to this system, drugs are put into five categories: A, B, C, D, and X. Drugs in category A are the least dangerous, and categories B, C, and D are increasingly more dangerous. Those in category X are ­contraindicated

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d­uring pregnancy because of proven teratogenicity.26 The law does not require classification of drugs that were in use before 1983. Because many drugs are suspected of causing fetal abnormalities, and even those that were once thought to be safe are now being viewed critically, it is recommended that women in their childbearing years avoid unnecessary use of drugs. This pertains to nonpregnant women as well as pregnant women because many developmental defects occur early in pregnancy. As happened with thalidomide, the damage to the embryo may occur before pregnancy is suspected or confirmed. A drug that is often abused and can have deleterious effects on the fetus is alcohol. Fetal Alcohol Syndrome.  The term fetal alcohol syndrome (FAS) refers to a group of physical, behavioral, and cognitive fetal abnormalities that occur secondary to drinking alcohol while pregnant.31,32 It has been estimated that approximately 0.5 to 2.0 cases per 100 live births have FAS.33 Alcohol, which is lipid soluble and has a molecular weight between 600 and 1000, passes freely across the placental barrier. Concentrations of alcohol in the fetus are at least as high as in the mother. Unlike other teratogens, the harmful effects of alcohol are not restricted to the sensitive period of early gestation but extend throughout pregnancy. Alcohol has widely variable effects on fetal development, ranging from minor abnormalities to FAS. There may be prenatal or postnatal growth retardation; CNS involvement, including neurologic abnormalities, developmental delays, behavioral dysfunction, intellectual impairment, and skull and brain malformation; and a characteristic set of facial features that include small palpebral fissures (i.e., eye openings), a thin vermilion border (upper lip), and an elongated, flattened midface and philtrum (i.e., the groove in the middle of the upper lip)34–36 (Fig. 7.13). The facial features of FAS may not

Microcephaly Epicanthal folds

Flat nasal bridge Small palpebral fissures

Smooth philtrum Small chin

Short nose Thin vermilion border (upper lip)

FIGURE 7.13  •  Clinical features of FAS.

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be as apparent in the newborn but become more prominent as the infant develops. As the children grow into adulthood, the facial features become more subtle, making diagnosis of FAS in older people more difficult. Each of these defects can vary in severity, probably reflecting the timing of alcohol consumption in terms of the period of fetal development, amount of alcohol consumed, and hereditary and environmental influences. The criteria for FAS diagnosis require the documented presence of three of the following findings: 1. Three facial abnormalities (smooth philtrum, thin vermilion border on the upper lip, and small palpebral fissures) 2. Growth deficits (prenatal or postnatal height or weight, or both, below the 10th percentile) 3. CNS abnormalities (e.g., head circumference below the 10th percentile, global cognitive or intellectual deficits, motor functioning delays, problems with attention or hyperactivity) The amount of alcohol that can be safely consumed during pregnancy is unknown. Even small amounts of alcohol consumed during critical periods of fetal development may be teratogenic. For example, if alcohol is consumed during the period of organogenesis, a variety of skeletal and organ defects may result. If alcohol is consumed later in gestation, when the brain is undergoing rapid development, there may be behavioral and cognitive disorders in the absence of physical abnormalities. Chronic alcohol consumption throughout pregnancy may result in a variety of effects, ranging from physical abnormalities to growth retardation and compromised CNS functioning. Evidence suggests that short-lived high concentrations of alcohol, such as those that occur with binge drinking, may be particularly significant, with abnormalities being unique to the period of exposure.33 Because of the possible effect on the fetus, it is recommended that women abstain completely from alcohol during pregnancy.

Key Points TERATOGENIC AGENTS •  Teratogenic agents such as radiation, chemicals and drugs, and infectious organisms are agents that produce abnormalities in the developing embryo. •  The stage of development of the embryo determines the susceptibility to teratogens. The period during which the embryo is most susceptible to teratogenic agents is the time during which rapid differentiation and development of body organs and tissues are taking place, usually from days 15 to 60 postconception.

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Infectious Agents Many microorganisms cross the placenta and enter the fetal circulation, often producing multiple malformations. The acronym TORCH stands for toxoplasmosis, other, rubella (i.e., German measles), cytomegalovirus, and herpes, which are the agents most frequently implicated in fetal anomalies.4 Other infections include varicella–zoster virus infection, listeriosis, leptospirosis, Epstein-Barr virus infection, tuberculosis, and syphilis.4 Human immunodeficiency virus (HIV) and human parvovirus (B19) have been suggested as additions to the list. The TORCH screening test examines the infant’s serum for the presence of antibodies to these agents. However, the titers for serum antibodies against the TORCH agents in the mother and newborn usually are not diagnostic, and the precise cause of the disorder often remains uncertain. Infections with the TORCH agents are reported to occur in 1% to 5% of newborn infants and are among the major causes of neonatal morbidity and mortality.4 Common clinical and pathologic manifestations include growth retardation and abnormalities of the brain (microcephaly, hydrocephalus), eye, ear, liver, hematopoietic system (anemia, thrombocytopenia), lungs (pneumonitis), and heart (myocarditis, congenital heart disorders).4 These manifestations vary among symptomatic newborns, however, and only a few present with multisystem abnormalities. Toxoplasmosis is a protozoal infection caused by Toxoplasma gondii, which can be deleterious to pregnant woman and the unborn fetus.37 The domestic cat can carry the organism, excreting the protozoa in its feces. It has been suggested that pregnant women should avoid contact with excrement from the family cat. The introduction of the rubella vaccine has virtually eliminated the congenital rubella syndrome in most developed countries. Rubella remains endemic in many developing countries, however, where it is the major preventable cause of hearing impairment, blindness, and adverse ­neurodevelopmental outcome. The epidemiology of cytomegalovirus infection is largely unknown. Some infants are severely affected at birth, and others, although having evidence of the infection, have no symptoms. In some symptom-free infants, brain damage becomes evident over a span of several years. There also is evidence that some infants contract the infection during the first year of life, and in some of them the infection leads to retardation a year or two later. Herpes simplex virus type 2 infection is considered to be a genital infection and usually is transmitted through sexual contact. The infant acquires this infection in utero or in passage through the birth canal.

Folic Acid Deficiency Although most birth defects are related to exposure to a teratogenic agent, deficiencies of nutrients and vitamins also may be a factor. Folic acid deficiency has been implicated in the development of neural tube defects (NTD) (e.g., anencephaly, spina bifida, encephalocele). Studies have shown a significant decrease in neural tube defects when folic acid was taken long term by women of reproductive age.38 Therefore, it is r­ ecommended that all women of childbearing age receive

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400 mg (0.4 mg) of folic acid daily and then continue upon becoming pregnant. For women with increased risk for an NTD, including those who have previously had an affected pregnancy and those taking specific anticonvulsant drugs, the recommendation is for 4 mg of folic acid daily.39

IN SUMMARY A teratogenic agent is one that produces abnormalities during embryonic or fetal life. It is during the early part of pregnancy (15 to 60 days after conception) that environmental agents are most apt to produce their deleterious effects on the developing embryo. A number of environmental agents can be damaging to the unborn child, including radiation, drugs and chemicals, and infectious agents. FAS is a risk for infants of women who regularly consume alcohol during pregnancy. Because many drugs have the potential for causing fetal abnormalities, often at an early stage of pregnancy, it is recommended that women of childbearing age avoid unnecessary use of drugs. The acronym TORCH stands for toxoplasmosis, other, rubella, cytomegalovirus, and herpes, which are the infectious agents most frequently implicated in fetal anomalies. It also has been shown that folic acid deficiency can contribute to NTDs.

DIAGNOSIS AND COUNSELING After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the process of genetic assessment. •• Describe methods used in arriving at a prenatal diagnosis, including ultrasonography, amniocentesis, chorionic villus sampling, percutaneous umbilical fetal blood sampling, and laboratory methods to determine the biochemical and genetic makeup of the fetus. The birth of a defective child is a traumatic event in any parent’s life. Usually two issues must be resolved. The first deals with the immediate and future care of the affected child and the second with the possibility of future children in the family having a similar defect. Genetic assessment and counseling can help to determine whether the defect was inherited and the risk of recurrence. Prenatal diagnosis provides a means of determining whether the unborn child has certain types of abnormalities. It is important that the parents are aware of the potential complications of acquiring more information from these invasive genetic tests.

Genetic Assessment Effective genetic counseling involves accurate diagnosis and communication of the findings and of the risks of recurrence

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to the parents and other family members who need such information. Counseling may be provided after the birth of an affected child, or it may be offered to people at risk for having defective children (i.e., siblings of people with birth defects). A team of trained counselors can help the family to understand the problem and can support their decisions about having more children. Assessment of genetic risk and prognosis usually is directed by a clinical geneticist, often with the aid of laboratory and clinical specialists. A detailed family history (i.e., pedigree), a pregnancy history, and detailed accounts of the birth process and postnatal health and development are included. A careful physical examination of the affected child and often of the parents and siblings usually is needed. Laboratory tests, including chromosomal analysis and biochemical studies, often precede a definitive diagnosis.

Prenatal Screening and Diagnosis The purpose of prenatal screening and diagnosis is not just to detect fetal abnormalities but also to allay anxiety and provide assistance to prepare for a child with a specific disability. Prenatal screening cannot be used to rule out all possible fetal abnormalities. It is limited to determining whether the fetus has (or probably has) designated conditions indicated by late maternal age, family history, or well-defined risk factors. There are multiple methods that can assist in diagnosing a fetus regarding genetic disorders, including ultrasonography, maternal serum (blood) screening tests, amniocentesis, chorionic villus sampling, and percutaneous umbilical fetal blood sampling (Fig. 7.14). Prenatal diagnosis can also provide the information needed for prescribing prenatal treatment for the fetus. For example, if congenital adrenal hyperplasia is diagnosed, the mother can be treated with adrenal cortical hormones to prevent masculinization of a female fetus. Ultrasonography Ultrasonography is a noninvasive diagnostic method that uses reflections of high-frequency sound waves to visualize soft tissue structures. Since its introduction in 1958, it has been used during pregnancy to determine the number of fetuses, fetal size and position, amount of amniotic fluid, and placental location. It also is possible to assess fetal movement, breathing movements, and heart pattern. There is also good evidence that early ultrasonography (i.e., before 14 weeks) accurately determines gestational age. Improved resolution and real-time units have enhanced the ability of ultrasound scanners to detect congenital anomalies. Ultrasonography makes possible the in utero diagnosis of cardiac defects, hydrocephalus, spina bifida, facial defects, congenital heart defects, congenital diaphragmatic hernias, disorders of the gastrointestinal tract, skeletal anomalies, and various other defects. Three-dimensional (3D) sonography has become useful in better assessing facial profiles and abdominal wall defects. A fetal echocardiogram can be done as follow-up for possible cardiac anomalies. Fetal MRI

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156   UNIT II  Cell Function and Growth Fetoscope Ultrasonography transducer

Syringe for collecting chorionic villus sample

Transabdominal amniocentesis

Cordocentesis

Umbilical cord Transcervical chorionic villus sampling

Amniotic cavity

Catheter

Chorion frondosum

Vagina Cervix

Rectum

FIGURE 7.14  •  Methods of prenatal screening.

can be done to better assess skeletal, neurological, and other anomalies. Intrauterine diagnosis of congenital abnormalities permits better monitoring, further workup and planning with appropriate specialties, preterm delivery for early correction, selection of cesarean section to reduce fetal injury, and, in some cases, intrauterine therapy. Maternal Serum Markers Maternal blood testing began in the early 1980s with the test for AFP. Since that time, a number of serum factors have been studied as screening tests for fetal anomalies. Current maternal testing favors first trimester screening for all women between 11 and 13 weeks combining nuchal translucency seen on sonogram with PAPP-A level, hCG level, and maternal age to determine a risk for trisomy 21, 13, and 18. PAPP-A, which is secreted by the placenta, has been shown to play an important role in promoting cell differentiation and proliferation in various body systems. In complicated pregnancies, the PAPP-A concentration increases with gestational age until term. Decreased PAPP-A levels in the first trimester (between 10 and 13 weeks) have been shown to be associated with Down syndrome. When used along with

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maternal age, free β-hCG, and ultrasonographic measurement of nuchal translucency, serum PAPP-A levels can reportedly detect 85% to 95% of affected pregnancies with a false-­ positive rate of approximately 5%. A maternal serum AFP can then be done alone in the second trimester to assess for NTDs, though for pregnant women with access to good quality sonography centers, a level II ultrasound for anatomical viewing of the spine can exclude greater than 99% of spinal defects. For pregnant women presenting too late for first trimester screening, the quad screen using AFP, hCG, inhibin A, and unconjugated estriol is used to screen for trisomy and NTDs between 15 and 22 weeks of pregnancy. The use of ultrasonography to verify fetal age can reduce the number of falsepositive tests with this screening method. AFP is a major fetal plasma protein and has a structure similar to the albumin found in postnatal life. AFP is made initially by the yolk sac, gastrointestinal tract, and liver. Fetal plasma levels of AFP peak at approximately 10 to 13 weeks’ gestation and decrease until the third trimester when the level peaks again. Maternal and amniotic fluid levels of AFP are elevated in pregnancies where the fetus has an NTD

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(i.e., ­anencephaly and open spina bifida) or certain other malformations such as an anterior abdominal wall defect in which the fetal integument is not intact. Although NTDs have been associated with elevated levels of AFP, decreased levels have been associated with Down syndrome. A complex glycoprotein, hCG, is produced exclusively by the outer layer of the trophoblast shortly after implantation in the uterine wall. It increases rapidly in the first 8 weeks of gestation, declines steadily until 20 weeks, and then plateaus. The single maternal serum marker that yields the highest detection rate for Down syndrome is an elevated level of hCG. Inhibin A, which is secreted by the corpus luteum and fetoplacental unit, is also a maternal serum marker for fetal Down syndrome. Unconjugated estriol is produced by the placenta from precursors provided by the fetal adrenal glands and liver. It increases steadily throughout pregnancy to a higher level than that normally produced by the liver. Unconjugated estriol levels are decreased in Down syndrome and trisomy 18.

Key Points DIAGNOSIS AND COUNSELING •  Sonography, first trimester screening, quad screening, amniocentesis, chorionic villi sampling, and percutaneous umbilical cord blood sampling (PUBS) are important procedures that allow prenatal diagnosis and management.

Amniocentesis Amniocentesis is an invasive diagnostic procedure that involves the withdrawal of a sample of amniotic fluid from the pregnant uterus usually using a transabdominal approach (see Fig. 7.14). The procedure is useful in women with elevated risk on first trimester screen or quad screen, abnormal fetal findings on sonogram, or in parents who are carriers or with a strong family history of an inherited disease. Ultrasonography is used to gain additional information and to guide the placement of the amniocentesis needle. The amniotic fluid and cells that have been shed by the fetus are studied. Amniocentesis can be performed on an outpatient basis starting at 15 weeks. For chromosomal analysis, the fetal cells are grown in culture and the result is available in 10 to 14 days. Beyond prenatal diagnosis, amniocentesis can also be done throughout the pregnancy as needed for testing. In cases of suspected chorioamnionitis, an amniocentesis can be done to assess for infection of the amniotic fluid. Fetal lung maturity can be assessed by amniocentesis by looking for the lecithin/sphingomyelin (L/S) ratio and presence of phosphatidyl glycerol to help with delivery planning in some cases. Chorionic Villus Sampling Chorionic villus sampling is an invasive diagnostic procedure that obtains tissue that can be used for fetal chromosome studies, DNA analysis, and biochemical studies. Sampling

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of the chorionic villi usually is done after 10 weeks of gestation.58 Performing the test before 10 weeks is not recommended because of the danger of limb reduction defects in the fetus. The chorionic villi are the site of exchange of nutrients between the maternal blood and the embryo—the chorionic sac encloses the early amniotic sac and fetus, and the villi are the primitive blood vessels that develop into the placenta. The sampling procedure can be performed using either a transabdominal or transcervical approach (see Fig. 7.14). The fetal tissue does not have to be cultured, and fetal chromosome analysis can be made available in 24 hours. DNA analysis and biochemical tests can be completed within 1 to 2 weeks.40 Percutaneous Umbilical Cord Blood Sampling PUBS is an invasive diagnostic procedure that involves the transcutaneous insertion of a needle through the uterine wall and into the umbilical artery. It is performed under ultrasonographic guidance and can be done any time after 16 weeks of gestation. It is used for prenatal diagnosis of hemoglobinopathies, coagulation disorders, metabolic and cytogenetic disorders, and immunodeficiencies. Fetal infections such as rubella and toxoplasmosis can be detected through measurement of immunoglobulin M antibodies or direct blood cultures. Results from cytogenetic studies usually are available within 48 to 72 hours. Because the procedure carries a greater risk of pregnancy loss compared to amniocentesis, it usually is reserved for situations in which rapid cytogenetic analysis is needed or in which diagnostic information cannot be obtained by other methods. In the process of doing PUBS to assess fetal anemia, a blood transfusion can be administered to the fetus as needed. Cytogenetic and Biochemical Analyses Amniocentesis and chorionic villus sampling yield cells that can be used for cytogenetic and DNA analyses. Biochemical analyses can be used to detect abnormal levels of AFP and abnormal biochemical products in the maternal blood and in specimens of amniotic fluid and fetal blood. Cytogenetic studies are used for fetal karyotyping to determine the chromosomal makeup of the fetus. They are done to detect abnormalities of chromosome number and structure. Karyotyping also reveals the sex of the fetus. This may be useful when an inherited defect is known to affect only one sex. Analysis of DNA is done on cells extracted from the amniotic fluid, chorionic villi, or fetal blood from percutaneous umbilical sampling to detect genetic defects such as inborn errors of metabolism. The defect may be established through direct demonstration of the molecular defect or through methods that break the DNA into fragments that can be studied to determine the presence of an abnormal gene. Direct demonstration of the molecular defect is done by growing the amniotic fluid cells in culture and measuring the enzymes that the cultured cells produce. Many of the enzymes are expressed in the chorionic villi. This permits earlier prenatal diagnosis because

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the cells do not need to be subjected to prior culture. DNA studies are used to detect genetic defects that cause inborn errors of metabolism, such as Tay-Sachs disease, glycogen storage diseases, and familial hypercholesterolemia. Prenatal diagnoses are possible for more than 70 inborn errors of metabolism. The newest realm of fetal diagnosis involves looking at fetal DNA in the maternal blood. Some private companies and many research institutions are exploring the efficacy of looking at fetal DNA for sex determination and other genetic testing. More research is needed before this will be offered to all women.

IN SUMMARY Genetic and prenatal diagnosis and counseling are done in an effort to determine the risk of having a child with a genetic or chromosomal disorder. They often involve a detailed family history (i.e., pedigree), examination of any affected and other family members, and laboratory studies including chromosomal analysis and biochemical studies. They usually are done by a genetic counselor and a specially prepared team of health care professionals. Prenatal screening and diagnosis are used to detect fetal abnormalities. Ultrasonography is used for fetal anatomic imaging. It is used for determination of fetal size and position and for the presence of structural anomalies. Maternal serum screening is used to identify pregnancies that are at increased risk of adverse outcomes such as Down syndrome and NTDs. Amniocentesis and chorionic villus sampling may be used to obtain specimens for cytogenetic and biochemical studies.

3. A couple has been informed that their newborn child has the features of Down syndrome, and it is suggested that genetic studies be performed. A. The child is found to have trisomy 21. Use Figure 7.8, which describes the events that occur during meiosis, to explain the origin of the third chromosome. B. If the child had been found to have the robertsonian chromosome, how would you explain the origin of the abnormal chromosome? 4. An 8-year-old boy has been diagnosed with mitochondrial myopathy. His major complaints are those of muscle weakness and exercise intolerance. His mother gives a report of similar symptoms, but to a much lesser degree. A. Explain the cause of this boy’s symptoms. B. Mitochondrial disorders follow a nonmendelian pattern of inheritance. Explain. Define the terms homoplasmy and heteroplasmy in relation to the diversity of tissue involvement and symptoms in people with mitochondrial disorders. 5. A 26-year-old woman is planning to become pregnant. A. What information would you give her regarding the effects of medications and drugs on the fetus? What stage of fetal development is associated with the greatest risk? B. What is the rationale for ensuring that she has an adequate intake of folic acid before conception? C. She and her husband have an indoor cat. What precautions should she use in caring for the cat?

REVIEW EXERCISES 1. A 23-year-old woman with sickle cell disease and her husband want to have a child but worry that the child will be born with the disease. A. What is the mother’s genotype in terms of the sickle cell gene? Is she heterozygous or homozygous? B. If the husband is found not to have the sickle cell gene, what is the probability of their child having the disease or being a carrier of the sickle cell trait? 2. A couple has a child who was born with a congenital heart disease. A. Would you consider the defect to be the result of a single gene or a polygenic trait? B. Would these parents be at greater risk of having another child with a heart defect or would they be at equal risk of having a child with a defect in another organ system, such as cleft palate?

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References 1. Center for Disease Control and Prevention. (2010). Birth defects and congenital anomalies. [Online]. Available: http://www.cdc.gov/nchs/fastats/ bdefects.htm. Accessed November 27, 2011. 2. Hall J. E. (2011). Guyton and Hall textbook of medical physiology (12th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 3. Nussbaum R. L., McInnes R. R., Willard H. F. (2007). Thompson & Thompson genetics in medicine (7th ed., pp. 115–146, 382–387, 443–458, 485–490). Philadelphia, PA: Elsevier Saunders. 4. Rubin R., Strayer, D. (Eds.). (2012). Pathology: Clinicopathologic foundations of medicine (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 5. Judge N. P., Dietz H. C. (2005). Marfan syndrome. Lancet 366(9501), 1965–1976. 6. Gonzales E. A. (2009). Marfan syndrome. Journal of American Academy of Nurse Practitioners 21(12), 663–670. 7. Odell A. N., Amusa G. A. (2011). Aortic aneurysm with valvular insufficiency: Is it due to Marfan syndrome or hypertension? A case report and review of literature. Journal of Vascular Nursing 29(1), 16–22. 8. Sponseller P. D., Erkula G., Skolasky R. L., et al. (2010). Improving clinical recognition of Marfan syndrome. Journal of Bone & Joint Surgery. American Volume 92(9), 1868–1875.

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Chapter 7  Genetic and Congenital Disorders    159 9. Vassilyadi M., Keene D. (2011). Extensive central nervous system involvement in optic pathway gliomas in neurofibromatosis type 1. Pediatric Blood & Cancer 57(4), 6688–6690. 10. Gumbiene L., Petrulioniene Z., Rucinskas K., et al. (2011). Pulmonary hypertension: A fatal complication of neurofibromatosis type I. Respiratory Care 56(11), 1844–1848. 11. Avery R. A., Liu G. T. (2010). Picture of the month-quiz case. Lisch nodules, ectropion uveae, and optic pathway glioma due to neurofibromatosis type 1. Archives of Pediatrics & Adolescent Medicine 164(5), 489–490. 12. Targum S. D., Lang W. (2010). Neurobehavioral problems associated with PKU. Psychiatry 7(12), 29–32. 13. Blau N., van Spronsen F. J., Levy H. L. (2010). Phenylketonuria. Lancet 3766(9750), 1417–1427. 14. Trefz F. K., Belanger-Quentana A. (2010). Sapropterin dihydrochloride: A new drug and a new concept in the management of PKU. Drugs of Today 46(8), 589–600. 15. Alberg C., Levine S., Burton H. (2010). Tay sachs disease carrier testing in the United Kingdom Jewish population. British Journal of Midwifery 18(4), 220–224. 16. Tsuji D., Akeboshi H, Matsuoka K., et al. (2011). Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis. Annals of Neurology 69(4), 691–670. 17. Centers for Disease Control and Prevention. (2011). Fragile X syndrome. [Online]. Available: http://www.cdc.gov/ncbddd/fxs/data.html. Accessed December 2, 2011. 18. Koster M. P., Wortelboer E. J., Stouknbeck P., et al. (2011). Modeling down syndrome screening performance using first trimester serum markers. Ultrasound in Obstetrics & Gynecology 38(2), 134–139. 19. Agrawal K., Panda K. (2011). A modified surgical schedule for primary management of cleft lip and palate in developing countries. Cleft Palate Craniofacial Journal 48(1), 1–8. 20. Centers for Disease Control and Prevention. (2011). Birth Defects. [Online]. Available: http://www.cdc.gov/ncbddd/birthdefects/data.html. Accessed December 2, 2011. 21. Zwaan O. H., Reinhardt D., Hitzler J., et al., (2010). Acute leukemia in children with down syndrome. Hematology/Oncology Clinics of North America 24(1), 19–34. 22. Sharma J., Friedmen D., Dave-Sherma S., et al. (2009). Aortic distensibility and dilation in turner syndrome. Cardiology in the Young 19(6), 568–572. 23. Jergensen K. T., Rostgaard K., Bache I., et al. (2010). Autoimmune diseases in women with Turner syndrome. Arthritis & Rheumatism 62(3), 658–666. 24. Sybert V. P., McCauley E. (2004). Turner’s syndrome. New England Journal of Medicine 351, 1227–1238. 25. Wattendorf D. J., Muenke M. (2005). Klinefelter syndrome. American Family Physician 72, 2259–2262.

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26. Young V. S. L. (2005). Teratogenicity and drugs in breast milk. In KodaKimble M. A., Young L. Y., Kradjan W. A. (Eds.), Applied therapeutics: The clinical use of drugs (8th ed., pp. 47-1–47-15). Philadelphia, PA: Lippincott Williams & Wilkins. 27. Lanfranco F., Kamischke A., Zitzmann M., et al. (2004). Klinefelter syndrome. Lancet 364, 273–283. 28. Ferlin A., Schipilliti M., Foresta C. (2011). Bone density and risk of osteoporosis in Klinefelter syndrome. Acta Paediatrica 100(6), 878–884. 29. Dimauro S., Davidzon G. (2005). Mitochondrial DNA and disease. Annals of Medicine 37, 222–232. 30. Chaturvedi S., Bala K., Thakur G., et al. (2005). Mitochondrial encephalomyopathies: Advances in understanding. Medical Science Monitor 11, RA238–RA246. 31. Bailey B. A., Sokol R. J. (2008). Pregnancy and alcohol use: Evidence and recommendations for prenatal care. Clinical Obstetrics and Gynecology 51(2), 436–444. 32. Warren K. R., Hewitt B. G., Thomas J. D. (2011). Fetal alcohol spectrum disorders: Research challenges & opportunities. Alcohol Research & Health 34(1), 4–14. 33. Centers for Disease Control and Prevention. (2011). Fetal Alcohol Spectrum Disorders. [Online]. Available: http://www.cdc.gov/ncbddd/ fasd/data.html. Accessed December 3, 1951. 34. Sokol R. J., Delaney-Black V., Nordstrom B. (2003). Fetal alcohol ­syndrome. Journal of the American Medical Association 290, 2996–2999. 35. Wattendorf D. J., Muenke M. (2005). Fetal alcohol spectrum disorders. American Family Physician 72, 279–285. 36. Riley E. P., McGee C. L. (2005). Fetal alcohol spectrum disorders: An overview with emphasis on changes in brain and behavior. Experimental Biology and Medicine 230, 357–365. 37. Feldman D. M., Timms D., Borgida A. F. (2010). Toxoplasmosis, parvovirus, and CMV in pregnancy. Clinics in Laboratoy Medicine 30(3), 709–720. 38. Houghton L. A., Gray A. R., Rose M. C., et al. (2011). Longterm effect of low dose folic acid intake: Potential effect of mandatory fortification in the prevention of neural tube defects. American Journal of Clinical Nutrition 94(1), 136–141. 39. Centers for Disease Control and Prevention. (2012). Folic acid: Recommendations. [Online]. Available: www.cdc.gov/ncbddd/folicacid/ recommendations.html. Accessed March 27, 2013. 40. Wilson R. D. (2000). Amniocentesis and chorionic villus sampling. Current Opinion in Obstetrics and Gynecology 12, 81–86.

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8

Neoplasia

Sheila Grossman

CONCEPTS OF CELL DIFFERENTIATION AND GROWTH The Cell Cycle Cell Proliferation Cell Differentiation

CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS Terminology Benign Neoplasms Malignant Neoplasms Cancer Cell Characteristics Invasion and Metastasis Tumor Growth

ETIOLOGY OF CANCER

Genetic and Molecular Basis of Cancer Cancer-Associated Genes Epigenetic Mechanisms Molecular and Cellular Pathways Role of the Microenvironment Carcinogenesis Host and Environmental Factors Heredity Hormones Immunologic Mechanisms Chemical Carcinogens Radiation Oncogenic Viruses

CLINICAL MANIFESTATIONS

Tissue Integrity Systemic Manifestations Anorexia and Cachexia Fatigue and Sleep Disorders Anemia Paraneoplastic Syndromes

SCREENING, DIAGNOSIS, AND TREATMENT Screening Diagnostic Methods Tumor Markers Cytologic and Histologic Methods Staging and Grading of Tumors Cancer Treatment Surgery Radiation Therapy Chemotherapy Hormonal Therapy Biotherapy Targeted Therapy

CHILDHOOD CANCERS

Incidence and Types Embryonal Tumors Biology of Childhood Cancers Diagnosis and Treatment Radiation Therapy Chemotherapy

Cancer is the second leading cause of death in the United States. For the year 2011, it was estimated that 1,596,670 people in the United States would be newly diagnosed with cancer and 5,671,950 people would die of the disease.1 These numbers do not include cancer in situ or basal and squamous cell skin cancers.1 Approximately 11.7 million Americans alive in 2007 had a history of cancer.1 Trends in cancer survival demonstrate that relative 5-year survival rates have improved since the early 1990s.1 Although the mortality rate has decreased, the number of cancer deaths has increased due to the aging and expanding population. Cancer is not a single disease. It can originate in almost any organ, with skin cancers being the most common in the United States. Excluding skin cancers, the prostate is the most common site in men and the breast is the most common site in women. The ability to cure cancer varies considerably and depends on the type of cancer and the extent of the disease at time of diagnosis. Cancers such as Hodgkin disease, testicular cancer, and osteosarcoma, which only a few decades ago had poor prognoses, are today cured in many cases. However, lung cancer, which is the leading cause of death in men and women in the United States,1 is resistant to therapy, and although some progress has been made in its treatment, mortality rates remain high. This chapter is divided into six sections: •• Concepts of cell differentiation and growth •• Characteristics of benign and malignant neoplasms •• Etiology of cancer •• Clinical manifestations •• Diagnosis and treatment •• Childhood cancers

160

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The Cell Cycle

CONCEPTS OF CELL DIFFERENTIATION AND GROWTH

The cell cycle is an orderly sequence of events that occur as a cell duplicates its contents and divides (Fig. 8.1). During the cell cycle, genetic information is duplicated and the duplicated chromosomes are appropriately aligned for distribution between two genetically identical daughter cells. The cell cycle is divided into four phases, referred to as G1, S, G2, and M. G1 (gap 1) occurs after the postmitosis phase when DNA synthesis stops and ribonucleic acid (RNA) and protein synthesis and cell growth take place.2 During the S phase, DNA synthesis occurs, causing two separate sets of chromosomes to develop, one for each daughter cell. G2 (gap 2) is the premitotic phase and is similar to G1 in that DNA synthesis stops, but RNA and protein synthesis continue. The phases, G1, S, and G2, are referred to as interphase. The M phase is the phase of nuclear division, or mitosis, and cytoplasmic division. Continually dividing cells, such as the skin’s stratified squamous epithelium, continue to cycle from one mitotic division to the next. When environmental conditions are adverse, such as nutrient or growth factor unavailability, or when cells are highly specialized, cells may leave the cell cycle, becoming mitotically quiescent, and reside in a resting state known as G0. Cells in G0 may reenter the cell cycle in response to extracellular nutrients, growth factors, hormones, and other signals such as blood loss or tissue injury that trigger cell growth.3 Highly specialized and terminally differentiated cells, such as neurons, may permanently stay in G0. Within the cell cycle, pauses can be made if the specific events of the cell cycle phases have not been completed. For

After completing this section of the chapter, you should be able to meet the following objectives: •• Define neoplasm and explain how neoplastic growth differs from the normal adaptive changes seen in atrophy, hypertrophy, and hyperplasia. •• Describe the phases of the cell cycle.

Cancer is a disorder of altered cell differentiation and growth. The resulting process is called neoplasia, meaning “new growth,” and the new growth is called a neoplasm. Unlike changes in tissue growth that occur with hypertrophy and hyperplasia, the growth of a neoplasm tends to be uncoordinated and relatively autonomous in that it lacks normal regulatory controls over cell growth and division. Normal tissue renewal and repair involves two components: cell proliferation and differentiation. Proliferation, or the process of cell division, is an adaptive process for new cell growth to replace old cells or when additional cells are needed.2 Differentiation describes the mechanism by which cells become increasingly more specialized with each mitotic division.2 Apoptosis is a form of programmed cell death that eliminates senescent cells, cells with deoxyribonucleic acid (DNA) damage, or unwanted cells.2

IN

RP H TE

hours to m ASE (22 any S Phase

yea rs)

DNA replication G1 Phase

G2 Phase

Mitochondria

Growth

e

s ha op Pr

e phas

tok ines is

Meta

e Cy

Anap hase

as

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ph

FIGURE 8.1 • Cell cycle. The cell cycle’s four step are illustrated beginning with G1 and proceeding to M. The first growth phase (G1), DNA synthesis phase (S), Second growth phase (G2), and mitosis (M) are illustrated. (From McConnell T. H., Hull K. L. (2011). Human form human function: Essentials of anatomy & physiology (p. 77, Figure 3.10). Philadelphia, PA: Lippincott Williams & Wilkins.)

Te lo

Organelle duplication

MITOSIS (1–3 hours

)

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162   UNIT II  Cell Function and Growth

example, mitosis is prevented until DNA is properly replicated. In addition, chromosome separation in mitosis is delayed until all spindle fibers have attached to the chromosomes. These are opportunities for checking the accuracy of DNA replication. These DNA damage checkpoints allow for any defects to be identified and repaired, thereby ensuring that each daughter cell receives a full complement of genetic information, identical to that of the parent cell.2,3 The cyclins are a group of proteins that control the entry and progression of cells through the cell cycle. Cyclins bind to proteins called cyclin-dependent kinases (CDKs). Kinases are enzymes that phosphorylate proteins. The CDKs phosphorylate specific target proteins and are expressed continuously during the cell cycle but in an inactive form, whereas the cyclins are synthesized during specific phases of the cell cycle and then degraded by ubiquitination once their task is completed.4 Different arrangements of cyclins and CDKs are associated with each stage of the cell cycle (Fig. 8.2). For example, cyclin B and CDK1 control the transition from G2 to M. As the cell moves into G2, cyclin B is synthesized and binds to CDK1. The cyclin B–CDK1 complex then directs the events leading to mitosis, including DNA replication and assembly of the mitotic spindle. Although each phase of the cell cycle is monitored carefully, the transition from G2 to M is considered to be one of the most important checkpoints in the cell cycle. In addition to the synthesis and degradation of the cyclins, the cyclin–CDK complexes are regulated by the binding of CDK inhibitors (CKIs). The CKIs are particularly important in regulating cell cycle checkpoints during which mistakes in DNA replication are repaired.4,5 Manipulation of cyclins, CDKs, and CKIs is the basis for development of newer forms of drug therapy that can be used in cancer treatment.6

Cell Proliferation Cell proliferation is the process of increasing cell numbers by mitotic cell division. In normal tissue, cell proliferation is regulated so that the number of cells actively dividing is equivalent to the number dying or being shed. In humans, there are two major categories of cells: gametes and somatic cells. The gametes (ovum and sperm) are haploid, having only one set of chromosomes from one parent, and are designed specifically for sexual fusion. After fusion, a diploid cell containing both sets of chromosomes is formed. This cell is the somatic cell that goes on to form the rest of the body. In terms of cell proliferation, the 200 various cell types of the body can be divided into three large groups: (1) the welldifferentiated neurons and cells of skeletal and cardiac muscle cells that rarely divide and reproduce; (2) the progenitor or parent cells that continue to divide and reproduce, such as blood cells, skin cells, and liver cells; and (3) the undifferentiated stem cells that can be triggered to enter the cell cycle and produce large numbers of progenitor cells if needed.2 The rates of reproduction of cells vary greatly. White blood cells and cells that line the gastrointestinal tract live several days and must be replaced constantly. In most tissues, the rate of cell reproduction is greatly increased when tissue is injured or lost. Bleeding, for example, stimulates reproduction of the blood-forming cells

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DNA damage Oncogenic activation Hypoxia

Growth factors and cytokines

p53

CDK inhibitors

Protooncogenes

Cyclins D, E CDK 2, 4, 6 P Rb

Rb

E2F E2F Go G1

M

APOPTOSIS

R S

G2 Cyclins A and B CDKs FIGURE 8.2  •  Regulation of the cell cycle. Cells are triggered to go to G1 from G0 by growth factors and cytokines via protooncogene activation. A significant time in the movement of cells from G1 to S phase is the restriction point R. An important regulatory event in this process is the phosphorylation of RB by CDKs, which causes the release of transcriptional activator E2F. CDKs are suppressed by CKIs that are regulated by p53. Tumor suppression proteins block cell cycle progression within G1. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 170). Philadelphia, PA: Lippincott Williams & Wilkins.)

of the bone marrow. In some types of tissue, the genetic program for cell replication normally is suppressed but can be reactivated under certain conditions. The liver, for example, has extensive regenerative capabilities under certain conditions.

Key Points CELL PROLIFERATION AND GROWTH •  Tissue growth and repair involve cell proliferation, differentiation, and apoptosis. •  Apoptosis is a form of programmed cell death that eliminates senescent and some types of injured cells (e.g., those with DNA damage or hydrogen peroxide–induced injury).

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Understanding

The Cell Cycle

A cell reproduces by performing an orderly sequence of events called the cell cycle. The cell cycle is divided into four phases of unequal duration that include the (1) synthesis (S) and mitosis (M) phases that are separated by (2) two gaps (G1 and G2). There is also (3) a dormant phase (G0) during which the cell may leave the cell cycle. Movement through each of these phases is mediated at (4) specific checkpoints that are controlled by specific enzymes and proteins called cyclins.

Synthesis and Mitosis Synthesis (S) and mitosis (M) represent the two major phases of the cell cycle. The S phase, which takes about 10 to 12 hours, is the period of DNA synthesis and replication of the chromosomes. The M phase, which usually takes less than an hour, involves formation of the mitotic spindle and cell division with formation of two daughter cells.

S G1 G2 M

G0

Gaps 1 and 2 Because most cells require time to grow and double their mass of proteins and organelles, extra gaps (G) are inserted into the cell cycle. G1 is the stage during which the cell is starting to prepare for DNA replication and mitosis through protein synthesis and an increase in organelle and cytoskeletal elements. G2 is the premitotic phase. During this phase, enzymes and other proteins needed for cell division are synthesized and moved to their proper sites.

S G1 G2 G0

M

Continued

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164   UNIT II  Cell Function and Growth

Understanding

The Cell Cycle (Continued) Gap 0

G0 is the stage after mitosis during which a cell may leave the cell cycle and either remain in a state of inactivity or reenter the cell cycle at another time. Labile cells, such as blood cells and those that line the gastrointestinal tract, do not enter G0 but continue cycling. Stable cells, such as hepatocytes, enter G0 after mitosis but can reenter the cell cycle when stimulated by the loss of other cells. Permanent cells, such as neurons that become terminally differentiated after mitosis, leave the cell cycle and are no longer capable of cell renewal.

S G1 Stable cells (e.g., hepatocytes)

G2 M

G0 Permanent cells (e.g., nerves)

Checkpoints and Cyclins In most cells, there are several checkpoints in the cell cycle, at which time the cycle can be arrested if previous events have not been completed. For example, the G1/S checkpoint monitors whether the DNA in the chromosomes is damaged by radiation or chemicals, and the G2/M checkpoint prevents entry into mitosis if DNA replication is not complete. The cyclins are a family of proteins that control entry and progression of cells through the cell cycle. They function by activating proteins called CDKs. Different combinations of cyclins and CDKs are associated with each stage of the cell cycle. In addition to the synthesis and degradation of the cyclins, the cyclin–CDK complexes are regulated by the binding of CKIs. The CDK inhibitors are particularly important in regulating cell cycle checkpoints during which mistakes in DNA replication are repaired.

Cell Differentiation Cell differentiation is the process whereby proliferating cells become progressively more specialized cell types. This process results in a fully differentiated, adult cell that has a specific set of structural, functional, and life expectancy characteristics. For example, the red blood cell is a terminally differentiated cell that has been programmed to develop into a concave disk, which functions as a vehicle for oxygen transport and lives approximately 3 months.

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G1S checkpoint (checks for DNA damage)

S G1

Cyclin E Cyclin A Cyclin B

G2

M G0

G2M checkpoint (checks for damaged or unduplicated DNA)

The various cell types of the body originate from a single cell—the fertilized ovum. As the embryonic cells increase in number, they engage in a coordinated process of ­differentiation that is necessary for the development of all the various organs of the body. The process of differentiation is regulated by a combination of internal processes involving the expression of specific genes and external stimuli provided by neighboring cells, the extracellular matrix, exposure to substances in the maternal circulation, and growth factors, cytokines, oxygen, and nutrients.

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What make the cells of one organ different from those of another organ are the specific genes that are expressed and the particular pattern of gene expression. Although all cells have the same complement of genes, only a small number of these genes are expressed in postnatal life. When cells, such as those of the developing embryo, differentiate and give rise to committed cells of a particular tissue type, the appropriate genes are maintained in an active state, while the rest remain inactive. Normally, the rate of cell reproduction and the process of cell differentiation are precisely controlled in prenatal and postnatal life so that both of these mechanisms cease once the appropriate numbers and types of cells are formed. The process of differentiation occurs in orderly steps. With each progressive step, increased specialization is exchanged for a loss of ability to develop different cell characteristics and different cell types. As a cell becomes more highly specialized, the stimuli that are able to induce mitosis become more limited. Neurons, which are highly specialized cells, lose their ability to divide and reproduce once development of the nervous system is complete. More importantly, there are very few remaining precursor cells to direct their replacement. However, appropriate numbers of these cell types are generated in the embryo that loss of a certain percentage of cells does not affect the total cell population and specific functions. In some tissues, such as the skin and mucosal lining of the gastrointestinal tract, a high degree of cell renewal continues throughout life. Even in these continuously renewing cell populations, the more specialized cells are unable to divide. These cell populations rely on progenitor or parent cells of the same lineage that have not yet differentiated to the extent that they have lost their ability to divide. These cells are sufficiently differentiated so that their daughter cells are limited to the same cell line, but they are insufficiently differentiated to preclude the potential for active proliferation. However, their cell renewal properties are restricted by growth factors required for cell division. Another type of cell, called a stem cell, remains incompletely differentiated throughout life. Stem cells are reserve cells that remain quiescent until there is a need for cell replenishment, in which case they divide, producing other stem cells and cells that can carry out the functions of the differentiated cell. When a stem cell divides, one daughter cell retains the stem cell characteristics, and the other daughter cell becomes a progenitor cell that proceeds through a process that leads to terminal differentiation (Fig. 8.3). The progeny of each progenitor cell follows more restricted genetic programs, with the differentiating cells undergoing multiple mitotic divisions in the process of becoming a mature cell type and with each generation of cells becoming more specialized. In this way, a single stem cell can give rise to the many cells needed for normal tissue repair or blood cell production. When the dividing cells become fully differentiated, the rate of mitotic division is reduced. In the immune system, for example, appropriately stimulated B lymphocytes become progressively more differentiated as they undergo successive mitotic divisions, until they become mature plasma cells that no longer can divide but are capable of secreting large amounts of antibody.

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Stem cell

Stem cell

Progenitor cell Daughter cells

Differentiated cells

FIGURE 8.3  •  Mechanism of stem cell–mediated cell replacement. Division of a stem cell with an unlimited potential for proliferation results in one daughter cell, which retains the characteristics of a stem cell, and a second daughter cell that differentiates into a progenitor or parent cell, with a limited potential for differentiation and proliferation. As the daughter cells of the progenitor cell proliferate, they become more differentiated, until they reach the stage where they are fully differentiated.

Stem cells have two important properties, that of selfrenewal and potency. Self-renewal means that the stem cells can undergo numerous mitotic divisions while ­maintaining an undifferentiated state.2,7 The term potency is used to define the differentiation potential of stem cells. Totipotent stem cells are those produced by fertilization of the egg. The first few cells produced after fertilization are totipotent and can differentiate into embryonic and extraembryonic cells. Totipotent stem cells give rise to pluripotent stem cells that can differentiate into the three germ layers of the embryo. Multipotent stem cells are cells such as hematopoietic stem cells that give rise to only a few cell types. Finally, unipotent stem cells produce only one cell type but retain the property of self-renewal. It has become useful to categorize stem cells into two basic categories: embryonic stem cells and adult stem cells (sometimes called somatic stem cells).2,7 Embryonic stem cells are pluripotent cells derived from the inner cell mass of the blastocyst stage of the embryo. These give rise to the three embryonic germ cell layers. As development progresses, the embryo forms germline stem cells for reproduction and somatic stem cells for organogenesis. Both the germline stem cells and the somatic stem cells retain the property of selfrenewal. Adult stem cells reside in specialized microenvironments that differ depending on tissue type. These stem cells have important roles in homeostasis as they contribute to tissue regeneration and replacement of cells lost to cell death.8 An important role of stem cells in the pathogenesis of cancer has been identified, and it continues to be studied.7–11 Cancer stem cells (called tumor-initiating cells [TICs]) have been identified in breast, prostate, acute myeloid leukemia (AML), and other cancers.12 To maintain their self-renewing properties, these stem cells express cell cycle inhibitors. There is also strong experimental support for the idea that, in certain cancers, cancer stem cells are the initial target for malignant transformation.12 If confirmed, identifying these findings could

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have important implications for cancer treatment. For ­example, drugs can be targeted at eliminating proliferating cells.

IN SUMMARY The term neoplasm refers to an abnormal mass of tissue in which the growth exceeds and is uncoordinated with that of the normal tissues. Unlike normal cellular adaptive processes such as hypertrophy and hyperplasia, neoplasms do not obey the laws of normal cell growth. They serve no useful purpose, they do not occur in response to an appropriate stimulus, and they continue to grow at the expense of the host. The process of cell growth and division is called the cell cycle. It is divided into four phases: G1, the postmitotic phase, during which protein synthesis and cell growth take place; S, the phase during which DNA synthesis occurs, giving rise to two separate sets of chromosomes; G2, the premitotic phase, during which RNA and protein synthesis continues; and M, the phase of cell mitosis or cell division. The G0 phase is a resting or quiescent phase in which nondividing cells reside. The entry into and progression through the various stages of the cell cycle are controlled by cyclins, CDKs, and CDK inhibitors. Normal tissue renewal and repair involves cell proliferation, differentiation, and apoptosis. Proliferation, or the process of cell division, is an inherent adaptive mechanism for cell replacement when old cells die or additional cells are needed. Differentiation is the process of specialization whereby new cells acquire the structure and function of the cells they replace. Apoptosis is a form of programmed cell death that eliminates senescent cells, cells with damaged DNA, or unwanted cells. Body cells can be divided into two large groups: the well-differentiated neurons and cells of skeletal and cardiac muscle that rarely divide and reproduce, and the progenitor or parent cells that continue to divide and reproduce, such as blood cells, skin cells, and liver cells. A third category of cells are the stem cells that remain quiescent until there is a need for cell replenishment, in which case they divide, producing other stem cells and cells that can carry out the functions of differentiated cells. Stem cells have two important properties, those of self-renewal and potency. Self-renewal means that the stem cells can undergo numerous mitotic divisions while maintaining an undifferentiated state. The term potency is used to define the differentiation potential of stem cells. There are two main categories of stem cells. Embryonic stem cells are pluripotent cells derived from the inner cell mass of the blastocyst stage of the embryo. Adult stem cells reside in specific microenvironments and have significant roles in homeostasis as they contribute to tissue regeneration and replacement of cells lost to apoptosis. Cancer stem cells have been identified in breast, prostate, AML, and other cancers.

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CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS After completing this section of the chapter, you should be able to meet the following objectives: •• Relate the properties of cell differentiation to the development of a cancer cell clone and the behavior of the tumor. •• Trace the pathway for hematologic spread of a metastatic cancer cell. •• Use the concepts of growth fraction and doubling time to explain the growth of cancerous tissue.

Body organs are composed of two types of tissue: parenchymal tissue and stromal or supporting tissue. The parenchymal tissue cells represent the functional components of an organ. The parenchymal cells of a tumor determine its behavior and are the component for which a tumor is named. The supporting tissue includes the extracellular matrix and connective tissue that surround the parenchymal cells. The lymphatic and blood vessels provide nourishment and support for the parenchymal cells.

Terminology Traditionally, by definition a tumor is a swelling that can be caused by a number of conditions, including inflammation and trauma. In addition, the term has been used to define a mass of cells that arises because of overgrowth. Although not synonymous, the terms tumor and neoplasm often are used interchangeably. Neoplasms usually are classified as benign or malignant. Neoplasms that contain well-differentiated cells that are clustered together in a single mass are considered to be benign. These tumors usually do not cause death unless their location or size interferes with vital functions. In contrast, malignant neoplasms are less well differentiated and have the ability to break loose, enter the circulatory or lymphatic system, and form secondary malignant tumors at other sites. Tumors usually are named by adding the suffix -oma to the parenchymal tissue type from which the growth originated.2 Thus, a benign tumor of glandular epithelial tissue is called an adenoma, and a benign tumor of bone tissue is called an osteoma. The term carcinoma is used to designate a malignant tumor of epithelial tissue origin. In the case of a malignant tumor of glandular epithelial tissue, the term adenocarcinoma is used. Malignant tumors of mesenchymal origin are called sarcomas (e.g., osteosarcoma). Papillomas are benign, microscopic or macroscopic finger-like projections that grow on any surface. A polyp is a growth that projects from a mucosal surface, such as the intestine. Although the term usually implies a benign neoplasm, some malignant tumors also appear as polyps.2 Adenomatous ­polyps are ­considered precursors to adenocarcinomas of the colon. Oncology is the study of tumors and

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TABLE 8.1 NAMES OF SELECTED BENIGN AND MALIGNANT TUMORS ACCORDING TO TISSUE TYPES TISSUE TYPE

BENIGN TUMORS

MALIGNANT TUMORS

Papilloma Adenoma

Squamous cell carcinoma Adenocarcinoma

Fibroma Lipoma Chondroma Osteoma Hemangioma Lymphangioma

Fibrosarcoma Liposarcoma Chondrosarcoma Osteosarcoma Hemangiosarcoma Lymphangiosarcoma Lymphosarcoma

Leiomyoma Rhabdomyoma

Leiomyosarcoma Rhabdomyosarcoma

Nerve cell Glial tissue

Neuroma Glioma

Nerve sheaths Meninges

Neurilemmoma Meningioma

Neuroblastoma Glioblastoma, astrocytoma, medulloblastoma, oligodendroglioma Neurilemmal sarcoma Meningeal sarcoma

Epithelial Surface Glandular

Connective Fibrous Adipose Cartilage Bone Blood vessels Lymph vessels Lymph tissue

Muscle Smooth Striated

Neural Tissue

Hematologic Granulocytic Erythrocytic Plasma cells Lymphocytic Monocytic

Myelocytic leukemia Erythrocytic leukemia Multiple myeloma Lymphocytic leukemia or lymphoma Monocytic leukemia

Endothelial Tissue Blood vessels Lymph vessels

Hemangioma Lymphangioma

their treatment. Table  8.1 lists the names of selected benign and malignant tumors according to tissue types. Benign and malignant neoplasms usually are distinguished by the following: •• Cell characteristics •• Rate of growth

Hemangiosarcoma Lymphangiosarcoma

•• Manner of growth •• Capacity to invade and metastasize to other parts of the body •• Potential for causing death The characteristics of benign and malignant neoplasms are summarized in Table 8.2.

TABLE 8.2 CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS CHARACTERISTICS

BENIGN

MALIGNANT

Cell characteristics

Well-differentiated cells that resemble cells in the tissue of origin Usually progressive and slow; may come to a standstill or regress Grows by expansion without invading the ­surrounding tissues; usually encapsulated Does not spread by metastasis

Cells are undifferentiated, with anaplasia and atypical structure that often bears little resemblance to cells in the tissue of origin Variable and depends on level of differentiation; the more ­undifferentiated the cells, the more rapid the rate of growth Grows by invasion, sending out processes that infiltrate the ­surrounding tissues Gains access to blood and lymph channels to metastasize to other areas of the body

Rate of growth Mode of growth Metastasis

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Benign Neoplasms Benign tumors are composed of well-differentiated cells that resemble the cells of the tissues of origin and are characterized by a slow, progressive rate of growth that may come to a standstill or regress.12 For unknown reasons, benign tumors have lost the ability to suppress the genetic program for cell proliferation but have retained the program for normal cell differentiation. They grow by expansion and remain localized to their site of origin, lacking the capacity to infiltrate, invade, or metastasize to distant sites. Because they expand slowly, they develop a surrounding rim of compressed connective tissue called a fibrous capsule.2 The capsule is responsible for a sharp line of demarcation between the benign tumor and the adjacent tissues, a factor that facilitates surgical removal. Benign tumors are usually much less of a threat to health and well-being than malignant tumors, and they usually do not cause death unless they interfere with vital functions because of their anatomic location. For instance, a benign tumor growing in the cranial cavity can eventually cause death by compressing brain structures. Benign tumors also can cause disturbances in the function of adjacent or distant structures by producing pressure on tissues, blood vessels, or nerves. Some benign tumors are also known for their ability to cause alterations in body function by abnormally producing hormones.

Key Points BENIGN AND MALIGNANT NEOPLASMS •  A neoplasm, benign or malignant, represents a new growth. •  Benign neoplasms are well-differentiated tumors that resemble the tissues of origin but have lost the ability to control cell proliferation. They grow by expansion, are enclosed in a fibrous capsule, and do not cause death unless their location is such that it interrupts vital body functions. •  Malignant neoplasms are less well-differentiated tumors that have lost the ability to control both cell proliferation and differentiation. They grow in a disorganized and uncontrolled manner to invade surrounding tissues, have cells that break loose and travel to distant sites to form metastases, and inevitably cause suffering and death unless their growth can be controlled through treatment.

Malignant Neoplasms Malignant neoplasms, which invade and destroy nearby tissue and spread to other parts of the body, tend to grow rapidly and spread widely and have the potential to cause death. Because of their rapid rate of growth, malignant tumors may compress blood vessels and outgrow their blood supply, causing ischemia and tissue injury. Some malignancies secrete hormones or cytokines,

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FIGURE 8.4  •  Metastatic cancer. The mesentery attached to a part of the small bowel has small nodules of metastatic ovarian carcinoma attached. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 166). Philadelphia, PA: Lippincott Williams & Wilkins.)

liberate enzymes and toxins, or induce an ­inflammatory response that injures normal tissue as well as the tumor itself. A number of malignancies secrete vascular endothelial cell growth factor (VEGF), which increases the blood supply to the tumor and facilitates more rapid growth.2 There are two types of VEGF. VEGF-1 is used in embryonic development, but also may be present with some types of cancer metastasis. VEGF-2 is the most significant receptor a­ssociated with pathological angiogenesis and lymphangiogenesis with tumors.13 There are two categories of malignant neoplasms—solid tumors and hematologic cancers. Solid tumors initially are confined to a specific tissue or organ. As the growth of the primary solid tumor progresses, cells detach from the original tumor mass, invade the surrounding tissue, and enter the blood and lymph systems to spread to distant sites, a process termed metastasis (Fig. 8.4). Hematologic cancers involve cells normally found in the blood and lymph, thereby making them disseminated diseases from the beginning (Fig. 8.5). Carcinoma in situ is a localized preinvasive lesion (Fig. 8.6). As an example, in breast ductal carcinoma in situ, the cells have not crossed the basement membrane. Depending on its location, in situ lesions usually can be removed surgically or treated so that the chances of recurrence are small. For example, carcinoma in situ of the cervix is essentially 100% curable. Cancer Cell Characteristics Cancer cells are characterized by two main features—abnormal and rapid proliferation and loss of differentiation. Loss of differentiation means that they do not exhibit normal features and properties of differentiated cells and hence are more similar to embryonic cells. The term anaplasia describes the loss of cell differentiation in cancerous tissue.2 Undifferentiated cancer cells are marked by a number of morphologic changes. Both the cells and nuclei display variations in size and shape, a condition referred to as pleomorphism. Their nuclei are variable

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FIGURE 8.5  •  Hematogenous spread of cancer. A malignant tumor (bottom) has attached to adipose tissue and penetrated into a vein. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 167). Philadelphia, PA: Lippincott Williams & Wilkins.)

in size and bizarre in shape, their chromatin is coarse and clumped, and their nucleoli are often considerably larger than ­normal (Fig. 8.7A). Frequently, the nuclei contain an abnormal ­number of chromosomes (aneuploidy). The cells of undifferentiated tumors usually display greater numbers of cells in mitosis due to their high rate of proliferation. They also display atypical, bizarre mitotic figures, sometimes producing tripolar, tetrapolar, or multipolar spindles (Fig. 8.7B). Highly anaplastic cancer cells, whatever their tissue of origin, begin to resemble undifferentiated or embryonic cells more than they do their tissue of origin. Some cancers display only slight anaplasia, whereas others display marked anaplasia. The cytologic/histologic g­ rading

FIGURE 8.6  •  Carcinoma in situ. The uterine cervix displays neoplasia squamous cells occupying the entire epithelium however confined to the mucosa by the underlying intact basement membrane. (From R ­ ubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 164). Philadelphia, PA: Lippincott Williams & Wilkins.)

of tumors is based on the degree of differentiation and the number of proliferating cells. The closer the tumor cells resemble comparable normal tissue cells, both morphologically and functionally, the lower the grade. Accordingly, on a scale ranging from grades I to IV, grade I neoplasms are well differentiated and grade IV are poorly differentiated and display marked anaplasia.2

A FIGURE 8.7  •  Anaplastic features of malignant tumors. (A) The cells of this anaplastic carcinoma are highly pleomorphic (i.e., they vary in size and shape). The nuclei are hyperchromatic and are large relative to the cytoplasm. Multinucleated tumor giant cells are present (arrows). (B) A malignant cell in metaphase exhibits an abnormal mitotic figure. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 162). Philadelphia, PA: Lippincott Williams & Wilkins.)

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TABLE 8.3 COMPARISON OF NORMAL CELL CHARACTERISTICS WITH THOSE OF CANCER CELLS CHARACTERISTICS

NORMAL CELLS

CANCER CELLS

Growth Differentiation Genetic stability Growth factor dependence Density-dependent Cell-to-cell adhesion Anchorage dependence Cell-to-cell communication Cell life span Antigen expression Substance ­production (e.g., proteases, hormones) Cytoskeletal composition and arrangement

Regulated High Stable Dependent High High High High Limited Absent Normal

Unregulated Low Unstable Independent Low inhibition Low Low Low Unlimited May be present Abnormal

Normal

Abnormal

r­eceptors or signaling proteins that may inappropriately ­activate growth signaling pathways in the cells. Cell Density–Dependent Inhibition.  Cancer cells often lose cell density–dependent inhibition, which is the cessation of growth after cells reach a particular density. This is sometimes referred to as contact inhibition because cells often stop growing when they come into contact with each other. In wound healing, contact inhibition causes tissue growth to cease at the point where the edges of the wound come together. Cancer cells, however, tend to grow rampantly without regard for adjacent tissue. Possible explanations for cancer cell loss of density-dependent contact inhibition include growth factor independence, oxidative mechanisms,14,15 and alterations in interactions between cell adhesion and cell growth signaling pathways (e.g., surface integrin receptors, mitogen-activated protein [MAP] kinase, and focal adhesion kinase [FAK] phosphorylation).14,16

Genetic Instability.  Most cancer cells exhibit a characteristic called genetic instability that is often considered to be a hallmark of cancer. The concept arose after the realization that uncorrected mutations in normal cells are rare because of the numerous ­cellular mechanisms to prevent them. To account for the high frequency of mutations in cancer cells, it is thought that cancer cells have a “mutation phenotype” with genetic instability that contributes to the development and progression of cancer.2 Characteristics of genetic instability include aneuploidy, in which chromosomes are lost or gained; intrachromosomal instability, which includes insertions, deletions, and amplifications; microsatellite instability, which involves short, repetitive sequences of DNA; and point mutations.

Cell Cohesiveness and Adhesion. The reduced tendency of cancer cells to stick together (i.e., loss of cohesiveness and adhesiveness) permits shedding of the tumor’s surface cells; these cells appear in the surrounding body fluids or secretions and often can be detected using cytologic methods. Cadherins are adhesion molecules that link one cell with adjacent cells. Extracellularly, the cadherins of one cell bind to cadherins of adjacent cells, causing cell-to-cell attachment. Intracellularly, cadherins are connected to the actin cytoskeleton through protein intermediates, including the catenins. The cadherin– catenin–actin complex, acting with other proteins, has been proposed to be involved with cell migration, apoptosis, and cell cycle regulation. In some cancers, the cell adhesion molecule E-cadherin appears to play an important role in the lack of cohesiveness of cancer cells and the increased tendency for cancer cells to break free and migrate into the surrounding tissues. E-cadherin is reduced at the cell surface, whereas its partner protein β-catenin accumulates within the cancer cells and associates with the actin cytoskeletal-binding protein actinin-4. It has been postulated that the resulting β-catenin interaction with actinin-4 in the absence of E-cadherin may be the “switch” that shuts off cancer cell-to-cell adhesion and activates cancer cell motility and other mechanisms that facilitate invasion and metastasis.17

Growth Factor Independence. Another characteristic of cancer cells is the ability to proliferate even in the absence of growth factors. This characteristic is often observed when cancer cells are propagated in cell culture—the addition of serum, which is rich in growth factors, is unnecessary for the cancers to proliferate. Normal cells grown in culture often die without serum or growth factor addition. In some cases, this is because the cancer cells can rapidly divide without growth factor binding to its receptor. Breast cancer cells that do not express estrogen receptors are an example. These cancer cells grow even in the absence of estrogen, which is the normal growth stimulus for breast duct epithelial cells. Some cancer cells may produce their own growth factors and secrete them into the culture medium, whereas others have a­ bnormal

Anchorage Dependence.  Cancer cells also differ from their normal counterparts in attaining anchorage independence. Normal epithelial cells must be anchored to either neighboring cells or the underlying extracellular matrix to live and grow. If normal cells become detached, they often undergo a type of apoptosis known as anoikis, a term from the Greek for “homeless.” Normal epithelial cells must be attached to either other cells or extracellular matrix to stay alive. Cancer cells, however, frequently remain viable and multiply without normal attachments to other cells and the extracellular matrix. Cancer cells often survive in microenvironments different from those of normal cells. Although the process of anchorage independence is complex and incompletely understood, recent studies have made progress in understanding the genes and mechanistic pathways involved.18

The characteristics of altered proliferation and differentiation are associated with a number of other changes in cell characteristics and function that distinguish cancer cells from their normally differentiated counterparts. These changes are listed in Table 8.3.

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Cell-to-Cell Communication.  Another characteristic of cancer cells is faulty cell-to-cell communication, a feature that may in turn contribute to other characteristics of cancer cells. Impaired cell-to-cell c­ommunication may interfere with formation of intercellular connections and responsiveness to membranederived signals. For example, changes in gap j­unction proteins, which enable cytoplasmic continuity and communication between cells, have been described in some types of cancer.19 Life Span. Cancer cells differ from normal cells by being immortal, with an unlimited life span. If normal, noncancerous cells are harvested from the body and grown under culture conditions, most cells divide a limited number of times, usually about 50 population doublings, then become senescent and fail to divide further. In contrast to the limited life span of normal cells, cancer cells may divide an infinite number of times, hence achieving immortality. Telomeres are short, repetitive nucleotide sequences at outermost extremities of chromosome arms. Telomeres shorten with each cell division. When length is diminished sufficiently, chromosomes can no longer replicate, and cell division will not occur. Most cancer cells maintain high levels of telomerase, an enzyme that prevents telomere shortening. This keeps telomeres from aging and attaining the critically short length that is associated with cellular replicative senescence. Antigen Expression.  Cancer cells also express a number of cell surface molecules or antigens that are immunologically identified as foreign. The genes of a cell code these tissue antigens. Many transformed cancer cells revert to embryonic patterns of gene expression and produce antigens that are immunologically distinct from the antigens that are expressed by cells of the well-differentiated tissue from which the cancer originated. Some cancers express fetal antigens that are not produced by comparable cells in the adult. Tumor antigens may be clinically useful as markers to indicate the presence, recurrence, or progressive growth of a cancer. Production of Enzymes, Hormones, and Other Substances.  Cancer cells may produce substances that normal cells of the tissue of origin either do not produce or secrete in lesser amounts. They may also secrete degradative enzymes that enable invasion and metastatic spread. Cancer cells may also assume hormone synthesis or production and secretion of procoagulant substances that affect clotting mechanisms. Cytoskeletal Changes.  Finally, cancer cells may show cytoskeletal changes and abnormalities. These may involve the appearance of abnormal intermediate filament types or changes in actin filaments and microtubules that facilitate invasion and metastasis. Actin, microtubules, and their regulatory proteins remain the focus of many cancer-related investigations. Invasion and Metastasis Unlike benign tumors, which grow by expansion and usually are surrounded by a capsule, cancer spreads by direct invasion

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and extension, seeding of cancer cells in body cavities, and metastatic spread through the blood or lymph pathways. The word cancer is derived from the Latin word meaning “crablike” because cancers grow and spread by sending ­crablike projections into the surrounding tissues. Most ­ ­ cancers ­synthesize and secrete enzymes that break down proteins and contribute to the infiltration, invasion, and penetration of the surrounding tissues. The lack of a sharp line of demarcation separating them from the surrounding tissue makes the complete surgical removal of malignant tumors more difficult than removal of benign tumors. Often it is necessary for the surgeon to excise portions of seemingly normal tissue bordering the tumor for the pathologist to establish that cancer-free margins are present around the excised tumor and to ensure that the remaining tissue is cancer free. The seeding of cancer cells into body cavities occurs when a tumor sheds cells into these spaces. Most often, the peritoneal cavity is involved, but other spaces such as the pleural cavity, pericardial cavity, and joint spaces may be involved. Seeding into the peritoneal cavity is particularly common with ovarian cancers. Similar to tissue culture, tumors in these sites grow in masses and are often associated with fluid accumulation (e.g., ascites, pleural effusion).2 Seeding of cancers into other areas of the body is often a complication postoperatively after removal of a cancer. The term metastasis is used to describe the development of a secondary tumor in a location distant from the primary tumor.2,13 Because metastatic tumors frequently retain many of the characteristics of the primary tumor from which they were derived, it usually is possible to determine the site of the primary tumor from the cellular characteristics of the metastatic tumor. Some tumors tend to metastasize early in their developmental course, whereas others do not metastasize until later. Occasionally, a metastatic tumor will be found far advanced before the primary tumor becomes clinically detectable. Malignant tumors of the kidney, for example, may go completely undetected and be asymptomatic until a metastatic lesion is found in the lung. Metastasis occurs through the lymph channels (i.e., lymphatic spread) and the blood vessels (i.e., hematogenic spread).2 In many types of cancer, the first evidence of disseminated disease is the presence of tumor cells in the lymph nodes that drain the tumor area. When metastasis occurs by the lymphatic route, the tumor cells lodge first in the initial lymph node that receives drainage from the tumor site. Once in this lymph node, the cells may die because of the lack of a proper environment, grow into a discernible mass, or remain dormant for unknown reasons. If they survive and grow, the cancer cells may spread from more distant lymph nodes to the thoracic duct and then gain access to the vasculature. The term sentinel node is used to describe the initial lymph node to which the primary tumor drains.2 Because the initial metastasis in breast cancer is almost always lymphatic, lymphatic spread and therefore extent of disease may be determined through lymphatic mapping and sentinel lymph node biopsy. This is done by injecting a radioactive tracer and/or blue dye into the tumor to determine the first lymph node in

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the route of lymph drainage from the cancer. Once the s­ entinel lymph node has been identified, it is examined to determine the presence or absence of cancer cells. The procedure is also used to map the spread of melanoma and other cancers that have their initial metastatic spread through the lymphatic system. With hematologic spread, the blood-borne cancer cells may enter the venous flow that drains the site of the primary neoplasm. Cancer cells may also enter tumor-associated blood vessels that either infiltrate the tumor or are found at the periphery of the tumor. Before entering the general circulation, venous blood from the gastrointestinal tract, pancreas, and spleen is routed through the portal vein to the liver. The liver is therefore a common site for metastatic spread of cancers that originate in these organs. Although the site of hematologic spread usually is related to vascular drainage of the primary tumor, some tumors metastasize to distant and unrelated sites. One explanation is that cells of different tumors tend to metastasize to specific target organs that provide suitable microenvironments containing substances such as cytokines or growth factors that are needed for their survival.2 For example, transferrin, a growth-promoting substance isolated from lung tissue, has been found to stimulate the growth of malignant cells that typically metastasize to the lungs. Other organs that are preferential sites for metastasis contain particular cytokines, growth factors, and other microenvironmental characteristics that facilitate metastatic tumor survival and growth. The selective nature of hematologic spread indicates that metastasis is a finely orchestrated, multistep process, and only a small, select clone of cancer cells has the right combination of gene products to perform all of the steps needed for establishment of a secondary tumor. To metastasize, a cancer cell must be able to break loose from the primary tumor, invade the surrounding extracellular matrix, gain access to a blood vessel, survive its passage in the bloodstream, emerge from the bloodstream at a favorable location, invade the surrounding tissue, begin to grow, and establish a blood supply (Fig. 8.8). However, there is also growing evidence for the significant role of the cancer cell ecosystem—which includes, but is not limited to, the extracellular matrix, neural cells, leukocytes, endothelial cells, adipocytes, fibroblasts, and macrophages— in enabling cancer cells to establish metastatic sites2 (Fig. 8.9). Considerable evidence suggests that cancer cells capable of metastasis secrete enzymes that break down the surrounding extracellular matrix, allowing them to move quickly through the degraded matrix and gain access to a blood vessel.20 Once in the circulation, the tumor cells are vulnerable to destruction by host immune cells. Some tumor cells gain protection from the antitumor host cells by aggregating and adhering to circulating blood components, particularly platelets, to form tumor emboli. Tumor cells that survive their travel in the circulation must be able to halt their passage by adhering to the vessel wall. Tumor cells express various cell surface attachment factors such as laminin receptors that facilitate their anchoring to laminin in the basement membrane. After attachment, the tumor cells secrete proteolytic enzymes such as type IV collagenase that degrade the basement membrane and facilitate the

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Carcinoma in situ

Basement membrane

A cancer cell becomes capable of invasion (expresses surface adhesion molecules)

Tumor cell adhesion molecules bind to underlying extracellular matrix

Tumor cells disrupt and invade extracellular matrix

Release of proteolytic enzymes

Repeated binding to and dissolution of extracellular matrix Tumor cells metastasize by way of blood vessels or lymphatics Blood vessel

Lymphatic

FIGURE 8.8 • Mechanisms of tumor metastasis. Steps by which a malignant tumor penetrates basement membrane and then invades the extracellular environment. First the tumor acquires the ability to bind components of the extracellular matrix. Many adhesion molecules mediate this binding. Then proteolytic enzymes are released from the tumor cells and the extracellular matrix degrades. The invading cancer moves through the extracellular environment and then penetrates through to blood vessels and lymphatics via the same mechanisms. (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 193). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Leukocytes

Macrophages

Cancer cells

Endothelial cells

Neural cells FIGURE 8.9 • The cancer cell ecosystem. The new cancer cells interact with the nonmalignant cells in their environment. (From Rubin R., Strayer ­ D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 194). Philadelphia, PA: Lippincott Williams & Wilkins.)

Fibroblasts

migration of the tumor cells through the capillary membrane into the interstitial area, where they subsequently establish growth of a secondary tumor. Once in the distant tissue site, the process of metastatic tumor development depends on the establishment of blood vessels and specific growth factors that promote proliferation of the tumor cells. Tumor cells as well as other cells in the microenvironment secrete factors that enable the development of new blood vessels within the tumor, a process termed angiogenesis.2 The presence of stimulatory or inhibitor growth factors correlates with the site-specific pattern of metastasis. Tumor Growth Once cells have an adequate blood supply, the rate of tissue growth in normal and cancerous tissue depends on three factors: 1. The number of cells that are actively dividing or moving through the cell cycle. 2. The duration of the cell cycle. 3. The number of cells that are being lost relative to the number of new cells being produced. One of the reasons cancerous tumors often seem to grow so rapidly relates to the size of the cell pool that is actively engaged in cycling. It has been shown that the cell cycle time of cancerous tissue cells is not necessarily shorter than that of normal cells. Rather, cancer cells do not die on schedule and growth factors prevent cells from exiting the cycle cell and entering the G0 phase. Thus, a greater percentage of cells are actively engaged in cycling than occurs in normal tissue. The ratio of dividing cells to resting cells in a tissue mass is called the growth fraction. The doubling time is the

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Adipocytes

length of time it takes for the total mass of cells in a tumor to double. As the growth fraction increases, the doubling time decreases. When normal tissues reach their adult size, equilibrium between cell birth and cell death is reached. Cancer cells, however, continue to divide until limitations in blood supply and nutrients inhibit their growth. When this happens, the doubling time for cancer cells decreases. If tumor growth is plotted against time on a semilogarithmic scale, the initial growth rate is exponential and then tends to decrease or flatten out over time. This characterization of tumor growth is called the Gompertzian model and is used for studying the effects of medications on cancer cells.2 By conventional radiographic methods, a tumor usually is undetectable until it has doubled 30 times and contains more than 1 billion (109) cells. At this point, it is approximately 1 cm in size. Methods to identify tumors at smaller sizes are under investigation. In some cases, the application of ultrasonography and magnetic resonance imaging (MRI) enable detection of tumors smaller than 1 cm. After 35 doublings, the mass contains more than 1 trillion (1012) cells, which is a sufficient number to kill the host.

IN SUMMARY Neoplasms may be either benign or malignant. Benign and malignant tumors differ in terms of cell characteristics, manner of growth, rate of growth, potential for metastasis, ability to produce generalized effects, tendency to cause tissue destruction, and capacity to cause death. The growth of a benign tumor is restricted to the site of origin, and the tumor usually does not cause death unless it

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interferes with vital functions. Malignant neoplasms grow in a poorly controlled fashion that lacks normal organization, spreads to distant parts of the body, and causes death unless tumor growth and metastasis are inhibited or stopped by treatment. There are two basic types of cancer: solid tumors and hematologic tumors. In solid tumors, the primary tumor is initially confined to a specific organ or tissue, whereas hematologic cancers are disseminated from the onset. Cancer is a disorder of cell proliferation and differentiation. The term anaplasia is used to describe the loss of cell differentiation in cancerous tissue. Undifferentiated cancer cells are marked by a number of morphologic changes, including variations in size and shape, a condition referred to a pleomorphism. The characteristics of altered proliferation and differentiation are associated with a number of other changes in cell characteristics and cell function, including genetic instability; growth factor independence; loss of cell density–dependent inhibition, cohesiveness and adhesion, and anchorage dependence; faulty cell-tocell communication; indefinite cell life span (immortality); expression of altered tissue antigens; abnormal secretion of degradative enzymes that enable invasion and metastatic spread, or ectopic production of hormones; and abnormal cytoskeletal characteristics. The spread of cancer occurs through three pathways: direct invasion and extension, seeding of cancer cells in body cavities, and metastatic spread through vascular or lymphatic pathways. Only a proportionately small clone of cancer cells is capable of metastasis. To metastasize, a cancer cell must be able to break loose from the primary tumor, invade the surrounding extracellular matrix, gain access to a blood vessel, survive its passage in the bloodstream, emerge from the bloodstream at a favorable location, invade the surrounding tissue, and begin to grow. The rate of growth of cancerous tissue depends on the ratio of dividing to resting cells (growth fraction) and the time it takes for the total cells in the tumor to double (doubling time). A tumor is usually undetectable until it has doubled 30 times and contains more than 1 billion cells.

ETIOLOGY OF CANCER After completing this section of the chapter, you should be able to meet the following objectives: •• Describe various types of cancer-associated genes and cancer-associated cellular and molecular pathways. •• Describe genetic events and epigenetic factors that are important in tumorigenesis. •• State the importance of cancer stem cells, angiogenesis, and the cell microenvironment in cancer growth and metastasis.

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The causes of cancers are very diverse and complex. It is ­useful to discuss causation in terms of: 1. The genetic and molecular mechanisms that are involved and that characterize the transformation of normal cells to cancer cells 2. The external and more contextual factors such as age, heredity, and environmental agents that contribute to the development and progression of cancer. Together, both mechanisms contribute to a multidimensional web of causation by which cancers develop and progress over time.

Genetic and Molecular Basis of Cancer The molecular pathogenesis of most cancers is thought to originate with genetic damage or mutation with resultant changes in cell physiology that transform a normally functioning cell into a cancer cell. Epigenetic factors that involve silencing of a gene or genes may also be involved in the molecular pathogenesis of cancer. In recent years, an important role of cancer stem cells in the pathogenesis of cancer has been identified, and it continues to be elucidated. Finally, the cellular microenvironment, which involves multiple cell types, the complex milieu of cytokines and growth factors, and the extracellular matrix, is now recognized as an important contributor to cancer development, growth, and progression. Cancer-Associated Genes Most cancer-associated genes can be classified into two broad categories based on whether gene overactivity or underactivity increases the risk for cancer. The category associated with gene overactivity involves protooncogenes, which are normal genes that become cancer-causing oncogenes if mutated. Protooncogenes encode for normal cell proteins such as growth factors, growth factor receptors, growth factor signaling molecules, and transcription factors that promote cell growth or increase growth factor–­dependent signaling. For example, the protooncogene, C-Myc is linked with oral squamous cell carcinoma. Increased protooncogenic activity is influenced by one’s diet, so this leads to fostering a balanced diet to attempt to decrease protooncogenic activity.21,22 The category associated with gene underactivity comprises the tumor suppressor genes, which, by being less active, create an environment in which cancer is promoted. Tumor suppressor genes include the retinoblastoma (RB) gene, which normally prevents cell division, and the TP53 gene, which normally becomes activated in DNA-damaged cells to initiate apoptosis.2,23 Loss of RB activity may accelerate the cell cycle and lead to increased cell proliferation,24 whereas inactivity of TP53 may increase the survival of DNA-damaged cells. The TP53 gene has become a reliable prognostic indicator.23 There are a number of genetic events that can lead to oncogene formation or loss of tumor suppressor gene function.

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Genetic Events Leading to Oncogene Formation or Activation.  There are a number of genetic events that create or activate oncogenes. A common event is a point mutation in which there is a single nucleotide base change due to an insertion, deletion, or substitution. An example of an oncogene caused by point mutations is the ras oncogene, which has been found in many cancers. Members of the ras protooncogene family are important signal-relaying proteins that transmit growth signals to the nucleus. Hence, activation of the ras oncogene can increase cell proliferation. Chromosomal translocations have traditionally been associated with cancers such as Burkitt lymphoma and chronic myelogenous leukemia (CML). In Burkitt lymphoma, the myc protooncogene, which encodes a growth signal protein, is translocated from its normal position on chromosome 8 to chromosome 142,3 (Fig. 8.10C). The outcome of the translocation in CML is the appearance of the so-called Philadelphia chromosome involving chromosomes 9 and 22 and the formation of an abnormal fusion protein, a hybrid oncogenic protein (bcr–abl) that promotes cell proliferation (Fig. 8.10A and B). Biotechnology and genomics are enabling the identification

9

of gene translocations and an increased understanding of how these translocations, even within the same chromosome, contribute to tumorigenesis by the creation of abnormal fusion proteins that promote cell proliferation. Another genetic event common in cancer is gene amplification. Multiple copies of certain genes may lead to overexpression, with higher-than-normal levels of proteins that increase cell proliferation. For example, the human epidermal growth factor receptor-2 (HER-2/neu) gene is amplified in many breast cancers; its presence indicates an aggressive tumor with a poor prognosis.25 One of the agents used in treatment of HER-2/neu–overexpressing breast cancers is trastuzumab (Herceptin), a monoclonal antibody that selectively binds to HER-2, thereby inhibiting the proliferation of tumor cells that overexpress HER-2. Genetic Events Leading to Loss of Tumor Suppressor Gene Function.  Tumor suppressor genes inhibit the proliferation of cells in a tumor. When this type of gene is inactivated, a genetic signal that normally inhibits cell proliferation is removed, thereby causing unregulated growth to begin.

22

8

14

bcr CH

c-abl

c-myc

CH

bcr/abl fusion gene

A

Philadelphia chromosome

B

C

myc oncogene

FIGURE 8.10  •  Oncogene activation by chromosomal translocation. (A) Chronic myelogenous leukemia. Reciprocal translocation occurs at the breaks at the ends of the long arms of chromosomes 9 and 22. This results in the Philadelphia chromosome (Ph1), which contains a new fusion gene coding for a hybrid oncogenic protein (bcr–abl), presumably involved in the pathogenesis of chronic myelogenous leukemia. (B) Karyotypes of a patient with CML showing the results of reciprocal translocations between chromosomes 9 and 22. The Philadelphia chromosome is recognized by a smaller-than-normal chromosome 22 (22q-). One chromosome 9 (9q+) is larger than its normal counterpart. (C) Burkitt lymphoma. Chromosomal breaks involve the long arms of chromosomes 8 and 14. The c-myc gene on chromosome 8 is translocated to a region on chromosome 14 adjacent to the gene coding for the constant region of an immunoglobulin heavy chain (CH). (From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 174). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Multiple tumor suppressor genes have been found, that ­connect with various types of cancer.2 Of particular interest in this group is the TP53 gene, which is on the short arm of chromosome 17, and codes for the p53 protein. Mutations in the TP53 gene have been associated with lung, breast, and colon cancer.23 The TP53 gene also appears to initiate apoptosis in radiation- and chemotherapy-damaged tumor cells. Although a single mutation generally plays an important role in oncogene activation, the malfunction of tumor suppressor genes may require “two hits” to contribute to total loss of function, as suggested by the two-hit hypothesis of carcinogenesis2 (Fig. 8.11). The first “hit” may be a point mutation in an allele of a particular chromosome; later, a second “hit” occurs that involves the companion allele of the gene. In hereditary cases, the first hit is inherited from an affected parent and is therefore present in all somatic cells of the body. In RB, the second hit occurs in one of many retinal cells (all of which already carry the mutated gene). In sporadic (noninherited) cases, both mutations (hits) occur in a single somatic cell, whose progeny then form the cancer. In people carrying an inherited mutation, such as a mutated RB allele, all somatic cells are perfectly normal, except for the increased risk of developing cancer. That person is said to be heterozygous at the gene locus. Cancer develops when a person becomes homozygous for the mutant allele, a c­ ondition

referred to as loss of heterozygosity which confers a poor prognosis.2 For example, loss of heterozygosity is known to occur in hereditary cancers, in which a mutated gene is inherited from a parent, and other conditions (e.g., radiation exposure) are present that make people more susceptible to cancer. Epigenetic Mechanisms In addition to mechanisms that involve DNA and chromosomal structural changes, there are molecular and cellular mechanisms, termed epigenetic mechanisms, which involve changes in the patterns of gene expression without a change in the DNA. Epigenetic mechanisms may “silence” genes, such as tumor suppressor genes, so that even though the gene is present, it is not expressed and a cancer-suppressing protein is not made. One such mechanism of epigenetic silencing is by methylation of the promoter region of the gene, a change that prevents transcription and causes gene inactivity. Genes silenced by hypermethylation can be inherited, and epigenetic silencing of genes could be the initial “hit” in the two-hit hypothesis described previously.22 The epigenetic mechanisms that alter expression of genes associated with cancer are still under investigation. The two hypomethylating agents available to treat myelodysplastic syndrome (MDS) and AML are azacitidine and decitabine.2

Chromosome 13

Inherited retinoblastoma

A

Somatic mutation Normal Germline allele mutation

Sporadic retinoblastoma

B

Retinoblastoma

Somatic mutation Normal alleles

Somatic mutation Normal Somatic allele mutation

Retinoblastoma

FIGURE 8.11  •  The “two-hit” origin of RB. (A) A child with an inherited form of RB is born with a germline mutation in one allele of the RB gene located on the long arm of chromosome 13. A second somatic mutation in the retina leads to inactivation of the normally functioning RB allele and subsequent development of RB. (B) In sporadic (noninherited) cases of RB, the child is born with two normal RB alleles. It requires two independent somatic mutations to inactivate RB gene function and allow for the appearance of a neoplastic clone. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 178). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Chapter 8  Neoplasia   177

Molecular and Cellular Pathways There are numerous molecular and cellular mechanisms with a myriad of associated pathways and genes that are known or suspected to facilitate the development of cancer. Genes that increase susceptibility to cancer or facilitate cancer include defects in DNA repair mechanisms, defects in growth factor signaling pathways, evasion of apoptosis, avoidance of cellular senescence, development of sustained angiogenesis, and metastasis and invasion. In addition, associated genetic mutations are involved that enable invasion of and survival in neighboring tissue, as well as evasion of immune detection and attack. DNA Repair Defects. Genetic mechanisms that regulate repair of damaged DNA have been implicated in the process of oncogenesis (Fig. 8.12). The DNA repair genes affect cell proliferation and survival indirectly through their ability to repair damage in protooncogenes, genes impacting apoptosis, and tumor suppressor genes.2 Genetic damage may be caused by the action of chemicals, radiation, or viruses, or it may be inherited in the germline. Significantly, it appears that the acquisition of a single-gene mutation is not sufficient to transform normal cells into cancer cells. Instead, cancerous transformation appears to require the activation of multiple independently mutated genes.

Carcinogenic agent

Normal cell DNA repair (DNA repair genes) DNA damage Failure of DNA repair

• Activation of growth-promoting oncogenes • Inactivation of tumor suppressor genes • Alterations in genes that control apoptosis

Unregulated cell differentiation and growth

Malignant neoplasm

FIGURE 8.12  •  Flow chart depicting the stages in the development of a malignant neoplasm resulting from exposure to an oncogenic agent that produces DNA damage. When DNA repair genes are present (red arrow), the DNA is repaired and gene mutation does not occur.

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Defects in Growth Factor Signaling Pathways.  A ­relatively common way in which cancer cells gain autonomous growth is through mutations in genes that control growth factor signaling pathways. These signaling pathways connect the growth factor receptors to their nuclear targets.2 Under normal conditions, cell proliferation involves the binding of a growth factor to its receptor on the cell membrane, activation of the growth factor receptor on the inner surface of the cell membrane, transfer of the signal across the cytosol to the nucleus by signal-transducing proteins that function as second messengers, induction and activation of regulatory factors that initiate DNA transcription, and entry of the cell into the cell cycle (Fig. 8.13). Many of the proteins involved in the signaling pathways that control the action of growth factors exert their effects through kinases, enzymes that phosphorylate proteins. In some types of cancer such as CML, mutation in a protooncogene controlling tyrosine kinase activity occurs, causing unregulated cell growth and proliferation. Evasion of Apoptosis. Faulty apoptotic mechanisms have an important role in cancer. The failure of cancer cells to undergo apoptosis in a normal manner may be due to a number of problems. There may be altered cell survival signaling, overly active Ras proteins, TP53 mutations, down-regulation of death receptors (e.g., TRAIL), stabilization of the mitochondria, inactivation of proapoptotic proteins (e.g., methylation of caspase-8), overactivity of nuclear factor kappa B (NF-κB), heat-shock protein production, or failure of immune cells to induce cell death.26 Alterations in apoptotic and antiapoptotic pathways, genes, and proteins have been found in many cancers. One example is the high levels of the antiapoptotic protein Bcl-2 that occur secondary to a chromosomal translocation in certain B-cell lymphomas. The mitochondrial membrane is a key regulator of the balance between cell death and survival. Proteins in the Bcl-2 family reside in the inner mitochondrial membrane and are either proapoptotic or antiapoptotic. Because apoptosis is considered a normal cellular response to DNA damage, loss of normal apoptotic pathways may contribute to cancer by enabling DNA-damaged cells to survive. Evasion of Cellular Senescence. Another normal cell response to DNA damage is cellular senescence. As stated earlier, cancer cells are characterized by immortality due to high levels of telomerase that prevent cell aging and senescence. High levels of telomerase and prevention of telomere shortening may also contribute to cancer and its progression because senescence is considered to be a normal response to DNA damage in cells as well as a tumor suppressor mechanism, and in model systems, short telomeres limit cancer growth.27,28 Development of Sustained Angiogenesis.  Even with all the aforementioned genetic abnormalities, tumors cannot enlarge unless angiogenesis occurs and ­supplies them with the blood

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Growth factor Growth factor receptor Outer cell membrane

Inner cell membrane P

P

P

P

Signaltransducing proteins

P

P MAP kinase P

P MAP kinase P P

vessels necessary for survival. Angiogenesis is required not only for continued tumor growth but for metastasis. The molecular basis for the angiogenic switch is unknown, but it appears to involve increased production of angiogenic factors or loss of angiogenic inhibitors. The normal TP53 gene seems to inhibit angiogenesis by inducing the synthesis of an antiangiogenic molecule called thrombospondin-1.2 With mutational inactivation of both TP53 alleles (as occurs in many cancers), the levels of thrombospondin-1 drop precipitously, tilting the balance in favor of angiogenic factors. Angiogenesis is also influenced by hypoxia and release of proteases that are involved in regulating the balance between angiogenic and antiangiogenic factors. Because of the crucial role of angiogenic factor in tumor growth, bevacizumab, a monoclonal antibody, has been approved to treat metastatic colorectal and renal cell carcinomas, non–small cell lung cancer, and some brain tumors.2 Antiangiogenesis therapy is showing synergistic antitumor actions when combined with conventional forms of chemotherapy in the treatment of these cancers. It is being studied in other cancers as well. Furthermore, antiangiogenesis therapy may have more broad-based actions. For example, it is now thought that cancer cells are a heterogeneous population of cells that include a cancer stem cell population characterized by mitotic quiescence and an increased ability to survive chemotherapy agents, which make cancer stem cells particularly difficult to treat. Cancer stem cells may reside close to blood vessels, where they receive signals for self-renewal.

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Nucleus

FIGURE 8.13  • Pathway for genes regulating cell growth and replication. Stimulation of a normal cell by a growth factor results in activation of the growth factor ­receptor and signaling proteins that transmit the growth-promoting signal to the nucleus, where it modulates gene transcription and progression through the cell cycle. Many of these signaling proteins exert their effects through enzymes called kinases that phosphorylate proteins. MAP, mitogen-activated protein.

Invasion and Metastasis. Finally, multiple genes and molecular and cellular pathways are known to be involved in invasion and metastasis. There is evidence that cancer cells with invasive properties are actually members of the cancer stem cell population discussed previously. This evidence suggests that genetic programs that are normally operative in stem cells during embryonic development may become operative in cancer stem cells, enabling them to detach, cross tissue boundaries, escape death by anoikis, and colonize new tissues.29 The MET protooncogene, which is expressed in both stem cells and cancer cells, is a key regulator of invasive growth. Findings suggest that adverse conditions such as tissue hypoxia, which are commonly present in cancerous tumors, trigger this invasive behavior by activating the MET tyrosine kinase receptor. Role of the Microenvironment Traditionally, the molecular and cellular biology of cancer has focused on the cancer itself. More recently, the important role of the microenvironment in the development of cancer and metastasis has been described. The microenvironment of the cancer cell consists of multiple cell types, including macrophages, fibroblasts, endothelial cells, and a variety of immune and inflammatory cells; the extracellular matrix; and the primary signaling substances such as cytokines, chemokines, and hormones. For example, signaling of the cytokine transforming growth factor-beta (TGF-β) is known to be important in the cellular pathway leading to cancer cell f­ormation

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or suppression.30 The ability of TGF-β to cause the cancer to progress and metastasize, however, depends on the microenvironment of various cell types and cross talk of signals among the cell types. In some cases, the phenotype of a cancer cell can actually normalize when it is removed from the tumor microenvironment and placed in a normal environment, and vice versa. Finally, essential steps needed for tumor growth and metastasis, such as angiogenesis and metastatic tumor survival, depend on the microenvironment. Carcinogenesis The process by which carcinogenic (cancer-causing) agents cause normal cells to become cancer cells is hypothesized to be a multistep mechanism that can be divided into three stages: initiation, promotion, and progression (Fig. 8.14). Initiation is the first step and describes the exposure of cells to a carcinogenic agent that causes them to be vulnerable to cancer transformation.2 The carcinogenic agents can be chemical, physical, or biologic and produce irreversible changes in the genome of a previously normal cell. Because the effects of initiating agents are irreversible, multiple divided doses may achieve the same effects as a single exposure to the same total dose or to small amounts of highly carcinogenic substances. The cells most susceptible to mutagenic alterations are those that are actively synthesizing DNA.

Normal cell

Carcinogenic agent (chemicals, radiation, viruses)

Normal cell line

DNA damage and cell mutation

Malignant tumor

Promotion

Progression

FIGURE 8.14  •  The processes of initiation, promotion, and progression in the clonal evolution of malignant tumors. Initiation involves the ­exposure of cells to appropriate doses of a carcinogenic agent; promotion, the unregulated and accelerated growth of the mutated cells; and progression, the acquisition of malignant characteristics by the tumor cells.

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Host and Environmental Factors Because cancer is not a single disease, it is reasonable to assume that it does not have a single cause. More likely, cancer occurs because of interactions among multiple risk factors or repeated exposure to a single carcinogenic agent. Among the traditional risk factors that have been linked to cancer are heredity, hormonal factors, immunologic mechanisms, and environmental agents such as chemicals, radiation, and cancer-causing viruses. More recently, there has been interest in obesity as a risk factor for cancer. A strong and consistent relationship has been reported between obesity and mortality from all cancers among men and women.31 Obese people tend to produce increased amounts of androgens, a portion of which is converted to the active form of estrogen in adipose tissue, causing a functional state of hyperestrogenism. Because of the association of estrogen with postmenopausal breast cancer and endometrial cancer, the relation is stronger among women than among men.31

Initiation

Mutated cell

Activation of oncogenes by promoter agent

Promotion is the second step that allows for prolific growth of cells triggered by multiple growth factors and chemicals.2 Promotion is reversible if the promoter substance is removed. Cells that have been irreversibly initiated may be promoted even after long latency periods. The latency period varies with the type of agent, the dosage, and the characteristics of the target cells. Many chemical carcinogens are called complete carcinogens because they can initiate and promote neoplastic transformation. Progression is the last step of the process that manifests when tumor cells acquire malignant phenotypic changes that promote invasiveness, metastatic competence, autonomous growth tendencies, and increased karyotypic instability.

Heredity A hereditary predisposition to approximately 50 types of cancer has been observed in families. Breast cancer, for example, occurs more frequently in women whose grandmothers, mothers, aunts, or sisters also have experienced a breast malignancy. A genetic predisposition to the development of cancer has been documented for a number of cancerous and precancerous lesions that follow mendelian inheritance patterns. Two tumor suppressor genes, called BRCA1 (breast carcinoma 1) and BRCA2 (breast carcinoma 2), have been identified in genetic susceptibility to breast and ovarian cancer.2 People carrying a BRCA mutation have a lifetime risk (if they live to the age of 85 years) of 80% for developing breast cancer. The lifetime risk for developing ovarian cancer is 10% to 20% for carriers of BRCA2 mutations and 40% to 60% for BRCA1 mutations.2 These genes have also been associated with an increased risk of prostate, pancreatic, colon, and other cancers. Several cancers exhibit an autosomal dominant inheritance pattern that greatly increases the risk of developing a tumor.2 The inherited mutation is usually a point mutation occurring in a single allele of a tumor suppressor gene. People who inherit the mutant gene are born with one normal and one

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mutant copy of the gene.32,33 For cancer to develop, the normal gene must be inactivated, usually through a somatic mutation. RB, a rare childhood tumor of the retina, is an example of a cancer that follows an autosomal dominant inheritance pattern. About 1/3 of RBs are inherited, and carriers of the mutant RB tumor suppressor gene have a significantly increased risk for developing RB, usually with bilateral involvement.32–34 Familial adenomatous polyposis of the colon also follows an autosomal dominant inheritance pattern. It is caused by mutation of another tumor suppressor gene, the APC gene.9 In people who inherit this gene, hundreds of adenomatous polyps may develop, and a percentage may become cancerous.35 Hormones Hormones have received considerable research attention with respect to cancer of the breast, ovary, and endometrium in women and of the prostate and testis in men. Although the link between hormones and the development of cancer is unclear, it has been suggested that it may reside with the ability of hormones to drive the cell division of a malignant phenotype. Because of the evidence that endogenous hormones affect the risk of these cancers, concern exists regarding the effects on cancer risk if the same or closely related hormones are administered for therapeutic purposes.

Virtually all of the components of the immune system have the potential for eradicating cancer cells, including T lymphocytes, B lymphocytes and antibodies, macrophages, and natural killer (NK) cells. The T-cell response is undoubtedly one of the most important host responses for controlling the growth of antigenic tumor cells. It is responsible for direct killing of tumor cells and for activation of other components of the immune system. The T-cell immunity to cancer cells reflects the function of two subsets of T cells: the CD4+ helper T cells and CD8+ cytotoxic T cells. The finding of tumor-­reactive antibodies in the serum of people with cancer supports the role of the B cell as a member of the immune surveillance team. Antibodies can destroy cancer cells through c­ omplement-mediated mechanisms or through antibody-dependent cellular cytotoxicity, in which the antibody binds the cancer cell to another effector cell, such as the NK cell, that does the actual killing of the cancer cell. NK cells do not require antigen recognition and can lyse a wide variety of target cells. The cytotoxic activity of NK cells can be augmented by the cytokines interleukin (IL)-2 and interferon, and its activity can be amplified by immune T-cell responses. Macrophages are important in tumor immunity as antigen-presenting cells to initiate the immune response and as potential effector cells to participate in tumor cell lysis.

Immunologic Mechanisms There is substantial evidence for the immune system’s participation in resistance against the progression and spread of cancer. The central concept, known as the immune surveillance hypothesis, first proposed in 1909, postulates that the immune system plays a central role in resistance against the development of tumors.2,33 In addition to cancer–host interactions as a mechanism of cancer development, immunologic mechanisms provide a means for the detection, classification, and prognostic evaluation of cancers and as a potential method of treatment. Immunotherapy is a cancer treatment modality designed to heighten the person’s general immune responses in order to increase tumor destruction. It has been suggested that the development of cancer might be associated with impairment or decline in the surveillance capacity of the immune system. For example, increases in cancer incidence have been observed in people with immunodeficiency diseases and in those with organ transplants who are receiving immunosuppressant drugs. The incidence of cancer also is increased in older adults, in whom there is a known decrease in immune activity. The association of Kaposi sarcoma with acquired immunodeficiency syndrome (AIDS) further emphasizes the role of the immune system in preventing malignant cell proliferation. It has been shown that most tumor cells have molecular configurations that can be specifically recognized by immune T cells or by antibodies and hence are termed tumor antigens. The most relevant tumor antigens fall into two categories: unique, tumor-specific antigens found only on tumor cells and tumor-associated antigens found on tumor cells and normal cells.

Chemical Carcinogens A carcinogen is an agent capable of causing cancer. The role of environmental agents in causation of cancer was first noted in 1775, when the high incidence of scrotal cancer in chimney sweeps was identified and related to the possibility of exposure to coal soot in the chimneys.2 Over the next two centuries, many chemicals have been shown to transform cells in the laboratory and to be carcinogenic in animals (Chart 8.1). These agents include both natural (e.g., aflatoxin B1) and artificial products (e.g., vinyl chloride). Chemical carcinogens can be divided into two groups: (1) direct-reacting agents, which do not require activation in the body to become carcinogenic, and (2) indirect-reacting agents, called procarcinogens or initiators, which become active only after metabolic conversion. Direct- and indirectacting initiators form highly reactive species (i.e., electrophiles and free radicals) that bind with the nucleophilic ­residues on DNA, RNA, or cellular proteins. The action of these reactive species tends to cause cell mutation or alteration in synthesis of cell enzymes and structural proteins in a manner that alters cell replication and interferes with cell regulatory controls. The carcinogenicity of some chemicals is augmented by agents called promoters that, by themselves, have little or no cancer-causing ability. It is believed that promoters exert their effect by changing the expression of genetic material in a cell, increasing DNA synthesis, enhancing gene amplification (i.e., number of gene copies that are made), and altering intercellular communication. Exposure to many chemical carcinogens is associated with lifestyle risk factors, such as smoking, dietary factors, and alcohol consumption. Cigarette smoke contains both

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Chart 8.1 CHEMICAL AND ENVIRONMENTAL AGENTS KNOWN TO BE CARCINOGENIC IN HUMANS Polycyclic Hydrocarbons Soots, tars, and oils Cigarette smoke Industrial Agents Aniline and azo dyes Arsenic compounds Asbestos β-Naphthylamine Benzene Benzo[a]pyrene Carbon tetrachloride Insecticides, fungicides Nickel and chromium compounds Polychlorinated biphenyls Vinyl chloride Food and Drugs Smoked foods Nitrosamines Aflatoxin B1 Diethylstilbestrol Anticancer drugs (e.g., alkylating agents, cyclophosphamide, chlorambucil, nitrosourea)

p­ rocarcinogens and promoters. It is directly associated with lung and laryngeal cancer and has also been linked with multiple other types of cancer. Chewing tobacco or tobacco products increases the risk of cancers of the oral cavity and esophagus. It has been estimated that 30% of all cancer deaths and 87% of lung cancer deaths in the United States are related to tobacco use.36 Not only is the smoker at risk, but others passively exposed to cigarette smoke are at risk. Each year, about 3400 nonsmoking adults die of lung cancer as a result of environmental tobacco smoke.36 Environmental tobacco smoke has been classified as a “group A” carcinogen based on the U.S. Environmental Protection Agency’s system of carcinogen classification. There is also strong evidence that certain elements in the diet contain chemicals that contribute to cancer risk. Many dietary carcinogens occur either naturally in plants (e.g., aflatoxins) or are used to preserve foods.37 For example, benzo[a] pyrene and other polycyclic hydrocarbons are converted to carcinogens when foods are fried in fat that has been reused multiple times. Among the most potent of the procarcinogens are the polycyclic aromatic hydrocarbons. The polycyclic aromatic hydrocarbons are of particular interest because they are produced from animal fat in the process of charcoal-broiling meats and are present in smoked meats and fish. They also

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are produced in the combustion of tobacco and are present in cigarette smoke. Cancer of the colon has been associated with high dietary intake of fat and red meat and a low intake of dietary fiber. A high-fat diet was thought to be carcinogenic because it increases the flow of primary bile acids that are converted to secondary bile acids in the presence of anaerobic bacteria in the colon, producing carcinogens. Studies have identified obesity and lowered physical activity with an increased risk of colon cancer.31 Alcohol is associated with a variety of cancers; the causative mechanisms are very complex. The first and most toxic metabolite of ethanol is acetaldehyde that can cause point mutations in some cells.2 In addition, ethanol can alter DNA methylation and interfere with retinoid metabolism, which is important in antioxidant mechanisms. The carcinogenic effect of cigarette smoke can be enhanced by concomitant consumption of alcohol; people who smoke and drink considerable amounts of alcohol are at increased risk for development of cancer of the oral cavity, larynx, and esophagus. The effects of carcinogenic agents usually are dose dependent—the larger the dose or the longer the duration of exposure, the greater the risk that cancer will develop. Some chemical carcinogens may act in concert with other carcinogenic influences, such as viruses or radiation, to induce neoplasia. There usually is a time delay ranging from 5 to 30 years from the time of chemical carcinogen exposure to the development of overt cancer. This is unfortunate because many people may have been exposed to the agent and its carcinogenic effects before the association was recognized. This occurred, for example, with the use of diethylstilbestrol, which was widely used in the United States from the mid1940s to 1970 to prevent miscarriages. But it was not until the late 1960s that many cases of vaginal adenosis and adenocarcinoma in young women were found to be the result of their exposure in utero to diethylstilbestrol.38 Radiation The effects of ionizing radiation in carcinogenesis have been well documented in atomic bomb survivors, in people diagnostically exposed, and in industrial workers, scientists, and physicians who were exposed during employment. Malignant epitheliomas of the skin and leukemia were significantly elevated in these populations. Between 1950 and 1970, the death rate from leukemia alone in the most heavily exposed population groups of atomic bomb survivors in Hiroshima and Nagasaki was 147 per 100,000 people, 30 times the expected rate.39 The type of cancer that developed depended on the dose of radiation, the person’s gender, and the age at which exposure occurred. For instance, approximately 25 to 30 years after total-body or trunk irradiation, there were increased incidences of leukemia and cancers of the breast, lung, stomach, thyroid, salivary gland, gastrointestinal system, and lymphoid tissues. The length of time between exposure and the onset of cancer is related to the age of the person. For example, children exposed to ionizing radiation in utero have an increased risk for developing leukemias and childhood tumors, ­particularly

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2  to 3 years after birth. This latency period for leukemia extends to 5 to 10 years if the child was exposed after birth and to 20 years for certain solid tumors.40 As another example, the latency period for the development of thyroid cancer in infants and small children who received radiation to the head and neck to decrease the size of the tonsils or thymus was as long as 35 years after exposure. The association between sunlight and the development of skin cancer has been reported for more than 100 years. Ultraviolet radiation consists of relatively low-energy rays that do not deeply penetrate the skin. The evidence supporting the role of ultraviolet radiation in the cause of skin cancer includes skin cancer that develops primarily on the areas of skin more frequently exposed to sunlight (e.g., the head and neck, arms, hands, and legs), a higher incidence in lightcomplexioned people who lack the ultraviolet-filtering skin pigment melanin, and the fact that the intensity of ultraviolet exposure is directly related to the incidence of skin cancer, as evidenced by higher rates occurring in Australia and the American Southwest.40 Some studies also suggest that intense, episodic exposure to sunlight, particularly during childhood, is more connected to the development of melanoma than prolonged, low-intensity exposure. As with other carcinogens, the effects of ultraviolet radiation usually are additive, and there usually is a long delay between the time of exposure and detection of the cancer. Oncogenic Viruses An oncogenic virus is one that can induce cancer. It has been suspected for some time that viruses play an important role in the development of certain forms of cancer, particularly leukemia and lymphoma. Interest in the field of viral oncology, particularly in human populations, has burgeoned with the discovery of reverse transcriptase and the development of recombinant DNA technology and, more recently, with the discovery of oncogenes and tumor suppressor genes. Viruses, which are small particles containing genetic material (DNA or RNA), enter a host cell and become incorporated into its chromosomal DNA, taking control of the cell’s machinery for the purpose of producing viral proteins. A large number of DNA and RNA viruses (i.e., retroviruses) have been shown to be oncogenic in animals. However, only a few viruses have been linked to cancer in humans. Four DNA viruses have been identified in human cancers: the human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human herpesvirus-8 (HHV-8),2 which causes Kaposi sarcoma in people with AIDS. There are over 60 genetically different types of HPV. Some types (i.e., types 1, 2, 4, 7) have been shown to cause benign squamous papillomas (i.e., warts). HPVs also have been implicated in squamous cell carcinoma of the cervix and anogenital region. HPV types 16 and 18, which are considered the most highly related to cervical cancer, and, less commonly, HPV types 31, 33, 35, and 51 are found in approximately 85% of squamous cell carcinomas of the cervix and presumed precursors (i.e., severe cervical dysplasia and carcinoma in situ).2

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Two ­vaccines to protect against specific HPV types are now ­available for young women and men. EBV is a member of the herpesvirus family. It has been implicated in the pathogenesis of four human cancers: Burkitt lymphoma; nasopharyngeal cancer; B-cell lymphomas in immunosuppressed people, such as those with AIDS; and in some cases of Hodgkin lymphoma. Burkitt lymphoma, a tumor of B lymphocytes, is endemic in parts of East Africa and occurs sporadically in other areas worldwide. In people with normal immune function, the EBV-driven B cell proliferation is r­eadily controlled and the person becomes asymptomatic or experiences a self-limited episode of infectious ­mononucleosis. In regions of the world where Burkitt lymphoma is endemic, concurrent malaria or other infections cause impaired immune function, allowing sustained B-lymphocyte proliferation. The incidence of nasopharyngeal cancer is high in some areas of China, particularly southern China, and in the Cantonese population in Singapore. An increased risk of B-cell lymphomas is seen in people with drug-suppressed immune systems, such as people with transplanted organs. HBV is the etiologic agent in the development of hepatitis B, cirrhosis, and hepatocellular carcinoma. A significant correlation between elevated rates of hepatocellular carcinoma worldwide and the prevalence of HBV carriers has been found.2 Other etiologic factors also may contribute to the development of liver cancer. The precise mechanism by which HBV induces hepatocellular cancer has not been determined, although it has been suggested that it may be the result of prolonged HBV-induced liver damage and regeneration. Although there are a number of retroviruses (RNA viruses) that cause cancer in animals, human T-cell leukemia virus-1 (HTLV-1) is the only known retrovirus to cause cancer in humans. HTLV-1 is associated with a form of T-cell leukemia that is endemic in parts of Japan and found sporadically in some other areas of the world.41 Similar to the human immunodeficiency virus (HIV) responsible for AIDS, HTLV-1 is attracted to CD4+ T cells, and this subset of T cells is therefore the major target for cancerous transformation. The virus requires transmission of infected T cells through sexual intercourse, infected blood, or breast milk.

IN SUMMARY The causes of cancer are highly complex and can be viewed from two perspectives: (1) the molecular and cellular origins and mechanisms and (2) the external and contextual causative factors, including age, heredity, and environmental agents, that influence its inception and growth. In most cases, the molecular pathogenesis of cancer is thought to have its o­ rigin in genetic damage or mutation that changes cell physiology and transforms a normally functioning cell into a ­cancer cell. However, the complexity of the causation and pathogenesis of cancer is becoming increasingly apparent as more is learned about the roles of epigenetic mechanisms, cancer stem cells, and the microenvironment in tumorigenesis.

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The types of genes involved in cancer are numerous, with the two main categories being the protooncogenes, which control cell growth and replication, and tumor suppressor genes, which are growth-inhibiting regulatory genes. Genetic and molecular mechanisms that increase susceptibility to cancer or facilitate cancer include defects in DNA repair mechanisms, defects in growth factor signaling pathways, evasion of apoptosis, development of sustained angiogenesis, and invasion and metastasis. Because cancer is not a single disease, it is likely that multiple factors interact at the molecular and cellular levels to transform normal cells into cancer cells. Genetic and epigenetic damage may be the result of interactions between multiple risk factors or repeated exposure to a single carcinogen. Among the risk factors that have been linked to cancer are heredity, hormonal factors, immunologic mechanisms, and environmental agents such as chemicals, radiation, and cancer-causing viruses.

CLINICAL MANIFESTATIONS After completing this section of the chapter, you should be able to meet the following objectives: •• Characterize the mechanisms involved in the anorexia and cachexia, fatigue and sleep disorders, anemia, and venous thrombosis experienced by people with cancer. •• Define the term paraneoplastic syndrome and explain its pathogenesis and manifestations.

There probably is not a single body function left unaffected by the presence of cancer. Because tumor cells replace normally functioning parenchymal tissue, the initial manifestations of cancer usually reflect the primary site of involvement. For example, cancer of the lung initially produces impairment of respiratory function; as the tumor grows and metastasizes, other body structures become affected. Cancer also produces generalized manifestations such as fatigue, anorexia and cachexia, anemia, decreased resistance to infections, and symptoms unrelated to the tumor site (paraneoplastic syndromes). Many of these manifestations are compounded by the side effects of methods used to treat the disease. In its late stages, cancer often causes pain. Pain is one of the most dreaded aspects of cancer, and pain management is one of the major treatment concerns for persons with incurable cancers.

Tissue Integrity Cancer disrupts tissue integrity. As cancers grow, they compress and erode blood vessels, causing ulceration and necrosis along with frank bleeding and sometimes hemorrhage. One of the early warning signals of colorectal cancer is blood in the

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stool. Cancer cells also may produce enzymes and metabolic toxins that are destructive to the surrounding tissues. Usually, tissue damaged by cancerous growth does not heal normally. Instead, the damaged area persists and often continues to grow; a sore that does not heal is another warning signal of cancer. Cancer has no regard for normal anatomic boundaries; as it grows, it invades and compresses adjacent structures. Abdominal cancer, for example, may compress the viscera and cause bowel obstruction. The development of effusions or fluid in the pleural, pericardial, or peritoneal spaces is often the presenting sign of some tumors.2 Direct involvement of the serous surface seems to be the most significant inciting factor, although many other mechanisms, such as obstruction of lymphatic flow, may play a role. It has been reported that almost 50% of undiagnosed effusions in people not known to have cancer turn out to be due to malignancy. Lung cancers, breast cancers, and lymphomas account for about 75% of malignant pleural effusions.2,42 Most people with pleural effusions are symptomatic at presentation, with chest pain, shortness of breath, and cough. More than any other malignant neoplasms, ovarian cancers are associated with the accumulation of fluid in the peritoneal cavity. Abdominal discomfort, swelling and a feeling of heaviness, and increase in abdominal girth, which reflect the presence of peritoneal effusions or ascites, shortness of breath, and difficulty breathing are common presenting symptoms in ovarian cancer.42

Systemic Manifestations Many of the clinical manifestations of cancer, including anorexia and cachexia, fatigue and sleep disorders, and anemia, are not directly related to the presence of a tumor mass but to altered metabolic pathways and the presence of circulating cytokines and other mediators. Although research has produced amazing insights into the causes and cures for cancer, much still is needed regarding management of the associated side effects of the disease.2 Anorexia and Cachexia Many cancers are associated with weight loss and wasting of body fat and muscle tissue, accompanied by profound weakness, anorexia, and anemia. This wasting syndrome is often referred to as the cancer anorexia–cachexia syndrome.43 It is a common manifestation of most solid tumors, with the exception of breast cancer. It has been estimated that it is a significant cause of morbidity and mortality in 80% of people with advanced cancer and is responsible for death in up to 20% of cases.44 The condition is more common in children and older adults and becomes more pronounced as the disease progresses. People with cancer cachexia also respond less well to chemotherapy and are more prone to toxic side effects. Although anorexia, reduced food intake, and abnormalities of taste are common in people with cancer and often are accentuated by treatment methods, the extent of weight loss and protein wasting cannot be explained in terms of ­diminished food intake alone. In contrast to starvation due to lack of

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food intake, where weight is preferentially lost from the fat c­ ompartment, in cachexia, it is lost from both the fat and skeletal muscle compartments.43 Furthermore, the protein loss that occurs with starvation is divided equally between skeletal muscle and visceral proteins, whereas in cachexia, visceral proteins are relatively well preserved. Thus, there is a loss of liver mass in starvation, but an increase in cachectic people because of hepatic recycling of nutrients and the acute-phase response. Finally, and more important, weight loss that occurs with starvation is usually reversed by refeeding, whereas oral or parenteral nutritional supplementation does not reverse cachexia. The mechanisms of cancer cachexia appear to reside in a hypermetabolic state and altered nutrient metabolism that are specific to the tumor-bearing state. Tumors tend to consume large amounts of glucose, with a resultant increase in lactate formation because the tumor oxygen levels are too low to support the citric acid cycle and mitochondrial oxidative phosphorylation. The lactate that is produced then circulates to the liver, where it is converted back to glucose. The production of glucose (gluconeogenesis) from lactate uses adenosine triphosphate (ATP) and is very energy inefficient, contributing to the hypermetabolic state of cachectic people. Another mechanism for the increasing energy expenditure in cachectic people is the increased expression of mitochondrial uncoupling proteins that uncouple the oxidative phosphorylation process, so that energy is lost as heat. Abnormalities in fat and protein metabolism have also been reported. During starvation in people without cancer, ketones derived from fat replace the glucose normally used by the brain, leading to decreased gluconeogenesis from amino acids with conservation of muscle mass, whereas in people with cancer cachexia, amino acids are not spared and there is depletion of lean body mass, a condition thought to contribute to decreased survival time. Although the mechanisms of the cancer anorexia– cachexia syndrome remain incompletely understood, they are probably multifactorial, resulting from a persistent inflammatory response in conjunction with production of specific cytokines and catabolic factors by the tumor. The syndrome shows similarities to that of the acute-phase response seen with tissue injury, infection, or inflammation, in which liver protein synthesis changes from synthesis of albumin to acute-phase proteins such as C-reactive protein, fibrinogen, and α1-antitrypsin. The acute-phase response is known to be activated by cytokines such as tumor necrosis factor-α (TNF-α) and IL-1 and IL-6, suggesting that they may also play a role in cancer cachexia.45 High serum levels of these cytokines have been observed in people with cancer, and their levels appear to correlate with progression of the tumor. TNF-α, secreted primarily by macrophages in response to tumor cell growth or gram-negative bacterial infections, was the first cytokine associated with cachexia and wasting to be identified. It causes anorexia by suppressing satiety centers in the hypothalamus and increasing the synthesis of lipoprotein lipase, an enzyme that facilitates the release of fatty acids from lipoproteins so that they can be used by tissues. IL-1 and IL-6 share many of the features of TNF-α in terms of the ability to initiate cachexia.

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Fatigue and Sleep Disorders Fatigue and sleep disturbances are two of the most frequent side effects experienced by people with cancer.46 Cancerrelated fatigue is characterized by feelings of tiredness, weakness, and lack of energy and is distinct from the normal tiredness experienced by healthy people in that it is not relieved by rest or sleep. It occurs both as a consequence of the cancer itself and as a side effect of cancer treatment. Cancer-related fatigue may be an early symptom of malignant disease and has been reported by more than a third of people at the time of diagnosis.46 Furthermore, the symptom often remains for months or even years after treatment. The cause of cancer-related fatigue is largely unknown, but is probably multifactorial and involves the dysregulation of several interrelated physiologic, biochemical, and psychological systems. The basic mechanisms of fatigue have been broadly categorized into two components: peripheral and central.47 Peripheral fatigue, which occurs in the neuromuscular junctions and muscles, results from the inability of the peripheral neuromuscular apparatus to perform a task in response to central stimulation. Mechanisms implicated in peripheral fatigue include a lack of ATP and the buildup of metabolic by-products such as lactic acid. Central fatigue arises in the central nervous system (CNS) and is often described as difficulty in initiating or maintaining voluntary activities. One hypothesis proposed to explain cancer-related fatigue is that cancer and cancer treatments result in dysregulation of brain serotonin (5-hydroxytryptamine [5-HT]) levels or function. There is evidence that proinflammatory cytokines, such as TNF-α, can influence 5-HT metabolism.47 Although cancer-related fatigue and sleep disorders are distinct conditions, they are closely linked in terms of prevalence and symptoms.48 People with cancer report poor sleep quality, disturbed initiation and maintenance of sleep, insufficient sleep, nighttime awakening, and restless sleep. As with fatigue, precipitating factors include the diagnosis of cancer, type and stage of cancer, pain, and side effects of treatment (e.g., nausea, vomiting). Once it begins, insomnia is often self-perpetuating because of the natural tendency to compensate for sleep loss by napping, going to bed earlier, and getting out of bed later. It may also be that the fatigue that occurs with cancer or anticancer therapy may, in fact, prompt people to extend their sleep opportunity and thus becomes a contributing factor to ongoing insomnia. Correlations have also been noted between fatigue and daytime symptoms of sleep problems, such as daytime sleepiness and napping. Anemia Anemia is common in people with various types of cancers. It may be related to blood loss, hemolysis, impaired red blood cell production, or treatment effects.2 For example, drugs used in treatment of cancer are cytotoxic and can decrease red blood cell production. Also, there are many mechanisms through which erythrocyte production can be impaired in people with malignancies, including nutritional deficiencies, bone marrow failure, and a blunted erythropoietin response

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to hypoxia. Inflammatory cytokines generated in response to tumors decrease erythropoietin production, resulting in a decrease in erythrocyte production. Cancer-related anemia is associated with reduced treatment effectiveness, increased mortality, increased transfusion requirements, and reduced performance and quality of life. Hypoxia, a characteristic feature of advanced solid tumors, has been recognized as a critical factor in promoting tumor resistance to radiation therapy and some chemotherapeutic agents. Severe anemia may delay surgical interventions when preoperative transfusions are required. Similarly, low hemoglobin levels before or during chemotherapy may require dose reductions or delays in administration, resulting in a decrease in overall treatment effectiveness. Cancer-related anemia is often treated with recombinant human erythropoietin.

Paraneoplastic Syndromes In addition to signs and symptoms at the sites of primary and metastatic disease, cancer can produce manifestations in sites that are not directly affected by the disease. Such manifestations are collectively referred to as paraneoplastic syndromes.2 Some of these manifestations are caused by the elaboration of hormones by cancer cells, and others from the

production of circulating factors that produce hematopoietic, neurologic, and dermatologic syndromes (Table 8.4). These syndromes are most commonly associated with lung, breast, and hematologic malignancies.2 A variety of peptide hormones are produced by both benign and malignant tumors. Although not normally expressed, the biochemical pathways for the synthesis and release of peptide hormones (e.g., antidiuretic [ADH], adrenocorticotropic [ACTH], and parathyroid [PTH] hormones) are in most cells.49 Thus, the three most common endocrine syndromes associated with cancer are the syndrome of inappropriate ADH secretion, Cushing syndrome due to ectopic ACTH production, and hypercalcemia.2 Hypercalcemia of malignancy does not appear to be related to PTH but to a PTH-related protein that shares several biologic actions with PTH.2 Hypercalcemia also can be caused by cancers such as multiple myeloma or bony metastases from other cancers. Some paraneoplastic syndromes are associated with the production of circulating mediators that produce hematologic complications.2 For example, a variety of cancers may produce procoagulation factors that contribute to an increased risk for venous thrombosis and nonbacterial thrombotic endocarditis. Sometimes, unexplained thrombotic events are the first indication of an undiagnosed malignancy. The precise relationship

TABLE 8.4 COMMON PARANEOPLASTIC SYNDROMES TYPE OF SYNDROME

ASSOCIATED TUMOR TYPE

PROPOSED MECHANISM

Small cell lung cancer, others Small cell lung cancer, bronchial carcinoid cancers Squamous cell cancers of the lung, head, neck, ovary

Production and release of ADH by tumor Production and release of ACTH by tumor

Endocrinologic Syndrome of inappropriate ADH ACTH–Cushing syndrome Humoral hypercalcemia

Production and release of polypeptide factor with close relationship to PTH

Hematologic Venous thrombosis Nonbacterial thrombolytic endocarditis and anemia of malignancy Neurologic Eaton-Lambert syndrome Myasthenia gravis

Pancreatic, lung, most solid tumor metastatic cancers Advanced cancers

Production of procoagulation factors

Small cell lung cancer

Autoimmune production of antibodies to motor end-plate structures Autoimmune generating abnormal neuron transmission

Thymoma

Dermatologic Cutaneous syndromes

Gastric carcinoma and other

Acanthosis nigricans Pemphigus Ichthyosis Extramammary Paget

Cancers

Possibly caused by production of growth factors (epidermal) by tumor cells Sometimes occur prior to cancer

Damage to renal glomerulus

Renal Nephrotic syndrome

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Renal cancers

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between coagulation disorders and cancer is still unknown. Several malignancies, such as mucin-producing adenocarcinomas, release thromboplastin and other substances that activate the clotting system. The symptomatic paraneoplastic neurologic disorders are relatively rare, with the exception of the Lambert-Eaton myasthenic syndrome, which affects about 3% of people with small cell lung cancer, and myasthenia gravis, which affects about 15% of people with thymoma.50 The LambertEaton syndrome, or reverse myasthenia gravis, is seen almost exclusively in small cell lung cancer. It produces muscle weakness in the limbs rather than the initial bulbar and ocular muscle weakness seen in myasthenia gravis. The origin of paraneoplastic neurologic disorders is thought to be immune ­mediated.50 The altered immune response is initiated by the production of onconeural antigens (e.g., antigens normally expressed in the nervous system) by the cancer cells. The immune system, in turn, recognizes the onconeural antigens as foreign and mounts an immune response. In many cases, the immune attack controls the growth of the cancer. The antibodies and cytotoxic T cells are not sufficient to cause neurologic disease unless they cross the blood–brain barrier and react with neurons expressing the onconeural antigen.50 A wide variety of cutaneous syndromes are associated with malignancies and may precede, be concurrent with, or follow the discovery of cancer. Among the paraneoplastic dermatologic disorders is acanthosis nigricans, characterized by pigmented hyperkeratoses consisting of symmetric, verrucous, and papillary lesions that occur in skin flexures, particularly the axillary and perineal areas.2 The lesions are usually symmetric and may be accompanied by pruritus. The condition is usually associated with adenocarcinomas of the gastrointestinal tract, particularly gastric carcinoma, but may be associated with a variety of adenocarcinomas, including lung, breast, ovarian, and even hematologic cancers. The pathogenesis of these lesions is uncertain. The paraneoplastic syndromes may be the earliest indication that a person has cancer and should be regarded as such.51 They may also represent significant clinical problems, may be potentially lethal in people with cancer, and may mimic metastatic disease and confound treatment. Diagnostic methods focus on both identifying the cause of the disorder and on locating the malignancy responsible. The treatment of paraneoplastic syndromes involves concurrent treatment of the underlying cancer and suppression of the mediator causing the syndrome.

IN SUMMARY There probably is no single body function left unaffected by the presence of cancer. Because tumor cells replace normally functioning parenchymal tissue, the initial manifestations of cancer usually reflect the primary site of involvement. Cancer compresses blood vessels, obstructs lymph flow, disrupts tissue integrity, invades serous cavities, and compresses visceral organs. It may result in development of effusion (i.e., fluid) in the pleural, pericardial,

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or peritoneal spaces and generalized manifestations such as anorexia and cachexia, fatigue and sleep disorders, and anemia. It may also produce paraneoplastic syndromes that arise from the ability of neoplasms to secrete hormones and other chemical mediators to produce endocrine, hematopoietic, neurologic, and dermatologic syndromes. Many of these manifestations are compounded by the side effects of methods used to treat the disease.

SCREENING, DIAGNOSIS, AND TREATMENT After completing this section of the chapter, you should be able to meet the following objectives: •• Explain the mechanism by which radiation exerts its beneficial effects in the treatment of cancer. •• Differentiate between the action of direct DNAinteracting and indirect DNA-interacting chemotherapeutic agents and cell cycle–specific and cell cycle–independent drugs. •• Describe the three mechanisms whereby biotherapy exerts its effects.

Screening Screening represents a secondary prevention measure for the early recognition of cancer in an otherwise asymptomatic population.2 Screening can be achieved through observation (e.g., skin, mouth, external genitalia), palpation (e.g., breast, thyroid, rectum and anus, prostate, lymph nodes), and laboratory tests and procedures (e.g., Papanicolaou [Pap] smear, colonoscopy, mammography). It requires a test that will specifically detect early cancers or premalignancies, is cost-­ effective, and results in improved therapeutic outcomes.2 For most cancers, stage at presentation is related to curability, with the highest rates reported when the tumor is small and there is no evidence of metastasis. For some tumors, however, metastasis tends to occur early, even from a small primary tumor. For other cancers, such as cancer of the pancreas, no screening methods are currently available. More sensitive screening methods such as tumor markers are being developed for these forms of cancer. Lung cancer is the leading cause of cancer death; however, there are no standard screening guidelines.52 Physicians and other providers need to determine if it is costeffective for specific people with certain risk factors to have periodic chest x-rays and CAT scans.52 Cancers for which current screening or early detection has led to improvement in outcomes include cancers of the breast (mammography), cervix (Pap smear), colon and rectum (rectal examination, fecal occult blood test, and colonoscopy), prostate (prostate-specific antigen [PSA] testing and transrectal ultrasonography), and malignant melanoma (self-­examination). Although not as clearly defined, it is recommended that screening for other types of cancers such as

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c­ ancers of the thyroid, testicles, ovaries, lymph nodes, and oral cavity be done at the time of periodic health examinations.

Diagnostic Methods The methods used in the diagnosis and staging of cancer are determined largely by the location and type of cancer suspected. A number of procedures are used in the diagnosis of cancer, including blood tests for tumor markers, cytologic studies and tissue biopsy, endoscopic examinations, ultrasonography, x-ray studies, MRI, computed tomography (CT), and positron emission tomography (PET). Tumor Markers Tumor markers are antigens expressed on the surface of tumor cells or substances released from normal cells in response to the presence of tumor.2,49 Some substances, such as hormones and enzymes, that are produced normally by the involved tissue become overexpressed as a result of cancer. Other tumor markers, such as oncofetal proteins, are produced during fetal development and are induced to reappear later in life as

a result of benign and malignant neoplasms. Tumor markers are used for screening, establishing prognosis, monitoring treatment, and detecting recurrent disease. Table 8.5 identifies some of the more commonly used tumor markers and summarizes their source and the cancers associated with them. The serum markers that have proved most useful in clinical practice are human chorionic gonadotropin (hCG), CA-125, PSA, α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and CD blood cell antigens.2 A hormone normally produced by the placenta, hCG, is used as a marker for diagnosing, prescribing treatment, and following the disease course in people with high-risk gestational trophoblastic tumors. PSA is used as a marker in prostate cancer, and CA-125 is used as a marker in ovarian cancer. Markers for leukemia and lymphomas are grouped by so-called cluster of differentiation (CD) antigens. The CD antigens help to distinguish among T and B lymphocytes, monocytes, granulocytes, and NK cells, and immature variants of these cells.2 Some cancers express fetal antigens that are normally present only during embryonal development.2 The two that have proved most useful as tumor markers are AFP and CEA. AFP

TABLE 8.5 TUMOR MARKERS MARKER

SOURCE

ASSOCIATED CANCERS

Fetal yolk sac and gastrointestinal structures early in fetal life Breast tissue protein

Primary liver cancers; germ cell cancer of the testis Tumor marker for tracking breast cancer; liver, lung Breast cancer recurrence and metastasis Colorectal cancer and cancers of the ­pancreas, lung, and stomach

Antigens AFP CA 15-3 CA 27.29 CEA

Breast tissue protein Embryonic tissues in gut, pancreas, liver, and breast

Hormones hCG

Hormone normally produced by placenta

Calcitonin

Hormone produced by thyroid parafollicular cells Hormones produced by chromaffin cells of the adrenal gland

Catecholamines (epinephrine, ­norepinephrine) and metabolites

Gestational trophoblastic tumors; germ cell cancer of testis Thyroid cancer Pheochromocytoma and related tumors

Specific Proteins Monoclonal immunoglobulin PSA

Abnormal immunoglobulin produced by neoplastic cells Produced by the epithelial cells lining the acini and ducts of the prostate

Multiple myeloma Prostate cancer

Mucins and Other Glycoproteins CA-125 CA-19-9

Produced by müllerian cells of ovary Produced by alimentary tract epithelium

Ovarian cancer Cancer of the pancreas, colon

Present on leukocytes

Used to determine the type and level of ­differentiation of leukocytes involved in different types of leukemia and lymphoma

Cluster of Differentiation CD antigens

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is synthesized by the fetal liver, yolk sac, and ­gastrointestinal tract and is the major serum protein in the fetus. Elevated levels are encountered in people with primary liver cancers and have also been observed in some testicular, ovarian, pancreatic, and stomach cancers. CEA normally is produced by embryonic tissue in the gut, pancreas, and liver and is elaborated by a number of different cancers. Depending on the serum level adopted for significant elevation, CEA is elevated in approximately 60% to 90% of colorectal carcinomas, 50%  to 80% of pancreatic cancers, and 25% to 50% of gastric and breast tumors.2 As with most other tumor markers, elevated levels of CEA and AFP are found in other, noncancerous conditions, and elevated levels of both depend on tumor size, so that neither is useful as an early screening test for cancer. As diagnostic tools, tumor markers have limitations. Nearly all markers can be elevated in benign conditions, and most are not elevated in the early stages of malignancy. Hence, tumor markers have limited value as screening tests. Furthermore, they are not in themselves specific enough to permit a diagnosis of a malignancy, but once a malignancy has been diagnosed and shown to be associated with elevated levels of a tumor marker, the marker can be used to assess response to therapy. Examples of tumor markers that assist in evaluating peoples’ response to therapy, and if a recurrence of breast cancer may be occurring, are CA 15-3 and CA 27-29, both antigens that are found in breast tissue.3 Extremely elevated levels of a tumor marker can indicate a poor prognosis or the need for more aggressive treatment. Perhaps the greatest value of tumor markers is in monitoring therapy in people with widespread cancer. The level of most cancer markers tends to decrease with successful treatment and increase with recurrence or spread of the tumor. Cytologic and Histologic Methods Histologic and cytologic studies are laboratory methods used to examine tissues and cells. Several sampling approaches are available, including cytologic smears, tissue biopsies, and needle aspiration.2 Papanicolaou Test. The Pap test is a cytologic method used for detecting cancer cells. It consists of a microscopic examination of a properly prepared slide by a cytotechnologist or pathologist for the purpose of detecting the presence of abnormal cells. The usefulness of the Pap test relies on the fact that the cancer cells lack the cohesive properties and intercellular junctions that are characteristic of normal tissue. Without these characteristics, cancer cells tend to exfoliate and become mixed with secretions surrounding the tumor growth. Although the Pap test is widely used as a screening test for cervical cancer, it can be performed on other body secretions, including nipple drainage, anal washings, pleural or peritoneal fluid, and gastric washings. Tissue Biopsy.  Tissue biopsy, which is of critical importance in diagnosing the correct cancer and histology, involves the removal of a tissue specimen for microscopic study. Biopsies

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are obtained in a number of ways, including needle biopsy; endoscopic methods, such as bronchoscopy or cystoscopy, which involve the passage of an endoscope through an orifice and into the involved structure; or laparoscopic methods. In some instances, a surgical incision is made from which biopsy specimens are obtained. Excisional biopsies are those in which the entire tumor is removed. The tumors usually are small, solid, palpable masses. If the tumor is too large to be completely removed, a wedge of tissue from the mass can be excised for examination. Appropriate preservation of the specimen includes prompt immersion in a fixative solution such as formalin, with preservation of a portion of the specimen in a special fixative for electron microscopy, or prompt refrigeration to permit optimal hormone, receptor, and other types of molecular analysis. A quick frozen section may be done to determine the nature of a mass lesion or evaluate the margins of an excised tumor to ascertain that the entire neoplasm has been removed.2 Fine-needle aspiration is another approach that is widely used. The procedure involves aspirating cells and attendant fluid with a small-bore needle. The method is most commonly used for assessment of readily palpable lesions in sites such as the thyroid, breast, and lymph nodes. Modern imaging techniques have also enabled the method to be extended to deeper structures such as the pelvic lymph nodes and pancreas. Immunohistochemistry. Immunohistochemistry involves the use of antibodies to facilitate the identification of cell products or surface markers.2 For example, certain anaplastic carcinomas, malignant lymphomas, melanomas, and sarcomas look very similar under the microscope, but must be accurately identified because their treatment and prognosis are quite different. Antibodies against intermediate filaments have proved useful in such cases because tumor cells often contain intermediate filaments characteristic of their tissue of origin.2 Immunohistochemistry can also be used to determine the site of origin of metastatic tumors. Many people with cancer present with metastasis. In cases in which the origin of the metastasis is obscure, immunochemical detection of tissuespecific or organ-specific antigens can often help to identify the tumor source. Immunohistochemistry can also be used to detect molecules that have prognostic or therapeutic significance. For example, detection of estrogen receptors on breast cancer cells is of prognostic and therapeutic significance because these tumors respond to antiestrogen therapy. Microarray Technology.  Microarray technology uses “gene chips” that can simultaneously perform miniature assays to detect and quantify the expression of large numbers of genes.2 The advantage of microarray technology is the ability to analyze a large number of changes in cancer cells to determine overall patterns of behavior that could not be assessed by conventional means. DNA arrays are now commercially available to assist in making clinical decisions regarding breast cancer treatment. In addition to identifying tumor types, microarrays have been used for predicting prognosis and response to therapy, examining tumor changes after therapy, and classifying hereditary tumors.2

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Staging and Grading of Tumors The two basic methods for classifying cancers are grading according to the histologic or cellular characteristics of the tumor and staging according to the clinical spread of the disease. Both methods are used to determine the course of the disease and aid in selecting an appropriate treatment or management plan. Grading of tumors involves the microscopic examination of cancer cells to determine their level of differentiation and the number of mitoses. Cancers are classified as grades I, II, III, and IV with increasing anaplasia or lack of differentiation. Staging of cancers uses methods to determine the extent and spread of the disease. Surgery may be used to determine tumor size and lymph node involvement. The clinical staging of cancer is intended to group people according to the extent of their disease. It is useful in determining the choice of treatment for individual people, estimating prognosis, and comparing the results of different treatment regimens. The TNM system of the American Joint Committee on Cancer (AJCC) is used by most cancer facilities.53 This system, which is briefly described in Chart 8.2, classifies the disease into stages using three tumor components: •• T stands for the size and local spread of the primary tumor. •• N refers to the involvement of the regional lymph nodes. •• M describes the extent of the metastatic involvement. The time of staging is indicated as clinical–diagnostic staging (cTNM), postsurgical resection–pathologic staging (pTNM), surgical–evaluative staging (sTNM), retreatment staging (rTNM), and autopsy staging (aTNM).53

Cancer Treatment The goals of cancer treatment methods fall into three categories: curative, control, and palliative. The most common modalities are surgery, radiation therapy, chemotherapy, hormonal

Chart 8.2 TNM CLASSIFICATION SYSTEM T (Tumor) Tx Tumor cannot be adequately assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1–4 Progressive increase in tumor size or involvement N (Nodes) Nx Regional lymph nodes cannot be assessed N0 No evidence of regional node metastasis N1–3 Increasing involvement of regional lymph nodes M (Metastasis) Mx Not assessed M0 No distant metastasis M1 Distant metastasis present, specify sites

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t­herapy, and biotherapy. The treatment of cancer involves the use of a carefully planned program that combines the benefits of multiple treatment modalities and the expertise of an interdisciplinary team of specialists, including medical, surgical, and radiation oncologists; clinical nurse specialists; nurse practitioners; pharmacists; and a variety of ancillary personnel. Surgery Surgery is the oldest treatment for cancer and, until recently, the only treatment that could cure people with cancer. Surgery is now used for diagnosis, staging of cancer, tumor removal, and palliation (i.e., relief of symptoms) when a cure cannot be achieved. The type of surgery to be used is determined by the extent of the disease, the location and structures involved, the tumor growth rate and invasiveness, the surgical risk to the patient, and the quality of life the patient will experience after the surgery. Surgery often is the first treatment used with solid tumors. If the tumor is small and has well-defined margins, the entire tumor often can be removed. If, however, the tumor is large or involves vital tissues, surgical removal may be difficult, if not impossible. Surgery provides several approaches for cancer treatment. For example, it can be the primary, curative treatment for cancers that are locally or regionally contained, have not metastasized, or have not invaded major organs. It also is used as a component of adjuvant therapy in combination with chemotherapy or radiation therapy in other types of cancers. Surgical techniques also may be used to control oncologic emergencies such as gastrointestinal hemorrhages. Another approach includes using surgical techniques for cancer prophylaxis in families that have a high genetically confirmed risk for developing cancer. For instance, a total colectomy with a colostomy may be suggested for a person with familial adenomatous polyposis coli because of the increased risk for developing cancer by 40 years of age. Surgical techniques have expanded to include cryosurgery, chemosurgery, laser surgery, and laparoscopic surgery. Cryosurgery involves the instillation of liquid nitrogen into the tumor through a probe. It is used in treating cancers of the liver and prostate. Chemosurgery is used in skin cancers. It involves the use of a corrosive paste in combination with multiple frozen sections to ensure complete removal of the tumor. Laser surgery uses a laser beam to resect a tumor. It has been used effectively in retinal and vocal cord surgery. Laparoscopic surgery involves the performance of abdominal surgery through two small incisions—one for viewing within the cavity and the other for insertion of the instruments to perform the surgery. Cooperative efforts among cancer centers throughout the world have helped to standardize and improve surgical ­procedures, determine which cancers benefit from surgical intervention, and establish in what order surgical and other treatment modalities should be used. Increased emphasis also has been placed on the development of surgical techniques that preserve body image and form without compromising essential function. Nerve- and tissue-sparing surgeries are

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the primary method used if at all possible even if complete removal of the tumor is the goal. Radiation Therapy Radiation therapy is one of the most commonly used methods of cancer treatment.2 It can be used alone as a primary method of therapy or as an adjuvant treatment with surgery, chemotherapy, or both. It can also be used as a palliative treatment to reduce symptoms such as bone pain resulting from metastasis in people with advanced cancers. Radiation is used to treat oncologic emergencies such as superior vena cava syndrome, spinal cord compression, or bronchial obstruction. Radiation therapy uses high-energy particles or waves to destroy or damage cancer cells. The absorption of energy from radiation in tissue leads to the ionization of molecules or creation of free radicals. Radiation can also produce effects indirectly by interacting with water (which makes up approximately 80% of a cell’s volume) to produce free radicals, which damage cell structures. Radiation can interrupt the cell cycle process, kill cells, or damage DNA in the cells.2 Radiation must produce double-stranded breaks in DNA to kill a cell, owing to the high capacity of cells for repairing single-stranded breaks. The therapeutic effects of radiation therapy derive from the fact that the rapidly proliferating and poorly differentiated cells of a cancerous tumor are more likely to be injured than are the more slowly proliferating cells of normal tissue. To some extent, however, radiation is injurious to all rapidly proliferating cells, including those of the bone marrow and the mucosal lining of the gastrointestinal tract. Normal tissue usually is able to recover from radiation damage more readily than cancerous tissue. In addition to its lethal effects, radiation also produces sublethal injury. Recovery from sublethal doses of radiation occurs in the interval between the first dose of radiation and subsequent doses.2,54 This is why large total doses of radiation can be tolerated when they are divided into multiple, smaller fractionated doses.54 The radiation dose that is chosen for treatment of a particular cancer is determined by factors such as the radiosensitivity of the tumor type, the size of the tumor, and, more important, the tolerance of the surrounding tissues.2,54 The term radiosensitivity describes the inherent properties of a tumor that determine its responsiveness to radiation. It varies widely among the different types of cancers and is thought to vary as a function of their position in the cell cycle. Fastgrowing cancers have cells that typically are more radiosensitive than slow-growing cancers. The combination of selected cytotoxic drugs with radiation has demonstrated a radiosensitizing effect on tumor cells by altering the cell cycle distribution, increasing DNA damage, and decreasing DNA repair. Radiosensitizers include 5-fluorouracil, capecitabine, paclitaxel, gemcitabine, and cisplatin.55 Radiation responsiveness describes the manner in which a radiosensitive tumor responds to irradiation. One of the major determinants of radiation responsiveness is tumor oxygenation because oxygen is a rich source of free radicals that form

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and destroy essential cell components during irradiation.54 Many rapidly growing tumors outgrow their blood supply and become deprived of oxygen. The hypoxic cells of these tumors are more resistant to radiation than normal or well-oxygenated tumor cells. Methods of ensuring adequate oxygen delivery, such as adequate hemoglobin levels, are important. Dose–response curves, which express the extent of lethal tissue injury in relation to the dose of radiation, are determined by the number of cells that survive graded, fractional doses of radiation. The use of more frequent fractionated doses increases the likelihood that the cancer cells will be dividing and in the vulnerable period of the cell cycle during radiation administration. This type of dose also allows time for normal tissues to repair the radiation damage. An important focus of research has been the search for drugs to reduce the biologic effects of radiation on normal tissue. These drugs, known as radioprotectants, would preferentially protect normal cells from the cytotoxic effects of radiation. One drug, amifostine, was considered as possibly decreasing the effect of radiation and impacting survival, but this was found to be incorrect in a study of people with pelvic, lung, and head and neck cancer.56 Therefore, although there has been some promising developments, more research is necessary regarding radioprotectants. Administration. Therapeutic radiation can be delivered in one of three ways: external beam or teletherapy, with beams generated at a distance and aimed at the tumor in a person; brachytherapy, in which a sealed radioactive source is placed close to or directly in the tumor site; and systemic therapy, when radioisotopes are given orally or injected into the tumor site.2 Radiation from any source decreases in intensity as a function of the square of the distance from the source. Teletherapy, which is the most commonly used form of radiation therapy, maintains intensity over a large volume of tissue by increasing the source to surface distance. In brachytherapy, the source to surface distance is small; therefore, the effective treatment volume is small. External-beam radiation is most frequently used with a linear accelerator or a cobalt-60 machine.2 The linear accelerator is the preferred machine because of its versatility and precision of dose distribution, as well as the speed with which treatment can be given. Linear accelerators produce ionizing radiation through a process in which electrons are accelerated at a very high rate, strike a target, and produce high-energy x-rays (photons). The linear accelerator can vary the level of radiation energy that is delivered so that different depths can be treated. Various beam-modifying approaches are used to define and shape the beam, thereby increasing the radiation damage to the tumor site while sparing the normal surrounding tissues. The person is fitted with a plastic mold or cast to keep the body still, while radiation beams are delivered to the body from several directions. Intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3-D CRT) are advanced forms of external radiation therapy. As with 3-D CRT, computer imaging techniques are used to calculate the most efficient dosages and combinations of radiation

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t­reatment. This precise mapping of the tumor allows for the delivery of radiation beams that conform to the contours of the tumor, reducing the dose and therefore the toxicity to adjacent normal tissue. Because of its precision, it is even more important that the person remain in the right place and perfectly still during the treatment. This usually requires fabricating a special cast or mold before treatment to keep the body in place. Brachytherapy involves the insertion of sealed radioactive sources into a body cavity (intracavitary) or directly into body tissues (interstitial). Brachytherapy means “short therapy,” implying that the radiation effect is limited to areas close to the radiation source.56 Brachytherapy can be subdivided into highdose radiation (HDR) and low-dose radiation (LDR) according to the rate at which the radiation is delivered. HDR uses a single highly radioactive source that is attached to a cable and housed in a robotic machine referred to as an HDR remote afterloader. When the treatment is delivered, the radiation source is pushed from the remote afterloader through a tube to a location near the tumor site. Remote afterloading machines make it possible to insert a radioactive material (e.g., cesium-137, iridium-192) into a tumor area for a specific time and remove it while oncology personnel are outside the treatment room. This minimizes staff radiation exposure and decreases treatment times by allowing use of intermediate- and high-dose radioactive sources.56 In contrast, the radiation source for LDR brachytherapy may be packed into catheter devices or sealed radiation sources (e.g., beads, seeds) and placed directly in or near the area being treated. LDR therapy can be temporary or permanent. Temporary LDR brachytherapy can be accomplished as an inpatient procedure, with radiation applicators and sources remaining in the person for a few days. Radioactive materials with a relatively short half-life, such as iodine-125 or palladium-103, are commonly encapsulated and used in permanent implants (e.g., seed implants used to treat prostate cancer). Unsealed internal radiation sources are injected intravenously or administered by mouth. Iodine-131, which is given by mouth, is used in the treatment of thyroid cancer. Stereotactic radiosurgery is a method of destroying brain tumors and brain metastases by delivering a single large dose of radiation through stereotactically directed narrow beams. Gamma knife radiosurgery allows the application of focused radiation for limited brain metastasis and is associated with fewer long-term complications, such as cognitive dysfunction, compared to whole-brain radiation. Adverse Effects.  Unfortunately radiation therapy negatively effects normal tissue that is rapidly proliferative similar to malignant cells. During radiation treatment, injury to normal cells can produce adverse effects. Tissues within the treatment fields that are most frequently affected are the skin, the mucosal lining of the gastrointestinal tract, and the bone marrow. Anorexia, nausea, emesis, and diarrhea are common with abdominal and pelvic irradiation. These symptoms are usually controlled by medication and dietary measures. The primary systemic effect is fatigue. Most of these side effects are temporary and reversible.

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Radiation can also cause bone marrow suppression, particularly when it is delivered to the bone marrow in skeletal sites. Subsequently, the complete blood count is affected, resulting in an initial decrease in the number of the leukocytes, followed by a decrease in thrombocytes (platelets) and, finally, red blood cells. This predisposes the person to infection, bleeding, and anemia, respectively. Frequent blood counts are used during radiation therapy to monitor bone marrow function. External-beam radiation must first penetrate the skin and, depending on the total dose and type of radiation used, skin reactions may develop. With moderate doses of radiation, the hair falls out spontaneously or when being combed after the 10th to the 14th day. With larger doses, erythema develops (much like sunburn) and may turn brown, and at higher doses, patches of dry or moist desquamation may develop. Fortunately, reepithelialization takes place after the treatments have been stopped. Mucositis or desquamation of the oral and pharyngeal mucous membranes, which sometimes may be severe, may occur as a predictable side effect in people receiving head and neck irradiation. Pain and difficulty eating and drinking can negatively affect the person’s nutritional status. Pelvic radiation can cause impotence or erectile dysfunction in men and vaginal irritation, dryness, and discharge, dyspareunia, and, as a late effect, vaginal stenosis in women. Chemotherapy Cancer chemotherapy has evolved as one of the major systemic treatment modalities for cancer. Unlike surgery and radiation, chemotherapy is a systemic treatment that enables drugs to reach the site of the tumor as well as other distant sites. Chemotherapeutic drugs may be the primary form of treatment, or they may be used as part of a multimodal treatment plan. It is the primary treatment for most hematologic and some solid tumors, including choriocarcinoma, testicular cancer, acute and chronic leukemia, non-Hodgkin and Hodgkin lymphomas, and multiple myeloma. In people with widespread disseminated disease, chemotherapy provides only palliative rather than curative therapy at present. Cancer chemotherapeutic drugs exert their effects through several mechanisms. At the cellular level, they exert their lethal action by targeting processes that prevent cell growth and replication. Chemotherapy kills cancer cells by stopping DNA, RNA, and protein synthesis; influencing enzyme production; and generally preventing cell mitosis.2 Under ideal conditions, anticancer drugs would eradicate cancer cells without damaging normal tissues. Although in the process of development, targeted cancer agents are not available without toxic effects. For most chemotherapy drugs, the relationship between tumor cell survival and drug dose is exponential, with the number of cells surviving being proportional to the drug dose and the number of cells at risk for exposure being proportional to the destructive action of the drug. Chemotherapeutic drugs are most effective in treating tumors that have a high growth fraction because of their ability to kill rapidly dividing cells.

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A major problem in cancer chemotherapy is the development of cellular resistance. Experimentally, drug resistance can be highly specific to a single agent and is usually based on genetic changes in a given tumor cell. In other instances, a multidrug-resistant phenomenon encompassing anticancer drugs with differing structures occurs. This type of resistance often involves the increased expression of transmembrane transporter genes involved in drug efflux. Chemotherapy drugs are commonly classified according to their site and mechanism of action. Chemotherapy drugs that have similar structures and effects on cell function usually are grouped together, and these drugs usually have similar side effect profiles. Direct DNA-interacting and indirect DNA-interacting agents are two major categories of chemotherapy drugs.2 Other systemic agents include hormonal and molecularly targeted agents. Cancer chemotherapy drugs may also be classified as either cell cycle specific or cell cycle nonspecific. Drugs are cell cycle specific if they exert their action during a specific phase of the cell cycle. For example, methotrexate, an antimetabolite, acts by interfering with DNA synthesis and thereby interrupts the S phase of the cell cycle. Drugs that are cell cycle nonspecific exert their effects throughout all phases of the cell cycle. The alkylating agents are cell cycle nonspecific and act by disrupting DNA when the cells are in the resting state as well as when they are dividing. Because chemotherapy drugs differ in their mechanisms of action, cell cycle–specific and cell cycle–nonspecific agents are often combined to treat cancer. Direct DNA-Interacting Agents.  The direct DNA-interacting agents include the alkylating agents, antitumor antibiotics, and topoisomerase inhibitors. As a class, the alkylating agents exert their cytotoxic effects by transferring their alkyl group to many cellular constituents.57 Alkylation of DNA within the cell nucleus is probably the major interaction that causes cell death. Alkylating agents have direct vesicant effects and can damage tissues at the site of injection as well as produce systemic toxicity. Toxicities are generally dose related and occur particularly in rapidly proliferating tissues such as bone marrow, the gastrointestinal tract, and reproductive tissues. The antitumor antibiotics are substances produced by bacteria that in nature appear to provide protection against hostile microorganisms. As a class they bind directly to DNA and frequently undergo electron transfer reactions to generate free radicals in close proximity to DNA, resulting in DNA damage in the form of single breaks or cross-links. All of the anticancer antibiotics in clinical use are originally isolated by the soil microbe, Streptomyces.57 These include the anthracyclines, dactinomycin, bleomycin, and mitomycin. The anthracycline antibiotics (e.g., doxorubicin and daunorubicin) are among the most widely used cytotoxic cancer drugs.57 The main dose-limiting toxicity of all anthracyclines is cardiotoxicity and myelosuppression, with neutropenia more commonly observed than thrombocytopenia. Two forms of cardiotoxicity can occur—acute and chronic. The acute form occurs within the first 2 to 3 days of therapy and presents with

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arrhythmias, conduction disorders, other electrocardiographic changes, pericarditis, and myocarditis.57 This form is usually transient and in most cases asymptomatic. The chronic form of cardiotoxicity results in a dose-dependent dilated cardiomyopathy. Efforts to minimize the toxicity profile of the antitumor antibiotics have resulted in the development of analog compounds (e.g., idarubicin, epirubicin). Liposome technology has been used with two antitumor antibiotics (i.e., doxorubicin and daunorubicin) to develop chemotherapy drugs that are encapsulated by coated liposomes. The DNA topoisomerase inhibitors block cell division by interfering with the action of the topoisomerase enzymes that break and rejoin phosphodiester bonds in the DNA strands to prevent them from tangling during separation and unwinding of the double helix.57 Topoisomerase I produces single-strand breaks (nicks) and topoisomerase II double-strand breaks. The epipodophyllotoxins (etoposide and teniposide) are topoisomerase II inhibitors that block cell division in the late S to G2 phase of the cell cycle. The camptothecins (topotecan, irinotecan) inhibit the action of topoisomerase I, the enzyme responsible for cutting and rejoining single DNA strands. Inhibition of this enzyme interferes with resealing of the breaks and DNA damage. Indirect DNA-Interacting Agents. The indirect DNAinteracting agents include the antimetabolites and mitotic spindle inhibitors. The antimetabolites (folic acid antagonists and purine and pyrimidine antagonists) interrupt the biochemical pathways relating to nucleotide and nucleic acid synthesis. Antimetabolites can cause DNA damage indirectly through misincorporation into DNA, abnormal timing of DNA synthesis, or by causing abnormal functioning of purine and pyrimidine biosynthetic enzymes.57 They tend to convey their greatest effect during the S phase of the cell cycle. Because of their S-phase specificity, the antimetabolites have been shown to be more effective when given as a prolonged infusion. Common side effects include stomatitis, diarrhea, and myelosuppression. The plant alkaloids, including the vinca alkaloids and taxanes, are drugs affecting the microtubule structures required for formation of the cytoskeleton and mitotic spindle.57 Although each group of drugs affects the microtubule, their mechanism of action differs. The vinca alkaloids (e.g., vinblastine, vincristine) inhibit tubulin polymerization, which disrupts assembly of microtubules. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a stop, which then leads to cell death. Vinblastine is a potent vesicant and care must be taken in its administration. Toxicities include nausea and vomiting, bone marrow suppression, and alopecia. Despite similarities in their mechanisms of action, vincristine has a different spectrum of actions and toxicities than vinblastine. The main dose-limiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction (e.g., orthostatic hypotension, sphincter problems, paralytic ileus), cranial nerve palsies, ataxia, seizures, and coma have

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been observed. The taxanes (e.g., paclitaxel, docetaxel) differ from the vinca alkaloids in that they stabilize the microtubules against depolymerization. The stabilized microtubules are unable to undergo the normal changes necessary for cell cycle completion. These drugs are administered intravenously and require the use of a vehicle that can cause hypersensitivity reactions. In addition to hypersensitivity reactions, their side effect profile includes myelosuppression and peripheral neurotoxicity in the form of glove-and-stocking numbness and paresthesia. Combination Chemotherapy. Combination chemotherapy has been found to be more effective than treatment with a single drug. Combination chemotherapy creates a more hostile environment for tumor cell growth through higher drug concentrations and prevents the development of resistant clones of cancer cells. With this method, several drugs with different mechanisms of action, metabolic pathways, times of onset of action and recovery, side effects, and times of onset of side effects are used. Drugs used in combination must be individually effective against the tumor and may be synergistic with each other. Routes of administration and dosage schedules are carefully designed to ensure optimal delivery of the active forms of the drugs to a tumor during the sensitive phase of the cell cycle. Administration.  Many of the cancer chemotherapy drugs are administered intravenously. Venous access devices (VADs) often are used for people with poor venous access and those who require frequent or continuous intravenous therapy. The VAD can be used for home administration of chemotherapy drugs, blood sampling, and administration of blood components. These systems access the venous circulation either through an externalized catheter or an implanted catheter with access ports. In some cases, the drugs are administered by continuous infusion using an ambulatory infusion pump that allows the person to remain at home and maintain his or her activities. Adverse Effects.  Chemotherapy is administered on a dose– response basis (i.e., the more drug administered, the greater the number of cancer cells killed). Chemotherapeutic drugs affect neoplastic cells and the rapidly proliferating cells of normal tissue. The nadir (i.e., lowest point) is the point of maximal toxicity for a given adverse effect of a drug and is stated in the time it takes to reach that point. Because many toxic effects of chemotherapeutic drugs persist for some time after the drug is discontinued, the nadir times and recovery rates are useful guides in evaluating the effects of cancer therapy. Some side effects appear immediately or after a few days (acute), some within a few weeks (intermediate), and others months to years after chemotherapy administration (long term). Most chemotherapeutic drugs cause pancytopenia due to bone marrow suppression, resulting in neutropenia (causing infections), anemia (resulting in fatigue), and thrombocytopenia (increasing risk for bleeding). The availability

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of h­ematopoietic growth factors (e.g., granulocyte colonystimulating factor [G-CSF] and IL-11, a cytokine, which stimulates platelet production) has shortened the period of myelosuppression, thereby reducing the need for hospitalizations due to infection and bleeding. The growth factor epoetin alfa, a form of the protein erythropoietin manufactured by the kidneys to help produce red blood cells is used with a select population of people. The drug has been under scrutiny since 2004 when it was found that it could promote tumor progression and shorten survival. The risk–benefit of epoetin needs to be weighed carefully before the drug is given for ­chemotherapy-induced anemia.58 Anorexia, nausea, and vomiting are common problems associated with cancer chemotherapy.2 The severity of the vomiting is related to the emetic potential of the particular drug. These symptoms can occur within minutes or hours of drug administration and are thought to be due to stimulation of the chemoreceptor trigger zone in the medulla that initiates vomiting. The chemoreceptor trigger zone responds to levels of chemicals circulating in the blood. The acute symptoms usually subside within 24 to 48 hours and often can be relieved by antiemetics. The pharmacologic approaches to prevent chemotherapy-induced nausea and vomiting have greatly improved over the past several decades. Serotonin receptor (5-HT3) antagonists (e.g., ondansetron, granisetron, dolasetron, palonosetron) facilitate the use of highly emetic chemotherapy drugs by more effectively reducing the nausea and vomiting induced by these drugs. These antiemetics are effective when given by both the oral and intravenous routes. Alopecia or hair loss results from impaired proliferation of the hair follicles and is a side effect of a number of cancer drugs. It usually is temporary, and the hair tends to regrow when treatment is stopped. The rapidly proliferating structures of the reproductive system are particularly sensitive to the action of cancer drugs. Women may experience changes in menstrual flow or have amenorrhea. Men may have a decreased sperm count (i.e., oligospermia) or absence of sperm (i.e., azoospermia). Teratogenic or mutagenic effects can also occur from taking chemotherapy. Chemotherapy drugs are toxic to all cells. The mutagenic, carcinogenic, and teratogenic potential of these drugs has been strongly supported by both animal and human studies. Because of these potential risks, special care is required when handling or administering the drugs. Drugs, drug containers, and administration equipment require special disposal as hazardous waste. The Occupational Safety and Health Administration (OSHA), the Oncology Nursing Society (ONS), and the American Society of Hospital Pharmacists (ASHP) have created chemotherapy guidelines dedicated to their safe administration. Epidemiologic studies have shown an increased risk for second malignancies such as acute leukemia after l­ong-term use of alkylating agents. These second malignancies are thought to result from direct cellular changes produced by the drug or from suppression of the immune response.

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Hormonal Therapy Hormonal therapy consists of administration of drugs designed to disrupt the hormonal environment of cancer cells. The actions of hormones and antihormones depend on the presence of specific receptors in the tumor. Among the tumors that are known to be responsive to hormonal manipulation are those of the breast, prostate, and endometrium. Additionally, other cancers, such as Kaposi sarcoma and renal, liver, ovarian, and pancreatic cancer, can be treated with hormonal therapy. The theory behind the majority of hormone-based cancer treatments is to deprive the cancer cells of the hormonal signals that otherwise would stimulate them to divide. The therapeutic options for altering the hormonal environment in the woman with breast cancer or the man with prostate cancer include surgical and pharmacologic measures. Surgery involves the removal of the organ responsible for the hormone production that is stimulating the target tissue (e.g., oophorectomy in women or orchiectomy in men). Pharmacologic methods focus largely on reducing circulating hormone levels or changing the hormone receptors so that they no longer respond to the hormone. Pharmacologic suppression of circulating hormone levels can be effected through pituitary desensitization, as with the administration of androgens, or through the administration of gonadotropin-releasing hormone (GnRH) analogs that act at the level of the hypothalamus to inhibit gonadotropin production and release. Another class of drugs, the aromatase inhibitors, is used to treat some forms of early-stage breast cancer. These drugs act by interrupting the biochemical processes that convert the adrenal androgen androstenedione to estrone.59 Aromatization of an androgenic precursor into an estrogen occurs in body fat. Because estrogen promotes the growth of breast cancer, estrogen synthesis in adipose tissue can be an important factor in breast cancer growth in postmenopausal women. Hormone receptor function can be altered by the administration of pharmacologic doses of exogenous hormones that act by producing a decrease in hormone receptors, or by antihormone drugs (i.e., antiestrogens [tamoxifen, fulvestrant] and antiandrogens [flutamide, bicalutamide, nilutamide]) that bind to hormone receptors, making them inaccessible to hormone stimulation. Initially, people often respond favorably to hormonal treatments, but eventually the cancer becomes resistant to hormonal manipulation, and other approaches must be sought to control the disease. Biotherapy Biotherapy involves the use of immunotherapy and biologic response modifiers as a means of changing the person’s own immune response to cancer.57 The major mechanisms by which biotherapy exerts its effects are modifications of host responses or tumor cell biology. Immunotherapy.  Immunotherapy techniques include active and passive, or adoptive, immunotherapy. Active immunotherapy involves nonspecific treatments such as bacille

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­ almette-Guérin (BCG). BCG is an attenuated strain of the C bacterium that causes bovine tuberculosis. It acts as a nonspecific stimulant of the immune system and is instilled into the bladder as a means of treating superficial bladder cancer. Passive or adoptive immunotherapy involves the transfer of cultured immune cells into a tumor-bearing host. Early research efforts with adoptive immunotherapy involved the transfer of sensitized NK cells or T lymphocytes, combined with cytokines, to the tumor-bearing host in an attempt to augment the host’s immune response. However, randomized clinical trials demonstrated no benefit from the addition of the cellular component beyond the benefit from the cytokines alone. Further research has focused on using antigen-presenting dendritic cells as delivery vehicles for tumor antigens. Biologic Response Modifiers.  Biologic response modifiers can be grouped into three types: cytokines, which include the interferons and ILs; monoclonal antibodies (MoAbs); and hematopoietic growth factors. Some agents, such as interferons, have more than one biologic function, including antiviral, immunomodulatory, and antiproliferative actions. The interferons are endogenous polypeptides that are synthesized by a number of cells in response to a variety of cellular or viral stimuli. The three major types of interferons are alpha (α), beta (β), and gamma (γ), each group differing in terms of their cell surface receptors.2,57 The interferons appear to inhibit viral replication and also may be involved in inhibiting tumor protein synthesis and in prolonging the cell cycle, increasing the percentage of cells in the G0 phase. Interferons stimulate NK cells and T lymphocyte killer cells. Interferon-γ has been approved for the treatment of hairy cell leukemia, AIDSrelated Kaposi sarcoma, and CML and as adjuvant therapy for people at high risk for recurrent melanoma.57 The ILs are cytokines that affect communication between cells by binding to receptor sites on the cell surface membranes of the target cells. Of the 18 known ILs, IL-2 has been the most widely studied. A recombinant human IL-2 (rIL-2, aldesleukin) has been approved by the FDA and is being used for the treatment of metastatic renal cell and melanoma.57 MoAbs are highly specific antibodies (e.g., IgG, which is the most commonly used immunoglobulin) derived from cloned cells.2,57 Scientists have developed methods for producing large quantities of MoAbs that are specific for tumor cells. For a MoAb to be therapeutic as a cancer treatment modality, a specific target antigen should be present on cancer cells only. The MoAbs act by interfering with cell membrane–bound targets by blocking the ligand–receptors, immune modulation, complement-mediated cytotoxicity, and antibody-related cell cytotoxicity.60 Targeted Therapy Targeted cancer therapy uses drugs that selectively attack malignant cells without causing harm to normal cells.2,57 It focuses on altered molecules and signaling pathways that allow cancer cells to grow and spread in an uncontrolled manner. The first targeted therapies were the MoAbs.

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Other targeted therapies include small molecules that block specific enzymes and growth factors involved in cancer cell growth. The protein tyrosine kinases are intrinsic components of the signaling pathways for growth factors involved in the proliferation of lymphocytes and other cell types. Imatinib mesylate (Gleevec) is a protein tyrosine kinase inhibitor indicated in the treatment of chronic myelogenous leukemia. The epidermal growth factor receptor signaling pathway has long been proposed as a target for an anticancer drug. Angiogenesis is continually being explored for targeted cancer therapy.57 An antiangiogenic agent, bevacizumab, targets and blocks vascular endothelial growth factor, which is released by many cancers to stimulate proliferation of new blood vessels. It was approved in 2004 for metastatic colon cancer and non–small cell cancer.3 The combination of bevacizumab and chemotherapy was found to increase objective responses, median time to progression, and survival time of people with metastatic colorectal cancer, compared with chemotherapy alone.61 Another class of drugs, the apoptosis-inducing drugs, causes cancer cells to undergo apoptosis by interfering with proteins involved the process. The FDA approved bortezomib in 2008 as first-line treatment for multiple myeloma.62 It causes cancer cells to die by blocking enzymes known as proteosomes, which help regulate cell function and growth.

IN SUMMARY The methods used in the diagnosis of cancer vary with the type of cancer and its location. Because many cancers are curable if diagnosed early, health care practices designed to promote early detection are important. Histologic studies are done in the laboratory using cells or tissue specimens. There are two basic methods of classifying tumors: grading according to the histologic or tissue characteristics and clinical staging according to spread of the disease. The TNM system for clinical staging of cancer takes into account tumor size, lymph node involvement, and presence of metastasis. Treatment plans that use more than one type of therapy, often in combination, are providing cures for a number of cancers that a few decades ago had a poor prognosis and are increasing the life expectancy in other types of cancer. Surgical procedures are more precise and less invasive, preserving organ function and resulting in better qualityof-life outcomes. Newer radiation equipment and novel radiation techniques permit greater and more controlled destruction of cancer cells while sparing normal tissues. Cancer chemotherapy has evolved as one of the major systemic treatment modalities for cancer. Unlike surgery and radiation, chemotherapy is a systemic treatment that enables drugs to reach the site of the tumor as well as other distant sites. The major classifications of chemotherapy drugs are the direct DNA-interacting (alkylating agents, antitumor antibiotics, and topoisomerase inhibitors) and indirect DNA-interacting agents (antimetabolites and

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mitotic spindle inhibitors). Cancer chemotherapeutic drugs may also be classified as either cell cycle specific or cell cycle nonspecific depending on whether they exert their action during a specific phase of the cell cycle. Other systemic agents include hormonal and molecularly targeted agents that block specific enzymes and growth factors involved in cancer cell growth.

CHILDHOOD CANCERS After completing this section of the chapter, you should be able to meet the following objectives: •• Cite the most common types of cancer affecting infants, children, and adolescents. •• Describe how cancers that affect children differ from those that affect adults. •• Discuss possible long-term effects of radiation therapy and chemotherapy on adult survivors of childhood cancer.

Cancer in children is relatively rare, accounting for about 1% of all malignancies in the United States.63 Although rare, cancer remains the second leading cause of death among children 1 to 14 years of age in the United States.63 In the United States in 2011, 11,210 children were diagnosed with cancer and 1320 children died of cancer.63 Common cancers that occur in children include leukemia, non-Hodgkin and Hodgkin lymphomas, and bone cancers (osteosarcoma and Ewing sarcoma). The overall survival rate for children is 80%.64

Incidence and Types The spectrum of cancers that affect children differs markedly from those that affect adults. Although most adult cancers are of epithelial cell origin (e.g., lung cancer, breast cancer, colorectal cancers), childhood cancers differ in that they generally involve the hematopoietic system, nervous system, soft tissues, bone, and kidneys.64 During the first year of life, embryonal tumors such as Wilms tumor, RB, and neuroblastoma are among the most common types of tumors. Embryonal tumors along with acute leukemia, non-Hodgkin lymphoma, and gliomas have a peak incidence in children 2 to 5 years of age. As children age, especially after they pass puberty, bone malignancies, Hodgkin lymphoma, gonadal germ cell tumors (testicular and ovarian carcinomas), and various carcinomas such as thyroid cancer and malignant melanoma increase in incidence. Embryonal Tumors A number of the tumors of infancy and early childhood are embryonal in origin, meaning that they exhibit features of organogenesis similar to that of embryonic development. Because of

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this characteristic, these tumors are frequently designated with the suffix “blastoma” (e.g., nephroblastoma [Wilms tumor], RB, neuroblastoma).2 Wilms tumor and neuroblastoma are particularly illustrative of this type of childhood tumor. Neuroblastoma.  Neuroblastomas arise from the primordial neural crest tissue in the sympathetic nervous system and adrenal medulla.65 It is the second most common solid malignancy in childhood after brain tumors. About 40% of neuroblastomas arise in the adrenal gland, with the remainder occurring anywhere along the sympathetic chain, most commonly in the paravertebral region of the abdomen and posterior mediastinum. Tumors may arise in numerous other sites, including the pelvis, neck, and within the brain. Clinical manifestations vary with the primary site and neuroendocrine function of the tumor. In children younger than 2 years of age, neuroblastoma generally presents with large abdominal masses, fever, and possibly weight loss. Bone pain suggests metastatic disease. About 90% of the tumors, regardless of location, secrete catecholamines, which is an important diagnostic feature (i.e., elevated blood levels of catecholamines and elevated urine levels of catecholamine metabolites).65,66 Unfortunately, neuroblastoma is also an extremely malignant neoplasm, particularly in children with advanced disease.66,67 Although the 5-year survival rate has improved, neuroblastoma continues to account for approximately 15% of all childhood cancer deaths. Infants tend to have a better prognosis than older children.64 Almost all children with neuroblastoma are diagnosed before 5 years of age, and the younger the child is diagnosed, the more positive the prognosis is.68

Biology of Childhood Cancers As with adult cancers, there probably is no single cause of childhood cancer. Although a number of genetic conditions are associated with childhood cancer, such conditions are relatively rare, suggesting an interaction between genetic susceptibility and environmental exposures. There are some inheritable conditions that increase susceptibility to childhood and even adult cancer. An example is Down syndrome, which actually increases the risk of acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML).2,69 Although constituting only a small percentage of childhood cancers, the biology of a number of these tumors illustrates several important biologic aspects of neoplasms, such as the two-hit theory of recessive tumor suppressor genes (e.g., RB gene mutation in RB); defects in DNA repair; and the histologic similarities between organogenesis and oncogenesis. Syndromes associated with defects in DNA repair include xeroderma pigmentosa, in which there is increased risk of skin cancers owing to defects in repair of DNA damaged by ultraviolet light. The development of childhood cancers has also been linked to genomic imprinting. The inactivation is determined by whether the gene is inherited from the mother or father. For example, the maternal allele for the insulin-like growth factor-2 (IGF-2) gene normally is inactivated (imprinted). In some

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Wilms tumors, loss of imprinting (re-expression of the maternal allele) can be demonstrated by overexpression of the IGF-2 protein, which is an embryonal growth factor.70

Diagnosis and Treatment Because most childhood cancers are curable, early detection is imperative. In addition, there are several types of cancer for which less therapy is indicated than for more advanced disease. In fact, early detection often minimizes the amount and duration of treatment required for cure and may therefore not only increase the potential for cure but spare the child intensive or prolonged treatment. Unfortunately, there are no early warning signs or screening tests for cancer in children. Prolonged fever, persistent lymphadenopathy, unexplained weight loss, growing masses (especially in association with weight loss), and abnormalities of CNS function should be viewed as warning signs of cancer in children. Because these signs and symptoms of cancer are often similar to those of common childhood diseases, it is easy to miss a cancer diagnosis in the early stages. Diagnosis of childhood cancers involves many of the same methods used in adults. Histologic examination is usually an essential part of the diagnostic procedure. Accurate disease staging is especially beneficial in childhood cancers, in which the potential benefits of treatment must be carefully weighed against potential long-term effects. The treatment of childhood cancers is complex, intensive, prolonged, and continuously evolving. It usually involves appropriate multidisciplinary and multimodal therapies, as well as the evaluation for recurrent disease and late effects of the disease and therapies used in its treatment. Two modalities are frequently used in the treatment of childhood cancer, with chemotherapy being the most widely used, followed, in order of use, by surgery, radiation therapy, and biologic agent therapy. Chemotherapy is more widely used in treatment of children with cancer than in adults because children better tolerate the acute adverse effects and, in general, pediatric tumors are more responsive to chemotherapy than adult cancers.70 With improvement in treatment methods, the number of children who survive childhood cancer continues to increase. As a result of cancer treatment, almost 80% of children and adolescents with a diagnosis of cancer become long-term survivors.63 Unfortunately, therapy may produce late sequelae, such as impaired growth, neurologic dysfunction, hormonal dysfunction, cardiomyopathy, pulmonary fibrosis, and risk for second malignancies. Thus, one of the growing challenges is providing appropriate health care to survivors of childhood and adolescent cancers.71 Radiation Therapy Radiation therapy poses the risk of long-term effects for survivors of childhood cancer. The late effects of radiation therapy are influenced by the organs and tissues included in the treatment field, type of radiation administered, daily fractional

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and c­ umulative radiation dose, and age at treatment. There is increased risk for melanoma, squamous cell carcinoma, and basal cell carcinoma. Musculoskeletal changes are also common after radiation. Even with current methods, survivors may have changes leading to pain and altered musculoskeletal function. Cranial radiation therapy (CRT) has been used to treat brain tumors, ALL, head and neck soft tissue tumors, and RB. The most common late effect of moderate- to high-dose whole-brain radiation is diminished intellectual function.72 Brain tumor survivors treated at a younger age are particularly susceptible. Cranial radiation is also associated with neuroendocrine disorders, particularly growth hormone deficiency. Thus, children reaching adulthood after CRT may have reduced physical stature. The younger the age and the higher the radiation dose, the greater the deviation from normal growth. Growth hormone deficiency in adults is associated with increased prevalence of dyslipidemia, insulin resistance, and cardiovascular mortality. Moderate doses of CRT are also associated with obesity, particularly in female patients.72 For many years, whole-brain radiation or CRT was the primary method of preventing CNS relapse in children with ALL. Recognition of cognitive dysfunction associated with CRT has led to the use of other methods of CNS prophylaxis.72 Radiation to the chest or mantle field (lymph nodes of neck, subclavicular, axillary, and mediastinal areas) is often used in treatment of Hodgkin and non-Hodgkin lymphomas and metastases to the lung. This field exposes the developing breast tissue, heart, and lungs to ionizing radiation. Female survivors who were treated with this type of radiation face significant risk for development of breast cancer.72 Much of the heart is exposed in chest and mantle radiation fields, resulting in subsequent premature coronary artery, valvular, and pericardial disease. Exposure of the lungs to radiation therapy can result in a reduction in pulmonary function. Thyroid disease, particularly hypothyroidism, is common after mantle or neck radiation. Childhood cancer survivors treated with abdominal or pelvic radiation are also at risk for a variety of late health problems involving the gastrointestinal tract, liver, spleen, kidneys, and genitourinary tract structures, including the gonads.72 Gastrointestinal tract complications include chronic mucosal inflammation that interferes with absorption and digestion of nutrients. Chronic radiation injury to the kidneys may interfere with glomerular or tubular function, and fibrosis from pelvic radiation may adversely affect bladder capacity and function. The adverse effects of radiation on gonadal function vary by age, sex, and cumulative dose. Delayed sexual maturation in boys and girls can result from irradiation of the gonads. In boys, sperm production is reduced in a dose-dependent manner. In girls, radiation to the abdomen, pelvis, and spine is associated with increased risk of ovarian failure, especially if the ovaries are in the treatment field. Chemotherapy Chemotherapy also poses the risk of long-term effects for survivors of childhood cancer. Potential late effects of alkylating agents include dose-related gonadal injury (hypogonadism,

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infertility, and early menopause).72 Alkylating agent therapy has also been linked to dose-related secondary acute myelogenous leukemia, pulmonary fibrosis, kidney disease, and bladder disorders. Anthracyclines, including doxorubicin and daunomycin, which are widely used in treatment of childhood cancers, can result in cardiomyopathy and eventual congestive heart failure.72 The late effects of cisplatin and carboplatin, the most frequently used nonclassic alkylators, are nephrotoxicity, ototoxicity, and neurotoxicity. Although combination chemotherapy increases the effectiveness of treatment, it may also be associated with increased risk of side effects if the agents have a similar spectrum of toxicity. Intrathecal combination chemotherapy to prevent relapse of ALL in the CNS, which is a sanctuary for ALL cells, is known to cause significant and persistent cognitive impairment in many children.

IN SUMMARY Although most adult cancers are of epithelial cell origin, most childhood cancers usually involve the hematopoietic system, nervous system, or connective tissue. Heritable forms of cancer tend to have an earlier age of onset, a higher frequency of multifocal lesions in a single organ, and bilateral involvement of paired organs or multiple primary tumors. The early diagnosis of childhood cancers often is missed because the signs and symptoms mimic those of other childhood diseases. With improvement in treatment methods, the number of children who survive childhood cancer is continuing to increase. As these children approach adulthood, there is continued concern that the lifesaving therapy they received during childhood may produce late effects, such as impaired growth, cognitive dysfunction, hormonal dysfunction, cardiomyopathy, pulmonary fibrosis, and risk for second malignancies.

REVIEW EXERCISES 1. A 30-year-old woman has experienced heavy menstrual bleeding and is told she has a uterine tumor called a leiomyoma. She is worried she has cancer. A. What is the difference between a leiomyoma and leiomyosarcoma? B. How would you explain the difference to her? 2. Among the characteristics of cancer cells are lack of cell differentiation, impaired cell-to-cell adhesion, and loss of anchorage dependence. A. Explain how each of these characteristics contributes to the usefulness of the Pap smear as a screening test for cervical cancer. Continued

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3. A 12-year-old boy is seen at the pediatric cancer clinic with osteosarcoma. His medical history reveals that his father had been successfully treated for RB as an infant. A. Relate the genetics of the RB gene and the “two-hit” hypothesis to the development of osteosarcoma in the son of the man who had RB. 4. A 48-year-old man presents at his health care clinic with complaints of leg weakness. He is a heavy smoker and has had a productive cough for years. Subsequent diagnostic tests reveal he has a small cell lung cancer with brain metastasis. His proposed plan of treatment includes chemotherapy and radiation therapy. A. What is the probable cause of the leg weakness, and is it related to the lung cancer? B. Relate this man’s smoking history to the development of lung cancer. C. Explain the mechanism of cancer metastasis. D. Explain the mechanisms whereby chemotherapy and irradiation are able to destroy cancer cells while having a lesser or no effect on normal cells. 5. A 17-year-old-girl is seen by a guidance counselor at her high school because of problems in keeping up with assignments in her math and science courses. She tells the counselor that she had leukemia when she was 2 years old and was given radiation treatment to the brain. She confides that she has always had more trouble with learning than her classmates and thinks it might be due to the radiation. She also relates that she is shorter than her classmates, and this has been bothering her. A. Explain the relationship between CRT and decreased cognitive function and short stature. B. What other neuroendocrine problems might this girl have as a result of the radiation treatment?

References 1. American Cancer Society. (2011). Cancer facts and figures. [Online]. Available: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf. Retrieved December 28, 2011. 2. Rubin R., Strayer D. S. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 3. Yarbro C. H., Wujcik D., Gobel B. H. (Eds.). (2011). Cancer nursing: Principles & practice (7th ed.). Sudbury, MA: Jones & Bartlett Publishers. 4. Ross M. H., Pawlina W. (2011). Histology: A text and atlas with correlated cell and molecular biology (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 5. Fraczek M., Wozniak Z., Ramsey D., et al. (2008). Clinicopathologic significance and prognostic role of cyclin E and cyclin A expression in laryngeal epithelial lesions. Acta Oto-Laryngologica 128(3), 329–334.

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6. Shapiro G. I. (2006). Cyclin-dependent kinase pathways as targets for cancer treatment. Journal of Clinical Oncology 24(11), 1770–1783. 7. Leeper N. J., Hunter A. L., Cooke J. P. (2010). Stem cell treatment for vascular regeneration: Adult, embryonic, and induced pluripotent. Circulation 122(5), 517–526. 8. Pessina A., Gribaldo L. (2006). The key role of adult stem cells: Therapeutic perspectives. Current Medical Research and Opinion 22(11), 2287–2300. 9. Sueblinvong V., Weiss D. J. (2010). Stem cells and cell therapy approaches in lung biology and diseases. Translational Research: The Journal of Laboratory and Clinical Medicine 156(3), 188–205. 10. Jeganathan V. S. E., Palanisamy M. (2010). Treatment viability of stem cells in ophthalmology. Current Opinion in Ophthalmology 21(3), 213–217. 11. Power C., Rasko J. E. (2011). Promises and challenges of stem cell research for regenerative medicine. Annals of Internal Medicine 155(10), 706–713. 12. Liu S., Wicha M. S. (2010). Targeting breast cancer stem cells. Journal of Clinical Oncology 28(25), 4006–4012. 13. Ma W. W., Adjei A. A. (2009). Novel agents on the horizon for cancer treatment. CA: Cancer Journal for Clinicians 59, 111–137. 14. Swat A., Dolado I., Rojas J. M., et al. (2009). Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38a mitogen-activated protein kinase via sprouty2 downregulation. Molecular and Cellular Biology 29(12), 3332–3343. 15. Pani G., Colavitti R., Bedogni B., et al. (2000). A redox signaling mechanism for density-dependent inhibition of cell growth. Journal of Biological Chemistry 49, 38891–38899. 16. Zhang L., Bewick M., Lafrenie R. M. (2002). Role of Raf-1 and FAK in cell density-dependent regulation of integrin-dependent activation of MAP kinase. Carcinogenesis 23, 1251–1258. 17. Hayashida Y., Honda K., Idogawa M., et al. (2005). E-cadherin regulates the association between β-catenin and actinin-4. Cancer Research 65, 8836–8845. 18. Shen Y., Jia Z., Nagele R. G., et al. (2006). Src uses Cas to suppress Fhl1 in order to promote nonanchored growth and migration of tumor cells. Cancer Research 66, 1543–1552. 19. Carruba G., Webber M. M., Quader S. T. A., et al. (2002). Regulation of cell-to-cell communication in non-tumorigenic and malignant human prostate epithelial cells. The Prostate 50, 73–82. 20. Lee H. O., Mullins S. R., Franco-Baraza J., et al. (2011). FAP overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer 11, 245. 21. Perez-Sayans M., Suarez-Penaranda J. M., Pilar G. D., et al. (2011). Myc proteins are oncogenes involved in cell proliferation, regulation, differentiation, and apoptosis. Oral Oncology 47(8), 688–692. 22. Duthie S. J. (2011). Epigenetic modifications and human pathologies: Cancer and cardiovascular disease. Proceedings of the Nutrition Society 70(1), 47–56. 23. Olivier M., Taniere P. (2011). Somatic mutations in cancer prognosis and prediction: Lessons from TP53 and EGFR gene. Current Opinion in Oncology 23(1), 88–92. 24. Reiderman Y. I., Kiss S., Mukai S. (2007). Molecular genetics of RB1— the retinoblastoma gene. Seminars in Ophthalmology 22(4), 247–254. 25. Cuziak J., Dowsett M., Peneda S., et al. (2011). Prognostic value of a combined estrogen receptor, progesterone receptor, Ki67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the genomic health recurrence score in early breast cancer. Journal of Clinical Oncology 29(32), 4273–4278. 26. Schulze-Bergkamen H., Krammer P. H. (2004). Apoptosis in cancer: Implications for therapy. Seminars in Oncology 31, 90–119. 27. Feldser D. M., Grieder C. W. (2007). Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11, 461–469. 28. Sedivy J. M. (2007). Telomeres limit cancer growth by inducing senescence: Long-sought in vivo evidence obtained. Cancer Cell 11, 389–391. 29. Boccaccio C., Comoglio P. M. (2006). Invasive growth: A MET-driven genetic programme for cancer and stem cells. Nature Reviews Cancer 6, 637–645.

7/9/2013 8:07:19 PM

Chapter 8  Neoplasia   199 30. Bierie B., Moses H. L. (2006). TGFβ: The molecular Jekyll and Hyde. Nature Reviews Cancer 6, 506–520. 31. Pendyala S., Neff L. M., Suarez-Farinas M., et al. (2011). Diet induced weight loss reduces colorectal inflammation: Implications for colorectal crcinogenesis. The American Journal of Clinical Nutrition 93(2), 234–242. 32. Canty C. A. (2009). Retinoblastoma: An overview for advanced practice nurses. Journal of the American Academy of Nurse Practitioners 21(3), 149–155. 33. Nichols E., Walther S., Chao E., et al. (2009). Recent advances in retinoblastoma genetic research. Current Opinion in Ophthalmology 20(5), 351–355. 34. Chantada G. L., Quddoumi I., Cantruk S., et al. (2011). Strategies to manage retinoblastoma in developing countries. Pediatric Blood & Cancer 56(3), 341–348. 35. Church J. (2009). Familial adenomatous polyposis. Surgical Oncology Clinics of North America 18(4), 585–598. 36. American Cancer Society. (2011). Tobacco related cancers fact sheet. [Online]. Available: http://www.cancer.org/Cancer/CancerCauses/TobaccoCancer/ tobacco-related-cancer-fact-sheet. Retrieved December 29, 2011. 37. Ferguson L. R., Philpoh M. (2008). Nutrition and mutagenesis. Annual Review of Nutrition 28, 313–329. 38. Poskanzer D. C., Herbst A. (1977). Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero. Cancer 39, 1892–1895. 39. Jablon S., Kato H. (1972). Studies of the mortality of A-bomb survivors: Radiation dose and mortality, 1950–1970. Radiation Research 50, 649–698. 40. Ruddon R. W. (Ed.). (1995). Cancer biology. New York: Oxford University Press. 41. Matsumoto S., Yamasaki K., Tsuji K., et al. (2008). Human T lymphotropic virus type 1 infection and gastric cancer development in Japan. Journal of Infectious Disease 198(1), 10–15. 42. Pace E., DiSano C., Ferraro M., et al. (2008). Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions. European Journal of Cancer 47(2), 296–304. 43. Walz D. A., Lyon D. E. (2010). Cancer related anorexia-cachexia syndrome. Clinical Journal of Oncology Nursing 14(3), 283–287. 44. Hopkinson J. B., Wright D. N., Foster C. (2008). Management of weight loss and anorexia. Annals of Oncology 19(Suppl. 7), vii289–vii293. 45. Bauza G., Milla G., Kasije N., et al. (2011). The effects of injury magnitude on the kinetics of the acute phase response. Journal of Trauma 70(4), 948–953. 46. Reidy A. (2011). Cancer-related fatigue: Physical assessment is not enough. British Journal of Nursing 10, S32–S39. 47. Ryan J. L., Carroll J. K., Ryan E. P., et al. (2007). Mechanisms of cancerrelated fatigue. Oncologist 12(Suppl. 1), 22–34. 48. Roscoe J. A., Kaufman M. E., Matteson-Rusby S. E., et al. (2007). Cancerrelated fatigue and sleep disorders. Oncologist 12(Suppl. 1), 35–42. 49. Precht L. M., Lowe K. A., Atwood M., et al. (2010). Neoadjuvant chemotherapy of breast cancer: Tumor markers as predictors of pathologic response, recurrence, and survival. Breast Journal 16(4), 362–368. 50. Prommer E. (2010). Neuromuscular paraneoplastic syndromes: The Lambert Eaton myasthenia syndrome. Journal of Palliative Medicine 13(9), 1159–1162. 51. Pelosof L. C., Gerber D. E. (2010). Paraneoplastic syndromes: An approach to diagnosis and treatment. Mayo Clinic Proceedings 85(9), 838–854. 52. Henderson S., DeGroff A., Richards T., et al. (2011). A qualitative analysis of lung cancer screening practice by primary care physicians. Journal of Community Health 36(6), 949–956.

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53. American Joint Committee on Cancer. (2010). Cancer staging. [Online]. Available: http://www.cancerstaging.org/mission/whatis.html. Retrieved December 28, 2011. 54. Willers H., Held K. D. (2006). Introduction to clinical radiation biology. Hematology/Oncology Clinics of North America 20, 1–24. 55. Thomas C. T., Ammar A., Farrell J. J., et al. (2006). Radiation modifiers: Treatment overview and future investigations. Hematology/Oncology Clinics of North America 20, 119–139. 56. Bourhis J., Blanchard P., Mallard E., et al. (2011). Effect of amifostine on survival among patients treated with radiotherapy: A meta analysis of individual patient data. Journal of Clinical Oncology 29(18), 1590–2597. 57. Lehne R. A. (2010). Pharmacology for nursing care (7th ed.). Philadelphia, PA: Saunders. 58. U. S. Food and Drug Administration. (2011). Oncologic drug advisory committee. [Online]. Available: http://www.fda.gov/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ default.htm. Retrieved December 29, 2011. 59. Glack S., Goronki F. (2011). Clinical and economic benefits of aromatase inhibitor therapy in early-stage breast cancer. American Journal of Health-System Pharmacy 68(18), 1699–1706. 60. Weiner G. J. (2007). Monoclonal antibody mechanisms of action in cancer. Immunologic Research 39, 271–278. 61. Sharkey R. M., Goldenberg D. M. (2006). Targeted therapy of cancer: New prospects for antibodies and immunoconjugates. CA: Cancer Journal for Clinicians 56, 226–243. 62. National Cancer Institute. (2010). FDA approval for bortezomid. [Online]. Available: http://www.cancer.gov/cancertopics/druginfo/fda-bortezomib. Retrieved December 29, 2011. 63. American Cancer Society. (2011). Cancer in children. [Online]. Available: http://www.cancer.org/Cancer/CancerinChildren/DetailedGuide/cancerin-children-key-statistics. Retrieved December 29, 2011. 64. Ball J., Bindle R., Cowen K. (2012). Principles of pediatric nursing: Caring for children (5th ed.). Boston, MA: Pearson. 65. Mazur K. A. (2010). Neuroblastoma: What the nurse practitioner should know. Journal of the American Academy of Nurse Practitioners 22(5), 236–245. 66. Kim S., Chung D. H. (2006). Pediatric malignancies: Neuroblastoma and Wilms’ tumor. Surgical Clinics of North America 86, 469–487. 67. Perivein T., Lackner H., Sovinz P., et al. (2011). Survival and late effects in children with stage 4 neuroblastoma. Pediatric Blood & Cancer 57(4), 629–635. 68. Park J. R., Eggert A., Caron H. (2006). Neuroblastoma: Biology, prognosis and treatment. Pediatric Clinics of North America 55(1), 97–120. 69. Zwann C. M., Reinhardt D., Hitzler J., et al. (2010). Acute leukemias in children with Down syndrome. Hematology/Oncology Clinics of North America 24 (1), 19–34. 70. Sharon J., Liebman M. A., Williams B. R. (2005). Recombinant polyclonal antibodies for cancer treatment. Journal of Cell Biochemistry 96(2), 305–313. 71. National Cancer Institute. (2008). The childhood cancer survival study: An overview. [Online]. Available: http://www.cancer.gov/cancertopics/ coping/ccss. Retrieved December 29, 2011. 72. Oeffinger K. C., Mertens A. C., Sklar C. A., et al. (2006). Chronic health conditions in adult survivors of childhood cancer. New England Journal of Medicine 355, 1572–1582.

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Unit 3

Disorders of Integrative Function Mrs. Iona Smith, 38 years old, presents with a malar (butterfly) rash, generalized joint discomfort, fatigue, and intense photosensitivity. She is worked up for systemic lupus erythematosus (SLE). Mrs. Smith states that she has experienced these symptoms ­intermittently for about 9 months and is under considerable stress. Her extended family (parents, sister, two brothers, and grandmother) were all killed in a motor vehicle accident about 1 year ago when they were traveling to her home for Christmas. She and her husband have a child with Asperger autism, and her husband recently lost his job. Lacking health care insurance, she has put off going to a doctor. Upon questioning, she has no personal or family history of SLE. The clinic health care provider does some blood work and schedules a return appointment in 3 weeks. The blood work indicates an elevated white blood cell count and lymphocytes count, a decreased platelet count, and hemolytic anemia. Serologic testing identifies three autoantibodies in Mrs. Smith’s blood sample that are strongly indicative of SLE: anti-Smith antibody, lupus anticoagulant, and antinuclear antibody (ANA). She also has significant amounts (+2) of protein in her urine, indicating that she is already experiencing some degree of renal disease. Her symptoms and clinical results lead to the diagnosis of SLE. Iona’s case is discussed in greater detail in Chapter 9 and Chapter 11.

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Stress and Adaptation HOMEOSTASIS

Constancy of the Internal Environment Control Systems Feedback Systems

STRESS AND ADAPTATION

The Stress Response Neuroendocrine Responses Immune Responses Coping and Adaptation to Stress Adaptation Factors Affecting the Ability to Adapt

DISORDERS OF THE STRESS RESPONSE

Effects of Acute Stress Effects of Chronic Stress Posttraumatic Stress Disorder Treatment and Research of Stress Disorders Treatment Research

9 Sheila Grossman

Stress has become an increasingly discussed topic in today’s world. The concept is discussed extensively in the health care fields and is found in economics, political science, business, and education. In the popular press, the physiologic response to stress is often implicated as a contributor to a variety of individual physical and mental challenges and societal problems. Approximately 25% of Americans perceive their stress level as high, which reflects a score of 8 to 10 on a 10-point scale. Fifty percent of Americans perceive their stress levels to be moderate, indicating a score of 4 to 7 on this 10-point scale.1 The remaining 25% are not accounted for regarding their perception of stress since they feel it is not continuously high, moderate, or low. Current stressors include terrorism, paying bills, maintaining one’s health, keeping a job, and the economy. Iona has been living with extremely stressful events, including the death of multiple family members, possibly some guilt since the family members were traveling to her home for the holidays, and dealing with her son who has Asperger autism. Now she also has the added stress of her husband losing his job. Iona will need to gain skills in managing stress and resources to assist her with her son as well as her own health. She should be referred to a psychologist and social worker who will be able to assist her in stress management. Otherwise these added stresses in her life will cause her to experience multiple exacerbations of her disease. In 1910, when Sir William Osler delivered his Lumleian Lectures on “angina pectoris,” he described the relationship of stress and strain to angina pectoris.2 Approximately 15 years later, Walter Cannon, well known for his work in physiology, began to use the word stress in relation to his laboratory experiments on the “fight-or-flight” response. It seems possible that the term emerged from his work on the homeostatic features of living organisms and their tendency to “bound back” and “resist disruption” when acted on by an “external force.”3 At about the same time, Hans Selye, who became known for his research and publications on stress, began using the term

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stress in a very special way to mean an orchestrated set of bodily responses to any form of noxious stimulus.4 The content in this chapter has been organized into three sections: homeostasis, the stress response and adaptation to stress, and disorders of the stress response.

HOMEOSTASIS After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the concept of homeostasis. •• Describe the components of a control system, in­­ cluding the function of a negative feedback system.

The concepts of stress and adaptation have their origin in the complexity of the human body and the interactions between the body cells and its many organ systems. These interactions require that a level of homeostasis or constancy be maintained during the many changes that occur in the internal and external environments. In effecting a state of constancy, homeostasis requires feedback control systems that regulate cellular function and integrate the function of the different body systems.

Constancy of the Internal Environment The environment in which body cells live is not the external environment that surrounds the organism, but rather the local fluid environment that surrounds each cell. Claude Bernard, a 19th century physiologist, was the first to describe clearly the central importance of a stable internal environment, which he termed the milieu intérieur.5 Bernard recognized that body fluids surrounding the cells (extracellular fluids) and the various organ systems provide the means for exchange between the external and the internal environments. It is from this internal environment that body cells receive their nourishment, and it is into this fluid that they secrete their wastes. Even the contents of the gastrointestinal tract and lungs do not become part of the internal environment until they have been absorbed into the extracellular fluid. A multicellular organism is able to survive only as long as the composition of the internal environment is compatible with the survival needs of the individual cells. For example, even a small change in the pH of the body fluids can disrupt the metabolic processes of the individual cells. The concept of a stable internal environment was supported by Walter B. Cannon, who proposed that this kind of stability, which he called homeostasis, was achieved through a system of carefully coordinated physiologic processes that oppose change.6 Cannon pointed out that these processes were largely automatic and emphasized that homeostasis involves resistance to both internal and external disturbances.

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In his book Wisdom of the Body, published in 1939, Cannon presented four tentative propositions to describe the general features of homeostasis.6 With this set of propositions, Cannon emphasized that when a factor is known to shift homeostasis in one direction, it is reasonable to expect the existence of mechanisms that have the opposite effect. In the homeostatic regulation of blood sugar, for example, mechanisms that both raise and lower blood sugar would be expected to play a part. As long as the responding mechanism to the initiating disturbance can recover homeostasis, the integrity of the body and the status of normality are retained.

Control Systems The ability of the body to function and maintain homeostasis under conditions of change in the internal and external environment depends on the thousands of physiologic control systems that regulate body function. A homeostatic control system consists of a collection of interconnected components that function to keep a physical or chemical parameter of the body relatively constant. The body’s control systems regulate cellular function, control life processes, and integrate functions of the different organ systems. Of recent interest have been the neuroendocrine control systems that influence behavior. Biochemical messengers that exist in our brain serve to control nerve activity, regulate information flow, and, ultimately, influence behavior.1 These control systems mediate the physical, emotional, and behavioral reactions to stressors that, taken together, are called the stress response. Just like any control system, each stress response involves a sensor to detect the change, an integrator to sum all incoming data and compare it with “normal,” and effector(s) to try to reverse the change. For instance, a hiker’s eyes (sensor) see a snake (stressor). Her cerebral cortex (integrator) determines that the snake is a threat, and activates the heart, respiratory muscles, and many other organs (effectors) to assist her escape. More complex stressors invoke more complex control systems, and sometimes the stress response cannot restore balance and homeostasis. For instance, negative physical and psychological experiences during the prenatal and childhood periods can impact one’s adult health.7 The impact may appear decades later, in the form of mental health issues, cancer, and even weakened bones. Therefore, it is important to identify early negative experiences and treat them, not only for the current health of the child but also for the future health of the adult.8 In addition, it is prudent for people to try to create a feeling of balance within, in order to improve neural circuitry, for example, by keeping a reflective journal of one’s interactions with people who may ordinarily stress them and describing how, applying new methods of communication both in talking with these people and responding to their questions, one may create a less stressful image of their daily interactions with a specific group of people. This should facilitate some physiological benefits.9 By trying to follow this advice, the brain will attempt to reorganize itself for the future by changing

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the prefrontal cortex and restructuring its neural ­pathways.9 This increased neuroplasticity in the brain will improve emotional balance, flexibility, immune and cardiac function, and increase empathy ability.8 Results of studies also suggest assisting people in trying to remember their old experiences and taking some time to imagine possible future scenarios so they can be more prepared to manage future stressful experiences.10 These studies validate the need for Iona to meet with a psychologist and a social worker who can assist her in stress management and possibly help her identify some past experience(s) that may need to be discussed. Working with these professionals may help her brain reorganize itself to deal more effectively with her son and his autism as well as managing appropriate rest times for herself.

KEY POINTS HOMEOSTASIS •  Homeostasis is the purposeful maintenance of a stable internal environment by coordinated ­physiologic processes that oppose change. •  The physiologic control systems that ­oppose change operate by negative feedback ­mechanisms consisting of a sensor that detects a change, an integrator/comparator that sums and compares incoming data with a set point, and an effector system that returns the sensed function to within the range of the set point.

Feedback Systems Most control systems in the body operate by negative feedback mechanisms, which function in a manner similar to the thermostat on a heating system. When the monitored function or value decreases below the set point of the system, the feedback mechanism causes the function or value to increase. When the function or value is increased above the set point, the feedback mechanism causes it to decrease (Fig. 9.1). For example, in the negative feedback mechanism that controls blood glucose levels, an increase in blood glucose stimulates an increase in insulin, which enhances the removal of glucose from the blood. When glucose has been taken up by cells and blood glucose levels fall, insulin secretion is inhibited and glucagon and other counterregulatory mechanisms stimulate the release of glucose from the liver, which causes the blood glucose to return to normal. The same is true for all endocrine organ hormones that are connected to the pituitary for their stimulating hormone and the hypothalamus for their releasing hormone. For example, when thyroxine (T4) in the thyroid is low, it triggers the pituitary to increase thyroid-stimulating hormone (TSH), which then increases with the purpose being to increase T4 secretion from the thyroid.

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Glucose sensor in beta cells

Decreased insulin release and addition of glucose to the blood

Decrease in blood glucose

Increase in blood glucose

Increased insulin release and removal of glucose from the blood

Glucose sensor in beta cells

FIGURE 9.1  •  Illustration of negative feedback control mechanisms using blood glucose as an example.

The reason most physiologic control systems function under negative rather than positive feedback mechanisms is that a positive feedback mechanism interjects instability rather than stability into a system. It produces a cycle in which the initiating stimulus produces more of the same. For example, in a positive feedback system, exposure to an increase in environmental temperature would invoke compensatory mechanisms designed to increase rather than decrease body temperature.

IN SUMMARY Physiologic and psychological adaptation involves the ability to maintain the constancy of the internal environment (homeostasis) and behavior in the face of a wide range of changes in the internal and external environments. It involves control and negative feedback systems that regulate cellular function, control life’s processes, regulate behavior, and integrate the function of the different body systems.

STRESS AND ADAPTATION After completing this section of the chapter, you should be able to meet the following objectives: •• State Selye’s definition of stress. •• Explain the interactions among components of the nervous system in mediating the stress response. •• Describe the stress responses of the autonomic nervous system, the endocrine system, the immune system, and the musculoskeletal system.

The increased focus on health promotion has heightened interest in the roles of stress and biobehavioral stress responses in the development of disease. Stress may contribute directly to the production or exacerbation of a disease, or it may

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c­ ontribute to the development of behaviors such as smoking, overeating, and drug abuse that increase the risk of disease.10

The Stress Response In the early 1930s, the world-renowned endocrinologist Hans Selye was the first to describe a group of specific anatomic changes that occurred in rats that were exposed to a variety of different experimental stimuli. He came to an understanding that these changes were manifestations of the body’s attempt to adapt to stimuli. Selye described stress as “a state manifested by a specific syndrome of the body developed in response to any stimuli that made an intense systemic demand on it.”11 As a young medical student, Selye noticed that patients with diverse disease conditions had many signs and symptoms in common. He observed, “whether a man suffers from a loss of blood, an infectious disease, or advanced cancer, he loses his appetite, his muscular strength, and his ambition to accomplish anything. Usually the patient also loses weight and even his facial expression betrays that he is ill.”12 Selye referred to this as the “syndrome of just being sick.” In his early career as an experimental scientist, Selye noted that a triad of adrenal enlargement, thymic atrophy, and gastric ulcers appeared in rats he was using for his studies. These same three changes developed in response to many different or nonspecific experimental challenges. He assumed that the hypothalamic–pituitary–adrenal (HPA) axis played a pivotal role in the development of this response. To Selye, the response to stressors was a process that enabled the rats to resist the experimental challenge by using the function of the system best able to respond to it. He labeled the response the general adaptation syndrome (GAS): general because the effect was a general systemic reaction, adaptive because the response was in reaction to a stressor, and syndrome because the physical manifestations were coordinated and dependent on each other.11 According to Selye, the GAS involves three stages: the alarm stage, the resistance stage, and the exhaustion stage. The alarm stage is characterized by a generalized stimulation of the sympathetic nervous system and the HPA axis, resulting in the release of catecholamines and cortisol. During the resistance stage, the body selects the most effective and economic channels of defense. During this stage, the increased cortisol levels, which were present during the first stage, drop because they are no longer needed. If the stressor is prolonged or overwhelms the ability of the body to defend itself, the exhaustion stage ensues, during which resources are depleted and signs of “wear and tear” or systemic damage appear.13 Selye contended that many ailments, such as various emotional disturbances, mildly annoying headaches, insomnia, upset stomach, gastric and duodenal ulcers, certain types of rheumatic disorders, and cardiovascular and kidney diseases, appear to be initiated or encouraged by the “body itself because of its faulty adaptive reactions to potentially injurious agents.”12

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With a new diagnosis of SLE, Iona is manifesting the last stage of the stress response. She has certainly depleted many of her body’s resources and is experiencing “wear and tear” and systemic damage, such as renal disease and some type of joint inflammatory disorder. The events or environmental agents responsible for initiating the stress response were called stressors. According to Selye, stressors could be endogenous, arising from within the body, or exogenous, arising from outside the body.12 In explaining the stress response, Selye proposed that two factors determine the nature of the stress response—the properties of the stressor and the conditioning of the person being stressed. Selye indicated that not all stress was detrimental; hence, he coined the terms eustress and distress.13 He suggested that mild, brief, and controllable periods of stress could be perceived as positive stimuli to emotional and intellectual growth and development. It is the severe, protracted, and uncontrolled situations of psychological and physical distress that are disruptive of health.12 For example, the joy of becoming a new parent and the sorrow of losing a parent are completely different experiences, yet their stressor effect—the nonspecific demand for adjustment to a new situation—can be similar. It is increasingly clear that the physiologic stress response is far more complicated than can be explained fully by a classic stimulus–response mechanism. Stressors tend to produce different responses in different people or in the same person at different times, indicating the influence of the adaptive capacity of the person, or what Selye called conditioning factors. These conditioning factors may be internal (e.g., genetic predisposition, age, sex) or external (e.g., exposure to environmental agents, life experiences, dietary factors, level of social support).12 The relative risk for development of a stress-related pathologic process seems, at least in part, to depend on these factors. Richard Lazarus, a well-respected psychologist who devoted his career to the study of stress and emotions, considered “meanings and values to be at the center of human life and to represent the essence of stress, emotion and adaptation.”14 There is evidence that the hypothalamic–pituitary– adrenocortical axis, the adrenomedullary hormonal system, and the sympathetic nervous system are differentially activated depending on the type and intensity of the stressor.15 Iona has two internal conditioning factors for SLE, such as being female and in her late thirties. She also has external conditioning factors, such as life experiences and level of social support. With so many stressors in her life, she is most vulnerable for the stress response to go awry. Neuroendocrine Responses The manifestations of the stress response are strongly influenced by both the nervous and endocrine systems. The neuroendocrine systems integrate signals received along n­ eurosensory

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TABLE 9.1 HORMONES INVOLVED IN THE NEUROENDOCRINE RESPONSES TO STRESS HORMONES ASSOCIATED WITH THE STRESS RESPONSE

SOURCE OF THE HORMONE

Catecholamines (NE, epinephrine)

LC, adrenal medulla

Corticotropin-releasing factor (CRF) Adrenocorticotropic hormone (ACTH) Glucocorticoid hormones (e.g., cortisol)

Hypothalamus

Mineralocorticoid hormones (e.g., aldosterone) Antidiuretic hormone (ADH, vasopressin)

Adrenal cortex

Anterior pituitary Adrenal cortex

Hypothalamus, posterior pituitary

pathways and from circulating mediators that are carried in the bloodstream. In addition, the immune system both affects and is affected by the stress response. Table 9.1 summarizes the action of hormones involved in the neuroendocrine responses to stress. The results of the coordinated release of these neurohormones include the mobilization of energy, a sharpened focus and awareness, increased cerebral blood flow and glucose utilization, enhanced cardiovascular and respiratory functioning, redistribution of blood flow to the brain and muscles, modulation of the immune response, inhibition of reproductive function, and a decrease in appetite.15 The stress response is a normal, coordinated physiologic system meant to increase the probability of survival, but also designed to be an acute response—turned on when necessary to bring the body back to a stable state and turned off when the challenge to homeostasis abates. Therefore, under normal circumstances, the neural responses and the hormones that are released during the response do not persist long enough to cause damage to vital tissues. Since the early 1980s, the term allostasis has been used by some investigators to describe the physiologic changes in the neuroendocrine, autonomic, and immune systems that occur in response to either real or perceived challenges to homeostasis. The persistence or accumulation of these allostatic changes (e.g., immunosuppression, activation of the sympathetic nervous and renin–angiotensin–aldosterone systems) has been called an allostatic load, and this concept has been used to measure the cumulative effects of stress on humans.16 The integration of the components of the stress response, which occurs at the level of the central nervous system (CNS), is complex and not completely understood. It relies

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PHYSIOLOGIC EFFECTS Produces a decrease in insulin release and an increase in glucagon release resulting in increased glycogenolysis, gluconeogenesis, lipolysis, proteolysis, and decreased ­glucose uptake by the peripheral tissues; an increase in heart rate, cardiac contractility, and vascular smooth muscle contraction; and relaxation of bronchial smooth muscle Stimulates ACTH release from the anterior pituitary and increased activity of the LC neurons Stimulates the synthesis and release of cortisol Potentiates the actions of epinephrine and glucagon; inhibits the release and/or actions of the ­reproductive hormones and thyroid-stimulating hormone; and ­produces a decrease in immune cells and inflammatory mediators Increases sodium absorption by the kidney Increases water absorption by the kidney; produces vasoconstriction of blood vessels; and stimulates the release of ACTH

on communication along neuronal pathways of the cerebral cortex, the limbic system, the thalamus, the hypothalamus, the pituitary gland, and the reticular activating system (RAS; Fig. 9.2). The cerebral cortex is involved with vigilance, cognition, and focused attention and the limbic system with the emotional components (e.g., fear, excitement, rage, anger) of the stress response. The thalamus functions as the relay center and is important in receiving, sorting out, and distributing sensory input. The hypothalamus coordinates the responses of the endocrine and autonomic nervous systems (ANS). The RAS modulates mental alertness, ANS activity, and skeletal muscle tone, using input from other neural structures. The musculoskeletal tension that occurs during the stress response reflects increased activity of the RAS and its influence on the reflex circuits that control muscle tone. Adding to the complexity of this system is the fact that the individual brain circuits that participate in the mediation of the stress response interact and regulate the activity of each other. For example, reciprocal connections exist between neurons in the hypothalamus that initiate release of corticotropin-releasing factor (CRF) and neurons in the locus caeruleus (LC) associated with release of norepinephrine (NE). Thus, NE stimulates the secretion of CRF, and CRF stimulates the release of NE.16 Locus Caeruleus. Central to the neural component of the neuroendocrine response to stress is an area of the brain stem called the locus caeruleus.16 The LC is densely populated with neurons that produce NE and is thought to be the central integrating site for the ANS response to stressful stimuli (Fig. 9.3). The LC–NE system has afferent pathways to the

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Vigilance, cognition, focused attention

Cerebral cortex

Thalamus

Limbic system

Emotional responses

Hypothalamus

Reticular activating system

Increased alertness and arousal

Sensory input

Spinal cord reflexes

Locus ceruleus

CRF Anterior pituitary gland

Autonomic nervous system

Increased muscle tension

ACTH Adrenal cortex

Adrenal medulla Epinephrine Norepinephrine

Cortisol Supplementation and prolongation of fightor-flight response Alteration in glucose, fat, and protein metabolism

Suppression of inflammatory and immune responses

Increased heart rate and blood pressure Pupil dilation Dry mouth Increased blood coagulability

FIGURE 9.2  •  Neuroendocrine pathways and physiologic responses to stress. (ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor.)

hypothalamus, the limbic system, the hippocampus, and the cerebral cortex. The LC–NE system confers an adaptive advantage during a stressful situation. The sympathetic nervous system manifestation of the stress reaction has been called the fight-or-flight response. This is the most rapid of the stress responses and represents the basic survival response of our primitive ancestors when confronted with the perils of the wilderness and its inhabitants. The increase in sympathetic activity in the brain increases attention and arousal and thus probably intensifies memory. The heart and respiratory rates increase, the hands and feet become moist, the pupils dilate, the mouth becomes dry, and the activity of the gastrointestinal tract decreases. Corticotropin-Releasing Factor.  CRF is central to the endocrine component of the neuroendocrine response to stress (see Fig. 9.3). CRF is a small peptide hormone found in both the hypothalamus and in extrahypothalamic structures, such as the limbic system and the brain stem. It is both an important

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endocrine regulator of pituitary and adrenal activity and a neurotransmitter involved in ANS activity, metabolism, and behavior.16 Receptors for CRF are distributed throughout the brain as well as many peripheral sites. CRF from the hypothalamus induces secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH, in turn, stimulates the adrenal gland to synthesize and secrete the glucocorticoid hormones (e.g., cortisol). The glucocorticoid hormones have a number of direct or indirect physiologic effects that mediate the stress response, enhance the action of other stress hormones, or suppress other components of the stress system. In this regard, cortisol acts not only as a mediator of the stress response but as an inhibitor, such that overactivation of the stress response does not occur.16 Cortisol maintains blood glucose levels by antagonizing the effects of insulin and enhances the effect of catecholamines on the cardiovascular system. It also suppresses osteoblast activity, hematopoiesis, protein and collagen synthesis, and immune responses. All of these functions are meant to p­ rotect the ­organism against

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Immune system (cytokines) Hypothalamus CRF

Adrenal gland Cortisol

Brain stem Locus Ceruleus Pituitary ACTH Autonomic nervous system manifestations FIGURE 9.3 • Neuroendocrine–immune system regulation of the stress response. (ACTH, adrenocorticotropic hormone; CRF, corticotropinreleasing factor.)

the effects of a stressor and to focus energy on regaining balance in the face of an acute challenge to homeostasis. Angiotensin II.  Stimulation of the sympathetic nervous system also activates the peripheral renin–angiotensin–aldosterone system (RAAS), which mediates a peripheral increase in vascular tone and renal retention of sodium and water. These changes contribute to the physiologic changes that occur with the stress response and, if prolonged, may contribute to pathologic changes. Angiotensin II, peripherally delivered or locally produced, also has CNS effects; angiotensin II type 1 (AT1) receptors are widely distributed in the hypothalamus and LC. Through these receptors, angiotensin II enhances CRF formation and release, contributes to the release of ACTH from the pituitary, enhances stress-induced release of vasopressin from the posterior pituitary, and stimulates the release of NE from the LC.16 Other Hormones.  A wide variety of other hormones, including growth hormone, thyroid hormone, and the reproductive hormones, also are responsive to stressful situations. Systems responsible for reproduction, growth, and immunity are directly linked to the stress system, and the hormonal effects of the stress response profoundly influence these systems. Although growth hormone is initially elevated at the onset of stress, the prolonged presence of cortisol leads to suppression of growth hormone, insulin-like growth factor 1 (IGF-1), and other growth factors, exerting a chronically inhibitory effect on growth. In addition, CRF directly increases somatostatin, which in turn inhibits growth hormone secretion. Although the connection is speculative, the effects of stress on growth hormone may provide one of the vital links to understanding failure to thrive in children.

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Stress-induced cortisol secretion also is associated with decreased levels of thyroid-stimulating hormone and inhibition of conversion of thyroxine (T4) to the more biologically active triiodothyronine (T3) in peripheral tissues. Both changes may serve as a means to conserve energy at times of stress. Antidiuretic hormone (ADH) released from the posterior pituitary is also involved in the stress response, particularly in hypotensive stress or stress due to fluid volume loss. ADH, also known as vasopressin, increases water retention by the kidneys and produces vasoconstriction of blood vessels. In addition, vasopressin synthesized in parvocellular neurons of the hypothalamus and transported to the anterior pituitary appears to synergize the capacity of CRF to stimulate the release of ACTH. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) also plays a role in the stress response through neurons that innervate the hypothalamus, amygdala, and other limbic structures. Administration of 5-HT receptor agonists to laboratory animals was shown to increase the secretion of several stress hormones. Other hormones that have a possible role in the stress response include vasoactive intestinal peptide (VIP), neuropeptide Y, cholecystokinin (CCK), and substance P. CRF also influences the release or nonrelease of reproductive hormones. Sepsis and severe trauma can induce anovulation and amenorrhea in women and decreased spermatogenesis and decreased levels of testosterone in men. Immune Responses The hallmark of the stress response, as first described by Selye, are the endocrine–immune interactions (i.e., increased corticosteroid production and atrophy of the thymus) that are known to suppress the immune response. In concert, these two components of the stress system, through endocrine and

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neurotransmitter pathways, produce the physical and behavioral changes designed to adapt to acute stress. Much of the ­literature regarding stress and the immune response focuses on the causal role of stress in immune-related diseases. It has also been suggested that the reverse may occur. That is, emotional and psychological manifestations of the stress response may be a reflection of alterations in the CNS resulting from the immune response (see Fig. 9.3). Immune cells such as monocytes and lymphocytes can penetrate the blood–brain barrier and take up residence in the brain, where they secrete chemical messengers called cytokines that influence the stress response. The exact mechanism by which stress produces its effect on the immune response is unknown and probably varies from person to person, depending on genetic and environmental factors. The most significant arguments for interaction between the neuroendocrine and immune systems derive from evidence that the immune and neuroendocrine systems share common signal pathways (i.e., messenger molecules and receptors), that hormones and neuropeptides can alter the function of immune cells, and that the immune system and its mediators can modulate neuroendocrine function.16 Receptors for a number of CNS-controlled hormones and neuromediators reportedly have been found on lymphocytes. Among these are receptors for glucocorticoids, insulin, testosterone, prolactin, catecholamines, estrogens, acetylcholine, and growth hormone, suggesting that these hormones and neuromediators influence lymphocyte function. For example, cortisol is known to suppress immune function, and pharmacologic doses of cortisol are used clinically to suppress the immune response. It has been observed that the HPA axis is activated by cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor that are released from immune cells. With SLE there is an increase in lymphocytes, and these can migrate to the brain where they secrete cytokines, which trigger inflammation. Also the immunological system can be modulated to recognize one’s own cells as antigens and destroy their own cells. This is seen in the autoimmune disorder, SLE (Iona’s diagnosis). A second possible route for neuroendocrine regulation of immune function is through the sympathetic nervous system and the release of catecholamines. The lymph nodes, thymus, and spleen are supplied with ANS nerve fibers. Centrally acting CRF activates the ANS through multisynaptic descending pathways, and circulating epinephrine acts synergistically with CRF and cortisol to inhibit the function of the immune system. Not only is the quantity of immune expression changed because of stress, but the quality of the response is changed. Stress hormones differentially stimulate the proliferation of subtypes of T lymphocyte helper cells. Because these T helper cell subtypes secrete different cytokines, they stimulate different aspects of the immune response. One subtype tends to stimulate T lymphocytes and the cellular-mediated immune response, whereas a second type tends to activate B lymphocytes and humoral-mediated immune responses.16

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KEY POINTS STRESS AND ADAPTATION •  Stress is a state manifested by symptoms that arise from the coordinated activation of the ­neuroendocrine and immune systems, which Selye called the general adaptation syndrome. •  The hormones and neurotransmitters (catecholamines and cortisol) that are released during the stress response function to alert the individual to a threat or challenge to homeostasis, to enhance cardiovascular and metabolic activity in order to manage the stressor, and to focus the energy of the body by suppressing the activity of other ­systems that are not immediately needed. •  The ability to adapt is influenced by previous learning, physiologic reserve, time, genetic ­endowment, age, health status and nutrition, sleep–wake cycles, and psychosocial factors.

Coping and Adaptation to Stress The ability to adapt to a wide range of environments and stressors is not peculiar to humans. According to René Dubos (a microbiologist noted for his study of human responses to the total environment), “adaptability is found throughout life and is perhaps the one attribute that distinguishes most clearly the world of life from the world of inanimate matter.”17 Living organisms, no matter how primitive, do not submit passively to the impact of environmental forces. They attempt to respond adaptively, each in its own unique and most suitable manner. The higher the organism is on the evolutionary scale, the larger its repertoire of adaptive mechanisms and its ability to select and limit aspects of the environment to which it responds. The most fully evolved mechanisms are the social responses through which people or groups modify their environments, their habits, or both to achieve a way of life that is best suited to their needs. Adaptation Human beings, because of their highly developed nervous system and intellect, usually have alternative mechanisms for adapting and have the ability to control many aspects of their environment. Air conditioning and central heating limit the need to adapt to extreme changes in environmental temperature. The availability of antiseptic agents, immunizations, and antibiotics eliminates the need to respond to common infectious agents. At the same time, modern technology creates new challenges for adaptation and provides new sources of stress, such as noise and air pollution, increased exposure to harmful chemicals, and changes in biologic rhythms imposed by shift work and global travel. Of particular interest are the differences in the body’s response to events that threaten the integrity of the body’s

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physiologic environment and those that threaten the integrity of the person’s psychosocial environment. Many of the body’s responses to physiologic disturbances are controlled on a moment-by-moment basis by feedback mechanisms that limit their application and duration of action. For example, the baroreflex-mediated rise in heart rate that occurs when a person moves from the recumbent to the standing position is almost instantaneous and subsides within seconds. Furthermore, the response to physiologic disturbances that threaten the integrity of the internal environment is specific to the threat; the body usually does not raise the body temperature when an increase in heart rate is needed. In contrast, the response to psychological disturbances is not regulated with the same degree of specificity and feedback control. Instead, the effect may be inappropriate and sustained. Factors Affecting the Ability to Adapt Adaptation implies that an individual has successfully created a new balance between the stressor and the ability to deal with it. The means used to attain this balance are called coping strategies or coping mechanisms. Coping mechanisms are the emotional and behavioral responses used to manage threats to our physiologic and psychological homeostasis. According to Lazarus, how we cope with stressful events depends on how we perceive and interpret the event.18 Is the event perceived as a threat of harm or loss? Is the event perceived as a challenge rather than a threat? Physiologic reserve, time, genetics, age, health status, nutrition, sleep–wake cycles, hardiness, and psychosocial factors influence a person’s appraisal of a stressor and the coping mechanisms used to adapt to the new situation (Fig. 9.4). Physiologic and Anatomic Reserve. The trained athlete is able to increase cardiac output six- to sevenfold during exercise. The safety margin for adaptation of most body systems is considerably greater than that needed for normal activities. The red

Nutrition

Genetics and age

Hardiness

Adaptive capacity

Psychosocial factors

Physiologic reserve

Sleep– wake cycles

Rapidity with which need for adaptation occurs

FIGURE 9.4  •  Factors affecting adaptation.

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blood cells carry more oxygen than the tissues can use, the liver and fat cells store excess nutrients, and bone tissue stores calcium in excess of that needed for normal neuromuscular function. The ability of body systems to increase their function given the need to adapt is known as the physiologic reserve. Many of the body organs, such as the lungs, kidneys, and adrenals, are paired to provide anatomic reserve as well. Both organs are not needed to ensure the continued existence and maintenance of the internal environment. Many people function normally with only one lung or one kidney. In kidney disease, for example, signs of renal failure do not occur until approximately 80% of the functioning nephrons have been destroyed. Time.  Adaptation is most efficient when changes occur gradually rather than suddenly. It is possible, for instance, to lose a liter or more of blood through chronic gastrointestinal bleeding over a week without manifesting signs of shock. However, a sudden hemorrhage that causes rapid loss of an equal amount of blood is likely to cause hypotension and shock. Genetics.  Adaptation is further affected by the availability of adaptive responses and flexibility in selecting the most appropriate and economical response. The greater the number of available responses, the more effective is the capacity to adapt. Genetics can ensure that the systems that are essential to adaptation function adequately. Even a gene that has deleterious effects may prove adaptive in some environments. In Africa, the gene for sickle cell anemia persists in some populations because it provides some resistance to infection with the parasite that causes malaria. Age.  The capacity to adapt is decreased at the extremes of age. The ability to adapt is impaired by the immaturity of an infant, much as it is by the decline in functional reserve that occurs with age. For example, the infant has difficulty concentrating urine because of immature renal structures and therefore is less able than an adult to cope with decreased water intake or exaggerated water losses. A similar situation exists in the elderly owing to age-related changes in renal function. Gender. Within the last decade, primarily because females have been included in basic science and clinical investigations, differences between the sexes in cardiovascular, respiratory, endocrine, renal, and neurophysiologic function have been found, and it has been hypothesized that sex hormones are the basis of these biologic differences. Technological advances in cellular and molecular biology have made it clear, however, that there are fundamental differences in the locale and regulation of individual genes in the male and female genome. These differences have general implications for the prevention, diagnosis, and treatment of disease and specific implications for our understanding of the sex-based differences in response to life’s stressors. Given the nature of sex-based differences, it is not surprising that there are differences in the physiologic stress

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response in both the HPA axis and in the ANS. Premenopausal women tend to have a lower activation of the sympathetic nervous system than men in response to stressors. Gender-based differences in activation of the stress response may partially explain differences in susceptibility to diseases in which the stress response may play a causal role. These research results are not definitive but are intriguing and can serve as a springboard for further research. Health Status. Physical and mental health status determines physiologic and psychological reserves and is a strong determinant of the ability to adapt. For example, people with heart disease are less able to adjust to stresses that require the recruitment of cardiovascular responses. Severe emotional stress often produces disruption of physiologic function and limits the ability to make appropriate choices related to long-term adaptive needs. Those who have worked with acutely ill people know that the will to live often has a profound influence on survival during life-threatening illnesses. Nutrition.  There are 50 to 60 essential nutrients, including minerals, lipids, certain fatty acids, vitamins, and specific amino acids. Deficiencies or excesses of any of these nutrients can alter a person’s health status and impair the ability to adapt. The importance of nutrition to enzyme function, immune response, and wound healing is well known. On a worldwide basis, malnutrition may be one of the most common causes of immunodeficiency. Among the problems associated with dietary excess are obesity and alcohol abuse. Obesity is a common problem. It predisposes a person to a number of health problems, including atherosclerosis and hypertension. Alcohol is commonly used in excess. It acutely affects brain function and, with longterm use, can seriously impair the function of the liver, brain, and other vital structures. Sleep–Wake Cycles.  Sleep is considered to be a restorative function in which energy is restored and tissues are regenerated.19 Sleep occurs in a cyclic manner, alternating with periods of wakefulness and increased energy use. Biologic rhythms play an important role in adaptation to stress, development of illness, and response to medical treatment. Many rhythms such as rest and activity, work and leisure, and eating and drinking oscillate with a frequency similar to that of the 24-hour light–dark solar day. The term circadian, from the Latin circa (“about”) and dies (“day”), is used to describe these 24-hour diurnal rhythms. Sleep disorders and alterations in the sleep–wake cycle have been shown to alter immune function, the normal circadian pattern of hormone secretion, and physical and psychological functioning.19,20 The two most common manifestations of an alteration in the sleep–wake cycle are insomnia and sleep deprivation or increased somnolence. In some people, stress may produce sleep disorders, and in others, sleep disorders may lead to stress. Acute stress and environmental

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d­ isturbances, loss of a loved one, recovery from surgery, and pain are common causes of transient and short-term insomnia. Air travel and jet lag constitute additional causes of altered sleep–wake cycles, as does shift work. Hardiness.  Studies by social psychologists have focused on individuals’ emotional reactions to stressful situations and their coping mechanisms to determine those characteristics that help some people remain healthy despite being challenged by high levels of stressors. For example, the concept of hardiness describes a personality characteristic that includes a sense of having control over the environment, a sense of having a purpose in life, and an ability to conceptualize stressors as a challenge rather than a threat.21 Many studies by nurses and social psychologists suggest that hardiness is correlated with positive health outcomes.22 Psychosocial Factors. Several studies have related social factors and life events to illness. Scientific interest in the social environment as a cause of stress has gradually broadened to include the social environment as a resource that modulates the relation between stress and health. Presumably, people who can mobilize strong supportive resources from within their social relationships are better able to withstand the negative effects of stress on their health. Close relationships with others can involve positive effects as well as the potential for conflict and may, in some situations, leave the person less able to cope with life stressors.

IN SUMMARY The stress response involves the activation of several physiologic systems (sympathetic nervous system, the HPA axis, and the immune system) that work in a coordinated fashion to protect the body against damage from the intense demands made on it. Selye called this response the general adaptation syndrome. The stress response is divided into three stages: the alarm stage, with activation of the sympathetic nervous system and the HPA axis; the resistance stage, during which the body selects the most effective defenses; and the exhaustion stage, during which physiologic resources are depleted and signs of systemic damage appear. The activation and control of the stress response are mediated by the combined efforts of the nervous and endocrine systems. The neuroendocrine systems integrate signals received along neurosensory pathways and from circulating mediators that are carried in the bloodstream. In addition, the immune system both affects and is affected by the stress response. Adaptation is affected by a number of factors, including experience and previous learning, the rapidity with which the need to adapt occurs, genetic endowment and age, health status, nutrition, sleep–wake cycles, hardiness, and psychosocial factors.

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DISORDERS OF THE STRESS RESPONSE After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the physiologic and psychological effects of a chronic stress response. •• Describe the characteristic of posttraumatic stress disorder. •• List four nonpharmacologic methods of treating stress.

For the most part, the stress response is meant to be acute and time limited. The time-limited nature of the process renders the accompanying catabolic and immunosuppressive effects advantageous. It is the chronicity of the response that is thought to be disruptive to physical and mental health. Stressors can assume a number of patterns in relation to time. They may be classified as acute time limited, chronic intermittent, or chronic sustained. An acute time-limited stressor is one that occurs over a short time and does not recur. A chronic intermittent stressor is one to which a person is chronically exposed. The frequency or chronicity of circumstances to which the body is asked to respond often determines the availability and efficiency of the stress responses. The response of the immune system, for example, is more rapid and efficient on second exposure to a pathogen than it is on first exposure. However, chronic exposure to a stressor can fatigue the system and impair its effectiveness.

Effects of Acute Stress The reactions to acute stress are those associated with the ANS, the fight-or-flight response. The manifestations of the stress response—a pounding headache; a cold, moist skin; and a stiff neck—are all part of the acute stress response. Centrally, there is facilitation of neural pathways mediating arousal, alertness, vigilance, cognition, and focused attention, as well as appropriate aggression. The acute stress response can result from either psychologically or physiologically threatening events. In situations of life-threatening trauma, these acute responses may be lifesaving in that they divert blood from less essential to more essential body functions. Increased alertness and cognitive functioning enable rapid processing of information and arrival at the most appropriate solution to the threatening situation. However, for people with limited coping abilities, either because of physical or mental health, the acute stress response may be detrimental (Table 9.2). This is true of people with preexisting heart disease in whom the overwhelming sympathetic behaviors associated with the stress response can lead to arrhythmias. For people with other chronic health problems, such as headache disorder, acute stress may precipitate a recurrence. In healthy people, the acute stress response can redirect attention from behaviors that promote health, such as

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TABLE 9.2 POSSIBLE STRESS-INDUCED HEALTH PROBLEMS •  Mood disorders •  Anxiety •  Depression •  PTSD •  Eating disorders •  Sleep disorders •  Diabetes type 2 •  Hypertension •  Infection •  Exacerbation of autoimmune disorders •  Gastrointestinal problems •  Pain •  Obesity •  Eczema •  Cancer •  Atherosclerosis •  Migraine

attention to proper meals and getting adequate sleep. For those with health problems, it can interrupt compliance with medication regimens and exercise programs. In some situations, the acute arousal state actually can be life-threatening, physically immobilizing the person when movement would avert catastrophe (e.g., moving out of the way of a speeding car).

Effects of Chronic Stress The stress response is designed to be an acute self-limited response in which activation of the ANS and the HPA axis is controlled in a negative feedback manner. As with all negative feedback systems, pathophysiologic changes can occur in the stress response system. Function can be altered in several ways, including when a component of the system fails; when the neural and hormonal connections among the components of the system are dysfunctional; and when the original stimulus for the activation of the system is prolonged or of such magnitude that it overwhelms the ability of the system to respond appropriately. In these cases, the system may become overactive or underactive. Chronicity and excessive activation of the stress response can result from chronic illnesses as well as contribute to the development of long-term health problems. Chronic activation of the stress response is an important public health issue from both a health and a cost perspective. Stress is linked to a myriad of health disorders, such as diseases of the cardiovascular, gastrointestinal, immune, and neurologic systems, as well as depression, chronic alcoholism and drug abuse, eating disorders, accidents, and suicide.

Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) is seen frequently. It is characterized by a severe stress response secondary to experiencing previous trauma. The person may remember the traumatic event, or PTSD may occur with no recollection of an earlier stressful experience. PTSD that is manifested 6 months

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after the traumatic event is called PTSD with delayed onset.22 PTSD was formerly called battle fatigue or shell shock because it was first characterized in soldiers returning from combat. Although war is still a significant cause of PTSD, other major catastrophic events, such as weather-related disasters (hurricanes, earthquakes, and floods), airplane crashes, terrorist bombings, and rape or child abuse, also may result in development of the disorder. People who are exposed to traumatic events are also at risk for development of major depression, panic disorder, generalized anxiety disorder, and substance abuse.22 They may also have physical symptoms and illnesses (e.g., hypertension, asthma, and chronic pain syndromes). PTSD is characterized by a constellation of symptoms that are experienced as states of intrusion, avoidance, and hyperarousal. Intrusion refers to the occurrence of “flashbacks” during waking hours or nightmares in which the past traumatic event is relived, often in vivid and frightening detail. Avoidance refers to the emotional numbing that accompanies this disorder and disrupts important personal relationships. Because a person with PTSD has not been able to resolve the painful feelings associated with the trauma, depression is commonly a part of the clinical picture. Survivor guilt also may be a product of traumatic situations in which the person survived the disaster but loved ones did not. Hyperarousal refers to the presence of increased irritability, difficulty concentrating, an exaggerated startle reflex, and increased vigilance and concern over safety. In addition, memory problems, sleep disturbances, and excessive anxiety are commonly experienced by people with PTSD. For a diagnosis of PTSD to be made, the person must have experienced, witnessed, or confronted a traumatic event, which caused a response in the person involving horror and fear. The triad of symptoms of intrusion, avoidance, and hyperarousal that characterize PTSD must be present together for at least 1 month, and the disorder must have caused clinically significant distress.22 Although the pathophysiology of PTSD is not completely understood, the revelation of physiologic changes related to the disorder has shed light on why some people recover from the disorder, whereas others do not. It has been hypothesized that the intrusive symptoms of PTSD may arise from exaggerated sympathetic nervous system activation in response to the traumatic event. People with chronic PTSD have been shown to have increased levels of NE and increased activity of α2-adrenergic receptors. Recent neuroanatomic studies have identified alterations in two brain structures (the amygdala and hippocampus). Positron emission tomography and functional magnetic resonance imaging have shown increased reactivity of the amygdala and hippocampus and decreased reactivity of the anterior cingulate and orbitofrontal areas. These areas of the brain are involved in fear responses. The hippocampus also functions in memory processes. Differences in hippocampal function and memory processes suggest a neuroanatomic basis for the intense problems suffered by people diagnosed with PTSD. People with PTSD demonstrate decreased cortisol levels, increased sensitivity of cortisol receptors, and an enhanced negative feedback inhibition of cortisol release with the dexamethasone suppression test. Dexamethasone is a synthetic

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glucocorticoid that mimics the effects of cortisol and directly inhibits the action of CRF and ACTH. The hypersuppression of cortisol observed with the dexamethasone test suggests that persons with PTSD do not exhibit a classic stress response as described by Selye. Because this hypersuppression has not been described in other psychiatric disorders, it may serve as a relatively specific marker for PTSD. Little is known about the risk factors that predispose people to the development of PTSD. Statistics indicate there is a need for studies to determine risk factors for PTSD as a means of targeting people who may need intensive therapeutic measures after a life-threatening event. Research also is needed to determine the mechanisms by which the disorder develops so that it can be prevented or, if that is not possible, so that treatment methods can be developed to decrease the devastating effects of this disorder on affected people and their families.23 Health care professionals need to be aware that people who present with symptoms of depression, anxiety, and alcohol or drug abuse may in fact be suffering from PTSD. The patient history should include questions concerning the occurrence of violence, major loss, or traumatic events in the person’s life. Debriefing, or talking about the traumatic event at the time it happens, often is an effective therapeutic tool. Crisis teams are often among the first people to attend to the emotional needs of those caught in catastrophic events. Some people may need continued individual or group therapy. Often concurrent pharmacotherapy with antidepressant and antianxiety agents is useful and helps the person participate more fully in therapy. Most importantly, the person with PTSD should not be made to feel responsible for the disorder or that it is evidence of a so-called character flaw. It is not uncommon for people with this disorder to be told to “get over it” or “just get on with it, because others have.” There is ample evidence to suggest that there is a biologic basis for the individual differences in responses to traumatic events, and these differences need to be taken into account.

Treatment and Research of Stress Disorders The change that occurs in the biochemical stress response system of people who have experienced some type of mistreatment as a child so that they are not able to respond effectively to stressors in the future is called the traumatic stress response.24 Evidence supports that early intervention can assist the person in adapting new and effective coping mechanisms to better manage stress in the future.24 Additionally, a study conducted with caregivers of a spouse or family member demonstrates that those who reported higher levels of caregiver stress also had poorer self-perceived health. When early interventions for stress management were given to these caregivers, there were less negative self-identified behaviors.25 Several studies have supported the use of early interventions to assist in managing stress. In fact, one study describes how resilience development was conducted with oncology nurses to decrease their burnout. Findings of the study indicated the program was successful and recommended to be implemented for all nurses.26

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Treatment The treatment of stress should be directed toward helping ­people avoid coping behaviors that impose a risk to their health and providing them with alternative stress-reducing strategies. People who are overwhelmed by the number of life stressors to which they have been exposed can use purposeful priority setting and problem solving. Other nonpharmacologic methods used for stress reduction are relaxation techniques, guided imagery, music therapy, massage, and biofeedback. Relaxation.  Practices for evoking the relaxation response are numerous. They are found in virtually every culture and are credited with producing a generalized decrease in sympathetic system activity and musculoskeletal tension. Progressive muscle relaxation is one method of relieving tension. Tension can be defined physiologically as the inappropriate contraction of muscle fibers. Progressive muscle relaxation, which has been modified by a number of therapists, consists of systematic contraction and relaxation of major muscle groups.2 As the person learns to relax, the various muscle groups are combined. Eventually, the person learns to relax individual muscle groups without first contracting them. Imagery.  Guided imagery is another technique that can be used to achieve relaxation. One method is scene visualization, in which the person is asked to sit back, close the eyes, and concentrate on a scene narrated by the therapist. Whenever possible, all five senses are involved. The person attempts to see, feel, hear, smell, and taste aspects of the visual experience. Other types of imagery involve imagining the appearance of each of the major muscle groups and how they feel during tension and relaxation. Music Therapy.  Music therapy is used for both its physiologic and psychological effects. It involves listening to selected pieces of music as a means of ameliorating anxiety or stress, reducing pain, decreasing feelings of loneliness and isolation, buffering noise, and facilitating expression of emotion. Music usually is selected based on a person’s musical preference and past experiences with music. Depending on the setting, headphones may be used to screen out other distracting noises. Radio and television music is inappropriate for music therapy because of the inability to control the selection of pieces that are played, the interruptions that occur (e.g., commercials and announcements), and the quality of the reception. Biofeedback.  Biofeedback is a technique in which a person learns to control physiologic functioning. It involves electronic monitoring of one or more physiologic responses to stress with immediate feedback of the specific response to the person undergoing treatment. Research Research in stress has focused on personal reports of the stress situation and the physiologic responses to stress. A number of

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interview guides and written instruments are available for measuring the personal responses to stress and coping in adults. Measurements of vital signs, ACTHs, glucocorticoids (cortisol) and glucose levels, and immunological counts are all part of current research studies involving stress. People who are critically ill and on ventilators were assigned to listen to music or not were studied regarding their vital signs and sedation levels (Ramsay Sedation Scale). All were medicated with the same sedative and dosed according to weight. The experimental group (those who were given music) had higher levels of sedation as evidenced by higher Ramsay scores than those in the control group, although there was no difference in vital signs.27 Having maintained higher levels of sedation on the Ramsay Sedation Scale was deemed to be a positive outcome for preventing stress.27 A study conducted with Puerto Rican women living in the United States showed that many experienced stress as evidenced by increased respiratory rate, heart rate, and blood pressure.28 These women were found to have a statistically significantly higher chance to develop cardiovascular disease, arthritis, abdominal obesity, hypertension, and diabetes mellitus in the future.28 Evidence from another study illustrates that Ecuadorian women with high stress are developing SLE, which is an autoimmune disorder that causes systemic inflammation.29 Research that attempts to establish a link between the stress response and disease needs to be interpreted with caution owing to the influence that individual differences have in the way people respond to stress. Not everyone who experiences stressful life events develops a disease. The evidence for a link between the stress response system and the development of disease in susceptible people is compelling but not conclusive. No study has established a direct cause-andeffect relationship between the stress response and disease occurrence. For example, depressive illness often is associated with an increase in both plasma cortisol and cerebrospinal fluid concentrations of CRF. The question that arises is whether this increased plasma cortisol is a cause or an effect of the depressive state. Although health care professionals continue to question the role of stressors and coping skills in the pathogenesis of disease states, we must resist the temptation to suggest that any disease is due to excessive stress or poor coping skills.

IN SUMMARY Stress in itself is neither negative nor deleterious to health. The stress response is designed to be time limited and protective, but in situations of prolonged activation of the response because of overwhelming or chronic stressors, it could be damaging to health. PTSD is an example of chronic activation of the stress response as a result of experiencing a severe trauma. In this disorder, memory of the traumatic event seems to be enhanced. Flashbacks of the event are accompanied by intense activation of the neuroendocrine system.

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Treatment of stress should be aimed at helping people avoid coping behaviors that can adversely affect their health and providing them with other ways to reduce stress. Nonpharmacologic methods used in the treatment of stress include relaxation techniques, guided imagery, music therapy, massage techniques, and biofeedback. Research in stress has focused on personal reports of the stress situation and the physiologic responses to stress. A number of interview guides and written instruments are available for measuring the personal responses to acute and chronic stressors. Methods used for studying the physiologic manifestations of the stress response include electrocardiographic recording of heart rate, blood pressure measurement, electrodermal measurement of skin resistance associated with sweating, and biochemical analyses of hormone levels.

REVIEW EXERCISES 1. A 21-year-old college student notices that she frequently develops “cold sores” during the stressful final exam week. A. What is the association between stress and the immune system? B. One of her classmates suggests that she listen to music or try relaxation exercises as a means of relieving stress. Explain how these interventions might work in relieving stress. 2. A 75-year-old woman with congestive heart failure complains that her condition gets worse when she worries and is under stress. A. Relate the effects stress has on the neuroendocrine control of cardiovascular function and its possible relationship to a worsening of the woman’s congestive heart failure. B. She tells you that she dealt with much worse stresses when she was younger and never had any problems. How would you explain this? 3. A 30-year-old woman who was rescued from a collapsed building has been having nightmares recalling the event, excessive anxiety, and loss of appetite and is afraid to leave her home for fear something will happen. A. Given her history and symptoms, what is the likely diagnosis? B. How might she be treated?

References 1. Harvard College President & Fellows. (2011). Understanding the stress response. Harvard Mental Health Letter 3, 4–6. 2. Osler W. (1910). The Lumleian lectures in angina pectoris. Lancet 1, 696–700, 839–844, 974–977. 3. Cannon W. B. (1935). Stresses and strains of homeostasis. American Journal of Medical Science 189, 1–5.

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4. Selye H. (1946). The general adaptation syndrome and diseases of adaptation. Journal of Clinical Endocrinology 6, 117–124. 5. Millard R. W., Wang Y. (2009). Milieu interieur: The search for myocardial arteriogenic signals. Journal of the American College of Cardiology 53(23), 2148–2149. 6. Cannon W. B. (1939). The wisdom of the body (pp. 299–300). New York: WW Norton. 7. Shonkoff J. P., Boyce T., McEwen B. S. (2009). Neuroscience, molecular biology, and the childhood roots of health disparities. Journal of The American Medical Association 301(21), 2252–2259. 8. Finkelhor D., Shattuck A., Turner H., et al. (2013). Improving the adverse childhood experiences study scale. Journal of The American Medical Association Pediatrics 167(1), 70–75. 9. Siegel D. J. (2007). The mindful brain: Reflection and attunement in the cultivation of well-being. New York: WW Norton. 10. Schacter D. L., Addis D. R. (2009). Remembering the past to imagining the future: A cognitive neuroscience perspective. Military Psychiatry 21(Suppl. 1), A108–S112. 11. Selye H. (1976). The stress of life (rev. ed.). New York: McGraw-Hill. 12. Selye H. (1973). The evolution of the stress concept. American Scientist 61, 692–699. 13. Selye H. (1974). Stress without distress (p. 6). New York: New American Library. 14. Lazarus R. (1999). Stress and emotion: A new synthesis (p. 6). New York: Springer. 15. McEwen B. S., Gianaros P. J. (2011). Stress and allostasis—induced brain plasticity. Annual Review of Medicine 62, 431–445. 16. Hall J. E. (2011). Guyten and Hall textbook of medical physiology (12th ed.). Philadelphia, PA: Saunders. 17. Dubos R. (1965). Man adapting (pp. 256, 258, 261, 264). New Haven, CT: Yale University. 18. Lazarus R. (2000). Evolution of a model of stress, coping, and discrete emotions. In Rice V. H. (Ed.), Handbook of stress, coping, and health (pp. 195–222). Thousand Oaks, CA: Sage. 19. Kanathur N., Harrington J., Lee-Chiong T. (2010). Circadian rhythm sleep disorders. Clinics in Chest Medicine 31(2), 319–325. 20. Vander Zee E. A., Boersma G. I., Hut R. A. (2009). The neurobiology of circadian rhythms. Current Opinion in Pulmonary Medicine 15(6), 534–539. 21. Hague A., Leggat S. G. (2010). Enhancing hardiness among health care workers: The perceptions of senior managers. Health Services Management Research 23(2), 54–59. 22. Gorroll A. H., Mulley A. G. (2009). Primary care medicine: Office evaluation and management of the adult patient (6th ed., pp. 128–1439). Philadelphia, PA: Lippincott Williams & Wilkins. 23. Gros D. F., Simms L. J., Acierno R. (2010). Specificity of PTSD symptoms. Journal of Nervous & Mental Disease 198(12), 885–890. 24. Wilson K. R., Hansen D. J., Li M. (2011). The traumatic stress response in child maltreatment and resultant neuropsychological effects. Aggression & Violent Behavior 16(2), 87–97. 25. Lu Y. Y., Wykle M. (2007). Relationships between caregiver stress and self-car behaviors in response to symptoms. Clinical Nursing Research 16(1), 29–43. 26. Grafton E., Gillespie B., Henderson S. (2010). Resilience: The power within. Oncology Nursing Forum 37(6), 698–705. 27. Dijkstra B. M., Gamel C., van der Bijl J. J., et al. (2010). The effects of music on physiological responses and sedation scores in sedated, mechanically ventilated patients. Journal of Clinical Nursing 19, 1030–1039. 28. Mattei J., Demissie S., Falcon L. M., et al. (2010). Allostatic load is associated with chronic conditions in the Boston Puerto Rican Health. Social Science & Medicine 70(12), 1988–1996. 29. Miles A. (2011). Emerging chronic illness: Women and lupus erythematosus in Ecuador. Health Care for Women International 32(8), 651–668.

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Alterations in Temperature Regulation BODY TEMPERATURE REGULATION Mechanisms of Heat Production Mechanisms of Heat Loss Radiation Conduction Convection Evaporation

INCREASED BODY TEMPERATURE

Fever Mechanisms Purpose Patterns Clinical Manifestations Diagnosis Treatment Fever in Children Fever in Older Adults Hyperthermia Heat Cramps Heat Exhaustion Heatstroke Drug Fever Malignant Hyperthermia Neuroleptic Malignant Syndrome

DECREASED BODY TEMPERATURE Hypothermia Neonatal Hypothermia Perioperative Hypothermia Clinical Manifestations Diagnosis and Treatment Therapeutic Hypothermia

10 Sheila Grossman

Body temperature, at any given point in time, represents a b­alance between heat gain and heat loss. Body heat is ­generated in the core tissues of the body, transferred to the skin surface by the blood, and released into the environment surrounding the body. Body temperature rises in fever because of cytokine- and toll-like receptor-mediated changes in the set point of the temperature-regulating center in the hypothalamus. Body temperature rises in hyperthermia because of excessive heat production, inadequate heat dissipation, or a failure of thermoregulatory mechanisms. Body temperature falls during hypothermia due to exposure to cold. This chapter is organized into three sections: body temperature regulation, increased body temperature (fever and hyperthermia), and decreased body temperature (hypothermia).

BODY TEMPERATURE REGULATION After completing this section of the chapter, you should be able to meet the following objectives: •• Differentiate between body core temperature and skin temperature. •• Identify the differences between methods used for measuring body temperature. •• Define the terms conduction, radiation, convection, and evaporation, and relate them to the mechanisms for gain and loss of heat from the body. Most biochemical processes in the body are affected by changes in temperature. Metabolic processes speed up or slow down depending on whether body temperature is rising or ­falling. Core body temperature (i.e., intracranial, intrathoracic, and intraabdominal) normally is maintained within a range of 36.0°C to 37.5°C (97.0°F to 99.5°F).1 Within this range, there are individual differences. For example, core temperature of most females increases approximately 0.5°C to 1.0°C during postovulation time of their menstrual cycle.1

216

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Rectal temperature °C

Chapter 10  Alterations in Temperature Regulation    217

38 Heat dissipation 37

36

35 6 AM

Transport of core heat during vasoconstriction Transport of core heat during vasodilation Insulation

Noon

6 PM

Midnight

6 AM

Time FIGURE 10.1  •  Normal diurnal variations in body temperature.

There are also diurnal variations. Internal core temperatures reach their ­highest point in late afternoon and evening and their lowest point in the early morning hours (Fig. 10.1). In fact, the core body temperature is generally lowest between 3:00 and 6:00 am and highest during the late afternoon, 3:00 to 6:00 pm.1 Body temperature reflects the difference between heat production and heat loss and varies with exercise and extremes of environmental temperature. For instance, exercise can increase metabolic heat production 10-fold.1 Thankfully, thermoregulatory responses such as sweating simultaneously increase heat loss, and thus keep body temperature from rising dangerously high. Shivering, on the other hand, increases metabolic heat production. This thermoregulatory response can offset the increased heat loss resulting from cold ambient conditions. Properly protected and hydrated, the body can function in environmental conditions that range from −50°C (−58°F) to +50°C (122° F). The failure to adequately manage heat production and/or loss results in devastating consequences. For instance, ice crystals can form in tissues exposed to very cold and damp ambient temperatures. At the other extreme, very high temperatures (+45°C, 113° F) cause proteins to coagulate and/or aggregate. As will be discussed later in this chapter, much smaller, systemic changes in body temperature can be equally devastating, leading to tissue damage, organ failure, coma, and even death.2

Key Points THERMOREGULATION •  Core body temperature is a reflection of the balance between heat gain and heat loss by the body. Metabolic processes produce heat, which must be dissipated. •  The hypothalamus is the thermal control center for the body, receives information from peripheral and central thermoreceptors, and compares that information with its temperature set point. •  An increase in core temperature is effected by vasoconstriction and shivering, a decrease in temperature by vasodilation and sweating.

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FIGURE 10.2 • Control of heat loss. Body heat is produced in the deeper core tissues of the body, which is insulated by the ­subcutaneous tissues and skin to protect against heat loss. During vasodilation, ­ circulating blood transports heat to the skin surface, where it dissipates into the surrounding environment. Vasoconstriction decreases the transport of core heat to the skin surface, and ­vasodilation increases transport.

Most of the body’s heat is produced by the deeper core ­tissues (i.e., muscles and viscera), which are insulated from the environment and protected against heat loss by an outer shell of subcutaneous tissues and skin (Fig. 10.2). The thickness of the shell depends on blood flow. In a warm environment, blood flow is increased and the thickness of the outer shell is decreased, allowing for greater dissipation of heat. In a cold environment, the vessels supplying blood flow to the skin and underlying tissues, including those of the limbs and more superficial muscles of the neck and trunk, constrict. This increases the thickness of the shell and helps to minimize the loss of core heat for the body. The subcutaneous fat layer ­contributes to the insulation value of the outer shell because of its thickness and because it conducts heat only about one third as effectively as other tissues. Temperatures differ in various parts of the body, with core temperatures being higher than those at the skin surface. In general, the rectal temperature is used as a measure of core temperature and is considered the most accurate parameter.3 Rectal temperatures usually range from 37.3°C (99.1°F) to 37.6°C (99.6°F). Core temperatures may also be obtained from the esophagus using a flexible thermometer, from a pulmonary artery catheter that is used for thermodilution measurement of cardiac output, or from a urinary catheter with a thermosensor that measures the temperature of urine in the bladder. Because of location, pulmonary artery and e­ sophageal temperatures closely reflect the temperatures of the heart and thoracic organs. The pulmonary artery catheter is the preferred measurement when body temperatures are changing rapidly

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218   UNIT III  Disorders of Integrative Function

and need to be followed reliably on an acutely ill person in an intensive care setting. The oral temperature, taken sublingually, is usually 0.2°C (0.36°F) to 0.51°C (0.9°F) lower than the rectal temperature. However, it usually follows changes in core temperature closely. The axillary temperature also can be used as an ­estimate of core temperature. However, the parts of the axillary fossa must be pressed closely together for an extended period (5 to 10 minutes for a glass thermometer) because this method requires considerable heat to accumulate before the final temperature is reached. Ear-based thermometry uses an infrared sensor to measure the flow of heat from the tympanic membrane and ear canal.4 It is popular in all health care settings because of its ease and speed of measurement, acceptability to all people, and cost savings in the personnel time that is required to take a temperature. However, there is continuing debate regarding the accuracy of this method.5,6 There is evidence to suggest that ear thermometry can predict rectal temperatures in normothermic and febrile older adults.4 In addition, studies with children demonstrate little evidence that the child’s age and gender and the environmental temperature or humidity impacted the reliability of the tympanic temperature.5 Pacifier thermometers and skin temperature strips for children have also raised concerns about accuracy and are best used to monitor trends as opposed to absolute measurements. Core body and skin temperatures are sensed and ­integrated by thermoregulatory regions in the hypothalamus

(particularly, the preoptic–anterior hypothalamic area) and other brain structures (i.e., thalamus and cerebral cortex). Temperature-sensitive ion channels, identified as a subset of the transient receptor potential family (thermoTRPs), present in peripheral and central sensory neurons are activated by innocuous (warm and cool) and noxious (hot and cold) stimuli.6 Peripheral signals regarding temperature are initiated by changes in local membrane potentials that are transmitted to the brain through dorsal root ganglia.6 The set point of the hypothalamic thermoregulatory center is set so that the temperature of the body core is regulated within the normal range of 36.0°C (96.8°F) to 37.5°C (99.5°F). When body temperature begins to rise above the set point, the hypothalamus signals the central and peripheral nervous systems to initiate heat-dissipating behaviors. Likewise, when the temperature falls below the set point, signals from the hypothalamus elicit physiologic behaviors that increase heat conservation and production. Core temperatures above 41°C (105.8°F) or below 34°C (93.2°F) usually mean that the body’s ability to thermoregulate has been impaired. Body responses that p­ roduce, conserve, and dissipate heat are described in Table 10.1. Spinal cord injuries that transect the cord at T6 or above can seriously impair temperature regulation because the thermoregulatory centers in the hypothalamus can no longer control skin blood flow and sweating. In addition to reflexive and automatic thermoregulatory mechanisms, humans engage in voluntary behaviors to help regulate body temperature based on their conscious

TABLE 10.1 HEAT GAIN AND HEAT LOSS RESPONSES USED IN REGULATION OF BODY TEMPERATURE HEAT GAIN

HEAT LOSS

Body Response

Mechanism of Action

Body Response

Mechanism of Action

Vasoconstriction of the ­superficial blood vessels

Confines blood flow to the inner core of the body, with the skin and subcutaneous tissues acting as insulation to prevent loss of core heat

Dilatation of the superficial blood vessels

Delivers blood containing core heat to the periphery where it is ­dissipated through radiation, conduction, and convection

Contraction of the ­pilomotor muscles that surround the hairs on the skin

Reduces the heat loss surface of the skin

Sweating

Increases heat loss through evaporation

Assumption of the huddle position with the extremities held close to the body

Reduces the area for heat loss

Shivering

Increases heat production by the muscles

Increased production of epinephrine

Increases the heat production associated with metabolism

Increased production of ­thyroid hormone

Is a long-term mechanism that increases metabolism and heat production

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Chapter 10  Alterations in Temperature Regulation    219

­sensation of being too hot or too cold. These behaviors include the selection of proper clothing and regulation of environmental temperature through heating systems and air conditioning. Body positions that hold the extremities close to the body ­prevent heat loss and are commonly assumed in cold weather.

Mechanisms of Heat Production Metabolism is the body’s main source of heat production or thermogenesis. Many factors impact the metabolic rate, including •• Metabolic rate of each cell •• Any factor that may increase the basal metabolic rate (BMR), such as that caused by muscle activity •• Extra metabolism caused by hormones, such as ­thyroxine, growth hormone, or testosterone •• Any extra metabolism caused by the sympathetic ­nervous system stimulation on cells •• Extra metabolism caused by increased cellular chemical activity •• Thermogenic effect of food digestion, absorption, or storage3 There is a 0.55°C (1°F) increase in body temperature for every 7% increase in metabolism. The sympathetic neurotransmitters, epinephrine and norepinephrine, which are released when an increase in body temperature is needed, act at the cellular level to shift body metabolism to heat production rather than energy generation. This may be one of the reasons fever tends to produce feelings of weakness and fatigue. Thyroid hormone increases cellular metabolism, but this response u­ sually requires several weeks to reach maximal effectiveness. Fine involuntary actions such as shivering and chattering of the teeth can produce a three- to fivefold increase in body temperature. Shivering is initiated by impulses from the hypothalamus. Although shivering is an attempt to decrease the body temperature, it actually increases it and increases the use of oxygen by approximately 40%.7 The first muscle change that occurs with shivering is a general increase in muscle tone, followed by an oscillating rhythmic tremor involving the spinal-level reflex that controls muscle tone.8 Physical exertion increases body temperature. Muscles convert most of the energy in the fuels they consume into heat rather than mechanical work. With strenuous exercise, more than three fourths of the increased metabolism resulting from muscle activity appears as heat within the body, and the remainder appears as mechanical work.

Mechanisms of Heat Loss Most of the body’s heat losses occur at the skin surface as heat from the blood moves to the skin and from there into the surrounding environment. There are numerous arteriovenous (AV) anastomoses under the skin surface that allow blood to move directly from the arterial to the venous system.3 These AV anastomoses are much like the radiators in a ­heating s­ ystem. When the shunts are open, body heat is freely

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dissipated to the skin and surrounding environment; when the shunts are closed, heat is retained in the body. The blood flow in the AV anastomoses is controlled almost exclusively by the sympathetic nervous system in response to changes in core temperature and environmental temperature. Contraction of the pilomotor muscles of the skin, which raises skin hairs and produces goose bumps, also aids in heat conservation by reducing the surface area available for heat loss. Heat is lost from the body through radiation, conduction, and convection from the skin surface; through the evaporation of sweat and insensible perspiration; through the exhalation of air that has been warmed and humidified; and through heat lost in urine and feces. Of these mechanisms, only heat losses that occur at the skin surface are directly under hypothalamic control. Radiation Radiation is the transfer of heat through air or a vacuum. Heat from the sun is carried by radiation. Heat loss by radiation varies with the temperature of the environment. Environmental temperature must be less than that of the body for heat loss to occur. In a nude person sitting inside a normal-temperature room, approximately 60% of body heat typically is dissipated by radiation.3 Conduction Conduction is the direct transfer of heat from one molecule to another. Blood carries, or conducts, heat from the inner core of the body to the skin surface. Normally only a small amount of body heat is lost through conduction to a cooler surface. Cooling blankets or mattresses that are used for reducing fever rely on conduction of heat from the skin to the cool surface of the mattress. Heat also can be conducted in the opposite direction—from the external environment to the body surface. For instance, body temperature may rise slightly after a hot bath. Water has a specific heat several times greater than air, so water absorbs far greater amounts of heat than air does. The loss of body heat can be excessive and life threatening in situations of cold water immersion or cold exposure in damp or wet clothing. The conduction of heat to the body’s surface is influenced by blood volume. In hot weather, the body compensates by increasing blood volume as a means of dissipating heat. A mild swelling of the ankles during hot weather provides evidence of blood volume expansion. Exposure to cold produces a cold diuresis and a reduction in blood volume as a means of controlling the transfer of heat to the body’s surface.9 Convection Convection refers to heat transfer through the circulation of air currents. Normally, a layer of warm air tends to remain near the body’s surface. Convection causes continual removal of the warm layer and replacement with air from the s­ urrounding environment. The wind-chill factor that often is included in the weather report combines the effect of convection due to wind with the still-air temperature.

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220   UNIT III  Disorders of Integrative Function

Evaporation Evaporation involves the use of body heat to convert water on the skin to water vapor. Water that diffuses through the skin independent of sweating is called insensible perspiration. Insensible perspiration losses are greatest in a dry environment. Sweating occurs through the sweat glands and is controlled by the sympathetic nervous system. Sweating is mediated by acetylcholine. This is unlike other sympathetically mediated functions in which the catecholamines serve as neuromediators. The impact of this is that anticholinergic drugs, such as atropine, can interfere with heat loss by interrupting sweating. Evaporative heat losses involve insensible perspiration and sweating, with 0.58 cal being lost for each gram of water that is evaporated.3 As long as body temperature is greater than the atmospheric temperature, heat is lost through radiation. However, when the temperature of the surrounding environment becomes greater than skin temperature, evaporation is the only way the body can rid itself of heat. Any condition that prevents evaporative heat losses causes the body temperature to rise.

IN SUMMARY Core body temperature is normally maintained within a range of 36.0°C to 37.5°C (97.0°F to 99.5°F). Core body and skin temperatures are sensed and integrated by thermoregulatory regions in the hypothalamus and other brain structures that function to modify heat production and heat loss as a means of regulating body temperature. Metabolic processes that occur within deeper core structures (i.e., muscles and viscera) of the body produce most of the body’s heat. The sympathetic neurotransmitters (epinephrine and norepinephrine) and thyroid hormone act at the cellular level to shift body metabolism to heat production, whereas shivering and chattering of the teeth use the heat liberated from involuntary muscle movements to increase body temperature. Most of the body’s heat losses occur at the skin surface as heat from the blood moves through the skin and from there into the surrounding environment. Heat is lost from the skin through radiation, conduction, convection, and evaporation of perspiration and sweat. Contraction of the pilomotor muscles of the skin aids in heat conservation by reducing the surface area available for heat loss.

INCREASED BODY TEMPERATURE After completing this section of the chapter, you should be able to meet the following objectives: •• Characterize the physiology of fever. •• Differentiate between the physiologic mechanisms involved in fever and hyperthermia. •• Compare the mechanisms of malignant hyperthermia and neuroleptic malignant syndrome.

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Both fever and hyperthermia describe conditions in which body temperature is higher than the normal range. Fever is due to an upward displacement of the thermostatic set point of the thermoregulatory center in the hypothalamus. This is in ­contrast to hyperthermia, in which the set point is unchanged, but the mechanisms that control body temperature are ­ineffective in maintaining body temperature within a normal range during situations when heat production outpaces the ability of the body to dissipate that heat.

Fever Fever, or pyrexia, describes an elevation in body temperature that is caused by an upward displacement of the thermostatic set point of the hypothalamic thermoregulatory center. Temperature is one of the most frequent physiologic responses to be monitored during illness.

Key Points FEVER •  Fever represents an increase in body ­temperature that results from a cytokine-induced increase in the set point of the thermostatic center in the ­hypothalamus. •  Fever is a nonspecific response that is mediated by endogenous pyrogens released from host cells in response to infectious or noninfectious disorders.

Mechanisms Many proteins, breakdown products of proteins, and certain other substances released from bacterial cell membranes can cause a change in the set point to rise. Fever is resolved when the condition that caused the increase in the set point is removed. Fevers that are regulated by the hypothalamus ­usually do not rise above 41°C (105.8°F), suggesting a ­built-in thermostatic safety mechanism. Temperatures above that level are usually the result of superimposed activity, such as convulsions, hyperthermic states, or direct impairment of the temperature control center. Pyrogens are exogenous or endogenous substances that produce fever. Exogenous pyrogens are derived from outside the body and include such substances as bacterial products, bacterial toxins, or whole microorganisms. Exogenous pyrogens induce host cells to produce fever-producing ­ mediators called endogenous pyrogens. When bacteria or breakdown products of bacteria are present in blood or tissues, ­phagocytic cells of the immune system engulf them. These phagocytic cells digest the bacterial products and then release pyrogenic cytokines, principally interleukin-1 (IL-1), interleukin-6 ­ ­ (IL-6), and tumor necrosis factor-α (TNF-α), into the bloodstream for transport to the hypothalamus, where they exert their action.3 These cytokines induce p­ rostaglandin E2 (PGE2), which is a metabolite of

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Chapter 10  Alterations in Temperature Regulation    221

a­ rachidonic acid (an intramembrane fatty acid). It is hypothesized that when interleukin (IL-1B) interacts with the endothelial cells of the blood–brain barrier in the capillaries of the organum vasculosum laminae terminalis (OVLT), which is in the third ventricle above the optic chiasm, PGE2 is released into the hypothalamus.1 At this point, PGE2 binds to receptors in the hypothalamus to induce increases in the thermostatic set point through the second messenger cyclic adenosine monophosphate (cAMP). In response to the increase in its thermostatic set point, the hypothalamus initiates shivering and vasoconstriction that raise the body’s core temperature to the new set point, and fever is established. Although the central role of PGE2 in raising the set point of the hypothalamic thermoregulatory center and producing fever is not questioned, research suggests that the febrile response to invading gram-negative bacteria and their products (mainly endotoxic lipopolysaccharides) is mediated by PGE2.1 In addition to their fever-producing actions, the endogenous pyrogens mediate a number of other responses. For example, IL-1 and TNF-α are inflammatory mediators that produce other signs of inflammation such as leukocytosis, anorexia, and malaise. Many noninfectious disorders, such as myocardial infarction, pulmonary emboli, and neoplasms, produce fever. In these conditions, the injured or abnormal cells incite the production of endogenous pyrogens. For example, trauma and surgery can be associated with up to 3 days of fever. Some malignant cells, such as those of leukemia and Hodgkin disease, secrete chemical mediators that function as endogenous pyrogens. A fever that has its origin in the central nervous system is sometimes referred to as a neurogenic fever. It usually is caused by damage to the hypothalamus due to central nervous system trauma, intracerebral bleeding, or an increase in intracranial pressure. Neurogenic fever is characterized by a high temperature that is resistant to antipyretic therapy and is not associated with sweating. Purpose The purpose of fever is not completely understood. However, from a purely practical standpoint, fever is a valuable index to health status. For many, fever signals the presence of an infection and may legitimize the need for medical treatment. There is little research to support the belief that fever is harmful unless the temperature rises above 40°C (104°F). However, animal studies have demonstrated a clear survival advantage in infected members with fever compared with animals that were unable to produce a fever. It has also been shown that small elevations in temperature such as those that occur with fever enhance immune function by T lymphocyte proliferation.3 Many of the microbial agents that cause infection grow best at normal body temperatures, and their growth is inhibited by temperatures in the fever range. Yet, fever is negative in many situations such as in older adults who have cardiac or pulmonary disease because

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it causes more of a demand for oxygen. For every elevated 1°C of temperature, the BMR increases by 7% and causes increased work of the heart. Fever can also produce confusion, tachycardia, and tachypnea. Cell damage can occur when temperatures are elevated greater than 42.2°C (108°F), and this can ultimately cause life-threatening acidosis, hypoxia, and hyperkalemia.9 Patterns The patterns of temperature change in people with fever vary. Additionally, the average diurnal variation in temperature yields a peak rise in the late afternoon or early evening.2 These patterns can be described as intermittent, remittent, sustained, or relapsing (Fig. 10.3). An intermittent fever is one in which temperature returns to normal at least once every 24 hours. In a remittent fever, the temperature does not return to normal and varies a few degrees in either direction. In a sustained or continuous fever, the temperature remains above normal with minimal variations (usually 10,000 Da) such as proteins, polysaccharides, lipids, and free nucleic acids. Antigens are recognized by specific receptors present on the surface of lymphocytes and by the antibodies or immunoglobulins secreted in response to the antigen. Antigens can take the form of any foreign substance including bacteria, fungi, viruses, protozoa, parasites, and nonmicrobial agents such as plant pollens, insect venom, and transplanted organs.

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Understanding

The Complement System

The complement system provides one of the major effector mechanisms of both humoral and innate immunity. The system consists of a group of proteins (complement proteins C1 through C9) that are normally present in the plasma in an inactive form. Activation of the complement system is a highly regulated process, involving the sequential breakdown of the complement proteins to generate a cascade of cleavage products capable of proteolytic enzyme activity. This allows for tremendous amplification because each enzyme molecule activated by one step can generate multiple activated enzyme molecules at the next step. Complement activation is inhibited by proteins that are present on normal host cells; thus, its actions are limited to microbes and other antigens that lack these inhibitory proteins. The reactions of the complement system can be divided into three phases: (1) the initial activation phase, (2) the early-step inflammatory responses, and (3) the late-step membrane attack responses.

Initial Activation Phase There are three pathways for recognizing microbes and activating the complement system: (1) the alternative pathway, which is activated on microbial cell surfaces in the absence of antibody and is a component of innate immunity; (2) the classical pathway, which is activated by certain types of antibodies bound to antigen and is part of humoral immunity; and (3) the lectin pathway, which is activated by a plasma lectin that binds to mannose on microbes and activates the classical system pathway in the absence of antibody.

Antibody

Classical pathway

Alternative pathway

Lectin pathway

Microbe

Mannosebinding lectin

C3

Complement protein

Early-Step Inflammatory Responses The central component of complement for all three pathways is the activation of the complement protein C3 and its enzymatic cleavage into a larger C3b fragment and a smaller C3a fragment. The smaller 3a fragment stimulates inflammation by acting as a chemoattractant for neutrophils. The larger 3b fragment becomes attached to the microbe and acts as an opsonin for phagocytosis. It also acts as an enzyme to cleave C5 into two components: a C5a fragment, which produces vasodilation and increases vascular permeability, and a C5b fragment, which leads to the late-step membrane attack responses.

C3

3b bound to microbe

b

C3

C3a

C3b

Chemotaxis

C3b

C5 Phagocytosis

Vascular dilation and permeability

C5a

Continued

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290   UNIT IV  Infection, Inflammation, and Immunity

Understanding

The Complement System (Continued)

Late-Step Membrane Attack In the late-step responses, C3b binds to other complement proteins to form an enzyme that cleaves C5, generating C5a and C5b fragments. C5a stimulates the influx of neutrophils and the vascular phase of acute inflammation. The C5b fragment, which remains attached to the microbe, initiates the formation of a complex of complement proteins C6, C7, C8, and C9 into a membrane attack complex protein, or pore, that allows fluids and ions to enter and cause cell lysis.

C5

Membrane attack complex

C5b C5b C6,C7,C8,C9

Lysis of microbe

Antigens possess immunologically active sites called antigenic determinants, or epitopes. These are smaller, discrete components of the antigen that have a unique molecular shape, which can be recognized by and bound to a specific Ig receptor found on the surface of the lymphocyte or by an antigen-binding site of a secreted antibody (Fig. 13.4). It is not unusual for a single antigen to possess several antigenic determinants and, therefore, be capable of stimulating several different T and B lymphocytes. For example, different proteins that comprise the influenza virus may function as unique antigens (A, B, C, H, and N antigens), each of which contains several antigenic determinants. Hundreds of antigenic determinants are found on structures such as the bacterial cell wall. Low molecular weight molecules (350 beats/minute) is a fatal arrhythmia unless it is successfully treated with defibrillation. Arrhythmogenic cardiomyopathies are inherited disorders of the ion channels that control the electrical activity of the heart. Among the inherited arrhythmogenic disorders are congenital LQTS, SQTS, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Alterations in the conduction of impulses through the AV node lead to disturbances in the transmission of impulses from the atria to the ventricles. There can be a delay in transmission (i.e., first-degree heart block), failure to conduct one or more impulses (i.e., second-degree heart block), or complete failure to conduct impulses between the atria and the ventricles (i.e., third-degree heart block). Conduction disorders of the bundle of His and Purkinje system, called bundle branch blocks, cause a widening of and changes in the configuration of the QRS complex of the ECG. The diagnosis of disorders of cardiac rhythm and conduction typically is accomplished using surface ECG recordings or electrophysiologic studies. Surface electrodes can be used to obtain a 12-lead ECG; signal-averaged electrocardiographic studies in which multiple samples of QRS waves are averaged to detect ventricular late action potentials; and Holter monitoring, which provides continuous ECG recordings for up to 48 hours and loop recording, which provides continuous recording up to 1 year. Electrophysiologic studies use electrode catheters inserted into the right heart through a peripheral vein as a means of directly stimulating the heart while obtaining an intracardiac ECG recording. Both medications and electrical devices are used in the treatment of arrhythmias and conduction disorders. Antiarrhythmic drugs act by modifying disordered formation and conduction of impulses that induce cardiac muscle contraction. They include drugs that act by blocking the fast sodium channels, β-adrenergic blocking drugs that decrease sympathetic outflow to the heart, drugs that act by inhibiting the potassium current and repolarization, calcium channel–blocking agents, cardiac glycosides (i.e., digitalis drugs), and adenosine, which is used for emergency intravenous treatment of paroxysmal supraventricular tachycardia involving the AV mode. Electrical devices include temporary and permanent cardiac pacemakers that

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are used to treat symptomatic bradycardias or to provide overdrive pacing procedures; defibrillators that are used to treat atrial and ventricular fibrillation; external or internally implanted cardioversion devices, which can be used to treat ventricular tachycardia; and RF ablation and cryoablation therapy, which are used to destroy specific irritable foci in the heart. Surgical procedures can be performed to excise irritable or dysfunctional tissue, to replace cardiac valves, or to provide better blood supply to the myocardial muscle wall.

Review Exercises 1. A 75-year-old woman with a history of congestive heart failure comes to the clinic complaining of feeling tired. Her heart rate is 121 beats/minute, and the rhythm is irregular. A. What type of arrhythmia do you think she might be having? What would it look like if you were to obtain an ECG? B. What causes this irregularity? C. Why do you think she is feeling tired? D. What are some of the concerns with this type of arrhythmia? 2. A 45-year-old man appears at the urgent care center with complaints of chest discomfort, shortness of breath, and generally not feeling well. You assess vital signs and find that his temperature is 99.2°F, blood pressure 180/90, pulse 90 and slightly irregular, and respiratory rate 26. You do an ECG, and the readings from the anterior leads indicate that he is experiencing an ischemic episode. A. You attach him to a cardiac monitor and see that his underlying rhythm is normal sinus rhythm, but he is having frequent premature contractions that are more than 0.10 sec in duration. What type of premature contractions do you suspect? B. What would you expect his pulse to feel like? C. What do you think the etiology of this arrhythmia might be? How might it be treated?

References 1. Guyton A. C., Hall J. E. (2010). Textbook of medical physiology (11th ed., pp. 1115–1127, 1157). Philadelphia, PA: Elsevier Saunders. 2. Rubart M., Zipes D. P. (2012). Genesis of cardiac arrhythmias: Electrophysiologic considerations. In Bonow R.O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 653–687). Philadelphia, PA: Elsevier Saunders. 3. Ho S. Y., Becker A. E. (2011). Anatomy of electrophysiology. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 911–924). New York: McGraw-Hill.

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Chapter 33  Disorders of Cardiac Conduction and Rhythm    865 4. Malouf J. F., Edwards W. D., Tajik A. J. (2011). Functional anatomy of the heart. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 63–93). New York: McGraw-Hill. 5. Levy M. N., Pappano A. J. (2007). Cardiovascular physiology (9th ed., pp. 13–54). Philadelphia, PA: Mosby Elsevier. 6. Fogoros R. N. (2006). Electrophysiologic testing. Malden, MA: Blackwell Science. 7. Katz A. M. (2006). Physiology of the heart (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 8. Woods S. L., Froelicher E. S., Motzer S. U., et al. (2010). Cardiac nursing (6th ed., 300–387). Philadelphia, PA: Lippincott Williams & Wilkins. 9. Rajaganesha R., Ludlam C. L., Fancis D. P, et al. (2008). Accuracy of ECG lead placement among technicians, nurses, general physicians, and cardiologist. International Journal of Clinical Practice 62, 65–70. 10. Mirvis D. M., Goldberger A. L. (2011). Electrocardiography. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 107–151). Philadelphia, PA: Elsevier Saunders. 11. Ioannidis J. P., Salem D., Chew P. W., et al. (2001). Accuracy and clinical effect of out-of-hospital electrocardiography in the diagnosis of acute cardiac ischemia: A meta-analysis. Annals of Emergency Medicine 37, 461–470. 12. Chun A. A., McGee S. R. (2004). Bedside diagnosis of coronary artery disease: A systematic review. American Journal of Medicine 117, 334–343. 13. Yang M. J., Tran D. X., Weiss J. N., et al. (2007). The pinwheel experiment revisited: Effects of cellular electrophysiological properties on vulnerability to cardiac reentry. American Journal of Physiology: Heart and Circulatory Physiology 293, H1781–H1790. 14. Luqman N., Sung R. J., Wang C. L., et al. (2007). Myocardial ischemia and ventricular fibrillation: Pathophysiology and clinical implications. International Journal of Cardiology 119, 283–290. 15. Kuo S. R., Trayanova N. A. (2006). Action potential morphology heterogeneity in the atrium and its effect on atrial reentry: A two-dimensional and quasi-three-dimensional study. Philosophical Transactions of the Royal Society, Series A: Mathematical, Physical and Engineering Sciences 364, 1349–1366. 16. McMillan D. E., Burr R. L. (2010). Heart rate variability. In Woods S. L., Froelicher E. S., Motzer S. U., et al. (Eds.), Cardiac nursing. (6th ed., 388–399). Philadelphia, PA: Lippincott Williams & Wilkins. 17. Olgin J. L., Zipes D. P. (2012). Specific arrhythmias: Diagnosis and treatment. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (13th ed., pp. ­771–823). Philadelphia, PA: Elsevier Saunders. 18. Bonvini R. F., Hendiri T., Anwar A. (2006). Sinus arrest and moderate hyperkalemia. Annales de Cardiologie et d’Angeiologie (Paris) 55, 161–163. 19. Jacobson C. (2010). Arrhythmias and conduction disturbances. In Woods S. L., Froelicher E. S., Motzer S. U., et al. (Eds.), Cardiac nursing. (6th ed., 333–387). Philadelphia, PA: Lippincott Williams & Wilkins. 20. Prystrowky E. N., Fogel R. I. (2011). Approach to a patient with cardiac arrhythmias. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 949–960). New York: McGraw-Hill. 21. Keller K. B., Lemberg L. (2007). Iatrogenic sick sinus syndrome. American Journal of Critical Care 16, 294–297. 22. Kastor J. A. (2000). Sick sinus syndrome. In Kastor J. A. (Ed.), Arrhythmias (pp. 566–591). Philadelphia, PA: WB Saunders. 23. Keller K. B., Lemberg L. (2006). Sick sinus syndrome. American Journal of Critical Care 15, 222–229. 24. Kahn A. M., Krummen D. E., Feld G. K., et al. (2007). Localizing circuits of atrial macroreentry using electrocardiographic planes of coherent atrial activation. Heart Rhythm 4, 445–451. 25. Prystowsky E. N., Padanilam B. J., Waldo A. L. (2011). Atrial fibrillation, atrial flutter, and atrial tachycardia. In Fuster V., Walsh R. A., Harrington, R.A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 963–982). New York: McGraw-Hill.

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26. Fuster V., Rydén L. E., Asinger R. W., et al. (2001). ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation): developed in Collaboration with the North American Society of Pacing and Electrophysiology. Journal of American College of Cardiology 38(4), 1231–1266. 27. Wyse D. G., Love J. C., Yao Q., et al. (2001). Atrial fibrillation: A risk factor for increased mortality—an AVID registry analysis. Journal of Interventional Cardiac Electrophysiology 5, 267–273. 28. Khan I. A. (2002). Long QT syndrome: Diagnosis and management. American Heart Journal 143, 7–14. 29. Goldenburg I, Moss A. J. (2008). Long QT syndrome. Journal of American College of Cardiology 51, 2291–2300. 30. Tan H. L., Hou C. J., Lauer M. R., et al. (1995). Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Annals of Internal Medicine 122, 701–714. 31. Bigger T. J., Jr. (2000). Ventricular premature complexes. In Kastor J. A. (Ed.), Arrhythmias (pp. 310–325). Philadelphia, PA: WB Saunders. 32. Vijayaraman P, Ellenbogen K. A. (2011). Bradyarrhythmias and Pacemaker. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 1025–1057). New York: McGraw-Hill. 33. Tester D. J., Ackerman M. J. (2012). Genetics of cardiac arrhythmias. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 81–90). Philadelphia, PA: Elsevier Saunders. 34. Napolitano C., Prior S. G., Schwartz P. J., et al. (2005). Genetic testing in long QT syndrome: Development and validation of an efficient approach to genotyping in clinical practice. Journal of American Medical Association 294, 2975. 35. Zereba W., Cygankiewicz I. (2008). Long Qt syndrome and SQT syndrome. Progress in Cardiovascular Diseases 51, 264. 36. Priori S. G., Napolitano C. (2006). Role of genetic analysis in cardiology: Part I. Mendelian diseases: Cardiac channelopathies. Circulation 113, 1130–1135. 37. Miller J. M., Zipes D. P. (2012). Diagnosis of cardiac arrhythmias. Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 702–709). Philadelphia, PA: Elsevier Saunders. 38. Bashore T. M., Granger C. B. (2007). The heart. In Tierney L. M, McPhee S. J., Papadakis M. A. (Eds.), Current medical diagnosis and treatment (46th ed., pp. 376–386). New York: McGraw-Hill. 39. Blancher S. (2010). Cardiac electrophysiology procedures. In Woods S. L., Froelicher E. S., Motzer S. U., et al. (Eds.), Cardiac nursing. (6th ed., 400–419). Philadelphia, PA: Lippincott Williams & Wilkins. 40. Woosley R. L. (2011). Antiarrhythmic drugs. In Fuster V., Walsh, R. A., Harrington, R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 1071–1087). New York: McGraw-Hill. 41. Forgoros R. A. (2007). Antiarrhythmic drugs (2nd ed.) Philadelphia, PA: Blackwell. 42. Kerber R. E. (2011). The implantable cardioverter defibrillator. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 1088–1093. New York: McGraw-Hill. 43. O’Neill M. D., Jais P., Hocini M., et al. (2007). Catheter ablation for atrial fibrillation. Circulation 116, 1515–1523. 44. Miller J. M., Zipes D. P. (2012). Therapy for cardiac arrhythmias. Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 710–744). Philadelphia, PA: Elsevier Saunders. 45. Lukac P., Hjortdal V. E., Pedersen A. K., et al. (2007). Prevention of atrial flutter with cryoablation may be proarrhythmogenic. Annals of Thoracic Surgery 83, 1717–1723. 46. Collins K. K., Rhee E. K., Kirsh J. A., et al. (2007). Cryoablation of accessory pathways in the coronary sinus in young patients: A multicenter study from the Pediatric and Congenital Electrophysiology Society’s Working Group on Cryoablation. Journal of Cardiovascular Electrophysiology 18, 592–597.

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866   UNIT VIII  Disorders of Cardiovascular Function 47. Drew B. J., Califf R. M., Funk M., et al. (2005). AHA scientific statement: Practice standards for electrocardiographic monitoring in hospital settings: An American Heart Association Scientific Statement from the Councils on Cardiovascular Nursing, Clinical Cardiology, and Cardiovascular Disease in the Young: Endorsed by the International Society of Computerized Electrocardiology and the American Association of Critical-Care Nurses. Journal of Cardiovascular Nursing 20, 76–106.

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48. Chen P., Antzelevitch C. (2011). Mechanisms of cardiac arrhythmias and conduction disturbances. In Fuster V., Walsh R. A., Harrington R. A, et al. (Eds.), Hurst’s the heart (13th ed., pp. 925–948). New York: McGraw-Hill.

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Heart Failure and Circulatory Shock HEART FAILURE

Pathophysiology of Heart Failure Control of Cardiac Performance and Output Systolic versus Diastolic Dysfunction Right versus Left Ventricular Dysfunction High-Output versus Low-Output Failure Compensatory Mechanisms Acute Heart Failure Syndromes Clinical Manifestations of Heart Failure Respiratory Manifestations Fatigue, Weakness, and Mental Confusion Fluid Retention and Edema Cachexia and Malnutrition Cyanosis Arrhythmias and Sudden Cardiac Death Diagnosis and Treatment Diagnosis Treatment

CIRCULATORY FAILURE (SHOCK)

Pathophysiology of Circulatory Shock Cardiogenic Shock Pathophysiology Clinical Manifestations Treatment Hypovolemic Shock Pathophysiology Clinical Manifestations Treatment Distributive Shock Neurogenic Shock Anaphylactic Shock Sepsis and Septic Shock Obstructive Shock Complications of Shock Acute Lung Injury/Acute Respiratory Distress Syndrome Acute Renal Failure Gastrointestinal Complications Disseminated Intravascular Coagulation Multiple Organ Dysfunction Syndrome

HEART FAILURE IN CHILDREN AND OLDER ADULTS Heart Failure in Infants and Children Clinical Manifestations Diagnosis and Treatment Heart Failure in Older Adults Clinical Manifestations Diagnosis and Treatment

34 Jaclyn Conelius

Adequate perfusion of body tissues depends on the pumping ability of the heart, a vascular system that transports blood to the cells and back to the heart, sufficient blood to fill the circulatory system, and tissues that are able to extract and use oxygen and nutrients from the blood. Heart failure and circulatory shock are separate conditions that reflect failure of the circulatory system. Both conditions exhibit common compensatory mechanisms even though they differ in terms of pathogenesis and causes.

HEART FAILURE After completing this section of the chapter, you should be able to meet the following objectives: •• Explain how the Frank-Starling mechanism, sympathetic nervous system, renin–angiotensin–aldosterone mechanism, natriuretic peptides, endothelins, and myocardial hypertrophy and remodeling function as adaptive and maladaptive mechanisms in heart failure. •• Differentiate high-output versus low-output heart failure, systolic versus diastolic heart failure, and rightsided versus left-sided heart failure in terms of causes, impact on cardiac function, and major manifestations. •• Differentiate chronic heart failure from acute heart failure syndromes and methods of diagnosis, assessment, and management. Heart failure has been defined as a complex syndrome r­ esulting from any functional or structural disorder of the heart that results in or increases the risk of developing manifestations of low cardiac output and/or pulmonary or systemic congestion.1,2 In the United States, heart failure affected an estimated approximately 5 million people in 2007. Heart failure can occur in any age group but primarily affects older adults. Although morbidity and mortality rates from other cardiovascular diseases have decreased over the past several decades, 867

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the incidence of heart failure is increasing at an alarming rate. Approximately 400,000 to 700,000 people are diagnosed with heart failure each year. The syndrome of heart failure can be produced by any heart condition that reduces the pumping ability of the heart. Among the most common causes of heart failure are coronary artery disease, hypertension, dilated cardiomyopathy, and valvular heart disease.1 Because many of the processes leading to heart failure are long-standing and progress gradually, heart failure can often be prevented or its progression slowed by early detection and intervention. The importance of these approaches is emphasized by the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines that have incorporated a classification system of heart failure that includes four stages: 1. Stage A—High risk for developing heart failure, but no identified structural abnormalities and no signs of heart failure 2. Stage B—Presence of structural heart disease, but no history of sign and symptoms of heart failure 3. Stage C—Current or prior symptoms of heart failure with structural heart disease 4. Stage D—Advanced structural heart disease and symptoms of heart failure at rest on maximum medical therapy1 This staging system recognizes that there are established risk factors and structural abnormalities that are characteristic of the four stages of heart failure. People normally progress from one stage to another unless disease progression is slowed or stopped by treatment.

Key Points HEART FAILURE •  The function of the heart is to move deoxygenated blood from the venous system through the right heart into the pulmonary circulation, and oxygenated blood from the pulmonary circulation through the left heart and into the arterial circulation. •  Systolic dysfunction represents a decrease in ­cardiac myocardial contractility and an impaired ability to eject blood from the left ventricle, ­whereas diastolic dysfunction represents an ­abnormality in ventricular relaxation and filling.

Pathophysiology of Heart Failure Cardiac output is the amount of blood that the ventricles eject each minute. The heart has the amazing capacity to adjust its cardiac output to meet the varying needs of the body. During sleep, the cardiac output declines, and during exercise, it increases markedly. The ability to increase cardiac output

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d­ uring increased activity is called the cardiac reserve. For example, competitive swimmers and long-distance runners have large cardiac reserves. During exercise, the cardiac output of these athletes rapidly increases to as much as five to six times their resting level.3 In sharp contrast with healthy athletes, people with heart failure often use their cardiac reserve at rest. For them, just climbing a flight of stairs may cause shortness of breath because they have exceeded their cardiac reserve. Control of Cardiac Performance and Output Cardiac output, which is the major determinant of cardiac performance, reflects how often the heart beats each minute (heart rate) and how much blood it pumps with each beat (stroke volume) and can be expressed as the product of the heart rate and stroke volume (i.e., cardiac output = heart rate × stroke volume). The heart rate is regulated by a balance between the activity of the sympathetic nervous system, which produces an increase in heart rate, and the parasympathetic nervous system, which slows it down, whereas the stroke volume is a function of preload, afterload, and myocardial contractility.3–6 Preload and Afterload. The work that the heart performs consists mainly of ejecting blood that has returned to the ventricles during diastole into the pulmonary or systemic circulation. It is determined largely by the loading conditions, or what are called the preload and afterload. Preload reflects the volume or loading conditions of the ventricle at the end of diastole, just before the onset of systole. It is the volume of blood stretching the heart muscle at the end of diastole and is normally determined by the venous return to the heart. During any given cardiac cycle, the maximum volume of blood filling the ventricle is present at the end of diastole. Known as the end-diastolic volume, this volume causes an increase in the length of the myocardial muscle fibers. Within limits, as end-diastolic volume or preload increases, the stroke volume increases in accord with the Frank-Starling mechanism. Afterload represents the force that the contracting heart muscle must generate to eject blood from the filled heart. The main components of afterload are the systemic (peripheral) vascular resistance and ventricular wall tension. When the systemic vascular resistance is elevated, as with arterial hypertension, an increased left intraventricular pressure must be generated to first open the aortic valve and then move blood out of the ventricle and into the systemic circulation. This increased pressure equates to an increase in ventricular wall stress or tension. As a result, excessive afterload may impair ventricular ejection and increase wall tension. Myocardial Contractility. Myocardial contractility, also known as inotropy, refers to the contractile performance of the heart. It represents the ability of the contractile elements (actin and myosin filaments) of the heart muscle to interact and shorten against a load.3–6 Contractility increases cardiac output independent of preload and afterload.

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The interaction between the actin and myosin filaments during cardiac muscle contraction (i.e., cross-bridge attachment and detachment) requires the use of energy supplied by the breakdown of adenosine triphosphate (ATP) and the presence of calcium ions (Ca++). ATP provides the energy needed for cross-bridge formation during cardiac muscle contraction and for cross-bridge detachment during muscle relaxation. As with skeletal muscle, when an action potential passes over the cardiac muscle fiber, the impulse spreads to the interior of the muscle fiber along the membranes of the transverse (T) tubules. The T tubule action potentials in turn act to cause release of Ca++ from the sarcoplasmic reticulum (Fig. 34.1). These Ca++ ions diffuse into the myofibrils and catalyze the chemical reactions that promote sliding of the actin and myosin filaments along one another to produce muscle shortening. In addition to the Ca++ ions released from the sarcoplasmic reticulum, a large quantity of extracellular Ca++ also diffuses into the sarcoplasm through voltage-dependent L-type Ca++ channels in T tubules at the time of the action potential. Without the extra Ca++ that enters through the L-type Ca++ channels, the strength of the cardiac contraction would be considerably weaker. Opening of the L-type Ca++ ­channels is K+

Cardiac glycosides

Na+

facilitated by the second messenger cyclic adenosine monophosphate (cAMP), the formation of which is coupled to β-adrenergic receptors. The catecholamines (norepinephrine and epinephrine) exert their inotropic effects by binding to these receptors. The L-type calcium channel also contains several other types of drug receptors. The dihydropyridine Ca++ channel blocking drugs (e.g., nifedipine) exert their effects by binding to one site, while diltiazem and verapamil appear to bind to closely related but not identical receptors in another region. Blockade of the Ca++ channels in cardiac muscle by these drugs results in a reduction in contractility throughout the heart and a decrease in sinus node pacemaker rate and in atrioventricular node conduction velocity. Another mechanism that can modulate inotropy is the sodium ion (Na+)/Ca++ exchange pump and the ATPasedependent Ca++ pump on the myocardial cell membrane (see Fig. 34.1). These pumps transport Ca++ out of the cell, thereby preventing the cell from becoming overloaded with Ca++. If Ca++ extrusion is inhibited, the rise in intracellular Ca++ can increase inotropy. Digitalis and related cardiac glycosides are inotropic agents that exert their effects by inhibiting the Na+/potassium ion (K+)–ATPase pump, which increases Catecholamines

ATP

β-adrenergic receptor

ATP

Na+

Ca++

Ca++ 5

T tubule 1

Troponin C

2

Tropomyosin

cAMP

Ca++

– Ca++

Actin

3

Ca++ 4

Myosin

Sarcoplasmic reticulum

L-type calcium channels

FIGURE 34.1 • Schematic representation of the role of calcium ions (Ca++) in cardiac excitation–­ contraction coupling. The influx (site 1) of extracellular Ca++ through the L-type Ca++ channels in the T tubules during excitation triggers (site 2) release of Ca++ by the sarcoplasmic reticulum. This Ca++ binds to troponin C (site 3). The Ca++–troponin complex interacts with tropomyosin to unblock active sites on the actin and myosin filaments, allowing cross-bridge attachment and contraction of the myofibrils (systole). Relaxation (diastole) occurs as a result of calcium reuptake by the sarcoplasmic reticulum (site 4) and extrusion of intracellular Ca++ by the sodium Na+/Ca++ exchange transporter or, to a lesser extent, by the Ca++ ATPase pump (site 5). Mechanisms that raise systolic Ca++ increase the level of developed force (inotropy). Binding of catecholamines to β-adrenergic receptors increases Ca++ entry by phosphorylation of the Ca++ channels through a ­cyclic adenosine monophosphate (cAMP)-dependent second messenger mechanism. The cardiac glycosides increase intracellular Ca++ by inhibiting the Na+/K+–ATPase pump. The elevated intracellular Na+ reverses the Na+/Ca++ exchange transporter (site 5), so less Ca++ is removed from the cell. (Modified from Klabunde R. E. (2005). Cardiovascular physiology concepts (p. 46). Philadelphia, PA: Lippincott Williams & Wilkins.)

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i­ ntracellular Na+; this in turn leads to an increase in intracellular Ca++ through the Na+/Ca++ exchange pump. Systolic versus Diastolic Dysfunction Classification separates the pathophysiology of heart failure into systolic and diastolic failure or dysfunction based on the ventricular ejection fraction.5 Ejection fraction is the percentage of blood pumped out of the ventricles with each contraction. A normal ejection faction is about 55% to 70%. In systolic ventricular dysfunction, myocardial contractility is impaired, leading to a decrease in the ejection fraction and cardiac output. Diastolic ventricular dysfunction is characterized by a normal ejection fraction but impaired diastolic ventricular relaxation, leading to a decrease in ventricular filling that ultimately causes a decrease in preload, stroke volume, and cardiac output. Many people with heart failure have combined elements of both systolic and diastolic ventricular dysfunction, and the division between systolic and diastolic dysfunction may be somewhat artificial, particularly as it relates to manifestations and treatment.6 It is important to note that ventricular dysfunction is not synonymous with heart failure. It can, however, lead to heart failure. With both systolic and diastolic ventricular dysfunction, compensatory mechanisms are usually able to maintain adequate resting cardiac function until the later stages of heart failure. Systolic Dysfunction. Systolic dysfunction is primarily defined as a decrease in myocardial contractility, characterized by an ejection fraction of less than 40%. A normal heart ejects approximately 65% of the blood that is present in the ventricle at the end of diastole. In systolic heart failure, the ejection fraction declines progressively with increasing degrees of myocardial dysfunction. In very severe forms of heart failure, the ejection fraction may drop to a single-digit percentage. With a decrease in ejection fraction, there is a resultant increase in end-diastolic volume (preload), ventricular dilation, and ventricular wall tension and a rise in ventricular end-diastolic pressure.7 The increased volume, added to the normal venous return, leads to an increase in ventricular preload. The rise in preload is thought to be a compensatory mechanism to help maintain stroke volume through the Frank-Starling mechanism despite a drop in ejection fraction. Although it serves as a compensatory mechanism, increased preload can also lead to one of the most deleterious consequences of systolic ventricular dysfunction—accumulation of blood in the atria and the venous system (which empties into the atria), causing pulmonary or peripheral edema. Systolic dysfunction commonly results from conditions that impair the contractile performance of the heart (e.g., ischemic heart disease and cardiomyopathy), produce a volume overload (e.g., valvular insufficiency and anemia), or generate a pressure overload (e.g., hypertension and valvular stenosis) on the heart. The extent of systolic ventricular dysfunction can be estimated by measuring the cardiac output and ejection fraction and by assessment for manifestations of left-sided heart failure, particularly pulmonary congestion.

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Diastolic Dysfunction.  Although heart failure is commonly associated with impaired systolic function, in approximately 55% of cases systolic function has been preserved and heart failure occurs exclusively on the basis of left ventricular diastolic dysfunction.6,8 Although such hearts contract normally, relaxation is abnormal. The abnormal filling of the ventricle compromises cardiac output, especially during exercise. For any given ventricular volume, ventricular pressures are elevated, leading to signs of pulmonary and systemic venous congestion identical to those seen in people with a dilated, poorly contracting heart. The prevalence of diastolic failure increases with age and is higher in women than men and in people with hypertension and atrial fibrillation.6,8 Among the conditions that cause diastolic dysfunction are those that impede expansion of the ventricle (e.g., pericardial effusion, constrictive pericarditis), those that increase wall thickness and reduce chamber size (e.g., myocardial hypertrophy, hypertrophic cardiomyopathy), and those that delay diastolic relaxation (e.g., aging, ischemic heart disease).8 Aging is often accompanied by a delay in relaxation of the heart during diastole such that diastolic filling begins while the ventricle is still stiff and resistant to stretching to accept an increase in volume. A similar delay occurs in myocardial ischemia, resulting from a lack of energy to break the rigor that forms between the actin and myosin filaments and to move Ca++ out of the cytosol and back into the sarcoplasmic reticulum.8 Diastolic function is further influenced by the heart rate, which determines how much time is available for ventricular filling. An increase in heart rate shortens the diastolic filling time.9 Thus, diastolic dysfunction can be aggravated by tachycardia or an arrhythmia and improved by a reduction in heart rate, which allows the heart to fill over a longer period. With diastolic dysfunction, blood is unable to move freely into the left ventricle, causing an increase in intraventricular pressure at any given volume. The elevated pressures are transferred from the left ventricle into the left atrium and pulmonary venous system, causing a decrease in lung compliance, which increases the work of breathing and evokes symptoms of dyspnea. Cardiac output is decreased, not because of a reduced ventricular ejection fraction as seen with systolic dysfunction but because of a decrease in the volume (preload) available for adequate cardiac output. Inadequate cardiac output during exercise may lead to fatigue of the legs and the accessory muscles of respiration. Right versus Left Ventricular Dysfunction Heart failure has been classified according to the side of the heart (right ventricular or left ventricular) that is primarily affected (Fig. 34.2). Although the initial event that leads to heart failure may be primarily right or left ventricular in origin, long-term heart failure usually involves both sides. The pathophysiologic changes that occur in the myocardium itself, including the compensatory responses in conditions like myocardial infarction, are not significantly different between right and left ventricular dysfunction and are not addressed in detail in this section.

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Right heart failure

Left heart failure

Congestion of peripheral tissues

Dependent edema and ascites

Liver congestion

GI tract congestion

Signs related to impaired liver function

Decreased cardiac output

Activity intolerance and signs of decreased tissue perfusion

Anorexia, GI distress, weight loss

Pulmonary congestion

Impaired gas exchange

Pulmonary edema

Orthopnea Cyanosis and signs of hypoxia Paroxysmal Cough with frothy sputum nocturnal dyspnea

FIGURE 34.2  •  Manifestations of left- and right-sided heart failure. (GI, gastrointestinal.)

Right Ventricular Dysfunction. Right-sided heart ­ failure impairs the ability to move deoxygenated blood from the systemic circulation into the pulmonary circulation. Consequently, when the right ventricle fails, there is a reduction in the amount of blood moved forward into the pulmonary circulation and then into the left side of the heart, ultimately causing a reduction of left ventricular cardiac output. Also, if the right ventricle does not move the blood forward, there is accumulation or congestion of blood into the systemic venous system. This causes an increase in right ventricular end-diastolic, right atrial, and systemic venous pressures. A major effect of rightsided heart failure is the development of peripheral edema (see Fig. 34.2). Because of the effects of gravity, the edema is most pronounced in the dependent parts of the body. When the person is in the upright position, edema is seen in the lower extremities; when the person is supine, the edema is seen in the area over the sacrum. The accumulation of edema fluid is evidenced by a gain in weight (i.e., 1 pint [568 mL] of accumulated fluid results in a 1 lb [0.45 kg] weight gain). Daily measurement of weight can be used as a means of assessing fluid accumulation in a person with chronic heart failure. As a rule, a weight gain of more than 2 lb (0.90 kg) in 24 hours or 5 lb (2.27 kg) in 1 week is considered a sign of worsening failure.9 Right-sided heart failure also produces congestion of the viscera. As venous distention progresses, blood backs up in the hepatic veins that drain into the inferior vena cava, and the liver becomes engorged. This may cause hepatomegaly and right upper quadrant pain. In severe and prolonged right-sided

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failure, liver function is impaired and hepatic cells may die. Congestion of the portal circulation also may lead to engorgement of the spleen and the development of ascites. Congestion of the gastrointestinal tract may interfere with digestion and absorption of nutrients, causing anorexia and abdominal discomfort. The jugular veins, which are above the level of the heart, are normally not visible in the standing position or when sitting with the head at higher than a 30-degree angle. In severe right-sided failure, the external jugular veins become distended and can be visualized when the person is sitting up or standing. The causes of right ventricular dysfunction include conditions that impede blood flow into the lungs or compromise the pumping effectiveness of the right ventricle. Left ventricular failure is the most common cause of right ventricular failure. Sustained pulmonary hypertension also causes right ventricular dysfunction and failure. Pulmonary hypertension occurs in people with chronic pulmonary disease, severe pneumonia, pulmonary embolus, or aortic or mitral stenosis. When the right heart failure occurs in response to chronic pulmonary disease, it is referred to as cor pulmonale.10 Other common causes include stenosis or regurgitation of the tricuspid or pulmonic valves, right ventricular infarction, and cardiomyopathy. Right ventricular dysfunction with heart failure is also caused by congenital heart defects such as tetralogy of Fallot and ventricular septal defect. Left Ventricular Dysfunction. Left-sided heart failure impairs the movement of blood from the low-pressure pulmonary circulation into the high-pressure arterial side of the

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872   UNIT VIII  Disorders of Cardiovascular Function

systemic circulation. With impairment of left heart function, there is a decrease in cardiac output to the systemic circulation. Blood accumulates in the left ventricle, left atrium, and pulmonary circulation, which causes an elevation in ­pulmonary venous pressure (see Fig. 34.2). When the pressure in the pulmonary capillaries (normally approximately 10 mm Hg) exceeds the capillary osmotic pressure (normally approximately 25 mm Hg), there is a shift of intravascular fluid into the interstitium of the lung and development of pulmonary edema (Fig. 34.3). An episode of pulmonary edema often occurs at night, after the person has been reclining for some time and the gravitational forces have been removed from the circulatory system. It is then that the edema fluid that had been sequestered in the lower extremities during the day is returned to the vascular compartment and redistributed to the pulmonary circulation. The most common causes of left ventricular dysfunction are hypertension and acute myocardial infarction. Left ventricular heart failure and pulmonary congestion can develop

Normal

Capillary colloidal osmotic pressure 25 mm Hg

Capillary filtration pressure 10 mm Hg Arterial

Venous

Pulmonary edema

Capillary colloidal osmotic pressure 25 mm Hg

Capillary filtration pressure >25 mm Hg Arterial

Venous

FIGURE 34.3 • Mechanism of respiratory symptoms in left-sided heart failure. In the normal exchange of fluid in the pulmonary capillaries (top), the capillary filtration pressure that moves fluid out of the capillary into the lung is less than the capillary colloidal osmotic pressure that pulls fluid back into the capillary. Development of pulmonary edema (bottom) occurs when the capillary filtration pressure exceeds the capillary colloidal osmotic pressure that pulls fluid back into the capillary.

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very rapidly in people with acute myocardial infarction. Even when the infarcted area is small, there may be a surrounding area of ischemic tissue. This may result in large areas of ventricular wall hypokinesis or akinesis and rapid onset of pulmonary congestion and edema. Stenosis or regurgitation of the aortic or mitral valve also creates the level of left-sided backflow that results in pulmonary congestion. As pulmonary pressure rises as a result of congestion, it may progress to produce right-sided heart failure. High-Output versus Low-Output Failure High- and low-output heart failures are described in terms of cardiac output. High-output failure is an uncommon type of heart failure that is caused by an excessive need for cardiac output. With high-output failure, the function of the heart may be supranormal but inadequate owing to excessive metabolic needs. Causes of high-output failure include severe anemia, thyrotoxicosis, conditions that cause arteriovenous shunting, and Paget disease. Low-output failure is caused by disorders that impair the pumping ability of the heart, such as ischemic heart disease and cardiomyopathy. Low-output failure is characterized by clinical evidence of systemic vasoconstriction with cold, pale, and sometimes cyanotic extremities.9 In advanced forms of low-output failure, marked reductions in stroke volume are evidenced by a narrowing of the pulse pressure. In contrast, in high-output failure, the extremities are usually warm and flushed and the pulse pressure is widened or at least normal. Compensatory Mechanisms In heart failure, the cardiac reserve is largely maintained through compensatory or adaptive responses such as the Frank-Starling mechanism, activation of neurohumoral influences such as the sympathetic nervous system reflexes, the renin–angiotensin–aldosterone mechanism, NPs, locally produced vasoactive substances, and myocardial hypertrophy and remodeling9 (Fig. 34.4). The first of these adaptations occurs rapidly over minutes to hours of myocardial dysfunction and may be adequate to maintain the overall pumping performance of the heart at relatively normal levels. Myocardial hypertrophy and remodeling occur slowly over months to years and play an important role in the long-term adaptation to hemodynamic overload. In the failing heart, early decreases in cardiac function may go unnoticed because these compensatory mechanisms maintain the cardiac output. However, these mechanisms contribute not only to the adaptation of the failing heart but also to the pathophysiology of heart failure.9 Frank-Starling Mechanism. The Frank-Starling mechanism operates through an increase in preload (Fig. 34.5). With increased diastolic filling, there is increased stretching of the myocardial fibers and more optimal approximation of the heads on the thick myosin filaments to the troponin binding sites on the thin actin filaments, with a resultant increase in

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Chapter 34  Heart Failure and Circulatory Shock    873

Vascular resistance (afterload)

Frank-Starling mechanism

Cardiac contractility Heart rate

Cardiac output Myocardial hypertrophy and remodeling

Renal blood flow

Venous return (preload)

Sympathetic reflexes

Vascular tone

Reninangiotensinaldosterone mechanism

Angiotensin II

Aldosterone Adrenal gland

FIGURE 34.4 • Compensatory mechanisms in heart failure. The Frank-Starling mechanism, sympathetic reflexes, renin–angiotensin–aldosterone mechanism, and myocardial hypertrophy function in maintaining cardiac output for the failing heart.

Vascular volume

the force of the next contraction. In the normally f­ unctioning heart, the Frank-Starling mechanism serves to match the ­outputs of the two ventricles. As illustrated in Figure 34.5, there is no one single Frank-Starling curve.4 An increase in contractility, or inotropy, will increase cardiac output at any

Cardiac output (L/min)

3 cm

5.5 cm

A 5

B

C

D

12

22

Left ventricular end-diastolic pressure (mm Hg) FIGURE 34.5  •  Left ventricular function curves. Curve A: Normal function curve, with a normal cardiac output and optimal left ventricular enddiastolic (LVED) filling pressure. Curve B: Compensated heart failure with normal cardiac output at higher LVED pressures. Curve C: Decompensated heart failure with a decrease in cardiac output and elevated LVED, with eventual elevation of pulmonary capillary pressure and development of pulmonary congestion. Curve D: Cardiogenic shock, with an extreme decrease in cardiac output and marked increase in LVED pressures.

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Sodium and water retention

end-diastolic volume, causing the curve to move up and to the left, whereas a decrease in inotropy will cause the curve to move down and to the right. In heart failure, inotropy is decreased compared with normal. Thus, the stroke volume will not be as high as with normal inotropy, regardless of the increase in preload. In heart failure, a decrease in cardiac output and renal blood flow leads to increased sodium and water retention, a resultant increase in vascular volume and venous return to the heart, and an increase in ventricular end-diastolic volume. Within limits, as preload and ventricular end-diastolic ­volume increase, there is a resultant increase in cardiac output. Although this may preserve the resting cardiac output, the resulting chronic elevation of left ventricular end-diastolic pressure is transmitted to the atria and the pulmonary circulation, causing pulmonary congestion. An increase in muscle stretch, as occurs with the FrankStarling mechanism, also causes an increase in ventricular wall tension with a resultant increase in myocardial oxygen consumption. Because increased wall tension increases myocardial oxygen requirements, it can produce ischemia and contribute to further impairment of inotropy, moving the Frank-Starling curve farther down and to the right (see Fig. 34.5). In this situation, the increase in preload is no longer contributing to compensation but rather causing heart ­failure to worsen. The use of diuretics in people with heart ­failure helps to reduce vascular volume and ventricular filling, thereby unloading the heart and reducing ventricular wall tension.

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Sympathetic Nervous System Activity.  Stimulation of the sympathetic nervous system plays an important role in the compensatory response to decreased cardiac output and stroke volume.9,11 Both cardiac sympathetic tone and catecholamine (epinephrine and norepinephrine) levels are elevated during the late stages of most forms of heart failure. By direct stimulation of heart rate and cardiac contractility, regulation of vascular tone, and enhancement of renal sodium and water retention, the sympathetic nervous system initially helps to maintain perfusion of the various body organs. In people who progress to more severe heart failure, blood is diverted to the more critical cerebral and coronary circulations. Although the sympathetic nervous system response is meant to augment blood pressure and cardiac output and is the most immediate compensatory mechanism, it can become maladaptive. An increase in sympathetic activity by stimulation of the β-adrenergic receptors of the heart leads to tachycardia, vasoconstriction, and cardiac arrhythmias. Acutely, tachycardia significantly increases the workload of the heart, thus increasing myocardial oxygen demand and leading to cardiac ischemia, myocyte damage, and decreased contractility (inotropy).11 Cardiac ischemia and cardiomyopathy both contribute to worsening of heart failure. By promoting arrhythmias, the catecholamines released with sympathetic nervous system stimulation also may contribute to the high rate of sudden death seen with heart failure. There is evidence that prolonged sympathetic stimulation may also lead to desensitization of β-adrenergic receptors without affecting α-adrenergic receptors.4 Even though circulating norepinephrine levels are increased in people with heart failure, the lack of functioning β-adrenergic receptors in relation to α-adrenergic receptors may lead to vasoconstriction and an increase in systemic vascular resistance. An increase in systemic vascular resistance causes an increase in cardiac afterload and ventricular wall stress, thus increasing myocardial oxygen consumption. Other effects include decreased renal perfusion and additional augmentation of the renin–angiotensin–aldosterone system, as well as decreased blood flow to skin, muscle, and abdominal organs.11 Renin–Angiotensin–Aldosterone Mechanism. One of the most important effects of lowered cardiac output in heart failure is a reduction in renal blood flow and glomerular filtration rate, which leads to sodium and water retention. With decreased renal blood flow, there is a progressive increase in renin secretion by the kidneys with parallel increases in circulating levels of angiotensin II. The increased concentration of angiotensin II contributes directly to a generalized and excessive vasoconstriction, as well as facilitating norepinephrine release and inhibiting reuptake of norepinephrine by the sympathetic nervous system.11 Angiotensin II also provides a powerful stimulus for aldosterone production by the adrenal cortex. Aldosterone increases tubular reabsorption of sodium, with an accompanying increase in water retention. Because aldosterone is metabolized in the liver, its levels are further increased when heart

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f­ ailure causes liver congestion. Angiotensin II also increases the level of antidiuretic hormone (ADH), which serves as a vasoconstrictor and inhibitor of water excretion. In heart failure, the progressive accumulation of fluid leads to ventricular dilation and increased wall tension. The increased oxygen demand that accompanies increased wall tension eventually outweighs the compensatory Frank-Starling mechanism, reducing inotropy and progressing heart failure. In addition to their individual effects on sodium and water balance, angiotensin II and aldosterone are also involved in regulating the inflammatory and reparative processes that follow tissue injury.12 In this capacity, they stimulate inflammatory cytokine production (e.g., tumor necrosis factor [TNF] and interleukin-6), attract inflammatory cells (e.g., neutrophils and macrophages), activate macrophages at sites of injury and repair, and stimulate the growth of fibroblasts and synthesis of collagen fibers. Fibroblast and collagen deposition results in ventricular hypertrophy and myocardial wall fibrosis, which decreases compliance (i.e., increases stiffness), ultimately causing inappropriate remodeling of the heart and progression of both systolic and diastolic ventricular dysfunction.13 Thus, the progression of heart failure may be augmented by aldosterone-mediated effects on both the vasculature and myocardium. Natriuretic Peptides.  The heart muscle produces and secretes a family of related peptide hormones, the cardiac natriuretic hormones or NPs, that have potent diuretic, natriuretic, and vascular smooth muscle effects and also interact with other neurohumoral mechanisms that affect cardiovascular function. Two of the four known NPs most commonly associated with heart failure are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).14 As the name indicates, ANP is released from atrial cells in response to atrial stretch, pressure, or fluid overload. BNP is primarily secreted by the ventricles as a response to increased ventricular pressure or fluid overload. In early heart failure, NT-proBNP can be detected as a precursor for BNP in the blood. Although the NPs are not secreted from the same chambers in the heart, they have very similar functions. In response to increased chamber stretch and pressure, they promote rapid and transient natriuresis and diuresis through an increase in the glomerular filtration rate and an inhibition of tubular sodium and water reabsorption. The NPs also facilitate complex interactions with the neurohormonal system, inhibiting the sympathetic nervous system, the renin–angiotensin–aldosterone system, endothelin inflammatory cytokines, and vasopressin.14 Suppression of the sympathetic nervous system causes both venous and arterial dilation with consequent reduction in venous return to the heart (decreased preload) and cardiac filling pressures, and a decrease in afterload (arterial vasodilation). Inhibition of angiotensin II and vasopressin by the NPs reduces renal fluid retention. In addition, the NPs directly affect the central nervous system and the brain, inhibiting the secretion of vasopressin and the function of the salt appetite and thirst center.14

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Circulating levels of both ANP and BNP are reportedly elevated in people with heart failure. BNP and NT-pro BNP levels can be detected through blood work and commercial assays. The concentrations are well correlated with the extent of ventricular dysfunction, increasing up to 30-fold in ­people with advanced heart disease.14 Assays of BNP are used clinically in the diagnosis of heart failure and to predict the severity of the condition. Many of the medications used to treat heart failure (e.g., diuretics, such as spironolactone, and the angiotensin-converting enzyme [ACE] inhibitors) reduce BNP concentrations. Therefore, many people with chronic stable heart failure have BNP levels in the normal diagnostic range. However, digoxin and beta-blockers appear to increase BNP levels. There are drugs designed to inhibit degradation on NPs as a potential for therapy. Endothelins. The endothelins, released from the endothelial cells throughout the circulation, are potent vasoconstrictor peptides. Like angiotensin II, endothelin can also be synthesized and released by a variety of cell types, such as cardiac myocytes. Four endothelin peptides (endothelin-1 [ET-1], ET-2, ET-3, and ET-4) have been identified.14 However, all of their physiological functions remain unclear. It has been found that the endothelins induce vascular smooth muscle cell proliferation and cardiac myocyte hypertrophy; increase the release of ANP, aldosterone, and catecholamines; and exert antinatriuretic effects on the kidneys. Production of ET-1 is regulated by many factors that are significant for cardiovascular function and have implications for heart failure. For example, it is enhanced by angiotensin II, vasopressin, and norepinephrine and by factors such as shear stress and endothelial stretching.14 Plasma ET-1 levels also correlate directly with pulmonary vascular resistance, and it is thought that the peptide may play a role in mediating pulmonary hypertension in people with heart failure. There are at least two types of endothelin receptors—type A and type B.14 Type A receptor is associated with smooth muscle constriction and hypertrophy while Type B receptor is associated with vasodilation. Since ET-1 can act on the heart to cause hypertrophy and sodium and water retention, an endothelin receptor antagonist is now available for use in people with pulmonary arterial hypertension due to severe heart failure. Inflammatory Mediators. There is ongoing research examining the relationship between inflammatory markers, especially C-reactive protein (CRP), and heart failure. Elevated CRP levels have been associated with adverse consequences in people with heart failure. They have also been shown to be predictive of the development of heart failure in high-risk groups. Of particular interest are the interactions between CRP and mediators, such as angiotensin II and norepinephrine. This inflammatory relationship continues to be examined. However, it is difficult to test since it is not understood how to decrease the inflammatory effect in heart failure.

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Myocardial Hypertrophy and Remodeling. The development of myocardial hypertrophy constitutes one of the principal mechanisms by which the heart compensates for an increase in workload.9 Although ventricular hypertrophy improves the work performance of the heart, it is also an important risk factor for subsequent cardiac morbidity and mortality. Inappropriate hypertrophy and remodeling can result in changes in structure (i.e., muscle mass, chamber dilation) and function (i.e., impaired systolic or diastolic function) that often lead to further pump dysfunction and hemodynamic overload. Myocardial hypertrophy and remodeling involve a series of complex events at both the molecular and cellular levels. The myocardium is composed of myocytes, or muscle cells, and nonmyocytes. The myocytes are the functional units of cardiac muscle. Their growth is limited by an increment in cell size, as opposed to an increase in cell number. The nonmyocytes include cardiac macrophages, fibroblasts, vascular smooth muscle, and endothelial cells. These cells, which are present in the interstitial space, remain capable of an increase in cell number and provide support for the myocytes. The nonmyocytes also determine many of the inappropriate changes that occur during myocardial hypertrophy. For example, uncontrolled cardiac fibroblast growth is associated with increased synthesis of collagen fibers, myocardial fibrosis, and ventricular wall stiffness. Not only does ventricular wall stiffness increase the workload of the heart, but the fibrosis and remodeling that occur may lead to electrical conduction abnormalities in which the heart contracts in an uncoordinated manner, known as cardiac dyssynchrony, causing reduced systolic heart function.14 Recent research has focused on the type of hypertrophy that develops in people with heart failure. At the cellular level, cardiac muscle cells respond to stimuli from stress placed on the ventricular wall by pressure and volume overload by initiating several different processes that lead to hypertrophy. These include stimuli that produce the following: •• Symmetric hypertrophy with a proportionate increase in muscle length and width, as occurs in athletes •• Concentric hypertrophy with an increase in wall thickness, as occurs in hypertension •• Eccentric hypertrophy with a disproportionate increase in muscle length, as occurs in dilated cardiomyopathy15 (Fig. 34.6) When the primary stimulus for hypertrophy is pressure overload, the increase in wall stress leads to parallel replication of myofibrils, thickening of the individual myocytes, and concentric hypertrophy. Concentric hypertrophy may preserve systolic function for a time, but eventually the work performed by the ventricle exceeds the vascular reserve, predisposing to ischemia. When the primary stimulus is ventricular volume overload, the increase in wall stress leads to replication of myofibrils in series, elongation of the cardiac muscle cells, and eccentric hypertrophy. Eccentric hypertrophy leads

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876   UNIT VIII  Disorders of Cardiovascular Function

A

B

C

FIGURE 34.6 • Different types of myocardial hypertrophy. (A) Normal symmetric hypertrophy with proportionate increases in myocardial wall thickness and length. (B) Concentric hypertrophy with a disproportionate increase in wall thickness. (C) Eccentric hypertrophy with a disproportionate decrease in wall thickness and ventricular dilation.

to a decrease in ventricular wall thickness with an increase in diastolic volume and wall tension.

Clinical Manifestations of Heart Failure

Acute Heart Failure Syndromes

The manifestations of heart failure depend on the extent and type of cardiac dysfunction that is present and the rapidity with which it develops. A person with previously stable compensated heart failure may develop signs of heart failure for the first time when the condition has advanced to a critical point, such as with a progressive increase in pulmonary hypertension in a person with mitral valve regurgitation. Overt heart failure also may be precipitated by conditions such as infection, emotional stress, uncontrolled hypertension, or fluid overload.7 Many people with serious underlying heart disease, regardless of whether they have previously experienced heart failure, may be relatively asymptomatic as long they carefully adhere to their treatment regimen. A dietary excess of sodium is a frequent cause of sudden cardiac decompensation. The manifestations of heart failure reflect the physiologic effects of the impaired pumping ability of the heart, decreased renal blood flow, and activation of the sympathetic compensatory mechanisms. The severity and progression of symptoms depend on the extent and type of dysfunction that is present (systolic versus diastolic, right- versus left-sided). The signs and symptoms include shortness of breath and other respiratory manifestations, fatigue and limited exercise tolerance, fluid retention and edema, cachexia and malnutrition, and cyanosis. People with severe heart failure may exhibit diaphoresis and tachycardia.

The acute heart failure syndromes (AHFS) are “defined as gradual or rapid change in heart failure signs and symptoms resulting in a need for urgent therapy.”14 These symptoms are primarily the result of severe pulmonary edema due to elevated left ventricular filling pressures, with or without a low cardiac output.14 The syndromes are among the most common disorders seen in emergency departments, and chronic heart failure, often complicated by episodes of acute worsening, is the most common cause of the syndrome. AHFS are thought to encompass three different types of conditions: 1. Worsening of chronic systolic or diastolic dysfunction that appears to respond to treatment, approximately 80% 2. New-onset acute heart failure that occurs secondary to a precipitating event such as a large myocardial infarction or a sudden increase in blood pressure superimposed on a noncompliant left ventricle 3. Worsening of end-stage/advanced heart failure that is refractory to treatment, with predominantly left ventricular systolic dysfunction associated with a lowoutput state16,17 The difference between new-onset AHFS and AHFS caused by chronic heart failure is in the degree of physiologic response, which is more pronounced in the new-onset AHFS and subtler in chronic heart failure because of the compensatory pathophysiology. For example, with new-onset AHFS, the person will have a stronger sympathetic response with enhanced pulmonary vascular permeability causing rapid and dramatic symptoms of pulmonary edema. Because many compensatory mechanisms operate in people with chronic heart failure, they tolerate higher pulmonary vascular pressures. Chronic changes in neurohormonal regulation lead to stronger activation of the angiotensin–aldosterone ­system with a resultant volume overload, and venous congestion is more prominent in both the systemic and pulmonary circulations.16

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Respiratory Manifestations Shortness of breath due to congestion of the pulmonary circulation is one of the major manifestations of left-sided heart failure. Perceived shortness of breath (i.e., breathlessness) is called dyspnea. Dyspnea related to an increase in activity is called exertional dyspnea. Orthopnea is shortness of breath that occurs when a person is supine. Gravitational forces cause fluid to become sequestered in the lower legs and feet when the person is standing or sitting. When the person assumes the recumbent position, fluid from the legs and dependent parts of the body is mobilized and redistributed to an already distended pulmonary circulation. Paroxysmal nocturnal dyspnea is a sudden attack of dyspnea that occurs during sleep. It disrupts sleep, and the person awakens with a feeling of extreme

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suffocation that resolves when he or she sits up. Initially, the ­experience may be interpreted as awakening from a bad dream. A subtle and often overlooked symptom of heart failure is a chronic dry, nonproductive cough that becomes worse when the person is lying down. Bronchospasm due to congestion of the bronchial mucosa may cause wheezing and difficulty in breathing. This condition is sometimes referred to as cardiac asthma.7 Cheyne-Stokes Respiration. Cheyne-Stokes respiration is a pattern of periodic breathing characterized by gradual increase in depth (and sometimes rate) of breathing to a maximum, followed by a decrease resulting in apnea. Although no longer associated solely with heart failure, it is recognized as an independent risk factor for worsening of heart failure. It has been suggested that Cheyne-Stokes respirations may not be just a marker for increasing severity of heart failure but may also aggravate it.14 During sleep, Cheyne-Stokes breathing causes recurrent awakening and thereby reduces slow-wave and rapid eye movement (REM) sleep. The recurrent cycling of hypoventilation/apnea and hyperventilation may also increase sympathetic activity and predispose to arrhythmias. Nocturnal oxygen has been seen to improve sleep, exercise tolerance, and cognitive function. Acute Pulmonary Edema. Acute pulmonary edema is the most dramatic symptom of AHFS. It is a life-threatening condition in which capillary fluid moves into the alveoli.7 The accumulated fluid in the alveoli and airways causes lung stiffness, makes lung expansion more difficult, and impairs the gas exchange function of the lung. With the decreased ability of the lungs to oxygenate the blood, the hemoglobin leaves the pulmonary circulation without being fully oxygenated, resulting in shortness of breath and cyanosis. The person with severe pulmonary edema is usually seen sitting and gasping for air. The pulse is rapid, the skin is moist and cool, and the lips and nail beds are cyanotic. As the pulmonary edema worsens and oxygen supply to the brain drops, confusion and stupor appear. Dyspnea and air hunger are accompanied by a productive cough with frothy (resembling beaten egg whites) and often blood-tinged sputum—the effect of air mixing with the serum albumin and red blood cells that have moved into the alveoli. The movement of air through the alveolar fluid produces fine crepitant sounds called crackles, which can be heard with chest auscultation. As fluid moves into the larger airways, the crackles become louder and coarser. Fatigue, Weakness, and Mental Confusion Fatigue and weakness often accompany diminished output from the left ventricle. Cardiac fatigue is different from general fatigue in that it usually is not present in the morning but appears and progresses as activity increases during the day. In acute or severe left-sided failure, cardiac output may fall to levels that are insufficient for providing the brain with adequate oxygen, and there are indications of mental confusion and disturbed behavior. Confusion, impairment ­ of memory, anxiety, restlessness, and insomnia are common

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in elderly persons with advanced heart failure, particularly in those with cerebral atherosclerosis. These symptoms may confuse the diagnosis of heart failure in older adults because of their myriad of other causes associated with aging. Fluid Retention and Edema Many of the manifestations of heart failure result from the increased capillary pressures (increased hydrostatic pressures) that develop in the peripheral circulation in people with right-sided heart failure and in the pulmonary circulation in people with left-sided heart failure. The increased capillary pressure reflects an overfilling of the vascular system because of increased sodium and water retention and venous congestion, referred to earlier as backward failure, resulting from impaired cardiac output.7,14 Nocturia is a nightly increase in urine output that occurs relatively early in the course of heart failure. It occurs because of the increased cardiac output, renal blood flow, and glomerular filtration rate that follow the increased blood return to the heart when the person is in a supine position. Oliguria, which is a decrease in urine output, is a late sign related to a severely reduced cardiac output and resultant renal failure. Transudation of fluid into the pleural cavity (hydrothorax) or the peritoneal cavity (ascites) may occur in people with advanced heart failure. Because the pleural veins drain into both the systemic and pulmonary venous beds, hydrothorax is observed more commonly in persons with hypertension involving both venous systems.7,14 Pleural effusion occurs as the excess fluid in the lung interstitial spaces crosses the visceral pleura, which in turn overwhelms the capacity of the pulmonary lymphatic system. Ascites occurs in people with increased pressure in the hepatic veins and veins draining the peritoneum. It usually reflects right ventricular failure and long-standing ­elevation of systemic venous pressure in chronic heart failure.7,14 Cachexia and Malnutrition Cardiac cachexia is a condition of malnutrition and tissue wasting that occurs in people with end-stage heart failure. A number of factors probably contribute to its development, including the fatigue and depression that interfere with food intake, congestion of the liver and gastrointestinal structures that impairs digestion and absorption and produces feelings of fullness, and the circulating toxins and mediators released from poorly perfused tissues that impair appetite and contribute to tissue wasting. Cyanosis Cyanosis is the bluish discoloration of the skin and mucous membranes caused by excess desaturated hemoglobin in the blood; it often is a late sign of heart failure. Cyanosis may be central, caused by arterial desaturation resulting from impaired pulmonary gas exchange, or peripheral, caused by venous desaturation resulting from extensive extraction of oxygen at the capillary level. Central cyanosis is caused by conditions that impair oxygenation of the arterial blood, such as pulmonary edema, left heart failure, or right-to-left cardiac

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shunting. Peripheral cyanosis is caused by conditions such as low-output failure that result in delivery of poorly oxygenated blood to the peripheral tissues, or by conditions such as peripheral vasoconstriction that cause excessive removal of oxygen from the blood. Central cyanosis is best monitored in the lips and mucous membranes because these areas are not subject to conditions, such as a cold environment, that cause peripheral cyanosis. People with right-sided or left-sided heart failure may develop cyanosis especially around the lips and in the peripheral parts of the extremities. Arrhythmias and Sudden Cardiac Death Both atrial and ventricular arrhythmias occur in people with heart failure. Atrial fibrillation is the most common arrhythmia. Clinical manifestations associated with atrial fibrillation are related to loss of atrial contraction, tachycardia, irregular heart rate, and symptoms related to a drop in blood pressure.12,13,18 There is also strong evidence that people with heart failure are at increased risk for sudden cardiac arrest; that is, unwitnessed death or death that occurs within 1 hour of the symptom onset.12,13,18 In people with ventricular dysfunction, sudden death is caused most commonly by ventricular tachycardia or ventricular fibrillation.12,13,18

Diagnosis and Treatment Diagnosis Diagnostic methods in heart failure are directed toward establishing the cause of the disorder and determining the extent of the dysfunction. Medical guidelines for diagnosis and treatment are clearly described in the AHA guidelines for heart failure management.1,2 Because heart failure represents the failure of the heart as a pump and can occur in the course of a number of heart diseases or other systemic disorders, the diagnosis of heart failure often is based on signs and symptoms related to the failing heart itself, such as shortness of breath and fatigue. The functional classification of the New York Heart Association (NYHA) is one guide to classifying the extent of dysfunction. The NYHA functional classification classifies dysfunction into four classes:1,2 1. Class I—People who have known heart disease without symptoms during ordinary activity 2. Class II—People who have heart disease who have slight limitations but not extreme fatigue, palpitations, dyspnea, or angina pain during regular activity 3. Class III—People with heart disease who are comfortable at rest but ordinary activity does result in fatigue, palpitations, dyspnea, and angina pain 4. Class IV—People who have marked progressive cardiac disease and are not comfortable at rest or ­minimal activity1,2 The methods used in the diagnosis of heart failure include risk factor assessment, history and physical examination, laboratory studies, electrocardiography, chest radiography, and

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echocardiography. The history should include information related to dyspnea, cough, nocturia, generalized fatigue, and other signs and symptoms of heart failure. A complete physical examination includes assessment of heart rate, heart sounds, blood pressure, jugular veins for venous congestion, lungs for signs of pulmonary congestion, and lower extremities for edema. Laboratory tests are used in the diagnosis of anemia and electrolyte imbalances, and to detect signs of chronic liver congestion. Measurements of BNP and NT-proBNP can be useful if the diagnosis of heart failure is uncertain and as risk stratification. The use of serial BNP or NT-proBNP levels has not yet been well established.2 Echocardiography plays a key role in assessing right and left ventricular wall motion (normal, akinesis, or hypokinesis), wall thickness, ventricular chamber size, valve function, heart defects, ejection fraction, and pericardial disease.2 Electrocardiographic findings may indicate atrial or ventricular hypertrophy, underlying disorders of cardiac rhythm, or conduction abnormalities such as right or left bundle branch block. Radionuclide ventriculography and cardiac angiography are recommended if there is reason to suspect coronary artery disease as the underlying cause for heart failure. Chest x-rays provide information about the size and shape of the heart and pulmonary vasculature. The cardiac silhouette can be used to detect cardiac hypertrophy and dilatation. Chest x-rays can indicate the relative severity of the failure by revealing if pulmonary edema is predominantly vascular or interstitial, or has advanced to the alveolar and bronchial stages. Cardiac magnetic resonance imaging (CMRI) and cardiac computed tomography (CCT) are used to document ejection fraction, ventricular preload, and regional wall motion. Invasive hemodynamic monitoring may be used for assessment in acute, life-threatening episodes of heart failure. These monitoring methods include central venous pressure (CVP), pulmonary artery pressure monitoring, thermodilution measurements of cardiac output, and intra-arterial measurements of blood pressure. CVP reflects the amount of blood returning to the heart. Measurements of CVP are best obtained by a catheter inserted into the right atrium through a peripheral vein, or by the right atrial port (opening) in a pulmonary artery catheter. This pressure is decreased in hypovolemia and increased in right heart failure. The changes that occur in CVP over time usually are more significant than the absolute numeric values obtained during a single reading. Ventricular volume pressures are obtained by means of a flow-directed, balloon-tipped pulmonary artery catheter. This catheter is introduced through a peripheral or central vein and then advanced into the right atrium. The balloon is then inflated with air, enabling the catheter to float through the right ventricle into the pulmonary artery until it becomes wedged in a small pulmonary vessel (Fig. 34.7). With the balloon inflated, the catheter monitors pulmonary capillary pressures (also called pulmonary capillary wedge pressure [PCWP]), which is in direct communication with pressures from the left heart. The pulmonary capillary pressures provide a means of assessing the pumping ability of the left heart.

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Chapter 34  Heart Failure and Circulatory Shock    879 Pulmonary artery catheter

FIGURE 34.7  •  Balloon-tipped pulmonary artery catheter positioned in a small pulmonary vessel. The PCWP, which reflects the left ventricular diastolic pressure, is measured with the balloon inflated.

Intra-arterial blood pressure monitoring provides a means for continuous monitoring of blood pressure. It is used in people with acute heart failure when aggressive intravenous medication therapy or a mechanical assist device is required. Measurements are obtained through a small catheter inserted into a peripheral artery, usually the radial artery. The catheter is connected to a pressure transducer, and beat-by-beat measurements of blood pressure are recorded. The monitoring system displays the contour of the pressure waveform and the systolic, diastolic, and mean arterial pressures, along with the heart rate and rhythm. Remember Mr. Brown from the unit opener case study? He was diagnosed with high blood pressure and hypercholesteremia. His subsequent cardiac catheterization revealed mild ischemic occlusion that did not meet the criteria for a cardiac stent or angioplasty. This result, along with his low ejection fraction of 40%, indicated that the supply of oxygen to his heart muscle was moderately impaired, reducing the force developed by the left ventricle. Therefore, he was diagnosed with ischemic cardiomyopathy and was classified as having Stage B (American Heart Association) and Class II (New York Heart Association) heart failure. Treatment The goals of treatment are determined by the rapidity of onset and severity of the heart failure. People with AHFS require urgent therapy directed at stabilizing and correcting the cause of the cardiac dysfunction. For people with chronic heart failure, the goals of treatment are directed toward relieving the symptoms, improving the quality of life, and reducing or

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eliminating risk factors (e.g., hypertension, diabetes, obesity) with a long-term goal of slowing, halting, or reversing the cardiac dysfunction.1,2,14,17 Treatment measures for both acute and chronic heart failure include nonpharmacologic and pharmacologic approaches. Mechanical support devices, including the intra-aortic balloon pump (for acute failure) and the ventricular assist device (VAD), sustain life in people with severe heart failure. Heart transplantation remains the treatment of choice for many people with end-stage heart failure. Nonpharmacologic Methods.  Exercise intolerance is typical in people with chronic heart failure.19 Consequently, individualized exercise training is important to maximize muscle conditioning. People who are not accustomed to exercise and those with more severe heart failure are started at a lower intensity and shorter sessions than those who are mostly asymptomatic. Sodium and fluid restriction and weight management are important for all people with heart failure; the degree of sodium and fluid restriction is individualized to the severity of heart failure. Counseling, health teaching, and ongoing evaluation programs help people with heart failure to manage and cope with their treatment regimen. Pharmacologic Treatment. Once heart failure is moderate to severe, pharmacologic in conjunction with nonpharmacologic management is important to prevent and treat acute heart failure and manage chronic heart failure. Evidence-based agents recommended for treatment and management include diuretics, ACE inhibitors or angiotensin II receptor blockers, β-adrenergic blockers, and digoxin.1,2,14,17,20 The choice of pharmacologic agents is based on symptomatology of the person. Diuretics are among the most frequently prescribed medications for moderate to severe heart failure.1,2,20 They promote the excretion of fluid and help to sustain cardiac output and tissue perfusion by reducing preload and allowing the heart to operate at a more optimal part of the Frank-Starling curve. Thiazide and loop diuretics are used. In emergencies, such as acute pulmonary edema, loop diuretics such as furosemide can be administered intravenously. When given as a bolus infusion, intravenous furosemide acts within minutes to increase venous capacitance so that right ventricular output and pulmonary capillary pressures are decreased. The ACE inhibitors, which prevent the conversion of angiotensin I to angiotensin II, have been used effectively in the treatment of chronic heart failure. The renin–angiotensin– aldosterone system is activated early in the course of heart failure and plays an important role in its progression. It results in an increase in angiotensin II, which causes vasoconstriction, unregulated ventricular remodeling, and increased aldosterone production with a subsequent increase in sodium and water retention by the kidneys. ACE ­inhibitors have been shown to limit these harmful complications. The angiotensin II receptor blockers appear to have similar but more limited beneficial effects. They have the advantage of not causing a cough, which is a troublesome side effect of the ACE i­nhibitors for

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880   UNIT VIII  Disorders of Cardiovascular Function

many people. Aldosterone has a number of deleterious effects in people with heart failure. Aldosterone receptor antagonists may be used in combination with other agents for people with moderately severe to severe heart failure. β-Adrenergic receptor blocking drugs are used to decrease left ventricular dysfunction associated with activation of the sympathetic nervous system. Large clinical trials have shown that long-term therapy with β-adrenergic receptor blocking agents reduces morbidity and mortality in people with chronic heart failure. The mechanism of this benefit remains unclear, but it is likely that chronic elevations of catecholamines and sympathetic nervous system activity cause progressive myocardial damage, leading to a worsening of left ventricular function and a poorer prognosis in people with heart failure. Large, landmark clinical trials of people with stable NYHA class II and III heart failure have demonstrated significant reductions in the overall mortality rate with treatment with various β-adrenergic receptor blocking agents.21,22 Digitalis has been a recognized treatment for heart failure for over 200 years. The various forms of digitalis are called cardiac glycosides. They improve cardiac function by increasing the force and strength of ventricular contractions. By decreasing sinoatrial node activity and decreasing conduction through the atrioventricular node, they also slow the heart rate and increase diastolic filling time. Although not a diuretic, digitalis promotes urine output by improving cardiac output and renal blood flow. The role of digitalis in the treatment of heart failure has been studied in clinical trials over the past several decades. The results of these studies remain controversial and mixed; there seems to be a growing consensus that although it does not necessarily reduce mortality rates, digitalis can possibly prevent clinical deterioration and hospitalization. Vasodilator drugs have not been extensively studied as a lone treatment for the management of heart failure but can be effective in symptom management. Agents such as isosorbide dinitrate and hydralazine may be added to other standard medications for patients with chronic heart failure. Vasodilators such as nitroglycerin, nitroprusside, and nesiritide (B-type NP) are used in AHFS to improve left heart performance by decreasing the preload (through vasodilation) or reducing the afterload (through arteriolar dilation), or both.23,24 Oxygen Therapy.  Oxygen therapy increases the oxygen content of the blood and is most often used in people with acute episodes of heart failure. Continuous positive airway pressure (CPAP) is recommended to reduce the need for endotracheal intubation in patients with AHFS.25 Because CPAP increases intrathoracic pressure, it also has the potential for decreasing venous return and left ventricular preload, thereby improving the cardiac ejection fraction and stabilizing the hemodynamic status in persons with severe heart failure. Bilevel positive airway pressure (BiPAP), which is like CPAP but also delivers higher pressures during inspiration, is argued by some to be superior to CPAP in that it decreases the respiratory rate and heart rate and improves oxygenation more quickly or more substantially than CPAP.25

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Cardiac Resynchronization and Implantable Cardioverter– Defibrillators.  Some people with heart failure have abnormal intraventricular conduction that results in dyssynchronous and ineffective contractions.26 Cardiac resynchronization therapy involves the placement of pacing leads into the right and left ventricles as a means of resynchronizing the contraction of the two ventricles. Cardiac resynchronization has been shown to improve ventricular function and blood pressure, improve quality of life, and reduce the risk of death.23 People with heart failure are at significant risk of sudden cardiac death from ventricular fibrillation or ventricular tachycardia. Implantation of a cardioverter–defibrillator is indicated in selected patients with heart failure to prevent sudden cardiac death.23 A cardioverter–defibrillator is a programmable implanted device that monitors the cardiac rhythm. It has the capacity to pace the heart and deliver electrical shocks to terminate lethal arrhythmias when needed. Mechanical Support and Heart Transplantation. Refractory heart failure reflects deterioration in cardiac function that is unresponsive to medical or surgical interventions. With improved methods of treatment, more people are reaching a point where a cure is unachievable and death is imminent without mechanical support or heart transplantation. Since the early 1960s, significant progress has been made in improving the efficacy of VADs, which are mechanical pumps used to support ventricular function. VADs are used to decrease the workload of the myocardium while maintaining cardiac output and systemic arterial pressure. This decreases the workload on the ventricle and allows it to rest and recover. In the past, VADs require an invasive open chest procedure for implantation but is not less invasive. They may be used in people who fail or have difficulty being weaned from cardiopulmonary bypass after cardiac surgery, those who develop cardiogenic shock after myocardial infarction, those with end-stage cardiomyopathy, and those who are awaiting cardiac transplantation. Earlier and more aggressive use of VADs as a bridge to transplantation and destination therapy (permanent support) has been shown to increase survival.23 VADs that allow the patient to be mobile and managed at home are sometimes used for long-term or permanent support for treatment of end-stage heart failure, rather than simply as a bridge to transplantation. VADs can be used to support the function of the left ventricle, right ventricle, or both.23 Heart transplantation is the preferred treatment for people with end-stage cardiac failure and otherwise good life expectancy.2,27 Despite the overall success of heart transplantation, donor availability remains a key problem, and only about 5000 procedures are completed each year with thousands being denied transplantation each year. Other novel surgical therapies that are being explored include left ventricular remodeling. Left ventricular remodeling is a surgical procedure designed to restore the size and shape of the ventricle and is thought to be a viable surgical alternative to cardiac transplantation for people with severe left ventricular dysfunction.28

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Chapter 34  Heart Failure and Circulatory Shock    881

IN SUMMARY Heart failure occurs when the heart fails to pump sufficient blood to meet the metabolic needs of body tissues. The physiology of heart failure reflects the interplay between a decrease in cardiac output that accompanies impaired function of the failing heart and the compensatory mechanisms that preserve the cardiac reserve. Compensatory mechanisms include the Frank-Starling mechanism, sympathetic nervous system activation, the renin–angiotensin–aldosterone mechanism, NPs, the endothelins, and myocardial hypertrophy and remodeling. In the failing heart, early decreases in cardiac function may go unnoticed because these compensatory mechanisms maintain the cardiac output. Unfortunately, the mechanisms were not intended for long-term use, and in severe and prolonged heart failure, the compensatory mechanisms no longer are effective and instead contribute to the progression of heart failure. Heart failure may be described in terms of systolic versus diastolic dysfunction and right ventricular versus left ventricular dysfunction. With systolic dysfunction, there is impaired ejection of blood from the heart during systole; with diastolic dysfunction, there is impaired filling of the heart during diastole. Right ventricular dysfunction is characterized by congestion in the peripheral circulation, and left ventricular dysfunction by congestion in the pulmonary circulation. Heart failure can present as a chronic condition characterized by decreased cardiac function or as an AHFS. The AHFS represents a gradual or rapid change in heart failure signs and symptoms, indicating need for urgent therapy. These symptoms are primarily the result of pulmonary congestion due to elevated left ventricular filling pressures with or without a low cardiac output. The manifestations of heart failure include edema, nocturia, fatigue and impaired exercise tolerance, cyanosis, signs of increased sympathetic nervous system activity, and impaired gastrointestinal function and malnutrition. In right-sided failure, there is dependent edema of the lower parts of the body, engorgement of the liver, and ascites. In left-sided failure, pulmonary congestion with shortness of breath and chronic, nonproductive cough are common. The diagnostic methods in heart failure are directed toward establishing the cause and extent of the disorder. Treatment is directed toward correcting the cause whenever possible, improving cardiac function, maintaining the fluid volume within a compensatory range, and d­ eveloping an  activity ­pattern consistent with individual limitations in cardiac reserve. Among the medications used in the ­treatment of heart failure are diuretics, ACE inhibitors and angiotensin receptor blocking agents, β-adrenergic receptor blockers, digoxin, and vasodilators. Mechanical support devices, including the VAD, sustain life in persons with severe heart failure. Heart transplantation remains the treatment of choice for many persons with end-stage heart failure.

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CIRCULATORY FAILURE (SHOCK) After completing this section of the chapter, you should be able to meet the following objectives: •• Compare the causes, pathophysiology, and chief characteristics of cardiogenic, hypovolemic, obstructive, and distributive shock. •• Describe the complications of shock as they relate to the lungs, kidneys, gastrointestinal tract, and blood clotting. •• State the rationale for treatment measures to correct and reverse shock.

Circulatory shock can be described as an acute failure of the circulatory system to supply the peripheral tissues and organs of the body with an adequate blood supply, resulting in cellular hypoxia.3 Most often hypotension and hypoperfusion are present, but shock may occur in the presence of normal vital signs. Shock is not a specific disease but a syndrome that can occur in the course of many life-threatening traumatic conditions or disease states. It can be caused by an alteration in cardiac function (cardiogenic shock), a decrease in blood volume (hypovolemic shock), excessive vasodilation with maldistribution of blood flow (distributive shock), or obstruction of blood flow through the circulatory system (obstructive shock). The main types of shock are summarized in Chart 34.1 and depicted in Figure 34.8.

Chart 34.1

CLASSIFICATION OF CIRCULATORY SHOCK

Cardiogenic Myocardial damage (myocardial infarction, contusion) Sustained arrhythmias Acute valve damage, ventricular septal defect Cardiac surgery Hypovolemic Loss of whole blood Loss of plasma Loss of extracellular fluid Obstructive Inability of the heart to fill properly (cardiac tamponade) Obstruction to outflow from the heart (pulmonary embolus, cardiac myxoma, pneumothorax, or ­dissecting aneurysm) Distributive Loss of sympathetic vasomotor tone (neurogenic shock) Presence of vasodilating substances in the blood ­(anaphylactic shock) Presence of inflammatory mediators (septic shock)

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882   UNIT VIII  Disorders of Cardiovascular Function

Normal

Shock

Cardiogenic

Hypovolemic

Obstructive

Distributive

FIGURE 34.8  •  Types of shock.

Pathophysiology of Circulatory Shock Circulatory failure results in hypoperfusion of organs and tissues, which in turn results in insufficient supply of oxygen and nutrients for cellular function. There are compensatory physiologic responses that eventually decompensate into various shock states if the condition is not properly treated in a timely manner. The most immediate of the compensatory mechanisms are the sympathetic and renin systems, which are designed to maintain cardiac output and blood pressure. There are two types of adrenergic receptors for the sympathetic nervous system: α and β. The β receptors are further subdivided into β1 and β2 receptors. Stimulation of the α receptors causes vasoconstriction; stimulation of β1 receptors, an increase in heart rate and force of myocardial contraction; and of β2 receptors, vasodilation of the skeletal muscle beds and relaxation of the bronchioles. In shock, there is an increase in sympathetic outflow that results in increased epinephrine and norepinephrine release, and activation of both α and β receptors. Thus, increases in heart rate and vasoconstriction occur in most types of shock. There also is an increase in renin

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release, leading to an increase in angiotensin II, which augments vasoconstriction and leads to an aldosterone-mediated increase in sodium and water retention by the kidneys. In addition, there is local release of vasoconstrictors, including norepinephrine, angiotensin II, vasopressin, and endothelin, which contribute to arterial and venous vasoconstriction. The compensatory mechanisms that the body recruits are not effective over the long term and become detrimental when the shock state is prolonged. The intense vasoconstriction causes a decrease in tissue perfusion and insufficient supply of oxygen. Cellular metabolism is impaired, vasoactive inflammatory mediators such as histamine are released, production of oxygen free radicals is increased, and excessive lactic acid and hydrogen ions result in intracellular acidity.4 Each of these factors promotes cellular dysfunction or death. If circulatory function is reestablished, whether the shock is irreversible or the patient will survive is determined largely at the cellular level. Shock ultimately exerts its effect at the cellular level, with failure of the circulation to supply the cell with the oxygen and nutrients needed for production of ATP. The cell uses ATP for a number of purposes, including operation of the sodium–potassium membrane pump that moves sodium out

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Chapter 34  Heart Failure and Circulatory Shock    883

of the cell and potassium back into the cell. The cell uses two pathways to convert nutrients to energy. The first is the anaerobic (non–oxygen-dependent) glycolytic pathway, which is located in the cytoplasm. Glycolysis converts glucose to ATP and pyruvate. The second pathway is the aerobic (oxygendependent) pathway, called the citric acid cycle, which is located in the mitochondria. When oxygen is available, pyruvate from the glycolytic pathway moves into the mitochondria and enters the citric acid cycle, where it is transformed into ATP and the metabolic by-products carbon dioxide and water. When oxygen is lacking, pyruvate does not enter the citric acid cycle; instead, it is converted to lactic acid. The anaerobic pathway, although allowing energy production to continue in the absence of oxygen, is relatively inefficient and produces significantly less ATP than the aerobic pathway. In severe shock, cellular metabolic processes are essentially anaerobic owing to the decreased availability of oxygen. Excess amounts of lactic acid accumulate in the cellular and the extracellular compartments, and limited amounts of ATP are produced. Without sufficient energy production, normal cell function cannot be maintained. The sodium–potassium membrane pump is impaired, resulting in excess sodium inside the cells and potassium loss from cells. The increase in intracellular sodium results in cellular edema and increased cell membrane permeability. Mitochondrial activity becomes severely depressed and lysosomal membranes may rupture, resulting in the release of enzymes that cause further intracellular destruction. This is followed by cell death and the release of intracellular contents into the extracellular space. The destruction of the cell membrane activates the arachidonic acid cascade, release of inflammatory mediators, and production of oxygen free radicals that extend cellular damage. The extent of the microvascular injury and organ dysfunction is primarily determined by the extent of the shock state and whether it is prolonged. Interventions are targeted at both prevention and early intervention, when possible.

Key Points CIRCULATORY SHOCK •  Circulatory shock can result from failure of the heart as a pump, a loss of fluid from the vascular compartment (hypovolemic shock), obstruction of flow through the vascular compartment (obstructive shock), or an increase in the size of the vascular compartment that interferes with the distribution of blood (distributive shock). •  The manifestations of shock reflect both the impaired perfusion of body tissues and the body’s attempt to maintain tissue perfusion through conservation of water by the kidney, translocation of fluid from extracellular to the intravascular compartment, and activation of sympathetic nervous system mechanisms that increase heart rate and divert blood from less to more essential body tissues.

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Cardiogenic Shock Cardiogenic shock occurs when the heart fails to pump blood sufficiently to meet the body’s demands (see Fig. 34.8). Clinically, it is defined as decreased cardiac output, hypotension, hypoperfusion, and indications of tissue hypoxia, despite adequate intravascular volume.29 Cardiogenic shock may occur suddenly from a number of causes, including myocardial infarction, myocardial contusion, sustained arrhythmias, and cardiac surgery. Cardiogenic shock also may ensue as an endstage condition of coronary artery disease or cardiomyopathy. Pathophysiology The most common cause of cardiogenic shock is myocardial infarction. Most people who die of cardiogenic shock have had extensive damage to the contracting muscle of the left ventricle because of a recent infarct or a combination of recent and old infarctions.30 Cardiogenic shock can occur with other types of shock because of inadequate coronary blood flow. Regardless of cause, people with cardiogenic shock have a decrease in stroke volume and cardiac output, which results in insufficient perfusion to meet cellular demands for oxygen. The poor cardiac output is due to decreased myocardial contractility, increased afterload, and excessive preload.29 Mediators and neurotransmitters, including norepinephrine, produce an increase in systemic vascular resistance, which increases afterload and contributes to the deterioration of cardiac function. Preload, or the filling pressure of the heart, is increased as blood returning to the heart is added to blood that previously was not pumped forward, resulting in an increase in left ventricular end-systolic volume. Activation of the renin– angiotensin–aldosterone mechanism worsens both preload and afterload by producing an aldosterone-mediated increase in fluid retention and an angiotensin II–mediated increase in vasoconstriction. The increased resistance (i.e., afterload) to ejection of blood from the left ventricle, in combination with a decrease in myocardial contractility, results in an increase in end-systolic ventricular volume and preload, which further impairs the heart’s ability to pump effectively. Eventually, coronary artery perfusion is impaired because of the increased preload and afterload, and cardiac function decreases because of poor myocardial oxygen supply. There is an increase in intracardiac pressures due to volume overload and ventricular wall tension in both diastole and systole. Excessive pressures decrease coronary artery perfusion during diastole, and increased wall tension decreases coronary artery perfusion during systole. If treatment is unsuccessful, cardiogenic shock may result in a systemic inflammatory response syndrome. This is evidenced by increased white blood cell count, increased temperature, and release of inflammatory markers such as CRP.29 Clinical Manifestations Signs and symptoms of cardiogenic shock include indications of hypoperfusion with hypotension, although a preshock state of hypoperfusion may occur with a normal blood pressure. The lips, nail beds, and skin may become cyanotic because

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884   UNIT VIII  Disorders of Cardiovascular Function

of stagnation of blood flow and increased extraction of oxygen from the hemoglobin as it passes through the capillary bed. Mean arterial and systolic blood pressures decrease due to poor stroke volume, and there is a narrow pulse pressure and near-normal diastolic blood pressure because of arterial vasoconstriction.30,31 Urine output decreases because of lower renal perfusion pressures and the increased release of aldosterone. Elevated preload is reflected in a rise in CVP and PCWP. Neurologic changes, such as alterations in cognition or consciousness, may occur because of low cardiac output and poor cerebral perfusion. Treatment Treatment of cardiogenic shock requires striking a precarious balance between improving cardiac output, reducing the workload and oxygen needs of the myocardium, and increasing coronary perfusion. Fluid volume must be regulated within a level that maintains the filling pressure and optimizes stroke volume in people not fluid overloaded. Pulmonary edema and arrhythmias should be monitored, corrected, or prevented to increase stroke volume and decrease the oxygen demands of the heart. Coronary artery perfusion is increased by promoting coronary artery vasodilation, increasing blood pressure, decreasing ventricular wall tension, and decreasing intracardiac pressures. Pharmacologic treatment includes the use of vasodilators such as nitroprusside and nitroglycerin. Both nitroprusside and nitroglycerin cause coronary artery dilation, which increases myocardial oxygen delivery. Nitroprusside causes arterial and venous dilation, producing a decrease in venous return to the heart and a reduction in arterial resistance against which the left heart must pump.29 At lower doses, the main effects of nitroglycerin are on the venous vascular beds and coronary arteries. At high doses, it also dilates the arterial beds. Both medications may result in a decrease in diastolic arterial pressure that results in a lower systemic vascular resistance (afterload). The systolic arterial pressure is maintained by an increase in ventricular stroke volume, which is ejected against the lowered systemic vascular resistance. The improvement in heart function increases stroke volume and enables blood to be redistributed from the pulmonary vascular bed to the systemic circulation. Positive inotropic agents are used to improve cardiac contractility. Both dobutamine and milrinone are effective medications in that they result in increased contractility and arterial vasodilation. Dobutamine is a synthetic agent consisting of two isomers, one of which is a potent β1-adrenergic receptor agonist and α1-adrenergic receptor antagonist and the other is a mild β2-adrenergic receptor agonist and α1-adrenergic receptor agonist. The combination tends to produce vasodilation and a positive inotropic action. Milrinone increases myocardial contractility by increasing the movement of Ca++ into myocardial cells during an action potential (see Fig. 34.1). The increase in stroke volume results in a decrease in endsystolic volume and a reduction in preload. With a decrease in preload pressures, coronary artery perfusion is improved

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during diastole. Thus, stroke volume and myocardial oxygen supply are improved with a minimal increase in myocardial oxygen demand. Catecholamines increase cardiac contractility but must be used with extreme caution because they also result in arterial constriction and increased heart rates, which worsen the imbalance between myocardial oxygen supply and demand. The intra-aortic balloon pump, also referred to as counterpulsation, enhances coronary and systemic perfusion, yet decreases afterload and myocardial oxygen demands.32 The device, which pumps in synchrony with the heart, consists of a 10-inch-long balloon that is inserted through a catheter into the descending aorta (Fig. 34.9). The balloon is timed to inflate during ventricular diastole and deflate just before

Left subclavian artery

Renal artery

FIGURE 34.9  •  Aortic balloon pump. Proper position of the ­balloon catheter; illustrating percutaneous insertion. (From Morton P. G., ­Fontaine D. K. (2009). Critical care nursing: A holistic approach (9th ed., p. 369). Philadelphia, PA: JB Lippincott.

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Chapter 34  Heart Failure and Circulatory Shock    885

v­ entricular systole. Diastolic inflation creates a pressure wave in the ascending aorta that increases coronary artery blood flow and a less intense wave in the lower aorta that enhances organ perfusion. The abrupt balloon deflation at the onset of systole results in a displacement of blood volume that lowers the resistance to ejection of blood from the left ventricle. Thus, the heart’s pumping efficiency is increased, myocardial oxygen supply is increased, and myocardial oxygen consumption is decreased. When cardiogenic shock is caused by myocardial infarction, several aggressive interventions can be used successfully. Fibrinolytic therapy, percutaneous coronary intervention, or CABG may be used to prevent or treat cardiogenic shock.31 Reperfusion of the coronary arteries is expected to improve myocardial function.

Hypovolemic Shock Hypovolemic shock is characterized by diminished blood volume such that there is inadequate filling of the vascular compartment3,29,33 (see Fig. 34.8). It occurs when there is an acute loss of 15% to 20% of the circulating blood volume. The decrease may be caused by an external loss of whole

blood (e.g., hemorrhage), plasma (e.g., severe burns), or extracellular fluid (e.g., severe dehydration or loss of gastrointestinal fluids with vomiting or diarrhea). Hypovolemic shock also can result from an internal hemorrhage or from third-space losses, when extracellular fluid is shifted from the vascular compartment to the interstitial space or compartment. Pathophysiology Hypovolemic shock, which has been the most widely studied type of shock, is often used as a prototype in discussions of the manifestations of shock. Figure 34.10 shows the effect of removing blood from the circulatory system during approximately 30 minutes.3 Approximately 10% of the total blood volume can be removed without changing cardiac output or arterial pressure. The average blood donor loses approximately 500 mL or 10% of their blood without experiencing adverse effects. As increasing amounts of blood (10% to 25%) are removed, the stroke volume falls but arterial pressure is maintained because of sympathetic-mediated increases in heart rate and vasoconstriction. Vasoconstriction results in an increased diastolic pressure and narrow pulse pressure. Blood pressure is the product of cardiac output and systemic v­ ascular

Acute bleeding or other conditions leading to decrease in blood volume Compensatory mechanisms

Mechanisms to maintain cardiovascular function

Mechanisms to maintain blood volume

Hypothalamus Liver Heart

Stimulation of thirst Posterior pituitary

Increased heart rate and cardiac contractility

Blood vessels Vasoconstriction of vessels in skin and nonvital organs

Constriction of veins and sinusoids with mobilization of blood stored in liver Stimulation of ADH release

Renin-angiotensinaldosterone mechanism

Kidney

Adrenal cortex Release of aldosterone

Sodium and water retention

Decreased urine output FIGURE 34.10  •  Compensatory mechanisms used to maintain circulatory function and blood volume in hypovolemic shock. (ADH, antidiuretic hormone.)

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resistance (blood pressure = cardiac output × systemic vascular resistance). An increase in systemic vascular resistance maintains mean arterial pressure for a short time despite decreased cardiac output. Cardiac output and tissue perfusion decrease before signs of hypotension appear. Cardiac output and arterial pressure fall to zero when approximately 30% to 40% of the total blood volume has been removed.3,29 Compensatory Mechanisms.  Without compensatory mechanisms to maintain cardiac output and blood pressure, the loss of vascular volume would result in a rapid progression from the initial to the progressive and irreversible stages of shock. The most immediate of the compensatory mechanisms are the sympathetic-mediated responses designed to maintain cardiac output and blood pressure (Fig. 34.10). Within seconds after the onset of hemorrhage or the loss of blood volume, tachycardia, increased cardiac contractility, vasoconstriction, and other signs of sympathetic and adrenal medullary activity appear. The sympathetic vasoconstrictor response also mobilizes blood that has been stored in the venous side of the circulation as a means of increasing venous return to the heart. There is considerable capacity for blood storage in the large veins of the abdomen, and approximately 350 mL of blood that can be mobilized in shock is stored in the liver.3 Sympathetic stimulation does not initially cause constriction of the cerebral and coronary vessels, and blood flow to the heart and brain is maintained at essentially normal levels as long as the mean arterial pressure remains above 70 mm Hg.3 Compensatory mechanisms designed to restore blood volume include absorption of fluid from the interstitial spaces, conservation of sodium and water by the kidneys, and thirst. Extracellular fluid is distributed between the interstitial spaces and the vascular compartment. When there is a loss of vascular volume, capillary pressures decrease and water is drawn into the vascular compartment from the interstitial spaces. The maintenance of vascular volume is further enhanced by renal mechanisms that conserve fluid. A decrease in renal blood flow and glomerular filtration rate results in activation of the renin–angiotensin–aldosterone mechanism, which produces an increase in sodium reabsorption by the kidneys. The decrease in blood volume also stimulates centers in the hypothalamus that regulate ADH release and thirst. ADH, also known as vasopressin, constricts the peripheral arteries and veins and greatly increases water retention by the kidneys. Although the mechanism of ADH is more sensitive to changes in serum osmolality, a decrease of 10% to 15% in blood volume serves as a strong stimulus for thirst.3,29 During the early stages of hypovolemic shock, vasoconstriction decreases the size of the vascular compartment and increases systemic vascular resistance. This response usually is all that is needed when the injury is slight and blood loss is minimal. As hypovolemic shock progresses, vasoconstriction of the blood vessels that supply the skin, skeletal muscles, kidneys, and abdominal organs becomes more severe, with a further decrease in blood flow and conversion to anaerobic metabolism resulting in cellular injury.

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Clinical Manifestations The signs and symptoms of hypovolemic shock depend on its severity and are closely related to low peripheral blood flow and excessive sympathetic stimulation. They include thirst, increased heart rate, cool and clammy skin, decreased arterial blood pressure, decreased urine output, and changes in mentation. Laboratory tests of hemoglobin and hematocrit provide information regarding the severity of blood loss or hemoconcentration due to dehydration. Serum lactate and arterial pH provide information about the severity of acidosis due to anaerobic metabolism. Metabolic acidosis revealed by arterial blood gas measurement is the gold standard diagnostic test.29,33 Acute, fatal hemorrhagic shock is characterized by metabolic acidosis, coagulopathy, and hypothermia, followed by circulatory failure.33 An increase in heart rate is an early sign of hypovolemic shock, as the body tries to maintain cardiac output despite the decrease in stroke volume. As shock progresses, the pulse becomes weak and thready, indicating vasoconstriction and reduced filling of the vascular compartment. Thirst is an early symptom in hypovolemic shock. Although the underlying cause is not fully understood, it probably is related to decreased blood volume and increased serum osmolality. Arterial blood pressure is decreased in moderate to severe shock. However, controversy exists over the value of blood pressure measurements in the early diagnosis and management of shock. This is because compensatory mechanisms tend to preserve blood pressure until shock is relatively far advanced. Furthermore, a normal arterial pressure does not ensure adequate perfusion and oxygenation of vital organs at the cellular level. This does not imply that blood pressure should not be closely monitored in people at risk for development of shock, but it does indicate the need for other assessment measures. As shock progresses, the respirations become rapid and deep, to compensate for the increased production of acid and decreased availability of oxygen. Decreased intravascular volume results in decreased venous return to the heart and a decreased CVP. When shock becomes severe, the peripheral veins may collapse. Sympathetic stimulation leads to intense vasoconstriction of the skin vessels, which results in cool and mottled skin. In hemorrhagic shock, the loss of red blood cells results in pallor of the skin and mucous membranes. Urine output decreases very quickly in hypovolemic shock. Compensatory mechanisms decrease renal blood flow as a means of diverting blood flow to the heart and brain. Oliguria of 20 mL/hour or less indicates inadequate renal perfusion. Continuous measurement of urine output is essential for assessing the circulatory and volume status of the person in shock. Restlessness, agitation, and apprehension are common in early shock because of increased sympathetic outflow and increased levels of epinephrine. As the shock progresses and blood flow to the brain decreases, restlessness is replaced by altered arousal and mentation. Loss of consciousness and coma may occur if the person does not receive or respond to treatment.

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Treatment The duration and amount of fluid loss is directly related to mortality. Therefore, the treatment of hypovolemic shock is directed toward correcting or controlling the underlying cause and improving tissue perfusion. Ongoing loss of blood must be corrected. Oxygen is administered to increase oxygen delivery to the tissues. Medications usually are administered intravenously. Frequent measurements of heart rate and cardiac rhythm, blood pressure, and urine output are used to assess the severity of circulatory compromise and to monitor treatment. In hypovolemic shock, the goal of treatment is to restore vascular volume.29,33 This can be accomplished through intravenous administration of fluids and blood. The crystalloids (e.g., isotonic saline and Ringer lactate) are readily available and effective, at least temporarily. Plasma volume expanders (e.g., pentastarch and colloidal albumin) have a high molecular weight, do not necessitate blood typing, and remain in the vascular space for longer periods than crystalloids such as dextrose and saline. The use of crystalloids versus colloids has not been studied in large clinical trials. Therefore, the use of one versus the other to decrease morbidity has not been established.29 Blood or blood products (packed or frozen red cells) are administered based on hematocrit and hemodynamic findings. Fluids and blood are best administered based on volume indicators such as CVP and urine output. Vasoactive medications are agents capable of constricting or dilating blood vessels. Considerable controversy exists about the advantages or disadvantages related to the use of these drugs. As a general rule, vasoconstrictor agents are not used as a primary form of therapy in hypovolemic shock and may be detrimental. These agents are given only when volume deficits have been corrected yet hypotension persists.

Distributive Shock Distributive or vasodilatory shock is characterized by loss of blood vessel tone, enlargement of the vascular compartment, and displacement of the vascular volume away from the heart and central circulation.29,34 In distributive shock, the capacity of the vascular compartment expands to the extent that a normal volume of blood does not fill the circulatory system (see Fig. 34.8). Therefore, this type of shock is also referred to as normovolemic shock. Two main causes result in the loss of vascular tone: a decrease in the sympathetic control of vasomotor tone or the release of excessive vasodilator substances. It can also occur as a complication of vessel damage resulting from prolonged and severe hypotension due to hemorrhage, known as irreversible or late-phase hemorrhagic shock.34 There are three shock states that share the basic circulatory pattern of distributive shock: neurogenic shock, anaphylactic shock, and septic shock.29 Neurogenic Shock Neurogenic shock is caused by decreased sympathetic control of blood vessel tone due to a defect in the vasomotor center

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in the brain stem or the sympathetic outflow to the blood vessels.3 The term spinal shock describes the neurogenic shock that occurs in persons with spinal cord injury. Output from the vasomotor center can be interrupted by brain injury, the depressant action of drugs, general anesthesia, hypoxia, or lack of glucose (e.g., insulin reaction). Fainting due to emotional causes is a transient form of impaired sympathetic outflow. Many general anesthetic agents can cause a neurogenic shock–like reaction, especially during induction, because of interference with sympathetic nervous system function. Spinal anesthesia or spinal cord injury above the midthoracic region can interrupt the transmission of outflow from the vasomotor center. In contrast to other shock states due to the loss of blood volume or impaired cardiac function, the heart rate in neurogenic shock often is slower than normal, and the skin is dry and warm. This type of distributive shock is rare and usually transitory. Anaphylactic Shock Anaphylaxis is a clinical syndrome that represents the most severe systemic allergic reaction.35–37 Anaphylactic shock results from an immunologically mediated reaction in which vasodilator substances such as histamine are released into the blood. These substances cause vasodilation of arterioles and venules along with a marked increase in capillary permeability. The vascular response in anaphylaxis is often accompanied by life-threatening laryngeal edema and bronchospasm, circulatory collapse, contraction of gastrointestinal and uterine smooth muscle, and urticaria (hives) or angioedema. Etiology. Among the most frequent causes of anaphylactic shock are reactions to medications, such as penicillin; foods, such as nuts and shellfish; and insect venoms. The most common cause is stings from insects of the order Hymenoptera (i.e., bees, wasps, and fire ants). Latex allergy causes lifethreatening anaphylaxis in a growing segment of the population. Health care workers and others who are exposed to latex are developing latex sensitivities that range from mild urticaria, contact dermatitis, and mild respiratory distress to anaphylactic shock.38 The onset and severity of anaphylaxis depend on the sensitivity of the person and the rate and quantity of antigen exposure. Clinical Manifestations. Signs and symptoms associated with impending anaphylactic shock include the following: •• Abdominal cramps •• Apprehension •• Warm or burning sensation of the skin •• Itching •• Urticaria (i.e., hives) •• Coughing •• Choking •• Wheezing •• Chest tightness •• Difficulty in breathing

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After blood begins to pool peripherally, there is a precipitous drop in blood pressure and the pulse becomes so weak that it is difficult to detect. Life-threatening airway obstruction may ensue as a result of laryngeal angioedema or bronchial spasm. Anaphylactic shock often develops suddenly; death can occur within minutes unless appropriate medical intervention is promptly instituted. Treatment.  Treatment includes immediate discontinuation of the inciting agent or institution of measures to decrease its absorption (e.g., application of ice to the site of an insect bite); close monitoring of cardiovascular and respiratory function; and maintenance of respiratory gas exchange, cardiac output, and tissue perfusion. Epinephrine is given in an anaphylactic reaction because it constricts blood vessels and relaxes the smooth muscle in the bronchioles, thus restoring cardiac and respiratory function.36 Other treatment measures include the administration of oxygen, antihistamine drugs, and corticosteroids. The person should be placed in a supine position. This is extremely important because venous return can be severely compromised in the sitting position. This in turn produces a pulseless mechanical contraction of the heart and predisposes to arrhythmias. In several cases, death has occurred immediately after assuming the sitting position.36 Prevention. The prevention of anaphylactic shock is preferable to treatment. Once a person has been sensitized to an antigen, the risk of repeated anaphylactic reactions with subsequent exposure is high. All health care providers should question people regarding previous drug reactions and inform people as to the name of the medication they are to receive before it is administered or prescribed. People with known hypersensitivities should wear Medic Alert jewelry and carry an identification card to alert medical personnel if they become unconscious or unable to relate this information. People who are at risk for anaphylaxis should be provided with emergency medications (e.g., epinephrine autoinjector) and instructed in procedures to follow in case they are inadvertently exposed to the offending antigen.36 Sepsis and Septic Shock Septic shock, which is the most common type of vasodilatory shock, is associated with severe infection and the systemic response to infection (Fig. 34.11).39–41 Sepsis is currently defined as suspected or proven infection, plus a systemic inflammatory response syndrome (e.g., fever, tachycardia, tachypnea, elevated white blood cell count, altered mental state, and hyperglycemia in the absence of diabetes).42 Severe sepsis is defined as sepsis with organ dysfunction (e.g., hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia, or obtundation).42 Septic shock is defined as severe sepsis with hypotension, despite fluid resuscitation.42 It is estimated that sepsis occurs in 500 people each day in the United States.43 The growing incidence has been attributed to enhanced awareness of the diagnosis, increased

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Microorganisms

Suspected or proven infection

Diffuse endothelium disruption and impaired microvascular function

Systemic inflammatory response

Severe sepsis with organ dysfunction

Hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia

Septic shock FIGURE 34.11  •  Pathogenic mechanisms leading from infection to septic shock.

number of resistant organisms, growing number of immunocompromised and older adults, and greater use of invasive procedures. With early intervention and advances in t­ reatment methods, the mortality rate has decreased. However, the number of deaths has increased because of the increased prevalence.41 Pathophysiology. The pathogenesis of sepsis involves a complex process of cellular activation resulting in the release of proinflammatory mediators such as cytokines; recruitment of neutrophils and monocytes; involvement of neuroendocrine reflexes; and activation of complement, coagulation, and fibrinolytic systems. Initiation of the response begins with activation of the innate immune system by pattern-recognition receptors (e.g., toll-like receptors [TLRs]) that interact with

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specific molecules present on microorganisms. Binding of TLRs to epitopes on microorganisms stimulates transcription and release of a number of proinflammatory and antiinflammatory mediators. Two of these mediators, TNF-α and interleukin-1, are involved in leukocyte adhesion, local inflammation, neutrophil activation, suppression of erythropoiesis, generation of fever, tachycardia, lactic acidosis, ­ventilation– perfusion abnormalities, and other signs of sepsis as discussed earlier. Although activated neutrophils kill microorganisms, they also injure the endothelium by releasing mediators that increase vascular permeability. In addition, activated endothelial cells release nitric oxide, a potent vasodilator that acts as a key mediator of septic shock. Another important aspect of sepsis is an alteration of the procoagulation–anticoagulation balance with an increase in procoagulation factors and a decrease in anticoagulation factors. Lipopolysaccharide on the surface of microorganisms stimulates endothelial cells lining blood vessels to increase their production of tissue factor, thus activating coagulation.40 Fibrinogen is then converted to fibrin, leading to the formation of microvascular thrombi that further amplify tissue injury. In addition, sepsis lowers levels of protein C, protein S, antithrombin III, and tissue factor pathway inhibitor, substances that modulate and inhibit coagulation. Lipopolysaccharide and TNF-α also decrease the synthesis of thrombomodulin and endothelial protein C receptor, impairing activation of protein C, and they increase the synthesis of plasminogen activator inhibitor-1, impairing fibrinolysis.40,44 Clinical Manifestations. Sepsis and septic shock typically manifests with hypotension and warm, flushed skin. Whereas other forms of shock (i.e., cardiogenic, hypovolemic, and obstructive) are characterized by a compensatory increase in systemic vascular resistance, septic shock often presents with a decrease in systemic vascular resistance. There is ­hypovolemia due to arterial and venous dilatation, plus leakage of plasma into the interstitial spaces. Abrupt changes in cognition or behavior are due to reduced cerebral blood flow and may be early indications of septic shock. Regardless of the underlying cause, fever and increased leukocytes are present. An elevated serum lactate or metabolic acidosis indicates anaerobic metabolism due to tissue hypoxia or ­cellular dysfunction and altered cellular metabolism.41,45 Tissue ­ hypoxia produces continued production and activation of inflammatory ­mediators, ­resulting in further increases in vascular permeability, impaired vascular regulation, and altered hemostasis. Treatment.  The treatment of sepsis and septic shock focuses on control of the causative agent and support of the circulation. Early use of antibiotics is essential, followed by antibiotic therapy specific to the infectious agent.44,45 However, antibiotics do not treat the inflammatory response to the infection. Thus, the cardiovascular status of the person must be supported to increase oxygen delivery to the cells and

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cellular injury. Swift and aggressive fluid prevent further ­ ­administration is needed to compensate for third spacing. Equally aggressive use of vasoconstrictive agents, such as vasopressin, norepinephrine, and phenylephrine, is needed to counteract the vasodilation caused by inflammatory mediators. A positive inotrope, such as dobutamine or milrinone, may be used to augment cardiac output. Ongoing assessment of oxygen, CVP, central or mixed venous oxygen saturation, mean arterial pressure, and urinary output and laboratory measurements of blood cultures, serum lactate, base deficit, and pH are used to evaluate the progression of sepsis and adequacy of treatment.39–43,45 Among the more recent advances in the treatment of sepsis are the use of intensive insulin therapy for hyperglycemia and the administration of recombinant human activated protein C.44 It has been demonstrated that intensive insulin therapy that maintained blood glucose levels at 80 to 110 mg/dL (4.4 to 6.1 mmol/L) resulted in lower mortality and morbidity than did conventional therapy that maintained blood glucose levels at 180 to 200 mg/dL (10 to 11 mmol/L).44 Hyperglycemia is potentially harmful because it acts as a procoagulant, induces apoptosis, impairs neutrophil function, increases the risk of infection, and impairs wound healing.40 Recombinant human activated protein C (drotrecogin alfa), a naturally occurring anticoagulant factor that acts by inactivating coagulation factors Va and VIII, is the first agent that has demonstrated effectiveness in the treatment of sepsis.40 In addition to its anticoagulant actions, activated protein C has direct anti-inflammatory properties, including blocking the production of cytokines by monocytes and blocking cell adhesion. Activated protein C also has antiapoptotic actions that may contribute to its effectiveness. The use of corticosteroids, once considered a mainstay in the treatment of sepsis, remains controversial. There is little to no evidence that the use of corticosteroids can improve patient outcomes. It should only be considered when fluid resuscitation and vasoactive support have not shown any improvement in the status of the person with sepsis.

Obstructive Shock The term obstructive shock describes circulatory shock that results from mechanical obstruction of the flow of blood through the central circulation (great veins, heart, or lungs; see Fig. 34.8). Obstructive shock may be caused by a number of conditions, including dissecting aortic aneurysm, cardiac tamponade, pneumothorax, atrial myxoma, and evisceration of abdominal contents into the thoracic cavity because of a ruptured hemidiaphragm. The most frequent cause of obstructive shock is pulmonary embolism. The primary physiologic result of obstructive shock is elevated right heart pressure due to impaired right ventricular function. Pressures are increased despite impaired venous return to the heart. Signs of right heart failure occur, including elevation of CVP and jugular venous distention. Treatment modalities focus on correcting the cause of the disorder,

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frequently with surgical interventions such as pulmonary embolectomy, pericardiocentesis (i.e., removal of fluid from the pericardial sac) for cardiac tamponade, or the insertion of a chest tube for correction of a tension pneumothorax or hemothorax. In severe or massive pulmonary embolus, fibrinolytic drugs may be used to break down the clots causing the obstruction.

Complications of Shock Many body systems are destroyed by shock. Five major complications of severe shock are the following: 1. Pulmonary injury 2. Acute renal failure 3. Gastrointestinal ulceration 4. Disseminated intravascular coagulation (DIC) 5. Multiple organ dysfunction syndrome (MODS) These complications of shock are serious and often fatal. Acute Lung Injury/Acute Respiratory Distress Syndrome Acute lung injury/acute respiratory distress syndrome (ALI/ ARDS) is a potentially lethal form of pulmonary injury that may be either the cause or result of shock. ARDS is a more severe aspect of ALI and is differentiated primarily for early intervention, prevention, and research purposes. ALI/ARDS is marked by the rapid onset of profound dyspnea that usually occurs 12 to 48 hours after the initiating event. The respiratory rate and effort of breathing increase. Arterial blood gas analysis establishes the presence of profound hypoxemia that is refractory to supplemental oxygen. The hypoxemia results from impaired matching of ventilation and perfusion and from the greatly reduced diffusion of blood gases across the thickened alveolar membranes. The exact cause of ALI/ARDS is unknown. Neutrophils are thought to play a key role in its pathogenesis. A cytokinemediated activation and accumulation of neutrophils in the pulmonary vasculature and subsequent endothelial injury are thought to cause leaking of fluid and plasma proteins into the interstitium and alveolar spaces.46,47 The fluid leakage causes atelectasis, impairs gas exchange, and makes the lung stiff and more difficult to inflate. Abnormalities in the production, composition, and function of surfactant may contribute to alveolar collapse and gas exchange abnormalities. Inappropriate ­vasodilation and vasoconstriction worsen the ventilation and perfusion mismatch. Interventions for ALI/ARDS focus on increasing the oxygen concentration in the inspired air and supporting ventilation mechanically to optimize gas exchange while avoiding oxygen toxicity and preventing further lung injury.47 Although the delivery of high levels of oxygen using high-pressure mechanical ventilatory support and positive end-expiratory pressure may correct the hypoxemia, the mortality rate varies from 35% to 40%.48 The major causes are the initiating incident and multiple organ system failure.

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Acute Renal Failure The renal tubules are particularly vulnerable to ischemia, and acute renal failure is an important factor in mortality due to severe shock. Most cases of acute renal failure are due to impaired renal perfusion or direct injury to the kidneys. The degree of renal damage is related to the severity and duration of shock. The normal kidney is able to tolerate severe ischemia for 15 to 20 minutes. The renal dysfunction most frequently seen after severe shock is acute tubular necrosis. Acute tubular necrosis usually is reversible, although return to normal renal function may require weeks or months. Continuous monitoring of urinary output during shock provides a means of assessing renal blood flow. Frequent monitoring of serum creatinine and blood urea nitrogen levels also provides valuable information regarding renal status. Mediators implicated in septic shock are powerful vasoconstrictors capable of activating the sympathetic nervous system and causing intravascular clotting. They have been shown to trigger all the separate physiologic mechanisms that contribute to the onset of acute renal failure. Gastrointestinal Complications The gastrointestinal tract is particularly vulnerable to ischemia because of the changes in distribution of blood flow to its mucosal surface. In shock, there is widespread constriction of blood vessels that supply the gastrointestinal tract, causing a redistribution of blood flow and a severe decrease in mucosal perfusion. People may experience loss of appetite, nausea, or vomiting. Superficial mucosal lesions of the stomach and duodenum can develop within hours of severe trauma, sepsis, or burns. Bowel obstruction or bleeding may occur after the decrease in perfusion in shock. Hemorrhage usually has its onset within 2 to 10 days after the original insult and often begins without warning. Poor perfusion in the gastrointestinal tract has been credited with allowing intestinal bacteria to enter the bloodstream, thereby contributing to the development of sepsis and shock.49 Histamine type 2 receptor antagonists, proton pump inhibitors, or sucralfate may be given prophylactically to prevent gastrointestinal ulcerations caused by shock.44 Nasogastric tubes, when attached to intermittent suction, also help to diminish the accumulation of hydrogen ions in the stomach. Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) is characterized by widespread activation of the coagulation system with resultant formation of fibrin clots and thrombotic occlusion of small and midsized vessels. The systemic formation of fibrin results from increased generation of thrombin, the simultaneous suppression of physiologic anticoagulation mechanisms, and the delayed removal of fibrin as a consequence of impaired fibrinolysis. Clinically overt DIC is reported to occur in as much as 1 in every 1000 people in the United States.50 As with other systemic inflammatory responses, the derangement

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of coagulation and fibrinolysis is thought to be mediated by inflammatory mediators and cytokines. The contribution of DIC to morbidity and mortality in sepsis depends on the underlying clinical condition and the intensity of the coagulation disorder. Depletion of the ­platelets and coagulation factors increases the risk of ­bleeding. Deposition of fibrin in the vasculature of organs contributes to ischemic damage and organ failure. However, it remains uncertain whether DIC was a predictor of unfavorable ­outcome or merely a marker of the seriousness of the underlying condition causing the DIC. The management of sepsis-induced DIC focuses on treatment of the underlying disorder and measures to interrupt the coagulation process. Anticoagulation therapy and administration of blood products50 may be used. Multiple Organ Dysfunction Syndrome Multiple organ dysfunction syndrome (MODS) represents the presence of altered organ function in an acutely ill person such that homeostasis cannot be maintained without intervention. As the name implies, MODS commonly affects multiple organ systems, including the kidneys, lungs, liver, brain, and heart. MODS is a particularly life-threatening complication of shock, especially septic shock. It has been reported as the most frequent cause of death in the noncoronary intensive care unit. Mortality rates vary from 30% to 100%, depending on the number of organs involved.51 Mortality rates increase with an increased number of organs failing. A high mortality rate is associated with failure of the brain, liver, kidneys, and lungs. The pathogenesis of MODS is not clearly understood, and current management therefore is primarily supportive. Major risk factors for the development of MODS are severe trauma, sepsis, prolonged periods of hypotension, hepatic dysfunction, infarcted bowel, advanced age, and alcohol abuse.51 Interventions for multiple organ failure are focused on support of the affected organs.

IN SUMMARY Circulatory shock is an acute emergency in which body tissues are deprived of oxygen and cellular nutrients or are unable to use these materials in their metabolic processes. Circulatory shock may develop because the heart is unable to adequately pump blood through the circulatory system (cardiogenic shock), there is insufficient blood in the ­circulatory system (i.e., hypovolemic shock), there is a maldistribution of blood due to abnormalities in the vascular resistance (i.e., distributive shock), or blood flow or venous return is obstructed (i.e., obstructive shock). Three types of shock share the basic circulatory pattern of distributive shock: neurogenic shock, anaphylactic shock, and septic shock. Sepsis and septic shock, which is the most common of the three types, is associated with a severe, overwhelming inflammatory response and has a high mortality rate.

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The manifestations of hypovolemic shock, which serves as a prototype for circulatory shock, are related to low peripheral blood flow and excessive sympathetic stimulation. The low peripheral blood flow produces thirst, changes in skin temperature, decreased blood pressure, increased heart rate, decreased venous pressure, decreased urine output, and changes in the sensorium. The intense vasoconstriction that serves to maintain blood flow to the heart and brain causes a decrease in tissue perfusion, impaired cellular metabolism, liberation of lactic acid, and, eventually, cell death. Whether the shock is irreversible or the patient will survive is determined largely by changes that occur at the cellular level. The complications of shock result from the deprivation of blood flow to vital organs or systems, such as the lungs, kidneys, gastrointestinal tract, and blood coagulation system. Shock can cause or be accompanied by ALI/ARDS, which is characterized by changes in the permeability of the alveolar–capillary membrane with development of interstitial edema and severe hypoxemia that does not respond to oxygen therapy. The renal tubules are particularly vulnerable to ischemia, and acute renal failure is an important complication of shock. Gastrointestinal ischemia may lead to gastrointestinal bleeding and increased vascular permeability to intestinal bacteria, which can cause further sepsis and shock. DIC is characterized by formation of small clots in the circulation. It is thought to be caused by inappropriate activation of the coagulation cascade because of toxins or other products released as a result of the shock state. Multiple organ failure, perhaps the most ominous complication of shock, rapidly depletes the body’s ability to compensate and recover from a shock state.

HEART FAILURE IN CHILDREN AND OLDER ADULTS After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the causes of heart failure in infants and children. •• Explain how the aging process affects cardiac function and predisposes to ventricular dysfunction. •• Identify how the signs and symptoms of heart failure may differ between younger and older adults.

Heart Failure in Infants and Children As in adults, heart failure in infants and children results from the inability of the heart to maintain the cardiac output required to sustain metabolic demands.52 The etiology of heart failure, however, is very different between children and

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adults. Structural (congenital) heart defects are the most common cause of heart failure in children. Surgical correction of congenital heart defects may cause heart failure as a result of intraoperative manipulation of the heart and resection of heart tissue, with subsequent alterations in pressure, flow, and resistance relations. Usually, the heart failure that results is acute and resolves after the effects of the surgical procedure have subsided. Another cause of heart failure in children is cardiomyopathy related to a genetic or inherited disorder, infectious disease, drugs, toxins, and Kawasaki disease.52 Chart 34.2 lists

Chart 34.2

CAUSES OF HEART FAILURE IN CHILDREN

Newborn Period Congenital heart defects Severe left ventricular outflow disorders Hypoplastic left heart Critical aortic stenosis or coarctation of the aorta Large arteriovenous shunts Ventricular septal defects Patent ductus arteriosus Transposition of the great vessels Heart muscle dysfunction (secondary) Asphyxia Sepsis Hypoglycemia Hematologic disorders (e.g., anemia) Infants 1 to 6 Months Congenital heart disease Large arteriovenous shunts (ventricular septal defect) Heart muscle dysfunction Myocarditis Cardiomyopathy Pulmonary abnormalities Bronchopulmonary dysplasia Persistent pulmonary hypertension Toddlers, Children, and Adolescents Acquired heart disease Cardiomyopathy Viral myocarditis Rheumatic fever Endocarditis Systemic disease Sepsis Kawasaki disease Renal disease Sickle cell disease Congenital heart defects Nonsurgically treated disorders Surgically treated disorders

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some of the more common causes of heart failure in children, which include the following: •• Inflammatory heart disorders (e.g., myocarditis, rheumatic fever, bacterial endocarditis, Kawasaki disease) •• Cardiomyopathy •• Congenital heart disorders Clinical Manifestations Many of the signs and symptoms of heart failure in infants and children are similar to those in adults. In children, overt symptoms of heart failure occur late in the disease process.53 Breathlessness, tachypnea, and tachycardia felt as palpitations are the most common symptoms.52 Other symptoms include fatigue, effort intolerance, cough, anorexia, and abdominal pain. A subtle sign of cardiorespiratory distress in infants and children is a change in disposition or responsiveness, including irritability or lethargy. Sympathetic stimulation produces peripheral vasoconstriction and diaphoresis. Decreased renal blood flow often results in a decrease in urine output despite adequate fluid intake. When right ventricular function is impaired, systemic venous congestion develops. Hepatomegaly due to liver congestion often is one of the first signs of systemic venous congestion in infants and children. However, dependent edema or ascites rarely is seen unless the CVP is extremely high. Because of their short, fat necks, jugular venous distention is difficult to detect in infants. It is not a reliable sign until the child is of school age or older. A third heart sound, or gallop rhythm, is a common finding in infants and children with heart failure. It results from rapid filling of a noncompliant ventricle. However, it is difficult to distinguish at high heart rates. Most commonly, children develop interstitial pulmonary edema rather than alveolar pulmonary edema. This reduces lung compliance and increases the work of breathing, causing tachypnea and increased respiratory effort. Older children display use of accessory muscles (i.e., scapular and sternocleidomastoid). Head bobbing and nasal flaring may be observed in infants. Signs of respiratory distress often are the first and most noticeable indication of heart failure in infants and young children. Pulmonary congestion may be mistaken for bronchiolitis or lower respiratory tract infection. The infant or young child with respiratory distress often grunts with expiration. This grunting effort (essentially, exhaling against a closed glottis) is an instinctive effort to increase end-expiratory pressures and prevent collapse of small airways and the development of atelectasis. Respiratory crackles are u­ ncommon in infants and usually suggest development of a respiratory tract infection. Wheezes may be heard, particularly if there is a large left-to-right shunt. Infants with heart failure often show increased tachypnea, fatigue, and diaphoresis during feeding.52 Weight gain is slow owing to high energy requirements and low calorie intake. Diaphoresis occurs (because of increased sympathetic tone) particularly over the head and neck. They may have repeated

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Chapter 34  Heart Failure and Circulatory Shock    893

lower respiratory tract infections. Peripheral perfusion usually is poor, with cool extremities; tachycardia is common (resting heart rate >150 beats/minute); and the respiratory rate is increased (resting rate >50 breaths/minute).52 Diagnosis and Treatment Diagnosis of heart failure in infants and children is based on symptomatology, chest radiographic films, electrocardiographic findings, echocardiographic techniques to assess cardiac structures and ventricular function (i.e., end-systolic and end-diastolic diameters), arterial blood gases to determine intracardiac shunting and ventilation–perfusion inequalities, and other laboratory studies to determine anemia and electrolyte imbalances. Treatment of heart failure in infants and children includes measures aimed at improving cardiac function and eliminating excess intravascular fluid. Oxygen delivery must be supported and oxygen demands controlled or minimized. Whenever possible, the cause of the disorder is corrected (e.g., medical treatment of sepsis and anemia, surgical correction of congenital heart defects). With congenital anomalies that are amenable to surgery, medical treatment often is needed for a time before surgery and usually is continued in the immediate postoperative period. For some children, only medical management can be provided. Medical management of heart failure in infants and children is similar to that in the adult, although it is tailored to the special developmental needs of the child. Inotropic agents such as digitalis often are used to increase cardiac contractility. Diuretics may be given to reduce preload and vasodilating medications used to manipulate the afterload. Medication doses must be carefully tailored to control for the child’s weight and conditions such as reduced renal function. Daily weighing and accurate measurement of intake and output are imperative during acute episodes of failure. Most children feel better in the semiupright position. An infant seat is useful for infants with chronic heart failure. Activity restrictions usually are designed to allow children to be as active as possible within the limitations of their heart disease. Infants with heart failure often have problems feeding. Small, frequent feedings usually are more successful than larger, less frequent feedings. Severely ill infants may lack sufficient strength to suck and may need to be tube fed. The treatment of heart failure in children should be designed to allow optimal physical and psychosocial development. It requires the full involvement of the parents, who often are the primary care providers. Therefore, parent education and support are essential.

Heart Failure in Older Adults Heart failure is largely a disease of aging. It is one of the most common causes of disability in older adults and is the most frequent hospital admission and discharge diagnosis for older adults (those older than 65 years) in the United States and Canada.54 Among the factors that have contributed to

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the increased numbers of older adults with heart failure are the improved therapies for ischemic and hypertensive heart ­disease.55 Thus, people who would have died from acute myocardial disease 20 years ago are now surviving but with residual left ventricular dysfunction. Advances in treatment of other diseases have also contributed indirectly to the rising prevalence of heart failure in the older population. Coronary heart disease, hypertension, arrhythmias, and valvular heart disease (particularly aortic stenosis and mitral regurgitation) are common causes of heart failure in older adults.56 In contrast to the etiology in middle-aged people with heart failure, factors other than systolic failure contribute to heart failure in older adults. Preserved left ventricular function may be seen in 40% to 80% of older adults with heart failure.57 Aging is associated with impaired left ventricular filling due to changes in myocardial relaxation and compliance. These alterations lead to a shift in the left ventricular pressure–volume relationship, such that small increases in left ventricular volume lead to greater increases in left ventricular diastolic pressure. This increase in diastolic pressure further compromises left ventricular filling and leads to increases in left atrial, pulmonary venous, and pulmonary capillary pressures, and thus predisposes to pulmonary congestion and heart failure.58 Although diastolic heart failure accounts for less than 10% of heart failure cases in people younger than 60 years of age, it accounts for greater than 50% of cases after age 75 years.58 There are a number of changes associated with aging that contribute to the development of heart failure in older adults.55,56,59 First, reduced responsiveness to β-adrenergic stimulation limits the heart’s capacity to maximally increase heart rate and contractility. A second major effect of aging is increased vascular stiffness, which leads to a progressive increase in systolic blood pressure with advancing age, which in turn contributes to the development of left ventricular hypertrophy and altered diastolic filling. Third, in addition to increased vascular stiffness, the heart itself becomes stiffer and less compliant with age. The changes in diastolic stiffness result in important alterations in diastolic filling and atrial function. A reduction in ventricular filling not only affects cardiac output but produces an elevation in diastolic pressure that is transmitted back to the left atrium, where it stretches the muscle wall and predisposes to atrial ectopic beats and atrial fibrillation. The fourth major effect of cardiovascular aging is altered myocardial metabolism at the level of the mitochondria. Although older mitochondria may be able to generate sufficient ATP to meet the normal energy needs of the heart, they may not be able to respond under stress. Clinical Manifestations The manifestations of heart failure in older adults often are masked by other disease conditions.2 Nocturia and nocturnal incontinence is an early symptom but may be caused by other conditions such as prostatic hypertrophy. Lower extremity edema may reflect venous insufficiency. Impaired perfusion

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894   UNIT VIII  Disorders of Cardiovascular Function

Chart 34.3

MANIFESTATIONS OF HEART FAILURE IN OLDER ADULTS

Symptoms Nocturia or nocturnal incontinence Fatigue Cognitive impairment (e.g., problem solving, decision making) Depression Restlessness/acute delirium Sleep disturbance History of falls Loss of appetite Signs Dependent edema (ankles when sitting up and sacral edema when supine) Pulmonary crackles (usually late sign)

of the gastrointestinal tract is a common cause of anorexia and profound loss of lean body mass. Loss of lean body mass may be masked by edema. Exertional dyspnea, orthopnea, and impaired exercise tolerance are cardinal symptoms of heart failure in both younger and older adults with heart failure. However, with increasing age, which is often accompanied by a more sedentary lifestyle, exertional dyspnea becomes less prominent. Instead of dyspnea, the prominent sign may be restlessness. Chart 34.3 summarizes the clinical manifestations of heart failure in older adults. Physical signs of heart failure, such as elevated jugular venous pressure, hepatic congestion, S3 gallop, and pulmonary crackles, occur less commonly in older adults, in part because of the increased incidence of diastolic failure, in which signs of right-sided heart failure are late manifestations and a third heart sound is typically absent.59 Instead, behavioral changes and altered cognition such as short-term memory loss and impaired problem solving are more common. Depression is common in older adults with heart failure and shares the symptoms of sleep disturbances, cognitive changes, and fatigue.2 Older adults also maintain a precarious balance between the managed symptom state and acute symptom exacerbation. During the managed symptom state, they are relatively symptom-free while adhering to their treatment regimen. Acute symptom exacerbation, often requiring emergency medical treatment, can be precipitated by seemingly minor conditions such as poor adherence to sodium restriction, infection, or stress. Failure to promptly seek medical care is a common cause of progressive acceleration of symptoms. Diagnosis and Treatment The diagnosis of heart failure in older adults is based on the history, physical examination, chest radiograph, and electro-

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cardiographic findings.56,60–63 However, the presenting symptoms of heart failure often are difficult to evaluate. Symptoms of dyspnea on exertion are often interpreted as a sign of “getting older” or attributed to deconditioning from other diseases. Ankle edema is not unusual in older adults because of decreased skin turgor and the tendency of older adults to be more sedentary with the legs in a dependent position. Treatment of heart failure in older adults involves many of the same methods as in younger people, with medication dose adaptations to reduce age-related adverse and toxic events.2 ACE inhibitors may be particularly beneficial to preserve cognitive and functional capacities.2 Activities may be restricted to a level that is commensurate with the cardiac reserve. Seldom is bed rest recommended or advised. Bed rest causes rapid deconditioning of skeletal muscles and increases the risk of complications such as orthostatic hypotension and thromboemboli. Instead, carefully prescribed exercise programs can help to maintain activity tolerance. Even walking around a room usually is preferable to continuous bed rest. Sodium restriction usually is indicated. Since older adults have the highest hospital readmission rates, education is extremely important and it is imperative to involve the family members and caregivers in their management and treatment. It is also important to have a multidisciplinary approach to their care with frequent contact since they will have other comorbid conditions and can deteriorate rapidly.

IN SUMMARY The mechanisms of heart failure in children and older adults are similar to those in adults. However, the causes and manifestations may differ because of age. In children, heart failure is seen most commonly during infancy and immediately after heart surgery. It can be caused by congenital and acquired heart defects and is characterized by fatigue, effort intolerance, cough, anorexia, abdominal pain, and impaired growth. Treatment of heart failure in children includes correction of the underlying cause whenever possible. For congenital anomalies that are amenable to surgery, medical treatment often is needed for a time before surgery and usually is continued in the immediate postoperative period. For many children, only medical management can be provided. In older adults, age-related changes in cardiovascular functioning contribute to heart failure but are not in themselves sufficient to cause heart failure.64 The clinical manifestations of heart failure often are different and superimposed on other disease conditions. Therefore, heart failure often is more difficult to diagnose in older adults than in younger people. Because older adults are more susceptible to adverse and toxic medication reactions, medication doses need to be adapted and more closely monitored.

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Chapter 34  Heart Failure and Circulatory Shock    895

Review Exercises 1. A 75-year-old male with long-standing hypertension and angina due to coronary heart disease presents with ankle edema, nocturia, increased shortness of breath with activity, and a chronic nonproductive cough. He has a past history of smoking two packs per day and is an ex-alcoholic. His blood pressure is 170/80 and his heart rate is 100. Electrocardiography and chest radiography indicate the presence of left ventricular hypertrophy. A. Relate the presence of uncontrolled hypertension and coronary artery disease to the development of heart failure in this man. B. Explain the significance of left ventricular hypertrophy in terms of both a compensatory mechanism and as a pathologic mechanism in the progression of heart failure. C. Explain the management and treatment for this diagnosis. 2. A 21-year-old man is admitted to the emergency department with excessive blood loss after an automobile injury. He is alert and anxious, his skin is cool and moist, his heart rate is 135, and his blood pressure is 100/85. He is receiving intravenous fluids, which were started at the scene of the accident by an emergency medical technician. He has been typed and cross-matched for blood transfusions and a urinary catheter has been inserted to monitor his urinary output. His urinary output has been less than 10 mL since admission and his blood pressure has dropped to 85/70. Efforts to control his bleeding have been unsuccessful and he is being prepared for emergency surgery. A. Use information regarding the compensatory mechanisms in circulatory shock to explain this man’s presenting symptoms, including urinary output. B. The treatment of hypovolemic shock is usually directed at maintaining the circulatory volume through fluid resuscitation rather than maintaining the blood pressure through the use of vasoactive medications. Explain. References 1. Hunt S. A., Abraham W. T., Chin M. H., et al. (2005). ACC/AHA 2005 guidelines for diagnosis and management of chronic heart failure in the adult. Circulation 112, e154–e235. 2. Jessup M., Abraham W. T., Casey P., et al. (2009). 2009 focused update: ACCF/AHA guidelines for the diagnosis and management if heart failure in adults. Circulation 119, 1977–2016. 3. Guyton A. C., Hall J. E. (2011). Textbook of medical physiology (12th ed., pp. 101–113, 255–264, 273–282). Philadelphia, PA: Elsevier Saunders.

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4. Opie L. H., Hasenfuss G. (2012). Mechanisms of cardiac contraction and relaxation. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 459–486). Philadelphia, PA: Elsevier Saunders. 5. Greenburg B., Kahn A. M. (2012). Clinical assessment of heart failure. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 505–517). Philadelphia, PA: Elsevier Saunders. 6. Tzanetos K., Delong D., Wu R. C. (2009). Office management of patients with diastolic heart failure. Canadian Medical Association Journal 180, 520–527. 7. Mann D. (2012). Management of heart failure with reduced ejection fraction. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. ­543–577). Philadelphia, PA: Elsevier Saunders. 8. Haney S., Sur D., Xu Z. (2005). Diastolic heart failure: A review and primary care perspective. Journal of the American Board of Family Practice 18, 189–195. 9. Mann D. (2012). Pathophysiology of heart failure. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 487–504). Philadelphia, PA: Elsevier Saunders. 10. Vieillard-Baron A., Jardin F. (2008). Acute right ventricular dysfunction: Focus on acute cor pulmonale. In Contemporary cardiology: Pulmonary hypertension (pp. 363–381). Totowa, NJ: Humana Press. 11. Soine L. A. (2010). Heart failure and cardiogenic shock. In Woods S. L., Froelicher E. S., Motzer S. U., et al. (Eds.), Cardiac nursing (6th ed., pp. 555–594). Philadelphia, PA: Lippincott Williams & Wilkins. 12. Chinali M., Joffe W., Aurigemma G. P., et al. (2010). Risk factors and comorbidities in a community-wide sample of patients hospitalized with acute systolic or diastolic heart failure: The Worcester Heart Failure Study. Coronary Heart Disease 21, 137–143. 13. Ambrosy A., Wilcox J., Nodan S., et al. (2011). Acute heart failure syndromes: Assessment and reconstructing the heart. Journal of Cardiovascular Medicine 12, 258–283. 14. Francis G. S., Wilson-Tang W. H., Walsh R. A. (2011). Pathophysiology of heart failure. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 719–738). New York: McGraw-Hill. 15. Halder M. K., Walsh R. A. (2011). Molecular and cellular biology of the normal, hypertrophied, and falling heart. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 138–152). New York: McGraw-Hill. 16. Filippatos G., Zannad F. (2007). An introduction to acute heart failure syndromes: Definition and classification. Heart Failure Review 12, 87–90. 17. Coons J. C., McGraw M., Murall S. (2011). Pharmacotherapy for acute heart failure syndromes. American Journal of Health-System Pharmacists 68, 21–35. 18. Follath F., Yilmaz M. B., Delgado J. F., et al. (2011). Clinical presentation, management and outcomes in the acute heart failure global survey of standard treatment (ALARM-HF). Intensive Care Medicine 37, 619–626. 19. Piña H. L. (Chair, Writing Group). (2003). Exercise and heart failure: A statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Circulation 107, 1210–1225. 20. Somberg J. C., Molnar J. (2009). The management of acute heart failure and diuretic therapy. American Journal of Therapeutics 16, 93–97. 21. Gheorghiade M., Filippatos G. S., Felker G. M. (2012). Diagnosis and management of acute heart failure syndromes. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 517–542). Philadelphia, PA: Elsevier Saunders. 22. MERIT-HF Study Group. (1999). Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353, 2001–2007. 23. Abraham W. T., Hasan A. (2011). Diagnosis and management of heart failure. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 748–780). New York: McGraw-Hill.

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896   UNIT VIII  Disorders of Cardiovascular Function 24. Metra M., Teerlink J. R., Voors A. A., et al (2009). Vasodilators in the treatment of acute heart failure: what we know, what we don’t. Heart Failure Review 14, 299–307. 25. Stoltzfus S. (2006). The role of noninvasive ventilation: CPAP and BiPAP in the treatment of congestive HF. Dimensions of Critical Care Nursing 25(2), 66–70. 26. Kerber R. E. (2011). The implantable cardioverter defibrillator. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 1088–1093). New York: McGraw-Hill. 27. Acker M. A., Jessup M. (2012). Surgical management of heart failure. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 601–616). Philadelphia, PA: Elsevier Saunders. 28. Patel N. D., Barreiro C. J., Williams J. A., et al. (2005). Surgical ventricular remodeling for patients with clinically advanced congestive HF and severe left ventricular dysfunction. Journal of Heart and Lung Transplantation 24, 2202–2210. 29. Moronville M., Mieure K., Santyana E. (2011). Evaluation and management of shock states: hypovolemic, distributive and cardiogenic shock. Journal of Pharmacy Practice 24, 44–60. 30. Yazdani S. K., Ladich E., Virmani R. (2011). Pathology of myocardial ischemia, infarction, reperfusion, and sudden death. In Fuster V., Walsh R. A., Harrington R. A., et al. (Eds.), Hurst’s the heart (13th ed., pp. 1306–1313). New York: McGraw-Hill. 31. O’Donovan K. (2011). Cardiogenic shock: complicating myocardial infarction: an overview. British Journal of Cardiac Nursing 6, 280–285. 32. Mehra M., Griffith B. P. (2012). Assisted circulation in the treatment of heart failure. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 617–626). Philadelphia, PA: Elsevier Saunders. 33. Dutton R. P. (2007). Current concepts in hemorrhagic shock. Anesthesiology Clinics 25, 23–34. 34. Landry D. W., Oliver J. A. (2001). The pathogenesis of vasodilatory shock. New England Journal of Medicine 345, 588–595. 35. Lieberman P. (2006). Anaphylaxis. Medical Clinics of North America 90, 77–95. 36. Brown S. G. A. (2007). The pathophysiology of shock in anaphylaxis. Immunology and Allergy Clinics of North America 27, 165–175. 37. Linton E., Watson D. (2010). Recognition, assessment, and management of anaphylaxis. Nursing Standard 24(46), 35–39. 38. Pollart S. M., Warniment S., Mori T. (2009). Latex allergy. American Family Physician 80(12), 1413–1420. 39. Nguyen H. B., Rivers E. P., Abrahamian F. M. (2006). Severe sepsis and septic shock: Review of the literature and emergency department management guidelines. Annals of Emergency Medicine 48, 28–54. 40. Russell J. A. (2006). Management of sepsis. New England Journal of Medicine 355, 1699–1711. 41. Vincent J. L., Taccone F., Schmit X. (2007). Classification, incidence, and outcomes of sepsis and multiple organ failure. Contributions to Nephrology 156, 64–74. 42. Lovick K. (2009). Prompt and aggressive management of sepsis gives patients the best chance of survival. Nursing Times 47, 20–22. 43. Goncalvez J. P., Lailer L. (2010). Evidence-based acute management of sepsis: Rapid intervention in critical hours. Perioperative Nursing Clinics 5, 189–202. 44. Steen C. (2009). Developments in the management of patients with sepsis. Nursing Standard 23, 48–55. 45. Reade M., Huang D. T., Bell D., et al. (2010). Variability in management of early severe sepsis. Emergency Medical Journal 27, 110–115. 46. Abraham E. (2003). Neutrophils and acute lung injury. Critical Care Medicine 31, S195–S199.

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47. Bream-Rouwenhorst H. R., Beltz E. A., Ross M. B., et al. (2008). Recent developments in the management of acute respiratory distress syndrome in adults. American Journal of Health-System Management 65, 29–36. 48. Rubenfeld G. D., Herridge M. S. (2007). Epidemiology and outcomes of acute lung injury. Chest 131, 554–562. 49. Lu Q., Xu D., Sharpe S., et al. (2011). The anatomic sites of disruption of the mucus layer directly correlate with areas of trauma/hemorrhagic shock-induced gut injury. Journal of Trauma 70(3), 630–635. 50. Levi M., Toh C. H., Thachil J., et al. (2009). Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. British Journal of Haematology 145(1), 24–33. 51. Balk R. A. (2000). Pathogenesis and management of multiple organ dysfunction or failure in acute sepsis and septic shock. Critical Care Clinics 16, 337–352. 52. Bernstein D. (2004). Heart failure. In Behrman R. E., Kliegman R. M., Nelson W., et al. (Eds.), Nelson textbook of pediatrics (17th ed., pp. 1582– 1587). Philadelphia, PA: Elsevier Saunders. 53. Rosenthal D., Chrisant M., Edens E., et al. (2004). International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. Journal of Heart and Lung Transplantation 23, 1313–1333. 54. American Heart Association. (2011). Heart disease and stroke statistics: 2011 update at a glance [Online]. Available: www.americanheart.org/ downloadable/heart/.pdf. Accessed October 1, 2011. 55. Thomas S., Rich M. W. (2007). Epidemiology, pathophysiology, and prognosis of heart failure in the elderly. Clinics in Geriatric Medicine 23, 1–10. 56. Schwartz J. B., Zipes D. P. (2012). Cardiovascular disease in the elderly. In Bonow R.O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 1727–1756). Philadelphia, PA: Elsevier Saunders. 57. Chen M. A. (2009). Heart failure with preserved ejection fraction in older adults. The American Journal of Medicine 122, 713–723. 58. Dhesi P., Willix R. D., Phan A., et al. (2010). Heart failure in the elderly: diastolic failure, medical therapy, women and end-of-life. Aging Health 6(4), 429–437. 59. Rich M. W. (2011). Heart failure in older adults. Medical Clinics of North America 95(3), 439–461. 60. Ahmed A., Waagstein F., Pitt B. et al (2009). Effectiveness of digoxin in reducing one-year mortality in chronic heart failure in digitalis investigation group trial. American Journal of Cardiology 103, 82–87. 61. Dhaliwal A. S., Bredikis A., Habib G., et al. (2008). Digoxin and clinical outcomes in systolic heart failure patients on contemporary background heart failure therapy. American Journal of Cardiology 102, 1356–1360. 62. Antman E. M., Morrow D. A. (2012). ST-elevation myocardial infarction: Pathology, pathophysiology, and clinical features; and ST-elevation myocardial infarction: Management. In Bonow R. O., Mann D. L., Zipes D. P., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (9th ed., pp. 1087–1110, 1111–1171). Philadelphia, PA: Elsevier Saunders. 63. Cheng J. W., Ryback I. (2010). Use of digoxin for heart failure and atrial fibrillation in elderly patients. The American Journal of Geriatric Pharmacology 8, 419–427. 64. Imazio M., Cotroneo A., Gaschino G., et al. (2008). Management of heart failure in elderly people. International Journal of Clinical Practice 62, 270–280.

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Unit 9

Disorders of Respiratory Function 24-year-old Ms. French presents to the emergency department with shortness of breath (SOB) and a nonproductive cough. Her vital signs are as follows: temperature, 99.3°F; heart rate, 132 beats/minute; respiratory rate, 20 breaths/minute; blood pressure, 110/64 mm Hg; and pulse oximetry, 94% on room air. Physical examination reveals decreased breath sounds on the right side, sharp chest pain with inspiration, and soreness in her right calf. Ms. French has taken oral contraceptives daily for 6 years but takes no other medications. She smokes 1 pack of cigarettes per day. There is no significant family history. An electrocardiogram (ECG) shows sinus tachycardia. Chest x-ray is not significant. A computed tomography (CT) scan reveals a small thrombus in the right main pulmonary artery. Arterial blood gases (ABGs) at time of presentation are as follows: pH, 7.47; PaCO2, 31 mm Hg; PaO2, 86 mm  Hg; SaO2, 93%; and HCO −3, 24 mEq/L. These values indicate she is in respiratory alkalosis. Serum levels are within normal limits, except d-dimer, 0.7 mg/L (normal: Pv

Zone 2 Pa > PA > Pv

Alveolar PA Pa

Pv

Arterial

Venous Distance

Zone 3 Pa > Pv > PA Blood flow

At very low oxygen levels, the local flow may be almost abolished. In regional hypoxia, which occurs with atelectasis, vasoconstriction is localized to a specific region of the lung. In this case, vasoconstriction has the effect of directing blood flow away from the hypoxic regions of the lungs. When alveolar hypoxia no longer exists, blood flow is restored. Generalized hypoxia, which occurs at high altitudes and in people with chronic hypoxia due to lung disease, causes vasoconstriction throughout the lung. Prolonged hypoxia can lead to pulmonary hypertension and increased workload on the right heart, causing cor pulmonale. A low blood pH produces a similar effect, particularly when alveolar hypoxia is present (e.g., during circulatory shock). Shunt Shunt refers to blood that moves from the right to the left side of the circulation without being oxygenated. As with dead air space, there are two types of shunts: physiologic and anatomic. In an anatomic shunt, blood moves from the venous to the arterial side of the circulation without moving through the lungs. Anatomic intracardiac shunting of blood occurs with congenital heart defects. In a physiologic shunt, there is mismatching of ventilation and perfusion within the lung. This results in insufficient ventilation to provide the oxygen needed to oxygenate the blood flowing through the alveolar capillaries. Physiologic shunting of blood usually results from destructive lung disease that impairs ventilation or from heart failure that interferes with movement of blood through sections of the lungs.

Mismatching of Ventilation and Perfusion The gas exchange properties of the lung depend on matching ventilation and perfusion, ensuring that equal amounts of air and blood are entering the respiratory portion of the lungs. Both dead air space and shunt produce a mismatching of ventilation and perfusion, as depicted in Figure 35.20. With shunt (depicted on the left), there is perfusion without

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FIGURE 35.19  •  The uneven distribution of blood flow in the lung results from different pressures affecting the capillaries, which are affected by body position and gravity. (From West J. B. (2008). Respiratory physiology: The essentials (8th ed., p. 44). Philadelphia, PA: Lippincott Williams & Wilkins.)

ventilation, resulting in a low ventilation–perfusion ratio. It occurs in conditions such as atelectasis in which there is airway obstruction. With dead air space (depicted on the right), there is ventilation without perfusion, resulting in a high ventilation–perfusion ratio. It occurs in conditions such as pulmonary embolism, which impairs blood flow to a part of the lung. The arterial blood leaving the pulmonary circulation reflects mixing of blood from normally ventilated and perfused areas of the lung as well as areas that are not ventilated (dead air space) or perfused (shunt). Many of the conditions that cause mismatching of ventilation and perfusion involve both dead air space and shunt. In chronic obstructive lung disease, for example, there may be impaired ventilation in one area of the lung and impaired perfusion in another area.

Airways Venous blood

Perfusion without ventilation

Arterial blood

Alveolus

Ventilation without perfusion

Normal FIGURE 35.20  •  Matching of ventilation and perfusion. (Center) Normal matching of ventilation and perfusion; (left) perfusion without ventilation (i.e., shunt); (right) ventilation without perfusion (i.e., dead air space).

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Chapter 35  Structure and Function of the Respiratory System    919

In a person with pulmonary embolism like Ms. French, ventilation/perfusion mismatch occurs because blood flow to part of the lung is impaired. Ms. French’s increased respiratory rate is a clinical manifestation of her impaired gas exchange from the ventilation/ perfusion mismatch.

Diffusion Diffusion occurs in the respiratory portions of the lung and refers to the movement of gases across the alveolar–­capillary membrane. The Fick law of diffusion can describe gas diffu· sion in the lung. The Fick law states the volume of a gas (V gas) diffusing across the membrane per unit time is directly proportional to the partial pressure difference of the gas (P1 − P2), the surface area (SA) of the membrane, and the diffusion coefficient (D) and is inversely proportional to the thickness (T) of the membrane (Fig. 35.21).1 Several factors influence the diffusion of gases in the lung. The administration of high concentrations of oxygen increases the difference in partial pressure between the two sides of the membrane and increases the diffusion of the gas. Diseases that destroy lung tissue (i.e., surface area for d­ iffusion) or increase the thickness of the alveolar–capillary membrane adversely influence the diffusing capacity of the lungs. The removal of one lung, for example, reduces the diffusing capacity by one half. The thickness of the alveolar–­capillary membrane and the distance for diffusion are increased in p­ eople with pulmonary edema or pneumonia. The ­ characteristics . SA x D (P1 – P2 ) Vgas = T

. Vgas = P1

P2

of the gas and its molecular weight and solubility constitute the diffusion coefficient and determine how rapidly a gas diffuses through the respiratory membranes. For example, carbon dioxide diffuses 20 times more rapidly than oxygen because of its greater solubility in the respiratory membranes. The diffusing capacity provides a measure of the rate of gas transfer in the lungs per partial pressure gradient. Because the initial alveolar–capillary difference for oxygen cannot be measured, carbon monoxide (CO) is used to determine the diffusing capacity. Measuring CO has several advantages: •• Its uptake is not limited by diffusion or blood flow. •• There is essentially no CO in venous blood. •• Its affinity for hemoglobin is 210 times that of oxygen, ensuring that its partial pressure will remain essentially zero in the pulmonary capillary. The most common technique for making this measurement is the single-breath test. This test involves the inhalation of a single breath of dilute CO, followed by a breath-hold of 10  seconds. The diffusing capacity can be calculated using the lung volume and the percentage of CO in the alveoli at the beginning and end of the 10-second breath-hold.

Oxygen and Carbon Dioxide Transport Although the lungs are responsible for the exchange of gases with the external environment, it is the blood that transports these gases between the lungs and body tissues. The blood carries oxygen and carbon dioxide in the physically dissolved state and in combination with hemoglobin. Carbon dioxide also is converted to bicarbonate and transported in that form. Dissolved oxygen and carbon dioxide exert a partial pressure that is designated in the same manner as the partial ­pressures in the gas state. In the clinical setting, blood gas measurements are used to determine the partial pressure of oxygen (PO2) and carbon dioxide (PCO2) in the blood. Arterial blood commonly is used for measuring blood gases. Venous blood is not used because venous levels of oxygen and carbon dioxide reflect the metabolic demands of the tissues rather than the gas exchange function of the lungs. The PO2 of arterial blood normally is above 80 mm Hg, and the PCO2 is in the range of 35 to 45 mm Hg (Table 35.3). Normally, the ABGs are the same or nearly the same as the partial pressure of the gases in the alveoli. The arterial PO2 often is written PaO2, and the alveolar PO2 as PAO2, with the same types of d­ esignations

Surface area (SA)

TABLE 35.3 A  RTERIAL BLOOD GAS RANGES Thickness (T) FIGURE · 35.21  •  The Fick law of diffusion states that the diffusion of a gas (Vgas) across a sheet of tissue is related to the surface area (SA) of the tissue, the diffusion constant (D) for the gas, and the partial pressure difference (P1 − P2) on either side of the tissue and is inversely proportional to the thickness (T) of the tissue.

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PARAMETER

RANGE

1.  pH = acid or base 2. PCO2 = partial pressure of carbon dioxide 3. HCO –3 = bicarbonate 4. PO2 = partial pressure of oxygen

7.35–7.45 35–45 mm Hg 22–26 mEq/L 80–100 mm Hg

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920   UNIT IX  Disorders of Respiratory Function

being used for PCO2. This text uses PO2 and PCO2 to designate both arterial and alveolar levels of the gases. Oxygen Transport Oxygen is transported in two forms: •• In chemical combination with hemoglobin •• In the dissolved state Hemoglobin carries about 98% to 99% of oxygen in the blood and is the main transporter of oxygen. The remaining 1% to 2% of the oxygen is carried in the dissolved state. Only the dissolved form of oxygen passes through the capillary wall, diffuses through the cell membrane, and makes itself available for use in cell metabolism. The oxygen content (measured in mL/100 mL) of the blood includes the oxygen carried by hemoglobin and in the dissolved state. Hemoglobin Transport. Hemoglobin is a highly efficient carrier of oxygen. Hemoglobin with bound oxygen is called oxyhemoglobin. When oxygen is removed, it is called deoxygenated or reduced hemoglobin. Each gram of hemoglobin carries approximately 1.34 mL of oxygen when it is fully saturated. This means that a person with a hemoglobin level of 14 g/100 mL carries 18.8 mL of oxygen per 100 mL of blood. In the lungs, oxygen moves across the alveolar–capillary membrane, through the plasma, and into the red blood cell, where it forms a loose and reversible bond with the hemoglobin molecule. In normal lungs, this process is rapid. Therefore, even with a fast heart rate the hemoglobin is almost completely saturated with oxygen during the short time it spends in the pulmonary capillaries. As the oxygen moves out of the capillaries in response to the needs of the tissues, the hemoglobin saturation drops. It is approximately 95% to 97% saturated as the blood leaves the left side of the heart. It then drops to approximately 75% saturation as the mixed venous blood returns to the right side of the heart. Dissolved Oxygen. The partial pressure of oxygen represents the level of dissolved oxygen in plasma. The amount of dissolved oxygen depends on its partial pressure and its solubility in the plasma. In the normal lung at 760 mm Hg atmospheric pressure, the PO2 of arterial blood is approximately 100 mm Hg. The solubility of oxygen in plasma is fixed and very small. For every 1 mm Hg of PO2 present, 0.003 mL of oxygen becomes dissolved in 100 mL of plasma. This means that at a normal arterial PO2 of 100 mm Hg, the blood carries only 0.3 mL of dissolved oxygen in each 100 mL of plasma. This amount (­approximately 1%) is very small compared with the amount that can be carried in an equal amount of blood when oxygen is attached to hemoglobin. However, this small amount can become a lifesaving mode of transport in cases of CO poisoning, when most of the hemoglobin sites are occupied by CO and are unavailable for transport of oxygen. The use of a hyperbaric chamber, in which 100% oxygen can be administered at high atmospheric pressures, increases the amount of oxygen that can be carried in the dissolved state and is used for people with severe

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burns, especially those impacting the respiratory system, and in people with multiple types of wounds such as the immunosuppressed or those with diabetes who have trouble healing. Binding Affinity of Hemoglobin for Oxygen.  The efficiency of the hemoglobin transport system depends on the ability of the hemoglobin molecule to bind oxygen in the lungs and release it as it is needed in the tissues. Oxygen that remains bound to hemoglobin cannot participate in tissue metabolism. The term affinity refers to hemoglobin’s ability to bind oxygen. Hemoglobin binds oxygen more readily when its affinity is increased and releases it more readily when its affinity is decreased. The hemoglobin molecule is composed of four polypeptide chains with an iron-containing heme group. Because oxygen binds to the iron atom, each hemoglobin molecule can bind four molecules of oxygen when it is fully saturated. Oxygen binds cooperatively with the heme groups on the hemoglobin molecule. After the first molecule of oxygen binds to hemoglobin, the molecule undergoes a change in shape. As a result, the second and third molecules bind more readily, and binding of the fourth molecule is even easier. In a like manner, the unloading of the first molecule of oxygen enhances the unloading of the next molecule and so on. Thus, the affinity of hemoglobin for oxygen changes with hemoglobin saturation. Hemoglobin’s affinity for oxygen is also influenced by pH, carbon dioxide concentration, and body temperature. It binds oxygen more readily under conditions of increased pH (alkalosis), decreased carbon dioxide concentration, and decreased body temperature, and it releases it more readily under conditions of decreased pH (acidosis), increased carbon dioxide concentration, and fever. For example, increased tissue metabolism generates carbon dioxide and metabolic acids and thereby decreases the affinity of hemoglobin for oxygen. Heat also is a by-product of tissue metabolism, explaining the effect of fever on oxygen binding. Red blood cells contain a metabolic intermediate called 2,3-diphosphoglycerate (2,3-DPG) that also affects the affinity of hemoglobin for oxygen. An increase in 2,3-DPG enhances unloading of oxygen from hemoglobin at the tissue level. Conditions that increase 2,3-DPG include exercise, hypoxia that occurs at high altitude, and chronic lung disease.1 The Oxygen Dissociation Curve.  The relation between the oxygen carried in combination with hemoglobin and the PO2 of the blood is described by the oxygen–hemoglobin dissociation curve, which is shown in Figure 35.22. The x-axis of the graph depicts the PO2 or dissolved oxygen. It reflects the partial pressure of the oxygen in the lungs (i.e., the PO2 is approximately 100 mm Hg when room air is being breathed, but can rise to 200 mm Hg or higher when oxygen-enriched air is breathed). The left y-axis depicts hemoglobin saturation or the amount of oxygen that is carried by the hemoglobin. The right y-axis depicts oxygen content or total amount of the oxygen content being carried in the blood. The S-shaped oxygen dissociation curve has a flat top portion representing binding of oxygen to hemoglobin in the lungs and a steep portion representing its release into the

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Chapter 35  Structure and Function of the Respiratory System    921

Understanding

Oxygen Transport

All body tissues rely on oxygen (O2) that is transported in the blood to meet their metabolic needs. Oxygen is carried in two forms: dissolved and bound to hemoglobin. About 98% of O2 is carried by hemoglobin, and the remaining 2% is carried in the dissolved state. Dissolved oxygen is the only form that diffuses across cell membranes and produces a partial pressure (PO2), which, in turn, drives diffusion. The transport of O2 involves (1) transfer from the alveoli to the pulmonary capillaries in the lung, (2) hemoglobin binding and transport, and (3) the dissociation from hemoglobin in the tissue capillaries.

Alveoli-to-Capillary Transfer

Lung

In the lung, O2 moves from the alveoli to the pulmonary capillaries as a dissolved gas. Its movement occurs along a concentration gradient. It moves from the alveoli, where the partial pressure of PO2 is about 100 mm Hg, to the venous end of the pulmonary capillaries with their lesser O2 concentration and lower PO2. The dissolved O2 moves rapidly between the alveoli and the pulmonary capillaries, such that the PO2 at the arterial end of the capillary is almost, if not exactly, the same as that in the alveoli.

Alveolus

O2

O2 Pulmonary capillary

Red blood cell

PO2

HbO2

Hemoglobin Binding and Transport Oxygen, which is relatively insoluble in plasma, relies on hemoglobin for transport in the blood. Once oxygen has diffused into the pulmonary capillary, it moves rapidly into the red blood cells and reversibly binds to hemoglobin to form HbO2. The hemoglobin molecule contains four heme units, each capable of attaching an oxygen molecule. Hemoglobin is 100% saturated when all four units are occupied and is usually about 97% saturated in the systemic arterial blood. The capacity of the blood to carry O2 is dependent both on hemoglobin levels and the ability of the lungs to oxygenate the hemoglobin.

O2

Heme

β2

α2

β1

α1

Continued

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922   UNIT IX  Disorders of Respiratory Function

Understanding

Oxygen Transport (Continued)

Oxygen Dissociation in the Tissues The dissociation or release of O2 from hemoglobin occurs in the tissue capillaries where the PO2 is less than that of the arterial blood. As oxygen dissociates from hemoglobin, it dissolves in the plasma and then moves into the tissues where the PO2 is less than that in the capillaries. The affinity of hemoglobin for O2 is influenced by the carbon dioxide (PCO2) content of the blood and its pH temperature and 2,3-diphosphoglycerate (2,3-DPG), a by-product of glycolysis in red blood cells. Under conditions of high metabolic demand, in which the PCO2 is increased and the pH is decreased, the binding affinity of hemoglobin is decreased. During decreased metabolic demand, when the PCO2 is decreased and the pH is increased, the affinity is increased.

Tissue capillaries

HbO2

PO2

O2

O2 Body cells

t­issue capillaries (see Fig. 35.22A). The S shape of the curve reflects the effect that oxygen saturation has on the conformation of the hemoglobin molecule and its affinity for oxygen. At approximately 100 mm Hg PO2, a plateau occurs. At this point the hemoglobin is approximately 98% saturated. Increasing the alveolar PO2 above this level does not increase the hemoglobin saturation. Even at high altitudes, when the partial pressure of oxygen is considerably decreased, the hemoglobin remains relatively well saturated. At 60 mm Hg PO2, for example, the hemoglobin is still approximately 89% saturated. The steep portion of the dissociation curve—between 60 and 40 mm Hg—represents the removal of oxygen from the hemoglobin as it moves through the tissue capillaries. This portion of the curve reflects a considerable transfer of oxygen from hemoglobin to the tissues with only a small drop in PO2. This ensures a gradient for oxygen to move into body cells. The tissues normally remove approximately 5 mL of oxygen per 100 mL of blood, and the hemoglobin of mixed venous blood is approximately 75% saturated as it returns to the right side of the heart. In this portion of the dissociation curve (saturation 85 years) and African Americans.13 The strongest risk factor for developing asthma is a genetic predisposition for the development of an immunoglobulin E (IgE)-mediated response to common allergens.14 IgE is the antibody involved in causing allergic reactions and inflammation.14 Other risk factors for childhood asthma include family history of asthma, allergies, antenatal exposure to tobacco smoke and pollution, and multiple potentially overlapping genetic predispositions.15 Asthma severity is ­ impacted by ­several factors including genetics, age of onset, pollution exposure, atopy, degree of exposure to triggers, environmental triggers such as tobacco smoke and dust mites, and the presence of gastroesophageal reflux disease or respiratory infections13 (see “Severe or Refractory Asthma”). Reflux during sleep can also contribute to nocturnal asthma.14 Etiology and Pathogenesis The common denominator underlying asthma is an exaggerated hyperresponsiveness to a variety of stimuli. Airway inflammation manifested by the presence of inflammatory cells (particularly eosinophils, lymphocytes, and mast cells) and by damage to the bronchial epithelium contributes to the pathogenesis of the disease. There are two subsets of T-helper cells (T1H and T2H) that develop from the same precursor CD4+ T

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l­ ymphocyte.16–18 T1H cells differentiate in response to microbes and stimulate the differentiation of B cells into immunoglobulin (Ig)M– and IgG-producing plasma cells. T2H cells, on the other hand, respond to allergens and helminths (intestinal parasites) by stimulating B cells to differentiate into IgE-producing plasma cells, produce growth factors for mast cells, and recruit and activate eosinophils. In people with allergic asthma, T-cell differentiation appears to be skewed toward a proinflammatory T2H response. Although the molecular basis for this preferential differentiation is unclear, it seems likely that both genetic and environmental factors play a role.16–19 Cytokines also have an apparent role in the chronic inflammatory response and complications of asthma. Tumor necrosis factor (TNF)-α and interleukins 4 and 5 (IL-4, IL-5) participate in the pathogenesis of bronchial asthma through their effects on the bronchial epithelial and smooth muscle cells.20–22 Studies suggest that TNF-α, an inflammatory cytokine that is stored and released from mast cells, plays a critical role in the initiation and amplification of airway inflammation in persons with asthma. TNF-α is credited with increasing the migration and activation of inflammatory cells (i.e., eosinophils and neutrophils) and contributing to all aspects of airway remodeling, including proliferation and activation of fibroblasts, increased production of extracellular matrix glycoproteins, and mucous cell hyperplasia.22 It has been determined that frequent viral respiratory infections predispose people with asthma to experience an exacerbation of their disease. In fact, frequent viral respiratory infections may also cause the development of asthma in some people.17 When these respiratory infections are frequent at an early age, there is evidence that the T-helper 2 (T2H) response is exaggerated. When the CD4 T2H cytokines IL-4, IL-5, and IL-13 are released, the airways are predisposed for an allergic response, which favors the production of IgE.16–18 The National Heart, Lung, and Blood Institute’s Expert Panel Report 3 (NHLBI EPR 3): Guidelines for the Diagnosis and Management of Asthma defined asthma as a chronic inflammatory disorder of the airways. The immunological aspects of asthma including the cascade of neutrophils, eosinophils, lymphocytes, and mast cells cause epithelial injury. This causes airway inflammation, which further increases hyperresponsiveness and decreased airflow.14 There are multiple mediators and cell types that cause the inflammation and airway bronchoconstriction in asthma. When mast cells are activated, the release of histamine; prostaglandin D2; cytokines such as IL-1 to IL-5, interferon, TNF, and granulocyte–macrophage colony-stimulating factor; and leukotrienes causes massive bronchoconstriction and inflammation of pulmonary vasculature endothelium. Mast cells can trigger multiple cytokine release, which causes major inflammation of the airway. The contraction of the airways and subsequent swelling leads to further airway obstruction. The mast cell release may be linked to exercise-induced asthma (EIA), which is when individuals only experience wheezing and bronchospasm during exercise.19,20 The cause of EIA is unclear but the following two theories are possible explanations. One theory explaining the cause of EIA is based

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970   UNIT IX  Disorders of Respiratory Function

on the loss of heat and water from the tracheobronchial tree because of the need for warming and humidifying large volumes of air.21 The response commonly is exaggerated when the person exercises in a cold environment. The second theory supporting EIA is the airway rewarming hypothesis, which states that airways cool and then warm during any ­exercise.21 This causes congestion in the bronchiolar vessels that ­surround the bronchial tree and allows fluid exudates to move into the mucosa of the airway, which triggers the inflammatory cascade. It is important to assess the type of air (polluted, cold, or warm), level of exercise, presence/absence of respiratory infectious process, and individual’s asthma stability when identifying if a person has EIA.19 Eosinophils tend to be present in airways of people with asthma and generate inflammatory enzymes and release leukotrienes and many proinflammatory enzymes.14,22 It is common to have increased neutrophils in sputum and airways of people experiencing asthma exacerbations.22 The release of leukotrienes causes more mucus secretion, which often obstructs the airway further and causes more histamine release from the mast cells.21 This inflammatory process produces recurrent episodes of airway obstruction, characterized by wheezing, breathlessness, chest tightness, and a cough that often is worse at night and in the early morning. These episodes, which usually are reversible either spontaneously or with treatment, also cause an associated increase in bronchial responsiveness to a variety of stimuli.17 Chronic inflammation can lead to airway remodeling, in which case airflow limitations may be only partially reversible.14 This may be due to the long-term effects of the inflammation on the airway structures.14 There is a small group of people with the clinical triad of asthma, chronic rhinosinusitis with nasal polyps, and precipitation of asthma and rhinitis attacks in response to ­aspirin and other NSAIDs.22 The mechanism of the hypersensitivity reaction is complex and not fully understood, but most evidence points toward an abnormality in arachidonic acid (AA) metabolism. Cyclooxygenase (COX), the rate-limiting enzyme in AA metabolism, exists in two main forms: COX-1 and COX-2. COX-1 is responsible for the synthesis of protective prostaglandins and COX-2 for the synthesis of mediators of inflammation and bronchoconstriction. It has been hypothesized that in people with aspirin-induced asthma, the inhibition of COX-1 shunts the metabolism of AA away from the production of protective prostaglandins and toward the generation of COX-2 and other mediators of inflammation and bronchoconstriction.22 Avoidance of aspirin and all NSAIDs is a necessary part of the treatment program. In addition, both emotional factors and changes in hormone levels are thought to contribute to an increase in asthma symptoms. Emotional factors produce bronchospasm by way of vagal pathways. They can act as a bronchospastic t­ rigger, or they can increase airway responsiveness to other triggers through noninflammatory mechanisms. The role of sex h­ ormones in asthma is unclear, although there is much c­ ircumstantial evidence to suggest that they may be important. In fact, research

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shows girls with an early menarche (2 times a week but 60%–30%

>1 time a week

Frequent

FEV1.0 or PEF ≤60% predicted PEF variability >30%

FEV1.0, forced expiratory volume in 1 second; PEF, peak expiratory flow rate. Adapted from National Asthma Education and Prevention Program. (2003). Expert Panel report 2: Guidelines for the diagnosis and management of asthma: Update of selected topics—2002. National Institutes of Health publication no. 02-5074. Bethesda, MD: National Institutes of Health.

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972   UNIT IX  Disorders of Respiratory Function

A program of desensitization may be undertaken in people with persistent asthma who react to allergens, such as house dust mites, that cannot be avoided. This involves the injection of selected antigens (based on skin tests) to stimulate the production of IgG antibodies that block the IgE response. A course of allergen immunotherapy is typically of 3 to 5 years’ duration.14 The Expert Panel recommends a stepwise approach to pharmacologic therapy based on the classification systems discussed previously.14 The first line of treatment with any of the persistent forms of asthma includes an inflammatory controller drug that would include inhaled corticosteroids (ICS), mast cell stabilizers, and leukotriene modifiers. ICS are considered the most effective in preventing airway inflammation and generally the drug used. The quick-relief medications such as the short-acting β2-adrenergic agonists (SABA) (e.g., albuterol, levalbuterol, pirbuterol) relax bronchial smooth muscle and provide prompt relief of symptoms, usually within 30 minutes. They are administered by inhalation (i.e., metered-dose inhaler [MDI] or nebulizer), and their recommended use is in alleviating acute attacks of asthma because regular use does not produce beneficial effects.14 The anticholinergic medications (e.g., ipratropium) block the postganglionic efferent vagal pathways that cause bronchoconstriction. These medications, which are administered by inhalation, produce bronchodilation by direct action on the large airways and do not change the composition or viscosity of the bronchial mucus. It is thought that they may provide some additive benefit for treatment of asthma exacerbations when administered with inhaled β2-adrenergic agonists.14 A short course of systemic corticosteroids, administered orally or parenterally, may be used for treating an acute flare. Although their onset of action is slow (>4 hours), systemic corticosteroids may be used in the treatment of moderate to severe exacerbations because of their action in preventing the progression of the exacerbation, speeding recovery, and preventing early relapses.14 The anti-inflammatory agents sodium cromolyn and nedocromil are also used to prevent an asthmatic attack. These agents act by stabilizing mast cells, thereby preventing release of the inflammatory mediators that cause an asthmatic attack. They are used prophylactically to prevent early and late responses but are of no benefit when taken during an attack. Due to the immunomodulatory properties of vitamin D and its abilities to modify proinflammatory and anti-inflammatory responses in the immunological system, there have been studies suggesting a correlation of vitamin D and more effective management of childhood and asthma exacerbations as well as with steroid-resistant asthma.27 Severe or Refractory Asthma Severe or refractory asthma represents a subgroup of approximately 5% of people with asthma who have more troublesome disease as evidenced by high medication requirements to maintain good symptom control or those who continue to have persistent symptoms despite high medication use.30 These people are at increased risk for fatal or near-fatal asthma.

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Little is known about the causes of severe asthma. Among the proposed risk factors are genetic predisposition, continued allergen or tobacco exposure, infection, intercurrent sinusitis or gastroesophageal reflux disease, and lack of compliance or adherence with treatment measures.30 It has been proposed that because asthma is a disease involving multiple genes, mutations in genes regulating cytokines, growth factors, or receptors for medications used in treatment of asthma (β2-adrenergic agonist or glucocorticoid) could be involved. Environmental factors include both allergen and tobacco exposure, with the strongest response occurring in response to house dust, c­ockroach allergen, and Alternaria exposure. Infections may also play a role. Respiratory syncytial virus infections are implicated in children, and pathogens such as mycoplasma and chlamydiae may play a role in adults. Gastroesophageal reflux and chronic sinusitis may also play a role. Although the cause of death during an acute asthmatic attack is largely unknown, both cardiac arrhythmias and asphyxia due to severe airway obstruction have been implicated. It has been suggested that an underestimation of the severity of the attack may be a contributing factor. Deterioration often occurs rapidly during an acute attack, and underestimation of its severity may lead to a lifethreatening delay in seeking medical attention. Frequent and repetitive use of β2-adrenergic agonist inhalers far in excess of the recommended doses may temporarily blunt symptoms and mask the severity of the condition. It has been suggested that people who have a fatal or near-fatal asthmatic attack may not ­perceive its severity.31 That is, they may not perceive the severity of their condition and consequently not take appropriate measures in terms of seeking medical or emergency treatment. The long-acting beta2-agonists (LABA) such as salmeterol and formoterol are used to treat severe refractory asthma only if no other treatment is effective. The l­ ong-acting β2-adrenergic agonists have durations of action of at least 12 hours and should not be used to treat acute symptoms or exacerbations. These drugs have a black box warning from the U.S. Food and Drug Administration due to their possibility of causing asthma death, especially if they are used as a monotherapy. Research is also focusing on the use of allergen immunotherapy treatment aimed at T2H cytokines in specific groups of people with severe asthma. However, only one is currently available.28,29 The only licensed anti-IgE therapy for severe asthma is omalizumab, which has severe potential systemic side effects.29 Asthma in Older Adults For older adults with asthma, who already have a decreased immunological function due to aging, it is important to be aware of how this lowered immunity impacts their airway inflammation. Studies demonstrate these changes in immune function can seriously affect their conditions.32 Asthma in Children Asthma is a leading cause of chronic illness in children and is responsible for approximately 14.4 million number of lost school days/year. It is the most frequent admitting diagnosis

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Chapter 37  Disorders of Ventilation and Gas Exchange    973

in children’s hospitals. Based on information collected by the Centers for Disease Control and Prevention, asthma may have its onset at any age. In addition, asthma is more prevalent in black than white children and results in more frequent disability and more frequent hospitalizations in black children.33 As with adults, asthma in children commonly is associated with an IgE-related reaction. It has been suggested that IgE directed against respiratory viruses in particular may be important in the pathogenesis of wheezing illnesses in infants (i.e., bronchiolitis), which often precede the onset of asthma. Other contributing factors include exposure to environmental allergens such as pet dander, dust mite antigens, and cockroach allergens. Exposure to environmental tobacco smoke also contributes to asthma in children. The signs and symptoms of asthma in infants and small children vary with the stage and severity of an attack. Because airway patency decreases at night, many children have acute signs of asthma at this time. Often, previously well infants and children develop what may seem to be a cold with rhinorrhea, rapidly followed by irritability, a tight and nonproductive cough, wheezing, tachypnea, dyspnea with prolonged expiration, and use of accessory muscles of respiration. Cyanosis, hyperinflation of the chest, and tachycardia indicate increasing severity of the attack. Wheezing may be absent in children with extreme respiratory distress. The symptoms may progress rapidly and require a trip to the emergency department or hospitalization. The Expert Panel of the NAEPP has developed guidelines for management of asthma in infants and children from 0 to 4 years, 5 to 11 years, and for adults and children older than 12 years of age.14 As with adults and older children, the Expert Panel recommends a stepwise approach to diagnosing and managing asthma in infants and children from 0 to 4 years and from 5 to 11 years.14,34

Chronic Obstructive Pulmonary Disease COPD is characterized by chronic and recurrent obstruction of airflow in the pulmonary airways. Airflow obstruction usually is progressive and is accompanied by inflammatory responses to noxious particles or gases. COPD is a leading cause of morbidity and mortality worldwide. It has been estimated that approximately 24 million Americans43 have some degree of COPD and 12.1 million are diagnosed with COPD. COPD is the fourth leading cause of death in the United States.35 In 2006, COPD claimed the lives of more than 120,970 people in the United States, with the number of women dying from the disease surpassing that of men.35 According to the National Heart, Lung, and Blood Institute, the national projected annual cost for COPD in 2010 was $49.9 billion.36 The most common cause of COPD is smoking, as evidenced by the fact that 80% to 85% of people with COPD have a history of smoking.45 A second, less common factor is a hereditary deficiency in α1-antitrypsin. Other predisposing factors are asthma and airway hyperresponsiveness.

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Unfortunately, clinical findings are almost always absent during the early stages of COPD, and as many as 50% of smokers may have undiagnosed COPD.37 By the time symptoms appear or are recognized, the disease is usually far advanced. For smokers with early signs of airway disease, there is hope that early recognition, combined with appropriate treatment and smoking cessation, may prevent or delay the usually relentless progression of the disease. Etiology and Pathogenesis The mechanisms involved in the pathogenesis of COPD usually are multiple and include inflammation and fibrosis of the bronchial wall, hypertrophy of the submucosal glands and hypersecretion of mucus, and loss of elastic lung fibers and alveolar tissue.37 Inflammation and fibrosis of the bronchial wall, along with excess mucus secretion, obstruct airflow and cause mismatching of ventilation and perfusion. Destruction of alveolar tissue decreases the surface area for gas exchange, and loss of elastic fibers impairs the expiratory flow rate, increases air trapping, and predisposes to airway collapse. The term chronic obstructive pulmonary disease encompasses two types of obstructive airway disease: emphysema, with enlargement of airspaces and destruction of lung tissue, and chronic obstructive bronchitis, with increased mucus production, obstruction of small airways, and a chronic ­ ­productive cough. People with COPD often have overlapping features of both disorders. Emphysema.  Emphysema is characterized by a loss of lung elasticity and abnormal enlargement of the airspaces distal to the terminal bronchioles, with destruction of the alveolar walls and capillary beds (Fig. 37.9). Enlargement of the airspaces leads to hyperinflation of the lungs and produces an increase in total lung capacity (TLC). Two of the recognized causes of emphysema are smoking, which incites lung injury, and an inherited deficiency of α1-antitrypsin, an antiprotease enzyme that protects the lung from injury. AAT deficiency is the second most severe genetic problem affecting the lungs and is a result of a mutated ATT gene at gene locus 14.38 ATT is a protease inhibitor that helps to protect the lung from protease enzymes such as neutrophil elastase, which damages healthy lung tissue as well as assists in removing bacteria during acute respiratory dysfunction.38 Emphysema is thought to result from the breakdown of elastin and other alveolar wall components by enzymes, called proteases, which digest proteins. Normally, antiprotease enzymes, including α1-antitrypsin, protect the lung. Cigarette smoke and other irritants stimulate the movement of inflammatory cells into the lungs, resulting in increased release of elastase and other proteases. In smokers in whom COPD develops, antiprotease production and release may be inadequate to neutralize the excess protease production such that the process of elastic tissue destruction goes unchecked (Fig. 37.10). The type and amount of α1-antitrypsin that a person has is determined by a pair of codominant genes referred to as

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974   UNIT IX  Disorders of Respiratory Function

A

B

FIGURE 37.9  •  Panacinar emphysema. (A) A whole mount of the left lung from a person with severe emphysema reveals widespread destruction of pulmonary parenchyma that in some areas leaves behind a lacy network of supporting tissue. (B) The lung from a person with α1-antitrypsin deficiency shows a panacinar pattern of emphysema. The loss of alveolar walls has resulted in markedly enlarged airspaces. (From Rubin R., Strayer D. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 569). Philadelphia, PA: Lippincott Williams & Wilkins.)

Attraction of inflammatory cells

Smoking

Release of elastase

1

1

Macrophages and neutrophils

1

Destruction of elastic fibers in lung

Emphysema

FIGURE 37.10  • Protease (elastase)–antiprotease (antitrypsin) mechanisms of emphysema. The effects of smoking and an inherited α1-antitrypsin deficiency on the destruction of elastic fibers in the lung and development of emphysema are shown.

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PI (protein inhibitor) genes. An α1-antitrypsin deficiency is inherited as an autosomal recessive disorder. There are more than 75 mutations of the gene. ATT deficiency is most common in people of Scandinavian descent. Most people with clinically diagnosed emphysema before the age of 40 years have an α1-antitrypsin deficiency. Smoking and repeated respiratory tract infections, which also decrease α1-antitrypsin levels, contribute to the risk for emphysema in persons with α1-antitrypsin deficiency. Laboratory methods are available for measuring α1-antitrypsin levels. Human α1-antitrypsin is available for replacement therapy in people with a hereditary deficiency of the enzyme. There are two commonly recognized types of emphysema: centriacinar or centrilobular, and panacinar (Fig. 37.11). The centriacinar type affects the bronchioles in the central part of the respiratory lobule, with initial preservation of the alveolar ducts and sacs.37 It is the most common type of emphysema and is seen predominantly in male smokers. The panacinar type produces initial involvement of the peripheral alveoli and later extends to involve the more central bronchioles. This type of emphysema is more common in people with α1-antitrypsin deficiency. It also is found in smokers in association with centriacinar emphysema. In such cases, the panacinar pattern tends to occur in the lower parts of the lung and centriacinar emphysema is seen in the upper parts of the lung.

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Chapter 37  Disorders of Ventilation and Gas Exchange    975 Alveolar duct

Respiratory bronchioles Terminal bronchiole

Septum

Alveoli NORMAL ACINUS Respiratory bronchioles

Alveolar duct

Respiratory bronchioles

Septum

Terminal bronchiole

Alv Alveolar ducts and alveoli

Septum

Terminal bronchiole

Chronic inflammation and fibrosis

Alveoli

CENTRILOBULAR EMPHYSEMA

PANACINAR EMPHYSEMA

FIGURE 37.11  •  Centriacinar panacinar and paraseptal are the types of emphysema. (From Rubin R., Strayer D. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins.)

Chronic Bronchitis. Chronic bronchitis represents airway obstruction of the major and small airways.37 The condition is seen most commonly in middle-aged men and is associated with chronic irritation from smoking and recurrent infections. A clinical diagnosis of chronic bronchitis requires the history of a chronic productive cough for at least 3 consecutive months in at least 2 consecutive years.48 Typically, the cough has been present for many years, with a gradual increase in acute exacerbations that produce frankly purulent sputum. The earliest feature of chronic bronchitis is hypersecretion of mucus in the large airways, associated with hypertrophy of the submucosal glands in the trachea and b­ ronchi.37 Although mucus hypersecretion in the large airways is the cause of sputum overproduction, it is now thought that accompanying changes in the small airways (small bronchi and ­bronchioles) are ­physiologically important in the airway obstruction that develops in chronic bronchitis.37 Histologically, these changes include a marked increase in goblet cells and excess mucus production with plugging of the airway lumen, inflammatory infiltration, and fibrosis of the bronchiolar wall. It is thought that both the submucosal hypertrophy in the larger airways and the increase in goblet cells in the smaller airways are a protective reaction against tobacco smoke and other p­ ollutants. Viral and bacterial infections are common in people with chronic

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bronchitis and are thought to be a result rather than a cause of the problem. Clinical Manifestations The clinical manifestations of COPD usually have an insidious onset. People characteristically seek medical attention in the fifth or sixth decade of life, with manifestations such as fatigue, exercise intolerance, cough, sputum production, or shortness of breath. The productive cough usually occurs in the morning and the dyspnea becomes more severe as the disease progresses. Frequent exacerbations of infection and respiratory insufficiency are common, causing absence from work and eventual disability. The late stages of COPD are characterized by recurrent respiratory infections and chronic respiratory failure. Death usually occurs during an exacerbation of illness associated with infection and respiratory failure. The mnemonics “pink puffer” and “blue bloater” have been used to differentiate the clinical manifestations of emphysema and chronic obstructive bronchitis. People with predominant emphysema are classically referred to as pink puffers, a reference to the lack of cyanosis, the use of accessory muscles, and pursed-lip (“puffer”) breathing. With loss of lung elasticity and hyperinflation of the lungs, the airways often collapse during expiration because pressure in ­surrounding lung tissues exceeds airway pressure. Air becomes trapped

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976   UNIT IX  Disorders of Respiratory Function

A

B

FIGURE 37.12 • Characteristics of normal chest wall and chest wall in emphysema. The normal chest wall and its cross-section are illustrated on the left (A). The barrel-shaped chest of emphysema and its crosssection are illustrated on the right (B). (From Smeltzer S. C., Bare B., Hinkle J., et al. (2010). Brunner and Suddarth’s textbook of medical-surgical nursing (12th ed., p. 604). Philadelphia, PA: Lippincott Williams & Wilkins.)

in the alveoli and lungs, producing an increase in the anteroposterior dimensions of the chest, the so-called barrel chest that is typical of people with emphysema (Fig. 37.12). Such people have a dramatic decrease in breath sounds throughout the chest. Because the diaphragm may be functioning near its maximum ability, the person is vulnerable to diaphragmatic fatigue and acute respiratory failure. People with a clinical syndrome of chronic bronchitis are classically labeled blue bloaters, a reference to cyanosis and fluid retention associated with right-sided heart failure. In practice, differentiation between the two types of COPD is often difficult. This is because people with COPD often have some degree of both emphysema and chronic bronchitis. The manifestations of COPD represent a progressive change in respiratory function. There is moderate to severe respiratory impairment due to obstruction of airflow, which is greater on expiration than inspiration, resulting in increased work of breathing but decreased effectiveness. The development of exertional dyspnea, often described as increased effort to breathe, heaviness, air hunger, or gasping, can be insidious and is often reported in the sixth decade. Activities involving significant arm work, particularly above the shoulders, are particularly difficult for persons with COPD. Activities that allow the person to brace the arms and use the accessory muscles are better tolerated. As the disease progresses, breathing becomes increasingly more labored, even at rest. The expiratory phase of respiration is prolonged, and expiratory wheezes and crackles can be heard on auscultation. People with severe airflow

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obstruction may also exhibit use of the accessory muscles, sitting in the characteristic “tripod” position to facilitate use of the sternocleidomastoid, scalene, and intercostal muscles.49 Pursed-lip breathing enhances airflow because it increases the resistance to the outflow of air and helps to prevent airway collapse by increasing airway pressure. Eventually, people with COPD are unable to maintain normal blood gases by increasing their breathing effort. Hypoxemia, hypercapnia, and cyanosis develop, reflecting an imbalance between ventilation and perfusion. Severe hypoxemia, in which arterial PO2 levels fall below 55 mm Hg, causes reflex vasoconstriction of the ­pulmonary vessels and further impairment of gas exchange in the lung. It is more common in people with the chronic bronchitis form of COPD. Hypoxemia also stimulates red blood cell production, causing polycythemia. The increase in pulmonary ­vasoconstriction and subsequent elevation in pulmonary artery pressure further increase the work of the right ventricle. As a result, people with COPD may develop right-sided heart failure with peripheral edema (i.e., cor pulmonale). However, signs of overt right-sided heart failure are seen less frequently since the advent of supplemental oxygen therapy. Diagnosis The diagnosis of COPD is based on a careful history and physical examination, pulmonary function studies, chest radiographs, and laboratory tests. Airway obstruction prolongs the expiratory phase of respiration and affords the

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potential for impaired gas exchange because of mismatching of ventilation and perfusion. The FVC is the amount of air that can be forcibly exhaled after maximal inspiration. In an adult with normal respiratory function, this should be achieved in 4 to 6 seconds. In people with chronic lung disease, the time required for FVC is increased, the FEV1.0 is decreased, and the ratio of FEV1.0 to FVC is decreased. In severe disease, the FVC is markedly reduced. Lung volume measurements reveal a marked increase in RV, an increase in TLC, and elevation of the RV-to-TLC ratio. These and other measurements of expiratory flow are determined by spirometry and are used in the diagnosis of COPD. Spirometry measurements can be used in staging disease severity. For example, an FEV1.0-to-FVC ratio of less than 70% with an FEV1.0 of 80% or more, with or without symptoms, indicates mild disease, and an FEV1.0to-FVC ratio of less than 70% with an FEV1.0 of less than 50%, with or without symptoms, indicates severe disease.35 Other diagnostic measures become important as the disease advances. Measures of exercise tolerance, nutritional status, hemoglobin saturation, and arterial blood gases can be used to assess the overall impact of COPD on health status and to direct treatment. Treatment The treatment of COPD depends on the stage of the disease and often requires an interdisciplinary approach. Smoking cessation is the only measure that slows the progression of the disease. Education of people with COPD and their families is a key to successful management of the disease. Psychosocial rehabilitation must be individualized to meet the specific needs of people with COPD and their families. These needs vary with age, occupation, financial resources, social and recreational interests, and interpersonal and family relationships. People in more advanced stages of the disease often require measures to maintain and improve physical and ­psychosocial functioning, pharmacologic interventions, and oxygen therapy. Avoidance of cigarette smoke and other environmental airway irritants is imperative. Wearing a cold-weather mask often prevents dyspnea and bronchospasm due to cold air and wind exposure. Respiratory tract infections can prove life threatening to people with severe COPD. A person with COPD should avoid exposure to others with known respiratory tract infections and should avoid attending large gatherings during periods of the year when influenza or respiratory tract infections are prevalent. Immunization for influenza and pneumococcal infections decreases the likelihood of their occurrence. Maintaining and improving physical and psychosocial functioning is an important part of the treatment program for people with COPD. A long-term pulmonary rehabilitation program can significantly reduce episodes of hospitalization and add measurably to a person’s ability to manage and cope with his or her impairment in a positive way. This program includes breathing exercises that focus on restoring the function of the diaphragm, reducing the work of breathing, and improving gas exchange. Physical conditioning with

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a­ ppropriate exercise training increases maximal oxygen consumption and reduces ventilatory effort and heart rate for a given workload. Work simplification and energy conservation strategies may be needed when impairment is severe. The pharmacologic treatment of COPD includes the use of bronchodilators, including inhaled adrenergic and anticholinergic agents. Inhaled β2-adrenergic agonists have been the mainstay of treatment of COPD. It has been suggested that long-acting inhaled β2-adrenergic agonists may be even more effective than the short-acting forms of the drug. The anticholinergic drugs (e.g., ipratropium bromide, tiotropium bromide), which are administered by inhalation, produce bronchodilation by blocking parasympathetic cholinergic receptors that ­produce contraction of bronchial smooth muscle. These ­medications, which are administered by inhalation, produce bronchodilation by direct action on the large airways and do not change the composition or viscosity of the bronchial mucus. They also reduce the volume of sputum without altering its viscosity. Because these drugs have a slower onset and longer duration of action, they usually are used on a regular basis rather than on an as-needed basis. Inhalers that combine an anticholinergic drug with a β2-adrenergic agonist are available. Inhaled corticosteroids often are used in treatment of COPD; there is controversy regarding their usefulness. An explanation for this lack of effect may be related to the fact that corticosteroids prolong the action of neutrophils and hence do not suppress the neutrophilic inflammation seen in COPD. Because corticosteroids are useful in relieving asthma symptoms, they may benefit people with asthma concomitant with COPD. Inhaled corticosteroids also may be beneficial in treating acute exacerbations of COPD, minimizing the undesirable effects that often accompany systemic use. Oxygen therapy is prescribed for selected people with significant hypoxemia (arterial PO2 < 55 mm Hg). Administration of continuous low-flow (1 to 2 L/minute) oxygen to maintain arterial PO2 levels between 55 and 65 mm Hg decreases dyspnea and pulmonary hypertension and improves neuropsychological function and activity tolerance. The overall goal of oxygen therapy is to maintain a hemoglobin oxygen saturation of at least 90%.45 Because the ventilatory drive associated with hypoxic stimulation of the peripheral chemoreceptors does not occur until the arterial PO2 has been reduced to about 60 mm Hg or less, increasing the arterial PO2 above 60 mm Hg tends to depress the hypoxic stimulus for ventilation and often leads to hypoventilation and carbon dioxide retention.

Bronchiectasis Bronchiectasis is an uncommon type of COPD characterized by a permanent dilation of the bronchi and bronchioles caused by destruction of the muscle and elastic supporting tissue as the result of a continuous cycle of infection and inflammation (Fig. 37.13). It is not a primary disease but is considered secondary to acquiring frequent infections. In the past, bronchiectasis often followed a necrotizing bacterial pneumonia that frequently complicated measles, pertussis, or influenza.

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varicose veins. Bronchiolar obliteration is not as severe and various symptoms can occur. Bronchiectasis can present in either of two forms: a local obstructive process involving a lobe or segment of a lung or a diffuse process involving much of both lungs.37 Localized bronchiectasis is most commonly caused by conditions such as tumors, foreign bodies, and mucus plugs that produce atelectasis and infection due to obstructed drainage of bronchial secretions. It can affect any area of the lung, the area being determined by the site of obstruction or infection. Generalized bronchiectasis usually is bilateral and most commonly affects the lower lobes. It is due largely to inherited impairments of host mechanisms or acquired disorders that permit introduction of infectious organisms into the airways. They include inherited conditions such as CF, in which airway ­obstruction is caused by impairment of normal mucociliary function; c­ ongenital and acquired immunodeficiency states, which p­ redispose to respiratory tract infections; lung infection (e.g., tuberculosis, fungal infections, lung abscess); and exposure to toxic gases that cause airway obstruction.

FIGURE 37.13 • Bronchiectasis. The resected upper lobe shows widely dilated bronchi, with thickening of the bronchial walls and ­collapse and fibrosis of the pulmonary parenchyma. (From Rubin R., Strayer D. S. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 545, Fig. 12.10). Philadelphia, PA: Lippincott Williams & Wilkins.)

Tuberculosis was also commonly associated with bronchiectasis. Thus, with the advent of antibiotics that more effectively treat respiratory infections such as tuberculosis and with immunization against pertussis and measles, there has been a marked decrease in the prevalence of bronchiectasis except with people who are living longer with CF. Etiology and Pathogenesis Mucus obstruction and chronic persistent infection are the etiology of bronchiectasis. Regardless of which may come first, both cause damage to the bronchial walls, leading to weakening and dilation. On gross examination, bronchial dilation is classified as saccular, cylindrical, or varicose. Saccular bronchiectasis involves the proximal third to fourth generation of bronchi.37 These bronchi become severely dilated and end blindly in dilated sacs, with collapse and fibrosis of more distal lung tissue. Cylindrical bronchiectasis involves uniform and moderate dilation of the sixth to eighth generations of airways. It is a milder form of disease than saccular bronchiectasis and leads to fewer symptoms. Varicose bronchiectasis involves the second through eighth branchings of bronchi and results in bronchi that resemble

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Clinical Manifestations Bronchiectasis is associated with a number of abnormalities that profoundly affect respiratory function, including atelectasis, obstruction of the smaller airways, and diffuse bronchitis. People with bronchiectasis have recurrent bronchopulmonary infection; coughing; production of copious amounts of foulsmelling, purulent sputum; and hemoptysis. Weight loss and anemia are common. In addition, the manifestations of bronchiectasis are similar to those seen in chronic bronchitis and emphysema. As in the latter two conditions, chronic bronchial obstruction leads to marked dyspnea and cyanosis. Clubbing of the fingers, which is not usually seen in other types of obstructive lung diseases, is more common in moderate to advanced bronchiectasis. Diagnosis and Treatment Diagnosis is based on history and imaging studies. The condition often is evident on chest radiographs. High-resolution CT scanning of the chest allows for definitive diagnosis. Accuracy of diagnosis is important because interventional bronchoscopy or surgery may be palliative or curative in some types of obstructive disease. Treatment consists of early recognition and treatment of infection along with regular postural drainage and chest physical therapy. Persons with this disorder benefit from many of the rehabilitation and treatment measures used for chronic bronchitis and emphysema.

Cystic Fibrosis CF, which is the major cause of severe chronic respiratory disease in children, is an autosomal recessive disorder involving the exocrine glands in the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts.39 CF affects about 30,000 children and adults in the United States and more than

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Chapter 37  Disorders of Ventilation and Gas Exchange    979

10 million persons are asymptomatic carriers of the defective gene.39 The defective gene, cystic fibrosis transmembrane regulator (CFTR), and its protein product cause excessive thick mucus that obstructs lungs and the pancreas. In addition to chronic respiratory disease, CF is manifested by pancreatic exocrine deficiency and elevation of sodium chloride in the sweat. Nasal polyps, sinus infections, pancreatitis, and cholelithiasis also are seen with CF. Most boys with CF have congenital bilateral absence of the vas deferens with azoospermia. Etiology and Pathogenesis CF is caused by mutations in a single gene on the long arm of chromosome 7 that encodes for the CFTR, which functions as a chloride (Cl−) channel in epithelial cell membranes. Mutations in the CFTR gene render the epithelial membrane relatively impermeable to the chloride ion (Fig. 37.14).

Chromosome 7 CFTR gene mutation

Respiratory tract secretions

Cl-

Na+ H2O

Airway epithelial cell

Defective Cl - secretion with excessive Na + and H2O absorption

Abnormal thick and viscid respiratory tract secretions

Development of a microenvironment that is protective of microbial agents

Defective mucociliary clearance

Chronic airway obstruction and bacterial infection

Neutrophil influx; release of elastase and inflammatory mediators

Development Developementofofchronic chronicbronchitis, bronchitis, bronchiectasis, bronchiectasis,respiratory respiratoryfailure failure FIGURE 37.14  •  Pathogenesis of cystic fibrosis.

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There are greater than 1000 possible CTFR changes that can occur. However, 70% of CF individuals have F 508, which is a ­deletion of 3 bases that cause the loss of phenylalanine and a more severe phenotype.40 Others have a partial loss of CTFR so their phenotype is less severe and often goes unnoticed until they have an acute injury such as pneumonia and may need intubation and mechanical ventilation. The impact on impaired Cl− transport is relatively t­ issue specific. In the sweat glands, the concentration of sodium (Na+) and Cl− secreted into the lumen of the gland remains unaffected, whereas the reabsorption of Cl− through the CFTR and accompanying reabsorption of Na+ in the ducts of the gland fail to occur. This defect accounts for the high concentration of NaCl in the sweat of persons with CF.40 In the normal airway epithelium, Cl− is secreted into airway lumen through the CFTR. The impaired transport of Cl− ultimately leads to a series of secondary events, including increased absorption of Na+ and water from the airways into the blood. This lowers the water content of the mucociliary blanket coating the respiratory epithelium, causing it to become more viscid. The resulting dehydration of the mucous layer leads to defective mucociliary function and accumulation of viscid secretions that obstruct the airways and predispose to recurrent pulmonary infections. Similar transport abnormalities and pathophysiologic events take place in the pancreatic and biliary ducts and in the vas deferens in boys. Clinical Manifestations Respiratory manifestations of CF are caused by an accumulation of viscid mucus in the bronchi, impaired mucociliary clearance, and lung infections. Chronic bronchiolitis and bronchitis are the initial lung manifestations. However, after months and years, structural changes in the bronchial wall lead to bronchiectasis. In addition to airway obstruction, the basic genetic defect that occurs with CF predisposes to chronic infection with a surprisingly limited number of organisms, the most common being Pseudomonas aeruginosa.40 Soon after birth, initial infection with bacterial pathogens occurs and is associated with an excessive neutrophilic inflammatory response that appears to be independent of the infection itself. There is ­evidence that the CF airway epithelial cells or surface liquids provide a favorable environment for harboring these organisms. P. aeruginosa, in particular, has a propensity to undergo mucoid transformation in this environment.40 The complex polysaccharide produced by these organisms provides a hypoxic environment and generates a biofilm that protects Pseudomonas against antimicrobial agents. Pulmonary inflammation is another cause of decline in respiratory function in people with CF and may precede the onset of chronic infection. Pancreatic function is often abnormal to some degree with individuals with CF. Steatorrhea, diarrhea, and abdominal pain and discomfort are common. In the newborn, meconium ileus may cause intestinal obstruction, a fatal condition if left untreated. The degree of pancreatic involvement is highly variable. In some children, the defect is relatively mild,

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and in others, the involvement is severe and impairs intestinal absorption. In addition to exocrine pancreatic insufficiency, hyperglycemia may occur, especially after 10 years of age, when many people with CF develop diabetes mellitus.39 Diagnosis and Treatment Early diagnosis and treatment are important in delaying the onset and severity of chronic illness in children with CF. Diagnosis is based on the presence of respiratory and gastrointestinal manifestations typical of CF, a history of CF in a sibling, or a positive newborn screening test result. Confirmatory laboratory tests include the sweat test, assessment of bioelectrical properties of respiratory epithelia in the nasal membrane, and genetic tests for CFTR gene mutations. The sweat test, using pilocarpine iontophoresis to collect the sweat followed by chemical analysis of its chloride content, remains the standard approach to diagnosis. Newborns with CF have elevated blood levels of immunoreactive trypsinogen, presumably because of secretory obstruction in the ­pancreas. Newborn screening consists of a test for determination of immunoreactive trypsinogen. Twenty years after cloning the CFTR gene, there are still no approved treatments for correcting the genetic defects in CF or to reverse the ion transport abnormalities associated with the dysfunctional CFTR. Drugs focused at the CFTR gene are known as protein repair therapy and are being trialed and predicted to be of use in the future.41 Thus, treatment measures are directed toward slowing the progression of secondary organ dysfunction and sequelae such as chronic lung infection and pancreatic insufficiency.41 They include the use of antibiotics to prevent and manage infections, the use of chest physical therapy (chest percussion and postural drainage) and mucolytic agents to prevent airway obstruction, and pancreatic enzyme replacement, and nutritional therapy. Appropriate antibiotic therapy directed against bacterial pathogens isolated from the respiratory tract is an essential component in the management of CF lung disease. Indications for oral antibiotics include the presence of respiratory tract symptoms and identification of pathogenic organisms in respiratory tract cultures. Intravenous antibiotics are used for progressive and unrelenting symptoms. People with CF who have complete loss of exocrine pancreas function and have inadequate digestion of fats and ­proteins require diet adjustment, pancreatic enzyme replacement, and supplemental vitamins and minerals. Many people with CF have a higher-than-normal caloric need because of the increased work of breathing and perhaps because of the increased metabolic activity related to the basic defect. Pancreatic enzyme dosage and product type are individualized for each person. Progress of the disease is variable. Improved medical management has led to longer survival. Today, many people with the disease can expect to live into their 30s, 40s, and beyond.39 Lung transplantation is being used as a treatment for people with end-stage lung disease. Current hopes reside in

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research that would make gene therapy a feasible alternative for people with the disease.

IN SUMMARY Obstructive ventilatory disorders are characterized by airway obstruction and limitation in expiratory airflow. Asthma is a chronic inflammatory disorder of the airways characterized by airway hyperreactivity, airway narrowing, and airway remodeling. T1H cells differentiate in response to microbes and stimulate the differentiation of B cells into immunoglobulin (Ig)M– and IgG-producing plasma cells. Whereas, T2H cells respond to allergens by stimulating B cells to differentiate into IgE-producing plasma cells, produce growth factors for mast cells, and recruit and activate eosinophils. In people with allergic asthma, T-cell differentiation appears to be skewed toward a proinflammatory T2H  response. It appears that both genetic and ­environmental factors play a role in the development of asthma or reactive airway disease. COPD describes a group of conditions characterized by obstruction to airflow in the lungs. Among the conditions associated with COPD are emphysema, chronic bronchitis, and bronchiectasis. Emphysema is characterized by a loss of lung elasticity, abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles, and hyperinflation of the lungs. Chronic bronchitis is caused by inflammation of major and small airways and is characterized by edema and hyperplasia of submucosal glands and excess mucus secretion into the bronchial tree. A history of a chronic productive cough that has persisted for at least 3 months and for at least 2 consecutive years in the absence of other disease is necessary for the diagnosis of chronic bronchitis. Emphysema and chronic bronchitis are manifested by eventual mismatching of ventilation and perfusion. As the condition advances, signs of respiratory distress and impaired gas exchange become evident, with development of hypercapnia and hypoxemia. Bronchiectasis is a less common form of COPD that is characterized by an abnormal dilation of the large bronchi associated with infection and destruction of the bronchial walls. CF is an autosomal recessive genetic disorder manifested by chronic lung disease, pancreatic exocrine deficiency, and elevation of sodium chloride in the sweat. The disorder is caused by a mutation of a single gene on the long arm of chromosome 7 that codes for the CFTR, which functions in the transepithelial transport of the chloride ion. The defect causes exocrine gland secretions to become exceedingly viscid, and it promotes colonization of the respiratory tract with P. aeruginosa and other organisms such as Staphylococcus aureus. Accumulation of viscid mucus in the bronchi, impaired mucociliary function, and infection contribute to the development of chronic lung disease and a decreased life expectancy.

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CHRONIC INTERSTITIAL (RESTRICTIVE) LUNG DISEASES After completing this section of the chapter, you should be able to meet the following objectives: •• State the difference between chronic obstructive pulmonary diseases and interstitial lung diseases in terms of their pathology and manifestations. •• Cite the characteristics of occupational dusts that determine their pathogenicity in terms of the production of pneumoconiosis. •• Describe the pathophysiology of idiopathic pulmonary fibrosis. •• Describe the causes of hypersensitivity pneumonitis. •• Describe the systemic pathophysiology of organ involvement in sarcoidosis.

The diffuse interstitial lung diseases (ILDs) are a diverse group of lung disorders that produce similar inflammatory and fibrotic changes in the interstitium or interalveolar septa of the lung. Because the ILDs result in a stiff and noncompliant lung, they are commonly classified as restrictive lung disorders. In contrast to obstructive lung diseases, the lungs are stiff and difficult to expand, despite normally functioning airways.

Etiology and Pathogenesis of Interstitial Lung Diseases The ILDs may be acute or insidious in onset. They may be rapidly progressive, slowly progressive, or static in their course. They include occupational lung diseases such as the pneumoconioses, which are caused by the inhalation of inorganic dusts such as silica, coal dust, and asbestos; hypersensitivity pneumonitis42; lung diseases caused by exposure to toxic drugs (e.g., methotrexate, bleomycin, phenytoin, amiodarone); and granulomatous disorders such as sarcoidosis (Chart 37.2). Some of the most common ILDs are caused by exposure to inhaled dust and particles and, in others, no specific cause can be found. In contrast to the obstructive lung diseases, which ­primarily involve the airways of the lung, the interstitial lung disorders exert their effects on the collagen and elastic connective tissue found in the delicate interstitium of the alveolar walls. Certain ILDs affect the distal part of the alveoli and this causes physiologic restrictions and decreased lung volumes.8 Other ILDs impact the interstitium closer to the proximal aspect of the acinus near the bronchioles, which causes physiologic obstruction but does not impact the lung volumes.8 Many of these diseases also involve the airways, arteries, and veins. In general, these lung diseases share a pattern of lung dysfunction that includes diminished lung ­volumes, reduced diffusing capacity of the lung, and varying degrees of hypoxemia. It is thought that these disorders are initiated by some type of injury to the alveolar epithelium, followed by an

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CHART 37.2

CAUSES OF INTERSTITIAL LUNG DISEASE*

Occupational and Environmental Inhalants Pneumoconioses   Coal miner’s pneumoconiosis  Silicosis  Asbestosis Hypersensitivity pneumonitis   Farmer’s lung   Pigeon breeder’s lung Drugs and Therapeutic Agents Cancer drugs  Bleomycin  Busulfan  Cyclophosphamide  Methotrexate Amiodarone Immunologic Lung Disease Sarcoidosis Collagen vascular disease   Systemic lupus erythematosus   Rheumatoid arthritis  Scleroderma *This list is not intended to be inclusive.

inflammatory process that involves the alveoli and interstitium of the lung. An accumulation of inflammatory and immune cells causes continued damage to lung tissue and replacement of normally functioning lung tissue with fibrous scar tissue.

Clinical Manifestations In general, the ILDs are characterized by clinical changes consistent with restrictive rather than obstructive changes in the lung, although some people have both components. People with ILDs have dyspnea, tachypnea, and eventual cyanosis, without evidence of wheezing or signs of airway obstruction. Usually, there is an insidious onset of breathlessness that ­initially occurs during exercise and may progress to the point at which the person is totally incapacitated. Typically, a person with a restrictive lung disease breathes with a tachypneic pattern of breathing, in which the respiratory rate is increased and the tidal volume is decreased. This pattern of breathing serves to maintain minute volume yet reduces the work of breathing because it takes less work to move air through the airways at an increased rate than it does to stretch a stiff lung to accommodate a larger tidal volume. A nonproductive cough may develop, particularly with continued exposure to the inhaled irritant, along with clubbing of the fingers and toes. Lung volumes, including vital capacity and TLC, are reduced in ILD. In contrast to COPD, in which expiratory flow rates are reduced, the FEV1.0 usually is preserved, even though the ratio of FEV1.0 to FVC may increase. Although resting

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arterial blood gases usually are normal early in the course of the disease, arterial PO2 levels may fall during exercise. In persons with advanced disease, hypoxemia often is present, even at rest. In the late stages of the disease, hypercapnia and respiratory acidosis develop. Alterations in the alveolar– capillary membrane, as well as an increase in shunt resulting from unventilated regions of the lung, are thought to cause the impaired diffusion of gases in people with ILD.

Diagnosis and Treatment The diagnosis of ILD requires a comprehensive personal and family history, with particular emphasis on exposure to environmental, occupational, and other injurious agents. Chest radiographs and other imaging may be used as an initial diagnostic method, and serial chest films often are used to follow the progress of the disease. A surgical lung biopsy specimen for histologic study and culture is the preferred diagnostic examination.8 The treatment goals for people with ILD focus on identifying and removing the injurious agent, suppressing the inflammatory response, preventing progression of the disease, and providing supportive therapy for people with advanced disease. In general, the treatment measures vary with the type of lung disease. Immunosuppressants and corticosteroid drugs frequently are used. Many of the supportive treatment measures used in the late stages of the disease, such as oxygen therapy and measures to prevent infection, are similar to those discussed for people with COPD. For some people a lung transplant may be the only potentially effective treatment.

Key Points INTERSTITIAL LUNG DISEASES •  ILDs result from inflammatory conditions that ­affect the interalveolar structures of the lung and produce lung fibrosis and a stiff lung. •  A stiff and noncompliant lung is difficult to inflate, increasing the work of breathing and causing ­decreased exercise tolerance due to hypoxemia. •  Because of the increased effort needed for lung expansion, people with ILD tend to take small but more frequent breaths.

Occupational and Environmental Interstitial Lung Diseases The occupational and environmental ILDs include the pneumoconioses, drug-induced ILD, and the hypersensitivity d­ iseases. The pneumoconioses are caused by the inhalation of inorganic dusts and particulate matter. The h­ ypersensitivity diseases result from the inhalation of organic dusts and related occupational antigens. A third type of occupational lung disease, byssinosis, a disease that affects cotton workers, has characteristics of the pneumoconioses and hypersensitivity lung diseases.

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Among the pneumoconioses are silicosis, found in h­ ardrock miners, foundry workers, sandblasters, pottery makers, and workers in the slate industry; coal miner’s pneumoconiosis; asbestosis, found in asbestos miners, manufacturers of asbestos products, and installers and removers of a­ sbestos insulation; talcosis, found in talc miners, millers, or drug abusers and in infants or small children who accidentally inhale powder containing talc; and berylliosis, found in ore extraction workers and alloy production workers. The danger of exposure to asbestos dust is not confined to the workplace. The dust pervades the general environment because it was used in the construction of buildings and in other applications before its health hazards were realized. It has been mixed into paints and plaster, wrapped around water and heating pipes, used to insulate hair dryers, and woven into theater curtains, hot pads, and ironing board covers. Important etiologic determinants in the development of the pneumoconioses are the size of the dust particle, its chemical nature and ability to incite lung destruction, and the concentration of dust and the length of exposure to it. The most dangerous particles are those in the range of 1 to 5 mm.42 These small particles are carried through the inspired air into the alveolar structures, whereas larger particles are trapped in the nose or mucous linings of the airways and removed by the mucociliary blanket. Exceptions are asbestos and talc particles, which range in size from 30 to 60 mm but find their way into the alveoli because of their density. All particles in the alveoli must be cleared by the lung macrophages. Macrophages are thought to transport engulfed particles from the small bronchioles and the alveoli, which have neither cilia nor mucus-secreting cells, to the mucociliary escalator or to the lymphatic channels for removal from the lung. This clearing function is hampered when the function of the macrophage is impaired by factors such as cigarette smoking, consumption of alcohol, and hypersensitivity reactions. This helps to explain the increased incidence of lung disease among smokers exposed to asbestos. In silicosis, the ingestion of silica particles leads to the destruction of the lung macrophages and the release of substances resulting in inflammation and fibrosis.42 Tuberculosis and other diseases caused by mycobacteria are common in people with silicosis. Because the macrophages are responsible for protecting the lungs from tuberculosis, the destruction of macrophages accounts for an increased susceptibility to tuberculosis in people with silicosis. The concentration of some dusts in the environment strongly influences their effects on the lung. For example, acute silicosis is seen only in people whose occupations entail intense exposure to silica dust over a short period. It is seen in sandblasters, who use a high-speed jet of sand to clean and polish bricks and the insides of corroded tanks; in t­ unnelers; and in rock drillers, particularly if they drill through ­sandstone. Acute silicosis is a rapidly progressive disease, usually leading to severe disability and death within 5 years of diagnosis. In contrast to acute silicosis, which is caused by exposure to extremely high concentrations of silica dust, the symptoms related to chronic, low-level exposure to silica dust usually do not begin to develop until after many years of exposure, and then the symptoms often are insidious in onset and slow to progress.

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Drug-Induced Interstitial Lung Disease Drugs can cause a variety of both acute and chronic alterations in lung function. For example, some of the cytotoxic drugs (e.g., bleomycin, busulfan, methotrexate, cyclophosphamide) used in treatment of cancer cause pulmonary damage as a result of direct toxicity of the drug and by stimulating the influx of inflammatory cells into the alveoli.42 Amiodarone, a drug used to treat resistant cardiac arrhythmias, is ­preferentially sequestered in the lung and causes significant pneumonitis in 5% to 15% of people receiving it.42 Hypersensitivity Pneumonitis The hypersensitivity occupational lung disorders (e.g., hypersensitivity pneumonitis or also termed extrinsic allergic alveolitis) are caused by intense and often prolonged exposure to inhaled organic dusts and related occupational antigens.8 Those affected have a heightened sensitivity to the antigen. The most common forms of hypersensitivity pneumonitis are farmer’s lung, which results from exposure to moldy hay; pigeon breeder’s lung, provoked by exposure to the serum, excreta, or feathers of birds; bagassosis, from contaminated sugar cane; and humidifier or air conditioner lung, caused by mold in the water reservoirs of these appliances. Unlike asthma, this type of hypersensitivity reaction involves primarily the alveoli. These disorders cause progressive fibrotic lung disease, which can be prevented by the removal of the environmental agent.

Sarcoidosis Sarcoidosis is a systemic disorder in which granulomas are found in affected tissues and organ systems, particularly the lung and lymphatic system.8 An important qualification is that these granulomas occur in the absence of exogenous (infection or environmental) agents known to cause granulomatous inflammation. The disorder predominantly affects people between 10 and 40 years of age, although it can occur in older people. The incidence of sarcoidosis in the United States is approximately 10.9 of 100,000 persons per year for whites and 35.5 of 100,000 persons per year for blacks.8 Etiology and Pathogenesis The characteristic lesion of sarcoidosis is the noncaseating granuloma. Unlike the granulomatous lesions that develop in tuberculosis and histoplasmosis, the collection of tissue macrophages composing the granulomas in sarcoidosis do not show evidence of necrosis or caseation. In addition to granulomas, in which multinuclear giant cells are frequently seen, there is often alveolitis or inflammation of the alveoli. The cause of sarcoidosis remains obscure. It is thought that the disorder may result from exposure of genetically predisposed persons to specific environmental agents.43 Support for a genetic influence comes from epidemiologic studies that have demonstrated the higher incidence in American Blacks and Scandinavian populations. Additional evidence comes from familial clustering of the disease. Analysis of

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human leukocyte antigen (HLA) genes located in the major histocompatibility complex also suggests that unique HLA genes can be linked to disease susceptibility and prognosis. Despite advances, including the identification of sarcoidosis genetic factors, a specific etiologic agent has yet to be identified. Clinical Manifestations Sarcoidosis has variable manifestations and an u­ npredictable course of progression in which any organ system can be affected. The organs that most commonly manifest ­symptoms are the lungs, lymph nodes, skin, and eyes. People with sarcoidosis frequently seek health care either as a result of abnormalities detected on an incidental chest film or because of insidious onset of respiratory symptoms (shortness of breath, nonproductive cough, chest pain) or constitutional signs and symptoms (e.g., fever, sweating, anorexia, weight loss, fatigue, myalgia).42 Eye involvement (anterior uveitis) and skin involvement (skin papules and plaques) are particularly common extrathoracic manifestations, but there may be cardiac, neuromuscular, hematologic, hepatic, endocrine, and lymph node findings.8,42 Sarcoidosis follows an unpredictable course characterized by either progressive chronicity or periods of activity interspersed with remissions, sometimes permanent, that may be spontaneous or induced by corticosteroid therapy. The disease is thought to be connected to abnormal immunological function since there is an increase in ratio of CD4+ and CD8+ lymphocytes and increased proinflammatory cytokines.8 Approximately 65% to 75% of people recover with minimal clinical and radiographic abnormalities.42 Diagnosis and Treatment The diagnosis of sarcoidosis is based on history and physical examination, tests to exclude other diseases, chest radiography, and biopsy to obtain confirmation of noncaseating granulomas. The use of CT scans and magnetic resonance imaging (MRI) as routine methods for diagnosis of sarcoidosis remains controversial. For example, increased angiotensin-converting enzyme (ACE) is commonly seen with sarcoidosis; however, it is not specific so is deemed controversial.8 Treatment is directed at interrupting the granulomatous inflammatory process that is characteristic of the disease and managing the associated complications. When treatment is indicated, corticosteroid drugs are used. These agents produce clearing of the lung, as seen on the chest radiograph, and improve pulmonary function, but it is not known whether they affect the long-term outcome of the disease.

IN SUMMARY The ILDs are characterized by fibrosis and decreased compliance of the lung. They include the occupational and environmental lung diseases and granulomatous disorders, such as sarcoidosis. These disorders are thought to result from an inflammatory process that begins in the alveoli

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and extends to involve the interstitial tissues of the lung. Unlike COPD, which affects the airways, ILDs affect the supporting collagen and elastic tissues that lie between the airways and blood vessels. These lung diseases generally decrease lung volumes, reduce the diffusing capacity of the lung, and cause various degrees of hypoxemia. Because lung compliance is reduced, people with this form of lung disease tend to maintain their minute volume by a rapid, shallow breathing pattern.

DISORDERS OF THE PULMONARY CIRCULATION After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the cause of pulmonary embolism and the clinical manifestations of the disorder. •• Describe the pathophysiology of pulmonary hypertensive disorders. •• Describe the rationale for right ventricular hypertrophy with cor pulmonale.

As blood moves through the pulmonary capillaries, o­ xygen content increases and carbon dioxide decreases. These processes depend on the matching of ventilation (i.e., gas exchange) and perfusion (i.e., blood flow). This section ­discusses two major problems of the pulmonary circulation: pulmonary embolism and pulmonary hypertension.

Key Points DISORDERS OF THE PULMONARY CIRCULATION •  Pulmonary thromboemboli are blood clots that originate in the systemic venous system and become lodged in a pulmonary blood vessel as they move from the right heart into and through the pulmonary circulation. •  Pulmonary hypertension is an elevated pulmonary arterial pressure. It may arise as a primary disorder of the pulmonary arteries in which an abnormal thickening of the vessel wall increases the resistance to blood flow, or as a secondary disorder due to chronic lung disorders or environmental conditions that produce hypoxemia and a resultant constriction of small pulmonary arteries, cardiac disorders that increase pulmonary venous pressure, or thromboembolic disorders that occlude pulmonary blood vessels.

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FIGURE 37.15  •  Pulmonary embolism. The main pulmonary artery and its bifurcation have been opened to reveal a large saddle embolus. (Rubin R., Strayer D. S. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 275, Fig. 7.12). Philadelphia, PA: Lippincott Williams & Wilkins.)

Pulmonary Embolism Pulmonary embolism develops when a blood-borne substance lodges in a branch of the pulmonary artery and obstructs blood flow. The embolism may consist of a thrombus (Fig. 37.15), air that has accidentally been injected during intravenous infusion, fat that has been mobilized from the bone marrow after a fracture or from a traumatized fat depot, or amniotic fluid that has entered the maternal circulation after rupture of the membranes at the time of delivery. Approximately 50,000 deaths/year in the United States are a result of a pulmonary embolism.42 Etiology and Pathogenesis Almost all pulmonary emboli are thrombi that arise from deep vein thrombosis (DVT) in the lower and upper extremities.42 The presence of thrombosis in the deep veins of the legs or pelvis often is unsuspected until embolism occurs. The effects of emboli on the pulmonary circulation are related to mechanical obstruction of the pulmonary circulation and neurohumoral reflexes causing vasoconstriction. Obstruction of pulmonary blood flow causes reflex bronchoconstriction in the affected area of the lung, wasted ventilation and impaired gas exchange, and loss of alveolar surfactant. Pulmonary hypertension and right heart failure may develop when there is massive vasoconstriction

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Chapter 37  Disorders of Ventilation and Gas Exchange    985

because of a large embolus. Although small areas of infarction may occur, frank pulmonary infarction is uncommon. Among the physiologic factors that contribute to venous thrombosis is Virchow triad, which consists of venous stasis, venous endothelial injury, and hypercoagulability states. The thrombophilias (e.g., antithrombin III deficiency, protein C and S deficiencies, factor V Leiden mutation) are a group of inherited disorders affecting coagulation that make an individual prone to development of venous thromboemboli.42 Venous stasis and venous endothelial injury can result from prolonged bed rest, trauma, surgery, childbirth, fractures of the hip and femur, myocardial infarction and congestive heart failure, and spinal cord injury. People undergoing orthopedic surgery and gynecologic cancer surgery are at particular risk, as are immobilized persons. Hypercoagulability is related to various factors. Cancer cells can produce thrombin and synthesize procoagulation factors, increasing the risk for thromboembolism. Use of oral contraceptives, pregnancy, and hormone replacement therapy are thought to increase the resistance to endogenous anticoagulants. Refer back to Ms. French in discussion about pulmonary embolism etiology. Ms. French, who you met at the beginning of the unit, presented to the emergency department with soreness in her right calf. This was because the embolus originated in the saphenous vein of her right leg and then broke free and traveled to the pulmonary circulation. Ms. French’s history of cigarette smoking and use of estrogen-based oral contraceptives increased her risk for thrombus development, because these agents cause vasoconstriction and inflammation. Clinical Manifestations The manifestations of pulmonary embolism depend on the size and location of the obstruction. Chest pain, dyspnea, and increased respiratory rate are the most frequent signs and symptoms of pulmonary embolism. Pulmonary infarction often causes pleuritic pain that changes with respiration; it is more severe on inspiration and less severe on expiration. Moderate hypoxemia without carbon dioxide retention occurs as a result of impaired gas exchange. Small emboli that become lodged in the peripheral branches of the pulmonary artery may go unrecognized unless the person is compromised, such as occurs in the elderly or acutely ill. Repeated small emboli gradually reduce the size of the pulmonary capillary bed, resulting in pulmonary hypertension. People with moderatesized emboli often present with breathlessness accompanied by pleuritic pain, apprehension, slight fever, and cough productive of blood-streaked sputum. Tachycardia often occurs to compensate for decreased oxygenation, and the breathing pattern is rapid and shallow. People with massive emboli usually present with sudden collapse, crushing substernal chest pain, shock, and sometimes loss of consciousness. The pulse is rapid and weak, the blood pressure is low, the neck veins are

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distended, and the skin is cyanotic and diaphoretic. Massive pulmonary emboli often are fatal. Refer back to Ms. French in discussion about pulmonary embolism clinical features. On presentation, Ms. French’s heart rate was elevated (132 beats/minute) and the electrocardiogram (ECG) showed sinus tachycardia. Her breathing was rapid and shallow. In a person with pulmonary embolism, tachycardia and tachypnea often occur to compensate for decreased oxygenation. Diagnosis The diagnosis of pulmonary embolism is based on clinical signs and symptoms, blood gas determinations, venous thrombosis studies, troponin, d-dimer testing, lung scans, and helical CT scans of the chest. Laboratory studies and radiologic films are useful in ruling out other conditions that might give rise to similar symptoms. Because emboli can cause an increase in pulmonary vascular resistance, the ECG may be used to detect signs of right heart strain. Because most pulmonary emboli originate from DVT, venous studies such as lower limb compression ultrasonography, impedance plethysmography, and contrast venography are often used as initial diagnostic procedures. Of these, lower limb compression ultrasonography has become an important noninvasive means for detecting DVT. d-dimer testing involves the measurement of plasma d-dimer, a degradation product of coagulation factors that have been activated as the result of a thromboembolic event. Troponin levels may be increased due to stretching of the right ventricle by a large pulmonary infarction. The ventilation–perfusion scan uses radiolabeled albumin, which is injected intravenously, and a radiolabeled gas, which is inhaled. A scintillation (gamma) camera is used to scan the various lung segments for blood flow and distribution of the radiolabeled gas. Ventilation–perfusion scans are useful only when their results are either normal or indicate a high probability of pulmonary embolism. Helical (spiral) CT angiography requires administration of an intravenous radiocontrast medium. It is sensitive for the detection of emboli in the proximal pulmonary arteries and provides another method of diagnosis. Pulmonary angiography involves the passage of a venous catheter through the right heart and into the pulmonary artery under fluoroscopy. Although it remains the most accurate method of diagnosis, it is infrequently done since it is such an invasive procedure. An embolectomy sometimes is performed during this procedure. Refer back to Ms. French in discussion about pulmonary embolism diagnostics. d-dimer testing involves the measurement of plasma d-dimer, a degradation product of coagulation factors that have been activated as the result of a thromboembolic event. Recall that Ms. French’s d-dimer levels were elevated.

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Treatment The treatment goals for pulmonary emboli focus on preventing DVT and the development of thromboemboli; ­protecting the lungs from exposure to thromboemboli when they occur; and, in the case of large and life-threatening pulmonary emboli, sustaining life and restoring pulmonary blood flow. Thrombolytic therapy using recombinant tissue plasminogen activator may be indicated in people with multiple or large emboli. Prevention focuses on identifying people at risk, avoidance of venous stasis and hypercoagulability states, and early detection of venous thrombosis. It is important that people start to become mobile as soon as possible after surgery or illness. For people at risk, graded compression elastic stockings and intermittent pneumatic compression (IPC) boots can be used to prevent venous stasis. Surgical interruption of the vena cava may be indicated when pulmonary embolism poses a life-threatening risk. Pharmacologic prophylaxis involves the use of anticoagulant drugs. Anticoagulant therapy may be used to decrease the likelihood of DVT, thromboembolism, and fatal pulmonary embolism after major surgical procedures. Low molecular weight heparin, which can be administered subcutaneously on an outpatient basis, often is used. Warfarin, an oral anticoagulation drug, may be used for people with a long-term risk for development of thromboemboli.

Pulmonary Hypertension The pulmonary circulation is a low-pressure system designed to accommodate varying amounts of blood delivered from the right heart and to facilitate gas exchange. The main pulmonary artery and major branches are relatively thin-walled, compliant vessels. The distal pulmonary arterioles also are thin walled and have the capacity to dilate, collapse, or constrict depending on the presence of vasoactive substances released from the endothelial cells of the vessel, neurohumoral influences, flow velocity, oxygen tension, and alveolar ventilation. Pulmonary hypertension is a disorder characterized by an elevation of pressure within the pulmonary circulation, namely, the pulmonary arterial system. The elevation in pressure may be acute or chronic, depending on the causative factors. Etiology and Pathogenesis A number of factors can contribute to the pathogenesis of pulmonary arterial hypertension (PAH), including a decrease in the cross-sectional area of the pulmonary arteries, a loss of blood vessels from either scarring or destructive processes affecting the alveolar walls, vasoconstriction in response to hypoxia, the need to accommodate excessive inflow of blood flow without any anatomic changes in the pulmonary arteries or arterioles, or the occlusion of outflow from the pulmonary circulation due to elevated pressures within the left atrium or ventricle.

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The disorder may be due to changes in the arterial wall, often referred to as pulmonary arterial hypertension, or it may occur as a secondary condition related to the occlusion of the pulmonary circulation by pulmonary emboli or to disruption of the pulmonary circulation due to heart or lung disease. Pulmonary Arterial Hypertension The term pulmonary arterial hypertension (PAH) is used to describe a type of pulmonary hypertension that has its o­ rigin in the pulmonary arteries. The World Health Organization (WHO) categorized pulmonary hypertension into five groups related to their disease mechanism.44 •• Group I is pulmonary arterial or idiopathic hypertension. •• Group II is pulmonary venous hypertension. •• Group III is pulmonary hypertension associated with hypoxemia. •• Group IV is pulmonary hypertension due to chronic thrombotic or embolic disease or both. •• Group V comprises miscellaneous disorders that cause PAH.44 PAH is a rare and debilitating disorder characterized by abnormal proliferation and contraction of vascular smooth muscle, coagulation abnormalities, and marked intimal fibrosis leading to obliteration or obstruction of the pulmonary arteries and arterioles (Fig. 37.16). The resulting increase in pressure results in progressive right heart failure, low cardiac output, and death if left untreated. The past decade has witnessed dramatic advances in the treatment of PAH, with medical therapies targeting specific pathways that are believed to play pathogenetic roles in development of the disorder. Despite these achievements, PAH remains a serious, life-threatening condition. Etiology and Pathogenesis. The familial form of PAH appears to be inherited as an autosomal dominant trait with a variable but low penetrance, with some people inheriting the trait without exhibiting the disease. The bone morphogenetic protein receptor type II gene (BMPR2), which codes for a member of the transforming growth factor-β (TGF-β) superfamily of receptors, was identified as causative of familial PAH. Mutations in these receptors are thought to prevent TGF-β and related molecules from exerting an inhibitory effect on smooth muscle and endothelial cell proliferation.45 Other conditions associated with PAH include collagen vascular disorders (e.g., scleroderma), drugs and toxins, human immunodeficiency virus (HIV) infection, portal hypertension, and persistent pulmonary hypertension in the newborn.42 Although the specific mechanisms responsible for the vascular changes that occur in PAH remain unknown, a number of mechanisms have been proposed. These include enhanced expression of the serotonin transporter, diminished levels of nitric oxide and prostacyclin, and increased levels of several growth factors, including endothelin, vascular endothelial growth factor, and platelet-derived growth ­factor.

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Chapter 37  Disorders of Ventilation and Gas Exchange    987

effects on vascular smooth muscle. The endothelium also produces prostacyclin (PGI2), an inhibitor of platelet aggregation and potent vasodilator. Results of studies relating these mechanisms to the structure and function of the pulmonary arterial circulation have already been translated into targeted therapies for PAH, with the probability that more will be investigated in the future. Clinical Manifestations.  PAH is defined by persistent elevation in pulmonary artery pressure with normal left ventricular pressures, differentiating it from left-sided heart failure. Symptoms typically progress from shortness of breath and decreasing exercise tolerance to right heart failure, with marked peripheral edema and functional limitations. Other common symptoms include fatigue, angina, and syncope (fainting) or near-syncope.

A

Diagnosis and Treatment. The diagnosis of primary pulmonary hypertension is based on an absence of disorders that cause secondary hypertension and mean pulmonary artery pressures greater than 25 mm Hg at rest or 30 mm Hg with exercise. Treatment consists of measures to improve right heart function as a means of reducing fatigue and peripheral edema. Supplemental oxygen may be used to increase exercise tolerance. This agent often improves symptoms, sometimes dramatically, in people who have not responded to other vasodilators. Sildenafil (e.g., Viagra) a highly selective phosphodiesterase-5 inhibitor, which acts in a manner similar to nitric oxide to produce vasodilation, is another treatment of pulmonary hypertension.46 Lung transplantation may be an alternative for people who do not respond to other forms of treatment. Secondary Pulmonary Hypertension Although pulmonary hypertension can develop as a primary disorder, most cases develop secondary to conditions such as chronic hypoxemia due to COPD, ILD, or sleep-disordered breathing; increased resistance to pulmonary venous drainage due to conditions such as diastolic dysfunction of the left heart or disorders of mitral or aortic valves; or chronic thromboembolic disorders.

B FIGURE 37.16 • Pulmonary artery hypertension. A small pulmonary artery occluded by concentric intimal fibrosis and thickening of the media. (From Rubin R., Strayer D. S. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 592, Fig. 12.75). Philadelphia, PA: Lippincott Williams & Wilkins.)

The ­ endothelium-relaxing factor, nitric oxide, is a potent ­pulmonary vasodilator that is produced locally in the lung and has profound effects on smooth muscle relaxation and ­proliferation. Endothelin 1 is a peptide produced by the vascular endothelium that has potent vasoconstrictor and paracrine

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Etiology and Pathogenesis. Continued exposure of the pulmonary vessels to hypoxemia is a common cause of pulmonary hypertension. Unlike blood vessels in the systemic circulation, most of which dilate in response to hypoxemia and hypercapnia, the pulmonary vessels constrict. The stimulus for constriction seems to originate in the airspaces near the smaller branches of the pulmonary arteries. In regions of the lung that are poorly ventilated, the response is adaptive in that it diverts blood flow away from the poorly ventilated areas to those areas that are more adequately ventilated. This effect, however, becomes less beneficial as more and more areas of the lung become poorly ventilated. Pulmonary hypertension is a common problem in people with advanced COPD or ILD. It also may develop at high altitudes in people with normal lungs.

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People who experience marked hypoxemia d­ uring sleep (such as those with sleep apnea) often experience marked elevations in pulmonary arterial pressure. Elevation of pulmonary venous pressure is common in conditions such as mitral valve disorders or left ventricular diastolic dysfunction. In each of these alterations, the elevated left atrial pressure is transmitted to the pulmonary circulation. Continued increases in left atrial pressure can lead to medial hypertrophy and intimal thickening of the small pulmonary arteries, causing sustained hypertension. Another cause of secondary pulmonary hypertension is obstruction of pulmonary blood flow due to pulmonary thromboemboli. People who are promptly treated for acute pulmonary thromboembolism with anticoagulants rarely develop pulmonary hypertension. However, in some people chronic obstruction of the pulmonary vascular bed develops because of impaired resolution of the thromboemboli. Clinical Manifestations, Diagnosis, and Treatment. The signs and symptoms of secondary pulmonary hypertension reflect both the elevated pulmonary arterial pressure and the underlying heart or lung disease. As with primary pulmonary hypertension, diagnosis is based on radiographic findings, echocardiography, and Doppler ultrasonography. Treatment measures are directed toward the underlying disorder. Vasodilator therapy may be indicated for some people.

Cor Pulmonale The term cor pulmonale refers to right heart failure resulting from primary lung disease or pulmonary hypertension. The increased pressures and work result in hypertrophy and eventual failure of the right ventricle. The manifestations of cor pulmonale include the signs and symptoms of the primary lung disease and the signs of right-sided heart failure. Signs of right-sided heart failure include venous congestion, peripheral edema, shortness of breath, and a productive cough, which becomes worse during periods of heart failure. Plethora (i.e., redness), cyanosis, and warm, moist skin may result from the compensatory polycythemia and desaturation of arterial blood that accompany chronic lung disease. Drowsiness and altered consciousness may occur as the result of carbon dioxide retention. Management of cor pulmonale focuses on the treatment of the lung disease and heart failure (Fig. 37.17). Low-flow oxygen therapy may be used to reduce the pulmonary hypertension and polycythemia associated with severe hypoxemia caused by chronic lung disease.

IN SUMMARY Pulmonary vascular disorders include pulmonary ­embolism and pulmonary hypertension. Pulmonary embolism develops when a blood-borne substance lodges in a branch of the pulmonary artery and obstructs blood flow. The embolus can consist of a thrombus, air, fat, or amniotic fluid. The most common form is thromboemboli arising from the

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Pulmonary disorders such as bronchiectasis, cystic fibrosis, scleroderma, or neuromuscular disorders

Causes changes in bronchioles such as dilation and fibrosis, dehydration of the mucous layer, inflammation, defective mucociliary function, release of inflammatory mediators, obstruction

Increases the pulmonary vasculature resistance and causes hypoxia

Pulmonary hypertension occurs which causes the lumen to vasoconstrict and increase hypoxia

The vasoconstricted pulmonary artery causes the right ventricle to work harder to pump the blood into the lungs so the right ventricle hypertrophies

FIGURE 37.17  •  Pathogenesis of cor pulmonale.

deep venous channels of the lower extremities. Pulmonary hypertension is the elevation of pulmonary arterial ­pressure. It has been categorized into five groups. Cor pulmonale describes right heart failure caused by primary pulmonary disease and long-standing pulmonary hypertension.

ACUTE RESPIRATORY DISORDERS After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the pathologic lung changes that occur in acute respiratory distress syndrome. •• Describe the clinical manifestations of acute respiratory failure. •• Differentiate between the causes and manifestations of hypoxemic and hypercapnic/hypoxemic respiratory failure. •• Describe the treatment of respiratory failure.

The function of the respiratory system is to add oxygen to the blood and remove carbon dioxide. Disruptions in this function occur with ALI/respiratory distress syndrome and acute

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Chapter 37  Disorders of Ventilation and Gas Exchange    989

respiratory failure. Although the mechanisms that disrupt gas exchange may vary, both conditions represent a life-threatening situation with high risks of morbidity and mortality.

CHART 37.3

Acute Lung Injury/Acute Respiratory Distress Syndrome

Aspiration Near drowning Aspiration gastric contents

CONDITIONS IN WHICH ARDS CAN DEVELOP*

Acute respiratory distress syndrome (ARDS) was first described in 1967 in adults and initially called adult respiratory distress syndrome. It later was renamed acute respiratory distress syndrome because it also affects children. After a consensus conference in 1994, ALI and ARDS were differentiated by the extent of hypoxemia, as evaluated by the PF (PO2 to FiO2) ratio.47 ARDS is a more severe aspect of ALI and is differentiated primarily for early intervention, prevention, and research purposes. ARDS may result from a number of conditions, including aspiration of gastric contents, major trauma (with or without fat emboli), sepsis secondary to pulmonary or nonpulmonary infections, acute pancreatitis, hematologic disorders, metabolic events, and reactions to drugs and toxins (Chart 37.3).

Drugs, Toxins, and Therapeutic Agents Free-base cocaine smoking Heroin Inhaled gases (e.g., smoke, ammonia) Breathing high concentrations of oxygen Radiation

Etiology and Pathogenesis Although a number of conditions may lead to ALI/ARDS, they all produce similar pathologic lung changes that include diffuse epithelial cell injury with increased permeability of the alveolar–capillary membrane (Fig. 37.18). The increased permeability permits fluid, plasma proteins, and blood cells to move out of the vascular compartment into the interstitium and alveoli of the lung.48 Diffuse alveolar cell damage leads to accumulation of fluid, surfactant inactivation, and formation of a hyaline membrane that is impervious to gas exchange. As the disease progresses, the work of breathing becomes greatly increased as the lung stiffens and becomes more difficult to inflate.

Disseminated Intravascular Coagulation

Infections Septicemia Trauma and Shock Burns Fat embolism Chest trauma Multiple Blood Transfusions *This list is not intended to be inclusive.

There is increased intrapulmonary shunting of blood, impaired gas exchange, and refractory hypoxemia despite high supplemental oxygen therapy. Gas exchange is further compromised by alveolar collapse resulting from abnormalities in surfactant production. When injury to the alveolar epithelium is severe, disorganized epithelial repair may lead to fibrosis (Fig. 37.19).

Protein-rich edematous fluid

Platelets Alveolus

Sloughing type I cells

Type II alveolar cell

Alveolar macrophage

Fibrin Cellular debris

Inactivated surfactant

Edematous interstitium FIGURE 37.18  •  The mechanism of lung changes in ARDS. Injury and increased permeability of the alveolar capillary membrane allow fluid, protein, cellular debris, platelets, and blood cells to move out of the vascular compartment and enter the interstitium and alveoli. Activated neutrophils release a variety of products that damage the alveolar cells and lead to edema, surfactant inactivation, and formation of a hyaline membrane. (PAF, platelet-activating factor.)

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Hyaline membrane

Leukotrienes Oxidants PAF Proteases

Injured endothelial cells

Capillary

Neutrophil Red blood cells

Plasma proteins

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990   UNIT IX  Disorders of Respiratory Function

Direct or indirect lung injury

Mediator release

Alveolar epithelial changes

Endothelial changes

Shift in fluid and protein

Type I cell damage

Type II cell dysfunction

Thickened alveolar–capillary membrane

Surfactant function

Impaired gas diffusion

Increased capillary permeability

Pulmonary vasoconstriction

Interstitial pulmonary edema

Regionally altered flow state

Surface tension and compliance

Alveolar collapse

Ventilation– perfusion mismatch

Work of breathing

Intrapulmonary shunt

Hypoxemia refractory to supplemental oxygen FIGURE 37.19  •  Pathophysiological cascade. This is initiated by an injury, which triggers the mediator release. The multiple effects result in changes to the alveoli, vascular tissue, and bronchi. The ultimate effect is ventilation–perfusion mismatching and refractory hypoxemia. (From Morton P. G. Fontaine D. K. (2009). Critical care nursing: A holistic approach (9th ed., p. 675). Philadelphia, PA: Lippincott Williams & Wilkins.)

The pathogenesis of ALI/ARDS is unclear, although both local and systemic inflammatory responses occur so often when a person has been diagnosed with ARDS they already have leaky capillary syndrome in other organs such as the pancreas. Neutrophils accumulate early in the course of the disorder and are considered to play a role

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in the pathogenesis of ALI/ARDS. Activated neutrophils ­synthesize and release a variety of products, including proteolytic enzymes, toxic oxygen species, and phospholipid products that increase the inflammatory response and cause further injury to the capillary endothelium and alveolar epithelium.

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Chapter 37  Disorders of Ventilation and Gas Exchange    991

Clinical Manifestations and Diagnosis Clinically, ALI/ARDS is marked by a rapid onset of respiratory distress, usually within 12 to 18 hours of the initiating event, an increase in respiratory rate, and signs of respiratory failure. Marked hypoxemia occurs that is refractory to treatment with supplemental oxygen therapy, which results in a decrease in the PF ratio. Many people with ARDS have a systemic response that results in multiple organ failure, particularly of the renal, gastrointestinal, cardiovascular, and central nervous systems. Chest radiography shows diffuse bilateral infiltrates of the lung tissue in the absence of cardiac dysfunction. Treatment The treatment goals in ARDS are to supply oxygen to vital organs and provide supportive care until the condition causing the pathologic process has been reversed and the lungs have had a chance to heal.50 Assisted ventilation using high concentrations of oxygen may be required to correct the hypoxemia. Extensive study has been conducted to determine optimal pressures and volumes to correct the hypoxemia yet prevent further lung injury due to the barotrauma often seen with mechanics of ventilation. Also specific nutritional formulas to be used with these people with ARDS and ARF have been found to increase outcomes.50

CHART 37.4

CAUSES OF RESPIRATORY FAILURE*

Hypoxemic Respiratory Failure Chronic obstructive pulmonary disease Interstitial (restrictive) lung disease Severe pneumonia Atelectasis Hypercapnic/Hypoxemic Respiratory Failure Upper airway obstruction   Infection (e.g., epiglottitis)  Laryngospasm  Tumors Weakness or paralysis of respiratory muscles   Brain injury   Drug overdose   Guillain-Barré syndrome   Muscular dystrophy   Spinal cord injury Chest wall injury Impaired Diffusion Pulmonary edema Acute lung injury/acute respiratory distress syndrome *This list is not intended to be inclusive.

Acute Respiratory Failure Respiratory failure can be viewed as a failure in gas exchange due to either heart or lung failure, or both. It is not a specific disease but can occur in the course of a number of conditions that impair ventilation, compromise the matching of ventilation and perfusion, or impair gas diffusion. Acute respiratory failure may occur in previously healthy people as the result of acute disease or trauma involving the respiratory system, or it may develop in the course of a chronic neuromuscular or lung disease. Respiratory failure is a condition in which the respiratory system fails in one or both of its gas exchange functions— oxygenation of mixed venous blood and elimination of carbon dioxide. The function of the respiratory system can be said to consist of two aspects: gas exchange (movement of gases across the alveolar–capillary membrane) and ventilation (movement of gases into and out of the alveoli due to the action of the respiratory muscles, respiratory center in the CNS, and the pathways that connect the centers in the CNS with the respiratory muscles). Thus, respiratory failure is commonly divided into two types: 1. Hypoxemic respiratory failure due to failure of the gas exchange function of the lung 2. Hypercapnic/hypoxemic respiratory failure due to ventilatory failure52 The classification should not be viewed as rigid since lung disorders that cause impaired gas exchange can be ­complicated by ventilatory failure. In addition, ventilatory failure can be accompanied by lung disorders that impair

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gas diffusion. Causes of respiratory failure are summarized in Chart 37.4. Hypoxemic Respiratory Failure In people with hypoxemic respiratory failure, two major pathophysiologic factors contribute to the lowering of arterial PO2–ventilation–perfusion mismatching or impaired diffusion. Mismatching of Ventilation and Perfusion.  The mismatching of ventilation and perfusion occurs when areas of the lung are ventilated but not perfused or when areas are perfused but not ventilated. Usually the hypoxemia seen in situations of ventilation–perfusion mismatching is more severe in relation to hypercapnia than that seen in hypoventilation. Severe mismatching of ventilation and perfusion often is seen in people with advanced COPD. These disorders contribute to the retention of carbon dioxide by reducing the effective alveolar ventilation, even when total ventilation is maintained. This occurs because a region of the lung is not perfused and gas exchange cannot take place or because an area of the lung is not being ventilated. Maintaining a high ventilation rate effectively prevents hypercapnia but also increases the work of breathing. The hypoxemia associated with ventilation–perfusion disorders often is exaggerated by conditions such as hypoventilation and decreased cardiac output. For example, sedation can cause hypoventilation in people with severe COPD, resulting in further impairment of ventilation. Likewise, a

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992   UNIT IX  Disorders of Respiratory Function

decrease in cardiac output because of myocardial infarction can exaggerate the ventilation–perfusion impairment in a person with mild pulmonary edema or COPD. The beneficial effect of oxygen administration on PO2 levels in ventilation–perfusion disorders depends on the degree of mismatching that is present. Because oxygen administration increases the diffusion gradient in ventilated portions of the lung, it usually is effective in raising arterial PO2 levels. However, high-flow oxygen may decrease the respiratory drive and produce an increase in PCO2. Impaired Diffusion. Impaired diffusion describes a condition in which gas exchange between the alveolar air and pulmonary blood is impeded because of an increase in the distance for diffusion or a decrease in the permeability or surface area of the respiratory membranes to the movement of gases. It most commonly occurs in conditions such as ILD, ALI/ ARDS, pulmonary edema, and pneumonia. Conditions that impair diffusion may produce severe hypoxemia but no hypercapnia because of the increase in ventilation and greater diffusion rate of carbon dioxide. Hypoxemia resulting from impaired diffusion can be partially or completely corrected by the administration of high concentrations of oxygen. In this case, the high concentration of oxygen serves to overcome the decrease in diffusion by establishing a larger alveolar-to-capillary diffusion gradient. Hypercapnic/Hypoxemic Respiratory Failure In the hypercapnic form of respiratory failure, people are unable to maintain a level of alveolar ventilation sufficient to eliminate CO2 and keep arterial O2 levels within normal range. Because ventilation is determined by a sequence of events ranging from generation of impulses in the CNS to movement of air through the conducting airways, there are several stages at which problems can adversely affect the total minute ventilation. Hypoventilation or ventilatory failure occurs when the volume of “fresh” air moving into and out of the lung is significantly reduced. It is commonly caused by conditions ­outside the lung such as depression of the respiratory center (e.g., drug overdose, brain injury), diseases of the nerves supplying the respiratory muscles (e.g., Guillain-Barré syndrome, spinal cord injury), disorders of the respiratory muscles (e.g., muscular dystrophy), exacerbation of chronic lung disease (e.g., COPD), or thoracic cage disorders (e.g., severe scoliosis or crushed chest). Hypoventilation has two important effects on arterial blood gases. First, it almost always causes an increase in PCO2. The rise in PCO2 is directly related to the level of ventilation; reducing the ventilation by one half causes a doubling of the PCO2. Thus, the PCO2 level is a good diagnostic measure for hypoventilation. Second, it may cause hypoxemia, although the hypoxemia that is caused by hypoventilation can be readily abolished by the administration of supplemental oxygen.

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Clinical Manifestations Acute respiratory failure is usually manifested by varying degrees of hypoxemia and hypercapnia. There is no absolute definition of the levels of PO2 and PCO2 that indicate respiratory failure. Respiratory failure is conventionally defined by an arterial PO2 of less than 50 mm Hg, an arterial PCO2 of more than 50 mm Hg, or both when prior blood values have been normal. It is important to emphasize that these cutoff ­values are not rigid but simply serve as a general guide in combination with history and physical assessment information. The signs and symptoms of acute respiratory failure are those of the underlying disease combined with signs of hypoxemia and hypercapnia/hypoxemia. Respiratory ­acidosis is usually present because the retention of CO2 results in increased production of acids. Hypoxemia is accompanied by increased respiratory drive and increased sympathetic tone. Potential signs of hypoxemia include cyanosis, restlessness, confusion, anxiety, delirium, fatigue, tachypnea, hypertension, cardiac arrhythmias, and tremor. The initial cardiovascular effects are tachycardia with increased cardiac output and increased blood pressure. Serious arrhythmias may be triggered. The pulmonary vasculature constricts in response to low alveolar PO2. If severe, the pulmonary vasoconstriction may result in acute right ventricular failure with manifestations such as jugular vein distention and dependent edema. Profound acute hypoxemia can cause convulsions, retinal hemorrhages, and permanent brain damage. Hypotension and bradycardia often are preterminal events in people with hypoxemic respiratory failure, indicating the failure of compensatory mechanisms. Many of the adverse consequences of hypercapnia are the result of respiratory acidosis. Direct effects of acidosis include depression of cardiac contractility, decreased ­respiratory muscle contractility, and arterial vasodilation. Raised ­levels of PCO2 greatly increase cerebral blood flow, which may result in headache, increased cerebrospinal fluid pressure, and sometimes papilledema. The headache is due to dilation of the cerebral vessels. Additional indicators of hypercapnia are warm and flushed skin and hyperemic conjunctivae. Hypercapnia has nervous system effects similar to those of an anesthetic—hence the term carbon dioxide narcosis. There is progressive somnolence, disorientation, and, if the condition is untreated, coma. Mild to moderate increases in blood pressure are common. Air hunger and rapid breathing occur when alveolar PCO2 levels rise to approximately 60 to 75 mm Hg; as PCO2 levels reach 80 to 100 mm Hg, the person becomes lethargic and sometimes semicomatose. Treatment The treatment of the person with acute respiratory failure consists of specific therapy directed toward the underlying disease, respiratory supportive care directed toward maintenance of adequate gas exchange, and general supportive care. A number of treatment modalities are available, including the establishment of an airway and the use of anti-inflammatory bronchodilators, mucolytics, and antibiotics for respiratory infections. The main therapeutic goal in acute hypoxemic respiratory failure is to ensure adequate oxygenation of vital organs, which is generally accomplished by mechanical ventilation.

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Chapter 37  Disorders of Ventilation and Gas Exchange    993

IN SUMMARY The hallmark of ALI and ARDS is a pronounced inflammatory response that affects the lung and may or may have already resulted in systemic organ failure. In fact, the damage to the lung in ARDS may not be the initial manifestation but part of a multiorgan shutdown due to leaky capillary syndrome. The acute inflammatory response ­ results in damage and dysfunction of the alveolar–capillary membrane of the lung. Classically, there is interstitial edema of lung tissue, an increase in surface tension caused by inactivation of surfactant, collapse of the alveolar structures, a stiff and noncompliant lung that is difficult to inflate, and impaired diffusion of the respiratory gases with severe hypoxia that is totally refractory to oxygen therapy. Acute respiratory failure is a condition in which the lungs fail to oxygenate the blood adequately (hypoxemic respiratory failure) or prevent undue retention of carbon dioxide (hypercapnic/hypoxemic respiratory failure). The causes of respiratory failure are many. It may arise acutely in people with previously healthy lungs, or it may be superimposed on chronic lung disease. Treatment of acute respiratory failure is directed toward treatment of the underlying disease, maintenance of adequate gas exchange and tissue oxygenation, and general supportive care. When alveolar ventilation is inadequate to maintain PO2 or PCO2 levels because of impaired respiratory function or neurologic failure, mechanical ventilation may be necessary. There are multiple problems that can result from the barotraumas caused by the mechanical ventilation to the lung parenchyma. This condition is caused by ventilator-induced lung injury (VILI), which needs to be prevented if at all possible. Lung protective strategies are focused on increasing compliance and decreasing shear stresses, which occur with the frequent alveolar collapse secondary to the high pressure needed to ventilate the lungs.

Review Exercises 1. A 30-year-old man is brought to the emergency department with a knife wound to the chest. On visual inspection, asymmetry of chest movement during inspiration, displacement of the trachea, and absence of breath sounds on the side of the wound are noted. His neck veins are distended, and his pulse is rapid and thready. A rapid diagnosis of tension pneumothorax is made. A. Explain the observed respiratory and cardiovascular function in terms of the impaired lung expansion and the air that has entered the chest as a result of the injury. B. What type of emergent treatment is necessary to save this man’s life?

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2. A 10-year-old boy who is having an acute asthmatic attack is brought to the emergency department by his parents. The boy is observed to be sitting up and struggling to breathe. His breathing is accompanied by use of the accessory muscles, a weak cough, and audible wheezing sounds. His pulse is rapid and weak and both heart and breath sounds are distant on auscultation. His parents relate that his asthma began to worsen after he developed a “cold,” and now he doesn’t even get relief from his “albuterol” inhaler. A. Explain the changes in physiologic function underlying this boy’s signs and symptoms. B. The boy is treated with a systemic corticosteroid and inhaled anticholinergic and b2-adrenergic agonist and then transferred to the intensive care unit. Explain the action of each of these medications in terms of relieving this boy’s symptoms. 3. A 62-year-old man with an 8-year history of chronic bronchitis reports to his health care ­provider with complaints of increasing shortness of breath, ankle swelling, and a feeling of fullness in his upper abdomen. The expiratory phase of his respirations is prolonged and expiratory wheezes and crackles are heard on auscultation. His blood pressure is 160/90 mm Hg, his red blood cell count is 6.0 × 106 mL (normal 4.2 to 5.4 × 106 mL), his hematocrit is 65% (normal male value 40% to 50%), his arterial PO2 is 55 mm Hg, and his O2 saturation, which is 85% while he is resting, drops to 55% during walking exercise. A. Explain the physiologic mechanisms responsible for his edema, hypertension, and elevated red blood cell count. B. His arterial PO2 and O2 saturation indicate that he is a candidate for continuous low-flow oxygen. Explain the benefits of this treatment in terms of his activity tolerance, blood pressure, and red blood cell count. C. Explain why the oxygen flow rate for persons with COPD is normally titrated to maintain the arterial PO2 between 60 and 65 mm Hg. 4. An 18-year-old woman is admitted to the emergency department with a suspected drug overdose. Her respiratory rate is slow (4 to 6 breaths/ minute) and shallow. Arterial blood gases reveal a PCO2 of 80 mm Hg and a PO2 of 60 mm Hg. A. What is the cause of this woman’s high PCO2 and low PO2? B. Hypoventilation almost always causes an increase in PCO2. Explain. C. Even though her PO2 increases to 90 mm Hg with institution of oxygen therapy, her PCO2 remains elevated. Explain.

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994   UNIT IX  Disorders of Respiratory Function

References 1. Boron W. F., Boulpaep E. L. (2009). Medical physiology (2nd ed., pp. 613–651). Philadelphia, PA: WB Saunders. 2. West J. B. (2008). Respiratory physiology: The essentials (8th ed., pp. 1–169). Philadelphia, PA: Lippincott Williams & Wilkins. 3. Fernandez M., Burns K., Calhoun B., et al. (2007). Evaluation of a new pulse oximeter sensor. American Journal of Critical Care 16(2), 146–152. 4. Toftegaard M., Rees S. E., Andreassen S. (2009). Evaluation of a method for converting venous values of acid-base and oxygenation status to arterial values. Emergency Medical Journal 26, 268–272. 5. Gattinoni L., Carlesso E., Cressoni M. (2011). Assessing gas exchange in acute lung injury/acute respiratory distress syndrome: Diagnostic techniques and prognostic relevance. Current Opinion in Critical Care 17(1), 18–23. 6. Aboab J., Louis B., Honson B., et al. (2006). Relation between PaO2/FIO2 ratio and FIO2: A mathematical description. Intensive Care Medicine 32, 1494–1497. 7. Morton R. G., Fontaine D K. (2009). Critical care nursing: A holistic approach (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 8. Andreoli T., Benjamin I., Griggs R., et al. (Eds.). (2010). Andreoli and Carpenter’s Cecil Essentials of Medicine (8th ed., pp. 187–254). St. Louis, MO: Elsevier. 9. Des Jardin T., Burton G. G, (2006).Pleural diseases. In Clinical manifestations and assessments of respiratory diseases (5th ed., pp. 318–327). Philadelphia, PA: Elsevier. 10. Alfano M. (2010). Catamenial pneumothorax. Current Opinion in Pulmonary Medicine. 16(4), 381–386. 11. Lai J- I., Po-Chou L., Wang W.- S., et al. (2010). Barotrauma related extensive pneumothorax, pneumomediastinum, and subcutaneous emphysema in a patient with acute respiratory distress syndrome with low tidal volume. Postgraduate Medical Journal 86(1019), 567–568. 12. Centers for Disease Control and Prevention. (2009). Asthma FASTSTATS 2009. Retrieved December 14, 2010 from http://www.cdc.gov/asthma/ faststats.html 13. National Heart Lung Blood Institute. (2010). National Asthma Education and Prevention Program (NAEP) NHLBI. [Online]. Available: http:// hp2010.nhlbihin.net/naepp.htm. Retrieved December 14, 2010. 14. Expert panel report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma (2007). [Online]. Available: http://www.nhlbi.nih.gov/guidelines/asthma/epr3/resource.pdf. Retrieved December 13, 2010. 15. Sly P. (2011). The early origins of asthma: Who is really at risk? Current Opinion in Allergy and Clinical Immunology 11(1), 24–28. 16. Robinson D. S. (2010). The role of the T cell in asthma. Journal of Allergy and Clinical Immunology 126(6):1081–1091. 17. Ramsey C. D., Celedón J. C. (2005). The hygiene hypothesis and asthma. Current Opinion in Pulmonary Medicine 11(1),14–18. 18. Berry M. A., Hargadon B., Shelley S., et al. (2006). Evidence of a role of tumor necrosis factor-α in refractory asthma. New England Journal of Medicine 354, 697–708. 19. Galli S. J., Kalesnikoff J., Grimbaldeston M. A., et al. (2005). Mast cells as “tunable” effector and immunoregulatory cells: Recent advances. Annual Review of Immunology 23, 749–86. 20. Fahey J. V. (2009). Eosinophilic and neutrophilic inflammation in asthma insights from clinical studies. Proceedings of the American Thoracic Society 6(3), 256–259. 21. House D. T., Ramirez E. G. (2008). Emergent management of asthma exacerbations. Advanced Emergency Nursing Journal 30(2), 122–138. 22. Finkelman F. D., Boyce J. A., Vercelli D., et al. (2010). Key advances in mechanisms of asthma, allergy, and immunology in 2009. Journal of Allergy and Clinical Immunology 125(2), 312–318. 23. Al-Sahab B., Hamadeh M. J., Ardern C.I., et al. (2011). Early menarche predicts incidence of asthma in early adulthood. American Journal of Epidemiology. 173(1):64–70. 24. Foschino B., Costa V. R., Resta O., et al. (2010). Menopausal asthma: A new biological phenotype? Allergy 65(10), 1306–1312. 25. Haxhiu M. A., Rust C. F., Brooks C., et al. (2006). CNS determinants of sleep-related worsening of airway functions: Implications for nocturnal asthma. Respiratory Physiology and Neurobiology 151, 1–30.

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26. Sutherland E. R. (2005). Nocturnal asthma. Journal of Allergy and Clinical Immunology 116, 1179–1186. 27. Mak G., Hanania N. A. (2011). Vitamin D and asthma. Current Opinion in Pulmonary Medicine 17(1), 1–5. 28. Sutherland T. J., Sears M. R., McLachlan C. R., et al. (2009). Leptin, adiponectin, and asthma: Findings from a population-based cohort study. Annals of Allergy, Asthma & Immunology 103(2), 101–107. 29. Morjaria J. B., Proiti M., Polosa R. (2011). Stratified medicine in selecting biologics for the treatment of severe asthma. Current Opinion in Allergy and Clinical Immunology. 11(1), 58–63. 30. Gibeon D. S. Campbell D. A., Menzies-Gow A. N. (2010). The systematic assessment of difficult-to-treat asthma: Why do it? Clinical Pulmonary Medicine 17(6), 255–259. 31. Magadle R., Berar-Yanay N., Weiner P. (2002). The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest 121, 329–333. 32. Mathur S. K. (2010). Impact of aging on the lung. Seminars in Respiratory and Critical Care Medicine 31(5), 587–595. 33. Akinbami L. (2006). Centers for Disease Control and Prevention National Center for Health Statistics. The state of childhood asthma, United States, 1980–2005. Advanced Data. (381), 1–24. Available: http://www.cdc.gov/ nchs/data/ad/ad381.pdf. Retrieved December 22, 2010. 34. Gupta R. S., Weiss K. B. (2009). The 2007 National Asthma Education and Prevention Program Asthma Guidelines: Accelerating their implementation and facilitating their impact on children with asthma. Pediatrics 123, S193–S198. 35. American Lung Association Epidemiology and Statistics Unit Research and Program Services Division. (2010). Trends in COPD (emphysema and chronic bronchitis) morbidity and mortality. Available: http://www. lungusa.org/finding-cures/our-research/epidemiology-and-statistics-rpts. html. Retrieved December 29, 2010. 36. National Heart Lung and Blood Institute. (2009). Morbidity and mortality: 2009 Chart book on cardiovascular, lung and blood diseases. Available: http://www.nhlbi.nih.gov/. Retrieved December 29, 2010. 37. Bearsley M. B., Travis W. D., Rubin E. (2008). The respiratory system. In Rubin R., Strayer D. S. (Eds.), Rubin’s pathology: Clinicopathologic foundations of medicine (5th ed., pp. 510–518, 525–534, 536–545). Philadelphia, PA: Lippincott Williams & Wilkins. 38. Richmond R. J., Zellner K.M. (2005). A1 Antitrypsin deficiency: Incidence and implications. Dimensions of Critical Care 24(6), 255–262. 39. Cystic Fibrosis Foundation (2009). About cystic fibrosis. Available: http:// www.cff.org/AboutCF/. Retrieved December 22, 2010. 40. Boyle M. P. (2007). Adult cystic fibrosis. Journal of American Medical Association, 298(15), 1787–1793. 41. Becq F. (2010). Cystic fibrosis transmembrane conductance regulator modulators for personalized drug treatment of cystic fibrosis: Progress to date. Drugs 70(3), 241–259. 42. Husain A. N., Kumar A. (2005). The lung. In Kumar A., Abbas A., Faustio N. (Eds.), Robbins and Cotran Pathologic basis of disease (7th ed., pp. 711–772). St. Louis, MO: Elsevier. 43. Weinberger S. E. (2006). A 47 year old woman with sarcoidosis. Journal of the American Medical Association 296(17), 2133–2140. 44. Simonneau G., Robbins I. M., Beghetti M., et al. (2009). Updated clinical classification of pulmonary hypertension. Journal of American College of Cardiology 54, S43–S54. 45. Ulrich S., Szamalik- Hoegel J., Hersberger M., et al. (2010). Sequence variants in BPMR2 and genes involved in the serotonin and nitric oxide pathways in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Respiration 79(4), 279–287. 46. Croxtail H., Lyseng-Williams K. (2010). Tadalafil in pulmonary arterial hypertension. Drugs 70(4) 479–488. 47. Bernard G. R. A., Artigas K. L., Brigham J., et al. (Consensus Committee). (1994). The American-European Consensus Conference on ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. American Journal of Respiratory Critical Care Medicine 149, 1807–1814.

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Chapter 37  Disorders of Ventilation and Gas Exchange    995 48. George K. J. (2008). A systematic approach to care: Acute respiratory distress syndrome. Journal of Trauma Nursing 15(1), 19–24. 49. Pathak V., Islam T. (2011). Neuromuscular blockers improve outcomes in severe and early acute respiratory distress syndrome. New England Journal of Medicine 363, 1107–1116. 50. Hamilton L. A., Trobaught K. A. (2011). Acute respiratory distress syndrome: Use of specialized nutrients in pediatric patients and infants. Nutrition in Clinical Practice 26(1), 26–30.

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51. Turner K. L., Moore F. A., Martindale R. (2011). Nutrition support for the ALI/ARDS patient: A review. Nutrition in Clinical Practice 26(1), 14–25. 52. Markou N. K., Myrianthefs P. M., Batlopoulos G. J. (2004). Respiratory failure: An overview. Critical Care Nursing Quarterly 27, 353–379.

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Unit 10

Disorders of Renal Function and Fluids and Electrolytes Joseph Reterez, 45 years old, is admitted to the Emergency Department with abdominal and flank discomfort, distension of the abdomen, anorexia, fatigue, and nausea. He says that his urine is really cloudy and he thinks there is some blood visible in the urine. His mother, his maternal grandfather, and two maternal uncles died in their late 40s from renal disease, but no one in his family has had genetic testing. His assessment shows an increased abdominal girth, enlarged kidneys, mild (1+) pedal edema, and bilateral flank pain. His vital signs are as follows: temperature, 100.1°F; blood pressure, 145/92 mm Hg (indicative of hypertension); pulse, 92/minute; and respiratory rate, 14/minute. Significant (abnormal) blood chemistry values include the following: blood urea nitrogen (BUN), 45 mg/dL (normal, 8 to 20 mg/dL); creatinine, 2.0 mg/dL (normal, 0.3 to 1.2 mg/dL); and serum sodium, 147 mEq/L (normal, 135 to 145 mEq/L). His urine specimen shows mildly elevated (+1) protein and the presence of RBCs. Genetic testing reveals a mutation in the PKD1 gene, a common cause of adult polycystic kidney disease. Mr. Reterez’s diagnosis is discussed in Chapter 41.

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Structure and Function of the Kidney KIDNEY STRUCTURE AND FUNCTION

Gross Structure and Location Renal Blood Supply The Nephron The Glomerulus Tubular Components of the Nephron Urine Formation Glomerular Filtration Tubular Reabsorption and Secretion Regulation of Urine Concentration Regulation of Renal Blood Flow Neural and Humoral Control Mechanisms Autoregulatory Mechanisms Effect of Increased Protein and Glucose Load Elimination Functions of the Kidney Renal Clearance Regulation of Sodium and Potassium Elimination Regulation of pH pH-Dependent Elimination of Organic Ions Uric Acid Elimination Urea Elimination Drug Elimination Endocrine Functions of the Kidney The Renin–Angiotensin–Aldosterone Mechanism Erythropoietin Vitamin D Action of Diuretics Diuretics That Block Sodium Reabsorption Osmotic Diuretics

TESTS OF RENAL FUNCTION

Urine Tests Glomerular Filtration Rate Blood Tests Serum Creatinine Blood Urea Nitrogen Cystoscopy Ultrasonography Radiologic and Other Imaging Studies

38 Sheila Grossman

The kidneys are remarkable organs. Each is smaller than a person’s fist, but in a single day, the two organs process approximately 22% to 25% of cardiac output or 1100 mL/minute.1,2 As part of their function, the kidneys filter physiologically essential substances, such as sodium (Na+) and potassium (K+) ions, from the blood and selectively reabsorb those substances that are needed to maintain the normal composition of internal body fluids. Substances that are not needed, or are in excess of those needed, pass into the urine. In regulating the volume and composition of body fluids, the kidneys perform excretory and endocrine functions. The renin–angiotensin mechanism participates in the regulation of blood pressure and the maintenance of circulating blood volume, and erythropoietin stimulates red blood cell production.2 The discussion in this chapter focuses on the structure and function of the kidneys and tests of renal function.

KIDNEY STRUCTURE AND FUNCTION After completing this section of the chapter, you should be able to meet the following objectives: •• Explain why the kidney receives such a large percentage of the cardiac output and describe the mechanisms for regulating renal blood flow. •• Describe the structure and function of the glomerulus and tubular components of the nephron in terms of regulating the composition of the extracellular fluid compartment. •• Describe how the kidney produces concentrated or dilute urine.

Gross Structure and Location The kidneys are paired, bean-shaped organs that lie outside the peritoneal cavity in the back of the upper abdomen, one on each side of the vertebral column at the level of the 998

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Chapter 38  Structure and Function of the Kidney    999 Diaphragm

T11 T12

Adrenal gland

Renal artery Renal vein Left kidney

Right kidney

Aorta Inferior vena cava

Ureter

Bladder Urethra FIGURE 38.1 • Kidneys, ureters, and bladder. (The right kidney is usually lower than the left.)

12th ­thoracic to 3rd lumbar vertebrae (Fig. 38.1).1 The right kidney normally is situated lower than the left, presumably because of the position of the liver. In the adult, each kidney is approximately 10 to 12 cm long, 5 to 6 cm wide, and 2.5 cm deep and weighs approximately 113 to 170 g.1 The medial border of the kidney is indented by a deep fissure called the

hilus. It is here that blood vessels and nerves enter and leave the kidney. The ­ureters, which connect the kidneys with the bladder, also enter the kidney at the hilus.2 The kidney is a multilobular structure, composed of between 8 and 18 lobes.2 Each lobe is composed of nephrons, which are the functional units of the kidney. Each kidney contains approximately 800,000 to 1,000,000 nephrons.2 Each nephron has a glomerulus that filters the blood and a system of tubular structures that selectively reabsorb material from the filtrate back into the blood and secrete materials from the blood into the filtrate as urine is being formed. On longitudinal section, a kidney can be divided into an outer cortex and an inner medulla (Fig. 38.2). The cortex, which is reddish-brown, contains the glomeruli and convoluted tubules of the nephron and blood vessels. The medulla consists of light-colored, cone-shaped masses—the renal pyramids. The columns of cortex that extend into the medulla divide the renal pyramids. Each pyramid, topped by a region of cortex, forms a lobe of the kidney. The apices of the pyramids form the papillae (i.e., 8 to 18 per kidney, corresponding to the number of lobes), which are perforated by the openings of the collecting ducts.2 The renal pelvis is a wide, funnel-shaped structure at the upper end of the ureter. It is made up of the calyces or cuplike structures that drain the upper and lower halves of the kidney.1,2 The kidney is sheathed in a fibrous external capsule and surrounded by a mass of fatty connective tissue, especially at its ends and borders. The adipose tissue protects the kidney from mechanical blows and assists, together with the attached blood vessels and fascia, in holding the kidney in place. Although the kidneys are relatively well protected, they may be bruised by blows to the loin or by compression between the lower ribs and the ileum. The kidneys are located outside the peritoneal cavity. Therefore, injury and rupture do not produce the same threat of peritoneal involvement as that of other organs such as the liver or spleen.

Renal cortex Renal blood vessel Renal medulla Renal papillae Renal column (Bertin) Renal pelvis

Calyx (cut edge)

Renal artery Calyx

Capsule

Ureter

FIGURE 38.2  •  Internal structure of the kidney.

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1000   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Renal Blood Supply A single renal artery that arises on either side of the aorta supplies each kidney. As the renal artery approaches the kidney, it divides into five segmental arteries that enter the hilus of the kidney. In the kidney, each segmental artery branches into several lobular arteries that supply the upper, middle, and lower parts of the kidney.2 The lobular arteries further subdivide to form the interlobular arteries at the level of the corticomedullary junction (Fig. 38.3). These arteries give off branches, the arcuate arteries, which arch across the top of the pyramids. Small intralobular arteries radiate from the ­arcuate arteries to supply the cortex of the kidney. The afferent arterioles that supply the glomeruli arise from the intralobular arteries.3 Although nearly all the blood flow to the kidneys passes through the cortex, less than 10% is directed to the medulla and only approximately 1% goes to the papillae.2 Under conditions of decreased perfusion or increased sympathetic ­nervous system stimulation, blood flow is redistributed away from the cortex toward the medulla. This redistribution of blood flow decreases glomerular filtration while maintaining the ­urine-concentrating ability of the kidneys, a factor that is important during conditions such as shock.

The Nephron Each kidney is composed of more than approximately 1 million tiny, closely packed functional units called nephrons

(Fig. 38.4A).2 The kidney has no ability to regenerate n­ ephrons. Therefore, with aging, there is a generalized decrease in functioning nephrons.2 In fact, adults tend to lose approximately 10% of their nephrons each decade beginning at 40  years of age.2 Each nephron consists of a glomerulus, a proximal convoluted tubule, a loop of Henle, a distal convoluted tubule, and a collecting duct. Blood is filtered in the glomerulus. In the proximal tubule, loop of Henle, distal tubule, and ­collecting duct, water, electrolytes, and other substances needed to maintain the constancy of the internal environment are reabsorbed into the bloodstream, while other unneeded materials are secreted into the tubular filtrate for elimination. Nephrons can be roughly grouped into two categories— cortical nephrons and juxtamedullary nephrons. Cortical nephrons make up approximately 85% of the nephrons and originate in the superficial part of the cortex2 (see Fig. 38.4B). Cortical nephrons have short, thick loops of Henle that penetrate only a short distance into the medulla. The remaining 15% are juxtamedullary nephrons.2 These nephrons originate deeper in the cortex and have longer and thinner loops of Henle that penetrate the entire length of the medulla. The juxtamedullary nephrons are largely concerned with urine concentration.2 Two capillary systems supply the nephrons—the glomerulus and the peritubular capillary network (see Fig. 38.4A). The glomerulus is a unique, high-pressure capillary filtration

RENAL LOBE

Afferent arteriole Efferent arteriole

Renal corpuscle

Distal tubule

Glomerular capsule Glomerulus

Cortex

Proximal tubule Interlobular artery Arcuate artery

Medulla

Interlobar artery and vein

Descending limb Ascending limb Nephron loop of Henle

Collecting duct

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FIGURE 38.3  •  Arterial supply of the kidney. (From Rubin E., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p.754). Philadelphia, PA: Lippincott ­Williams & Wilkins.)

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Chapter 38  Structure and Function of the Kidney    1001

system located between two arterioles, the afferent and the efferent arterioles. Because the arterioles are high-resistance vessels and the afferent arteriole has a larger diameter than the efferent arteriole, the blood pressure in the glomerulus is extraordinarily high for a capillary bed and easily forces fluid and solutes out of the blood into the glomerular capillary along its entire length.2 The peritubular capillaries originate from the efferent arteriole. They are low-pressure vessels that are adapted for reabsorption rather than filtration.2 These capillaries surround all portions of the tubules, an arrangement that permits rapid movement of solutes and water between the fluid in the tubular lumen and the blood in the capillaries. In the deepest part of the renal cortex, the efferent arterioles serving the juxtaglomerular glomeruli also continue into long, thin-walled looping vessels called the vasa recta.2 The vasa recta accompany the long loops of Henle in the medullary portion of the kidney to assist in exchange of substances flowing in and out of that portion of the kidney.2 The peritubular capillaries rejoin to form the venous channels by which blood leaves the kidneys and empties into the inferior vena cava.2

Key Points THE NEPHRON •  The nephron, which is the functional unit of the kidney, is composed of a vascular component, which connects to the circulatory system, and a tubular component, which has connections to both the circulatory system and the elimination functions of the kidney. •  The tubular portion of the nephron processes the glomerular filtrate (urine), facilitating the reabsorption of substances from the tubular fluid into the peritubular capillaries and the secretion of substances from the peritubular capillaries into the urine filtrate.

The Glomerulus The glomerulus consists of a compact tuft of capillaries encased in a thin, double-walled capsule called Bowman capsule.2 Blood flows into the glomerular capillaries from the afferent arteriole and flows out of the glomerular capillaries

Proximal convoluted tubule Efferent arteriole

Bowman capsule Juxtaglomerular apparatus

Glomerulus

Afferent arteriole Interlobular artery Interlobular vein

Distal convoluted tubule

Cortex

Cortex Medulla Outer stripe

Collecting tubule Descending limb

Peritubular capillary

Inner stripe

Outer medulla

Ascending limb

Inner medulla

Loop of Henle

A

To papilla

B

FIGURE 38.4  • (A) Nephron showing the glomerular and tubular structures along with the blood supply. (B) Comparison of differences in location of tubular structures of the cortical and juxtamedullary nephrons.

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1002   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

into the efferent arteriole, which leads into the peritubular capillaries. Fluid and particles from the blood are filtered through the capillary membrane into a fluid-filled space in Bowman capsule, called Bowman space. The portion of the blood that is filtered into the capsule space is called the filtrate.2 The mass of capillaries and its surrounding epithelial capsule are collectively referred to as the renal corpuscle (Fig. 38.5A).2 The glomerular capillary membrane is composed of three layers: 1. Capillary endothelial layer 2. Basement membrane 3. Single-celled capsular epithelial layer (see Fig. 38.5B) The endothelial layer lines the glomerulus and interfaces with blood as it moves through the capillary. This layer contains many small perforations called fenestrations.4 The epithelial layer that covers the glomerulus is continuous with the epithelium that lines Bowman capsule. The cells of the epithelial layer have unusual octopus-like structures that possess a large number of extensions, or foot processes (i.e., podocytes), which are embedded in the basement membrane (see Fig. 38.5B). These foot processes form slit pores through which the glomerular filtrate passes.4 The basement membrane consists of a homogeneous acellular meshwork of collagen fibers, glycoproteins, and mucopolysaccharides (see Fig. 38.5C). The endothelial and epithelial layers of the glomerular capillary have porous structures, and thus the basement membrane determines the permeability of the glomerular capillary membrane. The spaces between the fibers that make up the basement membrane represent the pores of a filter and determine the sizedependent permeability barrier of the glomerulus. The size of the pores in the basement membrane normally prevents red blood cells and plasma proteins from passing through the glomerular membrane into the filtrate. There is evidence that the epithelium plays a major role in producing the basement membrane components, and the epithelial cells probably are active in forming new basement membrane material ­throughout life. Alterations in the structure and function of the glomerular basement membrane are responsible for the leakage of proteins and blood cells into the filtrate that occurs in many forms of glomerular disease.2 Another important component of the glomerulus is the mesangium.4 In some areas, the capillary endothelium and the basement membrane do not completely surround each capillary. Instead, the mesangial cells, which lie between the capillary tufts, provide support for the glomerulus in these areas (see Fig. 38.5B).4 The mesangial cells produce an intercellular substance similar to that of the basement membrane. This substance covers the endothelial cells where they are not covered by basement membrane.4 The mesangial cells possess phagocytic properties and remove macromolecular materials that enter the intercapillary spaces. Mesangial cells also exhibit contractile properties in response to neurohumoral substances and are thought to

Porth9781451146004-ch038.indd 1002

Proximal tubule Efferent arteriole

Bowman space

A

Afferent arteriole Mesangial matrix

Mesangial cell

Epithelial podocytes Endothelial cell Basement membrane

Glomerular capsule

Bowman space

B

Bowman's space

Lumen of capillary

C

Glomerular basement membrane

Epithelial foot processes

Endothelium

FIGURE 38.5 •  Renal corpuscle. (A) Structures of the glomerulus. (B) Cross section of the glomerular membrane showing the position of the endothelium, basement membrane, and epithelial foot processes. (C) Position of the mesangial cells in relation to the capillary loops and Bowman capsule.

contribute to the regulation of blood flow through the glomerulus. In normal glomeruli, the mesangial area is narrow and contains only a small number of cells. Mesangial hyperplasia and increased mesangial matrix occur in a number of glomerular diseases.4

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Chapter 38  Structure and Function of the Kidney    1003

Tubular Components of the Nephron As stated above, the nephron tubule is divided into four segments: 1. A highly coiled segment called the proximal convoluted tubule, which drains Bowman capsule 2. A thin, looped structure called the loop of Henle 3. A distal coiled portion called the distal convoluted tubule 4. A collecting tubule, which joins with several tubules to collect the filtrate4 The filtrate passes through each of these segments before reaching the pelvis of the kidney. The proximal tubule is a highly coiled structure that dips toward the renal pelvis to become the descending limb of the loop of Henle. The ascending loop of Henle returns to the region of the renal corpuscle, where it becomes the distal tubule.4 The distal convoluted tubule, which begins at the juxtaglomerular complex, is divided into two segments—the diluting segment and the late distal tubule. The late distal tubule fuses with the collecting tubule. Like the distal tubule, the collecting duct is divided into two segments—the cortical collecting tubule and the inner medullary collecting tubule.4 Throughout its course, the tubule is composed of a single layer of epithelial cells resting on a basement membrane. The structure of the epithelial cells varies with tubular ­function. The cells of the proximal tubule have a fine, villous structure that increases the surface area for reabsorption. They also are rich in mitochondria, which support active transport processes. The epithelial layer of the thin segment of the loop of Henle has few mitochondria, indicating minimal metabolic activity and reabsorptive function.4

Urine Formation Urine formation involves the filtration of blood by the glomerulus to form an ultrafiltrate of urine and the tubular reabsorption of electrolytes and nutrients needed to maintain the constancy of the internal environment while eliminating waste materials. Glomerular Filtration Urine formation begins with the filtration of essentially protein-free plasma through the glomerular capillaries into Bowman space. The movement of fluid through the glomerular capillaries is determined by the same factors (i.e., capillary filtration pressure, colloidal osmotic pressure, and capillary permeability) that affect fluid movement through other capillaries in the body.2 The glomerular filtrate has a chemical composition similar to plasma, but it contains almost no proteins because large molecules do not readily cross the glomerular wall. Approximately 125 mL of filtrate is formed each minute.4 This is called the glomerular filtration rate (GFR). This rate can vary from a few milliliters per minute to as high as 200 mL/minute. The average adult has a GFR of 125 mL/ minute or 180 L/day.2

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The location of the glomerulus between two arterioles allows for maintenance of a high-pressure filtration system. The capillary filtration pressure (approximately 60 mm Hg) in the glomerulus is approximately two to three times higher than that of other capillary beds in the body. The filtration pressure and the GFR are regulated by the constriction and relaxation of the afferent and efferent arterioles. Constriction of the efferent arteriole increases resistance to outflow from the glomeruli and increases the glomerular pressure and the GFR. Constriction of the afferent arteriole causes a reduction in the renal blood flow, glomerular filtration pressure, and GFR.2 The afferent and the efferent arterioles are innervated by the sympathetic nervous system and are sensitive to vasoactive hormones, such as angiotensin II, as well. During periods of strong sympathetic stimulation, such as shock, constriction of the afferent arteriole causes a marked decrease in renal blood flow and thus glomerular filtration pressure. Consequently, urine output can fall almost to zero.2 Tubular Reabsorption and Secretion From Bowman capsule, the glomerular filtrate moves into the tubular segments of the nephron. In its movement through the lumen of the tubular segments, the glomerular filtrate is changed considerably by the tubular transport of water and ­solutes. Tubular transport can result in r­eabsorption of ­substances from the tubular fluid into the peritubular c­ apillaries or secretion of substances into the tubular fluid from the blood in the peritubular capillaries2 (Fig. 38.6). The basic mechanisms of transport across the tubular epithelial cell membrane are similar to those of other cell membranes in the body and include active and passive transport mechanisms. Water and urea are passively absorbed along concentration gradients. Sodium, K+, chloride (Cl−), calcium (Ca++), and phosphate (PO4−) ions, as well as urate, glucose, and amino acids are reabsorbed using primary or secondary active transport mechanisms to move across the tubular membrane. Some substances, such as hydrogen, potassium, and urate ions, are secreted into the tubular fluids. Under normal conditions, only approximately 1 mL of the 125 mL of glomerular filtrate that is formed each minute is excreted in the urine.2 The other 124 mL is reabsorbed in the tubules. This means that the average output of urine is approximately 60 mL/hour. Renal tubular cells have two membrane surfaces through which substances must pass as they are reabsorbed from the tubular fluid. The outside membrane that lies adjacent to the interstitial fluid is called the basolateral membrane, and the side that is in contact with the tubular lumen and tubular filtrate is called the luminal membrane.4 In most cases, ­substances move from the tubular filtrate into the tubular cell along a concentration gradient, but they require facilitated transport or carrier systems to move across the basolateral membrane into the interstitial fluid, where they are absorbed into the peritubular capillaries. The bulk of energy used by the kidney is for active sodium transport mechanisms that facilitate sodium ­reabsorption and

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1004   UNIT X  Disorders of Renal Function and Fluids and Electrolytes Peritubular capillary

Proximal tubular cell

Blood

Glomerulus

Tubular lumen Tubular fluid

H2O Na+

Na+ K+

Bowman capsule Glomerular filtrate

ATP

Reabsorption

Peritubular capillary Glucose Amino acids

Tubule

Na+ H+

Secretion Basolateral cell membrane

To blood To urine FIGURE 38.6  •  Reabsorption and secretion of substances between the renal tubules and peritubular capillaries.

cotransport of other electrolytes and substances such as glucose and amino acids. This is called secondary active transport or cotransport (Fig. 38.7). Secondary active transport depends on the energy-dependent Na+/K+-adenosine triphosphatase (ATPase) pump on the basolateral side of renal tubular cells.2 The pump maintains a low intracellular sodium concentration that facilitates the downhill (i.e., from a higher to lower concentration) movement of sodium from the filtrate across the luminal membrane. Cotransport uses a carrier system in which the downhill movement of one substance such as sodium is coupled to the uphill movement (i.e., from a lower to higher concentration) of another substance such as glucose or an amino acid. A few substances, such as the hydrogen (H+) ion, are secreted into the tubule using countertransport, in which the movement of one substance, such as sodium, enables the movement of a second substance in the opposite direction.2 Proximal Tubule.  Approximately 65% of all reabsorptive and secretory processes that occur in the tubular system take place in the proximal tubule. There is almost complete reabsorption of nutritionally important substances, such as ­glucose, amino acids, lactate, and water-soluble vitamins (Fig. 38.8). Electrolytes, such as Na+, K+, Cl−, and b­ icarbonate (HCO3−), are 65% to 80% reabsorbed.2 As these solutes move into the tubular cells, their concentration in the tubular lumen

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Glucose Amino acids

K+

Luminal cell membrane

FIGURE 38.7 • Mechanism for secondary active transport or cotransport of glucose and amino acids in the proximal tubule. The energy-dependent sodium–potassium pump on the basal lateral surface of the cell maintains a low intracellular gradient that facilitates the downhill movement of sodium and glucose or amino acids (cotransport) from the tubular lumen into the tubular cell and then into the peritubular capillary.

decreases, providing a concentration gradient for the osmotic reabsorption of water and urea. The proximal tubule is highly permeable to water, and the osmotic movement of water occurs so rapidly that the concentration difference of solutes on either side of the membrane seldom is more than a few milliosmoles.2 Many substances, such as glucose, are freely filtered in the glomerulus and reabsorbed by energy-dependent cotransport carrier mechanisms. The maximum amount of substance that these transport systems can reabsorb per unit time is called the transport maximum. The transport maximum is related to the number of carrier proteins that are available for transport and usually is sufficient to ensure that all of a filtered substance such as glucose can be reabsorbed rather than being eliminated in the urine. The plasma level at which the substance appears in the urine is called the renal threshold. Under some circumstances, the amount of substance filtered in the glomerulus exceeds the transport maximum. For example, when the blood glucose level is elevated in uncontrolled diabetes mellitus, the amount that is filtered in the glomerulus often exceeds the transport maximum (approximately 320 mg/minute), and glucose spills into the urine.2 In addition to reabsorbing solutes and water, cells in the proximal tubule also secrete organic cations and anions into the urine filtrate (see Figs. 38.6 and 38.8). Many of these organic anions and cations are end products of metabolism (e.g., urate, oxalate) that circulate in the plasma. The proximal tubule also secretes exogenous organic compounds such as

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Chapter 38  Structure and Function of the Kidney    1005

Proximal tubule • Reabsorption: Na+, Cl–, HCO3–, K+, H2O, glucose, amino acids • Secretion: H+, organic acids and bases

Early distal tubule • Reabsorption: Na+, Cl–, Ca++, Mg++

Late distal tubule and collecting duct • Principal cells Reabsorption: Na+Cl– Secretion: K+; ADH-mediated H2O reabsorption • Intercalated cells Reabsorption: HCO3–, K+ Secretion: H+

Thin descending loop of Henle • Reabsorption: H2O

Thick ascending loop of Henle • Reabsorption: Na+, Cl–, K+, Ca++, HCO3–, Mg++ • Secretion: H+

FIGURE 38.8  •  Sites of tubular water (H2O), glucose, amino acids, Na+ (sodium), Cl− (chloride), HCO3− (bicarbonate), K+ (potassium), Ca++ (calcium), and Mg++ (magnesium) reabsorption, and organic acids and bases, H+ (hydrogen), and K+ secretion.

penicillin, aspirin, and morphine. Many of these compounds can be bound to plasma proteins and are not freely filtered in the glomerulus. Therefore, excretion by filtration alone eliminates only a small portion of these potentially toxic substances from the body.2 The Loop of Henle.  The loop of Henle plays an important role in controlling the concentration of the urine. It does this by establishing a high concentration of osmotically active particles in the interstitium surrounding the medullary collecting tubules where the antidiuretic hormone (ADH) exerts its effects. The loop of Henle is divided into three segments—the thin descending segment, the thin ascending segment, and the thick ascending segment. The loop of Henle, taken as a whole, always reabsorbs more sodium and chloride than water. This is in contrast to the proximal tubule, which reabsorbs sodium and water in equal proportions. The thin descending limb is highly permeable to water and moderately permeable to urea, sodium, and other ions. As the urine filtrate moves down the descending limb, water moves out of the filtrate into the surrounding interstitium. Thus, the osmolality of the filtrate reaches its highest point at the elbow of the loop of Henle. In contrast to the descending limb, the ascending limb of the loop of Henle is impermeable to water.2 In this segment, solutes are reabsorbed, but water cannot follow and remains in the filtrate. As a result, the tubular filtrate becomes more and more dilute, often reaching an osmolality of 100 mOsm/kg of H2O as it enters the distal convoluted tubule, compared with the 285 mOsm/kg of H2O in plasma.2 This allows for excretion of free water from the body. For this reason, it is often called the diluting segment.2 The thick segment of the loop of Henle begins in the ascending limb where the epithelial cells become thickened. As with the thin ascending limb, this segment is impermeable

Porth9781451146004-ch038.indd 1005

to water. The thick segment contains a Na+/K+/2Cl− cotransport system4 (Fig. 38.9). This system involves the cotransport of a positively charged Na+ and a positively charged K+ ion accompanied by two negatively charged Cl− ions. The gradient for the operation of this cotransport system is provided by the basolateral Na+/K+-ATPase pump, which maintains a low intracellular sodium concentration. Approximately 20% to 25% of the filtered load of sodium, potassium, and chloride is reabsorbed in the thick loop of Henle. Movement of these ions out of the tubule leads to the development of a transmembrane

Peritubular capillary

Thick ascending loop of Henle cell

Tubular lumen Tubular fluid

Blood

H2O

Na+

Na+ 2Cl– K+

ATP

K+ Cl– K+

Basolateral cell membrane

Luminal cell membrane

FIGURE 38.9 • Sodium, chloride, and potassium reabsorption in the thick segment of the loop of Henle.

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1006   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

potential that favors the passive reabsorption of small divalent cations such as calcium and magnesium.4 The thick ascending loop of Henle is the site of the powerful “loop” diuretics (e.g., furosemide [Lasix]), which exert their action by inhibiting the Na+/K+/2Cl− cotransporters. Distal and Collecting Tubules. Like the thick ascending loop of Henle, the distal convoluted tubule is relatively impermeable to water, and reabsorption of sodium chloride from this segment further dilutes the tubular fluid. Sodium reabsorption occurs through a Na+/Cl− cotransport mechanism. Approximately 5% of filtered sodium chloride is reabsorbed in this section of the tubule. Unlike the thick ascending loop of Henle, neither Ca++ nor Mg++ is passively absorbed in this segment of the tubule. Instead, Ca++ ions are actively reabsorbed in a process that is largely regulated by parathyroid hormone and possibly by vitamin D. The thiazide diuretics exert their action by inhibiting sodium chloride reabsorption in this segment of the renal tubules. The late distal tubule and the cortical collecting tubule constitute the site where aldosterone exerts its action on sodium reabsorption and potassium secretion and elimination. Although responsible for only 2% to 5% of sodium chloride reabsorption, this site is largely responsible for determining the final sodium concentration of the urine.2 The late distal tubule with the cortical collecting tubule also is the major site for regulation of potassium excretion by the kidney. When the body is confronted with a potassium excess, as occurs with a diet high in potassium content, the amount of p­ otassium secreted at this site may exceed the amount filtered in the glomerulus. The mechanism for sodium reabsorption and potassium secretion in this section of the nephron is distinct from other tubular segments. This tubular segment is composed of two types of cells, the intercalated cells, where potassium is reabsorbed and hydrogen is secreted, and the ­principal cells, where aldosterone exerts its action.4 The secretion of H+ ions into the tubular fluid by the intercalated cells is accompanied by the reabsorption of HCO3− ions. The intercalated cells can also reabsorb K+ ions. The principal cells reabsorb Na+ and facilitate the movement of K+ into the urine filtrate (Fig. 38.10). Under the influence of aldosterone, sodium moves from the urine filtrate into principal cells; from there, it moves into the surrounding interstitial fluid and peritubular capillaries. Potassium moves from the peritubular capillaries into the principal cells and then into the urine filtrate.4 Regulation of Urine Concentration The kidney responds to changes in the osmolality of the extracellular fluids by producing either concentrated or dilute urine. The ability of the kidney to respond in this manner depends on the establishment of a high concentration of osmotically active particles (approximately 1200 mOsm/kg of H2O) in the interstitium of the kidney medulla and the action of the ADH in regulating the water permeability of the surrounding medullary collecting tubules (see Understanding: How the Kidney Concentrates Urine).4

Porth9781451146004-ch038.indd 1006

Peritubular capillary

Collecting duct principal cell

Tubular lumen Tubular urine

Blood

Na+ K+

Na+

ATP

K+

Basolateral cell membrane

Luminal cell membrane

FIGURE 38.10  •  Mechanism of sodium reabsorption and potassium secretion by principal cells of the late distal and collecting tubules. Aldosterone exerts its action by increasing the activity of the Na+/K+-ATPase pump that transports sodium outward through the basolateral membrane of the cell and into the blood at the same time it pumps potassium into the cell. Aldosterone also increases the permeability of the luminal membrane for potassium.

In approximately one fifth of the juxtamedullary n­ ephrons, the loops of Henle and special hairpin-shaped capillaries called the vasa recta descend into the medullary portion of the kidney. There they form a countercurrent system that controls water and solute movement so that water is kept out of the area surrounding the tubule and solutes are retained.4 The term countercurrent refers to a flow of fluids in opposite directions in adjacent structures. In this case, there is an exchange of solutes between the adjacent descending and ascending loops of Henle and between the ascending and descending sections of the vasa recta. Because of these exchange processes, a high concentration of osmotically active particles (approximately 1200 mOsm/ kg of H2O) collects in the interstitium of the kidney medulla. The presence of these osmotically active particles in the interstitium surrounding the medullary collecting tubules facilitates the ADH-mediated reabsorption of water4 (Fig. 38.11). ADH assists in maintenance of the extracellular fluid volume by controlling the permeability of the medullary collecting tubules. Osmoreceptors in the hypothalamus sense an increase in osmolality of extracellular fluids and stimulate the release of ADH from the posterior pituitary gland. In exerting its effect, ADH, also known as vasopressin, binds to receptors on the basolateral side of the tubular cells.4 Binding of ADH to the vasopressin receptors causes water channels, known as aquaporin-2 channels, to move into the luminal side of the tubular cell membrane, producing a marked increase in water permeability. At the basolateral side of the membrane, water

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Understanding

How the Kidney Concentrates Urine

The osmolarity of body fluids relies heavily on the ability of the kidney to produce dilute or concentrated urine. Urine concentration depends on three factors: (1) the osmolarity of interstitial fluids in the urine-concentrating part of the kidney, (2) the antidiuretic hormone (ADH), and (3) the action of ADH on the cells in the collecting tubules of the kidney.

NaCl

H2O H2O

K+

300

Na+

Cortex

In approximately one fifth of the juxtamedullary nephrons, the loops of Henle and special hairpin-shaped capillaries called the vasa recta descend into the medullary portion of the kidney to form a countercurrent system—a set of parallel passages in which the contents flow in opposite directions. The countercurrent design serves to increase the osmolarity in this part of the kidney by promoting the exchange of solutes between the adjacent descending and ascending loops of Henle and between the descending and ascending sections of the vasa recta. Because of these exchange processes, a high concentration of osmotically active particles (approximately 1200 mOsm/kg of H2O) collects in the interstitium ­surrounding the collecting tubules where the ADH-mediated reabsorption of water takes place.

Osmolality (mOsm)

H2O NaCl H2O

NaCl Urea

NaCl

H 2O

H2O

NaCl Urea

600 NaCl Urea

800

H2O

NaCl Urea

NaCl NaCl H2O Urea

H 2O

Vasa recta 1200

Antidiuretic Hormone

Medulla

Osmolarity

Loop of Henle

Collecting tubule

Hypothalamus

ADH, which regulates the ability of the kidneys to concentrate urine, is synthesized by neurons in the hypothalamus and transported down their axons to the posterior pituitary gland and then released into the circulation. One of the main stimuli for synthesis and release of ADH is an increase in serum osmolarity. ADH release is also controlled by cardiovascular reflexes that respond to changes in blood pressure or blood volume.

Osmoreceptors

Posterior pituitary gland

ADH

Urine: decreased flow and concentrated

Continued

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1008   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Understanding

How the Kidney Concentrates Urine (Continued)

Action of ADH ADH, also known as vasopressin, acts at the level of the collecting tubule to increase water absorption. It exerts its action by binding to vasopressin receptors on the basolateral membrane of the tubular cell. Binding of ADH to the vasopressin receptors causes water channels (aquaporin-2 channels) to move into the luminal side of the cell membrane, which is normally impermeable to water. Insertion of the channels allows water from the tubular fluids to move into the tubular cell and then out into the surrounding hyperosmotic interstitial fluid on the basolateral side of the cell, and from there it moves into the peritubular capillaries for return to the circulatory system. Thus, when ADH is present, the water that moved from the blood into the urine filtrate in the glomeruli is returned to the circulatory system, and when ADH is absent, the water is excreted in the urine.

exits the tubular cell into the hyperosmotic interstitium of the medullary area, where it enters the peritubular capillaries for return to the vascular system.4

Regulation of Renal Blood Flow In the adult, the kidneys are perfused with 1000 to 1300 mL of blood per minute, or 20% to 25% of the cardiac output. This large blood flow is mainly needed to ensure a sufficient GFR for the removal of waste products from the blood, rather than for the metabolic needs of the kidney. Feedback mechanisms, both intrinsic (e.g., autoregulation, local hormones) and extrinsic (e.g., sympathetic nervous system, blood-borne hormones), normally keep blood flow and GFR constant despite changes in arterial blood pressure.2 Neural and Humoral Control Mechanisms The kidney is richly innervated by the sympathetic nervous system. Increased sympathetic activity causes constriction of the afferent and efferent arterioles and thus a decrease in renal blood flow. Intense sympathetic stimulation such as occurs in shock and trauma can produce marked decreases in renal blood flow and GFR, even to the extent of causing blood flow to cease altogether.

Porth9781451146004-ch038.indd 1008

Basolateral Blood

Vasopressin receptor

Luminal

Collecting duct epithelium

Tubular urine

Cyclic AMP Aquaporin-2 channels

ADH ATP

H2O

H 2O

H2O

Several humoral substances, including angiotensin II, ADH, and the endothelins, produce vasoconstriction of renal vessels. The endothelins are a group of peptides released from damaged endothelial cells in the kidney and other tissues.2 Although not thought to be an important regulator of renal blood flow during everyday activities, endothelin 1 (ET-1) may play a role in reduction of blood flow in conditions such as postischemic acute renal failure.4 In this situation, ET-1 can be a most potent vasoconstrictor and worsen the acute renal failure. Other substances such as dopamine, nitric oxide, and prostaglandins (i.e., E2 and I2) produce vasodilation. Nitric oxide, a vasodilator produced by the vascular endothelium, appears to be important in preventing excessive vasoconstriction of renal blood vessels and allowing normal excretion of sodium and water. Prostaglandins are a group of mediators of cell function that are produced locally and exert their effects locally. Although prostaglandins do not appear to be of major importance in regulating renal blood flow and GFR under ­normal conditions, they may protect the kidneys against the vasoconstricting effects of sympathetic stimulation and angiotensin II.4 Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthesis may cause reduction in renal blood flow and GFR under certain conditions and should be used cautiously with people who have hypertension.5

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Chapter 38  Structure and Function of the Kidney    1009

Hypotension or hypovolemia

Renal hypoperfusion

Afferent arteriolar stretch

NaCl delivery to macula densa Renin release

Renin substrate (angiotensinogen)

Angiotensin I

Angiotensin II

Sympathetic neural tone (baroreceptors) Converting enzyme

Aldosterone secretion

Renal Na+ reabsorption FIGURE 38.11  •  Pathway of angiotensin production. (From Rennke H. G., Denker B. M. (2010). Renal pathophysiology: The essentials (3rd ed., p. 50). Philadelphia, PA: Lippincott Williams & Wilkins.)

Autoregulatory Mechanisms A process called autoregulation maintains the constancy of renal blood flow. Normally, autoregulation of blood flow is designed to maintain blood flow at a level consistent with the metabolic needs of the tissues. In the kidney, autoregulation of blood flow also must allow for precise regulation of solute and water excretion. For autoregulation to occur, the resistance to blood flow through the kidneys must be varied in direct proportion to the arterial pressure. The exact mechanisms responsible for the intrarenal regulation of blood flow are unclear. One of the proposed mechanisms is a direct effect on vascular smooth muscle that causes the blood vessels to relax when there is an increase in blood pressure and to constrict when there is a decrease in pressure. A second proposed mechanism is the juxtaglomerular complex.2 The Juxtaglomerular Complex.  The juxtaglomerular complex is thought to represent a feedback control system that links changes in the GFR with renal blood flow. The juxtaglomerular complex is located at the site where the distal tubule extends back to the glomerulus and then passes between the afferent and efferent arterioles2 (Fig. 38.12A). The distal tubular site that is nearest to the glomerulus is characterized by densely nucleated cells called the macula densa.2 In the adjacent afferent arteriole, the smooth muscle cells of the media are modified as special secretory cells called ­juxtaglomerular cells. These cells contain granules of inactive renin, an enzyme that functions in the conversion of angiotensinogen

Porth9781451146004-ch038.indd 1009

Systemic blood pressure (−)

Extracellular volume expansion

(−) Renin release

to angiotensin.2 Renin functions by means of angiotensin II to produce vasoconstriction of the efferent arteriole as a means of preventing large decreases in the GFR. Angiotensin II also increases sodium reabsorption indirectly by stimulating aldosterone secretion from the adrenal gland and directly by increasing sodium reabsorption by the proximal tubule cells. Because of its location between the afferent and efferent arterioles, the juxtaglomerular complex is thought to play an essential feedback role in linking the level of arterial blood pressure and renal blood flow to the GFR and the composition of the distal tubular fluid (see Fig. 38.12B). It is thought to monitor the systemic arterial blood pressure by sensing the stretch of the afferent arteriole and the concentration of sodium chloride in the tubular filtrate as it passes through the macula densa. This information is then used in determining how much renin should be released to keep the arterial blood pressure within its normal range and maintain a relatively constant GFR.2 It is thought that a decrease in the GFR slows the flow rate of the urine filtrate in the ascending loop of Henle, thereby increasing sodium and chloride reabsorption. This, in turn, decreases the delivery of sodium chloride to the macula densa. The decrease in delivery of sodium chloride to the macula densa has two effects: It decreases resistance in the afferent arterioles, which raises g­ lomerular filtration pressure, and it increases the release of renin from the juxtaglomerular cells. The renin from these cells functions as an enzyme to convert angiotensinogen to angiotensin I, which is converted to angiotensin II.2 Finally, angiotensin II acts to constrict the

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1010   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Juxtaglomerular apparatus

Renal sympathetic neurons Renin-producing granular cells Macula densa

Af fer e

Distal tubule

n re fe Ef

le rio r te a t

Extraglomerular mesangial cells

nt ar

r te e iol Bowman’s capsule

Bowman’s capsule

Glomerular mesangial cells

efferent arteriole as a means of producing a further increase in the glomerular filtration pressure and thereby returning the GFR toward a more normal range. Effect of Increased Protein and Glucose Load Even though renal blood flow and glomerular filtration are relatively stable under most conditions, two conditions can increase renal blood flow and glomerular filtration. These are an increased amount of protein in the diet and an increase in blood glucose. With ingestion of a high-protein diet, renal blood flow increases 20% to 30% within 1 to 2 hours. Although the exact mechanism for this increase is uncertain, it is thought to be related to the fact that amino acids and sodium are absorbed together in the proximal tubule (secondary active transport). As a result, delivery of sodium to the macula densa is decreased, which elicits an increase in renal blood flow through the juxtaglomerular complex feedback mechanism.2 The resultant increase in blood flow and GFR allows sodium excretion to be maintained at a near-normal level while increasing the ­excretion of the waste products of protein metabolism, such as urea. The same mechanism is thought to explain the large increases in renal blood flow and

Porth9781451146004-ch038.indd 1010

FIGURE 38.12  • Juxtaglomerular apparatus and macula densa in tubuloglomerular feedback. The juxtaglomerular apparatus and macula densa cells at the beginning of the distal tubule are in close ­proximity. Chloride delivery is sensed by the N+ K+ 2Cl− cotransporter in the thick ascending limb and feedback regulates GFR. Renin release is also regulated at this site. (From Rennke H. G., Denker B. M. (2010). Renal pathophysiology: The essentials (3rd ed., p. 21.). Philadelphia, PA: Lippincott Williams & Wilkins.)

GFR that occur with high blood glucose levels in people with uncontrolled diabetes mellitus.

Elimination Functions of the Kidney The functions of the kidney focus on elimination of water, waste products, excess electrolytes, and unwanted substances from the blood.2 Renal Clearance Renal clearance is the volume of plasma that is completely cleared each minute of any substance that finds its way into the urine. It is determined by the ability of the substance to be filtered in the glomeruli and the capacity of the renal tubules to reabsorb or secrete the substance. Every substance has its own clearance rate, the units of which are always volume of plasma per unit time. It can be determined by measuring the amount of a substance that is excreted in the urine (i.e., urine concentration × urine flow rate in milliliters per minute) and dividing by its plasma concentration.6 Inulin, a large polysaccharide, is freely filtered in the glomeruli and neither reabsorbed nor secreted by the tubular cells.2 After intravenous injection, the amount that appears in the urine is equal to the

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Chapter 38  Structure and Function of the Kidney    1011

amount that is filtered in the glomeruli (i.e., the clearance rate is equal to the GFR). Because of these properties, inulin can be used as a laboratory measure of the GFR.2 Some substances, such as urea, are freely filtered in the glomeruli, but the volume that is cleared from the plasma is less than the GFR, indicating that at least some of the substance is being reabsorbed. At normal plasma levels, glucose has a clearance of zero because it is reabsorbed in the tubules and none appears in the urine. Regulation of Sodium and Potassium Elimination Elimination of sodium and potassium is regulated by the GFR and by humoral agents that control their reabsorption. Aldosterone functions in the regulation of sodium and potassium elimination. Atrial natriuretic peptide (ANP) contributes to the regulation of sodium elimination. Sodium reabsorption in the distal tubule and collecting duct is highly variable and depends on the presence of aldosterone, a hormone secreted by the adrenal gland. In the presence of aldosterone, almost all the sodium in the distal tubular fluid is reabsorbed, and the urine essentially becomes sodium free. In the absence of aldosterone, virtually no sodium is reabsorbed from the distal tubule. The remarkable ability of the distal tubular and collecting duct cells to alter sodium reabsorption in relation to changes in aldosterone allows the kidneys to excrete urine with sodium levels that range from a few tenths of a gram to 40 g/day.2 Like sodium, potassium is freely filtered in the ­glomerulus, but unlike sodium, potassium is reabsorbed from and secreted into the tubular fluid. The secretion of potassium into the tubular fluid occurs in the distal tubule and, like that of sodium, is regulated by aldosterone. Only approximately 70  mEq of potassium is delivered to the distal tubule each day, but the average person consumes this much and more ­potassium in the diet. Excess potassium that is not filtered in the glomerulus and delivered to the collecting tubule therefore must be secreted (i.e., transported from the blood) into the tubular fluid for elimination from the body.2 In the absence of aldosterone, as in Addison disease, potassium secretion becomes minimal. In these circumstances, potassium reabsorption exceeds secretion, and blood levels of potassium increase. ANP, discovered in 1981, is a hormone believed to have an important role in salt and water excretion by the kidney. It is synthesized in muscle cells of the atria of the heart and released when the atria are stretched. The actions of ANP include vasodilation of the afferent and efferent arterioles, which results in an increase in renal blood flow and GFR. ANP inhibits aldosterone secretion by the adrenal gland and sodium reabsorption from the collecting tubules through its action on aldosterone and through direct action on the tubular cells.2 ANP also inhibits ADH release from the posterior pituitary gland, thereby increasing excretion of water by the kidneys. ANP also has vasodilator properties. Whether these effects are sufficient to produce long-term changes in blood pressure is uncertain.

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Regulation of pH The kidneys regulate body pH by conserving base bicarbonate and eliminating hydrogen ions (H+). Neither the blood buffer systems nor the respiratory control mechanisms for carbon dioxide elimination can eliminate hydrogen ions from the body. The kidneys accomplish this. Virtually all the hydrogen ions excreted in the urine are secreted into the tubular fluid by means of tubular secretory mechanisms. The lowest tubular fluid pH that can be achieved is 4.4 to 4.5.7 The ability of the kidneys to excrete hydrogen ions depends on buffers in the urine that combine with the hydrogen ion. The three major urine buffers are bicarbonate (HCO3−), phosphate (HPO4−), and ammonia (NH3). Bicarbonate ions, which are present in the urine filtrate, combine with hydrogen ions that have been secreted into the tubular fluid; this results in the formation of carbon dioxide and water. The carbon dioxide is then absorbed into the tubular cells and bicarbonate is regenerated. The phosphate ion is a metabolic end product that is filtered into the tubular fluid. It combines with a secreted hydrogen ion and is not reabsorbed. Ammonia is synthesized in tubular cells by deamination of the amino acid glutamine. It diffuses into the tubular fluid and combines with the hydrogen ion. An important aspect of this buffer system is that the deamination process increases whenever the body’s hydrogen ion concentration remains elevated for 1 to 2 days.2

Key Points THE FUNCTIONS OF THE KIDNEY •  The kidney regulates the composition and pH of body fluids through the reabsorption and elimination or conservation of sodium, potassium, hydrogen, chloride, and bicarbonate ions. •  It serves to regulate the osmolality of the extracellular fluid through the action of ADH. •  It plays a central role in blood pressure regulation through the renin–angiotensin–aldosterone mechanism and the regulation of salt and water elimination.

pH-Dependent Elimination of Organic Ions The proximal tubule actively secretes large amounts of different organic anions. Foreign anions (e.g., salicylates, ­ penicillin) and endogenously produced anions (e.g., bile acids, uric acid) are actively secreted into the tubular fluid. Most of the anions that are secreted use the same transport system, allowing the kidneys to rid the body of many different drugs and environmental agents.2 Because the same transport system is shared by different anions, there is competition for transport such that elevated levels of one substance tend to

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1012   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

inhibit the secretion of other anions. The proximal tubules also possess an active transport system for organic cations that is analogous to that for organic ions. Uric Acid Elimination Uric acid is a product of purine metabolism. Excessively high blood levels (i.e., hyperuricemia) can cause gout, and excessive urine levels can cause kidney stones. Uric acid is freely filtered in the glomerulus and is reabsorbed and secreted into the proximal tubules.3 Uric acid is one of the anions that use the previously described anion transport system in the proximal tubule. Tubular reabsorption normally exceeds secretion, and the net effect is removal of uric acid from the filtrate. Although the rate of reabsorption exceeds secretion, the secretory process is homeostatically controlled to maintain a constant plasma level. Many people with elevated uric acid levels secrete less uric acid compared to people with normal uric acid levels.3 Uric acid uses the same transport systems as other anions, such as aspirin, sulfinpyrazone, and probenecid. Small doses of aspirin compete with uric acid for secretion into the tubular fluid and reduce uric acid secretion, and large doses compete with uric acid for reabsorption and increase uric acid excretion in the urine. Because of its effect on uric acid secretion, aspirin is not recommended for treatment of gouty arthritis. Thiazide and loop diuretics (i.e., furosemide and ethacrynic acid) also can cause hyperuricemia and gouty arthritis, presumably through a decrease in extracellular fluid volume and enhanced uric acid reabsorption.4 Urea Elimination Urea is an end product of protein metabolism. The normal adult produces 25 to 30 g/day. The quantity rises when a high-protein diet is consumed, when there is excessive tissue breakdown, or in the presence of gastrointestinal bleeding.2 With gastrointestinal bleeding, the blood proteins are broken down to form ammonia in the intestine. The ammonia is then absorbed into the portal circulation and converted to urea by the liver before being released into the bloodstream. The kidneys, in their role as regulators of blood urea nitrogen (BUN) levels, filter urea in the glomeruli and then reabsorb it in the tubules. This enables maintenance of a normal BUN, which is in the range of 8 to 25 mg/dL (2.9 to 8.9 mmol/L).2 During periods of dehydration, the blood volume and GFR drop, and BUN levels increase. The renal tubules are permeable to urea, which means that the longer the tubular fluid remains in the kidneys, the greater is the reabsorption of urea into the blood. Only small amounts of urea are reabsorbed into the blood when the GFR is high, but relatively large amounts of urea are returned to the blood when the GFR is reduced. Drug Elimination Many drugs are eliminated in the urine. These drugs are selectively filtered in the glomerulus and reabsorbed or secreted

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into the tubular fluid. Only drugs that are not bound to plasma proteins are filtered in the glomerulus and therefore able to be eliminated by the kidneys. Many drugs are weak acids or weak bases and are present in the renal tubular fluid partly as water-soluble ions and partly as nonionized lipid-soluble molecules.8

Endocrine Functions of the Kidney In addition to their function in regulating body fluids and electrolytes, the kidneys function as an endocrine organ in that they produce chemical mediators that travel through the blood to distant sites where they exert their actions. The kidneys participate in control of blood pressure in the following ways: •• Via the renin–angiotensin–aldosterone mechanism •• Via regulation of red blood cell production through the synthesis of erythropoietin •• Via calcium metabolism by activating vitamin D The Renin–Angiotensin–Aldosterone Mechanism The renin–angiotensin–aldosterone mechanism plays an important part in short- and long-term regulation of blood pressure. Renin is an enzyme that is synthesized and stored in the juxtaglomerular cells of the kidney. This enzyme is thought to be released in response to a decrease in renal blood flow or a change in the composition of the distal tubular fluid, or as the result of sympathetic nervous system stimulation. Renin itself has no direct effect on blood pressure. Rather, it acts enzymatically to convert a circulating plasma protein called angiotensinogen to angiotensin I. Angiotensin I, which has few vasoconstrictor properties, leaves the kidneys and enters the circulation; as it is circulated through the lungs, ­angiotensin-converting enzyme catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor, and it acts directly on the kidneys to decrease salt and water excretion. Both mechanisms have relatively short periods of action. Angiotensin II also stimulates aldosterone secretion by the adrenal gland. Aldosterone acts on the distal tubule to increase sodium reabsorption and exerts a longerterm effect on the maintenance of blood pressure. Renin also functions via angiotensin II to produce constriction of the efferent arteriole as a means of preventing a serious decrease in glomerular filtration pressure.2 Erythropoietin Erythropoietin is a polypeptide hormone that regulates the differentiation of red blood cells in the bone marrow. Between 89% and 95% of erythropoietin is formed in the kidneys. The synthesis of erythropoietin is stimulated by tissue hypoxia, which may be brought about by anemia, residence at high altitudes, or impaired oxygenation of tissues due to cardiac or pulmonary disease. Persons with end-stage kidney disease often are anemic because of an inability of the k­ idneys

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Chapter 38  Structure and Function of the Kidney    1013

Action of Diuretics

to produce erythropoietin. This anemia usually is managed by the administration of a recombinant erythropoietin ­(epoetin alfa) p­ roduced through DNA technology to stimulate erythropoiesis.9

Diuretics are drugs that increase urine volume. Many diuretic agents (loop diuretics, thiazide diuretic, and potassium-­sparing diuretics) exert their effects by blocking the ­reabsorption of sodium in the renal tubules. Others exert osmotic effects that prevent water reabsorption in the water-permeable parts of the nephron.8

Vitamin D Activation of vitamin D occurs in the kidneys. Vitamin D increases calcium absorption from the gastrointestinal tract and helps to regulate calcium deposition in bone. It also has a weak stimulatory effect on renal calcium absorption. Although vitamin D is not synthesized and released from an endocrine gland, it often is considered as a hormone because of its pathway of molecular activation and mechanism of action. Vitamin D exists in two forms—natural vitamin D (cholecalciferol), produced in the skin from ultraviolet irradiation, and synthetic vitamin D (ergocalciferol), derived from irradiation of ergosterol. The active form of vitamin D is 1,25-dihydroxycholecalciferol. Cholecalciferol and ergocalciferol must undergo chemical transformation to become active: first to 25-hydroxycholecalciferol in the liver and then to 1,25-dihydroxycholecalciferol in the kidneys. People with end-stage renal disease are unable to transform vitamin D to its active form and may require pharmacologic preparations of the active vitamin (calcitriol) for maintaining mineralization of their bones.4 New research is in process to develop vitamin D compounds to assist people with chronic renal disease.10

Diuretics That Block Sodium Reabsorption Most diuretics share the same mechanism of action—­ blockade of sodium and chloride reabsorption. By blocking the reabsorption of these solutes, diuretics create an osmotic pressure gradient within the nephron that prevents the passive reabsorption of water. Thus, diuretics cause water and sodium to be retained in the nephron, thereby promoting the excretion of both. The increase in urine flow that a diuretic produces is related to the amount of sodium and chloride reabsorption that it blocks. Because the amount of sodium becomes progressively less as the urine filtrate flows from the proximal tubule to the collecting ducts, drugs that act early in the nephron have the opportunity to block the greatest amount of sodium reabsorption. Approximately 65% of sodium that is filtered in the glomeruli of the kidney is reabsorbed in the proximal tubule, 20% is reabsorbed in the thick ascending loop of Henle, 10% in the early distal convoluted tubule, and 2% to 5% is reabsorbed in the late distal and cortical collecting tubules (Fig. 38.13).4

Osmotic diuretics Proximal tubule Accounts for 65% of filtered sodium reabsorption Thiazide diuretics Early distal tubule Accounts for 10% of filtered sodium reabsorption Filtered sodium Potassium-sparing diuretics Late distal tubule Accounts for 2% to 5% of filtered sodium reabsorption

Loop diuretics Thick ascending loop of Henle Accounts for 20% of filtered sodium reabsorption

FIGURE 38.13  • Tubular sites of ­ iuretic action and percentage of ­sodium d reabsorption.

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Urine output

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1014   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

The so-called loop diuretics exert their effect in the thick ascending loop of Henle. Because of their site of action, these drugs are the most effective diuretic agents available. These drugs inhibit the coupled Na+/K+/2Cl− transport system on the luminal side of the ascending loop of Henle (see Fig. 38.10). By inhibiting this transport system, they reduce the reabsorption of sodium chloride, decrease potassium reabsorption, and increase calcium and magnesium elimination.8 Prolonged use can cause significant loss of magnesium in some people. Because calcium is actively reabsorbed in the distal convoluted tubule, loop diuretics usually do not cause hypocalcemia. The loop diuretics may also increase uric acid retention and impair glucose tolerance. The thiazide diuretics act by preventing the reabsorption of sodium chloride in the early distal convoluted tubule. Because of their site of action, the thiazide diuretics are less effective than loop diuretics in terms of effecting diuresis. The thiazide diuretics produce increased losses of potassium in the urine, uric acid retention, and some impairment in glucose tolerance. In contrast to the situation in the loop of Henle, where the loop diuretics inhibit calcium reabsorption, the thiazide diuretics actually enhance calcium reabsorption in the distal convoluted tubule.8 The aldosterone antagonists, also called potassiumsparing diuretics, reduce sodium reabsorption and decrease potassium secretion in the late distal tubule and cortical collecting tubule site regulated by aldosterone (see Fig. 38.11). Because potassium secretion is linked to sodium reabsorption in this segment of the tubule, these agents are also effective in reducing potassium excretion and may, in some cases, cause severe hyperkalemia. These agents also tend to interfere with secretion of hydrogen ions in the collecting duct, explaining in part the metabolic acidosis sometimes seen with the use of these agents.8 There are two types of potassium-sparing diuretics— those that act as direct aldosterone antagonists and those that act independently of aldosterone. The first type (e.g., spironolactone) binds to the mineralocorticoid receptor in the tubule, preventing aldosterone from entering the cell and exerting its effects. The second type (e.g., triamterene, amiloride) does not bind to the receptor, but instead directly interferes with sodium entry through the sodium-selective ion channel. The potassium-sparing diuretics produce only mild diuresis because they inhibit such a small percentage of sodium reabsorption. However, as the name implies, their main use is in combination with other diuretics to inhibit K+ secretion by the principal cells. These diuretics may also be used during states of mineralocorticoid (i.e., aldosterone) excess.8 Osmotic Diuretics The osmotic diuretics act in the proximal tubule and ascending loop of Henle, both of which are highly permeable to water. In contrast to the loop, thiazide, and ­potassium-sparing diuretics that exert their effects by blocking specific tubular Na+ transport mechanisms, the osmotic diuretics, which are filtered but not reabsorbed, cause water to be retained

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in the urine filtrate and promote water diuresis. One such agent, mannitol, is used mainly to reduce increased intracranial pressure but is occasionally used to promote prompt removal of toxins. Because it is not absorbed, mannitol must be given parenterally to act as a diuretic. If given orally, it causes osmotic diarrhea.8

IN SUMMARY The kidneys perform excretory and endocrine functions. In the process of excreting wastes, the kidneys filter the blood and then selectively reabsorb those materials that are needed to maintain a stable internal environment. The kidneys rid the body of metabolic wastes, regulate fluid volume, regulate the concentration of electrolytes, assist in maintaining acid–base balance, aid in regulation of blood pressure through the renin–angiotensin–­ aldosterone mechanism and control of extracellular fluid volume, regulate red blood cell production through erythropoietin, and aid in calcium metabolism by activating vitamin D. The nephron is the functional unit of the kidney. It is composed of a glomerulus, which filters the blood, and a tubular component, where electrolytes and other substances needed to maintain the constancy of the internal environment are reabsorbed back into the bloodstream, while unneeded materials are secreted into the tubular filtrate for elimination. Urine concentration occurs in the collecting tubules under the influence of ADH. ADH maintains extracellular volume by returning water to the v­ ascular compartment, producing concentrated urine by removing water from the tubular filtrate. The GFR is the amount of filtrate that is formed each minute as blood moves through the glomeruli. It is regulated by the arterial blood pressure and renal blood flow in the normally functioning kidney. The ­juxtaglomerular complex is thought to represent a feedback control system that links changes in the GFR with renal blood flow. Renal clearance is the volume of plasma that is completely cleared each minute of any substance that finds its way into the urine. It is determined by the ability of the substance to be filtered in the glomeruli and the capacity of the renal tubules to reabsorb or secrete the substance. Diuretics are drugs that increase urine volume. Many diuretic agents (loop diuretics, thiazide diuretics, and potassium-sparing diuretics) exert their effect by blocking the reabsorption of sodium at specific sites in the renal tubules. Others exert osmotic effects that prevent water reabsorption in the water-permeable parts of the nephron. The effectiveness of a diuretic is related to its site of action. Accordingly, diuretics such as the loop diuretics that act in the thick ascending loop of Henle, where approximately 20% of sodium reabsorption takes place, produce the greatest diuresis.

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Chapter 38  Structure and Function of the Kidney    1015

TESTS OF RENAL FUNCTION After completing this section of the chapter, you should be able to meet the following objectives: •• Explain the value of urine-specific gravity in evaluating renal function. •• Explain the concept of the glomerular filtration rate. •• Explain the value of serum creatinine and blood urea nitrogen levels in evaluating renal function.

The function of the kidneys is to filter the blood, selectively reabsorb those substances that are needed to maintain the constancy of body fluid, and excrete metabolic wastes. The composition of urine and blood provides valuable information about the adequacy of renal function. Radiologic tests, endoscopy, and renal biopsy afford means for viewing the gross and microscopic structures of the kidneys and urinary system.

Urine Tests Urine is a clear, amber-colored fluid that is approximately 95% water and 5% dissolved solids. The kidneys normally produce approximately 1.5 L of urine each day. Normal urine contains metabolic wastes and few or no plasma proteins, blood cells, or glucose molecules. Urine tests can be performed on a single urine specimen or on a 24-hour urine specimen. First-voided morning specimens are useful for qualitative protein and specific gravity testing. A freshly voided specimen is most reliable. Urine specimens that have been left standing may contain lysed red blood cells, disintegrating casts, and rapidly multiplying bacteria.6 Table 38.1 describes urinalysis values for normal urine.

Casts are molds of the distal nephron lumen. A gellike substance called Tamm-Horsfall mucoprotein, which is formed in the tubular epithelium, is the major protein constituent of urinary casts.4 Casts composed of this gel but devoid of cells are called hyaline casts. These casts develop when the protein concentration of the urine is high (as in nephrotic syndrome), urine osmolality is high, and urine pH is low. The inclusion of granules or cells in the matrix of the protein gel leads to the formation of various other types of casts.4 Proteinuria represents excessive protein excretion in the urine. Because of the glomerular capillary filtration barrier, less than 150 mg/L of protein is excreted in the urine over 24 hours in a healthy person. Urine tests for proteinuria are used to detect abnormal filtering of albumin in the glomeruli or defects in its reabsorption in the renal tubules. A protein reagent dipstick can be used as a rapid screening test for the presence of proteins in the urine. Once the presence of proteinuria has been detected, a 24-hour urine test is often used to quantify the amount of protein that is present.6 Albumin, which is the smallest of the plasma proteins, is filtered more readily than globulins or other plasma proteins. Thus, microalbuminuria tends to occur long before clinical proteinuria becomes evident. A dipstick test for microalbuminuria is available for screening purposes. The microalbuminuria dipstick method, however, only indicates an increase in urinary albumin that is below the detectable range of the standard proteinuria test. It does not specify the amount of albumin that is present in the urine. Therefore, a 24-hour urine collection is the standard method for detecting microalbuminuria (an albumin excretion >30 mg/day is abnormal).6 The specific gravity of urine varies with its concentration of solutes. Urine-specific gravity provides a valuable index of the hydration status and functional ability of the kidneys. Healthy kidneys can produce concentrated urine with a specific gravity of 1.030 to 1.040. During periods of marked hydration, the specific gravity can approach 1.000. With diminished renal function, there is a loss of renal c­ oncentrating ability,

TABLE 38.1 NORMAL VALUES FOR ROUTINE URINALYSIS GENERAL CHARACTERISTICS AND MEASUREMENTS

CHEMICAL DETERMINATIONS

Color: yellow amber Appearance: clear to slightly hazy Specific gravity: 1.005–1.025 with a normal fluid intake pH: 4.5–8.0; average person has a pH of about 5 to 6 Volume: 600–2500 mL/24 hour; average volume is 1200 mL/24 hour

Glucose: negative Ketones: negative Blood: negative Protein: negative Bilirubin: negative Urobilinogen: 0.5–4.0 mg/day Nitrate for bacteria: negative Leukocyte esterase: negative

MICROSCOPIC EXAMINATION OF SEDIMENT Casts negative: occasional hyaline casts Red blood cells: negative or rare Crystals: negative (none) White blood cells: negative or rare Epithelial cells: few; hyaline casts 0–1/lpf (low-power field)

From Fischbach F., Dunning M. B. (2009). A manual of laboratory and diagnostic tests (8th ed., p. 199). Philadelphia, PA: Lippincott Williams & Wilkins.

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Glomerular Filtration Rate The GFR provides a gauge of renal function. It can be measured clinically by collecting timed samples of blood and urine. Creatinine, a product of creatine metabolism by the muscle, is filtered by the kidneys but not reabsorbed in the renal tubule. Creatinine levels in the blood and urine can be  used to measure GFR. The clearance rate for creatinine is the amount that is completely cleared by the kidneys in 1 ­minute. The formula is expressed as C = UV/P, in which C is the clearance rate (mL/minute), U is the urine concentration (mg/dL), V is the urine volume excreted (mL/minute or 24 hours), and P is plasma concentration (mg/dL).6 Normal creatinine clearance is 115 to 125 mL/minute.6 This value is corrected for body surface area, which reflects the muscle mass where creatinine metabolism takes place. The test may be done on a 24-hour basis, with blood being drawn when the urine collection is completed. In another method, two 1-hour urine specimens are collected, and a blood sample is drawn in between.

Blood Tests Blood tests can provide valuable information about the kidneys’ ability to remove metabolic wastes from the blood and maintain normal electrolyte and pH composition of the blood. Normal blood values are listed in Table 38.2. Serum levels of potassium, phosphate, BUN, and creatinine increase in renal failure.2 Serum pH, calcium, and bicarbonate levels decrease in renal failure. Serum Creatinine Serum creatinine levels reflect the GFR. Because these measurements are easily obtained and relatively inexpensive, they often are used as a screening measure of renal function. Creatinine is a product of creatine metabolism in muscles; its formation and release are relatively constant and proportional to the amount of muscle mass present. Creatinine is freely filtered in the glomeruli, is not reabsorbed from the tubules into the blood, and is only minimally secreted into the tubules from the blood. Therefore, its blood values depend closely on the GFR. The normal creatinine value is approximately 0.7 mg/dL of blood for a woman with a small frame, approximately 1.0  mg/dL of blood for a normal adult man, and approximately 1.5 mg/dL of blood (60 to 130 mmol/L) for a muscular

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TABLE 38.2 NORMAL BLOOD CHEMISTRY LEVELS SUBSTANCE

NORMAL VALUE*

BUN Creatinine Sodium Chloride Potassium Carbon dioxide (CO2 content) Calcium Phosphate Uric acid Male Female pH

8.0–20.0 mg/dL (2.9–7.1 mmol/L) 0.6–1.2 mg/dL (50–100 mmol/L) 135–145 mEq/L (135–145 mmol/L) 98–106 mEq/L (98–106 mmol/L) 3.5–5 mEq/L (3.5–5 mmol/L) 24–29 mEq/L (24–29 mmol/L) 8.5–10.5 mg/dL (2.1–2.6 mmol/L) 2.5–4.5 mg/dL (0.77–1.45 mmol/L) 2.4–7.4 mg/dL (140–440 µmol/L) 1.4–5.8 mg/dL (80–350 µmol/L) 7.35–7.45

*Values may vary among laboratories, depending on the method of analysis used.

man.6 There is an age-related decline in creatinine clearance in many older adults because muscle mass and the GFR decline with age. A normal serum creatinine level usually indicates normal renal function. In addition to its use in calculating the GFR, the serum creatinine level is used in estimating the functional capacity of the kidneys (Fig. 38.14). If the value doubles, the GFR (and renal function) probably has fallen to one half of its normal state. A rise in the serum creatinine level to three times its normal value suggests that there is a 75% loss of renal function, and with creatinine values of 10 mg/dL or more, it can be assumed that approximately 90% of renal function has been lost.6 Recently it has been proposed that another serum protein, cystatin-C (a cysteine protease inhibitor), could be useful as a marker of GFR because it has a stable production rate, is freely filtered at the glomerulus, and in several studies has shown a greater sensitivity in detecting a decreased GFR, which could assist in determining a quicker management plan. For example, one study used serum creatinine,

Serum creatinine (mg/dL)

and the urine specific gravity may fall to levels of 1.006 to 1.010 (usual range is 1.010 to 1.025 with normal fluid intake).6 Urine osmolality, which depends on the number of particles of solute in a unit of solution, is a more exact measurement of urine concentration than specific gravity.6 More information concerning renal function can be obtained if the serum and urine osmolality tests are done at the same time. The normal ratio between urine and serum osmolality is 3:1. A high urineto-serum ratio is seen in concentrated urine. With poor concentrating ability, the ratio is low.

10 9 8 7 6 5 4 3 2 1 0

10

20 30 40 50 60 70 80 90 Percentage of normal renal function (average adult male)

100

FIGURE 38.14  •  Relation between the percentage of renal function and serum creatinine levels.

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Chapter 38  Structure and Function of the Kidney    1017

urine albumin to creatinine ratios (ACR), and cystatin-C levels and found the ACR and cystatin-C parameters to be better predictors for diagnosing end-stage renal disease.11 Another study found that cystatin-C levels are a better predictor of GFR in people postrenal transplant compared to other parameters.12 Further clinical studies are needed to determine the clinical efficacy of cystatin-C as a marker and to determine whether there is an advantage to its use compared with creatinine. Blood Urea Nitrogen Urea is formed in the liver as a by-product of protein metabolism and is eliminated entirely by the kidneys. BUN therefore is related to the GFR but, unlike creatinine, also is influenced by protein intake, gastrointestinal bleeding, and hydration status. In gastrointestinal bleeding, the intestinal flora breaks down the blood, and the nitrogenous waste is absorbed into the portal vein and transported to the liver, where it is converted to urea. During dehydration, elevated BUN levels result from increased concentration. Approximately two thirds of renal function must be lost before a significant rise in the BUN level occurs. The BUN is less specific for renal insufficiency than creatinine, but the BUN–creatinine ratio may provide useful diagnostic information. The ratio normally is approximately 10:1. Ratios greater than 15:1 represent prerenal conditions, such as congestive heart failure and upper gastrointestinal tract bleeding, that produce an increase in BUN, but not in creatinine. A  ratio of less than 10:1 occurs in people with liver disease and in those who receive a low-protein diet or chronic dialysis, because BUN is more readily dialyzable than creatinine.6

Cystoscopy Cystoscopy provides a means for direct visualization of the urethra, bladder, and ureteral orifices. It relies on the use of a cystoscope, an instrument with a lighted lens. The cystoscope is inserted through the urethra into the bladder. Biopsy specimens, lesions, small stones, and foreign bodies can be removed from the bladder. Urethroscopy may be used to remove stones from the ureter and aid in the treatment of ureteral disorders such as ureteral strictures.

Ultrasonography Ultrasonographic studies use the reflection of ultrasonic waves to visualize the deep structures of the body. The procedure is painless, noninvasive, and requires no patient preparation. Ultrasonography is used to visualize the structures of the kidneys and has proved useful in the diagnosis of many urinary tract disorders, including congenital anomalies, renal abscesses, hydronephrosis, and kidney stones. It can differentiate a renal cyst from a renal tumor. The use of ultrasonography also enables accurate placement of needles for renal biopsy and catheters for percutaneous nephrostomy.6

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Radiologic and Other Imaging Studies Radiologic studies include a simple flat plate of the kidneys, ureters, and bladder that can be used to determine the size, shape, and position of the kidneys and observe any radiopaque stones that may be in the kidney pelvis or ureters. In excretory urography, or intravenous pyelography, a radiopaque dye is injected into a peripheral vein. The dye is then filtered by the glomerulus and excreted into the urine, and x-ray films are taken as the dye moves through the kidneys and ureters.6 Urography is used to detect space-occupying lesions of the kidneys, pyelonephritis, hydronephrosis, vesicoureteral reflux, and kidney stones.6 Some people are allergic to the dye used for urography and may have an anaphylactic reaction after its administration. Every person undergoing urographic studies should be questioned about previous reactions to the dye or to similar dyes. If the test is considered essential in such people, premedication with antihistamines and corticosteroids may be used. The dye also reduces renal blood flow. Acute renal failure can occur, particularly in people with vascular disease or preexisting renal insufficiency. Other diagnostic tests include computed tomographic (CT) scans, magnetic resonance imaging (MRI), radionuclide imaging, and renal angiography. CT scans may be used to outline the kidneys and detect renal masses and tumors. MRI is becoming readily available and is used in imaging the kidneys, retroperitoneum, and urinary bladder. It is particularly useful in evaluating vascular abnormalities in and around the kidneys. Radionuclide imaging involves the injection of a radioactive material that subsequently is detected externally by a scintillation camera, which detects the radioactive emissions. Radionuclide imaging is used to evaluate renal function and structures, as well as the ureters and bladder. It is particularly useful in evaluating the function of kidney transplants. Renal angiography provides x-ray pictures of the blood vessels that supply the kidneys. It involves the injection of a radiopaque dye directly into the renal artery. A catheter usually is introduced through the femoral artery and advanced under fluoroscopic view into the abdominal aorta. The catheter tip then is maneuvered into the renal artery, and the dye is injected.6 This test is used to evaluate people suspected of having renal artery stenosis, abnormalities of renal blood vessels, or vascular damage to the renal arteries after trauma.

IN SUMMARY Urinalysis and blood tests that measure serum levels of pH, electrolytes, and by-products of metabolism provide valuable information about renal function. Urine specific gravity is used to assess the kidneys’ ability to concentrate urine. Dipstick and 24-hour urine tests for proteinuria and microalbuminuria are used to detect abnormal filtering of albumin in the glomeruli or defects in its reabsorption in the renal tubules. Creatinine is a product of creatine metabolism in muscles that is freely filtered in the glomeruli and

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1018   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

neither reabsorbed nor secreted in the tubules; therefore, serum creatinine levels are commonly used to estimate the GFR. Urea is formed in the liver as a by-product of protein metabolism and is eliminated entirely by the kidneys. BUN is therefore related to the GFR but, unlike creatinine, also is influenced by protein intake, gastrointestinal bleeding, and hydration status. Cystoscopic examinations can be used for direct visualization of the urethra, bladder, and ureters. Ultrasonography can be used to determine kidney size, and renal radionuclide imaging can be used to evaluate the kidney ­structures. Radiologic methods, such as excretory urography, provide a means by which kidney structures such as the renal calyces, pelvis, ureters, and bladder can be outlined. Other diagnostic tests include CT scans, MRI, radionuclide imaging, and renal angiography.

Review Exercises 1. A 32-year-old woman with diabetes is found to have a positive result on a urine dipstick test for microalbuminuria. A subsequent 24-hour urine specimen reveals an albumin excretion of 50 mg (an albumin excretion >30 mg/day is abnormal). A. Use the structures of the glomerulus in Figure 38.5 to provide a possible explanation for this finding. Why specifically test for the albumin rather than the globulins or other plasma proteins? B. Strict control of blood sugars and treatment of hypertension have been shown to decrease the progression of kidney disease in persons with diabetes. Explain the physiologic rationale for these two types of treatments. 2. A 10-year-old boy with bed-wetting was placed on an ADH nasal spray at bedtime as a means of treating the disorder. A. Explain the rationale for using ADH to treat bed-wetting. 3. A 54-year-old man, seen by his physician for an elevated blood pressure, was found to have a serum creatinine of 2.5 and BUN of 30. He complains that he has been urinating more frequently than usual, and his first morning urine specimen reveals dilute urine with a specific gravity of 1.010. A. Explain the elevation of serum creatinine in terms of renal function. B. Explain the inability of people with early renal failure to produce concentrated urine as ­evidenced by the frequency of urination and the low specific gravity of his first morning urine specimen.

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4. A 60-year-old woman with a diagnosis of hypertension is being treated with a thiazide diuretic. A. What diuretic effect would you expect the woman to have based on the percentage of sodium reaching the site where the diuretic exerted its action? B. What type of effects might be expected in terms of renal losses of potassium and calcium?

References 1. Ross M., Pawlina W. (2011). Histology: A text and atlas with correlated cell and molecular biology (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2. Hall J. E. (2011). Guyton and Hall textbook of medical physiology (12th ed.). Philadelphia, PA: Elsevier Saunders. 3. Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 4. Boron W. F., Boulpaep E. L. (2009). Medical physiology (2nd ed., pp. 448–466). St. Louis, MO: Saunders Elsevier. 5. Pratt N., Roughead E. E., Ryan P., et al. (2010). Differential impact of NSAIDS on rate of adverse events that require hospitalization in high risk and general veteran populations: A retrospective cohort study. Drugs & Aging 27(1), 63–71. 6. Fischbach F., Dunning M. (2009). A manual of laboratory and diagnostic tests (8th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 7. Rennke H. G., Denker B. M. (2010). Renal pathophysiology: The essentials (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 8. Lehne R. A. (2010). Pharmacology for nursing care (7th ed.). St. Louis, MO: Elsevier. 9. Fain J. A. (2009). Understanding diabetes mellitus and kidney disease. Nephrology Nursing Journal 36(5), 465–470. 10. Cunningham J., Zehnder D. (2011). New vitamin D analogs and changing therapeutic paradigms. Kidney International 79(7), 702–707. 11. Peralta C. A., Shlipak M. G., Judd S., et al. (2011). Detection of chronic kidney disease with creatinine, cystatin-c, and urine albumin-to-creatinine ratio and association with progression to end stage renal disease and mortality. Journal of American Medicine Association 304(15), 1545–1552. 12. Bargnoux A. S., Cavalier E., Cristol J. P., et al. (2011). Cystatin C is a reliable marker for estimation of glomerular filtration rate in renal transplantation: Validation of a new turbidimetric assay using monospecific sheep antibodies. Clinical Chemistry and Laboratory Medicine 49(2), 265–270.

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39

Disorders of Fluid and Electrolyte Balance COMPOSITION AND COMPARTMENTAL DISTRIBUTION OF BODY FLUIDS

Dissociation of Electrolytes Diffusion and Osmosis Diffusion Osmosis Tonicity Compartmental Distribution of Body Fluids Intracellular Fluid Volume Extracellular Fluid Volume Capillary–Interstitial Fluid Exchange Edema Third-Space Accumulation

SODIUM AND WATER BALANCE

Body Water Balance Gains and Losses Sodium Balance Gains and Losses Mechanisms of Regulation Thirst and Antidiuretic Hormone Disorders of Thirst Disorders of Antidiuretic Hormone Disorders of Sodium and Water Balance Isotonic Fluid Volume Deficit Isotonic Fluid Volume Excess Hyponatremia Hypernatremia

Sheila Grossman

Hypophosphatemia Hyperphosphatemia Disorders of Magnesium Balance Gains and Losses Hypomagnesemia Hypermagnesemia

Fluids and electrolytes are present in body cells, in the tissue spaces between the cells, and in the blood that fills the vascular compartment. Body fluids transport gases, nutrients, and wastes; help generate the electrical activity needed to power body functions; take part in the transforming of food into energy; and otherwise maintain the overall function of the body. Although fluid volume and composition remain relatively constant in the presence of a wide range of changes in intake and output, conditions such as environmental stresses and disease can impair intake, increase losses, and interfere with mechanisms that regulate fluid volume, composition, and distribution. This chapter discusses the composition and compartmental distribution of body fluids; sodium and water balance; potassium balance; and calcium, phosphorus, and magnesium balance.

POTASSIUM BALANCE

Regulation of Potassium Balance Gains and Losses Mechanisms of Regulation Disorders of Potassium Balance Hypokalemia Hyperkalemia

CALCIUM, PHOSPHORUS, AND MAGNESIUM BALANCE Mechanisms Regulating Calcium, Phosphorus, and Magnesium Balance Vitamin D Parathyroid Hormone Disorders of Calcium Balance Gains and Losses Hypocalcemia Hypercalcemia Disorders of Phosphorus Balance Gains and Losses

COMPOSITION AND COMPARTMENTAL DISTRIBUTION OF BODY FLUIDS After completing this section of the chapter, you should be able to meet the following objectives: •• Differentiate the intracellular from the extracellular fluid compartments in terms of distribution and composition of water, electrolytes, and other osmotically active solutes. •• Relate the concept of a concentration gradient to the processes of diffusion and osmosis. •• Describe the control of cell volume and the effect of isotonic, hypotonic, and hypertonic solutions on cell size. 1019

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1020   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Intracellular water

Extracellular (plasma) water

Extracellular (interstitial) water

only about 2% in the ECF.1 Potassium is the most abundant intracellular electrolyte. The cell membrane serves as the primary barrier to the movement of substances between the ECF and ICF compartments. Lipid-soluble substances (e.g., oxygen [O2] and carbon dioxide [CO2]), which dissolve in the lipid bilayer of the cell membrane, pass directly through the membrane, whereas many ions (e.g., sodium [Na+] and potassium [K+]) rely on transport mechanisms such as the Na+/K+ pump located in the cell membrane for movement across the membrane.2 Because the Na+/K+ pump relies on adenosine triphosphate (ATP) and the enzyme ATPase for energy, it is often referred to as the Na+/K+-ATPase membrane pump. Water crosses the cell membrane by osmosis using special transmembrane protein channels that are called aquaporins.3

Dissociation of Electrolytes FIGURE 39.1 •  Distribution of body water. The extracellular space includes the vascular compartment and the interstitial spaces.

Body fluids are distributed between the intracellular fluid (ICF) and extracellular fluid (ECF) compartments. The ICF compartment consists of fluid contained within all of the billions of cells in the body. It is the larger of the two compartments, with approximately two thirds of the body water in healthy adults. The remaining one third of body water is in the ECF compartment, which contains all the fluids outside the cells, including those in the interstitial or tissue spaces and blood vessels (Fig. 39.1). The ECF, including blood plasma and interstitial fluids, contains large amounts of sodium and chloride and moderate amounts of bicarbonate but only small quantities of potassium, magnesium, calcium, and phosphorus. In contrast to the ECF, the ICF contains almost no calcium; small amounts of sodium, chloride, bicarbonate, and phosphorus; moderate amounts of magnesium; and large amounts of potassium (Table 39.1). It is the ECF levels of electrolytes in the blood or blood plasma that are measured clinically. Although blood levels usually are representative of the total-body levels of an electrolyte, this is not always the case, particularly with p­ otassium, which has

Body fluids contain water and electrolytes. Electrolytes are substances that dissociate in solution to form charged particles, or ions. For example, a sodium chloride (NaCl) molecule ­dissociates to form a positively charged Na+ and a negatively charged Cl− ion. Particles that do not dissociate into ions such as glucose and urea are called nonelectrolytes. Positively charged ions are called cations because they are attracted to the cathode of a wet electric cell, and negatively charged ions are called anions because they are attracted to the anode. The ions found in body fluids carry one charge (i.e., monovalent ion) or two charges (i.e., divalent ion). Because of their attraction forces, positively charged cations are always accompanied by negatively charged anions. Thus, all body fluids contain equal amounts of anions and cations. However, cations and anions may be exchanged one for another, providing they carry the same charge. For example, a positively charged H+ ion may be exchanged for a positively charged K+ ion, and a negatively charged HCO3− ion may be exchanged for a negatively charged Cl− ion.

Diffusion and Osmosis Diffusion Diffusion is the movement of charged or uncharged particles along a concentration gradient. All molecules and ions, ­including

TABLE 39.1 CONCENTRATIONS OF EXTRACELLULAR AND INTRACELLULAR ELECTROLYTES IN ADULTS ELECTROLYTE

Sodium Potassium Chloride Bicarbonate Calcium Phosphorus Magnesium

EXTRACELLULAR CONCENTRATION*

INTRACELLULAR CONCENTRATION*

Conventional Units

SI Units

Conventional Units

135–145 mEq/L 3.5–5.0 mEq/L 98–106 mEq/L 24–31 mEq/L 8.5–10.5 mg/dL 2.5–4.5 mg/dL 1.8–3.0 mg/dL

135–145 mmol/L 3.5–5.0 mmol/L 98–106 mmol/L 24–31 mmol/L 2.1–2.6 mmol/L 0.8–1.45 mmol/L 0.75–1.25 mmol/L

10–14 mEq/L 140–150 mEq/L 3–4 mEq/L 7–10 mEq/L 20 mEq/L [20 mmol/L]), (3) urine osmolality in excess of plasma osmolality, (4) absence of edema and volume depletion, and (5) normal renal, thyroid, and adrenal function.17

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The treatment of SIADH depends on its severity. In mild cases, treatment consists of fluid restriction. If fluid restriction is not sufficient, diuretics such as mannitol and furosemide (Lasix) may be given to promote diuresis and free-water clearance. Lithium and the antibiotic demeclocycline inhibit the action of ADH on the renal collecting ducts and sometimes are used in treating the disorder. In cases of severe water intoxication, a hypertonic (e.g., 3%) NaCl solution may be administered intravenously. The recently developed antagonists to the antidiuretic action of ADH (aquaretics) offer a new therapeutic approach to the treatment of euvolemic hyponatremia.13 These agents (e.g., conivaptan) are specific ADH V2 receptor antagonists and result in aquaresis (i.e., the electrolyte-sparing excretion of free water).

Disorders of Sodium and Water Balance Disorders of sodium and water balance can be divided into two main categories: 1. Isotonic contraction or expansion of ECF volume 2. Hypotonic dilution (hyponatremia) or hypertonic ­concentration (hypernatremia) of extracellular sodium brought about by changes in extracellular water (Fig. 39.7) Isotonic disorders usually are confined to the ECF compartment, producing a contraction (fluid volume deficit) or expansion (fluid volume excess) of the interstitial and vascular fluids. Disorders of sodium concentration produce a change in the osmolality of the ECF, with movement of water from the ECF compartment into the ICF compartment (hyponatremia) or from the ICF compartment into the ECF compartment (hypernatremia). Isotonic Fluid Volume Deficit Fluid volume deficit is characterized by a decrease in the ECF, including the circulating blood volume. The term isotonic fluid volume deficit is used to differentiate the type of fluid deficit in which there are proportionate losses in sodium and water from water deficit and the hyperosmolar state associated with hypernatremia. Unless other fluid and electrolyte imbalances are present, the concentration of plasma electrolytes remains essentially unchanged. When the effective circulating blood volume is compromised, the condition is often referred to as hypovolemia. Etiology. Isotonic fluid volume deficit results when water and electrolytes are lost in isotonic proportions (Table 39.4). It is almost always caused by a loss of body fluids and is often accompanied by a decrease in fluid intake. It can occur because of a loss of gastrointestinal fluids, polyuria, or sweating due to fever and exercise. Fluid intake may be reduced because of a lack of access to fluids, impaired thirst, unconsciousness, oral trauma, impaired swallowing, or neuromuscular problems that prevent fluid access.

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1034   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Proportionate changes in sodium and water

Disproportionate changes in sodium and water

Loss of sodium and water

Gain of sodium and water

Loss of sodium or gain of water

Gain of sodium or loss of water

Isotonic fluid deficit in ECF compartment

Isotonic fluid excess in ECF compartment

Hyponatremia

Hypernatremia

Contraction of fluids in interstitial and vascular compartments of the ECF

Expansion of fluids in the interstitial and vascular compartments of the ECF

Water movement from extracellular to intracellular compartment

Water movement from intracellular to extracellular compartment

280 mOsm

280 mOsm

280 mOsm

280 mOsm

280 mOsm

260 mOsm Water

280 mOsm

300 mOsm Water

Intracellular fluid (ICF) Extracellular fluid (ECF)

FIGURE 39.7  •  Effect of isotonic fluid excess and deficit and of hyponatremia and hypernatremia on movement of water between the extracellular (ECF) and intracellular fluid (ICF) compartments.

In a single day, 8 to 10 L of ECF is secreted into the gastrointestinal tract. Most of it is reabsorbed in the ileum and proximal colon, and only approximately 150 to 200 mL/day is eliminated in the feces. Vomiting and diarrhea interrupt the reabsorption process and, in some situations, lead to increased secretion of fluid into the intestinal tract. In Asiatic cholera, death can occur within a matter of hours as the cholera organism causes excessive amounts of fluid to be secreted into the bowel. These fluids are then lost as vomitus or excreted as diarrheal fluid. Gastrointestinal suction, fistulas, and drainage tubes can remove large amounts of fluid from the gastrointestinal tract. Excess sodium and water losses also can occur through the kidney. Certain forms of kidney disease are characterized by salt wasting due to impaired sodium reabsorption. Fluid volume deficit also can result from osmotic diuresis or injudicious use of diuretic therapy. Glucose in the urine filtrate prevents reabsorption of water by the renal tubules, causing a loss of sodium and water. In Addison disease, a condition of chronic adrenocortical insufficiency, there is unregulated loss of sodium in the urine with a resultant loss of ECF. This is accompanied by increased potassium retention. The skin acts as an exchange surface for heat and as a vapor barrier to prevent water from leaving the body. Body surface losses of sodium and water increase when there is excessive sweating or when large areas of skin have been damaged. Hot weather and fever increase sweating. In hot weather, water losses through sweating may be increased by as much as 1 to 3 L/hour, depending on acclimatization.2 The respiratory rate and sweating usually are increased as body temperature

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rises. As much as 3 L of water may be lost in a single day as a result of fever. Burns are another cause of excess fluid loss. Evaporative losses can increase 10-fold with severe burns, up to 3 to 5 L/day.2 Third-space losses cause sequestering of ECF in the serous cavities, extracellular spaces in injured tissues, or lumen of the gut.7 Because the fluid remains in the body, fluid volume deficit caused by third spacing does not usually cause weight loss. Clinical Manifestations.  The manifestations of fluid volume deficit reflect a decrease in ECF volume. They include thirst, loss of body weight, signs of water conservation by the kidney, impaired temperature regulation, and signs of reduced interstitial and vascular volume (see Table 39.4). A loss in fluid volume is accompanied by a decrease in body weight. One liter of water weighs 1 kg (2.2 lb). A mild ECF deficit exists when weight loss equals 2% of body weight. In a person who weighs 68 kg (150 lb), this percentage of weight loss equals 1.4 L of water. To be accurate, weight must be measured at the same time each day with the person wearing the same amount of clothing. Because the ECF is trapped in the body in people with third-space losses, their body weight may not decrease. Thirst is a common symptom of fluid deficit, although it is not always present in the early stages of isotonic fluid deficit. It develops as the effective circulatory volume decreases to a point sufficient to stimulate the thirst mechanism. Urine output decreases and urine osmolality and specific ­gravity

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1035

TABLE 39.4 CAUSES AND MANIFESTATIONS OF ISOTONIC FLUID VOLUME DEFICIT CAUSES

MANIFESTATIONS

Inadequate Fluid Intake Oral trauma or inability to swallow Inability to obtain fluids (e.g., impaired mobility) Impaired thirst sensation Therapeutic withholding of fluids Unconsciousness or inability to express thirst

Acute Weight Loss (% Body Weight) Mild fluid volume deficit: 2% Moderate fluid volume deficit: 2%–5% Severe fluid deficit: 8% or greater

Excessive Gastrointestinal Fluid Losses Vomiting Diarrhea Gastrointestinal suction Draining gastrointestinal fistula

Increased Serum Osmolality Thirst Increased hematocrit and BUN

Excessive Renal Losses Diuretic therapy Osmotic diuresis (hyperglycemia) Adrenal insufficiency (Addison disease) Salt-wasting kidney disease Excessive Skin Losses Fever Exposure to hot environment Burns and wounds that remove skin Third-Space Losses Intestinal obstruction Edema Ascites Burns (first several days)

increase as ADH levels rise because of a decrease in vascular volume. Although there is an isotonic loss of fluid from the vascular compartment, the other blood components such as red blood cells (RBCs) and BUN become more concentrated. The fluid content of body tissues decreases as fluid is removed from the interstitial spaces. The eyes assume a sunken appearance and feel softer than normal as the fluid content in the anterior chamber of the eye is decreased. Fluids add resiliency to the skin and underlying tissues that is referred to as skin or tissue turgor. Tissue turgor is assessed by pinching a fold of skin between the thumb and forefinger. The skin should immediately return to its original configuration when the fingers are released.19 If 3% to 5% of body water is lost in children, there is fairly normal turgor, whereas with 6% to 9% loss of body water, there is poor turgor and a sunken anterior fontanel.8 Decreased tissue turgor is less predictive of fluid deficit in older persons (>65 years) because of the loss of tissue elasticity. In infants, fluid deficit may be evidenced by depression of the anterior fontanel due to a decrease in cerebrospinal fluid. Arterial and venous volumes decline during periods of fluid deficit, as does filling of the capillary circulation. As the volume in the arterial system declines, the blood pressure decreases, the heart rate increases, and the pulse becomes

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Compensatory Increase in Antidiuretic Hormone Decreased urine output Increased osmolality and specific gravity

Decreased Vascular Volume Postural hypotension Tachycardia, weak and thready pulse Decreased vein filling and increased vein refill time Hypotension and shock Decreased ECF Volume Depressed fontanel in an infant Sunken eyes and soft eyeballs Impaired Temperature Regulation Elevated body temperature

weak and thready. Postural hypotension (a drop in blood pressure on standing) is an early sign of fluid deficit. On the venous side of the circulation, the veins become less prominent. When volume depletion becomes severe, signs of hypovolemic shock and vascular collapse appear. Diagnosis and Treatment.  Diagnosis of fluid volume deficit is based on a history of conditions that predispose to sodium and water losses, weight loss, and observations of altered physiologic function indicative of decreased fluid volume. Intake and output measurements afford a means for assessing fluid balance. However, these measurements may not represent actual losses and gains, largely because accurate measurements of intake and output often are difficult to obtain and insensible losses are difficult to estimate. Measurement of heart rate and blood pressure provides useful information about vascular volume. A simple test to determine venous refill time consists of compressing the distal end of a vein on the dorsal aspect of the hand when it is not in the dependent position. The vein is then emptied by “milking” the blood toward the heart. The vein should refill almost immediately when the occluding finger is removed. In the case of decreased venous volume, as occurs in fluid

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1036   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

d­ eficit, venous refill time increases. Capillary refill time is also increased. Capillary refill can be assessed by applying pressure to a fingernail for 5 seconds and then releasing the pressure and observing the time (normally 1 to 2 seconds) it takes for the color to return to normal.20 Treatment of fluid volume deficit consists of fluid replacement and measures to correct the underlying cause. Usually, isotonic electrolyte solutions are used for fluid replacement. Acute hypovolemia and hypovolemic shock can cause renal damage. Therefore, prompt assessment of the degree of fluid deficit and adequate measures to resolve the deficit and treat the underlying cause are essential. Isotonic Fluid Volume Excess Fluid volume excess represents an isotonic expansion of the ECF compartment with increases in both interstitial and vascular volumes. Although increased fluid volume is usually the result of a disease condition, this is not always true. For example, a compensatory isotonic expansion of body fluids can occur in healthy people during hot weather as a mechanism for increasing body heat loss. Etiology. Isotonic fluid volume excess almost always results from an increase in total body sodium that is accompanied by a proportionate increase in body water. Although it can occur as the result of excessive sodium intake, it is most commonly caused by a decrease in sodium and water elimination by the kidney. Among the causes of decreased sodium and water elimination are disorders of renal function, heart failure, liver ­failure, and corticosteroid excess (Table 39.5). Heart failure produces a decrease in the effective circulating volume and renal blood flow and a compensatory increase in sodium and water retention. People with severe congestive heart failure

maintain a precarious balance between sodium and water intake and output. Even small increases in sodium intake can precipitate a state of fluid volume excess and a worsening of heart failure. A condition called circulatory overload results from an increase in blood volume; it can occur during infusion of intravenous fluids or transfusion of blood if the amount or rate of administration is excessive. Liver failure (e.g., cirrhosis of the liver) impairs aldosterone metabolism and decreases effective circulating volume and renal perfusion, leading to increased salt and water retention. The corticosteroid hormones increase sodium reabsorption by the kidneys. People taking corticosteroid medications and those with Cushing disease often have problems with sodium retention. Clinical Manifestations. Isotonic fluid volume excess is manifested by an increase in interstitial and vascular fluids. It is characterized by weight gain over a short period of time. Mild fluid volume excess represents a 2% gain in weight; moderate fluid volume excess, a 5% gain in weight; and severe fluid volume excess, a gain of 8% or more in weight8 (see Table 39.5). The presence of edema is characteristic of isotonic fluid excess. When the excess fluid accumulates gradually, as often happens in debilitating diseases and starvation, edema fluid may mask the loss of tissue mass. There may be a decrease in BUN and hematocrit as a result of dilution due to expansion of the plasma volume. An increase in vascular volume may be evidenced by distended neck veins, slow-emptying peripheral veins, a full and bounding pulse, and an increase in central venous pressure. When excess fluid accumulates in the lungs (i.e., pulmonary edema), there are complaints of shortness of breath and difficult breathing, respiratory crackles, and a ­productive cough. Ascites and pleural effusion may occur with severe fluid volume excess.

TABLE 39.5 CAUSES AND MANIFESTATIONS OF ISOTONIC FLUID VOLUME EXCESS CAUSES

MANIFESTATIONS

Inadequate Sodium and Water Elimination Congestive heart failure Renal failure Increased corticosteroid levels Hyperaldosteronism Cushing disease Liver failure (e.g., cirrhosis)

Acute Weight Gain (% Body Weight) Mild fluid volume excess: 2% Moderate fluid volume excess: 5% Severe fluid volume excess: 8% or greater

Excessive Sodium Intake in Relation to Output Excessive dietary intake Excessive ingestion of sodium-containing ­medications or home remedies Excessive administration of sodium-containing parenteral fluids Excessive Fluid Intake in Relation to Output Ingestion of fluid in excess of elimination Administration of parenteral fluids or blood at an excessive rate

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Increased Interstitial Fluid Volume Dependent and generalized edema Increased Vascular Volume Full and bounding pulse Venous distention Pulmonary edema Shortness of breath Crackles Dyspnea Cough

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1037

Diagnosis and Treatment.  Diagnosis of fluid volume excess is usually based on a history of factors that predispose to sodium and water retention, weight gain, and manifestations such as edema and cardiovascular symptoms indicative of an expanded ECF volume. The treatment of fluid volume excess focuses on providing a more favorable balance between sodium and water intake and output. A sodium-restricted diet is often prescribed as a means of decreasing extracellular sodium and water levels. Diuretic therapy is commonly used to increase sodium elimination. When there is a need for intravenous fluid administration or transfusion of blood components, the procedure requires careful monitoring to prevent fluid overload. Hyponatremia The normal plasma concentration of sodium ranges from 135 to 145 mEq/L (135 to 145 mmol/L). Plasma sodium values reflect the sodium concentration expressed in milliequivalents or millimoles per liter, rather than an absolute amount. Because sodium and its attendant anions account for 90% to 95% of the osmolality of ECF, serum osmolality (normal range, 275 to 295 mOsm/kg) usually changes with changes in plasma sodium concentration. Hyponatremia represents a plasma sodium concentration below 135 mEq/L (135 mmol/L). It is one of the most common electrolyte disorders seen in general hospital patients and is also common in the outpatient population, particularly in older adults. A number of age-related events make the older adult population more vulnerable to hyponatremia, including a decrease in renal function accompanied by limitations in sodium conservation. Although older people maintain body fluid homeostasis under most circumstances, the ability to withstand environmental, drug-related, and disease-associated stresses becomes progressively limited. Types and Etiology.  Because of the effects of osmotically active particles such as glucose, hyponatremia can present as a hypotonic or hypertonic state.21 Hypertonic (translocational) hyponatremia results from an osmotic shift of water from the ICF to the ECF compartment, such as that occurring in hyperglycemia (the correction for hyperglycemia is a 1.6-mEq/L [1.6 mmol/L] increase in plasma sodium for every 100 mg/dL rise in plasma glucose above the normal 100 mg/dL [5.5 mmol/L]). In this case, the sodium in the ECF becomes diluted as water moves out of cells in response to the osmotic effects of the elevated blood glucose level. Hypotonic (dilutional) hyponatremia, by far the most common type of hyponatremia, is caused by water retention. It can be classified as hypovolemic, euvolemic, or hypervolemic based on accompanying ECF fluid volumes.12,21 Because of its effect on both sodium and water elimination, diuretic therapy can cause either hypovolemic or euvolemic hyponatremia. Hypovolemic hypotonic hyponatremia occurs when water is lost along with sodium, but to a lesser extent. Among the causes of hypovolemic hyponatremia are excessive sweating in hot weather, particularly during heavy exercise, which leads

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to loss of salt and water. Hyponatremia develops when water, rather than electrolyte-containing liquids, is used to replace fluids lost in sweating. Another potential cause of hypovolemic hyponatremia is the loss of sodium from the gastrointestinal tract caused by frequent gastrointestinal irrigations with distilled water. Isotonic fluid loss, such as that occurring in vomiting or diarrhea, does not usually lower plasma sodium levels unless these losses are replaced with disproportionate amounts of orally ingested or parenterally administered water. Gastrointestinal fluid loss and ingestion of excessively diluted formula are common causes of acute hyponatremia in infants and children. Hypovolemic hyponatremia is also a common complication of adrenal insufficiency and is attributable to a decrease in aldosterone levels. A lack of aldosterone increases renal losses of sodium, and a cortisol deficiency leads to increased release of ADH with water retention. Euvolemic or normovolemic hypotonic hyponatremia represents retention of water with dilution of sodium while maintaining the ECF volume within a normal range. It is usually the result of SIADH. The risk of normovolemic hyponatremia is increased during the postoperative period. During this time ADH levels are often high, producing an increase in water reabsorption by the kidney. Although these elevated levels usually resolve in about 72 hours, they can persist for as long as 5 days. The hyponatremia becomes exaggerated when electrolyte-free fluids (e.g., 5% glucose in water) are used for fluid replacement. Hypervolemic hypotonic hyponatremia is seen when hyponatremia is accompanied by edema-associated disorders such as decompensated heart failure, advanced liver disease, and renal disease. Although the total body sodium is increased in heart failure, the effective circulating volume is often sensed as inadequate by the baroreceptors (i.e., relative arterial underfilling), resulting in increased ADH levels (nonosmotic ADH secretion).22 Abuse of the drug, methylenedioxymethamphetamine (MDMA), also known as “ecstasy,” can lead to severe neurologic symptoms, including seizures, brain edema, and herniation due to severe hyponatremia. Clinical Manifestations. The manifestations of hypotonic hyponatremia are largely related to sodium dilution (Table  39.6). Serum osmolality is decreased, and cellular swelling occurs owing to the movement of water from the ECF to the ICF compartment. The manifestations of hyponatremia depend on the rapidity of onset and the severity of the sodium dilution. The signs and symptoms may be acute (i.e., onset within 48 hours), as in severe water intoxication, or more insidious in onset and less severe, as in chronic hyponatremia. Because of water movement, hyponatremia produces an increase in intracellular water, which is responsible for many of the clinical manifestations of the disorder. Fingerprint edema is a sign of excess intracellular water. This phenomenon is demonstrated by pressing the finger firmly over the bony surface of the sternum for 15 to 30 seconds. Fingerprint edema exists if an indented fingerprint remains in the sternum where the pressure was applied.

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1038   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

TABLE 39.6 CAUSES AND MANIFESTATIONS OF HYPONATREMIA CAUSES

MANIFESTATIONS

Hypotonic Hyponatremia Hypovolemic (decreased serum sodium with decreased ECF volume) Use of excessively diluted infant formula Administration of sodium-free parenteral solutions Gastrointestinal losses Vomiting, diarrhea Sweating, with sodium-free fluid replacement Repeated irrigation of body cavities with sodium-free solutions Irrigation of gastrointestinal tubes with distilled water Tap water enemas Use of nonelectrolyte irrigating solutions during prostate surgery Third spacing (paralytic ileus, pancreatitis) Diuretic use Mineralocorticoid deficiency (Addison disease) Salt-wasting nephritis Euvolemic (Decreased Serum Sodium With Normal ECF Volume) Increased ADH levels Trauma, stress, pain SIADH Use of medications that increase ADH Diuretic use Glucocorticoid deficiency Hypothyroidism Psychogenic polydipsia Endurance exercise MDMA (“ecstasy”) abuse Hypervolemic (Decreased Serum Sodium With Increased ECF Volume) Decompensated heart failure Advanced liver disease Kidney failure without nephrosis

Laboratory Values Serum sodium levels below 135 mEq/L (135 mmol/L) Hypotonic hyponatremia Serum osmolality < 280 mOsm/kg Dilution of blood components, including hematocrit, BUN Hypertonic hyponatremia Serum osmolality > 280 mOsm/kg

Hypertonic Hyponatremia (Osmotic Shift of Water from the ICF to the ECF Compartment) Hyperglycemia

Manifestations largely related to ­hyperosmolality of ECFs

Muscle cramps, weakness, and fatigue reflect the effects of hyponatremia on skeletal muscle function and are often early signs of hyponatremia. These effects commonly are observed in persons with hyponatremia that occurs during heavy exercise in hot weather. Gastrointestinal manifestations such as nausea and vomiting, abdominal cramps, and diarrhea may develop. The cells of the brain and nervous system are the most seriously affected by increases in intracellular water. Symptoms include apathy, lethargy, and headache,

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Signs Related to Hypo-Osmolality of ECFs and Movement of Water into Brain Cells and Neuromuscular Tissue Muscle cramps Weakness Headache Depression Apprehension, feeling of impending doom Personality changes Lethargy Stupor, coma Gastrointestinal Manifestations Anorexia, nausea, vomiting Abdominal cramps, diarrhea Increased ICF Fingerprint edema

which can progress to disorientation, confusion, gross motor weakness, and depression of deep tendon reflexes. Seizures and coma occur when plasma sodium levels reach extremely low levels. These severe effects, which are caused by brain swelling, may be irreversible. If the condition develops slowly, signs and symptoms do not develop until plasma sodium levels approach 120 mEq/L (120 mmol/L) (i.e., severe hyponatremia).21 The term water intoxication is often used to describe the neurologic effects of acute hypotonic hyponatremia.

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1039

Diagnosis and Treatment. Diagnosis of hyponatremia is based on laboratory reports of a decreased plasma sodium concentration, plasma and urine osmolality, and urine sodium concentration; assessment of the person’s volume status; presence of conditions that predispose to sodium loss or water retention; and signs and symptoms indicative of the disorder. The treatment of hyponatremia with water excess focuses on the underlying cause. When hyponatremia is caused by water intoxication, limiting water intake or discontinuing medications that contribute to SIADH may be sufficient. The administration of a saline solution orally or intravenously may be needed when hyponatremia is caused by sodium deficiency. Symptomatic hyponatremia (i.e., neurologic manifestations) is often treated with hypertonic saline solution and a loop diuretic, such as furosemide, to increase water elimination. This combination allows for correction of plasma sodium levels while ridding the body of excess water. New, specific ADH V2 receptor antagonists to the antidiuretic action of ADH (aquaretics) offer a new therapeutic approach to the treatment of euvolemic hyponatremia.23 There is concern about the rapidity with which plasma sodium levels are corrected, particularly in people with chronic symptomatic hyponatremia. Cells, particularly those in the brain, tend to defend against changes in cell volume caused by changes in ECF osmolality by increasing or decreasing their concentration of organic osmolytes.23,24 In the case of prolonged water intoxication, brain cells reduce their concentration of osmolytes as a means of preventing an increase in cell volume. It takes several days for brain cells to restore the osmolytes lost during hyponatremia. Thus, treatment measures that produce rapid changes in serum osmolality may cause a dramatic change in brain cell volume. One of the reported effects of rapid treatment of hyponatremia is an osmotic demyelinating condition called central pontine myelinolysis, which produces serious neurologic sequelae and sometimes causes death.23 This complication occurs more commonly in premenopausal women and in people with hypoxia. Hypernatremia Hypernatremia implies a plasma sodium level above 145 mEq/L (145 mmol/L) and a serum osmolality greater than 295 mOsm/kg. Because sodium is functionally an impermeable solute, it contributes to tonicity and induces movement of water across cell membranes. Hypernatremia is characterized by hypertonicity of ECF and almost always causes cellular dehydration.25 Etiology.  Hypernatremia represents a deficit of water in relation to the body’s sodium stores. It can be caused by net loss of water or sodium gain. Net water loss can occur through the urine, gastrointestinal tract, lungs, or skin. A defect in thirst or inability to obtain or drink water can interfere with water replacement. Rapid ingestion or infusion of sodium

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with insufficient time or opportunity for water ingestion can produce a disproportionate gain in sodium (Table 39.7). This can occur with critically ill people who present with multiple needs for fluid resuscitation and electrolyte balance. In fact hypernatremia is an independent risk factor linked highly with increased mortality.26 Hypernatremia almost always follows a loss of body fluids that have a lower-than-normal concentration of sodium, so that water is lost in excess of sodium. This can result from increased losses from the respiratory tract during fever or strenuous exercise, from watery diarrhea, or when osmotically active tube feedings are given with inadequate amounts of water. With pure water loss, each body fluid compartment loses an equal percentage of its volume. Because approximately one third of the water is in the ECF compartment, compared with the two thirds in the ICF compartment, more actual water volume is lost from the ICF than the ECF compartment.2 Normally, water deficit stimulates thirst and increases water intake. Therefore, hypernatremia is more likely to occur in infants and in people who cannot express their thirst or obtain water to drink. With hypodipsia, or impaired thirst, the need for fluid intake does not activate the thirst response. Hypodipsia is particularly prevalent among older adults. In people with DI, hypernatremia can develop when thirst is impaired or access to water is impeded. The therapeutic administration of sodium-containing solutions may also cause hypernatremia. Hypertonic saline solution intended for intra-amniotic instillation for therapeutic abortion may inadvertently be injected intravenously, causing hypernatremia. Rarely, salt intake occurs rapidly, as in taking excess salt tablets or during near-drowning in salt water. Clinical Manifestations. The clinical manifestations of hypernatremia caused by water loss are largely those of ECF loss and cellular dehydration (see Table 39.7). The severity of signs and symptoms is greatest when the increase in plasma sodium is large and occurs rapidly. Body weight is decreased in proportion to the amount of water that has been lost. Because blood plasma is roughly 90% to 93% water, the concentrations of blood cells and other blood components increase as ECF water decreases. Thirst is an early symptom of water deficit, occurring when water losses are equal to 0.5% of body water. Urine output is decreased and urine osmolality increased because of renal water-conserving mechanisms. Body temperature frequently is elevated, and the skin becomes warm and flushed. The vascular volume decreases, the pulse becomes rapid and thready, and the blood pressure drops. Hypernatremia produces an increase in serum osmolality and results in water being pulled out of body cells. As a result, the skin and mucous membranes become dry, and salivation and lacrimation are decreased. The mouth becomes dry and sticky, and the tongue becomes rough and fissured. Swallowing is difficult. The subcutaneous tissues assume a firm, rubbery ­texture. Most  ­significantly, water is

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1040   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

TABLE 39.7 CAUSES AND MANIFESTATIONS OF HYPERNATREMIA CAUSES

MANIFESTATIONS

Excessive Water Losses Watery diarrhea Excessive sweating Increased respirations due to conditions such as tracheobronchitis Hypertonic tube feedings Diabetes insipidus

Laboratory Values Serum sodium level above 145 mEq/L (145 mmol/L) Increased serum osmolality Increased hematocrit and BUN

Decreased Water Intake Unavailability of water Oral trauma or inability to swallow Impaired thirst sensation Withholding water for therapeutic reasons Unconsciousness or inability to express thirst Excessive Sodium Intake Rapid or excessive administration of sodium-containing parenteral solutions Near-drowning in salt water

Thirst and Signs of Increased ADH Levels Polydipsia Oliguria or anuria High urine specific gravity Intracellular Dehydration Dry skin and mucous membranes Decreased tissue turgor Tongue rough and fissured Decreased salivation and lacrimation Signs Related to Hyperosmolality of ECFs and Movement of Water Out of Brain Cells Headache Agitation and restlessness Decreased reflexes Seizures and coma Extracellular Dehydration and Decreased Vascular Volume Tachycardia Weak and thready pulse Decreased blood pressure Vascular collapse

pulled out of the cells in the CNS, causing decreased reflexes, agitation, headache, and restlessness. Coma and seizures may develop as hypernatremia progresses. Diagnosis and Treatment.  The diagnosis of hypernatremia is based on history, physical examination findings indicative of dehydration, and results of laboratory tests. The treatment of hypernatremia includes measures to treat the underlying cause of the disorder and fluid replacement therapy to treat the accompanying dehydration. Replacement fluids can be given orally or intravenously. The oral route is preferable. Oral glucose–electrolyte replacement solutions are available for the treatment of infants with diarrhea.27 Until recently, these solutions were used only early in diarrheal illness or as a first step in reestablishing oral intake after parenteral replacement therapy. These solutions are now widely available in grocery stores and pharmacies for use in the treatment of diarrhea and other dehydrating disorders in infants and young children. One of the serious aspects of fluid volume deficit is dehydration of brain and nerve cells. Serum osmolality should be corrected slowly in cases of chronic hypernatremia. If hypernatremia is corrected too rapidly before the osmolytes have had a chance to dissipate, the plasma may become relatively hypotonic in relation to brain cell osmolality. When this occurs, water moves into the brain cells, causing cerebral edema and potentially severe neurologic impairment.

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IN SUMMARY Body fluids are distributed between the ICF and ECF compartments. Regulation of fluid volume, solute concentration, and distribution between the two compartments depends on water and sodium balance. Water provides approximately 90% to 93% of fluid volume, and sodium salts approximately 90% to 95% of extracellular solutes. Both water and sodium are absorbed from the gastrointestinal tract and eliminated by the kidneys. The main regulator of sodium and water is the maintenance of the effective circulating blood volume, which is monitored by stretch receptors in the vascular system, which exert their effects through ADH and the sympathetic nervous system, and those in the kidney, which exert their effects through the sympathetic nervous system and the RAAS. Body water and serum osmolality are also regulated by thirst, which controls water intake, and ADH, which controls urine concentration and renal output. Isotonic fluid disorders result from contraction or expansion of ECF volume brought about by proportionate losses of sodium and water. Isotonic fluid volume deficit is characterized by a decrease in ECF volume. It causes thirst, decreased vascular volume and circulatory function, decreased urine output, and increased urine specific gravity. Isotonic fluid volume excess is characterized by

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1041

an increase in ECF volume. It is manifested by signs of increased vascular volume and edema. Alterations in extracellular sodium concentration are brought about by a disproportionate gain (hyponatremia) or loss (hypernatremia) of water. As the major cation in the ECF compartment, sodium controls the ECF osmolality and its effect on cell volume. Hyponatremia can present as a hypertonic (translocational) hyponatremia in which water moves out of the cell in response to elevated blood glucose levels or as a hypotonic (dilutional) hyponatremia that is caused by retention of water by the body in excess of sodium. Hypotonic hyponatremia, which can present as a hypovolemic, euvolemic, or hypervolemic state, is characterized by water being pulled into the cell from the ECF compartment, causing cells to swell. It is manifested by muscle cramps and weakness; nausea, vomiting, abdominal cramps, and diarrhea; and CNS signs such as headache, lethargy, depression of deep tendon reflexes, and in severe cases seizure and coma. Hypernatremia represents a disproportionate loss of body water in relation to sodium. It is characterized by intracellular water being pulled into the ECF compartment, causing cells to shrink. It is manifested by thirst and decreased urine output; dry mouth and decreased tissue turgor; signs of decreased vascular volume (tachycardia, weak and thready pulse); and CNS signs, such as decreased reflexes, agitation, headache, and in severe cases seizures and coma.

POTASSIUM BALANCE After completing this section of the chapter, you should be able to meet the following objectives: •• Characterize the distribution of potassium in the body and explain how extracellular potassium levels are regulated in relation to body gains and losses. •• Relate the functions of potassium to the manifestations of hypokalemia and hyperkalemia.

Regulation of Potassium Balance Potassium is the second most abundant cation in the body and the major cation in the ICF compartment. Approximately 98% of body potassium is contained within body cells, with an intracellular concentration of 140 to 150 mEq/L (140 to 150 mmol/L).2 The potassium content of the ECF (3.5 to 5 mEq/L [3.5 to 5 mmol/L]) is considerably lower. Because potassium is an intracellular ion, total body stores of potassium are related to body size and muscle mass. In adults, total body potassium is approximately 50 mEq/kg of body weight.28 Gains and Losses Potassium intake is normally derived from dietary sources. In healthy people, potassium balance usually can be m ­ aintained

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by a daily dietary intake of 50 to 100 mEq. Additional amounts of potassium are needed during periods of trauma and stress. The kidneys are the main source of potassium loss. Approximately 80% to 90% of potassium losses occur in the urine, with the remainder being lost in stools or sweat. Mechanisms of Regulation Normally, the ECF concentration of potassium is precisely regulated at about 4.2 mEq/L (4.2 mmol/L). The precise control is necessary because many cell functions are sensitive to even small changes in ECF potassium levels. An increase in potassium of as small an amount as 0.3 to 0.4 mEq/L (0.3 to 0.4 mmol/L) can cause serious cardiac dysrhythmias and even death. Plasma potassium is largely regulated through two mechanisms: (1) renal mechanisms that conserve or eliminate potassium and (2) a transcellular shift between the ICF and ECF compartments. Renal Regulation.  The major route for potassium elimination is the kidney. Unlike other electrolytes, the regulation of potassium elimination is controlled by secretion from the blood into the tubular filtrate rather than through reabsorption from the tubular filtrate into the blood. Potassium is filtered in the glomerulus, reabsorbed along with sodium and water in the proximal tubule and with sodium and chloride in the thick ascending loop of Henle, and then secreted into the late distal and cortical collecting tubules for elimination in the urine. The latter mechanism serves to “fine-tune” the concentration of potassium in the ECF. Aldosterone plays an essential role in regulating potassium elimination by the kidney. The effects of aldosterone on potassium elimination are mediated through an Na+/K+ exchange mechanism located in the late distal and cortical collecting tubules of the kidney. In the presence of aldosterone, Na+ is transported back into the blood and K+ is secreted in the tubular filtrate for elimination in the urine. The rate of aldosterone secretion by the adrenal gland is strongly controlled by plasma potassium levels. For example, an increase of less than 1 mEq/L (1 mmol/L) of potassium causes aldosterone levels to triple.2 The effect of plasma potassium on aldosterone secretion is an example of the powerful feedback regulation of potassium elimination. In the absence of aldosterone, as occurs in people with Addison disease, renal elimination of potassium is impaired, causing plasma potassium levels to rise to dangerously high levels. Aldosterone is often referred to as a mineralocorticoid hormone because of its effect on sodium and potassium. The term mineralocorticoid activity is used to describe the aldosterone-like actions of other adrenocortical hormones, such as cortisol. There is also a K+/H+ exchange mechanism in the cortical collecting tubules of the kidney. When plasma potassium levels are increased, K+ is secreted into the urine and H+ is reabsorbed into the blood, producing a decrease in pH and metabolic acidosis. Conversely, when potassium levels are

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1042   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

low, K+ is reabsorbed and H+ is secreted in the urine, leading to metabolic alkalosis. Extracellular–Intracellular Shifts.  To avoid an increase in extracellular potassium levels, excess potassium is temporarily shifted into RBCs and other cells such as those of muscle, liver, and bone. This movement is controlled by the function of the Na+/K+-ATPase membrane pump and the permeability of the ion channels in the cell membrane. Among the factors that alter the intracellular–­extracellular distribution of potassium are serum osmolality, acid–base disorders, insulin, and β-adrenergic stimulation. Acute increases in serum osmolality cause water to leave the cell. The loss of cell water produces an increase in intracellular potassium, causing it to move out of the cell into the ECF. The H+ and K+ ions, which are positively charged, can be exchanged between the ICF and ECF in a cation shift (Fig.  39.8). In metabolic acidosis, for example, H+ moves into body cells for buffering, causing K+ to leave and move into the ECF.8 Both insulin and the catecholamines (e.g., epinephrine) increase cellular uptake of K+ by increasing the activity of the Na+/K+-ATPase membrane pump.1 Insulin produces an increase in cellular uptake of potassium after a meal. The catecholamines, particularly epinephrine, facilitate the movement of potassium into muscle tissue during periods of physiologic stress. β-Adrenergic agonist drugs, such as pseudoephedrine and albuterol, have a similar effect on potassium distribution. Exercise also produces compartmental shifts in potassium. Repeated muscle contraction releases potassium into the ECF. Although the increase usually is small with modest exercise, it can be considerable during exhaustive exercise. Even the repeated clenching and unclenching of the fist during a blood draw can cause potassium to move out of cells and artificially elevate plasma potassium levels.

Intracellular

Extracellular

K+ Na+/K +ATPase pump

+ +

Na+ Epinephrine Insulin

K+

H+

FIGURE 39 8  •  Mechanisms regulating transcellular shifts in ­potassium.

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KEY POINTS POTASSIUM BALANCE •  Potassium is mainly an intracellular ion with only a small, but vital, amount being present in the ECFs. •  The distribution of potassium between the intracellular and extracellular compartments regulates electrical membrane potentials controlling the excitability of nerve and muscle cells as well as contractility of skeletal, cardiac, and smooth muscle tissue. •  Two major mechanisms function in the control of serum potassium: (1) renal mechanisms that conserve or eliminate potassium and (2) transcellular buffer systems that remove potassium from and release it into the serum as needed. Conditions that disrupt the function of either mechanism can result in a serious alteration in serum potassium levels.

Disorders of Potassium Balance As the major intracellular cation, potassium is critical to many body functions. It is involved in a wide range of body functions, including the maintenance of the osmotic integrity of cells, acid–base balance, and the kidney’s ability to concentrate urine. Potassium is necessary for growth and it contributes to the intricate chemical reactions that transform carbohydrates into energy, change glucose into glycogen, and convert amino acids to proteins. Potassium also plays a critical role in conducting nerve impulses and the excitability of skeletal, cardiac, and smooth muscle. It does this by regulating the following: •• The resting membrane potential •• The opening of the sodium channels that control the flow of current during the action potential •• The rate of membrane repolarization Changes in nerve and muscle excitability are particularly important in the heart, where alterations in plasma potassium can produce serious cardiac arrhythmias and conduction defects. Changes in plasma potassium also affect skeletal muscles and the smooth muscle in blood vessels and the gastrointestinal tract. The resting membrane potential is determined by the ratio of ICF to ECF potassium concentration (Fig. 39.9). A decrease in plasma potassium causes the resting membrane potential to become more negative, moving it further from the threshold for excitation. Thus, it takes a greater stimulus to reach threshold and open the sodium channels that are responsible for the action potential. An increase in plasma potassium has the opposite effect; it causes the resting membrane potential to become more positive, moving it closer to threshold. With severe hyperkalemia, there may be prolonged depolarization that can decrease excitability. The rate of ­repolarization varies with

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1043

plasma potassium levels. It is more rapid in hyperkalemia and delayed in hypokalemia. Both the inactivation of the sodium channels and the rate of membrane repolarization are important clinically because they predispose to cardiac arrhythmias or conduction defects. Hyperkalemia is one of the most lifethreatening electrolyte disturbances especially with children.29

Threshold potential

Hyperkalemia

Resting membrane potential

Normal Hypokalemia

Normal Hypokalemia Hyperkalemia FIGURE 39.9  •  Effect of changes in plasma hypokalemia (red) and hyperkalemia (blue) on the resting membrane potential, activation and opening of the sodium channels at threshold potential, and the rate of repolarization during a nerve action potential.

Hypokalemia Hypokalemia refers to a decrease in plasma potassium levels below 3.5 mEq/L (3.5 mmol/L). Because of transcellular shifts, temporary changes in plasma potassium may occur as the result of movement between the ICF and ECF compartments. Etiology.  The causes of potassium deficit can be grouped into three categories: (1) inadequate intake; (2) excessive gastrointestinal, renal, and skin losses; and (3) redistribution between the ICF and ECF compartments (Table 39.8).30 Inadequate Intake  Inadequate intake is a frequent cause of hypokalemia. A potassium intake of at least 40 to 50 mEq/ day is needed daily. Insufficient dietary intake may result

TABLE 39.8 CAUSES AND MANIFESTATIONS OF HYPOKALEMIA CAUSES

MANIFESTATIONS

Inadequate Intake Diet deficient in potassium Inability to eat Administration of potassium-free parenteral solutions

Laboratory Values Serum potassium level below 3.5 mEq/L (3.5 mmol/L)

Excessive Renal Losses Diuretic therapy (except potassium- sparing diuretics) Diuretic phase of renal failure Increased mineralocorticoid levels Primary hyperaldosteronism Treatment with corticosteroid drugs

Impaired Ability to Concentrate Urine Polyuria Urine with low osmolality and specific gravity Polydipsia Gastrointestinal Manifestations Anorexia, nausea, vomiting Constipation Abdominal distention Paralytic ileus

Excessive Gastrointestinal Losses Vomiting Diarrhea Gastrointestinal suction Draining gastrointestinal fistula

Neuromuscular Manifestations Muscle flabbiness, weakness, and fatigue Muscle cramps and tenderness Paresthesias Paralysis

Transcompartmental Shift Administration of β-adrenergic agonist (e.g., albuterol) Administration of insulin for treatment of diabetic ketoacidosis Alkalosis, metabolic or respiratory

Cardiovascular Manifestations Postural hypotension Increased sensitivity to digitalis toxicity Changes in electrocardiogram Cardiac dysrhythmias CNS Manifestations Confusion Depression Acid–Base Disorders Metabolic alkalosis

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1044   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

from the inability to obtain or ingest food or from a diet that is low in potassium-containing foods. Potassium intake is often inadequate in persons on fad diets and those who have eating disorders. Older adults are particularly likely to have potassium deficits. Many have poor eating habits as a consequence of living alone; they may have limited income, which makes buying foods high in potassium difficult; they may have difficulty chewing many foods that have high potassium content because of dental problems; or they may have problems with swallowing. Excessive Losses. The kidneys are the main source of potassium loss. Approximately 80% to 90% of potassium losses occur in the urine, with the remaining losses occurring in the stool and sweat. The kidneys do not have the homeostatic mechanisms needed to conserve potassium during periods of insufficient intake. After trauma and in stress situations, urinary losses of potassium are generally increased and can cause a serious hypokalemia.30 This means that a potassium deficit can develop rather quickly if intake is inadequate. Renal losses also can be increased by medications such as thiazides, metabolic alkalosis, magnesium depletion, and increased levels of aldosterone. Some antibiotics, particularly amphotericin B and gentamicin, are impermeable anions that require the presence of positively charged cations for elimination in the urine; this causes potassium wasting. Diuretic therapy, with the exception of potassium-­ sparing diuretics, is the most common cause of hypokalemia. Both thiazide and loop diuretics increase the loss of potassium in the urine. The degree of hypokalemia is directly related to diuretic dose and is greater when sodium intake is higher.31 Magnesium depletion causes renal potassium wasting. Magnesium deficiency often coexists with potassium depletion due to diuretic therapy or disease processes such as diarrhea. Importantly, the ability to correct potassium deficiency is impaired when magnesium deficiency is present. Renal losses of potassium are accentuated by aldosterone and cortisol. Increased potassium losses occur in situations such as trauma and surgery that produce a stress-related increase in these hormones. Primary aldosteronism, caused by either a tumor or hyperplasia of the cells of the adrenal cortex that secrete aldosterone, produces severe potassium losses and a decrease in plasma potassium levels.32 Cortisol binds to aldosterone receptors and exerts aldosterone-like effects on potassium elimination. Other rare, genetic disorders that can also result in hypokalemia are the Bartter, Gitelman, and Liddle syndromes. Bartter syndrome, which involves the Na+/K+/2Cl− cotransporter in the thick loop of Henle, is manifested by metabolic alkalosis, hypercalciuria or excessive loss of calcium in the urine, and normal blood pressure.33 Because the loop diuretics act at the same site in the kidney, these features are identical to those seen with chronic loop diuretic ingestion. The manifestations of Gitelman syndrome, which involves the Na+/Cl− transporter in the distal tubule, are similar to those of Bartter syndrome, but with hypocalciuria and hypomagnesemia due to renal m ­ agnesium w ­ asting.34 Because this is the site where

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the thiazide diuretics exert their action, these manifestations are identical to those seen with chronic thiazide diuretic ingestion. Liddle syndrome has manifestations similar to Bartter syndrome, but with high blood pressure due to excessive sodium reabsorption.35 Although potassium losses from the skin and the gastrointestinal tract usually are minimal, these losses can become excessive under certain conditions. For example, burns increase surface losses of potassium. Losses due to sweating increase in persons who are acclimated to a hot climate, partly because increased secretion of aldosterone during heat acclimatization increases the loss of potassium in urine and sweat. Gastrointestinal losses also can become excessive; this occurs with vomiting and diarrhea and when gastrointestinal suction is being used. The potassium content of liquid stools, for example, is approximately 40 to 60 mEq/L (40 to 60 mmol/L). Transcellular Shifts.  Because of the high ratio of intracellular to extracellular potassium, conditions that produce a redistribution of potassium from the ECF to the ICF compartment can cause a marked decrease in plasma potassium levels (see Fig. 39.8). Insulin increases the movement of glucose and potassium into cells; therefore, potassium deficit often develops during treatment of diabetic ketoacidosis. A wide variety of β2-adrenergic agonist drugs (e.g., decongestants and bronchodilators) shift potassium into cells and cause transient hypokalemia. Clinical Manifestations.  The manifestations of hypokalemia include alterations in renal, gastrointestinal, cardiovascular, and neuromuscular function (see Table 39.8). These manifestations reflect both the intracellular functions of potassium as well as the body’s attempt to regulate ECF potassium levels within the very narrow range needed to maintain the normal electrical activity of excitable tissues such as nerve and muscle cells. The signs and symptoms of potassium deficit seldom develop until plasma potassium levels have fallen to levels below 3 mEq/L (3 mmol/L). They are typically gradual in onset, and therefore the disorder may go undetected for some time. The renal processes that conserve potassium during hypokalemia interfere with the kidney’s ability to concentrate urine. Urine output and plasma osmolality are increased, urine specific gravity is decreased, and complaints of polyuria, nocturia, and thirst are common (an example of nephrogenic DI). Metabolic alkalosis and renal chloride wasting are signs of severe hypokalemia.36 There are numerous signs and symptoms associated with gastrointestinal function, including anorexia, nausea, and vomiting. Atony of the gastrointestinal smooth muscle can cause constipation, abdominal distention, and, in severe hypokalemia, paralytic ileus. When gastrointestinal symptoms occur gradually and are not severe, they often impair potassium intake and exaggerate the condition. The most serious effects of hypokalemia are those affecting cardiovascular function. Postural hypotension is common. Most people with plasma potassium levels below 3 mEq/L (3 mmol/L) demonstrate electrocardiographic (ECG) changes

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1045 Normal

R Delay in AV node

T

P

U

Q S Hypokalemia PR prolongation

Depressed ST segment Low T

Prominent U wave

Hyperkalemia Widening of QRS

Peaked T

PR prolongation

Low P wave

FIGURE 39.10  •  ECG changes with hypokalemia and hyperkalemia.

typical of hypokalemia. These changes include prolongation of the PR interval, depression of the ST segment, flattening of the T wave, and appearance of a prominent U wave (Fig. 39.10). Normally, potassium leaves the cell during the repolarization phase of the action potential, returning the membrane potential to its normal resting value. Hypokalemia reduces the permeability of the cell membrane to potassium and thus produces a decrease in potassium efflux that prolongs the rate of repolarization and lengthens the relative refractory period. The U wave normally may be present on the ECG but should be of lower amplitude than the T wave. With hypokalemia, the amplitude of the T wave decreases as the U-wave amplitude increases. Although these changes in electrical activity of the heart usually are not serious, they may predispose to sinus bradycardia and ectopic ventricular arrhythmias. Digitalis toxicity can be provoked in people treated with this drug, and there is an increased risk of ventricular arrhythmias, particularly in people with underlying heart disease. The dangers associated with digitalis toxicity are compounded in people who are receiving diuretics that increase urinary losses of potassium.

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Complaints of weakness, fatigue, and muscle cramps, particularly during exercise, are common in moderate h­ ypokalemia (plasma potassium 3 to 2.5 mEq/L [3 to 2.5 mmol/L]). Muscle paralysis with life-threatening respiratory insufficiency can occur with severe hypokalemia (plasma potassium 12 mg/dL) is associated with muscle and respiratory paralysis, complete heart block, and cardiac arrest. Treatment. The treatment of hypermagnesemia includes cessation of magnesium administration. Calcium is a direct antagonist of magnesium, and intravenous administration of calcium may be used. Peritoneal dialysis or hemodialysis may be required.

IN SUMMARY Calcium, phosphorus, and magnesium are major divalent ions in the body. Calcium is a major divalent cation. Approximately 99% of body calcium is found in bone; less than 1% is found in the ECF compartment. The calcium in bone is in dynamic equilibrium with ECF calcium. Of the three forms of ECF calcium (i.e., protein bound, complexed, and ionized), only the ionized form can cross the cell membrane and contribute to cellular function. Ionized calcium has a number of functions. It contributes to ­neuromuscular function, plays a vital role in the blood clotting process, and participates in a number of enzyme reactions. Alterations in ionized calcium levels produce neural effects; neural excitability is increased in hypocalcemia and decreased in hypercalcemia.

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Phosphorus is largely an ICF anion. It is incorporated into the nucleic acids and ATP. The most common causes of altered levels of ECF phosphate are alterations in intestinal absorption, transcompartmental shifts, and disorders of renal elimination. Phosphorus deficit causes signs and symptoms of neural dysfunction, disturbed musculoskeletal function, and hematologic disorders. Most of these manifestations result from a decrease in cellular energy stores due to a deficiency in ATP and O2 transport by 2,3DPG in the RBC. Phosphorus excess occurs with renal failure and PTH deficit. It is associated with decreased plasma calcium levels. Magnesium is the second most abundant ICF cation. It acts as a cofactor in many intracellular enzyme reactions and is required for cellular energy metabolism, functioning of the Na+/K+-ATPase membrane pump, nerve c­ onduction, ion transport, and potassium and calcium channel a­ ctivity. Magnesium blocks the outward movement of potassium in cardiac cells; when magnesium levels are low, the channel permits outward flow of potassium, resulting in low levels of intracellular potassium. It acts on calcium channels to inhibit the movement of calcium into cells. Magnesium deficiency can result from insufficient intake, excessive losses, or movement between the ECF and ICF compartments. Hypomagnesemia impairs PTH release and the actions of PTH; it leads to a reduction in ICF potassium and impairs the ability of the kidney to ­conserve potassium. Hypermagnesemia usually is related to renal insufficiency and the injudicious use of magnesium-containing medications such as antacids, mineral supplements, or laxatives. It can cause neuromuscular dysfunction with hyporeflexia, muscle weakness, and confusion. Magnesium decreases acetylcholine release at the ­myoneural junction and may cause neuromuscular blockade and respiratory paralysis.

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1060   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

REVIEW EXERCISES 1. A 40-year-old man with advanced acquired immunodeficiency syndrome (AIDS) presents with an acute chest infection. Investigations ­confirm a diagnosis of Pneumocystis jirovecij (formerly P. carinii) pneumonia. Although he is being treated appropriately, his plasma sodium level is 118 mEq/L (118 mmol/L). Results of adrenal function tests are normal. A. What is the likely cause of his electrolyte disturbance? B. What are the five cardinal features of this condition? 2. A 70-year-old woman who is taking furosemide (a loop diuretic) for congestive heart failure complains of weakness, fatigue, and cramping of the muscles in her legs. Her plasma potassium is 2 mEq (2 mmol/L), and her plasma sodium is 140 mEq/L (140 mmol/L). She also complains that she notices a “strange heartbeat” at times. A. What is the likely cause of this woman’s symptoms? B. An ECG shows depressed ST segment and low T-wave changes. Explain the physiologic mechanism underlying these changes. C. What would be the treatment for this woman? 3. A 50-year-old woman presents with symptomatic hypercalcemia. She has a recent history of breast cancer treatment. A. How do you evaluate this person with increased plasma calcium levels? B. What is the significance of the recent history of malignancy? C. What further tests may be indicated?

References 1. Rhoades R. A., Bell D. R. (2009). Medical physiology: Principles for clinical medicine (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2. Hall J. E. (2011). Guyton and Hall textbook of medical physiology (12th ed.). Philadelphia, PA: Elsevier Saunders. 3. Nielsen S., Kwon T. H., Frekiaer, J., et al. (2007). Regulation and dysregulation of aquaporins in water balance disorders. Journal of Internal Medicine 261(1), 53–64. 4. Rennke H. G., Denker B. M. (2010). Renal pathophysiology: The essentials (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 5. Poaage E., Singer M., Armer J., et al. (2008). Demystifying lymphedema: Development of the lymphedema putting evidence into practice card. Clinical Journal of Oncology Nursing 12(6), 951–964. 6. Zuther J. E. (2005). Lymphedema management: The comprehensive guide for practitioners. New York: Thieme Medical Publishers. 7. Morton P. G., Fontaine D. K. (2009). Critical care nursing: A holistic approach (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 8. Ball J., Bindler R., Cowen, K. (2012). Principles of pediatric nursing: Caring for children (5th ed.). Boston, MA: Pearson.

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9. McKinley M. J., Johnson A. K. (2004). The physiological regulation of thirst and fluid intake. News in Physiological Sciences 19, 1–6. 10. Zizza C. A, Ellison K. J., Wernette C. M. (2009). Total water intakes of community living of middle-old and oldest-old adults. Journal of Gerontological Series A: Biological Sciences and Medical Sciences 64A(4), 481–486. 11. Valente S., Fisher D. (2010). Recognizing and managing psychogenic polydipsia in mental health. Journal for Nurse Practitioners 6(7), 546–550. 12. Lin M., Liu S. J., Lim I. T. (2005). Disorders of water imbalance. Emergency Medicine Clinics of North America 23, 749–770. 13. Palm C., Pistrosch F., Herbrig K., et al. (2006). Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. American Journal of Medicine 119(7 Suppl. 1), S87–S92. 14. Makaryus A. N., McFarlane S. I. (2006). Diabetes insipidus: Diagnosis and treatment of a complex disease. Cleveland Clinic Journal of Medicine 73, 65–71. 15. Eknoyan G. (2010). A history of diabetes insipidus: Paving the road to internal water balance. American Journal of Kidney Diseases 56(6), 1175–1183. 16. Sands J. M., Bichet D. G. (2006). Nephrogenic diabetes insipidus. Annals of Internal Medicine 144, 186–194. 17. Robertson G. L. (2006). Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. American Journal of Medicine 119 (7 Suppl. 1), S36–S42. 18. Decauyo G. (2009). The syndrome of inappropriate secretion of antidiuretic hormone. Seminars in Nephrology 29(3), 239–256. 19. de Vries F. C., de Jager C. P. (2011). Images in clinical medicine: Decreased skin turgor. New England Journal of Medicine 364(4), e6. 20. Jensen S. (2011). Nursing health assessment: A best practice approach. Philadelphia, PA: Lippincott Williams & Wilkins. 21. Gohl K. P. (2004). Management of hyponatremia. American Family Physician 69, 2387–2394. 22. Schrier R. W. (2006). Water and sodium retention in edematous disorders: Role of vasopressin and aldosterone. American Journal of Medicine 119(7 Suppl. 1), S47–S53. 23. Haskal R. (2007). Current issues for nurse practitioners: Hyponatremia. Journal of American Academy of Nurse Practitioners 19(11), 563–579. 24. Elhassan E. A., Schrier, R. W. (2011). Hyponatremia: Diagnosis, complications, and management including V2 receptor antagonists. Current Opinion in Nephrology & Hypertension 20(2), 161–168. 25. Adrogue H. J., Madias N. E. (2000). Hypernatremia. New England Journal of Medicine 342, 1493–1499. 26. Lindner G., Funk G., Schwartz C., et al. (2007). Hypernatremia in the critically ill is an independent risk factor for mortality. American Journal of Kidney Diseases 50(6), 952–957. 27. Rao M. C. (2004). Oral rehydration therapy. Annual Review of Physiology 66, 183–417. 28. Schaefer T. J., Wolford R. W. (2005). Disorders of potassium. Medical Clinics of North America 23, 723–747. 29. Lenhardt A., Kemper M. (2011). Pathogenesis, diagnosis, and management of hyperkalemia. Pediatric Nephrology 26(3), 377–384. 30. Palmer B. F. (2010). A physiologic based approach to the evaluation of a patient with hypokalemia. American Journal of Kidney Diseases 56(6), 1184–1190. 31. Reungjul S., Pratipanwatr T, Johnson R. J., et al. (2008). Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Current Opinion in Nephrology & Hypertension 17(5), 470–476. 32. Fallo F., Bertello C., Tizzani D., et al. (2011). Concurrent primary aldosteronism and subclinical cortisol hypersecretion: A prospective study. Journal of Hypertension 29(9), 1773–1777. 33. Yamazaki H., Nozu K., Narita I., et al. (2009). Atypical phenotype of type I Bartter syndrome accompanied by focal segmental glomerulosclerosis. Pediatric Nephrology 24(2), 415–418. 34. Slovacek L. (2009). Gitelman’s syndrome: A hereditary disorder characterized by hypokalemia and hypomagnesemia. European Journal of General Medicine 6(2), 127–130.

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Chapter 39  Disorders of Fluid and Electrolyte Balance    1061 35. Tapolyai M., Uysal A., Dossabhoy N. R., et al. (2010). High prevalence of Liddle syndrome phenotype among hypertensive United States veterans in northwest Louisiana. Journal of Clinical Hypertension 12(11), 856–860. 36. Bircan Z., Mutlu H., Cheong H. I. (2010). Differential diagnosis of hereditary nephrogenic diabetes insipidus with desmopressin infusion test. Indian Journal of Pediatrics 77(11), 1329–1331. 37. Kim J. B., Lee G. M., Kim S. J., et al. (2011). Expression patterns of two potassium channel genes in skeletal muscle cells of patient with familial hypokalemic periodic paralysis. Neurology India 59(4), 527–531. 38. Tangiera E. D. (2004). Hyperparathyroidism. American Family Physician 69, 333–340. 39. Hollander-Rodriguez J. C., Calvert J. F. (2006). Hyperkalemia. American Family Physician 73, 283–290. 40. Barker M. C. (2010). Combined spinal/general anesthesia with postop femoral nerve block for total potassium replication in a patient with familial hyperkalemic periodic paralysis: A case report. American Association of Nurse Anesthetists 78(3), 191–194. 41. Vraets A., Lin Y., Callum J. L. (2011). Transfusion associated hyperkalemia. Transfusion Medicine Reviews 25(3), 184–196. 42. Ross M. H., Pawlina W. (2011). Histology: A text and atlas with correlated cell and molecular biology (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 43. Quarles L. D. (2003). Extracellular calcium-sensing receptors in the parathyroid gland, kidney, and other tissues. Current Opinion in Nephrology and Hypertension 12, 349–355. 44. Karamanakos S. N., Markou K. B., Panagopoulis K., et al. (2010). Complications and risk factors related to the extent of surgery in thyroidectomy. Results from 2,043 procedures. Hormones 9(4), 318–325. 45. Clark O. H. (2003). How should patients with primary hyperparathyroidism be treated? Journal of Clinical Endocrinology and Metabolism 88, 3011–3014. 46. Goodman W. G. (2003). Medical management of secondary hyperparathyroidism in chronic renal failure. Nephrology, Dialysis and Transplantation 18(Suppl. 3), S2–S8. 47. Eddington H., Kalra P. A. (2010). The association of chronic kidney disease- mineral bone disorder and cardiovascular risk. Journal of Renal Care 36(Suppl. 1), 61–67. 48. Kuang D. O., You H., Ding F., et al. (2009). Intima-media thickness of the maintenance hemodialysis patients: A cross sectional study. Blood Purification 28(3), 181–186. 49. Hervas J. G., Prados D., Cerezo S. (2003). Treatment of hyperphosphatemia with sevelamer hydrochloride in hemodialysis patients. Kidney International 85, 69–72. 50. Egl M., Kim I., Nichol A., et al. (2011). Ionized calcium concentrations and outcomes in critical illness. Critical Care Medicine 39(2), 314–321. 51. Magnotti L. J., Bradburn E. H., Webb D. L., et al. (2011). Admission calcium levels predict the need for multiple transfusions: A prospective study of 591 critically ill trauma patients. Journal of Trauma 70(2), 391–397.

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52. Buckley M. S., Leblance J. M., Cawley M. J. (2010). Electrolyte disturbances associated with commonly prescribed medications in the intensive care unit. Critical Care Medicine 38 (6 Suppl.), S253–264. 53. Dunphy L. M., Winland-Brown J. E., Porter B. O., et al. (2011). Primary care: The art and science of advanced practice nursing (3rd ed.). Philadelphia, PA: FA Davis. 54. Lehne R. (2010). Pharmacology for Nursing Care (7th ed.). St. Louis, MO: Elsevier. 55. Assadi F. (2009). Hypercalcemia: An evidence-based approach to clinical cases. Iranian Journal of Kidney Disease 3(2), 71–79. 56. Yarbro C. H., Wujcik D., Gobel B. H. (Eds.) (2011). Oncology nursing: Principles and practice (7th ed.). Sudbury, MA: Jones & Bartlett Publishers. 57. Lietman S. A., Germain-Lee E. L., Levine M. A. (2010). Hypercalcemia in children and adolescents. Current Opinion in Pediatrics 22(4), 508–515. 58.Wang C., Chen Y., Shiang J., et al. (2009). Hypercalcemic crisis successfully treated with prompt calcium–free hemodialysis. American Journal of Emergency Medicine 1174, E1–E3. 59. Schiav S. C., Kumar R. (2004). The phosphatonin pathway: New insights in phosphate homeostasis. Kidney International 65, 1–14. 60. Berndt T. J., Schiavi S., Kumar R. (2005). “Phosphatonins” and the regulation of phosphorus homeostasis. American Journal of Physiology: Renal Physiology 289(6), F1170–F1182. 61. Marinella M. A. (2009). Refeeding syndrome: An important aspect of supportive oncology. Journal of Supportive Oncology 7(1), 11–16. 62. Roman-Garcia P., Carullo-Lopez N., Cannata-Andia J. B. (2009). Pathogenesis of bone and mineral related disorders in chronic kidney disease: Key role of hyperphosphatemia. Journal of Renal Care 35(Suppl. 1), 34–38. 63. Gums J. G. (2004). Magnesium in cardiovascular and other disorders. American Journal of Health-System Pharmacy 61, 1569–1576. 64. Hunter L. A., Gibbins K. L. (2011). Magnesium sulfate: Past, present, and future. Journal of Midwifery & Women’s Health 56(6), 566–574. 65. Rouse D. J. (2011). Using magnesium sulfate for fetal neuroprotection. Contemporary Obstetrics/Gynecology 56(4), 54–60. 66. Konrad M., Schlingmann K. P., Gundermann T. (2003). Insights into the molecular nature of magnesium homeostasis. American Journal of Physiology: Renal Physiology 286, F599–F605. 67. Konrad M., Weber S. (2003). Recent advances in molecular genetics of hereditary magnesium-losing disorders. Journal of the American Society of Nephrology 14, 249–260. 68. Assadi F. (2010). Hypomagnesemia: An evidence-based approach to clinical cases. Iranian Journal of Kidney Diseases 4(1), 13–19. 69. Topf J. M., Murray P. T. (2003). Hypomagnesemia and hypermagnesemia. Reviews in Endocrine and Metabolic Disorders 4, 195–206.

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Disorders of Acid–Base Balance MECHANISMS OF ACID–BASE BALANCE

Acid–Base Chemistry Metabolic Acid and Bicarbonate Production Carbon Dioxide and Bicarbonate Production Production of Fixed or Nonvolatile Acids and Bases Calculation of pH Regulation of pH Chemical Buffer Systems Respiratory Control Mechanisms Renal Control Mechanisms Laboratory Tests Carbon Dioxide and Bicarbonate Levels Base Excess or Deficit Anion Gap

40 Theresa A. Kessler

The need for precise regulation of hydrogen ion (H+) ­balance is similar in many ways to that of other ions in the body. Membrane excitability, enzyme systems, and chemical reactions all depend on the H+ concentration being regulated within a narrow physiologic range to function in an optimal way. Many conditions, pathologic or otherwise, can alter H+ concentration and acid–base balance. This chapter has been organized into two sections: Mechanisms of Acid–Base Balance and Disorders of Acid–Base Balance.

DISORDERS OF ACID–BASE BALANCE

Metabolic Versus Respiratory Acid–Base Disorders Compensatory Mechanisms Single Versus Mixed Acid–Base Disorders Metabolic Acidosis Etiology Clinical Manifestations Treatment Metabolic Alkalosis Etiology Clinical Manifestations Treatment Respiratory Acidosis Etiology Clinical Manifestations Treatment Respiratory Alkalosis Etiology Clinical Manifestations Treatment

MECHANISMS OF ACID–BASE BALANCE After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the three forms of carbon dioxide transport and their contribution to acid–base balance. •• Describe the intracellular and extracellular mechanisms for buffering changes in body pH. •• Compare the roles of the kidneys and respiratory ­system in regulation of acid–base balance.

Normally, the concentration of body acids and bases is regulated so that the pH of extracellular body fluids is maintained within a very narrow range of 7.35 to 7.45. This balance is maintained through mechanisms that generate, buffer, and eliminate acids and bases. This section of the chapter focuses on acid–base chemistry, the production and regulation of metabolic acids and bicarbonate, calculation of pH, and laboratory tests of acid–base balance.

Acid–Base Chemistry An acid is a molecule that can release an H+, and a base is an ion or molecule that can accept or combine with an H+.1−3 For example, hydrochloric acid (HCl) dissociates in water to form hydrogen (H+) and chloride (Cl−) ions. A base, such as 1062

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Chapter 40  Disorders of Acid–Base Balance    1063

the bicarbonate ion (HCO3−), is a base because it can combine with H+ to form carbonic acid (H2CO3). Most of the body’s acids and bases are weak acids and bases, the most important being H2CO3, which is a weak acid derived from carbon dioxide (CO2), and bicarbonate (HCO3−), which is a weak base. Acids and bases exist as buffer pairs or systems—a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. When an acid (HA) is added to water, it dissociates reversibly to form H+ and its conjugate anion (A−). An example of this is HA × H+ + A−. The degree to which an acid dissociates and acts as an H+ donor determines whether it is a strong or weak acid. Strong acids, such as sulfuric acid, dissociate completely. Weak acids, such as acetic acid, dissociate only to a limited extent. The same is true of a base and its ability to dissociate and accept an H+. The concentration of H+ in body fluids is low compared with other ions.1 For example, the sodium ion (Na+) is present at a concentration approximately 3.5 million times that of H+. Because it is cumbersome to work with such a small number, the H+ concentration is commonly expressed in terms of the pH. Specifically, pH represents the negative logarithm (log10) of the H+ concentration expressed in milliequivalents per liter (mEq/L).1 Thus, a pH value of 7.0 implies an H+ concentration of 10–7 (0.0000001 mEq/L). Because the pH is inversely related to the H+ concentration, a low pH indicates a high concentration of H+, and a high pH indicates a low concentration. The dissociation constant (K) is used to describe the degree to which an acid or base in a buffer system dissociates.1,2 The symbol pK refers to the negative log10 of the dissociation constant for an acid and represents the pH at which an acid is 50% dissociated.3 Use of a negative log10 for the dissociation constant allows pH to be expressed as a positive value. Each acid in an aqueous solution has a characteristic pK that varies slightly with temperature and pH. At normal body temperature, the pK for the bicarbonate buffer system of the extracellular fluid (ECF) compartment is 6.1.1−3

Key Points MECHANISMS OF ACID–BASE BALANCE •  The pH is regulated by extracellular (carbonic acid [H2CO3]/bicarbonate [HCO3−]) and intracellular (proteins) systems that buffer changes in pH that would otherwise occur because of the metabolic production of volatile (CO2) and nonvolatile (i.e., sulfuric and phosphoric) acids.

Metabolic Acid and Bicarbonate Production Acids are continuously generated as by-products of metabolic processes (Fig. 40.1). Physiologically, these acids fall into two groups: the volatile acid H2CO3 and all other nonvolatile or

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Food intake Digestion Absorption Cell metabolism of food Sulfate Phosphate Chloride

H+

CO2

Chemical buffering

Respiratory response

H+ Bound by body buffer bases

CO2

Renal response

Extracellular fluid [HCO3-]

CO2

Sulfate Phosphate Chloride

New HCO3–

Extracellular fluid [HCO3–] H+ Excreted (combined with urinary buffer bases) Excreted Sulfate Phosphate Chloride

FIGURE 40.1 • The maintenance of normal blood pH by chemical buffers, the respiratory system, and the kidneys. On a mixed diet, pH is threatened by the production of strong acids (sulphuric, hydrochloric, and phosphoric) mainly as the result of protein metabolism. These strong acids are buffered in the body by chemical buffer bases, such as extracellular fluid (ECF) bicarbonate (HCO3−). The respiratory system disposes of carbon dioxide (CO2). The kidneys eliminate hydrogen ions (H+) combined with urinary buffers and anions in the urine. At the same time, they add new HCO3− to the ECF, to replace the HCO3− consumed in buffering strong acids. (From Rhodes RA, Tanner GA. (2003). Medical physiology (2nd ed., p. 429). Philadelphia, PA: Lippincott Williams & Wilkins.)

fixed acids. The difference between the two types of acids arises because H2CO3 is in equilibrium with CO2 (H2CO3 ↔ CO2 + H2O), which is volatile and leaves the body by way of the lungs. Therefore, the lungs and their capacity to exhale CO2 determine H2CO3 concentration. The lungs do not eliminate fixed or nonvolatile acids (e.g., sulfuric, hydrochloric, phosphoric). Instead, they are buffered by body proteins or extracellular buffers, such as HCO3−, and then eliminated by the kidney. Carbon Dioxide and Bicarbonate Production Body metabolism results in the production of approximately 15,000 mmol of CO2 each day.4 Carbon dioxide is transported in the circulation in three forms: 1. As a dissolved gas 2. As bicarbonate 3. As carbaminohemoglobin (see “Understanding: Carbon Dioxide Transport”)

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1064   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Understanding

Carbon Dioxide Transport

Body metabolism results in a continuous production of carbon dioxide (CO2). As CO2 is formed during the metabolic process, it diffuses out of body cells into the tissue spaces and then into the circulation. It is transported in the circulation in three forms: (1) dissolved in the plasma, (2) as bicarbonate, and (3) attached to hemoglobin.

Plasma Body cell

A small portion (about 10%) of the CO2 that is produced by body cells is transported in the dissolved state to the lungs and then exhaled. The amount of dissolved CO2 that can be carried in plasma is determined by the partial pressure of the gas (PCO2) and its solubility coefficient (0.03 mL/100 mL plasma for each 1  mm Hg PCO2). Thus, each 100 mL of arterial blood with a PCO2 of 40 mm Hg would contain 1.2 mL of dissolved CO2. It is the carbonic acid (H2CO3) formed from hydration of dissolved CO2 that contributes to the pH of the blood.

CO2

CO2 dissolved in plasma

10% transported as CO2 dissolved in plasma

Bicarbonate Carbon dioxide in excess of that which can be carried in the plasma moves into the red blood cells, where the enzyme ­carbonic anhydrase (CA) catalyzes its conversion to carbonic acid (H2CO3). The H2CO3, in turn, dissociates into hydrogen (H+) and bicarbonate (HCO3−) ions. The H+ combines with hemoglobin and the HCO3− diffuses into plasma, where it participates in acid–base regulation. The movement of HCO3− into the plasma is made possible by a special transport system on the red blood cell membrane in which HCO3− ions are exchanged for chloride ions (Cl−).

Hemoglobin The remaining CO2 in the red blood cells combines with hemoglobin to form carbaminohemoglobin (HbCO2). The ­ ­combination of CO2 with hemoglobin is a reversible reaction characterized by a loose bond, so that CO2 can be easily released in the alveolar capillaries and exhaled from the lung.

CO2 H2O

CO2 dissolved in plasma

CO2 + H2O CA H2CO3 Hb

H+ + HCO3– HHb

Cl– (Chloride shift) HCO3– (dissolved)

70% transported as HCO3– dissolved in plasma

CO2 CO2 dissolved in plasma

CO2 HbCO2 Hemoglobin (Hb)

Red blood cell

20% carried as carbaminohemoglobin (HbCO2)

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Chapter 40  Disorders of Acid–Base Balance    1065

Collectively, dissolved CO2 and HCO3− account for approximately 77% of the CO2 that is transported in the ECF; the remaining CO2 travels as carbaminohemoglobin (CO2 bound to amino acids in hemoglobin).1 Although CO2 is a gas and not an acid, a small percentage of the gas combines with water to form H2CO3. The reaction that generates H2CO3 from CO2 and water is catalyzed by an enzyme called carbonic anhydrase, which is present in large quantities in red blood cells, renal tubular cells, and other tissues in the body. The rate of the reaction between CO2 and water is increased approximately 5000 times by the presence of carbonic anhydrase. Were it not for this enzyme, the reaction would occur too slowly to be of any significance in maintaining acid–base balance. Because it is almost impossible to measure H2CO3, CO2 measurements are commonly used when calculating pH. The H2CO3 content of the blood can be calculated by multiplying the partial pressure of CO2 (PCO2) by its solubility coefficient, which is 0.03. This means that the concentration of H2CO3 in the arterial blood, which normally has a PCO2 of approximately 40 mm Hg, is 1.20 mEq/L (40 × 0.03 = 1.20), and that for venous blood, which normally has a PCO2 of approximately 45 mm Hg, is 1.35 mEq/L. Production of Fixed or Nonvolatile Acids and Bases The metabolism of dietary proteins and other nutrients results in the generation of fixed or nonvolatile acids and bases.2,4,5 Oxidation of the sulfur-containing amino acids (e.g., methionine, cysteine) results in the production of sulfuric acid. Oxidation of arginine and lysine produces hydrochloric acid, and oxidation of phosphorus-containing nucleic acids yields phosphoric acid. Incomplete oxidation of glucose results in the formation of lactic acid and incomplete oxidation of fats, the production of ketoacids. The major source of base is the metabolism of amino acids such as aspartate and glutamate and the metabolism of certain organic anions (e.g., citrate, lactate, acetate). Acid production normally exceeds base production during the breakdown of consumed foods.2 A normal diet results in 50 to 100 mEq of H+ each day as nonvolatile sulfuric acid.4 Consumption of a vegetarian diet, which contains large amounts of organic anions, results in the net production of base.

Calculation of pH The plasma pH can be calculated using an equation called the Henderson-Hasselbalch equation.1,2 This equation uses the pK of the bicarbonate buffer system, which is 6.1, and log10 of the HCO3− to dissolved CO2 (H2CO3) ratio: pH = 6.1 + log10 (HCO3−/PCO2 × 0.03) The pH designation was created to express the low value of H+ more easily.2 It should be noted that it is the ratio rather than the absolute values for bicarbonate and dissolved CO2 that determines pH (e.g., when the ratio is 20:1, the pH = 7.4). Plasma pH decreases when the ratio is less than 20:1, and it increases when the ratio is greater than 20:1  (Fig.  40.2).

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Because it is the ratio rather than the a­ bsolute values of HCO3− or CO2 that determines pH, the pH can remain within a relatively normal range as long as changes in HCO3− are accompanied by similar changes in CO2, or vice versa. For example, the pH will remain at 7.4 when plasma HCO3− has increased from 24 to 48 mEq/L as long as CO2 levels have also doubled. Likewise, the pH will remain at 7.4 when plasma HCO3− has decreased from 24  to 12 mEq/L as long as CO2 levels have also been reduced by one half. Plasma pH only indicates the balance or ratio and not where problems originate.6

Regulation of pH The pH of body fluids (or change in H+ concentration) is regulated by three major mechanisms: 1. Chemical buffer systems of the body fluids, which immediately combine with excess acids or bases to prevent large changes in pH 2. The lungs, which control the elimination of CO2 3. The kidneys, which eliminate H+ and both reabsorb and generate new HCO3− Chemical Buffer Systems The moment-by-moment regulation of pH depends on chemical buffer systems of the intracellular (ICF) and extracellular fluids (ECF). As previously discussed, a buffer system consists of a weak base and its conjugate acid pair or a weak acid and its conjugate base pair. In the process of preventing large changes in pH, the system trades a strong acid for a weak acid or a strong base for a weak base. The three major buffer systems that protect the pH of body fluids are 1. The bicarbonate buffer system 2. Proteins 3. The transcellular H+/K+ exchange system1,3,7,8 These buffer systems act immediately to combine with excess acids or bases and prevent large changes in pH from occurring during the time it takes for the respiratory and renal mechanisms to become effective. Even though these buffer systems act immediately, they have a limited effect on pH and cannot correct large or long-term changes.7 Bone represents an additional source of acid–base buffering.5 Excess H+ ions can be exchanged for Na+ and K+ on the bone surface, and dissolution of bone minerals with release of compounds such as sodium bicarbonate (NaHCO3) and calcium carbonate (CaCO3) into the ECF can be used for buffering excess acids. It has been estimated that as much as 40% of buffering of an acute acid load takes place in bone. The role of bone buffers is even greater in the presence of chronic acidosis. The consequences of bone buffering include demineralization of bone and predisposition to development of kidney stones because of increased urinary excretion of calcium. People with chronic kidney disease are at particular risk for reduction in bone calcium due to acid retention.

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1066   UNIT X  Disorders of Renal Function and Fluids and Electrolytes 7.4 6.9

7.9

24

1.2

HCO3– (mEq/L)

H2CO3 (mEq/L)

A

pH = 6.1 + log10 (ratio HCO3–: H2CO3)

Ratio: HCO3–: H2CO3 = 20:1 7.4

7.4 7.7

6.9

7.9

6.9

7.9

12

0.6

HCO3– (mEq/L)

1.2

24

H2CO3 (mEq/L)

HCO3– (mEq/L)

Ratio: HCO3–: H2CO3 = 10:1

B

H2CO3 (mEq/L)

Ratio: HCO3–: H2CO3 = 40:1

D

7.4 6.9

7.4 7.9

6.9

7.9

12

0.6

12

0.6

HCO3– (mEq/L)

H2CO3 (mEq/L)

HCO3– (mEq/L)

H2CO3 (mEq/L)

C

Ratio: HCO3–: H2CO3 = 20:1

E

Ratio: HCO3–: H2CO3 = 20:1

FIGURE 40.2  •  Normal and compensated states of pH and acid–base balance represented as a balance scale. (A) When the ratio of bicarbonate (HCO3−) to carbonic acid (H2CO3, arterial CO2 × 0.03) = 20:1, the pH = 7.4. (B) Metabolic acidosis with a HCO3−:H3CO3 ratio of 10:1 and a pH of 7.1. (C) Respiratory compensation lowers the H3CO3 to 0.6 mEq/L and returns the HCO3−:H3CO3 ratio to 20:1 and the pH to 7.4. (D) Respiratory alkalosis with a HCO3−:H3CO3 ratio of 40:1 and a pH of 7.7. (E) Renal compensation eliminates HCO3−, reducing serum levels to 12 mEq/L, returning the HCO3−:H3CO3 ratio to 20:1 and the pH to 7.4. Normally, these compensatory mechanisms are capable of buffering large changes in pH but do not return the pH completely to normal as illustrated here. (From Rhoades R. A., Bell D. R. (Eds.) (2009). Medical physiology: Principles for clinical medicine (3rd ed., p. 445). Philadelphia, PA: Lippincott Williams & Wilkins.)

Bicarbonate Buffer System. The HCO3− buffer system, which is the most powerful ECF buffer, uses H2CO3 as its weak acid and a bicarbonate salt such as sodium bicarbonate (NaHCO3) as its weak base.1,2 It substitutes the weak H2CO3 for a strong acid such as hydrochloric acid (HCl + NaHCO3 × H2CO3 + NaCl) or the weak bicarbonate base for a strong base such as sodium hydroxide (NaOH + H2CO3 × NaHCO3 + H2O). The bicarbonate buffer system is a particularly efficient system because its components can be readily added or removed from the body.1−3 Metabolism provides an ample supply of CO2, which can replace any H2CO3 that is lost when

Porth9781451146004-ch040.indd 1066

excess base is added, and CO2 can be readily eliminated when excess acid is added. Likewise, the kidney can conserve or form new HCO3− when excess acid is added, and it can excrete HCO3− when excess base is added. Protein Buffer Systems.  Proteins are the largest buffer system in the body.1,2 Proteins are amphoteric, meaning that they can function either as acids or bases. They contain many ionizable groups that can release or bind H+. The protein buffers are largely located in cells, and H+ ions and CO2 diffuse across cell membranes for buffering by intracellular proteins.

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Chapter 40  Disorders of Acid–Base Balance    1067

Albumin and plasma globulins are the major protein buffers in the vascular compartment. Hydrogen–Potassium Exchange. The transcompartmental exchange of H+ and potassium ions (K+) provides another important system for regulation of acid–base balance. Both ions are positively charged, and both ions move freely between the ICF and ECF compartments. When excess H+ is present in the ECF, it moves into the ICF in exchange for K+, and when excess K+ is present in the ECF, it moves into the ICF in exchange for H+. Thus, alterations in potassium levels can affect acid–base balance, and changes in acid–base balance can influence potassium levels. Potassium shifts tend to be more pronounced in metabolic acidosis than in respiratory acidosis.3 Also, metabolic acidosis caused by an accumulation of nonorganic acids (e.g., hydrochloric acid that occurs in diarrhea, phosphoric acid that occurs in chronic kidney disease) produces a greater increase in extracellular K+ levels than does acidosis caused by an accumulation of organic acids (e.g., lactic acid, ketoacids). Respiratory Control Mechanisms The second line of defense against acid–base disturbances is the control of extracellular CO2 by the lungs. Increased ventilation decreases PCO2, whereas decreased ventilation increases PCO2. The blood PCO2 and pH are important regulators of ventilation. Chemoreceptors in the brain stem and the peripheral chemoreceptors in the carotid and aortic bodies sense changes in PCO2 and pH and alter the ventilatory rate. When the H+ concentration is above normal, the respiratory system is stimulated resulting in increased ventilation. This control of pH is rapid, occurring within minutes, and is maximal within 12 to 24 hours. Although the respiratory response is rapid, it does not completely return the pH to normal. It is only about 50% to 75% effective as a buffer system.1,2 This means that if the pH falls from 7.4 to 7.0, the respiratory system can return the pH to a value of about 7.2 to 7.3.1 In acting rapidly, however, it prevents large changes in pH from occurring while waiting for the much more slowly reacting kidneys to respond. Although CO2 readily crosses the blood–brain barrier, there is a lag for entry of HCO3−. Thus, blood levels of HCO3− change more rapidly than cerebrospinal fluid (CSF) levels. In metabolic acidosis, for example, there is often a primary decrease in pH of the cerebral fluids and a slower decrease in HCO3−. When metabolic acid–base disorders are corrected rapidly, the respiratory response may persist because of a delay in adjustment of CSF HCO3− levels. Renal Control Mechanisms The kidneys play three major roles in regulating acid–base balance.2,4 The first is through the excretion of H+ from fixed acids that result from protein and lipid metabolism. The second is accomplished through the reabsorption of the HCO3− that is filtered in the glomerulus, so this important buffer is not lost in the urine. The third is the production of new HCO3− that is released back into the blood.1 The renal mechanisms for regulating acid–base balance cannot adjust the pH within

Porth9781451146004-ch040.indd 1067

­ inutes, as respiratory mechanisms can, but they begin to m adjust the pH in hours and continue to function for days until the pH has returned to normal or near-normal range. Hydrogen Ion Elimination and Bicarbonate Conser­ vation. The kidneys regulate pH by excreting excess H+, reabsorbing HCO3−, and producing new HCO3−. Bicarbonate is freely filtered in the glomerulus (approximately 4300 mEq/day) and reabsorbed in the tubules.1 Loss of even small amounts of HCO3− impairs the body’s ability to buffer its daily load of metabolic acids. Because the amount of H+ that can be filtered in the glomeruli is relatively small compared with HCO3−, its elimination relies on secretion of H+ from the blood into the urine filtrate in the tubules. Most (85%-to-90%) of the H+ secretion and reabsorption of HCO3− takes place in the proximal tubule.4 The process begins with a coupled Na+/H+ transport system in which H+ is secreted into the tubular fluid and Na+ is reabsorbed into the tubular cell (Fig. 40.3). The secreted H+ combines with filtered HCO3− to form H2CO3. The H2CO3 then decomposes into CO2 and H2O, catalyzed by a brush border carbonic anhydrase. The CO2 and H2O that are formed readily cross the luminal membrane and enter the tubular cell. Inside the cell, the reactions occur in reverse. The CO2 and H2O combine to form a new H2CO3 molecule in a carbonic anhydrase-mediated reaction. The H2CO3, in turn, is dissociated into HCO3− and H+. The HCO3− is then reabsorbed into the blood along with Na+, and the newly generated H+ is secreted into the tubular fluid to begin another cycle. Normally, only a few of the secreted H+ ions remain in the tubular fluid because the secretion of H+ is roughly equivalent to the number of HCO3− ions filtered in the glomerulus.

Tubular lumen (Urine filtrate)

Tubular cell

Peritubular capillary (Extracellular fluid)

HCO3– + Na+ Na+ H+

Na+ +

Na+ –

H + HCO3

ATP

K+

H2CO3 H2CO3 CA H2O + CO2

CA H2O + CO2

CO2

FIGURE 40.3 • Hydrogen ion (H+) secretion and bicarbonate ion (HCO3−) reabsorption in a renal tubular cell. Carbon dioxide (CO2) diffuses from the blood or urine filtrate into the tubular cell, where it combines with water in a carbonic anhydrase (CA)–catalyzed reaction that yields carbonic acid (H2CO3). The H2CO3 dissociates to form H+ and HCO3−. The H+ is secreted into the tubular fluid in exchange for Na+. The Na+ and HCO3− enter the ECF. (ATP, adenosine triphosphate.)

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1068   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

Tubular Buffer Systems. Because an extremely acidic urine filtrate would be damaging to structures in the urinary tract, the minimum urine pH is about 4.5.1,2 Once the urine pH reaches this level of acidity, H+ secretion ceases. This limits the amount of unbuffered H+ that can be eliminated by the ­kidney. When the amount of free H+ secreted into the tubular fluid threatens to cause the pH of the urine to become too acidic, it must be carried in another form. This is accomplished by combining H+ ions with intratubular buffers before they are excreted in the urine. There are two important intratubular buffer systems: the phosphate and ammonia buffer systems.1,9 The HCO3− that is generated by these two buffer systems is new bicarbonate, demonstrating one of the ways that the kidney is able to replenish the ECF stores of HCO3−. The phosphate buffer system uses HPO42– and H2PO4− that are present in the tubular filtrate. Both forms of phosphate become concentrated in the tubular fluid because of their relatively poor absorption and because of reabsorption of water from the tubular fluid. Another factor that makes phosphate so effective as a urinary buffer is the fact that urine pH is close to the pK of the phosphate buffer system. The process of H+ secretion in the tubules is the same as that used for reabsorption of HCO3−. As long as there is excess HCO3− in the tubular fluid, most of the secreted H+ combines with HCO3−. However, once all the HCO3− has been reabsorbed and is no longer available to combine with H+, any excess H+ combines with HPO42– to form H2PO4− (Fig. 40.4). After H+ combines with HPO42–, it can be excreted as NaH2PO4, carrying the excess H+ with it. Another important but more complex buffer system is the ammonia buffer system. The excretion of H+ and

g­ eneration of HCO3− by the ammonia buffer system occurs in three major steps: 1. The synthesis of ammonium (NH4+) from the amino acid glutamine in the proximal tubule 2. The reabsorption and recycling of NH4+ within the medullary portion of the kidney 3. The buffering of H+ ions by NH3 in the collecting tubules1,3 The metabolism of glutamate in the proximal tubule results in the formation of two NH4+ and two HCO3− ions1,3 (Fig. 40.5). The two NH4+ ions are secreted into the tubular fluid by a countertransport mechanism in exchange for Na+. The two HCO3− ions move out of the tubular cell along with the reabsorbed Na+ to enter the peritubular capillary system. Thus, for each molecule of glutamine metabolized in the proximal tubule, two NH4+ ions are secreted into the tubular Distal convoluted tubule

Glutamine NH4+ H+ NH3

pH = 6.7

Na+

H++ NH3 NH4+

pH = 7.4

Proximal convoluted tubule

2Cl– Na+

Tubular cell

Peritubular capillary (Extracellular fluid)

NH4+

+

NH4

Na+

H+ + NH3 NH3

NH4+ NH4+

Tubular lumen (Urine filtrate)

Na+

NH4+ H+

+ NH3 NH3 + H+

H+

Na+

NaHPO4– + Na+ H+

Collecting duct

H+

HCO3–

ATP

K+

NH4+ pH = 7.4

H2CO3 NaH2PO4

H2O + CO2

HCO3– CO2

CA

FIGURE 40.4  The renal phosphate buffer system. The •  ­monohydrogen phosphate ion (HPO42–) enters the renal tubular fluid in the glomerulus. An H+ combines with the HPO42– to form H2PO4− and is then excreted into the urine in combination with Na+. The HCO3− moves into the ECF along with the Na+ that was exchanged during secretion of the H+. (ATP, adenosine triphosphate; CA, carbonic anhydrase.)

Porth9781451146004-ch040.indd 1068

pH ~ 6 FIGURE 40.5 •  Acidification along the nephron. The pH of tubular urine decreases along the proximal convoluted tubule, rises along the descending limb of the Henle loop, falls along the ascending limb, and reaches its lowest values in the collecting ducts. Ammonia (NH3 + NH4) is chiefly produced in proximal tubule cells and is secreted into the tubular urine. NH4 is reabsorbed in the thick ascending limb and accumulates in the kidney medulla. NH3 diffuses into acidic collecting duct urine, where it is trapped as NH4. (From Rhoades R. A., Bell D. R. (Eds.) (2009). Medical physiology: Principles for clinical medicine (3rd ed., p. 450). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Chapter 40  Disorders of Acid–Base Balance    1069

filtrate, and two HCO3− ions are reabsorbed into the blood. The HCO3− generated by this process constitutes new HCO3−. A significant portion of the NH4+ secreted by the proximal tubular cells is reabsorbed in the thick ascending loop of Henle, where the NH4+ substitutes for K+ on the Na+/K+/2Cl− cotransporter.9 The NH4+ that is reabsorbed by the thick ascending loop of Henle accumulates in the medullary interstitium of the kidney, where it exists in equilibrium with NH3 (see Fig. 40.5). Although both NH4+ and NH3 are present in the medullary interstitial fluid, only NH3 is lipid soluble and can diffuse across the collecting duct cells into the tubular fluid. Once in the tubular fluid, NH3 combines with secreted H+ to form NH4+. NH4+ is not lipid soluble, and thus is trapped in the tubular fluid and excreted in urine. Note that the source of the H+ secreted by the cells of the collecting tubules is CO2 and H2O. Thus, for each H+ that is produced in the cells and secreted, an additional new HCO3− is generated and added to the blood. One of the most important features of the ammonia buffer system is that it is subject to physiologic control. Under normal conditions, the amount of H+ eliminated by the ammonia buffer system is about 50% of the acid excreted and 50% of new HCO3− regenerated.1 However, with chronic acidosis, it can become the dominant mechanism for H+ excretion and new HCO3− generation. The urine anion gap, which is an indirect method for assessing urine NH4+ levels, can be used to assess kidney function in terms of H+ elimination. Potassium–Hydrogen Exchange. Plasma K+ levels influence renal elimination of H+ and vice versa. Hypokalemia is a potent stimulus for H+ secretion and HCO3− reabsorption. When plasma K+ levels fall, there is movement of K+ from the ICF into the ECF compartment and a reciprocal movement of H+ from the ECF into the ICF compartment. A similar process occurs in the distal tubules of the kidney, where the H+/K+-adenosine triphosphatase (ATPase) exchange pump actively reabsorbs K+ as well as secretes H+.1,3 An elevation in plasma K+ levels has the opposite effect. Plasma K+ levels are similarly altered by acid–base balance. Thus, acidosis tends to increase H+ elimination and decrease K+ elimination, with a  resultant increase in plasma potassium levels, whereas alkalosis tends to decrease H+ e­limination and increase K+ elimination, with a resultant decrease in plasma K+ levels.5 Aldosterone also influences H+ elimination by the kidney. It acts in the collecting duct to stimulate H+ secretion indirectly, while increasing Na+ reabsorption and K+ secretion. Thus, hyperaldosteronism tends to lead to a decrease in plasma K+ levels and an increase in pH because of increased H+ secretion, whereas hypoaldosteronism has the opposite effect. Chloride–Bicarbonate Exchange. Another mechanism that the kidneys use in regulating HCO3− is the chloride–­ bicarbonate anion exchange that occurs in association with Na+ reabsorption. Normally, Cl− is absorbed along with Na+ throughout the tubules. In situations of volume depletion due to vomiting and chloride depletion, the kidneys are forced to substitute HCO3− for the Cl− anion, thereby increasing its absorption of HCO3−. Hypochloremic alkalosis refers to an

Porth9781451146004-ch040.indd 1069

increase in pH induced by excess HCO3− reabsorption due to a decrease in Cl− levels, and hyperchloremic acidosis refers to a decrease in pH because of decreased HCO3− reabsorption due to an increase in Cl− levels.

Laboratory Tests Laboratory tests that are used in assessing acid–base balance include arterial blood gases and pH, CO2 content and HCO3− levels, base excess or deficit, and blood and urine anion gaps. Although useful in determining whether acidosis or alkalosis is present, measurements of the blood pH provide little information about the cause of an acid–base disorder. Carbon Dioxide and Bicarbonate Levels The PCO2 of the arterial blood gas measurement provides a means of assessing the respiratory component of acid–base balance. Arterial blood gases are used because venous blood gases are highly variable, depending on metabolic demands of the various tissues that empty into the vein from which the sample is being drawn. The H2CO3 levels can be determined from arterial blood gas measurements using the PCO2 and the solubility coefficient for CO2 (normal arterial PCO2 is 35 to 45 mm Hg). Arterial blood gases also provide a measure of blood oxygen (PO2) levels. This measure can be important in assessing respiratory function. The CO2 content refers to the total CO2 in the blood, including dissolved CO2, that is contained in HCO3−, and that attached to hemoglobin (carbaminohemoglobin [CO2HHb]). The normal range of values for venous HCO3− concentration is 24 to 31 mEq/L (24 to 31 mmol/L), and arterial is 22 to 26 mEq/L. Base Excess or Deficit The total base excess or deficit, also referred to as the whole blood buffer base, measures the level of all the buffer systems of the blood—hemoglobin, protein, phosphate, and HCO3−. The base excess or deficit describes the amount of a fixed acid or base that must be added to a blood sample to achieve a pH of 7.4 (normal ± 2 mEq/L).10 For clinical purposes, base excess or deficit can be viewed as a measurement of bicarbonate excess or deficit and indicates a nonrespiratory change in acid–base balance. A base excess indicates metabolic alkalosis, and a base deficit indicates metabolic acidosis. Anion Gap The anion gap (AG), a diagnostic concept, describes the difference between the plasma concentration of the major measured cation (Na+) and the sum of the measured anions (Cl− and HCO3−).1,11 This difference represents the concentration of unmeasured anions, such as phosphates, sulfates, organic acids, and proteins (Fig. 40.6). Normally, the AG measured by flame atomic emission spectrometry (FAES) ranges between 8 and 16 mEq/L (a value range of 12 to 20 mEq/L is normal when potassium is included in the calculation).1,12,13 Because albumin is an anion, it is often measured and used in determining the AG in people with decreased albumin levels. For every 1 g/dL decline in plasma albumin concentration, a

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1070   UNIT X  Disorders of Renal Function and Fluids and Electrolytes mEq/L

Sodium 142 mEq/L

Anion gap 12 mEq/L

Acidosis due to excess chloride levels

Chloride 116 mEq/L Bicarbonate 14 mEq/L

Anion gap 12 mEq/L

100

Sodium 142 mEq/L

110

Sodium 142 mEq/L

120

Chloride 103 mEq/L Bicarbonate 27 mEq/L

130

Anion gap 25 mEq/L

Normal

140

Acidosis due to excess organic acids

Chloride 103 mEq/L Bicarbonate 14 mEq/L

150

FIGURE 40.6 • The anion gap in acidosis due to excess metabolic ­acids and excess plasma chloride levels. Unmeasured anions such as phosphates, sulfates, and organic acids increase the anion gap because they replace bicarbonate. This assumes there is no change in sodium content.

correction factor should be added to the gap that is calculated from the formula: AG = Na+ – (Cl− + HCO3−).7,14 The AG is used typically in diagnosing causes of metabolic acidosis.4,15 An increased level is found in conditions such as lactic acidosis and ketoacidosis that result from elevated levels of metabolic acids.1,13 A low AG is found in conditions that produce a fall in unmeasured anions (primarily albumin) or rise in unmeasured cations. The latter can occur in hyperkalemia, hypercalcemia, hypermagnesemia, lithium intoxication, or multiple myeloma, in which an abnormal immunoglobulin is produced.10 The anion gap of urine is useful as a diagnostic tool.13 Urine electrolyte determinations do not include bicarbonate. Instead, the urine anion gap uses the difference between the measurable cations (Na+ and K+) and anions (Cl−) to provide an estimate of ammonium (NH4+) excretion.13 Because ammonium is a cation, the value of the anion gap becomes more negative as the ammonium level increases. In normal persons secreting 20 to 40 mmol of ammonium per liter, the urine anion gap is close to zero representing electroneutrality. In metabolic acidosis, the amount of unmeasured NH4+ should increase if renal excretion of H+ is intact; as a result, the urine anion gap should become more negative.

IN SUMMARY Normal body function depends on the precise regulation of acid–base balance. The pH of the ECF is normally maintained within the narrow physiologic range of 7.35 to 7.45. Metabolic processes produce volatile and fixed or nonvolatile metabolic acids that must be buffered and eliminated from the body. The volatile acid, H2CO3, is in equilibrium with dissolved CO2, which is eliminated through the lungs. The nonvolatile metabolic acids, which are derived mainly from protein metabolism and incomplete carbohydrate and fat metabolism, are excreted by the kidneys. It is the

Porth9781451146004-ch040.indd 1070

ratio of the HCO3− concentration to dissolved CO2 (H2CO3 ­concentration) that determines the pH of the ECFs. When this ratio is 20:1, the pH is 7.4. The ability of the body to maintain pH within the ­normal physiologic range depends on respiratory and renal mechanisms and on chemical buffers in the ICF and ECF, the most important of which is the HCO3− buffer system. The respiratory regulation of pH is rapid but does not return the pH completely to normal. The kidneys aid in regulation of pH by eliminating H+ ions, conserving HCO3− ions, and producing new HCO3− ions. In the process of eliminating H+, it uses the phosphate and ammonia buffer systems. Body pH is also affected by the distribution of exchangeable cations (K+ and H+) and anions (Cl− and HCO3−). Laboratory tests used in assessing acid–base balance include arterial blood gas measurements, CO2 content and HCO3− levels, base excess or deficit, and the anion gap. The base excess or deficit describes the amount of a fixed acid or base that must be added to a blood sample to achieve a pH of 7.4. The anion gap describes the difference between the plasma concentration of the major measured cation (Na+) and the sum of the anions (Cl− and HCO3−). This difference represents the concentration of unmeasured anions, such as phosphates, sulfates, and organic acids, which are present. The urine anion gap uses the difference between the measurable cations (Na+ and K+) and anions (Cl−) to provide an estimate of ammonium (NH4+) excretion and the ability of the kidney to rid the body of excess H+.

DISORDERS OF ACID–BASE BALANCE After completing this section of the chapter, you should be able to meet the following objectives: •• Define metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. •• Describe the common causes of metabolic and respiratory acidosis and metabolic and respiratory alkalosis. •• Contrast and compare the clinical manifestations and treatments of metabolic and respiratory acidosis and of metabolic and re spiratory alkalosis. The terms acidosis and alkalosis describe the clinical ­conditions that arise as a result of changes in dissolved CO2 and HCO3− concentrations. An alkali represents a ­combination of one or more alkali metals such as sodium or potassium with a highly basic ion such as a hydroxyl ion (OH−). Sodium b­ icarbonate is the main alkali in the ECF. Although the definitions differ somewhat, the terms alkali and base are often used interchangeably. Hence, the term alkalosis has come to mean the opposite of acidosis. Typically, imbalances in acid–base result in acidosis. Alkalosis is usually compensatory.6

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Chapter 40  Disorders of Acid–Base Balance    1071

TABLE 40.1 SUMMARY OF SINGLE ACID–BASE DISTURBANCES AND THEIR COMPENSATORY RESPONSES ACID–BASE IMBALANCE

PRIMARY DISTURBANCE

Metabolic acidosis

↓pH and HCO3− HCO3− < 22 mEq/L

Metabolic alkalosis

↑pH and HCO3− HCO3− > 26 mEq/l

Respiratory acidosis

↓pH and ↑PCO2 PCO2 > 45 mm Hg

Respiratory alkalosis

↑pH and ↓PCO2 PCO2 < 35 mm Hg

RESPIRATORY COMPENSATION AND PREDICTED RESPONSE*

RENAL COMPENSATION AND PREDICTED RESPONSE*†

↑ventilation and ↓PCO2 1 mEq/L ↓HCO3− →   1 to 1.2 mm Hg ↓PCO2 ↓ventilation and ↑PCO2 1 mEq/L ↑HCO3− →  0.7 mm Hg ↑PCO2 None

↑H+ excretion and ↑HCO3− reabsorption if no renal disease ↓H+ excretion and ↓HCO3− reabsorption if no renal disease ↑H+ excretion and ↑HCO3− reabsorption   Acute: 1 mm Hg ↑PCO2 →   0.1 mEq/L ↑HCO3−   Chronic: 1 mm Hg ↑PCO2 →  0.3 mEq/L ↑HCO3− ↓H+ excretion and ↓HCO3− reabsorption   Acute: 1 mm Hg ↓PCO2 →   0.2 mEq/L ↓HCO3−   Chronic: 1 mm Hg ↓PCO2 →   0.4 mEq/L ↓HCO3−

None

Note: Predicted compensatory responses are in italics. *If blood values are the same as predicted compensatory values, a single acid–base disorder is present; if values are different, a mixed acid–base disorder is present.16 † Acute renal compensation refers to duration of minutes to several hours; chronic renal compensation refers to a duration of several days.16

Metabolic Versus Respiratory Acid–Base Disorders There are two types of acid–base disorders: metabolic and respiratory (Table 40.1). Metabolic disorders produce an alteration in the plasma HCO3− concentration and result from the addition to or loss from the ECF of nonvolatile acid or alkali. A reduction in pH due to a decrease in HCO3− is called metabolic acidosis, and an elevation in pH due to increased HCO3− levels is called metabolic alkalosis. Respiratory disorders involve an alteration in the PCO2, reflecting an increase or decrease in alveolar ventilation. Respiratory acidosis is characterized by a decrease in pH, reflecting a decrease in ventilation and an increase in PCO2. Respiratory alkalosis involves an increase in pH, resulting from an increase in alveolar ventilation and a decrease in PCO2.

Compensatory Mechanisms Acidosis and alkalosis typically involve a primary or i­nitiating event and a compensatory or adaptive state that results from homeostatic mechanisms that attempt to correct or ­prevent large changes in pH. For example, a person may have a primary metabolic acidosis as a result of overproduction of ketoacids and respiratory alkalosis because of a compensatory increase in ventilation (see Table 40.1). Compensatory mechanisms provide a means to control pH when correction is impossible or cannot be achieved

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immediately. Often, compensatory mechanisms are interim measures that permit survival while the body attempts to correct the primary disorder. Compensation requires the use of mechanisms that are different from those that caused the primary disorder. For example, the lungs cannot compensate for respiratory acidosis that is caused by lung disease, nor can the kidneys compensate for metabolic acidosis that occurs because of chronic kidney disease. The body can, however, use renal mechanisms to compensate for respiratory-induced changes in pH, and it can use respiratory mechanisms to compensate for metabolically induced changes in acid–base balance. Because compensatory mechanisms become more effective with time, there are often differences between the level of pH change that is present in acute and chronic acid–base disorders. There is a distinction between acute and chronic respiratory acid–base disorders but not for metabolic acid–base disorders.3 This difference is due to the fact that renal compensation for a respiratory disorder may take days, but the respiratory compensation for a metabolic disorder is within minutes to hours.3 Single Versus Mixed Acid–Base Disorders Thus far, we have discussed acid–base disorders as if they existed as a single primary disorder such as metabolic acidosis, accompanied by a predicted compensatory response (i.e., hyperventilation and respiratory alkalosis). It is not uncommon, however, for people to present with more than one primary disorder or a mixed disorder.3,16 For example, a person may ­present with

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a low plasma HCO3− concentration due to metabolic a­ cidosis and a high PCO2 due to chronic lung disease. Values for the predicted renal or respiratory compensatory responses can be used in the diagnosis of these mixed acid–base disorders3 (see Table 40.1). If the values for the compensatory response fall outside the predicted plasma values, it can then be concluded that more than one disorder (i.e., a mixed disorder) is present. Because the respiratory response to changes in HCO3− occurs almost immediately, there is only one predicted compensatory response for primary metabolic acid–base disorders. This is in contrast to the primary respiratory disorders, which have two ranges of predicted values, one for the acute and one for the chronic response. Renal compensation takes several days to become fully effective. The acute compensatory response represents the HCO3− levels before renal compensation has occurred, and the chronic response after it has occurred. Thus, the values for the plasma pH tend to be more normal in the chronic phase.

Key Points METABOLIC ACID–BASE IMBALANCE •  Metabolic acidosis can be defined as a decrease in plasma HCO3− and pH that is caused by an   excess of production or accumulation of fixed ­acids or loss of HCO3− ion. Compensatory ­responses include an increase in ventilation and elimination of CO2 and the reabsorption and ­ eneration of bicarbonate by the kidney. g •  Metabolic alkalosis can be defined as an increase in plasma HCO3− and pH that is initiated by excess H+ ion loss or HCO3− ion gain and maintained by conditions that impair the ability of the kidney to excrete the excess HCO3− ion. Compensatory responses include a decreased respiratory rate with retention of PCO2 and increased elimination of HCO3− by the kidney.

Metabolic Acidosis Metabolic acidosis involves a decreased plasma HCO3− ­concentration along with a decrease in pH. In metabolic acidosis, the body compensates for the decrease in pH by increasing the respiratory rate in an effort to decrease PCO2 and H2CO3 levels. The PCO2 can be expected to fall by 1 to 1.5 mm Hg for each 1-mEq/L fall in HCO3−.3,17 Etiology Metabolic acidosis can be caused by one or more of the following four mechanisms: 1. Increased production of fixed metabolic acids or ingestion of fixed acids such as salicylic acid 2. Inability of the kidneys to excrete the fixed acids produced from normal metabolism

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3. Excessive loss of bicarbonate through the kidneys or gastrointestinal tract 4. Increased plasma Cl− concentration5 The anion gap is often useful in determining the cause of the metabolic acidosis (Chart 40.1). The presence of excess metabolic acids produces an increase in the anion gap as sodium salt of the offending acid (e.g., sodium lactate) replaces sodium bicarbonate. Diarrhea is the most frequent cause of a normal AG metabolic acidosis.1 When the acidosis results from an increase in plasma Cl− levels (e.g., hyperchloremic acidosis), the anion gap also remains within normal levels. The pneumonic “MUDPILES” can be used to remember the most common etiologies of a high AG acidosis (Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Isoniazid, Lactic acid, Ethanol [ethylene glycol], and Salicylates [starvation]).18 The causes of metabolic acidosis are summarized in Table 40.2. Lactic Acidosis.  Acute lactic acidosis is the most common type of metabolic acidosis in people who are hospitalized and develops when there is excess production or diminished removal of lactic acid from the blood.7 Lactic acid is produced by the anaerobic metabolism of glucose. Most cases

Chart 40.1 THE ANION GAP IN DIFFERENTIAL DIAGNOSIS OF METABOLIC ACIDOSIS Decreased Anion Gap (16 mEq/L)13 Presence of unmeasured metabolic anion Diabetic ketoacidosis Alcoholic ketoacidosis Lactic acidosis Starvation Renal insufficiency Presence of drug or chemical anion Salicylate poisoning Methanol poisoning Ethylene glycol poisoning Normal Anion Gap (8–16 mEq/L)13 Loss of bicarbonate Diarrhea Pancreatic fluid loss Ileostomy (unadapted) Chloride retention Renal tubular acidosis Ileal loop bladder Parenteral nutrition (arginine, histidine, and lysine)

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TABLE 40.2 CAUSES AND MANIFESTATIONS OF METABOLIC ­ACIDOSIS CAUSES

MANIFESTATIONS

Excess Metabolic Acids (Increased Anion Gap) Excessive production of metabolic acids Lactic acidosis (e.g., strenuous exercise) Diabetic ketoacidosis Alcoholic ketoacidosis Fasting and starvation Poisoning (e.g., isoniazid, salicylate, ­methanol, paraldehyde, ethylene glycol) Impaired elimination of metabolic acids Kidney failure or dysfunction Uremic acidosis (e.g., severe renal failure)

Blood pH, HCO3−, CO2 pH decreased HCO3− (primary) decreased PCO2 (compensatory) decreased

Excessive Bicarbonate Loss (Normal Anion Gap) Loss of intestinal secretions Diarrhea (severe) Intestinal suction Intestinal or biliary fistula Increased renal losses Renal tubular acidosis Treatment with carbonic anhydrase inhibitors Hypoaldosteronism Increased Chloride Levels (Normal Anion Gap) Excessive reabsorption of chloride by the kidney Sodium chloride infusions Treatment with ammonium chloride Parenteral hyperalimentation

of ­lactic acidosis are caused by inadequate oxygen delivery, as in shock or cardiac arrest.7,19 Such conditions not only increase lactic acid production, but they tend to impair lactic acid clearance because of poor liver and kidney perfusion. Mortality rates are high for people with lactic acidosis due to shock and tissue hypoxia.20 Severe sepsis is also commonly associated with lactic acidosis.21 Lactic acidosis can occur during periods of intense exercise in which the metabolic needs of the exercising muscles outpace their aerobic capacity for production of ATP, causing them to revert to anaerobic metabolism and the production of lactic acid.19 Lactic acidosis is associated with disorders in which tissue hypoxia does not appear to be present. It has been reported in people with leukemia, lymphomas, and other cancers; those with poorly controlled diabetes; and in people with severe liver failure.7 Mechanisms causing lactic acidosis in these conditions are poorly understood. Some conditions such as neoplasms may produce local increases in tissue metabolism and lactate production, or they may interfere with blood flow to noncancerous cells.

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Gastrointestinal Function Anorexia Nausea and vomiting Abdominal pain Neural Function Weakness Lethargy General malaise Confusion Stupor Coma Depression of vital functions Cardiovascular Function Peripheral vasodilation Decreased heart rate Cardiac arrhythmias Skin Warm and flushed Skeletal System Bone disease (e.g., chronic acidosis) Signs of Compensation Increased rate and depth of respiration (i.e., Kussmaul breathing) Hyperkalemia Acid urine Increased ammonia in urine

A variety of drugs can produce life-threatening lactic acidosis by inhibiting mitochondrial function. These drugs include the biguanide antidiabetic drugs (metformin)19,22 and the antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine [AZT]) that are used to treat acquired immunodeficiency syndrome (AIDS).19 A relatively rare form of lactic acidosis, called d-lactic acidosis, can occur in people with intestinal disorders that involve the generation and absorption of d-lactic acid (l-lactic acid is the usual cause of lactic acidosis).23 It most commonly occurs in people with jejunoileal bypass surgery for the treatment of obesity or who have short bowel syndrome, in which there is impaired absorption of carbohydrate in the small intestine.23 In these cases, the unabsorbed carbohydrate is delivered to the colon, where it is converted to d-lactic acid by an overgrowth of gram-positive anaerobes. People with d-lactic acidosis experience episodic periods of metabolic acidosis often brought on by eating a meal high in carbohydrates. Neurological manifestations include confusion, cerebellar ataxia, slurred speech, and loss of memory. They may complain of feeling (or appear)

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intoxicated. Treatment includes use of antimicrobial agents to decrease the number of d-lactic acid–producing microorganisms in the bowel along with a low-carbohydrate diet. Ketoacidosis.  Ketoacids (i.e., acetoacetic and β-hydroxybutyric acid), produced in the liver from fatty acids, are the source of fuel for many body tissues. An overproduction of ketoacids occurs when carbohydrate stores are inadequate or when the body cannot use available carbohydrates as a fuel. Under these conditions, fatty acids are mobilized from adipose tissue and delivered to the liver, where they are converted to ketones. Ketoacidosis develops when ketone production by the liver exceeds tissue use.4 The most common cause of ketoacidosis is uncontrolled diabetes mellitus, in which an insulin deficiency leads to the release of fatty acids from adipose cells with subsequent production of excess ketoacids.2,7 Ketoacidosis may also develop as the result of fasting or food deprivation, during which the lack of carbohydrates produces a self-limited state of ketoacidosis.4,12 Ketones are formed during the oxidation of alcohol, a process that occurs in the liver. A condition called alcoholic ketoacidosis can develop in people who engage in excess alcohol consumption and can be fatal clinically.4,24 It usually follows prolonged alcohol ingestion, particularly if accompanied by decreased food intake and vomiting: conditions that result in using fatty acids as an energy source. Ketone formation may be further enhanced by the hypoglycemia that results from alcohol-induced inhibition of glucose synthesis (i.e., gluconeogenesis) by the liver and impaired ketone elimination by the kidneys because of dehydration. An ECF volume deficit caused by vomiting and decreased fluid intake often contributes to the acidosis. Numerous other factors, such as elevations in cortisol, growth hormone, glucagon, and catecholamines, mediate free fatty acid release and thereby contribute to the development of alcoholic ketoacidosis. Salicylate Toxicity.  Salicylates are another potential source of metabolic acids. Acetylsalicylic acid (Aspirin) is readily absorbed in the stomach and small bowel and then rapidly converted to salicylic acid in the body.4,24 Although aspirin is the most common cause of salicylate toxicity, other salicylate preparations such as methyl salicylate, sodium salicylate, and salicylic acid may produce similar effects. Salicylate overdose produces serious toxic effects, including death. The weightbased, acute ingestion of 150 mg/kg or 6.5 g of aspirin requires referral to an emergency department to prevent a fatality.25 A variety of acid–base disturbances occur with salicylate toxicity. The salicylates cross the blood–brain barrier and directly stimulate the respiratory center, causing hyperventilation and respiratory alkalosis. The kidneys compensate by secreting increased amounts of HCO3−, K+, and Na+, thereby contributing to the development of metabolic acidosis. Salicylates also interfere with carbohydrate metabolism, which results in increased production of metabolic acids. One of the treatments for salicylate toxicity is alkalinization of the plasma. Salicylic acid, which is a weak acid, exists in equilibrium with the alkaline salicylate anion. It is the

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salicylic acid that is toxic because of its ability to cross cell membranes and enter brain cells. The salicylate anion crosses membranes poorly and is less toxic. With alkalinization of the ECFs, the ratio of salicylic acid to salicylate is greatly reduced. This allows salicylic acid to move out of cells into the ECF along a concentration gradient. The renal elimination of salicylates follows a similar pattern when the urine is alkalinized. Methanol and Ethylene Glycol Toxicity.  Ingestion of methanol and ethylene glycol results in the production of metabolic acids and causes metabolic acidosis. Both produce an osmolar gap because of their small size and osmotic properties. Methanol (wood alcohol) is a component of shellac, varnish, deicing solutions, and other commercial products. A person addicted to alcohol sometimes consumes it as a substitution for ethanol.4 Methanol can be absorbed through the skin or gastrointestinal tract or inhaled through the lungs. A dose as small as 10 mL can be toxic.18 In addition to metabolic acidosis, methanol produces severe optic nerve and central nervous system toxicity. Organ system damage occurs after a 24-hour period in which methanol is converted to formaldehyde and formic acid. Ethylene glycol is a solvent found in products ranging from antifreeze and deicing solutions to carpet and fabric cleaners. It tastes sweet and is intoxicating, factors that contribute to its abuse potential. Ethylene glycol is the leading cause of death from a chemical agent in the United States.12 It is rapidly absorbed from the intestine, making treatment with gastric lavage and syrup of ipecac ineffective. Acidosis occurs as ethylene glycol is converted to oxalic and lactic acid. Manifestations of ethylene glycol toxicity occur in three stages: 1. Neurologic symptoms ranging from drunkenness to coma, which appear during the first 12 hours 2. Cardiorespiratory disorders such as tachycardia and pulmonary edema 3. Flank pain and acute renal failure caused by plugging of the tubules with oxalate crystals (from excess oxalic acid production)12 The enzyme alcohol dehydrogenase metabolizes methanol and ethylene glycol into their toxic metabolites. This is the same enzyme that is used in the metabolism of ethanol. Because alcohol dehydrogenase has a greater affinity for ethanol than its affinity for methanol or ethylene glycol, intravenous or oral ethanol is used as an antidote for methanol and ethylene glycol poisoning. Extracellular volume expansion and hemodialysis are also used. Fomepizole (Antizol) is approved by The U.S. Food and Drug Administration as an antidote for methanol and ethylene glycol poisoning.26 In a manner similar to ethanol, it is thought to act as an inhibitor of alcohol dehydrogenase, thereby preventing the formation of the toxic ethylene glycol metabolites. Decreased Renal Function. Chronic kidney disease is the most common cause of chronic metabolic acidosis. The kidneys normally conserve HCO3− and secrete H+ ions into the urine as a means of regulating acid–base balance. In chronic

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kidney disease, there is loss of both glomerular and tubular function, with retention of nitrogenous wastes and metabolic acids. The most prominent effect of these changes is on the musculoskeletal system. In a condition called renal tubular acidosis, glomerular function is normal, but the tubular secretion of H+ or reabsorption of HCO3− is abnormal.27 Increased Bicarbonate Losses. Increased HCO3− losses occur with the loss of bicarbonate-rich body fluids or with impaired conservation of HCO3− by the kidney. Intestinal secretions have a high HCO3− concentration. Consequently, excessive loss of HCO3− occurs with severe diarrhea; small bowel, pancreatic, or biliary fistula drainage; ileostomy drainage; and intestinal suction. In diarrhea of microbial origin, HCO3− is also secreted into the bowel as a means of neutralizing the metabolic acids produced by the microorganisms causing the diarrhea. Creation of an ileal bladder, which is done for conditions such as neurogenic bladder or surgical removal of the bladder because of cancer, involves the implantation of the ureters into a short, isolated loop of ileum that serves as a conduit for urine collection. With this procedure, contact time between the urine and ileal bladder is normally too short for significant anion exchange, and HCO3− is lost in the urine.28 Hyperchloremic Acidosis.  Hyperchloremic acidosis occurs when Cl− levels are increased. Because Cl− and HCO3− are exchangeable anions, the plasma HCO3− decreases when there is an increase in Cl−. Hyperchloremic acidosis can occur as the result of abnormal absorption of Cl− by the kidneys or as a result of treatment with chloride-containing medications (i.e., sodium chloride, amino acid–chloride hyperalimentation solutions, and ammonium chloride). Ammonium chloride is broken down into NH4+ and Cl−. The ammonium ion is converted to urea in the liver, leaving the Cl− free to react with H+ to form HCl. The administration of intravenous sodium chloride or parenteral hyperalimentation solutions that contain an amino acid–chloride combination can cause acidosis in a similar manner.15 With hyperchloremic acidosis, the anion gap remains within the normal range, whereas plasma Cl− levels are increased and HCO3− levels are decreased. Clinical Manifestations Metabolic acidosis is characterized by a decrease in pH ( 7.0) and in the presence of bacteria that possess an enzyme called urease, which splits the urea in the urine into ammonia and carbon dioxide.15 The ammonia that is formed takes up a hydrogen

ion to become an ammonium ion, increasing the pH of the urine so that it becomes more alkaline. Because phosphate levels are increased in alkaline urine and because magnesium always is present in the urine, struvite stones form. These stones enlarge as the bacterial count grows, and they can increase in size until they fill an entire renal pelvis (Fig. 41.7). Because of their shape, they often are called staghorn stones.15 They almost always are associated with UTIs and represent about 15% of all kidney stones.15 Because these stones act as a foreign body, treatment of the infection often is difficult. Struvite stones usually are too large to be passed and require lithotripsy or surgical removal. Uric acid stones develop in conditions of gout and high concentrations of uric acid in the urine and account for about 7% of all stones.15 Hyperuricosuria also may contribute to calcium stone formation by acting as a nucleus for calcium oxalate stone formation. Unlike radiopaque calcium stones, uric acid stones are not visible on x-ray films. Uric acid stones form most readily in acidic urine.15 Thus, these stones can be treated by raising the urinary pH to 6 to 6.5 with potassium alkali salts. Cystine stones account for less than 1% to 3% of kidney stones overall, but represent a significant proportion of childhood calculi.15 They are seen in cystinuria, which results from an autosomal recessive genetic defect in renal transport of cystine so there is a decrease in cystine tubular absorption. These stones resemble struvite stones except that infection is unlikely to be present. Clinical Manifestations One of the major manifestations of kidney stones is pain. Depending on location, there are two types of pain associated with kidney stones: renal colic and noncolicky renal pain.15 Renal colic is the term used to describe the colicky pain that

TABLE 41.2 COMPOSITION, CONTRIBUTING FACTORS, AND TREATMENT OF KIDNEY STONES TYPE OF STONE

CONTRIBUTING FACTORS

TREATMENT

Calcium (oxalate and phosphate)

Hypercalcemia and hypercalciuria Immobilization

Treatment of underlying conditions Increased fluid intake Thiazide diuretics

Magnesium ammonium phosphate (struvite) Uric acid (urate)

Cystine

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Hyperparathyroidism Vitamin D intoxication Diffuse bone disease Milk-alkali syndrome Renal tubular acidosis Hyperoxaluria Intestinal bypass surgery Urea-splitting UTIs

Formed in acid urine with pH of approximately 5.5 Gout High-purine diet Cystinuria (inherited disorder of amino acid metabolism)

Dietary restriction of foods high in oxalate Treatment of UTI Acidification of the urine Increased fluid intake Increased fluid intake Allopurinol for hyperuricosuria Alkalinization of urine Increased fluid intake Alkalinization of urine

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FIGURE 41.7 • Staghorn stones. The kidney shows hydronephrosis and stones that are casts of the dilated calices. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 800). Philadelphia, PA: Lippincott Williams & Wilkins.)

accompanies stretching of the collecting system or ureter. The symptoms of renal colic are caused by stones 1 to 5 mm in diameter that can move into the ureter and obstruct flow. Classic ureteral colic is manifested by acute, intermittent, and excruciating pain in the flank and upper outer quadrant of the abdomen on the affected side. The pain may radiate to the lower abdominal quadrant, bladder area, perineum, or scrotum in the man. The skin may be cool and clammy, and nausea and vomiting are common. Noncolicky pain is caused by stones that produce distention of the renal calyces or renal pelvis. The pain usually is a dull, deep ache in the flank or back that can vary in intensity from mild to severe. The pain is often exaggerated by drinking large amounts of fluid. Diagnosis and Treatment People with kidney stones often present with acute renal colic, and the diagnosis is based on symptomatology and diagnostic tests, which include urinalysis, plain film radiography, intravenous pyelography (IVP), and abdominal ultrasonography.17 Urinalysis provides information related to hematuria, infection, the presence of stone-forming crystals, and urine pH. Most stones are radiopaque and readily visible on a plain radiograph of the abdomen. The noncontrast spiral CT scan is the imaging modality of choice in people with acute renal colic.17 IVP uses an intravenously injected contrast medium that is filtered in the glomeruli to visualize the collecting ­system of the kidneys

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and ureters. Abdominal ultrasonography is highly sensitive to hydronephrosis, which may be a manifestation of ureteral obstruction. A new imaging technique called nuclear scintigraphy uses bisphosphonate markers as a means of imaging stones.17 The method has been credited with identifying stones that are too small to be detected by other methods. Treatment of acute renal colic usually is supportive. Pain relief may be needed during acute phases of obstruction, and antibiotic therapy may be necessary to treat UTIs. Most stones that are less than 5 mm in diameter pass spontaneously. All urine should be strained during an attack in the hope of retrieving the stone for chemical analysis and determination of type. This information, along with a careful history and laboratory tests, provides the basis for long-term preventive measures. A major goal of treatment in people who have passed kidney stones or have had them removed is to prevent their recurrence. Prevention requires investigation into the cause of stone formation using urine tests, blood chemistries, and stone analysis. Underlying disease conditions, such as hyperparathyroidism, are treated. Adequate fluid intake reduces the concentration of stone-forming crystals in the urine and needs to be encouraged. Depending on the type of stone that is formed, dietary changes, medications, or both may be used to alter the concentration of stone-forming elements in the urine. For example, people who form calcium oxalate stones may need to decrease their intake of foods that are high in oxalate (e.g., spinach, Swiss chard, cocoa, chocolate, pecans, peanuts). More children who have a vegetarian diet and rely on plant sources for the majority of their protein are being diagnosed with kidney stones. Therefore, they may need to use other sources of protein to supplement the diet.18 Also, it is important to realize that gallstones and kidney stones have been correlated with insulin resistance. However, only gallstones have been identified as a possible risk factor for developing type 2 diabetes mellitus.19 Calcium supplementation with calcium salts such as calcium carbonate and calcium phosphate also may be used to bind oxalate in the intestine and decrease its absorption. Thiazide diuretics lower urinary calcium by increasing tubular reabsorption so that less remains in the urine. Drugs that bind calcium in the gut (e.g., cellulose phosphate) may be used to inhibit calcium absorption and urinary excretion. Measures to change the pH of the urine also can influence kidney stone formation. In persons who lose the ability to lower the pH of (or acidify) their urine, there is an increase in the divalent and trivalent forms of urine phosphate that combine with calcium to form calcium phosphate stones. The formation of uric acid stones is increased in acid urine; stone formation can be reduced by raising the pH of urine to 6.0 to 6.5 with potassium alkali (e.g., potassium citrate) salts. Table  41.2 summarizes measures for preventing the recurrence of different types of kidney stones. In some cases, stone removal may be necessary. Several methods are available for removing kidney stones––ureteroscopic removal, percutaneous removal, and extracorporeal lithotripsy.12 All these procedures eliminate the need for an open surgical procedure, which is another form of treatment.

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Open stone surgery may be required to remove large calculi or those that are resistant to other forms of removal. Ureteroscopic removal involves the passage of an instrument through the urethra into the bladder and then into the ­ureter. The development of high-quality optics has improved the ease with which this procedure is performed and its outcome. The procedure, which is performed under fluoroscopic guidance, involves the use of various instruments for dilating the ureter and for grasping, fragmenting, and removing the stone. Preprocedure radiologic studies using a contrast medium (i.e., excretory urography) are done to determine the position of the stone and direct the placement of the ureteroscope.17 Percutaneous nephrolithotomy is the treatment of choice for removal of renal or proximal ureteral calculi.17 It involves the insertion through the flank of a small-gauge needle into the collecting system of the kidney. The needle tract is then dilated, and an instrument called a nephroscope is inserted into the renal pelvis. The procedure is performed under fluoroscopic guidance. Preprocedure radiologic and ultrasonographic examinations of the kidney and ureter are used to determine the placement of the nephroscope. Stones up to 1 cm in diameter can be removed through this method. Larger stones must be broken up with an ultrasonic lithotriptor (i.e., stone breaker). A nonsurgical treatment, called extracorporeal shockwave lithotripsy, uses acoustic shock waves to fragment calculi into sandlike particles that are passed in the urine over the next few days. Because of the large amount of stone particles that are generated during the procedure, a ureteral stent (i.e., a tubelike device used to hold the ureter open) may be inserted to ensure adequate urine drainage.

IN SUMMARY Obstruction of urine flow can occur at any level of the urinary tract. Among the causes of urinary tract obstruction are developmental defects, pregnancy, infection and inflammation, kidney stones, neurologic defects, and prostatic hypertrophy. Obstructive disorders produce stasis of urine, increase the risk for infection and calculi formation, and produce progressive dilation of the renal collecting ducts and renal tubular structures, which causes renal atrophy. Hydronephrosis refers to urine-filled dilation of the renal pelvis and calices associated with progressive atrophy of the kidney due to obstruction of urine outflow. Unilateral hydronephrosis may remain silent for long periods because the unaffected kidney can maintain adequate kidney function. With partial bilateral obstruction, the earliest manifestation is an inability to concentrate urine, reflected by polyuria and nocturia. Complete bilateral obstruction results in oliguria and anuria and renal failure. Kidney stones are a major cause of upper urinary tract obstruction. There are four types of kidney stones: calcium (i.e., oxalate and phosphate) stones, which are associated with increased serum calcium levels; magnesium ammonium phosphate (i.e., struvite) stones, which are associated

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with UTIs; uric acid stones, which are related to elevated uric acid levels; and cystine stones, which are seen in cystinuria. A major goal of treatment for persons who have passed kidney stones or have had them removed is to identify stone composition and prevent their recurrence. Treatment measures depend on stone type and include adequate fluid intake to prevent urine saturation, dietary modification to decrease intake of stone-forming constituents, treatment of UTI, measures to change urine pH, and the use of diuretics that decrease the calcium concentration of urine.

URINARY TRACT INFECTIONS After completing this section of the chapter, you should be able to meet the following objectives: •• List three physiologic mechanisms that protect against UTIs. •• Describe factors that predispose to UTIs in children, sexually active women, pregnant women, and older adults. •• Cite measures used in the diagnosis and treatment of UTIs.

UTIs are a frequent type of bacterial infection seen by health care providers. UTIs include several distinct entities, including asymptomatic bacteriuria, symptomatic infections, lower UTIs such as cystitis, and upper UTIs such as pyelonephritis. Because of their ability to cause renal damage, upper UTIs are considered more serious than lower UTIs. Acute pyelonephritis represents an infection of the renal parenchyma and renal pelvis. Improperly treated, it can lead to sepsis, renal abscesses, chronic pyelonephritis, and chronic renal failure. Approximately 7 million visits to a primary care provider are made each year for treatment of lower UTIs.15

Key Points URINARY TRACT INFECTIONS •  Infection is facilitated by host conditions that disrupt washout of the agent from the UT through urine flow, change the protective properties of the mucin lining of the UT, disrupt the protective function of the normal bacterial flora, or impair the function of the immune system. •  Virulence of the agent is derived from its ability to gain access to and thrive in the UT environment, adhere to the tissues of the lower or upper UT, evade the destructive effects of the host’s immune system, and develop resistance to antimicrobial agents.

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Etiology and Pathogenesis Most uncomplicated lower UTIs are caused by Escherichia coli.3,12 Other uropathic pathogens include Staphylococcus saprophyticus in uncomplicated UTIs, and both non–E. coli gram-negative rods (Proteus mirabilis, Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa) and gram-positive cocci (Staphylococcus aureus) in complicated UTIs.3,15,20 Most UTIs are caused by bacteria that enter through the urethra. Bacteria can also enter through the bloodstream usually in immunocompromised people and neonates. Although the distal portion of the urethra often contains pathogens, the urine formed in the kidneys and found in the bladder normally is sterile or free of bacteria. This is because of the washout phenomenon, in which urine from the bladder normally washes bacteria out of the urethra. When a UTI occurs, it is usually from bacteria that have colonized the urethra, vagina, or perianal area. There is an increased risk for UTIs in people with urinary obstruction and reflux, in people with neurogenic disorders that impair bladder emptying, in women who are sexually active, in postmenopausal women, in men with diseases of the prostate,21 and in older adults.20 Instrumentation and urinary catheterization are the most common predisposing factors for nosocomial UTIs. UTIs occur more commonly in women with diabetes than in women without the disease (due to their alkaline urine).12 People with diabetes are also at increased risk for complications associated with UTIs, including pyelonephritis, and they are more susceptible to fungal infections (particularly Candida species) and infections with gram-negative pathogens other than E. coli.22 Host–Agent Interactions Because certain people tend to be predisposed to development of UTIs, considerable interest has been focused on host–pathogen interactions and factors that increase the risk for UTI.22 UTIs are more common in women than men, specifically women between the ages of 16 and 35 years, at which time they are more than 40 times likely to develop a UTI than age-matched men.22 In men, the longer length of the urethra and the antibacterial properties of the prostatic fluid provide some protection from ascending UTIs until approximately 50 years of age.22 After this age, prostatic hypertrophy becomes more common, and with it may come obstruction and increased risk for UTI. For older adults with urinary catheters, a biofilm builds up and promotes more bacterial growth. Therefore, these older adults with decreased immunological function need meticulous surveillance for signs of infection.23 Host Defenses.  In the development of a UTI, host defenses are matched against the virulence of the pathogen. The host defenses of the bladder include •• The washout phenomenon, whereby bacteria are removed from the bladder and urethra during voiding •• The bladder lining, which assists in providing a barrier to protect against bacterial invasion •• The body’s immune response

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In the ureters, peristaltic movements facilitate the movement of urine from the renal pelvis through the ureters and into the bladder. Immune mechanisms, particularly secretory immunoglobulin (Ig) A, appear to provide an important antibacterial defense. Phagocytic blood cells further assist in the removal of bacteria from the urinary tract. Other important host factors include the normal flora of the periurethral area in women and prostate secretions in men.3 In women, the normal flora of the periurethral area, which consists of organisms such as Lactobacillus, provides defense against the colonization of uropathic bacteria. Alterations in the periurethral environment, such as that occurring with a decrease in estrogen levels during menopause or the use of antibiotics, can alter the protective periurethral flora, allowing uropathogens to colonize and enter the urinary tract. In men, the prostatic fluid has antimicrobial properties that protect the urethra from colonization. Pathogen Virulence.  Not all bacteria are capable of adhering and infecting the urinary tract. Of the many strains of E. coli, only those with increased ability to adhere to the epithelial cells of the urinary tract are able to produce UTIs. These bacteria have fine protein filaments, called pili or fimbriae, that help them adhere to receptors on the lining of urinary tract structures.24 The two main types of pili (types 1 and P) found on E. coli that cause UTIs are morphologically similar, but differ in their ability to mediate hemagglutination in the presence of mannose. Type P pili are mannose resistant and were named because of their high incidence in E. coli that cause pyelonephritis and because of their association with the P blood group system.25 P pili have been observed in over 90% of E. coli strains causing pyelonephritis but less than 20% of strains causing lower UTIs.24,25 Evidence suggests that probiotic therapies may be helpful instead of empirically administering antibiotics for every lower UTI, with this information regarding P pili.26 Obstruction and Reflux Obstruction and reflux are other contributing factors in the development of UTIs. Any microorganisms that enter the bladder normally are washed out during voiding. When outflow is obstructed, urine remains in the bladder and acts as a medium for microbial growth. The microorganisms in the contaminated urine can then ascend along the ureters to infect the kidneys. The presence of residual urine correlates closely with bacteriuria and with its recurrence after treatment. Another aspect of bladder outflow obstruction and bladder distention is increased intravesical pressure, which compresses blood vessels in the bladder wall, leading to a decrease in the mucosal defenses of the bladder. In UTIs associated with stasis of urine flow, the obstruction may be anatomic or functional. Anatomic obstructions include urinary tract stones, prostatic hyperplasia, pregnancy, and malformations of the ureterovesical junction. Functional obstructions include neurogenic bladder, infrequent voiding, detrusor (bladder) muscle instability, and constipation.

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Chapter 41  Disorders of Renal Function    1095

Ureter Bladder wall

RELAXED

MICTURITION

Flap MICTURITION

NORMAL

A

B

SHORT INTRAVESICAL URETER

FIGURE 41.8 •  Anatomic features of the ureter and bladder and their relationship to vesicoureteral reflux. (A) In the normal bladder, the distal portion of the intravesical ureter courses between the mucosa and the muscularis of the bladder. A mucosal flap is thus formed. On micturition, the elevated intravesicular pressure compresses the flap against the bladder wall, thereby occluding the lumen. (B) Persons with a congenitally short intravesical ureter have no mucosal flap because the entry of the ureter into the bladder approaches a right angle. Thus, micturition forces urine into the ureter. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 795). Philadelphia, PA: Lippincott Williams & Wilkins.)

Reflux occurs when urine from the urethra moves into the bladder (i.e., urethrovesical reflux).3 In women, urethrovesical reflux can occur during activities such as coughing or squatting, in which an increase in intra-abdominal pressure causes the urine to be squeezed into the urethra and then to flow back into the bladder as the pressure decreases. This also can happen when voiding is abruptly interrupted. Because the urethral orifice frequently is contaminated with bacteria, the reflux mechanism may cause bacteria to be drawn back into the bladder. A second type of reflux mechanism, vesicoureteral reflux, occurs at the level of the bladder and ureter. Normally, the distal portion of the ureter courses between the muscle layer and the mucosal surface of the bladder wall, forming a flap (Fig. 41.8). The flap is compressed against the bladder wall during micturition, preventing urine from being forced into the ureter. In persons with vesicoureteral reflux, the ureter enters the bladder at an approximate right angle such that urine is forced into the ureter during micturition.3 It is seen most commonly in children with UTIs and is believed to result from congenital defects in length, diameter, muscle structure, or innervation of the submucosal segment of the ureter. Vesicoureteral reflux also is seen in adults with obstruction to bladder outflow, primarily due to increased bladder volume and pressure. Catheter-Induced Infection Urinary catheters are tubes made of latex or plastic. They are inserted through the urethra into the bladder for the purpose of draining urine. They are a source of urethral irritation and provide a means for entry of microorganisms into the urinary tract.23

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Catheter-associated bacteriuria remains the most frequent cause of gram-negative septicemia in hospitalized patients. Studies have shown that bacteria adhere to the surface of the catheter and initiate the growth of a biofilm that then covers the surface of the catheter.23 The biofilm tends to protect the bacteria from the action of antibiotics and makes treatment difficult. A closed drainage system (i.e., closed to air and other sources of contamination) and careful attention to perineal hygiene (i.e., cleaning the area around the urethral meatus) help to prevent infections in persons who require an indwelling catheter. Careful hand washing and early detection and treatment of UTIs also are essential.

Clinical Manifestations The manifestations of UTI depend on whether the infection involves the lower (bladder) or upper (kidney) urinary tract and whether the infection is acute or chronic. The majority of UTIs are acute uncomplicated bladder infections that occur in women. Upper UTIs affect the parenchyma and pelvis of the kidney (pyelonephritis).15 They are less common and occur more frequently in children and adults with urinary tract obstructions or other predisposing conditions such as diabetes. An acute episode of cystitis (bladder infection) is characterized by frequency of urination, lower abdominal or back discomfort, and burning and pain on urination (i.e., ­dysuria).12,15 Occasionally, the urine is cloudy and foul smelling. In adults, fever and other signs of infection usually are absent. If there are no complications, the symptoms disappear within 48 hours

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of treatment. The symptoms of cystitis also may represent urethritis caused by Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus, or vaginitis attributable to Trichomonas vaginalis or Candida species.3

Diagnosis and Treatment The diagnosis of UTI usually is based on symptoms and on examination of the urine for the presence of microorganisms. When necessary, x-ray films, ultrasonography, and CT and renal scans are used to identify contributing factors, such as obstruction. Urine tests are used to establish the presence of bacteria in the urine and for a diagnosis of UTI. A commonly accepted criterion for diagnosis of a UTI is the presence of 100,000 colony-forming units (CFU) or more bacteria per milliliter (mL) of urine.17 Colonization usually is defined as the multiplication of microorganisms in or on a host without apparent evidence of invasiveness or tissue injury.17 Pyuria (the presence of less than five to eight leukocytes per high-power field) indicates a host response to infection rather than asymptomatic bacterial colonization.17 A Gram stain may be done to determine the type (gram positive or gram negative) of organism that is present. A urine culture may be done to confirm the presence of pathogenic bacteria in urine specimens, allow for their identification, and permit the determination of their sensitivity to specific antibiotics. Chemical screening (urine dipstick) for markers of infection may provide useful information but is less sensitive than microscopic analysis.12,15 These tests are relatively inexpensive, easy to perform, and can be done in the clinic setting or even in the home. Bacteria reduce nitrates in the urine to nitrites, providing a means for chemical analysis. Similarly, activated leukocytes secrete leukocyte esterase, which can be detected chemically. Leukocyte esterase is specific (94% to 98%) and reliably sensitive (75% to 96%) for detecting uropathogens equivalent to 100,000 CFU/mL urine.17 Nitrite tests may be negative if the causative organism is not nitrate producing (e.g., enterococci, S. saprophyticus). The nitrite test can also be negative if the urine specimen is too diluted. The treatment of UTI is based on the pathogen causing the infection, and the presence of contributing host–agent factors. Other considerations include whether the infection is acute, recurrent, or chronic. Most acute lower UTIs, which occur mainly in women and are generally caused by E. coli, are treated successfully with a short course of antimicrobial therapy. Forcing fluids may relieve signs and symptoms, and this approach is used as an adjunct to antimicrobial treatment. Recurrent lower UTIs are those that recur after treatment. They are due either to bacterial persistence or reinfection. Bacterial persistence usually is curable by removal of the infectious source (e.g., urinary catheter or infected bladder stones). Reinfection is managed principally through education regarding pathogen transmission prevention measures. Cranberry juice has been suggested as a preventive measure

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for women with recurrent UTIs. Evidence suggests that cranberry juice reduces bacterial adherence to the epithelial lining of the urinary tract.27 Because of its mechanism of action, the juice is also being studied with periodontal disease and Helicobacter pylori-associated gastritis and has been documented as an antioxidant and possible cholesterol-lowering therapy.27 Chronic UTIs are more difficult to treat. Because they often are associated with obstructive uropathy or reflux flow of urine, diagnostic tests usually are performed to detect such abnormalities.12 When possible, the condition causing the reflux flow or obstruction is corrected. Men, in particular, should be investigated for obstructive disorders or a prostatic focus of infection.

Infections in Special Populations UTIs affect persons of all ages. In infants, they occur more often in boys than in girls. After the first year of life, UTIs occur more often in girls. This is because of the shorter length of the female urethra and because the vaginal vestibule can be easily contaminated with fecal flora. Approximately half of all adult women have at least one UTI during their lifetime.15 The major risk factors for women of 16 to 35 years of age are related to sexual intercourse and use of spermicidal agents.15 The anterior urethra usually is colonized with bacteria; urethral massage or sexual intercourse can force these bacteria back into the bladder. Urinary Tract Infections in Pregnant Women Pregnant women are at increased risk for UTIs. Normal changes in the functioning of the urinary tract that occur during pregnancy predispose to UTIs.28 These changes involve the collecting system of the kidneys and include dilation of the renal calyces, pelves, and ureters that begin during the first trimester and become most pronounced during the third trimester. This dilation of the upper urinary system is accompanied by a reduction in the peristaltic activity of the ureters that is thought to result from the muscle-relaxing effects of progesterone-like hormones and mechanical obstruction from the enlarging uterus. In addition to the changes in the kidneys and ureters, the bladder becomes displaced from its pelvic position to a more abdominal position, producing further changes in ureteral position. Asymptomatic UTIs are common, with a prevalence of 2% to 14% in pregnant women.28 The complications of asymptomatic UTIs during pregnancy include persistent bacteriuria, acute and chronic pyelonephritis, and preterm delivery of infants with low birth weight. Evidence suggests that few women become bacteriuric during pregnancy. Rather, it appears that symptomatic UTIs during pregnancy reflect preexisting asymptomatic bacteriuria and that changes occurring during pregnancy simply permit the prior urinary colonization to progress to symptomatic infection and invasion of the kidneys.

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Chapter 41  Disorders of Renal Function    1097

Urinary Tract Infections in Children UTIs occur most frequently during the first 6 months of life. After that, occurrence greatly decreases, especially in boys.29 Children who are at increased risk for bacteriuria or symptomatic UTIs are premature infants discharged from neonatal intensive care units, children with systemic or immunologic disease or urinary tract abnormalities such as neurogenic bladder or vesicoureteral reflux, those with a family history of UTI or urinary tract anomalies with reflux, and girls younger than 5 years of age with a history of UTI.29 UTIs in children frequently involve the upper urinary tract (pyelonephritis). In children in whom renal development is not complete, pyelonephritis can lead to hypertension, renal scarring, and permanent kidney damage.29 The incidence of scarring is greatest in children with gross vesicoureteral reflux or obstruction, in children with recurrent UTIs, and in those with a delay in treatment. Clinical Manifestations.  Unlike adults, children frequently do not present with the typical signs of a UTI.29 Many neonates with UTIs have bacteremia and may show signs and symptoms of septicemia, including fever, hypothermia, apneic spells, poor skin perfusion, abdominal distention, diarrhea, vomiting, lethargy, and irritability. Older infants may ­present with feeding problems, failure to thrive, diarrhea, vomiting, fever, and foul-smelling urine. Toddlers often present with abdominal pain, vomiting, diarrhea, abnormal voiding patterns, foul-smelling urine, fever, and poor growth. In older children with lower UTIs, the classic features—enuresis, frequency, dysuria, and suprapubic discomfort—are more common. Fever is a common sign of UTI in children, and the possibility of UTI should be considered in any child with unexplained fever. Diagnosis and Treatment. Diagnosis is based on a careful history of voiding patterns and symptomatology; physical examination to determine fever, hypertension, abdominal or suprapubic tenderness, and other manifestations of UTI; and urinalysis to determine bacteriuria, pyuria, proteinuria, and hematuria. A positive urine culture that is obtained correctly is essential for the diagnosis.29 Additional diagnostic methods may be needed to determine the cause of the disorder. Vesicoureteral reflux is the most commonly associated abnormality in UTIs, and reflux nephropathy is an important cause of end-stage renal disease in children and adolescents. Children with a relatively uncomplicated first UTI may turn out to have significant reflux. Therefore, even a single documented UTI in a child requires careful diagnosis. Urinary symptoms in the absence of bacteriuria suggest vaginitis, urethritis, sexual molestation, the use of irritating bubble baths, pinworms, or viral cystitis. In adolescent girls, a history of dysuria and vaginal discharge makes vaginitis or vulvitis a consideration. The approach to treatment is based on the clinical severity of the infection, the site of infection (i.e., lower versus upper urinary tract), the risk for sepsis, and the presence of

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structural abnormalities.29 The immediate treatment of infants and young children is essential. Most infants with symptomatic UTIs and many children with clinical evidence of acute upper UTIs require hospitalization, rehydration, and intravenous antibiotic therapy. Follow-up is essential for children with febrile UTIs to ensure resolution of the infection. Follow-up urine cultures often are done at the end of treatment to ensure the antibiotic was effective. Imaging studies often are recommended for all children after their first UTI to detect renal scarring, vesicoureteral reflux, or other abnormalities. Urinary Tract Infections in Older Adults UTIs are relatively common in older adults.30 They are the second most common form of infection, after respiratory tract infections, among otherwise healthy community-dwelling older adults. Most of these infections follow invasion of the urinary tract by the ascending route. Several factors predispose older adults to UTIs, including immobility resulting in poor bladder emptying, bladder outflow obstruction caused by prostatic hyperplasia or kidney stones, bladder ischemia caused by urine retention, constipation, senile vaginitis, and diminished bactericidal activity of urine and prostatic secretions. Added to these risks are other health problems that necessitate instrumentation of the urinary tract. Older adults with bacteriuria have varying symptoms, ranging from the absence of symptoms to the presence of typical UTI symptoms. Even when symptoms of lower UTIs are present, they may be difficult to interpret because older adults without UTIs commonly experience urgency, frequency, and incontinence. Alternatively, older adults may have vague symptoms such as anorexia, fatigue, weakness, or change in mental status. Even with more serious upper UTIs (e.g., pyelonephritis), the classic signs of infection such as fever, chills, flank pain, and tenderness may be altered or absent in older adults.30 Sometimes, no symptoms occur until the infection is far advanced.

IN SUMMARY UTI is the second most common type of bacterial infection seen by health care professionals. Infections can range from asymptomatic bacteriuria to severe kidney infections that cause irreversible kidney damage. Predisposition to infection is determined by host defenses and pathogen virulence. Host defenses include the washout phenomenon associated with voiding, the protective mucin lining of the bladder, and the local immune defenses. Pathogen virulence is enhanced by the presence of pili that facilitate adherence to structures in the urinary tract, lipopolysaccharides that bind to host cells and elicit an inflammatory reaction, and enzymes that break down RBCs and make iron available for bacterial metabolism and multiplication. Most UTIs ascend from the urethra and bladder. A number of factors interact in determining the predisposition to

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development of UTIs, including urinary tract obstruction, urine stasis and reflux, pregnancy-induced changes in urinary tract function, age-related changes in the urinary tract, changes in the protective mechanisms of the bladder and ureters, impaired immune function, and virulence of the pathogen. Urinary tract catheters and urinary instrumentation contribute to the incidence of UTIs. Early diagnosis and treatment of UTI are essential to preventing permanent kidney damage.

layer of epithelial cells that surrounds the outer surface of the capillary and lines the inner surface of the Bowman capsule. The epithelial cells are attached to the basement membrane by long, footlike processes (podocytes) that encircle the outer surface of the capillaries. The glomerular capillary membrane is selectively permeable, allowing water and small particles (e.g., electrolytes, and dissolved particles, such as glucose and amino acids) to leave the blood and enter the Bowman space and preventing larger particles (e.g., plasma proteins and blood cells) from leaving the blood.6 Glomerulonephritis, an inflammatory process that involves glomerular structures, is the second leading cause of kidney failure worldwide and it ranks third, after diabetes and hypertension, as a cause of chronic kidney disease in the United States.3 There are many causes of glomerular disease. The disease may occur as a primary condition in which the glomerular abnormality is the only disease present, or it may occur as a secondary condition in which the glomerular abnormality results from another disease, such as diabetes mellitus or SLE. See Figure 41.10 for an algorithm regarding primary versus secondary glomerulonephritis.

DISORDERS OF GLOMERULAR FUNCTION After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the two types of immune mechanisms involved in glomerular disorders. •• Use the terms proliferation, sclerosis, membranous, diffuse, focal, segmental, and mesangial to explain changes in glomerular structure that occur with glomerulonephritis. •• Briefly describe the difference among the nephritic syndromes, rapidly progressive glomerulonephritis, nephrotic syndrome, asymptomatic glomerular disorders, and chronic glomerulonephritis.

Etiology and Pathogenesis of Glomerular Injury The causative agents or triggering events that produce glomerular injury include immunologic, nonimmunologic, and hereditary mechanisms. Most cases of primary and many cases of secondary glomerular disease probably have an immune ­origin.3 Although many glomerular diseases are driven by immunologic events, a variety of nonimmunologic metabolic (e.g., diabetes), hemodynamic (e.g., hypertension), and toxic (e.g., drugs, chemicals) stresses can induce glomerular injury, either alone or along with immunologic mechanisms. Hereditary glomerular diseases such as Alport syndrome, although relatively rare, are an important category of glomerular disease because of their association with progressive loss of renal function and transmission to future generations.

The glomeruli are tufts of capillaries that lie between the afferent and efferent arterioles. The capillaries of the glomeruli are arranged in lobules and supported by a stalk consisting of mesangial cells and a basement membrane–like extracellular matrix (Fig. 41.9). The glomerular capillary membrane is composed of three structural layers: an endothelial cell layer that lines the inner surface of the capillary, a basement membrane made up of a network of matrix proteins, and a

2

EP

EN 5 1

MC MM

4 GBM

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3

FIGURE 41.9 • Schematic representation of three glomerular capillaries depicting the sites of immune complex formation. Subepithelial deposits are seen in postinfectious glomerulonephritis (1) and membranous nephropathy (2) and are likely to be assembled locally by an in situ mechanism. Subendothelial deposits (3) and mesangial deposits (4) may also form locally but are more often the result of passive entrapment of preformed circulating immune complexes. Anti-GBM antibodies bind in a linear pattern to the GBM (5), and since the specific antigen is part of the heavily cross-linked basement membrane, electron-dense deposits at the ultrastructural level are missing. EN, endothelial cell; EP, visceral epithelial cell or podocyte; MC, mesangial cell; MM, mesangial matrix. (From Rennke H. G., Denker B. M. (2010). Renal pathophysiology: The essentials (3rd ed., p. 244). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Chapter 41  Disorders of Renal Function    1099 Anti-GBM Glomerulonephritis

Immune Complex Glomerulonephritis

Circulating anti-GBM antibodies with linear GBM staining for IgG

ANCA Glomerulonephritis

Glomerular immune complex localization with granular capillary wall and/or mesangial staining

Circulating ANCA with paucity of glomerular immunoglobulin staining

With lung hemorrhage

Without lung hemorrhage

Without lung hemorrhage

Vasculitis with no asthma or granulomas

Granulomas and no asthma

Eosinophilia, asthma and granulomas

Goodpasture syndrome

Anti-GBM glomerulonephritis

ANCA glomerulonephritis

Microscopic polyangiitis

Wegener granulomatosis

Churg-Strauss syndrome

IgA-dominant and no vasculitis

IgA-dominant and systemic vasculitis

IgA nephropathy

Henoch-Schonlein purpura

..

Systemic lupus erythematosus

Acute streptococcal infection

Thick capillary walls and endocapillary hypercellularity

Subepithelial dense deposits

Other features

Lupus nephritis

Acute post-streptococcal glomerulonephritis

Acute post-streptococcal glomerulonephritis

Membranous glomerulopathy

Many others

FIGURE 41.10 •  Algorithm demonstrating the integration of pathologic findings with clinical data to make a diagnosis of a specific form of primary or secondary glomerulonephritis. An important initial categorization is an anti-GBM, immune complex or antineutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis. Once this determination is made, more specific diagnoses depend on additional clinical or pathologic observations. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 765). Philadelphia, PA: Lippincott Williams & Wilkins.)

Two types of immune mechanisms have been implicated in the development of glomerular disease: 1. Injury resulting from antibodies reacting with fixed glomerular antigens or antigens planted within the glomerulus 2. Injury resulting from circulating antigen–antibody complexes that become trapped in the glomerular membrane (Fig. 41.11)

Antigens responsible for development of the immune response may be of endogenous origin, such as autoantibodies to deoxyribonucleic acid (DNA) in SLE, or they may be of exogenous origin, such as streptococcal membrane antigens in poststreptococcal glomerulonephritis. Frequently, the source of the antigen is unknown. The cellular changes that occur with glomerular disease include increases in glomerular or inflammatory cell

Epithelial cell Foot process Basement membrane

FIGURE 41.11  •   Immune mechanisms of glomerular disease. (A) Antiglomerular membrane antibodies leave the circulation and interact with ­antigens that are present in the basement membrane of the glomerulus. (B) Antigen– antibody complexes circulating in the blood become trapped as they are filtered in the glomerulus.

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Subendothelial deposit Circulating antigen–antibody complexes Antigen Antibody

A

Antiglomerular membrane antibodies

B

Circulating antigen–antibody complex deposition

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number (proliferative or hypercellular), basement membrane t­hickening (membranous), and changes in noncellular glomerular components (sclerosis and fibrosis).3,6 An increase in cell numbers is characterized by one or more of the following: proliferation of endothelial and mesangial cells, leukocyte infiltration (neutrophils, monocytes, and in some cases, lymphocytes), and formation of crescents (half-moon–shaped collections of proliferating epithelial cells and infiltrating leukocytes) in the Bowman space.3,6 Basement membrane thickening involves deposition of dense noncellular material on the endothelial and epithelial sides of the basement membrane or within the membrane itself. Sclerosis refers to an increase in the amount of extracellular material in the mesangial, subendothelial, or subepithelial tissue of the glomerulus, and fibrosis refers to the deposition of collagen fibers. Glomerular changes can be diffuse, involving all glomeruli and all parts of the glomeruli; focal, in which only some glomeruli are affected and others are essentially normal; segmental, involving only a certain segment of each glomerulus; or mesangial, affecting only mesangial cells.3,6 Figure 41.9B illustrates the location of lesions associated with various types of glomerular disease.

Types of Glomerular Disease The clinical manifestations of glomerular disorders generally fall into one of five categories: 1. Nephritic syndromes 2. Rapidly progressive glomerulonephritis 3. The nephrotic syndrome 4. Asymptomatic disorders of urinary sediment (i.e., hematuria, proteinuria) 5. Chronic glomerulonephritis3 The nephritic syndromes produce a proliferative inflammatory response, whereas the nephrotic syndrome produces increased permeability of the glomerulus. Because most glomerular disorders can produce mixed nephritic and nephrotic syndromes, a definitive diagnosis often requires renal biopsy. Acute Nephritic Syndrome The acute nephritic syndrome is the clinical correlate of acute glomerular inflammation. In its most dramatic form, the acute nephritic syndrome is characterized by sudden onset of hematuria (either microscopic or grossly visible, with red cell casts), variable degrees of proteinuria, diminished GFR, oliguria, and signs of impaired renal function. Inflammatory processes that occlude the glomerular capillary lumen and damage the capillary wall cause it. This damage to the capillary wall allows RBCs to escape into the urine and produce hemodynamic changes that decrease the GFR. Extracellular fluid accumulation, hypertension, and edema develop because of the decreased GFR and enhanced tubular reabsorption of salt and water. The acute nephritic syndrome may occur in such systemic diseases as SLE. Typically, however, it is associated with acute proliferative glomerulonephritis such as postinfectious glomerulonephritis.

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Key Points GLOMERULAR DISORDERS •  Glomerular disorders affect the semipermeable properties of the glomerular capillary membrane that allow water and small particles to move from the blood into the urine filtrate, while preventing blood cells and plasma proteins from leaving the circulation. •  The nephritic syndromes produce a decrease in glomerular permeability and manifestations related to a decrease in GFR, fluid retention, and nitrogenous waste accumulation. •  The nephrotic syndrome produces an increase in glomerular permeability and manifestations of altered body function related to a massive loss of plasma proteins in the urine.

Acute Postinfectious Glomerulonephritis.  Acute postinfectious glomerulonephritis usually occurs after infection with certain strains of group A β-hemolytic streptococci and is caused by deposition of immune complexes of antibody and bacterial antigens.3 It also may occur after infections by other organisms, including staphylococci, a viral agent, such as hepatitis, and various parasites.3 Although the disease is seen primarily in children, people of any age can be affected. The acute phase of postinfectious glomerulonephritis is characterized by diffuse glomerular enlargement and hypercellularity. The hypercellularity is caused by infiltration of leukocytes, both neutrophils and monocytes, and proliferation of endothelial and mesangial cells.3 There is also swelling of endothelial cells. The combination of proliferation, swelling, and leukocyte infiltration obliterates the glomerular capillary lumens. There may be interstitial edema and inflammation, and the tubules often contain RBCs. In the first weeks of disease, immunofluorescence microscopy typically reveals granular deposits of IgG and the complement component C3 in the mesangium and along the basement membrane (Fig. 41.12). The classic case of poststreptococcal glomerulonephritis follows a streptococcal infection by approximately 7 to 12 days. This is the time needed for the development of antibodies. The primary infection usually involves the pharynx, but could be skin triggered. Oliguria, which develops as the GFR decreases, is one of the first symptoms. Proteinuria and hematuria follow because of increased glomerular capillary wall permeability. Materials in the urine degrade the RBCs, and cola-colored urine may be the first sign of the disorder. Sodium and water retention gives rise to edema (particularly of the face and hands) and hypertension. Important laboratory findings include an elevated antistreptococcal antibody (ASO) titer, a decline in serum concentrations of C3 and other components of the complement cascade, and cryoglobulins (i.e., large immune complexes) in the serum.

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Chapter 41  Disorders of Renal Function    1101

FIGURE 41.12  •  Acute postinfectious glomerulonephritis. An immunofluorescence micrograph demonstrates granular staining for ­complement C3 in capillary walls and the mesangium. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 776). Philadelphia, PA: Lippincott Williams & Wilkins.)

Treatment of acute poststreptococcal glomerulonephritis includes elimination of the streptococcal infection with antibiotics and providing supportive care. The disorder carries an excellent prognosis and rarely causes chronic kidney disease.3 Rapidly Progressive Glomerulonephritis Rapidly progressive glomerulonephritis is a clinical syndrome characterized by signs of severe glomerular injury that does not have a specific cause. As its name indicates, this type of glomerulonephritis is rapidly progressive, often within a matter of months. The disorder involves focal and segmental proliferation of glomerular cells and recruitment of monocytes and macrophages with formation of crescent-shaped structures that obliterate the Bowman space.6 Rapidly proliferative glomerulonephritis may be caused by a number of immunologic disorders, some systemic and others restricted to the kidney. Among the diseases associated with this form of glomerulonephritis are immune complex disorders such as SLE, small-vessel vasculitides (e.g., microscopic polyangiitis), and an immune disorder called Goodpasture syndrome. Goodpasture Syndrome. Goodpasture syndrome is an uncommon and aggressive form of glomerulonephritis that is caused by antibodies to the alveolar and glomerular basement membrane (GBM). The anti-GBM antibodies cross-react with the pulmonary alveolar basement membrane to produce the syndrome of pulmonary hemorrhage associated with renal failure. The pathologic hallmark of anti-GBM glomerulonephritis is diffuse linear staining of GBMs for IgG (Fig. 41.13). The cause of the disorder is unknown, although influenza infection, exposure to hydrocarbon solvent (found in paints and dyes), various drugs, and cancer have been implicated in

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FIGURE 41.13 •  Anti-GBM glomerulonephritis. Linear immunofluorescence for IgG is seen along the GBM. Contrast this with the granular pattern of immunofluorescence typical of most types of immune complex deposition within the capillary wall. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 782). Philadelphia, PA: Lippincott Williams & Wilkins.)

some people. There is some thought that Goodpasture syndrome has a genetic predisposition, but this is not conclusive. Treatment includes plasmapheresis to remove circulating anti-GBM antibodies and immunosuppressive therapy (i.e., corticosteroids and cyclophosphamide) to inhibit antibody production.31 Nephrotic Syndrome The nephrotic syndrome is characterized by massive proteinuria (>3.5 g/day) and lipiduria (e.g., free fat, oval bodies, fatty casts), along with an associated hypoalbuminemia ( 300 mg/dL).3 The nephrotic syndrome is not a specific glomerular disease, but a constellation of clinical findings that result from an increase in glomerular permeability and loss of plasma proteins in the urine3 (Fig. 41.14). Pathogenesis. Any increase in glomerular membrane permeability allows proteins to escape from the plasma into the glomerular filtrate. Massive proteinuria results, leading to hypoalbuminemia. Generalized edema, which is a hallmark of the nephrotic syndrome, results from the loss of colloidal osmotic pressure of the blood with subsequent accumulation of fluid in the interstitial tissues.3 There is also salt and water retention, which aggravates the edema. This appears to be due to several factors, including a compensatory increase in aldosterone, stimulation of the sympathetic nervous system, and a reduction in secretion of natriuretic factors. Initially, the edema presents in dependent parts of the body such as the lower extremities, but becomes more generalized as the disease progresses. Dyspnea due to pulmonary edema, pleural effusions, and diaphragmatic compromise due to ascites can develop in persons with nephrotic syndrome.

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almost always is caused by primary idiopathic glomerular disease, whereas in adults, it often is a secondary disorder.3

Glomerular damage

Increased permeability to proteins Proteinuria ( 3.5 g/24 h)

Hypoproteinemia

Decreased plasma oncotic pressure

Compensatory synthesis of proteins by liver

Edema

Hyperlipidemia

FIGURE 41.14  •  Pathophysiology of the nephrotic syndrome.

The hyperlipidemia that occurs in people with nephrosis is characterized by elevated levels of triglycerides and ­low-density lipoproteins (LDLs). Levels of high-density lipoproteins (HDLs) usually are normal. Because of the elevated LDL levels, people with nephrotic syndrome are at increased risk for development of atherosclerosis. The largest proportion of protein lost in the urine is albumin, but globulins also may be lost. As a result, people with nephrosis may be vulnerable to infections, particularly those caused by staphylococci and pneumococci.3 This decreased resistance to infection probably is related to loss of both immunoglobulins and low molecular weight complement components in the urine. Many binding proteins also are lost in the urine. Consequently, the plasma levels of many ions (iron, copper, zinc) and hormones (thyroid and sex hormones) may be low because of decreased binding proteins. Many drugs require protein binding for transport. Hypoalbuminemia reduces the number of available protein-binding sites, thereby producing a potential increase in the amount of free (active) drug that is available. Etiology.  The glomerular derangements that occur with nephrosis can develop as a primary disorder or secondary to changes caused by systemic diseases such as diabetes mellitus and SLE. Among the primary glomerular lesions leading to nephrotic syndrome are minimal-change disease (lipoid nephrosis), focal segmental glomerulosclerosis, and membranous glomerulonephritis.3 The relative frequency of these causes varies with age. In children younger than 15 years of age, nephrotic syndrome

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Minimal-Change Disease (Lipoid Nephrosis). Minimalchange disease is characterized by diffuse loss (through fusion) of the foot processes of cells in the epithelial layer of the glomerular membrane. It is most commonly seen in children, but may occasionally occur in adults. The cause of minimalchange nephrosis is unknown. Although minimal-change disease does not progress to renal failure, it can cause significant complications, including predisposition to infection with gram-positive organisms, a tendency toward thromboembolic events, hyperlipidemia, and protein malnutrition. Membranous Glomerulonephritis.  Membranous glomerulo­ nephritis is the most common cause of primary nephrosis in adults, most commonly those in the fifth and sixth decades of life and almost always after 30 years of age.3 The disorder is caused by diffuse thickening of the GBM due to deposition of immune complexes. The disorder may be idiopathic or associated with a number of disorders, including autoimmune diseases such as SLE, infections such as chronic hepatitis B, and metabolic disorders such as diabetes mellitus. The presence of immunoglobulins and complement in the subendothelial deposits suggests that the disease represents a chronic immune complex–mediated disorder. The disorder usually begins with an insidious onset of the nephrotic syndrome or, in a small percentage of people, with non-nephrotic proteinuria. Hematuria and mild hypertension may be present. The progress of the disease is variable. Some people experience a complete remission, others have repeated remissions and relapses, and still others progress to complete renal failure and even death. Spontaneous remissions and a relatively benign outcome occur more commonly in women and those with proteinuria in the non-nephrotic range. Treatment is controversial. Focal Segmental Glomerulosclerosis.  Focal segmental glo­ merulosclerosis is characterized by sclerosis (i.e., increased collagen deposition) of some, but not all glomeruli, and in the affected glomeruli, only a portion of the glomerular tuft is involved.3 It is a particularly common cause of nephrotic syndrome in Hispanic and African Americans. Although focal segmental sclerosis often is an idiopathic syndrome, it may be associated with reduced oxygen in the blood (e.g., sickle cell disease and cyanotic congenital heart disease), human immunodeficiency virus (HIV) infection, or intravenous drug abuse, or it may occur as a secondary event reflecting glomerular scarring due to other forms of glomerulonephritis.3 The presence of hypertension and decreased renal function distinguishes focal sclerosis from minimal-change disease. In addition, research indicates that urinary excretion of CD80 (B7.1) is elevated with minimal-change disease, but not with focal segmental glomerulosclerosis.32 The disorder

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u­ sually is treated with corticosteroids. Most people with the disorder progress to kidney failure within 5 to 10 years. Asymptomatic Hematuria or Proteinuria Many cases of glomerulonephritis result in mild asymptomatic illness that is not recognized or brought to the attention of a health care professional, and therefore remains undiagnosed. Population-based screening studies have shown that kidney damage as evidenced by proteinuria, hematuria, low GFR, or a combination of these features is present in the population. Disorders such as Henoch-Schönlein purpura often resolve without permanent kidney damage, whereas others, such as IgA nephropathy and Alport syndrome, can progress to chronic kidney disease and renal failure. Immunoglobulin A Nephropathy. Immunoglobulin A ne-phro­pathy (i.e., Berger disease) is a primary glomerulonephritis characterized by the presence of glomerular IgA immune complex deposits. It can occur at any age, but most commonly, the peak age of diagnosis is between 15 and 30 years of age.3 The disease occurs more commonly in men than women and is the most common cause of glomerular nephritis in Asians. The disorder is characterized by the deposition of IgAcontaining immune complexes in the mesangium of the glomerulus. Once deposited in the kidney, the immune complexes are associated with glomerular inflammation. The cause of the disorder is unknown and there is a need for more specific classifications of the stages of IgA nephropathy so more information can be interpreted. Therefore, the International IgA Nephropathy Network is developing IgAN classifications to assist providers in diagnosing this disease.33 Some people with the disorder have elevated serum IgA levels. Early in the disease, many people with the disorder have no obvious symptoms and are unaware of the problem. In these people, IgA nephropathy is suspected during routine screening or examination for another condition. In other people, the disorder presents with gross hematuria that is preceded by upper respiratory tract infection, gastrointestinal tract symptoms, or a flulike illness. The hematuria usually lasts 2 to 6 days. Approximately one half of the people with gross hematuria have a single episode, whereas the remainder experience a gradual progression in the disease with recurrent episodes of hematuria and mild proteinuria. Progression usually is slow, extending over several decades. Immunofluorescence microscopy is essential for diagnosis of IgA nephropathy.3 The diagnostic finding is mesangial staining for IgA more intense than staining for IgG or IgM (Fig. 41.15). At present, there are no satisfactory treatment measures for IgA nephropathy. The role of immunosuppressive drugs such as steroids and cytotoxic drugs is not clear. There has been recent interest in the use of omega-3 fatty acids in delaying the progression of the disease. Henoch-Schönlein Purpura Nephritis. Henoch-Schönlein purpura is a small-vessel vasculitis that causes a purpuric rash

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FIGURE 41.15 • IgA nephropathy. An immunofluorescence micrograph shows deposits of IgA in the mesangial areas. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 781, Fig. 16.47). Philadelphia, PA: ­Lippincott Williams & Wilkins.)

largely of the lower extremities, arthritis or arthralgia, abdominal pain, and renal involvement identical to that of IgA nephropathy. The disease is seen most commonly in children but can also occur in adults. Renal involvement is not always present initially, but its incidence increases with time and is more common in older children, who have associated abdominal pain and a persistent rash. Although hematuria and proteinuria are the most common presentation, some people present with manifestations of acute nephritis, and others may present with combined nephritis and nephrotic manifestations. Most people recover fully over a period of several weeks. Corticosteroids are the most effective treatment and have been found to decrease the duration and intensity of abdominal and joint pain.34 Alport Syndrome Alport syndrome represents a hereditary defect of the GBM that results in hematuria and may progress to chronic renal failure. It tends to be associated with defects in the ears or eyes.3The syndrome is caused by type IV collagen mutations.3 Approximately 85% of cases are inherited as an X-linked autosomal dominant trait, whereas others have autosomal dominant and recessive patterns of inheritance.3 In X-linked pedigrees, boys are usually affected more seriously than girls. Affected boys usually progress to renal failure as adults, but progression may occur during adolescence. Although many girls never have more than mild hematuria with or without mild proteinuria, some have more significant disease and may even progress to kidney failure. Diagnosis of Alport syndrome is often made after examination of the urine of a child from a family with multiple cases of hereditary nephritis. Children may initially present with heavy microscopic hematuria, followed by the development of proteinuria. Many, but not all, people with Alport syndrome have sensorineural deafness and various eye disorders, including lens dislocation, posterior cataracts, and

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­corneal ­dystrophy. The hearing loss is bilateral and often is first detected during adolescence. Chronic Glomerulonephritis Chronic glomerulonephritis represents the chronic phase of a number of specific types of glomerulonephritis.3 Some forms of acute glomerulonephritis (e.g., poststreptococcal glomerulonephritis) undergo complete resolution, whereas others progress at variable rates to chronic glomerulonephritis. Some people who present with chronic glomerulonephritis have no history of glomerular disease. These cases may represent the end result of relatively asymptomatic forms of glomerulonephritis. Histologically, the condition is characterized by small kidneys with sclerosed glomeruli. In most cases, chronic glomerulonephritis develops insidiously and slowly progresses to chronic kidney disease over a period of years.

and evidence of deteriorating renal function (i.e., rising serum creatinine, and a decrease in calculated GFR). Oral corticosteroids and angiotensin-converting enzyme (ACE) inhibitors are the mainstays of treatment. People with more advanced disease may require treatment with immunosuppressive agents (e.g., intravenous cyclophosphamide or oral mycophenolate mofetil). Clinical trials using other immunosuppressant agents are ongoing. Diabetic Glomerulosclerosis Diabetic nephropathy is a major cause of chronic kidney disease and the most common cause of kidney failure treated by renal replacement therapy in the United States.3 It occurs in both types 1 and 2 diabetes mellitus. It is more prevalent among African Americans, Asians, and Native Americans than whites.

Clinical Manifestations.  The clinical manifestations of lupus nephritis depend on the site of immune complex–mediated injury. Immune complexes confined to the mesangium cause less inflammation than subendothelial immune complexes, which have greater exposure to inflammatory cells and mediators in the blood, and which therefore are more likely to produce inflammation.3 The World Health Organization (WHO) classifies the renal glomerular lesions of SLE as class I, normal; class II, mesangial proliferation; class III, focal and segmental proliferation; class IV, diffuse proliferation; and class V, membranous proliferation.35

Pathophysiology.  The lesions of diabetic nephropathy most commonly involve the glomeruli. Widespread thickening of the glomerular capillary basement membrane occurs in almost all people with diabetes and can occur without evidence of proteinuria. This is followed by a diffuse increase in mesangial matrix, with mild proliferation of mesangial cells. As the disease progresses, the mesangial cells impinge on the capillary lumen, reducing the surface area for glomerular filtration. In nodular glomerulosclerosis, also known as KimmelstielWilson syndrome, there is nodular deposition of hyaline in the mesangial portion of the glomerulus.3 As the sclerotic process progresses in the diffuse and nodular forms of glomerulosclerosis, there is complete obliteration of the glomerulus, with impairment of renal function. Although the mechanisms of glomerular change in diabetes are uncertain, they are thought to represent enhanced or defective synthesis of the GBM and mesangial matrix with an inappropriate incorporation of glucose into the noncellular components of these glomerular structures.3 Alternatively, hemodynamic changes that occur secondary to elevated blood glucose levels may contribute to the initiation and progression of diabetic glomerulosclerosis.3 It has been hypothesized that elevations in blood glucose produce an increase in GFR and glomerular pressure that leads to enlargement of glomerular capillary pores by a mechanism that is, at least partly, mediated by angiotensin II. This enlargement results in an increase in the protein content of the glomerular filtrate, which in turn requires increased endocytosis of the filtered proteins by tubular endothelial cells, a process that ultimately leads to nephron destruction and progressive deterioration of renal function.

Diagnosis and Treatment. Because of the high risk for kidney disease, all people with SLE should undergo routine urinalysis to monitor for the appearance of hematuria or proteinuria. If urinary abnormalities are noted, renal biopsy is often performed. Treatment depends on the extent of glomerular involvement. People with class I or II glomerulonephritis usually require no treatment. Progression to higher classes is usually accompanied by an increase in lupus serology activity

Clinical Manifestations and Treatment.  The clinical manifestations of diabetic glomerulosclerosis are closely linked to those of diabetes. The increased GFR that occurs in people with early alterations in renal function is associated with microalbuminuria, which is defined as urinary albumin excretion of 30 to 300 mg in 24 hours.17 Microalbuminuria is an important predictor of future diabetic nephropathies. In many cases, these early changes in glomerular function can be reversed by

Glomerular Lesions Associated with Systemic Disease Many immunologic, metabolic, or hereditary systemic diseases are associated with glomerular injury. In some diseases, such as SLE, diabetes mellitus, and hypertension, the glomerular involvement may be a major clinical manifestation. Systemic Lupus Erythematosus Glomerulonephritis Renal involvement is clinically evident in 40% to 85% of people with SLE and is seen more commonly in black women.3 The pathogenesis of SLE is uncertain, but seems to be related to dysregulated B-cell immunity with production of autoantibodies to a variety of nuclear, cytoplasmic, extracellular matrix, and cell membrane components.3 Most glomerular injury is triggered by the formation of immune complexes within the glomerular capillary wall.

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Chapter 41  Disorders of Renal Function    1105

careful control of blood glucose levels. Inhibition of angiotensin by ACE inhibitors or angiotensin receptor blockers (ARBs) has been shown to have a beneficial effect, possibly by reversing increased glomerular pressure.36Hypertension and cigarette smoking have been implicated in the progression of diabetic nephropathy. Hypertensive Glomerular Disease Mild to moderate hypertension causes sclerotic changes  in renal arterioles and small arteries, referred to as benign nephrosclerosis.3It is most prevalent and most aggressive among blacks. Among African Americans, hypertension is the leading cause of end-stage renal disease. Hypertensive nephropathy is associated with a number of changes in kidney structure and function. The kidneys are smaller than normal and are usually affected bilaterally. On histologic examination, there is narrowing of the arterioles and small arteries, caused by thickening and scarring of the vessel walls. As the vascular structures thicken and perfusion diminishes, blood flow to the nephron decreases, causing patchy tubular atrophy, interstitial fibrosis, and a variety of changes in glomerular structure and function. Although uncomplicated hypertensive nephrosclerosis is not usually associated with significant abnormalities in renal function, a few people may progress to end-stage renal disease. Three groups of people are at particular risk for development of renal failure—blacks, people with more severe BP elevations, and people with a second underlying disease, such as diabetes.

IN SUMMARY Glomerulonephritis, an inflammatory process that involves glomerular structures, is the second leading cause of kidney failure worldwide and ranks third, after diabetes and hypertension, as a cause of chronic kidney disease in the United States. The disease may occur as a primary condition in which the glomerular abnormality is the only disease present, or it may occur as a secondary condition in which the glomerular abnormality results from another disease, such as diabetes mellitus or SLE. Most cases of primary and many cases of secondary glomerular disease probably have an immune origin. The clinical manifestations of glomerular disorders generally fall into one of five categories: the nephritic syndromes, rapidly progressive glomerulonephritis, nephrotic syndrome, asymptomatic disorders (i.e., hematuria, proteinuria), and chronic glomerulonephritis. The nephritic syndrome evokes an inflammatory response in the glomeruli and is characterized by hematuria with red cell casts in the urine, a diminished GFR, azotemia, oliguria, and hypertension. The nephrotic syndrome affects the integrity of the glomerular capillary membrane and is characterized by massive proteinuria, hypoalbuminemia, generalized edema, lipiduria, and hyperlipidemia. Asymptomatic

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hematuria and proteinuria represent glomerular disorders that are not recognized or brought to the attention of a health care professional, and therefore remain undiagnosed. Chronic glomerulonephritis represents the chronic phase of a number of specific types of glomerulonephritis. Secondary causes of glomerular kidney disease include SLE, diabetes mellitus, and hypertension.

TUBULOINTERSTITIAL DISORDERS After completing this section of the chapter, you should be able to meet the following objectives: •• Differentiate between the defects in tubular function that occur in proximal and distal tubular acidosis. •• Explain the pathogenesis of kidney damage in acute and chronic pyelonephritis.

Several disorders affect renal tubular structures, including the proximal and distal tubules. Most of these disorders also affect the interstitial tissue that surrounds the tubules. These disorders, sometimes referred to as tubulointerstitial disorders, include acute tubular necrosis, renal tubular acidosis, acute and chronic pyelonephritis, and the effects of drugs and toxins. Tubulointerstitial renal diseases may be divided into acute and chronic disorders. The acute disorders are characterized by their sudden onset and by signs and symptoms of interstitial edema. They include acute pyelonephritis and acute hypersensitivity reaction to drugs. The chronic disorders produce interstitial fibrosis, atrophy, and mononuclear infiltrates. Most people with chronic disorders are asymptomatic until late in the course of the disease. In the early stages, tubulointerstitial diseases commonly are manifested by fluid and electrolyte imbalances that reflect subtle changes in tubular function. These clinical manifestations can include inability to concentrate urine, as evidenced by polyuria and nocturia; interference with acidification of urine, resulting in metabolic acidosis; and diminished tubular reabsorption.3

Renal Tubular Acidosis Renal tubular acidosis (RTA) refers to a group of tubular defects in reabsorption of bicarbonate ions (HCO3−) or excretion of hydrogen ions (H+) that result in metabolic acidosis and its subsequent complications, including metabolic bone disease, kidney stones, and growth failure in children. Proximal tubular disorders that affect bicarbonate reabsorption, and distal tubular defects that affect the secretion of fixed metabolic acids are the two major types of RTA. A third type of RTA results from aldosterone deficiency or resistance to its action that leads to impaired reabsorption of sodium ions (Na+) with decreased elimination of H+ and potassium ions (K+). Renal acidosis also occurs in kidney failure.

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Proximal Renal Tubular Acidosis Proximal RTA involves a defect in proximal tubular reabsorption, the nephron site where 85% of filtered HCO3− is reabsorbed. With the onset of impaired tubular HCO3− reabsorption, there is a loss of HCO3− in the urine that reduces plasma HCO3− levels. The concomitant loss of Na+ in the urine leads to contraction of the extracellular fluid volume with increased aldosterone secretion and a resultant decrease in serum K+ levels. With proximal tubular defects in acid–base regulation, the distal tubular sites for secretion of the fixed acids into the urine continue to function, and the reabsorption of HCO3− eventually resumes, albeit at a lower level of serum HCO3−. Whenever serum levels rise above this decreased level, HCO3− is lost in the urine. People with proximal RTA generally have plasma HCO3− levels greater than 15 mEq/L and seldom develop severe acidosis. Proximal RTA may occur as a hereditary or acquired disorder and may involve an isolated defect in HCO3− reabsorption or accompany other defects in proximal tubular function (Fanconi syndrome). Isolated defects in HCO3− reabsorption are relatively rare. The term Fanconi syndrome is used to describe a generalized proximal tubular dysfunction in which the RTA is accompanied by impaired reabsorption of glucose, amino acids, phosphate, and uric acid. Children with Fanconi syndrome are likely to have growth retardation, rickets, osteomalacia, and abnormal vitamin D metabolism in addition to mild acidosis associated with proximal RTA. Children and infants with proximal RTA require alkali therapy because of the high incidence of growth retardation due to acidemia. Potassium supplements are also needed because of increased loss of potassium that occurs with alkali therapy. Adults may also require alkali therapy. Vitamin D and phosphate are appropriate treatments for rickets and hypophosphatemia. Distal Renal Tubular Acidosis Distal RTA has its origin in the distal convoluted tubule and the collecting duct, where about 15% of the filtered bicarbonate is reabsorbed. The clinical syndrome of distal RTA includes hypokalemia, hyperchloremic metabolic acidosis, inability to acidify the urine, nephrocalcinosis, and nephrolithiasis. Additional features include osteomalacia or rickets. Distal RTA results from a distal tubular defect in H+ secretion with failure to acidify the urine. Because the secretion of H+ in the distal tubules is linked to sodium reabsorption, failure to secrete H+ results in a net loss of sodium bicarbonate in the urine. This results in contraction of fluids in the extracellular fluid compartment, a compensatory increase in aldosterone levels, and development of hypokalemia. The persistent acidosis, which requires buffering by the skeletal system, causes calcium to be released from bone. Increased losses of calcium in the urine lead to increased levels of parathyroid hormone, osteomalacia, bone pain, impaired growth in children, and development of kidney stones and nephrocalcinosis. Long-term treatment of distal RTA requires alkali supplementation. Greater amounts are needed for children because

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of the need for base deposition in growing bone and because bicarbonate wastage is greater in children than in adults. Alkali therapy generally allows for correction of potassium wasting and hypokalemia.

Pyelonephritis Pyelonephritis refers to infection of the kidney parenchyma and renal pelvis. There are two forms of pyelonephritis— acute and chronic. Acute Pyelonephritis Acute pyelonephritis represents an upper UTI, specifically the renal parenchyma and renal pelvis. Risk factors for complicated acute pyelonephritis are those that increase the host’s susceptibility or reduce the host response to infection. People with diabetes mellitus are at increased risk. A less frequent and more serious type of acute pyelonephritis, called necrotizing pyelonephritis, is characterized by necrosis of the renal papillae. It is particularly common in people with diabetes and may also be a complication of acute pyelonephritis when there is significant urinary tract obstruction. Etiology. Gram-negative bacteria, including E. coli and Proteus, Klebsiella, Enterobacter, and Pseudomonas species, are the most common causative agents. The infection usually ascends from the lower urinary tract, with the exception of S. aureus, which is usually spread through the bloodstream. Factors that contribute to the development of acute pyelonephritis are catheterization and urinary instrumentation, vesicoureteral reflux, pregnancy, and neurogenic bladder. Hematogenous acute pyelonephritis occurs most often in debilitated, chronically ill people and those receiving immunosuppressive therapy. Immunosuppression favors the development of subclinical (silent) pyelonephritis and infections caused by nonenteric, aerobic, gram-negative rods, and Candida. Clinical Manifestations.  Acute pyelonephritis tends to present with an abrupt onset of chills, high fever, and an ache or tenderness in the costovertebral angle (flank area of the back) that is unilateral or bilateral.15 Lower urinary tract symptoms, including dysuria, frequency, and urgency, also are common. Nausea and vomiting may occur along with abdominal pain. Palpation or percussion over the costovertebral angle on the affected side usually causes pain. Pyuria occurs but is not diagnostic because it also occurs in lower UTIs. The development of necrotizing papillitis is associated with a much poorer prognosis. Treatment. Acute pyelonephritis is treated with appropriate antimicrobial drugs and may also require intravenous hydration. Unless obstruction or other complications occur, the symptoms usually disappear within several days. Treatment with an appropriate antimicrobial agent usually is continued for 10 to 14 days. People with complicated acute p­ yelonephritis

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Chapter 41  Disorders of Renal Function    1107

and those who do not respond to outpatient treatment may require hospitalization. Chronic Pyelonephritis Chronic pyelonephritis represents a progressive process. There is scarring and deformation of the renal calyces and pelvis3 (Fig. 41.16). The disorder appears to involve a bacterial infection superimposed on obstructive abnormalities or vesicoureteral reflux. Chronic obstructive pyelonephritis is associated with recurrent bouts of inflammation and scarring, which eventually lead to chronic pyelonephritis. Reflux, which is the most common cause of chronic pyelonephritis, results from superimposition of infection on congenital vesicoureteral reflux or intrarenal reflux. Reflux may be unilateral with involvement of a single kidney or bilateral, leading to scarring and atrophy of both kidneys with the eventual development of chronic renal insufficiency. Clinical Manifestations.  Chronic pyelonephritis may cause many of the same symptoms as acute pyelonephritis, or its onset may be insidious. Often, there is a history of recurrent episodes of UTI or acute pyelonephritis. Loss of tubular function and the ability to concentrate urine give rise to polyuria, nocturia, and mild proteinuria. Severe hypertension often is a contributing factor in the progress of the disease. Chronic pyelonephritis is a significant cause of renal failure

Drug-Related Nephropathies Drug-related nephropathies involve functional or structural changes in the kidneys that occur after exposure to a drug. Because of their large blood flow and high filtration pressure, the kidneys are exposed to any substance that is in the blood. The kidneys also are active in the metabolic ­transformation

FIGURE 41.16 • Chronic pyelonephritis. (A) The cortical surface contains many irregular, depressed scars (reddish areas). (B) There is marked dilation of calices caused by inflammatory destruction of papillae, with atrophy and scarring of the overlying cortex. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s ­pathology: Clinicopathologic foundations of medicine (6th ed., p. 797). Philadelphia, PA: Lippincott Williams & Wilkins.)

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A

of drugs and therefore are exposed to a number of toxic metabolites. The tolerance to drugs varies with age and ­ depends on renal function, state of hydration, BP, and the pH of the urine. Older adults are particularly susceptible to kidney damage caused by drugs and toxins. The dangers of nephrotoxicity are increased when two or more drugs capable of producing kidney damage are given at the same time. Drugs and toxic substances can damage the kidneys by causing a decrease in renal blood flow, obstructing urine flow, directly damaging tubulointerstitial structures, or producing hypersensitivity reactions.3 Some drugs, such as diuretics, high molecular weight radiocontrast media, the immunosuppressive drugs cyclosporine and tacrolimus, and the nonsteroidal anti-inflammatory drugs (NSAIDs), can cause acute prerenal failure by decreasing renal blood flow. Persons at particular risk are those who already have compromised renal blood flow. Other drugs such as sulfonamides and vitamin C (due to oxalate crystals) can form crystals that cause kidney damage by obstructing urinary flow in the tubules. Acute drug-related hypersensitivity reactions produce tubulointerstitial nephritis, with damage to the tubules and interstitium. This condition was observed initially in persons who were sensitive to the sulfonamide drugs; currently, it is observed most often with the use of methicillin and other synthetic antibiotics, and with the use of furosemide and the thiazide diuretics in persons sensitive to these drugs. At the onset, there is fever, eosinophilia, hematuria, mild proteinuria, and in approximately one fourth of cases, a rash. In approximately 50% of cases, signs and symptoms of acute renal failure develop. Withdrawal of the drug commonly is followed by complete recovery, but there may be permanent damage in some persons, usually in older persons. Drug nephritis may not be recognized in its early stage because it is relatively uncommon.

B

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NSAIDs also have the potential for damaging renal ­structures, including medullary interstitial cells. Prostaglandins (particularly PGI2 and PGE2) contribute to the regulation of tubular blood flow.3 The deleterious effects of NSAIDs on the kidney are thought to result from their ability to inhibit prostaglandin synthesis. People particularly at risk are older adults because of age-related changes in renal function, people who are dehydrated or have a decrease in blood volume, and those with preexisting hypertension and kidney disease or renal insufficiency.

IN SUMMARY Tubulointerstitial diseases affect the tubules and the surrounding interstitium of the kidneys. These disorders include RTA, acute and chronic pyelonephritis, and the effects of drugs and toxins. RTA describes a form of systemic acidosis that results from tubular defects in bicarbonate reabsorption or hydrogen ion secretion. Pyelonephritis, or infection of the kidney and kidney pelvis, can occur as an acute or a chronic condition. Acute pyelonephritis ­typically is caused by ascending bladder infections or infections that come from the bloodstream; it usually is successfully treated with appropriate antimicrobial drugs. Chronic pyelonephritis is a progressive disease that produces scarring and deformation of the renal calyces and pelvis. Drug-induced impairment of tubulointerstitial structure and function usually is the result of direct toxic injury, decreased blood flow, or hypersensitivity reactions.

­ alignant abdominal tumor in children.3 It may occur in one m or both kidneys. The incidence of bilateral Wilms tumor is 5% in sporadic cases and up to 20% in familial cases.3 Histologically, the tumor is composed of elements that resemble normal fetal tissue—blastemic, stromal, and epithelial. An important feature of Wilms tumor is its association with other congenital anomalies, including aniridia (absence of the iris), hemihypertrophy (enlargement of one side of the face or body), and other congenital anomalies, usually of the genitourinary system. Several chromosomal abnormalities have been associated with Wilms tumor. One Wilms tumor gene, WT1, which is located on chromosome 11, encodes a transcription factor that is critical for normal kidney development.3 Wilms tumor usually is a solitary mass that occurs in any part of the kidney. It usually is sharply demarcated and variably encapsulated (Fig. 41.17). The tumors grow to a large size, distorting kidney structure. The tumors usually are staged using the National Wilms’ Tumor Study Group classification37: •• Stage I tumors are limited to the kidney and can be excised with the capsular surface intact. •• Stage II tumors extend into the renal capsule, but can be excised. •• Stage III tumors extend to the abdomen, but not beyond. •• Stage IV tumors have undergone hematogenous metastasis, most commonly involving the lung.

MALIGNANT TUMORS OF THE KIDNEY After completing this section of the chapter, you should be able to meet the following objectives: •• Characterize Wilms tumor in terms of age of onset, possible oncogenic origin, manifestations, and treatment. •• Cite the risk factors for renal cell carcinoma, describe its manifestations, and explain why the 5-year ­survival rate has been so low.

There are two major groups of malignant tumors of the ­kidney—embryonic kidney tumors (i.e., Wilms tumor), which occur during childhood, and renal cell carcinoma, which occurs in adults.

Wilms Tumor Wilms tumor (nephroblastoma) is one of the most common primary neoplasms of young children. It usually presents between 3 and 5 years of age and is the most common

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FIGURE 41.17  •  Wilms tumor. A cross section of a pale tan n ­ eoplasm attached to a residual portion of the kidney. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 805). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Chapter 41  Disorders of Renal Function    1109

The common presenting signs are a large asymptomatic abdominal mass and hypertension.37 The tumor is often discovered inadvertently, and it is not uncommon for the mother to discover it while bathing the child. Some children may present with abdominal pain, vomiting, or both. Treatment involves surgery, chemotherapy, and sometimes radiation therapy. Long-term survival rates have increased to 90% for stages I through III.37

Renal Cell Carcinoma Cancer of the kidney incidence peaks in people in their sixties and seventies. The increased use of imaging procedures such as ultrasonography, CT scanning, and magnetic resonance imaging (MRI) has contributed significantly to earlier diagnosis and more accurate staging of kidney cancers. Renal cell carcinoma accounts for approximately 80% to 90% of kidney tumors.3 The tumor may arise from any portion of the kidney, but most commonly affects the poles, especially the upper pole. Etiology and Pathogenesis The cause of renal cell carcinoma remains unclear. Epidemiologic evidence suggests a correlation between heavy smoking and kidney cancer. Obesity also is a risk factor, particularly in women. The risk for renal cell carcinoma also is increased in people with acquired cystic kidney disease associated with chronic renal insufficiency. There are pathologic variants of renal cell carcinoma that reflect differences in cellular pathology, genetic profile, and clinical features ranging from benign to highly malignant. Categories include clear cell carcinoma (70% to 85% of cases) (Fig. 41.18), papillary or chromophilic tumors (10% to 15%),

and chromophobic tumors (5% to 10%).38 Clear cell tumors have a clear cytoplasm, usually show chromosome 3 deletions, and arise from proximal tubular epithelial cells. Papillary renal cell tumors tend to be bilateral and multifocal, show trisomy 7 or 17, and arise from proximal tubular cells. Chromophobic tumors are characterized by multiple chromosomal losses but do not exhibit 3 deletions or trisomy 7 or 17, and have an indolent clinical course.38 Collecting duct tumors arise from the collecting ducts within the renal medulla, are very rare, affect younger people, and are very aggressive. Oncocytomas do not exhibit chromosomal changes and are considered benign. Clinical Manifestations Kidney cancer is largely a silent disorder during its early stages, and symptoms usually denote advanced disease. Presenting features include hematuria, flank pain, and presence of a palpable flank mass. Gross or microscopic hematuria, which occurs in the majority of cases, is an important clinical clue. It is, however, intermittent and may be microscopic. As a result, the tumor may reach considerable size before it is detected. Because of the widespread use of ultrasonography and CT scanning for diverse indications, renal tumors are being detected incidentally in people with no urologic symptoms. Diagnosis and Treatment Kidney cancer is suspected when there are findings of hematuria and a renal mass. Ultrasonography and CT scanning are used to confirm the diagnosis. MRI may be used when involvement of the inferior vena cava is suspected. Renal cancer is commonly staged using the American Joint Committee on Cancer staging system (Tumor, Node, Metastasis system). Surgery (radical nephrectomy with lymph node dissection) is the treatment of choice for all resectable tumors. Nephron-sparing surgery may be done when both kidneys are involved or when an associated disease such as hypertension or diabetes mellitus threatens the contralateral kidney. Singleagent and combination chemotherapy agents have been used with limited success.

IN SUMMARY

FIGURE 41.18  •  Clear cell renal cell carcinoma. The kidney contains a large irregular neoplasm with a variegated cut surface. Yellow areas correspond to lipid-containing cells. (From Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 806, Fig. 16.88). Philadelphia, PA: Lippincott Williams & Wilkins.)

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There are two major groups of renal neoplasms—embryonic kidney tumors (i.e., Wilms tumor) that occur during childhood and adult renal cell carcinomas. Wilms tumor is one of the most common malignant tumors of children. The most common presenting signs are a large abdominal mass and hypertension. Treatment is surgery, chemotherapy, and sometimes radiation therapy. The long-term survival rate for children with Wilms tumor is approximately 90%, with an aggressive plan of treatment. Renal cancer accounts for about 3% of all cancers, with a peak incidence in people in their sixties and seventies. Renal cell carcinoma accounts for 80% to 90% of kidney

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1110   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

tumors. These tumors are characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to chemotherapy and radiation therapy. Because of the widespread use of ultrasonography and CT scanning for diverse indications, renal tumors are being detected incidentally in people with no urologic symptoms. Diagnostic methods include ultrasonography and CT scans. The treatment of choice is surgical resection. Prognosis depends on the stage of the cancer. The 5-year survival rate is 90% if the tumor has not extended beyond the renal capsule, but drops considerably if metastasis has occurred.

Review Exercises 1. A 36-year-old man is admitted to the emergency department with a sudden onset of severe, intermittent, cramping pain that makes him feel nauseated. He describes the pain as originating in the left groin and radiating toward the flank. Microscopic examination of his urine reveals the presence of RBCs. His temperature is normal, and he does not exhibit signs of sepsis. A. What is the probable cause of this man’s pain? B. What diagnostic measure could be used to confirm the cause of his pain? C. A plain-film radiograph reveals a 4- to 5-mm kidney stone in the left ureter. What are the chances that this man will pass the stone spontaneously? D. What type of medications and other treatments should this man receive? E. Once the stone has been passed, what type of measures can he use to prevent stone recurrence? 2. A 6-year-old boy is diagnosed with acute glomerulonephritis that developed after a streptococcal throat infection. At this time, the following manifestations are noted: a decrease in urine output, increasing lethargy, hyperventilation, and generalized edema. Trace amounts of protein are detected in his urine. Blood analysis reveals the following: pH = 7.35, HCO3 = 18 mEq/L, hematocrit = 29%, Na = 132 mEq/L, K = 5.6 mEq/L, BUN = 62 mg/dL, creatinine = 4.1 mg/dL, and albumin = 2 g/dL. A. What is the probable cause of this boy’s ­glomerular disease? B. Use the laboratory values in the Appendix to interpret his laboratory test results. Which values are significant and why? C. Is he progressing to uremia? How can you tell?

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3. A 26-year-old woman makes an appointment with her health care provider, complaining of urinary frequency, urgency, and burning. She reports that her urine is cloudy and smells abnormal. Her urine is cultured, and she is given a prescription for antibiotics. A. What is the most likely cause of the woman’s symptoms? B. What microorganism is most likely responsible for the infection? C. What factors may have predisposed her to this disorder? D. What could this woman do to prevent future infection?

References 1. National Kidney Foundation. (2011). Fact sheets: The problem of kidney and urologic diseases. [Online]. Available: www.kidney.org. Accessed June 12, 2011. 2. Minnesota Department of Health Fact Sheet. (2005). Renal agenesis/ hypoplasia. [Online]. Available: http://www.health.state.mn.us/divs/fh/ mcshn/bd/renal.pdf. Accessed June 13, 2011. 3. Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 4. Neild G. (2009). What do we do about chronic renal failure in young adults? II. Adult outcomes of pediatric renal disease. Pediatric Nephrology 24(10), 1921–1928. 5. Mansoor O., Chandar J., Rodriguez M. M., et al. (2011). Long-term risk of chronic kidney disease in unilateral multicystic dysplastic kidney. Pediatric Nephrology 26(4), 597–603. 6. Rennke H. G., Denker B. M. (2010). Renal pathophysiology: The essentials (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 7. Irshad A., Ackerman S., Ravenel J. (2011). Horseshoe kidney imaging. Medscape: Drugs, diseases, & procedures. [Online]. Available: http://emedicine.medscape.com/article/378396-overview#showall. Accessed June  13, 2011. 8. Reed B. Y., Masourni A., Elhasson E., et al. (2011). Angiogenic growth factors correlate with disease severity in young patients with autosomal dominant polycystic kidney disease. Kidney International 79(1), 128–134. 9. Xu H. W., Yu S. Q., Mei C. L., et al. (2011). Screening for intracranial aneurysm in 355 patients with autosomal dominant polycystic kidney disease. Stroke 42(1), 204–206. 10. Meijer E., Boertien W. E., Nauta F. L., et al. (2010). Association of urinary biomarkers with disease severity in patients with autosomal dominant polycystic kidney disease: A cross sectional analysis. American Journal of Kidney Diseases 56(5), 883–895. 11. Torres V. E., Meijer E., Bae K. T., et al. (2011). Rationale and design of the TEMPO (tolvaptan efficacy & safety in management of autosomal dominant polycystic kidney disease & its outcomes) 3–4 study. American Journal of Kidney Diseases 57(5), 692–699. 12. Goroll A. H., Mulley A. G. (2009). Primary care medicine: Office evaluation and management of the adult patient. Philadelphia, PA: Lippincott Williams & Wilkins. 13. Guay-Woodford L., Desmond R. A. (2011). Autosomal recessive polycystic kidney disease: The clinical experience in North America. Pediatrics 111(5), 1072–1080. 14. McConnell T. H., Hull K. (2011). Human form human function: Essentials of anatomy & physiology. Philadelphia, PA: Lippincott Williams & Wilkins.

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Chapter 41  Disorders of Renal Function    1111 15. Dunphy L. M., Winland–Brown J. E., Porter B., et al. (2011). Primary care: The art and science of advanced practice nursing (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 16. Worcester E. M., Coe F. I. (2010). Calcium kidney stones. New England Journal of Medicine 363(10), 954–963. 17. Fischbach F., Dunning M. B. (2009). A manual of laboratory and diagnostic tests (8th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 18. Sas D. J., Hulsey T. C, Shatat I. F., et al. (2010). Increasing incidence of kidney stones in children evaluated in the emergency department. Journal of Pediatrics 157(1), 132–137. 19. Weikert C., Weikert S., Schulze M. B., et al. (2010). Presence of gallstones or kidney stones and risk of type 2 diabetes. American Journal of Epidemiology 171(4), 447–454. 20. Perry M. (2011). Treating symptomatic UTIs in older people. Practice Nursing 22(1), 21–23. 21. Raynor M. C., Carson C. C. (2011). Urinary infections in men. Medical Clinics of North America 95(1), 43–54. 22. Smeltzer S. C., Bare B. G., Hinkle J. L., et al. (2010). Brunnner & Suddarth’s textbook of medical-surgical nursing (12th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 23. Gray M. (2010). Reducing catheter associated urinary tract infections in the critical care unit. AACN Advanced Critical Care 21(3), 247–257. 24. Ross M., Pawlina W. (2011). Histology: A text and atlas with correlated cell and molecular biology (6th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 25. Nguyen H. T. (2008). Bacterial infections of the genitourinary tract. In Tanagho E. A., McAninch J. W. (Eds.), Smith’s general urology (16th ed.). New York, NY: Lange Medical Books/McGraw-Hill. 26. Rudick C. N., Billips B. K., Pavlov V. I., et al. (2010). Host-pathogen interactions mediating pain of UTI. Journal of Infectious Diseases 201(8), 1240–1249. 27. Nowak R., Schmidt W. (2008). Cranberry juice for prophylaxis of urinary tract infections—conclusions from clinical experience and research. Phytomedicine 15(9), 653–667.

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28. Johnson E. K., Wolf J. S. (2011). Medscape/references: Drugs, diseases, & procedures. Urinary tract infections in pregnancy. [Online.] Available: http://emedicine.medscape.com/article/452604-overview#aw2aab6b6. Accessed June 13, 2011. 29. Zorc J. J., Kidoo D. A., Shaw K. N. (2005). Diagnosis and management of pediatric urinary tract infections. Clinical Microbiology Reviews 18(2), 417–422. 30. Fain J. A. (2009). Understanding diabetes mellitus and kidney disease. Nephrology Nursing Journal 36(5), 465–470. 31. Walsh M., Catapano F., Szpirt W., et al. (2011). Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: A meta analysis. American Journal of Kidney Diseases 57(4), 566–574. 32. Garin E. H., Mu W., Arthur J. M., et al. (2010). Urinary CD80 is elevated in minimal change disease but not in focal segmented glomerulonephrosis. Kidney International 78(3), 296–302. 33. Roufosse C. A., Cook H. T. (2009). Pathologic predictors of prognosis in immunological IgA nephropathy: A review. Current Opinion in Nephrology & Hypertension 18(3), 212–219. 34. Saulsbury F. T. (2010). Henoch-Schonlein purpura. Current Opinion in Rheumatology 22(5), 598–602. 35. Weening J. J., D’Agati V. D., Schwartz M. M. (2004). The classification of glomerulonephritis in systemic lupus erythematosus. Journal of the American Society of Nephrology 15, 241–250. 36. Lehne R. A. (2009). Pharmacology for nursing care (7th ed.). St. Louis, MO: Elsevier. 37. Ross J. H. (2006). Wilm’s tumor: Update strategies for evaluation and management. Contemporary Urology 18(11), 18–22, 25. 38. Kell S. D. (2011). Renal cell carcinoma: Treatment options. British Journal of Nursing 20(9), 536–539.

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Acute Renal Injury and Chronic Kidney Disease ACUTE RENAL INJURY

Types of Acute Renal Injury Prerenal Failure Postrenal Failure Intrarenal Renal Failure or Acute Kidney Injury Diagnosis and Treatment

CHRONIC KIDNEY DISEASE

Definition and Classification Assessment of Glomerular Filtration Rate and Other Indicators of Renal Function Clinical Manifestations Accumulation of Nitrogenous Wastes Fluid, Electrolyte, and Acid–Base Disorders Disorders of Calcium and Phosphorus Metabolism and Bone Disease Hematologic Disorders Cardiovascular Disorders Gastrointestinal Disorders Neuromuscular Disorders Altered Immune Function Disorders of Skin Integrity Sexual Dysfunction Elimination of Drugs Treatment Measures to Slow Progression of the Disorder Dialysis and Transplantation Dietary Management

CHRONIC KIDNEY DISEASE IN CHILDREN AND OLDER ADULTS Chronic Kidney Disease in Children Etiology Clinical Manifestations Treatment Chronic Kidney Disease in Older Adults Etiology and Diagnosis Clinical Manifestations Treatment

42 Sheila Grossman

Renal failure is a condition in which the kidneys fail to remove metabolic end products from the blood and regulate the fluid, electrolyte, and pH balance of the extracellular fluids. The underlying cause may be renal disease, systemic disease, or urologic defects of nonrenal origin. Renal failure can occur as an acute or a chronic disorder. Acute renal injury is abrupt in onset and often is reversible if recognized early and treated appropriately. In contrast, chronic kidney disease is the end result of irreparable damage to the kidneys. It develops slowly, usually over the course of a number of years. In fact, 80% of the nephrons need to be nonfunctioning before the symptoms of chronic kidney disease are manifested. Approximately 26 million American adults, or 1 in 9 adults, have some form of renal disease.1

ACUTE RENAL INJURY After completing this section of the chapter, you should be able to meet the following objectives: •• Describe acute renal injury in terms of its causes, treatment, and outcome. •• Differentiate the prerenal, intrarenal (acute renal injury), and postrenal forms of acute renal injury in terms of the mechanisms of development and manifestations. Acute renal injury or also termed acute kidney injury (AKI) represents a rapid decline in kidney function sufficient to increase blood levels of nitrogenous wastes and impair fluid and electrolyte balance.1 Unlike chronic kidney disease (CKD) and failure, acute renal injury is potentially reversible if the precipitating factors can be corrected or removed before permanent kidney damage has occurred.

1112

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Chapter 42  Acute Renal Injury and Chronic Kidney Disease    1113

Acute renal injury is a common threat to seriously ill people in intensive care units, with a mortality rate ranging from 40% to 90%.2,3 Although treatment methods such as dialysis and renal replacement therapies are effective in ­correcting life-threatening fluid and electrolyte disorders, the mortality rate from acute renal failure has not improved substantially over the last few decades.4 This probably is because acute renal injury is seen more often in older adults than before, and because it frequently is superimposed on other life-threatening conditions, such as trauma, shock, and sepsis and comorbidities such as cardiovascular disease, diabetes, and respiratory disease.4 The most common indicator of AKI is azotemia, an accumulation of nitrogenous wastes (urea nitrogen, uric acid, and creatinine) in the blood and a decrease in the glomerular filtration rate (GFR). New biomarkers for more accurate diagnosing of acute renal kidney injury are discussed. As a result, excretion of nitrogenous wastes is reduced, and fluid and electrolyte balance cannot be maintained.

Key Points ACUTE RENAL FAILURE/INJURY •  Acute renal failure/injury is caused by conditions that produce an acute shutdown in renal function. •  It can result from decreased blood flow to the kidney (prerenal failure), disorders that disrupt the structures in the kidney (intrarenal failure), or disorders that interfere with the elimination of urine from the kidney (postrenal failure). •  Acute renal failure, although it causes an accumulation of products normally cleared by the kidney, is a potentially reversible process if the factors causing the condition can be corrected.

Types of Acute Renal Injury Acute renal injury can be caused by several types of conditions, including a decrease in blood flow without ischemic injury; ischemic, toxic, or obstructive tubular injury; and obstruction of urinary tract outflow. The causes of acute renal failure commonly are categorized as prerenal, intrarenal, and postrenal2 (Fig. 42.1). Collectively, prerenal and intrarenal causes account for 80% to 95% of acute renal failure cases.3 Causes of renal failure within these categories are summarized in Chart 42.1. Prerenal Failure Prerenal failure, the most common form of acute renal failure, is characterized by a marked decrease in renal blood flow. It is reversible if the cause of the decreased renal blood flow can be identified and corrected before kidney damage occurs. Causes of prerenal failure include profound depletion

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Prerenal (marked decrease in renal blood flow)

Intrinsic (damage to structures within the kidney)

Postrenal (obstruction of urine outflow from the kidney)

FIGURE 42.1  •  Types of acute renal failure.

of vascular ­volume (e.g., hemorrhage, loss of extracellular fluid volume), impaired perfusion due to heart failure and cardiogenic shock, and decreased vascular filling because of increased vascular capacity (e.g., anaphylaxis or sepsis). Older adults are ­particularly at risk because of their

Chart 42.1

CAUSES OF ACUTE KIDNEY INJURY

Prerenal Hypovolemia Hemorrhage Dehydration Excessive loss of gastrointestinal tract fluids Excessive loss of fluid due to burn injury Decreased vascular filling Anaphylactic shock Septic shock Heart failure and cardiogenic shock Decreased renal perfusion due to sepsis, vasoactive mediators, drugs, diagnostic agents Intrarenal Acute tubular necrosis/acute renal injury Prolonged renal ischemia Exposure to nephrotoxic drugs, heavy metals, and organic solvents Intratubular obstruction resulting from hemoglobinuria, myoglobinuria, myeloma light chains, or uric acid casts Acute renal disease (acute glomerulonephritis, pyelonephritis) Postrenal Bilateral ureteral obstruction Bladder outlet obstruction

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1114   UNIT X  Disorders of Renal Function and Fluids and Electrolytes

p­ redisposition to hypovolemia and their high prevalence of renal vascular disorders. Some vasoactive mediators, drugs, and diagnostic agents stimulate intense intrarenal vasoconstriction and can induce glomerular hypoperfusion and prerenal failure. Examples include endotoxins, radiocontrast agents such as those used for cardiac catheterization, cyclosporine (an immunosuppressant drug that is used to prevent transplant rejection), and nonsteroidal anti-inflammatory drugs (NSAIDs).2 Many of these drugs also cause acute tubular necrosis (ATN; discussed later). In addition, several commonly used classes of drugs can impair renal adaptive mechanisms and can convert compensated renal hypoperfusion into prerenal failure. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduce the effects of renin on renal blood flow; when combined with diuretics, they may cause prerenal failure in persons with decreased blood flow due to large-vessel or small-­ vessel kidney disease. Prostaglandins have a vasodilatory effect on renal blood vessels. NSAIDs can reduce renal blood flow through inhibition of prostaglandin synthesis. In some persons with diminished renal perfusion, NSAIDs can precipitate prerenal failure. Normally, the kidneys receive 20% to 25%% of the cardiac output.5 This large blood supply is required for the glomeruli to remove metabolic wastes and regulate body fluids and electrolytes. Fortunately, the normal kidney can tolerate relatively large reductions in blood flow before renal damage occurs. As renal blood flow is reduced, the GFR decreases, the amount of sodium and other substances that are filtered by the glomeruli is reduced, and the need for energy-dependent mechanisms to reabsorb these substance is reduced.5 As the GFR and urine output approach zero, oxygen consumption by the kidney approximates that required to keep renal tubular cells alive. When blood flow falls below this level, which is about 20% to 25% of normal, ischemic changes occur.5 Because of their high metabolic rate, the tubular epithelial cells are most vulnerable to ischemic injury. Improperly treated, prolonged renal hypoperfusion can lead to ischemic tubular necrosis with significant morbidity and mortality. However, the majority of people who experience the prolonged renal hypoperfusion do not have tubular epithelial necrosis, so the term ATN is being used less frequently and AKI refers to this intrarenal pathology.6 Prerenal failure is manifested by a sharp decrease in urine output and a disproportionate elevation of blood urea nitrogen (BUN) in relation to serum creatinine levels. The kidney normally responds to a decrease in the GFR with a decrease in urine output. Thus, an early sign of prerenal failure is a sharp decrease in urine output. A low fractional excretion of sodium (35 inches)

– – Increased High Very high Extremely high

– – High Very high Very high Extremely high

*Disease risk for type 2 diabetes, hypertension, and cardiovascular disease. †Increased waist circumference also can be a marker for increased risk, even in people of normal weight. BMI, body mass index. Expert Panel. (1998). Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. National Institutes of Health. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/ NBK2003/

have a 50% to 100% increased risk of premature death from all causes compared to people with a healthy weight.24 Obesity affects nearly every body system (see Fig. 47.5). Cardiac disease is increased, as well as hypertension, hypertriglyceridemia, and decreased HDL cholesterol. Significant weight gain increases the risk of developing type 2 diabetes, obstructive sleep apnea, gastric reflux, urinary stress incontinence, and gallbladder disease. Limited mobility and increased joint disorders are functional results of increased weight on the body’s skeletal system. In women, obesity can contribute to infertility, higher risk pregnancy, gestational ­diabetes, maternal hypertension, and difficulty in labor and delivery. Infants who are born to obese

mothers are more likely to be high birth weight, contributing to an increased rate of cesarean section delivery. Several types of cancer are seen in higher frequency in people who are obese, including endometrial, colon, gallbladder, prostate, kidney, and postmenopausal breast cancer. Obesity also causes nonalcoholic steatohepatitis and fatty liver disease.11,12,14 In the United States as well as in other countries, there are many negative stereotypes associated with obesity.25,26 People, especially women, are expected to be thin, and obesity may be seen as a sign of lack of self-control. Obesity may negatively affect employment and educational opportunities, as well as marital status.26 Obesity may also play a role in a person’s treatment by health professionals.25,27 Although nurses, ­physicians, and other health professionals are aware of the low success rate and difficulty in treating weight problems, they still may place the blame on the obese person.25,27

Prevention and Treatment of Obesity

FIGURE 47.5  •  Complications of obesity. (From Rubin R., Strayer D. (Eds.). (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (p. 1085). Philadelphia, PA: Lippincott Williams & Wilkins.)

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Prevention Obesity in epidemic proportions has led to much discussion on methods of prevention; yet few effective approaches have resulted.17 More research is now being focused on prevention efforts directed at children and adolescents. Most interventions involve modification of lifestyle behaviors to promote healthy food choices and more physical activity. Public debate is also focused on policy methods to regulate availability of less desirable food choices, such as high-calorie snacks and sweetened drinks. However, evidence on the effectiveness of these methods is limited.17 Major public education and policy efforts are now being undertaken by federal agencies. We Can! is a national educational program developed by the NIH to help children between 8 and 13 years old achieve or stay at a healthy weight by ­encouraging healthy eating, increasing physical activity, and reducing screen time for the family as a whole. Another pro-

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Chapter 47  Alterations in Nutritional Status    1255

FIGURE 47.6 • ChooseMyPlate.gov, developed by the USDA, ­outlines a healthy eating pattern by demonstrating the five food groups using a familiar mealtime cue, the place setting.

gram, entitled ChooseMyPlate.gov (see Fig. 47.6), developed by the USDA, translates dietary guidelines into demonstrable ­eating behaviors. Successful prevention measures will utilize not only governmental agency strategies and regulatory measures, but also private-sector initiatives and communication as well.18,24 Treatment The current recommendation is that treatment is indicated in all people who have a BMI of 30 or higher and in those who have a BMI of 25 to 29.9 or a high waist circumference and an additional two or more risk factors.28 Treatment should focus on individualized lifestyle modification through a combination of a reduced calorie diet, increased physical activity, and behavior therapy. These three modes of therapy form the basis of all weight management programs. Pharmacotherapy and surgery are available as adjuncts to lifestyle changes in people who meet specific criteria. Before treatment begins, an assessment should be made of the degree of overweight and the overall risk status. This should include assessment of the following risk factors or complications: coronary heart disease and other atherosclerotic diseases, sleep apnea, gynecologic abnormalities, osteoarthritis, gallstones, stress incontinence, cigarette smoking, hypertension, high LDL cholesterol levels, reduced HDL cholesterol levels, high triglyceride levels, prediabetes or type 2 diabetes, family history of premature coronary heart disease, and physical inactivity.28 It also is advisable to determine the person’s barriers and readiness to lose weight. Several factors can be evaluated to make this assessment. These include reasons and motivations for weight loss, previous history of weight-loss attempts, social support, attitude toward physical activity, ability to participate in physical activity, time available for attempting intervention, understanding the causes of obesity and its contribution to disease, and, finally, barriers the person has for making changes. Dietary Therapy. The two major components of all diet ­therapy are caloric restriction and diet composition. While diet modification and caloric restriction are important components of weight-loss therapy, no one method has been shown

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to be most effective.17 Therefore, dietary therapy should be individually prescribed based on the person’s overweight ­status and risk profile. The diet should be a personalized plan with realistic goals. Caloric restriction may vary from low-calorie diets (LCDs) to very-low-calorie diets (VLCDs). LCDs typically restrict caloric intake to 1200 kcal/day. This results in a variable reduction, depending on the initial dietary intake of the individual. VLCDs restrict calories to approximately 450 kcal/day, primarily made up of protein. This diet has higher risks, including abnormal heart rhythms and cholelithiasis. Anyone on this diet should be under direct supervision of a medical professional. A more conservative dietary approach is to reduce the current dietary intake by 500 to 1000 kcal/day. Total caloric intake should be distributed in four or five meals or snacks throughout the day. Portion control is an effective technique to help achieve calorie reduction. Many overweight people have not practiced or monitored portion size. Keeping daily diet logs of all food ingested helps to increase awareness of both content and frequency. Meal replacements, such as protein shakes with vitamins and minerals, may also be used as a substitute for solid food meals. After caloric restriction is determined, diet composition should be addressed. There are many methods of altering dietary content, including low-fat diets, and low-­carbohydrate/highprotein diets. Low-fat diets strive to limit daily calories from fat to 10% to 15% of total calorie intake. This level may be difficult to achieve and often is less palatable. Low-carbohydrate/highprotein diets became popular in the 1960s and 1970s. Although effective for weight loss, especially in the initial stages, they can contribute to health risks. Higher protein diets can increase the risk of kidney stones, and the decrease in fiber can also increase risks of cancer and raise cholesterol levels. Physical Activity.  There is convincing evidence that increased physical activity decreases the risk of overweight and obesity. In addition, it reduces cardiovascular and diabetes risk beyond that achieved by weight loss alone. Although physical activity is an important part of weight-loss therapy and helps with maintaining weight loss, it does not independently lead to a significant weight loss.17 It may, however, help reduce abdominal fat, increase cardiorespiratory fitness, and prevent the decrease in muscle mass that often occurs with weight loss. Exercise should be started slowly with the duration and intensity increased independently of each other. The goal for adults should be a minimum of 150 to 300 minutes or more of moderate to vigorous activity per week to achieve and maintain a healthy weight.7,17 Behavior Therapy.  Lifestyle modification is an essential factor in treating weight loss. Strategies include helping participants learn to self-monitor eating habits, including where and when they eat, and identifying situations that trigger eating behavior. Techniques for changing behavior include stress management, stimulus control, problem solving, contingency management, cognitive restructuring, social support, and relapse prevention.28 Another important aspect to behavior modification is helping the person to set realistic weight-loss goals. Weight loss from

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1256   UNIT XI  Disorders of Gastrointestinal Function

diet therapy, exercise, and behavioral therapy typically is 10% below the initial baseline.17 In many cases, this level can lessen health risks, but often falls short of individual expectations. Pharmacotherapy. Drugs approved by the U.S. FDA can be used as an adjunct to the aforementioned regimen in some people with a BMI of 30 or more with no other risk factors or diseases, and for people with a BMI of 27 or more with concomitant risk factors or diseases.28 The risk factors and diseases defined as warranting pharmacotherapy are coronary heart disease, type 2 diabetes, metabolic syndrome, gynecologic abnormalities, osteoarthritis, gallbladder disease, stress incontinence, and sleep apnea. Medications that have been approved for the treatment of obesity generally fall into one of two categories: 1. Reduction of food intake via the central nervous system. 2. Action primarily outside the brain. Medications that primarily act via the central nervous system either block or activate portions of the neurotransmitter systems that are involved in signaling hunger and satiety. Pathways, which may be affected, include norepinephrine, serotonin, dopamine, and histamine. The endocannabinoid system is also known to affect food intake and is the focus of research for effective weight reduction therapy. Many psychoactive drugs have been shown to produce weight loss or weight gain as a side effect of their desired treatment goal, further emphasizing that these complex pathways exist. Drug development in this category, while promising in early stages, has thus far resulted in no effective, safe long-term treatments. Several sympathomimetic drugs have been approved for short-term therapy of 12 weeks or less. Drugs that act peripherally include those that cause the blockade of lipase absorption in the gastrointestinal track (“fat-blockers”) and newer drugs that target areas in the pancreas and intestine as well as the brain to help reduce food intake, increase insulin secretion, and slow gastric emptying. A growing area of research and drug utilization includes non-FDA–approved usage of medications approved for other indications. Examples include antidepressants such as bupropion and fluoxetine, antiepileptic drugs such as topiramate, and antidiabetic medications such as metformin, pramlintide, and exenatide. With all such applications, use should be carefully monitored for any untoward side effects, as well as for desired weight-loss effects.17 Weight-Loss (Bariatric) Surgery. In people with clinically severe obesity (a BMI > 40) and in those with a BMI greater than 35 who have comorbid conditions who have failed ­medical attempts to control weight, surgical therapy is ­currently the most effective treatment of obesity. Weight-loss surgery provides medically significant weight loss sustained for 5 years in most people.28 There are three types of weight-loss surgery: (1) restrictive procedures, which reduce the amount of food that can be

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taken in, (2) malabsorptive procedures, which bypass sections of the intestine and result in less nutrients being absorbed, and (3) combined restrictive and malabsorptive procedures. Restrictive procedures include the adjustable gastric band and the sleeve gastrectomy, while the malabsorptive procedures include the biliopancreatic diversion with duodenal switch. The Roux-en-Y gastric bypass is the combined restrictive and malabsorptive procedure. Each surgery has specific risks and potential complications and requires lifelong nutritional monitoring after surgery. The key to long-term success and maintenance of weight loss after these surgical procedures is participation in a program that provides guidance in nutrition, physical activity, behavioral therapy, and social support. One major benefit of weight-loss surgery is resolution or remission of comorbid disease states. The significant improvement of type 2 diabetes symptoms in particular has prompted the International Diabetes Federation to endorse bariatric surgery eligibility for type 2 diabetics with BMIs greater than 35, and for people with BMIs greater than 30 who have not responded adequately to conventional therapy.29

IN SUMMARY Obesity is defined as having excess body fat accumulation with multiple organ-specific pathologic consequences. Genetic, socioeconomic, cultural, and environmental factors; psychological influences; and activity levels have been implicated as causative factors in the development of obesity. There are two types of obesity—upper body and lower body obesity. Upper body obesity is associated with a higher incidence of health risks. The health risks associated with obesity affect almost every body system. The treatment of obesity focuses on nutritionally adequate weight-loss diets, behavior modification, exercise, social support, and, in situations of marked obesity, pharmacotherapy and surgical methods.

UNDERNUTRITION AND EATING DISORDERS After completing this section of the chapter, you should be able to meet the following objectives: •• State the difference between protein–calorie starvation (i.e., marasmus) and protein malnutrition (i.e., kwashiorkor). •• Explain the effect of malnutrition on muscle mass, respiratory function, acid–base balance, wound healing, immune function, bone mineralization, the menstrual cycle, and testicular function. •• Compare the eating disorders of anorexia and bulimia nervosa (BN) and the complications associated with each.

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Undernutrition continues to be a major health problem throughout the world. Globally, undernourished rates peaked sharply to an estimated 1.023 million people in 2009 following the worldwide food and economic crisis. Rates were expected to decline in 2010 by 9.6%, to an estimated 9.25 million.30 Developing countries have a prevalence of 16% undernourished populations and are responsible for 98% of the overall total.30 In developed countries, undernutrition is most commonly seen in the pediatric and older adult populations.31,32

Malnutrition and Starvation Malnutrition and starvation are conditions in which a person does not receive or is unable to use an adequate amount of nutrients for body function. An adequate diet should provide adequate energy in the form of carbohydrates, fats, and proteins; essential amino acids and fatty acids for use as building blocks for synthesis of structural and functional proteins and lipids; and vitamins and minerals, needed to function as coenzymes or hormones in vital metabolic processes, or, as in the case of calcium and phosphate, as important structural components of bone. Among the many causes of malnutrition are poverty and ignorance, acute and chronic illness, and self-imposed dietary restriction. Homeless people, older adults, and children of the poor often demonstrate the effects of protein and energy malnutrition, as well as vitamin and mineral deficiencies. Even the affluent may fail to recognize that infants, adolescents, and pregnant women have increased nutritional needs. Some types of malnutrition are caused by acute and chronic illnesses, such as occurs in people with Crohn disease who are unable to absorb nutrients from their food. Anorexia nervosa and less overt eating disorders affect a large population of people who are concerned about body image or athletic performance. Protein–Energy Malnutrition Protein and energy (calorie) malnutrition represents a depletion of the body’s lean tissues caused by starvation or a combination of starvation and catabolic stress. The lean tissues are the fat-free, metabolically active tissues of the body, namely, the skeletal muscles, viscera, and cells of the blood and immune system. Because lean tissues are the largest body compartment, their rate of loss is the main determinant of total body weight in most cases of protein–energy malnutrition. Much of the literature on malnutrition and starvation has dealt with infants and children in underdeveloped countries in which food deprivation results in an inadequate intake of protein and calories to meet the body’s energy needs. Protein– energy malnutrition in this population commonly is divided into two distinct conditions: marasmus (protein and calorie deficiency) and kwashiorkor (protein deficiency). The pathologic changes for both types of malnutrition include humoral and cellular immunodeficiencies resulting from protein deficiency and lack of immune mediators. There is impaired synthesis of pigments of the hair and skin (e.g., hair color may change and the skin may become hyperpigmented) because of a lack of substrate (tyrosine) and coenzymes.

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Marasmus represents a progressive loss of muscle mass and fat stores due to inadequate food intake that is equally deficient in calories and protein.31 It results in a reduction in body weight adjusted for age and size. The child with marasmus has a wasted appearance, with loss of muscle mass, stunted growth, and loss of subcutaneous fat; a protuberant abdomen (from muscular hypotonia); wrinkled skin; sparse, dry, and dull hair; and depressed heart rate, blood pressure, and body temperature. Diarrhea is common. Because immune function is impaired, concurrent infections occur and place additional stress on an already weakened body. An important characteristic of marasmus is growth failure; if sufficient food is not provided, these children will not reach their full potential stature.31 Kwashiorkor results from a deficiency in protein in diets relatively high in carbohydrates.31 The term kwashiorkor comes from an African word meaning “the disease suffered by the displaced child,” because the condition develops soon after a child is displaced from the breast after the arrival of a new infant and placed on a starchy gruel feeding. Kwashiorkor is a more severe form of malnutrition than marasmus. Unlike marasmus, severe protein deficiency is associated with extensive loss of the visceral protein compartment with a resultant hypoalbuminemia that gives rise to generalized or dependent edema. The child with kwashiorkor usually presents with edema, desquamating skin, discolored hair, anorexia, and extreme apathy (Fig. 47.7). There are “flaky paint” lesions of the skin on the face, extremities, and perineum, and the hair becomes a sandy or reddish color, with linear depigmentation (flag sign).31 There is generalized growth failure and muscle wasting as in marasmus, but subcutaneous fat is normal because calorie intake is adequate. Other manifestations include skin lesions, hepatomegaly and distended abdomen, cold extremities, and decreased cardiac output and tachycardia. Marasmus–kwashiorkor is an advanced protein–energy deficit coupled with increased protein requirement or loss. This results in a rapid decrease in anthropometric measurements, with obvious edema and wasting and loss of organ mass. One essential aspect of severe protein–energy m ­ alnutrition is fatty degeneration of such diverse organs as the heart and liver. This degeneration causes subclinical and overt cardiac dysfunction, especially when malnutrition is accompanied by edema. A second injurious aspect is the loss of subcutaneous fat, which markedly reduces the body’s capacity for temperature regulation and water storage. As a consequence, malnourished children become dehydrated and hypothermic more quickly and more severely than normally nourished children. Most children with severe protein–energy malnutrition have asymptomatic infections because their immune system fails to respond appropriately. Their immune system is so depressed that many are unable to produce the fever that is typical of an acute infection. Malnutrition in Trauma and Illness In industrialized societies, protein–energy malnutrition most often occurs secondary to trauma or illness. Kwashiorkor-like protein malnutrition occurs most commonly in association with hypermetabolic acute illnesses, such as trauma, burns, and

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1258   UNIT XI  Disorders of Gastrointestinal Function

Flag sign

Hair changes Growth failure Apathy, irritability

Anemia Muscle wasting Fatty liver

Villous atrophy of small intestine, diarrhea

Depigmentation of skin Dermatoses

Edema (hypoalbuminemia)

FIGURE 47.7  •  Clinical manifestations of kwashiorkor.

­sepsis.33 Marasmus-like secondary protein–energy ­malnutrition typically results from chronic illnesses such as chronic obstructive pulmonary disease, congestive heart failure, cancer, and HIV infection.21 Approximately half of all people with cancer experience tissue wasting, in which the tumor induces metabolic changes leading to a loss of adipose tissue and muscle mass.1 In people with severe injury or illness, net protein breakdown is accelerated and protein rebuilding disrupted. Protein mass is lost from the liver, gastrointestinal tract, kidneys, and heart. As protein is lost from the liver, hepatic synthesis of serum proteins decreases and decreased levels of serum proteins are observed. There is a decrease in immune cells. Wound healing is poor, and the body is unable to fight off infection because of multiple immunologic malfunctions. The gastrointestinal tract undergoes mucosal atrophy with loss of villi in the small intestine, resulting in malabsorption. The loss of protein from cardiac muscle leads to a decrease in myocardial contractility and cardiac output. The muscles used for breathing become weakened,

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and ­respiratory f­unction becomes compromised as muscle proteins are used as a fuel source. A reduction in respiratory function has many implications, especially for people with burns, trauma, infection, or chronic respiratory disease, and for people who are being mechanically ventilated because of respiratory failure. In people who are hospitalized, malnutrition increases morbidity and mortality rates, incidence of complications, and length of stay. Malnutrition may present at the time of admission or develop during hospitalization. The hospitalized person often finds eating a healthful diet difficult and commonly has restrictions on food and water intake in preparation for tests and surgery. Pain, medications, special diets, and stress can decrease appetite. Even when the person is well enough to eat, being alone in a room where unpleasant treatments may be given is not conducive to eating. Although people who are hospitalized may appear to need fewer calories because they are on bed rest, their actual need for caloric intake may be higher because of other energy expenditures. For example, more calories are expended during fever, when the metabolic rate is increased. There also may be an increased need for protein to support tissue repair after trauma or surgery. Diagnosis No single diagnostic measure is sufficiently accurate to serve as a reliable test for malnutrition. Techniques of nutritional assessment include evaluation of dietary intake, anthropometric measurements, clinical examination, and laboratory tests.21 Evaluation of weight is particularly important. Body weight can be assessed in relation to height using the BMI. Evaluation of body composition can be performed by inspection or using anthropometric measurements such as skinfold thickness. Serum albumin and prealbumin are used in the diagnosis of protein–calorie malnutrition. Albumin, which has historically been used as a determinant of nutrition status, has a relatively large body pool and a half-life of 20 days and is less sensitive to changes in nutrition than prealbumin, which has a shorter half-life and a relatively small body pool.21 Treatment The treatment of severe protein–energy malnutrition involves the use of measures to correct fluid and electrolyte abnormalities and replenish proteins, calories, and micronutrients.21 Treatment is started with modest quantities of proteins and calories based on the person’s actual weight. Concurrent administration of vitamins and minerals is needed. Either the enteral or parenteral route can be used. The treatment should be undertaken slowly to avoid complications. The administration of water and sodium with carbohydrates can overload a heart that has been weakened by malnutrition and result in heart failure. Enteral feedings can result in malabsorptive symptoms due to abnormalities in the gastrointestinal tract. Refeeding edema is benign-dependent edema that results from renal sodium reabsorption and poor skin and blood vessel integrity. It is treated by elevation of the dependent area and modest sodium restrictions. Diuretics are ineffective and may aggravate electrolyte deficiencies.

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Eating Disorders Eating disorders affect an estimated 24 million Americans of all ages and gender.34 These illnesses, which include anorexia nervosa, bulimia nervosa, and binge-eating disorder and their variants, incorporate serious disturbances in eating, such as restriction of intake and binging, with an excessive concern over body shape or body weight.35 Eating disorders manifest in both men and women, with occurrence in women at slightly higher rates. However, BED is more prevalent in men than AN and bulimia combined.35 Eating disorders are more prevalent in industrialized societies and occur in all socioeconomic and major ethnic groups. A combination of genetic, neurochemical, developmental, and sociocultural factors is thought to contribute to the development of the disorders.35 Criteria for the diagnosis of AN and BN have been established.36 BED and eating disorders not otherwise specified (EDNOS) have also been identified by specific diagnostic criteria. Although these criteria allow clinicians to make a diagnosis in people with a specific eating disorder, the symptoms often occur along a continuum between those of AN and BN. Preoccupation with weight and excessive self-evaluation of weight and shape are common to all disorders, and people with eating disorders may demonstrate a mixture of symptoms from the disorders.36 People with eating disorders may require concomitant evaluation for psychiatric illness because eating disorders often are accompanied by mood, anxiety, and personality disorders. Anorexia Nervosa AN is an eating disorder that usually begins in adolescence and is characterized by determined dieting, often accompanied by compulsive exercise and, in a subgroup of people, purging behavior with or without binge eating, resulting in sustained low weight. Other features include a disturbed body image, a pervasive fear of becoming obese, and an obsession with severely restricted caloric intake and frequently with excessive physical exercise. AN is more prevalent among young women compared to men.34,35 The causes of anorexia appear to be multifactorial, with determinants that include genetic influence; personality traits of perfectionism and compulsiveness; anxiety disorders; family history of depression and obesity; and peer, familial, and cultural pressures with respect to appearance. Diagnostic criteria for AN are: (1) a refusal to maintain a minimally normal body weight for age and height (e.g., at least 85% of minimal expected weight or BMI ≥ 17.5); (2) an intense fear of gaining weight or becoming fat; (3) a disturbance in the way one’s body size, weight, or shape is perceived; and (4) amenorrhea (in girls and women after menarche).37 Other psychiatric disorders often coexist with AN, including major depression or dysthymia, and obsessive-compulsive disorder. Alcohol and substance abuse may also be present, more often among those with binging-purging type of AN.35 Many organ systems are affected by the malnutrition that accompanies AN. The severity of the ­abnormalities tends to be related to the degree of malnutrition and is reversed by

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r­ efeeding. The most frequent complication of anorexia is amenorrhea and loss of secondary sex characteristics with decreased levels of estrogen, which can eventually lead to osteoporosis. Bone loss can occur, and symptomatic compression fractures and kyphosis have been reported.35 Constipation, cold intolerance, and failure to shiver when cold, bradycardia, hypotension, decreased heart size, electrocardiographic changes, blood and electrolyte abnormalities, and increased growth of lanugo (i.e., fine hair) are common. Abnormalities in cognitive function may also occur. The brain loses both white and gray matter during severe weight loss; weight restoration results in return of white matter, but some loss of gray matter persists.35 Unexpected sudden deaths have been reported; the risk appears to increase as weight drops to less than 35% to 40% of ideal weight. It is believed that these deaths are caused by myocardial degeneration and heart failure rather than arrhythmias. One of the most challenging aspects of the treatment of anorexia is the inability of the person with anorexia to recognize that there is a problem. People with the disorder are usually willing to talk about their preoccupation with weight loss, food refusal and rituals about food, and excessive exercise routines; purging and laxative use; and withdrawal from activities and relationships, but have difficulty recognizing this behavior as pathological.35 Because anorexia is a form of starvation, it can lead to death if left untreated. A multidisciplinary approach appears to be the most effective method of treating people with the disorder.35,36 The goals of treatment are eating and weight gain; resolution of issues with the family; healing of pain from the past; and efforts to work on psychological, relationship, and emotional issues. Specialized eating disorder treatment programs may include in-patient hospitalization, partial hospitalization, or intensive outpatient specialty eating disorder programs, depending on the level of weight loss, medical complications, and availability of family support. Bulimia Nervosa BN is defined by recurrent binge eating and activities such as vomiting; fasting; excessive exercise; and use of diuretics, laxatives, or enemas to compensate for that behavior. The criteria for BN are: (1) recurrent binge eating (at least two times per week for 3 months); (2) inappropriate compensatory behaviors such as self-induced vomiting, abuse of laxatives or diuretics, fasting, or excessive exercise that follow the binge-eating episode; (3) self-evaluation that is unduly influenced by body shape and weight; and (4) a determination that the eating disorder does not occur exclusively during episodes of AN.34,37 In contrast to AN, which is characterized by a weight that is less than 85% of the normal value, most people with BN are of normal weight. The diagnostic criteria for BN now include subtypes to distinguish people who compensate by purging (e.g., vomiting or abuse of laxatives or diuretics) and those who use nonpurging behaviors (e.g., fasting or excessive exercise). The disorder may be associated with other psychiatric disorders such as anxiety disorder or depression. There is also an association with substance abuse and risky and self-destructive behaviors.35 The complications of BN include those resulting from overeating, self-induced vomiting, and cathartic and diuretic

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abuse.35 Among the complications of self-induced vomiting are dental disorders, parotitis, and fluid and electrolyte disorders. Dental abnormalities, such as sensitive teeth, increased dental caries, and periodontal disease, occur with frequent vomiting because the high acid content of the vomitus causes tooth enamel to dissolve. Esophagitis, dysphagia, and esophageal strictures are common. With frequent vomiting, there often is reflux of gastric contents into the lower esophagus because of relaxation of the lower esophageal sphincter. Vomiting may lead to aspiration pneumonia, especially in intoxicated or debilitated people. Potassium, chloride, and hydrogen are lost in the vomitus, and frequent vomiting predisposes to metabolic acidosis with hypokalemia. An unexplained physical response to vomiting is the development of benign, painless parotid gland enlargement. The weights of people with BN may fluctuate, although not to the dangerously low levels seen in AN. Their thoughts and feelings range from fear of not being able to stop eating to a concern about gaining too much weight. They also experience feelings of sadness, anger, guilt, shame, and low self-esteem. Treatment strategies include psychological and pharmacologic treatments. Cognitive behavioral therapy and interpersonal therapy are predominantly used.35 These therapies are designed to help the person become aware of other ways to cope with the feelings that precipitate the desire to purge and to try to correct maladaptive beliefs regarding their self image. Unlike people with AN, people with BN or binge eating are upset by the behaviors practiced and the thoughts and feelings experienced, and they are more willing to accept help. Antidepressants such as serotonin reuptake inhibitors have been found to be useful in t­ reating b­ ulimia and BEDs and one, fluoxetine, has received U.S. FDA approval for treatment.35 Eating Disorder Not Otherwise Specified EDNOS is a diagnostic category for people who have eating disorder symptoms but do not meet the full criteria for either AN or BN. Within this group is the subgroup, BED. Binge-Eating Disorder. Binge eating is characterized by recurrent episodes of binge eating at least 2 days per week for 6 months and at least three of the following: (1) eating rapidly; (2) eating until becoming uncomfortably full; (3) eating large amounts when not hungry; (4) eating alone because of embarrassment; and (5) disgust, depression, or guilt because of eating episodes. The great majority of people with BED are overweight, and, in turn, obese people have a higher prevalence of BED than the nonobese population.34,35,38 The primary goal of therapy for BED is to establish a regular, healthful eating pattern. People with BED who have been successfully treated for their eating disorder have reported that making meal plans, eating a balanced diet of three regular meals a day, avoiding high-sugar foods and other binge foods, recording food intake and binge-eating episodes, exercising regularly, finding alternative activities, and avoiding alcohol and drugs are helpful in maintaining their more healthful ­eating behaviors after treatment.

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IN SUMMARY Undernutrition can range from a selective deficiency of a single nutrient to starvation, in which there is deprivation of all nutrients. Malnutrition and starvation are among the most widespread causes of morbidity and mortality in the world. Protein–energy malnutrition in this population commonly is divided into two distinct conditions: marasmus (protein and calorie deficiency) and kwashiorkor (protein deficiency). Malnutrition is common during illness, recovery from trauma, and hospitalization. The effects of malnutrition and starvation on body function are widespread. They include loss of muscle mass, impaired wound healing, impaired immunologic function, decreased appetite, loss of calcium and phosphate from bone, anovulation and amenorrhea in women, and decreased testicular function in men. AN and BN are eating disorders that result in malnutrition. In AN, distorted attitudes about eating lead to determined dieting, weight loss to below 85% of normal body weight, and malnutrition. BN is characterized by secretive episodes or binges of eating large quantities of easily consumed, high-calorie foods, followed by compensatory behaviors such as fasting, self-induced vomiting, or abuse of laxatives or diuretics. EDNOS is a new diagnostic category for patients who have eating disorders such as BED, but do not meet the full criteria for either AN or BN.

Review Exercises 1. A 25-year-old woman is 65 inches (165 cm) tall and weighs 300 lb (136 kg). She works as a receptionist in an office, brings her lunch to work with her, spends her evenings watching television, and gets very little exercise. She reports that she has been fat ever since she was a little girl, has tried “every diet under the sun,” and when she diets she loses some weight, but gains it all back again. A. Calculate her BMI B. How would you classify her obesity? C. What are her risk factors for obesity? D. What would be one of the first steps in helping her develop a plan to lose weight? 2. A 16-year-old high school student is brought into the physician’s office by her mother, who is worried because her daughter insists on dieting because she thinks she is too fat. The daughter is 67 inches (170 cm) tall and weighs 96 lb (43.5 kg). Her history reveals that she is a straightA student, plays in the orchestra, and is on the track team. Although she had been having regular

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menstrual periods, she has not had a period in 4 months. She is given a tentative diagnosis of AN. A. What are the criteria for a diagnosis of AN? B. What is the physiologic reason for her amenorrhea? C. What are some of the physiologic manifestations associated with malnutrition and severe weight loss?

References 1. Guyton A. C., Hall J. E. (2011). Textbook of medical physiology (12th ed., pp. 807–810, 859–866, 880–887). Philadelphia, PA: Elsevier Saunders. 2. Alvarez-Castro P., Sangiao-Alvarellos S., Brandón-Sandá I., et al. (2011). Endocrine function in obesity. Endocrinology Nutrition 58, 422–432. 3. Levine J. A. (2004). Nonexercise activity thermogenesis (NEAT). Nutri­ tional Reviews 62, S82–S97. 4. Otten J. J., Hellwig J. P., Meyers L. D. (2006). Dietary reference intakes: The essential guide to nutrient requirements. Washington, DC: National Academy Press. 5. Panel on Macronutrients, Panel on the Definition of Dietary Fiber, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. (2005). Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids (macronutrients). Washington, DC: National Academies Press. 6. U.S. Department of Agriculture, Food and Nutrition Information Center. (2013). [Online]. Available: http://fnic.nal.usda.gov/interactiveDRI/. Accessed September 28, 2011. 7. U.S. Department of Agriculture and U.S. Department of Health and Human Services. (2010). Dietary guidelines for Americans, 2010 (7th ed.). Washington, DC: U.S. Government Printing Office. 8. Suzuki K., Simpson K. A., Minnion J. S., et al. (2010). The role of gut hormones and the hypothalamus in appetite regulation. Endocrine Journal 57(5), 359–372. 9. Office of Surveillance, Epidemiology, and Laboratory Services, Public Health genomics. (2010). Obesity and genetics. [Online]. Available: http://www.cdc.gov/genomics/resources/diseases/obesity/index.htm Accessed September 27, 2011. 10. Temelkova-Kurktschiev T., Stefanov T. (2011). Lifestyle and genetics in obesity and type 2 diabetes. Experimental and Clinical Endocrinology and Diabetes 120, 1–6. 11. World Health Organization. Obesity and overweight. (2010). [Online]. Available: http://www.who.it/mediacentre/factsheets/fs311/en/index.html#. Accessed September 28, 2011. 12. Division of Nutrition, Physical Activity, Evaluation and Treatment of Overweight and Obesity in Adults. (2010). [Online]. Available: http:www. cdc.gov/obesity/causes/index.html. Updated June 21, 2010. Accessed September 27, 2011. 13. Boardley D., Pobocik R. S. (2009). Obesity on the rise. Primary Care: Clinics in Office Practice 36, 243–255. 14. Bray G. A. (2004). The epidemic of obesity and changes in food intake: The Fluoride Hypothesis. Physiological Behavior 82, 115–121. 15. U.S. Department of Health and Human Services. (2000). The practical guide: Identification, evaluation, and treatment of overweight and obesity in adults. NIH publication no. 00-4084. Rockville, MD: U.S. Department of Health and Human Services, National Institutes of Health; National Heart, Lung, and Blood Institute; North American Association of the Study of Obesity. 16. Calzada P., Anderson-Worts P. (2009). The obesity epidemic: Are minority individuals equally affected? Primary Care: Clinics in Office Practice 36, 307–317.

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17. Bray G. A. (2010). Obesity. In Feldman M., et al. (Eds.), Sleisenger and Fordtran’s gastrointestinal and liver disease (9th ed., pp. 100–114). Philadelphia, PA: Elsevier. 18. Swinburn B. A., Sacks G., Hall K. D., et al. (2011). The global obesity pandemic: Shaped by global drivers and local environments. Lancet 378, 804–814. 19. Koch F. S., Sepa A., Ludvigsson J. (2008). Psychological stress and obesity. Journal of Pediatrics 159, 839–844. 20. Talen M. R., Mann M. M. (2009). Obesity and mental health. Primary Care: Clinics in Office Practice 36, 287–305. 21. Baron R. B. (2011). Nutrition. In McPhee S. J., Papadakis M. A., Rabow M. (Eds.), Current diagnosis and treatment (50th ed., pp. 1201–1221). New York: McGraw-Hill. 22. Gallagher E. J., LeRoith D., Karnieli E. (2008). The metabolic syndrome—from insulin resistance to obesity and diabetes. Endocrinology and Metabolism Clinics of North America 37, 559–579. 23. Danaei G., Ding E. L., Mozaffarian D., et al. (2009). The preventable causes of death in the United States: Comparative risk assessment of dietary, lifestyle and metabolic risk factors. Public Library of Science Medicine 6(4), 1–23. 24. Gortmaker S. L., Swinburn B. A., levy D., et al. (2011). Changing the future of obesity: Science, policy and action. Lancet 378, 838–847. 25. Puhl R. M., Heuer C. A. (2010). The stigma of obesity: A review and update. Obesity 17, 941–964. 26. Puhl R. M., Heuer C. A. (2010). Obesity stigma: Important considerations for public health. American Journal of Public Health 100(6), 1019–1028. 27. Teixeira M. E., Budd G. M. (2010). Obesity stigma: A newly recognized barrier to comprehensive and effective type 2 diabetes management. Journal of the American Academy of Nurse Practitioners 10, 527–533. 28. Woodard G., Morton J. (2010). Bariatric surgery. In Feldman M., et al. (Eds.), Sleisenger and Fordtran’s gastrointestinal and liver disease (9th ed., pp. 115–119). Philadelphia, PA: Elsevier. 29. International Diabetes Federation. (2011). Bariatric surgical and procedural interventions in the treatment of obese patients with type 2 diabetes position statement. [Online]. Available: http://www.idf.org/position-­statements. Accessed November 10, 2011. 30. Food and Agricultural Organizations of the United Nations. (2010). The state of food insecurity in the world (pp. 8–11). Rome, Italy: FAO. 31. Grover Z., Looi C. E. (2009). Protein energy malnutrition. Pediatric Clinics of North America 56, 1055–1068. 32. Visvanathan R., Capman I. M. (2009). Undernutrition and anorexia in the older person. Gastroenterology Clinics of North America 38, 393–409. 33. Mehta N. M., Duggan C. P. (2009). Nutritional deficiencies during critical illness. Pediatric Clinics of North America 56, 1143–1160. 34. National Association of Anorexia Nervosa and Associated Disorders. Statistics on eating disorders. (2013). [Online]. Available: http://www. anad.org/get-information/about-eating-disorders/eating-disorders-­ statistics/. Accessed November 21, 2011. 35. Becker A. E., Baker C. W. (2010). Eating disorders. In Feldman M, et al. (Eds.), Sleisenger and Fordtran’s gastrointestinal and liver disease (9th ed., pp. 121–138). Philadelphia, PA: Elsevier. 36. American Psychiatric Association. (2006). Practice guideline for the treatment of patients with eating disorders (3rd ed.). [Online]. Available: http://www.psychiatryonline.com/content.aspx?aID=138722. Accessed November 21, 2011. 37. American Psychiatric Association. (2000). Diagnostic and statisti cal manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. 38. Gonzalez J. E. (2011). Genes and obesity: A cause and effect relationship. Endocrinology Nutrition 58, 492–496.

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Unit 12

Disorders of Endocrine Function Emily Toronto, 7 years old, has been feeling nauseous for the last few days, and her mother states she has been very thirsty and urinating frequently over the last 2 months. Today she has vomited three times and is lethargic. Her mother says her breath smells “fruity,” and she seems slightly confused. Emily’s past medical history is unremarkable, but her grandfather has type 1 diabetes mellitus. She is admitted to the pediatric unit. Arterial blood gas analysis indicates that she is in metabolic acidosis (arterial pH, 7.29; PaCO2, 42 mm Hg [normal, 35 to 45 mm Hg]). Blood chemistry test results include the following: bicarbonate (HCO3−), 10 mEq/L; glucose, 650 mg/dL; calcium, 10.4 mg/dL; magnesium, 1.1 mg/dL; phosphate, 3.2 mg/dL (normal, 2.7 to 4.5 mg/dL); blood urea nitrogen (BUN), 44 mg/dL; and creatinine, 2.4 mg/dL. Urinalysis reveals the presence of small amounts (1+) of ketones. Her CBC with differential is unremarkable, but her glycosylated hemoglobin level (hemoglobin A1c) is 10% (normal, 4% to 7%). Her vital signs are as follows: temperature, 98.3°F; pulse, 126/minute and normal sinus rhythm; and blood pressure, 118/76 mm Hg. Her respiratory rate is fast (46/minute) and irregular. She is diagnosed with diabetic ketoacidosis and type 1 diabetes mellitus. The pathophysiology of Emily’s disorder is discussed in greater detail in Chapters 48 and 50 (see Appendix A to compare Emily’s blood test results with the normal values).

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48

Mechanisms of Endocrine Control

Sally Gerard

THE ENDOCRINE SYSTEM

Hormones Hormone Effects and Actions Structural Classification Synthesis and Release Transport Metabolism and Elimination Mechanisms of Action Control of Hormone Levels Hypothalamic–Pituitary Regulation Feedback Regulation Diagnostic Tests Blood Tests Urine Tests Stimulation and Suppression Tests Genetic Tests Imaging

The endocrine system is involved in all of the integrative aspects of life, including growth, sex differentiation, metabolism, and adaptation to an ever-changing environment. This chapter focuses on the general aspects of endocrine function, organization of the endocrine system, hormone receptors and hormone actions, and regulation of hormone levels.

THE ENDOCRINE SYSTEM After completing this section of the chapter, you should be able to meet the following objectives: •• State the function of a hormone receptor and the difference between cell-surface hormone receptors and intracellular hormone receptors. •• Describe the role of the hypothalamus in regulating pituitary control of endocrine function. •• State the major difference between positive and negative feedback control mechanisms.

The endocrine system uses chemical substances called h­ ormones as a means of regulating and integrating body functions. The endocrine system participates in the regulation of digestion and the usage and storage of nutrients, growth and development, electrolyte and water metabolism, and reproductive functions. The endocrine network of organs and mediators does not work in isolation. It is closely integrated with the central and peripheral nervous systems as well as with the immune systems, leading to currently used terminology such as “neuroendocrine” or “neuroendocrine-immune” systems for describing their interactions.1

Hormones Hormones generally are thought of as chemical messengers that are transported in body fluids. They are highly specialized organic molecules produced by endocrine organs that exert their action on specific target cells.1 Hormones do not initiate 1264

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Chapter 48  Mechanisms of Endocrine Control    1265

reactions but function as modulators of cellular and systemic responses. Hormones can be released from the endocrine glands; the brain; and other organs such as the heart, liver, and adipose tissue.2 Most hormones are present in body fluids at all times, but in greater or lesser amounts depending on the needs of the body. A characteristic of hormones is that a single hormone can exert various effects in different tissues or, conversely, several different hormones can regulate a single function. For example, the heart is the principal source of atrial natriuretic peptide, which acts to induce natriuresis in a distant target organ—the kidney. Erythropoietin, a traditional circulating hormone, is made in the kidney and stimulates erythropoiesis in the bone marrow.2 Lipolysis, which is the release of free fatty acids from adipose tissue, is an example of a single function that is regulated by several hormones, including the catecholamines, insulin, and glucagon, but also by the cytokine, tumor necrosis factor-α. Table 48.1 lists the major actions and sources of body hormones. Hormone Effects and Actions Depending on where the biologic effect of a hormone is elicited in relation to where it is released, the effects can be grouped in one of four ways—endocrine, paracrine, autocrine, or intracrine (Table 48.2). The effect is endocrine when a hormone is released into the circulation and then travels in the blood to produce a biologic effect on distant target cells.1 Alternately, some hormones and hormone-like substances never enter the bloodstream but instead act locally in the vicinity in which they are released. When they act locally on cells other than those that produced the hormone, the action is called paracrine. The action of sex steroids on the ovary is a paracrine action. The hormone effect is autocrine when a hormone produces a biologic effect on the same cell that produced it.1 For example, the release of insulin from pancreatic beta cells can inhibit the release of additional insulin from the same cells. The final classification of hormone effect, intracrine, describes a hormone that is synthesized and acts intracellularly in the same cell.1

Key Points HORMONES •  Hormones function as chemical messengers, moving through the blood to distant target sites of ­action (endocrine), or acting more locally as paracrine or autocrine messengers that incite more local effects. The term intracrine describes a hormone that is synthesized and acts within the same cell. •  Hormones exert their actions by interacting with high-affinity receptors, which in turn are linked to one or more effector systems in the cell. Some hormone receptors are located on the surface of the cell and act through second-messenger mechanisms, and others are located in the cell, where they modulate the synthesis of enzymes, transport proteins, or structural proteins.

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Structural Classification Hormones, which have diverse structures ranging from single amino acids to complex proteins and lipids, are divided into three categories: 1. Amines and amino acids 2. Peptides and proteins 3. Steroids (Chart 48.1). The first category, the amines, includes norepinephrine and epinephrine, which are derived from a single amino acid (i.e., tyrosine), and the thyroid hormones, which are derived from two-iodinated tyrosine amino acid residues.1 The second category, the peptides and proteins, constitute the majority of hormones and can be as small as thyrotropin-releasing hormone (TRH), which contains three amino acids, and as large and complex as growth hormone (GH), which has approximately 200 amino acids. Glycoproteins are large peptide hormones associated with a carbohydrate (e.g., follicle-stimulating hormone [FSH]). The third category consists of the steroid hormones, which are derivatives of cholesterol. Synthesis and Release The mechanisms for hormone synthesis and release vary with hormone structure, and they are not fully understood. Hormones, such as protein, are synthesized and stored in vesicles in the cytoplasm of the endocrine cell until secretion is required. While others, such as steroids, are secreted upon synthesis. The protein hormones comprise the most prominent class of hormones whose synthesis and release is vesicle mediated.1 Usually, synthesis involves the production of a precursor hormone, which is modified by the addition of peptides or sugar units. These precursor hormones often contain extra peptide units that ensure proper folding of the molecule and insertion of essential linkages. If extra amino acids are present, as in insulin, the precursor hormone is called a prohormone.1 Stimulation of the endocrine cell causes the vesicles to move to the cell membrane and release their hormones. The vesicle-mediated pathway is also used for secretion of a number of nonpolypeptide hormones and neurotransmitters such as the catecholamines (dopamine, epinephrine, and norepinephrine).1 Hormones synthesized by non–vesicle-mediated pathways include the glucocorticoids, androgens, estrogens, and mineralocorticoids—all steroids derived from cholesterol. These hormones are synthesized in the smooth endoplasmic reticulum, and steroid-secreting cells can be identified by their large amounts of smooth endoplasmic reticulum. Certain steroids serve as precursors for the production of other hormones. In the adrenal cortex, for example, progesterone and other steroid intermediates are enzymatically converted into aldosterone, cortisol, or androgens (see Chapter 41). Transport Hormones that are released into the bloodstream circulate as either free or unbound molecules, or as hormones attached to transport carriers (Fig. 48.1). Peptide hormones and protein hormones usually circulate unbound in the blood.1 Specific

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1266   UNIT XII  Disorders of Endocrine Function

TABLE 48.1 MAJOR ACTION AND SOURCE OF SELECTED HORMONES SOURCE

HORMONE

MAJOR ACTION

Hypothalamus

Releasing and inhibiting hormones  CRH  TRH  GHRH  GnRH Somatostatin Dopamine

Controls the release of pituitary hormones

Anterior pituitary

GH

ACTH TSH FSH

LH

Posterior pituitary

Adrenal cortex

Adrenal medulla Thyroid (follicular cells)

Parathyroid glands Pancreatic islet cells

Prolactin ADH (Arginine Vasopressin AVP) Oxytocin Mineralocorticosteroids, mainly aldosterone Glucocorticoids, mainly cortisol

Adrenal androgens, mainly dehydroepiandrosterone (DHEA) and androstenedione Epinephrine Norepinephrine Thyroid hormones: triiodothyronine (T3), thyroxine (T4) Calcitonin Parathyroid hormone (PTH) Insulin

Glucagon

Kidney Ovaries

Somatostatin 1,25-Dihydroxyvitamin D Estrogen Progesterone

Testes

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Androgens, mainly testosterone

Inhibits GH and TSH Inhibits prolactin release from the pituitary Inhibits FSH and LH Stimulates growth of bone and muscle, promotes protein synthesis and fat metabolism, decreases carbohydrate metabolism Stimulates synthesis and secretion of adrenal cortical hormones Stimulates synthesis and secretion of thyroid hormone Female: stimulates growth of ovarian follicle, ovulation Male: stimulates sperm production Female: stimulates development of corpus luteum, release of oocyte, production of estrogen and progesterone Male: stimulates secretion of testosterone, development of interstitial tissue of testes Prepares female breast for breast-feeding Increases water reabsorption by kidney Stimulates contraction of pregnant uterus, milk ejection from breasts after childbirth Increases sodium absorption, potassium loss by kidney Affects metabolism of all nutrients; regulates blood glucose levels, affects growth, has anti-inflammatory action, and decreases effects of stress Have minimal intrinsic androgenic activity; they are converted to testosterone and dihydrotestosterone (DHT) in the periphery Serve as neurotransmitters for the sympathetic nervous system Increase the metabolic rate; increase protein and bone turnover; increase responsiveness to catecholamines; necessary for fetal and infant growth and development Lowers blood calcium and phosphate levels Regulates serum calcium Lowers blood glucose by facilitating glucose transport across cell membranes of muscle, liver, and adipose tissue Increases blood glucose concentration by stimulation of glycogenolysis and glyconeogenesis Delays intestinal absorption of glucose Stimulates calcium absorption from the intestine Affects development of female sex organs and secondary sex characteristics Influences menstrual cycle; stimulates growth of uterine wall; maintains pregnancy Affect development of male sex organs and secondary sex characteristics; aid in sperm production

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Chapter 48  Mechanisms of Endocrine Control    1267 Endocrine cell

TABLE 48.2 HORMONE EFFECTS AND ­ACTIONS • Endocrine: Hormones are released to circulation to act on a target organ • Paracrine: Hormones act locally on cells in the vicinity of where they are released • Autocrine: Hormones produce a biologic action on the cell that released them • Intracrine: Hormone action is within the cell that produced it

Hormone

Bound hormone Free hormone

carrier proteins synthesized in the liver carry steroid hormones and thyroid hormone. The extent of carrier binding influences the rate at which hormones leave the blood and enter the cells. The half-life of a hormone—the time it takes for the body to reduce the concentration of the hormone by one half—is positively correlated with its percentage of protein binding.2 Thyroxine, which is more than 99% protein bound, has a halflife of 6 days. Aldosterone, which is only 15% bound, has a half-life of only 25 minutes. Drugs that compete with a hormone for binding with transport carrier molecules increase hormone action by increasing the availability of the active unbound hormone.1 For example, aspirin competes with thyroid hormone for binding to transport proteins. When this drug is administered to people with excessive levels of circulating thyroid hormone, such as during thyroid crisis, serious effects may occur due to the dissociation of free hormone from the binding proteins. Metabolism and Elimination Hormones secreted by endocrine cells must be inactivated continuously to prevent their accumulation.2 Intracellular and

Carrier protein

Blood vessel

Target cell Biologic effects FIGURE 48.1  •  Relationship of free and carrier-bound hormones.

extracellular mechanisms participate in the termination of hormone function. Most peptide hormones and catecholamines are water soluble and circulate freely in the blood. They are usually degraded by enzymes in the blood or tissues and then excreted by the kidneys and liver. In general, peptide hormones also have a short lifespan in the circulation. Their major mechanism of degradation is through binding to

Chart 48.1 CLASSES OF HORMONES BASED ON STRUCTURE Amines and Amino Acids

Peptides, Polypeptides, and Proteins

Steroids

Dopamine Epinephrine Norepinephrine Thyroid hormone

CRH GHRH TRH ACTH FSH LH TSH GH ADH Oxytocin Insulin Glucagon Somatostatin Calcitonin PTH Prolactin

Aldosterone Glucocorticoids Estrogens Testosterone Progesterone Androstenedione 1,25-Dihydroxyvitamin D DHT DHEA

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1268   UNIT XII  Disorders of Endocrine Function

cell-surface receptors, with subsequent uptake and ­degradation by peptide-splitting enzymes in the cell membrane or inside the cell.2 Steroid hormones are bound to protein carriers for transport and are inactive in the bound state. Their activity depends on the availability of transport carriers. Mechanisms of Action Hormones produce their effects through interaction with highaffinity receptors, which in turn are linked to one or more effector systems within the cell.1 These mechanisms involve many of the cell’s metabolic activities, ranging from ion transport at the cell surface to stimulation of nuclear transcription of complex molecules. The rate at which hormones react depends on their mechanism of action. The neurotransmitters, which control the opening of ion channels, have a reaction time of milliseconds.3 Thyroid hormone, which functions in the control of cell metabolism and synthesis of intracellular signaling molecules, requires days for its full effect to occur.3 Receptors.  Hormone receptors are complex molecular structures that are located either on the surface or inside target cells.1 The function of these receptors is to recognize a specific hormone and translate the hormonal signal into a cellular response. The structure of these receptors varies in a manner that allows target cells to respond to one hormone and not to others. For example, receptors in the thyroid are specific for thyroid-stimulating hormone (TSH), and receptors on the gonads respond to the gonadotropic hormones.3 The response of a target cell to a hormone varies with the number of receptors present and with the affinity of these receptors for hormone binding.1 A variety of factors influence the number of receptors that are present on target cells and their affinity for hormone binding. There are approximately 2000 to 100,000 hormone receptor molecules per cell.2 The number of hormone receptors on a cell may be altered for any of several reasons. Antibodies may destroy or block the receptor proteins. Increased or decreased hormone levels often induce changes in the activity of the genes that regulate receptor synthesis. For example, decreased hormone levels often produce an increase in receptor numbers by means of a process called up-regulation. This increases the sensitivity of the body to existing hormone levels.1 Likewise, sustained levels of excess hormone often bring about a decrease in receptor numbers by down-regulation, producing a decrease in hormone sensitivity.1 In some instances, the reverse effect occurs, and an increase in hormone levels appears to recruit its own receptors, thereby increasing the sensitivity of the cell to the hormone. The process of up-regulation and down-regulation of receptors is regulated largely by inducing or repressing the transcription of receptor genes.2 Some hormone receptors are located on the surface of the cell and act through second-messenger mechanisms, and others are located within the cell, where they modulate the synthesis of enzymes, transport proteins, or structural proteins.3 Chart 48.2 lists examples of hormones that act through the two types of receptors.

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Chart 48.2 HORMONE–RECEPTOR INTERACTIONS Second-Messenger Interactions Glucagon Insulin Epinephrine PTH TSH ACTH FSH LH ADH Secretin Intracellular Interactions Estrogens Testosterone Progesterone Adrenal cortical hormones Thyroid hormones

Cell-Surface Receptors. Because of their low solubility in the lipid layer of cell membranes, peptide hormones and catecholamines cannot readily cross the cell membrane. Instead, these hormones interact with surface receptors in a manner that incites the generation of an intracellular signal or message. The intracellular signal system is termed the second messenger, and the hormone is considered to be the first messenger. For example, the first messenger glucagon binds to surface receptors on liver cells to incite glycogen breakdown by way of the second-messenger system. A second type of receptor Intracellular Receptors.  mechanism is involved in mediating the action of hormones such as the steroid and thyroid hormones. These hormones are lipid soluble and pass freely through the cell membrane.1 They then attach to intracellular receptors and form a hormone–receptor complex that travels to the cell nucleus.1 The hormone–messenger complex binds to hormone response elements (HREs) that then activate or suppress intracellular mechanisms such as gene activity, with the subsequent production or inhibition of messenger RNA (mRNA) and protein synthesis.1

Control of Hormone Levels Hormone secretion varies widely over a 24-hour period. Some hormones, such as GH and adrenocorticotropic hormone (ACTH), have diurnal fluctuations that vary with the sleep–wake cycle.1 Others, such as the female sex hormones, are secreted in a complicated cyclic manner. The levels of hormones such as insulin and antidiuretic hormone (ADH) are regulated by feedback mechanisms that monitor substances

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Chapter 48  Mechanisms of Endocrine Control    1269

Understanding

Hormone Receptors

Hormones bring about their effects on cell activity by binding to specific cell receptors. There are two general types of receptors: (1) cell-surface receptors that exert their actions through cytoplasmic second-messenger systems and (2) intracellular nuclear receptors that modulate gene expression by binding to DNA or promoters of target genes.

Cell-Surface Receptors Water-soluble peptide hormones, such as PTH and glucagon, which cannot penetrate the lipid layer of the cell plasma membrane, exert their effects through intracellular second messengers. They bind to a portion of a membrane receptor that protrudes through the surface of the cell. This produces a structural change in the receptor molecule itself, causing activation of a hormone-regulated signal system located on the inner aspect of the cell membrane. This system allows the cell to sense extracellular events and pass this information to the intracellular environment. There are several types of cell-surface receptors, including G-protein–coupled receptors, which mediate the actions of catecholamines, prostaglandins, TSH, and others. Binding of the hormone to the receptor activates a G protein, which in turn acts on an effector such as adenyl cyclase to generate a second messenger such as cyclic adenosine monophosphate (cAMP). The second messenger, in turn, activates other enzymes that participate in cellular secretion, gene activation, or other target cell responses.

Hormone

(First messenger) Extracellular fluid

G-protein

Effector

(Transducer)

Adenyl cyclase

Receptor Intracellular fluid

Adenosine triphosphate (ATP)

Cyclic AMP (cAMP) Second messenger Target cell response

Continued

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1270   UNIT XII  Disorders of Endocrine Function

Understanding

Hormone Receptors (Continued)

Nuclear Receptors Steroid hormones, vitamin D, thyroid hormones, and other lipid-soluble hormones diffuse across the cell membrane into the cytoplasm of the target cell. Once inside, they bind to an intracellular receptor that is activated by the interaction. The activated hormone–receptor complex then moves to the nucleus, where the hormone binds to an HRE in the promoters on a target gene or to another transcription factor. Attachment to the HRE results in transcription of a specific mRNA. The mRNA then moves into the cytoplasm, where the “transcribed message” is translated and used by cytoplasmic ribosomes to produce new cellular proteins or changes in the production of existing proteins. These proteins promote a specific cellular response or, in some cases, the synthesis of a structural protein that is exported from the cell.

s

Hormone Extracellular fluid

Cell membrane

Intracellular fluid

s Nucleus

Receptor

s Receptor DNA

mRNA

Transcription

mRNA Translation

Ribosome

such as glucose (insulin) and water (ADH) in the body.1 The levels of many of the hormones are regulated by feedback mechanisms that involve the hypothalamic–pituitary target cell system.3 Hypothalamic–Pituitary Regulation The hypothalamus and pituitary (i.e., hypophysis) form a unit that exerts control over many functions of several endocrine glands as well as a wide range of other physiologic functions. These two structures are connected by blood flow in the hypophysial portal system, which begins in the hypothalamus and drains into the anterior pituitary gland, and by the nerve axons that connect the supraoptic and paraventricular nuclei of the hypothalamus with the posterior pituitary gland (Fig. 48.2).3 The pituitary is enclosed in the bony sella turcica and is bridged over by the diaphragma sellae.

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New proteins

Hypothalamic Hormones. The synthesis and release of anterior pituitary hormones are largely regulated by the action of releasing or inhibiting hormones from the hypothalamus, which is the coordinating center of the brain for endocrine, behavioral, and autonomic nervous system function.1 It is at the level of the hypothalamus that emotion, pain, body temperature, and other neural input are communicated to the endocrine system (see Fig. 48.4). The posterior pituitary hormones, ADH and oxytocin, are synthesized in the cell bodies of neurons in the hypothalamus that have axons that travel to the posterior pituitary.1 The hypothalamic hormones that regulate the secretion of anterior pituitary hormones include GH-releasing hormone (GHRH), somatostatin, dopamine, TRH, corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH).3 With the exception of GH and prolactin,

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Chapter 48  Mechanisms of Endocrine Control    1271 Source of releasing factors

Source of ADH and oxytocin

Primary capillary plexus

Superior hypophyseal artery To dural venous sinuses Artery of trabecula Posterior pituitary

Long portal veins Anterior pituitary Secretory cells

Hormones stored at fiber linings

FIGURE 48.2 • The hypothalamus and the anterior and posterior pituitary. The hypothalamic releasing or inhibiting hormones are transported to the anterior pituitary through the portal vessels. ADH and oxytocin are produced by nerve cells in the supraoptic and paraventricular nuclei of the hypothalamus and then transported through the nerve axon to the posterior pituitary, where they are ­released into the circulation.

ADH

Oxytocin

Interior hypophyseal artery

h­ypothalamic stimulatory hormones regulate most of the ­pituitary ­hormones. GH secretion is stimulated by GHRH; TSH by TRH; ACTH by CRH; and luteinizing hormone (LH) and FSH by GnRH.3 The activity of the hypothalamus is regulated by both hormonally mediated signals (e.g., negative feedback signals) and by neuronal input from a number of sources.3 Neuronal signals are mediated by neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, γ-aminobutyric acid (GABA), and opioids. Cytokines that are involved in immune and inflammatory responses, such as the interleukins, also are involved in the regulation of hypothalamic function. This is particularly true of the hormones involved in the hypothalamic–pituitary–adrenal axis. Thus, the hypothalamus can be viewed as a bridge by which signals from multiple systems are relayed to the pituitary gland3 (Fig. 48.3). Pituitary Hormones. The pituitary gland has been called the master gland because its hormones control the functions of many target glands and cells.1 Hormones produced by the anterior pituitary control body growth and metabolism (GH), function of the thyroid gland (TSH), glucocorticoid hormone levels (ACTH), function of the gonads (FSH and LH), and breast growth and milk production (prolactin).1 The functions of many of these hormones are discussed in other parts of

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GH TSH ACTH FSH LH Prolactin MSH

Sinusoids

this book (e.g., thyroid hormone, GH, and the corticosteroids in Chapter 49; the sex hormones in Chapters 52 and 54; and ADH from the posterior pituitary in Chapter 39). Feedback Regulation The level of many of the hormones in the body is regulated by negative feedback mechanisms.1 The function of this type of system is similar to that of the thermostat in a heating system. In the endocrine system, sensors detect a change in the hormone level and adjust hormone secretion so that body levels are maintained within an appropriate range.2 When the sensors detect a decrease in hormone levels, they initiate changes that cause an increase in hormone production. When hormone levels rise above the set point of the system, the sensors cause hormone production and release to decrease. For example, sensors in the hypothalamus or anterior pituitary gland detect an increase in thyroid hormone, and this causes a reduction in the secretion of TSH, with a subsequent decrease in the output of thyroid hormone from the thyroid gland. The feedback loops for the hypothalamic–pituitary feedback mechanisms are illustrated in Figure 48.4. Positive feedback control also occurs but is not well understood. In positive feedback control, rising levels of a hormone cause another gland to release a hormone that is stimulating to the first.2 An example of such a system is that

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External and internal stimuli

Hypothalamic neurosecretory cells

Central nervous system

Hypophyseal portal vein Releasing factor Adenohypophysis

Neurohypophysis Trophic hormone (corticotropin)

Simple loop General circulation Complex loop

Target gland (adrenal cortex)

Target gland hormone (aldosterone)

of the female ovarian hormone estradiol. Increased estradiol production during the follicular stage of the menstrual cycle causes increased gonadotropin (FSH) production by the anterior pituitary gland. This stimulates further increases in estradiol levels until the demise of the follicle, which is the source of estradiol, results in a fall in gonadotropin levels.2

Diagnostic Tests The field of endocrinology is one of the most laboratorydependent specialties in health care. However, a few guiding principles should be considered when approaching endocrine studies and disorders.4 No endocrine test is a substitute for a good physical examination and medical history.4 The person must be seen as a whole person, which includes many complex factors. One vital component to endocrine testing of any kind is strict adherence to all procedure and test r­ equirements.

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Target tissue (kidney) or process (electrolyte balance)

FIGURE 48.3 • Feedback mechanism of the endocrine system. (From Lippincott Williams & Wilkins (2010). Professional guide to pathophysiology (3rd ed., p. 464). Philadelphia, PA: Lippincott Williams & Wilkins.)

The possibility of error is always present and the quality of any endocrine test is only as good as the quality of the specimen presented for testing.4 Patient education regarding test preparation, timing, collection procedure, and storage are critical and will be discussed in relation to the specific test. Several techniques are available for assessing endocrine function and hormone levels. One technique measures the effect of a hormone on body function. Measurement of blood glucose, for example, is an indirect method of assessing insulin availability. The most common method is to measure hormone levels directly. Blood Tests Blood tests for endocrine disorders are vast and encompass a wide variety of strategies to assess endocrine function. Hormones can be measured directly or, very commonly, as physiologic indicators of hormone function. Blood hormone

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Chapter 48  Mechanisms of Endocrine Control    1273

levels provide information about hormone levels at a specific time. For example, blood insulin levels can be measured along with blood glucose after administration of a challenge dose of glucose to measure the time course of change in blood insulin levels. More detailed descriptions of specific testing will be discussed related to the endocrine system being evaluated.

CNS

Hypothalamus

Posterior pituitary (oxytocin and ADH)

Anterior pituitary

Growth hormone

TSH ACTH FSH LH

Thyroid (thyroid hormones) Adrenal gland (glucocorticoids)

Ovaries (estrogen and progesterone) Testes (testosterone) FIGURE 48.4  •  Control of hormone production by the ­hypothalamic– pituitary target cell feedback mechanism. Hormone levels from the target glands regulate the release of hormones from the anterior pituitary through a negative feedback system. The dashed line represents feedback control.

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Emily, the young girl who was introduced at the beginning of this unit, presented with a blood glucose of 650 mg/dL, which is far above normal blood glucose levels (70 to 110 mg/dL). Her glycated hemoglobin test (hemoglobin A1c) was also very high at 10% when the normal range for people with diabetes is 6% to 7%. Plasma hormone levels in plasma are measured using radioimmunoassay (RIA) methods based on the competitive binding of homones.1 This method uses a radiolabeled form of the hormone and a hormone antibody that has been prepared by a purified form of the hormone. The unlabeled hormone in the sample being tested competes with the radiolabeled hormone for attachment to the binding sites of the antibody.1 Measurement of the radiolabeled hormone–antibody complex then provides a means of arriving at a measure of the hormone level in the sample. Because hormone binding is competitive, the amount of radiolabeled hormone–antibody complex that is formed decreases as the amount of unlabeled hormone in the sample is increased. The limitations of RIA include a lack of specificity due to cross-reactivity with more than one hormone along with limited shelf life of the radiolabeled hormone and the cost for the disposal of radioactive waste.1 Newer techniques of RIA have been introduced, including the immunoradiometric assay (IRMA). IRMA uses the same principle of antibody recognition with two antibodies instead of one. These two antibodies are directed against two different parts of the molecule, and therefore IRMA assays are more specific.4 Other blood tests that are routinely measured in endocrine disorders include various autoantibodies. For example, anti-thyroid peroxidase (anti-TPO) antibodies are measured during the initial diagnostic work-up and subsequent followup of patients with Hashimoto thyroiditis.1 Other endocrine disorders that use autoantibody testing include type 1 diabetes, Graves disease, autoimmune hypoparathyroidism, and autoimmune Addison disease.4 Urine Tests Measurements of urinary hormone or hormone metabolite excretion often are done on a 24-hour urine sample and provide a better measure of hormone levels during that period compared to hormones measured in an isolated blood sample. The advantages of a urine test include the relative ease of obtaining urine samples and the fact that blood sampling is not required. The disadvantage is that reliably timed urine

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1274   UNIT XII  Disorders of Endocrine Function

c­ ollections often are difficult to obtain and rely on adequate renal function.4 For example, a person may be unable to urinate at specific timed intervals, and urine samples may be accidentally discarded or inaccurately preserved. Because many urine tests involve the measurement of a hormone metabolite rather than the hormone itself, drugs or disease states that alter hormone metabolism may interfere with the test result. Urine testing for hormones or metabolites underscores the need for a complete health history including medication use and specific adherence to test procedures. Stimulation and Suppression Tests Stimulation tests are used when hypofunction of an endocrine organ is suspected. A tropic or stimulating hormone can be administered to test the capacity of an endocrine organ to increase hormone production. The capacity of the target gland to respond is measured by an increase in the appropriate hormone.1 For example, the function of the hypothalamic–pituitary–thyroid system can be evaluated through stimulation tests using TRH and measuring TSH response. Failure to increase TSH levels after a TRH stimulation test suggests an inadequate capacity to produce TSH by the pituitary (i.e., the pituitary is dysfunctional in some way).4 Suppression tests are used when hyperfunction of an endocrine organ is suspected. When an organ or tissue is functioning autonomously (i.e., it is not responding to the normal negative feedback control mechanisms and continues to secrete excessive amounts of hormone), a suppression test may be useful to confirm the situation.5 For example, when a GH-secreting tumor is suspected, the GH response to a glucose load is measured as part of the diagnostic work-up. Normally, a glucose load would suppress GH levels. However, in adults with GH-secreting tumors (a condition known as acromegaly), GH levels are not suppressed (and paradoxically increase in 50% of cases).1 Genetic Tests The diagnosis of genetic diseases using deoxyribonucleic acid (DNA) analysis is rapidly becoming a routine part of endocrine practice. Completion of the human genome sequence has revealed the presence of about 23,000 genes.6 Advances in proteomics (i.e., examination of the proteome, which is all of the proteins expressed by a cell or tissue type) have complemented the considerable interest in the field of genomics (i.e., examination of the DNA) and transcriptomics (i.e., examination of the mRNA). It is proposed that compared with the size of the genome, the proteome is far larger, with several hundred thousand to several million different protein forms possible.6 Analysis of the proteins produced by normal and abnormal endocrine cells, tissues, and organs will lead to a better understanding of the pathophysiologic processes of endocrine conditions.3 This may also lead to selective targeting for new drug development. As the incidence of certain endocrine conditions, such as type 2 diabetes (DM2), have had such unprecedented growth, genetic discoveries in this field may lend ­critical

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support to treatment and prevention. Genetic studies of interrelated conditions such as DM2, metabolic syndrome, and obesity provide a complex study of genes in relation to race, ethnicity, socioeconomic conditions, and the evolution of mankind.6 Advances in genetic testing to evaluate the risk for, existence of, or treatment of endocrine disease is likely to expand greatly as the genetic factors of endocrine function are explored. Imaging Imaging studies are important in the diagnosis and follow-up of endocrine disorders. Imaging modalities related to endocrinology can be divided into isotopic and nonisotopic types. Isotopic imaging includes radioactive scanning of the thyroid (e.g., using radioiodine), parathyroids (e.g., using sestamibi), and adrenals.3 Nonisotopic imaging includes magnetic resonance imaging (MRI), which is the preferred choice for pituitary and hypothalamic imaging, and computed tomography (CT) scanning, which is preferred for adrenal lesions and abdominal endocrine lesions.3 Ultrasonographic scanning provides excellent and reproducible anatomic images for the thyroid, parathyroids, and neighboring structures. However, this is not considered definitive.3 Thyroid ultrasonography is recommended for managing thyroid nodules and can aid in visualization of the nodule for biopsy (fine-needle aspiration), which is necessary to help distinguish benign from malignant etiology.1 Dual-electron x-ray absorptiometry (DEXA) is used routinely for the diagnosis and monitoring of osteoporosis and metabolic bone diseases. Positron emission tomography (PET) scanning is being used more widely for evaluation of endocrine tumors. This PET scanning has expanded to PET/ CT imaging in which both types of images are acquired almost simultaneously for enhanced detail and identification of previously difficult structures.7

IN SUMMARY The endocrine system acts as a communication system that uses chemical messengers, or hormones, for the transmission of information from cell to cell and from organ to organ. Hormones act by binding to receptors that are specific for the different types of hormones. Many of the endocrine glands are under the regulatory control of other parts of the endocrine system. The hypothalamus and the pituitary gland form a complex integrative network that joins the nervous system and the endocrine system; this central network controls the output from many of the other glands in the body.1 Endocrine function can be assessed directly by measuring hormone levels or indirectly by assessing the effects that a hormone has on the body (e.g., assessment of insulin function through blood glucose). Imaging techniques are increasingly used to visualize endocrine structures, and genetic techniques are used to determine the presence of genes that contribute to the development of endocrine disorders.

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Understanding

Feedback Regulation of Hormone Levels

Like many physiologic systems, the endocrine system is regulated by feedback mechanisms that enable the endocrine cells to change their rate of hormone secretion. Feedback can be negative or positive and may involve complex feedback loops involving hypothalamic–pituitary regulation.

Negative Feedback With negative feedback, the most common mechanism of hormone control, some feature of hormone action directly or indirectly inhibits further hormone secretion so that the hormone level returns to an ideal level or set point. In the simple negative feedback loop, the amount of hormone or its effect on a physiologic mechanism regulates the response of the endocrine gland. After a meal, for example, a rise in blood glucose stimulates the pancreas to secrete insulin; insulin acts on target cells to take up the glucose, thus lowering blood glucose. The lowered glucose levels, in turn, suppress insulin release, causing blood glucose to rise.

Increase in hormone levels

Endocrine cell

Target cell Negative feedback and a decrease in hormone levels

Physiologic response

Hypothalamic–Pituitary Target Cell Feedback Hormones of the thyroid, adrenal cortex, and the gonads are regulated by more complex loops involving the hypothalamus and anterior pituitary gland. The hypothalamus produces a releasing hormone that stimulates the production of a tropic hormone by the anterior pituitary. The tropic hormone then stimulates the peripheral target gland to secrete its hormone, which acts on target cells to produce a physiologic response. A rise in blood levels of the target gland hormone also feeds back to the hypothalamus and anterior pituitary gland, resulting in a decrease in tropic hormone secretion and a subsequent reduction in hormone secretion by the target gland. As a result, blood levels of the hormone vary only within a narrow range.

CNS input

Hypothalamus

Releasing hormone

Anterior pituitary

Tropic hormone

Target gland

Hormone

Target cell

Physiologic effect

Continued

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1276   UNIT XII  Disorders of Endocrine Function

Understanding

Feedback Regulation of Hormone Levels (Continued)

Positive Feedback Increase in hormone levels

A small number of hormones are regulated by positive feedback. In this type of regulation, a hormone stimulates continued secretion until appropriate levels are reached. An example of positive feedback is the preovulatory surge in LH levels that trigger ovulation. At that time, an increase in estrogen levels exerts a positive feedback effect on the anterior pituitary secretion of LH. Endocrine cell

Target cell Positive feedback with continued hormone production

Physiologic response

References

REVIEW EXERCISES 1. Thyroid hormones are transported in the serum bound to transport proteins such as thyroid-­ binding globulin and albumin. A. Explain why free thyroxine (T4) levels are usually used to assess thyroid function rather than total T4 levels. 2. People who are being treated with exogenous forms of corticosteroid hormones often experience diminished levels of ACTH and exogenously produced cortisol. A. Explain, using information regarding the hypothalamic–pituitary feedback control of cortisol production by the adrenal cortex.

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1. Molina P. E. (2010). Endocrine physiology (3rd ed.). New York: Lange Medical Books/McGraw-Hill. 2. Fauci A., Braunwald E., Kasper D., et al. (2008) Harrison’s principles of internal medicine (17th ed.) Philadelphia, PA: McGraw-Hill Professional. 3. Gardner D. G. (Ed.) (2007). Greenspan’s basic and clinical endocrinology (8th ed.). New York: Lange Medical Books/McGraw-Hill. 4. Dons R., Wians F. (2009). Endocrine and metabolic disorders: Clinical lab testing manual. Boca Raton, FL: CRC Press. 5. Crowley L. (2010). An introduction to human disease. Pathology and pathophysiology correlations. Sudbury, MA: Jones and Bartlett. 6. Gibson G. (2009). It takes a genome. How a clash between our genes and modern life is making us sick. Saddle River, NJ: Pearson Education. 7. MacFall T. Gordon L., Davis P. (2008). Endocrine imaging: What role does PET and PET/CT play? Applied Radiology 37(5), 22–23.

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49

Disorders of Endocrine Control of Growth and Metabolism GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION Hypofunction and Hyperfunction Primary, Secondary, and Tertiary Disorders

PITUITARY AND GROWTH DISORDERS

Assessment of Hypothalamic–Pituitary Function Pituitary Tumors Hypopituitarism Growth and Growth Hormone Disorders Growth Hormone Growth Hormone Deficiency in Children Growth Hormone Deficiency in Adults Tall Stature in Children Growth Hormone Excess in Children Growth Hormone Excess in Adults Isosexual Precocious Puberty

THYROID DISORDERS

Control of Thyroid Function Actions of Thyroid Hormone Tests of Thyroid Function Alterations in Thyroid Function Hypothyroidism Congenital Hypothyroidism Acquired Hypothyroidism and Myxedema Myxedematous Coma Hyperthyroidism Etiology and Pathogenesis Clinical Manifestations Graves Disease Thyroid Storm

DISORDERS OF ADRENAL CORTICAL FUNCTION

Control of Adrenal Cortical Function Biosynthesis, Transport, and Metabolism Adrenal Androgens Mineralocorticoids. Glucocorticoids Pharmacologic Suppression of Adrenal Function Tests of Adrenal Function

Sheila Grossman

Congenital Adrenal Hyperplasia Adrenal Cortical Insufficiency Primary Adrenal Cortical Insufficiency Secondary Adrenal Cortical Insufficiency Acute Adrenal Crisis Glucocorticoid Hormone Excess (Cushing Syndrome) Clinical Manifestations Diagnosis and Treatment Incidental Adrenal Mass

The endocrine system affects all aspects of body function, including growth and development, energy metabolism, muscle and adipose tissue distribution, sexual development, fluid and electrolyte balance, and inflammation and immune responses. This chapter focuses on disorders of pituitary function, growth and growth hormone, thyroid function, and adrenal cortical function.

GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the mechanisms of endocrine hypofunction and hyperfunction. •• Differentiate among primary, secondary, and tertiary endocrine disorders.

1277

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1278   UNIT XII  Disorders of Endocrine Function

Hypofunction and Hyperfunction Disturbances of endocrine function can usually be divided into two categories—hypofunction and hyperfunction. Hypofunction of an endocrine gland can occur for a variety of reasons such as with the absence or impaired development of a gland or due to a deficiency or lack of an enzyme that is needed for hormone synthesis. The gland may be destroyed by a disruption in blood flow, infection, inflammation, autoimmune responses, or neoplastic growth. There may be a decline in function with aging, or the gland may atrophy as a result of drug therapy or for unknown reasons. Some endocrine-deficient states are associated with receptor defects. Hormone receptors may be absent, the receptor binding of hormones may be defective, or the cellular responsiveness to the hormone may be impaired. It is suspected that in some cases a gland may produce a biologically inactive hormone or that circulating antibodies may destroy an active hormone before it can exert its action. Hyperfunction usually is associated with excessive hormone production. This can result from excessive stimulation and hyperplasia of the endocrine gland or from a hormoneproducing tumor. A tumor can produce hormones that are not normally secreted by the tissue from which the tumor is derived (ectopic hormone production). For example, certain bronchogenic tumors and other cancerous tumors produce hormones such as antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH). A clinical example of this phenomenon is evidenced in the case of a woman with vaginal small cell ­carcinoma who also presented with Cushing syndrome. After testing, it was determined that the tumor was secreting ACTH.1

Primary, Secondary, and Tertiary Disorders Endocrine disorders in general can be divided into primary, secondary, and tertiary groups. Primary defects in endocrine function originate in the target gland responsible for producing the hormone. In secondary disorders of endocrine function, the target gland is essentially normal, but defective levels of stimulating hormones or releasing factors from the pituitary system alter its function. For example, total thyroidectomy produces a primary deficiency of thyroid hormones. Removal or destruction of the pituitary gland eliminates ACTH stimulation of the adrenal cortex and brings about a secondary deficiency. A tertiary disorder results from hypothalamic dysfunction (as may occur with craniopharyngiomas or cerebral irradiation). Thus, both the pituitary and target organ are understimulated.

IN SUMMARY Endocrine disorders are the result of hypofunction or hyperfunction of an endocrine gland. They can occur as a primary defect in hormone production by a target gland or as a secondary or tertiary disorder resulting from a defect in the hypothalamic–pituitary system that controls a target gland’s function.

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PITUITARY AND GROWTH DISORDERS After completing this section of the chapter, you should be able to meet the following objectives: •• Describe the clinical features and causes of hypopituitarism. •• Analyze the effects of a deficiency in growth hormone. •• Relate the functions of growth hormone to the ­manifestations of acromegaly and adult-onset growth hormone deficiency.

The pituitary gland, or hypophysis, is a pea-sized gland located at the base of the brain, where it lies in a ­saddle-shaped depression in the sphenoid bone called the sella turcica. A short funnel-shaped stalk, the infundibulum, connects the pituitary gland with the hypothalamus. The pituitary gland has two components—a posterior lobe (neurohypophysis) or neural component and an anterior lobe (adenohypophysis) or glandular component. The anterior lobe of the pituitary gland produces ACTH, thyroid-stimulating hormone (TSH), growth hormone (GH), the gonadotrophic hormones (follicle stimulating hormone [FSH] and luteinizing hormone [LH]), and prolactin. Four of these, ACTH, TSH, LH, and FSH, control the secretion of hormones from other endocrine glands: •• ACTH controls the release of cortisol from the adrenal gland. •• TSH controls the secretion of thyroid hormone from the thyroid gland. •• LH regulates sex hormones. •• FSH regulates fertility.

Assessment of Hypothalamic– Pituitary Function The assessment of hypothalamic–pituitary function has been made possible by many newly developed imaging and radioimmunoassay methods. Assessment of the baseline status of the hypothalamic–pituitary target cell hormones involves measuring the following (ideally the laboratory specimens are obtained before 8:00 am): •• Serum cortisol •• Serum prolactin •• Serum thyroxine and TSH •• Serum testosterone (male)/serum estrogen (female) and serum LH/FSH •• Serum GH/insulin-like growth factor-1 (IGF) •• Plasma osmolality and urine osmolality Imaging studies (e.g., magnetic resonance imaging [MRI] of the hypothalamus/pituitary) should also be performed

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Chapter 49  Disorders of Endocrine Control of Growth and Metabolism    1279

as required. When further information regarding pituitary ­function is required, combined hypothalamic–pituitary function tests are undertaken. These tests consist mainly of hormone stimulation tests (e.g., rapid ACTH stimulation test) or suppression tests (e.g., GH suppression test). It is often important to test pituitary function, especially if pituitary adenomas are discovered and surgery or radiation treatment is being considered. Diagnostic methods include both static and dynamic testing, and radiologic assessment as required. Any of the systems discussed previously may be affected by either deficiency or excess of the usual hormones secreted.

Pituitary Tumors Pituitary tumors can be divided into primary or secondary tumors (i.e., metastatic lesions). Tumors of the pituitary can be further divided into functional tumors that secrete pituitary hormones and nonfunctional tumors that do not secrete hormones. They can range in size from small lesions that do not enlarge the gland (microadenomas, 10 mm) that erode the sella turcica and impinge on surrounding cranial structures.2 Small, nonfunctioning tumors are found in up to 20% of adult autopsies. Benign adenomas account for most of the ­functioning anterior pituitary tumors. Carcinomas of the pituitary are less common tumors. Functional adenomas can be subdivided according to cell type and the type of hormone secreted (Table 49.1).

Hypopituitarism Hypopituitarism, which is characterized by a decreased secretion of pituitary hormones, is a condition that affects many of the other endocrine systems.2 The cause may be congenital or may result from a variety of acquired abnormalities (Chart 49.1). Hypopituitarism is associated with increased morbidity and mortality.

TABLE 49.1 FREQUENCY OF ADENOMAS OF THE ANTERIOR PITUITARY CELL TYPE

HORMONE

Lactotrope Somatotrope Lactotrope/ somatotrope Corticotrope

Prolactin (PRL) Growth hormone (GH) Mixed PRL/GH

32 21 6

Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Thyroid-stimulating hormone (TSH)

13

Gonadotrope

Thyrotrope Nonfunctional tumors

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FREQUENCY (%)