Porth’s Essentials of Pathophysiology [5th ed.] 1975107195, 9781975107192

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Library of Congress Cataloging-in-Publication Data ISBN-13: 978-1-975107-19-2 | eISBN: 9781975107208 ISBN-10: 1-975107-19-5 Library of Congress Control Number: 2019911909

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To my husband, Stephen Sr., and children—Richie, Robby, Stephen Jr., and Rachel—who always inspire me. To those pursuing or continuing a love for healthcare, with a special thanks for your dedication, compassion, and selflessness.

Contributors Contributors to Essentials of Pathophysiology, Fourth Edition

Jacqueline M. Akert, RNC, MSN, WHNP-BC Nurse Practitioner Women’s Health Aurora Health Care Waukesha, Wisconsin (Chapters 40, 41 with Patricia McCowen Mehring) Diane Book, MD Associate Professor, Neurology Co-Director Stroke & Neurovascular Program Froedtert Hospital & Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 37) Freddy W. Cao, MD, PhD Clinical Associate Professor College of Nursing University of Wisconsin–Milwaukee Milwaukee, Wisconsin (Chapters 18, 34) Paula Cox-North, PhD, ARNP

Clinical Assistant Professor Hepatitis & Liver Clinic Harborview Medical Center University of Washington School of Nursing Seattle, Washington (Chapters 29, 30) Herodotos Ellinas, MD, FAAP, FACP Assistant Professor Department of Anesthesiology Med–Anesthesia and PGY-1 Program Director Medical College of Wisconsin Milwaukee, Wisconsin (Chapters 11, 12, 13) Jason R. Faulhaber, MD Assistant Program Director, Fellowship in Infectious Diseases Division of Infectious Diseases, Carilion Clinic Assistant Professor, Virginia Tech, Carilion School of Medicine Adjunct Professor, Department of Biomedical Sciences, Jefferson College of Health Sciences Roanoke, Virginia (Chapters 15, 16) Anne M. Fink, RN, PhD Postdoctoral Research Associate College of Nursing University of Illinois–Chicago Chicago, Illinois (Chapters 19, 20 with Karen M. Vuckovic) Susan A. Fontana, PhD, APRN-BC Associate Professor and Family Nurse Practitioner College of Nursing University of Wisconsin–Milwaukee Milwaukee, Wisconsin (Chapter 38)

Kathleen E. Gunta, MSN, RN, OCNS-C Clinical Nurse Specialist Aurora St. Luke’s Medical Center Milwaukee, Wisconsin (Chapter 43) Nathan A. Ledeboer, PhD, D(ABMM) Associate Professor of Pathology Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 14) Kim Litwack, PhD, RN, FAAN, APNP Associate Dean for Academic Affairs Family Nurse Practitioner Advanced Pain Management University of Wisconsin–Milwaukee Milwaukee, Wisconsin (Chapter 35) Glenn Matfin, MSc (Oxon), MB, ChB, FACE, FACP, FRCP Medical Director International Diabetes Center Clinical Professor of Medicine University of Minnesota Minneapolis, Minnesota (Chapters 10, 31, 32, 33, 39) Patricia McCowen Mehring, RNC, MSN, WHNP Nurse Practitioner Women’s Health Milwaukee, Wisconsin (Chapters 40, 41 with Jacqueline M. Akert) Carrie J. Merkle, PhD, RN, FAAN Associate Professor College of Nursing The University of Arizona

Tucson, Arizona (Chapters 1, 2, 3, 4, 7) Kathleen Mussatto, PhD, RN Nurse Scientist Herma Heart Center Children’s Hospital of Wisconsin Assistant Clinical Professor of Surgery Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 19, Heart Disease in Infants and Children) Debra Bancroft Rizzo, RN, MSN, FNP-BC Nurse Practitioner Division of Rheumatology University of Michigan Ann Arbor, Michigan (Chapter 44) Jonathan Shoopman, MD Assistant Professor of Anesthesiology and Critical Care Medical College of Wisconsin Milwaukee, Wisconsin (Chapters 22, 23) Gladys Simandl, RN, PhD Professor Columbia College of Nursing Milwaukee, Wisconsin (Chapters 45, 46) Aoy Tomita-Mitchell, PhD Associate Professor Department of Surgery Children’s Research Institute Medical College of Wisconsin Milwaukee, Wisconsin (Chapters 5, 6)

Karen M. Vuckovic, RN, PhD, ACNS-BC Assistant Clinical Professor College of Nursing University of Illinois–Chicago Chicago, Illinois (Chapters 19, 20 with Anne M. Fink) Jill M. Winters, RN, PhD, FAHA President and Dean Columbia College of Nursing Milwaukee, Wisconsin (Chapter 9) Contributors to Porth’s Pathophysiology, Tenth Edition Sawsan Abuhammad, PhD Assistant Professor, Maternal and Child Health Jordan University of Science and Technology Irbid, Jordan Chapter 42: Structure and Function of the Male Genitourinary System Maeghan Arnold, MNSc, APRN, AGACNP-BC Clinical Instructor Practice Department College of Nursing University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 20: Disorders of Hearing and Vestibular Function Michele R. Arwood, DNP, MSN, BSN, CNS-BC, NE-BC, CJCP System Director, Quality and Accreditation Baptist Memorial Health Care Corporation Memphis, Tennessee Chapter 8: Disorders of Fluid and Electrolyte and Acid Base Balance Chapter 29: Structure and Function of the Respiratory System Trina Barrett, DNP, RN, CNE, CCRN

Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 3: Cellular Adaptation, Injury, and Death Cynthia Bautista, PhD, CCRN, SCRN, CCNS, ACNS-BC, FNCS Associate Professor Marion Peckham Egan School of Nursing and Health Studies Fairfield University Fairfield, Connecticut Chapter 13: Organization and Control of Neural Function Chapter 14: Somatosensory Function, Pain, Headache, and Temperature Chapter 15: Disorders of Motor Function Chapter 16: Disorders of Brain Function Hallie Bensinger, DNP, APN, FNP-BC Kaplan Nurse Consultant New York, New York Chapter 44: Structure and Function of the Female Reproductive System Chapter 45: Disorders of the Female Reproductive System Jami S. Brown, DHEd, RN, CNN Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 34: Acute Kidney Injury and Chronic Kidney Disease Melissa Brown, MS, RN Instructional Academic Staff College of Nursing University of Wisconsin–Milwaukee Milwaukee, Wisconsin Chapter 43: Disorders of the Male Reproductive System Jacqueline Rosenjack Burchum, DNSc, FNP-BC, CNE

Associate Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 21: Blood Cells and Hematopoietic System Chapter 23: Disorders of Red Blood Cells Kathy Diane Butler, DNP, APRN, FNP/GNP-BC, NP-C Clinical Associate Professor College of Nursing University of Memphis Memphis, Tennessee Chapter 49: Disorders of Musculoskeletal Function: Developmental and Metabolism Disorders, Activity Intolerance, and Fatigue Freddy W. Cao, MD, PhD Clinical Associate Professor College of Nursing University of Wisconsin–Milwaukee Milwaukee, Wisconsin Chapter 36: Structure and Function of the Gastrointestinal System Chapter 37: Disorders of Gastrointestinal Function Chapter 38: Disorders of Hepatobiliary and Exocrine Pancreas Function Jaclyn Conelius, PhD, FNP-BC, FHRS Associate Professor & FNP Track Coordinator Marion Peckham Egan School of Nursing & Health Studies Fairfield University Fairfield, Connecticut Chapter 28: Disorders of Cardiac Conduction and Rhythm Herodotos Ellinas, MD, FAAP/FACP Associate Professor Department of Anesthesiology Residency Program Director Medical College of Wisconsin Milwaukee, Wisconsin

Chapter 27: Disorders of Cardiac Function, and Heart Failure and Circulatory Shock Deena Garner, DNP, RN Clinical Instructor Practice Department College of Nursing University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 20: Disorders of Hearing and Vestibular Function Sandeep Gopalakrishnan, PhD Assistant Professor College of Nursing University of Wisconsin–Milwaukee Milwaukee, Wisconsin Chapter 7: Stress and Adaptation Chapter 9: Inflammation, Tissue Repair, and Wound Healing Chapter 12: Disorders of the Immune Response Lisa Hight, EdD Professor of Biology General Education–Biomedical Sciences – Biology Baptist College of Health Sciences Memphis, Tennessee Chapter 51: Structure and Function of the Skin Chapter 52: Disorders of Skin Integrity and Function Deborah L. Hopla, DNP, APRN-BC, FAANP Associate Professor Director MSN/FNP and DNP Programs Amy V. Cockcroft Leadership Fellow Department of Nursing School of Health Sciences Francis Marion University Florence, South Carolina Chapter 46: Sexually Transmitted Infections

Teresa Kessler, PhD, RN, ACNS-BC, CNE Professor, Kreft Endowed Chair for the Advancement of Nursing Science College of Nursing and Health Professions Valparaiso University Valparaiso, Indiana Chapter 8: Disorders of Fluid, Electrolyte, and Acid–Base Balance Christine Paquin Kurtz, DNP Associate Professor Nursing and Health Professions College of Nursing Valparaiso University Valparaiso, Indiana Chapter 17: Sleep and Sleep-Wake Disorders Elizabeth M. Long, DNP, APRN-BC, CNS Assistant Professor School of Nursing Lamar University Beaumont, Texas Chapter 18: Disorders of Thought, Emotion, and Memory Tracy McClinton, DNP, AG-ACNP, BC Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 30: Respiratory Tract Infections, and Neoplasms Chapter 31: Disorders of Ventilation and Gas Exchange Linda C. Mefford, PhD, MSN, APRN, NNP-BC, RNC-NIC Associate Professor of Nursing Lansing School of Nursing and Clinical Sciences Bellarmine University Louisville, Kentucky Chapter 26: Disorders of Blood Flow and Blood Pressure Regulation Chapter 32: Structure and Function of the Kidney Chapter 33: Disorders of Renal Function

Chapter 40: Mechanisms of Endocrine Control Chapter 41: Disorders of Endocrine Control Sarah Morgan, PhD, RN Clinical Associate Professor College of Nursing University of Wisconsin–Milwaukee Milwaukee, Wisconsin Chapter 47: Structure and Function of the Musculoskeletal System Chapter 48: Disorders of Musculoskeletal Function: Trauma, Infection, Neoplasms Chapter 50: Disorders of Musculoskeletal Function: Rheumatic Disorders Nancy A. Moriber, PhD, MSN, BSN, CRNA, APRN Assistant Professor Nurse Anesthesia School of Nursing Fairfield University Fairfield, Connecticut Chapter 11: Innate and Adaptive Immunity Emma Murray, DNP, APRN, ACNP-BC Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 30: Respiratory Tract Infections, Neoplasms, and Childhood Disorders Chapter 31: Disorders of Ventilation and Gas Exchange Cheryl Neudauer, PhD, MEd Faculty Department of Biology Minneapolis Community and Technical College Minneapolis, Minnesota Chapter 2: Cell and Tissue Characteristics Stephanie Nikbakht, DNP, PPCNP-BC

Assistant Professor College of Nursing University of Tennessee Health Science Center PNP, Division of Genetics Le Bonheur Children’s Hospital Memphis, Tennessee Chapter 30: Respiratory Tract Infections, Neoplasms, and Childhood Disorders Alyssa Norris, MS, RD, LDN, CLC Clinical Dietitian II Nutrition Therapy Le Bonheur Children’s Hospital Memphis, Tennessee Chapter 39: Alterations in Nutritional Status Keevia Porter, DNP, NP-C Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 35: Disorders of the Bladder and Lower Urinary Tract Michelle Rickard, DNP, CPNP-AC Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 6: Neoplasia Archie Sims, MSN Nurse Practitioner Hospitalist Palmetto Health Tuomey Sumter, South Carolina Chapter 1: Concepts of Health and Disease Diane Smith, DNP, FNP-BC

Clinical Professor University of Wisconsin–Milwaukee Milwaukee, Wisconsin Chapter 19: Disorders of Visual Function Ansley Grimes Stanfill, PhD, RN Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 4: Genetic Control of Cell Function and Inheritance Chapter 5: Genetic and Congenital Disorders Sharon Stevenson, DNP, APRN, PPCNP-BC Clinical Assistant Professor Practice Department College of Nursing University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 20: Disorders of Hearing and Vestibular Function James Mark Tanner, DNP, RN Assistant Clinical Professor BSN Program Director UAMS College of Nursing University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 25: Structure and Function of the Cardiovascular System Janet Tucker, PhD, RNC-OB Assistant Professor Loewenberg College of Nursing University of Memphis Memphis, Tennessee Chapter 39: Alterations in Nutritional Status Reba A. Umberger, PhD, RN, CCRN-K

Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 10: Mechanisms of Infectious Disease Chapter 32: Structure and Function of the Kidney Chapter 33: Disorders of Renal Function Melody Waller, PhD, RN Assistant Professor College of Nursing University of Tennessee Health Science Center Memphis, Tennessee Chapter 44: Structure and Function of the Female Reproductive System Chapter 45: Disorders of the Female Reproductive System Paige Wimberley, PhD, APRN, CNS-BC, CNE Associate Professor College of Nursing and Health Professions Arkansas State University Jonesboro, Arkansas Chapter 22: Disorders of Hemostasis Chapter 24: Disorders of White Blood Cells and Lymphoid Tissues Sachin Yende, MD, MS Professor Department of Critical Care Medicine and Clinical and Translational Sciences University of Pittsburgh Pittsburgh, Pennsylvania Chapter 10: Mechanisms of Infectious Disease

Reviewers Jennifer Armfield, DNP, RN, ACNP-BC Assistant Clinical Professor School of Nursing Northern Arizona University Flagstaff, Arizona Debbie Ciesielka, DEd, MSN, ANP-BC Associate Professor, MSN Program Coordinator Department of Nursing Clarion University Clarion, Pennsylvania Karen Cooper, MSN Assistant Professor Research College of Nursing Kansas City, Missouri Catherine Hogan, PhD, MPH, RN Assistant Professor Catherine MacAuley School of Nursing Maryville University St. Louis, Missouri Angela Jupiter-McCon, PhD

Associate Professor Joseph and Nancy Fail School of Nursing William Carey University Hattiesburg, Mississippi Katie R. Katz, DNP, FNP-BC, RN Assistant Professor School of Nursing Radford University Radford, Virginia Keerat Kaur, PhD Adjunct Professor School of Nursing & Healthcare Professions College of New Rochelle New Rochelle, Texas Christine Kessel, PhD, MSN, RN, CNE Interim Dean, Professor Department of Nursing Trinity College of Nursing & Health Sciences Rock Island, Illinois Heather LaPoint, RN, MSN-Ed, CNE, CCRN-E Assistant Professor Department of Nursing State University of New York at Plattsburgh Plattsburgh, New York Debra Marsala, DNS, ANP Adjunct Instructor Division of Nursing Keuka College Keuka Park, New York Sandra Nash, PhD, RN Assistant Professor Western Illinois University

Macomb, Illinois Catherine Pankonien, DNP, RNC-NIC Assistant Professor Wilson School of Nursing Midwestern State University Wichita Falls, Texas Diane Ryan, PhD, AGPCNP Associate Professor Department of Nursing Daemen College Amherst, New York Jennifer Sipe, MSN, CRNP Assistant Professor School of Nursing and Health Sciences La Salle University Philadelphia, Pennsylvania Monica Sousa, EdD, ACNS-BC, APRN Associate Professor Department of Nursing Western Connecticut State University Danbury, Connecticut Ann Tritak, EdD, RN Associate Dean, DNP Program Director School of Nursing Felician University Lodi, New Jersey Renee Wenzlaff, DNP, RN Associate Professor School of Nursing Milwaukee School of Engineering Milwaukee, Wisconsin

Jean Yockey, PhD, FNP, RN, CNE Assistant Professor Department of Nursing University of South Dakota Vermillion, South Dakota

Preface This book was written with the intent of presenting the subject matter of pathophysiology as the foundation for all future studies in the health sciences. The text provides necessary content for the beginning student to build upon while also serving those furthering their education by reinforcing the link between comprehending complex disease process and clinical decision-making. This text will serve as a reference long after the coursework is completed. This edition considers the many technologic advances allowing health care providers to diagnose earlier and with more accuracy. A diverse array of contributors for Porth’s Pathophysiology, 10th Edition (from which this Essentials book is derived)was selected based on subject expertise. This text focuses on the scientific basis upon which the practice components of the health professions are based. The evidence-based information provides data for best practices, ultimately improving health care outcomes. A holistic conceptual framework uses body systems as an organizing structure and demonstrates how the systems are interrelated. Selection of content was based on common causes of morbidity and mortality across the life span, and recent advances in the fields of genetics, epigenetics, immunology, microbiology, and molecular biology are included. Content is presented in a manner that is logical and understandable for students. One goal of the new edition is to provide critical information needed to understand complex health alterations while delivering the content in a reader-friendly format. The chapters are arranged so that fundamental concepts such as cellular adaptation, 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. Strengths of the text include the expanded chapters on health and disease; nutrition; sleep and sleep disorders; and thought, emotion, and mood disorders. Advances in health care are presented through the inclusion of international studies, World Health Organization guidelines, updated standards, and the health variants of diverse populations. Organization 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. Each such chapter provides the foundation for understanding the pathophysiology content presented in the subsequent chapters. The chapter outline that appears at the beginning of each chapter provides an overall view of the chapter content and organization. Features of This Book This book includes the following special features to help you master the essential content. Objectives Objectives appear at the beginning of each chapter to 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. Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Contrast disorders due to multifactorial inheritance with those caused by single-gene inheritance. 2. Cite the most susceptible period of intrauterine life for development of defects because of teratogenic agents.

3. 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. 4. Describe the process of genetic assessment. 5. Describe screening methods used for prenatal diagnosis including specificity and risks.

Key Terms and Glossary To enable you to better use and understand the vocabulary of your profession, throughout the text you will encounter key terms in bold purple. 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 the key 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. Lysosomes play an important role in the normal metabolism of certain substances in the body. In some inherited diseases known as lysosomal storage disorders, a specific lysosomal enzyme is absent or inactive, preventing digestion of certain cellular substances and allowing them to build up in cells.6 There are approximately 50 lysosomal storage disorders, each caused by a lack of activity of one or more lysosomal enzymes, and each disorder is rare. Boxes Boxes are used throughout the text to summarize and highlight key information. “Key Points” Boxes One of the ways to approach learning is to focus on the major ideas or concepts. Because health care is an applied science, it is imperative that rather than trying to memorize a list of related and unrelated bits of

information, you understand the content and relate it to cases you encounter. Health care providers must apply these concepts in the clinical setting, which requires an understanding of the underlying etiology, histology, symptoms, risk factors, and hallmark features of a particular disease. As you have probably already discovered, it is impossible to memorize everything that is in a particular section or chapter of the book. It has been said that pathophysiology is a new language for many students. So not only does your brain have to figure out where to store all the information, it must also be able to retrieve the information when you need it. This is best accomplished by understanding rather than memorizing information. 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. KEY POINTS Cellular Adaptations Cells are able to adapt to increased work demands or threats to survival by changing their size (atrophy and hypertrophy), number (hyperplasia), and form (metaplasia). Normal cellular adaptation occurs in response to an appropriate stimulus and ceases once the need for adaptation has ceased. “Summary Concepts” Boxes The “Summary Concepts” boxes at the end of each main section provide a review and a reinforcement of the important content that has been covered. Use the summaries to ensure that you have covered and understood what you have read. SUMMARY CONCEPTS

Neonates are protected against antigens in early life as a result of passive transfer of maternal IgG antibodies through the placenta and IgA antibodies in colostrum and breast milk. Many changes occur with aging, but the exact mechanisms are not completely understood. However, the elderly population is more prone to infection and autoimmune disorders secondary to altered response in both innate and adaptive immune function. “Understanding” Boxes “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. 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.

1 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. Tables and Charts Tables and charts are designed to present complex information in a format that makes it more meaningful and facilitates recall of the information. Tables, which have two or more columns, are often used for the purpose of comparing or contrasting information. Charts, which have one column, are used to summarize information. TABLE 20-1 Common Disorders Affecting the Vestibular System

Type of Disorder Acoustic neuroma

Pathology A noncancerous growth or tumor on the vestibulocochlear nerve

Benign paroxysmal Disorder of otoliths positional vertigo Dislodgement of otoliths that participate in the Ménière disease receptor function of the vestibular system Repeated stimulation of the vestibular system such as Motion sickness during car, air, and boat travel Acute viral or bacterial infection of the vestibular Labyrinthitis pathways Dizziness or vertigo occurs with or without headache; Vestibular migraine related to the neurotransmitter serotonin Illustrations and Photos The detailed, 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 that enable the disease processes to exert their effects. In addition, photographs provide a realistic view of selected pathologic processes and lesions.

Diagrammatic representation of the iron cycle, including its absorption from the gastrointestinal tract, transport in the circulation, storage in the liver, recycling from aged red cells destroyed in the spleen, and use in the bone marrow synthesis of red blood cells. FIGURE 23-3

Concept Mastery Alerts

Concept Mastery Alerts clarify fundamental nursing concepts to improve the reader’s understanding of potentially confusing topics, as identified by Misconception Alerts in Lippincott’s Adaptive Learning Powered by prepU. Concept Mastery Alert Smoking is an independent risk factor for the development of coronary artery disease and should be avoided, but it has not been identified as a direct cause of hypertension. Interactive Learning Resources Interactive learning tools available online enrich learning and are identified with icons in the text. Concepts in Action Animations bring physiologic and pathophysiologic concepts to life, explaining concepts that are difficult to understand. Interactive Tutorials include graphics and animations and provide interactive review exercises. Review Exercises The Review Exercises at the end of each chapter are designed to help you integrate and synthesize material and to help you verify your understanding of the material presented. If you are unable to answer a question, reread the relevant section in the chapter. (Answers are available for instructors at http://thepoint.lww.com/PorthEssentials5e.)

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 32-5 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 person with diabetes. Explain the physiologic rationale for these two types of treatments. 2. 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. 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, μ, 10−6) used for describing these values. Knowledge of normal values can help you to put abnormal values in context. A Comprehensive Package for Teaching and Learning To further facilitate teaching and learning, a carefully designed ancillary package has been developed to assist faculty and students. Instructor Resources Tools to assist you with teaching your course are available upon adoption of this text on at http://thepoint.lww.com/PorthEssentials5e.

A Test Generator features NCLEX-style questions mapped to chapter learning objectives. An extensive collection of materials is provided for each book chapter: Pre-lecture Quizzes (and answers) allow you to check students’ reading. PowerPoint Presentations provide an easy way to integrate the textbook with your students’ classroom experience; multiple-choice and true/false questions are included to promote class participation. Guided Lecture Notes walk you through the chapter, learning objective by learning objective, with integrated references to the PowerPoint presentations. Discussion Topics (and suggested answers) can be used in the classroom or in online discussion boards to facilitate interaction with your students. Assignments (and suggested answers) include group, written, clinical, and Web assignments to engage students in varied activities and assess their learning. Case Studies with related questions (and suggested answers) give students an opportunity to apply their knowledge to a client case similar to one they might encounter in practice. Answers to the Review Exercises in the book facilitate review of student responses to these exercises. Sample Syllabi are provided for 14-week and 28-week courses. An Image Bank lets you use the photographs and illustrations from this textbook in your course materials. An ebook serves as a handy resource. Strategies for Effective Teaching provide general tips for instructors related to preparing course materials and meeting student needs. Dosage Calculation Quizzes and Drug Monographs are convenient references. Access to all Student Resources is provided so that you can understand the student experience and use these resources in your course as well. Student Resources

An exciting set of free learning resources is available on to help students review and apply vital concepts. Multimedia engines have been optimized so that students can access many of these resources on mobile devices. Students can access all these resources at http://thepoint.lww.com/PorthEssentials5e using the codes printed in the front of their textbooks. NCLEX-Style Review Questions for each chapter help students review important concepts and practice for NCLEX. Interactive learning resources appeal to a variety of learning styles. As mentioned previously in this preface, icons in the text direct readers to relevant resources: Concepts in Action Animations bring physiologic and pathophysiologic concepts to life, explaining concepts that are difficult to understand. Interactive Tutorials include graphics and animations and provide interactive review exercises. Journal Articles offer access to current articles relevant to each chapter and available in Wolters Kluwer journals to familiarize students with nursing literature. Learning Objectives from the book. A Spanish–English Audio Glossary provides helpful terms and phrases for communicating with patients who speak Spanish. Adaptive Learning Powered by PrepU Lippincott’s Adaptive Learning Powered by prepU helps every student learn more, while giving instructors the data they need to monitor each student’s progress, strengths, and weaknesses. The adaptive learning system allows instructors to assign quizzes or students to take quizzes on their own that adapt to each student’s individual mastery level. Visit http://thePoint.lww.com/prepU to learn more. A Comprehensive, Digital, Integrated Course Solution: Lippincott CoursePoint

The same trusted solution, innovation, and unmatched support that you have come to expect from Lippincott CoursePoint is now enhanced with more engaging learning tools and deeper analytics to help prepare students for practice. This powerfully integrated digital learning solution combines learning tools, case studies, real-time data, and the most trusted nursing education content on the market to make curriculum-wide learning more efficient and to meet students where they are at in their learning. And now, it is easier than ever for instructors and students to use, giving them everything they need for course and curriculum success! Lippincott CoursePoint includes: Engaging course content provides a variety of learning tools to engage students of all learning styles. A more personalized learning approach gives students the content and tools they need at the moment they need it, giving them data for more focused remediation and helping to boost their confidence and competence. Powerful tools, including varying levels of case studies, interactive learning activities, and adaptive learning powered by PrepU, help students learn the critical thinking and clinical judgment skills to help them become practice-ready nurses. Unparalleled reporting provides in-depth dashboards with several data points to track student progress and help identify strengths and weaknesses. Unmatched support includes training coaches, product trainers, and nursing education consultants to help educators and students implement CoursePoint with ease.

Acknowledgments The expertise of the contributors for Porth’s Pathophysiology, 10th Edition (from which this Essentials book is derived) keeps the book at the forefront of advances in science and medicine. Their attention to detail and desire to share current, relevant, and essential information with learners are primary strengths of the text. For the fifth edition, several chapters were merged to improve flow of content, and chapters that include new discoveries were added. Thanks also to Dr. Rupa Lalchandani Tuan for her time and talent in helping to ensure the accuracy of the information and assisting in condensing it to reflect only essential content needed to understand disease processes. I would like to thank Jonathan Joyce, senior acquisitions editor, for keeping us on task so the project remained on track. Many thanks go to Meredith Brittain, senior development editor, for her edits and comments that kept the focus of this book consistent. I also want to thank Jennifer Forestieri, director of product development, who stepped in to help, and especially for all her encouragement. Thanks also to Tim Rinehart, who provided the chapter tracking updates. Lastly, I want to thank my family for their inspiration during this difficult time of transition in my life. I also want to thank all the professors who have kept in touch with me throughout this project, cheering me forward to produce a text that is understandable yet concise and that meets the learning needs of today’s health care professional.

Contents UNIT 1 • Concepts of Health and Disease Chapter 1 Concepts of Health and Disease Concepts of Health and Disease Health and Disease in Populations UNIT 2 • Cell Function and Growth Chapter 2 Cell and Tissue Characteristics Functional Components of the Cell Integration of Cell Function and Replication Movement across the Cell Membrane and Membrane Potentials Body Tissues Chapter 3 Cellular Adaptation, Injury, and Death Cellular Adaptation Cell Injury and Death Chapter 4 Genetic Control of Cell Function and Inheritance Genetic Control of Cell Function Chromosomes Patterns of Inheritance Gene Technology

Chapter 5 Genetic and Congenital Disorders Genetic and Chromosomal Disorders Disorders due to Environmental Influences Diagnosis and Counseling Chapter 6 Neoplasia Characteristics of Benign and Malignant Neoplasms Etiology of Cancer Clinical Manifestations Screening, Diagnosis, and Treatment Childhood Cancers UNIT 3 • Disorders of Integrative Function Chapter 7 Stress and Adaptation Homeostasis Stress and Adaptation Disorders of the Stress Response Chapter 8

Disorders of Fluid, Electrolyte, and Acid–Base Balance Composition and Compartmental Distribution of Body Fluids Sodium and Water Balance Potassium Balance Calcium, Phosphorus, and Magnesium Balance Mechanisms of Acid–Base Balance Disorders of Acid–Base Balance UNIT 4 • Infection, Inflammation, and Immunity Chapter 9 Inflammation, Tissue Repair, and Wound Healing The Inflammatory Response Tissue Repair and Wound Healing Chapter 10

Mechanisms of Infectious Disease

Infectious Diseases Mechanisms of Infection Diagnosis and Treatment of Infectious Diseases Bioterrorism and Emerging Global Infectious Diseases Chapter 11 Innate and Adaptive Immunity The Immune Response Innate Immunity Adaptive Immunity Developmental Aspects of the Immune System Chapter 12

Disorders of the Immune Response, Including HIV/AIDS Disorders of the Immune Response Immunodeficiency Disorders Hypersensitivity Disorders Transplantation Immunopathology Autoimmune Disease Acquired Immunodeficiency Syndrome and Human Immunodeficiency Virus The AIDS Epidemic and Transmission of HIV Infection Pathophysiology and Clinical Course Prevention, Diagnosis, and Treatment HIV Infection in Pregnancy and in Infants and Children UNIT 5 • Disorders of Neural Function Chapter 13 Organization and Control of Neural Function Nervous Tissue Cells Neurophysiology Developmental Organization of the Nervous System Structure and Function of the Spinal Cord and Brain The Autonomic Nervous System Chapter 14

Somatosensory Function, Pain, Headache, and Temperature Regulation

Organization and Control of Somatosensory Function Pain Alterations in Pain Sensitivity and Special Types of Pain Headache and Associated Pain Pain in Children and Older Adults Body Temperature Regulation Increased Body Temperature Decreased Body Temperature Chapter 15 Disorders of Motor Function Organization and Control of Motor Function Disorders of the Motor Unit Disorders of the Cerebellum and Basal Ganglia Upper Motor Neuron Disorders Chapter 16 Disorders of Brain Function Manifestations and Mechanisms of Brain Injury Traumatic Brain Injury Cerebrovascular Disease Infections and Neoplasms Seizure Disorders Chapter 17 Sleep and Sleep–Wake Disorders Neurobiology of Sleep Sleep Disorders Sleep and Sleep Disorders in Children and Older Adults Chapter 18 Disorders of Thought, Emotion, and Memory Psychiatric Disorders Types of Psychiatric Disorders Disorders of Memory and Cognition UNIT 6 • Disorders of Special Sensory Function Chapter 19 Disorders of Visual Function Disorders of the Accessory Structures of the Eye

Disorders of the Conjunctiva, Cornea, and Uveal Tract Intraocular Pressure and Glaucoma Disorders of the Lens and Lens Function Disorders of the Vitreous and Retina Disorders of Neural Pathways and Cortical Centers Disorders of Eye Movement Chapter 20 Disorders of Hearing and Vestibular Function Disorders of the Auditory System Disorders of Vestibular Function UNIT 7 • Disorders of the Hematopoietic System Chapter 21 Blood Cells and the Hematopoietic System Composition of Blood and Formation of Blood Cells Diagnostic Tests Chapter 22 Disorders of Hemostasis Mechanisms of Hemostasis Hypercoagulability States Bleeding Disorders Chapter 23 Disorders of Red Blood Cells The Red Blood Cell Blood Types and Transfusion Therapy Anemia Polycythemia Age-Related Changes in Red Blood Cells Chapter 24

Disorders of White Blood Cells and Lymphoid Tissues Hematopoietic and Lymphoid Tissues Non-neoplastic Disorders of White Blood Cells Neoplastic Disorders of Lymphoid and Hematopoietic Origin

UNIT 8 • Disorders of Cardiovascular Function Chapter 25

Structure and Function of the Cardiovascular System The Heart as a Pump Organization of the Circulatory System Principles of Blood Flow The Systemic Circulation and Control of Blood Flow The Microcirculation and Lymphatic System Neural Control of Circulatory Function Chapter 26

Disorders of Blood Flow and Blood Pressure Regulation Blood Vessel Structure and Function Regulation of Systemic Arterial Blood Pressure Disorders of Systemic Arterial Blood Flow Disorders of Systemic Venous Circulation Disorders of Blood Pressure Regulation Chapter 27

Disorders of Cardiac Function, and Heart Failure and Circulatory Shock Disorders of Cardiac Function Disorders of the Pericardium Coronary Artery Disease Cardiomyopathies Infectious and Immunologic Disorders Valvular Heart Disease Heart Failure and Circulatory Shock Heart Failure in Adults Heart Disease in Infants and Children Heart Failure in Children and Older Adults Circulatory Failure (Shock) Chapter 28 Disorders of Cardiac Conduction and Rhythm Cardiac Conduction System Disorders of Cardiac Rhythm and Conduction

UNIT 9 • Disorders of Respiratory Function Chapter 29

Structure and Function of the Respiratory System Structural Organization of the Respiratory System Exchange of Gases between the Atmosphere and the Lungs Exchange and Transport of Gases Control of Breathing Chapter 30

Respiratory Tract Infections, Neoplasms, and Childhood Disorders Respiratory Tract Infections Cancer of the Lung Respiratory Disorders in Children Chapter 31 Disorders of Ventilation and Gas Exchange Physiologic Effects of Ventilation and Diffusion Disorders Disorders of Lung Inflation Obstructive Airway Disorders Chronic Interstitial (Restrictive) Lung Diseases Disorders of the Pulmonary Circulation Acute Respiratory Disorders UNIT 10 • Disorders of Renal Function Chapter 32 Structure and Function of the Kidney Kidney Structure and Function Tests of Renal Function Chapter 33 Disorders of Renal Function Congenital and Inherited Disorders of the Kidneys Obstructive Disorders Urinary Tract Infections Disorders of Glomerular Function Tubulointerstitial Disorders Malignant Tumors of the Kidney

Chapter 34 Acute Kidney Injury and Chronic Kidney Disease Acute Kidney Injury Chronic Kidney Disease Chronic Kidney Disease in Children and Older Adults Chapter 35 Disorders of the Bladder and Lower Urinary Tract Control of Urine Elimination Alterations in Bladder Function Cancer of the Bladder UNIT 11 • Disorders of Gastrointestinal Function Chapter 36

Structure and Function of the Gastrointestinal System Structure and Organization of the Gastrointestinal Tract Motility Hormonal, Secretory, and Digestive Functions Digestion and Absorption The Gastrointestinal Immunity Chapter 37 Disorders of Gastrointestinal Function Common Manifestations of Gastrointestinal Disorders: Anorexia, Nausea, and Vomiting Disorders of the Esophagus Disorders of the Stomach Disorders of the Small and Large Intestines Chapter 38

Disorders of Hepatobiliary and Exocrine Pancreas Function The Liver and Hepatobiliary System Disorders of Hepatic and Biliary Function Disorders of the Gallbladder and Exocrine Pancreas Chapter 39 Alterations in Nutritional Status Nutritional Status Nutritional Needs

Overweight and Obesity Undernutrition and Eating Disorders UNIT 12 • Disorders of Endocrine Function Chapter 40 Mechanisms of Endocrine Control The Endocrine System Chapter 41

Disorders of Endocrine Control of Growth and Metabolism General Aspects of Altered Endocrine Function Pituitary and Growth Disorders Thyroid Disorders Disorders of Adrenal Cortical Function General Aspects of Altered Glucose Regulation Diabetes Mellitus and the Metabolic Syndrome Complications of Diabetes Mellitus UNIT 13 • Disorders of Genitourinary and Reproductive Function Chapter 42

Structure and Function of the Male Genitourinary System Structure of the Male Reproductive System Spermatogenesis and Hormonal Control of Male Reproductive Function Neural Control of Sexual Function and Changes with Aging Chapter 43 Disorders of the Male Reproductive System Disorders of the Penis Disorders of the Scrotum and Testes Disorders of the Prostate Chapter 44

Structure and Function of the Female Reproductive System

Reproductive Structures Menstrual Cycle Breasts Chapter 45 Disorders of the Female Reproductive System Disorders of the External Genitalia and Vagina Disorders of the Cervix and Uterus Disorders of the Fallopian Tubes and Ovaries Disorders of Pelvic Support and Uterine Position Menstrual Disorders Disorders of the Breast Infertility Chapter 46 Sexually Transmitted Infections Infections of the External Genitalia Vaginal Infections Vaginal–Urogenital–Systemic Infections Other Infections UNIT 14 • Disorders of Musculoskeletal Function Chapter 47

Structure and Function of the Musculoskeletal System Bony Structures of the Skeletal System Articulations and Joints Chapter 48

Disorders of Musculoskeletal Function: Trauma, Infection, Neoplasms Injury and Trauma of Musculoskeletal Structures Bone Infections Osteonecrosis Neoplasms Chapter 49

Disorders of Musculoskeletal Function: Developmental and Metabolic Disorders, Activity Intolerance, and Fatigue

Alterations in Skeletal Growth and Development Metabolic Bone Disease Activity Intolerance and Fatigue Chapter 50

Disorders of Musculoskeletal Function: Rheumatic Disorders Systemic Autoimmune Rheumatic Diseases Seronegative Spondyloarthropathies Osteoarthritis Syndrome Crystal-Induced Arthropathies Rheumatic Diseases in Children and Older Adults UNIT 15 • Disorders of Integumentary Function Chapter 51 Structure and Function of the Skin Structure and Function of the Skin Chapter 52 Disorders of Skin Integrity and Function Manifestations of Skin Disorders Primary Disorders of the Skin Ultraviolet Radiation and Thermal and Pressure Injuries Nevi and Skin Cancers Age-Related Skin Manifestations Appendix Glossary Index

UNIT 1

Concepts of Health and Disease

CHAPTER 1 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

Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Compare the World Health Organization definition of health to the Healthy People 2020 definition. 2. Define pathophysiology. 3. Describe the process of disease to include etiology, pathogenesis, morphologic changes, clinical manifestations, diagnosis, and clinical course. 4. Define the term epidemiology. 5. Compare the meaning of the terms incidence and prevalence as they relate to measures of disease frequency. 6. Differentiate primary, secondary, and tertiary levels of prevention. 7. Compare morbidity and mortality.

T

he 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, tissues, 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 also 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 pathophysiologic 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 wellbeing of populations.

(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 because of long-standing hypertension. (From Strayer D. S., Rubin R. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 16). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 1-1

Concepts of Health and Disease 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. Most importantly, health is what the individual perceives it to be, which may vary across time and the factors mentioned. 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 span.2 Every decade, the U.S. Department of Health and Human Services leads 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 an acute or chronic illness that one acquires or is born with and that causes physiologic dysfunction in one or more body systems. Each disease generally has specific signs and symptoms that characterize its pathology and identifiable etiology. The aspects of the disease process 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.

Summary of the general mechanisms of cancer. DNA, deoxyribonucleic acid. (From Strayer D. S., Rubin R. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 231). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 1-2

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, 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. This will assist in identifying the etiology of disease and in the development of individualized interventions.3 Pathogenesis Although 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. Diagnostic pathology has evolved greatly in the last few years to include immunologic and molecular biologic tools for studying disease states (Fig. 1-3).4

Granulation tissue. A photomicrograph of granulation tissue shows thin-walled capillary sprouts immunostained to highlight the basement membrane collagens. The infiltrating capillaries penetrate a loose connective tissue matrix containing mesenchymal cells and occasional inflammatory cells. (From Rubin R., Strayer D. S. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 113. Figure 3–9). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 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. 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. 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 person’s 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 by intraarterial 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 reviews information to decide whether a 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 disease (Fig. 1-4).5,6 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 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.

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. (2014). Clinical epidemiology: The essentials (5th ed., p. 109). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 1-4

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. 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. SUMMARY CONCEPTS The term pathophysiology may be defined as the physiology of altered health. A disease has been defined as any deviation from or interruption of the 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. 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.5 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, 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

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. 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 the 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. 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. 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). 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 quality of life. Morbidity is concerned 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 classification procedures (the International Classification of Diseases 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, leading causes of death in the United States are heart disease, cancer, chronic lower respiratory disease, and cerebrovascular diseases.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 crosssectional 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 enrolled in a cohort study (also called a longitudinal study) are followed over a period of time to observe a specific health outcome. Framingham Study One of the best-known examples of a cohort study is the Framingham Study, which was carried out in Framingham, MA.10 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 caregivers, 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 caregiver participants.11 Initially designed to explore the relationship between oral contraceptives and breast cancer, caregivers 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 caregivers 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 child-bearing, 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 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 75% to 85% 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. 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 There are three fundamental types of prevention—primary prevention, secondary prevention, and tertiary prevention (Fig. 1-5).8

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. (2014). Clinical epidemiology: The essentials (5th ed., p. 153). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 1-5

Primary prevention is directed at keeping disease from occurring by removing 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 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, blood pressure measurement, laboratory tests, and other procedures such as a colonoscopy that can be “applied reasonably rapidly to asymptomatic people.”8 Tertiary prevention is directed at clinical interventions that prevent further deterioration or reduce the complications of a disease that is already present. An example is the use of β-adrenergic drugs to reduce the risk of death in people who have had a heart attack.8 Another example is support groups for people with alcohol addiction. Evidence-Based Practice and Practice Guidelines Evidence-based practice and evidence-based practice guidelines have gained popularity with providers and the public as a means of improving the quality and efficiency of health care.13 Their development has been prompted by more educated consumers who are fueled by 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 have 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.”13 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 must consider benefits versus risks or impact on quality of life when applying these guidelines. 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 Practitioners with expertise in clinical content, experts in guideline development, and potential users of the guideline are best at evaluating the guidelines.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, Detection, Evaluation, and Treatment of High Blood Pressure, 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. SUMMARY CONCEPTS 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 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 progression and projected outcome of a disease without medical 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 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: https://www.healthypeople.gov/sites/default/files/HP2020_brochure_with_LHI_508_FNL.pdf. Accessed January 22, 2011. 3. Carlsten C., Brauer M., Brinkman F., et al. (2014). Genes, the environment and personalized medicine: We need to harness both environmental and genetic data to maximize personal and population health. EMBO Reports 15(7), 736–739. 4. Kumar V., Abbas A., Aster J. C. (2014). Robbins and Cotran pathologic basis of disease (9th ed., p. 40). Philadelphia, PA: Elsevier Saunders. 5. Fischbach F., Dunning M. B. (2014). A manual of laboratory and diagnostic tests (9th ed., pp. 12– 13, 96). Philadelphia, PA: Lippincott Williams & Wilkins. 6. Benjamin I. J., Griggs R. C., Wing E. J., et al. (2016). Andreoli and Carpenter’s Cecil essentials of medicine (9th ed., pp. 266–270). Philadelphia, PA: Elsevier Saunders. 7. American Association for Clinical Chemistry. (2017). How reliable is laboratory testing? [Online]. Available: https://labtestsonline.org/articles/laboratory-test-reliability. Accessed April 8, 2019. 8. Fletcher R. H., Fletcher S. W., Fletcher G. S. (2012). Clinical epidemiology: The essentials (5th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 9. Centers for Disease Control and Prevention. (2017). FastStats. Older persons’ health. [Online]. Available: https://www.cdc.gov/nchs/fastats/older-american-health.htm. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm. Accessed October 8, 2017. 10. Framingham Heart Study. (2001). Framingham Heart Study: Design, rationale, objectives, and research milestones. [Online]. Available: https://www.nhlbi.nih.gov/science/framingham-heartstudy-fhs. 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. Center for Disease Control and Prevention. (2017). Hepatitis C FAQs for health professionals. [Online]. Available: https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Accessed October 8, 2017. 13. Duke University Medical Center. (2017). What is evidenced-based practice? [Online]. Available: http://guides.mclibrary.duke.edu/ebmtutorial. Accessed October 8, 2017.

14. Berlin J. A., Golulb R. M. (2014). Meta-analysis as evidence building a better pyramid. JAMA 312(6), 603–606. doi:10.1001/jama.2014.8167. 15. National Asthma Education and Prevention Program. (2007). Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. [Online]. Available: https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed May 22, 2013.

UNIT 2

Cell Function and Growth

CHAPTER 2 Cell and Tissue Characteristics Functional Components of the Cell Protoplasm The Nucleus The Cytoplasm and Its Organelles Ribosomes Endoplasmic Reticulum Golgi Complex Lysosomes and Peroxisomes Proteasomes Mitochondria The Cytoskeleton Microtubules Microfilaments The Cell (Plasma) Membrane Integration of Cell Function and Replication Cell Communication Cell Receptors Cell Surface Receptors Intracellular 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 Passive Transport Active Transport and Cotransport Endocytosis and Exocytosis Ion Channels Membrane Potentials Graded Potentials Action Potential Body Tissues Cell Differentiation Embryonic Origin of Tissue Types Epithelial Tissue Basement Membrane Cell Junctions and Cell-to-Cell Adhesions Types of Epithelial Tissues Connective or Supportive Tissue Muscle Tissue Skeletal Muscle Cardiac Muscle Smooth Muscle Nervous Tissue Extracellular Matrix Learning Objectives After completing this chapter, you should be able to meet the following objectives: 1. Predict the effects of dysfunction in each cellular organelle. 2. Differentiate the four functions of the cell membrane. 3. Order the pathway for cell communication, from the receptor to the response, and explain why the process is often referred to as signal transduction. 4. Link the phases of the cell cycle to cell replication.

5. Predict how changes in oxygen delivery to cells change cellular respiration and levels of adenosine triphosphate and carbon dioxide. 6. Compare and contrast membrane transport mechanisms: diffusion, osmosis, active transport, endocytosis, and exocytosis. 7. Predict changes in membrane potentials based on diffusion of ions. 8. Link the process of cell differentiation to the development of organ systems in the embryo and the regeneration of tissues in postnatal life. 9. Compare and contrast the characteristics of the four different tissue types.

In most organisms, the cell is the smallest functional unit that has the characteristics necessary for life. Cells combine to form tissues based on their embryonic origin. These tissues combine to form organs. Although cells of different tissues and organs vary in structure and function, certain characteristics are common to all cells. Because most disease processes start at the cellular level, we need to understand cell function to understand disease processes. This chapter discusses the structural parts of cells, cell functions and growth, movement of substances such as ions across the cell membrane, and tissue types.

Functional Components of the Cell Most organisms, including humans, contain eukaryotic cells that are made up of internal membrane-bound compartments called organelles (“small organs” within cells); an example of an organelle is the nucleus. This is in contrast to prokaryotes, such as bacteria, that do not contain membranebound organelles. When seen under a microscope, three major components of a eukaryotic cell become evident—the nucleus, the cytoplasm, and the cell membrane (Fig. 2-1).

Cell organelles. DNA, deoxyribonucleic acid. (Reprinted from Leeper-Woodford. (2016). Lippincott illustrated reviews: Integrated systems (Fig. 2.1, p. 39). Philadelphia, PA: Wolters Kluwer, with permission.) FIGURE 2-1

Protoplasm Biologists call the intracellular fluid protoplasm. Protoplasm is composed of water, proteins, lipids, carbohydrates, and electrolytes.1 Water makes up 70% to 85% of the cell’s protoplasm.1 Proteins make up 10% to 20% of the protoplasm. Proteins are polar and soluble in water. Examples of proteins include enzymes necessary for cellular reactions, structural proteins, ion channels, and receptors.1 Lipids make up 2% to 3% of the protoplasm. Lipids are nonpolar and insoluble in water. They are the main parts of cell membranes surrounding the outside and inside of cells. Examples of lipids include phospholipids and cholesterol. Some cells also contain large quantities of triglycerides. In fat cells, triglycerides can make up as much as 95% of the total cell mass.1 Carbohydrates make up approximately 1% of the protoplasm. These serve primarily as a rapid source of energy.1 The major intracellular electrolytes include potassium, magnesium, phosphate, sulfate, and bicarbonate ions. Small quantities of the electrolytes sodium, chloride, and calcium ions are also present in cells. These electrolytes participate in reactions that are necessary for the cell’s

metabolism, and they help generate and send signals in neurons, muscle cells, and other cells. Two distinct regions of protoplasm exist in the cell: The karyoplasm or nucleoplasm is inside the nucleus. The cytoplasm is outside the nucleus. The cytosol is the fluid of the cytoplasm (cytoplasm = cytosol + organelles). KEY POINTS The Functional Organization of the Cell Organelles in the cytoplasm perform functions within cells similar to how organs in the body perform functions within the organism. The nucleus is the largest and most visible organelle in the cell. The nucleus is the control center for the cell. In eukaryotic cells, it contains genetic information that we inherit from our parents.1 Other organelles include the mitochondria, which help to make energy molecules that cells can use, and the lysosomes and proteasomes, which function as the cell’s digestive system. Ribosomes, which are not surrounded by membranes, are the cellular structures that make proteins; those proteins may help to make other molecules needed for cell function. The Nucleus The cell nucleus is a rounded or elongated structure near the center of the cell (see Fig. 2-1). All eukaryotic cells have at least one nucleus. Some cells contain more than one nucleus; osteoclasts (a type of bone cell) usually contain 12 or more nuclei.1 The nucleus can be thought of as the control center for the cell because it contains the instructions to make proteins, and proteins can then make other molecules needed for cellular function and survival.1 The nucleus contains deoxyribonucleic acid (DNA), which contains genes. Genes contain the instructions for cellular function and survival. For example, the insulin gene contains instructions to make insulin protein. In addition, genes are units of inheritance that pass information from parents to their children.

The nucleus also is the site for the synthesis of the three main types of ribonucleic acid (RNA). These RNA molecules move from the nucleus to the cytoplasm and carry out the synthesis of proteins. These three types of RNA are as follows: Messenger RNA (mRNA), which is made from genetic information transcribed from the DNA in a process called transcription. mRNA travels to ribosomes in the cytoplasm so these instructions can be used to make proteins. Ribosomal RNA (rRNA) is the RNA component of ribosomes, the site of protein production. Transfer RNA (tRNA) transports amino acids to ribosomes so that mRNA can be turned into a sequence of amino acids. This process, known as translation, uses the mRNA template to link amino acids to synthesize proteins.1 The Cytoplasm and Its Organelles The cytoplasm includes the fluid and organelles outside the nucleus but within the cell membrane surrounding the cell. Cytoplasm is a solution that contains water, electrolytes, proteins, fats, and carbohydrates.1 Pigments may also accumulate in the cytoplasm. Some pigments are normal parts of cells. One example is melanin, which gives skin its color. Some pigments are not normal parts of cells. For example, when the body breaks down old red blood cells, pigments in red blood cells are changed to the pigment bilirubin, which the body can excrete. Embedded in the cytoplasm are various organelles that function as the organs of the cell. In addition to the nucleus, which was discussed in the previous section, these organelles include the ribosomes, the endoplasmic reticulum (ER), the Golgi complex, lysosomes, peroxisomes, proteasomes, and mitochondria.1 Ribosomes The ribosomes are the sites of protein synthesis in the cell. There are two subunits of ribosomes that are made up of rRNA and proteins. During protein synthesis, the two ribosomal subunits are held together by a strand of mRNA.1 These active ribosomes either stay within the cytoplasm (Fig. 22) or are attached to the membrane of the ER, depending on where the protein will be used.1

Endoplasmic reticulum (ER), ribosomes, and Golgi apparatus. The rough ER (RER) consists of intricately folded membranes studded with ribosomes. Ribosomes are made of protein and ribosomal ribonucleic acid organized together. Golgi apparatus processes proteins synthesized on ribosomes. (Reprinted from Leeper-Woodford. (2016). Lippincott illustrated reviews: Integrated systems (Fig. 2.3, p. 41). Philadelphia, PA: Wolters Kluwer, with permission.) FIGURE 2-2

Endoplasmic Reticulum The ER is an extensive system of paired membranes and flat vesicles that connect various parts of the inner cell (see Fig. 2-2).1 Two forms of ER exist in cells—rough and smooth.

Rough ER has ribosomes attached, and the ribosomes appear under a microscope as “rough” structures on the ER membrane. Proteins made by the rough ER usually become parts of organelles or cell membranes, or are secreted from cells as a protein. For example, the rough ER makes (1) digestive enzymes found in lysosomes and (2) proteins that are secreted, such as the protein hormone insulin. The smooth ER is free of ribosomes and has a smooth structure when viewed through a microscope. Because it does not have ribosomes attached, the smooth ER does not participate in protein synthesis. Instead, the smooth ER is involved in the synthesis of lipids including steroid hormones. The smooth ER of the liver is involved in storage of extra glucose as glycogen as well as metabolism of some hormone drugs. If proteins build up in the ER faster than they can be removed, the cell is said to experience “ER stress.” The cell responds by slowing down protein synthesis and restoring homeostasis. Abnormal responses to ER stress, which can cause inflammation and even cell death, have been implicated in inflammatory bowel disease,2 a genetic form of diabetes mellitus,3 and a disorder of skeletal muscle known as myositis,4 as well as many other diseases. Golgi Complex The Golgi apparatus, sometimes called the Golgi complex, consists of four or more stacks of thin, flattened vesicles or sacs (see Fig. 2-3).1 Substances produced in the ER are carried to the Golgi complex in small, membranecovered transfer vesicles. The Golgi complex modifies these substances and packages them into secretory granules or vesicles. In addition to making secretory granules, the Golgi complex is thought to make large carbohydrate molecules that combine with proteins produced in the rough ER to form glycoproteins. The Golgi apparatus can receive proteins and other substances from the cell surface by a retrograde transport mechanism. Several bacterial toxins, such as Shiga and cholera toxins, and plant toxins, such as ricin, that have cytoplasmic targets have exploited this retrograde pathway.1

The processes of autophagy and heterophagy, showing the primary and secondary lysosomes, residual bodies, extrusion of residual body contents from the cell, and lipofuscin-containing residual bodies. FIGURE 2-3

Lysosomes and Peroxisomes Lysosomes can be thought of as the digestive system or the stomach of the cell. These small, membrane-enclosed sacs contain powerful enzymes that can break down excess and worn-out cell parts as well as foreign substances that are taken into the cell (e.g., bacteria taken in by phagocytosis). All of the lysosomal enzymes require an acidic environment, and the lysosomes maintain a pH of approximately 5 in their interior compared to the pH of the cytoplasm, which is approximately 7.2, protecting other cellular structures from being broken down by these enzymes should leakage occur. Primary lysosomes are membrane-bound intracellular organelles that contain a variety of enzymes that have not yet entered the digestive process. They receive their enzymes as well as their membranes from the Golgi apparatus. Primary lysosomes become secondary lysosomes after they fuse with membrane-bound vacuoles that contain material to be digested.

Lysosomes break down phagocytosed material by either heterophagy or autophagy (Fig. 2-3). Heterophagy (hetero, different; phagy, eat) refers to digestion of a substance phagocytosed from the cell’s external environment.5 An infolding of the cell membrane takes external materials into the cell to form a surrounding phagocytic vesicle, or phagosome. Primary lysosomes then fuse with phagosomes to form secondary lysosomes. Heterophagocytosis is most common in phagocytic white blood cells such as neutrophils and macrophages. Autophagy involves the digestion of damaged cellular organelles, such as mitochondria or ER, which the lysosomes must remove if the cell’s normal function is to continue.5 Autophagocytosis is most common in cells undergoing atrophy (cell degeneration). Lysosomes play an important role in the normal metabolism of certain substances in the body. In some inherited diseases known as lysosomal storage disorders, a specific lysosomal enzyme is absent or inactive, preventing digestion of certain cellular substances and allowing them to build up in cells.6 There are approximately 50 lysosomal storage disorders, each caused by a lack of activity of one or more lysosomal enzymes, and each disorder is rare. In Tay–Sachs disease, an autosomal recessive disorder, cells do not make hexosaminidase A, a lysosomal enzyme needed for degrading the GM2 ganglioside found in nerve cell membranes. Its accumulation in the nervous system and retina of the eye causes the most damage.6 Smaller than lysosomes, round membrane-bound organelles called peroxisomes contain a special enzyme that degrades peroxides (e.g., hydrogen peroxide) in the control of free radicals.6 In liver cells, peroxidases help make bile acids.5 Proteasomes Three major cellular mechanisms are involved in the breakdown of proteins, or proteolysis.5 One of these is by the previously described lysosomal degradation. The second mechanism is the caspase pathway that is involved in apoptotic cell death. The third method of proteolysis occurs within an organelle called the proteasome. Proteasomes are small organelles made up of protein complexes in the cytoplasm and nucleus.

These organelles recognize misformed and misfolded proteins that have been targeted for degradation. Mitochondria The mitochondria are the “power plants” of the cell because they contain enzymes that can change carbon-containing nutrients into energy that is easily used by cells. This multistep process is often referred to as cellular respiration because it requires oxygen.1 Cells store most of this energy as high-energy phosphate bonds in substances such as adenosine triphosphate (ATP) and use the ATP as energy in various cellular activities. Mitochondria are found close to the site of energy use in the cell (e.g., near the myofibrils in muscle cells). A large increase in mitochondria occurs in skeletal muscle repeatedly stimulated to contract. Mitochondria contain their own DNA and ribosomes and are selfreplicating. Mitochondrial DNA (mtDNA) is inherited from the mother and thought to be linked to certain diseases and aging. mtDNA is a doublestranded, circular molecule that contains the instructions to make 13 of the proteins needed for mitochondrial function. The DNA of the nucleus contains the instructions for the structural proteins of the mitochondria and other proteins needed for cellular respiration.5,7 Most cells in the body can be affected by mtDNA mutations.5 Mitochondria also function as key regulators of apoptosis, or programmed cell death. In cancer, there is too little apoptosis and in neurodegenerative diseases, there is too much apoptosis. The Cytoskeleton In addition to its organelles, the cytoplasm contains a cytoskeleton, or the skeleton of the cell. The cytoskeleton is a network of microtubules, microfilaments, intermediate filaments, and thick filaments (Fig. 2-4).5 The cytoskeleton controls cell shape and movement.

Cytoskeleton. The cytoskeleton is made up of microfilaments, microtubules, and intermediate filaments. (Reprinted with permission from Wingerd B. (2014). The human body (3rd ed., Fig. 3.10, p. 55). Philadelphia, PA: Wolters Kluwer.) FIGURE 2-4

Microtubules Microtubules are formed from protein subunits called tubulin. Microtubules are long, stiff, hollow structures shaped like cylinders.7 Microtubules can rapidly disassemble in one location and reassemble in another. This constant reassembling forms elements of the cytoskeleton by continuously shortening and lengthening the tubulin dimers, a process known as dynamic instability.6 Microtubules function in the development and maintenance of cell formation. Microtubules participate in transport mechanisms inside cells, including transport of materials in the long axons of neurons and melanin in skin cells. Microtubules are also part of other cell structures such as cilia and flagella7 (Fig. 2-5).

Microtubules and microfilaments of the cell. The microfilaments are associated with the inner surface of the cell and aid in cell motility. The microtubules form the cytoskeleton and maintain the position of the organelles. FIGURE 2-5

Another important role of microtubules is participating in mitosis (cell division). Some cancer drugs (e.g., vinblastine and vincristine) bind to microtubules and inhibit cell division.8

Cilia and Flagella Flagella and cilia (plural) are microtubule-filled cellular extensions surrounded by a membrane that is continuous with the cell membrane. Eukaryotic flagellated cells are generally classified as having only one flagellum (singular), whereas ciliated cells typically have a large number of cilia.7 In humans, sperm cells are the only cell type with flagella. Cilia are found on surfaces of many epithelial linings, including the nasal sinuses and bronchi in the upper respiratory system. Damage to cilia or ciliated cells causes a cough, which is then used to help remove these substances from the airways. Genetic defects can result in incorrect assembly of cilia.7 For example, primary ciliary dyskinesia, also called immotile cilia syndrome, causes problems in the cilia of the respiratory tract so that inhaled bacteria cannot be removed, leading to a chronic lung disease called bronchiectasis. Genetic defects can also cause fertility problems by affecting the cilia in the fallopian tubes or the flagella on sperm.7,9 A condition called polycystic kidney disease is linked to a genetic defect in the cilia of the renal tubular cells. Microfilaments Microfilaments are thin, thread-like cytoplasmic structures. There are three classes of microfilaments: 1. Thin microfilaments, which are similar to thin actin filaments in muscle 2. Intermediate filaments, which are a group of filaments with diameters between those of the thick and thin filaments 3. Thick myosin filaments, which are in muscle cells but may also exist temporarily in other cells5 Muscle contraction depends on the interaction between the thin actin filaments and thick myosin filaments. Microfilaments are also present in the microvilli of the intestine. The intermediate filaments help support and maintain the shape of cells.5 The neurofibrillary tangles found in the brain in Alzheimer disease are formed by aggregated microtubule-associated proteins and result in abnormal cytoskeletons in neurons.

The Cell (Plasma) Membrane The cell is surrounded by a thin membrane that separates the intracellular contents from the extracellular environment. (Note that this is different from a cell wall.) Cell walls add structure and strength. Human cells do not have cell walls because of the development of tissues, organs, and organ systems, which must have the ability to communicate. The cell membrane is one of the most important parts of the cell acting as a semipermeable structure that helps determine what can and cannot enter and exit cells. The cell membrane contains receptors for hormones, neurotransmitters, and other chemical signals, as well as transporters that allow ions to cross the membrane during electrical signaling in cells (such as neurons and muscle cells). It also helps regulate cell growth and division. The cell membrane is a dynamic and fluid structure made up of organized lipids, carbohydrates, and proteins (Fig. 2-6). The main part of the membrane is the lipid bilayer, made up mostly of phospholipids, with glycolipids and cholesterol.7 This lipid bilayer is a mostly impermeable barrier to all but lipid-soluble substances.

Structure of the cell membrane showing the hydrophilic (polar) heads and the hydrophobic (fatty acid) tails. (From McConnell T. H., Hull K. L. (2011). Human form, human function: Essentials of anatomy & physiology (p. 67). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 2-6

Phospholipid molecules are arranged so their hydrophilic, water-loving heads face outward on each side of the membrane, where there is watery extracellular or intracellular fluid, and their hydrophobic tails project toward the middle of the membrane. Although the lipid bilayer provides the basic structure of the cell membrane, proteins carry out most of the functions. The way proteins are associated with the cell membrane often determines their function. The integral proteins, called transmembrane proteins, cross the entire lipid bilayer and function on both sides of the membrane or transport molecules across it. Many transmembrane proteins form ion channels and are selective for which substances move through them. Mutations in channel proteins, often called channelopathies, can cause genetic disorders.10 For example, cystic fibrosis involves an abnormal chloride channel, which causes the epithelial cell membrane to be impermeable to the chloride ion. The defective chloride secretion with excessive sodium and water causes abnormally thick and viscid respiratory secretions, blocking the airways. Water channels or pores called aquaporins are also transmembrane proteins in the cell membrane. Changes in water transport through aquaporin can cause diseases, including diabetes insipidus. Carriers are another type of transmembrane protein that allows substances to cross membranes. Glucose transporters are examples of carriers, and changes in the movement of glucose through these carriers are involved in diabetes mellitus.8 The peripheral proteins are temporarily bound to one side or the other of the membrane and do not pass into the lipid bilayer, and they have functions involving the inner or outer side of the membrane where they are found. Several peripheral proteins are receptors for chemical signals or are involved in intracellular signaling systems. SUMMARY CONCEPTS The cell is a self-sufficient structure that functions similarly to the total organism. In most cells, a single nucleus controls cell function. It contains DNA, which provides the information necessary to make the various proteins the cell needs to stay alive and to transmit genetic information from one generation to another. The nucleus also

is where RNA is made. The three types of RNA (mRNA, rRNA, and tRNA) move to the cytoplasm to make proteins. The cytoplasm contains the cell’s organelles and cytoskeleton. Ribosomes are sites for protein synthesis in the cell. The ER transports substances from one part of the cell to another and makes proteins (rough ER), carbohydrates, and lipids (smooth ER). Golgi bodies modify substances made in the ER and package them into secretory granules for transport within the cell or for export from the cell. Lysosomes, which are viewed as the digestive system of the cell, contain enzymes that digest worn-out cell parts and foreign materials. The proteasome digests misformed and misfolded proteins. The mitochondria serve as power plants for the cell because they change nutrient energy into ATP to power cell activities. Mitochondria contain their own DNA, which is important for making mitochondrial RNAs and proteins used in oxidative metabolism. The cytoplasm also contains microtubules, microfilaments, intermediate filaments, and thick filaments. Microtubules help determine cell shape, provide a means of moving organelles through the cytoplasm, and help move cilia and chromosomes during cell division. Actin microfilaments and myosin thin filaments interact so that muscle cells can contract. The cell membrane is a lipid bilayer that surrounds the cell and separates it from its surrounding external environment. Although the lipid bilayer provides the basic structure of the cell membrane, proteins carry out most of the specific functions of the cell membrane. Peripheral proteins often function as receptor sites for signaling molecules, and transmembrane proteins frequently form transporters for ions and other substances.

Integration of Cell Function and Replication Cell Communication Cells in multicellular organisms need to communicate with each other to coordinate their function and control their growth. The human body has several ways of sending information between cells. These include direct

communication between neighboring cells through gap junctions, autocrine and paracrine signaling, and endocrine or synaptic signaling.7 Autocrine signaling (auto: self) occurs when a cell releases a chemical into the extracellular fluid that affects its own activity (Fig. 2-7).

Examples of endocrine (A), paracrine (B), and autocrine (C) secretions. FIGURE 2-7

Paracrine signaling acts mainly on nearby cells. Endocrine signaling relies on hormones carried in the bloodstream to cells throughout the body. Synaptic signaling occurs in the nervous system, where neurotransmitters are released from neurons to act only on neighboring cells at synapses. KEY POINTS Cell Communication Cells communicate with each other and with the internal and external environments in a number of ways; for example, electrical and chemical signaling systems control electrical potentials, the overall function of a cell, and gene activity needed for cell division and cell replication. Chemical messengers bind to protein receptors on the cell surface or inside of cells in a process called signal transduction. Cells can regulate their responses to chemical messengers by increasing or decreasing the number of receptors. Cell Receptors Signaling systems include receptors found either in the cell membrane (cell surface receptors) or within the cells (intracellular receptors). Receptors are activated by a variety of extracellular chemical signals or first messengers, including neurotransmitters, hormones and growth factors, and other chemical messengers. Receptors are proteins, and the chemicals that bind to them are called ligands. Signaling systems also include transducers and effectors that are involved in changing the signal into a response. The pathway may include additional intracellular molecules called second messengers.7 Many molecules involved in signal transduction are proteins because proteins can change their shape or conformation, thereby changing their function and consequently the functions of the cell. Often during signal transduction, enzymes called protein kinases catalyze the addition of a phosphate to proteins, and this changes their structure and function.7

Cell Surface Receptors Each cell type in the body contains a unique set of surface receptors that allow the cell to respond to a set of signaling molecules in a specific way. These proteins can increase or decrease in number according to the needs of the cell. When excess chemical signals are present, the number of active receptors decreases in a process called downregulation. When there are decreased chemical signals, the number of active receptors increases through upregulation. The three classes of cell surface receptor proteins are G-protein linked, ion channel linked, and enzyme linked.5 G-Protein–Linked Receptors With more than 1000 members, G-protein–linked receptors are the largest family of cell surface receptors.5 These receptors rely on the activity of membrane-bound, intracellular regulatory proteins to convert external signals (first messengers) into internal signals (second messengers). Because these regulatory proteins bind to guanosine diphosphate (GDP) and guanosine triphosphate (GTP), they are called G-proteins. G-protein– linked receptors participate in cellular responses for many types of first messengers.5 Although there are differences between the G-protein–linked receptors, all share a number of features.7 They all have an extracellular receptor part that binds to the chemical signal (first messenger). They all undergo shape changes when the receptor binds to a signal, and the shape change activates the intracellular G-protein. The G-proteins use a GTPase cycle, which functions as a molecular switch. In its activated (on) state, the G-protein binds GTP, and in its inactivated (off) state, it binds GDP.5 When GTP is bound, the G-protein is active. The activated G-protein has GTPase activity, which changes the bound GTP (with three phosphate groups) to GDP (with two phosphate groups), and the G-protein changes to its inactive state. Receptor activation causes the α subunit to separate from the receptor and the β and γ subunits and to send the signal from the first messenger to its effector protein. Often, the effector is an enzyme that converts an inactive precursor molecule into a second messenger, which diffuses into the cytoplasm and carries the signal beyond the cell membrane. A common second messenger is cyclic adenosine monophosphate (cAMP). It is activated by the enzyme

adenylyl cyclase, which generates cAMP by transferring phosphate groups from ATP to other proteins.1 This transfer changes the shape and function of these proteins. Such changes eventually produce the cell response to the first messenger, whether it is a secretion, muscle contraction or relaxation, a change in metabolism, or the opening of ion channels. Enzyme-Linked Receptors Like G-protein–linked receptors, enzyme-linked receptors are transmembrane proteins, with their ligand-binding site on the outer surface of the cell membrane.5 Instead of having an intracellular part that associates with a G-protein, their intracellular part either has enzyme activity or binds directly with an enzyme. There are several classes of enzyme-linked receptors, including those that activate or have tyrosine kinase activity. Enzyme-linked receptors stimulate cellular responses such as calcium entry into cells, increased sodium– potassium exchange across the cell membrane, and stimulation of glucose and amino acid entry into cells. Insulin, for example, acts by binding to a surface receptor with tyrosine kinase activity. The intracellular signaling cascades are involved in the function of growth factors. All growth factors function by binding to specific receptors that deliver signals to target cells. These signals have two general effects: (1) they stimulate protein synthesis from many genes that were silent in resting cells and (2) they stimulate cells to enter the cell cycle for cell division. Ion Channel–Linked Receptors Ion channel–linked receptors are involved in the rapid signaling between electrically excitable cells such as neurons and muscle cells.5 Remember that ions have charge, and when ions move through the membrane, they change local charges, or voltages, and there is an electrical signal in cells. Many neurotransmitters stimulate this type of signaling by opening or closing ion channels in the cell membrane. Intracellular Receptors Some signals, such as thyroid hormone and steroid hormones, do not bind to cell surface receptors but move across the cell membrane and bind to intracellular receptors, and they influence DNA activity. Many of these hormones bind to a cytoplasmic receptor, and the receptor–hormone

complex enters the nucleus. In the nucleus, the receptor–hormone complex binds to DNA to change protein synthesis.1 The Cell Cycle and Cell Division The life cycle of a cell is called the cell cycle. It is usually divided into five phases (Fig. 2-8):

The cell cycle. G0, nondividing cell; G1, cell growth; S, deoxyribonucleic acid (DNA) replication; G2, protein synthesis; and M, mitosis. (From Wingerd B. (2014). The human body. Concepts of anatomy and physiology (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 2-8

1. G0 is when the cell may leave the cell cycle and either remain in a state of inactivity or reenter the cell cycle at another time. 2. G1 is when the cell begins to prepare for mitosis by increasing proteins, organelles, and cytoskeletal elements. 3. S phase is the synthesis phase, when DNA synthesis or replication occurs and the centrioles begin to replicate. 4. G2 is the premitotic phase and is similar to G1 in terms of RNA activity and protein synthesis. 5. M phase is when cell mitosis occurs.7 Tissues may be made up mostly of cells in G0, but most tissues contain a combination of cells that are continuously moving through the cell cycle and cells that occasionally enter the cell cycle. Nondividing cells, such as neurons and skeletal and cardiac muscle cells, have left the cell cycle and are not capable of mitotic division in postnatal life.7 Cell Metabolism and Energy Sources Energy is the ability to do work. Cells use oxygen to transform nutrients into the energy needed for muscle contraction, the active transport of ions and other molecules across cell membranes, and the synthesis of enzymes, hormones, and other macromolecules. Energy metabolism refers to the processes by which the calorie-containing fats, proteins, and carbohydrates from the foods we eat are changed into energy or energy sources in the cell. Catabolism and anabolism are the two phases of metabolism. Catabolism breaks down nutrients and body tissues to produce energy. Anabolism builds more complex molecules from simpler ones. The special carrier for cellular energy is ATP. ATP molecules consist of adenosine, a nitrogenous base; ribose, a five-carbon sugar; and three phosphate groups (Fig. 2-9). The phosphate groups are attached by two high-energy bonds.7 Large amounts of free energy are released when ATP is cleaved to form adenosine diphosphate (ADP), which contains two phosphate groups. The free energy released from the cleaving ATP is used to drive reactions. Energy from nutrients is used to change ADP back to ATP. Because energy can be “saved or spent” using ATP, ATP is often called the energy currency of the cell.

Adenosine triphosphate (ATP) is the major source of cellular energy. (A) Each molecule of ATP contains two high-energy bonds, each containing about 12 kcal of potential energy. (B) The high-energy ATP bonds are in constant flux. They are generated by substrate (glucose, amino acid, and fat) metabolism and are consumed as the energy is expended. ADP, adenosine diphosphate. FIGURE 2-9

Energy transformation takes place within the cell through two types of energy production pathways: The anaerobic (i.e., without oxygen) glycolytic pathway occurs in the cytoplasm. The aerobic (i.e., with oxygen) pathway occurs in the mitochondria. UNDERSTANDING

Cell Metabolism

Cell metabolism is the process that changes the calorie-containing nutrients (carbohydrates, proteins, and fats) into ATP, which provides for the energy needs of the cell. ATP is formed through three major pathways: (1) the glycolytic pathway, (2) the citric acid cycle, and (3) the electron transport chain. Without oxygen, cells will use the glycolytic pathway in the cytosol and make two molecules of ATP from one glucose molecule. With oxygen and mitochondria, cells will make much more ATP per glucose molecule. Cells start the energy metabolism process with the anaerobic glycolytic pathway in the cytoplasm, and if oxygen is present, the pathway moves into the mitochondria for the aerobic pathway. Both pathways involve oxidation–reduction reactions involving an electron donor, which is oxidized in the reaction, and an electron acceptor, which is reduced in the reaction. In energy metabolism, the breakdown products of carbohydrate, fat, and protein metabolism donate electrons and are oxidized, and the coenzymes nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD) accept electrons and are reduced.7

1 Anaerobic Metabolism

Glycolysis (glycol, sugar; lysis, breaking down) is the process by which energy is released from glucose. It is an important energy provider for cells that lack mitochondria, the cell organelles where aerobic metabolism occurs. Glycolysis also provides energy in situations when delivery of oxygen to the cell is delayed or impaired (e.g., in skeletal muscle during the first few minutes of exercise). Glycolysis, which occurs in the cytoplasm of the cell, involves the splitting of the six-carbon glucose molecule into 2 three-carbon molecules of pyruvic acid. Because the reaction that splits glucose requires two molecules of ATP, there is a net gain of only two molecules of ATP from each molecule of glucose that is metabolized. The process is anaerobic and does not require oxygen (O2) or produce carbon dioxide

(CO2). When O2 is present, pyruvic acid moves into the mitochondria, where it enters the aerobic citric acid cycle. Under anaerobic conditions, such as cardiac arrest or circulatory shock, pyruvate is converted to lactic acid, allowing glycolysis to continue as a means of supplying cells with ATP when O2 is lacking. Converting pyruvate to lactic acid is reversible, and after the oxygen supply has been restored, lactic acid is converted back to pyruvate and used for energy or to make glucose.

2 Aerobic Metabolism

Aerobic metabolism occurs in the cell’s mitochondria and involves the citric acid cycle and the electron transport chain. It is here that the carbon compounds from the fats, proteins, and carbohydrates in our diet are broken down and their electrons combined with oxygen to form carbon dioxide, water, and ATP. Unlike lactic acid, which is an end product of anaerobic metabolism, carbon dioxide and water are generally harmless and easily eliminated from the body.7 Under aerobic conditions, both of the pyruvate molecules formed by the glycolytic pathway enter the mitochondria, where pyruvate combines with acetyl coenzyme to form acetyl coenzyme A (acetyl-CoA). The formation of acetyl-CoA begins the reactions in the citric acid cycle, also called the tricarboxylic acid or Krebs cycle. Some reactions release CO2, and some transfer electrons from the hydrogen atom to NADH or FADH. In addition to pyruvate from the glycolysis of glucose, fatty acid and amino acid breakdown products can also enter the citric acid cycle. Fatty acids, which are the major source of fuel in the body, are oxidized to acetyl-CoA for entry into the citric acid cycle.1,6,7

Oxidative metabolism takes place in the electron transport chain in the mitochondria.1,6,7 At the end of the citric acid cycle, each glucose molecule has yielded four new molecules of ATP (two from glycolysis and two from the citric acid cycle). In fact, the main function of these earlier stages is to make the electrons (e−) from glucose and other nutrients available for oxidation. Oxidation of the electrons carried by NADH and FADH2 is accomplished through a series of enzyme reactions in the mitochondrial electron transport chain. During these reactions, protons (H+) combine with O2 to form water (H2O), and large amounts of energy are released and used to add a high-energy phosphate bond to ADP, converting it to ATP. Because the formation of ATP involves the addition of a high-energy phosphate bond to ADP, the process is

sometimes called oxidative phosphorylation. There is a net yield of 36 molecules of ATP from one molecule of glucose (2 from glycolysis, 2 from the citric acid cycle, and 32 from the electron transport chain). In general, the net amount of ATP formed from each gram of protein that is metabolized is less than for glucose, whereas ATP formed from fat is greater (e.g., each 16-carbon fatty acid molecule makes about 129 molecules of ATP). SUMMARY CONCEPTS Cells communicate with each other by chemical messenger systems. In some tissues, chemical messengers move from cell to cell through gap junctions without entering the extracellular fluid. Other types of chemical messengers bind to cell surface or intracellular receptors. Three classes of cell surface receptor proteins are G-protein linked, ion channel linked, and enzyme linked. G-protein–linked receptors rely on molecules called G-proteins that work like an on–off switch to change external signals (first messengers) into internal signals (second messengers). Ion channel–linked signaling opens or closes ion channels formed in the cell membrane. Enzyme-linked receptors activate intracellular enzymes. Intracellular receptors bind to DNA to change protein synthesis. The life cycle of a cell is called the cell cycle. It is usually divided into five phases: G0, or the resting phase; G1, during which the cell begins to prepare for division; the S or synthetic phase, during which DNA replication occurs; G2, which is the premitotic phase and is similar to G1; and the M phase, during which cell division occurs. Cell division, or mitosis, is the process during which a parent cell divides into two daughter cells, each receiving an identical pair of chromosomes. Metabolism is the process whereby carbohydrates, fats, and proteins from the foods we eat are broken down and then changed into the energy needed for cell function. Energy is converted to ATP, the energy currency of the cell. Two sites of energy conversion are present in cells: the anaerobic glycolytic pathway in the cytoplasm and the aerobic pathways in the mitochondria. The most efficient of

these pathways is the aerobic citric acid cycle and electron transport chain in the mitochondria. This pathway requires oxygen and produces carbon dioxide and water as end products. The glycolytic pathway in the cytoplasm involves the breakdown of glucose to form ATP. This pathway can function without oxygen by producing lactic acid.

Movement across the Cell Membrane and Membrane Potentials The cell membrane serves as a barrier that controls which substances enter and leave the cell. This barrier allows substances that are essential for cellular function to enter the cell while keeping out substances that are harmful. Most cell membranes are semipermeable, meaning that some substances such as water can cross the membrane (the membranes are permeable to these substances), but other substances cannot cross the membrane (the membranes are impermeable to these substances). The cell membrane is responsible for differences in the composition of intracellular and extracellular fluids. For example, the extracellular fluid usually has higher concentrations of sodium, calcium, and chloride ions compared to the intracellular fluid, and the intracellular fluid usually has higher concentrations of potassium compared to the extracellular fluid. Movement of Substances across the Cell Membrane Movement through the cell membrane occurs in essentially three ways: By simple diffusion following the concentration gradient By carrier proteins, which are responsible for transporting only one type of molecule and may be involved in active transport By channel proteins, which transfer water-soluble molecules and serve as the ion selectivity filter (Fig. 2-10)

Movement of molecules through the plasma membrane. (Reprinted from Ross M. H., Pawlina W. (2015). Histology: A text and atlas with correlated cell and molecular biology (7th ed., Fig. 2.7, p. 31). Philadelphia, PA: Wolters Kluwer, with permission.) FIGURE 2-10

Vesicular transport allows the cell membrane to remain intact while allowing molecules to pass through. This process is achieved by endocytosis, which brings materials into the cell, and exocytosis, which removes substances from the cell (Fig. 2-11). The cell membrane can also engulf a particle, forming a membrane-bound vesicle; this membranecoated vesicle is moved into the cell by endocytosis. Substances can also leave the cell when a membrane-bound vesicle fuses with the membrane during exocytosis.5

Endocytosis and exocytosis are two major forms of vesicular transport. (Reprinted from Ross M. H., Pawlina W. (2015). Histology: A text and atlas with correlated cell and molecular biology (7th ed., Fig. 2.8, p. 32). Philadelphia, PA: Wolters Kluwer, with permission). FIGURE 2-11

Passive Transport Passive transport of substances across the cell membrane is influenced by chemical or electrical gradients and does not require an input of energy. A

difference in the number of particles on either side of the membrane creates a chemical gradient, and a difference in charged particles or ions creates an electrical gradient. Chemical and electrical gradients are often linked and are called electrochemical gradients.1 For example, positively charged sodium is higher outside the cell compared to the inside, and this creates both a chemical gradient (higher concentration) and an electrical gradient (higher charge). Diffusion Diffusion is the process by which substances become widely dispersed and reach a uniform concentration because of the energy from their spontaneous kinetic movements (Fig. 2-12A). Substances move from an area of higher to an area of lower concentration. An example of diffusion is when odorant molecules move from a pot of soup to your nose when you are cooking.1 Lipophilic (lipid-loving) substances such as oxygen, carbon dioxide, alcohol, and steroid hormones can diffuse through the lipid layer of the cell membrane. Hydrophilic (water-loving) substances cannot pass through the lipids of the membrane; instead, they diffuse through water-filled passages in the cell membrane (i.e., the integral proteins discussed previously such as ion channels, aquaporins, and carriers).

Mechanisms of membrane transport. (A) In diffusion, particles move freely to become equally distributed across the membrane. (B) In osmosis, osmotically active particles regulate the flow of water. (C) Facilitated diffusion uses a carrier system. (D) In active transport, selected molecules are transported across the membrane using the energy-driven (Na+/K+–ATPase) pump. (E) In pinocytosis, the membrane forms a vesicle that engulfs the particle and transports it across the membrane, where it is released. FIGURE 2-12

Facilitated Diffusion

As described earlier, small, lipophilic substances can pass through the lipids in cell membranes. Some substances, such as glucose, cannot pass through the cell membrane because they are not lipophilic or are too large to pass through the membrane. These substances need help to cross the membrane, and protein-assisted diffusion is aided by a transport protein. Substances move from areas of higher concentration to areas of lower concentration, and this does not require an input of energy (see Fig. 2-12C). For example, sodium ions can diffuse through ion channels from outside the cells, where sodium ions have higher concentration, to the inside of cells, where sodium ions have lower concentration. Substances can move through protein channels (such as ion channels or aquaporins) or through carriers. When substances move through carriers, they bind to the carrier on the membrane’s outer surface, are carried across the membrane attached to the carrier, and are then released on the inside of the membrane. The rate at which a substance moves across the membrane depends on the difference in concentration between the two sides of the membrane. Also important are the availability of transport proteins and how long it takes the substance to cross the membrane. Insulin, which stimulates the transport of glucose into cells, acts by increasing the number of glucose carriers in cell membranes. Osmosis Water usually crosses membranes through water channels (aquaporins) down the concentration gradient for water, moving from an area of higher water concentration to areas of lower water concentration (see Fig. 2-10B). This process is called osmosis and is driven by osmotic pressure.1 Osmosis is regulated by the concentration of substances (besides water) on either side of a membrane that cannot diffuse across the membrane (e.g., if there are no open sodium channels, sodium cannot diffuse across the membrane). When there is a difference in the concentration of impermeable substances across a membrane, water can move via aquaporins from the side with the lower concentration of particles to the side with the higher concentration of particles (and, in effect, moving from the side with higher water concentration to the side with lower water concentration). The movement of water continues until the concentration of substances on either

side of the membrane is equally diluted, or until the osmotic pressure opposes the flow of water. Active Transport and Cotransport Active transport mechanisms involve the input and use of energy. As we have learned, diffusion moves substances from an area of higher concentration to one of lower concentration, resulting in an equal distribution across the cell membrane. Sometimes, however, different concentrations of a substance are needed in the intracellular and extracellular fluids. For example, to function, a cell requires a much higher intracellular concentration of potassium ions than is present in the extracellular fluid while maintaining a much lower intracellular concentration of sodium ions than the extracellular fluid. In these situations, energy is required to pump the ions “uphill” or against their concentration gradient. When cells use an input of energy to move substances against an electrical or chemical gradient, the process is called active transport.1,7 The active transport system studied in the greatest detail is the sodium– potassium (Na+/K+)–ATPase pump (see Fig. 2-12D). This pump moves three sodium ions from inside the cell to outside the cell and moves two potassium ions from the outside of the cell to the inside of the cell. The Na+/K+–ATPase pump moves both of these ions against their concentration gradients.7 Energy used to do so comes from splitting and releasing energy from the high-energy phosphate bond in ATP by the enzyme ATPase, which is part of the Na+/K+–ATPase transport protein. If there is decreased activity of the Na+/K+–ATPase pump, the sodium ions will increase in the cell, increasing the osmotic pressure. Water will then diffuse into the cell, causing swelling. If this continues, the cell can burst and die. There are two types of active transport systems: primary active transport and secondary active transport. In primary active transport, the source of energy (e.g., ATP) is used directly in the transport of a substance. Secondary active transport mechanisms use the energy from the transport of one substance for the cotransport of a second substance. For example, when sodium ions diffuse into cells, the energy of this movement is used to drive the transport of a second substance against its concentration gradient. Similar to protein-assisted diffusion, secondary active transport mechanisms use membrane transport proteins. Secondary transport systems are classified

into two groups: cotransport or symport systems, in which substances are transported in the same direction, and countertransport or antiport systems, in which substances are transported in the opposite direction (Fig. 2-13).7 An example of cotransport occurs in the intestine, where the absorption of glucose and amino acids is linked to sodium transport.

Secondary active transport systems. (A) Symport or cotransport carries the transported solute (S) in the same direction as the sodium (Na+) ion. (B) Antiport or countertransport carries the solute and Na+ in the opposite direction. FIGURE 2-13

Endocytosis and Exocytosis Endocytosis is the process by which cells surround and take in materials from their surroundings. Substances are engulfed by small, membrane-

surrounded vesicles for movement into the cytoplasm. Endocytosis includes pinocytosis and phagocytosis. Pinocytosis (cell drinking) involves taking in small amounts of fluid or solid particles (such as proteins and solutions of electrolytes) (see Fig. 2-12E).5 Phagocytosis (cell eating) involves the engulfment and then killing or degrading of microorganisms or other particulate matter. During phagocytosis, a particle contacts the cell surface and is surrounded on all sides by the cell membrane, forming a phagocytic vesicle or phagosome. The phagosome fuses with a lysosome, and the ingested material is broken down by lysosomal enzymes. Certain white blood cells, such as macrophages and neutrophils, use phagocytosis to dispose of invading organisms, damaged cells, and unneeded extracellular parts.5 Some substances enter cells by receptor-mediated endocytosis, which requires substances to bind to a cell surface receptor to stimulate endocytosis.5,7 An example is low-density lipoproteins (LDLs), which carry cholesterol from the liver into cells for use. Problems with these receptors can keep LDL from entering cells, resulting in increased LDL in extracellular fluids (including the bloodstream). Exocytosis is a process for secretion of intracellular substances into the extracellular spaces. It is the reverse of endocytosis, in that a membranesurrounded secretory vesicle fuses to the inner side of the cell membrane, and an opening is created in the cell membrane. This opening allows the contents of the vesicle to be released into the extracellular fluid. Exocytosis is important in removing cellular debris and releasing substances, such as peptide hormones and neurotransmitters, which are made and stored in cells.5 Ion Channels The electrical charge on ions such as sodium and potassium makes it difficult for these ions to cross the lipid layer of the cell membrane. However, rapid movement of these ions is needed for many cell functions, such as nerve activity. This is accomplished by diffusion through selective ion channels.7 Channels are proteins that span the cell membrane with a watery (aqueous) center so that ions and other hydrophilic substances can remain in contact with the aqueous solution that fills the channel. Channels that

remain open are called leak channels. Other channels are gated channels, and specific stimuli cause the channels to undergo shape changes from one form to another. Gated channels can be closed and stimulated to open, or they can be open and stimulated to close (Fig. 2-14).7

Gated ion channels that open in response to a specific stimulus. (A) Voltage-gated channels are controlled by a change in membrane potential. (B) Ligand-gated channels are controlled by binding of a ligand to a receptor. (C) Mechanically gated channels, which are controlled by mechanical stimuli such as stretching, often have links that connect to the cytoskeleton. FIGURE 2-14

Three main types of gated channels are present in cell membranes: Voltage-gated channels, which open or close with changes in the membrane potential

Ligand-gated channels or chemically gated channels, which open or close when chemicals bind to the channels; these channels are also receptors, and the chemicals that bind to receptors are called ligands (e.g., the neurotransmitter acetylcholine) Mechanically gated, which open or close in response to such mechanical stimulations such as vibrations, tissue stretching, temperature, or pressure (see Fig. 2-14)7 The gates are what open or close ion channels. Once channels are open, specific ions may move through them. In the case of gated channels in cell membranes, the key can be voltage changes, ligand binding, or mechanical stimulations. The ultimate result of the opening of these gates is the movement of ions. Membrane Potentials As mentioned earlier, the concentrations of ions are often different on the two sides of the cell membrane, and this leads to differences in charge on the two sides of a cell membrane. These differences create electrical potentials across the cell membranes of most cells in the body, and these are called membrane potentials.5 In nerve or muscle cells, changes in the membrane potential are needed for nerve impulses and muscle contraction. In other types of cells, such as glandular cells, changes in the membrane potential stimulate hormone secretion and other functions (e.g., the secretion of insulin from beta cells in the pancreas). UNDERSTANDING

Membrane Potentials

Electrochemical potentials are present across the membranes of virtually all cells in the body. Some cells, such as nerve and muscle cells, are capable of generating rapidly changing electrical impulses, and these impulses are used to transmit signals along their membranes. In other cells, such as glandular cells, membrane potentials are used to signal the release of hormones or activate other functions of the cell. Generation of membrane potentials relies on (1) diffusion of current-carrying ions, (2)

development of an electrochemical equilibrium, (3) establishment of an RMP, and (4) triggering of action potentials.

1 Diffusion Potentials

A diffusion potential is a potential difference generated across a membrane when a current-carrying ion, such as the potassium (K+) ion,

diffuses down its concentration gradient. Two conditions are necessary for this to occur: (1) the membrane must be selectively permeable to a particular ion and (2) the concentration of the diffusible ion must be greater on one side of the membrane than on the other. The magnitude of the diffusion potential, measured in mV, depends on the size of the concentration gradient. The sign (+ or −) or polarity of the potential depends on the diffusing ion. It is negative on the inside when a positively charged ion such as K+ diffuses from the inside to the outside of the membrane, carrying its charge with it.

2 Equilibrium Potentials

An equilibrium potential is the membrane potential that exactly balances and opposes the net diffusion of an ion down its concentration gradient. As a cation diffuses down its concentration gradient, it carries its positive charge across the membrane, thereby generating an electrical force that will eventually retard and stop its diffusion. An electrochemical equilibrium is one in which the chemical forces driving diffusion and the repelling electrical forces are exactly balanced so that no further diffusion occurs. The equilibrium potential (EMF,

electromotive force) can be calculated by inserting the inside and outside ion concentrations into the Nernst equation. The Nernst Equation for Calculating an Equilibrium Potential The following equation, known as the Nernst equation, can be used to calculate the equilibrium potential (EMF in mV of a univalent ion at body temperature of 37°C).

For example, if the concentration of an ion inside the membrane is 100 mmol/L and the concentration outside the membrane is 10 mmol/L, the EMF (mV) for that ion would be −61 × log10 (100/10 [log10 of 10 is 1]). Therefore, it would take 61 mV of charge inside the membrane to balance the diffusion potential created by the concentration difference across the membrane for the ion. The EMF for potassium ions using a normal estimated intracellular concentration of 140 mmol/L and a normal extracellular concentration of 4 mmol/L is −94 mV:

This value assumes the membrane is permeable only to potassium. This value approximates the −70 to −90 mV RMP for nerve fibers measured in laboratory studies. When a membrane is permeable to several different ions, the diffusion potential reflects the sum of the equilibrium potentials for each of the ions.

3 Resting Membrane Potential

The RMP, which is necessary for electrical excitability, is present when the cell is not transmitting impulses. Because the resting membrane is permeable to K+, it is essentially a K+ equilibrium potential. This can be explained in terms of the large K+ concentration gradient (e.g., 140 mEq/L inside and 4 mEq/L outside), which causes the positively charged K+ to diffuse outward, leaving the nondiffusible, negatively charged intracellular anions (A−) behind. This causes the membrane to become polarized, with negative charges aligned along the inside and positive charges along the outside. The Na+/K+ membrane pump, which removes three Na+ from inside while returning only two K+ to the inside, contributes to the maintenance of the RMP.

4 Action Potentials

Action potentials involve rapid changes in the membrane potential. Each action potential begins with a sudden change from the negative RMP to a positive threshold potential, causing an opening of the membrane channels for Na+ (or other ions of the action potential). Opening of the Na+ channels allows large amounts of the positively charged Na+ ions to diffuse to the interior of the cell, causing the membrane potential to undergo depolarization or a rapid change to positive on the inside and negative on the outside. This is quickly followed by closing of Na+ channels and opening of the K+ channels, which leads to a rapid efflux of K+ from the cell and reestablishment of the RMP. Electrical potentials are measured in volts (V) or millivolts (mV; see later). Electrical potentials describe the ability of separated electrical charges of opposite polarity (+ and −) to do work. The potential difference

is the difference between the separated charges. The terms potential difference and voltage are synonymous.5 Voltage is always measured by comparing two points in a system. For example, the voltage in a car battery (6 or 12 V) is the potential difference between the two battery terminals. Because the total amount of charge that can be separated by a cell membrane is small, the potential differences in cells are small and are measured in mV, or 1/1000th of a volt (Fig. 2-15).

Membrane potential changes and ion currents. (Reprinted from Preston R. R., Wilson T. (2013). Lippincott’s illustrated reviews: FIGURE 2-15

Physiology (Fig. 2.8, p. 20). Philadelphia, PA: Wolters Kluwer, with permission.) Potential differences across the cell membrane can be measured by inserting a very fine electrode into the cell and another into the extracellular fluid surrounding the cell and connecting the two electrodes to a voltmeter. If cells are not stimulated and are at rest, this difference is called the resting membrane potential (RMP). The cell is said to be polarized at rest because the two sides of the membrane have different voltages. In most resting cells, sodium, calcium, and chloride ions are higher outside the cell, and potassium is higher inside the cell. If sodium or calcium channels are stimulated to open in resting cells, then these positively charged ions will diffuse down their concentration gradients from the outside of the cell, where they have a higher concentration, to the inside of the cell, where they have a lower concentration. This brings positive charge into the cell, causing the cell to be less negative (or more positive). Now, the difference between the inside and outside of the cell is less, so it is less polarized. This is called depolarization. If chloride channels are stimulated to open in resting cells, then negatively charged chloride ions will also diffuse from the outside of the cell to the inside of the cell. However, this brings negative charge into the cell, causing the cell to be more negative (or less positive). Now, the difference between the inside and outside of the cell is more, so it is more polarized. This is called hyperpolarization. If potassium channels are stimulated to open in resting cells, then positively charged potassium ions will diffuse down their concentration gradients from the inside of the cell, where they have a higher concentration, to the outside of the cell, where they have a lower concentration. This removes positive charge from the inside of the cell, causing the cell to be more negative (or less positive). Now the difference between the inside and outside of the cell is more, so it is more polarized. This is called hyperpolarization (note that like chloride diffusion, the inside of the cell is more negative, but chloride adds negative charge to the inside of the cell, and potassium diffusion removes positive charge from the inside of a cell). If cells are first depolarized (e.g., by sodium or calcium diffusing into cells) and then potassium diffuses out of cells, removing the positive

charge of potassium from the inside of the cell would be called repolarization. To summarize, at rest, specific ions have higher concentrations on one side of the membrane, resulting in differences in charge and chemical gradients on either side of the membrane. This establishes the RMP, where the two sides of the membrane are polarized. Ion channels can then be stimulated to open or close, changing where the ions (and their charges) move. If the inside of the cell becomes less negative, cells are considered depolarized. If the inside of the cell becomes more negative, cells are considered hyperpolarized (or repolarized if it was first depolarized). Graded Potentials In neurons, dendrites receive signals that change which ion channels are open. If sodium or calcium channels are opened, then the dendrites and cell body are depolarized, because this would result in positive charge traveling into the cell. This is called a graded potential because it is graded to the strength of the signal (stronger signals result in greater depolarization). If there is enough signal and depolarization, then an action potential is stimulated in the axon so that this signal can be passed to the next cell. Action Potential In neurons, if a graded potential is strong enough, then an action potential is generated in the axon of the neuron. The ion movement in graded potentials causes changes in voltage, and this stimulates voltage-gated sodium channels to open in the axon. Sodium ions rush into the cell, causing it to be less negative resulting in depolarization. This stimulates nearby voltagegated potassium channels to open, and potassium ions cause a positive charge resulting in repolarization. This sequence continues until the signal reaches the axon terminal. Some neurons in the central nervous system (CNS) have gap junctions with target neurons, and ions diffuse into the target neuron to stimulate the neuron. At the axon terminal, the depolarization from the action potential causes calcium channels to open. Calcium diffuses in to stimulate a chain of reactions that stimulate exocytosis of neurotransmitter.

SUMMARY CONCEPTS Movement of materials across the cell’s membrane is needed for survival of the cell. Diffusion is a process by which substances such as ions move down a concentration gradient, from an area of greater concentration to an area of lower concentration. Osmosis is the diffusion of only water molecules through a membrane down the concentration gradient for water, from where water is more concentrated (where there are fewer solutes) to where water is less concentrated (where there are more solutes). Protein-assisted diffusion allows small, hydrophilic (water-loving) substances such as ions or glucose to cross the cell’s membrane with the assistance of a transport protein that spans the membrane (a channel or a carrier protein). Another type of transport, called active transport, requires the cell to input energy to move substances against a concentration gradient, from an area of lower concentration to an area of higher concentration. Two types of active transport exist, primary and secondary, both of which require carrier proteins. The Na+/K+– ATPase pump is the best-known active transporter. Endocytosis is a process by which cells engulf materials from the surrounding medium. Small particles are ingested by a process called pinocytosis and larger particles by phagocytosis. Some particles require bonding with a ligand, and this process is called receptor-mediated endocytosis. Exocytosis involves the removal of large particles from the cell and is essentially the reverse of endocytosis. Ion channels are integral transmembrane proteins that span the width of the cell membrane and are either open (leakage channels) or gated to open or close (ligand-, voltage-, and mechanically gated channels). Electrochemical potentials exist across the membranes of many cells in the body because there are higher concentrations of specific ions on either side of the cell membrane. For example, in most cells, sodium, calcium, and chloride ions are higher outside the cell, and potassium ions are higher inside the cell. When most cells are at rest, there is more negative charge inside the cell than the outside, and the cell is said to be polarized. This is RMP, established by the difference

in electrical charge and chemical gradients. When cells are stimulated, ion channels can open or close, changing the ability for specific ions to diffuse. Ion diffusion that causes the inside of the cell to become more positive causes depolarization. Ion diffusion that causes the inside of the cell to become more negative causes hyperpolarization or repolarization if the cell was first depolarized.

Body Tissues Although all cells share certain characteristics, their structures and functions are specialized depending on where they are found in the body. For example, muscle, skin, and nervous cells are structurally distinct from one another and perform vastly different functions. Groups of cells that work together are called tissues. Four categories of tissue exist: 1. Epithelial tissue 2. Connective (supportive) tissue 3. Muscle tissue 4. Nervous tissue These tissues do not exist in isolated units but combine with other tissues to form the organs of the body. This section provides a brief overview of the cells in each of these four tissue types, the structures that hold these cells together, and the extracellular matrix in which they live. Cell Differentiation After conception, the fertilized egg undergoes a series of cell divisions, leading to approximately 200 different cell types. The formation of different types of cells and the placement of these cells into tissue types is called cell differentiation, a process controlled by a system that switches genes on (to increase transcription) and off (to decrease transcription). Embryonic cells must differentiate (become different) to develop into all of the various cell types and organ systems. Cells must then remain different after the signal that initiated cell differentiation is gone. The process of cell differentiation is controlled by cell memory, which is

maintained by proteins in the individual cells of a particular cell type. This means that after differentiation has occurred, the tissue type does not change back to an earlier stage of differentiation. Although most cells differentiate into specialized cell types, many tissues contain a few partially differentiated stem cells.1 These stem cells, which are still capable of cell division, serve as a reserve source for specialized cells throughout the life of the organism and make regeneration possible in some tissues. KEY POINTS Organization of Cells into Tissues Cells are organized into larger functional units called tissues. Tissues associate with other tissues to form the various organs of the body. Embryonic Origin of Tissue Types All of the approximately 200 different types of body cells can be classified into four basic or primary tissue types: (1) epithelial, (2) connective, (3) muscle, and (4) nervous (Table 2-1). These basic tissue types are often described by their embryonic origin. The embryo is essentially a threelayered tubular structure (Fig. 2-16):

Cross section of human embryo illustrating the development of the somatic and visceral structures. FIGURE 2-16

TABLE 2-1 Classification of Tissue Types

Tissue Type Epithelial Tissue

Location

Tissue Type Epithelial Tissue Covering and lining of body surfaces Simple epithelium Squamous Cuboidal Columnar Stratified epithelium Squamous keratinized Squamous nonkeratinized Cuboidal Columnar Transitional Pseudostratified Glandular Endocrine Exocrine Neuroepithelium Reproductive epithelium Connective Tissue

Location Lining of blood vessels, body cavities, alveoli of the lungs Collecting tubules of the kidney; covering of the ovaries Lining of the intestine and gallbladder Skin Mucous membranes of the mouth, esophagus, and vagina Ducts of the sweat glands Large ducts of the salivary and mammary glands; also found in the conjunctiva Bladder, ureters, renal pelvis Tracheal and respiratory passages Pituitary gland, thyroid gland, adrenal and other glands Sweat glands and glands in the gastrointestinal tract Olfactory mucosa, retina, tongue Seminiferous tubules of the testis; cortical portion of the ovary

Tissue Type Epithelial Tissue Embryonic connective tissue Mesenchymal Mucous Adult connective tissue Loose or areolar Dense regular Dense irregular Adipose Reticular Specialized connective tissue Bone Cartilage Hematopoietic Muscle Tissue Skeletal Cardiac Smooth

Location

Embryonic mesoderm Umbilical cord (Wharton jelly)Subcutaneous areas Tendons and ligaments Dermis of the skin Fat pads, subcutaneous layers Framework of lymphoid organs, bone marrow, liver Long bones, flat bones Tracheal rings, external ear, articular surfaces Blood cells, myeloid tissue (bone marrow)

Skeletal muscles Heart muscles Gastrointestinal tract, blood vessels, bronchi, bladder, and others

Nervous Tissue Central and peripheral neurons and nerve fibers Glial and ependymal cells in the CNS; Schwann and satellite cells in the PNS CNS, central nervous system; PNS, peripheral nervous system. Neurons Supporting cells

1. The outer layer of the tube is called the ectoderm. 2. The middle layer of the tube is called the mesoderm. 3. The inner layer of the tube is called the endoderm. All of the adult body tissues develop from these three cellular layers. Epithelial tissues develop from all three embryonic layers, connective tissue and muscle tissue develop mainly from the mesoderm, and nervous tissue develops from the ectoderm.

Epithelial Tissue Epithelial tissue covers the body’s outer surface and lines the internal closed cavities (including blood vessels) and body tubes that connect with the exterior of the body (gastrointestinal, respiratory, and genitourinary tracts). Epithelial tissue also forms the secretory portion of glands and their ducts. Epithelial tissue develops from all three embryonic layers.5 Most epithelia of the skin, mouth, nose, and anus develop from the outer ectoderm. 1. The endothelial lining of blood vessels develops from the middle mesoderm. 2. Linings of the respiratory tract, gastrointestinal tract, and glands of the digestive system develop from the inner endoderm. 3. Many types of epithelial tissue retain the ability to differentiate and undergo rapid proliferation for replacing injured cells. The cells that make up epithelial tissue have three general characteristics: They have three distinct surfaces: (1) a free surface or apical surface, (2) a lateral surface (on the sides of cells), and (3) a basal surface (at the base of the tissue). The basal surface of epithelial cells is attached to a basement membrane (below the epithelial cells, like a basement is below a house). Cells in epithelial tissues are close to neighboring cells and are joined to neighboring cells by cell-to-cell adhesion molecules (Fig. 2-17).5

Typical arrangement of epithelial cells in relation to underlying tissues and blood supply. Epithelial tissue has no blood supply of its own but relies on the blood vessels in the underlying connective tissue for nutrition (N) and elimination of wastes (W). FIGURE 2-17

Epithelial tissue is avascular (a, without; vascular, refers to blood vessels). Therefore, epithelial tissues receive oxygen and nutrients from the capillaries of the connective tissue on which the epithelial tissue rests (see Fig. 2-17). To survive, epithelial tissue must be kept moist. Even the skin epithelium, which seems dry, is kept moist by a waterproof layer of skin cells called keratinocytes, which make keratin; keratin prevents evaporation of moisture from deeper skin cells. Basement Membrane Underneath all types of epithelial tissue is an extracellular matrix, called the basement membrane. A basement membrane consists of (1) the basal lamina and (2) an underlying reticular layer. The terms basal lamina and basement membrane are often used interchangeably.6 Cell Junctions and Cell-to-Cell Adhesions

Cells of epithelial tissue are tightly joined together by specialized junctions. These specialized junctions enable the cells to form barriers to prevent the movement of water, solutes, and cells from one body compartment to the next. Three basic types of intercellular junctions are observed in epithelial tissues (Fig. 2-18):

Three types of intercellular junctions found in epithelial tissue: the continuous tight junction (zonula occludens); the adhering junction, which includes the adhesion belt (zonula adherens), desmosomes (macula adherens), and hemidesmosomes; and the gap junction. FIGURE 2-18

1. Continuous tight or occluding junctions (i.e., zonula occludens), which are found only in epithelial tissue, bind neighboring cells

together. This type of intercellular junction prevents materials such as macromolecules in the intestines from passing between cells and entering the bloodstream or body cavities.5 2. Adhering junctions are sites of strong adhesion between neighboring cells. The main role of adhering junctions is to prevent cells separating from each other. Adhering junctions are found in epithelial tissue and between cardiac muscle cells. 3. Gap junctions are sites of strong adhesion between neighboring cells with channels that link the cytoplasm of the two neighboring cells (like a tunnel between cells). Gap junctions are found in epithelial tissue and in many other types of cell-to-cell communication. For example, gap junctions allow ions to move between cells as part of electrical signals (e.g., in smooth muscle or cardiac muscle).5,7 Types of Epithelial Tissues Epithelial tissues are classified according to the: 1. Shape of the cells: squamous (thin and flat), cuboidal (cube shaped), and columnar (resembling a column) 2. Number of layers that are present: simple, stratified, and pseudostratified (Fig. 2-19)6

FIGURE 2-19

The various epithelial tissue types.

Simple Epithelium Simple epithelium contains a single layer of cells, all of which rest on the basement membrane. Simple squamous epithelium is adapted for filtration. In filtration, some substances are able to pass, whereas others cannot. Simple epithelium lines the blood vessels, lymph nodes, and alveoli of the lungs. A single layer of squamous (thin and flat) epithelium lines the heart and blood vessels and is called the endothelium. A similar type of layer forms the serous membranes that line the pleural, pericardial, and peritoneal cavities and cover the organs of these cavities. This type of layer is called the mesothelium. Simple cuboidal epithelium is found on the surface of the ovary and in the thyroid. Simple columnar epithelium lines the intestine. One specialized form of a simple columnar epithelium has hair-like projections called cilia, often with mucus-secreting cells called goblet cells. This form of simple columnar epithelium lines the airways of the respiratory tract.5 Stratified and Pseudostratified Epithelia Stratified epithelium contains more than one layer of cells, with only the deepest layer resting on the basement membrane. It is designed to protect body surfaces. Stratified squamous keratinized epithelium makes up the epidermis of the skin. Keratin is a tough, fibrous (like a fiber) protein in the outer cells of skin. A stratified squamous keratinized epithelium is made up of many layers. The layers closest to the basement membrane and underlying tissues are cuboidal or columnar. Cells become more irregular and thinner as they move closer to the surface of the skin. Surface cells become filled with keratin and die, are sloughed off, and then are replaced by deeper cells.

A stratified squamous nonkeratinized epithelium is found on moist surfaces such as the mouth and tongue. Stratified cuboidal and columnar epithelia are found in the ducts of salivary glands and the larger ducts of the mammary glands.5 In smokers, the normal columnar ciliated epithelial cells of the trachea and bronchi are often replaced with stratified squamous epithelium cells that are better able to withstand the irritating effects of cigarette smoke. Pseudostratified epithelium is a type of epithelium in which all of the cells are in contact with the underlying intercellular matrix, but some do not extend to the surface. A pseudostratified ciliated columnar epithelium with goblet cells forms the lining of most of the upper respiratory tract. Transitional epithelium is a stratified epithelium characterized by cells that can change shape and become thinner when the tissue is stretched. Such tissue can be stretched without pulling the superficial cells apart. Transitional epithelium is well adapted for the lining of organs that are constantly changing their volume, such as the urinary bladder. Glandular Epithelium Glandular epithelial tissue is formed by cells specialized to produce a fluid secretion.5 This process usually occurs with the intracellular synthesis of macromolecules. The macromolecules are usually stored in the cells in small, membrane-bound vesicles called secretory granules. For example, glandular epithelial cells can make, store, and secrete proteins (e.g., insulin), lipids (e.g., adrenocortical hormones, secretions of the sebaceous glands), and complexes of carbohydrates and proteins (e.g., saliva). Exocrine glands use ducts to secrete substances outside of the body or into body cavities, such as the sweat glands and lactating mammary glands. Endocrine glands are ductless and secrete hormones directly into the bloodstream. Connective or Supportive Tissue Connective or supportive tissue is the most common tissue in the body. As its name suggests, it connects and binds or supports the various tissues.5 Connective tissue is unique in that its cells produce the extracellular matrix that supports and holds tissues together. The capsules that surround organs of the body are composed of connective tissue. Adult connective tissue can be divided into two types (1): connective tissue proper, which includes

loose (areolar), adipose, reticular, and dense connective tissue; and (2) specialized connective tissue that functions to support the soft tissues of the body and store fat (cartilage, bone, and blood cells). Muscle Tissue Muscle tissue, whose main function is contraction, is responsible for movement of the body and its parts and for changes in the size and shape of internal organs. Muscle tissue contains two types of fibers that are responsible for contraction: thin and thick filaments. The thin filaments are made of actin, and the thick filaments are made of myosin. These two types of myofilaments make up most of the cytoplasm, which in muscle cells is called the sarcoplasm.7 There are three types of muscle tissues: skeletal, cardiac, and smooth. Skeletal and cardiac muscles are striated muscles, in which the actin and myosin filaments are arranged in large, parallel sarcomeres, giving the muscle fibers a striped or striated appearance when seen with a microscope. Smooth muscle does not have striations and is found in the iris of the eye, the walls of blood vessels, surrounding hollow organs (e.g., the stomach and urinary bladder), and hollow tubes (e.g., the ureters and common bile duct).7 Neither skeletal nor cardiac muscle can divide to replace injured cells. Smooth muscle, however, can divide. Some increases in smooth muscle are normal, as occurs in the uterus during pregnancy. Other increases are pathologic, such as the increase in smooth muscle that occurs in the arteries of people with chronic hypertension. Skeletal Muscle Skeletal muscle is the most abundant tissue in the body, making up 40% to 45% of the total body weight.7 Most skeletal muscles are attached to bones, and skeletal muscle contractions are responsible for movements of the skeleton. Each skeletal muscle is a separate organ made up of hundreds or thousands of muscle fibers (skeletal muscle cells are also called muscle fibers). Although muscle fibers are the main cell type, connective tissue, blood vessels, and nerve fibers are also present. The structures of skeletal muscle fibers/cells often start with the prefix sarco-. For example, the cytoplasm is called the sarcoplasm and is

contained within the sarcolemma (the cell membrane). Skeletal muscle cells have many nuclei. Throughout the sarcoplasm are the contractile proteins actin and myosin, which are arranged in parallel bundles called myofibrils (Fig. 2-20A). These contain actin thin filaments and myosin thick filaments. Each myofibril consists of regularly repeating units along the length of the myofibril, called sarcomeres (see Fig. 2-20B).7 Sarcomeres are the structural and functional units of cardiac and skeletal muscle. Sarcomeres appear as striations (stripes) under the microscope.

Connective tissue components of a skeletal muscle (A). Striations of the myofibril showing the overlap of contractile proteins and the A and I bands, the H zone, and the Z and M lines (B). The relaxed and contracted states of the myofibril showing the position of actin filaments (blue) between the myosin filaments (pink) in the relaxed muscle (top) and pulling of the Z membranes toward each FIGURE 2-20

other (bottom) as the muscle contracts (C). The sarcoplasmic reticulum with T tubules (D). The sarcoplasmic reticulum, which is comparable to the smooth ER (see Fig. 2-20C and D), stores calcium that is released during muscle contraction. Concentration levels of calcium ions in the sarcoplasmic reticulum are 10,000 times higher than in the sarcoplasm. The transverse or T tubules are extensions of the cell membrane and run perpendicular to the muscle fiber. The hollow portion or lumen of the transverse tubule is continuous with the extracellular fluid compartment. Action potentials are rapidly conducted over the surface of the muscle fiber and into the T tubules to the sarcoplasmic reticulum. The sarcoplasmic reticulum then releases calcium, starting muscle contraction. The membrane of the sarcoplasmic reticulum also has an active transport mechanism for pumping calcium back into the sarcoplasmic reticulum to stop muscle contraction. Skeletal Muscle Contraction Myosin makes up thick filaments. Myosin has (1) a thin tail, which provides the structural backbone for the filament, and (2) a globular (globelike) head. Each myosin head has a binding site for actin and a separate active site that catalyzes the breakdown of ATP to provide the energy to move the myosin head so it can pull on the actin filament during muscle contraction. Actin makes up the thin filaments. Actin is a globular (globe-like) protein that lines up in two rows that coil around each other to form a long helical strand. Two regulatory proteins associate with actin: (1) tropomyosin and (2) troponin (see Fig. 2-21A).

Molecular structure of the thin actin filament (A) and the thicker myosin filament (B) of striated muscle. The thin filament is a double-stranded helix of actin molecules with tropomyosin and troponin molecules lying along the grooves of the actin strands. (C) Sequence of events involved in sliding of adjacent actin and myosin filaments: (1) Cocking of the myosin head occurs as adenosine triphosphate (ATP) is split to adenosine diphosphate (ADP), (2) cross-bridge attachment, (3) power stroke during which the myosin head bends as it moves the actin forward, and (4) cross-bridge detachment occurs as a new ATP attaches to the myosin head. FIGURE 2-21

In the noncontracted state, tropomyosin blocks the myosin-binding sites on the actin filaments. During an action potential, calcium ions released from the sarcoplasmic reticulum into the sarcoplasm can bind to troponin (Fig. 2-21B). Binding of calcium to troponin moves the tropomyosin so that the myosin can bind to actin.5 When activated by ATP, the myosin–actin cross-bridges swivel, like the oars of a boat, as they become attached to the actin filament. During contraction, myosin binds and releases actin over and over again, moving down an actin filament. This pulls the thin and thick filaments past each other to shorten the sarcomeres, which shortens muscle fibers, which in turn shortens muscles (see Fig. 2-21C). When stimulation of muscles stops, the concentration of calcium in the sarcoplasm decreases as calcium is actively transported into the

sarcoplasmic reticulum by a membrane pump that uses energy from ATP. Cardiac Muscle Cardiac muscle is the main part of the heart. Like skeletal muscle cells, the actin and myosin filaments and associated proteins are arranged into sarcomeres, and these appear striated (striped) under a microscope. Also visible under the microscope are intercalated disks. Intercalated disks are where cardiac muscle cells join, and these contain gap junctions that allow ions to pass between cardiac muscle cells for coordinated contraction of the heart. Cardiac muscle cells are also called cardiac muscle fibers or cardiomyocytes. There are two types of cardiac muscle cells: 1. Autorhythmic cells or pacemaker cells make up about 1% of cardiac muscle cells and are found in the sinoatrial and atrioventricular nodes. These cells automatically go through action potentials without stimulation by the nervous system. 2. Cardiac contractile cells make up the rest of the cardiac muscle cells and are responsible for the contraction of the heart. Smooth Muscle Smooth muscle is often called involuntary muscle because its activity is spontaneous or is stimulated by the autonomic nervous system (the sympathetic or parasympathetic nervous systems). Smooth muscle contractions are slower and longer than skeletal or cardiac muscle contractions. Smooth muscle cells do not contain sarcomeres and therefore do not appear striated under a microscope. The bundles of filaments are not parallel to each other but instead crisscross through the cell. In smooth muscles, actin filaments are attached to structures called dense bodies (Fig. 2-22).5,10

Structure of smooth muscle showing the dense bodies. In smooth muscle, the force of contraction is transmitted to the cell membrane by bundles of intermediate fibers. FIGURE 2-22

The lack of regular overlapping of contractile filaments provides a greater range of tension development in smooth muscle. This is important in hollow organs that undergo changes in volume, with resulting changes in the length of the smooth muscle fibers in their walls. Even with the distention of a hollow organ, the smooth muscle fiber retains some ability to

develop tension, whereas such distention would stretch skeletal muscle beyond the area where the thick and thin filaments overlap. As with cardiac and skeletal muscles, smooth muscle contraction is started by an increase in intracellular calcium. Smooth muscle cells rely on extracellular calcium entering cells and the release of calcium from the sarcoplasmic reticulum for muscle contraction.5 Smooth muscle also lacks troponin, the calcium-binding regulatory protein found in skeletal and cardiac muscles. Instead, it relies on another calcium-binding protein called calmodulin. The calcium–calmodulin complex binds to and activates the myosin-containing thick filaments, which interact with actin. Types of Smooth Muscle Smooth muscle may be divided into two broad categories according to how it is activated. Multiunit smooth muscle is stimulated by a single nerve and depends on the autonomic nervous system for activation. An example is the smooth muscle in the iris. Single-unit smooth muscle can contract without outside stimulation. An example is the smooth muscle found in the uterus. Nervous Tissue Nervous tissue is distributed throughout the body as a communication system. Anatomically, the nervous system is divided into (1) the CNS, which consists of the brain and spinal cord, and (2) the peripheral nervous system (PNS), which consists of nervous tissue outside the CNS. Nerve cells are highly differentiated and most are not capable of regeneration in postnatal life. Structurally, nervous tissue consists of two cell types: (1) nerve cells, called neurons, and (2) glial or supporting cells. Most neurons consist of three parts: 1. The soma, or cell body, which contains the nucleus and most organelles 2. Dendrites, which are multiple elongated extensions that receive and carry stimuli from the environment, from sensory epithelial cells, and from other neurons to the cell 3. The axons, which are specialized for generating and conducting action potentials away from the cell body to other nerve cells, muscle cells, and glandular cells

Peripheral neurons can be classified as afferent and efferent neurons according to their function: 1. Afferent or sensory neurons carry information toward the CNS; they are involved in the reception of sensory information from the external environment and from within the body. 2. Efferent or motor neurons carry information away from the CNS; they are needed for control of muscle fibers and endocrine and exocrine glands. Communication between neurons and other cells, such as other neurons or muscle cells, occurs at specialized structures called synapses. A chemical synapse contains (1) the axon terminal of one neuron, (2) the area of the cell membrane that contains receptors on the target cell, and (3) the space between these two cells. At the chemical synapse, neurotransmitters bind to receptors on target cells such as another neuron or muscle cell. In addition, electrical synapses exist where neurons are linked through gap junctions that allow ions to pass from one cell to another. Neuroglia (glia means “glue”) or glial cells are the cells that support neurons. Examples of glial cells found in the CNS include the following: 1. Astrocytes, the most common glial cells, have many long extensions that surround blood vessels in the CNS. They provide structural support for neurons, and their extensions form a sealed barrier that protects the CNS. 2. Oligodendrocytes wrap around axons of CNS neurons to form myelin, which insulates neurons and speeds up action potentials. 3. Microglia are phagocytic cells. 4. Ependymal cells line the cavities of the brain and spinal cord and are in contact with the cerebrospinal fluid. Examples of glial cells in the PNS include the following: 1. Schwann cells (like oligodendrocytes in the CNS) wrap around axons of PNS neurons to form myelin, which insulates neurons and speeds up action potentials. 2. Satellite cells enclose and protect the dorsal root ganglia and autonomic ganglion cells.

Extracellular Matrix The discussion so far has focused on the cells in the different tissue types. Within tissues, cells are held together by cell junctions; the space between cells is filled with an extracellular matrix; and adhesion molecules form intercellular contacts. Tissues are not made up only of cells. A large part of tissue volume is made up of an extracellular matrix. This matrix is made up of a variety of proteins and polysaccharides (poly, many; saccharide, sugar; a polysaccharide is a molecule made up of many sugars).6 These proteins and polysaccharides are secreted by cells into the tissues and are organized into a supporting mesh in close association with the cells that made them. The amount and makeup of the matrix vary with the different tissues and their functions. For example, in bone, there are more matrices than the cells that surround it; in the brain, there are more cells, and the matrix is only a minor part.5 Two main classes of extracellular macromolecules make up the extracellular matrix: 1. Polysaccharide chains of a class called glycosaminoglycans, which are usually found linked to protein as proteoglycans (protein + sugar) 2. Fibrous (fiber-like) proteins (collagen, elastin, fibronectin, and laminin) that are found in the basement membrane Collagen is the most common protein in the body. It is a tough, nonliving, white fiber that gives form to skin, ligaments, tendons, and many other structures. Elastin acts like a rubber band; after being stretched, it returns to its original form. There are many elastin fibers in structures that are stretched frequently, such as the aorta and some ligaments.5 SUMMARY CONCEPTS Body cells are organized into four basic tissue types: epithelial, connective, muscle, and nervous. Epithelial tissue covers and lines the body surfaces and forms the functional components of glandular structures. Epithelial tissue is classified into three types (squamous, cuboidal, and columnar)

according to the shape of the cells and the number of layers that are present. The cells in epithelial tissue are held together by three types of intercellular junctions: tight, adhering, and gap junctions. Connective tissue supports and connects body structures; it forms the bones and skeletal system, joint structures, blood cells, and intercellular substances. Connective tissue can be divided into four types: loose or areolar, which fills body spaces and is characterized by plenty of ground substance; adipose, which stores fat; reticular, which forms the architectural framework in many structures of the body; and dense—regular and irregular—which forms structures such as tendons and ligaments (and the dermis of the skin). Muscle tissue is a specialized tissue that can contract. There are three types of muscle tissue: skeletal, cardiac, and smooth. Skeletal and cardiac muscle cells have actin, myosin, and other proteins arranged into sarcomeres, which appear as striations (stripes) under the microscope. Cardiac muscle cells are connected by gap junctions, which allow ions to pass between cells for coordinated contraction. Smooth muscles have actin and myosin in a different arrangement and so are not striated (and appear smooth). Actin and myosin filaments interact to shorten muscles, a process activated by the presence of calcium. In skeletal muscle, calcium is released from the sarcoplasmic reticulum in response to an action potential. Smooth and cardiac muscles are often called involuntary muscle because they contract spontaneously or through activity of the autonomic nervous system. The sarcoplasmic reticulum is less defined and depends on the entry of extracellular calcium ions for muscle contraction. Nervous tissue consists of two cell types: nerve cells, called neurons, and glial cells, which are the supporting cells. Nervous tissue is found throughout the body and is part of the body’s communication system. The nervous system is divided anatomically into the CNS, which consists of the brain and spinal cord, and the PNS, which is composed of nerve tissue outside the CNS. The extracellular matrix is made up of a variety of proteins and polysaccharides. The amount and makeup of matrix vary with the different tissues and their function.

Review Exercises 1. Tattoos consist of pigments that have been injected into the skin. A. Explain what happens to the dye once it has been injected and why it does not eventually wash away. 2. People who drink sufficient amounts of alcohol show rapid changes in CNS function, including both motor and behavioral changes, and the odor of alcohol can be detected on their breath. A. Use the concepts related to the lipid bilayer structure of the cell membrane to explain these observations. 3. The absorption of glucose from the intestine involves a cotransport mechanism in which the active primary transport of sodium ions is used to provide for the secondary transport of glucose. A. Hypothesize how this information might be used to design an oral rehydration solution for someone who is suffering from diarrhea. REFERENCES 1. Hall J. E. (2016). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Saunders. 2. Luo K., Cao S. S. (2015). Endoplasmic reticulum stress in intestinal epithelial cell function and inflammatory bowel disease. Gastroenterology Research and Practice 2015, 6. 3. Hasnain S. Z., Prins J. B., McGuckin M. A. (2016). Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes. Journal of Molecular Endocrinology 56, R33–R54. 4. Manole E., Bastian A. E., Butoianu N., et al. (2017). Myositis non-inflammatory mechanisms: An updated review. Journal of Immunoassay and Immunochemistry 38(2), 115–126. 5. Boron W. F., Boulpaep E. L. (2017). Medical physiology (3rd ed.). Philadelphia, PA: Saunders. 6. Ross M. H., Pawlina W. (2015). Histology: A text and atlas with correlated cell and molecular biology (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 7. Strayer D. S., Rubin E. (2014). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 8. Horani A., Brody S. L., Feerkol T. W. (2014). Picking up speed: Advances in the genetics of primary cilia dyskinesia. Pediatric Research 75(1–2), 158–164.

9. Spillane J., Kullmann D. M., Hanna M. G. (2016). Genetic neurological channelopathies: Molecular genetics and clinical phenotypes. Journal of Neurology, Neurosurgery, and Psychiatry 87(1), 37–48. 10. Goldsmith T. S. (2014). The evolution of aging. Crownsville, MD: Azinet Press.

CHAPTER 3 Cellular Adaptation, Injury, and Death Cellular Adaptation Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Intracellular Accumulations Pathologic Calcifications Dystrophic Calcification Metastatic Calcification Cell Injury and Death Causes of Cell Injury Injury from Physical Agents Radiation Injury Chemical Injury Injury from Biologic Agents Injury from Nutritional Imbalances Mechanisms of Cell Injury

Free Radical Injury Hypoxic Cell Injury Impaired Calcium Homeostasis Reversible Cell Injury and Cell Death Reversible Cell Injury Programmed Cell Death Necrosis Cellular Aging Learning Objectives After completing this section of the chapter, the learner will be able to meet the following objectives: 1. Describe cell changes that occur with atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia and state general conditions under which the changes occur. 2. Compare the pathogenesis and effects of intracellular accumulations and pathologic calcifications. 3. Describe the mechanisms whereby physical agents such as blunt trauma, electrical forces, and extremes of temperature produce cell injury. 4. Differentiate between the effects of ionizing and nonionizing radiation in terms of their ability to cause cell injury. 5. State the mechanisms and manifestations of cell injury associated with lead poisoning. 6. Relate free radical formation and oxidative stress to cell injury and death.

Cellular adaptation is a protective mechanism to prevent cellular and tissue harm because of stressors. When confronted with stresses that endanger its normal structure and function, the cell undergoes adaptive changes that permit survival and maintenance of function, or homeostasis. It is only when the stress is overwhelming or adaptation is ineffective that cell injury and death occur. This chapter focuses on cellular adaptation, injury, and death.

Cellular Adaptation Cells adapt to changes in the internal environment, just as the total organism adapts to changes in the external environment. Cells may adapt by undergoing changes in size, number, and type. These changes, occurring singly or in combination, may lead to the following cellular responses: Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Adaptive cellular responses also include intracellular accumulations and storage of products in abnormal amounts.1 There are numerous mechanisms that enable cellular adaptation, including factors produced by other cells or by the cells themselves. These mechanisms depend largely on signals transmitted by chemical messengers that exert their effects by altering gene function. In general, genes are either operating genes, which are needed for normal cell function, or genes that determine specialized function (differentiation) of a particular cell type. It is common in adaptive cellular responses for the operating gene to be unaffected although the specialized function (differentiation) genes are altered. Once the stimulus for adaptation is removed, the cell resumes its previous state of specialized function. Whether adaptive cellular changes are normal or abnormal depends on whether the response was initiated by an appropriate stimulus. Normal adaptive responses occur in response to need and an appropriate stimulus. After the need has been removed, the adaptive response ceases. KEY POINTS Cellular Adaptations Cells are able to adapt to increased work demands or threats to survival by changing their size (atrophy and hypertrophy), number

(hyperplasia), and form (metaplasia). Normal cellular adaptation occurs in response to an appropriate stimulus and ceases once the need for adaptation has ceased. Atrophy When confronted with a decrease in work demands or adverse environmental conditions, most cells are able to revert to a smaller size and a lower and more efficient level of functioning that is compatible with survival. This decrease in cell size is called atrophy and is illustrated in Figure 3-1 regarding atrophy of the endometrium. Cells that are atrophied reduce their oxygen consumption and other cellular functions by decreasing the number and size of their organelles and other structures. There are fewer mitochondria, myofilaments, and endoplasmic reticulum structures. When a sufficient number of cells are involved, the entire tissue or muscle atrophies.

Adaptive cell and tissue responses involving a change in cell size (hypertrophy and atrophy), number (hyperplasia), cell type (metaplasia), or size, shape, and organization (dysplasia). (From Anatomical Chart Company. Atlas of pathophysiology (p. 4). Springhouse, PA: Springhouse; 2002.) FIGURE 3-1

Cell size, particularly in muscle tissue, is related to workload. As the workload of a cell declines, oxygen consumption and protein synthesis decrease. Furthermore, proper muscle mass is maintained by sufficient levels of insulin and insulin-like growth factor-1 (IGF-1).2 IGF-1 and insulin are critical factors of muscle mass because of their ability to stimulate growth and limit protein degradation. When insulin and IGF-1 levels are low or processes are stimulated to break down large molecules

into smaller ones, catabolic signals are present and muscle atrophy occurs. Programmed cell death (apoptosis) may occur. Atrophy because of a decrease in cell size is due to the breakdown of the cytoskeleton via the ubiquitin (protein)–proteasome (protein complex) to signal protein breakdown.3,4 A decrease in size by number of cells is primarily by apoptosis. The general causes of atrophy can be grouped into five categories: 1. Disuse 2. Denervation 3. Loss of endocrine stimulation 4. Inadequate nutrition 5. Ischemia or decreased blood flow Disuse atrophy occurs when there is a reduction in skeletal muscle use. An extreme example of disuse atrophy is seen in the muscles of extremities that have been encased in plaster casts. Because atrophy is adaptive and reversible, muscle size is restored after the cast is removed and muscle use is resumed. Denervation atrophy is a form of disuse atrophy that occurs in the muscles of paralyzed limbs.3,5 Lack of endocrine stimulation also produces a form of disuse atrophy. In women, the loss of estrogen stimulation during menopause results in atrophic changes in the reproductive organs. With malnutrition and decreased blood flow, cells decrease their size and energy requirements as a means of survival. Hypertrophy Hypertrophy represents an increase in cell size and often tissue mass. It results from an increased workload imposed on an organ or body part and is commonly seen in cardiac and skeletal muscle tissue, which cannot adapt to an increase in workload through mitotic division and formation of more cells.1 Hypertrophy involves an increase in the functional components of the cell that allows it to achieve equilibrium between demand and functional capacity. For example, as muscle cells hypertrophy, additional actin and myosin filaments, cell enzymes, and adenosine triphosphate (ATP) are synthesized.1,5 Hypertrophy may occur as a result of normal physiologic or abnormal pathologic conditions. The increase in muscle mass associated with exercise

is an example of physiologic hypertrophy. Pathologic hypertrophy occurs as a result of disease conditions and may be adaptive or compensatory. The most common cause of hypertrophy of the chamber of the heart is left ventricular hypertrophy because of hypertension (Fig. 3-2). Compensatory hypertrophy is the enlargement of a remaining organ or tissue after a portion has been surgically removed or becomes inactive. For instance, if one kidney is removed, the remaining kidney enlarges to compensate for the loss (Fig. 3-3).

Atrophy of cells in endometrium. (A) A section of the normal uterus from a woman of reproductive age reveals a thick endometrium composed of proliferative glands in an abundant stroma. (B) The endometrium of a 75-year-old woman (shown at the same magnification) is thin and contains only a few atrophic and cystic glands. (Both slides are taken at the same magnification.) (From Rubin R., Strayer D. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 1–19, p. 17). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 3-2

Myocardial hypertrophy. Cross section of the heart of a patient with long-standing hypertension shows pronounced, concentric left ventricular hypertrophy. (From Rubin R., Strayer D. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 16). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 3-3

The initiating signals for hypertrophy appear to be related to ATP depletion, mechanical forces such as stretching of the muscle fibers, activation of cell degradation products, and hormonal factors.5 An example of hormonal changes in the hypertrophied heart is increased glycolysis. With an accelerated glycolytic rate, the increased source of energy improves the potential for adaptations in the hypertrophied heart.6 In the case of the heart, initiating signals can be divided into two broad categories6: 1. Biomechanical stress 2. Neurohumoral factors Signaling events regulate cardiac elasticity. Research shows intracellular signaling cascades promote protein synthesis and protein stability in which both can increase cardiomyocyte size. The exact mechanisms of how biomechanical signals are transduced across the cell membrane are unclear. The literature suggests the mechanisms involve stretch-sensitive ion channels, cell-to-cell adhesion, and other structural proteins. The complex

network links the extracellular matrix, cytoskeleton, sarcomere, Ca2+ handling proteins, and the nucleus.6 A limit is eventually reached beyond which further enlargement of the tissue mass can no longer compensate for the increased work demands. The limiting factors for continued hypertrophy might be related to limitations in blood flow. In hypertension, for example, the increased workload required to pump blood against an elevated arterial pressure in the aorta results in a progressive increase in left ventricular muscle mass and need for coronary blood flow. There continues to be interest in the signaling pathways that control the arrangement of contractile elements in myocardial hypertrophy. Research suggests that certain signal molecules can alter gene expression controlling the size and assembly of the contractile proteins in hypertrophied myocardial cells. For example, the hypertrophied myocardial cells of welltrained athletes have proportional increases in width and length. This is in contrast to the hypertrophy that develops with disease in which there is a nonproportional increase in width and length. For instance, in dilated cardiomyopathy, the hypertrophied cells have a relatively greater increase in length than width. In pressure overload, as occurs with hypertension, the hypertrophied cells have greater width than length.6 It is anticipated that further study of the signal pathways that determine the adaptive and nonadaptive features of cardiac hypertrophy will lead to new targets for treatment. Hyperplasia Hyperplasia refers to an increase in the number of cells in an organ or tissue. It occurs in tissues with cells that are capable of mitotic division, such as the epidermis, intestinal epithelium, and glandular tissue.1 Certain cells, such as neurons, rarely divide, limiting hyperplastic growth. Hyperplasia involves activation of genes controlling cell proliferation and the presence of intracellular messengers that control cell replication and growth. As with other normal adaptive cellular responses, hyperplasia is a controlled process that occurs in response to an appropriate stimulus and ceases after the stimulus has been removed. The stimuli that cause hyperplasia may be physiologic or nonphysiologic. The two common types of physiologic hyperplasia are hormonal and compensatory. Breast and uterine enlargements during pregnancy are

examples of a physiologic hyperplasia that results from estrogen stimulation. The regeneration of the liver that occurs after partial removal of the liver is an example of compensatory hyperplasia. Hyperplasia is also an important response of connective tissue in wound healing, during which proliferating fibroblasts and blood vessels contribute to wound repair. Although hypertrophy and hyperplasia are two distinct processes, they may occur together and are often triggered by the same mechanism.1 For example, the pregnant uterus undergoes both hypertrophy and hyperplasia as a result of estrogen stimulation. Most forms of nonphysiologic hyperplasia are due to excessive hormonal stimulation or the effects of growth factors on target tissues.2 For example, excessive estrogen production can cause endometrial hyperplasia and abnormal menstrual bleeding, increasing the risk of developing endometrial cancer.7 Skin warts are another example of hyperplasia caused by growth factors produced by certain viruses, such as the papillomaviruses. Metaplasia Metaplasia represents a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. Metaplasia is thought to involve the reprogramming of undifferentiated stem cells that are present in the tissue undergoing metaplastic changes.1 Metaplasia usually occurs in response to chronic irritation and inflammation and allows for substitution of cells that are better able to survive under circumstances in which a more fragile cell type might perish. However, the conversion of cell types remains with the primary tissue category (e.g., one type of epithelial cell may be converted to another type of epithelial cell, but not to a connective tissue cell). An example of metaplasia is the adaptive substitution of stratified squamous epithelial cells for the ciliated columnar epithelial cells in the trachea and large airways of a habitual cigarette smoker. The cervix also undergoes metaplasia because of hormonal changes in puberty or chronic irritation. Metaplasia is most often fully reversible when the irritant is removed.1 Dysplasia Dysplasia is characterized by deranged cell growth of a specific tissue that results in cells that vary in size, shape, and organization. Minor degrees of dysplasia are associated with chronic irritation or inflammation. The pattern

is most frequently encountered in areas of metaplastic squamous epithelium of the respiratory tract and uterine cervix. Although dysplasia is abnormal, it is adaptive in that it is potentially reversible after the irritating cause has been removed. Dysplasia is strongly implicated as a precursor of cancer.1 In cancers of the respiratory tract and the uterine cervix, dysplastic changes have been found adjacent to the foci of cancerous transformation. Through the use of the Papanicolaou (Pap) smear, it has been documented that cancer of the uterine cervix develops in a series of incremental epithelial changes ranging from severe dysplasia to invasive cancer.7 However, dysplasia is an adaptive process and as such does not necessarily lead to cancer. Intracellular Accumulations Intracellular accumulations represent the buildup of substances that cells cannot immediately use or eliminate. These substances may accumulate in the cytoplasm (frequently in the lysosomes) or in the nucleus. In some cases, the accumulation may be an abnormal substance that the cell has produced, and in other cases, the cell may be storing exogenous materials or products of pathologic processes occurring elsewhere in the body. An example would be the accumulation of beta-amyloid fragments, which progress to a skeletal muscle disorder called myositis.8 These substances may accumulate transiently or permanently, and they may be harmless or, in some cases, toxic. These substances can be grouped into three categories: 1. Normal body substances, such as lipids, proteins, carbohydrates, melanin, and bilirubin, that are present in abnormally large amounts 2. Abnormal endogenous products, such as those resulting from inborn errors of metabolism 3. Exogenous products, such as environmental agents and pigments, that cannot be broken down by the cell1 The accumulation of normal cellular constituents occurs when a substance is produced at a rate that exceeds its metabolism or removal. An example of this type of process is fatty changes in the liver because of intracellular accumulation of triglycerides. Liver cells normally contain some fat, which is either oxidized and used for energy or converted to triglycerides. This fat is derived from free fatty acids released from adipose

tissue. Abnormal accumulation occurs when the delivery of free fatty acids to the liver is increased, as in starvation and diabetes mellitus, or when the intrahepatic metabolism of lipids is disturbed, as in alcoholism. Intracellular accumulation can result from genetic disorders that disrupt the metabolism of selected substances. A normal enzyme may be replaced with an abnormal one, resulting in the formation of a substance that cannot be used or eliminated from the cell, or an enzyme may be missing, so that an intermediate product accumulates in the cell. For example, there are at least 10 genetic disorders that affect glycogen metabolism, most of which lead to the accumulation of intracellular glycogen stores. In the most common form of this disorder, von Gierke disease, large amounts of glycogen accumulate in the liver and kidneys because of a deficiency of the enzyme glucose-6-phosphatase. Without this enzyme, glycogen cannot be broken down to form glucose. The disorder leads not only to an accumulation of glycogen but also to a reduction in blood glucose levels. In Tay-Sachs disease, another genetic disorder, abnormal lipids accumulate in the brain and other tissues, causing motor and mental deterioration beginning at approximately 6 months of age, followed by death at 2 to 5 years of age. In a similar manner, other enzyme defects lead to the accumulation of other substances. Pigments are colored substances that may accumulate in cells. They can be endogenous (i.e., arising from within the body) or exogenous (i.e., arising from outside the body). Icterus, also called jaundice, is characterized by a yellow discoloration of tissue because of the retention of bilirubin, an endogenous bile pigment. This condition may result from increased bilirubin production from red blood cell destruction, obstruction of bile passage into the intestine, or toxic diseases that affect the liver’s ability to remove bilirubin from the blood. Lipofuscin is a yellow-brown pigment that results from the accumulation of the indigestible residues produced during normal turnover of cell structures (Fig. 3-4). The accumulation of lipofuscin increases with age, and it is sometimes referred to as the wear-and-tear pigment. It is more common in heart, nerve, and liver cells than other tissues and is seen more often in conditions associated with atrophy of an organ.

Accumulation of intracellular lipofuscin. A photomicrograph of the liver of an 80-year-old man shows golden cytoplasmic granules, which represent lysosomal storage of lipofuscin. (From Rubin R., Strayer D. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 11). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 3-4

One of the most common exogenous pigments is carbon in the form of coal dust. In coal miners or people exposed to heavily polluted environments, the accumulation of carbon dust blackens the lung tissue and may cause serious lung disease. The formation of a blue line along the margins of the gum is one of the diagnostic features of lead poisoning. Tattoos are the result of insoluble pigments introduced into the skin, where they are engulfed by macrophages and persist for a lifetime. The significance of intracellular accumulations depends on the cause and severity of the condition. Many accumulations, such as lipofuscin and mild fatty change, have no effect on cell function. Some conditions, such as the hyperbilirubinemia that causes jaundice, are reversible. Other disorders, such as glycogen storage diseases, produce accumulations that result in organ dysfunction and other alterations in physiologic function. Pathologic Calcifications

Pathologic calcification involves the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals. It is known as dystrophic calcification when it occurs in dead or dying tissue and as metastatic calcification when it occurs in normal tissue. Dystrophic Calcification Dystrophic calcification represents the macroscopic deposition of calcium salts in injured tissue.9 It is often visible to the naked eye as deposits that range from gritty, sand-like grains to firm, hard rock material. The pathogenesis of dystrophic calcification involves the intracellular or extracellular formation of crystalline calcium phosphate. The components of the calcium deposits are derived from the bodies of dead or dying cells as well as from the circulation and interstitial fluid. Dystrophic calcification is commonly seen in atheromatous lesions of advanced atherosclerosis, areas of injury in the aorta and large blood vessels, and damaged heart valves.9 Dystrophic calcifications are seen in human tissues in the absence of known calcium or phosphate imbalances— for example, in necrotic tissues or atherosclerotic plaques—and, when found, are used for the long-term management of chronic venous insufficiency.10 Metastatic Calcification In contrast to dystrophic calcification, which occurs in injured tissues, metastatic calcification occurs in normal tissues as a result of increased serum calcium levels (hypercalcemia). Almost any condition that increases the serum calcium level can lead to calcification in inappropriate sites such as the lung, renal tubules, and blood vessels.9 The major causes of hypercalcemia are hyperparathyroidism, either primary or secondary to phosphate retention in renal failure; increased mobilization of calcium from bone as in Paget disease, cancer with metastatic bone lesions, or immobilization; and vitamin D intoxication.10 SUMMARY CONCEPTS

Cells adapt to changes in their environment and in their work demands by changing their size, number, and characteristics. These adaptive changes are consistent with the needs of the cell and occur in response to an appropriate stimulus. The changes are usually reversed after the stimulus has been withdrawn.1 When confronted with a decrease in work demands or adverse environmental conditions, cells atrophy or reduce their size and revert to a lower and more efficient level of functioning. Hypertrophy results from an increase in work demands and is characterized by an increase in tissue size brought about by an increase in cell size and functional intracellular components. An increase in the number of cells in an organ or tissue that is still capable of mitotic division is called hyperplasia.9,11 Metaplasia occurs in response to chronic irritation and represents the substitution of cells of a type that is better able to survive under circumstances in which a more fragile cell type might succumb. Dysplasia is characterized by deranged cell growth of a specific tissue that results in cells that vary in size, shape, and appearance. It is often a precursor of cancer. Under some circumstances, cells may accumulate abnormal amounts of various substances. If the accumulation reflects a correctable systemic disorder, such as the hyperbilirubinemia that causes jaundice, the accumulation is reversible.10 If the disorder cannot be corrected, as often occurs in many inborn errors of metabolism, the cells become overloaded, causing cell injury and death. Pathologic calcification involves the abnormal tissue deposition of calcium salts. Dystrophic calcification occurs in dead or dying tissue. Although the presence of dystrophic calcification may only indicate the presence of previous cell injury, it is also a frequent cause of organ dysfunction (e.g., when it affects the heart valves). Metastatic calcification occurs in normal tissues as a result of elevated serum calcium levels. Almost any condition that increases the serum calcium level can lead to calcification in inappropriate sites such as the lung, renal tubules, and blood vessels.

Cell Injury and Death Cells can be injured in many ways. The extent to which any injurious agent can cause cell injury and death depends in large measure on the intensity and duration of the injury and the type of cell that is involved. Cell injury is usually reversible up to a certain point, after which irreversible cell injury and death occur. Whether a specific stress causes irreversible or reversible cell injury depends on the severity of the insult and on variables such as blood supply, nutritional status, and regenerative capacity. Cell injury and death are ongoing processes, and in the healthy state, they are balanced by cell renewal. KEY POINTS Cell Injury Cells can be damaged in a number of ways, including physical trauma, extremes of temperature, electrical injury, exposure to damaging chemicals, radiation damage, injury from biologic agents, and nutritional factors. Most injurious agents exert their damaging effects through uncontrolled free radical production, impaired oxygen delivery or utilization, or the destructive effects of uncontrolled intracellular calcium release. Causes of Cell Injury Cell damage can occur in many ways. For purposes of discussion, the ways by which cells are injured have been grouped into five categories: 1. Injury from physical agents 2. Radiation injury 3. Chemical injury 4. Injury from biologic agents 5. Injury from nutritional imbalances

Injury from Physical Agents Physical agents responsible for cell and tissue injury include mechanical forces, extremes of temperature, and electrical forces. They are common causes of injuries because of environmental exposure, occupational and transportation accidents, and physical violence and assault. Mechanical Forces Injury or trauma because of mechanical forces occurs as a result of body impact with another object. The body or the mass can be in motion or, as sometimes happens, both can be in motion at the time of impact. These types of injuries split and tear tissue, fracture bones, injure blood vessels, and disrupt blood flow. Extremes of Temperature Extremes of heat and cold cause damage to the cell, its organelles, and its enzyme systems. Exposure to low-intensity heat (43°C to 46°C), such as occurs with partial-thickness burns and severe heat stroke, causes cell injury by causing vascular injury, accelerating cell metabolism, inactivating temperature-sensitive enzymes, and disrupting the cell membrane. With more intense heat, coagulation of blood vessels and tissue proteins occurs. Exposure to cold increases blood viscosity and induces vasoconstriction by direct action on blood vessels and through reflex activity of the sympathetic nervous system. The resultant decrease in blood flow may lead to hypoxic tissue injury, depending on the degree and duration of cold exposure. Injury from freezing probably results from a combination of ice crystal formation and vasoconstriction. The decreased blood flow leads to capillary stasis and arteriolar and capillary thrombosis. Edema results from increased capillary permeability. Electrical Injuries Electrical injuries can affect the body through extensive tissue injury and disruption of neural and cardiac impulses. Voltage, type of current, amperage, pathway of the current, resistance of the tissue, and interval of exposure determine the effect of electricity on the body.12 Alternating current is usually more dangerous than direct current because it causes violent muscle contractions, preventing the person from releasing the electrical source and sometimes resulting in fractures and dislocations.

In electrical injuries, the body acts as a conductor of the electrical current.12 The current enters the body from an electrical source, such as an exposed wire, and passes through the body and exits to another conductor, such as the moisture on the ground or a piece of metal the person is holding. The pathway that a current takes is critical because the electrical energy disrupts impulses in excitable tissues. Current flow through the brain may interrupt impulses from respiratory centers in the brainstem, and current flow through the chest may cause fatal cardiac arrhythmias. The resistance to the flow of current in electrical circuits transforms electrical energy into heat. This is why the elements in electrical heating devices are made of highly resistive metals. Much of the tissue damage produced by electrical injuries is caused by heat production in tissues that have the highest electrical resistance. Resistance to electrical current varies from the greatest to the least in bone, fat, tendons, skin, muscles, blood, and nerves. The most severe tissue injury usually occurs at the skin sites where the current enters and leaves the body (Fig. 3-5). After electricity has penetrated the skin, it passes rapidly through the body along the lines of least resistance—through body fluids and nerves. Degeneration of vessel walls may occur, and thrombi may form as current flows along the blood vessels. This can cause extensive muscle and deep tissue injury. Thick, dry skin is more resistant to the flow of electricity than thin, wet skin. It is generally believed that the greater the skin resistance, the greater is the amount of local skin burn, and the less the resistance, the greater are the deep and systemic effects.

Electrical burn of the skin. The person was electrocuted after attempting to stop a fall from a ladder by grasping a highvoltage electrical line. (From Strayer D. S., Rubin E. (2015). Cell injury. In Rubin R., Strayer D. S. (Eds.), Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 8–21, p. 352). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 3-5

Radiation Injury Electromagnetic radiation comprises a wide spectrum of wave-propagated energy, ranging from ionizing gamma rays to radiofrequency waves (Fig. 36). A photon is a particle of radiation energy. Radiation energy above the ultraviolet (UV) range is called ionizing radiation because the photons have enough energy to knock electrons off atoms and molecules. Nonionizing radiation refers to radiation energy at frequencies below those of visible light. UV radiation represents the portion of the spectrum of electromagnetic radiation just above the visible range.12 It contains increasingly energetic rays that are powerful enough to disrupt intracellular bonds and cause sunburn.

FIGURE 3-6

Spectrum of electromagnetic radiation.

Ionizing Radiation Ionizing radiation impacts cells by causing ionization of molecules and atoms in the cell. This is accomplished by releasing free radicals that destroy cells and by directly hitting the target molecules in the cell.13 It can immediately kill cells, interrupt cell replication, or cause a variety of genetic mutations, which may or may not be lethal. Most radiation injury is caused by localized irradiation that is used in the treatment of cancer. Except for unusual circumstances such as the use of high-dose irradiation that precedes bone marrow transplantation, exposure to whole-body irradiation is rare. The injurious effects of ionizing radiation vary with the dose, dose rate (a single dose can cause greater injury than divided or fractionated doses), and the differential sensitivity of the exposed tissue to radiation injury. Because of the effect on deoxyribonucleic acid (DNA) synthesis and interference with mitosis, rapidly dividing cells of the bone marrow and intestine are much more vulnerable to radiation injury than tissues such as bone and skeletal muscle. Over time, occupational and accidental exposure to ionizing radiation can result in increased risk for the development of various types of cancers, including skin cancers, leukemia, osteogenic sarcomas, and lung cancer. This is especially true when the person is exposed to radiation during childhood.13 Many of the clinical manifestations of radiation injury result from acute cell injury, dose-dependent changes in the blood vessels that supply the irradiated tissues, and fibrotic tissue replacement. The cell’s initial response to radiation injury involves swelling, disruption of the mitochondria and other organelles, alterations in the cell membrane, and marked changes in the nucleus. The endothelial cells in blood vessels are particularly sensitive

to irradiation. During the immediate postirradiation period, only vessel dilation is apparent (e.g., the initial erythema of the skin after radiation therapy). Later or with higher levels of radiation, destructive changes occur in small blood vessels such as the capillaries and venules. Acute reversible necrosis is represented by such disorders as radiation cystitis, dermatitis, and diarrhea from enteritis. More persistent damage can be attributed to acute necrosis of tissue cells that are not capable of regeneration and chronic ischemia. Chronic effects of radiation damage are characterized by fibrosis and scarring of tissues and organs in the irradiated area (e.g., interstitial fibrosis of the heart and lungs after irradiation of the chest). Because the radiation delivered in radiation therapy inevitably travels through the skin, radiation dermatitis is common. There may be necrosis of the skin, impaired wound healing, and chronic radiation dermatitis. Ultraviolet Radiation UV radiation causes sunburn and increases the risk of skin cancers. The degree of risk depends on the type of UV rays, the intensity of exposure, and the amount of protective melanin pigment in the skin. Skin damage produced by UV radiation is thought to be caused by reactive oxygen species (ROS) and by damage to melanin-producing processes in the skin.14 UV radiation also damages DNA, resulting in the formation of pyrimidine dimers (i.e., the insertion of two identical pyrimidine bases into replicating DNA instead of one). Other forms of DNA damage include the production of single-stranded breaks and formation of DNA–protein cross-links. Normally, errors that occur during DNA replication are repaired by enzymes that remove the faulty section of DNA and repair the damage. The importance of DNA repair in protecting against UV radiation injury is evidenced by the vulnerability of people who lack the enzymes needed to repair UV-induced DNA damage. In a genetic disorder called xeroderma pigmentosum, an enzyme needed to repair sunlight-induced DNA damage is lacking. This autosomal recessive disorder is characterized by extreme photosensitivity and an increased risk of skin cancer in sun-exposed skin.14 Nonionizing Radiation Nonionizing radiation includes infrared light, ultrasound, microwaves, and laser energy. Unlike ionizing radiation, which can directly break chemical bonds, nonionizing radiation exerts its effects by causing vibration and

rotation of atoms and molecules.12 All of this vibrational and rotational energy is eventually converted to thermal energy. Low-frequency nonionizing radiation is used widely in radar, television, industrial operations (e.g., heating, welding, melting of metals, processing of wood and plastic), household appliances (e.g., microwave ovens), and medical applications (e.g., diathermy). Isolated cases of skin burns and thermal injury to deeper tissues have occurred in industrial settings and from improperly used household microwave ovens. Injury from these sources is mainly thermal and, because of the deep penetration of the infrared or microwave rays, tends to involve dermal and subcutaneous tissue injury. Chemical Injury Chemicals capable of damaging cells are everywhere around us. Air and water pollution contains chemicals capable of tissue injury, as does tobacco smoke and some processed or preserved foods. Some of the most damaging chemicals exist in our environment, including gases such as carbon monoxide, insecticides, and trace metals such as lead. Chemical agents can injure the cell membrane and other cell structures, block enzymatic pathways, coagulate cell proteins, and disrupt the osmotic and ionic balance of the cell. Corrosive substances such as strong acids and bases destroy cells as the substances come into contact with the body. Other chemicals may injure cells in the process of metabolism or elimination. Carbon tetrachloride (CCl4), for example, causes little damage until it is metabolized by liver enzymes to a highly reactive free radical (CCl3•). Carbon tetrachloride is extremely toxic to liver cells.13 Drugs Many drugs—alcohol, prescription drugs, over-the-counter drugs, and street drugs—are capable of directly or indirectly damaging tissues. Ethyl alcohol can harm the gastric mucosa, liver, developing fetus, and other organs. Antineoplastic and immunosuppressant drugs can directly injure cells. Other drugs produce metabolic end products that are toxic to cells. Acetaminophen, a commonly used over-the-counter analgesic drug, is detoxified in the liver, where small amounts of the drug are converted to a highly toxic metabolite. This metabolite is detoxified by a metabolic pathway that uses a substance (i.e., glutathione) normally present in the

liver. When large amounts of the drug are ingested, this pathway becomes overwhelmed and toxic metabolites accumulate, causing massive liver necrosis. Lead Toxicity Lead is a particularly toxic metal. Small amounts accumulate to reach toxic levels. There are numerous sources of lead in the environment, including flaking paint, lead-contaminated dust and soil, lead-contaminated root vegetables, lead water pipes or soldered joints, pottery glazes, newsprint, and toys made in foreign countries. Adults often encounter lead through occupational exposure. Children are exposed to lead through ingestion of peeling lead paint, by breathing dust from lead paint, or from playing in contaminated soil. There has been a decline in blood lead levels of both adults and children since the removal of lead from gasoline and from soldered food cans.15 High lead blood levels continue to be a problem, however, particularly among children. Research has found that low levels of lead in the blood can have devastating cognitive and intellectual deficits, as well as neurobehavioral problems in children. This finding led to the 2012 Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) reference for blood lead to decrease from 10 to 5 μg/dL.15 Lead is absorbed through the gastrointestinal tract or the lungs into the blood. A deficiency in calcium, iron, or zinc increases lead absorption. In children, most lead is absorbed through the lungs. Although children may have the same or a lower intake of lead, the absorption in infants and children is greater; thus, they are more vulnerable to lead toxicity.15,16 Lead crosses the placenta, exposing the fetus to levels of lead that are comparable with those of the mother. Lead is stored in the bone and eliminated by the kidneys. Although the half-life of lead is hours to days, bone deposits serve as a repository from which blood levels are maintained. In a sense, bone protects other tissues, but the slow turnover maintains blood levels for months to years. The toxicity of lead is related to its multiple biochemical effects. It has the ability to inactivate enzymes, compete with calcium for incorporation into bone, and interfere with nerve transmission and brain development. The major targets of lead toxicity are the red blood cells, the gastrointestinal tract, the kidneys, and the nervous system.

Anemia is a cardinal sign of lead toxicity. Lead competes with the enzymes required for hemoglobin synthesis and with the membraneassociated enzymes that prevent hemolysis of red blood cells. The resulting red cells are coarsely stippled and hypochromic, resembling those seen in iron-deficiency anemia. The life span of the red cell is also decreased. The gastrointestinal tract is the main source of symptoms in the adult. This is characterized by “lead colic,” a severe and poorly localized form of acute abdominal pain. A lead line formed by precipitated lead sulfite may appear along the gingival margins. The lead line is seldom seen in children. The kidneys are the major route for excretion of lead. Lead can cause diffuse kidney damage, eventually leading to renal failure. Even without overt signs of kidney damage, lead toxicity leads to hypertension. In the nervous system, lead toxicity is characterized by demyelination of cerebral and cerebellar white matter and death of cortical cells. When this occurs in early childhood, it can affect neurobehavioral development and result in lower IQ levels and poorer classroom performance.16 Peripheral demyelinating neuropathy may occur in adults. The most serious manifestation of lead poisoning is acute encephalopathy. It is manifested by persistent vomiting, ataxia, seizures, papilledema, impaired consciousness, and coma. Acute encephalopathy may manifest suddenly, or it may be preceded by other signs of lead toxicity such as behavioral changes or abdominal complaints. Because of the long-term neurobehavioral and cognitive deficits that occur in children with even moderately elevated lead levels, the Centers for Disease Control and Prevention has issued recommendations for childhood lead screening.15,16 A safe blood level of lead is still uncertain. At one time, 25 μg/dL was considered safe. Surveys have shown abnormally low IQs in children with lead levels as low as 10 to 15 μg/dL. Screening for lead toxicity involves the use of capillary blood obtained from a finger stick to measure free erythrocyte protoporphyrin (EP). Elevated levels of EP result from the inhibition by lead of the enzymes required for heme synthesis in red blood cells. The EP test is useful in detecting high lead levels but usually does not detect levels below 20 to 25 μg/dL, requiring confirmation from a venous blood sample. Treatment involves removal of the lead source and, in cases of severe toxicity, administration of a chelating agent. Asymptomatic children with blood

levels of 45 to 69 μg/dL usually are treated.16,17 A public health team should evaluate the source of lead because meticulous removal is needed. Mercury Toxicity Mercury has been used for industrial and medical purposes for hundreds of years. Mercury is toxic, and the hazards of mercury-associated occupational and accidental exposures are well known. Currently, mercury and lead are the most toxic metals. Mercury is toxic in four primary forms: mercury vapor, inorganic divalent mercury, methyl mercury, and ethyl mercury.16 Depending on the form of mercury exposure, toxicity involving the central nervous system and kidney can occur.16 In the case of dental fillings, the concern involves mercury vapor being released into the mouth. However, the amount of mercury vapor released from fillings is very small. The main source of methyl mercury exposure is from consumption of long-lived fish, such as tuna and swordfish. Fish concentrate mercury from sediments in the water. Only certain types of fish pose potential risk, however, and types such as salmon have miniscule amounts or no mercury. Because the developing brain is more susceptible to mercury-induced damage, it is recommended that young children and pregnant and nursing women avoid consumption of fish known to contain high mercury content. Thimerosal is an ethyl mercury–containing preservative that helps prevent microorganism growth in vaccines. Because of the concern of this preservative, it is hardly ever used in the United States. Injury from Biologic Agents Biologic agents differ from other injurious agents in that they are able to replicate and can continue to produce their injurious effects. These agents range from submicroscopic viruses to the larger parasites. Biologic agents injure cells by diverse mechanisms. Viruses enter the cell and become incorporated into its DNA synthetic machinery. Certain bacteria elaborate exotoxins that interfere with cellular production of ATP. Other bacteria, such as the gram-negative bacilli, release endotoxins that cause cell injury and increased capillary permeability. Injury from Nutritional Imbalances

Nutritional excesses and nutritional deficiencies predispose cells to injury. Obesity and diets high in saturated fats are thought to predispose people to atherosclerosis. The body requires more than 60 organic and inorganic substances in amounts ranging from micrograms to grams. These nutrients include minerals, vitamins, certain fatty acids, and specific amino acids. Dietary deficiencies can occur in the form of starvation, in which there is a deficiency of all nutrients and vitamins, or because of a selective deficiency of a single nutrient or vitamin. Iron-deficiency anemia, scurvy, beriberi, and pellagra are examples of injury caused by the lack of specific vitamins or minerals. The protein and calorie deficiencies that occur with starvation cause widespread tissue damage. Mechanisms of Cell Injury The mechanisms by which injurious agents cause cell injury and death are complex. Some agents, such as heat, produce direct cell injury. Other factors, such as genetic derangements, produce their effects indirectly through metabolic disturbances and altered immune responses.12 There seem to be at least three major mechanisms whereby most injurious agents exert their effects: Free radical formation Hypoxia and ATP depletion Disruption of intracellular calcium homeostasis (Fig. 3-7)

Mechanisms of cell injury. The injurious agents tend to cause hypoxia/ischemia (see middle arrow, which illustrates the manifestations that trigger anaerobic metabolism to develop and cellular injury). Also, on the left aspect of the figure, the free radical formation causes oxidation of cell structures leading to decreased adenosine triphosphate (ATP), and on the right side, the increased intracellular calcium damages many aspects of the cell that also FIGURE 3-7

causes ATP depletion. These three paths illustrate how injurious agents cause cell injury and death. DNA, deoxyribonucleic acid.

Free Radical Injury Many injurious agents exert damaging effects through reactive chemical species known as free radicals.18 Free radicals are highly reactive chemical species with an unpaired electron in the outer orbit (valence shell) of the molecule.12 The unpaired electron causes free radicals to be unstable and highly reactive, so that they react nonspecifically with molecules in the area. Moreover, free radicals can establish chain reactions consisting of many events that generate new free radicals. In cells and tissues, free radicals react with proteins, lipids, and carbohydrates, thereby damaging cell membranes; inactivate enzymes; and damage nucleic acids that make up DNA. The actions of free radicals may disrupt and damage cells and tissues. ROS are oxygen-containing molecules that include free radicals such as superoxide O2– and hydroxyl radical (OH•) and nonradicals such as hydrogen peroxide (H2O2).12 These molecules are produced endogenously by normal metabolic processes or cell activities, such as the metabolic burst that accompanies phagocytosis. However, exogenous causes, including ionizing and UV radiation, can cause ROS production in the body. Oxidative stress is a condition that occurs when the generation of ROS exceeds the ability of the body to neutralize and eliminate ROS.12 Oxidative stress can lead to oxidation of cell components, activation of signal transduction pathways, and changes in gene and protein expression. DNA modification and damage can occur as a result of oxidative stress. Although ROS and oxidative stress are clearly associated with cell and tissue damage, evidence shows that ROS do not always act in a random and damaging manner. Current studies have found that ROS are also important signaling molecules that are used in healthy cells to regulate and maintain normal activities and functions such as signaling pathways.18 Oxidative damage has been implicated in many diseases. Mutations in the gene for superoxide dismutase are linked with amyotrophic lateral sclerosis (ALS; so-called Lou Gehrig disease).19 Oxidative stress is thought to play an important role in the development of cancer.12 Reestablishment of blood flow after loss of

perfusion, as occurs during heart attack and stroke, is associated with oxidative injury to vital organs.20 The endothelial dysfunction that contributes to the development, progression, and prognosis of cardiovascular disease is thought to be caused in part by oxidative stress.20 In addition to the many diseases and altered health conditions associated with oxidative damage, oxidative stress has been linked with the age-related functional declines that underlie the process of aging.21 Antioxidants are natural and synthetic molecules that inhibit the reactions of ROS with biologic structures or prevent the uncontrolled formation of ROS. Antioxidants include enzymatic and nonenzymatic compounds.12 Catalase can catalyze the reaction that forms water from hydrogen peroxide. Nonenzymatic antioxidants include carotenes (e.g., vitamin A), tocopherols (e.g., vitamin E), ascorbate (vitamin C), glutathione, flavonoids, selenium, and zinc.12 Hypoxic Cell Injury Hypoxia deprives the cell of oxygen and interrupts oxidative metabolism and the generation of ATP. The actual time necessary to produce irreversible cell damage depends on the degree of oxygen deprivation and the metabolic needs of the cell. Some cells, such as those in the heart, brain, and kidney, require large amounts of oxygen to provide energy to perform their functions. Brain cells, for example, begin to undergo permanent damage after 4 to 6 minutes of oxygen deprivation. A thin margin can exist between the time involved in reversible and irreversible cell damage. During hypoxic conditions, hypoxia-inducible factors cause the expression of genes that stimulate red blood cell formation, produce ATP in the absence of oxygen, and increase angiogenesis (i.e., the formation of new blood vessels).19,20 Hypoxia can result from an inadequate amount of oxygen in the air, respiratory disease, ischemia (i.e., decreased blood flow because of vasoconstriction or vascular obstruction), anemia, edema, or inability of the cells to use oxygen. Ischemia is characterized by impaired oxygen delivery and impaired removal of metabolic end products such as lactic acid. In contrast to pure hypoxia, which depends on the oxygen content of the blood and affects all cells in the body, ischemia commonly affects blood flow through limited numbers of blood vessels and produces local tissue injury.

In some cases of edema, the distance for diffusion of oxygen may become a limiting factor in the delivery of oxygen.20 In hypermetabolic states, cells may require more oxygen than can be supplied by normal respiratory function and oxygen transport. Hypoxia also serves as the ultimate cause of cell death in other injuries. For example, a physical agent such as cold temperature can cause severe vasoconstriction and impair blood flow. Hypoxia causes a power failure in the cell, with widespread effects on the cell’s structural and functional components. As oxygen tension in the cell falls, oxidative metabolism ceases and the cell reverts to anaerobic metabolism, using its limited glycogen stores in an attempt to maintain vital cell functions. Cellular pH falls as lactic acid accumulates in the cell. This reduction in pH can have adverse effects on intracellular structures and biochemical reactions. Low pH can alter cell membranes and cause chromatin clumping and cell shrinkage. One important effect of reduced ATP is acute cell swelling caused by failure of the energy-dependent sodium/potassium (Na+/K+)–ATPase membrane pump, which extrudes sodium from and returns potassium to the cell. With impaired function of this pump, intracellular potassium levels decrease and sodium and water accumulate in the cell. The movement of water and ions into the cell is associated with multiple changes including widening of the endoplasmic reticulum, membrane permeability, and decreased mitochondrial function.12 In some instances, the cellular changes because of ischemia are reversible if oxygenation is restored. If the oxygen supply is not restored, however, there is a continued loss of enzymes, proteins, and ribonucleic acid through the hyperpermeable cell membrane. Injury to the lysosomal membranes results in the leakage of destructive lysosomal enzymes into the cytoplasm and enzymatic digestion of cell components. Leakage of intracellular enzymes through the permeable cell membrane into the extracellular fluid provides an important clinical indicator of cell injury and death. Impaired Calcium Homeostasis Calcium functions as an important second messenger and cytosolic signal for many cell responses. Various calcium-binding proteins, such as troponin and calmodulin, act as transducers for the cytosolic calcium signal. Calcium-/calmodulin-dependent kinases indirectly mediate the effects of

calcium on responses such as smooth muscle contraction and glycogen breakdown. Normally, intracellular calcium ion levels are kept extremely low compared with extracellular levels. The low intracellular calcium levels are maintained by membrane-associated calcium/magnesium (Ca2+/Mg2+)– ATPase exchange systems. Ischemia and certain toxins lead to an increase in cytosolic calcium because of increased influx across the cell membrane and the release of calcium from intracellular stores. The increased calcium level may inappropriately activate a number of enzymes with potentially damaging effects. These enzymes include the phospholipases, responsible for damaging the cell membrane; proteases that damage the cytoskeleton and membrane proteins; ATPases that break down ATP and hasten its depletion; and endonucleases that fragment chromatin. Although it is known that injured cells accumulate calcium, it is unknown whether this is the ultimate cause of irreversible cell injury. Reversible Cell Injury and Cell Death The mechanisms of cell injury can produce sublethal and reversible cellular damage or lead to irreversible injury with cell destruction or death (Fig. 38). Cell destruction and removal can involve one of two mechanisms:

Outcomes of cell injury: reversible cell injury, apoptosis and programmed cell removal, and cell death and necrosis. FIGURE 3-8

Apoptosis, which is designed to remove injured or worn-out cells Cell death or necrosis, which occurs in irreversibly damaged cells1 Reversible Cell Injury Reversible cell injury, although impairing cell function, does not result in cell death. Two patterns of reversible cell injury can be observed under the microscope: cellular swelling and fatty change. Cellular swelling occurs with impairment of the energy-dependent Na+/K+–ATPase membrane pump, usually as a result of hypoxic cell injury. Fatty changes are linked to intracellular accumulation of fat. When fatty changes occur, small vacuoles of fat disperse throughout the cytoplasm. The process is usually more ominous than cellular swelling, and although it is reversible, it usually indicates severe injury. These fatty changes may occur because normal cells are presented with an increased fat load or because injured cells are unable to metabolize the fat properly. In obese people, fatty infiltrates often occur within and between the cells of the liver and heart because of an increased fat load. Pathways for fat metabolism may be impaired during cell injury, and fat may accumulate in the cell as production exceeds use and export. The liver, where most fats are synthesized and metabolized, is particularly susceptible to fatty change, but fatty changes may also occur in the kidney, the heart, and other organs. Programmed Cell Death In most normal nontumor cells, the number of cells in tissues is regulated by balancing cell proliferation and cell death. Cell death occurs by necrosis or a form of programmed cell death called apoptosis.1 Apoptosis is a highly selective process that eliminates injured and aged cells, thereby controlling tissue regeneration. Cells undergoing apoptosis have characteristic morphologic features as well as biochemical changes. As shown in Figure 3-9, shrinking and condensation of the nucleus and cytoplasm occur. The chromatin aggregates at the nuclear envelope, and DNA fragmentation occurs. Then, the cell becomes fragmented into multiple apoptotic bodies in a manner that maintains the integrity of the

plasma membrane and does not initiate inflammation. Changes in the plasma membrane induce phagocytosis of the apoptotic bodies by macrophages and other cells, thereby completing the degradation process.

Apoptotic cell removal: shrinking of the cell structures (A), condensation and fragmentation of the nuclear chromatin (B and C), separation of nuclear fragments and cytoplasmic organelles into apoptotic bodies (D and E), and engulfment of apoptotic fragments by phagocytic cell (F). FIGURE 3-9

Apoptosis is thought to be responsible for several normal physiologic processes, including the programmed destruction of cells during embryonic development, hormone-dependent involution of tissues, death of immune cells, cell death by cytotoxic T cells, and cell death in proliferating cell populations. During embryogenesis, in the development of a number of organs such as the heart, which begins as a pulsating tube and is gradually modified to become a four-chambered pump, apoptotic cell death allows for the next stage of organ development. It also separates the webbed fingers and toes of the developing embryo (Fig. 3-10). Apoptotic cell death occurs in the hormone-dependent involution of endometrial cells during the menstrual cycle and in the regression of breast tissue after weaning from breast-feeding. The control of immune cell numbers and destruction of autoreactive T cells in the thymus have been credited to apoptosis.

Cytotoxic T cells and natural killer cells are thought to destroy target cells by inducing apoptotic cell death.

Examples of apoptosis: (A) separation of webbed fingers and toes in embryo; (B) development of neural connections; neurons that do not establish synaptic connections and receive survival factors may be induced to undergo apoptosis; (C) removal of cells from intestinal villi; new epithelial cells continuously form in the crypt, migrate to the villus tip as they age, and undergo apoptosis at the tip at the end of their life span; and (D) removal of senescent blood cells. FIGURE 3-10

Concept Mastery Alert

The involution that occurs in hormone-dependent cells, such as in breast tissue after weaning, occurs as a result of programmed cell death or apoptosis. Apoptosis is linked to many pathologic processes and diseases. For example, interference with apoptosis is known to be a mechanism that contributes to carcinogenesis.22 Apoptosis may also be implicated in neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and ALS. However, the exact mechanisms involved in these diseases remain under investigation. Two basic pathways for apoptosis have been described (Fig. 3-11). These are the extrinsic pathway, which is death receptor dependent, and the intrinsic pathway, which is death receptor independent. The execution phase of both pathways is carried out by proteolytic enzymes called caspases, which are present in the cell as procaspases and are activated by cleavage of an inhibitory portion of their polypeptide chain.

Extrinsic and intrinsic pathways of apoptosis. The extrinsic pathway is activated by signals such as Fas ligand (FasL) that on binding to the Fas receptor form a death-inducing complex by joining the Fas-associated death domain (FADD) to the death domain of the Fas receptor. The intrinsic pathway is activated by signals, such as ROS and DNA damage that induce the release of cytochrome c from mitochondria into the cytoplasm. Both pathways activate caspases to execute apoptosis. ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; IL, interleukin; LPS, lipopolysaccharide; ROS, reactive oxygen species; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand. FIGURE 3-11

The extrinsic pathway involves the activation of receptors such as tumor necrosis factor (TNF) receptors and the Fas ligand receptor.21 Fas ligand may be expressed on the surface of certain cells such as cytotoxic T cells or appear in a soluble form. When Fas ligand binds to its receptor, proteins congregate at the cytoplasmic end of the Fas receptor to form a deathinitiating complex. The complex then converts procaspase-8 to caspase-8. Caspase-8, in turn, activates a cascade of caspases that execute the process of apoptosis.2,21 The end result includes activation of endonucleases that cause fragmentation of DNA and cell death. In addition to TNF and Fas ligand, primary signaling molecules known to activate the extrinsic pathway include TNF-related apoptosis-inducing ligand, the cytokine interleukin-1, and lipopolysaccharide, the endotoxin found in the outer cell membrane of gram-negative bacteria. The intrinsic pathway, or mitochondrion-induced pathway, of apoptosis is activated by conditions such as DNA damage, ROS, hypoxia, decreased ATP levels, cellular senescence, and activation of the p53 protein by DNA damage.21 It involves the opening of mitochondrial membrane permeability pores with release of cytochrome c from the mitochondria into the cytoplasm. Cytoplasmic cytochrome c activates caspases, including caspase-3. Caspase-3 activation is a common step to both the extrinsic and intrinsic pathways. Furthermore, activation or increased levels of proapoptotic proteins, such as Bid and Bax, after caspase-8 activation in the extrinsic pathway can lead to mitochondrial release of cytochrome c, thereby bridging the two pathways for apoptosis. Many inhibitors of apoptosis within cells are known and thought to contribute to cancer and

autoimmune diseases.2 The therapeutic actions of certain drugs may induce or facilitate apoptosis. Apoptosis continues to be an active area of investigation to better understand and treat a variety of diseases. Necrosis Necrosis refers to cell death in an organ or tissue that is still part of a living organism.12 Necrosis differs from apoptosis because it causes loss of cell membrane integrity and enzymatic breakdown of cell parts and triggers the inflammatory process.1 In contrast to apoptosis, which functions in removing cells so new cells can replace them, necrosis often interferes with cell replacement and tissue regeneration. With necrotic cell death, there are marked changes in the appearance of the cytoplasmic contents and the nucleus. These changes often are not visible, even under the microscope, for hours after cell death. The dissolution of the necrotic cell or tissue can follow several paths. The cell can undergo liquefaction (i.e., liquefactive necrosis); it can be transformed to a gray, firm mass (i.e., coagulative necrosis); or it can be converted to a cheesy material by infiltration of fat-like substances (i.e., caseous necrosis).1 Liquefactive necrosis occurs when some of the cells die but their catalytic enzymes are not destroyed.1 An example of liquefactive necrosis is the softening of the center of an abscess with discharge of its contents. During coagulative necrosis, acidosis develops and denatures the enzymatic and structural proteins of the cell. This type of necrosis is characteristic of hypoxic injury and is seen in infarcted areas.1 Infarction (i.e., tissue death) occurs when an artery supplying an organ or part of the body becomes occluded and no other source of blood supply exists. As a rule, the shape of the infarction is conical and corresponds to the distribution of the artery and its branches. An artery may be occluded by an embolus, a thrombus, disease of the arterial wall, or pressure from outside the vessel. Caseous necrosis is a distinctive form of coagulative necrosis in which the dead cells persist indefinitely.1 It is most commonly found in the center of tuberculous granulomas or tubercles.1 Gangrene The term gangrene is applied when a considerable mass of tissue undergoes necrosis. Gangrene may be classified as dry or moist. In dry gangrene, the

part becomes dry and shrinks, the skin wrinkles, and its color changes to dark brown or black. The spread of dry gangrene is slow, and its symptoms are not as marked as those of wet gangrene. The irritation caused by the dead tissue produces a line of inflammatory reaction (i.e., line of demarcation) between the dead tissue of the gangrenous area and the healthy tissue. Dry gangrene usually results from interference with the arterial blood supply to a part without interference with venous return and is a form of coagulative necrosis. In moist or wet gangrene, the area is cold, swollen, and pulseless. The skin is moist, black, and under tension. Blebs form on the surface, liquefaction occurs, and a foul odor is caused by bacterial action. There is no line of demarcation between the normal and diseased tissues, and the spread of tissue damage is rapid. Systemic symptoms are usually severe, and death may occur unless the condition can be arrested. Moist or wet gangrene primarily results from interference with venous return from the part. Bacterial invasion plays an important role in the development of wet gangrene and is responsible for many of its prominent symptoms. Dry gangrene is confined almost exclusively to the extremities, but moist gangrene may affect the internal organs or the extremities. If bacteria invade the necrotic tissue, dry gangrene may be converted to wet gangrene. Gas gangrene is a special type of gangrene that results from infection of devitalized tissues by one of several Clostridium bacteria, most commonly Clostridium perfringens.1 These anaerobic and spore-forming organisms are widespread in nature, particularly in soil. Gas gangrene is prone to occur in trauma and compound fractures in which dirt and debris are embedded. Some species have been isolated in the stomach, gallbladder, intestine, vagina, and skin of healthy people. Characteristic of this disorder are the bubbles of hydrogen sulfide gas that form in the muscle. Gas gangrene is a serious and potentially fatal disease. Antibiotics are used to treat the infection, and surgical methods are used to remove the infected tissue. Amputation may be required to prevent spreading infection involving a limb. Hyperbaric oxygen therapy has been used, but clinical data supporting its efficacy have not been rigorously assessed. Cellular Aging Like adaptation and injury, aging is a process that involves the cells and tissues of the body. A number of theories have been proposed to explain the

cause of aging. These theories are not mutually exclusive, and aging is most likely complex with multiple causes. The main theories of aging can be categorized based on evolutionary, molecular, cellular, and systems-level explanations.1 The evolutionary theories focus on genetic variation and reproductive success. After the reproductive years have passed, it is not clear that continued longevity contributes to the fitness of the species. Thus, “antiaging” genes would not necessarily be selected, preserved, and prevalent in the gene pool. The molecular theories of cellular aging focus more on mutations or changes in gene expression. Because the appearance, properties, and function of cells depend on gene expression, this aspect is likely to be involved in aging at some level. Recent attention is being given to the socalled aging genes identified in model systems. There are a number of cellular theories of senescence that are currently under investigation, including those that focus on telomere shortening, free radical injury, and apoptosis. It has been known since the mid-1960s that many cells in culture exhibit a limit in replicative capacity, the so-called Hayflick limit of about 50 population doublings. This limit seems to be related to the length of the telomeres, which are DNA sequences at the ends of chromosomes. Each time a cell divides, the telomeres shorten until a critical minimal length is attained, senescence ensues, and further cell replication does not occur. Some cells have telomerase, an enzyme that “rebuilds” telomeres and lessens or prevents shortening. Cancer cells have high levels of telomerase, which prevents senescence and contributes to the cellular immortality that characterizes cancer. Telomere shortening appears to be related to other theories of cellular causes of aging. For example, free radicals and oxidative damage can kill cells and hasten telomere shortening. Caloric restriction, which appears to increase longevity, may be related to reduced mitochondrial free radical generation owing to reduced methionine or other dietary amino acid intake.23-25 Systems-level theories center on a decline in the integrative functions of organ systems such as the immunologic and neuroendocrine systems, which are necessary for overall control of other body systems. The immune system may decline with age and be less effective in protecting the body from infection or cancer. In addition, mutations and manipulations of genes such as daf-2, which is similar to human insulin/IGF-1 receptor genes, in

the aging worm model Caenorhabditis elegans cause significant changes in longevity.26 Pathways related to daf-2 may be responsible for relationships between caloric restriction and prolonged life span in rodents and other animals. The mechanisms that regulate aging are likely to be complex and multifactorial, as will be any interventions to prolong aging.27 SUMMARY CONCEPTS Cell injury can be caused by a number of agents, including physical agents, chemical agents, biologic agents, and nutritional factors. Among the physical agents that generate cell injury are mechanical forces that produce tissue trauma, extremes of temperature, electricity, radiation, and nutritional disorders. Chemical agents can cause cell injury through several mechanisms: they can block enzymatic pathways, cause coagulation of tissues, or disrupt the osmotic or ionic balance of the cell. Biologic agents differ from other injurious agents in that they are able to replicate and continue to produce injury. Among the nutritional factors that contribute to cell injury are excesses and deficiencies of nutrients, vitamins, and minerals. Injurious agents exert their effects largely through generation of free radicals, production of cell hypoxia, or dysregulation of intracellular calcium levels. Partially reduced oxygen species called free radicals are important mediators of cell injury in many pathologic conditions. They are an important cause of cell injury in hypoxia and after exposure to radiation and certain chemical agents. Lack of oxygen underlies the pathogenesis of cell injury in hypoxia and ischemia. Hypoxia can result from inadequate oxygen in the air, cardiorespiratory disease, anemia, or the inability of the cells to use oxygen. Increased intracellular calcium activates a number of enzymes with potentially damaging effects. Injurious agents may produce sublethal and reversible cellular damage or may lead to irreversible cell injury and death. Cell death can involve two mechanisms: apoptosis or necrosis. Apoptosis involves controlled cell destruction and is the means by which the body removes and replaces cells that have been produced in excess, developed improperly, have genetic damage, or are worn out.

Necrosis refers to cell death that is characterized by cell swelling, rupture of the cell membrane, and inflammation. Like adaptation and injury, aging is a process that involves the cells and tissues of the body. A number of theories have been proposed to explain the complex causes of aging, including those based on evolutionary mechanisms that explain aging as a consequence of natural selection, in which traits that maximize the reproductive capacity of an individual are selected over those that maximize longevity; molecular theories, such as those that explain aging as a result of changes in gene expression; cellular theories that explain cellular senescence in relation to telomere length or molecular events, free radical damage, accumulated wear and tear, or apoptosis; and systems theories that attribute cellular aging to a decline in the integrative functions of organ systems such as the neuroendocrine and immunologic systems.

Review Exercises 1. A 30-year-old man sustained a fracture of his leg 2 months ago. The leg has been encased in a cast, and he has just had it removed. He is amazed at the degree to which the muscles in his leg have shrunk. A. Would you consider this to be a normal adaptive response? Explain. B. Will these changes have an immediate and/or long-term effect on the function of the leg? 2. A 45-year-old woman has been receiving radiation therapy for breast cancer. A. Explain the effects of ionizing radiation in eradicating the tumor cells. B. Why is the radiation treatment given in smaller divided, or fractionated, doses rather than as a single large dose? C. Partway through the treatment schedule, the woman notices that her skin over the irradiated area has become reddened and irritated. What is the reason for this?

3. People who have had a heart attack may experience additional damage once blood flow has been restored, a phenomenon referred to as reperfusion injury. A. What is the proposed mechanism underlying reperfusion injury? B. What factors might influence this mechanism? 4. Every day, blood cells in our body become senescent and die without producing signs of inflammation, yet massive injury or destruction of tissue, such as occurs with a heart attack, produces significant signs of inflammation. A. Explain. REFERENCES 1. Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2. Rawlings D., Metzler G., Dutra M. W., et al. (2017). Altered B cell signalling in autoimmunity. Nature Reviews Immunology 17, 670–678. doi:10.1038/nri.2017.24. 3. Bodine S. C. (2013). Disuse-induced muscle wasting. The International Journal of Biochemistry 45, 2200–2208. doi:10.1016/j.biocel.2013.06.011. 4. Chowdhury M., Enenkel C. (2015). Intracellular dynamics of the ubiquitin-proteasome-system. F100Research 4(367), 1–16. doi:10.12688/f1000research.6835.2. 5. Schiaffino S., Dyar K. A., Cicilio S., et al. (2013). Mechanisms regulating skeletal muscle growth and atrophy. The FEBS Journal 280, 4294–4314. doi:10.1111/febs.12253. 6. Kundu B. K., Zhong M., Sen S., et al. (2015). Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: Review of a hypothesis. Cardiology 130, 211–220. doi:10.1159/000369782. 7. Baker J., Obermair A., Gebski V., et al. (2012). Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: A meta-analysis and systematic review of the literature. Gynecologic Oncology 125, 263–270. doi:10.1016/j.ygyno.2011.11.043. 8. Askanas V., Engel K., Nogalska A. (2012). Pathogenic considerations in sporadic inclusion-body myositis, a degenerative muscle disease associated with aging and abnormalities of myoproteostasis. Journal of Neuropathology and Experimental Neurology 71(8), 680–693. 9. Mohiuddin S. A., Badal S., Doiphode A., et al. (2012). Multiple supramassetric dystrophic calcinosis. Annals of Maxillofacial Surgery 2(1), 74–76. doi:10.4103/2231-0746.95328. 10. Smith E. R. (2016). Vascular calcification in uremia: New-age concepts about an old-age problem. Methods in Molecular Biology 1397:175–208. doi:10.1007/978-1-4939-3353-2_13. 11. Kim H. Y., Park J. H., Lee J. B., et al. (2017). A case of dystrophic calcification in the masseter muscle. Maxillofacial Plastic and Reconstructive Surgery 39(31), 1–5. doi:10.1186/s40902-0170130-4. 12. McConnell T. H., Hull K. L. (2011). Human form human function: Essentials of anatomy & physiology. Philadelphia, PA: Lippincott Williams & Wilkins. 13. Wu S., Powers S., Zhu W., et al. (2016). Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–57. doi:10.1038/nature16166.

14. Naik S. M., Shenoy A. M., Nanjundappa A., et al. (2013). Cutaneous malignancies in xeroderma pigmentosum: Earlier management improves survival. Indian Journal of Otolaryngology and Head & Neck Surgery 65(2), 162–167. doi:10.1007/s12070-012-0614-6. 15. Schnur J., John R. M. (2013). Childhood lead poisoning and the new Centers for Disease Control and Prevention guidelines for lead exposure. Journal of the American Association of Nurse Practitioners 26, 283–247. doi:10.1002/2327-6924.12112. 16. Centers for Disease Control and Prevention. (2014). Lead. [Online]. Available: http://www.cdc.gov/nceh/lead/. Accessed January 28, 2018. 17. Centers for Disease Control and Prevention. (2014). Lead prevention tips. [Online]. Available: http://www.cdc.gov/nceh/lead/tips.htm. Accessed January 28, 2018. 18. Ma Q. (2013). Role of Nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology 53, 401–426. doi:10.1146/annurev-pharmtox-011112-140320. 19. Niki E. (2014). Biomarkers of lipid peroxidation in clinical material. Biochimica et Biophysica Acta 1840, 809–817. doi:10.1016/j.bbagen.2013.03.020. 20. Semenza G. L. (2012). Hypoxia-inducible factors in physiology and medicine. Cell 148, 399– 408. doi:10.1016/j.cell.2012.01.021. 21. Wang J., Gao J., Li Y., et al. (2013). Functional polymorphisms in FAS and FASL contribute to risk of squamous cell carcinoma of the larynx and hypopharynx in a Chinese population. Gene 524, 193–196. doi:10.1016/j.gene.2013.04.034. 22. Okuda H., Xing F., Pandey P. R., et al. (2013). miR-7 Suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Research 73(4), 1434–1445. doi:10.1158/0008-5472.CAN-12-2037. 23. Brandhorst S., Choi I. Y., Min M., et al. (2015). A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and health span. Cell Metabolism 22, 86–99. doi:10.1016/j.cmet.2015.05.012. 24. Mendell J. T., Olson E. N. (2012). MicroRNAs in stress signaling and human disease. Cell 148, 1172–1187. doi:10.1016/j.cell.2012.02.005. 25. Saifan C., Saad M., Charabaty E. E., et al. (2013). Warfarin-induced calciphylaxis: A case report and review of literature. International Journal of General Medicine 6, 665–669. doi:10.2147/IJGM.S47397. 26. Gems D., Partridge L. (2013). Genetics of longevity in model organisms: Debates and paradigm shifts. The Annual Review of Physiology 75, 621–644. doi:10.1146/annurev-physiol-030212183712. 27. Eggermont A. M., Spatz A., Robert C. (2013). Cutaneous melanoma. Seminar 383, 816–827. doi:10.1016/S0140-6736(13)60802-8.

CHAPTER 4 Genetic Control of Cell Function and Inheritance Genetic Control of Cell Function DNA Structure and Function Double Helix and Base Pairing Packaging of DNA DNA Repair Genetic Variability From Genes to Proteins RNA Structure and Function Transcription Translation Regulation of Gene Expression Chromosomes Cell Division Chromosome Structure Patterns of Inheritance Definitions Genetic Imprinting Mendel Laws

Pedigree Gene Technology Genetic Mapping The Human Genome Project Genetic Mapping Methods Haplotype Mapping Recombinant DNA Technology Gene Isolation and Cloning Pharmaceutical Applications DNA Fingerprinting Gene Therapy RNA Interference Technology Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Compare and contrast the structure and function of DNA and RNA. 2. Explain how the DNA code is transcribed into RNA and translated into protein. 3. Describe ways in which gene expression is regulated. 4. Describe the processes of mitosis and meiosis. 5. Describe when a karyotype might be used for. 6. Discuss how a pedigree is used. 7. Compare the two types of cell division in humans. 8. Discuss the different patterns of inheritance. 9. Describe how haplotype mapping can be used to improve patient outcomes.

Our genetic information is stored within the structure of deoxyribonucleic acid (DNA), an extremely stable macromolecule. Genetic information directs the function of our cells, determines our appearance and how we respond to our environment, and serves as the unit of inheritance passed on from generation to generation. Genes also determine our disease susceptibility and how we react to drugs.

An understanding of the role that genetics plays in pathogenesis of disease has expanded greatly over the past century. This is due to the completion of the Human Genome Project in 2003, in which the entire human genome was sequenced. Building upon this information, researchers have shown us that many common diseases, including cancer, diabetes, and cardiovascular disease, have a genetic component. In the case of cancer, recent genetic advances have led to new methods for early detection and more effective treatment. Advances in recombinant DNA technology have provided the methods for producing human insulin, growth hormone, and clotting factors. This chapter includes discussions of genetic control of cell function, chromosomes, patterns of inheritance, and gene technology.

Genetic Control of Cell Function The DNA that contains our genetic information is an extremely stable molecule. Because of its stable structure, the genetic information carried in DNA can survive the many stages of cell division and the day-to-day process of cell renewal and tissue growth. Its stable structure also allows the information to survive the many processes of reduction division involved in gamete (i.e., ovum and sperm) formation, the fertilization process, and the mitotic cell divisions involved in the formation of a new organism from the single-celled fertilized ovum called the zygote. A second type of nucleic acid, ribonucleic acid (RNA), is involved in the actual synthesis of cellular proteins. The information contained in a given gene is first transcribed from DNA into RNA, processed in the nucleus, and then carried to the cytoplasm where it is translated and synthesized into proteins. Although DNA and RNA have received a lot of attention, it is the proteins that the genes encode that make up the majority of cellular structures and perform most life functions. Proteins are responsible for the functional diversity of cells. They perform most biologic functions, and it is at the protein level that many regulatory processes take place, many disease processes occur, and most drug targets are found. Concept Mastery Alert

The term proteome defines the complete set of proteins encoded by a genome. Proteomics, the study of the proteome, uses highly sophisticated technologic methods to examine the molecular and biochemical events in a cell. KEY POINTS The Role of DNA in Controlling Cell Function The information needed for the control of cell structure and function is embedded in the genetic information encoded within the DNA molecule. Although every cell in the body contains the same genetic information, each cell type uses only a portion of the information, depending on its specific function in the body. DNA Structure and Function The DNA molecule that stores the genetic information in the nucleus is a long, double-stranded, helical structure. DNA is composed of nucleotides, which consist of phosphoric acid, a five-carbon sugar called deoxyribose, and one of four nitrogenous bases (Fig. 4-1). These nitrogenous bases carry the genetic information and are divided into two groups: the pyrimidine bases, thymine (T) and cytosine (C), which have one nitrogen ring, and the purine bases, adenine (A) and guanine (G), which have two. The backbone of DNA consists of alternating groups of sugar and phosphate, with the paired bases projecting inward from the sides of the sugar molecule. Double Helix and Base Pairing The structure of DNA, as first described by James Watson and Frances Crick in 1953, is that of a spiral staircase, with the paired bases representing the steps (see Fig. 4-1). A precise and complementary pairing of purine and pyrimidine bases occurs in the double-stranded DNA molecule. Adenine is paired with thymine (A–T) and guanine is paired with cytosine (G–C). The paired bases on opposite DNA strands are bound together by

stable hydrogen bonds. The double-stranded structure of DNA molecules allows them to replicate precisely by separation of the two strands and also allows efficient and correct repair of damaged DNA molecules.

A replicating DNA helix. The DNA helix is unwound, and base pairing rules (A with T and G with C) operate to assemble a new DNA strand on each original strand. After DNA replication is complete, each DNA molecule (chromatid) consists of an old strand and a new synthesized strand. They are joined together at the centromere. (From McConnell T., Hull K. (2011). Human form human function: Essentials of anatomy & physiology (p. 78). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 4-1

Before cell division, the two strands of the helix separate and a complementary strand is duplicated next to each original strand such that the two strands become four strands. During cell division, the newly duplicated double-stranded molecules are separated into pairs made up of one old strand and one new strand. One pair is placed into each of the two daughter cells by the mechanics of mitosis (Fig. 4-2).1

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. FIGURE 4-2

Packaging of DNA The genome (total genetic content) is distributed in chromosomes. Each human somatic cell (cells other than the gametes [sperm and ovum]) has 23 pairs of different chromosomes, one pair derived from the individual’s mother and the other from the individual’s father. Twenty-two of these pairs are autosomes, whereas the last pair is made up of the sex chromosomes (either XX [female] or XY [male]). Genes are arranged linearly along each chromosome. Each chromosome contains one continuous, linear DNA helix. If stretched out, the DNA in the longest chromosome would reach

more than 7 cm in length. If the DNA of all 46 chromosomes were stretched and placed end to end, the total DNA would span a distance of about 2 m (>6 feet). Because of their large size, DNA molecules are combined with several types of protein and small amounts of RNA into a tightly coiled structure known as chromatin. A specific group of proteins called histones controls further folding of the DNA strands, which are essential for packaging the molecule.2 Figure 4-3 illustrates how the chromosomes are coiled in chromatin and then coiled around histones.

DNA strand organization. The DNA strands are shown in chromosomes for dividing cells and in chromatin for nondividing cells FIGURE 4-3

and are coiled around histones. (From McConnell T. H., Hull K. L. (2011). Human form human function: Essentials of anatomy & physiology (p. 71, Fig. 3.5). Philadelphia, PA: Lippincott Williams & Wilkins.) This folding solves a two-pronged problem. Making the DNA so tightly compacted and organized allows the huge amount of DNA to fit into the nucleus and also allows for faithful replication during cell division. The coiling and packaging can also work (alongside other mechanisms) to prevent certain genes from being accessed when they are not needed. When a specific gene is needed, chromatin must be induced to change its structure, a process called chromatin remodeling.3 Gene activation can be triggered by the acetylation of a histone protein, whereas the methylation of other histone proteins is correlated with gene inactivation. DNA Repair Rarely, accidental errors in replication 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 in the offspring. Genetic Variability The human genome sequence is almost exactly (99.9%) the same in all people. It is the small variation (0.01%) in gene sequence that is thought to account for the individual differences in physical traits, behaviors, and disease susceptibility. These normal 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 specific genetic variations and common complex diseases.4 From Genes to Proteins

Although DNA determines the type of biochemical product needed by the cell and directs its synthesis, it is RNA that is responsible for the actual assembly of the products. The RNA assembles the amino acids into functional protein by the process of translation. 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. Here, we will discuss messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). 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 mRNA is the template for protein synthesis. It is a long molecule containing several hundred to several thousand nucleotides. As mentioned before, four bases—guanine, adenine, cytosine, and thymine (in DNA) or uracil (in RNA)—make up the alphabet of the genetic code. A sequence of three of these bases in RNA forms the fundamental triplet code used in transmitting the genetic information needed for protein synthesis. This triplet code is called a codon (Table 4-1). 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). Several of the possible triplets code for the same amino acid; therefore, the genetic code is said to be redundant or degenerate. For example, the codons AAA and AAG both code for the amino acid lysine. Codons that specify the same amino acid are called synonyms. Synonyms usually have the same first two bases but differ in the third base, defined as wobble. TABLE 4-1 Triplet Codes for Amino Acids

Amino Acid Alanine

RNA Codons GCU GCC

GCA

GCG

Amino Acid RNA Codons Arginine CGU CGC CGA CGG AGA AGG Asparagine AAU AAC Aspartic acid GAU GAC Cysteine UGU UGC Glutamic acid GAA GAG Glutamine CAA CAG Glycine GGU GGC GGA GGG Histidine CAU CAC Isoleucine AUU AUC AUA Leucine CUU CUC CUA CUG UUA UUG Lysine AAA AAG Methionine AUG Phenylalanine UUU UUC Proline CCU CCC CCA CCG Serine UCU UCC UCA UCG AGC AGU Threonine ACU ACC ACA ACG Tryptophan UGG Tyrosine UAU UAC Valine GUU GUC GUA GUG Start (CI) AUG Stop (CT) UAA UAG UGA mRNA is formed from DNA by a process called transcription. In this process, the weak hydrogen bonds of the DNA nucleotides are temporarily broken so that free RNA nucleotides can pair with their exposed DNA counterparts of the DNA molecule (see Fig. 4-4). As with the base pairing of the DNA strands, complementary RNA bases pair with the DNA bases. Again in RNA, uracil (U) replaces thymine and pairs with adenine. As with DNA, guanine pairs with cytosine.

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.) FIGURE 4-4

Ribosomal RNA The ribosome is the physical structure in the cytoplasm where protein synthesis takes place. rRNA forms a little over half of the ribosome, with the remainder of the ribosome composed of the structural proteins and enzymes needed for protein synthesis. 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 tRNA is a clover-shaped molecule and works 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 to the mRNA codon, and the

second is complementary to the amino 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 is the process in which RNA is synthesized from the DNA template (Fig. 4-4). 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, there is a crucial thymine–adenine– thymine–adenine nucleotide sequence (called the TATA box) 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, continuing until it reaches the 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 into a mature mRNA molecule. 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. Although they are not used in making the protein product, introns are still important. 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 After the mRNA is processed (adding nucleic acids to the ends and splicing out the exons), it is a mature molecule and is passed into the cytoplasm of the cell, where translation occurs. Translation is the synthesis of a protein using the mRNA template. All proteins are made from amino acids, which are joined end to end to form the long polypeptide chains of protein molecules. Each polypeptide chain may have more than 300 amino acids in it. Translation requires the coordinated actions of mRNA, rRNA, and tRNA to make such a complex molecule (Fig. 4-5). The mRNA 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 (binding to rRNA), 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. Each of the 20 different tRNA molecules transports its specific amino acid to the ribosome for incorporation into the developing protein molecule.

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). As each amino acid is bound to the next by a peptide bond, its tRNA is released. FIGURE 4-5

Next, this new polypeptide chain must fold up into its unique threedimensional conformation. The folding of many proteins is made more efficient by special classes of proteins called molecular chaperones.5 These proteins also assist in the transport to the site in the cell where the protein will carry out its function and help to prevent misfolding of existing proteins. Disruption of these chaperoning mechanisms causes intracellular molecules to become denatured and insoluble. These denatured proteins tend to stick to one another, precipitate, and form inclusion bodies, which is

a pathologic process that occurs in Parkinson, Alzheimer, and Huntington diseases. During folding, other modifications can occur. 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. Other modifications may involve cleavage of the protein, which can happen to remove a specific amino acid sequence or to split the molecule into smaller chains. Regulation of Gene Expression Only about 2% of the genome encodes instructions for the synthesis of proteins; the remainder consists of noncoding regions that are structural or serve to determine where, when, and in what quantity proteins are made. The degree to which a gene or particular group of genes are actively being transcribed 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 induced, and when levels increase, it is repressed. Although control of gene expression occurs in many ways, many of the 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.6 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. Transcription factors are one component that allows neurons and liver cells to use the same DNA yet still have completely different structures and functions. Some of these, referred to as general transcription factors, are required for transcription of all 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.7

SUMMARY CONCEPTS Genes determine the types of proteins and enzymes made by the cell and therefore control both inheritance and day-to-day cell function. Genetic information is stored in a stable macromolecule called DNA. 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 vast majority of DNA is identical across human populations, with only 0.01% creating the individual differences in physical traits and behavior. A second type of nucleic acid called RNA is used to create a protein from the DNA code. There are three major types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). Transcription of mRNA is initiated by RNA polymerase and other associated factors that bind to the DNA at a specific site called the promoter region. Once transcribed, mRNA undergoes processing before moving to the cytoplasm of the cell. Translation occurs in the cytoplasm when the mRNA binds to the ribosome (rRNA) to create a polypeptide. tRNA acts as a carrier system for delivering the appropriate amino acids to the ribosomes. The degree to which a gene or a particular group of genes is active is called gene expression. Gene expression involves a set of complex interrelationships, 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 Most of the genetic information in a cell is organized, stored, and retrieved in 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 where one member of the pair is inherited from the father and the other member is inherited from the mother. Each species has a characteristic number of chromosomes. In the human, 46 chromosomes are present, and these are arranged into 23 pairs. Of the 23 pairs of human chromosomes, 22 are called autosomes, and each has been given a numeric designation for classification purposes (Fig. 4-6). The pairs of autosomal chromosomes each contain similar genes and have similar sequences and are therefore called homologous chromosomes. They are not identical, however, because one comes from the father and one comes from the mother.

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.) FIGURE 4-6

The sex chromosomes, which make up the 23rd pair of chromosomes, determine the sex of a person. Human males have an X and Y chromosome (i.e., an X chromosome from the mother and a Y chromosome from the father); human females have two X chromosomes (i.e., one from each parent). The much smaller Y chromosome contains the male-specific region that determines male sex.8 But only one X chromosome in the female is active in controlling the expression of genetic traits. Whether the active X chromosome is derived from the mother or father is determined within a few days after conception. The selection of either X is random for each possible 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.9 UNDERSTANDING

DNA-Directed Protein Synthesis

Deoxyribonucleic acid (DNA) contains the information to direct the synthesis of the many thousands of proteins that are contained in the different cells of the body. 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.

1 Transcription

Transcription occurs when the DNA is copied into 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 adding nucleotide sequences to the beginning and end of the molecule, and introns are spliced out. Changes to the splicing allow the production of 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 is translated into protein.

2 Translation

Translation begins when the mRNA carrying the instructions for a particular protein comes in contact with a ribosome and binds to a small subunit of the rRNA. It then travels through the ribosome while the tRNA 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. 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. Cell Division Two types of cell division occur in humans and many other animals: mitosis and meiosis. Mitosis involves the replication of DNA to duplicate somatic cells in the body and is represented by the cell cycle (Fig. 4-7). Each of the two resulting cells should have an identical set of 23 pairs of chromosomes. Meiosis is limited to replicating germ cells (Fig. 4-8). It results in the formation of gametes or reproductive cells (i.e., ovum and sperm), each of which has only a single set of 23 chromosomes. Meiosis is typically divided into two distinct phases, meiosis I and meiosis II. As in mitosis, the first step of meiosis I is to replicate the DNA during interphase. During metaphase I, all homologous autosomal chromosomes pair up, forming a tetrad of bivalents. The X and Y chromosomes are not homologs and do not form bivalents. Because the bivalents are lined up, an interchange of chromatid segments can occur in metaphase I. This process is called crossing-over (Fig. 4-9). 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). During anaphase of meiosis II, the 23 double-stranded chromosomes (two chromatids) divide at their centromeres. Each subsequent daughter cell will then receive 23 single-stranded chromatids.

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, Fig. 3.12). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 4-7

Meiosis. Meiosis is the cell division that produces gametes or reproductive cells. (From Stedman’s Medical Dictionary (2015). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 4-8

FIGURE 4-9

Crossing-over of DNA at the time of meiosis.

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. KEY POINTS Chromosomes DNA 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 requires the duplication of chromosomes. Duplication of chromosomes in a somatic cell line is completed by the process of mitosis, in which each daughter cell receives 23 pairs of chromosomes. Meiosis is limited to replicating germ cells and results in daughter cells that each have a single set of 23 chromosomes. Chromosome Structure Cytogenetics is the study of the structure and numeric characteristics of the cell’s chromosomes. Chromosome studies can be done on any tissue or cell that grows and divides in culture, but white blood cells or buccal (cheek) samples are frequently used for this purpose. After the cells have been cultured, a drug called colchicine is used to arrest mitosis in metaphase so that the chromosomes can be easily seen. A chromosome spread is prepared by fixing and spreading the chromosomes on a slide, and they are stained to show banding patterns specific to each chromosome. 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. 4-7). The completed picture is called a karyotype, and the procedure for preparing the picture is called karyotyping. In the metaphase spread, each chromosome takes the form of an “X” or “wishbone” pattern. The two chromatids are connected by a centromere. 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 letter of the alphabet.10 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. 4-10). 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.

Localization of representative inherited diseases on the X chromosome. G6PD, glucose-6-phosphate dehydrogenase; SCID, severe combined immunodeficiency (syndrome). (From Rubin R., Strayer D. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 6.32, p. 282). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 4-10

SUMMARY CONCEPTS The genetic information in a cell is organized in structures called chromosomes. In humans, the 46 chromosomes are arranged into 23 pairs. Twenty-two of these pairs are autosomes. Sex chromosomes make up the 23rd pair. Two types of cell division occur, meiosis and mitosis. Mitotic division occurs in somatic cells and results in two daughter cells, each with 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 photographic arrangement of a person’s chromosomes. It is prepared by special laboratory techniques in which cells are cultured, fixed, and stained to display identifiable banding patterns.

Patterns of Inheritance The characteristics inherited from a person’s parents are carried within genes found along the length of the chromosomes. Alternate forms of the same gene are possible, 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 sequence of base pairs. The phenotype refers to the recognizable traits, physical or biochemical, that are associated with a specific genotype. But 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 appear the same, but genotypically they are different. 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 effect in determining a trait. Multiple pairs of genes, many with alternate codes, determine most human traits. 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 also 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 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 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. 4-11). The transmission of this phenomenon is called genetic imprinting. Although rare, it is estimated that approximately 100 genes exhibit genetic imprinting.

A three-generation 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. FIGURE 4-11

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. In this case, the offspring will have only one working copy of the chromosome, resulting in possible problems.

KEY POINTS 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 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. Mendel Laws A main feature of inheritance is predictability: given certain conditions, the likelihood of the occurrence or recurrence of a specific trait in the offspring is remarkably predictable. The units of inheritance are the genes, and the pattern of single-gene transmission can often be predicted using Mendel laws of genetic transmission. Since Gregor Mendel’s original work was published in 1865, new discoveries have led to some modification of the original laws, but many of the basic principles still hold true. 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. 4-12).

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. FIGURE 4-12

The observable traits of single-gene inheritance are inherited by the offspring from the parents. The germ cells (i.e., sperm and ovum) of both parents undergo meiosis, in which the number of chromosomes is divided into half (from 46 to 23) and each germ cell receives only one allele from each pair (i.e., Mendel first law). According to Mendel second law, the alleles from the different gene loci segregate independently and recombine randomly in the offspring. 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 (aa) pairing; a dominant trait is one expressed in either a

homozygous (AA) or a heterozygous (Aa) pairing. If the trait follows simple mendelian inheritance, then all people with a dominant allele in either one or two copies will show the phenotype for that 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. Sometimes, the person who is heterozygous for a recessive trait (Aa) is called a carrier. That individual will not exhibit the phenotype for the recessive trait, but they “carry” the allele for the recessive trait. If they have offspring with someone who exhibits and is homozygous for the recessive trait, or with someone who is also a carrier, then that offspring could also exhibit the recessive trait. Such a situation might occur when two people who have a phenotype of brown eyes have a child with blue eyes. Brown (B) eyes are dominant to blue eyes (b), so both parents had to be genotypically heterozygous (Bb). Pedigree A pedigree is a graphic method (see Figs. 4-11 and 4-12) for portraying a family history for 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. SUMMARY CONCEPTS Inheritance patterns can calculate 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. The specific region of the DNA molecule where a particular gene is located is called a gene locus. Alternate forms of a gene are called alleles. Traits can be either recessive or dominant. A recessive trait is one expressed only when two copies (homozygous) of the recessive allele are present. Dominant traits are expressed when either one (heterozygous) or two

(homozygous) copies of the dominant allele is present. A pedigree is a graphic method for portraying a family history of an inherited trait.

Gene Technology The past several decades have seen phenomenal advances in the field of genetics. These advances have included the completion of the Human Genome Project, the establishment of the International HapMap Project to map the haplotypes of variations 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 genetics, because the application of genetic technology is becoming more evident in all areas of disease screening and management. Multiple new genetic diagnostics in use are able to assess people for various genetic alterations. Information obtained from these technologies greatly assists in planning the care and pharmacologic management of many types of diseases. Health care professionals need to be able to answer questions and explain to people and families the results of testing 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 a specific locus or to specific parts of the chromosome. Another type of mapping strategy, the haplotype map, focuses on identifying the slight variations in the human genome that affect a person’s susceptibility to disease and responses to environmental factors such as microbes, toxins, and drugs. 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 both determining the precise locations of genes and also 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 100,000 that were initially predicted from the number of different proteins in our body. Another surprising finding was mentioned earlier in this chapter. On average, any two unrelated people will still share 99.9% of their DNA sequence, indicating that the remarkable diversity among people is carried in about 0.1% of our DNA. 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 locus 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 germ cells sometimes exchange genetic material because of crossing-over (see Fig. 48). 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. Linkage analysis can be used clinically to identify affected people in a family with a known genetic defect. 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 proteins of these cells are then studied with the understanding that for a protein to be produced, a certain chromosome must be present and, therefore, the coding for that protein 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. 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.4 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 tagging SNPs. This approach reduces the number of SNPs required to examine an entire genome and makes 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 indicating disease susceptibility in one population versus another, as well as determining appropriate medications and therapies based on genotype. 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 both normal and abnormal gene structures is possible. 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 contains the gene of interest. Many restriction enzymes are commercially available that cut DNA at different recognition sites. The fragments of DNA can then 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. Pharmaceutical Applications 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. 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; and tissue plasminogen activator, which is frequently administered after a heart attack to dissolve thrombi. DNA Fingerprinting The technique of DNA fingerprinting also uses recombinant DNA technology, as well as basic principles of medical genetics.11 Using restriction enzymes, DNA is first cleaved at specific regions (Fig. 4-13). 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 a 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.

DNA fingerprinting. Restriction 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.) FIGURE 4-13

When used in forensic pathology, this procedure is applied to specimens from the suspect and the forensic specimen. This can be done with even very small samples of DNA (a single hair or a drop of blood or saliva) using amplification by polymerase chain reaction. The DNA banding patterns between samples are 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. 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. This type of therapy remains 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 the expression of 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 to attach to a particular chromosome or supplant an existing gene by knocking it out of its place. RNA Interference Technology One approach of gene therapy focuses on the previously described replacement of missing 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.12 RNAi is a naturally occurring process in which small pieces of double-stranded RNA (small interfering RNA) 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 disease-related drug targets. There also is considerable interest in harnessing RNAi for therapeutic purposes, including the treatment of human immunodeficiency virus 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. SUMMARY CONCEPTS Genomic mapping is a method used to assign genes to particular chromosomes or parts of a chromosome. Linkage studies assign a

chromosome location to genes based on their close association with other genes of known location or their tendency to be inherited together. 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. 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 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. REFERENCES 1. Meselson M., Stahl F. W. (1958). The replication of DNA in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 44(7), 671–682. 2. Biterge B., Schneider R. (2014). Histone variants: Key players of chromatin. Cell and Tissue Research 356(3), 457–466. doi:10.1007/s00441-014-1862-4. 3. Clapier C. R., Iwasa J., Cairns B. R., et al. (2017). Mechanisms of action and regulation of ATPdependent chromatin-remodelling complexes. Nature Reviews Molecular Cell Biology 18(7), 407–422. doi:10.1038/nrm.2017.26. 4. The International HapMap Consortium. (2003). The International HapMap Project. Nature 426(6968), 789–796. doi:10.1038/nature02168. 5. Brandvold K. R., Morimoto R. I. (2015). The chemical biology of molecular chaperones— Implications for modulation of proteostasis. Journal of Molecular Biology 427(18), 2931–2947. doi:10.1016/j.jmb.2015.05.010. 6. Spitz F., Furlong E. E. (2012). Transcription factors: From enhancer binding to developmental control. Nature Reviews Genetics 13(9), 613–626. doi:10.1038/nrg3207. 7. Blake J. A., Ziman M. R. (2014). Pax genes: Regulators of lineage specification and progenitor cell maintenance. Development 141(4), 737–751. doi:10.1242/dev.091785. 8. Hughes J. F., Rozen S. (2012). Genomics and genetics of human and primate y chromosomes. Annual Review of Genomics and Human Genetics 13, 83–108. doi:10.1146/annurev-genom090711-163855. 9. Rubin R., Strayer D. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine. Philadelphia, PA: Lippincott Williams & Wilkins. 10. Strayer D. S., Rubin E. (2015). Rubin’s pathology clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Wolters Kluwer. 11. Thompson R., Zoppis S., McCord B. (2012). An overview of DNA typing methods for human identification: Past, present, and future. Methods in Molecular Biology 830, 3–16. doi:10.1007/978-1-61779-461-2_1. 12. Fischer S. E. (2015). RNA interference and microRNA-mediated silencing. Current Protocols in Molecular Biology 112(26), 1–5. doi:10.1002/0471142727.mb2601s112.

CHAPTER 5 Genetic and Congenital Disorders Genetic and Chromosomal Disorders Single-Gene Disorders Autosomal Dominant Disorders Autosomal Recessive Disorders X-Linked Recessive Disorders X-Linked Dominant Disorders Fragile X Syndrome Inherited Multifactorial 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 DNA Analyses Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Contrast disorders due to multifactorial inheritance with those caused by single-gene inheritance. 2. Cite the most susceptible period of intrauterine life for development of defects because of teratogenic agents. 3. 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. 4. Describe the process of genetic assessment. 5. Describe screening methods used for prenatal diagnosis including specificity and risks.

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 Congenital defects may be caused by genetic factors or environmental factors that are active during embryonic or fetal development. Although congenital defects caused by genetic factors are present at birth, they may not make their appearance

until 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 Most genetic disorders are caused by changes in the deoxyribonucleic acid (DNA) sequence that alters the synthesis of a single gene product. Other genetic disorders are a result of chromosomal aberrations such as deletion or duplication errors, or are due to an abnormal number of chromosomes. The genes on each chromosome are arranged 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 physical or biochemical traits. If the trait is phenotypically seen in the heterozygote, the allele is said to be dominant. If it is phenotypically seen only in the homozygote, the allele is recessive. Many genes have more than one normal allele (alternate forms) at the same locus. This is called a polymorphism. Although most traits follow a dominant or recessive pattern, it is possible for both alleles of a gene pair to be phenotypically seen in the heterozygote, a condition called codominance. Blood group inheritance (e.g., AO, BO, AB) is an example of both codominance and polymorphism. A gene mutation is a biochemical event such as nucleotide change, deletion, or insertion that produces a new allele for a particular gene. A single mutant gene may be expressed in many different parts of the body. Marfan syndrome, for example, is a single gene defect in a connective tissue protein that has widespread effects involving skeletal, eye, and cardiovascular structures. The disorder may be inherited as a family trait or arise as a sporadic case because of 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 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 of concern is located on an autosomal or sex chromosome. In addition to disorders caused by mutations of genes located on the chromosomes within the nucleus, another (but more rare) class of disorders involves the mitochondrial genome and shows a maternal pattern of inheritance. Virtually all single-gene disorders lead to the formation of an abnormal protein or the decreased production of a gene product. These changes can result in many different types of systemic alterations. Table 5-1 lists some of the common single-gene disorders and their manifestations. TABLE 5-1 Some Disorders of Mendelian or Single-Gene Inheritance and Their Significance

Disorder Autosomal Dominant

Significance

Short-limb dwarfism Achondroplasia Chronic kidney disease Adult polycystic kidney Neurodegenerative disorder disease Premature atherosclerosis Huntington chorea Connective tissue disorder with abnormalities in Familial the skeletal, ocular, cardiovascular systems hypercholesterolemia Neurogenic tumors: fibromatous skin tumors, Marfan syndrome pigmented skin lesions, and ocular nodules in Neurofibromatosis (NF) NF-1; bilateral acoustic neuromas in NF-2 Osteogenesis imperfecta Brittle bone disease due to defects in collagen Spherocytosis synthesis von Willebrand disease Disorder of red blood cells Bleeding disorder Autosomal Recessive

Disorder

Significance Disorder of membrane transport of chloride ions in exocrine glands causing lung and pancreatic disease Excess accumulation of glycogen in the liver and Cystic fibrosis hypoglycemia (von Gierke disease); glycogen Glycogen storage accumulation in striated muscle in myopathic diseases forms Oculocutaneous albinism Hypopigmentation of skin, hair, eyes as a result Phenylketonuria of inability to synthesize melanin Sickle cell disease Lack of phenylalanine hydroxylase with Tay–Sachs disease 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 Immunodeficiency hypogammaglobulinemia Bleeding disorder Hemophilia A Muscular dystrophy Duchenne dystrophy Intellectual disability Fragile X syndrome 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. 5-1). 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.

Simple pedigree for inheritance of an autosomal dominant trait. Squares represent males, circles represent females. The shaded symbols represent 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. FIGURE 5-1

Autosomal dominant disorders also may manifest as a new mutation. Many autosomal dominant mutations are accompanied by reduced reproductive capacity; therefore, the defect is not repeated 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 from a parent. Although there is a 50% chance of inheriting a dominant genetic disorder from an affected parent, there can be wide variation in gene penetrance and expression. When a person inherits a dominant mutant gene but fails to exhibit the associated phenotype, the trait is described as having reduced penetrance. 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” in their family history. Autosomal dominant disorders also can display variable expressivity, meaning that they can be expressed differently in people who carry the mutant gene. Polydactyly or supernumerary digits, for example, may be expressed in either the fingers or the toes.2 Other disorders of autosomal

inheritance, Marfan syndrome and neurofibromatosis (NF), are described here. Marfan Syndrome Marfan syndrome is an autosomal dominant disorder of the connective tissue. The basic biochemical abnormality in Marfan syndrome affects fibrillin I, a major component of microfibrils found in the extracellular matrix.3 Fibrillin I is coded by the FBNI gene, which maps to chromosome 15q21. 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.3 Marfan syndrome affects several organ systems, including the eyes; the cardiovascular system; and the skeletal system (bones and joints).3 There is a wide range of variation in the phenotype for the disorder. The skeletal deformities 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. 5-2). 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 because of weakness of the suspensory ligaments. Myopia and predisposition to retinal detachment also are common. 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.

FIGURE 5-2

Clinical features of Marfan syndrome.

The diagnosis of Marfan syndrome is based on major and minor diagnostic criteria that include skeletal, cardiovascular, and ocular deformities. There is currently no cure for Marfan syndrome. Treatment plans include regular assessment of the at-risk systems. Neurofibromatosis NF is a condition that causes tumors to develop from the Schwann cells of the neurologic 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).4,5 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 22.4,6 Type 1 NF is a common disorder, characterized by cutaneous and subcutaneous neurofibromas that 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. 5-3). 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.7 They do not present any clinical problem but are useful in establishing a diagnosis.

Neurofibromatosis type 1. Multiple cutaneous neurofibromas are noted on the face and trunk. (From Strayer D. S., Rubin E. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 6–20C, p. 269). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 5-3

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. They are usually a uniform 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 greater than 1.5 cm in diameter suggest NF-1.8 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 including an increased incidence of learning disabilities, attention deficit disorders, abnormalities of speech, and complex partial and generalized tonic–clonic seizures. 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.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. The most frequent symptoms are headaches, hearing loss, and tinnitus. There may be associated intracranial and spinal meningiomas. Autosomal Recessive Disorders Autosomal recessive disorders are manifested only when both members of the gene pair are affected (homozygous). 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. 5-4). 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.

Sample pedigree for inheritance of an autosomal recessive trait. Squares represent males, circles represent females. When the symbols are half shaded, then that parent is a carrier of an autosomal recessive trait. When both parents are carriers, on each conception, there is a 25% chance of having an affected child (fullshaded circle or square), a 50% chance of a carrier child, and a 25% chance of a nonaffected or noncarrier child, regardless of sex. FIGURE 5-4

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. 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.9 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 are difficult to assess, all infants are screened for abnormal levels of serum phenylalanine.5 Infants with the disorder are treated with a special diet that restricts phenylalanine intake to prevent mental retardation as well as other neurodegenerative effects. Infants with elevated phenylalanine levels should begin treatment by 7 to 10 days of age, indicating the need for early diagnosis.9 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.10 Tay–Sachs disease is inherited as an autosomal recessive trait and occurs 10 times more frequently in offspring of Eastern European (Ashkenazi) Jews as compared to the general population, although targeted carrier screening efforts have shown success in reducing rates for this population.11 The GM2 ganglioside accumulates in the lysosomes of all organs in Tay– Sachs disease, but is most prominent in the brain neurons and retina.10 Microscopic examination reveals neurons ballooned with cytoplasmic vacuoles, each of which constitutes a markedly distended lysosome filled with gangliosides.10 In time, there is progressive destruction of neurons, including in the cerebellum, basal ganglia, brainstem, spinal cord, and autonomic nervous system. Involvement of the retina is detected by ophthalmoscopy as a cherry-red spot on the macula.10 Infants with Tay–Sachs disease appear normal at birth but begin to manifest progressive weakness, muscle flaccidity, and decreased responsiveness at approximately 6 to 10 months of age.10 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.10 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.11 X-Linked Recessive Disorders Sex-linked disorders are almost always associated with the X chromosome, and the inheritance pattern is predominantly recessive. Remember that the sex chromosomes for human females are XX and human males are XY. Because of the presence of a normal X, female heterozygotes (carriers) rarely experience the effects of a recessive defective gene, whereas all males who receive the gene are typically affected as they only have the mutant copy. The common pattern of inheritance in a family is one in which an unaffected mother is a carrier of the mutant allele. She is not affected herself because she has one normal X that is dominant over the mutant recessive X. Because she will contribute one of these two X chromosomes to each of her offspring, she has a 50% chance of transmitting the mutant gene to her sons (who only have one X and will be affected), and her daughters have a 50% chance of being carriers of the mutant gene (who have two X chromosomes and so will not be affected because of the presence of a normal X) (Fig. 5-5).

Sample pedigree for inheritance of an X-linked recessive trait. X-linked recessive traits are expressed phenotypically in the male offspring, whereas females are typically carriers for the trait. A small shaded circle represents a carrier female and the larger shaded square, the affected male. A carrier female will transmit her carrier status to 50% of her daughters and 50% of her sons will be affected. The affected male passes the mutant gene to all of his daughters, who become carriers of the trait. The affected male will have no affected sons. FIGURE 5-5

When the affected son procreates, he only has his mutant X or a normal Y to pass on to the next generation. In order to have a daughter, the father donates his only X chromosome, which combines with one of the mother’s two X chromosomes, resulting in a XX child. Because his X is mutated, he transmits the mutant gene to 100% of his daughters, who then become carriers. 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. Although rare, females can be affected with an X-linked recessive disorder. In order for this to happen, an affected male would need to have a child with a carrier female. In this case, 50% of the sons would be affected, and 50% of the daughters would be affected. The remaining daughters would be carriers like their mother. X-linked recessive disorders include color blindness, glucose-6-phosphate dehydrogenase deficiency, hemophilia A, and X-linked agammaglobulinemia. X-Linked Dominant Disorders X-linked dominant disorders are not as common as X-linked recessive disorders affecting both males and females that inherit a copy of the mutated X chromosome. For the females, the mutant X chromosome is dominant to the normal X chromosome. Although both sexes are affected, many times the mutation will be embryonic lethal for males (who only have the mutated X and a normal Y) or for homozygous mutant females. Affected females who are heterozygous with one mutant X chromosome and one normal X chromosome will transmit the disorder to 50% of their offspring regardless of sex. Affected males will have 100% affected

daughters or 100% normal sons. This is explained because all sons inherited their father’s Y chromosome, but the daughters inherited the mutated X chromosome from their father. Examples of X-linked dominant disorders include fragile X syndrome and Rett syndrome. Fragile X Syndrome Fragile X syndrome is a single-gene disorder that causes intellectual disability.12 The mutation occurs at Xq27 on the fragile site and is characterized by amplification of a cytosine, guanine, guanine (CGG) repeat.13 The disorder, which affects approximately 1 in 1250 males and 1 in 2500 females, is the most common form of inherited intellectual disability.12 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.13 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 a 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 triplet code that, when normal, controls gene activity. Once the repeat exceeds a threshold length for the disease, no FMRP is produced, resulting in the fragile X phenotype.13 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.12 Some physical abnormalities may be subtle or absent. Because girls have two X chromosomes, they are more likely to have relatively normal cognitive development, or they may show a learning disability in a particular area. Diagnosis of fragile X syndrome is based on mental and physical characteristics. DNA tests can be done to confirm the presence of an abnormal FMR1 gene. Fragile X screening is now often offered along with routine prenatal screening to determine if the woman is a carrier.

KEY POINTS Single-Gene Disorders Genetic disorders can be inherited as autosomal dominant disorders, in which the phenotype is seen in both the homozygous dominant or heterozygous genotype, or as autosomal recessive disorders, in which the phenotype is only seen in the homozygous recessive genotype. Sex-linked disorders almost always are associated with the X chromosome and are predominantly recessive. Inherited Multifactorial Disorders Multifactorial disorders are caused by the influence of multiple genes along with environmental factors. These traits do not follow the same clear-cut pattern of inheritance as do single-gene disorders because the appearance of the disorder phenotype will be dependent on environmental changes in addition to genetic mutations. Disorders of multifactorial inheritance can 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 an even 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 do exist for congenital disorders. 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 high for the same or a similar defect. For instance, this means that parents of a child with a cleft palate defect have an increased risk of having another child with a cleft palate defect. Third, first-degree relatives of an affected person have an increased risk (as compared with the general population) of having a child with the disease. The risk increases with increasing numbers of the incidence of the defect among relatives.

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.14 It is also one of the more conspicuous birth defects, resulting in an abnormal facial appearance and defective speech. 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.14 This process is under the control of many genes, and disturbances in these (whether hereditary or environmental) at this time may result in cleft lip with or without cleft palate (Fig. 5-6). The defect may also be caused by teratogens (e.g., rubella, anticonvulsant drugs) and is often encountered in children with chromosomal abnormalities.

FIGURE 5-6

Cleft lip and cleft palate.

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 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. 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. As the child ages, speech may be impaired because of these issues. Major advances in the care of children born with cleft lip and palate have occurred within the last quarter of the 20th century.15 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. Chromosomal Disorders Chromosomal disorders form a major category of genetic disease, accounting for a large proportion of early miscarriages, congenital malformations, and intellectual disability. The study of chromosomal disorders is called cytogenetics. During mitosis in human somatic cells, the chromosomes replicate so that each cell receives a total of 23 pairs of chromosomes. But in germ cells undergoing meiosis, these pairs are reduced so that each daughter cell only receives 23 individual chromosomes. At the time of conception, the set of 23 individual chromosomes in the ovum and the set of 23 individual chromosomes in the sperm join to produce an offspring with 23 pairs, or 46 total 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. Structural Chromosomal Abnormalities The aberrations underlying chromosomal disorders can be an abnormal number of chromosomes, but there can also be alterations to the structure of one or more chromosomes. Structural changes in chromosomes usually result from breakage in one or more of the chromosomes during meiosis followed by rearrangement or deletion of 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. 5-7). 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 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.

Structural abnormalities in the human chromosome. The deletion of a portion of a chromosome leads to loss of genetic material and shortened chromosome. A reciprocal translocation involves breaks on two nonhomologous chromosomes, with exchange of the acentric segment. An inversion requires two breaks FIGURE 5-7

in a single chromosome. If the breaks are on opposite sides of the centromere, the inversion is pericentric; it is paracentric if the breaks are on the same arm. A robertsonian translocation occurs when two nonhomologous acrocentric chromosomes break near their centromeres, after which the long arms fuse to form one large metacentric chromosome. Isochromosomes arise from faulty centromere division, which leads to duplication of the long arm (iso q) and deletion of the short arm, or the reverse (iso p). Ring chromosomes form involve 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.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 6–8, p. 253). Philadelphia, PA: Lippincott Williams & Wilkins.) 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 high 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 major unrestored breaks are eliminated within the next few replication cycles 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. Numeric Disorders Involving Autosomes

Having an abnormal number of chromosomes is referred to as aneuploidy. Many times, this happens when there 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. 5-8). Nondisjunction gives rise to germ cells that have an even number of chromosomes.16,17 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 often cause miscarriage in utero.

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 FIGURE 5-8

nondisjunction occurs at meiosis II, the affected gametes contain two of copies of one parenteral chromosome or a lack of chromosomes. Polysomy, or the presence of more than two chromosomes to a set, occurs when a germ cell (either egg or sperm) containing more than 23 chromosomes is involved in conception. In contrast to Down syndrome, most other trisomies are much more severe, and these infants rarely survive beyond the first years of life.6 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. 5-7) 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 a trisomy of the long arm of chromosome 21 (21q).18 The risk of having a child with Down syndrome increases with maternal age. 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 and are likely to have chromosomal abnormalities. A child with Down syndrome has specific physical characteristics that are evident at birth. 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. 5-9). 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. There often are accompanying congenital heart defects and an increased risk of gastrointestinal malformations. In addition, there is an increased risk of Alzheimer disease among older people with Down syndrome.

FIGURE 5-9

Clinical features of a child with Down syndrome.

There are several prenatal screening tests that can be done to determine the risk of having a child with Down syndrome.19 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. Between 10 and 13 weeks, women can have an ultrasound that assesses for nuchal translucency (sonolucent space on the back of the fetal neck). The fetus with Down syndrome tends to have a greater area of translucency as compared to a chromosomally normal infant. But the definitive diagnosis 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. 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 in the number (either excesses or deletions) are much better tolerated than those chromosomal abnormalities involving the autosomes. This is related in a large part to two factors that are peculiar to the sex chromosomes: 1. All but one X chromosome is inactivated. 2. There are very few genes that are carried on the Y chromosome. Although females 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. In somatic cells of females, only one X chromosome is transcriptionally active and creates protein from the DNA template. 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 will have the same active and inactive X chromosome. Although much of one X chromosome is inactivated in females, several regions do contain genes that escape inactivation and can 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. Turner Syndrome Turner syndrome describes an absence of all (45,X/0) or part of the X chromosome. Some women with Turner syndrome may have part of the X chromosome, and some may display a mosaicism where one or more additional cell lines are active. This disorder affects approximately 1 of every 2500 live births and is the most frequently occurring genetic disorder in women.20 Characteristically, a female with Turner syndrome is short in stature, but her body proportions are normal (Fig. 5-10). Females with Tuner syndrome lose the majority of their oocytes by the age of 2 years. Therefore, they do not menstruate and show no signs of secondary sex characteristics. There are variations in the syndrome, with abnormalities ranging from essentially a normal phenotype to cardiac abnormalities such as bicuspid aortic valve and coarctation of the aorta, and a small webbed neck.20

FIGURE 5-10

Clinical features of Turner syndrome.

Because the phenotype can be somewhat variable, the diagnosis of Turner syndrome often is delayed until late childhood or early adolescence in girls who do not present with all of the classic features of the syndrome. It is important to diagnose girls with Turner syndrome as early as possible,

so treatment plans can be implemented and managed throughout their lives. 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.20 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.19 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, but the cause of the nondisjunction is unknown. Advanced maternal age increases the risk, but only slightly. Klinefelter syndrome occurs in approximately 1 per 700 newborn male infants.19 Although the presence of the extra chromosome is fairly common, it is still a rare diagnosis as the phenotype is again variable. 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.19 Phenotypic changes common to Klinefelter syndrome include enlarged breasts, sparse facial and body hair, small testes, and the inability to produce sperm (Fig. 5-11). 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, but at puberty, the 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 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.19

FIGURE 5-11

Clinical features of Klinefelter syndrome.

Adequate management of Klinefelter syndrome requires a comprehensive neurodevelopmental evaluation. Males with Klinefelter syndrome have congenital hypogonadism and decreased sperm count. Androgen therapy is usually initiated when there is evidence of a testosterone deficit. If sperm are present, cryopreservation may be useful for future family planning.19 However, genetic counseling is advised because of the increased risk of autosomal and sex chromosomal abnormalities. Mitochondrial Gene Disorders The mitochondria contain their own DNA, which is distinct from the DNA contained in the cell nucleus. Although the majority of inherited disorders come from nuclear DNA abnormalities, there are multiple disease causing rearrangements and mutations that can occur in mitochondrial DNA (mtDNA). This DNA is packaged in a double-stranded circular chromosome and contains 37 genes: 2 ribosomal RNA genes, 22 transfer RNA genes, and 13 structural genes encoding subunits of the mitochondrial respiratory chain enzymes, which participate in oxidative phosphorylation and generation of adenosine triphosphate. Because mtDNA is inherited only from the mother, all disorders of mtDNA are also inherited on the maternal line. 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, allowing for a mixture of normal and mutant DNA. 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. mtDNA 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. 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 5-2 describes representative examples of disorders due to mutations in mtDNA. TABLE 5-2 Some Disorders of Organ Systems Associated with Mitochondrial DNA Mutations

Disorder Manifestations Chronic Progressive weakness of the extraocular muscles progressive external ophthalmoplegia Deafness Progressive sensorineural deafness, often associated with aminoglycoside antibiotics Kearns–Sayre Progressive weakness of the extraocular muscles of early syndrome onset with heart block, retinal pigmentation Leber hereditary Painless, subacute, bilateral visual loss, with central blind optic neuropathy spots (scotomas) and abnormal color vision Leigh disease Proximal muscle weakness, sensory neuropathy, developmental delay, ataxia, seizures, dementia, and visual impairment due to retinal pigment degeneration MELAS Mitochondrial encephalomyopathy (cerebral structural changes), lactic acidosis, and strokelike syndrome, seizures, and other clinical and laboratory abnormalities; may manifest only as diabetes mellitus MERRF Myoclonic epilepsy, ragged red fibers in muscle, ataxia, sensorineural deafness Myoclonic Myoclonic seizures, cerebellar ataxia, mitochondrial epilepsy with myopathy (muscle weakness, fatigue) ragged red fibers SUMMARY CONCEPTS Genetic disorders can affect a single gene (mendelian inheritance) or several genes (polygenic inheritance). Single-gene mutations 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, 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. X-linked recessive disorders, which are associated with the X chromosome, are typically transmitted by an unaffected carrier mother, who carries one normal X chromosome and one mutant 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. X-linked dominant disorders are less common than X-linked recessive, but do exist. 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. Polysomy refers to the presence of more than two chromosomes in a set. Alterations in chromosome structure involve deletion or addition of genetic material, or a translocation of genetic material from one chromosome pair to another. The mitochondria contain their own DNA, which is distinct from nuclear DNA. This mtDNA is only inherited maternally. 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 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, her general state of health, her nutritional status, and the drugs she takes undoubtedly influences the development of the unborn child. For example, maternal smoking is associated with lower than normal neonatal weight. Maternal use of alcohol is known to cause fetal abnormalities. Various drugs can cause early miscarriage. 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 derangements (Fig. 5-12).

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 Strayer D. S., Rubin E. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 6–2, p. 246). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 5-12

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 female and the embryo or fetus to the agent. 2. Through exposure of the soon to be pregnant female 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 female’s or a male’s reproductive cells. For the purposes of discussion, teratogenic agents have been divided into three groups: radiation, drugs and chemical substances, and infectious agents. Chart 5-1 lists commonly identified agents in each of these groups. CHART 5.1 TERATOGENIC AGENTS* Radiation Drugs and Chemical Substances Alcohol Anticoagulants Warfarin Antibiotics Quinolones Tetracycline Antiepileptics Anti-hypertension Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers Antipsychotics Lithium Cancer drugs Aminopterin 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.

*

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, but all efforts to shield the fetus are taken when possible. In situations where a study is necessary for the woman’s health, the benefits to her of having proper diagnostic imaging must outweigh potential theoretical risks to the fetus. Chemicals and Drugs Environmental chemicals and drugs can cross the placenta and cause damage to the developing embryo and fetus. Some of the best-documented 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. 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. 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. 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 those used in the treatment of cancer, the anticoagulant drug warfarin, several of the anticonvulsant drugs, ethyl alcohol, and cocaine. 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 (FDA) 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 during pregnancy because of proven teratogenicity. Recently, the FDA added modifications to the categories with narrative descriptions and potential reproductive risks.21 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. Fetal Alcohol Syndrome A drug that is often abused and can have deleterious effects on the fetus is alcohol. 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.21 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 many 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. There may be prenatal or postnatal growth retardation; central nervous system (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) (Fig. 5-13).22 The facial features of FAS may not 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 other environmental influences.

FIGURE 5-13

Clinical features of fetal alcohol syndrome.

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.22 Because of the possible effect on the fetus, it is recommended that women abstain completely from alcohol during pregnancy. 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.16 Other infections that can cause fetal anomalies include varicella-zoster virus infection, listeriosis, leptospirosis, Epstein–Barr virus infection, tuberculosis, and syphilis.16 Human immunodeficiency virus and human parvovirus (B19) have been suggested as other potential additions to the list. 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).16 These manifestations will vary among symptomatic newborns, however, and only a few present with multisystem abnormalities. 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. 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 (NTDs) (e.g., anencephaly, spina bifida, encephalocele). Studies have shown a significant decrease in NTDs when folic acid was taken long term by women of reproductive age. Therefore, it is recommended that all

women of childbearing age receive 400 μg (0.4 mg) of folic acid daily and then continue upon becoming pregnant. SUMMARY CONCEPTS 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. 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.

Diagnosis and Counseling Genetic Assessment 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 only 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) predesignated conditions as 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. 5-14). Prenatal diagnosis can also provide the information needed for prescribing prenatal treatment for the fetus or making appropriate plans for the birth of a child with a known disease.

FIGURE 5-14

Methods of prenatal screening.

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. But 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 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 magnetic resonance imaging can be done to better assess skeletal, neurologic, 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. 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. When used along with 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%. The quad screen checks for markers of four substances—AFP, hCG, estriol, and inhibin A—providing a formula for the probability of carrying a child with a chromosomal abnormality. AFP is a major fetal plasma protein 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 or certain

other malformations such as an anterior abdominal wall defect. 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 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. 5-14). 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. 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 of the chorionic villi usually is done after 10 weeks’ gestation. 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. 5-14). Percutaneous Umbilical Cord Blood Sampling Percutaneous umbilical cord blood sampling 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’ 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. Because the procedure carries a greater risk of pregnancy loss compared to amniocentesis, it is usually reserved for situations in which rapid cytogenetic analysis is needed or in which diagnostic information cannot be obtained by other methods. Cytogenetic and DNA Analyses Amniocentesis and chorionic villus sampling yield cells that can be used for cytogenetic and DNA analyses. Cytogenetic studies are used for fetal karyotyping to detect abnormalities of chromosome number and structure in the fetus. 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 can be done on cells extracted from the amniotic fluid, chorionic villi, or fetal blood from percutaneous umbilical sampling. These analyses 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. SUMMARY CONCEPTS 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. These examinations are usually 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 for some disorders. Amniocentesis and chorionic villus sampling may be used to obtain specimens for cytogenetic and biochemical studies.

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? 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 5-8, which describes the events that occur during meiosis, to explain the origin of the third chromosome 21. 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 non-mendelian pattern of inheritance. Explain. 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?

REFERENCES 1. Centers for Disease Control and Prevention. (2007). Birth defects and congenital abnormalities. [Online]. Available: https://www.cdc.gov/nchs/fastats/birth-defects.htm. Accessed November 15, 2017. 2. Malik S. (2014). Polydactyly: Phenotypes, genetics and classification. Clinical Genetics 85(3), 203–212. doi:10.1111/cge.12276. 3. Verstraeten A., Alaerts M., Van Laer L., et al. (2016). Marfan syndrome and related disorders: 25 years of gene discovery. Human Mutation 37(6), 524–531. doi:10.1002/humu.22977. 4. Hirbe A. C., Gutmann D. H. (2014). Neurofibromatosis type 1: A multidisciplinary approach to care. Lancet Neurology 13(8), 834–843. doi:10.1016/S1474-4422(14)70063-8. 5. Berry S. A., Brown C., Grant M., et al. (2013). Newborn screening 50 years later: Access issues faced by adults with PKU. Genetics in Medicine 5(8), 591–599. doi:10.1038/gim.2013.10. 6. Kresak J. L., Walsh M. (2016). Neurofibromatosis: A review of NF1, NF2, and schwannomatosis. Journal of Pediatric Genetics 5(2), 98–104. doi:10.1055/s-0036-1579766. 7. Abdolrahimzadeh B., Piraino D. C., Albanese G., et al. (2016). Neurofibromatosis: An update of ophthalmic characteristics and applications of optical coherence tomography. Clinical Ophthalmology 10, 851–860. doi:10.2147/OPTH.S102830. 8. Bernier A., Larbrisseau A., Perreault S. (2016). Cafe-au-lait macules and neurofibromatosis type 1: A review of the literature. Pediatric Neurology 60, 24.e1–29.e1. doi:10.1016/j.pediatrneurol.2016.03.003. 9. Al Hafid N., Christodoulou J. (2015). Phenylketonuria: A review of current and future treatments. Translational Pediatrics 4(4), 304–317. doi:10.3978/j.issn.2224-4336.2015.10.07. 10. Patterson M. C. (2013). Gangliosidoses. Handbook of Clinical Neurology 113, 1707–1708. doi:10.1016/B978-0-444-59565-2.00039-3. 11. Lew R. M., Burnett L., Proos A. L., et al. (2015). Ashkenazi Jewish population screening for TaySachs disease: The international and Australian experience. Journal of Paediatrics and Child Health 51(3), 271–279. doi:10.1111/jpc.12632. 12. Kidd S. A., Lachiewicz A., Barbouth D., et al. (2014). Fragile X syndrome: A review of associated medical problems. Pediatrics 134(5), 995–1005. doi:10.1542/peds.2013-4301. 13. Bagni C., Oostra B. A. (2013). Fragile X syndrome: From protein function to therapy. American Journal of Medical Genetics. Part A 161A(11), 2809–2821. doi:10.1002/ajmg.a.36241. 14. Seto-Salvia N., Stanier P. (2014). Genetics of cleft lip and/or cleft palate: Association with other common anomalies. European Journal of Medical Genetics 57(8), 381–393. doi:10.1016/j.ejmg.2014.04.003. 15. Smith D. M., Losee J. E. (2014). Cleft palate repair. Clinics in Plastic Surgery 41(2), 189–210. doi:10.1016/j.cps.2013.12.005. 16. Strayer D. S., Rubin E. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Wolters Kluwer. 17. Asim A., Kumar A., Muthuswamy S., et al. (2015). Down syndrome: An insight of the disease. Journal of Biomedical Science 22, 41. doi:10.1186/s12929-015-0138-y. 18. Groth K. A., Skakkebaek A., Host C., et al. (2013). Clinical review: Klinefelter syndrome—A clinical update. Journal of Clinical Endocrinology and Metabolism 98(1), 20–30. doi:10.1210/jc.2012-2382. 19. Milbrandt T., Thomas E. (2013). Turner syndrome. Pediatrics in Review 34(9), 420–421. doi:10.1542/pir.34-9-420. 20. Burkey B. W., Holmes A. P. (2013). Evaluating medication use in pregnancy and lactation: What every pharmacist should know. Journal of Pediatric Pharmacology and Therapeutics 18(3), 247– 258. doi:10.5863/1551-6776-18.3.247.

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CHAPTER 6 Neoplasia 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 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 Childhood Cancers Incidence and Types Embryonal Tumors Biology of Childhood Cancers Diagnosis and Treatment Radiation Therapy Chemotherapy Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Relate the properties of cell differentiation to the development of a cancer cell clone and the behavior of the tumor.

2. Trace the pathway for hematologic spread of a metastatic cancer cell. 3. Use the concepts of growth fraction and doubling time to explain the growth of cancerous tissue. 4. Describe various types of cancer-associated genes and cancerassociated cellular and molecular pathways. 5. Describe genetic events and epigenetic factors that are important in tumorigenesis. 6. State the importance of cancer stem cells, angiogenesis, and the cell microenvironment in cancer growth and metastasis. 7. Characterize the mechanisms involved in anorexia and cachexia, fatigue, sleep disorders, anemia, and venous thrombosis experienced by people with cancer. 8. Define the term paraneoplastic syndrome and explain its pathogenesis and manifestations. 9. Compare the different screening mechanisms for cancer. 10. Differentiate among the three types of cancer treatment (curative, control, and palliative), considering the risks and benefits of each approach. 11. Cite the most common types of cancer affecting infants, children, and adolescents. 12. Describe how cancers that affect children differ from those that affect adults.

Cancer is a leading cause of death in adults worldwide, second only to cardiovascular disease.1 It is the second leading cause of death in schoolaged children in the United States.2 Exposure to external factors such as tobacco, ultraviolet radiation, unhealthy diet, infectious agents, and carcinogens as well as internal factors such as gender, ethnicity, and genetics affect the incidence of cancer.3 Research has led to an enhanced understanding of the causes of cancer and improved screening tools and prevention modalities.3 Survival rates are affected by the type of cancer, stage at diagnosis, and what or if treatment is available.4 Review of previous chapters on cell differentiation, growth, and division will provide a foundation for understanding this chapter. This chapter is divided into five sections:

Characteristics of benign and malignant neoplasms Etiology of cancer Clinical manifestations Diagnosis and treatment Childhood cancers

Characteristics of Benign and Malignant Neoplasms 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. 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. Neoplasms usually are classified as benign or malignant. Neoplasms that contain well-differentiated cells (cell differentiation is the process whereby proliferating cells become progressively more specialized cell types) 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.5 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. Oncology is

the study of tumors and their treatment. Table 6-1 lists the names of selected benign and malignant tumors according to tissue types. TABLE 6-1 Names of Selected Benign and Malignant Tumors According to Tissue Types

Tissue Type

Benign Tumors

Malignant Tumors

Epithelial Surface Papilloma Squamous cell carcinoma Glandular Adenoma Adenocarcinoma Connective Fibrous Fibroma Fibrosarcoma Adipose Lipoma Liposarcoma Cartilage Chondroma Chondrosarcoma Bone Osteoma Osteosarcoma Blood Hemangioma Hemangiosarcoma vessels Lymph Lymphangioma Lymphangiosarcoma vessels Lymph Lymphosarcoma tissue Muscle Smooth Leiomyoma Leiomyosarcoma Striated Rhabdomyoma Rhabdomyosarcoma Neural Tissue Nerve cell Neuroma Neuroblastoma Glioblastoma, astrocytoma, medulloblastoma, Glial tissue Glioma oligodendroglioma Nerve Neurilemmoma Neurilemmal sarcoma sheaths Meninges Meningioma Meningeal sarcoma Hematologic Granulocytic Myelocytic leukemia Erythrocytic Erythrocytic leukemia

Tissue Type

Benign Tumors

Malignant Tumors

Plasma cells Multiple myeloma Lymphocytic Lymphocytic leukemia or lymphoma Monocytic Monocytic leukemia Endothelial Tissue Blood Hemangioma Hemangiosarcoma vessels Lymph Lymphangioma Lymphangiosarcoma vessels Benign and malignant neoplasms usually are distinguished by the following: Cell characteristics Rate of growth 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 6-2. TABLE 6-2 Characteristics of Benign and Malignant Neoplasms

Characteristics Benign Well-differentiated Cell cells that resemble characteristics cells in the tissue of origin

Malignant 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 Usually progressive differentiation; the more Rate of growth and slow; may come to undifferentiated the cells, the more a standstill or regress rapid the rate of growth Grows by expansion Grows by invasion, sending out without invading the Mode of growth processes that infiltrate the surrounding tissues; surrounding tissues usually encapsulated

Characteristics Benign Metastasis

Does not spread by metastasis

Malignant Gains access to blood and lymph channels to metastasize to other areas of the body

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.6 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.5 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 Cancer is a disorder of altered cell differentiation and growth. The resulting process is called neoplasia, which means “new growth.” 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. 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, release enzymes and toxins, or induce an inflammatory response that injures normal tissue as well as the tumor itself. 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. 6-1). Hematologic cancers involve cells normally found in the blood and lymph, thereby making them disseminated diseases from the beginning (Fig. 6-2).

Peritoneal carcinomatosis. The mesentery attached to a loop of small bowel is studded with small nodules of metastatic ovarian carcinoma. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 5–8, p. 175). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 6-1

Hematogenous spread of cancer. A malignant tumor (bottom) has attached to adipose tissue and penetrated into a vein. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 5–9, p. 175). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 6-2

Carcinoma in situ is a localized preinvasive lesion. 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.5 Undifferentiated cancer cells are marked by a number of morphologic changes. The cells of undifferentiated tumors usually display greater numbers of cells in mitosis because of their high rate of proliferation. They also display atypical, bizarre mitotic figures, sometimes producing spindles (Fig. 6-3B). Advanced anaplastic cancer cells begin to resemble undifferentiated or embryonic cells more than they do their tissue of origin. The cytologic/histologic grading 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.5

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 Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 5–2, p. 171). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 6-3

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 6-3. TABLE 6-3 Comparison of Normal Cell Characteristics with Those of Cancer Cells

Characteristics Growth Differentiation Genetic stability Growth factor dependence

Normal Cells Regulated High Stable Dependent

Cancer Cells Unregulated Low Unstable Independent

Characteristics

Normal Cells

Density dependent

High

Cell-to-cell adhesion Anchorage dependence Cell-to-cell communication Cell life span

High High High Limited

Antigen expression

Absent

Substance production (e.g., proteases, hormones) Cytoskeletal composition and arrangement

Cancer Cells Low inhibition Low Low Low Unlimited May be present

Normal

Abnormal

Normal

Abnormal

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.5 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 deoxyribonucleic acid (DNA); and point mutations. Growth Factor Independence Another characteristic of cancer cells is their ability to proliferate even in the absence of growth factors. Breast cancer cells that do not express estrogen receptors are an example. Some cancer cells may produce their own growth factors, whereas others have 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 certain 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. 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. Cancer cells, however, frequently remain viable and multiply without normal attachments to other cells and the extracellular matrix. Although the process of anchorage independence is complex and incompletely understood, recent studies have made progress in understanding the genes and mechanistic pathways involved.7 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 membrane-derived signals. For example, changes in gap junction proteins, which enable cytoplasmic continuity and communication between cells, have been described in some types of cancer.8 Life Span Cancer cells differ from normal cells by having 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 and fail to divide further. In contrast, cancer cells may divide an infinite number of times. 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 welldifferentiated 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 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 also 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).5 Seeding of cancers into other areas of the body is often a postoperative complication 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.5 Metastatic tumors frequently retain many of the characteristics of the primary tumor from which they were derived. This enables determination of the primary site of the tumor based on cellular characteristics of the metastatic tumor. Some tumors tend to metastasize early in their developmental course, whereas others do not metastasize until later. Metastasis occurs through the lymph channels and the blood vessels.5 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. 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.5 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 the route of lymph drainage from the cancer. Once the sentinel 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.5 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. 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. 6-4). 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 sites5 (Fig. 6-5).

Mechanisms of tumor invasion and metastasis. The mechanism by which a malignant tumor initially penetrates a confining basement membrane and then invades the surrounding extracellular environment involves several steps. (1) The tumor first acquires the ability to bind components of the extracellular matrix. These interactions are mediated by the expression of a number of adhesion molecules. (2) The tumor undergoes epithelial– mesenchymal transition (EMT) and traverses the basement membrane. (3) Proteolytic enzymes are then released from the tumor cells, and the extracellular matrix is degraded. (4) After moving through the extracellular environment, the invading cancer penetrates blood vessels and lymphatics by the same mechanisms. (5) After survival in blood vessels or lymphatics, the tumor exits the vascular system. (6) It establishes micrometastases at the site where it leaves the vasculature. (7) These micrometastases grow into gross masses of metastatic tumor. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 5–31, p. 196). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 6-4

The cancer cell ecosystem. The developing tumor cells interact with the nonmalignant cells in their environment, via production of soluble and other mediators. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 5–32, p. 197). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 6-5

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 cell cycle 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 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. SUMMARY CONCEPTS 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 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-to-cell communication; indefinite cell life span; 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).

Etiology of Cancer 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. 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 of cancer. The category associated with gene overactivity involves protooncogenes, which are normal genes that become cancer-causing oncogenes if mutated. Proto-oncogenes 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. 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.5,9 Loss of RB activity may accelerate the cell cycle and lead to increased cell proliferation,9 whereas inactivity of TP53 may increase the survival of DNA-damaged cells. The TP53 gene has become a reliable prognostic indicator.10 There are a number of genetic events that can lead to oncogene formation or loss of tumor suppressor gene function. Genetic Events Leading to Oncogene Formation or Activation Chromosomal translocations have traditionally been associated with cancers such as Burkitt lymphoma and chronic myelogenous leukemia (CML). In Burkitt lymphoma, the myc proto-oncogene, which encodes a growth

signal protein, is translocated from its normal position on chromosome 8 to chromosome 14 (Fig. 6-6C).5 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. 66A and B). Biotechnology and genomics are enabling the identification 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.

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 (CML). (B) Karyotypes of a person with CML showing the FIGURE 6-6

results of reciprocal translocations between chromosomes 9 and 22. The Philadelphia chromosome is recognized by a smaller-thannormal 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.) Another genetic event common in cancer is gene amplification. Multiple copies of certain genes may lead to overexpression, with higher-thannormal 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.11 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. Multiple tumor suppressor genes have been found that connect with various types of cancer.5 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.10 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 carcinogenesis (Fig. 6-7).5 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.

The “two-hit” origin of retinoblastoma. (A) A child with the inherited form of retinoblastoma is born with a germline mutation in one allele of the retinoblastoma gene located on the long arm of chromosome 13. This mutation is not sufficient for tumorigenesis, but the absence of two wild-type alleles weakens protection from tumor development in the event that the remaining allele becomes altered. Then, a second somatic mutation in the retina leads to the inactivation of the y functioning RB allele and the subsequent development of a retinoblastoma. (B) In sporadic cases of retinoblastoma, 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 Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 5–40, p. 208). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 6-7

Epigenetic Mechanisms In addition to mechanisms that involve DNA and chromosomal structural changes, there are molecular and cellular mechanisms, termed epigenetic mechanisms, that 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. The epigenetic mechanisms that alter expression of genes associated with cancer are still under investigation. 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. 6-8). The DNA repair genes affect cell proliferation and survival indirectly through their ability to repair damage in proto-oncogenes, genes impacting apoptosis, and tumor suppressor genes.5

Flowchart depicting the stages in the development of a malignant neoplasm resulting from exposure to an oncogenic agent that produces deoxyribonucleic acid (DNA) damage. When DNA repair genes are present (red arrow), the DNA is repaired and gene mutation does not occur. FIGURE 6-8

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.5 The pathway that regulates gene growth and division is explained in Figure 6-9.

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. FIGURE 6-9

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, downregulation of death receptors (e.g., tumor necrosis factor [TNF]–related apoptosis-inducing ligand), stabilization of the mitochondria, inactivation of proapoptotic proteins (e.g., methylation of caspase-8), overactivity of nuclear factor kappa B, heat shock protein production, or failure of immune cells to induce cell death.12 Alterations in apoptotic and antiapoptotic pathways, genes, and proteins have been found in many cancers. Evasion of Cellular Senescence Another normal cell response to DNA damage is cellular senescence. As stated earlier, cancer cells are characterized by longer life because of 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.13 Development of Sustained Angiogenesis Even with all the aforementioned genetic abnormalities, tumors cannot enlarge unless angiogenesis occurs and supplies them with the blood vessels necessary for survival. Angiogenesis is required not only for continued tumor growth but also 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 mutation of the TP53 gene seems to encourage angiogenesis. Angiogenesis is also influenced by hypoxia and release of proteases that are involved in regulating the balance between angiogenic and antiangiogenic factors.5 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. 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 detaching from tissue from which they belong

(anoikis), and colonize new tissues. The MET proto-oncogene, 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 or suppression.14 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. 6-10). Initiation is the first step and describes the exposure of cells to a carcinogenic agent that causes them to be vulnerable to cancer transformation.5 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.

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. DNA, deoxyribonucleic acid. FIGURE 6-10

Promotion is the second step that allows for prolific growth of cells triggered by multiple growth factors and chemicals.5 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. 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.15 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.16 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% of developing breast cancer. The lifetime risk of developing ovarian cancer is 10% to 20% for carriers of BRCA2 mutations and 40% to 60% for BRCA1 mutations.5 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.5 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 mutant copy of the gene.12,17 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 one third of RBs are inherited, and carriers of the mutant RB tumor suppressor gene have a significantly increased risk of developing RB, usually with bilateral involvement.18 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.19 In people who inherit this gene, hundreds of adenomatous polyps may develop, and a percentage may become cancerous.19 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 increase 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. 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.5,14 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. 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 Tcell 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 tumorreactive 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 complement-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. Chemical Carcinogens A carcinogen is an agent capable of causing cancer. 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) indirectreacting agents, called procarcinogens or initiators, which become active only after metabolic conversion. Direct- and indirect-acting initiators form highly reactive species (i.e., electrophiles and free radicals) that bind with the nucleophilic residues on DNA, ribonucleic acid (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 procarcinogens 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 40% of all cancers diagnosed in the United States are linked to tobacco use.20 Not only is the smoker at risk, but others passively exposed to cigarette smoke are also at risk. 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.21 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 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 highfat 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.15,22 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.5 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 the 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 mid-1940s to the 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.23

See Chart 6-1 for a list of chemical and environmental agents known to be carcinogenic to humans. CHART 6.1 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., chlorambucil, nitrosourea) Radiation

alkylating

agents,

cyclophosphamide,

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.24 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 of developing leukemias and childhood tumors, particularly 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.25 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 light-complexioned 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.26 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-8,2 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, and 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 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. 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.5 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.27 Similar to the human immunodeficiency virus 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. SUMMARY CONCEPTS 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 origin 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.

The types of genes involved in cancer are numerous, with the two main categories being the proto-oncogenes, which control cell growth and replication, and tumor suppressor genes, which are growthinhibiting 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 cancercausing viruses.

Clinical 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; see Table 6-4). 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 people with incurable cancers. TABLE 6-4 Common Paraneoplastic Syndromes

Type of Syndrome Endocrinologic Syndrome of inappropriate antidiuretic hormone (ADH) Adrenocorticotropic hormone (ACTH)– Cushing syndrome Humoral hypercalcemia

Associated Tumor Type

Proposed Mechanism

Small cell lung cancer, others

Production and release of ADH by tumor

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

Production and release of ACTH by tumor Production and release of polypeptide factor with close relationship to parathyroid hormone

Hematologic Venous thrombosis

Pancreatic, lung, Production of procoagulation most solid tumor factors metastatic cancers

Nonbacterial thrombolytic Advanced cancers endocarditis and anemia of malignancy Neurologic Eaton–Lambert syndrome

Small cell lung cancer

Myasthenia gravis

Thymoma

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

Dermatologic Possibly caused by production Gastric carcinoma Cutaneous syndromes of growth factors (epidermal) by and other tumor cells Acanthosis nigricans Cancers Sometimes occur prior to cancer Pemphigus Ichthyosis

Type of Syndrome

Associated Tumor Type

Extramammary Paget Renal Nephrotic syndrome Renal cancers

Proposed Mechanism Damage to renal glomerulus

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 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.5 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 are the most common causes of malignant pleural effusion.5,28 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, increase in abdominal girth, which reflect the presence of peritoneal effusions or ascites, shortness of breath, and increased urinary urgency or frequency are common presenting symptoms in ovarian cancer.29 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.5 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.30 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 50% to 80% of people with advanced cancer and is responsible for death in up to 20% of cases.31 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 because of lack of food intake, where weight is preferentially lost from the fat compartment, in cachexia, it is lost from both the fat and skeletal muscle compartments.30 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. 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. The production of glucose (gluconeogenesis) from lactate contributes to the hypermetabolic state of cachectic people. The increased expression of mitochondrial uncoupling proteins that uncouple the oxidative

phosphorylation process results in energy being lost as heat. Abnormalities in fat and protein metabolism have also been reported. 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. The acute-phase response is known to be activated by cytokines such as TNF-α and IL-1 and IL-6, suggesting that they may also play a role in cancer cachexia.25 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. Fatigue and Sleep Disorders Fatigue and sleep disturbances are two of the most frequent side effects experienced by people with cancer.27 Cancer-related 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.27 Furthermore, the symptom often remains for months or even years after treatment. Although cancer-related fatigue and sleep disorders are distinct conditions, they are closely linked in terms of prevalence and symptoms.27 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). 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.5 For example, drugs used in the 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 to hypoxia. Inflammatory cytokines generated in response to tumors decrease erythropoietin production, resulting in a decrease in erythrocyte production. SUMMARY CONCEPTS 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 the development of effusion (i.e., fluid) in the pleural, pericardial, or peritoneal spaces and generalized manifestations such as anorexia and cachexia, fatigue and sleep disorders, and anemia. Many of these manifestations are compounded by the side effects of methods used to treat the disease.

Screening, Diagnosis, and Treatment 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.5 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. More sensitive screening methods such as tumor markers are being developed for forms of cancer. Lung cancer guidelines were developed by the American Cancer Society and recommend the initiation of discussions with healthy people aged 55 to 74 years who have a minimum of 30 pack-year smoking history and who have stopped smoking in the last 15 years or continue to smoke.32 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 (selfexamination). Although not as clearly defined, it is recommended that screening for other types of cancers such as cancers 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, magnetic resonance imaging, computed tomography, and positron-emission tomography. 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.5,33 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.33 Table 6-5 identifies some of the more commonly used tumor markers and summarizes their source and the cancers associated with them. TABLE 6-5 Tumor Markers

Marker Antigens

Source

Associated Cancers

AFP

Fetal yolk sac and gastrointestinal structures early in fetal life

Primary liver cancers; germ cell cancer of the testis

CA 15-3

Breast tissue protein

CA 27-29 CEA

Tumor marker for tracking breast cancer; liver, lung Breast cancer recurrence and Breast tissue protein metastasis Embryonic tissues in Colorectal cancer and cancers of gut, pancreas, liver, the pancreas, lung, and stomach and breast

Hormones hCG Calcitonin

Hormone normally Gestational trophoblastic tumors; produced by germ cell cancer of testis placenta Hormone produced by thyroid Thyroid cancer parafollicular cells

Catecholamines Hormones produced (epinephrine, Pheochromocytoma and related by chromaffin cells norepinephrine) tumors of the adrenal gland and metabolites Specific Proteins Abnormal Monoclonal immunoglobulin Multiple myeloma immunoglobulin produced by neoplastic cells

Marker

Source Associated Cancers Produced by the epithelial cells lining PSA Prostate cancer the acini and ducts of the prostate Mucins and Other Glycoproteins Produced by CA 125 Müllerian cells of Ovarian cancer ovary Produced by CA 19-9 alimentary tract Cancer of the pancreas, colon epithelium Cluster of Differentiation Used to determine the type and Present on level of differentiation of CD antigens leukocytes leukocytes involved in different types of leukemia and lymphoma AFP, α-fetoprotein; CA, cancer antigen; CD, cluster of differentiation; CEA, carcinoembryonic antigen; hCG, human chorionic gonadotropin; PSA, prostate-specific antigen. The serum markers that have proved most useful in clinical practice are human chorionic gonadotropin (hCG), cancer antigen (CA) 125, PSA, αfetoprotein (AFP), carcinoembryonic antigen (CEA), and cluster of differentiation (CD) blood cell antigens.5 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 CD antigens. The CD antigens help to distinguish among T and B lymphocytes, monocytes, granulocytes, and NK cells and immature variants of these cells.5 Some cancers express fetal antigens that are normally present only during embryonal development.5 The two that have proved most useful as tumor markers are AFP and CEA. AFP 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.5 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.5 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 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 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.5 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 the 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.5 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.5 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 tissue-specific 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.5 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.5 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 tumor, node, metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) is used by most cancer facilities.31 This system, which is briefly described in Chart 6-2, 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. CHART 6.2 TNM CLASSIFICATION SYSTEM T (Tumor) Tx Tumor cannot be adequately assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1– Progressive increase in tumor size or 4 involvement N (Nodes) Nx Regional lymph nodes cannot be assessed N0 No evidence of regional node metastasis N1– Increasing involvement of regional lymph 3 nodes M (Metastasis) Mx Not assessed M0 No distant metastasis M1 Distant metastasis present, specify sites The time of staging is indicated as postsurgical resection–pathologic staging (pTNM), surgical–evaluative staging (sTNM), retreatment staging

(rTNM), and autopsy staging (aTNM).34 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 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 is used for the 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 person, and the quality of life the person 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. Increased emphasis has also been placed on the development of surgical techniques that preserve body image and form without compromising essential function. Nerve- and tissue-sparing surgeries are 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.5 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 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.5 Radiation must produce doublestranded 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. 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.5 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. Adverse Effects Radiation therapy negatively affects normal tissue that is rapidly proliferative similar to malignant cells. Tissues within the treatment fields that are most frequently affected are the skin, the mucosal lining of the gastrointestinal tract, and 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. 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 leukocytes, followed by a decrease in thrombocytes (platelets) and red blood cells. This predisposes the person to infection, bleeding, and anemia, respectively. Each type of radiation poses different adverse effects, and the pros and cons of each much be measured by the provider and the patient. 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. In people with widespread disseminated disease, chemotherapy may provide only palliative rather than curative therapy. Chemotherapy drugs are commonly classified according to their site and mechanism of action. 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.5 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. 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.35 Alkylation of DNA within the cell nucleus is probably the major interaction that causes cell death. Tissue damage at the site of injection and systemic toxicities can occur.

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. Cardiotoxicity and myelosuppression can occur with this treatment. 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.36 Indirect DNA-Interacting Agents The indirect DNA-interacting 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 or abnormal timing of DNA synthesis or by causing abnormal functioning of purine and pyrimidine biosynthetic enzymes.36 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 the formation of the cytoskeleton and mitotic spindle.37 Toxicities associated with the vinca alkaloids include nausea and vomiting, bone marrow suppression, and alopecia. The main dose-limiting toxicity is neurotoxicity. The taxanes differ from the vinca alkaloids in that they stabilize the microtubules against depolymerization. Hypersensitivity reactions, myelosuppression, and peripheral neurotoxicity are potential side effects. 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.

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. Biotherapy Biotherapy involves the use of immunotherapy and biologic response modifiers as a means of changing the person’s own immune response to cancer.38 The major mechanisms by which biotherapy exerts its effects are modifications of host responses or tumor cell biology. Immunotherapy The use of immunotherapy has proven to be an effective treatment strategy of malignancy and has less toxicity than chemotherapy regimens.39 Immunotherapy is a treatment that uses one’s own immune system to treat cancer by either stimulating the immune system to attack cancer cells or improving the individual’s immune system.40 Immunotherapy may be used as a single-agent treatment or used in conjunction with other treatment modalities.40 Types of cancer immunotherapy include monoclonal antibodies, immune inhibitors, cancer vaccines, and nonspecific immunotherapies.40 Monoclonal antibodies are made in the laboratory and target specific proteins or antigens often found on cancer cells allowing for an attack on specific cells.40 Immune inhibitors allow the body to recognize molecules on specific immune cells in order to create an immune response.40 Cancer vaccines are one of the latest biologic response modifiers that act by stimulating the immune system to fight a specific infection or disease, most often cancer-causing viruses such as hepatitis B and HPV.41,42

Biologic Response Modifiers Biologic response modifiers can be grouped into three types: cytokines, which include the interferons and ILs; monoclonal antibodies; and hematopoietic growth factors. 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, AIDS-related Kaposi sarcoma, and CML and as adjuvant therapy for people at high risk for recurrent melanoma.5,43 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 (aldesleukin) has been approved by the Food and Drug Administration and is being used for the treatment of metastatic renal cell and melanoma.43 SUMMARY CONCEPTS 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 quality-of-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 DNAinteracting (antimetabolites and mitotic spindle inhibitors) agents. 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 Cancer in children is relatively rare, accounting for about 1% of all malignancies in the United States.1 Although rare, cancer remains the second leading cause of death among school-age children in the United States.1 Common cancers that occur in children include leukemia, nonHodgkin and Hodgkin lymphomas, and bone cancers (osteosarcoma and Ewing sarcoma). The overall survival rate for children is 85%.2 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.44 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 this characteristic, these tumors are frequently designated with the suffix “blastoma” (e.g., nephroblastoma [Wilms tumor], RB, and 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.45 It is the second most common solid malignancy in childhood after brain tumors. Neuroblastoma is also an extremely malignant neoplasm, particularly in children with advanced disease. In children younger than 2 years, 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).45 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).2,46 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 pigmentosum, 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 factor2 (IGF-2) gene normally is inactivated (imprinted). In some Wilms tumors, loss of imprinting (reexpression of the maternal allele) can be demonstrated by overexpression of the IGF-2 protein, which is an embryonal growth factor.47 Diagnosis and Treatment Early detection often leads to less therapy and improved outcomes. Because of generalized symptoms experienced by children such as prolonged fever, fatigue, and bone pain, diagnosis is often delayed. When these symptoms are experienced in the setting of persistent lymphadenopathy, unexplained weight loss, growing masses (especially in association with weight loss), and abnormalities of the central nervous system (CNS) function, they 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 the 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.48 With improvement in treatment methods, the number of children who survive childhood cancer continues to increase. However, therapy may produce late sequelae, such as impaired growth, neurologic dysfunction, hormonal dysfunction, cardiomyopathy, pulmonary fibrosis, and the risk of second malignancies. Thus, one of the growing challenges is providing appropriate health care to survivors of childhood and adolescent cancers.49 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 and cumulative radiation dose, and age at treatment. There is increased risk of 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. Chemotherapy Chemotherapy also poses the risk of long-term effects for survivors of childhood cancer. Potential late effects of alkylating agents include doserelated gonadal injury (hypogonadism, infertility, and early menopause).49 Alkylating agent therapy has also been linked to dose-related secondary AML, pulmonary fibrosis, kidney disease, and bladder disorders. Anthracyclines, including doxorubicin and daunomycin, which are widely used in the treatment of childhood cancers, can result in cardiomyopathy and eventual congestive heart failure.49 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.

SUMMARY CONCEPTS 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 of secondary 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. 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 cranial radiation therapy 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. Centers for Disease Control and Prevention. (2016). Deaths and mortality. [Online]. Available: https://www.cdc.gov/nchs/fastats/deaths.htm. Accessed October 26, 2017. 2. Center for Disease Control and Prevention. (2014). Child health. [Online]. Available: https://www.cdc.gov/nchs/fastats/child-health.htm. Accessed October 20, 2017.

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25. Aoyagi T., Terracina K. P., Matsubara H., et al. (2015). Cancer cachexia, mechanism and treatment. World Journal of Gastrointestinal Oncology 7(4), 17–29. 26. Ruddon R. W. (Ed.) (1995). Cancer biology. New York, NY: Oxford University Press. 27. Bower J. E. (2014). Cancer-related fatigue-mechanisms, risk factors, and treatments. National Review of Clinical Oncology 11, 597–609. 28. Morgensztern D., Waqar S., Subramanian J., et al. (2012). Prognostic impact of malignant pleural effusion at presentation in patients with metastatic non-small-cell lung cancer. Journal of Thoracic Oncology 7, 1485–1489. 29. Gilbert L., Sampalis J., Karp I., et al. (2012). Assessment of symptomatic women for early diagnosis of ovarian cancer: Results from the prospective DOvE pilot project. Lancet 13, 285– 291. 30. Muliawati Y., Haroen H., Rotty L. (2012). Cancer anorexia—cachexia syndrome. The Indonesian Journal of Internal Medicine 44(2), 154–162. 31. Mirsadraee S., Oswal D., Alizadeh Y., et al. (2012). The 7th lung cancer TNM classification and staging system: Review of the changes and implications. World Journal of Radiology 4(4), 128– 134. 32. Wender R., Fontham E. T., Barrera E., et al. (2013). American Cancer Society lung cancer screening guidelines. A Cancer Journal for Clinicians 63, 106–117. 33. Duffy M. J. (2013). Tumor markers in clinical practice: A review focusing on common solid cancers. Medial Principles and Practice 22, 4–11. 34. Liang J., Gao P., Wang Z., et al. (2012). The integration of macroscopic tumor invasion of adjacent organs into TNM staging system for colorectal cancer. PLoS One 7(12), e52269. 35. Fu D., Calvo J. A., Samson L. D. (2012). Balancing repair and tolerance of DNA damage caused by alkylating agents. Nature 12, 104–120. 36. Yang F., Teves S. S., Kemp C. J., et al. (2014). Doxorubicin, DNA torsion, and chromatin dynamics. Biochimica et Biophysica Acta 1845, 84–89. 37. Mukhtar E., Adhami V. M., Kukhtar H. (2016). Targeting microtubules by natural agents for cancer therapy. Molecular Cancer Therapeutics 13(2), 275–284. 38. Kuroki M., Miyamoto S., Morisaki T., et al. (2012). Biological response modifiers used in cancer biotherapy. Anticancer Research 32, 2229–2234. 39. Myint Z. W., Goil G. (2017). Role of modern immunotherapy in gastrointestinal malignancies: A review of current clinical progress. Journal of Hematology and Oncology 10, 86–98. 40. American Cancer Society. (2017). Treatment and support. [Online]. Available: https://www.cancer.org/treatment.html. Accessed November 18, 2017. 41. Ott P. A., Fritsch E. F., Wu C. J., et al. (2014). Vaccines and melanoma. Hematology Oncology Clinics of North America 28, 559–569. 42. Joura E. A., Giuliano A. R., Iversen E. E., et al. (2015). A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. The New England Journal of Medicine 372(8), 711–723. 43. Lin F., Young H. (2014). Interferons: Success in anti-viral immunotherapy. Cytokine and Growth Factor Reviews 25, 369–376. 44. Siegel R. L., Miller K. D., Jemal A. (2018). Cancer statistics, 2018. CA: A Cancer Journal for Clinicians 68, 7–30. 45. Cheung N. V., Dyer M. A. (2013). Neuroblastoma: Developmental biology, cancer genomics and immunotherapy. Nature Reviews. Cancer 13, 397–411. 46. Bruwier A., Chantrain C. F. (2012). Hematological disorders and leukemia in children with Down syndrome. European Journal of Pediatrics 171, 1301–1307. 47. Harris L. K., Westwood M. (2012). Biology and significance of signaling pathways activated by IGF-II. Growth Factors 30(1), 1–12. 48. American Cancer Society. (2016). What are the differences between cancers in adults and children? [Online]. Available: https://www.cancer.org/cancer/childhood-non-hodgkin-

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UNIT 3

Disorders of Integrative Function

CHAPTER 7 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

Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Describe the concept of homeostasis. 2. Describe the components of a control system, including the function of a negative feedback system. 3. Explain the interactions among components of the nervous system in mediating the stress response. 4. Describe the stress responses of the autonomic nervous system, the endocrine system, the immune system, and the musculoskeletal system. 5. Explain adaptation and its physiologic purpose. 6. Discuss Selye’s general adaptation syndrome. 7. Describe the physiologic and psychological effects of a chronic stress response. 8. Describe the characteristic of posttraumatic stress disorder. 9. List five nonpharmacologic methods of treating stress.

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. The 2017 American Psychological Association’s (APA) Stress in America survey identified various sources of stress and its effect on the overall health and well-being of Americans living in the Unites States. Interestingly, it identified that 57% of Americans reported that the current political climate is a significant source of stress. Other significant stressors included stress related to personal safety and future, police violence toward minorities, work and economy, terrorism, mass shootings, and gun violence. Technology and social media have changed the way people around the world access information. According to the APA, 8 in 10 Americans are attached to their devices on any typical day and are considered as constant checkers of information on their personal electronic devices, and this

activity with technology is considered as a source of stress. The abovementioned stressors affect the health of our society, and the percentage of Americans reported to have at least one symptom of stress (headache, anxiety, depression, etc.) increased from 71% in August 2016 to 80% in January 2017.1 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 Cannon referred to the concept of a stable internal environment as homeostasis, which is achieved through a system of carefully coordinated physiologic processes that oppose change.4 Cannon pointed out that these processes were largely automatic and emphasized that homeostasis involves resistance to both internal and external disturbances. At about the same time, Hans Selye, who became known for his research and publications on stress, began using the term stress in a very special way to mean an orchestrated set of bodily responses to any form of noxious stimulus.5 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 The concepts of stress and adaptation have their origin in the complexity of the human body and the interactions between its 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

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.6 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. 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.7 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 them with “normal,” and effector(s) to try to reverse the change. For instance, a hiker’s eyes (sensor) see a snake (stressor), and the cerebral cortex (integrator) of the individual determines that the snake is a threat and activates the heart, respiratory muscles, and many other organs (effectors) to assist in escape.

More complex stressors invoke more complex control systems, and sometimes, the stress response cannot restore balance and homeostasis. For instance, adverse physical and psychological experiences early in life (prenatal and childhood periods) can impact one’s adult health.8 The impact may appear decades later, in the form of mental health issues, immune dysregulations, cardiovascular diseases, cancer, and so on.8 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.9 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. 7-1). 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 glycogen stores of liver, which causes the blood glucose to return to normal. The same is true for all endocrine 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 thyroidstimulating hormone (TSH), which then increases T4 secretion from the thyroid.

Illustration of negative feedback control mechanisms using blood glucose as an example. FIGURE 7-1

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 hypothetical positive feedback system, exposure to an increase in environmental temperature would invoke compensatory mechanisms designed to increase rather than decrease body temperature. SUMMARY CONCEPTS 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 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 contribute 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 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.12 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.”13 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.13 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.12 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.13 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).13 The relative risk for development of a stress-related pathologic process seems, at least in part, to depend on these factors. 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 the 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. Table 7-1 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.14 TABLE 7-1 Hormones Involved in the Neuroendocrine Responses to Stress

Hormones Associated with the Stress Response Catecholamines (e.g., NE, epinephrine)

Corticotropinreleasing factor

Source of the Physiologic Effects Hormone LC, adrenal medulla

Produce 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 Hypothalamus Stimulates ACTH release from the anterior pituitary and increased activity of the LC neurons

Hormones Associated with Source of the Physiologic Effects the Stress Hormone Response Adrenocorticotropic Anterior Stimulates the synthesis and release of hormone (ACTH) pituitary cortisol Glucocorticoid Adrenal cortex Potentiate the actions of epinephrine hormones (e.g., and glucagon; inhibit the release and/or cortisol) actions of the reproductive hormones and thyroid-stimulating hormone; and produce a decrease in immune cells and inflammatory mediators Mineralocorticoid Adrenal cortex Increase sodium absorption by the hormones (e.g., kidney aldosterone) Antidiuretic Hypothalamus, Increases water absorption by the hormone (e.g., posterior kidney; produces vasoconstriction of vasopressin) pituitary blood vessels; and stimulates the release of ACTH LC, locus coeruleus; NE, norepinephrine. The stress response is a normal, coordinated physiologic system not only 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. Concept Mastery Alert

The persistence or accumulation of the allostatic changes (e.g., immunosuppression, activation of the sympathetic nervous and renin–angiotensin–aldosterone systems) has been called an allostatic load or overload, and this concept has been used to measure the cumulative effects of stress on humans.15 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 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. 7-2). 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 (ANSs). 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 coeruleus (LC) associated with release of norepinephrine (NE). Thus, NE stimulates the secretion of CRF, and CRF stimulates the release of NE.15

Neuroendocrine pathways and physiologic responses to stress. ACTH, adrenocorticotropic hormone; CRF, corticotropinreleasing factor. FIGURE 7-2

Locus Coeruleus Central to the neural component of the neuroendocrine response to stress is an area of the brain stem called the LC.15 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. 7-3). The LC–NE system has afferent pathways to the hypothalamus, the limbic system, the hippocampus, and the cerebral cortex.

Neuroendocrine–immune system regulation of the stress response. ACTH, adrenocorticotropic hormone; CRF, corticotropinreleasing factor. FIGURE 7-3

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 may intensify 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. 7-3). CRF is a small peptide hormone secreted by the paraventricular nucleus (PVN) of the hypothalamus. It is both an important endocrine regulator of pituitary and adrenal activity and a neurotransmitter involved in ANS activity, metabolism, and behavior.15 Receptors for CRF are distributed throughout the brain as well as in many peripheral sites. CRF secreted from the hypothalamus in response to stress stimulus 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 also as an inhibitor, such that overactivation of the stress response does not occur.15 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, collagen synthesis, and immune responses. All of these functions are meant to protect the organism against 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, 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.15 Other Hormones

A wide variety of other hormones, including growth hormone, thyroid hormone, and the reproductive hormones, also are responsive to stressful stimuli. 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. Studies have shown that in females, stress and severe trauma can cause menstrual irregularities, anovulation, and amenorrhea.14 In males, stress can induce decreased spermatogenesis, ejaculatory disorders, decreased levels of testosterone, and infertility.16 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, 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. Stress-induced cortisol secretion also is associated with decreased levels of TSH 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 5HT 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, neuropeptide Y, cholecystokinin, and substance P. These hormones have well characterized physiologic roles in periphery, but they are also found in the CNS, and literature supports that they are involved in the stress response.17

Oxytocin is a neuropeptide/neurohormone produced in the PVN and supraoptic nucleus of the hypothalamus. A large body of literature suggests that oxytocin plays a significant role in reducing stress-related physiologic consequences. Exogenous delivery of oxytocin via intranasal route has shown reduction in psychosocial stress reactivity, fear and anxiety, and increases reward processing.18 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 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. 7-3). 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.15 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-α that are released from immune cells. 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 as well. 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 humoralmediated immune responses.15 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) 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. Adaptation is the ability to respond to challenges of physical or psychological homeostasis and to return to a balanced state. 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.”19 Living organisms, no matter how primitive, do not submit passively to the impact of environmental forces. 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. 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. Of particular interest are the differences in the body’s response to events that threaten the integrity of the body’s 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.20 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. 7-4).

FIGURE 7-4

Factors affecting adaptation.

Physiologic and Anatomic Reserve The safety margin for adaptation of most body systems is considerably greater than that needed for normal activities. The red 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. Technologic 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 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. Genderbased 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 long-term use, can seriously impair the function of the liver, brain, and other vital structures. Circadian Rhythm Sleep is considered to be a restorative function in which energy is restored and tissues are regenerated.21 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.21,22 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 disturbances, loss of a loved one, recovery from surgery, and pain are common causes of transient and shortterm 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.23

Many studies by nurses and social psychologists suggest that hardiness is correlated with positive health outcomes.24 Psychosocial Factors 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. Studies suggest that social support has direct and indirect positive effects on the health and well-being and serves as a buffer or modifier of the physical and psychosocial effects of stress.25 Social support has been viewed in terms of the number of relationships a person has and the person’s perception of these relationships. 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. SUMMARY CONCEPTS 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.

Disorders of the Stress Response 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 fightor-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 lifethreatening 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 (Chart 7-1). 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 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). CHART 7.1 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 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 a disabling syndrome caused by the chronic activation of the stress response as a result of experiencing a significant traumatic event. 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 after the traumatic event is called PTSD with delayed onset.26 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 the development of the disorder. In the United States, the most frequently reported traumatic events include physical and sexual assaults (with 52% prevalence) and accidents (with 50% prevalence).26 People who are exposed to traumatic events are also at risk for development of major depression, panic disorder, generalized anxiety disorder, and substance abuse.26 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.26 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. Recent neuroanatomic studies have identified alterations in neural systems that are part of the amygdala and hippocampus that play a significant role in fear learning, threat detection, executive function and emotion regulation, and contextual processing.26 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, which mimics the effects of cortisol and directly inhibits the action of CRF and ACTH. Little is known about the risk factors that predispose people to the development of PTSD. 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. Often concurrent pharmacotherapy

with antidepressant and antianxiety agents is useful and helps the person participate more fully in therapy. 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.27 Evidence supports that early intervention can assist the person in adapting new and effective coping mechanisms to better manage stress in the future.27 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.28 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.28 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. Herbert Benson, a physician who worked in developing the technique, described four elements integral to the various relaxation techniques: a repetitive mental device, a passive attitude, decreased mental tonus, and a

quiet environment. He developed a noncultural method that is commonly used for achieving relaxation.29 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. 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. 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. Several types of responses are used: electromyography (EMG), electrothermal, and electrodermal.30 The EMG response involves the measurement of electrical potentials from muscles to gain control over the contraction of skeletal muscles that occurs with anxiety and tension. The electrodermal sensors monitor skin temperature in the fingers or toes. The sympathetic nervous system exerts significant

control over blood flow in the distal parts of the body such as the digits of the hands and feet. Consequently, anxiety often is manifested by a decrease in skin temperature in the fingers and toes. Electrodermal sensors measure conductivity of skin in response to anxiety. Massage Therapy Massage is the manipulation of the soft tissues of the body to promote relaxation and relief of muscle tension. The technique that is used may involve a soft stroking along the length of the muscle (effleurage), application of pressure across the width of a muscle (petrissage), deep massage movement applied by a circular motion of the thumbs or fingertips (friction), squeezing across the width of a muscle (kneading), or use of light slaps or chopping actions (hacking).31 Research 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 stress and coping in adults. Measurements of vital signs, ACTHs, glucocorticoids (cortisol) and glucose levels, and immunologic counts are all part of current research studies involving stress. 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. SUMMARY CONCEPTS 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. 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. American Psychological Association. (2017). Stress in America: Coping with change. Washington, DC: American Psychological Association. 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. 4. Cannon W. B. (1939). The wisdom of the body (pp. 299–300). New York, NY: WW Norton. 5. Selye H. (1946). The general adaptation syndrome and diseases of adaptation. Journal of Clinical Endocrinology 6, 117–124. 6. Bernard C. (1878). Leçons sur les phénomènes de la vie communs aux animaux et aux vegetaux. Paris, France: Baillière JB. 7. Understanding the stress response. Chronic activation of this survival mechanism impairs health. (2016). Harvard Medical School. Harvard Health Publishing. Available: https://www.health.harvard.edu/staying-healthy/understanding-the-stress-response. Accessed February 24, 2018. 8. Momen N. C., Olsen J., Gissler M., et al. (2013). Early life bereavement and childhood cancer: A nationwide follow-up study in two countries. BMJ Open 3(5). 9. 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. 10. Schacter D. L., Gaesser B., Addis D. R. (2013). Remembering the past and imagining the future in the elderly. Gerontology 59(2), 143–151. 11. Selye H. (1976). The stress of life (rev. ed.). New York, NY: McGraw-Hill. 12. Selye H. (1974). Stress without distress (p. 6). New York, NY: New American Library. 13. Selye H. (1973). The evolution of the stress concept. American Scientist 61, 692–699. 14. Herman J. P., McKlveen J. M., Ghosal S., et al. (2016). Regulation of the hypothalamic-pituitaryadrenocortical stress response. Comprehensive Physiology 6(2), 603–621. 15. Hall J. E. (2015). Guyten and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Saunders. 16. Sengupta P., Dutta S., Krajewska-Kulak E. (2017). The disappearing sperms: Analysis of reports published between 1980 and 2015. American Journal of Men’s Health 11(4), 1279–1304. 17. Yam K. Y., Naninck E. F., Schmidt M. V., et al. (2015). Early-life adversity programs emotional functions and the neuroendocrine stress system: The contribution of nutrition, metabolic

hormones and epigenetic mechanisms. Stress 18(3), 328–342. 18. Sippel L. M., Allington C. E., Pietrzak R. H., et al. (2017). Oxytocin and stress-related disorders: Neurobiological mechanisms and treatment opportunities. Chronic Stress (Thousand Oaks) 1. doi:10.1177/2470547016687996. 19. Dubos R. (1965). Man adapting (pp. 256, 258, 261, 264). New Haven, CT: Yale University. 20. Lazarus R. (2011). Evolution of a model of stress, coping, and discrete emotions. In Rice V. H. (Ed.), Handbook of stress, coping, and health (2nd ed., pp. 195–222). Thousand Oaks, CA: Sage. 21. Buysse D. J. (2014). Sleep health: Can we define it? Does it matter? Sleep 37(1), 9–17. 22. Sollars P. J., Pickard G. E. (2015). The neurobiology of circadian rhythms. Psychiatric Clinics of North America 38(4), 645–665. 23. 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. 24. Jordan T. R., Khubchandani J., Wiblishauser M. (2016). The impact of perceived stress and coping adequacy on the health of nurses: A pilot investigation. Nursing Research and Practice 2016, 5843256. 25. Ozbay F., Johnson D. C., Dimoulas E., et al. (2007). Social support and resilience to stress: From neurobiology to clinical practice. Psychiatry (Edgmont) 4(5), 35–40. 26. Shalev A., Liberzon I., Marmar C. (2017). Post-traumatic stress disorder. The New England Journal of Medicine 376(25), 2459–2469. 27. De Bellis M. D., Woolley D. P., Hooper S. R. (2013). Neuropsychological findings in pediatric maltreatment: Relationship of PTSD, dissociative symptoms, and abuse/neglect indices to neurocognitive outcomes. Child Maltreatment 18(3), 171–183. 28. Kelley D. E., Lewis M. A., Southwell B. G. (2017). Perceived support from a caregiver’s social ties predicts subsequent care-recipient health. Preventive Medicine Reports 8, 108–111. 29. Benson H. (1977). Systemic hypertension and the relaxation response. The New England Journal of Medicine 296, 1152–1154. 30. Strada E. A., Portenoy R. K. Psychological rehabilitative, and integrative therapies for cancer pain. In Savarese D. M. F. (Ed.), UpToDate. Available: https://www.uptodate.com/contents/psychological-rehabilitative-and-integrative-therapies-forcancer-pain. Accessed February 24, 2018. 31. Salvo S. G. (2015). Massage therapy: Principles and practice (5th ed.). St. Louis, MO: Saunders.

CHAPTER 8 Disorders of Fluid, Electrolyte, and Acid–Base 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 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 Hypophosphatemia Hyperphosphatemia Disorders of Magnesium Balance Gains and Losses Hypomagnesemia Hypermagnesemia 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 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 Learning Objectives After completing this chapter, the learner will be able to meet the following objectives:

1. Differentiate the intracellular from the extracellular fluid compartments in terms of distribution and composition of water, electrolytes, and other osmotically active solutes. 2. Relate the concept of a concentration gradient to the processes of diffusion and osmosis. 3. Describe the control of cell volume and the effect of isotonic, hypotonic, and hypertonic solutions on cell size. 4. State the functions and physiologic mechanisms controlling body water levels and sodium concentration, including the effective circulating volume, sympathetic nervous system, renin–angiotensin– aldosterone system, and antidiuretic hormone. 5. Describe the relationship between antidiuretic hormone and aquaporin-2 channels in reabsorption of water by the kidney. 6. Compare the etiology, pathology, and clinical manifestations of diabetes insipidus and the syndrome of inappropriate antidiuretic hormone. 7. Characterize the distribution of potassium in the body and explain how extracellular potassium levels are regulated in relation to body gains and losses. 8. Relate the functions of potassium to the manifestations of hypokalemia and hyperkalemia. 9. Describe the associations among intestinal absorption, renal elimination, bone stores, and the functions of vitamin D and parathyroid hormone in regulating calcium, phosphorus, and magnesium levels. 10. Describe the intracellular and extracellular mechanisms for buffering changes in body pH. 11. Compare the roles of the kidneys and respiratory system in regulation of acid–base balance. 12. Describe the common causes of metabolic and respiratory acidosis and metabolic and respiratory alkalosis. 13. Contrast and compare the etiology and clinical manifestations of metabolic and respiratory acidosis and of metabolic and respiratory alkalosis.

Electrolytes significantly affect all cell functions and are maintained within a narrow range primarily by the kidneys. Hydrogen (H+) concentration is controlled by buffers, and an imbalance results in either acidosis or alkalosis. 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 transformation 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 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; and disorders of fluid and electrolyte balance. The content related to H+ balance has been organized into two sections: mechanisms of acid–base balance and disorders of acid–base balance.

Composition and Compartmental Distribution of Body Fluids Body fluids are distributed between the intracellular fluid (ICF) and extracellular fluid (ECF) compartments. The ICF compartment consists of fluid contained within all cells in the body and constitutes 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. 8-1).

Distribution of body water. The extracellular space includes the vascular compartment and the interstitial spaces. FIGURE 8-1

The ECF, including blood plasma and interstitial fluids, contains large amounts of sodium and chloride; moderate amounts of bicarbonate; and small amounts of potassium, magnesium, calcium, and phosphorus. The ICF contains almost no calcium; small amounts of sodium, chloride, bicarbonate, and phosphorus; moderate amounts of magnesium; and large amounts of potassium (Table 8-1).1 Potassium is the most abundant intracellular electrolyte. TABLE 8-1 Concentrations of Extracellular and Intracellular Electrolytes in Adults

Extracellular Concentration* Electrolyte Sodium

Conventional SI Units Units (mmol/L) 135–145 135–145 mEq/L

Intracellular Concentration*

Conventional SI Units (mmol/L) Units 10–14 mEq/L 10–14

Extracellular Concentration* Conventional SI Units Units (mmol/L) Potassium 3.5–5.0 3.5–5.0 mEq/L Chloride 98–106 98–106 mEq/L Bicarbonate 24–31 mEq/L 24–31 Calcium 8.5–10.5 2.1–2.6 mg/dL Phosphorus 2.5–4.5 0.8–1.45 mg/dL Magnesium 1.8–3.0 0.75–1.25 mg/dL Electrolyte

Intracellular Concentration*

Conventional SI Units (mmol/L) Units 140–150 140–150 mEq/L 3–4 mEq/L 3–4 7–10 mEq/L 7–10 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.2 In mild cases of SIADH, treatment consists of fluid restriction. Diuretics 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. 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) are specific ADH V2 receptor antagonists and result in aquaresis (i.e., the electrolytesparing 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. 8-6)

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 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 8-4). It is usually caused by a loss of body fluids and accompanied by a decrease in fluid intake. It can occur because of a loss of gastrointestinal fluids, polyuria, or sweating. 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. TABLE 8-4 Causes and Manifestations of Isotonic Fluid Volume Deficit

Causes

Manifestations

Causes Manifestations Inadequate Fluid Intake Acute Weight Loss (% Body Oral trauma or inability to swallow Weight) Inability to obtain fluids (e.g., Mild fluid volume deficit: 2% impaired mobility) Moderate fluid volume deficit: 2%– Impaired thirst sensation 5% Therapeutic withholding of fluids Severe fluid deficit: 8% or greater Unconsciousness or inability to Compensatory Increase in express thirst Antidiuretic Hormone Excessive Gastrointestinal Fluid Decreased urine output Losses Increased osmolality and specific Vomiting gravity Diarrhea Increased Serum Osmolality Gastrointestinal suction Thirst Draining gastrointestinal fistula Increased hematocrit and blood urea Excessive Renal Losses nitrogen Diuretic therapy Decreased Vascular Volume Osmotic diuresis (hyperglycemia) Postural hypotension Adrenal insufficiency (Addison Tachycardia, weak and thready pulse disease) Decreased vein filling and increased Salt-wasting kidney disease vein refill time Excessive Skin Losses Hypotension and shock Fever Decreased Extracellular Fluid Exposure to hot environment Volume Burns and wounds that remove skin Depressed fontanelle in an infant Third-Space Losses Sunken eyes and soft eyeballs Intestinal obstruction Impaired Temperature Regulation Edema Elevated body temperature Ascites Burns (first several days) Excess sodium and water losses also can occur through the kidney. Some kidney diseases are characterized by salt wasting because of 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, resultant loss of ECF, and 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. In hot weather, water losses through sweating may be increased by as much as 1 to 3 L/hour.2 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 8-4). A loss in fluid volume is accompanied by a decrease in body weight. One liter of water weighs 1 kg (2.2 lb). Mild ECF deficit exists when weight loss equals 2% of body weight. Because 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 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. Eyes become sunken and feel softer than normal as the fluid content in the anterior chamber decreases. Fluids add resiliency to the skin and underlying tissues (skin or tissue turgor). Tissue turgor is assessed by pinching a fold of skin between the thumb and the forefinger, which

should immediately return to its original configuration when the fingers are released.15 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 fontanelle.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 fontanelle because of a decrease in CSF. Arterial and venous volumes decline during periods of fluid deficit, as does filling of capillary circulation. As the volume in the arterial system declines, the blood pressure decreases, the heart rate increases, and the pulse becomes weak and thready. Postural hypotension is an early sign of fluid deficit. 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: accurate measurements 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 deficit, 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.16 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.

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, 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 is usually due to increased total body sodium 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 8-5). Heart failure decreases effective circulating volume and renal blood flow with a compensatory increase in sodium and water retention. People with severe congestive heart failure maintain a precarious balance between sodium and water. Small increases in sodium intake can precipitate fluid volume excess and a worsening of heart failure. Circulatory overload results from an increase in blood volume; it can occur during infusion or transfusion if the amount or rate of administration is excessive. Liver failure impairs aldosterone metabolism and decreases effective circulating volume and renal perfusion, leading to increased salt and water retention. Corticosteroid hormones increase sodium reabsorption by the kidneys. People taking corticosteroid medications and those with Cushing disease often have problems with sodium retention. TABLE 8-5 Causes and Manifestations of Isotonic Fluid Volume Excess

Causes

Manifestations

Causes Manifestations Inadequate Sodium and Water Elimination Acute Weight Gain (% Congestive heart failure Body Weight) Renal failure Mild fluid volume excess: Increased corticosteroid levels 2% Hyperaldosteronism Moderate fluid volume Cushing disease excess: 5% Liver failure (e.g., cirrhosis) Severe fluid volume Excessive Sodium Intake in Relation to excess: 8% or greater Output Increased Interstitial Excessive dietary intake Fluid Volume Excessive ingestion of sodium-containing Dependent and generalized medications or home remedies edema Excessive administration of sodium-containing Increased Vascular parenteral fluids Volume Excessive Fluid Intake in Relation to Output Full and bounding pulse Ingestion of fluid in excess of elimination Venous distention Administration of parenteral fluids or blood at Pulmonary edema an excessive rate Shortness of breath Crackles Dyspnea Cough 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 8-5). Edema is characteristic of isotonic fluid excess. When the excess fluid accumulates gradually, as happens in debilitating diseases and starvation, edema fluid may mask loss of tissue mass. There may be a decrease in BUN and hematocrit as a result of dilution because of plasma volume expansion. 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, there are complaints of shortness of breath and difficulty breathing, respiratory

crackles, and a productive cough. Ascites and pleural effusion may occur with severe fluid volume excess. 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 sodiumrestricted 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. Because sodium and its attendant anions account for 90% to 95% of the osmolality of ECF, serum osmolality (normally 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 a common electrolyte disorder seen in general hospital patients and in the outpatient population. A number of age-related events make the older adult population more vulnerable to hyponatremia, including decreased 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, hyponatremia can present as a hypotonic or hypertonic state.2 Hypertonic (translocational) hyponatremia results from an osmotic shift of water from the ICF to ECF such as that occurring in hyperglycemia. In this case, the sodium in the ECF becomes diluted as water moves out of cells in response to the osmotic effects of elevated blood glucose levels. Hypotonic (dilutional)

hyponatremia, 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.2,12 Due to its effect on sodium and water elimination, diuretic therapy can cause hypovolemic or euvolemic hyponatremia. Hypovolemic hypotonic hyponatremia occurs when water is lost along with sodium, resulting in low plasma level, but to a lesser extent.17 Among the causes of hypovolemic hyponatremia are excessive sweating in hot weather, particularly during heavy exercise, which leads to loss of salt and water. Hyponatremia develops when water, rather than electrolytecontaining liquids, is used to replace fluids lost in sweating. Another potential cause 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 the most common, accounting for up to 60% of all hyponatremia cases, and is usually a result of SIADH.17 The risk of normovolemic hyponatremia is increased during the postoperative period when 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 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).17 Clinical Manifestations The manifestations of hypotonic hyponatremia are largely related to sodium dilution (Table 8-6). Serum osmolality is decreased, and cellular swelling occurs owing to the movement of water from the ECF to the ICF. 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. Fingerprint edema is a sign of excess intracellular water and is demonstrated by pressing firmly over the bony surface of the sternum for 15 to 30 seconds. Fingerprint edema exists if an indent remains where the pressure was applied. TABLE 8-6 Causes and Manifestations of Hyponatremia

Causes Manifestations Hypotonic Hyponatremia Laboratory Values Hypovolemic (Decreased Serum Serum sodium levels below 135 mEq/L Sodium with Decreased ECF (135 mmol/L) Volume) Hypotonic hyponatremia Use of excessively diluted infant Serum osmolality 280 mOsm/kg formula Dilution of blood components, including Administration of sodium-free hematocrit, BUN parenteral solutions Hypertonic hyponatremia Gastrointestinal losses Serum osmolality >280 mOsm/kg Vomiting, diarrhea Signs Related to Hypoosmolality of Sweating, with sodium-free fluid ECFs and Movement of Water into replacement Brain Cells and Neuromuscular Tissue Repeated irrigation of body Muscle cramps cavities with sodium-free Weakness solutions Headache Irrigation of gastrointestinal tubes Depression with distilled water Apprehension, feeling of impending Tap water enemas doom

Personality changes Causes Manifestations Use of nonelectrolyte irrigating Lethargy solutions during prostate surgery Stupor, coma Gastrointestinal Manifestations Third spacing (paralytic ileus, Anorexia, nausea, vomiting pancreatitis) Abdominal cramps, diarrhea Diuretic use Increased ICF Mineralocorticoid deficiency Fingerprint edema (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 Hypertonic Hyponatremia Manifestations largely related to (Osmotic Shift of Water from hyperosmolality of ECFs the ICF to the ECF Compartment) Hyperglycemia ADH, antidiuretic hormone; BUN, blood urea nitrogen; ECF, extracellular fluid; ICF, intracellular fluid; MDMA, 3,4-

methylenedioxymethamphetamine; SIADH, syndrome of inappropriate antidiuretic hormone. 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. Concept Mastery Alert The cells of the brain and nervous system are the most seriously affected by increases in intracellular water. Symptoms include apathy, lethargy, and headache, 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).2 The term water intoxication is often used to describe the neurologic effects of acute hypotonic hyponatremia. 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. Saline solution administration is used 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. ADH V2 receptor antagonists to the antidiuretic action of ADH (aquaretics) offer treatment for euvolemic hyponatremia.15 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.2 Etiology Hypernatremia represents a deficit of water in relation to the body’s sodium stores due to a 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 with insufficient time or opportunity for water ingestion can produce a disproportionate gain in sodium (Table 87). This can occur with critically ill people who present with multiple needs for fluid resuscitation and electrolyte balance. Hypernatremia is an independent risk factor linked highly with increased mortality.17 TABLE 8-7 Causes and Manifestations of Hypernatremia

Causes

Manifestations

Causes Manifestations Excessive Water Losses Laboratory Values Watery diarrhea Serum sodium level above 145 mEq/L Excessive sweating (145 mmol/L) Increased respirations because of Increased serum osmolality conditions such as Increased hematocrit and BUN tracheobronchitis Thirst and Signs of Increased ADH Hypertonic tube feedings Levels Diabetes insipidus Polydipsia Decreased Water Intake Oliguria or anuria Unavailability of water High urine specific gravity Oral trauma or inability to Intracellular Dehydration swallow Dry skin and mucous membranes Impaired thirst sensation Decreased tissue turgor Withholding water for therapeutic Tongue rough and fissured reasons Decreased salivation and lacrimation Unconsciousness or inability to Signs Related to Hyperosmolality of express thirst ECFs and Movement of Water Out of Excessive Sodium Intake Brain Cells Rapid or excessive administration Headache of sodium-containing parenteral Agitation and restlessness solutions Decreased reflexes Near-drowning in salt water Seizures and coma Extracellular Dehydration and Decreased Vascular Volume Tachycardia Weak and thready pulse Decreased blood pressure Vascular collapse ADH, antidiuretic hormone; BUN, blood urea nitrogen; ECF, extracellular fluid. 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 and two thirds in the ICF compartment, more actual water volume is lost from the ICF than from 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. Clinical Manifestations The clinical manifestations of hypernatremia caused by water loss are largely those of ECF loss and cellular dehydration (see Table 8-7). The severity of signs and symptoms is greatest when the increase in plasma sodium is large and occurs rapidly. Body weight decreases in proportion to the amount of water 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 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 blood pressure drops. Hypernatremia produces an increase in serum osmolality and pulls water 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 and subcutaneous tissues assume a firm, rubbery texture. Most significantly, water is 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 Diagnosis of hypernatremia is based on history, physical findings of dehydration, and results of laboratory tests. Treatment of hypernatremia

includes treating the underlying cause and fluid replacement therapy to treat the accompanying dehydration. The oral route for replacement fluids is preferable. A serious aspect 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 osmolytes have 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. SUMMARY CONCEPTS Body fluids are distributed between the ICF and ECF compartments. Regulation of fluid volume, solute concentration, and distribution between the two compartments depend 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 that 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 due to 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 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. Sodium controls the ECF osmolality and its effect on cell

volume. Hyponatremia can present as hypertonic hyponatremia in which water moves out of the cell in response to elevated blood glucose levels or as hypotonic 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, 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 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.2 Gains and Losses Potassium intake is normally derived from dietary sources. Potassium balance usually can be maintained by a daily dietary intake of 50 to 100

mEq. Additional potassium is needed during periods of trauma and stress. Mechanisms of Regulation Normally, the ECF concentration of potassium is regulated at about 4.2 mEq/L (4.2 mmol/L). Precise control is necessary because many functions are sensitive to even small changes in ECF potassium levels. An increase in potassium of 0.3 to 0.4 mEq/L (0.3 to 0.4 mmol/L) can cause serious cardiac dysrhythmias and even death. A single meal may contain as much as 50 mEq, which means the daily intake can be as high as 200 mEq/L. Therefore, it is important for the kidneys to rapidly remove this extracellular potassium to avoid serious complications.2 Plasma potassium is largely regulated through: (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 via 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. 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 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 the muscle, liver, and bone. This is controlled by 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 βadrenergic 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. 8-8). 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 increase cellular uptake of K+ by increasing the activity of the Na+/K+-ATPase membrane pump.1 β-Adrenergic agonist drugs, such as pseudoephedrine and albuterol, have a similar effect on potassium distribution.

FIGURE 8-8

Mechanisms regulating transcellular shifts in potassium.

Exercise also produces compartmental shifts in potassium. Repeated muscle contraction releases potassium into the ECF, especially during exhaustive exercise. 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 mechanisms 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 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 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 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 primarily by the ratio of ICF to ECF potassium concentration (Fig. 8-9). A decrease in plasma potassium causes the resting membrane potential to become more negative, moving it further from the threshold. Thus, it takes a greater stimulus to open the sodium channels for an action potential. An increase in plasma potassium causes the resting membrane potential to become more positive, moving it closer to threshold. Severe hyperkalemia may cause prolonged depolarization that can decrease excitability. The rate of repolarization varies with plasma potassium levels. It is more rapid in hyperkalemia and delayed in hypokalemia. The inactivation of the sodium channels and rate of membrane repolarization are important because they predispose to cardiac arrhythmias or conduction defects. Hyperkalemia is one of the most life-threatening electrolyte disturbances, especially with children.18

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. FIGURE 8-9

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 a result of movement between the ICF and ECF compartments. Etiology The causes of potassium deficit can be (1) inadequate intake; (2) excessive gastrointestinal, renal, and skin losses; and (3) redistribution between the ICF and ECF compartments (Table 8-8).2 TABLE 8-8 Causes and Manifestations of Hypokalemia

Causes Inadequate Intake Diet deficient in potassium Inability to eat Administration of potassium-free parenteral solutions Excessive Renal Losses Diuretic therapy (except potassiumsparing diuretics) Diuretic phase of renal failure Increased mineralocorticoid levels Primary hyperaldosteronism Treatment with corticosteroid drugs Excessive Gastrointestinal Losses Vomiting Diarrhea Gastrointestinal suction Draining gastrointestinal fistula Transcompartmental Shift Administration of β-adrenergic agonist (e.g., albuterol) Administration of insulin for treatment of diabetic ketoacidosis Alkalosis, metabolic or respiratory

Manifestations Laboratory Values Serum potassium level below 3.5 mEq/L (3.5 mmol/L) Impaired Ability to Concentrate Urine Polyuria Urine with low osmolality and specific gravity Polydipsia Gastrointestinal Manifestations Anorexia, nausea, vomiting Constipation Abdominal distention Paralytic ileus Neuromuscular Manifestations Muscle flabbiness, weakness, and fatigue Muscle cramps and tenderness Paresthesias Paralysis Cardiovascular Manifestations Postural hypotension Increased sensitivity to digitalis toxicity Changes in electrocardiogram Cardiac dysrhythmias Central Nervous System Manifestations Confusion Depression Acid–Base Disorders Metabolic alkalosis

Inadequate Intake. Inadequate intake is a frequent cause of hypokalemia. A potassium intake of at least 40 to 50 mEq is needed daily. Insufficient dietary intake may

result from the inability to obtain or ingest food from a diet that is low in potassium. Potassium intake is often inadequate in persons on fad diets and those with eating disorders. Older adults are more likely to have potassium deficits due to poor eating habits, limited income, and difficulty chewing foods. Excessive Losses. The kidneys, which are the main source of potassium loss, 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.2 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. Magnesium depletion (often caused by diuretic therapy or diarrhea) results in renal potassium wasting. Importantly, the ability to correct potassium deficiency is impaired when magnesium deficiency is present. 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.2 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.2 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.2 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 because of renal magnesium wasting.2 Liddle syndrome has manifestations

similar to Bartter syndrome, but with high blood pressure because of excessive sodium reabsorption.2 Although potassium losses from the skin and the gastrointestinal tract usually are minimal, they can become excessive under certain conditions. For example, burns increase surface losses of potassium. Increased secretion of aldosterone during heat acclimatization increases the loss of potassium in urine and sweat. Gastrointestinal losses occur 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. 8-8). Insulin increases the movement of glucose and potassium into cells; and β2-adrenergic agonist drugs shift potassium into cells and cause transient hypokalemia.

Electrocardiographic changes with hypokalemia and hyperkalemia. AV, atrioventricular. FIGURE 8-10

Clinical Manifestations The manifestations of hypokalemia include alterations in renal, gastrointestinal, cardiovascular, and neuromuscular function (see Table 88). These manifestations reflect both the intracellular functions of potassium and 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. Metabolic alkalosis and renal chloride wasting are signs of severe hypokalemia.2 Signs and symptoms associated with gastrointestinal function include 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 on cardiovascular function. Postural hypotension is common. Most people with plasma potassium levels below 3 mEq/L (3 mmol/L) demonstrate electrocardiographic (ECG) changes typical of hypokalemia, which include prolongation of the PR interval, ST segment depression, T-wave flattening, and appearance of a prominent U wave (Fig. 8-10). 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, lengthens the relative refractory period, and produces a U wave. 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 and an increased risk of ventricular arrhythmias are risk factors 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. Weakness, fatigue, and muscle cramps, particularly during exercise, are common in moderate hypokalemia (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. SUMMARY CONCEPTS Calcium, phosphorus, and magnesium are major divalent ions in the body. Approximately 99% of body calcium is found in bone; less than 1% is found in the ECF compartment. 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 contributes to neuromuscular function, plays a vital role in the blood clotting process, and participates in a number of enzyme reactions. Neural excitability is increased in hypocalcemia and decreased in hypercalcemia. 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 neural dysfunction, disturbed musculoskeletal function, and hematologic disorders. Most of these result from a deficiency in ATP and O2 transport by 2,3-DPG 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 intracellular enzyme reactions and is required for cellular energy metabolism, functioning of the Na+/K+-ATPase membrane pump, nerve conduction, ion transport, and potassium and calcium channel activity. 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. More than half of the body’s magnesium can be found in the bones.2 Magnesium deficiency can result from insufficient intake, excessive losses, or movement between the ECF and ICF compartments. Hypomagnesemia impairs PTH release and PTH actions; 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.

Mechanisms of Acid–Base Balance The concentration of body acids and bases is regulated so that the pH of extracellular body fluids is 7.35 to 7.45. This is maintained through mechanisms that generate, buffer, and eliminate acids and bases. This section 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+.37-39 For example, hydrochloric acid (HCl) dissociates in water to form hydrogen (H+) and chloride (Cl−) ions. 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 carbonic acid (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. 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+. 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).1,3 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. Overall, there are three ways to assess changes in acid–base balance: (1) the more traditional method of the Henderson–Hasselbalch (physiologic) approach, which looks at the relationship between HCO3− and PCO2; (2) the standard base excess approach; and (3) the Stewart (quantitative) approach, which looks at strong ion differences and total weak acids.40,41 KEY POINTS Mechanisms of Acid–Base Balance pH is regulated by extracellular and intracellular systems that buffer changes in pH that would otherwise occur due to metabolic production of volatile and nonvolatile acids. Metabolic Acid and Bicarbonate Production

Acids are continuously generated as by-products of metabolic processes (Fig. 8-12). These acids fall into two physiologic groups: the volatile acid H2CO3 and all other nonvolatile or fixed acids. The difference between the two arises because H2CO3 is in equilibrium with CO2 (H2CO3 ↔ CO2 + H2O), which is volatile and leaves the body via 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, and phosphoric). Instead, these are buffered by body proteins or extracellular buffers, such as HCO3−, and then eliminated by the kidney.

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 (sulfuric, 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 kidneys FIGURE 8-12

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. The respiratory system disposes of carbon dioxide (CO2). (From Rhodes R. A., Bell D. R. (2017). Medical physiology principles for clinical medicine (5th ed., Fig. 24.2, p. 488). Philadelphia, PA: Wolters Kluwer.) Carbon Dioxide and Bicarbonate Production Body metabolism results in the production of approximately 15,000 mmol of CO2 each day.42 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”) Collectively, dissolved CO2 and HCO3− account for approximately 77% of the CO2 that is transported in the ECF; the remaining CO2 travels as carbaminohemoglobin.37 Although CO2 is a gas and not an acid, a small percentage combines with water to form H2CO3. This reaction that generates H2CO3 is catalyzed by CA, which is present in large quantities in RBCs, renal tubular cells, and other tissues. The rate of the reaction between CO2 and water is increased approximately 5000 times by the presence of CA. 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. H2CO3 content of the blood can be calculated by multiplying the partial pressure of CO2 (PCO2) by its solubility coefficient (0.03). The concentration of H2CO3 in 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.39,43 Oxidation of the sulfur-containing amino acids results in the production of sulfuric acid. Oxidation of arginine and lysine produces HCl, 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 results in the production of ketoacids. The major source of base is the metabolism of amino acids such as aspartate and glutamate and of certain organic anions. Acid production normally exceeds base production during the breakdown of consumed foods in a person eating a diet of meat and vegetables.3 A normal diet results in 50 to 100 mEq of H+ each day as nonvolatile sulfuric acid.6 A vegetarian diet, which contains large amounts of organic anions, results in the net production of base.39 Calculation of pH Plasma pH can be calculated with the Henderson–Hasselbalch equation, which uses the pKa of the bicarbonate buffer system (6.1) and log10 of the ratio of HCO3− to H2CO337-39: The pH designation was created to express the low value of H+ more easily.2 Plasma pH decreases when the ratio is less than 20:1 and increases when the ratio is greater than 20:1 (Fig. 8-13). Because it is the ratio of HCO3− or CO2 that determines pH, pH can remain within a normal range as long as changes in HCO3− are accompanied by similar changes in CO2, or vice versa. Plasma pH only indicates the balance or ratio, not where problems originate.9

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 FIGURE 8-13

mechanisms are capable of buffering large changes in pH but do not return the pH completely to normal as illustrated here. 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 ICF and 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 system37,39 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. Bone represents an additional source of acid–base buffering.10 Excess H+ 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 buffer excess acids. 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 CKD are at particular risk for reduction in bone calcium because of acid retention. UNDERSTANDING

Carbon Dioxide Transport

Metabolism results in a continuous production of carbon dioxide (CO2). As CO2 is formed, it diffuses out of cells into tissue spaces and 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.

1 Plasma

About 10% of CO2 produced is transported in the dissolved state to the lungs and 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). Each 100 mL of arterial blood with a PCO2 of 40 mm Hg

contains 1.2 mL of dissolved CO2. Carbonic acid (H2CO3) is formed from hydration of dissolved CO2, which contributes to blood pH.

2 Bicarbonate

Carbon dioxide in excess of that which can be carried in the plasma moves into RBCs where carbonic anhydrase (CA) catalyzes its conversion to carbonic acid (H2CO3). H2CO3 dissociates into H+ and HCO3−. H+ combines with hemoglobin and HCO3− diffuses into plasma, where it participates in acid–base regulation. The movement of HCO3− into plasma is via a transport system on the RBC membrane in which HCO3− ions are exchanged for chloride ions (Cl−). Ventilation and kidney handling of HCO3− determine plasma HCO3− concentration.7

3 Hemoglobin

Remaining CO2 in RBCs combines with hemoglobin to form carbaminohemoglobin (HbCO2).2 This reversible reaction creates a loose bond so CO2 can be released in capillaries and exhaled. 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 NaHCO3 as its weak base.37,38 It substitutes the weak H2CO3 for a strong acid such as HCl (NaHCO3 + HCl → H2CO3 + NaCl) or the weak bicarbonate base for a strong base such as sodium hydroxide (H2CO3 + NaOH → HCO3- + H2O). The bicarbonate buffer system is a particularly efficient system because its components can be readily added or removed from the body.37-39 Metabolism provides an ample supply of CO2, which can replace any H2CO3 that is lost when 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.37,38 They are amphoteric (can function either as acids or as bases) and 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. Due to slow movement of H+ and HCO3− across cell membranes, buffering extracellular acid–base imbalances is delayed for several hours.37 Albumin and plasma globulins are the major protein buffers in the vascular compartment. Hydrogen–Potassium Exchange The transcompartmental exchange of H+ and K+ is another important system for regulation of acid–base balance. H+ and K+ are positively charged and move freely between the ICF and ECF compartments. Excess H+ in the ECF moves into the ICF in exchange for K+, and excess K+ in the ECF moves into the ICF in exchange for H+. Thus, alterations in K+ levels can affect acid–base balance, and changes in acid–base balance can influence K+ levels. K+ shifts tend to be more pronounced in metabolic acidosis than in respiratory acidosis.3 Metabolic acidosis caused by an accumulation of nonorganic acids (e.g., HCl that occurs in diarrhea and phosphoric acid that occurs in CKD) produces a greater increase in extracellular K+ levels than does acidosis caused by an accumulation of organic acids (e.g., lactic acid and ketoacids). Respiratory Control Mechanisms The second line of defense against acid–base disturbances when chemical buffers do not minimize H+ changes is control of extracellular CO2 by the lungs.38,42 Increased ventilation decreases PCO2 and decreased ventilation increases PCO2. Blood PCO2 and pH are important regulators of ventilation. Chemoreceptors in the brainstem and peripheral chemoreceptors in the carotid and aortic bodies sense changes in PCO2 and pH and alter the ventilation rate. When the H+ concentration is above normal, the respiratory system is stimulated and ventilation is increased. This control of pH occurs within minutes and is maximal within 12 to 24 hours. Although the respiratory response is rapid, it does not completely return pH to normal. It is only about 50% to 75% effective as a buffer system.37,38 But in acting rapidly it prevents large changes in pH from occurring while waiting for the more slowly reacting kidneys to respond.

Renal Control Mechanisms The kidneys are the third line of defense in acid–base disturbances and play three major roles in regulating acid–base balance.38,39 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.37-39 The kidneys also play a role in controlling pH: in conditions of acid load, ammonium (NH4+) production and excretion allow for acid secretion and pH normalization.38 The renal mechanisms for regulating acid–base balance begin to 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 Conservation The kidneys regulate pH by excreting excess H+, reabsorbing HCO3−, and producing new HCO3−. HCO3− is freely filtered in the glomerulus and reabsorbed in the tubules.37,39 Loss of 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 H+ secretion and HCO3− reabsorption take place in the proximal tubule.42 It 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. 8-14). The secreted H+ combines with filtered HCO3− to form H2CO3. H2CO3 then decomposes into CO2 and H2O. 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: CO2 and H2O combine to form a new H2CO3 molecule in a CA-mediated reaction. The H2CO3, in turn, is dissociated into HCO3− and H+. 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.

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 extracellular fluid. ATP, adenosine triphosphate. FIGURE 8-14

Tubular Buffer Systems Because an extremely acidic urine filtrate would be damaging to the urinary tract, the minimum urine pH is about 4.5.37,38 Once the urine reaches this level of acidity, H+ secretion ceases. This limits the amount of unbuffered H+ eliminated by the kidney and 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.37,43 The HCO3− that is generated by these two buffer systems is new HCO3−, 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 are concentrated in the tubular fluid due to their relatively poor absorption and because of reabsorption of water from the tubular fluid. Another factor that makes phosphate effective as a urinary buffer is 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. 8-15). After H+ combines with HPO42–, it can be excreted as NaH2PO4, carrying the excess H+ with it.

The renal phosphate buffer system. The monohydrogen phosphate ion (HPO42–) enters the renal tubular fluid in the glomerulus. An H+ combines with HPO42– to form H2PO4− and is then excreted into the urine in combination with Na+. The HCO3− moves into the extracellular fluid (ECF) along with the Na+ that was FIGURE 8-15

exchanged during secretion of the H+. ATP, adenosine triphosphate; CA, carbonic anhydrase. Another important but more complex buffer system is the ammonia buffer system. The excretion of H+ and generation of HCO3− by the ammonia buffer system occur 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 tubules37,39 The metabolism of glutamate in the proximal tubule results in the formation of two NH4+ and two HCO3− ions1,3 (Fig. 8-16). 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. So, for each molecule of glutamine metabolized in the proximal tubule, two NH4+ are secreted into the tubular filtrate, and two HCO3− are reabsorbed into the blood. HCO3− generated in this way constitutes a new HCO3−.

Acidification along the nephron. The pH of tubular urine decreases along the proximal convoluted tubule, rises along the descending limb of the loop of Henle, falls along the ascending limb, and reaches its lowest values in the collecting ducts. Ammonia (NH3 FIGURE 8-16

+ 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 Rhodes R. A., Bell D. R. (2017). Medical physiology: Principles for clinical medicine (5th ed., Fig. 24.5, p. 492). Philadelphia, PA: Wolters Kluwer.) A significant portion of the NH4+ secreted by the proximal tubular cells is reabsorbed in the thick ascending loop of Henle where NH4+ substitutes K+ on the Na+/K+/2Cl− cotransporter.43 NH4+ is not lipid soluble and thus is trapped in the tubular fluid and excreted in urine. Note that the source of H+ secreted by the cells of the collecting tubules is CO2 and H2O. Thus, for each H+ produced in the cells and secreted, an additional new HCO3− is generated and added to the blood. 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.37 However, with chronic acidosis, it can become the dominant mechanism for H+ excretion and new HCO3− generation. The urine anion gap (AG), 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 Hypokalemia is a potent stimulus for H+ secretion and HCO3− reabsorption. When plasma K+ levels fall, K+ moves from ICF into ECF, whereas H+ moves from ECF into ICF. A similar process occurs in the distal tubules of the kidney, where the H+/K+-ATPase exchange pump actively reabsorbs K+ and secretes H+.37,39 Elevation in plasma K+ levels has the opposite effect. Thus, acidosis tends to increase H+ elimination and decrease K+ elimination, with an increase in plasma potassium levels, whereas alkalosis tends to decrease H+ elimination and increase K+ elimination, with a decrease in plasma K+ levels.45 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.

Chloride–Bicarbonate Exchange Another mechanism that the kidneys use in regulating HCO3− is the chloride–bicarbonate anion exchange that occurs with Na+ reabsorption. Cl− is absorbed with Na+ throughout the tubules. In situations of volume depletion, the kidneys substitute HCO3− for Cl−, thereby increasing absorption of HCO3−. Hypochloremic alkalosis refers to an increase in pH induced by excess HCO3− reabsorption because of a decrease in Cl− levels, and hyperchloremic acidosis refers to a decrease in pH because of decreased HCO3− reabsorption because of 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 AGs. 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 assesses 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 tissues that empty into the sampled vein. H2CO3 levels can be determined from arterial blood gas measurements using PCO2 and the solubility coefficient for CO2 (normal arterial PCO2 is 35 to 45 mm Hg). Arterial blood gases provide a measure of blood oxygen (PO2) levels, which can be important in assessing respiratory function. 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 venous HCO3− is 24 to 31 mEq/L (24 to 31 mmol/L) and of arterial HCO3− is 22 to 26 mEq/L (22 to 26 mmol/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−. 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). Base excess or deficit can be viewed as a measurement of HCO3− excess or deficit and indicates a nonrespiratory change in acid–base balance. Base excess indicates metabolic alkalosis, and base deficit indicates metabolic acidosis. Anion Gap The AG describes the difference between the plasma concentration of the major measured cation (Na+ and K+) and the sum of the measured anions (Cl− and HCO3−).37,44 This difference represents the concentration of unmeasured anions, such as phosphates, sulfates, organic acids, and proteins (Fig. 8-17). Normally, AG ranges between 8 and 16 mEq/L1 (a value range of 12 to 20 mEq/L is normal when potassium is included in the calculation).45 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 correction factor should be added to the gap that is calculated from the following formula: AG = Na+ – (Cl− + HCO3−).46 The AG is used in diagnosing causes of metabolic acidosis.39,47,48 An increased level is found in conditions such as lactic acidosis, alcoholic acidosis, poisoning by substances such as salicylate and ethylene glycol (antifreeze), and ketoacidosis that results from elevated levels of metabolic acids.37,44 A low AG is found in conditions that produce a fall in unmeasured anions or rise in unmeasured cations. The latter can occur in hyperkalemia, hypercalcemia, hypermagnesemia, lithium intoxication, or multiple myeloma (when an abnormal immunoglobulin is produced).44

The anion gap in acidosis because of 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. FIGURE 8-17

SUMMARY CONCEPTS 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 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 AG. Base excess or deficit is the amount of a fixed acid or base that must be added to a blood sample to achieve a pH of 7.4. The AG describes the difference between the plasma concentration of the major measured cations (Na+ and K+) and the sum of the anions (Cl− and HCO3−). This difference represents the concentration of unmeasured anions which are present.

Disorders of Acid–Base Balance 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 Na+ or K+ with a highly basic ion such as an OH−. Sodium bicarbonate is the main alkali in the ECF. Although definitions differ somewhat, alkali and base are often used interchangeably.37 Hence, the term alkalosis is the opposite of acidosis. Alkalosis is removal of excess H+ ions from body fluids, whereas acidosis is the addition of excess H+ ions. Typically, imbalances in acid– base result in acidosis. Alkalosis is usually compensatory. Metabolic Versus Respiratory Acid–Base Disorders There are two types of acid–base disorders: metabolic and respiratory (Table 8-16). Metabolic disorders produce an alteration in the plasma

HCO3− concentration and result from the addition of or loss from the ECF of nonvolatile acid or alkali. A reduction in pH because of a decrease in HCO3− is called metabolic acidosis, and an elevation in pH because of 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. TABLE 8-16 Summary of Single Acid–base Disturbances and Their Compensatory Responses

Acid–Base Primary Respiratory Imbalance Disturbance Compensation and Predicted Response* Metabolic ↓pH and ↑ventilation and ↓PCO2 acidosis HCO3− 1 mEq/L HCO3− < 22 ↓HCO3− → 1–1.2 mm mEq/L Hg ↓PCO2 Metabolic ↑pH and ↓ventilation and ↑PCO2 alkalosis HCO3− 1 mEq/L HCO3− > 26 ↑HCO3− → 0.7 mm Hg mEq/L ↑PCO2 Respiratory ↓pH and None acidosis ↑PCO2 PCO2 > 45 mm Hg

Renal Compensation and Predicted Response*,† ↑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 → .1 mEq/L ↑HCO3− Chronic: 1 mm Hg ↑PCO2 → 0.3 mEq/L ↑HCO3−

Acid–Base Primary Respiratory Imbalance Disturbance Compensation and Predicted Response* Respiratory ↑pH and None alkalosis ↓PCO2 PCO2 < 35 mm Hg

Renal Compensation and Predicted Response*,† ↓H+ excretion and ↓HCO3− reabsorption Acute: 1 mm Hg ↓PCO2 → .2 mEq/L ↓HCO3− Chronic: 1 mm Hg ↓PCO2 → .4 mEq/L ↓HCO3− 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.1 Acute renal compensation refers to a duration of minutes to several hours; chronic renal compensation refers to a duration of several days.1 †

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, there may be primary metabolic acidosis due to overproduction of ketoacids and respiratory alkalosis due to compensatory increase in ventilation (see Table 8-16). Compensatory mechanisms provide a means to control pH when correction is impossible or cannot be achieved immediately. Often, compensatory mechanisms are 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. The body can 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.39 This is because renal compensation for a respiratory disorder may take days, but the respiratory compensation for a metabolic disorder is within minutes to hours.39 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. It is not uncommon for people to present with more than one primary disorder or a “mixed disorder.”39 For example, a person may present with a low plasma HCO3− concentration because of metabolic acidosis and a high PCO2 because of chronic lung disease. Values for the predicted renal or respiratory compensatory responses can be used in the diagnosis of these mixed acid–base disorders39 (see Table 8-16). If the values for the compensatory response fall outside the predicted plasma values, it can then be concluded that 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. Primary respiratory disorders, on the other hand, have two ranges of predicted values, one for the acute and one for the chronic response. Renal compensation takes several days to be fully effective. The acute compensatory response represents HCO3− levels before renal compensation and the chronic response after renal compensation. Thus, plasma pH values 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 generation of bicarbonate by the kidney.

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. It is the most common acid–base disorder. 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 on average by 1.3 mm Hg for each 1 mEq/L fall in HCO3−,3 with a range of 1 to 1.5 mm Hg for each 1 mEq/L fall in HCO3−. 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 3. Excessive loss of bicarbonate through the kidneys or gastrointestinal tract 4. Increased plasma Cl− concentration37,46 The AG is useful in determining the cause of the metabolic acidosis (Chart 8-4). The presence of excess metabolic acids produces an increase in the AG as sodium salt of the offending acid replaces sodium bicarbonate. Diarrhea is a frequent cause of a normal AG metabolic acidosis.1 When the acidosis results from increased plasma Cl− levels (e.g., hyperchloremic acidosis), the AG 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]). The causes of metabolic acidosis are summarized in Table 817.49 Non–AG acidosis is most often caused by loss of large quantities of base because of profuse diarrhea or the administration of large amounts of solutions that contain Cl−, causing the AG to fall within normal limits.37 TABLE 8-17 Causes and Manifestations of Metabolic Acidosis

Causes

Manifestations

Causes 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) 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

CHART 8.4

Manifestations Blood pH, HCO3−, CO2 pH decreased HCO3− (primary) decreased PCO2 (compensatory) decreased 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

THE ANION GAP IN DIFFERENTIAL DIAGNOSIS OF METABOLIC ACIDOSIS Decreased Anion Gap (16 mEq/L)45 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 to 16 mEq/L)45 Loss of bicarbonate Diarrhea Pancreatic fluid loss Ileostomy (unadapted) Chloride retention Renal tubular acidosis Ileal loop bladder Parenteral nutrition (arginine, histidine, and lysine) Lactic Acidosis Acute lactic acidosis is a 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. Lactic acid is produced by the anaerobic metabolism of glucose. Most cases of lactic acidosis are

caused by inadequate oxygen delivery, or hypoxia, as in shock or cardiac arrest.50 Such conditions not only increase lactic acid production but also impair lactic acid clearance because of poor liver and kidney perfusion. Mortality rates are high because of shock and tissue hypoxia.51 Severe sepsis is commonly associated with lactic acidosis, and hyperlactatemia can be a strong predictor of mortality for people with sepsis.52 Lactic acidosis can occur during intense exercise in which the metabolic needs of the muscles outpace their aerobic capacity for production of ATP, causing them to revert to anaerobic metabolism and produce lactic acid.51 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. 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. Drugs such as the antidiabetic drug metformin can produce life-threatening lactic acidosis by inhibiting certain functions in the liver. Ketoacidosis Ketoacids 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. 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.42 A 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. 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.53 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.53,54 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.

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. Although aspirin is the most common cause of salicylate toxicity, other salicylate preparations such as salicylic acid may produce similar effects. Salicylate overdose produces serious toxic effects, including death. Serum salicylate levels along with clinical findings are important in predicting morbidity and mortality following ingestion.55 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. 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) can be absorbed through the skin or gastrointestinal tract or inhaled through the lungs. In addition to metabolic acidosis, methanol produces severe optic nerve and CNS 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. Its sweet taste leads to abuse and toxicity. Acidosis occurs as ethylene glycol is converted to oxalic and lactic acid. Decreased Renal Function CKD 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 CKD, 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 renal tubular acidosis, glomerular function is normal or mildly

impaired, but the tubular secretion of H+ or reabsorption of HCO3− is abnormal.56 Increased Bicarbonate Losses Increased HCO3− losses occur with loss of HCO3−-rich body fluids or with impaired conservation of HCO3− by the kidney. Intestinal secretions have a high HCO3− concentration, so excessive loss of HCO3− occurs with severe diarrhea; small bowel, pancreatic, or biliary fistula drainage; ileostomy drainage; ileal bladder and intestinal suction. In diarrhea of microbial origin, secreted HCO3− neutralizes metabolic acids produced by the microorganisms causing the diarrhea.57 Hyperchloremic Acidosis Hyperchloremic acidosis occurs when Cl− levels are increased out of proportion to Na+.46 Because Cl− and HCO3− are exchangeable anions, plasma HCO3− decreases when Cl− increases. Hyperchloremic acidosis can occur as the result of abnormal absorption of Cl− by the kidneys or treatment with chloride-containing medications (i.e., NaCl, amino acid– chloride solutions, and ammonium chloride). Ammonium chloride is broken down into NH4+ and Cl−. NH4+ is converted to urea in the liver, leaving Cl− free to react with H+ to form HCl. Administration of intravenous NaCl or parenteral hyperalimentation solutions that contain an amino acid–chloride combination can also cause acidosis.12 With hyperchloremic acidosis, the AG remains within the normal range, whereas plasma Cl− levels are increased and plasma HCO3− levels are decreased. Clinical Manifestations Metabolic acidosis is characterized by a decrease in pH (1 E m

Motility − − ± − + − − − − + +

Micrometers unless indicated.

*

Prions In the past, microbiologists have assumed that all infectious agents possess a genome of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) that codes to produce the essential proteins and enzymes necessary for survival and reproduction.3 Prions, discovered in 1982, are protein particles that are able to transmit infection by self-propagation.3,4 A number of prion-associated diseases have been identified, including Creutzfeldt–Jakob disease, multiple system atrophy, and kuru in humans. Animals are also affected, for example, bovine spongiform encephalopathy (or mad cow disease) in cattle.5 The various prion-associated diseases produce very similar pathologic processes and symptoms in the hosts and are collectively called transmissible neurodegenerative diseases (see Fig. 10-2). All are characterized by a slowly progressive, noninflammatory neuronal degeneration, leading to loss of coordination (ataxia), dementia, and death over a period ranging from months to years. The conversion of a cellular precursor protein (PrPC) into an abnormally folded protein (PrPSC) causes the protein to behave differently. The PrPSC is resistant to the action of proteases (enzymes that degrade excess or deformed proteins). Accumulation of these misfolded proteins becomes toxic to cells;

however, as they aggregate, they become less toxic to the cell and can then be captured in plaques, tangles, or inclusion bodies.4

Molecular pathogenesis of prion disorders. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 32.71, p. 1452). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 10-2

Prion diseases present significant challenges for management because of the pathogenic structure of PrPSC. It is very stable and, therefore, is resistant to treatment. Studies investigating transmission of prion diseases in animals clearly

demonstrate that prions replicate, leading researchers to investigate how proteins can reproduce in the absence of genetic material.3 It is believed that PrPSC aggregates into amyloid-like plaques in the brain and spreads within the axons of the nerve cells, causing progressively greater damage of host neurons and the eventual incapacitation of the host. Human transmission occurs primarily from eating infected meat or receiving an infected transplant organ or cornea. Viruses Viruses are the smallest obligate intracellular pathogens. They have no organized cellular structures but instead consist of a protein coat, or capsid, surrounding a nucleic acid core, or genome, of RNA or DNA—never both (Fig. 10-3). Some viruses are enclosed within a lipoprotein envelope derived from the cytoplasmic membrane of the parasitized host cell. Enveloped viruses include members of the herpesvirus group and paramyxoviruses (e.g., influenza and poxviruses). Certain enveloped viruses are continuously shed from the infected cell surface enveloped in buds pinched from the cell membrane.

(A) The basic structure of a virus includes a protein coat surrounding an inner core of nucleic acid (DNA or RNA). (B) Some viruses may also be enclosed in a lipoprotein outer envelope. FIGURE 10-3

The viruses of humans and animals have been categorized according to various characteristics. These include the type of viral genome (single-stranded or doublestranded DNA or RNA), physical characteristics (e.g., size, presence or absence of a membrane envelope), the mechanism of replication (e.g., retroviruses), the mode of transmission (e.g., arthropod-borne viruses, enteroviruses), target tissue, and the type of disease produced (e.g., hepatitis A, B, C, D, and E viruses), to name a few. Viruses are incapable of replication outside of a living cell. They must penetrate a susceptible living cell and use the biosynthetic structure of the cell to replicate.3 The process of viral replication is shown in Figure 10-4. Not every viral agent causes lysis and death of the host cell during the course of replication. Some viruses enter the host cell where it remains in a latent, nonreplicating state for long periods without causing disease. The virus may undergo active replication and produces symptoms of disease months to years later. Members of the herpesvirus group and adenovirus are examples of latent viruses. The resumption of the latent viral replication may produce symptoms of primary disease (e.g., genital herpes) or cause an entirely different symptomatology (e.g., shingles instead of chickenpox) (Fig. 105).

Schematic representation of the many possible consequences of viral infection of host cells, including cell lysis (poliovirus), continuous release of budding viral particles, or latency (herpesviruses) and oncogenesis (papovaviruses). FIGURE 10-4

Role of Epstein–Barr virus (EBV) in infectious mononucleosis (IM), nasopharyngeal carcinoma, and Burkitt lymphoma. EBV invades and replicates within the salivary glands or pharyngeal epithelium and is shed into the saliva and respiratory secretions. Additionally, in some people, the virus transforms pharyngeal epithelial cells, which can cause nasopharyngeal carcinoma. Then in some people who are not immune from childhood exposure, EBV can cause IM. EBV can infect B lymphocytes and stimulate the production of atypical lymphocytes, which kill virally infected B cells and suppress immunoglobulin production. Some infected B cells can transform into malignant lymphocytes of Burkitt lymphoma. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 9.9, p. 383). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 10-5

A family of viruses that has gained a great deal of attention is the Orthomyxoviridae or flu viruses. There has been attention focused on the hemagglutinin (H) subtype 5 and neuraminidase (N) subtype 1 or H5N1 variant, commonly known as the avian influenza virus, and the H1N1 variant, commonly known as swine flu.6 The Centers for Disease Control and Prevention (CDC) recommends rapid influenza diagnostic tests using real-time polymerase chain reaction (PCR) by trained personnel.6 Early infection control practices are important to prevent the spread of influenza.6 The retroviruses have a unique mechanism of replication. After entry into the host cell, the viral RNA genome is first translated into DNA by a viral enzyme called reverse transcriptase. The viral DNA copy is then integrated into the host chromosome where it exists in a latent state, similar to the herpesviruses. Reactivation and replication require a reversal of the entire process. In the case of HIV, when infected cells (CD4+ T cells) become activated, they release free virus by budding or cell–cell fusion. Lysis of CD4+ cells also releases HIV into the bloodstream, resulting in reduced CD4+ count and suppression of the immune response.3 In addition to causing infectious diseases, certain viruses also can transform normal host cells into malignant cells during the replication cycle. This group of viruses is referred to as oncogenic and includes certain retroviruses and DNA viruses, such as the herpesviruses, adenoviruses, and papovaviruses. Human papillomaviruses, members of the papovavirus family, cause cutaneous and genital warts, and several genotypes are associated with cervical cancer. Bacteria Bacteria are autonomously replicating unicellular organisms known as prokaryotes because they lack an organized nucleus. Compared with nucleated eukaryotic cells, the bacterial cells are small and structurally primitive.3 They are the smallest of all living cells and contain no organized intracellular organelles, and the genome consists of only a single double-stranded circular chromosome of DNA, which is associated with RNA and proteins.3 The prokaryotic cell is organized into an internal compartment called the cytoplasm, which contains the reproductive and metabolic machinery of the cell. The cytoplasm is surrounded by a flexible lipid membrane, called the cytoplasmic membrane.3 This is in turn usually enclosed within a rigid cell wall. The structure and synthesis of the cell wall determine the microscopic shape of the bacterium (e.g., spherical [cocci], helical [spirilla], or elongate [bacilli]). Further, bacteria can be divided into two types (gram-positive and gram-negative) based on their gram staining properties. Gram-positive bacteria produce a cell wall composed of a distinctive polymer known as peptidoglycan. This polymer is produced only by prokaryotes and is used as a target for some antibacterial therapies. Gram-negative bacteria produce an outer membrane

composed of lipopolysaccharide, which can induce shock in the host.3 Several bacteria synthesize an extracellular capsule composed of protein or polysaccharide. The capsule protects the organism from environmental hazards such as the immunologic defenses of the host.3 Figure 10-6 shows a variety of bacterial morphologies.

The variety of bacterial morphology. Examples of bacteria-related disease: Streptococci are gram-positive aerobic organisms that cause skin infections such as impetigo, scarlet fever, pharyngitis, endocarditis, pneumonia, and potentially fatal toxic shock and sepsis. Salmonella and Escherichia coli are gram-negative, rod-shaped bacteria that cause foodborne illnesses. Spirilla bacteria are gram-negative bacteria that cause bacterial diarrhea and peptic ulcers. (From Houser H. J., Sesser J. R. (2016). LWW’s medical assisting exam review for CMA, RMA, and CMAS certification. Philadelphia, PA: Wolters Kluwer.) FIGURE 10-6

Certain bacteria are motile as the result of external whiplike appendages called flagella. The flagella rotate like a propeller, transporting the organism through a liquid environment. Bacteria can also produce hairlike structures projecting from the cell surface called pili or fimbriae, which enable the organism to adhere to surfaces such as mucous membranes or other bacteria. Most prokaryotes reproduce asexually by simple cellular division. When the cocci divide in chains, they are called streptococci; in pairs, diplococci; and in clusters, staphylococci.3 The growth rate of bacteria varies significantly among

different species and depends greatly on physical growth conditions and the availability of nutrients. In nature, bacteria rarely exist as single cells floating in an aqueous environment. Rather, bacteria prefer to stick to and colonize environmental surfaces, producing structured communities called biofilms.7 The organization and structure of biofilms permit access to available nutrients and elimination of metabolic waste. Within the biofilm, individual organisms use chemical signaling as a form of primitive intercellular communication to represent the state of the environment. This is known as quorum sensing. These signals inform members of the community when sufficient nutrients are available for proliferation or when environmental conditions warrant dormancy or evacuation. Examples of biofilms abound in nature and are found on surfaces of aquatic environments and on humans. Bacteria are extremely adaptable life forms and have a well-defined set of growth parameters, including nutrition, temperature, light, humidity, and atmosphere. Bacteria with extremely strict growth requirements are called fastidious. For example, Neisseria gonorrhoeae, the bacterium that causes gonorrhea, cannot live for extended periods outside the human body.8 Some bacteria require oxygen for growth and metabolism and are called aerobes. Others cannot survive in an oxygencontaining environment and are called anaerobes. An organism capable of adapting its metabolism to aerobic or anaerobic conditions is called facultatively anaerobic. Another means of classifying bacteria according to microscopic staining properties is the acid-fast stain. Because of their unique cell membrane fatty acid content and composition, certain bacteria are resistant to the decolorization of a primary stain when treated with a solution of acid alcohol. These organisms are termed acid fast and include a number of significant human pathogens, most notably Mycobacterium tuberculosis.8 For purposes of taxonomy (i.e., identification and classification), each member of the bacterial kingdom is categorized into a small group of biochemically and genetically related organisms called the genus and further subdivided into distinct individuals within the genus called species. The genus and species assignment of the organism is reflected in its name (e.g., Staphylococcus [genus] aureus [species]). Spirochetes The spirochetes are a category of bacteria that are mentioned separately because of their unusual cellular morphology and distinctive mechanism of motility. The spirochetes are gram-negative rods but are unique in that the cell’s shape is helical and the length of the organism is many times its width. A series of filaments are wound about the cell wall and extend the entire length of the cell. These filaments propel the organism through an aqueous environment in a corkscrew motion. Spirochetes are anaerobic organisms and comprise three genera: Leptospira, Borrelia, and Treponema. Each genus has saprophytic and pathogenic strains. The

pathogenic leptospires infect a wide variety of wild and domestic animals. Infected animals shed the organisms into the environment through the urinary tract. Transmission to humans occurs by contact with infected animals or urinecontaminated surroundings. Leptospires gain access to the host directly through mucous membranes or breaks in the skin and can produce a severe and potentially fatal illness called Weil syndrome. In contrast, the borreliae are transmitted from infected animals to humans through the bite of an arthropod vector such as lice or ticks. Included in the genus Borrelia are the agents of relapsing fever (Borrelia recurrentis) and Lyme disease (Borrelia burgdorferi). Pathogenic Treponema species require no intermediates and are spread from person to person by direct contact. The most important member of the genus is Treponema pallidum, the causative agent of syphilis. Mycoplasmas The mycoplasmas are unicellular prokaryotes capable of independent replication. These organisms are less than one third the size of bacteria. The cell is composed of cytoplasm surrounded by a membrane, but unlike bacteria, the mycoplasmas do not produce a rigid peptidoglycan cell wall. As a consequence, the microscopic appearance of the cell is highly variable, ranging from coccoid forms to filaments, and the mycoplasmas are resistant to cell wall–inhibiting antibiotics, such as penicillins and cephalosporins. The mycoplasmas affecting humans are divided into three genera: Mycoplasma, Ureaplasma, and Acholeplasma. The first two require cholesterol from the environment to produce the cell membrane; the acholeplasmas do not. In the human host, mycoplasmas are commensals. However, a number of species are capable of producing serious diseases, including pneumonia (Mycoplasma pneumoniae), genital infections (Mycoplasma hominis and Ureaplasma urealyticum), maternally transmitted respiratory infections to infants with low birth weight (U. urealyticum), and potential complications during pregnancy.8,9 KEY POINTS Agents of Infectious Disease Microorganisms can be separated into eukaryotes (e.g., fungi and parasites), which contain a membrane-bound nucleus, and prokaryotes (e.g., bacteria), which do not have a defined nucleus. Eukaryotes and prokaryotes are organisms because they contain all the enzymes and biologic equipment necessary for replication and exploiting metabolic energy.

Rickettsiaceae, Anaplasmataceae, Chlamydiaceae, and Coxiella This interesting group of organisms combines the characteristics of viral and bacterial agents to produce disease in humans. All are obligate intracellular pathogens, like the viruses, but produce a rigid peptidoglycan cell wall, reproduce asexually by cellular division, and contain RNA and DNA, similar to the bacteria.2 The Rickettsiaceae depend on the host cell for essential vitamins and nutrients, but the Chlamydiaceae appear to scavenge intermediates of energy metabolism such as adenosine triphosphate. The Rickettsiaceae infect but do not produce disease in the cells of certain arthropods such as mites, fleas, ticks, and lice.8 The organisms are transmitted to humans through the bite of the arthropod (i.e., the vector) and produce a number of potentially lethal diseases, including Rocky Mountain spotted fever and epidemic typhus. Rocky Mountain spotted fever (transmitted to humans through a tick vector) is a reportable disease that has increased in frequency over the last decade; however, the death rate has decreased below 0.50%.10 The Chlamydiaceae are slightly smaller than the Rickettsiaceae and are structurally similar; however, they are transmitted directly between susceptible vertebrates without an intermediate arthropod vector. Transmission and replication of Chlamydiaceae occur through a defined life cycle. The infectious form, called an elementary body, attaches to and enters the host cell, where it transforms into a larger reticulate body.11 This undergoes active replication into multiple elementary bodies, which are then shed into the extracellular environment to initiate another infectious cycle. Transmission occurs by close person-to-person contact. Chlamydia trachomatis is transmitted sexually (it is a leading cause of sexually transmitted disease in men and women) and can cause conjunctivitis in newborns.8 Approximately 1% of community-acquired pneumonia cases are caused by C. psittaci.12 Organisms within the family Anaplasmataceae are also obligate intracellular organisms that resemble the Rickettsiaceae in structure and produce a variety of veterinary and human diseases, some of which have a tick vector. These organisms target host mononuclear and polymorphonuclear white blood cells for infection and, similar to the Chlamydiaceae, multiply in the cytoplasm of infected leukocytes within vacuoles called morulae. Unlike the Chlamydiaceae, however, the Anaplasmataceae do not have a defined life cycle and are independent of the host cell for energy production. The most common infections caused by Anaplasmataceae are human monocytic and granulocytic ehrlichiosis. Human monocytic ehrlichiosis is a disease caused by Ehrlichia chaffeensis and E. canis that can easily be confused with Rocky Mountain spotted fever. Clinical disease severity in ehrlichiosis ranges from mild to life threatening.13 Manifestations include generalized malaise, anorexia and nausea, fever, chills, headache, and body aches. Symptom onset occurs 1 to 2 weeks after a tick bite. A

rash may occur (more often in children) as well as gastrointestinal symptoms. Decreases in white blood cells (leukopenia) and platelets (thrombocytopenia) often occur. Severe sequelae may include acute respiratory distress syndrome, severe sepsis, and septic shock (which may lead to acute renal failure) as well as meningitis and meningoencephalitis.13 The disease is usually more severe in older adults and people with compromised immune function. Human granulocytic ehrlichiosis, which is caused by two species (Anaplasma phagocytophilum and Ehrlichia ewingii), is also transmitted by ticks. The symptoms are similar to those seen with human monocytotropic ehrlichiosis. The genus Coxiella contains only one species, C. burnetii. Like its rickettsial counterparts, it is a gram-negative intracellular organism that infects a variety of animals, including cattle, sheep, and goats.14 In humans, Coxiella infection produces a disease called Q fever, characterized by a nonspecific febrile illness often accompanied by headache, retro-orbital pain, chills, and mild pneumonia-like symptoms. The organism produces a highly resistant sporelike stage that is transmitted to humans when contaminated animal tissue is aerosolized (e.g., during meat processing) or by ingestion of contaminated milk. It can also be transmitted by exposure to infected animals.14 Fungi The fungi are free-living, eukaryotic saprophytes found in every habitat on earth. Some are members of the normal human microflora. Fortunately, few fungi are capable of causing diseases in humans, and most of these are incidental, self-limited infections of the skin and subcutaneous tissue. Serious fungal infections are rare and usually initiated through puncture wounds or inhalation. Despite their normally harmless nature, fungi can cause life-threatening opportunistic diseases when host defense capabilities have been disabled. The fungi can be separated into two groups, yeasts and molds, based on rudimentary differences in their morphology. The yeasts are single-celled organisms, approximately the size of red blood cells, which reproduce by a budding process. The buds separate from the parent cell and mature into identical daughter cells. Molds produce long, hollow, branching filaments called hyphae. Some molds produce cross walls, which segregate the hyphae into compartments, and others do not. A limited number of fungi are capable of growing as yeasts at one temperature and as molds at another. These organisms are called dimorphic fungi and include a number of human pathogens such as the agents of blastomycosis (Blastomyces dermatitidis), histoplasmosis (Histoplasma capsulatum), and coccidioidomycosis (Coccidioides immitis). The appearance of a fungal colony tends to reflect its cellular composition. Colonies of yeast are generally smooth with a waxy or creamy texture. Molds tend to produce cottony or powdery colonies composed of mats of hyphae collectively

called a mycelium. The mycelium can penetrate the growth surface or project above the colony like the roots and branches of a tree. Yeasts and molds produce a rigid cell wall layer that is chemically unrelated to the peptidoglycan of bacteria and is therefore not susceptible to the effects of penicillin-like antibiotics. Most fungi are capable of sexual or asexual reproduction. The former process involves the fusion of zygotes with the production of a recombinant zygospore. Asexual reproduction involves the formation of highly resistant spores called conidia or sporangiospores, which are borne by specialized structures that arise from the hyphae. Molds are identified in the laboratory by the characteristic microscopic appearance of the asexual fruiting structures and spores. Like the bacterial pathogens of humans, fungi can produce disease in the human host only if they can grow at the temperature of the infected body site. For example, a number of fungal pathogens called dermatophytes are incapable of growing at core body temperature (37°C), and the infection is limited to the cooler cutaneous surfaces. Diseases caused by these organisms, including ringworm, athlete’s foot, and jock itch—all examples of tinea—are collectively called superficial mycoses.3 Fungal infections can also be cutaneous, subcutaneous, deep-seated, and invasive infections. Systemic mycoses are serious fungal infections of deep tissues and, by definition, are caused by organisms capable of growth at 37°C. Yeasts such as Candida albicans are commensal flora of the skin, mucous membranes, and gastrointestinal tract and are capable of growth at a wider range of temperatures. Candida is considered an opportunistic infection in immunocompromised persons; however, it is a cause of infection in nonneutropenic people. Candida in the blood (candidemia) and in the abdomen (intra-abdominal candidiasis) are common causes of infection in the intensive care unit.15 In addition, aspergillosis is a lethal form of pneumonia.15 Intact immune mechanisms and competition for nutrients provided by the bacterial flora normally keep colonizing fungi in check. Alterations in either of these components by disease states or antibiotic therapy can upset the balance, permitting fungal overgrowth and setting the stage for opportunistic infections. Parasites In a strict sense, any organism that derives benefits from its biologic relationship with another organism is a parasite. In the study of clinical microbiology, however, the term parasite has evolved to designate members of the animal kingdom that infect and cause disease in other animals and includes protozoa, helminths, and arthropods. Intestinal microbiota exerts an immunoregulatory effect on the host’s immune response in the setting of intestinal parasites.16 Protozoa are unicellular animals with a complete complement of eukaryotic cellular machinery, including a well-defined nucleus and organelles. Reproduction may be sexual or asexual, and life cycles may be simple or complicated, with several maturation stages requiring more than one host for completion. Most are

saprophytes, but a few have adapted to the accommodations of the human environment and produce a variety of diseases, including malaria, amebic dysentery, and giardiasis.3 Protozoan infections can be passed directly from host to host such as through sexual contact, indirectly through contaminated water or food, or by way of an arthropod vector. Direct or indirect transmission results from the ingestion of highly resistant cysts or spores that are shed in the feces of an infected host. When the cysts reach the intestine, they mature into vegetative forms called trophozoites, which are capable of asexual reproduction or cyst formation. Most trophozoites are motile by means of flagella, cilia, or ameboid motion. The helminths are a collection of wormlike parasites that include the nematodes or roundworms, cestodes or tapeworms, and trematodes or flukes. The helminths reproduce sexually within the definitive host, and some require an intermediate host for the development and maturation of an offspring. Humans can serve as the definitive or intermediate host and, in certain diseases such as trichinosis, as both. Transmission of helminth diseases occurs primarily through the ingestion of fertilized eggs (ova) or the penetration of infectious larval stages through the skin— directly or with the aid of an arthropod vector. Helminth infections can involve many organ systems and sites, including the liver and lung, urinary and intestinal tracts, circulatory and central nervous systems, and muscle. Although most helminth diseases have been eradicated from the United States, they are still a major health concern of developing nations. The parasitic arthropods of humans and animals include the vectors of infectious diseases (e.g., ticks, mosquitoes, biting flies) and the ectoparasites. The ectoparasites infest external body surfaces and cause localized tissue damage or inflammation secondary to the bite or burrowing action of the arthropod. The most prominent human ectoparasites are mites (scabies), chiggers, lice (head, body, and pubic), and fleas.3 Transmission of ectoparasites occurs directly by contact with immature or mature forms of the arthropod or its eggs found on the infested host or the host’s clothing, bedding, or grooming articles such as combs and brushes. Many of the ectoparasites are vectors of other infectious diseases, including endemic typhus and bubonic plague (fleas) and epidemic typhus (lice). SUMMARY CONCEPTS Throughout life, humans are continuously and harmlessly exposed to and colonized by a multitude of microscopic organisms. This relationship is kept in check by the intact defense mechanisms of the host (e.g., mucosal and cutaneous barriers, normal immune function) and the innocuous nature of most environmental microorganisms. Those factors that weaken the host’s resistance or increase the virulence of colonizing microorganisms can disturb the equilibrium of the relationship and cause disease. There is an extreme

diversity of prokaryotic and eukaryotic microorganisms capable of causing infectious diseases in humans. Immunosuppression (related to underlying medical conditions or immunosuppressive therapy or aging [known as immunosenescence]) increases the risk of infections related to opportunistic and other pathogens. However, most infectious illnesses in humans continue to be caused by only a small fraction of the organisms that compose the microscopic world.

Mechanisms of Infection Epidemiology of Infectious Diseases Epidemiology is the study of the patterns and determinants of health with the goal of controlling disease and health problems.17 Descriptive epidemiology focuses on the pattern of disease and analytic epidemiology examines factors associated with disease.18 In order to interrupt or eliminate the spread of an infectious agent, factors related to the host, agent, and environment—the well-known triad of disease (see Fig. 10-1)—as well as modes of transmission must be considered. The term incidence is used to describe the number of new cases of an infectious disease that occur within a defined population (e.g., per 100,000 people) over an established period of time (e.g., monthly, quarterly, yearly). Disease prevalence indicates the number of active cases at any given time in a population. A disease is considered to be endemic in a particular geographic region if the incidence and prevalence are relatively stable. An epidemic describes an abrupt and unexpected increase in the incidence of disease over endemic rates. A pandemic refers to the spread of disease beyond continental boundaries. Rapid worldwide travel increases the risk of pandemic transmission of pathogenic microorganisms during outbreaks. Modes of Transmission Modes of transmission include direct and indirect mechanisms. The portal of entry refers to the process by which a pathogen enters the body, gains access to susceptible tissues, and causes disease. Among the potential modes of transmission are penetration, direct contact, ingestion, and inhalation. The portal of entry does not dictate the site of infection. Ingested pathogens may penetrate the intestinal mucosa, disseminate through the circulatory system, and cause diseases in other organs such as the lung or liver. Regardless of the mechanisms of entry, the transmission of infectious agents is directly related to the number of infectious agents absorbed by the host.

Penetration Any disruption in the integrity of the body’s surface barrier—skin or mucous membranes—is a potential site for invasion of microorganisms. The break may be the result of an accidental injury causing abrasions, burns, or penetrating wounds; medical procedures such as surgery or catheterization; or a primary infectious process that produces surface lesions such as chickenpox or impetigo. Translocation of bacteria from the gastrointestinal tract may also occur. Direct inoculation from intravenous drug use or an animal or arthropod bite can also occur. Direct Contact Some pathogens are transmitted directly from infected tissue or secretions to exposed, intact mucous membranes. This is especially true of certain sexually transmitted infections (STIs), such as gonorrhea, syphilis, chlamydia, and genital herpes, for which exposure of uninfected membranes to pathogens occurs during intimate contact. The transmission of STIs is not limited to sexual contact. Vertical transmission of these agents, from mother to child, can occur across the placenta or during birth when the mucous membranes of the child contact infected vaginal secretions of the mother. When an infectious disease is transmitted from mother to child during gestation or birth, it is classified as a congenital infection. The most frequently observed congenital infections include toxoplasmosis (caused by the parasite Toxoplasma gondii), syphilis, rubella, cytomegalovirus infection, and HSV infections (the TORCH infections), varicella zoster (chickenpox), parvovirus B19, group B streptococci (Streptococcus agalactiae), and HIV. Of these, cytomegalovirus is a common cause of congenital infection in the United States, occurring in 0.5% to 22% of all live births.19 The severity of congenital defects associated with these infections depends greatly on the gestational age of the fetus when transmission occurs, but most of these agents can cause profound mental retardation and neurosensory deficits, including blindness and hearing loss. HIV rarely produces overt signs and symptoms in the infected newborn, and it sometimes takes years for the effects of the illness to manifest. Ingestion The entry of pathogenic microorganisms or their toxic products through the oral cavity and gastrointestinal tract represents one of the more efficient means of disease transmission in humans. Many bacterial, viral, and parasitic infections, including cholera, typhoid fever, dysentery (amebic and bacillary), food poisoning, traveler’s diarrhea, cryptosporidiosis, and hepatitis A, are initiated through the ingestion of

contaminated food and water. This mechanism of transmission necessitates that an infectious agent survive the low pH and enzyme activity of gastric secretions and the peristaltic action of the intestines in numbers sufficient to establish infection, deemed an infectious dose. For organisms such as Vibrio cholerae, gastric acid secretions reduce the infectious dose; however, some agents such as Shigella and Giardia cysts cause infections at a lower dose because of their resistance to gastric acid.19 Ingested pathogens also must compete successfully with the normal bacterial flora of the bowel for nutritional needs. People with reduced gastric acidity because of disease or medication are more susceptible to infection by this route because the number of ingested microorganisms surviving the gastric environment is greater. Inhalation The respiratory tract of healthy people is equipped with a multiple-tiered defense system to prevent potential pathogens from entering the lungs. The surface of the respiratory tree is lined with a layer of mucus that is continuously swept up and away from the lungs and toward the mouth by the beating motion of ciliated epithelial cells. Humidification of inspired air increases the size of aerosolized particles, which are effectively filtered by the mucous membranes of the upper respiratory tract. Coughing also aids in the removal of particulate matter from the lower respiratory tract. Respiratory secretions contain antibodies and enzymes capable of inactivating infectious agents. Particulate matter and microorganisms that ultimately reach the lung are cleared by phagocytic cells. Despite this impressive array of protective mechanisms, a number of pathogens can invade the human body through the respiratory tract, including agents of bacterial pneumonia (Streptococcus pneumoniae, Legionella pneumophila), meningitis (Neisseria meningitidis, Haemophilus influenzae), and tuberculosis, as well as the viruses responsible for measles, mumps, chickenpox, influenza, and the common cold. Defective pulmonary function or mucociliary clearance caused by noninfectious processes such as cystic fibrosis, emphysema, or smoking can increase the risk of inhalation-acquired diseases. Concept Mastery Alert Chickenpox is spread through the air. KEY POINTS Epidemiology of Infectious Diseases

Epidemiology focuses on the incidence (number of new cases) and prevalence (number of active cases at any given time) of an infectious disease; the source of infection and its portal of entry, site of infection, and virulence factors of the infecting organism; and the signs and symptoms of the infection and its course. The ultimate goals of epidemiologic studies are the interruption of the spread of infectious diseases and their eradication. Source The source of an infectious disease refers to the location, host, object, or substance from which the infectious agent was acquired: essentially the “who, what, where, and when” of disease transmission. The source may be endogenous (acquired from the host’s own microbial flora, as would be the case in an opportunistic infection) or exogenous (acquired from sources in the external environment, such as water, food, soil, or air). The source of the infectious agent can also be another human being, as from mother to child during gestation (congenital infections); an inanimate object; an animal; or a biting arthropod (vector). Inanimate objects that carry an infectious agent are known as fomites. For example, rhinoviruses and many other nonenveloped viruses can be spread by contact with contaminated fomites such as handkerchiefs and toys. Zoonoses are a category of infectious diseases passed from other animal species to humans. When a disease originates in humans and moves to animals, it is known as “reverse zoonoses.”19 Zoonoses account for a large percentage (up to 70% of emerging viral diseases) of emerging infectious diseases. Examples of zoonoses include cat-scratch disease, HIV, rabies, plague, and influenza.19 The spread of infectious diseases (such as Lyme disease or West Nile virus [WNV]) through biting arthropod vectors is another route. Source can denote a place. For instance, infections that develop in people while they are hospitalized are called nosocomial or health care-associated infection and those that are acquired outside of health care facilities are called community acquired. The definitions used to distinguish between health care acquired and community acquired involve the timing of infection (development in less than 48 hours defines community acquired) as well as prior hospitalization, dialysis, and wound care. The source may also pertain to the body substance that is the most likely a vehicle for transmission, such as feces, blood, body fluids, respiratory secretions, and urine. Infections can be transmitted from person to person through shared inanimate objects (fomites) contaminated with infected body fluids. An example of this mechanism of transmission would include the spread of the HIV and hepatitis B virus through the use of shared syringes by intravenous drug users. Infection can also be spread through a complex combination of source, portal of entry, and vector. Source control is an important aspect of prevention and treatment.

Clinical Manifestations The term clinical manifestations refers to the collection of signs and symptoms expressed by the host during the disease course. This is also known as the clinical picture, or disease presentation, and can be characteristic of any given infectious agent. In terms of pathophysiology, symptoms are the outward expression of the struggle between invading organisms and the retaliatory inflammatory and immune responses of the host. The symptoms of an infectious disease may be specific and reflect the site of infection (e.g., diarrhea, rash, convulsions, hemorrhage, and pneumonia). Conversely, symptoms such as fever, myalgia, headache, and lethargy are relatively nonspecific and can be shared by a number of diverse infectious diseases. The symptoms of a diseased host can be obvious, as in the case of chickenpox or measles. Other, covert symptoms, such as an increased white blood cell count, may require laboratory testing to detect. Accurate recognition and documentation of symptomatology can aid in the diagnosis of an infectious disease. Disease Course The course of any infectious disease can be divided into several distinguishable stages after the point when the potential pathogen enters the host. These stages are the incubation period, the prodromal stage, the acute stage, the convalescent stage, and the resolution stage (Fig. 10-7). The stages are based on the progression and intensity of the host’s symptoms, which reflect the host’s response to infection over time. The duration of each phase and the pattern of the overall illness can be specific for different pathogens, thereby aiding in the diagnosis of an infectious disease.

Stages of a primary infectious disease as they appear in relation to the severity of symptoms and numbers of infectious agents. The clinical threshold corresponds with the initial expression of recognizable symptoms, whereas the critical threshold represents the peak of disease intensity. FIGURE 10-7

The incubation period is the phase during which the pathogen begins active replication without producing recognizable symptoms in the host. The incubation period may be short, as in the case of cholera (up to 24 hours), or prolonged, such as that of hepatitis B (up to 180 days) or HIV (months to years).3 The duration of the incubation period can be influenced by additional factors, including the general health of the host, the portal of entry, and the degree of the infectious dose of the pathogen. The hallmark of the prodromal stage is the initial appearance of symptoms in the host, although the clinical presentation during this time may be only a vague sense of malaise. The host may experience mild fever, myalgia, headache, and fatigue. These are constitutional changes shared by a great number of disease processes. The duration of the prodromal stage can vary considerably from host to host. The acute stage is the period during which the host experiences the maximum impact of the infectious process corresponding to rapid proliferation and dissemination of the pathogen. During this phase, toxic by-products of microbial metabolism, cell lysis, and the immune response mounted by the host combine to produce tissue damage and inflammation. The symptoms of the host are pronounced

and more specific than in the prodromal stage, usually typifying the pathogen and sites of involvement. The convalescent period is characterized by the containment of infection, progressive elimination of the pathogen, repair of damaged tissue, and resolution of associated symptoms. Similar to the incubation period, the time required for complete convalescence may be days, weeks, or months, depending on the type of pathogen and the voracity of the host’s immune response. The resolution is the total elimination of a pathogen from the body without residual signs or symptoms of disease. Sometimes, infections may lead to a chronic infectious state. Several notable exceptions to the classic presentation of an infectious process have been recognized. Chronic infectious diseases have a markedly protracted and sometimes irregular course. The host may experience symptoms of the infectious process continuously or sporadically for months or years without a convalescent phase. In contrast, subclinical or subacute illness progresses from infection to resolution without clinically apparent symptoms. A disease is called insidious if the prodromal phase is protracted; a fulminant illness is characterized by abrupt onset of symptoms with little or no prodrome. Fatal infections are variants of the typical disease course. Site of Infection Inflammation of an anatomic location is usually designated by adding the suffix -itis to the name of the involved tissue (e.g., bronchitis, infection of the bronchi and bronchioles; encephalitis, brain infection; endocarditis, infection of the heart valves). These are general terms, however, and they apply equally to inflammation from infectious and noninfectious causes. The suffix -emia is used to designate the presence of a substance in the blood (e.g., bacteremia, viremia, and fungemia describe the presence of these infectious agents in the bloodstream). The term sepsis, or septicemia, has been used to refer to the presence of microbial toxins in the blood. For the past three decades, the definition of sepsis focused on specific clinical manifestations of systemic inflammation (fever/hypothermia, tachycardia, tachypnea, and leukocytosis/leukopenia/bandemia) in the setting of a confirmed or suspected infection. The term severe sepsis was used for sepsis with organ failure, and the term septic shock was used when the organ failure was hypotension not responsive to fluid resuscitation. We now understand that sepsis is a dysregulated host response infection accompanied by life-threatening organ dysfunction.20 The type of pathogen, the portal of entry, and the competence of the host’s immunologic defense system ultimately determine the site of an infectious disease. Many pathogenic microorganisms are restricted in their capacity to invade the human body. Mycoplasma pneumoniae, influenza viruses, and L. pneumophila rarely cause disease outside the respiratory tract; infections caused by N. gonorrhoeae are generally confined to the genitourinary tract; and shigellosis and giardiasis seldom

extend beyond the gastrointestinal tract.3 These are considered localized infectious diseases. The bacterium Helicobacter pylori is an extreme example of a site-specific pathogen. Helicobacter pylori is a significant cause of gastric ulcers but has not been implicated in disease processes elsewhere in the human body. Bacteria, such as N. meningitidis, cause meningococcal disease, a prominent pathogen of children and young adults; Salmonella typhi, the cause of typhoid fever; and B. burgdorferi, the agent of Lyme disease, tend to disseminate from the primary site of infection to involve other locations and organ systems. These are all examples of systemic pathogens disseminated throughout the body by the circulatory system. Staphylococcus aureus can lead to many different types of infection (e.g., pneumonia, urinary tract infection, endocarditis, cellulitis). An abscess is a localized pocket of infection composed of devitalized tissue, microorganisms, and the host’s phagocytic white blood cells. In this case, the dissemination of the pathogen has been contained by the host, but white cell function within the toxic environment of the abscess is hampered, and the elimination of microorganisms is slowed if not actually stopped. Virulence Factors Virulence factors are substances or products generated by infectious agents that enhance their ability to cause disease. Although a large number of microbial products fit this description, they can be grouped generally into four categories: toxins, adhesion factors, evasive factors, and invasive factors (Table 10-3). TABLE 10-3 Examples of Virulence Factors Produced by Pathogenic Microorganisms

Factor

Category Organism Effect on Host Vibrio cholerae Cholera toxin Exotoxin Secretory diarrhea (bacterium) Corynebacterium Diphtheria toxin Exotoxin diphtheriae Inhibits protein synthesis (bacterium) Many gram-negative Lipopolysaccharide Endotoxin Fever, hypotension, shock bacteria Staphylococcus Rash, diarrhea, vomiting, Toxic shock toxin Enterotoxin aureus (bacterium) hepatitis Hemagglutinin Adherence Influenza virus Establishment of infection Neisseria Pili Adherence gonorrhoeae Establishment of infection (bacterium) Leukocidin Evasive S. aureus Kills phagocytes

Factor IgA protease Capsule Collagenase Protease Phospholipase Botulinum toxin Pneumolysin

Category Organism Haemophilus Evasive influenzae (bacterium) Cryptococcus Evasive neoformans (yeast) Pseudomonas Invasive aeruginosa (bacterium) Invasive Aspergillus (mold) Clostridium Invasive perfringens (bacterium) Clostridium Exotoxin botulinum (bacterium) Streptococcus Exotoxin pneumoniae (bacterium)

Effect on Host Inactivates antibody Prevents phagocytosis Penetration of tissue Penetration of tissue Penetration of tissue Neuroparalysis, inhibits acetylcholine release Inhibition of respiratory ciliated and phagocytic cell function

Toxins Toxins are substances that alter or destroy the normal function of the host or host’s cells. Toxin production is a trait chiefly monopolized by bacterial pathogens, although certain fungal and protozoan pathogens also elaborate substances toxic to humans. Bacterial toxins have a diverse spectrum of activity and exert their effects on a wide variety of host target cells. For classification purposes, however, the bacterial toxins can be divided into two main types: exotoxins and endotoxins. Exotoxins Exotoxins are proteins released from the bacterial cell during growth that may damage cells. Bacteria toxins have evolved several different strain-specific mechanisms to escape the immune system.21 Neurotoxins, enterotoxins, and cytotoxins are common terms used to describe exotoxins acting on neurons, the gastrointestinal system, and cells, respectively.3 Although these exotoxins were first described based on their activity, we now know that many are superantigens.22 Superantigens elicit a response by interaction with both the innate and adaptive immune system. They interact with major histocompatibility antigens on antigenpresenting cells as well as T cells to induce a potent inflammatory response that can act locally or systemically.21 Bacterial exotoxins enzymatically inactivate or modify

key cellular constituents, leading to cell death or dysfunction. Diphtheria toxin, for example, inhibits cellular protein synthesis. Endotoxins In contrast to exotoxins, endotoxins do not contain protein, are not actively released from the bacterium during growth, and have no enzymatic activity. Rather, endotoxins are complex molecules composed of lipid and polysaccharides found in the cell wall of gram-negative bacteria. Studies of different endotoxins have indicated that the lipid portion of the endotoxin confers the toxic properties to the molecule. Endotoxins are potent activators of a number of regulatory systems in humans. A small amount of endotoxin in the circulatory system (endotoxemia) can induce clotting, bleeding, inflammation, hypotension, and fever. The sum of the physiologic reactions to endotoxins is sometimes called endotoxic shock.23 Adhesion Factors No interaction between microorganisms and humans can progress to infection or disease if the pathogen is unable to attach to and colonize the host. The process of microbial attachment may be site specific (e.g., mucous membranes, skin surfaces), cell specific (e.g., T lymphocytes, respiratory epithelium, intestinal epithelium), or nonspecific (e.g., moist areas, charged surfaces). In any of these cases, adhesion requires a positive interaction between the surfaces of host cells and the infectious agent. The site to which microorganisms adhere is called a receptor, and the reciprocal molecule or substance that binds to the receptor is called a ligand or adhesin. Receptors may be proteins, carbohydrates, lipids, or complex molecules composed of all three. Similarly, ligands may be simple or complex molecules and, in some cases, highly specific structures. Ligands that bind to specific carbohydrates are called lectins. After initial attachment, a number of bacterial agents become embedded in a gelatinous matrix of polysaccharides called a slime or mucous layer. The slime layer serves two purposes: it anchors the agent firmly to host tissue surfaces, and it protects the agent from the immunologic defenses of the host.24 Many viral agents, including influenza, mumps, measles, and adenovirus, produce filamentous appendages or spikes called hemagglutinins that recognize carbohydrate receptors on the surfaces of specific cells in the upper respiratory tract of the host. Evasive Factors A number of factors produced by microorganisms enhance virulence by evading various components of the host’s immune system. Extracellular polysaccharides, including capsules, slime, and mucous layers, discourage engulfment and killing of pathogens by the host’s phagocytic white blood cells (i.e., neutrophils and

macrophages). Encapsulated organisms such as S. agalactiae, S. pneumoniae, N. meningitidis, and H. influenzae type b (before the vaccine) are a cause of significant morbidity and mortality in neonates and children who lack protective anticapsular antibodies. Certain bacterial, fungal, and parasitic pathogens avoid phagocytosis by excreting leukocidin C toxins, which cause specific and lethal damage to the cell membrane of host neutrophils and macrophages. Other pathogens, such as the bacterial agents of salmonellosis, listeriosis, and Legionnaire disease, are adapted to survive and reproduce within phagocytic white blood cells after ingestion, avoiding or neutralizing the usually lethal products contained within the lysosomes of the cell. Helicobacter pylori, the infectious cause of gastritis and gastric ulcers, produces a urease enzyme on its outer cell wall.3 The urease converts gastric urea into ammonia, thus neutralizing the acidic environment of the stomach and allowing the organism to survive in this hostile environment. Other unique strategies used by pathogenic microbes to evade immunologic surveillance have evolved solely to avoid recognition by host antibodies. Strains of S. aureus produce a surface protein (protein A) that immobilizes immunoglobulin G (IgG), holding the antigen-binding region harmlessly away from the organisms. This pathogen also secretes a unique enzyme called coagulase. Coagulase converts soluble human coagulation factors into a solid clot, which envelops and protects the organism from phagocytic host cells and antibodies. Haemophilus influenzae and N. gonorrhoeae secrete enzymes that cleave and inactivate secretory IgA, neutralizing the primary defense of the respiratory and genital tracts at the site of infection. Borrelia species, including the agents of Lyme disease and relapsing fever, alter surface antigens during the disease course to avoid immunologic detection. It appears that the capability to devise strategic defense systems and stealth technologies is not limited to humans. Invasive Factors Invasive factors are products produced by infectious agents that facilitate the penetration of anatomic barriers and host tissue. Most invasive factors are enzymes capable of destroying cellular membranes (e.g., phospholipases), connective tissue (e.g., elastases, collagenases), intercellular matrices (e.g., hyaluronidase), and structural protein complexes (e.g., proteases).23 It is the combined effects of invasive factors, toxins, and antimicrobial and inflammatory substances released by host cells to counter infection that mediate the tissue damage and pathophysiology of infectious diseases. SUMMARY CONCEPTS

Epidemiology is the study of factors, events, and circumstances that influence the transmission of disease. Incidence refers to the number of new cases of an infectious disease that occur in a defined population, and prevalence refers to the number of active cases that are present at any given time. Infectious diseases are considered endemic in a geographic area if the incidence and prevalence are expected and relatively stable. An epidemic refers to an abrupt and unexpected increase in the incidence of a disease over endemic rates, and a pandemic refers to the spread of disease beyond continental boundaries. The ultimate goal of epidemiology and epidemiologic studies is to devise strategies to interrupt or eliminate the spread of infectious disease. To accomplish this, infectious diseases are classified according to incidence, portal of entry, source, symptoms, disease course, site of infection, and virulence factors.

Diagnosis and Treatment of Infectious Diseases Diagnosis The diagnosis of an infectious disease requires two criteria: the recovery of a probable pathogen or some evidence of its presence from the infected sites of a diseased host and accurate documentation of clinical signs and symptoms compatible with an infectious process. In the laboratory, the diagnosis of an infectious agent is accomplished using three basic techniques: culture, serology, and the detection of characteristic antigens, genomic sequences, or metabolites produced by the pathogen. Culture Culture refers to the growth of a microorganism outside of the body, usually on or in artificial growth media such as agar plates or broth. The specimen from the host is inoculated into broth or onto the surface of an agar plate, and the culture is placed in a controlled environment such as an incubator until the growth of microorganisms becomes detectable. In the case of a bacterial pathogen, identification is based on microscopic appearance and Gram stain reaction, shape, texture, and color (i.e., morphology) of the colonies and by a panel of biochemical reactions that fingerprint salient biochemical characteristics of the organism. Certain bacteria such as Mycobacterium leprae, the agent of leprosy, and T. pallidum, the syphilis spirochete, do not grow on artificial media and require additional methods of identification. Fungi and mycoplasmas are cultured in much the same way as bacteria but with

more reliance on microscopic and colonial morphology for identification. Some fungi are very slow growing and may take weeks to identify by culture. Chlamydiaceae, Rickettsiaceae, and all human viruses are obligate intracellular pathogens.3 As a result, the propagation of these agents in the laboratory requires the inoculation of eukaryotic cells grown in culture (cell cultures). A cell culture consists of a flask containing a single layer, or monolayer, of eukaryotic cells covering the bottom and overlaid with broth containing essential nutrients and growth factors. When a virus infects and replicates within cultured eukaryotic cells, it produces pathologic changes in the appearance of the cell called the cytopathic effect (CPE). See Figure 10-8. The CPE can be detected microscopically, and the pattern and extent of cellular destruction are often characteristics of a particular virus.

The microscopic appearance of a monolayer of uninfected human fibroblasts grown in cell culture (A) and the same cells after infection with HSV (B), demonstrating the cytopathic effect caused by viral replication and concomitant cell lysis. FIGURE 10-8

Although culture media have been developed for the growth of certain humaninfecting protozoa and helminths in the laboratory, the diagnosis of parasitic infectious diseases has traditionally relied on microscopic or, in the case of worms,

visible identification of organisms, cysts, or ova directly from infected patient specimens. Serology Serology is an indirect means of identifying infectious agents by measuring serum antibodies in the diseased host. A tentative diagnosis can be made if the antibody level, also called antibody titer, against a specific pathogen rises during the acute phase of the disease and falls during convalescence. Serologic identification of an infectious agent is not as accurate as culture, but it may be a useful adjunct, especially for the diagnosis of diseases caused by pathogens such as the hepatitis B virus that cannot be cultured. The measurement of antibody titers has another advantage in that specific antibody types, such as IgM and IgG, are produced by the host during different phases of an infectious process. IgM-specific antibodies generally rise and fall during the acute phase of the disease, whereas the synthesis of the IgG class of antibodies increases during the acute phase and remains elevated until or beyond resolution.25 Measurements of class-specific antibodies are also useful in the diagnosis of congenital infections. IgM antibodies do not cross the placenta, but certain IgG antibodies are transferred passively from mother to child during the final trimester of gestation. Consequently, an elevated level of pathogenspecific IgM antibodies in the serum of a neonate must have originated from the child and therefore indicates congenital infection. A similarly increased IgG titer in the neonate does not differentiate congenital from maternal infection.25 Antigen detection incorporates features of culture and serology but reduces to a fraction the time required for diagnosis. In principle, this method relies on purified antibodies to detect antigens of infectious agents in specimens obtained from the diseased host. The source of antibodies used for antigen detection can be animals immunized against a particular pathogen or hybridomas. Fusing normal antibodyproducing spleen cells from an immunized animal with malignant myeloma cells creates hybridomas. The resulting hybrid synthesizes large quantities of antibody. An antibody produced by a hybridoma is called a monoclonal antibody and is highly specific for a single antigen and a single pathogen.26 Regardless of the source, the antibodies are labeled with a substance that allows microscopic or overt detection when bound to the pathogen or its products. In general, the three types of labels used for this purpose are fluorescent dyes, enzymes, and particles such as latex beads. Fluorescent antibodies allow visualization of an infectious agent with the aid of fluorescence microscopy. Enzyme-labeled antibodies are enzymes capable of converting a colorless compound into a colored substance, thereby permitting detection of antibody bound to an infectious agent without the use of a fluorescent microscope. Particles coated with antibodies clump together, or agglutinate, when the appropriate antigen is present in a specimen. Particle agglutination is especially useful when examining infected body fluids such as urine, serum, or spinal fluid. In

addition, newer technologies allow for simultaneous analysis of multiple antigens in a small sample volume by using antibody-coated beads, a fluorescent detection system, and software for quantification. DNA and RNA Sequencing Methods for identifying infectious agents through the detection of DNA or RNA sequences unique to a single agent have increasingly been used over the past decade. Several techniques have been devised to accomplish this goal, each having different degrees of sensitivity regarding the number of organisms that need to be present in a specimen for detection. The first of these methods is called DNA probe hybridization. Small fragments of DNA are cut from the genome of a specific pathogen and labeled with compounds (photoemitting chemicals or antigens) that allow detection. The labeled DNA probes are added to specimens from an infected host. If the pathogen is present, the probe attaches to the complementary strand of DNA on the genome of the infectious agent, permitting rapid diagnosis. The use of labeled probes has allowed visualization of particular agents within and around individual cells in histologic sections of a tissue. A second and more sensitive method of DNA detection is called the PCR (Fig. 10-9).25 This method makes multiple copies of a specific DNA segment using primers, a specific pair of oligonucleotides, and a heat-stable DNA polymerase.

Polymerase chain reaction. The target DNA is first melted using heat (generally around 94°C) to separate the strands of DNA. Primers that recognize specific sequences in the target DNA are allowed to bind as the reaction cools. Using a unique, thermostable DNA polymerase called Taq and an abundance of deoxynucleoside triphosphates, new DNA strands are amplified from the point of the primer attachment. The process is repeated many times (called cycles) until millions of copies of DNA are produced, all of which have the same length defined by the distance (in base pairs) between the primer binding sites. These copies are then detected by electrophoresis and staining or through the use of labeled DNA probes that, similar to the primers, recognize a specific sequence located in the amplified section of DNA. FIGURE 10-9

Real-time PCR uses the same principles as PCR but includes a fluorescencelabeled probe that specifically binds a target DNA sequence between the oligonucleotide primers. As the DNA is replicated by the DNA polymerase, the level of fluorescence in the reaction is measured. If fluorescence increases beyond a minimum threshold, the PCR is considered positive and indicates the presence of the target DNA in a specimen.27 Many of the gene detection technologies have been adapted for quantitation of the target DNA or RNA in serum specimens of people infected with viruses such as HIV and hepatitis C. If the therapy is effective, viral replication is suppressed and the viral load (level of viral genome) in the peripheral blood is reduced. Conversely, if mutations in the viral genome lead to resistant strains or if the antiviral therapy is ineffective, viral replication continues and the person’s viral load rises, indicating a need to change the therapeutic approach. Molecular biology has revolutionized medical diagnostics. Using techniques such as PCR, laboratories now can detect as little as one virus or bacterium in a single specimen, allowing for the diagnosis of infections caused by microorganisms that are impossible or difficult to grow in culture. These methods have increased sensitivity while decreasing the time required to identify the etiologic agent of infectious disease. For example, using standard viral culture, it can take days to weeks to grow a virus and correlate the CPE with the virus. Using molecular biologic techniques, laboratories are able to complete the same work in a few hours. The technique has more recently been coupled with PCR-electrospray ionization mass spectrometry (PCR/ESI-MS), which allows detection of over 800 different pathogens within approximately 6 hours.28 Antibiotic sensitivity testing is not possible using this technique, but it can detect antibiotic resistance markers. PCR/ESI-MS is a highly sensitive technique for detecting pathogens rapidly, with a sensitivity that is three times higher than standard culture.28 KEY POINTS Diagnosis and Treatment of Infectious Diseases The definitive diagnosis of an infectious disease requires recovery and identification of the infecting organism by microscopic identification of the agent in stains of specimens or sections of tissue, culture isolation and identification of the agents, demonstration of antibody- or cell-mediated immune responses to an infectious agent, or DNA or RNA identification of infectious agents. Treatment of infectious disease is aimed at eliminating the infectious organism and promoting recovery of the infected person. Treatment is provided by controlling/eradicating the infectious source through the use of

antimicrobial agents, immunotherapy, and, when necessary, surgical intervention (e.g., abscess drainage). Treatment The goal of treatment for an infectious disease is complete removal of the pathogen from the host and the restoration of normal physiologic function to damaged tissues. Most infectious diseases of humans are self-limiting in that they require little or no medical therapy for a complete cure. When an infectious process overcomes the body’s defenses, therapeutic intervention is essential. The choice of treatment may be medical through the use of antimicrobial agents; immunologic with antibody preparations, vaccines, or substances that stimulate and improve the host’s immune function; or surgical by removing infected tissues. The decision about which therapeutic modality or combination of therapies to use is based on the extent, urgency, and location of the disease process, the pathogen, and the availability of effective antimicrobial agents. Antimicrobial Agents It was not until the advent of World War II, after the introduction of sulfonamides and penicillin, that the development of antimicrobial compounds matured. Most antimicrobial compounds can be categorized roughly according to mechanism of anti-infective activity, chemical structure, and target pathogen (e.g., antibacterial, antiviral, antifungal, or antiparasitic agents). Antibacterial Agents Antibacterial agents are generally called antibiotics. Most antibiotics are actually produced by other microorganisms, primarily bacteria and fungi, as by-products of metabolism. Antibiotics usually are effective only against other prokaryotic organisms. An antibiotic is considered bactericidal if it causes irreversible and lethal damage to the bacterial pathogen and bacteriostatic if its inhibitory effects on bacterial growth are reversed when the agent is eliminated. Antibiotics can be classified into families of compounds with related chemical structure and activity (Table 10-4). TABLE 10-4 Classification and Activity of Antibacterial Agents (Antibiotics)

Family Penicillins Cephalosporins Monobactams Carbapenem

Example Ampicillin Cephalexin Aztreonam Imipenem

Target Site Cell wall Cell wall Cell wall Cell wall

Side Effects Allergic reactions Allergic reactions Rash Nausea, diarrhea

Family

Example

Aminoglycosides Tobramycin Tetracyclines

Doxycycline

Macrolides

Clarithromycin

Glycopeptides

Vancomycin

Quinolones

Ciprofloxacin

Miscellaneous

Chloramphenicol Rifampin Trimethoprim

Sulfonamides Oxazolidinone Streptogramin

Sulfadiazine

Target Site Ribosomes (protein synthesis) Ribosomes (protein synthesis) Ribosomes (protein synthesis) Ribosomes (protein synthesis) DNA synthesis Ribosomes (protein synthesis) Ribosomes (protein synthesis) Folic acid synthesis Folic acid synthesis

Ribosomes Linezolid (protein synthesis) Ribosomes Quinupristin/dalfopristin (protein synthesis)

Glycylcycline

Tigecycline

Ribosomes

Polymyxins

Colistin

Membrane

Side Effects Hearing loss Nephrotoxicity Gastrointestinal irritation Allergic reactions Teeth and bone dysplasia Colitis Allergic reactions Allergic reactions Hearing loss Nephrotoxicity Gastrointestinal irritation Tendon rupture Anemia Hepatotoxicity Allergic reactions Same as sulfonamides Allergic reactions Anemia Gastrointestinal irritation Diarrhea, thrombocytopenia Muscle and joint aches Nausea, vomiting, diarrhea Confusion, visual disturbances, vertigo, kidney damage

Family

Example

Target Site

Side Effects Nausea, vomiting, Membrane Lipopeptide Daptomycin constipation, diarrhea, depolarization headache Not all antibiotics are effective against all pathogenic bacteria. Some agents are effective only against gram-negative bacteria, and others are specific for grampositive organisms (e.g., vancomycin). The so-called broad-spectrum antibiotics, such as the newest class of cephalosporins, are active against a wide variety of grampositive and gram-negative bacteria. Members of the Mycobacterium genus, including M. tuberculosis, are extremely resistant to the effects of the major classes of antibiotics and require an entirely different spectrum of agents for therapy. The four basic mechanisms of the antibiotic action are interference with a specific step in bacterial cell wall synthesis (e.g., penicillins, cephalosporins, glycopeptides, monobactams, carbapenems), inhibition of bacterial protein synthesis (e.g., aminoglycosides, macrolides, ketolides, tetracyclines, chloramphenicol, oxazolidinones, streptogramins, and rifampin), interruption of nucleic acid synthesis (e.g., fluoroquinolones, nalidixic acid), and interference with normal metabolism (e.g., sulfonamides, trimethoprim).27 Despite lack of antibiotic activity against eukaryotic cells, many agents cause unwanted or toxic side effects in humans, including allergic responses (penicillins, cephalosporins, sulfonamides, glycopeptides), hearing and kidney impairment (aminoglycosides), and liver or bone marrow toxicity (chloramphenicol, fluoroquinolones, vancomycin). Of greater concern is the increasing prevalence of bacteria resistant to the effects of antibiotics. The ways in which bacteria acquire resistance to antibiotics are becoming as numerous as the types of antibiotics. Bacterial resistance mechanisms include the production of enzymes that inactivate antibiotics, such as β-lactamases, genetic mutations that alter antibiotic binding sites, alternative metabolic pathways that bypass antibiotic activity, and changes in the filtration qualities of the bacterial cell wall that prevent access of antibiotics to the target site in the organism. Antiviral Agents Until recently, few effective antiviral agents were available for treating human infections. The reason for this is host toxicity. Viral replication requires the use of eukaryotic host cell enzymes, and the drugs that effectively interrupt viral replication are likely to interfere with host cell reproduction as well. However, in response to the AIDS epidemic, the development of antiretroviral agents increased. Almost all antiviral compounds are synthetic, and with few exceptions, the primary target of antiviral compounds is viral RNA or DNA synthesis.27 During active viral replication, the nucleoside analogs inhibit the viral DNA polymerase, preventing duplication of the viral genome and spread of infectious viral progeny to other

susceptible host cells. Similar to the specificity of antibiotics, antiviral agents may be active against RNA viruses only, DNA viruses only, or occasionally both. Another class of antiviral agents developed solely for the treatment of HIV infections is the protease inhibitors (e.g., indinavir, ritonavir, saquinavir, tipranavir, atazanavir, nelfinavir). These drugs inhibit an HIV-specific enzyme that is necessary for late maturation events in the virus life cycle.27 Although the treatment of viral infections with antimicrobial agents is a relatively recent endeavor, reports of viral mutations resulting in resistant strains are very common. This is especially troubling in the case of HIV, in which resistance to relatively new antiviral agents, including nucleoside analogs and protease inhibitors, has already been described, prompting the need for combination or alternating therapy with multiple antiretroviral agents. Antifungal Agents The target site of the two most important families of antifungal agents is the cytoplasmic membranes of yeasts or molds. Fungal membranes differ from human cell membranes in that they contain the sterol ergosterol instead of cholesterol. The polyene family of antifungal compounds (e.g., amphotericin B, nystatin) preferentially binds to ergosterol and forms holes in the cytoplasmic membrane, causing leakage of the fungal cell contents and, eventually, lysis of the cell.27 The imidazole class of drugs (e.g., fluconazole, itraconazole, voriconazole, posaconazole) inhibits the synthesis of ergosterol, thereby damaging the integrity of the fungal cytoplasmic membrane.27 Both types of drugs bind to a certain extent to the cholesterol component of host cell membranes and elicit a variety of toxic side effects in treated people. The nucleoside analog 5-fluorocytosine (5-FC) disrupts fungal RNA and DNA synthesis but without the toxicity associated with the polyene and imidazole drugs. Unfortunately, 5-FC demonstrates little or no antifungal activity against molds or dimorphic fungi and is primarily reserved for infections caused by yeasts. A class of antifungal compounds called echinocandins inhibit the synthesis of β-1,3-glucan, a major cell wall polysaccharide found in many fungi, including C. albicans, Aspergillus species, and Pneumocystis carinii.27 The drugs included in this class are caspofungin, micafungin, and anidulafungin. These inhibitors are available for the treatment of people with fungal infections, such as candidiasis or invasive aspergillosis, which are refractory to treatment with other antifungal agents. Antiparasitic Agents Similar to other infectious diseases caused by eukaryotic microorganisms, treatment of parasitic illnesses is based on exploiting essential components of the parasite’s metabolism or cellular anatomy that are not shared by the host. Any relatedness between the target site of the parasite and the cells of the host increases the likelihood of toxic reactions in the host.

Resistance among human parasites to standard, effective therapy is a major concern. Resistant strains require more complicated, expensive, and potentially toxic therapy with a combination of agents. Immunotherapy Immunotherapy involves supplementing or stimulating the host’s immune response so that the spread of a pathogen is limited or reversed. Several products are available for this purpose, including intravenous immunoglobulin (IVIG) and cytokines. IVIG is a pooled preparation of antibodies obtained from normal, healthy immune human donors. Hyperimmune immunoglobulin preparations contain high titers of antibodies against specific pathogens, including hepatitis B virus, cytomegalovirus, rabies, and varicella-zoster virus. Cytokines are substances that stimulate white cell replication, phagocytosis, antibody production, and the induction of fever, inflammation, and tissue repair—all of which counteract infectious agents and hasten recovery. With the advent of genetic engineering and cloning, many cytokines, including interferons and interleukins, have been produced in the laboratory and are being evaluated experimentally as anti-infective agents. One of the most efficient but often overlooked means of preventing infectious diseases is immunization. Proper and timely adherence to recommended vaccination schedules in children and booster immunizations in adults effectively reduces the senseless spread of vaccinepreventable illnesses such as measles, mumps, pertussis, and rubella, which still occur with alarming frequency. Surgical Intervention Before the discovery of antimicrobial agents, surgical removal of infected tissues, organs, or limbs was occasionally the only option available to prevent the demise of the infected host. Today, medical therapy with antibiotics and other anti-infective agents is an effective solution for most infectious diseases. However, surgical intervention is still an important option for cases in which the pathogen is resistant to available treatments. Surgical interventions may be used to hasten the recovery process by providing access to an infected site by antimicrobial agents (drainage of an abscess), cleaning the site (debridement), or removing infected organs or tissue (e.g., appendectomy). In some situations, surgery may be the only means of affecting a complete cure, as in the case of endocarditis resulting in an infected heart valve, in which the diseased valve must be replaced with a mechanical or biologic valve to restore normal function. In other situations, surgical containment of a rapidly progressing infectious process such as gas gangrene may be the only means of saving a person’s life.

SUMMARY CONCEPTS The ultimate outcome of any interaction between microorganisms and the human host is decided by a complex and ever-changing set of variables that consider the overall health and physiologic function of the host and the virulence and infectious dose of the microbe. In many instances, disease is an inevitable consequence, but with continuing advances in science and technology, the majority of cases can now be eliminated or rapidly cured with appropriate therapy. It is the intent of those who study infectious diseases to understand thoroughly the pathogen, the disease course, the mechanisms of transmission, and the host response to infection. This knowledge will lead to the development of improved diagnostic techniques, revolutionary approaches to anti-infective therapy, and eradication or control of microscopic agents that cause frightening devastation and loss of life throughout the world.

Bioterrorism and Emerging Global Infectious Diseases Bioterrorism Anthrax is an ancient disease caused by the cutaneous inoculation, inhalation, or ingestion of the spores of Bacillus anthracis, a gram-positive bacillus. Anthrax is more commonly known as a disease of herbivores that can be transmitted to humans through contact with infected secretions, soil, or animal products. It is a rare disease in the United States, and so the sudden increase in cases over a short time indicated that the spread of the organism had been intentional. To prepare for the possibility of bioterrorist attacks, the CDC along with other federal, state, and local agencies has created the Laboratory Response Network (LRN).29,30 Potential agents of bioterrorism have been categorized into three levels (A, B, C) based on risk of use, transmissibility, invasiveness, and mortality rate. The agents placed in the highest bioterrorism threat level include B. anthracis, Yersinia pestis (the cause of bubonic plague), Francisella tularensis (the cause of tularemia), variola major virus (the cause of smallpox), and several hemorrhagic fever viruses (Ebola, Marburg, Lassa, and Junin). The toxin of the anaerobic gram-positive organism Clostridium botulinum, which causes the neuromuscular paralysis termed botulism, is also listed as a category A agent. The category B agents include agents of food-borne and waterborne diseases (Salmonella, Shigella, Vibrio cholerae, E. coli O157:H7), zoonotic infections (Brucella species, C. burnetii, Burkholderia mallei), and viral encephalitides (Venezuelan, Western, and Eastern equine

encephalitis viruses), as well as toxins from S. aureus, Clostridium perfringens, and Ricinus communis (the castor bean). Category C agents are defined as emerging pathogens and potential risks for the future, even though many of these organisms are causes of ancient diseases. Category C agents include M. tuberculosis, Nipah virus, Hantavirus, tick-borne and yellow fever viruses, and, the only protozoan of the group, Cryptosporidium parvum. Global Infectious Diseases Aided by a global market and the ease of international travel, the first years of the 21st century have witnessed the importation or emergence of a host of novel infectious diseases. During the late summer and early fall of 1999, WNV (an arthropod-borne flavivirus) was identified as the cause of an epidemic involving 56 people in the New York City area.31 This outbreak, which led to seven deaths (primarily in older adults), marked the first time that WNV had been recognized in the Western Hemisphere since its discovery in Uganda nearly 60 years earlier. Because WNV is a mosquito-borne disease and is transmitted to a number of susceptible avian (e.g., blue jays, crows, and hawks) and equine hosts, the potential for rapid and sustained spread of the disease across the United States was recognized early. By the fall of 2002, a national surveillance network had detected WNV activity in 2289 counties from 44 states, including Los Angeles County, and had identified more than 3000 human cases. The disease ranges in intensity from a nonspecific febrile illness to fulminant meningoencephalitis. In 2002 alone, 3389 cases of WNV-associated illness were identified in the United States with 201 deaths, making this the largest arboviral meningoencephalitis outbreak ever described in the Western Hemisphere. Efforts to prevent further spread of the disease are currently centered on surveillance of WNV-associated illness in birds, humans, and other mammals, as well as mosquito control.31 In the winter of 2002, SARS emerged as a global threat. The first inkling of the impending threat was when the Chinese Ministry of Health reported 305 cases of a mysterious and virulent respiratory tract illness that had appeared in Guangdong province in southern China in a 4-month period of time. The spread of the disease to household contacts of sick people and medical personnel caring for people with the disease identified it as highly transmissible. In a very short time, people with compatible symptoms were recognized in Hong Kong and Vietnam. The World Health Organization promptly issued a global alert and started international surveillance for people with typical symptomatology who had a history of travel to the endemic region. The Zika virus is a flavivirus transmitted by mosquitoes. It was first detected in 1947 among rhesus monkeys in Uganda. Human cases were first reported in Africa in the 1960s; however, in 2015, a cluster of cases of congenital microcephaly was linked to Zika.32,33 Many who had the virus had mild symptoms and might be unlikely to seek care, so the number of persons who contracted Zika is

unknown. The public health response provided testing, vector control, and prevention messages (e.g., mosquito netting, N,N-diethyl-meta-toluamide or diethyltoluamide (DEET), clothing that covers extremities). Zika has been detected in several body fluids and may also be sexually transmitted.32 For more details on cases of infectious disease detective work, refer to this website: www.who.int/en/ and www.cdc.gov. The International Society for Infectious Diseases maintains a LISTSERV known as ProMED-mail that provides early warning and rapid dissemination about infectious disease outbreaks: http://www.promedmail.org/. SUMMARY CONCEPTS The challenges associated with maintaining health throughout a global community are becoming increasingly apparent. Aided by a global market and the ease of international travel, the past decade has witnessed the importation and emergence of a host of novel infectious diseases. There is also the potential threat of the deliberate use of microorganisms as weapons of bioterrorism.

Review Exercises 1. Newborn infants who have not yet developed an intestinal flora are routinely given an intramuscular injection of vitamin K to prevent bleeding because of a deficiency in vitamin K–dependent coagulation factors. A. Use the concept of mutualism to explain why this is done. 2. People with human granulocytic ehrlichiosis may be coinfected with Lyme disease. A. Explain. 3. People with chronic lung disease are often taught to contact their health care provider when they notice a change in the color of their sputum (i.e., from white or clear to yellow- or brown-tinged) because it might be a sign of a bacterial infection. A. Explain. 4. Microorganisms are capable of causing infection only if they can grow at the temperature of the infected body site. A. Using this concept, explain the different sites of fungal infections because of the dermatophyte fungal species that cause tinea pedis (athlete’s foot) and Candida albicans, which causes

infections of the mouth (thrush) and female genitalia (vulvovaginitis). 5. The threat of global infections, such as SARS and HIV, continues to grow. A. What would you propose to be one of the most important functions of health care professionals in terms of controlling the spread of such infections? REFERENCES 1. Lloyd-Price J., Abu-Ali G., Huttenhower C. (2016). The healthy human microbiome. Genome Medicine 8, 51. doi:10.1186/s13073-016-0307-y. 2. Petersen C., Round J. L. (2014). Defining dysbiosis and its influence on host immunity and disease. Cellular Microbiology 16(7), 1024–1033. doi:10.1111/cmi.12308. 3. Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Wolters Kluwer Health. 4. Rayman J. B., Kandel E. R. (2017). Functional prions in the Brain. Cold Spring Harbor Perspectives in Biology 9(1), 1–14. doi:10.1101/cshperspect.a023671. 5. Prusiner S. B., Woerman A. L., Mordes D. A., et al. (2015). Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proceedings of the National Academy of Sciences of the United States of America 112(38), E5308–E5317. doi:10.1073/pnas.1514475112. 6. Rewar S., Mirdha D., Rewar P. (2015). Treatment and prevention of Pandemic H1N1 influenza. Annals of Global Health 81(5), 645–653. doi:10.1016/j.aogh.2015.08.014. 7. Solano C., Echeverz M., Lasa I. (2014). Biofilm dispersion and quorum sensing. Current Opinion in Microbiology 18, 96–104. doi:10.1016/j.mib.2014.02.008. 8. Goering R. V., Dockrell H. M., Zuckerman M., et al. (2013). Mim’s medical microbiology (5th ed.). Philadelphia, PA: Elsevier Saunders. 9. Donders G. G. G., Ruban K., Bellen G., et al. (2017). Mycoplasma/ureaplasma infection in pregnancy: To screen or not to screen. Journal of Perinatal Medicine 45(5), 505–515. doi:10.1515/jpm-2016-0111. 10. Centers for Disease Control and Prevention. (2017). Rocky mountain spotted fever. Available: http://www.cdc.gov/rmsf/stats/index.html. Accessed November 30, 2017. 11. Centers for Disease Control and Prevention. (2017). Disease specifics: Chlamydia pneumoniae. Available: https://www.cdc.gov/pneumonia/atypical/cpneumoniae/hcp/disease.html. Accessed November 30, 2017. 12. Hogerwerf L., De Gier B., Baan B., et al. (2017). Chlamydia psittaci (psittacosis) as a cause of communityacquired pneumonia: A systematic review and meta-analysis. Epidemiology and Infection 145(15), 3096– 3105. doi:10.1017/S0950268817002060. 13. Snowden J., Simonsen K. A. (2017). Ehrlichiosis. In: Stat Pearls [Internet]. Treasure Island, FL: StatPearls Publishing. Available: https://www.ncbi.nlm.nih.gov/books/NBK441966/. Accessed June, 2017. 14. Eldin C., Melenotte C., Mediannikov O., et al. (2017). From Q fever to Coxiella burnetii infection: A paradigm change. Clinical Microbiology Reviews 30(1), 115–190. doi:10.1128/CMR.00045-16. 15. Colombo A. L., de Almeida Junior J. N., Slavin M. A., et al. (2017). Candida and invasive mould diseases in non-neutropenic critically ill patients and patients with haematological cancer. Lancet Infectious Diseases 17(11), e344–e356. doi:10.1016/S1473-3099(17)30304-3. 16. Partida-Rodriguez O., Serrano-Vazquez A., Nieves-Ramirez M. E., et al. (2017). Human intestinal microbiota: Interaction between parasites and the host immune response. Archives of Medical Research 48(8), 1–2. doi:10.1016/j.arcmed.2017.11. 17. World Health Organization. (2017). Health topics: Epidemiology. Available: http://www.who.int/topics/epidemiology/en/. Accessed November 12, 2017. 18. Gordis L. (2014). Epidemiology (5th ed.). Philadelphia, PA: Elsevier Saunders. 19. Bennett J. E., Dolin R., Blaser M. J. (Eds.). (2015). Mandell, Douglas, and Bennett’s principles and practice of infectious diseases (8th ed.). Philadelphia, PA: Elsevier, Saunders.

20. Singer M., Deutschman C. S., Seymour C. W., et al. (2016). The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315(8), 801–810. doi:10.1001/jama.2016.0287. 21. Sastalla I., Monack D. M., Kubatzky K. F. (2016). Editorial: Bacterial exotoxins: How bacteria fight the immune system. Frontiers in Immunology 7, 300. doi:10.3389/fimmu.2016.00300. 22. Spaulding A. R., Salgado-Pabon W., Kohler P. L., et al. (2013). Staphylococcal and streptococcal superantigen exotoxins. Clinical Microbiology Reviews 26(3), 422–447. doi:10.1128/CMR.00104-12. 23. Hall J. (2015). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Saunders. 24. Shetty N. (2009). Infectious disease: Pathogenesis, prevalence and case studies. Chichester, England: John Wiley & Sons. 25. Fischbach F., Dunning M. B. (2015). A manual of laboratory and diagnostic tests (9th ed.). Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins. 26. Geskin L. J. (2015). Monoclonal antibodies. Dermatologic Clinics 33(4), 777–786. doi:10.1016/j.det.2015.05.015. 27. Woo T. M., Robinson M. V. (2016). Pharmacotherapeutics for nurse practitioner prescribers. Philadelphia, PA: F. A. Davis. 28. Vincent J. L., Brealey D., Libert N., et al. (2015). Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Critical Care Medicine 43(11), 2283–2291. doi:10.1097/CCM.0000000000001249. 29. Wagar E. (2016). Bioterrorism and the role of the clinical microbiology laboratory. Clinical Microbiology Reviews 29(1), 175–189. doi:10.1128/CMR.00033-15. 30. Center for Disease Control and Prevention. (2014). Laboratory response network. Available: https://emergency.cdc.gov/lrn/. Accessed December 13, 2017. 31. Center for Disease Control and Prevention. (2017). West Nile virus. Available: http://www.cdc.gov/ncidod/dvbid/westnile/index.htm. Accessed December 13, 2017. 32. Waddell L. A., Greig J. D. (2016). Scoping review of the zika virus literature. PLoS One 11(5), e0156376. doi:10.1371/journal.pone.0156376. 33. Journel I., Andrecy L. L., Metellus D., et al. (2017). Transmission of Zika Virus—Haiti, October 12, 2015 to September 10, 2016. Morbidity and Mortality Weekly Report 66(6), 172–176. doi:10.15585/mmwr.mm6606a4.

CHAPTER 11 Innate and Adaptive Immunity The Immune Response Cytokines and Their Role in Immunity General Properties of Cytokines Chemokines Innate Immunity Epithelial Barriers Cells of Innate Immunity Neutrophils and Macrophages Dendritic Cells Natural Killer Cells and Intraepithelial Lymphocytes Pathogen Recognition Pattern Recognition Toll-Like Receptors Soluble Mediators of Innate Immunity Opsonins Inflammatory Cytokines Acute-Phase Proteins The Complement System Adaptive Immunity Antigens

Cells of Adaptive Immunity Lymphocytes Major Histocompatibility Complex Molecules Antigen-Presenting Cells B Lymphocytes and Humoral Immunity Immunoglobulins Humoral Immunity T Lymphocytes and Cellular Immunity Helper T Cells and Cytokines in Adaptive Immunity Regulatory T Cells Cytotoxic T Cells Cell-Mediated Immunity Lymphoid Organs Thymus Lymph Nodes Spleen Other Secondary Lymphoid Tissues 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 Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Discuss the function of the immune system. 2. Compare and contrast the innate and adaptive immune response. 3. Understand the role of the chemical mediators that orchestrate the immune response. 4. Describe the cellular components of the innate immune response and their functions. 5. Understand the recognition systems for pathogens in innate immunity.

6. Describe the functions of the various cytokines involved in innate immunity. 7. Define the role of the complement system in immunity and inflammation. 8. Characterize the significance and function of major histocompatibility complex (MHC) molecules. 9. Compare the development and function of the T and B lymphocytes. 10. Differentiate between the processes of cellular and humoral immunity. 11. Describe the function of the five classes of immunoglobulins. 12. Describe the function of cytokines involved in the adaptive immune response. 13. Explain the transfer of passive immunity from mother to fetus and from mother to infant during breast-feeding. 14. Characterize the development of active immunity in the infant and small child. 15. Describe the changes in the immune response that occur during the normal aging process.

The human body is constantly exposed to potentially harmful microorganisms and foreign substances. A complete system composed of complementary and interrelated mechanisms defends against invasion by bacteria, viruses, and other foreign substances. Through recognition of specific patterns found on the surface of organisms and toxins, the body’s immune system can distinguish itself from these foreign substances and tell the difference between potentially harmful and nonharmful agents. In addition, the immune system can defend against abnormal cells and molecules that periodically develop within the body. The skin and its epithelial layers in conjunction with the body’s normal inflammatory processes make up the first line of the body’s defense and confer innate or natural immunity to the host. Once these protective barriers have been crossed, the body relies upon a second line of defense known as the adaptive immune response to eradicate infection by invading organisms. The adaptive immune response develops slowly over time but results in the development of antibodies that can rapidly target specific microorganisms and foreign substances when a second exposure occurs.

This chapter covers immunity and the immune system, including a complete discussion of innate and adaptive immunity. Concepts related to key cellular processes, recognition systems, and effector responses integral to the immune system are also presented. In addition, developmental aspects of the immune system are discussed.

The Immune Response Immunity can be defined as the body’s ability to defend against specific pathogens and/or foreign substances responsible for the development of disease. The immune response is initiated by the body’s various defense systems. Some responses become active almost immediately, whereas others develop slowly over time. It is the coordinated interaction of these mechanisms that allows the body to maintain normal internal homeostasis. However, when these mechanisms are either depressed or become overactive, illness and disease can occur. Innate immunity and adaptive immunity are complementary processes that work to protect the body. Innate immunity, the body’s first line of defense, occurs early and more rapidly in response to foreign substances, whereas adaptive immunity is usually delayed unless the host has been previously exposed (Table 11-1). TABLE 11-1 Features of Innate and Adaptive Immunity

Feature Time of response

Innate Adaptive Immediate (minutes/hours) Dependent upon exposure (first, delayed; second, immediate due to production antibodies) Diversity Limited to classes or groups Very large; specific for each of microbes unique antigen Microbe General patterns on Specific to individual microbes recognition microbes; nonspecific and antigens (antigen/antibody complexes) Nonself Yes Yes recognition

Feature Innate Adaptive Response Similar with each exposure Immunologic memory; more rapid to repeated and efficient with subsequent infection exposure Defense Epithelium (skin, mucous Cell killing; tagging of antigen by membranes), phagocytes, antibody for removal inflammation, fever Cellular Phagocytes T and B lymphocytes, components (monocytes/macrophages, macrophages, DCs, NK cells neutrophils), NK cells, DCs Molecular Cytokines, complement Antibodies, cytokines, components proteins, acute-phase complement system proteins, soluble mediators DC, dendritic cell; NK, natural killer. Intact innate immune mechanisms are essential for the initiation of the adaptive immune response, requiring communication between the two systems. Dendritic cells (DCs) are an essential component of both innate and adaptive immunity and serve as the communication link between the two immune responses through the release of cytokines and chemokines.1 As a result, innate immune cells are capable of communicating important information about the invading microorganism or foreign substance to the B and T lymphocytes, which are the key cells involved in adaptive immunity. These immune cells in turn recruit and activate additional phagocytes and molecules of the innate immune system to defend the host. Cytokines and Their Role in Immunity Cytokines, short-acting, biologically active, soluble substances, are an essential component of host defense mechanisms and the primary means with which cells of innate and adaptive immunity communicate. Chemokines are a subset of cytokines that consist of small protein molecules involved in both immune and inflammatory responses.2 They are responsible for directing the migration of leukocytes to both areas of injury and locations where immune responses have been activated such as lymph nodes, the spleen, Peyer patches, and the tonsils.2 Chemokines can work together to antagonize or activate chemokine receptors. The source and

function of the main cytokines that participate in innate and adaptive immunity are summarized in Table 11-2. TABLE 11-2 Cytokines and Chemokines of Innate and Adaptive Immunity

Cytokines Source Function Interleukin-1 Macrophages, Wide variety of biologic effects; activates (IL-1) endothelial endothelium in inflammation; induces fever and cells, some acute-phase response; stimulates neutrophil epithelial production cells Interleukin-2 CD4+, CD8+ Growth factor for activated T cells; induces (IL-2) T cells synthesis of other cytokines; activates cytotoxic T lymphocytes and NK cells Interleukin-3 CD4+ T cells Growth factor for progenitor hematopoietic (IL-3) cells Interleukin-4 CD4+ T2H Promotes growth and survival of T, B, and mast (IL-4) cells; causes T2H cell differentiation; activates cells, mast cells B cells and eosinophils; and induces IgE-type responses + Interleukin-5 CD4 T2H Induces eosinophil growth and development (IL-5) cells Interleukin-6 Macrophages, Stimulates the liver to produce mediators of (IL-6) endothelial acute-phase inflammatory response; also cells, T induces proliferation of antibody-producing lymphocytes cells by the adaptive immune system Interleukin-7 Bone marrow Primary function in adaptive immunity; (IL-7) stromal cells stimulates pre-B cells and thymocyte development and proliferation Interleukin-8 Macrophages, Primary function in adaptive immunity; (IL-8) endothelial chemoattracts neutrophils and T lymphocytes; cells regulates lymphocyte homing and neutrophil infiltration Interleukin- Macrophages, Inhibitor of activated macrophages and DCs; 10 (IL-10) some Tdecreases inflammation by inhibiting T1H cells helper cells and release of IL-12 from macrophages

Cytokines Source Function Interleukin- Macrophages, Enhances NK cell cytotoxicity in innate 12 (IL-12) DCs immunity; induces T1H cell differentiation in adaptive immunity Type I Macrophages, Inhibit viral replication; activate NK cells; and interferons fibroblasts increase expression of MHC-I molecules on (IFN-α, IFNvirus-infected cells β) Interferon-γ NK cells, Activates macrophages in both innate immune + (IFN-γ) CD4 and responses and adaptive cell-mediated immune + CD8 T responses; increases expression of MHC-I and lymphocytes MHC-II and antigen processing and presentation Tumor Macrophages, Induces inflammation, fever, and acute-phase necrosis T cells response; activates neutrophils and endothelial factor-α cells; kills cells through apoptosis (TNF-α) Chemokines Macrophages, Large family of structurally similar cytokines endothelial that stimulate leukocyte movement and regulate cells, T the migration of leukocytes from the blood to lymphocytes the tissues Granulocyte- T cells, Promotes neutrophil, eosinophil, and monocyte monocyte macrophages, maturation and growth; activates mature CSF (GM- endothelial granulocytes CSF) cells, fibroblasts Granulocyte Macrophages, Promotes growth and maturation of neutrophils CSF (Gfibroblasts, consumed in inflammatory reactions CSF) endothelial cells Monocyte Macrophages, Promotes growth and maturation of CSF (Mactivated T mononuclear phagocytes CSF) cells, endothelial cells

CSF, colony-stimulating factor; DC, dendritic cell; Ig, immunoglobulin; MHC, major histocompatibility complex; NK, natural killer; T1H, T-helper type 1; T2H, T-helper type 2. General Properties of Cytokines Cytokines are low-molecular-weight, pro- or anti-inflammatory proteins secreted by cells of the innate and adaptive immune systems that regulate many of the actions of these cells. Most of the major cytokines are the interleukins (ILs), interferons (IFNs), and tumor necrosis factor alpha (TNF-α). Cytokines work by binding to specific receptors on the cells that they target and then activating intracellular processes.3 ILs are produced by both the macrophages and lymphocytes in the presence of an invading microorganism or when the process of inflammation is initiated. Their primary function is to enhance the acquired immune response or regulate through suppression or enhancement the inflammatory process. IFNs are cytokines that primarily protect the host against viral infections and play a role in the modulation of the inflammatory response. Each type of IFN is produced by a specific cell of the immune response.4 UNDERSTANDING

Innate and Adaptive Immunity

The innate and adaptive immune systems mediate the body’s defenses through an integrated system in which numerous cells and molecules function cooperatively to protect the host against foreign invaders. The innate immune system stimulates adaptive immunity. Although they use different mechanisms to recognize invading pathogens, both types of immunity use many of the same mechanisms, including destruction of the pathogen by phagocytosis and the complement system, to clear the organism from the body.

1 Innate Immunity

Innate immunity (also called natural immunity) consists of the cellular and biochemical defenses that are normally in place before an encounter with an infectious agent and provide rapid protection against infection. The major effector components of innate immunity include epithelial cells, which block the entry of infectious agents and secrete antimicrobial enzymes, proteins, and peptides; phagocytic neutrophils and macrophages, which engulf and digest microbes; natural killer (NK) cells, which kill intracellular microbes and foreign agents; and the complement system, which amplifies the inflammatory response and uses the membrane attack response to lyse microbes. The cells of the innate immune system also produce chemical messengers that stimulate and influence the adaptive immune response. The innate immune system uses pattern recognition receptors (PRRs), which recognize microbial structures that are shared by microbes and are often necessary for their survival, but are not present on human cells. Thus, the innate immune system is able to distinguish between self and nonself, but it does not distinguish between invading agents.

2 Adaptive Immunity

Adaptive immunity (also called acquired immunity) refers to immunity that is acquired through previous exposure to infectious and other foreign agents. A defining characteristic of adaptive immunity is the ability not only to distinguish self from nonself but also to recognize and destroy specific foreign agents based on their distinct antigenic properties. The components of the adaptive immune system are the T and B lymphocytes and their products. There are two types of adaptive immune responses, humoral and cell-mediated immunity. Humoral immunity is mediated by the B lymphocytes (B cells) and is the principal defense against extracellular microbes and their toxins. The B cells differentiate into antibody-secreting plasma cells. The circulating antibodies then interact with and destroy the microbes that are present in the blood or mucosal surfaces. Cell-mediated, or cellular, immunity is mediated by the cytotoxic T lymphocytes (T cells) and functions in the elimination of intracellular pathogens (e.g., viruses). T cells develop receptors that recognize the viral peptides displayed on the surface of infected cells and then signal destruction of the infected cells. All cytokines are secreted in a brief, self-limited manner. They are rarely stored as preformed molecules but instead are synthesized when the cells that produce them are activated. Some of the cytokines exhibit pleiotropism, which means they can act on many different cell types.5 When these defenses malfunction, disease processes that originate in these tissues, such as asthma and psoriasis, can arise. Concept Mastery Alert Cytokines have the ability to act on different cell types so they are pleiotropic, not cell specific. They also have the ability to stimulate the same biologic factors as other cytokines or to overlap their effects. This is known as redundancy. In addition to being pleiotropic and redundant, several different cell types are capable of producing the same cytokine. This allows cytokines to have a broader spectrum of activity. For example, IL-1 is a proinflammatory

cytokine that is primarily produced by macrophages but can be produced by virtually all leukocytes, endothelial cells, and fibroblasts. Finally, cytokines can also function to initiate cascade reactions with one cytokine influencing the synthesis and actions of other cytokines. These effects may be localized or systemic, with the cytokines secreted into the bloodstream and transported to their site of action. Colony-stimulating factors (CSFs) are a unique subset of cytokines that participate in hematopoiesis and stimulate the production of large numbers of mature platelets, erythrocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and DCs. The CSFs were named according to the type of target cell on which they act (see Table 11-2). Although CSF is necessary for normal blood cell production, excess CSF is associated with several disease processes such as chronic obstructive pulmonary disease.6 Recombinant CSF is being used to increase the success rates of bone marrow transplantations. Chemokines Chemokines are small protein molecules that are involved in immune and inflammatory cellular responses and function to control the migration of leukocytes to their primary site of action in the immune response.2 The four distinct classes of chemokines are designated C, CC, CXC, and CX3C.7 The CC chemokines attract monocytes, lymphocytes, and eosinophils to sites of chronic inflammation. The CXC chemokines attract neutrophils to sites of acute inflammation. Chemokines communicate with their target cells by activating G protein– coupled receptors in the cells. As a result, they are capable of activating different populations of leukocytes based upon the needs of the situation.7 Chemokines are implicated in the development of a number of acute and chronic diseases, including atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, allergic asthma and chronic bronchitis, multiple sclerosis, systemic lupus erythematosus, and human immunodeficiency virus (HIV) infection. They also play a role in the body’s immune response against cancer cells through the enhancement of chemokines by activated T cells and other tumor-derived proteins.8,9 SUMMARY CONCEPTS

Immunity is the body’s defense against disease and invading microorganisms. Immune mechanisms can be divided into two types: innate and adaptive immunity. Innate immunity is the first line of defense and can distinguish between self and nonself through the recognition of cellular patterns on foreign substances and microbes. Adaptive immunity is part of the second line of defense and involves both humoral and cellular mechanisms that respond to cell-specific substances known as antigens. The adaptive immune response is capable of amplifying and sustaining its responses, of distinguishing self from nonself, and finally of memory in that it can recognize the antigen on repeat exposure in order to quickly produce a heightened response on subsequent encounters with the same microorganism. The innate and adaptive immune responses work in concert with one another to ensure that the homeostasis is maintained. Although cells of both the innate and adaptive immune systems communicate critical information about the invading microbe or pathogen by cell-to-cell contact, many interactions and cellular responses depend on the secretion of chemical mediators in the form of cytokines, chemokines, and CSFs. Cytokines are soluble proteins secreted by cells of both the innate and adaptive immune systems that mediate many of the functions of these cells. Chemokines are cytokines that stimulate the migration and activation of various immune and inflammatory cells. CSFs stimulate the growth and differentiation of bone marrow progenitors of immune cells and play a key role in hematopoiesis.

Innate Immunity KEY POINTS Innate Immunity Innate immunity consists of physical, chemical, cellular, and molecular defenses that are ready for activation and mediate rapid,

initial protection against infection. The innate immune response relies on the body’s ability to distinguish structures present on the surface of pathogens known as pathogen-associated molecular patterns (PAMPs) from structures on human cells. The phagocytic cells of the innate immune response express PRRs that bind with broad patterns shared by groups of microbes but that are not present on mammalian cells. Toll-like receptors (TLRs), a major type of PRR, are expressed on phagocytes and are potent activators of innate immune system cells and molecules. Cytokines and chemokines that are released from activated leukocytes regulate the activities of innate immunity, stimulate the inflammatory process, and initiate the adaptive immune response. Epithelial Barriers Physical, mechanical, and biochemical barriers against microbial invasion are found in all common portals of entry into the body, including the skin and respiratory, gastrointestinal, and urogenital tracts. The intact skin is by far the most formidable physical barrier available to infection because of its design. It comprises closely packed cells that are organized in multiple layers that are continuously shed. In addition, a protective layer of protein, known as keratin, covers the skin. The skin has simple chemicals that create a nonspecific, salty, acidic environment and antibacterial proteins, such as the enzyme lysozyme, that inhibit the colonization of microorganisms and aid in their destruction.10 Epithelial cells destroy the invading organisms by secreting antimicrobial enzymes, proteins, and peptides. Specialized cells in these linings, such as the goblet cells in the gastrointestinal tract, secrete a viscous material comprising high-molecular-weight glycoproteins known as mucin, which when hydrated forms mucus. The mucins bind to pathogens, thereby trapping them and washing away potential invaders. In the lower respiratory tract, hair-like, mobile structures called cilia protrude through the epithelial cells and move microbes trapped in the mucus up the tracheobronchial tree and toward the throat. The physiologic responses of coughing and sneezing further aid in their removal from the body.

Microorganisms that are trapped by mucus are then subjected to various chemical defenses present throughout the body, including lysozymes and the complement system. Lysozyme is a hydrolytic enzyme found in tears, saliva, and human milk, which is capable of breaking down bacterial cell walls. The complement system is found in the blood and is essential for the activity of antibodies. It is composed of 20 different enzyme precursors, which when activated by antigen–antibody complexes cause bacteria to clump together so that they are more susceptible to phagocytic immune cells (Fig. 11-1). In addition, recent research has shown that complement plays a key role in bridging the innate–adaptive immune responses through the release of C3 complement protein.11 In the stomach and intestines, death of microbes results from the action of digestive enzymes, acidic conditions, and the secretion of defensins, small positively charged peptides that quickly kill both gram-positive and gram-negative microorganisms by disrupting the microbial membrane.

Phagocytosis. (A) A phagocytic white blood cell moves through a capillary that is in an infected area and engulfs the bacteria. (B) The lysosome digests the bacteria that were in a vesicle. (From Cohen B. J. (2013). Memmler’s the human body in health and disease (12th ed.). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 11-1

When pathogens are able to breach the epithelial defenses, the innate immune response is initiated by the body’s leukocytes, which recognize common surface receptors present on the invading microorganisms. Cells of Innate Immunity

The cells of the innate immune response recognize microbes that share characteristics common to all of their surface receptors. Once recognized, the innate immune cells initiate a broad spectrum of responses that target the invading microorganisms. The key cells of innate immunity include neutrophils, macrophages, DCs, NK cells, and intraepithelial lymphocytes (IELs). They have both proinflammatory and anti-inflammatory effects on their targets and play an important role in priming adaptive immune responses.12,13 Neutrophils and Macrophages The leukocytes involved in the innate immune response are derived from myeloid stem cells and are subdivided into two distinct groups based on the presence or absence of specific staining granules in their cytoplasm. Leukocytes that contain granules are classified as granulocytes and include neutrophils, eosinophils, and basophils. Cells that lack granules are classified as agranulocytes and include lymphocytes, monocytes, and macrophages. However, lymphocytes are derived from lymphoid precursors and are not part of the innate immune response. Neutrophils, which are named for their neutral-staining granules, are the most abundant granulocytes found in the body and make up approximately 55% of all white blood cells. They are also known as polymorphonuclear neutrophils. They are phagocytic cells and are capable of amoeboid-like movement, which allows them to migrate throughout the body. They function as early responder cells in innate immunity. They are rare in the tissues and in body cavities and lie predominantly dormant in the blood and bone marrow until they are needed in the immune response.14 Eosinophils have large coarse granules and normally comprise only 1% to 4% of the total white cell count. In contrast to neutrophils, these cells do not ingest cellular debris but rather antigen–antibody complexes and viruses. They frequently become active in parasitic infections and allergic responses. Basophils make up less than 1% of the total white cell count and contain granules that release a multitude of substances including histamine and proteolytic enzymes. Their function is not completely understood, but they are believed to play a role in allergy and parasitic infection as well. The agranulocytes involved in innate immunity are part of the mononuclear phagocyte system and include the monocytes and

macrophages. Monocytes are the largest in size of all the white blood cells but make up only 3% to 7% of the total leukocyte count. They are released from the bone marrow into the bloodstream where they migrate into tissues and mature into macrophages and DCs so that they can participate in the inflammatory response and phagocytize foreign substances and cellular debris. Macrophages have a long life span, reside in the tissues, and act as the first phagocyte that invading organisms encounter upon entering the host.14 Macrophages are essential for the clearance of bacteria that breach the epithelial barrier in the intestine and other organ systems. They have remarkable flexibility that allows them to efficiently respond to environmental signals. Once activated, these cells engulf and digest microbes that attach to their cell membrane. The ability of these phagocytic cells to initiate this response is dependent upon the repetitive structures known as pathogen-associated molecular patterns (PAMPs) and the receptors that can recognize them known as pattern recognition receptors (PRRs). Phagocytosis of invading microorganisms helps to limit the spread of infection until adaptive immune responses can become fully activated. In addition to phagocytosis, macrophages and DCs process and present antigens in the initiation of the immune response acting as a major initiator of the adaptive immune response.1 These cells secrete substances that initiate and coordinate the inflammatory response or activate lymphocytes. Macrophages can also remove antigen–antibody complexes and, under the influence of T cells, destroy malignant host or virus-infected cells. Dendritic Cells DCs are specialized, bone marrow–derived leukocytes found in lymphoid tissue and are the bridge between the innate and adaptive immune systems. DCs are relatively rare cells that are found mainly in tissues exposed to external environments such as the respiratory and gastrointestinal systems.1 They are present primarily in an immature form that is available to directly sense pathogens, capture foreign agents, and transport them to secondary lymphoid tissues.1 Once activated, DCs undergo a complex maturation process in order to function as key antigen-presenting cells (APCs) capable of initiating adaptive immunity.1 They are responsible for the processing and presentation of antigens to the lymphocytes. DCs, like macrophages,

also release several communication molecules that direct the nature of adaptive immune responses. Natural Killer Cells and Intraepithelial Lymphocytes NK cells and IELs are two other cell types involved in the innate immune response. NK cells have the innate ability to spontaneously kill target organisms. Both types of cells rely on the recognition of specific PAMPs on the cell surface of the microorganism. NK cells are a heterogeneous population of lymphocytes that mediate spontaneous cytotoxicity against infected cells.15 Because they have the unique ability to target microorganisms without previous exposure, they are considered to be part of the innate immune response despite being of lymphoid origin. They resemble large granular lymphocytes and are capable of killing some types of tumor and/or infected cells without previous exposure to surface antigens. However, they have been shown to play an equally important role in limiting the spread of infection and assisting in the development of adaptive immune responses through the production of cytokines.15 NK cells can be excitatory or inhibitory, which ensures that only foreign cells are destroyed (see Fig. 11-2).15 In addition to their role as phagocytes, NK cells assist in T-cell polarization, DC maturation, and innate immune control of viral infection through the secretion of immune modulators and antiviral cytokines. NK cells comprise approximately 10% to 15% of peripheral blood lymphocytes but do not bear T-cell receptors (TCR) or cell surface immunoglobulins (Igs).

Natural killer (NK) cell receptors. (A) NK cells express activating receptors that respond to ligands from virus-infected or injured cells and inhibiting receptors that bind to the class I major histocompatibility complex (MHC-I) self-recognition molecules expressed by normal cells. Normal cells are not killed because inhibitory signals from normal MHC-I molecules override activating signals. (B) In virus-infected or tumor cells, increased expression of ligands for activating receptors and reduced expression or alteration of MHC molecules interrupt the inhibitory signals, allowing activation of NK cells and lysis of target cells. FIGURE 11-2

Pathogen Recognition The innate immune response plays a crucial role in the proinflammatory response to infection and relies upon the ability of host defenses to differentiate self from nonself so that only invading organisms are targeted. The leukocytes involved in this response recognize certain evolutionarily retained patterns present on the surface of pathogens and in response bind to its membrane and destroy the invading organism through the process of phagocytosis (Fig. 11-3).

Recognition systems of innate and adaptive immunity. MHC, major histocompatibility complex; NK, natural killer. FIGURE 11-3

Pattern Recognition Invading pathogens contain structures in their cell membranes termed PAMPs, which are recognized by the cells of the innate immune system because these cells possess receptors known as PRRs. Upon PAMP recognition, PRRs come in contact with the cell surface and/or send intracellular signals to the host that trigger proinflammatory and antimicrobial responses including the synthesis and release of cytokines, chemokines, and cell adhesion molecules.16 The PAMPs are made up of a combination of sugars, lipid molecules, proteins, or patterns of modified nucleic acids and are essential to the functioning and infectivity of the pathogen. The ability of the innate immune response to limit microbes early in the infectious process results from the binding of pathogens to the PRRs on leukocytes, which in turn initiates the signaling events that lead to complement activation, phagocytosis, and autophagy. Once initiated, white blood cells, neutrophils, and monocytes migrate from the blood to the tissues, along with other body fluids causing peripheral edema. Blood monocytes mature into macrophages as they traverse the tissues and join the macrophages and DCs already present in the tissues. PRRs present on these cells become activated as well, amplifying the inflammatory response. Toll-Like Receptors TLRs derive their name from the study of the Drosophila melanogaster toll protein, which is responsible for the resistance of Drosophila to bacterial and fungal infections.16 Structurally, TLRs are integral glycoproteins that possess an extracellular binding site and a cytoplasmic signaling toll/IL-1 domain that initiates the signaling cascade.16 Binding of PAMP to a TLR induces a conformational change in the receptor activating intracellular processes. TLRs play essential roles in maintaining tissue homeostasis by regulating wound healing, tissue repair, and tissue regeneration. TLRs can be found in most of the bone marrow cells including the macrophages, DCs, neutrophils, T cells, B cells, and non–bone marrow cells including epithelial cells and fibrocytes. Ten different TLRs have been identified in humans,

and they each recognize distinct PAMPs derived from various microorganisms including bacteria, viruses, fungi, and protozoa.17 Soluble Mediators of Innate Immunity Although cells of the innate immune system communicate critical information about invading microorganisms and self–nonself recognition through cell-to-cell contact, soluble mediators are also essential for many other aspects of the innate immune response. Development of innate immune response is very much dependent upon the secretion of soluble molecules such as opsonins, cytokines, and acute-phase proteins. Opsonins Opsonins are molecules that coat negatively charged particles on cell membranes and as a result enhance the recognition and binding of phagocytic cells to microorganisms. The process by which the cellular particles on microbes are coated is called opsonization. Once the opsonin binds to the microbe, it is able to activate the phagocyte after attachment to a PRR on the phagocytic cell. There are several opsonins important in innate immunity and the acute inflammatory process including acute-phase proteins, lectins, and complement. Components of the adaptive immune response can also act as opsonins. For example, when the humoral response is activated, IgG and IgM antibodies can coat cellular particles on pathogens and bind to Fc receptors on neutrophils and macrophages, enhancing the phagocytic function of innate cells. Inflammatory Cytokines Cytokines are low-molecular-weight proteins that serve as soluble chemical messengers and that mediate the interaction between immune and tissue cells. They are part of an integrated signaling network with extensive functions in both the innate (nonspecific) and adaptive immune defenses. The cytokines involved in innate immunity include TNF-α and lymphotoxin; IFN-γ, IFN-α, and IFN-β; IL-1, IL-6, and IL-12; and chemokines (see Table 11-2). These substances modify innate immunity by stimulating the development of cells involved in both innate and adaptive immunity, producing chemotaxis within leukocytes, and inhibiting viral

replication. Once an innate immune phagocyte is activated by PRR–PAMP binding with a pathogen, cytokines are released into the surrounding tissues where they exert their effect. If large numbers of cells are activated, then cytokines may be able to stimulate inflammatory processes in tissues far from the initial site of infection. Under normal circumstances, the duration of activity of cytokines is relatively short so that a prolonged immune response does not occur. TNF-α and lymphotoxins are cytokines that are structurally related and that have similar cytotoxic activities.18 The two cytokines differ in that TNF-α can be secreted by a variety of immune cells, but the lymphotoxins are predominantly secreted by activated lymphocytes and NK cells. These cytokines regulate development of the lymphoid tissues and the inflammatory process by enhancing adhesion of immune cells to pathogens and stimulating the release of other cytokines/chemokines.18 The IFNs are another family of cytokines that are critically involved in initiating and enhancing the cellular immune response to viral infection of host cells. In addition, they play a key role in amplifying the presentation of antigens to specific T cells forming the chemical bridge between the innate and adaptive immune response.18 Type I IFN-α and IFN-β are secreted by virusinfected cells, whereas type II, immune or IFN-γ, are mainly secreted by T cells, NK cells, and macrophages.18 IFNs activate macrophages, induce B cells to switch Ig type, alter T-helper response, inhibit cell growth, promote apoptosis, and induce an antiviral state in uninfected cells. Finally, ILs help to regulate the immune response by increasing the expression of adhesion molecules on endothelial cells, stimulating migration of leukocytes into infected tissues, and stimulating the production of antibodies by the cells of the adaptive immune response. Acute-Phase Proteins Two acute-phase proteins that are involved in the defense against infections are the mannose-binding lectin (MBL) and C-reactive protein (CRP). MBL and CRP are produced in the liver and released in response to tissue injury and inflammation.19,20 MBL binds specifically to mannose sugar residues, and CRP binds to both phospholipids and sugars that are found on the surface of microbes. These substances enhance the binding of phagocytic

cells to suboptimally opsonized invading microorganisms. They also act as activators of the alternative complement pathway. The Complement System The complement system is a powerful effector mechanism of both innate and adaptive immunity that allows the body to localize infection and destroy invading microorganisms. The complement system is composed of groups of proteins found in the circulation and in various extracellular fluids. The proteins of the complement system normally circulate as inactive precursors. When activated by components of the immune response, a series of proteolytic and protein–protein interactions is initiated that ultimately culminates in opsonization of invading pathogens, migration of leukocytes to the site of invasion, initiation of a localized inflammatory reaction, and ultimately lysis of the pathogen.21 For a complement reaction to occur, the complement components must be activated in the proper sequence. Inhibitor proteins and the instability of the activated complement proteins at each step of the process prevent uncontrolled activation of the complement system. There are three parallel but independent activation pathways of the complement system during the innate immune response: the classical, the lectin, and the alternative pathways. The reactions of the complement systems can be divided into three phases: 1. Initiation or activation 2. Amplification of inflammation 3. Late-stage membrane attack response The three pathways differ in the proteins used in the early stage of activation, but all ultimately converge on the key complement protein C3, which is essential for the amplification stage. Activated C3 then activates all subsequent complement molecules (C5 through C9), resulting in the ultimate lysis of cells. The classic pathway is initiated by an antigen–antibody complex (either IgG or IgM mediated), which causes a specific reactive site on the antibody to be “uncovered” so that it can bind directly to the C1 molecule in the complement system.22 Initially, a small amount of enzyme is produced, but with activation of successive complement proteins successively increasing,

concentrations of proteolytic enzymes are produced. This process is known as amplification. In the lectin or alternative complement pathway, inactive circulating complement proteins are activated when they are exposed to microbial surface polysaccharides, MBL, CRP, and other soluble mediators that are integral to innate immunity.23 Like the classic pathway, the lectin and alternative pathways create a series of enzymatic reactions that cleave successive complement proteins in the pathway. During the activation phase of the complement cascade, cleavage of C3 produces C3a and C3b. C3b is a key opsonin that coats bacteria and allows them to be phagocytized after binding to complement receptor on leukocytes. The presence of C3a triggers the migration of neutrophils into the tissues to enhance the inflammatory response. Production of C3a, C4a, and C5a also leads to activation of mast cells and basophils, causing them to release histamine, heparin, and other substances. These mediators of the inflammatory response increase tissue blood flow and increase localized capillary permeability, allowing leakage of fluids and protein into the area. In addition, they stimulate changes in the endothelial cells in order to stimulate chemotaxis of neutrophils and macrophages to the site of inflammation. During the late-phase membrane attack response of the complement cascade, cleavage of C5 triggers the assembly of a membrane attack complex from the C5 to C9 proteins. The resulting complex creates a tubelike structure, which penetrates the microbial cell membrane allowing the passage of ions, small molecules, and water into the cell, causing the cell to ultimately burst. The multiple and complementary functions of the complement system make it an integral component of innate immunity and inflammation. It also serves as an essential bridge between the innate and humoral responses. Pathophysiologic manifestations associated with deficiencies of complement range from increased susceptibility to infection to inflammatory tissue and autoimmune disorders that are the result of impaired activated complement clearance. SUMMARY CONCEPTS The innate immune system is a complex system that works in an organized, rapid, yet nonspecific fashion as the body’s first line of defense against invasion. It comprises the epithelial cells of the skin

and mucous membranes; phagocytic cells such as the neutrophils, macrophages, and NK cells; and a series of plasma proteins including cytokines, chemokines, and the proteins of the complement system. These defenses exist before the body encounters an invading microorganism and are activated independent of the adaptive humoral response. The epithelial cells of the skin and mucous membranes block the entry of infectious agents and secrete antimicrobial enzymes, proteins, and peptides in an attempt to prevent microorganisms from invading the internal environment. The phagocytes of the innate immune response engulf and digest infectious agents. They use PRRs, which are present on their membranes to recognize and bind broad patterns of molecules (PAMPs) shared by microbes and that are essential for their survival. TLRs are the most studied of all PRRs and are expressed on many of the cells of the innate immune system. TLRs are involved in response to widely divergent types of molecules that are commonly expressed by microbial but not mammalian cell types. Development of a healthy innate immune response is dependent not only upon the coordinated activity of the leukocytes but also on the secretion of chemical mediators and soluble molecules, such as opsonins, cytokines, acute-phase proteins, and complement proteins. Opsonins bind to and tag microorganisms for more efficient recognition by phagocytes. Activated leukocytes release cytokines that stimulate the migration of leukocytes to the site of inflammation, stimulate production of acute-phase proteins, and enhance phagocytosis. The complement system is a primary effector system that functions as part of both the innate and adaptive immune responses. It comprises a group of proteins that are activated by three distinct but convergent pathways: the classical, the lectin, and the alternative pathways. The primary function of the complement system is the promotion of inflammation and destruction of the microbes.

Adaptive Immunity

The adaptive immune system is the final line of defense against infection and is activated once the innate immune response initiates the inflammatory process. In contrast to innate immunity, the adaptive immune response is capable of targeting specific cells or organisms that it recognizes as foreign to the body through activation of various lymphocytes and their products, including antibodies. The lymphocytes involved in adaptive immunity have the unique ability to remember specific pathogen and mount a heightened immune response during repeat exposures. Each exposure results in a more rapid and aggressive response. Substances present on the surface of pathogens or other foreign substances that elicit adaptive immune responses are called antigens. Adaptive immunity involves two distinct but interconnected mechanisms: humoral and cell-mediated responses. Humoral immunity is mediated by B-lymphocyte activation and subsequent antibody production. It is the primary defense against extracellular microbes and toxins. In contrast, cell-mediated immunity involves the activation of specific T lymphocytes (T-helper and T-cytotoxic lymphocytes), which are responsible for the body’s defense against intracellular microbes such as viruses. KEY POINTS Adaptive Immunity The adaptive immune response involves a complex series of interactions between components of the immune system and the antigens of a foreign pathogen. It is able to distinguish between self and nonself, recognize and specifically react to large numbers of different microbes and pathogens, and remember the specific agents. Humoral immunity consists of protection provided by the Blymphocyte–derived plasma cells, which produce antibodies that travel in the blood and interact with circulating and cell surface antigens. Cell-mediated immunity provides protection through cytotoxic T lymphocytes, which protect against virus-infected or cancer cells.

Antigens Antigens, or immunogens, are substances or molecules that are foreign to the body but when introduced trigger the production of antibodies by B lymphocytes, leading to the destruction of the invader. Antigens are usually large macromolecules 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 Igs secreted in response to the presence of 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. 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. 11-4). 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.24

Multiple epitopes on a complex antigen being recognized by their respective (A, B, C) antibodies. FIGURE 11-4

Low-molecular-weight molecules may contain antigenic determinants but alone are usually unable to stimulate an immune response. These molecules are known as haptens. When they combine with an immunogenic carrier (usually a protein), they are able to function as antigens. Many haptens exist in nature and frequently create problems for humans. Urushiol is a toxin found in the oils on poison ivy that is responsible for initiating an allergic reaction.25 An allergic response to the antibiotic penicillin is an example of a medically important reaction because of hapten–carrier complexes. The penicillin molecule is very small and usually nonantigenic. However, in susceptible people, it can complex with carrier proteins in the body, which are then recognized as “foreign” and capable of initiating an antigen– antibody reaction. Cells of Adaptive Immunity

The principal cells of the adaptive immune system are the lymphocytes, APCs, and effector cells. Lymphocytes Lymphocytes make up approximately 36% of the total white cell count and are the primary cells of the adaptive immune response. They arise from the lymphoid stem cell line in the bone marrow and differentiate into two distinct but interrelated cell types: B lymphocytes and T lymphocytes. B lymphocytes are responsible for forming the antibodies that provide humoral immunity, whereas T lymphocytes provide cell-mediated immunity. T and B lymphocytes are unique in that they are the only cells in the body capable of recognizing organism-specific antigens present on the surfaces of microbial cells and other pathogens. As a result, adaptive immune processes are organism specific and possess the capacity for memory. The recognition of specific surface antigens by lymphocytes is made possible because of the presence of specific receptors or antibodies on the surface of B and T lymphocytes. Scientists have been able to identify these specific proteins and correlate them with a specific cellular function. This has led to the development of a classification system for these surface molecules known as the “cluster of differentiation” (CD). The nomenclature for the surface proteins uses the letters “CD” followed by a number that specifies the surface proteins that define the cell type or stage of cell differentiation and are recognized by a cluster or group of antibodies. The utilization of this nomenclature has spread to other immune cells and cytokines, all of which contribute to the acquired immune response. Leukocytes involved in the innate immune response, such as macrophages and DCs, also play a key role in adaptive immunity because they function as APCs. They are capable of processing complex antigens into epitopes, which are then displayed on their cell membranes in order to activate the appropriate lymphocytes. Functionally, there are two types of immune cells: regulatory cells and effector cells. The regulatory cells assist in preplanning and controlling the immune response, whereas effector cells carry out the elimination of the antigen. In the body, helper T lymphocytes activate other lymphocytes and phagocytes, whereas regulatory T cells (TREGS) keep these cells in check so that an exaggerated immune response

does not occur. Cytotoxic T lymphocytes, macrophages, and other leukocytes function as effector cells in different immune responses. Although T and B lymphocytes are generated from lymphoid stem cells in the bone marrow, they do not stay there to mature. Undifferentiated, immature lymphocytes migrate to lymphoid tissues, where they develop into distinct types of mature lymphocytes (Fig. 11-5). The T lymphocytes first migrate to the thymus gland where they divide rapidly and develop extensive diversity in their ability to react against different antigens.27 Each T lymphocyte develops specificity against a specific antigen. Once this differentiation occurs, the lymphocytes leave the thymus gland and migrate via the bloodstream to peripheral lymphoid tissue. At this time, they have been preprogrammed not to attack the body’s own tissues. Unfortunately, in many autoimmune diseases it is believed that this process goes astray. In contrast, the B lymphocytes mature primarily in the bone marrow and are essential for humoral, or antibody-mediated, immunity. Unlike the T lymphocytes, where the entire cell is involved in the immune response, B lymphocytes secrete antibodies, which then act as the reactive agent in the immune process. Therefore, the lymphocytes are distinguished by their function and response to antigens, their cell membrane molecules and receptors, their types of secreted proteins, and their tissue location. High concentrations of mature lymphocytes are found in the lymph tissue throughout the body including the lymph nodes, spleen, skin, and mucosal tissues.

FIGURE 11-5

Pathway for T- and B-cell differentiation.

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.

1 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.

2 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.

3 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. T and B lymphocytes possess all of the processes necessary for the adaptive immune response—specificity, diversity, memory, and self– nonself recognition. When antigens come in contact with the lymphocytes in the lymphoid tissues of the body, specific T cells become activated and specific B cells are stimulated to produce antibodies. Once the first encounter occurs, these cells can exactly recognize a particular microorganism or foreign molecule because each lymphocyte is capable of targeting a specific antigen and differentiating the invader from self or from other substances that may be similar to it. Cell-mediated and humoral immunity is capable of responding to millions of antigens each day because there is an enormous variety of lymphocytes that have been programmed and selected during cellular development. Once the invading substance or organism has been removed from the body, the lymphocytes “remember” the presenting antigen and can respond rapidly during the next encounter. These lymphocytes are called “memory” T and B lymphocytes. They remain in the body for a longer period of time than their predecessors and as a result can respond more rapidly on repeat exposure. The immune system usually can respond to commonly encountered microorganisms so efficiently that we are unaware of the response. B- and T-lymphocyte activation is triggered by antigen presentation to unique surface receptors (Fig. 11-6). The antigen receptor present on the B lymphocyte consists of membrane-bound Ig molecules that can bind a specific epitope. However, in order for B lymphocytes to produce antibodies, they require the help of specific T lymphocytes, called helper T cells. Although the B lymphocytes bind to one determinant (or hapten) on an antigen molecule, the antigen-specific helper T cell recognizes and binds to another determinant known as the “carrier.” The carrier is an APC, which has previously picked up the specified antigen. This interaction (B cell–T cell–APC) is restricted by the presence of self-recognition proteins known

as MHC molecules. This allows the lymphocyte to differentiate between self and foreign peptides.

Pathway for immune cell participation in an immune response. APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor. FIGURE 11-6

Once the B and T lymphocytes are activated and amplified by cytokines released as part of the innate response, the lymphocytes divide several times to form populations or clones of cells that continue to differentiate into several types of effector and memory cells. In the adaptive immune response, the effector cells destroy the antigens and the memory cells retain the ability to target antigen during future encounters. Major Histocompatibility Complex Molecules In order for the adaptive immune response to function properly, it must be able to discriminate between molecules that are native to the body and those that are foreign or harmful to the body. The T lymphocytes are designed to respond to a limitless number of antigens, but at the same time, they need to be able to ignore self-antigens expressed on tissues. The MHC molecules enable the lymphocytes to do just this. The MHC is a large cluster of genes located on the short arm of chromosome 6.27 The complex occupies approximately 4 million base pairs and contains 128 different genes, only some of which play a role in the immune response. The MHC genes are divided into three classes: I, II, and III, based upon their underlying function (Fig. 11-7).

Recognition by a T-cell receptor (TCR) on a CD4+ helper T (TH) cell of an epitope associated with a class II major histocompatibility complex (MHC) molecule on an antigen-presenting cell (APC) and by a TCR on a CD8+ cytotoxic T (TC) cell of an epitope associated with a class I MHC molecule on a virus-infected cell. FIGURE 11-7

The class I and II MHC genes are responsible for encoding human leukocyte antigens (HLAs), which are proteins found on cell surfaces and define the person’s tissue type. These molecules are present on the cell surface glycoproteins that form the basis for human tissue typing. Each person has a unique collection of MHC proteins that affect immune responses as well as susceptibility to a number of diseases. Because of the

number of MHC genes and the possibility of several alleles for each gene, it is almost impossible for any two people to have an identical MHC profile. The class I and II MHC genes also encode proteins that play an important role in antigen presentation. Protein fragments from inside the cell are displayed by MHC complex on the cell surface, allowing the immune system to differentiate between the body’s own tissues and foreign substances. Cells, which present unfamiliar peptide fragments on the cell surface, are attacked and destroyed by the B and T lymphocytes. Class III MHC genes encode for many of the components of the complement system and play an important role in the innate immune process. The MHC-I complexes are cell surface glycoproteins that contain a groove, which is able to accommodate a peptide fragment. MHC-I molecules interact with T-cytotoxic cells and activate them when presented with a foreign antigen peptide. MHC-I complexes may also present degraded viral protein fragments from infected cells. They are found on almost all nucleated cells in the body and are capable of signaling the immune system in response to all types of cellular changes.28 Class II MHC (MHC-II) molecules are found only on phagocytic APCs, immune cells that engulf foreign particles including bacteria and other microbes. This includes the macrophages, DCs, and B lymphocytes, which communicate with the antigen receptor and CD4 molecule on T-helper lymphocytes. Like class I MHC proteins, class II MHC proteins have a groove or cleft that binds a fragment of antigen. However, these bind fragments from pathogens that have been engulfed and digested during the process of phagocytosis. The engulfed pathogen is degraded into free peptide fragments within cytoplasmic vesicles and then complexed with the MHCII molecules on the surface of the cells. T-helper cells recognize these complexes on the surface of APCs and become activated. The first human MHC proteins discovered are called HLAs and are so named because they were identified on the surface of white blood cells. HLAs are the major target involved in organ transplant rejection and as a result are the focus of a great deal of research in immunology. Recent analysis of the genes for the HLA molecules has allowed for better understanding of the proteins involved in this response (Table 11-3). TABLE 11-3 Properties of Class I and II MHC Molecules

Properties HLA Distribution Antigens Class I HLA-A, Virtually all MHC HLA-B, nucleated cells HLA-C Class II MHC

Functions Present processed antigen to cytotoxic CD8+ T cells; restrict cytolysis to virus-infected cells, tumor cells, and transplanted cells Present processed antigenic fragments to CD4+ T cells; necessary for effective interaction among immune cells

HLAImmune cells, DR, antigenHLApresenting cells, DP, B cells, and HLAmacrophages DQ HLA, human leukocyte antigen; MHC, major histocompatibility complex.

HLA genes are inherited as a unit, called a haplotype, because the class I and II MHC genes are closely linked on one chromosome. Because each person inherits one chromosome from each parent, each person has two HLA haplotypes. Tissue typing in forensics and organ transplantation involves the identification of these haplotypes. In organ or tissue transplantation, the closer the matching of HLA types, the greater is the probability of identical antigens and the lower the chance of rejection.29,30 Antigen-Presenting Cells During the adaptive immune response, activation of a T lymphocyte requires the recognition of a foreign peptide (antigen) bound to a self-MHC molecule. This process requires the simultaneous delivery of stimulatory signals to the T lymphocyte by another specialized cell known as an APC. Therefore, APCs play a key role in bridging the innate and adaptive immune systems. Cells that function as APCs must be able to express both classes of MHC molecules and include the DCs, monocytes, macrophages, and B lymphocytes. Under certain conditions, endothelial cells are also able to function as APCs. APCs have been shown to play a key role in the development of autoimmune diseases and atherosclerosis. Activated T lymphocytes appear to promote the formation of atherosclerosis, and in experimental models, APC and T-cell deficiency have been associated with up to an 80% reduction in plaque formation.31

Macrophages function as the principal APC. They are key cells of the mononuclear phagocytic system and engulf and digest microbes and other foreign substances that gain access to the body. Because macrophages arise from monocytes in the blood, they can move freely throughout the body to the appropriate site of action. Tissue macrophages are scattered in connective tissue or clustered in organs such as the lung, liver, spleen, lymph nodes, peritoneum, central nervous system, and other areas. Macrophages are activated during the innate immune response where they engulf and break down complex antigens into peptide fragments. These fragments can then be associated with MHC-II molecules for presentation to cells of the “cell-mediated” response so that self–nonself recognition and activation of the immune response can occur. DCs are also responsible for presenting processed antigen to activated T lymphocytes. The star-like structure of the DCs provides an extensive surface area rich in MHC-II molecules important for initiation of adaptive immunity. DCs are found in tissues where antigen enters the body and in the peripheral lymphoid tissues. Both DCs and macrophages are capable of “specialization” depending upon their location in the body. For example, Langerhans cells are specialized DCs in the skin, whereas follicular DCs are found in the lymph nodes. Langerhans cells transport antigens found on the skin to nearby lymph nodes for destruction. They are also involved in the development of cell-mediated immune reactions such as allergic type IV contact dermatitis. Finally, DCs are found in the mucosal lining of the bowel and have been implicated in the development of inflammatory bowel diseases such as Crohn disease and ulcerative colitis. B Lymphocytes and Humoral Immunity The humoral immune response is mediated by antibodies, which are produced by the B lymphocytes. The primary functions of the B lymphocytes are the elimination of extracellular microbes and toxins and subsequent “memory” for a heightened response during future encounters. Humoral immunity is more important than cellular immunity in defending against microbes with capsules rich in polysaccharides and lipid toxins because only the B lymphocytes are capable of responding to and producing antibodies specific for many types of these molecules. The T cells, which are the mediators of cellular immunity, respond primarily to surface protein antigens.

B lymphocytes are produced in the bone marrow and are classified according to the MHC-II proteins, Ig, and complement receptors expressed on the cell membrane. At each stage of development, a cell-specific pattern of Ig gene is expressed, which then serves to designate the antibodyproducing cell type. The B-lymphocyte progenitors are known as pro-B and pre-B cells and develop into both mature and naïve B lymphocytes in the bone marrow. Naïve (or immature) B lymphocytes display IgM on the cell surface. These immature cells respond to antigen differently from a mature B cell. They can be functionally removed from the body as a result of interaction with a self-antigen, by undergoing programmed cell death (apoptosis) or by becoming nonresponsive in the presence of the antigen. Naïve B lymphocytes can leave the bone marrow and migrate to peripheral or secondary lymphoid tissues such as the spleen and lymph nodes where they can fully mature. Once they complete the process, they become capable of expressing IgD, in addition to the IgM on the cell membrane surface. Mature B lymphocytes can respond to all antigens and are capable of interacting with T cells. B-cell lines become committed to a specific antigen when they encounter antigens that match their encoded surface Ig receptor. In the presence of Thelper cell antigen presentation, they undergo a series of conformational changes that transform them into antibody-secreting plasma cells or into memory B cells (Fig. 11-8). Both cell types are necessary for the ultimate success of the humoral response. The antibodies produced by the plasma cells are released into the lymph and blood, where they can then bind and remove their specific antigen with the help of other immune effector cells and molecules. The memory B lymphocytes have a longer life span and are distributed to the peripheral tissues in preparation for subsequent antigen exposure.

Pathway for B-cell differentiation. MHC, major histocompatibility complex; TCR, T-cell receptor. FIGURE 11-8

Immunoglobulins Antibodies are protein molecules also known as Igs. Igs are classified into five different categories based upon their role in the humoral defense mechanisms. The five classes include IgG, IgA, IgM, IgD, and IgE (Table 11-4). The Ig comprises four polypeptide chains with at least two identical antigen-binding sites (Fig. 11-9). Each Ig is composed of two identical light (L) chains and two identical heavy (H) chains that form a characteristic “Y”-shaped molecule. The “Y” ends of the Ig molecules carry the antigenbinding sites and are called Fab (i.e., antigen-binding) fragments. The tail end of the molecule, which is called the Fc fragment, determines the function of the class of Igs. TABLE 11-4 Classes and Characteristics of Igs

Figure Class Percentage Characteristics of Total IgG 75.0 Displays antiviral, antitoxin, and antibacterial properties; only Ig that crosses the placenta; responsible for protection of newborn; activates complement and binds to macrophages

Figure Class Percentage Characteristics of Total IgA 15.0 Predominant Ig in body secretions, such as saliva, nasal and respiratory secretions, and breast milk; protects mucous membranes IgM 10.0 Forms the natural antibodies such as those for ABO blood antigens; prominent in early immune responses; activates complement IgD 0.2

Found in B lymphocytes; needed for maturation of B cells

IgE 0.004

Binds to mast cells and basophils; involved in parasitic infections, allergic and hypersensitivity reactions

Ig, immunoglobulin.

Schematic model of an immunoglobulin G molecule showing the constant and variable regions of the light and heavy chains. FIGURE 11-9

IgG (gamma globulin) is the most abundant of the Igs, making up 75% of the total circulating antibodies. It is a large molecule and is composed of two different kinds of polypeptide chain. IgG possesses antiviral, antibacterial, and antitoxin properties. It is present in all body fluids, readily enters the tissues, and is capable of crossing the placenta where it confers passive immunity upon the fetus. With the help of APCs, IgG binds to target cells as well as Fc receptors on NK cells and macrophages, leading to

lysis of the target cell. There are four subclasses of IgG (i.e., IgG1, IgG2, IgG3, and IgG4) with specificity for certain types of antigens. For example, IgG2 appears to target bacteria that are encapsulated with a lipopolysaccharide layer, such as Streptococcus pneumoniae.32,33 IgA is composed of two identical molecules and is the second most common Ig found in serum, accounting for approximately 15% of all antibodies. It is primarily a secretory Ig that is found in saliva, tears, colostrum (i.e., first milk of a nursing mother), and bronchial, gastrointestinal, prostatic, and vaginal secretions. Because it is primarily found in secretions, its primary function is in local immunity on mucosal surfaces. IgA prevents the attachment of viruses and bacteria to epithelial cells. IgM accounts for approximately 10% of all circulating antibodies. It is a five-membered macromolecule with identical heavy and light chains. It also functions as an effective agglutinating antibody, stimulating clumping of organisms for eventual lysis and elimination. IgM is the first antibody to be produced by the developing fetus and by immature B lymphocytes. IgD is found primarily on the cell membranes of B lymphocytes where it functions as a receptor for antigen. It circulates in the serum in extremely low levels where its function is essentially unknown but may play a role in B-cell differentiation. IgE is the least common serum IgE because it binds very tightly to the Fc receptors on basophils and mast cells. It is involved in inflammation and allergic responses by causing mast cell degranulation and release of chemical mediators including histamine. IgE is also essential for combating parasitic infections. Humoral Immunity Humoral immunity requires the presence of mature B lymphocytes capable of recognizing antigen and differentiating into antibody-secreting plasma cells. The ultimate response of the antigen–antibody complex formation can take several forms including antigen–antibody complex precipitation, agglutination of pathogens, neutralization of toxins, phagocytosis or lysis of invading organisms, immune cell activation, and complement activation. Two separate but interrelated responses occur in the development of humoral immunity: a primary and a secondary response (Fig. 11-10). A

primary immune response develops when the body first encounters the antigen. The antigen comes in contact with various APCs, is processed by these cells in association with the MHC-II molecules on the cells surface, and is then presented to the lymphocytes to initiate the immune process. APCs such as macrophages also secrete ILs, which are essential for activating the cell-mediated response via the CD4+ helper T cells. The activated CD4+ helper T cells trigger B cells to proliferate and differentiate into plasma cells that produce antibody. The primary immune response takes 1 to 2 weeks, but once generated, detectable antibody continues to rise for several more weeks even though the infectious process has resolved. The memory phase or secondary immune response occurs on subsequent exposure to the antigen. During the secondary response, the rise in antibody occurs sooner and reaches a higher level because of available memory cells.

Primary and secondary or memory phases of the humoral immune response to the same antigen. FIGURE 11-10

During the primary response, B lymphocytes proliferate and differentiate into antibody-secreting plasma cells. A fraction of the activated B cells remains intact in order to form a pool of memory B lymphocytes that then become available to efficiently respond to invasion during subsequent

exposure. Activated T cells can also generate primary and secondary cellmediated immune responses and the concurrent development of T-memory cells. The immunization process makes use of the primary and secondary phases of the humoral immune responses. The initial vaccination causes production of both plasma cells and memory cells. The plasma cells destroy the invading organism or toxin, and the memory cells provide defense against future exposure. “Booster” immunizations produce an immediate antigen–antibody response that simulates an immediate rise in antibody levels. T Lymphocytes and Cellular Immunity T lymphocytes serve many functions in the immune system including the activation of other T cells and B cells, control of intracellular viral infections, rejection of foreign tissue grafts, activation of autoimmune processes, and activation of delayed hypersensitivity reactions. These processes make up the body’s cell-mediated or cellular immunity. The effector phase of cell-mediated immunity is carried out by T lymphocytes and macrophages. T lymphocytes arise from lymphoid stem cells in the bone marrow, but unlike B lymphocytes, they migrate to the thymus gland to undergo the process of maturation. The thymus gland is richly innervated and produces several peptide hormones such as thymulin and thymopoietin, which are believed to be involved in T-cell maturation. T-cell precursors are attracted to the thymus by thymotaxin, a chemotactic factor secreted by the epithelial cells of the gland becoming CD4 (helper) and CD8 (cytotoxic) lymphocytes. These are the predominant lymphocytes in the body. Mature T lymphocytes leave the thymus and migrate to peripheral lymphoid tissues, where they multiply and differentiate into memory T cells and various other mature lymphocytes upon encountering an antigen. Helper T Cells and Cytokines in Adaptive Immunity The activation of helper T cells is the central event in the initiation of the humoral and cell-mediated immune response. CD4+ helper T cells (TH) serve as master regulators for the immune system. They become activated when their TCRs interact with antigens that are complexed with class II

MHC on the surface of APCs. Once CD4+ cells are activated, the cytokines they secrete in response influence the function of nearly all other cells of the immune system. Depending upon the specific cytokine that is released by the CD4+ T cell, the subsequent immunologic response will be activated. These cytokines are able to activate and regulate B cells, cytotoxic T lymphocytes, NK cells, macrophages, and other immune cells. The first cytokine to be produced by CD4+ T cells after activation is IL-2. IL-2 plays a major role in cell-mediated immunity and is necessary for the proliferation and function of helper T cells, cytotoxic T cells, B cells, and NK cells. There are other cytokines that are not produced by CD4+ cells, but are essential for its function. IL-1 is produced by inflammatory cells and is responsible for increasing the expression of adhesion molecules on endothelial cells, activating leukocyte migration, and stimulating antibody production.18 The activated CD4+ helper T cell can differentiate into two distinct subpopulations of helper T cells (i.e., T1H or T2H) based on the cytokines secreted by the APCs at the site of activation (Table 11-5). Macrophages and DCs produce IL-12, which directs CD4+ helper T cells to become the T1H subtype, whereas mast cells and T cells produce IL-4, which induces differentiation toward the T2H subtype. The T2H cells present antigen to the B lymphocytes, stimulating the differentiation into antibody-producing plasma cells. As part of the allergic or hypersensitivity response, T2H cells direct B lymphocytes to switch class and produce the IgE antibodies. TABLE 11-5 Comparison of Properties of Helper T-Cell Subtypes 1 (T1H) and 2 (T2H)

T1H Stimulus for Microbes differentiation to TH subtype Cells and IL-12 produced by cytokines macrophages and DCs influencing TH subtype maturation

T2H Allergens and parasitic worms IL-4 produced by mast cells and T cells

T1H Cytokines IFN-γ, IL-2 secreted by TH subtype Effector Phagocyte-mediated defense functions against infections, especially intracellular microbes; stimulates production of IgG

T2H IL-4, IL-5

IgE-mediated and eosinophil/mast cell– mediated immune reactions; stimulates production of IgE DC, dendritic cell; IFN, interferon; Ig, immunoglobulin; IL, interleukin. The distinct pattern of cytokine secreted by mature T1H and T2H cells determines whether a humoral or cell-mediated response will ultimately occur. Activated T1H cells produce the cytokines IL-2 and IFN-γ, whereas T2H cells produce IL-4 and IL-5. IL-5 is an activator of eosinophils that, along with IgE, functions in the control of helminth (intestinal parasite) infections. Some of the cytokines (e.g., IL-10) made by T2H cells are antiinflammatory and inhibit macrophage activation and suppress other T1H responses. In most immune responses, a balance between T1H and T2H cell activation will occur. Regulatory T Cells TREGS are a subset of T lymphocytes that function to control immune system responses. Different populations of TREGS produced in the thymus have been identified including those that express CD4 and CD25 on their surface. These cells represent a subset of CD4+ cells that act as “negative regulators” of the immune process because they suppress immune cell activities.34 TREGS inhibit the proliferation of other potentially harmful self-reactive lymphocytes in order to limit inflammation and tissue damage. Production of TREGS is highly dependent upon the presence of antigen, activation of a TCR by the antigen, and the release of cytokines. There is also recent evidence of the existence of regulatory CD8+ T cells that can selectively downregulate T cells activated by either self or foreign antigens. These cells differentiate into regulatory cells during the primary immune response and

function to suppress the secondary immune response. The CD8+ regulators are, therefore, primarily involved in self–nonself discrimination. The ability of the TREGS to control many aspects of the immune response has significant implications for clinical practice. Promise has been shown in the control of inflammatory bowel disease, experimental allergic encephalitis, and autoimmune diabetes. Cytotoxic T Cells The primary function of cytotoxic T (CD8+) cells is to monitor the activity of all cells in the body and destroy any that threatens the integrity of the body. CD8+ T cells recognize antigens that are presented on the cell surface by MHC class I–derived molecules that sample protein degradation productions from inside cells infected by viruses or transformed by cancer35 (Fig. 11-11). The ability of CD8+ cells to recognize the class I MHC– antigen complexes on infected target cells ensures that neighboring uninfected host cells, which express class I MHC molecules alone, are not indiscriminately destroyed. The CD8+ cytotoxic T lymphocytes destroy target cells by a variety of mechanisms including the release of cytolytic enzymes or by triggering membrane molecules and intracellular apoptosis. Apoptosis is a normal biologic process that eliminates excessive, dangerous, or damaged cells from the body. The CD8+ T cells play a large role in controlling replicating viruses and intracellular bacteria because antibody cannot readily penetrate the membrane of living cells.

Destruction of target cell by cytotoxic T cell. Cytokines released from the activated helper T cell enhance the potential of the cytotoxic T cell in destruction of the target cell. CD, cluster of differentiation; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor. FIGURE 11-11

Cell-Mediated Immunity In order for the cell-mediated immune response to carry out its function, healthy CD4+ and CD8+ T lymphocytes are required. Activated CD4+ helper

T cells release various cytokines that recruit and activate other CD8+ cytotoxic T cells, macrophages, and inflammatory cells. Cytokines (e.g., chemokines) stimulate migration types of inflammatory cells, which further enhance the phagocytic, metabolic, and enzymatic functions of the cellmediated immune response. This results in a more rapid and more efficient destruction of infected cells. This type of defense is important against many intracellular pathogens such as Mycobacterium species and Listeria monocytogenes but unfortunately plays a role in delayed hypersensitivity reactions. Allergic contact dermatitis (delayed hypersensitivity type IV) results from the activation of both CD4+ and CD8+ T-cell precursors in the lymph nodes draining the site where antigen was encountered. These “haptenated peptides” stimulate the recruitment of T cells at the site of antigen presentation, inducing inflammatory signals and apoptosis of epidermal cells, leading to the development of inflammation, the release of chemical mediators, and the development of clinical symptoms. In cell-mediated immune responses, the actions of T lymphocytes and effector macrophages predominate. The most aggressive and abundant phagocyte, the macrophage, becomes activated after exposure to T-cell cytokines, especially IFN-γ.3 The initial stages of cell-mediated immunity are initiated when an APC displays an antigen–class I or II MHC complex to the CD4+ helper T cell and activates it. The activated helper T cell then synthesizes various cytokines, which stimulate increased production of CD4+ helper T cells, which amplifies the response. Additional cytokine release also enhances the activity of cytotoxic T cells and effector macrophages. Lymphoid Organs The central and peripheral lymphoid organs are responsible for the production, maturation, and storage of large numbers of immune system cells including the B and T lymphocytes. These organs and tissues are widely distributed throughout the body and provide different, but often overlapping, functions (Fig. 11-12). The central lymphoid organs comprise the bone marrow and the thymus and are responsible for immune cell production and maturation. The tissues and cells of the peripheral lymphoid system store the cells of the immune system where they function to concentrate and process antigen as well as support cellular processes necessary for the development of fully functioning, adaptive immune

responses. The peripheral lymphoid tissues comprise the lymph nodes, spleen, tonsils, appendix, Peyer patches in the intestine, and mucosaassociated lymphoid tissues in the respiratory, gastrointestinal, and reproductive systems. Networks of lymph channels, blood vessels, and capillaries connect the lymphoid organs and transport immune cells, antigens, and cellular debris throughout the body.

FIGURE 11-12

Thymus

Central and peripheral lymphoid organs and tissues.

The thymus is an elongated, bilobed structure located in the mediastinum above the heart and serves as a specialized immune system organ. Each lobe is surrounded by a connective tissue capsule layer and is divided into lobules. The lobules can be divided into an outer cortex and a central medulla, which play different roles in the process of T-lymphocyte maturation. The outer cortex contains densely packed immature T lymphocytes (thymocytes). The inner medulla is a less dense area of tissue that contains fewer but more mature lymphocytes. The medulla not only comprises Hassall corpuscles but also stores DCs and macrophages (Fig. 11-13). The function of the Hassall corpuscles is unclear but does serve as a potent source of cytokines.

Structural features of the thymus gland. The thymus gland is divided into lobules containing an outer cortex densely packed with dividing thymocytes or premature T cells and an inner medulla that contains mature T lymphocytes, macrophages, dendritic cells, and Hassall corpuscles. FIGURE 11-13

The thymus is essential to the development of the immune system because it is responsible for the production of mature, immunocompetent T lymphocytes. The thymus is a fully developed organ at birth, weighing approximately 15 to 20 g. It is most active during the neonatal and preadolescent periods. At puberty, when the immune cells are well established in peripheral lymphoid tissues, the thymus begins to atrophy and is replaced by adipose tissue. Nevertheless, residual T-lymphocyte production continues throughout adult life. Precursor T cells enter the thymus as functionally and phenotypically immature T cells. They then mature during different cycles and move from the cortex to the medulla until they are released into the peripheral lymphoid tissues. Rapid cell division, maturation, and selection occur in the cortex under the influence of thymic hormones and cytokines. As the T cells mature, they develop the TCRs that differentiate them from other types of T cells. The majority of the thymocytes die in the cortex during the process of gene rearrangement and maturation because they fail to develop the appropriate receptor types on their cell membranes. Only those T cells capable of recognizing foreign antigen displayed by self-MHC are allowed to mature. This process is called thymic selection. Mature, immunocompetent T-helper and Tcytotoxic cells leave the thymus in 2 to 3 days and enter the peripheral lymphoid tissues through the bloodstream. Lymph Nodes Lymph nodes are small aggregates of lymphoid tissue located along lymphatic vessels throughout the body. The lymphatic vessels carry lymph, which is a clear sometimes yellow-tinged fluid that contains a variety of white blood cells (predominantly lymphocytes) and transports cellular debris and organisms to the lymph nodes to be removed from the body. Each lymph node processes lymph from a discrete, adjacent anatomic site. Lymph nodes are congregated in the axillae and groin and along the great

vessels of the neck, thorax, and abdomen. The lymph nodes receive lymph from the collecting ducts, which ultimately drain into the thoracic duct located in the left side of the chest at the level of the subclavian vein. Lymph nodes have two functions: removal of foreign material from lymph before it enters the bloodstream and serving as centers for proliferation and response of immune cells. Lymph nodes are bean-shaped, encapsulated tissues, approximately 0.5 to 1 cm in diameter. Lymph enters the node through afferent lymph channels and leaves through the efferent lymph vessels located deep in the node. Lymphocytes and macrophages move slowly through the lymph nodes so that they have adequate time to engulf microorganisms and interact with circulating antigen. The lymphatic system provides a large surface upon which macrophages and DCs can more easily present antigens to T lymphocytes. Lymph nodes are divided into three distinct and specialized areas—an outer cortex, a paracortex, and an inner medulla (Fig. 11-14). The T lymphocytes predominate in the paracortex and the B lymphocytes predominate in the follicles and germinal centers of the outer cortex. The T lymphocytes proliferate when antigens enter the paracortex of the lymph node. They then migrate to the outer cortex so that they can interact with B lymphocytes that are stored there. Within the follicles the lymphocytes continue to mature, replicate, and interact with the APCs present in the nodes (macrophages and follicular DCs). Activated B cells then migrate to the medulla of the lymph node, where they complete their maturation into plasma cells. Large quantities of antibodies are then released into the systemic circulation.

Structural features of a lymph node. Bacteria that gain entry to the body are filtered out of the lymph as it flows through the node. FIGURE 11-14

Spleen The spleen is a large, ovoid secondary lymphoid organ located high in the left upper quadrant of the abdominal cavity between the diaphragm and the stomach. The spleen filters antigens from the blood and is important in the response to systemic infections. It is divided into two systems: the white

pulp and the red pulp. The red pulp is well supplied with arteries and venous sinusoids and is the area where senescent (biologically aged) and injured red blood cells are removed. The white pulp contains lymphatic nodules and diffuse lymphoid tissue where concentrated areas of B and T lymphocytes, macrophages, and DCs exist. The lymphocytes (primarily T cells) that surround the central arterioles form the area called the periarterial lymphoid sheath. There is also a diffuse marginal zone that contains the follicles and germinal centers and is rich in B cells. This separates the white pulp from the red pulp and allows lymphocytes to move easily between the blood and the lymphatic tissue. A sequence of activation events similar to that seen in the lymph nodes occur in the spleen. Other Secondary Lymphoid Tissues Other secondary lymphoid tissues include the mucosa-associated lymphoid tissues, which are nonencapsulated clusters of lymphoid tissues located around membranes lining the respiratory, digestive, and urogenital tracts. These organ systems constantly come in contact with pathogens and toxins and, therefore, require the presence of immune cells in order to respond to the potential invasion by pathogens and harmful substances. In some tissues, the lymphocytes are organized in loose, nondescript clusters, but in other tissues such as the tonsils, Peyer patches in the intestine, and the appendix, their structure is better organized. These tissues contain all the cellular components (i.e., T cells, B cells, macrophages, and DCs) required to mount an immune response. Immunity at the mucosal layers helps to exclude many pathogens from the body and, as a result, protects the more vital internal structures. Active versus Passive Immunity The goal of the immune system is to protect the host against invasion by potentially dangerous pathogens, foreign substances, and other sources of harmful antigens. Adaptive immune responses accomplish this goal through the activation of cell-mediated and humoral responses. This type of protection can be induced in one of two ways: 1. After exposure to the offending substance and activation of B and T lymphocytes by the host (active immunity)

2. Through the transfer of antibodies against an antigen directly to the host (passive immunity) Active immunity is acquired when the host mounts an immune response to an antigen either through the process of vaccination or from environmental exposure. It is called active immunity because it requires the host’s own immune system to develop an immunologic response including the development of memory. Active immunity is usually long lasting but requires a few days to weeks after a first exposure to sufficiently develop an appropriate immunologic response that culminates in the destruction of the presenting antigen. However, with subsequent exposure, the immune system rapidly becomes fully activated because of the presence of memory B and T lymphocytes and circulating antibodies. The process by which active immunity is acquired through the administration of a vaccine is termed immunization. An acquired immune response can improve on repeated exposures to an injected antigen (booster vaccines) or a natural infection. Passive immunity is immunity transferred from another source. The most common form of passive immunity is that conferred from mother to fetus. During fetal development, maternal IgG antibodies are transferred to the fetus via the placenta. After birth, the neonate also receives IgG antibodies from the mother in breast milk or colostrum. Therefore, infants are provided with some degree of protection from infection for approximately 3 to 6 months, giving their own immune systems time to mature. Some protection against infectious disease can also be provided by the administration of Igs pooled from human or animal sources. Passive immunity produces only short-term protection that lasts weeks to months. Regulation of the Adaptive Immune Response In order for a host organism to remain healthy, the immune system must function properly. A weakened immune response may lead to immunodeficiency, but an inappropriate or excessive response can cause allergic reactions and autoimmune diseases. Therefore, the immune system must be capable of self-regulation. The process by which the body regulates itself is poorly understood but must involve all aspects of the innate and adaptive immune responses to be effective.

Each exposure to an antigen elicits a predictable response from the immune system. Once the immune system is activated, the response is amplified until it peaks and eventually subsides. This occurs because the body’s normal immune responses are self-limiting. Once the antigen is destroyed and the action of chemical mediators terminated, the immune response ceases. It is believed that anti-inflammatory cytokines and regulatory T lymphocytes play a role in this process.36 Tolerance also plays a role in the self-regulation of the immune response. Tolerance is the ability of the immune system to react to foreign antigens but remain nonreactive to self-antigens. Tolerance to self-antigens protects the body from harmful autoimmune responses. This is exquisitely important in vital organs such as the brain, testes, ovaries, and eyes where immunologic damage could be lethal to the organism. Many autoimmune diseases such as Hashimoto thyroiditis and insulindependent diabetes mellitus are caused by impairment in both B- and Tlymphocyte (specifically cytotoxic lymphocytes) functions resulting in direct cellular damage because the body’s immune system is no longer capable of distinguishing “self” from “nonself.”37,38 SUMMARY CONCEPTS Adaptive immunity comprises two distinct but interrelated processes: cell-mediated and humoral immunity. Together, they respond to foreign antigens, amplify and sustain immunologic responses, distinguish self from nonself, and confer “memory” so that a heightened response can be initiated on subsequent exposure to an organism. Antigens are usually substances foreign to the host that can stimulate an immune response. Antigens possess specific antigenic binding sites for the cells of the immune system known as epitopes. Epitopes allow the adaptive immune system to distinguish foreign antigens from normal cellular substances whose destruction would be detrimental to the organism. Adaptive immunity can be acquired actively or passively. Active immunity develops through immunization or by having a disease, whereas passive immunity develops when the host receives antibodies or immune cells from another source. An acquired immune response can improve with repeated exposure to an injected antigen or a natural infection.

The principal cells of the adaptive immune system are the B and T lymphocytes, APCs, and effector cells that are responsible for the elimination of antigens. The lymphocytes are produced and undergo maturation in the central lymphoid organs (bone marrow and thymus) and are subsequently stored in the peripheral lymphoid tissues. B lymphocytes differentiate into plasma cells that produce antibodies and provide for the elimination of microbes in the extracellular fluid (humoral immunity) as well as memory cells, which are responsible for the rapid immune response with repeat exposure. T lymphocytes differentiate into regulatory (helper T and TREGS) and effector (cytotoxic T cells) cells. APCs consist of macrophages and DCs that process and present antigen peptides to CD4+ helper T cells. During cellular maturation, T lymphocytes express specific molecules on the cellular surfaces that distinguish between the different cell types and that help determine the cells’ functionality. Regulatory CD4+ helper T cells help to modulate the immune response and are essential for the differentiation of B cells into antibody-producing plasma cells and the differentiation of T lymphocytes into effector CD8+ cytotoxic T cells. The CD8+ cytotoxic cells eliminate intracellular microbes, such as viruses and other pathogens. Cells of both the innate and adaptive immune responses produce cytokines that influence adaptive immune responses. These cytokines function as communication molecules for the B and T lymphocytes, stimulate cellular proliferation and differentiation, and ensure the appropriate development of cytotoxic effector and memory cells. People who are immunocompromised must be closely evaluated to determine the risk-to-benefit ratio when administering vaccines. Killed or inactive vaccines usually are safe, and booster may be required. For people who are immunocompromised and not associated with HIV or planned immunosuppression, such as congenital immunodeficiency, live virus vaccines are not generally administered. Immunosuppression affects B and/or T cells, causing a decreased or absent antibody response to vaccine. People who are HIV infected need evaluation and testing before live virus vaccines are administered.39

Developmental Aspects of the Immune System Development of the immune system begins early in fetal life at approximately 5 to 6 weeks gestation when the fetal liver actively begins hematopoiesis. At about the same time (6 weeks gestation), the thymus arises from the third branchial arch, with the cortex arising from its ectodermal layer and the medulla from the endoderm.40 Over the next 2 to 3 weeks, lymphoid cells initially migrate from the yolk sac and fetal liver and then from the bone marrow to colonize the fetal thymus.40 Development of the secondary lymphoid organs (i.e., spleen, lymph nodes, and mucosaassociated lymphoid tissues) begins soon after. The secondary lymphoid organs are rather small but well developed at birth and mature rapidly after exposure to microbes during the postnatal period. The thymus is the largest lymphoid tissue in the neonate relative to body size and normally reaches its mature weight by 1 year of age. Transfer of Immunity from Mother to Infant The neonate’s immune system is functionally immature at birth so protection against infection and toxic substances occurs through transfer of maternal IgG antibodies. Maternal IgG antibodies readily cross the placenta during fetal development and remain functional in the newborn for the first few months of life, providing passive immunity until Ig production is well established in the newborn. IgG is the only class of Igs able to cross the placenta. Maternally transmitted IgG is effective against most microorganisms and viruses that a neonate encounters. Maternal vaccination may therefore offer fetal and neonatal passive immunity against common infections such as influenza or herpes zoster.41 The largest amount of IgG crosses the placenta during the last weeks of pregnancy and is stored in fetal tissues. Infants born prematurely may be deficient in maternal antibodies and, therefore, more susceptible to infection. Because of transfer of IgG antibodies to the fetus, an infant born to a mother infected with HIV has a positive HIV antibody test result, although the child may not be infected with the virus. Cord blood does not normally contain IgM or IgA. If present, these antibodies are of fetal origin and represent exposure to intrauterine infection because maternal IgM and IgA antibodies do not readily cross the placenta.

Normally, the neonate begins producing IgM antibodies shortly after birth, as a result of exposure to the immense number of antigens normally found in the surrounding environment. However, this IgM is of lower binding affinity and effective against a limited range of antigens. It has also been demonstrated that premature infants can produce IgM as well as term infants. At approximately 6 days of age, the IgM rises sharply, and this rise continues until approximately 1 year of age, when the adult level is achieved. Serum IgA normally is not present at birth but detected in the neonate approximately 13 days after birth. The levels of IgA increase during early childhood and reach between 6 and 7 years of age. Although maternal IgA is not transferred in utero, it is transferred to the breast-fed infant in colostrum. Because IgA antibodies are associated with mucosal members, these antibodies provide local immunity for the intestinal system during early life. Immune Response in the Older Adult As we age, the ability of the immune system to protect the body from pathogenic organisms and environmental toxins declines as a result of an overall decline in immune responsiveness. This results from changes in both cell-mediated and humoral immune responses. As a result, older adults are more susceptible to infections, have more evidence of autoimmune and immune complex disorders, and have a higher incidence of cancer than do younger people. In addition, the immune system of older adults is less likely to respond appropriately to immunization. As a result, older adults have a weakened response to vaccination. Older adults also frequently have many comorbid conditions that impair normal immune function and compromise the immune response. The cause of the altered response in older adults is multifactorial. There is a continued decrease in the size of the thymus gland, which begins during puberty and affects overall T-cell production and function. The size of the thymus diminishes to 15% or less of its maximum size. There may also be a decrease in the number of the lymphocytes in the peripheral lymphoid tissue. The most common finding is a slight decrease in the proportion of T cells to other lymphocytes and a decrease in CD4+ and CD8+ cells. Aging also produces qualitative changes in lymphocyte function. Lymphocytes seem to exhibit altered responses to antigen stimulation

including unresponsiveness to activation. It appears that the CD4+ T lymphocyte is most severely affected because there is a decreased rate of synthesis of cytokines that stimulate the proliferation of lymphocytes and expression of the specific receptors that interact with the circulating cytokines. Specifically, IL-2, IL-4, and IL-12 levels decrease in older adults. Although actual B-cell function is compromised with age, the range of antigens that can be recognized by the B cells does not change. SUMMARY CONCEPTS Neonates are protected against antigens in early life as a result of passive transfer of maternal IgG antibodies through the placenta and IgA antibodies in colostrum and breast milk. Many changes occur with aging, but the exact mechanisms are not completely understood. However, the elderly population is more prone to infection and autoimmune disorders secondary to altered response in both innate and adaptive immune function.

Review Exercises 1. The systemic manifestations (e.g., generalized muscle aches, chills and fever, loss of appetite) that accompany a severe sore throat or acute respiratory infection are stimulated by reactions to cytokines of the innate immune system rather than by the antibodies or cell-mediated responses of the adaptive immune response. A. Explain. 2. A nursing student is working in a community clinic as a volunteer. Each time she enters the clinic, she suffers bouts of sneezing and runny nose. She has a history of mold allergy and her younger brother has asthma. Analysis at the allergy clinic indicates a strong reaction to latex. She is advised to avoid exposure to all forms of latex. A. What class of Ig and what type of mediator cells are responsible for the symptoms expressed in this person?

B. What type of T-helper cell and cytokines direct the expression of this humoral immune response? C. Is this an example of active or passive immunity? Is this likely to be a primary or secondary immune response? 3. A child 5 months of age presents with thrush, a yeast infection of the mouth. In the last 2 months, he has had recurrent bouts of otitis media. His tonsils are very small. Laboratory analysis indicates a low lymphocyte count and no T lymphocytes. Further analysis indicates a genetic mutation in the T-cell receptor molecule complex (TCR–CD3) that affects maturation of all T cells. The final diagnosis is severe combined immunodeficiency disease. A bone marrow transplant is being pursued with cells from his HLA-matched sibling. A. Why were infections not present in the first few months of this child’s life? B. What would be the impact of an absence of T cells on both humoral and cell-mediated immunity? C. Why would it not be advisable to administer a live virus vaccine in this child? REFERENCES 1. Breedveld A., Groot Kormelink T., van Egmond M., et al. (2017). Granulocytes as modulators of dendritic cell function. Journal of Leukocyte Biology 102, 1003–1016. 2. Cecchinato V., D’Agostino G., Raeli L, et al. (2016). Chemokine interaction with synergyinducing molecules: Fine tuning modulation of cell trafficking. Journal of Leukocyte Biology 99, 851–855. 3. Tangye S. G., Pelham S. J., Deenick M. K., et al. (2017). Cytokine-mediated regulation of human lymphocyte development and function: Insights from primary immunodeficiencies. Journal of Immunology 199, 1949–1958. 4. Leifer C. A., Medvedev A. E. (2016). Molecular mechanisms of regulation of Toll-like receptor signaling. Journal of Leukocyte Biology 100, 927–941. 5. Hoffman M. A., Kiecker F., Zuberbier T. (2016). A systematic review of the role of interleukin-17 and the interleukin-20 family in inflammatory skin diseases. Current Opinion in Allergy and Clinical Immunology 16, 451–457. 6. Fan V. S., Gharib S. A., Martin T. R., et al. (2016). COPD disease severity and innate immune response to pathogen-associated molecular patterns. International Journal of Chronic Obstructive Pulmonary Disease 111, 467–477. 7. Nagarsheth N., Wicha M. S., Zou W. (2017). Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nature Reviews Immunology 17(9), 559–572. doi:10.1038/nri2017.49.

8. Massara M., Bonavita O., Mantovani A., et al. (2016). Atypical chemokine receptors in cancer: Friends or foes? Journal of Leukocyte Biology 99, 927–933. 9. Yadava K., Bollyky P., Lawson M. A. (2016). The formation and function of tertiary lymphoid follicles in chronic pulmonary inflammation. Immunology 149, 262–269. 10. Martin S. F. (2015). New concepts in cutaneous allergy. Contact Dermatitis 72, 2–10. 11. Erdei A., Sandor N., Macsik-Valent B., et al. (2016). The versatile functions of complement C3derived ligands. Immunological Reviews 274, 127–140. 12. Spahn J. H., Li W., Kreisel D. (2014). Innate immune cells in transplantation. Current Opinion in Organ Transplantation 19, 14–19. 13. Isidro R. A., Appleyard C. B. (2016). Colonic macrophage polarization in homeostasis, inflammation and cancer. American Journal of Physiology—Gastrointestinal and Liver Physiology 311, G59–G73. 14. Liszewski M. K., Elvington M., Kulkarni H. S., et al. (2017). Complement’s hidden arsenal: New insights and novel functions inside the cell. Molecular Immunology 84, 2–9. doi:10.1016/j.molimm2017.01.004. 15. Adams N. M., O’Sullivan T. E., Geary C. D., et al. (2016). NK cell responses redefine immunological memory. Journal of Immunology 197, 2963–2970. 16. Shi M., Chen X., Ye K., et al. (2016). Application potential of toll-like receptors in cancer immunotherapy. Medicine 95, e3951. 17. Gao Y., Xiao M. D., Wang Y., et al. (2017). Association of single-nucleotide polymorphisms in toll-like receptor 2 gene with asthma susceptibility: A meta-analysis. Medicine 96, e6822. 18. De Paepe B., Creus K., De Bleecker J. L. (2009). Role of cytokines and chemokines in idiopathic inflammatory myopathies. Current Opinion in Rheumatology 21, 610–616. 19. Li J., Jiao Z., Qui H., et al. (2017). C-reactive protein and risk of ovarian cancer: A systematic review & meta-analysis. Medicine 96, e7822. 20. Nelson B., Zhou X., White M., et al. (2014). Recombinant human mannose-binding lectin dampens human alveolar macrophage inflammatory responses to influenza A virus in vitro. Journal of Leukocyte Biology 95, 715–722. 21. Kouser L., Madhukaran S. P., Shastri A., et al. (2015). Emerging and novel functions of complement protein C1q. Frontiers in Immunology 7, 317. doi:10.3389/fimmu.2015.00317. 22. Stites E., Le Quintrec M., Thurman J. M. (2015). The complement system and antibody-mediated transplant rejection. Journal of Immunology 195, 5525–5531. 23. Garred P., Genster N., Pilely K., et al. (2016). A journey through the lectin pathway of complement-MBL and beyond. Immunological Reviews 274, 74–97. 24. Guo C., Xie X., Li H., et al. (2015). Prediction of common epitopes on hemagglutinin of the Influenza A virus (H1 subtype). Experimental and Molecular Pathology 98, 79–84. 25. Kim J. H., Hu Y., Yongqing T., et al. (2016). CD1a on Langerhans cells controls inflammatory skin disease. Nature Immunology 17, 1159–1166. 26. Lucas B., James K. D., Cosway E. J., et al. (2016). Lymphotoxin beta receptor controls T cell progenitor entry to the thymus. Journal of Immunology 197, 2665–2672. 27. Zack E. (2014). Emerging therapies for autoimmune disorders. Journal of Infusion Nursing 37, 109–119. 28. Brzostek J., Gascoigne N. R. J. (2017). Thymic origins of T cell receptor alloreactivity. Transplantation 101, 1535–1541. 29. Cai J., Terasaki P. I., Zhu D., et al. (2016). Complement-fixing antibodies against denatured HLA and MICA antigens are associated with antibody mediated rejection. Experimental and Molecular Pathology 100(1), 45–50. doi:10.1016/j.yexmp.2015.11.023. 30. Irure J., Lopez-Hoyos M., Rodrigo E., et al. (2016). Antibody-mediated rejection in kidney transplantation without evidence of anti-HLA antibodies? Transplantation Proceedings 48, 2888– 2890.

31. Koltsova E. K., Garcia Z., Chodaczek G., et al. (2012). Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis. Journal of Clinical Investigation 122, 3114–3126. 32. Yamasaki R., Yabe U., Kataoka C., et al. (2010). The oligosaccharide of gonococcal lipooligosaccharide contains several epitopes that are recognized by human antibodies. Infection and Immunity 78, 3247–3257. 33. De la Torre M. C., Palomera E., Serra-Prat M., et al. (2016). IgG2 as an independent risk factor for mortality in patients with community-acquired pneumonia. Journal of Critical Care 35, 115– 119. 34. Furukawa A., Wisel S. A., Tang Q. (2016). Impact of immune-modulatory drugs on regulatory T cell. Transplantation 100, 2288–2300. 35. Bedoui S., Heath W. R., Mueller S. N. (2016). CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity. Immunological Reviews 272, 52–64. 36. Chen X., Oppenheim J. J. (2014). Th17 and Tregs: Unlikely allies. Journal of Leukocyte Biology 95, 723–731. 37. Ajjan R. A., Weetman A. P. (2015). The pathogenesis of Hashimoto’s thyroiditis: Further developments in our understanding. Hormone and Metabolic Research 47, 702–710. 38. Li M., Song L. J., Qin X. Y. (2014). Advances in the cellular immunological pathogenesis of type 1 diabetes. Journal of Cellular and Molecular Medicine 18, 749–758. 39. Rubin L. G., Levin M. J., Ljungman P., et al. (2014). 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clinical Infectious Diseases 58, 44–100. 40. Holt P. G., Jones C. A. (2000). The development of the immune system during pregnancy and early life. Allergy 55, 688–697. 41. Swamy G. K., Beigi R. H. (2015). Maternal benefits of immunization during pregnancy. Vaccine 33, 6436–6440.

CHAPTER 12 Disorders of the Immune Response, Including HIV/AIDS DISORDERS OF THE IMMUNE RESPONSE Immunodeficiency Disorders Humoral (B-Cell) Immunodeficiencies Transient Hypogammaglobulinemia of Infancy Primary Humoral Immunodeficiency Disorders Secondary Humoral Immunodeficiency Disorders Cell-Mediated (T-Cell) Immunodeficiencies Primary Cell–Mediated Immunodeficiency Disorders Secondary Cell–Mediated Immunodeficiency Disorders Combined T-Cell and B-Cell Immunodeficiencies Severe Combined Immunodeficiency Disorders Combined Immunodeficiency Disorders Disorders of the Complement System Primary Disorders of the Complement System Secondary Disorders of the Complement System Disorders of Phagocytosis Primary Disorders of Phagocytosis Secondary Disorders of Phagocytosis

Stem Cell Transplantation Hypersensitivity Disorders Type I, Immediate Hypersensitivity Disorders Anaphylactic (Systemic) Reactions Atopic (Local) Reactions Type II, Antibody-Mediated Disorders Complement-Activated Cell Destruction Antibody-Dependent Cell Cytotoxicity Complement- and Antibody-Mediated Inflammation Antibody-Mediated Cellular Dysfunction Type III, Immune Complex–Mediated Disorders Systemic Immune Complex Disorders Localized Immune Complex Reactions Type IV, Cell–Mediated Hypersensitivity Disorders Allergic Contact Dermatitis Hypersensitivity Pneumonitis Latex Allergy Transplantation Immunopathology Mechanisms Involved in Transplant Rejection Graft-Versus-Host Disease Autoimmune Disease Immunologic Tolerance B-Cell Tolerance T-Cell Tolerance Mechanisms of Autoimmune Disease Heredity Environmental Factors Diagnosis and Treatment of Autoimmune Disease ACQUIRED IMMUNODEFICIENCY SYNDROME AND HUMAN IMMUNODEFICIENCY VIRUS The Aids Epidemic and Transmission of HIV Infection Transmission of HIV Infection Pathophysiology and Clinical Course Molecular and Biologic Features of HIV Phases of HIV Infection Clinical Course

Opportunistic Infections Prevention, Diagnosis, and Treatment Prevention Diagnostic Methods Treatment Pharmacologic Management 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 Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Identify the differences between primary and secondary immunodeficiency disorders. 2. Compare and contrast the pathology and clinical manifestations of humoral (B-cell), cellular (T-cell), and combined T- and B-cell immunodeficiency disorders. 3. Discuss the pathophysiology and clinical manifestations of complement disorders. 4. Discuss the pathophysiology of phagocytosis disorders. 5. Describe the adaptive immune responses that protect against microbial agents and hypersensitivity responses. 6. Discuss the immune response involved in the development of types I, II, III, and IV hypersensitivity reactions. 7. Describe the pathogenesis of common hypersensitivity reactions. 8. Discuss the rationale for matching of major histocompatibility complex or human leukocyte antigen types in organ transplantation. 9. Describe the mechanisms and manifestations of graft-versus-host disease. 10. Discuss the possible mechanisms and criteria for an autoimmune disease.

11. Describe the mechanisms of HIV transmission and relate them to the need for public awareness and concern regarding the spread of AIDS. 12. Describe the virus responsible for AIDS including the alterations in immune function that occur in persons with AIDS. 13. Relate the altered immune function in persons with HIV infection and AIDS to the development of opportunistic infections, malignant tumors, nervous system manifestations, wasting syndrome, and metabolic disorders. 14. Differentiate between the enzyme immunoassay (enzyme-linked immunosorbent assay) and Western blot antibody detection tests for HIV infection. 15. Compare the progress of HIV infection in infants and children with HIV infection in adults.

Disorders of the Immune Response The human immune system is a complex, multidimensional system designed to protect the host against invasion by foreign substances, microorganisms, and toxins. In addition, it helps to protect against the proliferation of neoplastic cells and plays a key role in the process of inflammation and wound healing. Unfortunately, under certain circumstances, the immune system can become inefficient or hyperactive, causing the development of debilitating and/or life-threatening diseases. These disease processes can take the form of immunodeficiency disorders, allergic or hypersensitivity reactions, transplant rejection, and autoimmune disorders.

Immunodeficiency Disorders Immunodeficiency is defined as an abnormality in one or more parts of the immune system that results in an increased susceptibility to disease states normally eliminated by a properly functioning immune response.

Immunodeficiency syndromes can be classified as primary or secondary (acquired later in life). Primary immunodeficiency disorders are either congenital or inherited as sex-linked, autosomal dominant, or autosomal recessive traits. Secondary immunodeficiency disorders develop later in life because of other pathophysiologic states. The clinical manifestations and the impact on the client’s day-to-day function are dependent upon the specific immunodeficiency disorder and the degree of immune system dysfunction. The various categories of immunodeficiency disorders are summarized in Chart 12-1. CHART 12.1 IMMUNODEFICIENCY STATES Humoral (B-Cell) Immunodeficiency Primary X-linked hypogammaglobulinemia Common variable immunodeficiency Selective deficiency of IgG, IgA, and IgM Secondary Increased loss of immunoglobulin (nephrotic syndrome) Cellular (T-Cell) Immunodeficiency Primary Congenital thymic aplasia (DiGeorge syndrome) Hyper-IgM syndrome Secondary Malignant disease (Hodgkin disease and others) Transient suppression of T-cell production and function due to acute viral infection HIV/AIDS Combined B-Cell and T-Cell Immunodeficiency Primary Severe combined immunodeficiency syndrome X-linked

Autosomal recessive (ADA deficiency, Jak3 deficiency) Wiskott–Aldrich syndrome Ataxia–telangiectasia Combined immunodeficiency syndrome Secondary Irradiation Immune suppression and cytotoxic drugs Complement System Disorders Primary Hereditary deficiency of complement proteins Hereditary deficiency of C1 inhibitor (angioneurotic edema) Secondary Acquired disorders that consume complement factors Disorders of Phagocytosis Primary Chronic granulomatous disease Chédiak–Higashi syndrome Secondary Drug induced (corticosteroid and immunosuppressive therapy) Diabetes mellitus The immune system is made up of two distinct but interrelated systems: the innate and adaptive immune systems. These two systems work in concert to protect the body from infection and disease. The innate immune system is the body’s first line of defense against infection. It employs rapid yet nonspecific cellular and chemical responses. These include phagocytic leukocytes (i.e., neutrophils, macrophages); natural killer (NK) cells; chemical mediators, such as chemokines and cytokines; and the complement system. The adaptive immune system differs from the innate immune system in its ability to exhibit “memory” for invading organisms and toxic substances. The adaptive immune response develops more slowly but with a great deal of specificity. The T and B lymphocytes of the adaptive immune system possess the ability to express their receptors (T cells) and produce immunoglobulins (Igs) (B cells) in billions of different

combinations, which enables them to target billions of different epitopes, viruses, and microorganisms. The ability of the adaptive immune system to function effectively is dependent upon the interaction of two distinct but intimately connected mechanisms, the humoral (B cell–mediated) and cell-mediated (T cell– mediated) responses. The humoral immune response relies upon the ability of B lymphocytes to produce antigen-specific Igs and “memory” cells. In contrast, the cell-mediated response relies upon the ability of the T lymphocytes to produce various cytokines, to present antigen to B lymphocytes for destruction, and, in the case of cytotoxic T cells, to kill cells infected with intracellular organisms. Primary immunodeficiency diseases (PIDDs) are caused by genetic abnormalities of the immune system; this group consists of more than 130 distinct disorders.1 Recent estimates put the overall prevalence of PIDDs in the United States at 1:2000.2 Approximately 65% of these cases present as a primary antibody deficiency syndrome.1 An increased incidence rate has been attributed to an increased awareness and therefore diagnoses of PIDDs, not to an increase in the number of actual new cases.3 Most of these disorders are inherited as autosomal recessive traits, several are sex linked and caused by mutations in the X chromosome, and the causes of some have yet to be identified.3 The root cause of many of PIDDs involves mutations that affect the signaling pathways (e.g., cytokines and cytokine signaling, receptor subunits, and metabolic pathways) that dictate immune cell development and function. Autoimmunity is frequently associated with PIDDs because the ability of the immune system to differentiate self from nonself is also affected.1,3 For infants born with severe combined T- and B-cell immunodeficiency, early diagnosis is essential before the development of severe infections and the administration of live attenuated virus vaccines which could have devastating and life-threatening consequences.4 Children with PIDDs often present with a history of recurrent, severe infections that are resistant to treatment. In fact, the average age of referral for immune testing after recurrent severe infection is about 6 months of age.4 The infections frequently involve the respiratory tract and are the result of organisms not traditionally seen in this population. These include recurrent bouts of ear infections, sinus infections, and pneumonia within a 1-year period that are unresponsive to a long course (1 to 2 months) of antibiotics, failure to thrive

in infancy, persistent thrush or fungal infections, recurrent skin or organ abscesses, and a positive family history of primary immunodeficiency. Because these disorders are frequently inherited, a positive family history may help in the diagnosis. Areas of the world with high consanguinity (descended from the same ancestor) rates have been shown to have a much higher prevalence rate than that in the general population. In addition, identification of an infectious organism can help in the diagnosis of a specific form of PIDD.5 Table 12-1 summarizes types of infections that occur with the different types of primary immunodeficiency disorders. TABLE 12-1 Infectious Organisms Frequently Associated with Major Categories of Immunodeficiency Disorders

Immunodeficiency Viruses Bacteria Fungi Protozoa Disorder B-cell (humoral) Enteroviruses, Streptococcus No Giardia immunodeficiency poliovirus pneumoniae, lamblia Staphylococcus aureus, Haemophilus influenzae T-cell (cellHerpesvirus Salmonella Candida mediated) typhi, all albicans, immunodeficiency mycobacteria Coccidioides immitis, Histoplasma capsulatum, Aspergillus fumigatus Combined T-cell All S. pneumoniae, C. albicans, Toxoplasma and B-cell S. aureus, H. Pneumocystis gondii immunodeficiency influenzae, jirovecii Neisseria (formerly meningitidis, carinii) Mycoplasma hominis, enteric flora

Immunodeficiency Viruses Disorder Complement system disorders

Bacteria

Fungi

Protozoa

S. pneumoniae, S. aureus, H. influenzae Phagocytosis S. aureus, A. fumigatus, (neutrophils and enteric flora, C. albicans, monocytes) Pseudomonas Nocardia disorders aeruginosa, all asteroides mycobacteria From Alder R., Kalumuck K. (2013). Immunodeficiency disorders. Magill’s medical guide (Online Edition) [Serial Online]. Available from: Research Starters, Ipswich, MA. Accessed May 4, 2018; Nazi N., Ladomenou F. (2018). Gastrointestinal manifestations of primary immune deficiencies in children. International Reviews of Immunology 37(2), 111–118; Preston R. R., Wilson T. (2013). Lippincott’s illustrated reviews: Physiology. Philadelphia, PA: Wolters Kluwer; Rhoades R. A., Bell D. R. (2018). Medical physiology (5th ed.). Philadelphia, PA: Wolters Kluwer. Humoral (B-Cell) Immunodeficiencies Humoral immunodeficiencies are primarily associated with B-cell dysfunction and decreased Ig production. Because the B lymphocytes are essential for normal defense against bacterial invasion, people with humoral immunodeficiencies are at increased risk for recurrent infections by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and several gram-negative organisms, including Pseudomonas.6,7 Humoral immunity usually is not as important in defending against intracellular bacteria (mycobacteria), fungi, and protozoa, so recurrent infection with these organisms is usual. Because T-cell function is not affected, the body’s response to viral infection is normal. Transient Hypogammaglobulinemia of Infancy At birth, infants are protected from infection by maternal IgG antibodies that have crossed the placenta during fetal development. They are normally deficient in IgA, IgM, IgD, and IgE because these Igs do not normally cross the placenta. During the first 6 months of life, maternal antibody levels

gradually decline as the infant’s humoral immune system gradually takes over antibody production, reaching adult levels by 1 to 2 years of age. The most frequently occurring clinical manifestations include upper respiratory tract infections, lower respiratory tract infections (including pneumonia), allergies, and allergic asthma.8 Treatment of transient hypogammaglobulinemia of infancy (THI) is usually with prophylactic antibiotics, but some evidence exists that intravenous immunoglobulin (IVIg) may play a role in improving quality of life and stopping the cycle of infection often seen in these children.9 Most cases of THI resolve spontaneously by 3 years of age, but some persist into adolescence and are often associated with other primary immunodeficiency syndromes. Primary Humoral Immunodeficiency Disorders Primary immunodeficiency disorders that affect B-cell differentiation and antibody production are the most common and are the result of impaired differentiation and maturation of lymphoid stem cells in the bone marrow. Immature or naive B cells expressing surface IgM (IgM+) leave the bone marrow and migrate into the peripheral lymphoid tissues. After antigen and T-cell stimulation, they undergo “class switching” where they lose surface IgM and express other Ig types such as IgG, IgA, or IgE-secreting plasma B cells (Fig. 12-1).10 Primary humoral immunodeficiency disorders can interrupt the production of one or all of the Igs at any point along the differentiation and maturation cycle.

Stem cells to mature Ig-secreting plasma cells. Arrows indicate the stage of the maturation process that is interrupted in (A) transient hypogammaglobulinemia, (B) XLA, (C) CVID, and (D) IgG subclass deficiency. FIGURE 12-1

X-Linked Agammaglobulinemia X-linked agammaglobulinemia (XLA) is an inherited, sex-linked, recessive disorder that affects 1 in 250,000 males. XLA is a primary humoral immunodeficiency that is caused by a defect in early B-cell development leading to a severe decrease in the production, maturation, and survival of mature B lymphocytes. The end result is a profound hypogammaglobulinemia and severe susceptibility to infection. Affected males are prone to infections with encapsulated bacteria, such as S. pneumoniae, H. influenzae type b, Giardia lamblia, meningococcus, and various enteroviruses.11,12 The gene mutation for XLA is found on Xq21.3Xq22, which encodes for an intracellular signaling kinase, named Bruton tyrosine kinase (Btk).13 Most boys with XLA are asymptomatic at birth because of the presence of circulating maternal antibodies. Once these levels start to drop, affected males develop life-threatening infections that are unresponsive to antibiotic therapy. Diagnosis is based on demonstration of low or absent serum Igs.

Current therapy, which includes chronic administration of IVIg and prophylactic antibiotics, is only partially effective, expensive, and associated with severe long-term complications. New treatments are being tested that utilize gene therapy to promote B-lineage–specific Btk expression; these treatments have had some success.14 Common Variable Immunodeficiency Another form of humoral primary immunodeficiency associated with impaired B-cell differentiation and antibody production is common variable immunodeficiency (CVID). All people have low serum IgG levels, but some present with low IgA and/or low IgM as well, resulting in impaired antibody response to specific infections and vaccine challenge.15 CVID is a heterogeneous disorder, affecting males and females equally, and no one specific gene mutation has been identified. This disorder is the result of a failure of class switching in naïve B cells in the late maturation period.15 Normally, circulating B cells express surface IgM and IgD and, after antigen and T-cell stimulation in lymphoid tissues, lose these markers and express IgG, IgA, or IgE. Memory B cells will also express the surface marker CD27 or tumor necrosis factor [TNF] receptor subfamily, member 7 (TNFRSF7).16 Thus, people with CVID have a relatively normal number of nonfunctioning B lymphocytes. CD4 and/or CD8 T lymphocytes are usually not affected, but in many people, overall T-cell counts may be diminished, particularly as a result of loss of CD4+ naive T cells.16 Clinical manifestations of CVID can begin at any time of life and most commonly include recurrent bacterial and viral infections of the respiratory tract.15 Autoimmune disease (27%) is seen in people with CVID and is associated with both a reduction in overall T regulatory cell counts and impaired function.15,16 The most frequently seen autoimmune disorders diagnosed are immune thrombocytopenic purpura and autoimmune hemolytic anemia (AIHA), but cases of aseptic nonerosive seronegative inflammatory arthritis, inflammatory bowel disease, and vasculitis have been reported. Approximately 10% of people will present with a lymphoproliferative disorder at some point in their lives.16 Treatment methods for CVID are similar to those used for other primary humoral immunodeficiencies, with IVIg being the mainstay of therapy. Selective Immunoglobulin A Deficiency

Selective IgA deficiency (SIGAD) is the most common primary immunodeficiency disorder, which was first described in children with ataxia–telangiectasia (AT); the worldwide incidence varies with the ethnic background.17 The syndrome is characterized by moderate to marked reduction in levels of serum and secretory IgA. In the body, secretory IgA binds to and neutralizes intestinal pathogens and their toxic products, so IgA antibodies are normally not found in the bloodstream unless bacterial flora invasion has occurred. In most cases of SIGAD, clinical manifestations are mild to absent because IgG and IgM levels are normal and the humoral response to infection is adequate. However, in the fulminant form, the deficiency leads to an increased susceptibility to infections, particularly those of the respiratory and lower respiratory systems.17 In people diagnosed with SIGAD, the frequency of circulating anti-IgA antibodies has been reported to be from 20% to 40%, so anaphylaxis and allergic reactions to blood products are of real concern to practitioners.18 In people with SIGAD, B lymphocytes express surface IgA, but the cells appear to be developmentally arrested so that terminal differentiation into IgA-secreting plasma cells does not occur. The exact mechanism of IgA deficiency is unknown, but in many cases, genetic mutations in the TACI gene have been identified.19 SIGAD is genetically linked to CVID; both disorders appear to be the result of the same molecular defect.18 Many children with SIGAD will go on to develop CVID later in life and vice versa. SIGAD occurs in both men and women and in members of successive generations within families. This suggests autosomal inheritance with variable expressivity because many people have a family history of either SIGAD or CVID.18 There is no definitive treatment available for SIGAD unless there is a concomitant reduction in IgG levels. Immunoglobulin G Subclass Deficiency IgG antibodies can be divided into four subclasses designated as IgG1 through IgG4, based upon their underlying structure and function. People may present with deficiencies in one or more of the IgG subtypes, despite normal levels of overall serum IgG. Deficiencies of IgG1 and IgG2 are most common.20 Most circulating IgG belongs to the IgG1 (70%) and IgG2 (20%) subclasses. In general, antibodies directed against antigenic protein belong to the IgG1 and IgG3 subclasses, whereas antibodies directed

against carbohydrate and polysaccharide antigens are primarily of the IgG2 subclass. As a result, people who are deficient in IgG2 subclass antibodies may be at greater risk for development of sinusitis, otitis media, and pneumonia caused by polysaccharide-encapsulated microorganisms such as S. pneumoniae, H. influenzae type b, and Neisseria meningitidis. However, decreased antibodies of one or more subclasses may be found in healthy people. Treatment of IgG subclass deficiency is dependent upon the specific deficiency and clinical presentation. KEY POINTS Primary Immunodeficiency Disorders Primary immunodeficiency disorders are inherited abnormalities of immune function that render a person susceptible to diseases normally prevented by an intact immune system. They can be classified as B cell–mediated, T cell–mediated, or combined immunodeficiencies, which affect all aspects of the humoral and cell-mediated immune response. B cell–mediated immunodeficiency disorders affect antibody production and inhibit the ability of the immune system to defend against bacterial infections and toxins that circulate in body fluids (IgM and IgG) or enter the body through the mucosal surface of the respiratory or gastrointestinal tract (IgA). T cell–mediated immunodeficiency disorders result from defective expression of the T-cell receptor (TCR) complex, defective cytokine production, and defects in T-cell activation. They impair the ability of the immune system to protect against fungal, protozoan, viral, and intracellular bacterial infections (CD8+ cytotoxic T cells). Combined T- and B-cell immunodeficiency disorders affect all aspects of immune system and its function. Secondary Humoral Immunodeficiency Disorders

There are numerous causes of secondary hypogammaglobulinemia, including malnutrition, burns, gastrointestinal loss, nephrotic syndrome, and malignancy and as a side effect of certain medications.21 These conditions can result in an increase in Ig loss and/or a decrease in Ig production. For example, nephrotic syndrome is associated with loss of serum IgG as a result of abnormal glomerular filtration and subsequent urinary loss. Serum IgA and IgM remain normal or are slightly elevated because they are large molecular weight molecules that cannot be filtered by the glomerulus.21 In contrast, several malignancies such as leukemias and lymphomas are associated with antibody deficiencies because they decrease overall antibody production. Many commonly used medications can impair antibody levels by either mechanism and include several of the antiepileptics, antihypertensives, and glucocorticoids. The effects can usually be reversed by withdrawal of the medication. Cell-Mediated (T-Cell) Immunodeficiencies Cell-mediated immunodeficiencies are a heterogeneous group of disorders that arise from defects in one or more components of the cell-mediated immune response. Whereas B lymphocytes undergo a definitive path of differentiation that culminates in antibody production, the functions of mature T lymphocytes are immunologically diverse. T lymphocytes are made up of two distinct subpopulations: CD4+ helper T cells and CD8+ cytotoxic T cells. The subpopulations of T lymphocytes work collectively to protect against fungal, protozoan, viral, and intracellular bacterial infections; control malignant cell proliferation; and coordinate the overall immune response. Therefore, defects in different components of the system can result in a wide range of immunologic responses. Primary Cell–Mediated Immunodeficiency Disorders Of all the primary immunodeficiencies, the T cell–mediated disorders are considered to be the most severe. Those affected succumb to serious viral, fungal, and opportunistic infections within the first few months of life.22 The presence of maternal antibodies offers no immunologic advantage against these cell-mediated disorders. Children with the most severe T cell– mediated defects, such as severe combined immunodeficiency disorder (SCID), rarely survive beyond infancy or childhood because they are prone

to both opportunistic and nonopportunistic infections.22 Newly identified Tcell defects, such as the X-linked hyper-IgM syndrome, have a more favorable outcome with minimal to no treatment. Primary T-cell immunodeficiency disorders result from defective expression of the TCR complex, defective cytokine production, and defects in T-cell activation. People are usually diagnosed based upon their clinical presentation and family history. In the most severe types of cell-mediated immunodeficiency, immunologic evaluation reveals reduced numbers of lymphocyte subsets including T, B, and NK cells in peripheral blood smears and a depressed T-cell response to antigen stimulation.23 Traditionally, bone marrow transplantation has been the treatment of choice in children with the most severe forms of T-cell immunodeficiency. However, in more recent years, immunologic restoration of the immune system through allogeneic hematopoietic stem cell transplantation (HSCT)22 and gene therapy24 is becoming increasingly popular for the treatment of specific T-cell disorders. DiGeorge Syndrome DiGeorge syndrome or velocardiofacial syndrome is an embryonic developmental defect associated with chromosome 22q11.2 deletion.25,26 It occurs in approximately 1:4000 births. The incidence of this disorder is increasing because many of those now affected go on to give birth to affected children. The defect is thought to occur before the 12th week of gestation, when the thymus gland, parathyroid gland, and parts of the head, neck, and heart are developing. Children with DiGeorge syndrome present with a wide complex of defects including mild to moderate immunodeficiency resulting from a congenitally absent thymus, cardiac and renal anomalies, palatal abnormalities, hypoparathyroidism, skeletal defects, and developmental delays. Because of the presence of a limited number of thymic cells in aberrant locations, the severity of T-cell dysfunction ranges from no circulating T cells to normal counts The disorder affects both sexes. When the thymus is not absent but is extremely small and located outside of the mediastinum, growth and development of the thymus may occur with normal stimulation of the immune system. The facial disorders can include hypertelorism (i.e., increased distance between the eyes); micrognathia (i.e., abnormally small jaw); low-set, posteriorly angulated ears with associated

hearing loss; split uvula; a high-arched or cleft palate; and oropharyngeal and nasopharyngeal muscle weakness.26 Renal abnormalities affect approximately one third of children with DiGeorge syndrome. Fortunately, renal dysplasia and agenesis are rare consequences requiring immediate dialysis. Hypocalcemia and tetany may develop within 24 hours of birth as a result of absent or hypoplastic parathyroid glands. The immune system is affected in 75% of children with DiGeorge syndrome as a result of thymic hypoplasia.26 Children with severe T-cell dysfunction are more prone to recurrent or chronic viral, fungal, and intracellular bacterial infections. Impaired helper T-cell function affects antigen presentation to B cells and subsequent antibody production. This phenomenon appears to be limited to children as there is no clinical evidence that adults have an increased risk of infection. Treatment of DiGeorge syndrome is dependent upon the presenting symptoms. Cardiac anomalies are usually repaired shortly after birth. In children with true thymic aplasia and congenitally absent T cells, a thymus transplant or fully matched T-cell transplant is the treatment of choice to reconstitute T-cell immunity. As with any primary immunodeficiency, autoimmunity is a potential problem. Therefore, precautions must be taken during transplantation or transfusion therapy to prevent graft-versus-host disease (GVHD). X-Linked Immunodeficiency with Hyper-IgM The hyper–immunoglobulin M (HIGM) syndromes are a heterogeneous group of primary immunodeficiency disorders resulting from defective Ig class switch recombination during B-cell maturation leading to a deficiency in IgG, IgA, and IgE but elevated levels of IgM.27 This X-linked disorder is found only in males. The disorder results from the inability of T cells to signal B cells to undergo isotype switching to IgG and IgA. Thus, they continue to express only the IgM subclass of Igs. In most cases, it is the result of a genetic mutation resulting in a CD40 ligand deficiency. Its primary cause is a defect in cell-mediated immunity. Clinical manifestations of HIGM occur early in life with a median age of onset at less than 12 months.28 Children usually present with recurrent sinopulmonary infections that may progress to bronchiectasis and pneumonia. In approximately 40% of cases, the presenting symptom is an opportunistic infection such as Pneumocystis jiroveci pneumonia (PJP).29

Unfortunately, these children are at particular risk for the development of autoimmune disorders and malignancies of the biliary tree, intestine, and neuroendocrine system because of defects in CD40 signaling. Treatment is usually with Ig replacement and prophylactic antibiotic treatment. Secondary Cell-Mediated Immunodeficiency Disorders Secondary cell-mediated immunodeficiencies are more prevalent than primary deficiencies and are frequently associated with acute viral infections (e.g., measles virus, cytomegalovirus) and with certain malignancies such as Hodgkin disease and other lymphomas. Viral infections frequently impair cell immunity via direct infection of specific Tlymphocyte subpopulations (e.g., helper cells). Lymphotropic viruses such as human immunodeficiency virus (HIV) and human herpesvirus (HSV) type 6 selectively deplete the cell subtype that they invade, resulting in a concomitant loss of immunologic function associated with that subtype. People with malignancies can have impaired T-cell function because of either unregulated proliferation or depletion of a particular cell type. Some cases of T-cell immunodeficiency have no known etiology but are acquired later in life. Idiopathic CD4+ T-cell lymphocytopenia is a rare disorder characterized by a profound and persistent CD4+ T-cell defect that predisposes to the development of severe opportunistic infections in the absence of other immune defects.30 Regardless of the etiology, people with secondary cell-mediated immune dysfunction may display an increased susceptibility to infections caused by normally harmless pathogens (i.e., opportunistic infections) or may be unable to mount delayed hypersensitivity reactions (i.e., anergy). People with anergy have a diminished or absent reaction to antigen even in the presence of known infection. Combined T-Cell and B-Cell Immunodeficiencies Combined T-cell and B-cell lymphocyte disorders manifest with defects in both the humoral and cell-mediated immune responses. Collectively, these disorders are known as combined immunodeficiency syndrome (CIDS), but they are a diverse group caused by mutations in a multitude of genes that influence lymphocyte development or response, including lymphocyte receptors, cytokines, or major histocompatibility complex (MHC) antigens,

that could lead to combined immunodeficiency. The end result is a disruption in the communication pathways between the cells of the humoral and cell-mediated immune systems and failure of the adaptive immune response. The spectrum of disease resulting from combined immunodeficiency disorders (CIDs) ranges from mild to severe to, ultimately, fatal forms. Severe Combined Immunodeficiency Disorders SCIDs are a group of genetically diverse disorders characterized by profound deficiencies of T and B lymphocytes, and in some forms NK, with the subsequent loss of both humoral and cellular immunities.22 The reported incidence of SCIDs is 1:100,000 live births, and they collectively account for approximately 20% of primary immunodeficiency disorders.31 Affected infants are lymphopenic and lack T cells, which normally constitute 70% of the total circulating lymphocytes. They have a disease course that resembles that of acquired immunodeficiency syndrome (AIDS), with failure to thrive, chronic diarrhea, and the development of severe opportunistic infections. An SCID is usually fatal within the first 2 years of life, unless reconstitution of the immune system through bone marrow or HSCT can be accomplished. Early diagnosis is essential because the chances of successful treatment are better in infants who have not experienced severe opportunistic infections.31 X-linked mutations account for almost 45% of all cases as a result of defects in the common gamma chain of the cytokine receptor.32 Impaired receptor function results in defective T-lymphocyte differentiation and production. Although the B-cell production is unaffected, antibody production is impaired because of a lack of T-cell help. Mutations inherited as autosomal recessive traits account for the majority of the remaining cases of SCID including mutations in the genes that code for ADA gene, Janus kinase 3 (JAK3) gene, the α chain of the interleukin-7 receptor (IL-7Rα chain [also known as CD127]), and recombination-activating genes 1 and 2 (RAG1 and RAG2).31 Many of these mutations result in defects that impair T-cell maturation including defects in cytokine receptor control of T-cell differentiation, antigen gene receptor arrangement on T and B cells, or any other component of T-cell antigen receptor function necessary for normal Tcell development.

Combined Immunodeficiency Disorders CIDs are less severe than those categorized as SCIDs because they present with diminished, rather than absent, T-cell function and B-cell antibody production. Like SCID, the CIDs are a heterogeneous group of disorders with diverse genetic causes. They are often associated with other disorders such as AT and WAS.33 Like all primary immunodeficiencies, children with CID are prone to development of recurrent infections including pulmonary, skin, and urinary tract infections. They also have a higher incidence of chronic diarrhea and other gastrointestinal disorders, as well as gram-negative sepsis. Although they usually survive longer than do children with SCID, without treatment, they fail to thrive and often have a shortened life span. Ataxia–Telangiectasia AT is a rare autosomal recessive disorder caused by a gene mutation (ATM, ataxia–telangiectasia mutated) mapped to chromosome 11q22-23 with a worldwide prevalence estimated to be between 1 in 40,000 and 1 in 100,000 live births.34 ATM is a large serine/threonine kinase that is involved in the cellular response to breakage in the double strand of the DNA helix. This multisystem disorder is characterized by neurodegeneration, primarily of the cerebellum, and oculocutaneous telangiectasia. Ataxia is the predominant neurodegenerative feature, which usually goes undiagnosed until the child begins to walk. It is associated with both cellular and humor immune deficiencies with decreased lymphocyte counts and ratio of CD4 helper T cells to CD8 suppressor T cells. Lymphopenia, hypogammaglobulinemia, and cell-mediated immune dysfunction results in recurrent sinopulmonary infections. People with this disorder have an increased risk of cancer and radiation sensitivity. The most common malignancies that occur with this condition are lymphoid in origin, but solid tumors of the kidney (Wilms tumor) are frequently reported.34 Cognitive development is normal early in the disease process but levels off during childhood and ceases by 10 years of age. The majority of people display Ig deficiencies in IgA, IgE, and IgG, with the IgG2 and IgG4 subclasses being most affected. Ninety-five percent of all affected children demonstrate elevated serum α-fetoprotein (AFP) levels.34

Wiskott–Aldrich Syndrome Wiskott–Aldrich syndrome (WAS) is a severe, rare, and complex X-linked disorder characterized by the triad of thrombocytopenia, recurrent infections, and eczema, with an increased risk for the development of autoimmune disorders and lymphomas. The syndrome affects approximately one to four cases per 1,000,000 live male births and is caused by mutations in the WAS gene.35 For children lacking WAS protein (WASp) expression, life expectancy is approximately 15 years. WASp is a key regulator of actin assembly in all hematopoietic cells (including platelets) in response to signals arising at the cell membrane. Hemorrhage, ranging from mild to life threatening, is common and occurs in over 80% of cases. Abnormalities of humoral immunity include decreased serum levels of IgM and markedly elevated serum IgA and IgE concentrations. T-cell dysfunction is initially limited but increases over time resulting in greater susceptibility to infection and the development of malignancies of the mononuclear phagocytic system, including Hodgkin lymphoma and leukemia.35,36 Management of people with WAS focuses on treatment of eczema, control of infections, and management of bleeding episodes. Currently, the only definitive treatment is allogeneic HSCT , but this is associated with considerable risk of complications including death and transplant rejection.37 Disorders of the Complement System The complement system is an integral part of the innate immune response and essential to the integrity of the immune system, including the adaptive immune response. Activation of the complement system occurs via one of three ways: the classic, lectin-mediated, or alternative pathways. Regardless of the pathway, activation of the complement system promotes chemotaxis, opsonization, and phagocytosis of invasive pathogens and bacteriolysis. Alterations in any component of the complement system can lead to enhanced susceptibility to infectious diseases and to the development of a host of autoimmune processes. Primary Disorders of the Complement System

Primary disorders of the complement system can be transmitted as autosomal recessive, autosomal dominant, or autosomal codominant traits. In the case of codominance, heterozygotes usually have one functioning gene, and complement levels in most cases are sufficient to prevent disease. The majority of disorders associated with the complement system are the result of inappropriate activation and regulation of complement proteins, not necessarily deficiencies of complement proteins themselves.38 In fact, protein deficiencies of the classic and alternative pathways are rarely seen. Protein deficiencies of the lectin pathway, although more common, are not a major cause of primary complement disorders. Primary disorders of the complement system can involve one or more proteins, receptors, and/or control molecules at any point along the complement cascade. However, the clinical presentation is dependent upon the component affected. For example, defects in the classic pathway result in an increased of autoimmunity and infection with high-grade pathogens, whereas defects in the lectin pathway are associated with an increased risk of infection from unusual pathogens such as Cryptosporidium and Aspergillus.39 Because all three pathways converge at the activation of C3, defects that impact C3 or late-acting proteins affect activation of complement by all three pathways and are associated with marked increases in infection with high-grade pathogens, including Neisseria gonorrhoeae and N. meningitidis infection, hemolytic uremic syndrome, and adult-onset macular degeneration.40 It is now known that the complement system plays a key role in the control of the adaptive immune response. Subjects deficient in complement proteins frequently have significant defects in the adaptive immune response. C1q, C3, and C4 deficiencies are associated with a diminished immune response especially to T cell–dependent antigens.39 In addition, they have poor germinal center activity and poor immunologic memory. In the C1 subunit, C1q is essential for the binding of immune complexes and apoptotic cells, promoting their eventual removal from the circulation.38 These people, therefore, have an increased risk of infection from encapsulated bacteria, particularly S. pneumoniae. In addition, they are at increased risk for the development of autoimmune disease processes, particularly systemic lupus erythematosus (SLE) and other forms of vasculitis.

Defects in the lectin pathway have just recently been defined to involve the essential protein mannose-binding lectin (MBL). MBL does not require antibody presentation for activation, as does C1 in the classic pathway. MBL possesses a central core and radiating arms with an intertwined, chained collagen structure capable of binding bacterial surface polysaccharides. A single-gene defect that is carried as an autosomal dominant trait results in improper winding of the MBL molecule and abnormally low plasma concentrations (180/120 mm Hg) complicated by acute or worsening target-organ damage. It is critical that emergent interventions be implemented to return blood pressure to safe levels to prevent permanent organ dysfunction or death. Acute organ damage as a result of hypertensive emergency can include ischemic stroke, hypertensive encephalopathy, cardiac ischemia, and retinal hemorrhage.25,40,41 Diagnosis and Treatment Hypertension is diagnosed by sequential blood pressure measurements that indicate a consistent elevation of pressure within the systemic arterial circuit. Recent clinical management guidelines for adults in the United States, issued in November 2017, are presented in Table 26-3. TABLE 26-3 Classification of Blood Pressure in Adults (by the 2017 Guidelines of the American College of Cardiology and American Heart Association)

Blood Pressure Systolic Blood Pressure Diastolic Blood Pressure Classification (mm Hg) (mm Hg) Normal 5%

Age-specific classification criteria for children provided on website.

*

FEV1.0, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow rate; PEV, peak expiratory volume. Adapted from National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. (2007). Expert panel report 3: Guidelines for the diagnosis and management of asthma. Section 3, component 1: Measures of asthma assessment and monitoring. Bethesda, MD: National Heart, Lung, and Blood Institute (US). Available: https://www.ncbi.nlm.nih.gov/books/NBK7230.

Prevention measures to control factors contributing to asthma severity are aimed at limiting exposure to irritants and factors that increase asthma symptoms and precipitate asthma exacerbations. They include education of the person and family regarding measures used in avoiding exposure to irritants and allergens that are known to induce or trigger an attack. A careful history is often needed to identify all the contributory factors. Factors such as nasal polyps, a history of aspirin sensitivity, and gastroesophageal reflux should be considered. Annual influenza vaccination is recommended for people with persistent asthma. Nonpharmacologic management includes relaxation techniques and controlled breathing, which often help to allay the panic and anxiety that aggravate breathing difficulties. The hyperventilation that often accompanies anxiety and panic is known to act as an asthmatic trigger. In a child, measures to encourage independence as it relates to symptom control, along with those directed at helping to develop a positive self-concept, are essential. 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.11 The Expert Panel recommends a stepwise approach to pharmacologic therapy based on the classification systems discussed previously.11 The first line of treatment with any of the persistent forms of asthma includes an inflammatory controller drug that would include inhaled corticosteroids, mast cell stabilizers, and leukotriene modifiers. The quick-relief medications such as the short-acting β2-adrenergic agonists relax bronchial smooth muscle and provide prompt relief of symptoms, usually within 30 minutes. They are administered by inhalation to alleviate acute attacks of asthma because regular use does not produce beneficial effects.11 The anticholinergic medications 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. A short course of systemic

corticosteroids, administered orally or parenterally, may be used for treating an acute flare. 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. 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.23 These people are at increased risk for fatal or near-fatal 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.23 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 (β2adrenergic 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 Chlamydia 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 life-threatening 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.

The long-acting β2-adrenergic agonists such as salmeterol and formoterol are used to treat severe refractory asthma only if no other treatment is effective. Asthma in Older Adults For older adults with asthma, who already have a decreased immunologic 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.24 Asthma in Children Asthma is a leading cause of chronic illness in children and is responsible for approximately 13.8 million number of lost school days/year. It is the most frequent admitting diagnosis 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.25 As with adults, asthma in children commonly is associated with an IgErelated reaction. It has been suggested that IgE directed against respiratory viruses in particular may be important in the pathogenesis of wheezing illnesses in infants that 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. Infants with undiagnosed asthma may have a prolonged cough without cold symptoms, independent of wheezing.26 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 Global Initiative for Asthma (GINA) has developed a global strategy with guidelines for management and prevention of asthma in infants and children from 0 to 5 years, 6 to 11 years, and for adults and children aged 12 years and older. As with adults and older children, GINA recommends a stepwise approach to diagnosing and managing asthma in infants and children.26 Chronic Obstructive Pulmonary Disease COPD is characterized by chronic and recurrent obstruction of airflow in the pulmonary airways. Airflow obstruction is usually 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 30 million Americans27 have some degree of COPD; 16 million are diagnosed with COPD. Of those diagnosed, 56% are women. In the United States, COPD is the fourth leading cause of death following heart disease, cancer, and unintentional injuries.28 The most common cause of COPD is smoking, and approximately 80% of deaths related to COPD are associated with a history of smoking.29 A second, less common factor is a hereditary deficiency in α1-antitrypsin (AAT). Other predisposing factors are asthma and airway hyperresponsiveness. Although clinical findings may be absent during the early stages of COPD, any person with a chronic cough, sputum production, dyspnea, and a history to exposures of risk factors such as smoking or indoor/outdoor pollutions should be considered for the diagnosis of COPD.23,28,29 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 are usually 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.23,29 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 (COPD) 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.23,29 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. 31-9). 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 AAT, an antiprotease enzyme that protects the lung from injury.

Panacinar emphysema. (A) A whole mount of the left lung from people 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 α1antitrypsin disorder shows a panacinar pattern of emphysema. The loss of alveolar walls has resulted in markedly enlarged airspaces. (From Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 18-45, p. 710). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 31-9

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 AAT, 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. 3110).

The proteolysis–antiproteolysis theory of the pathogenesis of emphysema. Cigarette (tobacco) smoking is closely related to the development of emphysema. Some products in tobacco smoke induce an inflammatory reaction. The serine elastase in polymorphonuclear leukocytes, a particularly potent elastolytic agent, injures the elastic tissue of the lung. Normally, this enzyme activity is inhibited by α1-antitrypsin (AAT), but tobacco smoke, FIGURE 31-10

directly or through the generation of free radicals, inactivates AAT (protease inhibitor). (From Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 18-42, p. 708). Philadelphia, PA: Lippincott Williams & Wilkins.) The type and amount of AAT that a person has is determined by a pair of codominant genes referred to as protein inhibitor (PI) genes. An α2antitrypsin disorder (AATD) is inherited as an autosomal recessive disorder. Most people with clinically diagnosed emphysema before the age of 40 years have an AATD. Smoking and repeated respiratory tract infections, which also decrease AAT levels, contribute to the risk for emphysema in people with AATD. Laboratory methods are available for measuring AAT levels. Human AAT 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. 31-11). Centriacinar emphysema is mostly associated with cigarette smoking and affects the respiratory bronchioles predominantly in the upper lobes and in the superior lower lobes.23 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 AATD. It is also 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.

Types of emphysema. The acinus is the gas-exchanging structural unit of the lung distal to the terminal bronchiole. It consists of (from proximal to distal) respiratory bronchioles, alveolar ductus, alveolar sacs, and alveoli. In centrilobular (proximal acinar) emphysema, the respiratory bronchioles are predominantly involved. In paraseptal (distal acinar) emphysema, the alveolar ducts are particularly affected. In panacinar (panlobular) emphysema, the acinus is uniformly damaged. (From Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 18-43, p. 709). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 31-11

Chronic Bronchitis Chronic bronchitis represents airway obstruction of the major and small airways.23,30 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.30 Typically, the cough has been present for many years, with a gradual increase in acute exacerbations that produce frank 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 bronchi.23 Although mucus hypersecretion in the large airways is the cause of sputum overproduction, it is now thought that accompanying changes in the small airways are physiologically important in the airway obstruction that develops in chronic bronchitis.23 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. Viral and bacterial infections are common in people with chronic 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 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. 31-12). 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.

Characteristics of normal chest wall and chest wall in emphysema. (A) The normal chest wall and its cross section. (B) The barrel-shaped chest of emphysema and its cross section. A-P, anterior–posterior. (From Hinkle J. L., Cheever K. H. (2018). Brunner & Suddarth’s textbook of medical-surgical nursing (14th ed., Fig. 243, p. 637). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 31-12

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 WOB 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 people 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 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.23 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 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. Lung volume measurements reveal a marked increase in RV, an increase in TLC, and elevation of the RV/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 by measuring FEV1.0/FVC ratios. 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 and psychosocial rehabilitation of people with COPD and their families is a key to successful management of the disease. 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. A long-term pulmonary rehabilitation program includes breathing exercises that focus on restoring the function of the diaphragm, reducing the WOB, and improving gas exchange. Physical conditioning with appropriate 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. The anticholinergic agents, which are administered by inhalation, produce bronchodilation by blocking parasympathetic cholinergic receptors that produce contraction of bronchial smooth muscle. Oxygen therapy is prescribed for selected people with significant hypoxemia (arterial PO2 < 55 mm Hg). Administration of continuous lowflow (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 88% to 92%.27 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. 31-13). 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. 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.

Bronchiectasis. The resected upper lobe shows widely dilated bronchi, with thickening of the bronchial walls and collapse and fibrosis of the pulmonary parenchyma. (From Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of FIGURE 31-13

medicine (7th ed., Fig. 18-10, p. 686). Philadelphia, PA: Lippincott Williams & Wilkins.) 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 generations of bronchi.29 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 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. Localized or focal 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 or diffuse bronchiectasis is usually bilateral and most commonly affects the lower lobes.23 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; congenital and acquired immunodeficiency states, which predispose to respiratory tract infections; lung infection (e.g., tuberculosis, fungal infections, lung abscess); and exposure to toxic gases that cause airway obstruction. 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 foul-smelling, 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 is often 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. A person with this disorder benefits 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.31 CF affects about 30,000 children and adults in the United States, and more than 10 million persons are asymptomatic carriers of the defective gene.31 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.

Pathogenesis of cystic fibrosis. CFTR, cystic fibrosis transmembrane regulator. FIGURE 31-14

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. 31-14). There are greater than 1000 possible CFTR changes that can occur. However, the most common CFTR gene mutation is called the delta F508, in which the deletion of the amino acid phenylalanine at the 508 position results in a severe phenotype. Due to the deletion of this amino acid, chloride channels are misfolded and are not inserted into the cell membrane.32 Others have a partial loss or mutation of the CFTR gene, 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 due to the CFTR gene mutation ultimately affects the reabsorption of NaCl, which results in high concentrations of NaCl in the sweat of people with CF.33 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.23,32 Pseudomonas aeruginosa, in particular, has a propensity to undergo pathogenesis. Early colonization can cause recurring pulmonary infections.23 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 people with CF. Malabsorption and malnutrition may often be present along with symptoms of abdominal discomfort and diarrhea. Steatorrhea, diarrhea, and abdominal pain and discomfort are common associated symptoms. 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, and in others, the involvement is severe and impairs intestinal absorption. In addition, people with CF should be tested for diabetes mellitus because 30% of adults develop diabetes.23,33 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 chloride test, CFTR functional testing, and CFTR genetic analysis. The sweat test is performed by collecting the individual’s sweat, followed by chemical analysis of its chloride content. Sweat with a sodium and chloride content more than twice of normal is consistent with CF. The sweat test 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.34 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. Thus,

treatment measures are directed toward slowing the progression of secondary organ dysfunction and sequelae, such as chronic lung infection and pancreatic insufficiency. They include the use of oral and inhaled antibiotics to prevent and manage infections, bronchodilators, antiinflammatory medications, the use of chest physical therapy (chest percussion and postural drainage) and mucolytic agents to prevent airway obstruction, and nutritional therapy.35 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 WOB and perhaps because of the increased metabolic activity related to the basic defect. Progression of the disease is variable. Improved medical management has led to longer survival. Lung transplantation is being used as a treatment for people with end-stage lung disease. Pulmonary rehabilitation is also used in medical management of CF.35 Current hopes reside in research that would make gene therapy a feasible alternative for people with the disease. SUMMARY CONCEPTS 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. T2H cells respond to allergens by stimulating B cells to differentiate into IgEproducing 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.

Chronic Interstitial (Restrictive) Lung Diseases 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 dusts, gases, fumes, and asbestos; hypersensitivity pneumonitis; lung diseases caused by exposure to toxic drugs; and granulomatous disorders such as sarcoidosis (Chart 31-2). Some of the most common ILDs are caused by exposure to inhaled dust and particles, and in others, no specific cause can be found. CHART 31.2 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.

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.36 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.5 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 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 WOB 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 is

usually preserved, even though the ratio of FEV1.0 to FVC may increase. Although resting arterial blood gases are usually normal early in the course of the disease, arterial PO2 levels may fall during exercise. In a person with advanced disease, hypoxemia is often 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 are often used to follow the progress of the disease. A surgical lung biopsy specimen for histologic study and culture is the preferred diagnostic examination.36 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 are frequently 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 WOB 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 diseases. The pneumoconioses are caused by the inhalation of inorganic dusts and particulate matter. The hypersensitivity 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. Among the pneumoconioses are silicosis, found in hard rock 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 asbestos 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.37 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.37 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. 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 used in the 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.36 Amiodarone, a drug used to treat cardiac arrhythmias, is preferentially sequestered in the lung and can cause significant pneumonitis in individuals receiving more than 400 mg/day.36 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.37 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.36 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 the age of 10 and 40 years, although it can occur in older people. The incidence of sarcoidosis in the United States is approximately 10.9 per 100,000 person-years for whites and 35.5 per 100,000 person-years for blacks.36 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.36 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 unpredictable course of progression in which any organ system can be affected. Routine chest screenings detect 20% to 30% of pulmonary cases in asymptomatic people.36 The most commonly manifested symptoms occur in the lungs skin, eyes, and neurologic system. 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).36 Eye involvement (anterior uveitis) and skin involvement (skin papules and plaques) are particularly common extrathoracic manifestations. However, symptoms of sarcoidosis may affect any organ system, and there may be cardiac, neuromuscular, hematologic, hepatic, endocrine, or lymph node findings.36

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 immunologic function because there is an increase in ratio of CD4+ and CD8+ lymphocytes and increased proinflammatory cytokines.36 Although there is low risk of death or disability, the course of the disease varies. Approximately one third of people diagnosed with sarcoidosis have the progressive disease.36 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 as routine methods for diagnosis of sarcoidosis remains controversial.36 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. SUMMARY CONCEPTS 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 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 As blood moves through the pulmonary capillaries, oxygen 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. 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. 31-15), 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. When a pulmonary embolism occurs during the setting of a malignancy, the fatality rate is 25%.36

Pulmonary embolism. The main pulmonary artery and its bifurcation have been opened to reveal a large saddle embolus. (From Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 7–16, p. 308). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 31-15

Etiology and Pathogenesis Pulmonary emboli are thrombi that generally occur from deep vein thrombosis (DVT) in the lower and upper extremities.36 The presence of thrombosis in the deep veins of the legs or pelvis is often 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 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 a person prone to the development of venous thromboemboli.36 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. 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 moderate-sized 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 distended, and the skin is cyanotic and diaphoretic. Massive pulmonary emboli are often fatal. 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 electrocardiogram 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 because it is such an invasive procedure. Sometimes an embolectomy is performed during this procedure. 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 lifethreatening 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 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, is often used. Warfarin, an oral anticoagulation drug, may be used for people with a long-term risk for the 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 are also 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. The disorder may be due to changes in the arterial wall, often referred to as pulmonary arterial hypertension (PAH), 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 origin in the pulmonary arteries. The World Health Organization categorizes PAH into five groups related to their disease mechanism.38 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.38 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. 31-16). 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 the development of the disorder. Despite these achievements, PAH remains a serious, life-threatening condition.

Pulmonary artery hypertension. (A) A small pulmonary artery occluded by concentric intimal fibrosis and thickening of the media. (B) A plexiform lesion (arrow) is characterized by a glomeruloid proliferation of thin-walled vessels adjacent to a parent FIGURE 31-16

artery, which shows marked hypertensive changes of intimal fibrosis and medial thickening (curved arrows). (From Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 18-76, p. 733). Philadelphia, PA: Lippincott Williams & Wilkins.) 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.39 Other conditions associated with PAH include collagen vascular disorders (e.g., scleroderma), drugs and toxins, human immunodeficiency virus infection, portal hypertension, and persistent pulmonary hypertension in the newborn.38 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. 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. 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. 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. 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 may also develop at high altitudes in people with normal lungs. People who experience marked hypoxemia during 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. 31-17). Low-flow oxygen therapy may be used to reduce the pulmonary hypertension and polycythemia associated with severe hypoxemia caused by chronic lung disease.

FIGURE 31-17

Pathogenesis of cor pulmonale.

SUMMARY CONCEPTS 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 difference between the causes and manifestations of hypoxemic and hypercapnic/hypoxemic respiratory failure and 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 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 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. Acute Lung Injury/Acute Respiratory Distress Syndrome ARDS is the most severe form of ALI. The symptoms generally manifest with symptoms of diffuse crackles, dyspnea, cyanosis, tachypnea, tachycardia, and diaphoresis. The severity of lung dysfunction is evaluated by the PaO2/FiO2 ratio.40 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 31-3). CHART 31.3 CONDITIONS IN WHICH ARDS CAN DEVELOP*

Aspiration Near drowning Aspiration gastric contents Drugs, Toxins, and Therapeutic Agents Free-base cocaine smoking Heroin Inhaled gases (e.g., smoke, ammonia) Breathing high concentrations of oxygen Radiation Infections Septicemia Trauma and Shock Burns Fat embolism Chest trauma Disseminated Intravascular Coagulation Multiple blood transfusions *

This list is not intended to be inclusive.

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. 3118). 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.40 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 WOB becomes greatly increased as the lung stiffens and becomes more difficult to inflate. 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. 31-19).

The mechanism of lung changes in acute respiratory distress syndrome. 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. FIGURE 31-18

Pathophysiologic cascade is initiated by an injury resulting in 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. (2018). Critical care nursing: A holistic FIGURE 31-19

approach (11th ed., Fig. 27-2, p. 522). 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 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. 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 CNSs. Chest radiography shows diffuse bilateral infiltrates of the lung tissue in the absence of cardiac dysfunction. Treatment The treatment goals in ARDS are to (1) adequately oxygenate the lungs and vital organs; (2) recognize and treat underlying medical and surgical disorders; (3) prevent further lung injury and complications, including, but not limited to, venous thromboembolism, aspiration, nosocomial infections; and (4) ultimately decrease mortality.41 Assisted ventilation using high concentrations of oxygen may be required to correct the hypoxemia. 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 failure40 The classification should not be viewed as rigid because 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 gas diffusion. The causes of respiratory failure are summarized in Chart 31-4. CHART 31.4 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/ARDS *

This list is not intended to be inclusive.

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 is often 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 not only prevents hypercapnia but also increases the WOB.

The hypoxemia associated with ventilation–perfusion disorders is often exaggerated by conditions such as hypoventilation and decreased cardiac output. 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 is usually 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 occurs most commonly 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. Clinical Manifestations Acute respiratory failure is usually manifested by varying degrees of hypoxemia and hypercapnia. Respiratory failure is conventionally defined by an arterial PO2 of less than 50 mm Hg or 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 are often 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 semi-comatose. 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. SUMMARY CONCEPTS 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, 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? 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. 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 a person 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. REFERENCES 1. Boron W. F., Boulpaep E. L. (2017). Ventilation and perfusion of the lungs: Medical physiology (2nd ed., pp. 675.e1–699.e1). Philadelphia, PA: Elsevier, Inc. 2. West J. B. (2016). West’s pulmonary pathophysiology: The essentials (9th ed., pp. 3–44, 61–120). Philadelphia, PA: Wolters Kluwer. 3. Deacon A. J., Pratt O. W. (2017). Measurement of pulse oximetry, capnography and PH. Anesthesia and Intensive Care Medicine 18(12), 639–643. 4. Kim S. M., Kang S. W., Choi Y. C., et al. (2017). Successful extubation after weaning failure by noninvasive ventilation in patients with neuromuscular disease: Case series. Annals of Rehabilitation Medicine 41(3), 450–455. 5. Andreoli T., Benjamin I., Griggs R., et al. (Eds.). (2016). Disorders of the pleura, mediastinum, and chest wall. In Andreoli and Carpenter’s Cecil essentials of medicine (9th ed., pp. 248–253). St Louis, MO: Elsevier. 6. Kasper D. L., Fauci A. S. (2015). Disorders of the pleura. Harrison’s principles of internal medicine (19th ed., Ch 316). New York, NY: McGraw-Hill. 7. Sood A. (2015). Evaluation of respiratory impairment and disability. In Elias J. A., Fishman J. A., Kotloff R. M., et al. (Eds.), Fishman’s pulmonary diseases and disorders (5th ed., Ch 38). New York, NY: McGraw-Hill. Available: http://accessmedicine.mhmedical.com/content.aspx? bookid=1344§ionid=811880 8. Loannidis G., Lazaridis G, Baka S, et al. (2015). Barotrauma and pneumothorax. Journal of Thoracic Disease 7(Suppl 1), S38–S43. 9. Centers for Disease Control and Prevention. (2017). Asthma FASTSTATS 2017. Available: https://www.cdc.gov/nchs/fastats/asthma.htm. Accessed November 26, 2017. 10. National Heart Lung Blood Institute. (2017). National Asthma Education and Prevention Program (NAEP) NHLBI. Available: https://www.nhlbi.nih.gov/health-topics/asthma. Accessed December 12, 2017. 11. Barnes P. J. (2014). Asthma. In Kasper D., Fauci A., Hauser S., et al. (Eds.), Harrison’s principles of internal medicine (19th ed., Ch 309). New York, NY: McGraw-Hill. 12. Beigelman A., Bacharier L. B. (2016). Early life respiratory infections and asthma development: Role in disease pathogenesis and potential targets for disease prevention. Current Opinion in Allergy and Clinical Immunology 16(2), 172–178. doi:10.1097/ACI.0000000000000244 13. Gelfand E. W., Joetham A., Wang M., et al. (2017). Spectrum of T-lymphocyte activities regulating allergic lung inflammation. Immunological Reviews 278, 63–86. doi:10.1111/imr.12561

14. Kato A., Hulse K. E., Tan B. K., et al. B Lymphocyte lineage cells and the respiratory system. The Journal of Allergy and Clinical Immunology 131(4), 933–957. 15. Yang T., Li Y, Lyu Z, et al. (2017). Characteristics of proinflammatory cytokines and chemokines in airways of asthmatics: Relationships with disease severity and infiltration of inflammatory cells. Chinese Medical Journal 130(17), 2033–2040. 16. Meyer N., Woidacki K., Maurer M., et al. (2017). Safeguarding of fetal growth by mast cells and natural killer cells: Deficiency of one is counterbalanced by the other. Frontiers in Immunology 8, 711. 17. Kim H., Ellis A. K., Fischer D., et al. (2017). Asthma biomarkers in the age of biologics. Allergy, Asthma, and Clinical Immunology: Official Journal of the Canadian Society of Allergy and Clinical Immunology 13, 48. 18. Schauer S. G., Cuenca P. J., Johnson J. J., et al. (2013). Management of acute asthma in the emergency department. Emergency Medicine Practice 15(6), 1–28. 19. Hong C. C., Pajak A., Teitelbaum S. L., et al. (2014). Younger pubertal age is associated with allergy and other atopic conditions in girls. Pediatric Allergy and Immunology: Official publication of the European Society of Pediatric Allergy and Immunology 25(8), 773–780. 20. Keselman A., Heller N. (2015). Estrogen signaling modulates allergic inflammation and contributes to sex differences in asthma. Frontiers in Immunology 6, 568. 21. Kc P., Martin R. J. (2010). Role of central neurotransmission and chemoreception on airway control. Respiratory Physiology & Neurobiology 173(3), 213–222. 22. Lee E. J., Heo W., Kim J. Y., et al. (2017). Alteration of inflammatory mediators in the upper and lower airways under chronic intermittent hypoxia: Preliminary animal study. Mediators of Inflammation 2017, 4327237. 23. Loscalzo J. (2017). Chronic obstructive pulmonary disease. In Kasper D. L., Longo D. L., Fauci A. S., et al. (Eds.), Harrison’s pulmonary and critical care medicine (3rd ed., pp. 191–203). New York, NY: McGraw Hill. 24. Al-Alawi M., Hassan T., Chotirmall S. H. (2014). Advances in the diagnosis and management of asthma in older adults. The American Journal of Medicine 127(5), 370–378. Available: http://www.sciencedirect.com/science/article/pii/S0002934313011108. Accessed November 28, 2017. 25. Centers for Disease Control and Prevention. (2013). Asthma-related missed school days among children aged 5–17 years. Available: http://www.cdc.gov/asthma/asthma_stats/missing_days.htm. Accessed November 28, 2017. 26. Global Initiative for Asthma. (2017). Global strategy for asthma management and prevention (report). Available: https://ginasthma.org/wp-content/uploads/2019/04/wmsGINA-2017-mainreport-final_V2.pdf. Accessed November 27, 2017. 27. COPD Foundation. (2017). COPD Statistics across America. Available: http://www.copdfoundation.org/What-is-COPD/COPD-Facts/Statistics.aspx. Accessed November 28, 2017. 28. National Institutes of Health. (2017). COPD National action plan. Available: https://www.nhlbi.nih.gov/sites/default/files/media/docs/COPD%20National%20Action%20Plan %20508_0.pdf. Accessed May 24, 2019. 29. Global Initiative for Chronic Obstructive Lung Disease. (2018). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (2018 Report). Available: http://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20Nov_WMS.pdf. Accessed November 28, 2017. 30. Mejza F., Gnatiuc L., Buist A. S., et al. (2017). Prevalence and burden of chronic bronchitis symptoms: Results from the BOLD study. European Respiratory Journal 50(5). Available: https://www.ncbi.nlm.nih.gov/pubmed/20301692. Accessed May 24, 2017.

31. Cystic Fibrosis Foundation. (2017). About cystic fibrosis. Available: http://www.cff.org/AboutCF/. Accessed December 9, 2017. 32. U.S. National Library of Medicine. (2017). CFTR gene, cystic fibrosis transmembrane conductance regulator. Genetics home reference. Available: ghr.nlm.nih.gov/gene/CFTR#conditions. Accessed December 9, 2017. 33. Gemma V., Gemma M., Stephen M., et al. (2017). Diagnosis and management of cystic fibrosis: Summary of NICE guidance. British Medical Journal 359, j4574. 34. Farell P. M., White T. B., Ren C. L., et al. (2017). Diagnosis of cystic fibrosis: Consensus guidelines from the cystic fibrosis foundation. The Journal of Pediatrics 181, S4–S15. doi:10.1016/j.jpeds.2016.09.064. 35. National Institute of Health. (2013). How is cystic fibrosis treated? National Heart Lung and Blood Institute. Available: www.nhlbi.nih.gov/health/health-topics/topics/cf/treatment. Accessed December 10, 2017. 36. Jankowich M. D. (2016). Interstitial lung diseases. In Benjamin I. J., Griggs R. C., Wing E. J., et al. (Eds.), Andreoli and Carpenter’s Cecil essentials of medicine (9th ed., pp. 222–239). Philadelphia, PA: Saunders/Elsevier. 37. Kasper D. L., Fauci A. S. (2015). Occupational and environmental lung disease. In Kasper D. L., Longo D. L., Fauci A. S., et al. (Eds.), Harrison’s principles of internal medicine (19th ed.). New York, NY: McGraw Hill. 38. Kasper D. L., Fauci A. S. (2015). Pulmonary hypertension. In Harrison’s principles of internal medicine (19th ed.). New York, NY: McGraw Hill. 39. Girerd B., Lau E., Montani D., et al. (2017). Genetics of pulmonary hypertension in the clinic. Current Opinion in Pulmonary Medicine 23(5), 386–391. doi:10.1097/MCP.0000000000000414. 40. Selvakumar N., Casserly B., Rounds S. (2016). Essentials in critical care medicine. In Benjamin I. J., Griggs R. C., Wing E. J., et al. (Eds.), Andreoli and Carpenter’s: Cecil essentials of medicine (9th ed., pp. 259–265). Philadelphia, PA: Saunders/Elsevier. 41. Kasper D. L., Fauci A. S. (2015). Acute respiratory distress syndrome. In Kasper D. L., Longo D. L., Fauci A. S., et al. (Eds.), Harrison’s principles of internal medicine (19th ed.). New York, NY: McGraw Hill.

UNIT 10

Disorders of Renal Function

CHAPTER 32 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 Electrolytes 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 TESTS OF RENAL FUNCTION Urine Tests Glomerular Filtration Rate Blood Tests Serum Creatinine Blood Urea Nitrogen Cystoscopy and Ureteroscopy Ultrasonography Radiologic and Other Imaging Studies Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Describe the importance of maintaining adequate renal perfusion and the mechanisms for regulating renal blood flow. 2. Describe the structure and function of the nephron and the mechanisms through which renal regulation of extracellular fluid is accomplished. 3. Describe how the kidney produces concentrated or dilute urine. 4. Explain the value of urine specific gravity in evaluating renal function. 5. Explain the concept of the glomerular filtration rate. 6. Explain the value of serum creatinine and blood urea nitrogen levels in evaluating renal function.

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 the cardiac output, or 1100 mL/minute.1,2 A primary function of the kidney is to filter the blood to selectively reabsorb molecules needed for normal body function while excreting unneeded substances through the urine. The kidneys perform both excretory and endocrine functions to regulate the volume and composition of body fluids. This chapter focuses on the structure and function of the kidneys and tests of renal function.

Kidney Structure and Function Gross Structure and Location The kidneys are paired, bean-shaped organs that lie outside the peritoneal cavity in the posterior upper abdomen. One kidney lies on each side of the vertebral column at the level of the 12th thoracic to 3rd lumbar vertebrae (Fig. 32-1).1 The right kidney is typically situated lower than the left 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, where 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

Kidneys, ureters, and bladder. (The right kidney is usually lower than the left.) FIGURE 32-1

The kidney is a multilobular structure, composed of between 8 and 18 lobes.2 Each lobe is composed of nephrons, 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 needed substances back into the blood and secrete unneeded substances into the tubular filtrate that will become urine. On a longitudinal section, a kidney can be divided into an outer cortex and an inner medulla (Fig. 32-2). The cortex, which is

reddish brown, contains the glomeruli and convoluted tubules of the nephron and blood vessels. The medulla consists of light-colored, coneshaped masses—the renal pyramids. The columns of the cortex that extend into the medulla divide the renal pyramids. Each pyramid, topped by a region of the cortex, forms a lobe of the kidney. The apices of the pyramids form the papillae (with 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

FIGURE 32-2

Internal structure of the kidney.

The kidney is sheathed in a fibrous external capsule and surrounded by a mass of fatty connective tissue, particularly at the ends and borders. The adipose tissue protects the kidney from mechanical blows and assists the attached blood vessels and fascia to secure the kidney in place.3,4 Although

the kidneys are relatively well protected, they may be bruised by blows to the sides of the body or by compression between the lower ribs and the ileum. Because the kidneys are located outside the peritoneal cavity, injury does not produce the same threat of peritoneal involvement as with intraperitoneal organs, such as the liver or spleen. Renal Blood Supply A single renal artery arises on either side of the aorta to supply each kidney. As the renal artery approaches the kidney, it divides into five segmental arteries that enter the hilus. Inside 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. 32-3). These arteries branch into 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.5

Arterial supply of the kidney. (From Strayer D., Rubin E. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 904). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 32-3

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 can be 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.2 The Nephron The kidney has no ability to regenerate nephrons.2 Therefore, with aging, there is a generalized decrease in functioning nephrons.2 In fact, adults tend to lose approximately 10% of their nephrons for each decade beginning at 40 years of age.2 Each nephron consists of capillary structures (glomerulus and peritubular capillaries), a proximal convoluted tubule, a loop of Henle, a distal convoluted tubule, and a collecting duct. Blood is filtered in the glomerulus. In the other nephron structures, water, electrolytes, and substances needed to maintain the constancy of the internal environment are reabsorbed into the blood, whereas unneeded substances are secreted from the blood into the tubular filtrate for elimination (Fig. 32-4A).

(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. FIGURE 32-4

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. 32-4B). 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 the primary site of urine concentration.2 Two capillary systems supply the nephrons—the glomerulus and the peritubular capillary network (see Fig. 32-4A). The glomerulus is a unique, high-pressure capillary filtration system located between two arterioles, the afferent and the efferent arterioles. Because the arterioles are high-resistant

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. This elevated capillary hydrostatic pressure easily forces fluid and solutes out of the glomerular capillaries into the surrounding tubular structure, called the Bowman capsule.2 The peritubular capillaries originate from the efferent arteriole. They are low-pressure vessels that are adapted for reabsorption rather than filtration.2 These peritubular capillaries with low hydrostatic pressure surround all portions of the tubules, facilitating rapid reabsorption of water and solutes from the tubules to the blood. In the deepest part of the renal cortex, the efferent arterioles serving the juxtaglomerular nephron also continue into long, thin-walled looping vessels called the vasa recta.2 The vasa recta surround the long loops of Henle in the medullary portion of the kidney to facilitate exchange of substances in that portion of the nephron.2 The peritubular capillaries rejoin to form the venous channels through 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 vascular components (the glomerulus and peritubular capillaries) and tubular components. Fluid and solutes are filtered from the glomerular capillaries into the tubular structures, in which urine is formed for elimination from the body. In the tubular portion of the nephron, substances needed by the body are reabsorbed into the peritubular capillaries, whereas unneeded substances are secreted 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 into the efferent arteriole, which leads into the peritubular capillaries. Fluid and solutes 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. 32-5A).2

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. FIGURE 32-5

The glomerular capillary membrane is composed of three layers: 1. Capillary endothelial layer 2. Basement membrane 3. Single-celled capsular epithelial layer (see Fig. 32-5B) The endothelial layer lines the glomerulus and interfaces with blood moving through the capillary. This layer contains many small perforations called fenestrations,6 which allow movement of small molecular weight solutes out of the capillary lumen. The outer epithelial layer that covers the glomerulus is continuous with the epithelium that lines the 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 that lies between the capillary endothelium and the

outer epithelial layer (see Fig. 32-5B). These foot processes form slit pores through which the glomerular filtrate passes.6 The basement membrane consists of a homogeneous acellular meshwork of collagen fibers, glycoproteins, and mucopolysaccharides (see Fig. 325C). 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 act as pores of a filter to create a size-dependent permeability barrier for the glomerulus. The size of the pores in the basement membrane normally prevents red blood cells and plasma proteins from passing through the glomerulus into the filtrate. Evidence indicates that the epithelium plays a major role in producing the basement membrane components, with epithelial cells likely 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.6 In some areas, the capsular epithelium 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. 32-5B).6 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.6 The mesangial cells possess phagocytic properties and remove macromolecules that enter the intercapillary spaces. Mesangial cells also exhibit contractile properties in response to neurohumoral substances and are thought to 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.6 Tubular Components of the Nephron The nephron tubule is divided into four segments:

1. A highly coiled segment called the proximal convoluted tubule, which drains the 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 (or collecting duct), which joins with several tubules to collect the filtrate6 The filtrate passes through each of these segments before reaching the pelvis of the kidney. The proximal tubule 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.6 The distal convoluted tubule begins at the juxtaglomerular complex and is divided into two segments—the diluting segment and the late distal tubule. The late distal tubule fuses with the collecting tubule (or collecting duct). Like the distal tubule, the collecting duct is divided into two segments—the cortical collecting tubule and the inner medullary collecting tubule.6 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 are also 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.6 Urine Formation Urine formation involves (a) the filtration of blood through the glomerulus to form an ultrafiltrate of urine and (b) 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 the Bowman space. The movement of fluid through the glomerular capillaries is determined by the same factors

that facilitate fluid movement in all capillary beds: capillary hydrostatic pressure (filtration pressure), capillary colloidal osmotic pressure (reabsorptive pressure), and capillary permeability.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.6 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 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 renal blood flow (RBF), 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.2 Tubular Reabsorption and Secretion From the Bowman capsule, the glomerular filtrate moves into the tubular segments of the nephron. While moving through the lumen of the tubular segments, the chemical composition of glomerular filtrate is changed considerably by the tubular transport of water and solutes. Tubular transport can result in reabsorption of substances from the tubular filtrate into the peritubular capillaries or secretion of substances from the peritubular capillaries into the tubular filtrate2 (Fig. 32-6).

Reabsorption and secretion of substances between the renal tubules and peritubular capillaries. FIGURE 32-6

The basic mechanisms of transport across the tubular epithelial cell membrane are similar to those of other cell membranes in the body (including both active and passive transport mechanisms). Water and urea are passively absorbed along concentration gradients. Sodium (Na+), potassium (K+), chloride (Cl−), calcium (Ca2+), and phosphate ions, as well as urate, glucose, and amino acids, are reabsorbed across the tubular

epithelial cells and into the blood using primary or secondary active transport mechanisms. Some substances, such as hydrogen (H+), K+, and urate ions, are secreted from the blood, across the tubular epithelial cells, and into the tubular filtrate. Under normal conditions, only approximately 1 mL of the 125 mL of glomerular filtrate 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 adjacent to the interstitial fluid is called the basolateral membrane. The side in contact with the tubular lumen and tubular filtrate is called the luminal membrane.6 In most cases, substances move across the luminal membrane along a concentration gradient but require facilitated transport or active carrier systems to move across the basolateral membrane into the interstitial fluid, where the substances are absorbed into the peritubular capillaries. The bulk of energy used by the kidney supports active transport mechanisms that facilitate Na+ reabsorption with cotransport of other electrolytes and substances such as glucose and amino acids. This is called secondary active transport or cotransport (Fig. 32-7). 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 Na+ concentration that facilitates the downhill (i.e., from a higher to lower concentration) movement of Na+ 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 H+, are secreted into the tubule using countertransport, in which the movement of one substance, such as Na+, enables the movement of a second substance in the opposite direction.2

Mechanism for secondary active transport or cotransport of glucose and amino acids in the proximal tubule. The energydependent 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. ATP, adenosine triphosphate. FIGURE 32-7

Proximal Tubule Approximately 65% of all reabsorptive and secretory processes of the tubular system take place in the proximal tubule. Nutritionally, important substances (such as glucose, amino acids, lactate, and water-soluble vitamins) are almost completely reabsorbed, whereas electrolytes, such as Na+, K+, Cl−, and bicarbonate (HCO3−), are 65% to 80% reabsorbed2 (Fig. 32-8). As these solutes move into the tubular cells, their concentration in

the tubular lumen decreases, providing a concentration gradient for the osmotic reabsorption of water. 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

Sites of tubular water (H2O), glucose, amino acids, Na+ (sodium), Cl− (chloride), HCO3− (bicarbonate), K+ (potassium), Ca2+ (calcium), and Mg2+ (magnesium) reabsorption, and organic acids and bases, H+ (hydrogen), and K+ secretion. ADH, antidiuretic hormone. FIGURE 32-8

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 is usually sufficient to ensure that all of a filtered substance such as glucose can be reabsorbed rather than be 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. 32-6 and 32-8). 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, many of which 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 Na+ and Cl− than water. This is in contrast to the proximal tubule, which reabsorbs Na+ and water in equal proportions. The thin descending limb is highly permeable to water and moderately permeable to urea, Na+, 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 water as it enters the distal convoluted tubule, compared with the 285 mOsm/kg of water 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 to water. The thick segment contains a Na+/K+/2Cl− cotransport system6 (Fig. 32-9). 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 Na+, K+, and Cl− is reabsorbed in the thick loop of Henle. Movement of these ions out of the tubule leads to the development of a transmembrane potential that favors the passive reabsorption of small divalent cations such as Ca2+ and magnesium (Mg2+).6 The thick ascending loop of Henle is the site of action for the powerful “loop” diuretics (e.g., furosemide [Lasix]), which exert their action by inhibiting the Na+/K+/2Cl− cotransporters.7

Sodium, chloride, and potassium reabsorption in the thick segment of the loop of Henle. ATP, adenosine triphosphate. FIGURE 32-9

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. Reabsorption of Na+ 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 Ca2+ nor Mg2+ is passively absorbed in this segment of the tubule. Instead, Ca2+ ions are actively reabsorbed in a process that is largely regulated by parathyroid hormone and possibly by vitamin D.7 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.6 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 exits the tubular cell into the hyperosmotic interstitium of the medullary area, where it enters the peritubular capillaries for return to the vascular system.6 The late distal tubule and the cortical collecting tubule are the sites where aldosterone exerts its action on Na+ reabsorption and K+ secretion and elimination. Although responsible for only 2% to 5% of sodium chloride reabsorption, this site is largely responsible for determining the final Na+ concentration of the urine.2 When the body is confronted with a K+ excess, the amount of K+ secreted at this site may exceed the amount filtered in the glomerulus. The mechanism for Na+ reabsorption and K+ secretion in this section of the nephron is distinct from other tubular segments. This segment is composed of two types of cells, the intercalated cells, where K+ is reabsorbed and H+ is secreted, and the principal cells, where aldosterone exerts its action.6 The secretion of H+ into the tubular fluid by the intercalated cells is accompanied by the reabsorption of HCO3−. The intercalated cells can also reabsorb K+. The principal cells reabsorb Na+ and facilitate the movement of K+ into the urine filtrate (Fig. 32-10). Under the influence of aldosterone, Na+ moves from the urine filtrate into principal cells; from there, Na+ moves into the surrounding interstitial fluid and peritubular capillaries. At the same time, K+ moves in the opposite

direction, from the peritubular capillaries into the principal cells and then into the urine filtrate.6

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. ATPase, adenosine triphosphatase. FIGURE 32-10

Regulation of Urine Concentration

The kidney responds to changes in the osmolality of the extracellular fluid 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 in the interstitium of the kidney medulla and the action of ADH in regulating the water permeability of the surrounding medullary collecting tubules.6 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. 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.6 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 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 water.6 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 ADH, and (3) the action of ADH on the cells in the collecting tubules of the kidney.

1 Osmolarity.

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 collects in the interstitium surrounding the collecting tubules where the ADH-mediated reabsorption of water takes place.

2 Antidiuretic Hormone.

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.

3 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. 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 and extrinsic, 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 RBF. Intense sympathetic stimulation such as occurs in shock and trauma can produce marked decreases in RBF and GFR, even to the extent of causing blood flow to cease altogether. Consequently, urine output can fall almost to zero.2 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 RBF during everyday activities, endothelin 1 (ET-1) may play a role in reduction of blood flow in conditions such as postischemic acute renal failure.6 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 RBF and GFR under normal conditions, they may protect the kidneys against the vasoconstricting effects of sympathetic stimulation and angiotensin II.6

Nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthesis may cause reduction in RBF and GFR under certain conditions and should be used cautiously with people who have hypertension or kidney disease.8 Autoregulatory Mechanisms A process called autoregulation maintains the constancy of RBF. 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 GFR with RBF. 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. 32-11). 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 to angiotensin.2

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. GFR, glomerular FIGURE 32-11

filtration rate. (From Rennke H. G., Denker B. M. (2014). Renal pathophysiology: The essentials (4th ed., Fig. 1.9, p. 21). Philadelphia, PA: Lippincott Williams & Wilkins.) Renin functions by means of angiotensin II to produce vasoconstriction of the efferent arteriole to prevent 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. The renin–angiotensin– aldosterone (RAA) mechanism is illustrated in Figure 32-12.

Pathway of angiotensin production. (From Rennke H. G., Denker B. M. (2014). Renal pathophysiology: The essentials (4th ed., Fig. 2.6, p. 49). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 32-12

Because of its location between the afferent and efferent arterioles, the juxtaglomerular complex plays an essential role in linking RBF to both GFR and the composition of the distal tubular fluid. Specialized juxtaglomerular cells monitor the systemic arterial blood pressure by sensing the stretch of the afferent arteriole and also monitor 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 glomerular 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 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 Although relatively stable under most conditions, both RBF and GFR increase in response to conditions of increased dietary protein and increased blood glucose. Within 1 to 2 hours after ingestion of a high-protein meal, RBF 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 Na+ are absorbed together in the proximal tubule (by secondary active transport). As a result, delivery of Na+ to the macula densa is decreased, eliciting an increase in RBF through the juxtaglomerular complex feedback mechanism.2 The resultant increase in RBF and GFR allows Na+ 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 RBF and GFR that occur with high blood glucose levels in people with uncontrolled diabetes mellitus.2 Elimination Functions of the Kidney The primary functions of the kidney are 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.9 Regulation of Electrolytes Elimination of electrolytes, particularly Na+ and K+, is regulated by the GFR and by humoral agents that control their reabsorption. Aldosterone functions in the regulation of Na+ and K+ elimination. Reabsorption of Na+ in the distal tubule and collecting duct is highly variable and depends on the presence of aldosterone secretion 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 Free filtration of K+ also occurs at the glomerulus; however, K+ is reabsorbed from and secreted into the tubular fluid. The secretion of K+ into the tubular fluid occurs in the distal tubule and is also regulated by aldosterone. Only approximately 70 mEq of K+ is delivered to the distal tubule each day, but the average person consumes this much and more K+ in the diet. Excess K+ 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 filtrate) for elimination from the body.2 In the absence of aldosterone, as in Addison disease, K+ secretion becomes minimal. In these circumstances, K+ reabsorption exceeds secretion, and blood levels of K+ increase. Also contributing to the excretion of Na+ and water by the kidney are the natriuretic peptides, a group of peptides secreted by the heart in response to the stretch of cardiac muscle fibers. The primary renal effect of this group

of chemicals is to increase the renal excretion of sodium (natriuresis), with a resultant osmotic increase in the excretion of water. This loss of sodium and water leads to a reduction in cardiac preload, which creates a negative feedback loop to decrease cardiac muscle stretch.2 Atrial muscle cells release atrial natriuretic peptide (ANP) in response to muscle stretch. The primary effect of ANP is to inhibit sodium and water reabsorption, with action predominant in the collecting ducts. ANP also acts to disrupt the RAA cascade by inhibiting the renal secretion of renin. This disruption of the RAA cascade thus further decreases the reabsorption of sodium and water by the renal tubules.2 Regulation of pH The kidneys regulate body pH by conserving HCO3− and eliminating H+. Most H+ excreted in the urine is because of tubular secretory mechanisms. The lowest tubular fluid pH that can be achieved is 4.4 to 4.5.10,11 The ability of the kidneys to excrete H+ depends on buffers in the urine that combine with the H+. The three major urine buffers are bicarbonate (HCO3−), phosphate, and ammonia. The combination of HCO3− and H+ in the renal tubule results in the formation of carbonic acid, which then dissociates into carbon dioxide and water. The carbon dioxide is then absorbed into the tubular cells, and HCO3− is regenerated inside the tubule cells through the action of the enzyme carbonic anhydrase. In the second renal buffering system, phosphate ions (which are produced by cells as end products of metabolic processes) join with H+ in the renal tubules and then the resultant compound is eliminated in the urine. In the third renal buffering system, ammonia is synthesized in tubular cells by deamination of the amino acid glutamine (which is produced by the liver during amino acid metabolism and then transported to the kidneys). Ammonia diffuses into the tubular fluid, where it combines with H+, and the compound molecule is eliminated through the urine.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 water and substances, particularly the electrolytes Na+, K+, H+, Cl−, and HCO3−. The kidney regulates the osmolality of the extracellular fluid through the action of ADH. The kidney plays a central role in blood pressure regulation through the influences of the RAA and ANP mechanisms on Na+ 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 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 anions. Uric Acid Elimination Uric acid (an organic anion) is a product of purine metabolism. Excessively high blood levels (i.e., hyperuricemia) can cause gout, and high levels of uric acid in the urine can cause kidney stones. Uric acid is freely filtered in the glomerulus and is reabsorbed and secreted in the proximal tubules.5 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 those with normal uric acid levels.5 Urea Elimination

Urea is formed in the liver as a by-product of protein metabolism and is eliminated entirely by the kidneys. Healthy adults produce urea in the range of 25 to 30 g/day. Blood urea levels rise with a high-protein diet, excessive tissue breakdown, or gastrointestinal bleeding.2 In gastrointestinal bleeding, the intestinal flora breaks down the blood to form ammonia, which is then absorbed into the portal venous circulation and transported to the liver, where it is converted to urea before being released into the bloodstream. The kidneys then regulate blood urea nitrogen (BUN) levels, maintaining a normal BUN 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, causing BUN levels to increase. This rise in BUN occurs because when GFR is reduced, the filtrate moves more slowly through the tubules, allowing more time for urea resorption. In contrast, when the GFR is high, only small amounts of urea are reabsorbed into the blood.2 Drug Elimination Many drugs are eliminated in the urine. Only drugs that are not bound to plasma proteins are filtered in the glomerulus and, therefore, able to be eliminated by the kidneys.7 Because uric acid competes for the same anion transport systems as some drugs (such as aspirin, sulfinpyrazone, and probenecid), these drugs can affect the blood levels of uric acid and, therefore, may not be indicated for use in person with gout. Thiazide and loop diuretics (i.e., furosemide and ethacrynic acid) can also cause hyperuricemia and gout, presumably through a decrease in extracellular fluid volume and enhanced uric acid reabsorption.6 Endocrine Functions of the Kidney In addition to regulating body fluids and electrolytes, the kidneys function as an endocrine organ by producing chemical mediators that travel through the blood to distant sites where they exert their actions. Endocrine functions of the kidneys include: Assisting with blood pressure regulation through the RAA mechanism Regulation of red blood cell production through the synthesis of erythropoietin Assisting with calcium homeostasis by activating vitamin D

The Renin–Angiotensin–Aldosterone Mechanism As introduced earlier, the RAA mechanism plays an important part in shortand 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 RBF 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 longer term 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 glycoprotein hormone that is produced by fibroblasts in the renal interstitium and regulates the production of red blood cells in the bone marrow. 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 because of cardiac or pulmonary disease. Person with end-stage kidney disease is often anemic because of an inability of the kidneys to produce erythropoietin. This anemia is usually managed by the administration of a recombinant erythropoietin (epoetin alfa) produced through DNA technology to stimulate erythropoiesis.12 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 the 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 is often considered 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 1,25dihydroxycholecalciferol 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.6 SUMMARY CONCEPTS 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 RAA mechanism and control of extracellular fluid volume), regulate red blood cell production through erythropoietin production, 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, whereas 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 vascular 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 RBF in the normally functioning kidney. The juxtaglomerular complex is thought to represent a feedback control system that links changes in the GFR with RBF. 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.

Tests of 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 provide 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. Firstvoided morning specimens are useful for qualitative protein and specific gravity testing. A freshly voided specimen is the most reliable. Urine specimens that have been left standing may contain lysed red blood cells, disintegrating casts, and rapidly multiplying bacteria.9 Table 32-1 describes urinalysis values for normal urine. TABLE 32-1 Normal Values for Routine Urinalysis

Microscopic Chemical Examination of Determinations Sediment Glucose: negative Ketones: negative Color: yellow amber Casts negative: Blood: negative Appearance: clear to slightly occasional hyaline casts Protein: hazy Red blood cells: negative negative Specific gravity: 1.005–1.025 or rare Bilirubin: with a normal fluid intake Crystals: negative (none) negative pH: 4.5–8.0; average person has White blood cells: Urobilinogen: a pH of about 5–6 negative or rare 0.5–4.0 mg/day Volume: 600–2500 mL/24 hour; Epithelial cells: few; Nitrate for average volume is 1200 mL/24 hyaline casts 0–1/1pf bacteria: hour (low-power field) negative Leukocyte esterase: negative From Fischbach F., Dunning M. (2014). A manual of laboratory and diagnostic tests (9th ed., p. 192). Philadelphia, PA: Lippincott Williams & Wilkins. General Characteristics and Measurements

Casts are molds of the distal nephron lumen. A gel-like substance called Tamm–Horsfall mucoprotein, which is formed in the tubular epithelium, is the major protein constituent of urinary casts.6 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.6 Proteinuria is 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.9 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).9 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. With a normal fluid intake, the usual range of urine specific gravity is 1.010 to 1.025. 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 concentrating ability, and the urine specific gravity may fall to levels of 1.006 to 1.010.9 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.9 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 urine-to-serum ratio is seen in concentrated urine. With poor concentrating ability, the ratio is low.9 Glomerular Filtration Rate The GFR can be measured clinically by collecting timed samples of blood and urine. Creatinine is produced by muscles as a product of the metabolism of a molecule called creatine. The formation and release of creatinine 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 comparison of creatinine levels in the blood and urine can provide a useful measure of 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, where 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).9 Normal creatinine clearance is 115 to 125 mL/minute.9 This value is corrected for body surface area, which reflects the muscle mass where creatinine production takes place. The test may be done on a 24-hour basis, with a blood creatinine level drawn at the completion of a 24-hour urine collection. In another method, two 1-hour urine specimens are collected, with a blood sample drawn in between.9 Although the creatinine clearance test is the traditional method of measuring GFR, most labs are now reporting a calculated “estimated GFR” (or eGFR) as part of various metabolic panels. The eGFR estimates the GFR using a measured plasma creatinine in a mathematical formula accounting for additional factors such as age, sex, and race.12 Creatinine, which is a waste product of muscle metabolism, is filtered at the glomerulus, which allows serum creatinine levels to provide a good reflection of GFR. However, because creatinine is a molecule produced in the muscle and because muscle mass varies widely among different populations, creatinine levels can be less accurate as a GFR predictor among certain populations. Creatinine levels tend to increase among person with increased levels of physical activity, higher muscle mass, and diets higher in meat and in person with better health status.13 Additional biologic measures are being introduced into clinical practice to provide better assessment of GFR. The serum protein cystatin C has been demonstrated to serve as a useful marker of GFR because it is also filtered at the glomerulus but has a stable production rate across populations. An estimating equation for GFR that combines the effects of creatinine and cystatin C has been developed and demonstrated to perform better than eGFR equations based on either creatinine or cystatin C alone.14 Blood Tests Blood tests can provide valuable information about the kidneys’ ability to remove metabolic wastes and maintain normal electrolyte and pH composition of the blood. Normal blood values are listed in Table 32-2.

Serum levels of K+, phosphate, BUN, and creatinine increase in renal failure, whereas serum pH, Ca2+, and HCO3− levels decrease in renal failure.2 TABLE 32-2 Normal Blood Chemistry Levels

Substance BUN Creatinine Sodium Chloride Potassium Carbon dioxide (CO2 content) Calcium Phosphate Uric acid Male Female pH

Normal Value* 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. BUN, blood urea nitrogen. Serum Creatinine The normal creatinine value is approximately 0.7 mg/dL for a woman with a small frame, approximately 1.0 mg/dL for a normal adult man, and approximately 1.5 mg/dL (60 to 130 mmol/L) for a muscular man.9 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. 32-13). 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.9

Relation between the percentage of renal function and serum creatinine levels. FIGURE 32-13

Blood Urea Nitrogen Urea is an end product of protein metabolism, with blood levels regulated by the kidneys. BUN levels are, therefore, related to the GFR; however, unlike creatinine, BUN is also influenced by protein intake, gastrointestinal bleeding, and hydration status (see earlier discussion of urea elimination for specific mechanisms). Approximately two thirds of renal function must be lost before a significant rise in the BUN level occurs.9 Although BUN levels are less specific for renal insufficiency than plasma creatinine levels, the BUN-to-creatinine ratio provides useful diagnostic information. The ratio is normally 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 situations such as liver disease, low-protein diet, or chronic dialysis (because BUN is more readily dialyzable than creatinine).9

Cystoscopy and Ureteroscopy Cystoscopy is the visualization of the bladder by the insertion of an instrument called a cystoscope through the urethra into the bladder. Cystoscopy provides a means for direct visualization of the urethra, bladder, and ureteral insertion sites. Biopsy specimens, lesions, small stones, and foreign bodies can be removed from the bladder via the cystoscope. Ureteroscopy involves the use of a smaller, thinner scope that may be used to remove stones from the ureter and aid in the treatment of ureteral disorders, such as ureteral strictures.15 Ultrasonography 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.9 Radiologic and Other Imaging Studies Radiologic studies of the kidneys, ureters, and bladder can be used to determine the size, shape, and position of the kidneys and to 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.9 Urography is used to detect space-occupying lesions of the kidneys, pyelonephritis, hydronephrosis, vesicoureteral reflux, and kidney stones.9 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 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 is subsequently detected externally by a scintillation camera, which detects the radioactive emissions. Radionuclide

imaging is used to evaluate renal function and the structural integrity of the kidneys and urinary tract. 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 through the injection of a radiopaque dye directly into the renal artery.9 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. SUMMARY CONCEPTS 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 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, is also influenced by protein intake, gastrointestinal bleeding, and hydration status. Cystoscopic and ureteroscopic 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 to examine kidney structures such as the renal calyces, pelvis, ureters, and bladder. 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 32-5 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 person with diabetes. Explain the physiologic rationale for these two types of treatments. 2. 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. REFERENCES 1. Ross M., Pawlina W. (2015). Histology: A text and atlas with correlated cell and molecular biology (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2. Hall J. E. (2015). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Elsevier Saunders. 3. Saladin K. S. (2015). Anatomy & physiology: The unity of form and function (7th ed.). New York, NY: McGraw Hill. 4. McCance K. L., Huether S. E. (2014). Pathophysiology: The biologic basis of disease in adults and children (7th ed.). St. Louis, MO: Mosby Elsevier. 5. Rubin R., Strayer D. S. (Eds.). (2014). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins.

6. Boron W. F., Boulpaep E. L. (2016). Medical physiology (3rd ed.). St. Louis, MO: Saunders Elsevier. 7. Lehne R. A. (2016). Pharmacology for nursing care (9th ed.). St. Louis, MO: Elsevier. 8. Pham P. C., Khaing K., Sievers T. M., et al. (2017). 2017 updated on pain management in patients with chronic kidney diseases. Clinical Kidney Journal 10(5), 688–697. 9. Fischbach F., Dunning M. (2014). A manual of laboratory and diagnostic tests (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 10. Rennke H. G., Denker B. M. (2014). Renal pathophysiology: The essentials (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 11. Zeisberg M., Kalluri R. (2015). Physiology of the renal interstitium. Clinical Journal of the American Society of Nephrology 10(10), 1831–1840. 12. American Association for Clinical Chemistry. (2016). Estimated glomerular filtration rate (eGFR). [Online]. Available: https://labtestsonline.org/understanding/analytes/gfr/tab/glance. Accessed May 23, 2019. 13. Shilpak M. G., Mattes M. D., Peralta C. A. (2013). Update on cystatin C: Incorporation into clinical practice. American Journal of Kidney Disease 62(3), 595–603. 14. Karger A. B., Inker L. A., Coresh J., et al. (2017). Novel filtration markers for GFR estimation. Journal of the International Federation of Clinical Chemistry and Laboratory Medicine 28(4), 277–288. 15. NIH National Institute of Diabetes and Digestive and Kidney Diseases. (2015). Cystoscopy and ureteroscopy. [Online]. Available: https://www.niddk.nih.gov/health-information/diagnostictests/cystoscopy-ureteroscopy. Accessed May 23, 2019.

CHAPTER 33 Disorders of Renal Function Congenital and Inherited Disorders of the Kidneys Congenital Disorders of the Kidneys Agenesis and Hypoplasia Renal Dysplasia Alterations in Kidney Position and Form Inherited Cystic Kidney Diseases Autosomal Dominant Polycystic Kidney Disease Autosomal Recessive Polycystic Kidney Disease Nephronophthisis–Medullary Cystic Disease Complex Simple and Acquired Renal Cysts Obstructive Disorders Mechanisms of Renal Damage Hydronephrosis Clinical Manifestations Diagnosis and Treatment Renal Calculi Etiology and Pathogenesis Types of Stones Clinical Manifestations Diagnosis and Treatment

Urinary Tract Infections Etiology and Pathogenesis Host–Agent Interactions Obstruction and Reflux Catheter-Induced Infection Clinical Manifestations Diagnosis and Treatment Infections in Special Populations Urinary Tract Infections in Pregnant Women Urinary Tract Infections in Children Urinary Tract Infections in Older Adults Disorders of Glomerular Function Etiology and Pathogenesis of Glomerular Injury Types of Glomerular Disease Acute Nephritic Syndrome Rapidly Progressive Glomerulonephritis Nephrotic Syndrome Asymptomatic Hematuria or Proteinuria Alport Syndrome Chronic Glomerulonephritis Glomerular Lesions Associated with Systemic Disease Systemic Lupus Erythematosus Glomerulonephritis Diabetic Glomerulosclerosis Hypertensive Glomerular Disease Tubulointerstitial Disorders Renal Tubular Acidosis Proximal Renal Tubular Acidosis Distal Renal Tubular Acidosis Pyelonephritis Acute Pyelonephritis Chronic Pyelonephritis Drug-Related Nephropathies Malignant Tumors of the Kidney Wilms Tumor Renal Cell Carcinoma

Etiology and Pathogenesis Clinical Manifestations Diagnosis and Treatment Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Define the terms agenesis, hypoplasia, and dysgenesis, and discuss them as they refer to the development of the kidney. 2. Describe the inheritance, pathology, and manifestations of the different types of polycystic kidney disease. 3. List four common causes of urinary tract obstruction. 4. Define the term hydronephrosis and relate it to the destructive effects of urinary tract obstruction. 5. Describe the role of urine supersaturation, nucleation, and inhibitors of stone formation in the development of kidney stones. 6. List three physiologic mechanisms that protect against urinary tract infections (UTIs). 7. Describe factors that predispose to UTIs in children, sexually active women, pregnant women, and older adults. 8. Cite measures used in the diagnosis and treatment of UTIs. 9. Describe the two types of immune mechanisms involved in glomerular disorders. 10. Use the terms proliferation, sclerosis, membranous, diffuse, focal, segmental, and mesangial to explain changes in glomerular structure that occur with glomerulonephritis. 11. Differentiate among the nephritic syndromes, rapidly progressive glomerulonephritis, nephrotic syndrome, asymptomatic glomerular disorders, and chronic glomerulonephritis. 12. Contrast the defects in tubular function that occur in proximal and distal tubular acidosis. 13. Explain the pathogenesis of kidney damage in acute and chronic pyelonephritis. 14. Characterize Wilms tumor in terms of age of onset, possible oncogenic origin, manifestations, and treatment.

15. Cite the risk factors for renal cell carcinoma, describe its manifestations, and explain why the 5-year survival rate has been so low.

Kidney disease is a frequent cause of health care utilization and missed work among both men and women. Approximately 30 million people in the United States have chronic kidney disease, yet majority of them have mild disease and remain unaware.1 Kidney stones account for about 2.1 million annual emergency department (ED) visits in the United States,2 whereas urinary tract infections (UTIs) account for about 1 million ED visits and 7 million office visits.3 Although many forms of kidney disease originate in the kidneys, other forms develop secondary to the disorders, such as hypertension, diabetes mellitus, and systemic lupus erythematosus (SLE). The content in this chapter focuses on congenital disorders of the kidneys, obstructive disorders, UTIs, disorders of glomerular function, tubulointerstitial disorders, and neoplasms of the kidneys.

Congenital and Inherited Disorders of the Kidneys Congenital Disorders of the Kidneys The kidneys begin to develop early and begin producing urine by week 13 of gestation.4 Fetal urine is excreted into the amniotic cavity and is the main constituent of amniotic fluid. Thus, the relative amount of amniotic fluid can provide information about the status of fetal renal function. In pregnancies that involve infants with nonfunctional kidneys or outflow obstruction of urine from the kidneys, the amount of amniotic fluid is small. This condition is called oligohydramnios.5 Anomalies in shape and position are the most common congenital kidney problems. Less common are disorders involving a decrease in renal mass or a change in renal structure. The kidneys can be visualized as early as 12 weeks’ gestation by ultrasonography, allowing many fetal urinary abnormalities to be detected before birth.5,6 Congenital abnormalities represent up to 50% of pediatric and 7% of adult end-stage renal disease. It

is now recognized that single-gene mutations with high penetrance rates play a major role than previously recognized in these abnormalities.7 Agenesis and Hypoplasia Newborns with bilateral renal agenesis—a rare condition in which the kidney fails to develop at all—are stillborn or live for only a few hours.4,8 Unilateral renal agenesis occurs in about 1 of 1000 to 2000 newborn infants. Boys are affected more often than girls.4 Detection of unilateral agenesis may be delayed because the healthy kidney usually undergoes compensatory hypertrophy and performs the function of the missing kidney. Newborns with renal agenesis often have characteristic facial features, previously called Potter syndrome, resulting from the effects of oligohydramnios.4 Without the amniotic fluid to protect and cushion, the uterus may compress the developing fetus. The eyes are widely separated and have epicanthic folds, the ears are low set, the nose is beaklike, the chin is receding, and limb defects are often present.5 In renal hypoplasia, the kidneys do not develop to normal size and contain fewer renal lobes. Like agenesis, hypoplasia more commonly affects only one kidney. When both kidneys are affected, renal failure progressively develops. In some cases, although the number of nephrons is reduced, the nephrons enlarge in size as the kidneys work harder to compensate, thus increasing the risk for glomerular disease.5 The prevalence of renal hypoplasia is unknown because it is often an incidental finding and small kidneys may also result from atrophy and scarring.6 Renal Dysplasia Renal dysplasia is caused by an abnormality in the differentiation of kidney structures during embryonic development. It is characterized by undifferentiated tubular structures surrounded by primitive embryonic tissue and may contain smooth muscle and cartilage.5 Noncommunicating cysts of varying size may replace normal renal parenchyma. This occurs in approximately 1 of 4300 pregnancies.6 When cysts are present, the condition is referred to as cystic dysplasia. One or both kidneys may be involved, and the affected kidney may be abnormally large or abnormally small. Many forms of dysplasia are accompanied by other urinary tract abnormalities, especially disorders that cause obstruction to urine flow.

A multicystic kidney is one in which the kidney is replaced by cysts and does not function. The kidney does not have the usual kidney shape, but is rather a mass of cysts. The finding of an abdominal mass in newborns is commonly caused by unilateral multicystic renal dysplasia.5 The function of the opposite kidney is usually normal, and these children have an excellent prognosis after surgical removal of the affected kidney. Bilateral renal dysplasia causes oligohydramnios, leading to Potter facies, pulmonary hypoplasia, and renal failure. Alterations in Kidney Position and Form The development of the kidneys during embryonic life can result in ectopic kidneys that lie outside their normal position. One or both kidneys may be in an abnormal position. An ectopic kidney may be located within the pelvic cavity on the same or opposite side of its ureter or it may be located within the margins of the iliac crest or in the abdominal or chest cavities.6 Because of the abnormal position, kinking of the ureters and obstruction of urinary flow may occur. The most common alterations in kidney form—occurring in approximately 1 of every 500 births—is an abnormality called a horseshoe kidney.6 In this disorder, the upper or lower poles of the two kidneys are fused, producing a horseshoe-shaped structure that is continuous along the midline of the body anterior to the great vessels. Most horseshoe kidneys are fused at the lower pole (Fig. 33-1). The condition usually does not cause problems unless there is an associated defect in the renal pelvis or other urinary structures that obstructs urinary flow.

Horseshoe kidney. The kidneys are fused at the lower poles. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 907, Fig. 22-7). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-1

Inherited Cystic Kidney Diseases The inherited cystic kidney diseases are single-gene disorders transmitted through Mendelian patterns and include autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) as well as nephronophthisis (NPHP)–medullary cystic disease. Polycystic kidney diseases are a group of kidney disorders characterized by fluid-filled sacs or segments that have their origins in the tubular structures of the kidney. The cysts may be single or multiple and can vary in size from microscopic to several centimeters in diameter. Although they may arise as

a developmental abnormality or be acquired later in life, most forms are hereditary. In ADPKD, thousands of large cysts are derived from every segment of the nephron (Fig. 33-2).5 The tubule wall (which is lined by a single layer of tubular cells) expands and then rapidly closes the cyst off from the tubule of origin. In ARPKD, small, elongated cysts form in the collecting ducts and maintain contact with the nephron of origin (see Fig. 33-2).5 In acquired cystic disease, simple cysts develop in the kidney as a consequence of aging, dialysis, or other conditions that affect tubular function.

Polycystic kidney diseases. Polycystic kidney diseases include five kidney disorders with fluid-filled segments originating in the tubular structures of the kidney. (From Strayer D. S., Rubin E. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 909, Fig. 22-10). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-2

Autosomal Dominant Polycystic Kidney Disease ADPKD, also known as adult polycystic disease, is the most common hereditary form of renal cystic disease.5 ADPKD results in the formation of destructive fluid-filled cysts in the kidney and other organs. This inherited disorder is the fourth leading cause of end-stage renal disease in the United States. Adoption of consistent standards to define ADPKD provides the basis for accurate reporting to registries and evaluation of future interventions.9 These standards take into account factors beyond a stable glomerular filtration rate (GFR); they also include total kidney volume (TKV) to measure cyst expansion and development. The disease accounts for 5% of all cases of chronic kidney disease that require dialysis or transplantation.5 Emerging research on cases of ADPKD demonstrate mutations in the GANAB gene as well as the PKD1 and PKD2 genes.5,10 The products of these genes, polycystin-1 and polycystin-2, are found in the primary cilia that line the apical surface of the tubular epithelium. These primary cilia are thought to act as sensors of urinary flow and as signal transducers for tubular cell proliferation, differentiation, and apoptosis.5 The GANAB gene,

which codes for glucosidase, causes a mild form of disease accompanied by polycystic liver disease.10 Etiology and Pathogenesis Although the pathogenesis of ADPKD is not clear, it is thought that the cysts arise in segments of the renal tubules from a few epithelial cells.5 The epithelial cells lining the cysts of ADPKD have a high proliferation rate and are relatively undifferentiated. Concomitantly, a defective basement membrane immediately underlying the abnormal epithelium allows for dilation and cyst formation. Cysts frequently detach from the tubule and grow by active fluid secretion from the epithelial lining cells. Cysts arise in less than 2% of nephrons and that factors other than compression by the expanding cysts account for loss of functioning renal tissue.5 Apoptotic loss of renal tubular cells and accumulation of inflammatory mediators are now thought to contribute to the destruction of normal kidney tissue. Mutations in the PKD1 and PKD2 genes produce identical renal and extrarenal disease, but disease progression is typically more rapid in people with type I disease.5 Clinical Manifestations Typically, the progress of the kidney disease is slow, and end-stage renal failure (ESRF) is uncommon for adults before 40 years of age. Initially, the person with renal cysts is generally asymptomatic, with normal kidney and liver function. As the kidney disease progresses, the manifestations of ADPKD include pain from the enlarging cysts that may reach unbearable levels, episodes of gross hematuria from bleeding into a cyst, infected cysts from ascending UTIs, and hypertension resulting from compression of intrarenal blood vessels with activation of the renin–angiotensin mechanism. The kidneys are usually enlarged in people with ADPKD and may achieve enormous sizes (Fig. 33-3).5 The external contours of the kidneys are distorted by numerous cysts, some as large as 5 cm in diameter, which are filled with straw-colored fluid.5 Cysts also may be found in the liver and, less commonly, in the pancreas and spleen.

(A) Autosomal dominant polycystic disease. The kidneys are enlarged and studded with multiple fluid-filled structures (left). The parenchyma is almost entirely replaced by cysts of varying size (right). (B) Autosomal recessive polycystic kidney disease. The dilated cortical and medullary collecting ducts are arranged radially, and the external surface is smooth. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 909, Figs. 22-11 and 22-12). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-3

As the disease continues to progress, extrarenal manifestations such as aneurysms are frequent, underscoring the systemic nature of the disease. Approximately 10% of people with polycystic kidney disease have an associated intracranial aneurysm, and subarachnoid or intracerebral hemorrhages are the most serious complications, which may lead to death.11 Screening these people for intracranial aneurysm is particularly important when family history of hemorrhagic stroke or intracranial aneurysms exists.11 Diagnosis and Treatment Serum creatinine levels have not been found to be an effective predictor marker for worsening ADPKD, but TKV in relation to age is a reliable predictor of increasing cyst burden. Increased TKV is associated with hematuria, proteinuria, and decreased kidney function.12 Ultrasonography usually is the preferred technique for diagnosis of ADPKD in symptomatic people and for screening of asymptomatic family members. Computed

tomography (CT) may be used for detection of small cysts. Genetic linkage studies are used for diagnosis of ADPKD, but are usually reserved for cases in which radiographic imaging is negative and the need for a definitive diagnosis is essential, such as when screening family members for potential kidney donation. The treatment of ADPKD has been largely supportive, including treatment to control hypertension and modify lifestyle, as well as targeted prevention of complications through screening (e.g., cerebral aneurysm). Lifestyle interventions include following a low-sodium diet, drinking adequate fluids (2 to 3 L/day), and avoiding smoking and agents such as nonsteroidal anti-inflammatory agents, which can be nephrotoxic.13 Identification of drugs to delay progression of disease has failed until recently. Control of hypertension and prevention of ascending UTIs are important. Pain is a common complaint of people with ADPKD. A stepwise approach has been proposed to explore the underlying cause of pain. Pain management begins with nonpharmacologic approaches and can escalate to include complex invasive therapies.14 Dialysis and kidney transplantation are reserved for those who progress to kidney failure. However, it is important to note that prolonged dialysis will increase cyst formation even in people without ADPKD.5 Autosomal Recessive Polycystic Kidney Disease ARPKD is characterized by cystic dilation of the cortical and medullary collecting tubules. As shown in Figure 33-2, the surface of the kidney is generally smooth.5 It is rare in comparison with the autosomal dominant form. There is one case of ARPKD for about every 20,000 live births.15 ARPKD is caused by mutations in the PKHD1 gene. The gene product, fibrocystin, is found in the kidney, liver, and pancreas and appears to be involved in the regulation of cell proliferation and adhesion.5 Clinical Manifestations The typical infant with ARPKD presents with bilateral flank masses, accompanied by severe renal failure. The very large size of the kidneys restricts lung development and function. There are also varying degrees of liver fibrosis and portal hypertension.5,16 Potter facies and other defects associated with oligohydramnios may be present. Hypertension is usually

noted within the first few weeks of life and is often severe. Death during the perinatal period often results from pulmonary hypoplasia.5 Exceptional cases of ARPKD manifest in older children and adults. Treatment The treatment of ARPKD is largely supportive. Aggressive ventilatory support is often necessary in the neonatal period because of pulmonary hypoplasia and hypoventilation. Modern neonatal respiratory techniques and renal replacement therapy have increased the 10-year survival rate of children surviving beyond the first year of life. Morbidity and mortality in older children are related to complications from chronic renal failure and liver disease. Nephronophthisis–Medullary Cystic Disease Complex The NPHP–medullary cystic disease complex is a group of renal disorders that have their onset in childhood. Common characteristics of this ARPKD are small, shrunken kidneys and the presence of a variable number of cysts, usually concentrated at the corticomedullary junction.17 The initial insult involves the distal tubules, with tubular basement membrane disruption followed by chronic and progressive tubular atrophy involving both the medulla and cortex. Although the presence of medullary cysts is important, the cortical and tubular damage is the eventual cause of chronic kidney disease and failure.17 NPHP is a progressive form that typically advances to end-stage renal disease prior to adulthood.18 Affected children present first with polyuria, polydipsia, and enuresis, which reflect impaired ability of the kidneys to concentrate urine. Other manifestations of the disorders include salt wasting, growth retardation, anemia, and progressive renal insufficiency. The mean age of onset is specific to each of the three clinical variants (infantile, juvenile, and adolescent). Extrarenal complications may occur, including skeletal defects, ocular motor abnormalities, retinitis pigmentosa, liver fibrosis, cardiac septal and valve defects, and cerebellar abnormalities.18 Simple and Acquired Renal Cysts

Simple cysts are a common disorder of the kidney. The cysts may be single or multiple, unilateral or bilateral, and they usually are less than 1 cm in diameter, although they may grow larger. Most simple cysts do not produce signs or symptoms or compromise renal function. When symptomatic, the cysts may cause flank pain, hematuria, infection, and hypertension related to ischemia-produced stimulation of the renin–angiotensin system. They are most common in older adults. Although the cysts are benign, they may be confused clinically with renal cell carcinoma. An acquired form of renal cystic disease occurs in people with ESRF who have undergone prolonged dialysis treatment.5 Although the condition is largely asymptomatic, the cysts may bleed, causing hematuria. Tumors, usually adenomas but occasionally adenosarcomas, may develop in the walls of these cysts. SUMMARY CONCEPTS Approximately 10% of infants are born with potentially significant malformations of the urinary system. These abnormalities can range from bilateral renal agenesis to hypogenesis of one kidney. Renal dysplasia is caused by an abnormality in the differentiation of kidney structures during embryonic development. A multicystic kidney is one in which the kidney is replaced by cysts and does not function. The horseshoe kidney is a common developmental disorder in which the upper or lower poles of the two kidneys are fused, producing a horseshoe-shaped structure. Renal cystic disease is a condition in which there is dilation of tubular structures with cyst formation. Cysts may be single or multiple. Polycystic kidney disease is an inherited form of renal cystic disease; it can be inherited as an autosomal dominant or recessive trait. The autosomal dominant form of the disease (ADPKD) results in the formation of numerous fluid-filled cysts in the tubular structures of both kidneys with the threat of progression to chronic renal failure. Other manifestations of the disease include hypertension, cardiovascular abnormalities, cerebral aneurysms, and cysts in other organs such as the liver and pancreas (Fig. 33-3A). The autosomal recessive form (ARPKD) is characterized by cystic transformation of the collecting ducts (Fig. 33-3B). It is rare

compared with ADPKD and usually presents as severe renal dysfunction during infancy. The NPHP–medullary cystic disease complex is a group of hereditary disorders that usually have their onset during childhood and are characterized by the presence of cysts in the medullary portion of the kidney, renal atrophy, and eventual kidney failure. Single or multiple simple renal cysts most commonly occur in people older than 50 years of age.

Obstructive Disorders Urinary obstruction can occur in people of any age and can involve any level of the urinary tract, from the urethra to the renal pelvis (Fig. 33-4). Obstruction may be sudden or insidious, partial or complete, and unilateral or bilateral. The causes of urinary tract obstructions are summarized in Table 33-1.

FIGURE 33-4

Locations and causes of urinary tract obstruction.

TABLE 33-1 Causes of Urinary Tract Obstruction

Level of Obstruction Renal pelvis Ureter

Cause Renal calculi Papillary necrosis Renal calculi Pregnancy Tumors that compress the ureter Ureteral stricture Congenital disorders of the ureterovesical junction and ureteropelvic junction strictures

Level of Obstruction Bladder and urethra

Cause

Bladder cancer Neurogenic bladder Bladder stones Prostatic hyperplasia or cancer Urethral strictures Congenital urethral defects Obstructive uropathy is usually classified according to site, degree, and duration of obstruction.19 Lower urinary tract obstructions are located below the ureterovesical junction and are bilateral in nature. Upper urinary tract obstructions are located above the ureterovesical junction and are usually unilateral. The condition causing the obstruction can cause complete or partial occlusion of urine outflow. When the obstruction is of short duration (i.e., less than a few days), it is said to be acute and is usually caused by conditions such as renal calculi. An obstruction that develops slowly and is longer-lasting is said to be chronic and is usually caused by conditions such as congenital ureterovesical abnormalities. Bilateral acute urinary tract obstruction causes acute renal failure. Because many causes of acute obstruction are reversible, prompt recognition is important. When left untreated, an obstructed kidney undergoes atrophy and, in the case of bilateral obstruction, results in chronic renal failure. Mechanisms of Renal Damage The destructive effects of urinary obstruction on kidney structures are determined by the degree and the duration of the obstruction. The two most damaging effects of urinary obstruction are as follows: 1. Stasis of urine, which predisposes to infection and stone formation 2. Progressive dilation of the renal collecting ducts and renal tubular structures, which causes destruction and atrophy of renal tissue A common complication of urinary tract obstruction is infection. Stagnation of urine predisposes to infection, which may spread throughout the urinary tract. Once established, the infection is difficult to treat. Ureasplitting organisms that increase ammonia production and cause the urine to become alkaline often cause infection.5 When present, urinary calculi serve

as foreign bodies and contribute to the infection. Calcium salts precipitate more readily in stagnant alkaline urine; thus, urinary tract obstructions also predispose to stone formation. In situations of severe partial or complete obstruction, the impediment to the outflow of urine causes dilation of the renal pelvis and calices associated with progressive atrophy of the kidney. Even with complete obstruction, glomerular filtration continues for a period of time. Because of the continued filtration, the calices and pelvis of the affected kidney may become markedly dilated. The high pressure in the renal pelvis is transmitted back through the collecting ducts of the kidney, compressing renal vasculature, and causing renal atrophy. Initially, the functional alterations are largely tubular, manifested primarily by impaired urineconcentrating ability. Only later does the GFR begin to diminish. Hydronephrosis Hydronephrosis refers to urine-filled dilation of the renal pelvis and calices associated with progressive atrophy of the kidney because of obstruction of urine outflow. The degree of hydronephrosis depends on the duration, degree, and level of obstruction. In far-advanced cases, the kidney may be transformed into a thin-walled cystic structure with parenchymal atrophy, total obliteration of the pyramids, and thinning of the cortex (Fig. 33-5).5 The condition is usually unilateral. Bilateral hydronephrosis occurs only when the obstruction is below the level of the ureterovesical junction. When the obstruction affects the outflow of urine from the distal ureter, the increased pressure dilates the ureter, a condition called hydroureter (Fig. 33-6). Bilateral hydroureter may develop as a complication of bladder outflow obstruction because of prostatic hyperplasia.

Hydronephrosis. Bilateral urinary tract obstruction has led to conspicuous dilation of the ureters, pelvis, and calices. The kidney on the right shows severe cortical atrophy. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 951, Fig. 22-83). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-5

Hydroureter caused by ureteral obstruction in a woman with cancer of the uterus. FIGURE 33-6

Clinical Manifestations

The manifestations of urinary obstruction depend on the site of obstruction, the cause, and the rapidity with which the condition developed. The underlying pathologic process produces most of the early symptoms. Urinary tract obstruction encourages the growth of microorganisms and should be suspected in people with recurrent UTIs. Complete or partial unilateral hydronephrosis may remain silent for long periods because the unaffected kidney can maintain adequate kidney function. Obstruction may provoke pain because of distention of the collecting system and renal capsule. Acute supravesical obstruction, such as that because of a kidney stone lodged in the ureter, is associated with excruciatingly severe pain. By contrast, more insidious causes of obstruction, such as narrowing of the ureteropelvic junction, generally produce little pain but totally destroy the kidney. Complete bilateral obstruction results in oliguria, progressing to anuria and renal failure. Acute bilateral obstruction may mimic prerenal failure. With partial bilateral obstruction, the earliest manifestation is an inability to concentrate urine, reflected by polyuria and nocturia. Hypertension is an occasional complication of urinary tract obstruction. It is more common in cases of unilateral obstruction in which renin secretion is enhanced, probably secondary to impaired renal blood flow. In these circumstances, removal of the obstruction often leads to a reduction in blood pressure (BP). When hypertension accompanies bilateral obstruction, it is volume related. The relief of bilateral obstruction leads to a loss of volume and a decrease in BP. In some cases, relieving the obstruction does not correct the hypertension. Diagnosis and Treatment Early diagnosis of urinary tract obstruction is important because the condition usually is treatable and a delay in therapy may result in permanent damage to the kidneys. Diagnostic methods vary with the symptoms. Ultrasonography has been shown to be the single most useful noninvasive diagnostic modality for urinary obstruction. Radiologic methods, CT scans, and intravenous urography may also be used.20 Other diagnostic methods, such as urinalysis, are used to determine the extent of renal involvement and the presence of infection.

Treatment of urinary tract obstruction depends on the cause. Urinary stone removal may be necessary, or surgical treatment of structural defects may be indicated. Treatment of a complicated UTI because of urinary stasis is also important. Renal Calculi The most common cause of upper urinary tract obstruction is urinary calculi. Although stones can form in any part of the urinary tract, most develop in the kidneys. Renal calculi, or kidney stones, are a common pathophysiologic condition of the urinary tract, exceeded only by UTIs and prostate disorders. Kidney stones are polycrystalline aggregates comprising materials that the kidneys normally excrete in the urine. Etiology and Pathogenesis The etiology of urinary stone formation is complex. It is thought to encompass a number of factors, including increases in blood and urinary levels of stone components and interactions among the components, anatomic changes in urinary tract structures, metabolic and endocrine influences, dietary and intestinal absorption factors, and UTIs.5 Several factors contribute to stone formation, including a supersaturated urine, presence of a nucleus for crystal formation, and deficiency of inhibitors of stone formation.5 Kidney stone formation requires a supersaturated urine and an environment that allows the stone to grow. The risk for stone formation is increased when the urine is supersaturated with stone components (e.g., calcium salts, uric acid, magnesium ammonium phosphate, cystine). Supersaturation depends on urinary pH, temperature, solute concentration, ionic strength, and complexation. The greater the concentration of two ions, the more likely they are to precipitate. In addition to a supersaturated urine, kidney stone formation requires a nidus or nucleus that facilitates crystal aggregation. In supersaturated urine, stone formation begins with small clusters of crystals such as calcium oxalate. Most small clusters tend to disperse because the internal forces that hold them together are too weak to overcome the random tendency of ions to move apart. Larger ion clusters form nuclei and remain stable because

the attraction forces balance surface losses. Once they are stable, nuclei can grow at levels of supersaturation below that needed for their creation.21 The fact that many people experience supersaturation of their urine without development of kidney stones is believed to be a result of the presence of natural stone inhibitors, including magnesium and citrate. Citrate supplementation (potassium citrate) may be of benefit in some people with calcium stones, with the increased citrate concentration thought to decrease the calcium crystallization.20 KEY POINTS Kidney Stones Stones require a nidus to form and a urinary environment that supports continued crystallization of stone components. The development of kidney stones is influenced by the concentration of stone components in the urine, the ability of the stone components to complex and form stones, and the presence of substances that inhibit stone formation. Types of Stones Four basic types of kidney stones have been identified—calcium stones (i.e., oxalate or phosphate), magnesium ammonium phosphate stones, uric acid stones, and cystine stones.21,22 The causes and treatment measures for each of these types of renal stones are described in Table 33-2. Most kidney stones (75% to 80%) are calcium stones—calcium oxalate, calcium phosphate, or a combination of the two materials.21 Calcium stones usually are associated with increased concentrations of calcium in the blood and urine. Excessive bone resorption caused by immobility, bone disease, hyperparathyroidism, and renal tubular acidosis (RTA) all are contributing conditions. High oxalate concentrations in the blood and urine predispose to formation of calcium oxalate stones. Uric acid stones are associated with increased BMI and low urine pH.22 The prevalence of obesity seems to be contributing to increasing uric acid stones in the population over time.22 Emerging research indicates that 13% to 44% of calcium oxalate stones are

culture positive, with Escherichia coli and Pseudomonas spp. representing the leading organisms.23 TABLE 33-2 Composition, Contributing Factors, and Treatment of Kidney Stones

Type of Stone Contributing Factors Treatment Calcium (oxalate and Hypercalcemia and Treatment of phosphate) hypercalciuria underlying conditions Immobilization Increased fluid intake Hyperparathyroidism Thiazide diuretics Vitamin D intoxication Dietary restriction of Diffuse bone disease foods high in oxalate Milk-alkali syndrome Renal tubular acidosis Hyperoxaluria Intestinal bypass surgery Magnesium Urea-splitting UTIs Treatment of UTI ammonium phosphate Formed in acid urine with pH Acidification of the (struvite) urine of ∼5.5 Uric acid (urate) Increased fluid intake Gout Cystine Increased fluid intake High-purine diet Cystinuria (inherited disorder Allopurinol for of amino acid metabolism) hyperuricosuria Alkalinization of urine Increased fluid intake Magnesium ammonium phosphate stones, also called struvite stones, form only in alkaline urine (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.21 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. 33-7). Because of their shape, they often are called staghorn stones.21 They are typically associated with UTIs caused by urease-producing bacteria;

however, struvite accounts for a small percentage of all kidney stones.23 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.

Staghorn stones. The kidney shows hydronephrosis and stones that are casts of the dilated calices. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 951, Fig. 22-82). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-7

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.21 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.24 Thus, these stones can be treated by raising the urinary pH from 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.24 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.24 Renal colic is the term used to describe the colicky pain that 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.25 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.25 IVP uses an intravenously injected contrast medium that is filtered in the glomeruli to visualize the collecting system of the kidneys 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.25 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. Table 33-2 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.20 All these procedures eliminate the need for an open surgical procedure, which is another form of treatment. Open stone surgery may be required to remove large calculi or those that are resistant to other forms of removal. SUMMARY CONCEPTS 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 because of 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, 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 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 people 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 stoneforming constituents, treatment of UTI, measures to change urine pH, and the use of diuretics that decrease the calcium concentration of urine.

Urinary Tract Infections 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.3 KEY POINTS Urinary Tract Infections Infection is facilitated by host conditions that disrupt washout of the agent from the urinary tract through urine flow, change the protective properties of the mucin lining of the urinary tract, 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 environment, adhere to the tissues of the lower or upper urinary tract, evade the destructive effects of the host’s immune system, and develop resistance to antimicrobial agents. Etiology and Pathogenesis Most uncomplicated lower UTIs are caused by E. coli,5 and complicated UTIs are caused by a number of pathogens such as Klebsiella pneumoniae, Enterococcus faecalis, Enterobacter spp., Proteus mirabilis, and Pseudomonas aeruginosa.26 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. Thus, factors that impact colonization (e.g., having a prior UTI, sexual activity with a new partner, and changes in vaginal flora via pH changes) are risk factors for UTI.27 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, and in older adults.28 Instrumentation and urinary

catheterization are the most common predisposing factors for nosocomial UTIs because they bypass protective mechanisms.20 People with diabetes are at increased risk for complications associated with UTIs, including pyelonephritis, and they are more susceptible to fungal infections (particularly Candida species).29 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.28 UTIs are more common in women than men; specifically, young sexually active women are at higher risk. Every year in the United States, about 10% of all females experience a symptomatic UTI, with 60% of all females having a symptomatic UTI during their lifetime.28 In males, the longer length of the urethra and the antibacterial properties of the prostatic fluid, which contains immunoglobulins (IgA and IgG), provide some protection from ascending UTIs.30 When UTIs occur in males, they typically develop complicated UTI related to acute prostatitis.28 In older men, prostatic hypertrophy becomes more common and with it may result obstruction and increased risk for UTI. For older adults with indwelling urinary catheters, a biofilm builds up and promotes more bacterial growth. Therefore, older adults, who already have decreased immunologic function related to aging, need meticulous surveillance for signs of infection.21,31 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 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.5 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 Virulence factors help microorganisms to evade the host defenses and produce disease.28 Not all bacteria are capable of adhering to and infecting the urinary tract; only those with increased ability to adhere to the epithelial cells of the urinary tract are able to produce UTIs. Of the many strains of E. coli, some serogroups produce more infections with a higher clinical severity. For example, serotypes O, K, and H are associated with development of pyelonephritis.28 Uropathogenic E.coli strains capable of causing UTI are known as Enteropathogenic E. coli (EPEC). These bacteria have fine protein filaments, called pili or fimbriae, that enhance colonization by helping these bacteria adhere to receptors on the lining of urinary tract structures.28 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. Reflux occurs when urine from the urethra moves into the bladder (i.e., urethrovesical reflux).5 In women, urethrovesical reflux can occur during activities such as coughing or squatting, in which an increase in intraabdominal 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. 33-8). The flap is compressed against the bladder wall during micturition, preventing urine from being forced into the ureter. In people with vesicoureteral reflux, the ureter enters the bladder at an approximate right angle such that urine is forced into the ureter during micturition.5 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. The concave shape of the peripheral papilla may contribute to reflux. Vesicoureteral reflux also is seen in adults with obstruction to bladder outflow, primarily because of increased bladder volume and pressure.

Anatomic features of the bladder and kidney in pyelonephritis caused by ureterovesical reflux. In the normal bladder, the distal portion of the intravesical ureter courses between the mucosa and the muscularis, forming a mucosal flap. On micturition, the elevated intravesicular pressure compresses the flap against the bladder wall, occluding the lumen. People with congenital short intravesical ureter have no mucosal flap, because the angle of entry of the ureter into the bladder approaches a right angle. Thus, micturition forces urine into the ureter. In the renal pelvis, simple papillae of the central calyces are convex and do not readily allow reflux of urine. By contrast, the peripheral compound papillae are concave and permit entry of the refluxed urine. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 945, Fig. 22-72). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-8

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.21 Catheter-associated bacteriuria remains the most frequent cause of gramnegative infections in hospitalized people. Bacteria adhere to the surface of the catheter and initiate the growth of a biofilm that then covers the surface of the catheter.21 The biofilm tends to protect the bacteria from the host’s response and action of antibiotics, which 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 people who require an indwelling catheter. Careful handwashing 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).24 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).20,24 Occasionally, the urine is cloudy and foul smelling. Manifestations in children younger than 2 years of age are typically nonspecific, whereas children over 5 years tend to have the localized symptoms of cystitis mentioned above.28 In adults, fever and other signs of infection usually are absent. If there are no complications, the symptoms disappear within 48 hours 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.5 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 (CFUs) or more bacteria per milliliter (mL) of urine.25 Colonization usually is defined as the multiplication of microorganisms in or on a host without apparent evidence of invasiveness or tissue injury. Pyuria (the presence of 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 urine5 (Fig. 33-14).

FIGURE 33-14

Pathophysiology of the nephrotic syndrome.

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.5 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 because of pulmonary edema, pleural effusions, and diaphragmatic compromise because of ascites can develop in people with 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 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.5 This decreased resistance to infection probably relates 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 (MCD, lipoid nephrosis), focal segmental glomerulosclerosis, and membranous glomerulonephritis.5 The relative frequency of these causes varies with age. In children younger than 15 years of age, nephrotic syndrome almost always is caused by primary idiopathic glomerular disease, whereas in adults, it often is a secondary disorder.5

Minimal Change Disease (Lipoid Nephrosis). MCD 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 minimal change nephrosis is unknown. Although MCD 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 glomerulonephritis 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.5 The disorder is caused by diffuse thickening of the GBM because of 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 nonnephrotic 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 nonnephrotic range. Treatment is controversial. Focal Segmental Glomerulosclerosis. Focal segmental glomerulosclerosis 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.5 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 infection, or intravenous drug abuse, or it may occur as a secondary event reflecting glomerular scarring because of other forms of glomerulonephritis.5 Impairment of autophagy (a repair process necessary to maintain homeostasis post cell injury) may be responsible for limited regenerative capacity of podocytes.38 The presence of hypertension and decreased renal function distinguishes focal sclerosis from MCD. In addition, research indicates that people with MCD (a manifestation of nephrotic syndrome diagnosed by renal biopsy) may later progress to focal segmental glomerulosclerosis.39 The protein nephrin seems to be a marker for podocyte injury. People with MCD respond to varying degrees to corticosteroids. People who were treated and did not experience nephrin loss had a 96% remission rate compared with a 61% remission rate among those who experienced nephrin loss.39 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 nephropathy (IgAN) (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.5 The disease occurs more commonly in men than in women and is the most common cause of glomerular nephritis in Asians. The disorder is characterized by the deposition of IgA-containing 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. The classification system is based on biopsy findings in a minimum of eight glomeruli to yield a MEST-C score.40 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.5 The diagnostic finding is mesangial staining for IgA more intense than staining for IgG or IgM (Fig. 33-15). At present, there are no satisfactory treatment measures for IgA nephropathy.

Immunoglobulin-A (IgA) nephropathy. An immunofluorescence micrograph shows deposits of IgA in the mesangial areas. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 931, Fig. 22-48). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-15

Henoch–Schönlein Purpura Nephritis Henoch–Schönlein purpura is a small-vessel vasculitis that causes a purpuric rash largely of the lower extremities, arthritis or arthralgia, abdominal pain, and renal involvement identical to that of IgA nephropathy. Incidence has seasonal variation, with twice as many cases in the winter and fall.41 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. Some cases progress to end-stage renal disease. Corticosteroids are the most effective treatment and have been found to decrease the duration and intensity of abdominal and joint pain.41 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.5 The syndrome is caused by type IV collagen mutations. Approximately 85% of cases are inherited as an Xlinked autosomal dominant trait, whereas others have autosomal dominant and recessive patterns of inheritance.5 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 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.5 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. 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.5 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.5 It also involves dysregulated T-cell function, with the ratios of T-cell subpopulation playing an important role in SLE pathogenesis.42 Most glomerular injury is triggered by the formation of immune complexes within the glomerular capillary wall.

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.5 The World Health Organization (WHO) classified 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. Classification has been further refined to enhance communication between the pathologists and clinicians as well as to improve reproducibility and uniformity in reports.43 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 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. 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.5 It occurs in both type 1 and type 2 diabetes mellitus. It is more prevalent among African Americans, Asians, and Native Americans than whites. 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 Kimmelstiel–Wilson syndrome, there is nodular deposition of hyaline in the mesangial portion of the glomerulus.5 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.5 Alternatively, hemodynamic changes that occur secondary to elevated blood glucose levels may contribute to the initiation and progression of diabetic glomerulosclerosis.5 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. 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.25,44 Microalbuminuria is an important predictor of future diabetic nephropathies. In many cases, these early changes in glomerular function can be reversed by careful control of blood glucose levels. Inhibition of angiotensin by ACE inhibitors or angiotensin receptor blockers has been shown to have a beneficial effect, possibly by reversing increased glomerular pressure.45 Hypertension 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.5 It 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. SUMMARY CONCEPTS 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 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 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, RTA, 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.5 Renal Tubular Acidosis RTA refers to a group of tubular defects in reabsorption of bicarbonate ions (HCO_3) 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. Proximal Renal Tubular Acidosis Proximal RTA involves a defect in proximal tubular reabsorption, the nephron site where 85% of filtered HCO_3 is reabsorbed. With the onset of impaired tubular HCO_3 reabsorption, there is a loss of HCO_3 in the urine that reduces plasma HCO_3 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 HCO_3 eventually resumes, albeit at a lower level of serum HCO_3. Whenever serum levels rise above this decreased level, HCO_3 is lost in the urine. People with proximal RTA generally have plasma HCO_3 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 HCO_3 reabsorption or accompany other defects in proximal tubular function (Fanconi syndrome). Isolated defects in HCO_3 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 because of 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 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 Staphylococcus 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 pyelonephritis 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 pelvis5 (Fig. 33-16). 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.

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.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 947, Fig. 2276). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-16

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 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.5 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. People at particular risk are those who already have compromised renal blood flow. Other drugs such as sulfonamides and vitamin C (because of 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 people 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 people 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 people, usually in older people. Drug nephritis may not be recognized in its early stage because it is relatively uncommon.

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.5 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. SUMMARY CONCEPTS 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 is usually 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.

Malignant Tumors of the Kidney 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 malignant abdominal tumor in children. It may occur in one or both kidneys. The incidence of bilateral Wilms tumor is 5% in sporadic cases and up to 20% in familial cases.5 Histologically, the tumor comprises 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.5 Although genetic and epigenetic associations with Wilms tumor are known, they explain only 5% of the cases.46 Wilms tumor usually is a solitary mass that occurs in any part of the kidney. It is usually sharply demarcated and variably encapsulated (Fig. 3317). The tumors grow to a large size, distorting kidney structure. The tumors usually are staged using the National Wilms Tumor Study Group classification47:

Wilms tumor. A cross-section of a pale tan neoplasm attached to a residual portion of the kidney. (From Rubin R., Strayer D. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 956, Fig. 22-90). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-17

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. Stage V tumors have bilateral involvement when diagnosed.

The common presenting signs are a large asymptomatic abdominal mass and hypertension.47 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. Once diagnosed, care should be taken during physical examination to avoid vigorous physical examination, which could rupture the tumor capsule.47 Prognosis is dependent on the findings at the time of diagnosis (e.g., histology, stage, molecular markers, and age). The 5-year survival rate is 90%. Renal Cell Carcinoma Renal cell carcinoma is an often malignant tumor that accounts for up to 90% of all primary renal cancers.5 Cancer of the kidney incidence peaks in people in their 60s and 70s. 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. The tumor usually arises from the renal tubular or ductal epithelial cells.5 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. Clear cell carcinoma represents the majority of cases (70% to 75% of cases) (Fig. 33-18), with non–clear cell tumors (papillary or chromophilic tumors and chromophobic tumors) representing the remaining cases.48 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 trisomies 7, 16, and 17; and arise from proximal tubular

cells.5 Collecting duct tumors arise from the collecting ducts within the renal medulla, are very rare, affect younger people, and are very aggressive.

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.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 957, Fig. 22-92). Philadelphia, PA: Wolters Kluwer Health.) FIGURE 33-18

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).48 As with other forms of cancer, prognosis is based on staging at the time of diagnosis. Surgery (radical nephrectomy with lymph node dissection) is the treatment of choice for all resectable tumors. SUMMARY CONCEPTS 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 60s and 70s. Renal cell carcinoma accounts for 80% to 90% of kidney 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.5

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. 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? 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. Centers for Disease Control and Prevention. (2017). National chronic kidney disease fact sheet, 2017. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention. Available: https://www.cdc.gov/diabetes/pubs/pdf/kidney_factsheet.pdf. 2. Daniels B., Gross C. P., Molinaro A., et al. (2016). STONE PLUS: Evaluation of emergency department patients with suspected renal colic, using a clinical prediction tool combined with point-of-care limited ultrasonography. Annals of Emergency Medicine 67(4), 439–448. doi:10.1016/j.annemergmed.2015.10.020. 3. Simmering J. E., Tang F., Cavanaugh J. E., et al. (2017). The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011. Open Forum Infectious Diseases 4(1), ofw281. doi:10.1093/ofid/ofw281. 4. Children and Youth with Special Health Needs. (2017). Renal agenesis/hypoplasia fact sheet. Minnesota Department of Health. Available: http://www.health.state.mn.us/divs/cfh/topic/diseasesconds/renalagenesis.cfm 5. Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Wolters Kluwer Health. 6. Ramanathan S., Kumar D., Khanna M., et al. (2016). Multi-modality imaging review of congenital abnormalities of kidney and upper urinary tract. World Journal of Radiology 8(2), 132– 141. doi:10.4329/wjr.v8.i2.132. 7. Capone V. P., Morello W., Taroni F., et al. (2017). Genetics of congenital anomalies of the kidney and urinary tract: The current state of play. International Journal of Molecular Sciences 18(4), E796. doi:10.3390/ijms18040796. 8. National Organization for Rare Disorders. (2017). Renal agenesis, bilateral. Available: https://rarediseases.org/rare-diseases/renal-agenesis-bilateral 9. Perrone R. D., Neville J., Chapman A. B., et al. (2015). Therapeutic area data standards for autosomal dominant polycystic kidney disease: A report from the Polycystic Kidney Disease Outcomes Consortium (PKDOC). American Journal of Kidney Diseases 66(4), 583–590. doi:10.1053/j.ajkd.2015.04.044. 10. Sweeney W. E. Jr, Avner E. D. (2017). Emerging therapies for childhood polycystic kidney disease. Frontiers in Pediatrics 5, 77. doi:10.3389/fped.2017.00077. 11. Zhou Z., Xu Y., Delcourt C., et al. (2017). Is regular screening for intracranial aneurysm necessary in patients with autosomal dominant polycystic kidney disease? A systematic review and meta-analysis. Cerebrovascular Diseases 44(1–2), 75–82. doi:10.1159/000476073 12. Chapman A. B., Devuyst O., Eckardt K. U., et al. (2015). Autosomal-dominant polycystic kidney disease (ADPKD): Executive summary from a kidney disease: Improving global outcomes (KDIGO) controversies conference. Kidney International 88(1), 17–27. doi:10.1038/ki.2015.59. 13. Sommerer C., Zeier, M. (2016). Clinical manifestation and management of ADPKD in Western countries. Kidney Diseases (Basel, Switzerland) 2(3), 120–127. doi:10.1159/000449394.

14. Casteleijn N. F., Visser F. W., Drenth J. P., et al. (2014). A stepwise approach for effective management of chronic pain in autosomal-dominant polycystic kidney disease. Nephrology, Dialysis, Transplantation 29(Suppl 4), iv142–iv153. doi:10.1093/ndt/gfu073. 15. Guay-Woodford L. M., Bissler J. J., Braun M. C., et al. (2014). Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: Report of an international conference. The Journal of Pediatrics 165(3), 611–617. doi:10.1016/j.jpeds.2014.06.015. 16. Hartung E. A., Guay-Woodford L. M. (2014). Autosomal recessive polycystic kidney disease: A hepatorenal fibrocystic disorder with pleiotropic effects. Pediatrics 134(3), e833–e845. doi:10.1542/peds.2013-3646. 17. Srivastava S., Sayer J. A. (2014). Nephronophthisis. Journal of Pediatric Genetics 3(2), 103–114. doi:10.3233/PGE-14086. 18. Niaudet P. (2017). Clinical manifestations, diagnosis, and treatment of nephronophthisis. UpToDate. Available: https://www.uptodate.com/contents/clinical-manifestations-diagnosis-andtreatment-of-nephronophthisis 19. Frokiaer J. (2017). Urinary tract obstruction. In Skerecki K., Chertow G. M., Marsden P. A., et al. (Eds.), Brenner and Rector’s the kidney (10th ed.). Philadelphia, PA: Elsevier Health. 20. Goroll A. H., Mulley A. G. (2014). Primary care medicine: Office evaluation and management of the adult patient (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 21. Heuther S. E., McCance K. L. (Eds.). (2017). Understanding pathophysiology. St. Louis, MO: Elsevier. 22. Xu L. H. R., Adams-Huet B., Poindexter J. R., et al. (2017). Temporal changes in kidney stone composition and in risk factors predisposing to stone formation. Journal of Urology 197(6), 1465–1471. doi:10.1016/j.juro.2017.01.057. 23. Schwaderer A. L., Wolfe A. J. (2017). The association between bacteria and urinary stones. Annals of Translational Medicine 5(2), 32, 1–6. doi:10.21037/atm.2016.11.73. 24. Dunphy L. M., Winland-Brown J. E., Porter B., et al. (2015). Primary care: The art and science of advanced practice nursing (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 25. Panga K., Panga T., Panga T. (2017). Mosby’s diagnostic and laboratory test reference (13th ed.). St. Louis, MO: Elsevier. 26. Bader M. S., Loeb M., Brooks A. A. (2017). An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgraduate Medicine 129(2), 242–258. doi:10.1080/00325481.2017.1246055. 27. Center for Disease Control and Prevention. (2015). Urinary tract infection. Available: https://www.cdc.gov/antibiotic-use/community/for-patients/common-illnesses/uti.html 28. Sobel J. D., Kaye D. (2015). Urinary tract infections. In Bennet J. E., Dolin R., Blaser M. J. (Eds.), Mandell, Douglas, and Bennett’s principles and practice of infectious disease (Updated ed.). Philadelphia, PA: Elsevier. 29. Thomas L, Tracy C. R. (2015). Treatment of fungal urinary tract infection. The Urology Clinics of North America 42(4), 473–483. doi:10.1016/j.ucl.2015.05.010. 30. Silva J. A. F., Biancardi M. F., Stach-Machado D. R., et al. (2017). The origin of prostate glandsecreted IgA and IgG. Scientific Reports 7(1), 16488. doi:10.1038/s41598-017-16717-3. 31. Flores-Mireles A. L., Walker J. N., Caparon M., et al. (2015). Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nature Reviews Microbiology 13(5), 269–284. doi:10.1038/nrmicro3432. 32. Glaser A. P., Schaeffer A. J. (2015). Urinary tract infection and bacteriuria in pregnancy. The Urology Clinics of North America 42(4), 547–560. doi:10.1016/j.ucl.2015.05.004. 33. Bunting-Early T. E., Shaikh N., Woo L., et al. (2017). The need for improved detection of urinary tract infections in young children. Frontiers in Pediatrics 5, 24. doi:10.3389/fped.2017.00024.

34. Becknell B., Schober M., Korbel L., et al. (2015). The diagnosis, evaluation and treatment of acute and recurrent pediatric urinary tract infections. Expert Review of Anti-Infective Therapy 13(1), 81–90. doi:10.1586/14787210.2015.986097. 35. Umberger R., Callen B., Brown M. L. (2015). Severe sepsis in older adults. Critical Care Nursing Quarterly 38(3), 259–270. doi:10.1097/CNQ.0000000000000078. 36. Rowe T. A., Juthani-Mehta M. (2014). Diagnosis and management of urinary tract infection in older adults. Infectious Disease Clinics of North America 28(1), 75–89. doi:10.1016/j.idc.2013.10.004. 37. Rennke H. G., Denker B. M. (2014). Renal pathophysiology: The essentials (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 38. Fogo A. B. (2015). Causes and pathogenesis of focal segmental glomerulosclerosis. Nature Reviews Nephrology 11(2), 76–87. doi:10.1038/nrneph.2014.216. 39. van de Lest N. A., Zandbergen M., Ijpelaar DHT, et al. (2018). Nephrin Loss can be used to predict remission and long-term renal outcome in patients with minimal change disease. Kidney International Reports 3(1), 168–177. doi:10.1016/j.ekir.2017.09.011. 40. Trimarchi H., Barratt J., Cattran D. C., et al. (2017). Oxford Classification of IgA nephropathy 2016: An update from the IgA Nephropathy Classification Working Group. Kidney International 91(5), 1014–1021. doi:10.1016/j.kint.2017.02.003. 41. Heineke M. H., Ballering A. V., Jamin A., et al. (2017). New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schonlein purpura). Autoimmunity Reviews 16(12), 1246– 1253. doi:10.1016/j.autrev.2017.10.009. 42. Suarez-Fueyo A., Bradley S. J., Tsokos G. C. (2016). T cells in systemic lupus erythematosus. Current Opinion in Immunology 43, 32–38. doi:10.1016/j.coi.2016.09.001. 43. Kiremitci S., Ensari A. (2014). Classifying lupus nephritis: An ongoing story. Scientific World Journal 2014, 580620. doi:10.1155/2014/580620. 44. Fischbach F., Dunning M. B. (2015). A manual of laboratory and diagnostic tests (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 45. Burchum J. R., Rosenthal L. D. (2016). Lehne’s pharmacology for nursing care (9th ed.). St. Louis, MO: Elsevier. 46. Bahrami A., Joodi M., Maftooh M., et al. (2018). The genetic factors contributing to the development of Wilm’s tumor and their clinical utility in its diagnosis and prognosis. Journal of Cellular Physiology 233(4), 2882–2888. doi:10.1002/jcp.26021. 47. Chintagumpala M., Muscal J. A. (2017). Treatment and prognosis of Wilms tumor. In Pappo A. S. (Ed.), UpToDate. Available: https://www.uptodate.com/contents/treatment-and-prognosis-ofwilms-tumor 48. Barata P. C., Rini B. I. (2017). Treatment of renal cell carcinoma: Current status and future directions. CA: A Cancer Journal for Clinicians 67(6), 507–524. doi:10.3322/caac.21411.

CHAPTER 34 Acute Kidney Injury and Chronic Kidney Disease Acute Kidney Injury Types of Acute Kidney Injury Prerenal Acute Kidney Injury Intrarenal Acute Kidney Injury Postrenal 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 Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Describe acute kidney injury in terms of its causes, treatment, and outcome. 2. Differentiate the prerenal, intrarenal, and postrenal forms of acute kidney injury in terms of the mechanisms of development and manifestations. 3. State the most common causes of chronic kidney disease (CKD). 4. Explain the physiologic mechanisms underlying the common problems associated with CKD, including alterations in fluid and electrolyte balance and disorders of skeletal, hematologic, cardiovascular, immune, neurologic neurologic, and integumentary systems, and sexual function. 5. State the basis for adverse drug reactions in people with CKD. 6. Cite the possible complications of kidney transplantation.

7. List the causes of CKD in children and describe the special problems of children with kidney failure. 8. State why CKD is more common in older adults and describe measures to prevent or delay the onset of kidney failure in this population.

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 kidney injury is abrupt in onset and is often reversible if recognized early and treated appropriately. In contrast, chronic kidney disease (CKD) 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 CKD are manifested. Approximately 30 million American adults have some form of renal disease.1

Acute Kidney Injury Acute kidney injury (AKI) represents a rapid decline in kidney function that happens within a few hours or within a day. AKI causes a buildup of nitrogenous waste products and impairs fluid and electrolyte balance.1 Unlike CKD and failure, acute renal injury is potentially reversible if the precipitating factors can be corrected or removed before permanent kidney damage has occurred. AKI is a common threat to seriously ill people in intensive care units, with a mortality rate ranging from 15% to 60%.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 AKI has not improved substantially over the past few decades.4 This is probably because AKI is seen more often in older adults than before, and because it is most frequently superimposed by sepsis, hypovolemia, drug-/medication-related problems, and cardiogenic shock.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). As a result, excretion of nitrogenous wastes is reduced, and fluid and electrolyte balance cannot be maintained. KEY POINTS Acute Kidney Injury AKI is caused by conditions that produce an acute shutdown in renal function. It can result from decreased blood flow to the kidney (prerenal AKI), disorders that disrupt the structures in the kidney (intrarenal AKI), or disorders that interfere with the elimination of urine from the kidney (postrenal AKI). AKI, 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 Kidney Injury AKI 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 AKI are commonly categorized as prerenal, intrarenal, and postrenal2 (Fig. 34-1). Collectively, prerenal and intrarenal causes account for 80% to 95% of AKI cases.3 Causes of AKI within these categories are summarized in Chart 341.

FIGURE 34-1

Types of acute kidney injury.

CHART 34.1 CAUSES OF ACUTE KIDNEY INJURY Prerenal AKI Hypovolemia Hemorrhage Dehydration Excessive loss of gastrointestinal tract fluids Excessive loss of fluid because of burn injury Decreased vascular filling Anaphylactic shock Septic shock Heart failure and cardiogenic shock

Decreased renal perfusion because of sepsis, vasoactive mediators, drugs, and diagnostic agents Intrarenal AKI 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 AKI Bilateral ureteral obstruction Bladder outlet obstruction Prerenal Acute Kidney Injury Prerenal AKI, the most common form of AKI, 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 AKI include profound depletion of vascular volume (e.g., hemorrhage, loss of extracellular fluid volume), impaired perfusion because of 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 predisposition 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 AKI. 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 AKI in people with decreased blood flow because of 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 people with diminished renal perfusion, NSAIDs can precipitate prerenal AKI. 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 substances 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 “acute tubular necrosis” (ATN) is being used less frequently and AKI refers to this intrarenal pathology.6 Prerenal AKI 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 AKI is a sharp decrease in urine output. A low fractional excretion of sodium ( 88 cm (>35 in) in) Underweight 40) and in those with a BMI greater than 35 who have comorbid conditions and 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 10 years or more in most people.30 There are three types of weight loss surgery: (1) restrictive procedures, which reduce the amount of food that can be 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, whereas the malabsorptive procedures include the biliopancreatic diversion with duodenal switch. Each surgery has specific risks and potential complications and requires lifelong nutritional monitoring after surgery and support therapy by 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 and reduction of complications has prompted a joint statement by five international diabetes organizations that now include surgery in the treatment algorithm to improve outcomes.31 SUMMARY CONCEPTS 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 Undernutrition continues to be a major health problem throughout the world. Globally, undernourishment rates have been falling over the past few decades32,33 Developing countries have a prevalence of 12.9% undernourished populations and are responsible for 98% of the overall

total.33 In developed countries, undernutrition is most commonly seen in the pediatric and older adult populations.34 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 of vitamin and mineral deficiencies. The recognition that all infants, adolescents, and pregnant women have increased nutritional needs may be overlooked regardless of socioeconomic status. Some types of malnutrition are caused by acute and chronic illnesses, such as occur in people with Crohn disease who are unable to absorb nutrients from their food. AN 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. Protein–energy malnutrition in infants and children living in underdeveloped countries 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. Marasmus represents a progressive loss of muscle mass and fat stores because of inadequate food intake that is equally deficient in calories and protein.35 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.35 Kwashiorkor results from a deficiency in protein.35 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 is 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. 39-7). There are “flaky paint” lesions of the skin on the face and extremities. In addition, the hair becomes a sandy or reddish color, with linear depigmentation (flag sign).36,37 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.

FIGURE 39-7

Clinical manifestations of kwashiorkor.

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 malnutrition 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 do 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 sepsis.38 Marasmus-like secondary protein– energy malnutrition typically results from chronic illnesses such as chronic obstructive pulmonary disease, congestive heart failure, cancer, and HIV infection.35 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.39 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. Because 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, and respiratory function becomes compromised because 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. 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, nutritionfocused physical examination, and laboratory tests.2 Evaluation of body composition can be assessed with weight, edema, muscle wasting, and subcutaneous fat loss. 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 is prealbumin, which has a shorter half-life and a relatively small body pool.2 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. Concurrent administration of vitamins and minerals is needed. 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. Eating Disorders Eating disorders affect an estimated 30 million Americans of all ages and gender.40 These illnesses, which include AN, BN, and BED 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.40 Eating disorders manifest in both men and women, with occurrence in women at slightly higher rates. BED is the most common of the eating disorders in the United States.41 Eating disorders are more prevalent in industrialized societies and occur in all socioeconomic and major ethnic groups. A combination of genetic, biologic, behavioral, psychological, and social factors is thought to contribute to the development of the disorders.41 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.41 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.40,42 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).43 Other psychiatric disorders often coexist with AN, including major depression or dysthymia, and obsessive–compulsive disorder. 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 refeeding. 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.40 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; there is a correlation between gray matter loss and duration of illness.44 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 by 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.40 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.45 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.42,43 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.40 The complications of BN include those resulting from overeating, selfinduced vomiting, and cathartic and diuretic abuse.40 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 alkalosis 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.40 Antidepressants such as serotonin reuptake inhibitors have been found to be useful in treating bulimia and BEDs and one, fluoxetine, has received FDA approval for treatment.46 Eating Disorder Not Otherwise Specified 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.40,42 The primary goal of therapy for BED is to establish a regular, healthful eating pattern such as 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. SUMMARY CONCEPTS 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 in (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 in (170 cm) tall and weighs 96 lb (43.5 kg). Her history reveals that she is a straight-A student, plays in the orchestra, and is on the track team. Although she had been having regular 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. Mahan L., Raymon J. (2017). Karuse’s food and nutrition care process (14th ed., pp. 31–55, 41, 57–58). St. Louis, MO: Elsevier Saunders. 2. Rosen E. D., Spiegelman B. M. (2014). What we talk about when we talk about fat. Cell 156(0), 20–44. doi:10.1016/j.cell.2013.12.012. 3. Bowden V. R., Greenberg C. S. (2014). Children and their families: The continuum of nursing care (3rd ed.). Philadelphia, PA: Wolters Kluwer. 4. Loureiro L. L., Fonseca S., Castro N. G., et al. (2015). Basal metabolic rate of adolescent modern pentathlon athletes: Agreement between indirect calorimetry and predictive equations and the correlation with body parameters. PLoS ONE 10(11), e0142859. 5. Smith I. C., Bombardier E., Vigna C., et al. (2013). ATP consumption by sarcoplasmic reticulum Ca2+ pumps accounts for 40-50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle. PLoS ONE 8(7), e68924.

6. Villablance P., Alegria J., Mookadam F., et al. (2015). Nonexercise activity thermogenesis in obesity management. Mayo Clinic Proceedings 90(4), 509–519. 7. Kominiarek M., Rajan P. (2016). Nutrition recommendations in pregnancy and lactation. Medical Clinics of North America 100(6), 1199–1215. 8. 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. 9. U.S. Department of Health and Human Services and U.S. Department of Agriculture. (2015). Dietary Guidelines for Americans 2015–2020 (8th ed.). [Online]. Available: http://health.gov/dietaryguidelines/2015/guidelines/. Accessed March 8, 2018. 10. Adamska E., Ostrowska L., Górska M., et al. (2014). The role of gastrointestinal hormones in the pathogenesis of obesity and type 2 diabetes. Przegląd Gastroenterologiczny 9(2), 69–76. doi:10.5114/pg.2014.42498. 11. Perry B., Wang Y. (2012). Appetite regulation and weight control: The role of gut hormones. Nutrition & Diabetes 2(1), e26. 12. Hruby A., Hu F. B. (2015). The epidemiology of obesity: A big picture. PharmacoEconomics 33(7), 673–689. doi:10.1007/s40273-014-0243-x1. 13. Fu Z., Gilbert E. R., Liu D. (2013). Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Current Diabetes Reviews 9(1), 25–53. 14. Ogden C. L., Carroll M. D., Fryar C. D., et al. (2015). Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS data brief, no 219. Hyattsville, MD: National Center for Health Statistics. 15. Center for Disease Control and Infection. (2017). Childhood obesity facts. [Online]. Available: https://www.cdc.gov/obesity/data/childhood.html. Accessed March 25, 2018. 16. 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 March 9, 2018. 17. World Health Organization. (2018). Obesity and overweight. [Online]. Available: http://www.who.it/mediacentre/factsheets/fs311/en. Accessed March 9, 2018. 18. Rao K. R., Lal N., Giridharan N. V. (2014). Genetic & epigenetic approach to human obesity. The Indian Journal of Medical Research 140(5), 589–603. 19. Bray G. A. (2004). The epidemic of obesity and changes in food intake: The fluoride hypothesis. Physiological Behavior 82, 115–121. 20. Malik V. S., Willett W. C., Hu F. B. (2013). Global obesity: trends, risk factors and policy implications. Nature Reviews Endocrinology 9, 13–27. doi:10.1038/nrendo.2012.199. 21. Singh M. (2014). Mood, food, and obesity. Frontiers in Psychology 5, 925. 22. Caroleo M., Primerano A., Rania M., et al. (2018). A real world study on the genetic, cognitive and psychopathological differences of obese patients clustered according to eating behaviours. European Psychiatry 48, 58–64. 23. Wang H., Chen Y. E., Eitzman D. T. (2014). Imaging body fat: Techniques and cardiometabolic implications. Arteriosclerosis, Thrombosis, and Vascular Biology 34(10), 2217–2223. 24. Lee M., Wu Y., Fried S. (2013). Adipose tissue heterogeneity: Implication of depot differences in adipose tissue for obesity complications. Molecular Aspects of Medicine 341, 1–11. 25. Barreira T., Staiano A., Harrington D., et al. (2012). Anthropometric correlates of total body fat, abdominal adiposity, and cardiovascular disease risk factors in a biracial sample of men and women. Mayo Clinic Proceeding 87(5), 452–460. 26. National Heart, Lung, and Blood Institute. (2018). [Online]. Available: https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi_dis.htm. Accessed March 25,

2018. 27. Center for Disease Control. (2014). [Online]. Available: https://www.cdc.gov/healthreport/publications/compendium.pdf. Accessed March 9, 2018. 28. American Heart Association. (2018). [Online]. Available: http://www.heart.org/HEARTORG/HealthyLiving/HealthyKids/ChildhoodObesity/Overweightin-Children_UCM_304054_Article.jsp#.Wr2LLdPwZmA. Accessed March 25, 2018. 29. Kitahara C. M., Flint A. J., Berrington de Gonzalez A., et al. (2014). Association between class III obesity (BMI of 40–59 kg/m2) and mortality: A pooled analysis of 20 prospective studies. PLoS Medicine 11(7), e1001673. doi:10.1371/journal.pmed.1001673. 30. Flament M. F., Bissada H., Spettigue W. (2012). Evidence-based pharmacotherapy of eating disorders. International Journal of Neuropsychopharmacology 15(2), 189–207, doi:10.1017/S1461145711000381. 31. Rubino F., Nathan D., Eckel R., et al. (2017). Metabolic surgery in the treatment algorithm for type 2 diabetes: A joint statement by international diabetes organizations. Obesity Surgery 27(1), 2–21. 32. FAO, IFAD, UNICEF, WFP and WHO. (2017). The state of food security and nutrition in the world: Building resilience for peace and food security. Rome: FAO. 33. Roser M., Ritchie H. (2018). Hunger and undernourishment. [Online]. Available: https://ourworldindata.org/hunger-and-undernourishment. Accessed March 25, 2018. 34. Morley J. (2012). Undernutrition in older adults. Family Practice 29, 89–93. 35. Guyton A. C., Hall J. E. (2011). Textbook of medical physiology (12th ed., pp. 807–810, 859–866, 880–887). Philadelphia, PA: Elsevier Saunders. 36. Trehan I., Manary M. J. (2015). Management of severe acute malnutrition in low-income and middle-income countries. Archives of Disease in Childhood 100, 283–287. 37. Nigam P. K., Nigam P. (2017). Premature greying of hair (premature canities): A concern for parent and child. Pigmentary Disorders 4, 261. 38. Mehta N., Corkins M., Lyman B. (2013). Defining pediatric malnutrition: A paradigm shift toward etiology-related definitions. Journal of Parenteral and Enteral Nutrition 4(37), 460–481. 39. Bharadwaj S., Ginoya S., Tandon P., et al. (2016). Malnutrition: Laboratory markers vs nutritional assessment. Gastroenterology Report 4(4), 272–280. doi:10.1093/gastro/gow013. 40. National Eating Disorders Association. (2018). [Online]. Available: https://www.nationaleatingdisorders.org/learn. Accessed March 9, 2018. 41. National Institute of Mental Health. Eating disorders. (2016). [Online]. Available: https://www.nimh.nih.gov/health/topics/eating-disorders/index.shtml. Accessed March 9, 2018. 42. National Association of Anorexia Nervosa and Associated Disorders. Statistics on eating disorders. (2016). [Online]. Available: http://www.anad.org/get-information/about-eatingdisorders/eating-disorders-statistics/. Accessed March 9, 2018. 43. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. 44. Fonville L., Giampietro V., Williams S., et al. (2014). Alterations in brain structure in adults with anorexia nervosa and the impact of illness duration. Psychological Medicine 44(9), 1965–1975. doi:10.1017/S0033291713002389. 45. O’Brien P., MacDonald L., Anderson M., et al. (2013). Long-term outcomes after bariatric surgery: Fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Annals of Surgery 257(1), 87–94. 46. American Psychiatric Association. (2012). Guideline watch (August 2012): Practice guideline for the treatment of patients with eating disorders (3rd ed.). [Online]. Available: https://psychiatryonline.org/pb/assets/raw/sitewide/practice:guidelines/guidelines/eatingdisorders -watch.pdf. Accessed March 9, 2018.

UNIT 12

Disorders of Endocrine Function

CHAPTER 40 Mechanisms of Endocrine Control The Endocrine System Hormones Hormonal 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 Hormone Stimulation and Suppression Tests Genetic Testing Imaging Learning Objectives

After completing this chapter, the learner will be able to meet the following objectives: 1. Describe the function of a hormone receptor that differentiates between cell surface hormone receptors and intracellular hormone receptors. 2. Describe the role of the hypothalamus in regulating pituitary control of endocrine function. 3. State the major difference between positive and negative feedback control mechanisms.

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 The endocrine system uses chemical substances called hormones as a means of regulating and integrating body functions. The endocrine system participates in many essential body functions, including the regulation of digestion, the usage and storage of nutrients, growth and development, electrolyte and water metabolism, and reproductive functions. The endocrine network is closely integrated with the central and peripheral nervous systems as well as with the immune systems. Therefore, the terms “neuroendocrine” and “neuroendocrine–immune” are often used to describe these interactions.1,2 Hormones Hormones are chemical messengers that are transported in body fluids. They are highly specialized organic molecules produced by endocrine cells that exert their action on specific target cells. The word hormone is from the

Greek word for “arouse to activity.”2 Hormones do not perform reactions themselves, but instead hormones function as modulators of cellular and systemic responses. Most hormones are present in body fluids at all times, in greater or lesser amounts depending on the needs of the body.3,4 Hormones are released from various organs that are “endocrine glands,” including the pituitary gland, thyroid gland, adrenal glands, and pancreas. Many other organs and tissues throughout the body also actively secrete hormonal substances that regulate activities in other areas of the body. These endocrine tissues include organs such as the heart, kidneys, liver and gastrointestinal tract, as well as lymphocytes and adipose tissue.2,3 A characteristic of hormones is that a single hormone can exert a specific effect in distant body tissues. 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 is produced by the kidney in response to renal hypoxia and then travels through the blood to stimulate erythropoiesis in the bone marrow.3 In some situations, several different hormones work together to regulate a single function. 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. Lipolysis is regulated by the actions of the catecholamines, insulin, and glucagon as well as by a cytokine, tumor necrosis factor-α.5 Table 40-1 lists the major actions and sources of selected hormones. TABLE 40-1 Major Action and Source of Selected Hormones

Source Hormone Major Action Hypothalamus Releasing and inhibiting Controls the release of pituitary hormones hormones CRH Inhibits GH and TSH TRH Inhibits prolactin release from the GHRH pituitary GnRH Inhibits FSH and LH Somatostatin Dopamine

Source Anterior pituitary

Posterior pituitary

Adrenal cortex

Hormone GH

Major Action Stimulates growth of the bone and muscle, promotes protein synthesis and fat metabolism, decreases carbohydrate metabolism ACTH Stimulates synthesis and secretion TSH of adrenal cortical hormones FSHLH 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 Prolactin Prepares female breast for breastfeeding ADH (arginine Increases water reabsorption by vasopressin [AVP]) kidney Oxytocin Stimulates contraction of pregnant uterus, milk ejection from breasts after childbirth Mineralocorticosteroids, Increases sodium absorption, mainly aldosterone potassium loss by kidney Glucocorticoids, mainly Affects metabolism of all nutrients; cortisol regulates blood glucose levels, affects growth, has antiinflammatory action, and decreases effects of stress

Source

Adrenal medulla Thyroid (follicular cells)

Parathyroid glands Pancreatic islet cells

Kidney Ovaries

Hormone Major Action Adrenal androgens, Have minimal intrinsic androgenic mainly activity; they are converted to dehydroepiandrosterone testosterone and (DHEA) and dihydrotestosterone (DHT) in the androstenedione periphery Epinephrine Serve as neurotransmitters for the sympathetic nervous system Norepinephrine Thyroid hormones: Increase the metabolic rate; triiodothyronine (T3), increase protein and bone turnover; increase responsiveness to thyroxine (T4) catecholamines; necessary for fetal and infant growth and development Calcitonin Lowers blood calcium and phosphate levels Parathyroid hormone Regulates serum calcium (PTH) Insulin Lowers blood glucose by facilitating glucose transport across cell membranes of the muscle, liver, and adipose tissue Glucagon Increases blood glucose concentration by stimulation of glycogenolysis and glyconeogenesis Somatostatin Delays intestinal absorption of glucose 1,25-Dihydroxyvitamin Stimulates calcium absorption from D the intestine Estrogen Affects development of female sex organs and secondary sex characteristics

Source

Hormone Progesterone

Major Action Influences menstrual cycle; stimulates growth of uterine wall; maintains pregnancy Testes Androgens, mainly Affect development of male sex testosterone organs and secondary sex characteristics; aid in sperm production ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. Hormonal Actions Hormonal actions are classified based on the relationship between where the hormone is produced and where the biologic effects occur. Classifications include endocrine, paracrine, autocrine, intracrine, and neuroendocrine (Chart 40-1). 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.6 Paracrine hormones and hormonelike substances never enter the bloodstream, but instead act locally in the vicinity in which they are released. 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.6 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.7 Some hormonal effects are neuroendocrine, in which the hormone (a neurohormone) is produced and released from neurons and then travels through the blood to exert effects on target cells in the body. Vasopressin (antidiuretic hormone [ADH]) and epinephrine are examples of hormonal substances with neuroendocrine effects.6 Neurohormones are subtype of signaling molecules known as neurotransmitters, which are released from neurons and traverse the synaptic cleft for a variety of postsynaptic responses.3

CHART 40.1 HORMONAL 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. Neuroendocrine: Hormone produced within a neuron and then travels through circulation to exert effects on target cells. Structural Classification Hormones have diverse structures, ranging from single amino acids to complex proteins and lipids. Hormones may be classified into four categories based on their chemical structure.2 1. Amines and amino acids 2. Peptides proteins and glycoproteins 3. Steroids 4. Fatty acids Examples of hormones for each of these structural classifications are shown in Table 40-2. TABLE 40-2 Classes of Hormones Based on Structure

Amines and Peptides, Proteins, Amino Acids and Glycoproteins Dopamine CRH Epinephrine GHRH Norepinephrine TRH Thyroid hormone ACTH FSH

Steroids

Fatty Acids

Aldosterone Glucocorticoids Estrogens Testosterone Progesterone

Prostaglandins Thromboxanes Leukotrienes Prostacyclins

Amines and Amino Acids

Peptides, Proteins, and Glycoproteins LH TSH

Steroids

Fatty Acids

Androstenedione 1,25Dihydroxyvitamin D DHT DHEA

GH ADH Oxytocin Insulin Glucagon Somatostatin Calcitonin PTH Prolactin ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PTH, parathyroid hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. 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.2 The second category of hormones, the protein-based hormones, constitutes the majority of hormones. These protein hormones 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.2–4 Although the structures of most hormonal substances are within these first three categories, there is a fourth category of hormonal messenger molecules derived from fatty acids, including the group of

chemicals called the eicosanoids. Important among this class are the arachidonic acid derivatives, which include the prostaglandins.2 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 to produce more local effects. The term intracrine describes a hormone that is synthesized and acts within the same cell. The term neuroendocrine refers to hormonal substances produced by and secreted from neurons, which then travel through the blood to exert effects on target cells. Hormones exert their actions by interacting with high-affinity cellular receptors linked to one or more effector systems in the cell. Some hormone receptors are located on cell surfaces and act through second messenger mechanisms. Others are intracellular receptors, which can act to alter processes within the cell nucleus and thereby modulate the synthesis of proteins. Synthesis and Release The mechanisms for hormone synthesis and release are not fully understood and vary with hormone structure. Some hormones are synthesized and stored in vesicles in the cytoplasm of the endocrine cell until secretion is required. These vesicle-mediated hormones are released from the originating endocrine cell in response to some type of stimuli, which is often a negative feedback mechanism. Stimulation of the endocrine cell causes the vesicles to move to the cell membrane and release their hormones.3 The protein hormones are typically synthesized in the form of a precursor hormone that contains additional peptide units that ensure proper folding of the molecule and insertion of essential linkages. This type of precursor hormone molecule is called a prohormone.3 Cholesterol-based hormones are not stored in vesicles; instead, these lipid-soluble molecules, which are often produced in smooth endoplasmic

reticulum, typically leave the cell as soon as they are synthesized by diffusing across the cell membrane.3 Hormones synthesized by these non– vesicle-mediated pathways include the glucocorticoids, androgens, estrogens, and mineralocorticoids, which are all steroid hormones derived from cholesterol. Certain steroids serve as precursors for the production of other hormones.3 Transport When hormones are released into the bloodstream, they circulate either as free, unbound molecules or as hormones attached to transport carriers (Fig. 40-1). Peptide hormones and protein hormones are water-soluble molecules and usually do not require a transport carrier. Steroid hormones and thyroid hormones are lipophilic molecules and, therefore, do require a carrier protein for transport through the blood. The liver synthesizes specific carrier proteins for steroid hormones and thyroid hormones.3 The extent of protein 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 in the blood by one half—is positively correlated with its percentage of protein binding.3 Thyroxine, which is more than 99% protein bound, has a half-life as long as 6 days. In contrast, angiotensin II is freely water soluble with a half-life less than 1 minute.3 Drugs that compete with a hormone for binding with transport carrier molecules increase hormone action by increasing the availability of the active unbound hormone.8

FIGURE 40-1

Relationship of free and carrier-bound hormones.

Metabolism and Elimination Hormones secreted by endocrine cells must be inactivated continuously to prevent their accumulation. Intracellular and extracellular mechanisms participate in the inactivation 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 life span in the circulation. Their major mechanism of degradation is through binding to cell surface receptors, with subsequent uptake and degradation by peptide-splitting enzymes in the cell membrane or inside the cell.2,3 Most 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. Transport carriers may be specific carrier molecules for the individual hormone or may be plasma proteins such as albumin. Notable exceptions to the requirement of a protein carrier for steroid hormones are the mineralocorticoids, including aldosterone, which do not require protein carriers.2 Mechanisms of Action Hormones produce their effects through interaction with high-affinity receptors, which, in turn, are linked to one or more effector systems within the cell. 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.2,3 The rate at which hormones react depends on their mechanism of action. Receptors Hormone receptors are complex molecular structures (usually proteins) that are located either on the cell surface or inside target cells.3 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 is specific to a particular hormone, which 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 degree of responsiveness of a target cell to a hormone varies with the number of receptors present and with the affinity of these receptors for hormone binding.3 Antibodies may destroy or block the receptor proteins. Increased or decreased hormone levels often induce changes in the activity of the genes that synthesize hormone receptors. Decreased hormone levels often produce an increase in receptor numbers by means of a process called upregulation, increasing the sensitivity of the body to the hormone. Upregulation of hormone receptors may be an adaptive response when there are low levels of hormone in the body. Sustained levels of excess hormone often lead to a decrease in receptor numbers through downregulation of the cellular synthesis of receptors, producing a decrease in hormone sensitivity.3 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 upregulation and downregulation of receptors is regulated largely by inducing or repressing the transcription of receptor genes.3 Some hormone receptors are located on the surface of the cell and act through second messenger mechanisms to influence cellular activity, whereas other receptors are located inside the cell. Whether the receptors are cell surface receptors or intracellular receptors, the ultimate effect of the hormone is usually exerted in the cell nucleus with the modulation of protein synthesis.2,3 Chart 40-2 lists examples of hormones that act through the two types of receptors. CHART 40.2 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.

Peptide hormones and catecholamines tend to be water-soluble molecules that are electrically charged (polar) molecules. Because of their low lipid solubility and high electrical charge, peptide hormones and catecholamines cannot readily cross the lipid cellular membrane.2,3 Instead, these hormones interact with surface receptors to generate an intracellular signal through a second messenger signaling system, with the hormone acting as the first messenger. The first messenger hormone signals the need for action; however, the hormone itself never enters the cell. It is the second messenger molecules inside the cell that interact directly with the intracellular control mechanisms to effect the change.2,3 For example, the first messenger hormone glucagon binds to surface receptors on liver cells to send a second intracellular message for glycogen breakdown.2,3 Intracellular Receptors. Lipid-soluble hormones (such as steroid hormones and the thyroid hormones) are typically nonpolar and can pass freely through cell membranes to bind with intracellular receptors.2,3 The intracellular hormone–receptor complex can then directly exert the hormonal effects by entering the cell nucleus to bind with hormone response elements that activate or suppress intracellular mechanisms of protein synthesis.2,3 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.2 Others, such as the female sex hormones, are secreted in a complicated cyclic manner. The levels of hormones, such as insulin and ADH, are regulated by feedback mechanisms that monitor substances such as glucose (insulin) and water (ADH) in the body. 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 gland form a functional unit that exerts control over the activities of several endocrine glands and thus a wide range of physiologic functions. The hypothalamus is located centrally in the brain

and serves as the coordinating center of the brain for endocrine, behavioral, and autonomic nervous system function. It is at the level of the hypothalamus that emotion, pain, body temperature, and other neural inputs are communicated to the endocrine system.3 The pituitary gland is connected to the floor of the hypothalamus by the pituitary stalk, with the main structural portion of the pituitary gland encased in a bony structure called the sella turcica. The opening to the sella turcica is bridged over by the diaphragma sellae, which protects the pituitary gland from the transmission of the pressures from the cerebrospinal fluid.6 The pituitary gland is also called the “hypophysis.” The pituitary consists of two structurally different sections (Fig. 40-2):

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. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. FIGURE 40-2

1. The anterior pituitary, also called the adenohypophysis because of its glandular structure. The hypothalamus and anterior pituitary are connected by blood flow through the hypophyseal portal venous system, which begins in the hypothalamus and drains into the anterior pituitary gland. 2. The posterior pituitary, also called the neurohypophysis. The hypothalamus and posterior pituitary are connected through nerve axons from neurons that originate in the hypothalamus and connect the supraoptic and paraventricular nuclei of the hypothalamus with the posterior pituitary gland. 3. Melanocyte-stimulating hormones (MSH) are produced in the intermediate part of the pituitary gland. MSH regulates the production of melanin which provides protection against harmful ultraviolet rays from the sun. Hypothalamic Hormones The hypothalamus produces hormones that act upon the anterior pituitary to regulate the synthesis and release of anterior pituitary hormones. These hypothalamic hormones are called releasing hormones (RHs) or inhibiting hormones, based on the response sent to the anterior pituitary. RHs signal for the anterior pituitary to increase the synthesis and release of a particular hormone, whereas inhibiting hormones have the reverse effect—decreased hormonal release by the anterior pituitary. These RHs and inhibiting hormones travel to the anterior pituitary through a localized portal venous system2,3 (Fig. 40-2). 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).2,3 The hypothalamus also sends regulatory signals to the posterior pituitary; however, the route through which the message is conducted is through nerve tracts instead of through release of hormones into the blood. The posterior pituitary is called the neurohypophysis because it contains a series of neurons whose cell bodies are located in the hypothalamus and axons extend down into the posterior pituitary. The posterior pituitary can essentially be thought of as an extension of the hypothalamus. 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.2,3 The activity of the hypothalamus is regulated by both hormonally mediated signals (e.g., negative feedback signals) and neuronal input from a number of sources. Neuronal signals are mediated by neurotransmitters, such as acetylcholine, dopamine, norepinephrine, serotonin, γ-aminobutyric acid, and opioids. Cytokines that are involved in immune and inflammatory responses, such as the interleukins, are also 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 gland.2,3 (Fig. 40-3).

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. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CNS, central nervous system; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroidstimulating hormone. FIGURE 40-3

Pituitary Hormones The pituitary gland has been called the master gland because its hormones control the functions of many target glands and cells.2 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 luteinizing hormone [LH]), and breast growth and milk production (prolactin). Hypothalamic RHs regulate most of the pituitary hormones. GH secretion is stimulated by GHRH, TSH by TRH, ACTH by CRH, and LH and FSH by GnRH.2,3 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.

1 Cell Surface Receptors

Water-soluble peptide hormones (such as parathyroid hormone and glucagon) cannot penetrate the lipid layer of the cell plasma membrane and, therefore, 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 hormoneregulated 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. The second messenger, in turn, activates other enzymes that participate in cellular secretion, gene activation, or other target cell responses.

2 Nuclear Receptors

Steroid hormones, vitamin D, thyroid hormones, and other lipidsoluble hormones diffuse across the cell membrane into the cytoplasm of the target cell. Once inside the cell, these hormones bind to an intracellular receptor that is activated by the binding and then moves to

the nucleus, where the hormone binds to a hormone response element in the promoters on a target gene or to another transcription factor. This binding results in transcription of a specific messenger RNA, which moves into the cytoplasm, where the “transcribed message” is translated by cytoplasmic ribosomes to produce new cellular proteins or to change the production of existing proteins. This hormone-directed change in protein synthesis leads to cellular responses, such as the promotion of a specific intracellular response or the synthesis of specific proteins to be secreted from the cell. Feedback Regulation The level of many of the hormones in the body is regulated by negative feedback mechanisms.2,3 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. 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 the production and release of hormones decrease. The feedback loops for the hypothalamic–pituitary feedback mechanisms are illustrated in Figure 40-3. In positive feedback control, rising levels of a hormone cause another gland to release a hormone that is stimulating to the first.3 An example is 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.3 Diagnostic Tests Many techniques are available for assessing endocrine function and hormone levels. Diagnostic assessments include blood tests, urine tests, hormone stimulation and suppression tests, genetic testing, and diagnostic imaging studies. Blood Tests

Blood tests for endocrine disorders encompass a wide variety of strategies to assess endocrine function. Hormones can be measured directly or, very commonly, physiologic indicators of hormone function can be measured to indirectly reflect hormone levels. Blood hormone levels provide information about hormone levels at a specific time under specific conditions. 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.

1 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.

2 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 RH 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.

3 Positive Feedback

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. Hormone levels in plasma are measured using radioimmunoassay (RIA) methods based on the competitive binding of hormones.3 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 limitations of RIA include a lack of specificity because of cross-reactivity with more than one hormone.3 The immunoradiometric assay (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; therefore, IRMA is more specific.9 Enzyme-linked immunosorbent assay (ELISA) assesses endocrine function and does not require the use of radioisotopes. ELISA testing combines the use of antibody testing using two antibodies that use different antigen-binding sites (which allows higher specificity) with an enzyme testing approach (which has high sensitivity). The ELISA test method is widely used and has been demonstrated to be both cost-effective and accurate.3 Other blood tests that are routinely measured in endocrine disorders include tests for various autoantibodies.10,11 Urine Tests Measurements of urinary hormone or hormone metabolite excretion are often 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. In particular, a 24-hour urine sample for urinary cortisol levels is frequently performed in the diagnostic workup for Cushing syndrome.12 Hormone Stimulation and Suppression Tests Hormone 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.2 Suppression tests are used when hyperfunction of an endocrine organ is suspected. When an organ or a tissue is functioning autonomously, a suppression test may be useful to confirm the situation. Genetic Testing Genetic testing is rapidly becoming an important approach for the diagnosis of selected endocrine disorders. Some endocrine-related disorders for which specific genetic pathophysiologic markers have been identified include Xlinked hypophosphatemic rickets, epithelial thyroid carcinoma,

hypopituitarism, familial pheochromocytoma and paraganglioma, multiple endocrine neoplasia types I and II, and certain disorders of short stature, including Turner syndrome.2 A drawback to genetic testing is the cost, which, at this point in the development of the technology, can still be quite expensive.2 Imaging Imaging studies are important in the diagnosis and follow-up of endocrine disorders. Imaging modalities related to endocrinology can be divided into nonisotopic and isotopic types. Nonisotopic imaging includes magnetic resonance imaging (MRI) and computed tomography (CT) scanning, both of which provide important information about structural changes within solid tissue. An advantage of MRI is that it does not require the use of ionizing radiation (which is required for CT scanning). An issue that must be considered with CT scanning is the use of contrast agents. Nonradioactive iodine is often used as a contrast agent to enhance the quality of CT images. Iodine contrast preparations must be used with caution with a person with renal disease and allergies.2 Ultrasonographic scanning provides good structural imaging and has the advantages of providing a “real-time” image that does not use radioactive elements. Therefore, ultrasonography is frequently used to aid in visualization of a lesion for biopsy.2 Dual-electron x-ray absorptiometry is used routinely for the diagnosis and monitoring of osteoporosis and metabolic bone diseases.13 Isotopic imaging includes nuclear medicine imaging studies performed after administering a radioisotope, which is selectively taken up by the tissue being investigated.2 Positron emission tomography (PET) scanning is another isotopic method, which is being used more widely in evaluating selected endocrine disorders, such as detecting the presence of metastatic thyroid cancers. PET scanning involves the administration of a short-lived radionuclide emitter of positrons in a form that is taken up by body tissues.2 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. The advantage of PET/CT is that the CT component allows a good examination of the tissue structure,

whereas the PET component provides information about tissue function.14 PET/CT has been demonstrated to be useful in managing thyroid cancers.15 SUMMARY CONCEPTS 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 interconnects the nervous system and the endocrine system; this central network controls the output from many of the other glands in the body. 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 used to visualize endocrine structures, and genetic techniques are used to determine the presence of genetic markers specific for selected endocrine disorders.

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 endogenously produced cortisol. A. Explain, using information regarding the hypothalamic– pituitary feedback, control of cortisol production by the adrenal cortex.

REFERENCES 1. Verburg-van Kemenade B. M. L., Cohen N., Chadzinska M. (2017). Neuroendocrine-immune interaction: Evolutionarily conserved mechanisms that maintain allostasis in an ever-changing environment. Developmental and Comparative Immunology 66, 2–23. doi:10.1016/j.dci.2016.05.015. 2. Neal J. M. (2016). How the endocrine system works (2nd ed.). West Sussex: John Wiley & Sons. 3. Hall J. E. (2015). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Elsevier. 4. Saladin K. S. (2015). Anatomy & physiology: The unity of form and function (7th ed.). New York: McGraw Hill Education. 5. Fruhbeck G., Mendez-Gimenez L., Fernandez-Formoso J. A., et al. (2014). Regulation of adipocyte lipolysis. Nutrition Research Reviews 27, 63–93. doi:10.1017/S095442241400002X. 6. Rubin R., Strayer D. S., Saffitz J. E., et al. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.) Philadelphia, PA: Wolters Kluwer. 7. Styne D. M. (2016). Pediatric endocrinology: A clinical handbook. Switzerland: Springer. 8. Ildrose A. M. (2015). Acute and emergency care for thyrotoxicosis and thyroid storm. Acute Medicine and Surgery 2, 147–157. doi:10.1002/ams2.104. 9. Government of India Department of Atomic Energy Board of Radiation and Isotope Technology. (2016). Frequently asked questions: Medical & biological products. [Online]. Available: http://www.britatom.gov.in/htmldocs/faqs_ec3.html. Accessed June 21, 2019. 10. American Association for Clinical Chemistry. (2014). Autoantibodies. Available: https://labtestsonline.org/tests/autoantibodies. Accessed June 21, 2019. 11. Kemp E. H., Weetman A. P. (2015). Autoimmune hypoparathyroidism. In Brandi M., Brown E. (Eds.), Hypoparathyroidism. Milano: Springer. 12. American Association for Clinical Chemistry. (2016). Cushing syndrome. [Online]. Available: https://labtestsonline.org/conditions/cushing-syndrome. Accessed June 21, 2019. 13. The Royal Australian and New Zealand College of Radiologists. (2018). Bone mineral density scan (Bone Densitometry or DXA Scan). [Online]. Available: https://www.insideradiology.com.au/bone-mineral-density-scan-hp/. Accessed June 21, 2019. 14. The American Board of Nuclear Medicine. (2017). What is PET/CT? [Online]. Available: https://www.abnm.org/index.php/sample-page-2/what-is-petct/. Accessed June 21, 2019. 15. Marcus C., Whitworth P. W., Surasi D. S., et al. (2014). PET/CT in the management of thyroid cancers. American Journal of Roentgenology 202, 1316–1329. doi:10.2214/AJR.13.11673.

CHAPTER 41 Disorders of Endocrine Control of Growth and Metabolism General Aspects of Altered Endocrine Function Hypofunction, Hyperfunction, and Hormone Resistance Primary, Secondary, and Tertiary Disorders Pituitary and Growth Disorders Assessment of Hypothalamic–Pituitary Function Pituitary Tumors Hypopituitarism Growth and Growth Hormone Disorders Growth Hormone Short Stature in Children Growth Hormone Deficiency in Children Growth Hormone Deficiency in Adults Tall Stature in Children Growth Hormone Excess in Children Growth Hormone Excess in Adults 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 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 General Aspects of Altered Glucose Regulation Hormonal Control of Glucose, Fat, and Protein Metabolism Glucose Metabolism Fat Metabolism Protein Metabolism Glucose-Regulating Hormones Insulin Glucagon

Somatostatin, Amylin, and Gut-Derived Hormones Counter-Regulatory Hormones Epinephrine Growth Hormone Glucocorticoid Hormones Diabetes Mellitus and the Metabolic Syndrome Overview, Incidence, and Prevalence Testing for Diagnosis and Management Blood Tests Urine Tests Classifications and Pathophysiology Prediabetes Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus and the Metabolic Syndrome Gestational Diabetes Diabetes due to Other Causes Clinical Manifestations of Diabetes Mellitus Treatment Complications of Diabetes Mellitus Acute Complications of Diabetes Diabetic Ketoacidosis Hyperosmolar Hyperglycemic State Hypoglycemia Diabetic Complications Related to Counter-Regulatory Mechanisms The Somogyi Effect The Dawn Phenomenon Chronic Complications of Diabetes Mellitus Microvascular Complications Macrovascular Complications Diabetic Foot Ulcers Infections Learning Objectives After completing this chapter, the learner will be able to meet the following objectives:

1. Describe the mechanisms of endocrine hypofunction, hyperfunction, and hormone resistance. 2. Differentiate among primary, secondary, and tertiary endocrine disorders. 3. Describe the clinical features and causes of hypopituitarism. 4. Analyze the effects of a deficiency in growth hormone (GH). 5. Relate the functions of GH to the manifestations of acromegaly and adult-onset GH deficiency. 6. Characterize the synthesis, transport, and regulation of thyroid hormone. 7. Describe the various tests in the diagnosis and management of thyroid disorders. 8. Describe the function of the adrenal cortical hormones and their feedback regulation. 9. Relate the functions of the adrenal cortical hormones to Addison disease (i.e., adrenal insufficiency) and Cushing syndrome (i.e., glucocorticoid excess). 10. Discuss the functions of glucose, fats, and proteins in meeting the energy needs of the body. 11. Discuss the actions of insulin with respect to glucose, fat, and protein metabolism. 12. Explain what is meant by counter-regulatory hormones, and describe the actions of glucagon, epinephrine, GH, and the glucocorticoid hormones in regulation of blood glucose levels. 13. Discuss the statistics of incidence and prevalence of diabetes mellitus (DM). 14. Differentiate the types of blood and urine testing used in the diagnosis and management of DM. 15. Differentiate the distinguishing features of the four classifications of DM (type 1, type 2, gestational, and diabetes due to other causes). 16. Discuss the metabolic syndrome and its relationship with type 2 DM. 17. Differentiate among common acute complications of diabetes: diabetic ketoacidosis, hyperosmolar hyperglycemic state, and hypoglycemia. 18. Discuss the complications of diabetes related to counter-regulatory hormones: the Somogyi effect and the dawn phenomenon.

19. Differentiate among common chronic complications of diabetes: microvascular effects, macrovascular effects, diabetic foot ulcers, and infections.

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 the disorders of pituitary function, growth and growth hormone (GH), thyroid function, and adrenal cortical function. This chapter also addresses the increasingly prevalent conditions of diabetes mellitus (DM) and the metabolic syndrome.

General Aspects of Altered Endocrine Function Hypofunction, Hyperfunction, and Hormone Resistance Disturbances of endocrine function usually are related to either hypofunction or hyperfunction of an endocrine gland or to hormone resistance of the target cells. Hypofunction of an endocrine gland can occur for a variety of reasons, such as the absence or impaired development of a gland or deficiency of an enzyme needed for hormone synthesis. The gland may be destroyed by a disruption in blood flow, infection, inflammation, autoimmune responses, or neoplastic growth. Decline in function may occur with aging, or an endocrine gland may atrophy as a result of drug therapy or for unknown reasons. A gland may produce a biologically inactive hormone, or circulating antibodies may destroy an active hormone before it can exert its action.1-3 Endocrine hyperfunction usually is due to excessive hormone production. This can result from excessive stimulation and hyperplasia of the endocrine gland or from a hormone-producing tumor. A tumor can produce hormones that are not normally secreted by the tissue from which the tumor is derived (ectopic hormone production).1-3 Endocrine dysfunction because of hormone resistance may be associated with receptor defects at the target cells. Hormone receptors may be absent

or the receptor binding of hormones may be defective. Laron syndrome is a type of dwarfism that is caused by abnormalities in the receptors for GH in target tissues. Another mechanism associated with hormone resistance is an impaired intracellular responsiveness to stimulation by the hormone. This impaired cellular responsiveness occurs in congenital adrenal hyperplasia (CAH) in which the adrenal gland is receiving stimulation by adrenocorticotropic hormone (ACTH) but cannot respond appropriately because of a defect in the intracellular pathways within the adrenal cortex for production of cortisol.1-3 Primary, Secondary, and Tertiary Disorders Endocrine disorders can be considered as primary, secondary, and tertiary disorders, related to the cascade of hormonal responses regulated through the hypothalamic–pituitary–target endocrine gland axis. Primary disorders of endocrine function originate in the target endocrine gland responsible for producing the hormone.1,2 In secondary disorders of endocrine function, the target endocrine gland is essentially normal; however, the gland is not producing appropriate levels of hormone because it is not receiving appropriate stimulation from the pituitary gland. The actual source of dysfunction is at the level of the pituitary gland. An example of a secondary endocrine disorder is a pituitary adenoma that results in increased secretion of pituitary hormones and excessive stimulation of target endocrine glands such as the adrenal glands and thyroid gland.1,2 A tertiary disorder results from hypothalamic dysfunction (as may occur with craniopharyngiomas or cerebral irradiation). Thus, both the pituitary and target organ are understimulated.3 SUMMARY CONCEPTS Endocrine disorders typically occur as the result of either hypofunction or hyperfunction of an endocrine gland or as a result of hormone resistance by target cells. Endocrine disorders can be classified as a primary disorder (because of a dysfunction of a target endocrine gland of the hypothalamic–pituitary axis, such as the thyroid gland or the adrenal glands), a secondary disorder (because of

dysfunction of the pituitary gland), or a tertiary disorder (resulting from a defect in the hypothalamus).

Pituitary and Growth Disorders 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 that is the neural component (neurohypophysis) and an anterior glandular lobe (adenohypophysis).4,5 The anterior lobe of the pituitary gland produces ACTH, thyroidstimulating hormone (TSH), GH, the gonadotrophic hormones (folliclestimulating 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 in the ovaries and testes. FSH regulates fertility in the ovaries and testes.4,5 Assessment of Hypothalamic–Pituitary Function A general overview of the various strategies available for assessing endocrine function is provided in Chapter 40. Assessment of the baseline status of the hypothalamic–pituitary and target cell hormones may include measuring the following (ideally the laboratory specimens are obtained before 8:00 AM because of circadian variations): Serum cortisol Serum prolactin Serum thyroxine and TSH Serum testosterone (male), serum estrogen (female), and serum LH/FSH Serum GH and serum insulin-like growth factor-1 (IGF-1, also known as somatomedin C) Plasma osmolality and urine osmolality

Additional diagnostic methods include dynamic testing of hypothalamic– pituitary–adrenal (HPA) axis function, as well as the insulin tolerance test, glucagon stimulation test, and short Synacthen (corticotropin) test.6 Pituitary Tumors Pituitary tumors can be divided into primary and secondary tumors. 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. Small, nonfunctioning tumors are found in up to 27% of adult autopsies.1 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 41-1).1 TABLE 41-1 Frequency of Adenomas of the Anterior Pituitary

Cell Type

Hormone

Frequency (%) 26 14 15 8

Lactotrope Prolactin Somatotrope Growth hormone Corticotrope Adrenocorticotropic hormone Gonadotrope Follicle-stimulating hormone, luteinizing hormone Thyrotrope Thyroid-stimulating hormone 1 Adapted from Strayer D., Rubin E., Saffitz J. E., Schiller A. L. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Table 27.1, p. 1177). Philadelphia, PA: Wolters Kluwer, with permission.) Hypopituitarism Hypopituitarism is characterized by a decreased secretion of pituitary hormones and is associated with increased morbidity and mortality. The

cause may be congenital or may result from a variety of acquired abnormalities (Chart 41-1).2 CHART 41.1 CAUSES OF HYPOPITUITARISM Tumors and mass lesions—pituitary adenomas, cysts, metastatic cancer, and other lesions Pituitary surgery or radiation Infiltrative lesions and infections—hemochromatosis and lymphocytic hypophysitis Pituitary infarction—infarction of the pituitary gland after substantial blood loss during childbirth (Sheehan syndrome) Pituitary apoplexy—sudden hemorrhage into the pituitary gland Genetic diseases—rare congenital defects of one or more pituitary hormones Empty sella syndrome—an enlarged sella turcica that is not entirely filled with pituitary tissue Hypothalamic disorders—tumors and mass lesions (e.g., craniopharyngiomas and metastatic malignancies), hypothalamic radiation, infiltrative lesions (e.g., sarcoidosis), trauma, and infections Typically, approximately 75% of the anterior pituitary must be destroyed before hypopituitarism becomes clinically evident.2 The clinical manifestations of hypopituitarism usually occur gradually but can present as an acute and life-threatening condition. People usually complain of being chronically unfit, with weakness, fatigue, loss of appetite, impairment of sexual function, and cold intolerance. ACTH deficiency (secondary adrenal insufficiency) is the most serious endocrine deficiency, leading to weakness, nausea, anorexia, fever, and postural hypotension.3 Anterior pituitary hormone loss tends to follow a typical sequence, especially with progressive loss of pituitary reserve because of tumors or previous pituitary radiation therapy. The sequence of loss of pituitary hormones can be remembered by the mnemonic “Go Look For The Adenoma”:

GH (GH secretion typically is first to be lost) LH (results in sex hormone deficiency) FSH (causes infertility) TSH (leads to secondary hypothyroidism) ACTH (usually the last to become deficient, results in secondary adrenal insufficiency)7 Treatment of hypopituitarism includes treating any identified underlying cause. Hormone deficiencies should be treated as dictated by baseline hormone levels and more sophisticated pituitary testing where appropriate. Cortisol replacement is started when ACTH deficiency is present, thyroid replacement is started when TSH deficiency is detected, and sex hormone replacement is started when LH and FSH are deficient. GH replacement is indicated for pediatric GH deficiency and may also be used to treat GH deficiency in adults.1-3 Growth and Growth Hormone Disorders Several hormones are essential for normal body growth and maturation, including GH, insulin, thyroid hormone, and androgens. In addition to its actions on carbohydrate and fat metabolism, insulin plays an essential role in growth processes. Children with diabetes, particularly those who have difficulty with balancing blood sugar, often fail to grow normally even though GH levels are normal. When levels of thyroid hormone are lower than normal, bone growth and epiphyseal closure are delayed. Androgens such as testosterone and dihydrotestosterone exert anabolic growth effects through their actions on protein synthesis. Glucocorticoids at excessive levels inhibit growth, apparently because of their antagonistic effect on GH secretion.4,8,9 Growth Hormone GH, also called somatotropin, is a 191-amino acid polypeptide hormone synthesized and secreted by special cells in the anterior pituitary called somatotropes. It is now known that the rate of GH production in adults is almost as great as it is in children. GH is necessary for growth and contributes to the regulation of metabolic functions (Fig. 41-1). GH stimulates all aspects of cartilage growth. One of the most obvious effects of GH is on linear bone growth, resulting from its action on the epiphyseal

growth plates of long bones. The width of bone increases because of enhanced periosteal growth. Visceral and endocrine organs, skeletal and cardiac muscle, skin, and connective tissue all undergo increased growth in response to GH.1,4

Growth-promoting and anti-insulin effects of growth hormone. FFA, free fatty acids; IGF-1, insulin-like growth factor-1. FIGURE 41-1

Additionally, GH facilitates the rate of protein synthesis in the body. It enhances fatty acid mobilization, increases the use of fatty acids for fuel, and maintains or increases blood glucose levels by decreasing the use of glucose for fuel.4 GH has an initial effect of increasing insulin levels. However, the predominant effect of prolonged GH excess is to increase glucose levels despite an insulin increase. This is because GH induces a

resistance to insulin in the peripheral tissues, inhibiting the uptake of glucose by muscle and adipose tissues.4 Many of the effects of GH depend on IGFs, also called somatomedins, which are produced mainly by the liver. GH cannot directly cause bone growth. Instead, it acts indirectly by causing the liver to produce IGF. These IGF peptides act on cartilage and bone to promote their growth. At least four IGFs have been identified. Of these, IGF-1 (somatomedin C) appears to be the more important in terms of growth. It is also the most frequently measured IGF in laboratory tests. The IGFs have been sequenced and have structures similar to those of proinsulin. This explains the insulin-like activity of the IGFs and the weak action of insulin on growth. IGF levels are themselves influenced by a family of six-binding factors called IGFbinding proteins (IGFBPs).4 GH is carried unbound in the plasma and has a half-life of less than 50 minutes.4 Two hypothalamic hormones regulate the secretion of GH: GH-releasing hormone (GHRH) that increases GH release Somatostatin that inhibits GH release The secretion of GH fluctuates over a 24-hour period, with peak levels occurring 1 to 4 hours after onset of sleep. GH secretion is stimulated by hypoglycemia, fasting, starvation, increased blood levels of amino acids (particularly arginine), and decreased blood levels of fatty acids. Stress conditions such as trauma, excitement, emotional stress, and heavy exercise also increase GH, as does secretion of the hormone ghrelin by the stomach and the hormones estrogen and testosterone. GH is inhibited by increased glucose levels, levels of free fatty acids (FFAs) in the blood, cortisol, and obesity. GH levels also decrease with aging.4 KEY POINTS Growth Hormone Growth hormone (GH), which is produced by somatotropes in the anterior pituitary, is necessary for linear bone growth in children. It also increases the rate at which cells transport amino acids across their cell membranes, and it increases the rate at which they use fatty acids and decreases the rate at which they use carbohydrates.

The effects of GH on linear growth are dependent upon IGFs, which are produced mainly by the liver. Short Stature in Children Short stature is a condition in which height is less than the third percentile on the appropriate growth curve.10,11 Short stature, or growth retardation, may have a variety of endocrine causes, including GH deficiency, hypothyroidism, and panhypopituitarism (i.e., deficiency of all pituitaryderived hormones). A variety of other genetic and chromosomal causes of short stature have been noted, including Turner syndrome, Noonan syndrome, achondroplasia, and various types of skeletal dysplasias.12 Other conditions known to cause short stature include protein–calorie malnutrition, chronic diseases such as chronic kidney disease and poorly controlled DM, malabsorption syndromes (including celiac disease), and certain pharmacologic therapies such as steroids, anticonvulsants, and drugs for attention deficit and hyperactivity. Emotional disturbances can lead to functional endocrine disorders, causing psychosocial dwarfism, which is also referred to as psychosocial short stature. The causes of short stature are summarized in Chart 41-2.1,2,10,11 CHART 41.2 CAUSES OF SHORT STATURE Variants of Normal Genetic or “familial” short stature Constitutional short stature Low Birth Weight (e.g., Intrauterine Growth Retardation) Endocrine Disorders GH deficiency Primary GH deficiency Idiopathic GH deficiency Pituitary agenesis Secondary GH deficiency (panhypopituitarism) Biologically inactive GH production

Deficient IGF-1 production in response to normal or elevated GH (Larontype dwarfism) Hypothyroidism Diabetes mellitus in poor control Glucocorticoid excess Endogenous (Cushing syndrome) Exogenous (glucocorticoid drug treatment) Abnormal mineral metabolism (e.g., pseudohypoparathyroidism) Chronic Illness and Malnutrition Chronic organic or systemic disease (e.g., asthma, especially when treated with glucocorticoids; heart or renal disease) Nutritional deprivation Malabsorption syndrome (e.g., celiac sprue) Functional Endocrine Disorders (Psychosocial Dwarfism) Chromosomal Disorders (e.g., Turner Syndrome) Skeletal Abnormalities (e.g., Achondroplasia) GH, growth hormone; IGF, insulin-like growth factor. A thorough physical and history, including developmental history, is important in diagnosing growth disorders. Accurate measurement of height and weight is an important part of the physical examination of children, with careful evaluation and tracking on growth curves. Diagnosis of short stature is not made on a single measurement but is based on sequential height measurements, velocity of growth, and parental height.11,13 The diagnostic procedures for children with short stature include tests to exclude nonendocrine causes. Suggested tests for conditions that may cause short stature include: complete blood count (anemia), comprehensive metabolic panel (renal and hepatic disease), C-reactive protein (CRP) and erythrocyte sedimentation rate (inflammatory bowel disease), FSH and karyotyping (Turner syndrome and other chromosomal abnormalities), IGF1 (GH deficiency), TSH and free thyroxine (hypothyroidism), tissue transglutaminase and immunoglobulin-A (celiac disease), and urinalysis (renal disease).11 Test for IGFBP-3 may also be useful to assess for GH deficiency and chronic disease.11 Radiologic films are used to assess bone age, which often is delayed.14 Magnetic resonance imaging (MRI) of the hypothalamic–pituitary area is recommended if a lesion is clinically suspected.9 After the cause of short stature has been determined, treatment

with recombinant DNA GH is approved for certain disorders, including GH deficiency, certain genetic problems (such as Prader–Willi syndrome and Noonan syndrome), chronic renal disease, and idiopathic short stature.11 Familial and Constitutional Short Stature Two forms of short stature, genetic (familial) short stature and constitutional delay of growth and puberty, are not disease states but variations from population norms. These conditions require monitoring but not treatment. Genetically, short children tend to be well proportioned and to have a height close to the midparental height of their parents. The bone age and chronologic age of these children are equivalent. Children who have constitutional delay of growth have bone age that is less than the chronologic age, with the absence of other causes of decreased growth.11,13 Psychosocial Dwarfism (Psychosocial Short Stature) Psychosocial dwarfism involves a functional hypopituitarism and is seen in some emotionally deprived children. These children usually present with poor growth, potbelly, and poor eating and drinking habits. Typically, there is a history of disturbed family relationships in which the child has been severely neglected or disciplined. Often, the neglect is confined to one child in the family. GH function usually returns to normal after the child is removed from the constraining environment. The prognosis depends on improvement in behavior and catch-up growth.15 Growth Hormone Deficiency in Children Several forms of GH deficiency present in childhood. Children with GH deficiency often present with physical findings of short stature (pituitary dwarfism), increased subcutaneous fat in the abdominal area, immature facial features with frontal bossing, delayed dentition, and an underdeveloped nasal bridge.14 Several genetic mutations have been identified in the gene that codes for GH; however, some children present with idiopathic GH deficiency in which none of the known mutations are found. Childhood GH deficiency can also occur as a result of pituitary tumors. When short stature is caused by a GH deficiency, replacement therapy with GH produced by recombinant DNA technology is the treatment of choice. GH is administered by daily subcutaneous injection during the period of active growth and can be continued into adulthood.4,11,16

In a rare condition called Laron syndrome (or Laron dwarfism), the pathophysiologic problem is hormone resistance because of abnormal GH receptors. GH levels are normal or elevated; however, levels of IGF-1 are low. Laron syndrome can be treated with IGF-1 replacement. Transmission of Laron syndrome is through autosomal recessive inheritance, with over 30 different mutations of GH receptors identified.1 Growth Hormone Deficiency in Adults There are two categories of GH deficiency in adults: 1. GH deficiency that was present in childhood 2. GH deficiency that developed during adulthood, mainly as the result of hypopituitarism resulting from a pituitary tumor or its treatment Some of the differences between childhood and adult-onset GH deficiency are described in Table 41-2. TABLE 41-2 Differences between Childhood and Adult-Onset Growth Hormone Deficiency

Characteristic Childhood Onset Adult height ↓ Body fat ↑ Lean body mass ↓↓ Bone mineral density ↓ IGF-1 ↓↓ IGF binding protein-3 ↓ Low-density lipoprotein cholesterol ↑ High-density lipoprotein cholesterol NL, ↓ IGF, insulin-like growth factor; NL, normal.

Adult Onset NL ↑ ↓ NL, ↓ NL, ↓ NL ↑ ↓

The diagnosis of GH deficiency in adults is made by finding subnormal serum GH responses to provocative stimuli. A low IGF-1 level in the presence of low levels of three or more pituitary hormones indicates GH deficiency. Either the insulin tolerance test or the combination of the GHRH and arginine test is used as stimulation tests to detect GH deficiency.17

Treatment with recombinant GH replacement is indicated for adults with documented GH deficiency, with serum IGF-1 levels used to guide treatment.17 The risk of atherosclerosis has been shown to be increased in children with GH deficiency. Treatment with GH has been demonstrated to improve the lipid profile and reduce the thickness of the intimal layer of the carotid artery in this population.18 GH levels can also decline with aging, and there has been interest in the effects of declining GH levels in older adults (described as somatopause). GH replacement is obviously important in the growing child.19,20 Tall Stature in Children Height that is greater than the 97th percentile norms for age and sex is considered tall stature in children.11 As with short stature, normal variants of tall stature include familial tall stature and constitutional advancement of growth. Other causes of tall stature are genetic or chromosomal disorders such as Marfan syndrome, Klinefelter (XXY) syndrome, Fragile X syndrome, and Beckwith-Wiedemann syndrome. Treatment is not usually indicated for these non–GH-related causes of tall stature, or with the normal variants.11 Growth Hormone Excess in Children GH excess occurring before puberty and the fusion of the epiphyses of the long bones result in pituitary gigantism. All body tissues grow rapidly, including the bones.4 Excessive secretion of GH by somatotrope adenomas causes gigantism in the prepubertal child. It occurs when the epiphyses are not fused and high levels of IGF-1 stimulate excessive skeletal growth. The individual often has other complications because of the larger body mass and possible excessive secretion of other pituitary hormones. Fortunately, the condition is rare because of early recognition and treatment of the adenoma.3 Treatment for GH excess typically consists of administration of the medications octreotide and pegvisomant to decrease GH levels.11 Growth Hormone Excess in Adults When GH excess occurs in adulthood or after the epiphyses of the long bones have fused, the condition is referred to as acromegaly. The annual

incidence of acromegaly is three to four cases per 1 million people, with a prevalence of 30 to 60 cases per million.21 Etiology and Pathogenesis Clinical manifestations of acromegaly result from the effects on body cells from excess circulating blood levels of GH and IGF-1.21 The most common cause of acromegaly is a GH-secreting somatotrope adenoma in the pituitary gland. Approximately 75% of people with acromegaly have a somatotrope macroadenoma at the time of diagnosis, and most of the remainder has microadenomas.1 The other causes of acromegaly are hypothalamic tumors that result in excess secretion of GHRH, ectopic secretion of GHRH by nonendocrine tumors (such as carcinoid tumors or small-cell lung cancers), or, more rarely, GH secretion from nonendocrine tumors. The binding of the excess circulating GH with the GH receptors in hepatic cells triggers an excess secretion of IGF-1 from hepatic cells. Then, it is the circulating IGF-1 molecules that bind with the IGF-1 receptor molecules in peripheral tissues, which directly act to stimulate the tissue growth that produces the clinical manifestations of acromegaly.21 Clinical Manifestations The disorder usually has an insidious onset, with symptoms often present for a considerable period before a diagnosis is made. Because acromegaly is the production of excessive GH in adulthood, after the epiphyses of the long bones have closed, the person cannot grow taller; however, the soft tissues continue to grow. Enlargement of the small bones of the hands and feet and of the membranous bones of the face and skull results in a pronounced enlargement of the hands and feet, a broad and bulbous nose, a protruding lower jaw, and a slanting forehead (Fig. 41-2). The teeth become splayed, causing a disturbed bite and difficulty in chewing. The cartilaginous structures in the larynx and respiratory tract also become enlarged, resulting in a deepening of the voice and tendency to develop bronchitis. Vertebral changes often lead to kyphosis or hunchback. Bone overgrowth often leads to arthralgias and degenerative arthritis of the spine, hips, and knees. Virtually, every organ of the body is increased in size. Enlargement of the heart, the development of hypertension, and accelerated atherosclerosis can produce significant morbidity and mortality.1,2,21,22

FIGURE 41-2

Clinical manifestations of acromegaly.

The metabolic effects of excess levels of GH and IGF-1 include alterations in fat and carbohydrate metabolism. GH causes lipolysis, with the increased release of FFAs from adipose tissue leading to increased concentration of FFAs in body fluids. In addition, GH enhances the formation of ketones and the use of FFAs for energy in preference to use of carbohydrates and proteins. GH exerts multiple effects on carbohydrate metabolism, including decreased glucose uptake by tissues such as skeletal muscle and adipose tissue, increased glucose production by the liver, and increased insulin secretion.4 Each of these changes results in GH-induced insulin resistance. This leads to glucose intolerance, which stimulates the beta cells of the pancreas to produce additional insulin. Long-term elevation of GH results in overstimulation of the beta cells, which may cause them literally to “burn out.” The net result of these metabolic changes is impaired glucose regulation that often leads to the development of DM.22 Plasma levels of IGF-1 have been demonstrated to be more predictive of the risk for developing DM than are plasma GH levels. Higher plasma levels of IGF-1 have been associated with an increased risk for the development of diabetes in people with acromegaly; however, plasma concentrations of GH have not demonstrated the same correlation. Reported prevalence of DM in people with acromegaly ranges from 12% to 37.6%. When other forms of glucose dysregulation are considered (such as impaired fasting glucose [IFG] and impaired glucose tolerance), the reported prevalence rates for glucose dysregulation in people with acromegaly rise to 16% to 54%.22 Additional clinical manifestations associated with acromegaly are related to pituitary adenomas, as this is the etiologic cause of most cases of acromegaly. As the pituitary adenoma grows, it causes further dysfunction of the pituitary gland and surrounding brain structures. The pituitary gland is located in the pituitary fossa of the sphenoid bone (i.e., sella turcica), which lies directly below the optic nerve. Enlargement of the pituitary gland eventually causes erosion of the surrounding bone, and because of its location, this can lead to headaches, visual field defects resulting from compression of the optic nerve (classically, bitemporal hemianopia), and

palsies of cranial nerves III, IV, and VI. Compression of other pituitary structures can cause secondary hypothyroidism, hypogonadism, and adrenal insufficiency. Hypogonadism can result from direct damage to the hypothalamic or pituitary system or indirectly because of hyperprolactinemia owing to prevention of the prolactin inhibitory factor (dopamine) from reaching pituitary lactotropes (cells that secrete prolactin) because of damage by the pituitary tumor.1-3 Other manifestations include excessive sweating with an unpleasant odor, oily skin, heat intolerance, moderate weight gain, muscle weakness and fatigue, menstrual irregularities, and decreased libido. Hypertension is relatively common. Sleep apnea syndrome is present in up to 90% of people. The pathogenesis of sleep apnea syndrome is obstructive in the majority of people because of increased pharyngeal soft tissue accumulation. Paresthesias may develop because of nerve entrapment and compression caused by excess soft tissue and accumulation of subcutaneous fluid (especially carpal tunnel syndrome). Acromegaly is also associated with an increased risk of colonic polyps and colorectal cancer.1,21,22 The mortality rate of people with acromegaly is higher than the general population; however, advances in treatment have reduced the mortality rate from the previous two to three times the general population, to the current mortality rate that is less than two times the expected rate.21 Mortality in people with acromegaly is primarily due to cardiovascular disease (60%), respiratory disease (25%), and cancer (15%).21 The cardiovascular disease results from the combination of cardiomyopathy, hypertension, insulin resistance and hyperinsulinemia, and hyperlipidemia.21,22 Diagnosis Acromegaly often develops insidiously, with an estimated 20% of people already having developed DM at the time of the acromegaly diagnosis.22 The diagnosis of acromegaly is made via combination of a clinical examination revealing the typical physical features of the disorder (including enlargement of the hands and feet and coarsening of facial features) and diagnostic laboratory studies. Serum IGF-1 testing is the recommended initial laboratory test in evaluating a suspected diagnosis of acromegaly, and a finding of normal plasma IGF-1 levels essentially rules out the diagnosis. If the serum IGF-1 is elevated or equivocal, then the confirmatory test is a glucose challenge test. If serum GH levels are not

suppressed by a glucose load, then the diagnosis of acromegaly is confirmed. MRI scanning is the recommended first-line imaging approach to detect and localize pituitary lesions, with computed tomography (CT) scanning as the alternative if MRI is contraindicated. Visual field testing is also recommended because of the anatomic proximity of the pituitary gland to the optic chiasm.21 Treatment Treatment for acromegaly focuses on the correction of metabolic abnormalities, normalization of IGF-1 levels to age- and sex-matched control levels, removal or reduction of the tumor mass, relieving the central pressure effects, and improvement of adverse clinical features. Pituitary tumors are removed surgically using the transsphenoidal approach. Medical therapy is inoperable. Somatostatin is a hormone that can be effective in the medical management of acromegaly by producing feedback inhibition of GH secretion. Pegvisomant is a pegylated recombinant DNA analogue that incorporates nine different mutations, making the drug molecule different than the endogenous GH molecule. Pegvisomant can bind with the GH receptor sites and block GH binding; therefore, although GH levels remain elevated, the GH action on the target cells is reduced. A third class of drugs used in the treatment of acromegaly are the dopamine agonists, which exert their action by binding to dopamine receptors in the pituitary gland, thereby reducing pituitary secretion of both GH and prolactin. Radiotherapy is useful if surgical treatment is not possible and medical therapy is not well tolerated. Radiotherapy has demonstrated success with lowering serum GH levels; however, radiotherapy has not been as effective in lowering serum IGF-1 levels.21 Precocious Puberty Precocious puberty is defined as early activation of the hypothalamic– pituitary–gonadal axis, resulting in the early development of sexual characteristics and fertility. The American Academy of Pediatrics (in 2015) and the American Academy of Family Physicians (in 2017) both recommend a diagnosis of precocious puberty if signs of pubertal changes are noted before the age of 8 years for girls and 9 years for boys.23,24 Both organizations recognize recent research indicating that the population may be shifting toward a new normal of earlier ages of puberty, with black girls

entering puberty earlier than white girls and children who are obese entering puberty at earlier ages than children of normal body weight for age.23,24 Precocious sexual development may be idiopathic or may be caused by gonadal, adrenal, or hypothalamic disease. Benign and malignant tumors of the central nervous system (CNS) can cause precocious puberty. These tumors are thought to remove the inhibitory influences normally exerted on the hypothalamus during childhood. Diagnosis of precocious puberty is based on physical findings of early thelarche, adrenarche, and menarche in girls. The most common sign in boys is early genital enlargement. Radiologic findings may indicate advanced bone age. People with precocious puberty are usually tall for their age as children but short as adults because of the early closure of the epiphyses. MRI or CT may be used to exclude intracranial lesions. Depending on the cause of precocious puberty, the treatment may involve surgery, medication, or no treatment. Administration of a long-acting GnRH agonist results in a decrease in pituitary responsiveness to GnRH, leading to decreased secretion of gonadotropic hormones and sex steroids. Administration of GnRH may also help with reducing the incidence of short stature.23,24 SUMMARY CONCEPTS Pituitary tumors can result in deficiencies or excesses of pituitary hormones. Hypopituitarism, which is characterized by a decreased secretion of pituitary hormones, is a condition that affects many of the other endocrine systems. Depending on the extent of the disorder, it can result in decreased levels of GH, thyroid hormones, adrenal corticosteroid hormones, and testosterone in the male and estrogens and progesterone in the female. A number of hormones are essential for normal body growth and maturation, including GH, insulin, thyroid hormone, and androgens. GH exerts its growth effects through IGF-1. GH also exerts an effect on metabolism and is produced in the adult and in the child. Its metabolic effects include a decrease in peripheral use of carbohydrates and an increased mobilization and use of fatty acids. In children, alterations in growth include short stature, tall stature, and precocious puberty. Short stature is a condition in which the

attained height is below the third percentile on the appropriate growth curve for a child’s age and sex. Short stature can occur as a variant of normal growth (i.e., familial short stature or constitutional delay of growth and puberty) or can occur as the result of endocrine disorders, chronic illness, malnutrition, emotional disturbances, or chromosomal disorders. Short stature resulting from GH deficiency can be treated with human GH preparations. In adults, GH deficiency represents a deficiency carried over from childhood or one that develops during adulthood as the result of a pituitary tumor or its treatment. GH levels also can decline with aging, and there has been interest in the effects of declining GH levels with aging. Tall stature refers to the condition in which children are tall for their age and gender. It can occur as a variant of normal growth (i.e., familial tall stature or constitutional advancement of growth), as the result of a genetic or chromosomal abnormality or GH excess. GH excess in adults results in acromegaly, which involves proliferation of bone, cartilage, and soft tissue along with the metabolic effects of excessive hormone levels. Precocious puberty defines a condition of early activation of the hypothalamic–pituitary–gonadal axis, resulting in the development of appropriate sexual characteristics and fertility. It is associated with tall stature during childhood but may lead to short stature in adulthood because of the early closure of the epiphyses.

Thyroid Disorders Control of Thyroid Function The thyroid gland is a shield-shaped structure located immediately below the larynx in the anterior middle portion of the neck (Fig. 41-3A). It is composed of a large number of tiny, saclike structures called follicles (see Fig. 41-3B). These are the functional units of the thyroid. Each follicle is formed by a single layer of epithelial (follicular) cells and is filled with a secretory substance called colloid, which consists largely of a glycoprotein– iodine complex called thyroglobulin.4,9

(A) The thyroid gland. (B) Microscopic structure of thyroid follicles. (C) Cellular mechanisms for transport of iodide (I−), oxidation of I− by thyroid peroxidase (TPO), coupling of oxidized I− with thyroglobulin to form thyroid hormones, and movement of T3 and T4 into the follicular cell by pinocytosis and release into the blood. DIT, diiodotyrosine; MIT, monoiodotyrosine. FIGURE 41-3

The thyroglobulin that fills the thyroid follicles is a large glycoprotein molecule that contains about 100 tyrosine amino acid residues.4 It is these tyrosine molecules to which iodine is attached to create thyroid hormone. This process of thyroid synthesis occurs within the follicles of the thyroid gland.4

In the process of removing the iodine from the blood and storing it for future use, iodide is pumped into the follicular cells against a concentration gradient. Iodide (I−) is transported across the basement membrane of the thyroid cells by an intrinsic membrane protein called the Na+/I− symporter (NIS).4 At the apical border, a second I− transport protein called pendrin moves iodine into the colloid, where it is involved in hormonogenesis.4 The NIS derives its energy from Na+/K+-ATPase, which drives the process. As a result, the concentration of iodide in the normal thyroid gland is approximately 30 times than that in the blood.4 Once inside the follicle, most of the iodide is oxidized by the enzyme thyroid peroxidase (TPO) in a reaction that facilitates combination with a tyrosine molecule to form monoiodotyrosine (MIT) and then diiodotyrosine (DIT).4 Two DIT residues are coupled to form thyroxine (T4), or a MIT and a DIT are coupled to form triiodothyronine (T3).4 Only T4 (93%) and T3 (7%) are released into the circulation4 (see Fig. 41-3C). Although T3 is significantly more potent in its activity, T4 has a much longer half-life in the blood (7 days) than T3 (1 day); therefore, T4 serves as an effective storage molecule. The circulating T4 is converted to T3 when needed.9 Stimulation by TSH from the pituitary gland serves as the stimulus for the thyroid gland to secrete the T3 and T4 thyroid hormones into the blood.9 Thyroid hormones are bound to thyroxine-binding globulin (TBG) and other plasma proteins for transport in the blood. Only the free T3 or T4 hormone can enter target cells to exert the hormonal effect; the proteinbound forms cannot enter the cells. Protein-bound thyroid hormone forms a large reservoir that is slowly drawn on as free thyroid hormone is needed. There are three major thyroid-binding proteins: TBG, transthyretin (also known as thyroxine-binding prealbumin [TBPA]), and albumin. More than 99% of T4 and T3 is carried in these bound forms.4,25 A number of disease conditions and pharmacologic agents can decrease the amount of binding protein in the plasma or influence the binding of hormone. Several genetic alterations of TBG function have been identified, including an X-linked TBG deficiency associated with a gene on the long arm of the X chromosome.25 Glucocorticoid medications and systemic disease conditions such as protein malnutrition, nephrotic syndrome, and cirrhosis can decrease TBG concentrations of the thyroid-binding proteins. A variety of drugs, such as phenytoin, salicylates, and diazepam, can affect

the binding of thyroid hormone to normal concentrations of binding proteins or disrupt thyroid metabolism in other ways.26 The secretion of thyroid hormone is regulated by the hypothalamic– pituitary–thyroid feedback system (see Chapter 40, Fig. 40-3). In this system, thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus, controls the release of TSH from the anterior pituitary gland. TSH increases the overall activity of the thyroid gland by increasing thyroglobulin breakdown and the release of thyroid hormone from follicles into the bloodstream, activating the iodide pump (by increasing NIS activity), increasing the oxidation of iodide and the coupling of iodide to tyrosine, and increasing the number and the size of the follicle cells.4,9 Increased plasma levels of thyroid hormone lead to feedback inhibition of TRH or TSH. High levels of iodide also cause a temporary decrease in thyroid activity that lasts for several weeks, probably through a direct inhibition of TSH on the thyroid. Cold exposure is one of the strongest stimuli for increased thyroid hormone production and probably is mediated through TRH from the hypothalamus. Various emotional reactions can also affect the output of TRH and TSH.4 Actions of Thyroid Hormone Altered levels of thyroid hormone affect all the major organs in the body. Thyroid hormone has two major functions—it increases metabolism and protein synthesis and it is necessary for growth and development in children, including mental development and attainment of sexual maturity. These actions are mainly mediated by T3. In the cell, T3 binds to a nuclear receptor, resulting in transcription of specific thyroid hormone response genes.4 Metabolic Rate Thyroid hormone increases the metabolism of target cells throughout the body. The basal metabolic rate can increase by 60% to 100% above normal when large amounts of T4 are present.4 As a result of this higher metabolism, the rate of glucose, fat, and protein use increases. Lipids are mobilized from adipose tissue, and the catabolism of cholesterol by the liver is increased. Blood levels of cholesterol are decreased in hyperthyroidism and increased in hypothyroidism. Muscle proteins are

broken down and used as fuel, probably accounting for some of the muscle fatigue that occurs with hyperthyroidism. The absorption of glucose from the gastrointestinal tract is increased.4 Cardiovascular Function Cardiovascular and respiratory functions are strongly affected by thyroid function. With an increase in metabolism, there is a rise in oxygen consumption and production of metabolic end products, with an accompanying increase in vasodilation. Blood flow to the skin, in particular, is augmented as a means of dissipating the body heat that results from the higher metabolic rate. Blood volume, cardiac output, and ventilation are all increased as a means of maintaining blood flow and oxygen delivery to body tissues. Heart rate and cardiac contractility are enhanced as a means of maintaining the needed cardiac output. Blood pressure is likely to change little because the increase in vasodilation tends to offset the increase in cardiac output.4 Gastrointestinal Function Thyroid hormone enhances gastrointestinal function, causing an increase in motility and production of gastrointestinal secretions that often result in diarrhea. An increase in appetite and food intake accompanies the higher metabolic rate that occurs with increased thyroid hormone levels. At the same time, weight loss occurs because of the increased use of calories.4 Neuromuscular Effects Thyroid hormone has marked effects on neural control of muscle function and tone. Slight elevations in hormone levels cause skeletal muscles to react more vigorously, and a drop in hormone levels causes muscles to react more sluggishly. In the hyperthyroid state, a fine muscle tremor is present. The cause of this tremor is unknown, but it may represent an increased sensitivity of the neural synapses in the spinal cord that controls muscle tone. In the infant, thyroid hormone is necessary for normal brain development. The hormone enhances cerebration; in the hyperthyroid state, it causes extreme nervousness, anxiety, and difficulty in sleeping.4 Evidence suggests a strong interaction between the thyroid hormone and the sympathetic nervous system.4 Many of the signs and symptoms of hyperthyroidism suggest overactivity of the sympathetic division of the

autonomic nervous system, such as tachycardia, palpitations, and sweating. Tremor, restlessness, anxiety, and diarrhea may also reflect autonomic nervous system imbalances. Drugs that block sympathetic activity have proved to be valuable adjuncts in the treatment of hyperthyroidism because of their ability to relieve some of these undesirable symptoms.2 KEY POINTS Thyroid Hormone Thyroid hormone increases the metabolism and protein synthesis in nearly all of the tissues of the body. When hypothyroidism occurs in older children or adults, it produces a decrease in metabolic rate, an accumulation of a hydrophilic mucopolysaccharide substance (myxedema) in the connective tissues throughout the body, and an elevation in serum cholesterol. Hyperthyroidism has an effect opposite to that of hypothyroidism. It produces an increase in metabolic rate and oxygen consumption, increased use of metabolic fuels, and increased sympathetic nervous system responsiveness. Tests of Thyroid Function Various tests aid in the diagnosis of thyroid disorders. Measures of T3 (total and free), T4 (total and free), and TSH have been made available through immunoassay methods. The total T3 and T4 tests measure both the proteinbound and free components of each hormone. The free T3 and T4 tests measure the fractions that are not bound to plasma proteins, which are therefore free to enter cells to produce effects. TSH levels are used to differentiate between primary thyroid disorders (which originate at the thyroid gland) and secondary thyroid disorders (which originate at the pituitary gland). T3 and T4 levels (bound and free) are low in primary hypothyroidism; however, the TSH level is elevated. The assessment of thyroid autoantibodies (e.g., anti-TPO antibodies in Hashimoto thyroiditis)

is also important in the diagnostic workup and follow-up of people with thyroid disorders.2,9 The radioiodine (123I) uptake test measures the ability of the thyroid gland to concentrate and retain iodine from the blood. Thyroid scans (123I, 99mTcpertechnetate) can be used to detect thyroid nodules and determine the functional activity of the thyroid gland. Ultrasonography can be used to differentiate cystic from solid thyroid lesions, and CT and MRI scans are used to demonstrate tracheal compression or impingement on other neighboring structures. Fine-needle aspiration biopsy of a thyroid nodule has proved to be the best method for differentiation of benign from malignant thyroid disease.2,9 Alterations in Thyroid Function An alteration in thyroid function can represent a hypofunctional or a hyperfunctional state. The manifestations of these two altered states are summarized in Table 41-3. Disorders of the thyroid may be due to a congenital defect in thyroid development, or they may develop later in life, with a gradual or sudden onset. TABLE 41-3 Manifestations of Hypothyroid and Hyperthyroid States

Level of Organization Basal metabolic rate Sensitivity to catecholamines General features

Blood cholesterol levels

Hypothyroidism

Hyperthyroidism

Decreased Decreased

Increased Increased

Myxedematous features Exophthalmos (in Graves Deep voice disease) Impaired growth (child) Lid lag Accelerated growth (child) Increased Decreased

Level of Organization General behavior

Hypothyroidism

Hyperthyroidism

Intellectual disability Restlessness, irritability, (infant) anxiety Mental and physical Hyperkinesis sluggishness Wakefulness Somnolence Cardiovascular Decreased cardiac output Increased cardiac output function Bradycardia Tachycardia and palpitations Gastrointestinal Constipation Diarrhea function Decreased appetite Increased appetite Respiratory function Hypoventilation Dyspnea Muscle tone and Decreased Increased, with tremor and reflexes twitching Temperature Cold intolerance Heat intolerance tolerance Skin and hair Decreased sweating Increased sweating Coarse and dry skin and Thin and silky skin and hair hair Weight Gain Loss Goiter is an increase in the size of the thyroid gland (Fig. 41-4). It can occur in hypothyroid, euthyroid, and hyperthyroid states. Goiters may be diffuse, involving the entire gland without evidence of nodularity, or they may contain nodules. Diffuse goiters usually become nodular. Goiters may be toxic, producing signs of extreme hyperthyroidism, or thyrotoxicosis, or they may be nontoxic. Diffuse nontoxic and multinodular goiters are the result of compensatory hypertrophy and hyperplasia of follicular epithelium from some derangement that impairs thyroid hormone output.1,2,4

Nontoxic goiter. In a middle-aged woman with nontoxic goiter, the thyroid has enlarged to produce a conspicuous neck mass. (From Strayer D., Rubin E. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 27-11A, p. 1183). Philadelphia, PA: Wolters Kluwer.) FIGURE 41-4

The degree of thyroid enlargement is usually proportional to the extent and duration of thyroid deficiency. Multinodular goiters produce the largest thyroid enlargements. When sufficiently enlarged, they may compress the esophagus and trachea, causing difficulty in swallowing, a choking sensation, and inspiratory stridor. Such lesions may also compress the superior vena cava, producing distention of the veins of the neck and upper

extremities, edema of the eyelids and conjunctiva, and syncope with coughing.1,2,4 Hypothyroidism Hypothyroidism can occur as a congenital or an acquired defect. Congenital hypothyroidism develops prenatally and is present at birth. Acquired hypothyroidism develops because of primary disease of the thyroid gland or secondary to disorders of hypothalamic or pituitary origin. Congenital Hypothyroidism Congenital hypothyroidism is a common cause of preventable intellectual disability. Hypothyroidism in the infant may result from a congenital lack of the thyroid gland or from abnormal biosynthesis of thyroid hormone or deficient TSH secretion. With congenital lack of the thyroid gland, the infant usually appears normal and functions normally at birth because hormones have been supplied in utero by the mother.1,2,4 Thyroid hormone is essential for normal growth and brain development, almost half of which occurs during the first 6 months of life. If untreated, congenital hypothyroidism causes intellectual disability and impairs physical growth. The manifestations of untreated congenital hypothyroidism are referred to as cretinism. However, the term does not apply to the normally developing infant in whom replacement thyroid hormone therapy was instituted shortly after birth.1,2,4 Many countries throughout the world now routinely perform neonatal screening to detect congenital hypothyroidism during early infancy.27 Premature or sick newborn infants need to be screened with a comprehensive serum thyroid profile to prevent missing primary hypothyroidism in these infants. Transient congenital hypothyroidism (characterized by high TSH levels with low or normal thyroid hormone levels) has been recognized more frequently since the introduction of neonatal screening. The fetal and infant thyroid gland is sensitive to iodine excess. Iodine can cross the placenta, be excreted in breast milk, and is also readily absorbed by infant skin. Transient hypothyroidism may be caused by maternal or infant exposure to substances such as povidone–iodine used as a disinfectant (i.e., vaginal douche or skin disinfectant). Antithyroid drugs such as propylthiouracil and

methimazole can also cross the placenta and block fetal thyroid function.1,2,4,27 Congenital hypothyroidism is treated by thyroid hormone replacement. Evidence indicates that it is important to normalize T4 levels as rapidly as possible because a delay is accompanied by poorer psychomotor and mental development. When early and adequate thyroid hormone replacement treatment is implemented for congenital hypothyroidism, the risk of intellectual disability is very low.1,2,4,27 Acquired Hypothyroidism and Myxedema Hypothyroidism in older children and adults causes a general slowing down of metabolic processes and myxedema. Myxedema implies the presence of a nonpitting mucus type of edema caused by an accumulation of a hydrophilic mucopolysaccharide substance in the connective tissues throughout the body. The hypothyroid state may be mild, with only a few signs and symptoms, or it may progress to a life-threatening condition with angioedema.1,2,4 Etiology and Pathogenesis Acquired hypothyroidism can result from destruction or dysfunction of the thyroid gland (i.e., primary hypothyroidism), or it can be a secondary disorder caused by impaired pituitary function or as a tertiary disorder caused by a hypothalamic dysfunction. Primary hypothyroidism is much more common than secondary (and tertiary) hypothyroidism. It may result from thyroidectomy (i.e., surgical removal) or ablation of the gland with radiation for treatment of hyperthyroidism. Certain goitrogenic agents, such as lithium carbonate, and the antithyroid drugs propylthiouracil and methimazole in continuous dosage can block hormone synthesis and produce hypothyroidism with goiter. Large amounts of iodine can also block thyroid hormone production and cause hypothyroidism, particularly in people with autoimmune thyroid disease. Iodine deficiency, which can cause goiter and hypothyroidism, is uncommon in the United States because of the widespread use of iodized salt and other iodide sources. However, iodine deficiency continues to occur in less developed areas of the world.1,2,4 Subacute thyroiditis, which can occur in postpartum women, is another cause of hypothyroidism.28

The most common cause of acquired hypothyroidism is Hashimoto thyroiditis, an autoimmune disorder in which the thyroid gland may be totally destroyed by an immunologic process. It is the major cause of acquired hypothyroidism in children and adults.1,27 Hashimoto thyroiditis is predominantly a disease of women. The course of the disease varies. At the onset, only a goiter may be present. In time, hypothyroidism usually becomes evident. Although the disorder usually causes hypothyroidism, a hyperthyroid state may develop midcourse in the disease. The transient hyperthyroid state may be related to leakage of preformed thyroid hormone from damaged cells of the gland.1,2,4 Clinical Manifestations Hypothyroidism may affect almost all body functions. The manifestations of the disorder are related largely to two factors: the hypometabolic state resulting from thyroid hormone deficiency and myxedematous involvement of body tissues. The hypometabolic state associated with hypothyroidism is characterized by a gradual onset of weakness and fatigue, a tendency to gain weight despite a loss of appetite, and cold intolerance (Fig. 41-5). As the condition progresses, the skin becomes dry and rough and the hair becomes coarse and brittle. The face becomes puffy with edematous eyelids, and there is thinning of the outer third of the eyebrows. Gastrointestinal motility is decreased, producing constipation, flatulence, and abdominal distention. Delayed relaxation of deep tendon reflexes and bradycardia are sometimes noted. CNS involvement is manifested in mental dullness, lethargy, and impaired memory.1,2,4

FIGURE 41-5

Clinical manifestations of hypothyroidism.

Although the myxedematous fluid is usually most obvious in the face, it can collect in the interstitial spaces of almost any body structure and is responsible for many of the manifestations of the severe hypothyroid state. The tongue is often enlarged and the voice becomes hoarse and husky. Carpal tunnel and other entrapment syndromes are common, as is impairment of muscle function with stiffness, cramps, and pain. Mucopolysaccharide deposits in the heart cause generalized cardiac

dilation, bradycardia, and other signs of altered cardiac function. The signs and symptoms of hypothyroidism are summarized in Table 41-3.1,2,4 Diagnosis and Treatment Diagnosis of hypothyroidism is based on history, physical examination, and laboratory tests. A low serum T4 and elevated TSH levels are characteristic of primary hypothyroidism. The tests for antithyroid antibodies should be done when Hashimoto thyroiditis is suspected.1,2,4 Hypothyroidism is treated by replacement therapy with synthetic preparations of T3 or T4. Most people are treated with T4. Serum TSH levels are used to estimate the adequacy of T4 replacement therapy. When the TSH level is normalized, the T4 dosage is considered satisfactory (for primary hypothyroidism only). A “go low and go slow” approach should be considered in the treatment of older people with hypothyroidism because of the risk of inducing acute coronary syndromes in the susceptible individual. It is also important that people consistently take the form of T4 prescribed, so that their laboratory values are the most representative of their thyroid state. Therefore, people should remain on generic forms of T4 and, similarly, if people are put on brand names of T4, they should stay on the same drug.1,2,4,29 Myxedematous Coma Myxedematous coma is a life-threatening, end-stage expression of hypothyroidism. Long-standing hypothyroidism leads to a crisis state with severely reduced cellular metabolism that affects all organ systems throughout the body. Hypothermia also develops and is a strong predictor of mortality. The condition is associated with cardiovascular collapse, hypoventilation, and severe metabolic disorders that include hyponatremia, hypoglycemia, and lactic acidosis.8,30 Treatment includes aggressive management of precipitating factors; supportive therapy such as management of cardiorespiratory status, hyponatremia, and hypoglycemia; and thyroid replacement therapy. If hypothermia is present, active rewarming of the body is contraindicated because it may induce vasodilation and vascular collapse. Prevention is preferable to treatment and entails special attention to high-risk populations, such as women with a history of Hashimoto thyroiditis. These people

should be informed about the signs and symptoms of severe hypothyroidism and the need for early medical treatment.8,30 Hyperthyroidism Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormone.4 Etiology and Pathogenesis In most instances, thyrotoxicosis is due to hyperactivity of the thyroid gland, or hyperthyroidism. The most common cause of hyperthyroidism is Graves disease, which is accompanied by ophthalmopathy, dermopathy, and diffuses goiter. Other causes of hyperthyroidism are multinodular goiter, adenoma of the thyroid, and thyroiditis. Iodine-containing agents can induce hyperthyroidism as well as hypothyroidism. Thyroid crisis, or storm, is an acutely exaggerated manifestation of the thyrotoxic state.1,8 Clinical Manifestations Many of the manifestations of hyperthyroidism are related to the increase in oxygen consumption and use of metabolic fuels associated with the hypermetabolic state, as well as to the increase in sympathetic nervous system activity that occurs. Hyperthyroidism resembles those of excessive sympathetic nervous system activity, suggesting that thyroid hormone may heighten the sensitivity of the body to the catecholamines or that it may act as a pseudocatecholamine. With the hypermetabolic state, there are frequent complaints of nervousness, irritability, and fatigability (Fig. 41-6). Weight loss is common despite a large appetite. Other manifestations include tachycardia, palpitations, shortness of breath, excessive sweating, muscle cramps, and heat intolerance. The person appears restless and has a fine muscle tremor. Even in people without exophthalmos, there is an abnormal retraction of the eyelids and infrequent blinking such that they appear to be staring. The hair and skin are usually thin and have a silky appearance.1,8,31 Atrial fibrillation occurs in 10% to 15% of adults with hyperthyroidism.32 The signs and symptoms of hyperthyroidism are summarized in Table 41-3.

FIGURE 41-6

Clinical manifestations of hyperthyroidism.

The treatment of hyperthyroidism is directed toward reducing the level of thyroid hormone. This can be accomplished with eradication of the thyroid gland with radioactive iodine, through surgical removal of part or all of the gland, or the use of drugs that decrease thyroid function and thereby the effect of thyroid hormone on the peripheral tissues. Antithyroid drugs prevent the thyroid gland from converting iodine to its organic form or block the conversion of T4 to T3 in the tissues.1,8,31,33 Graves Disease Graves disease is a state of hyperthyroidism, goiter, and ophthalmopathy. It affects approximately 0.5% to 1% of the population under 40 years of age.1 Graves disease is an autoimmune disorder characterized by abnormal stimulation of the thyroid gland by thyroid-stimulating antibodies (TSH receptor antibodies) that act through the normal TSH receptors. It may be associated with other autoimmune disorders such as myasthenia gravis. The disease is associated with a major histocompatibility complex class 1 chain–related gene A (MICA), with genotypes MICA A5 correlated with Graves disease and MICA A6/A9 being preventive for Graves disease.1 The ophthalmopathy, which occurs in up to one-third of people with Graves disease, is thought to result from accumulation of T lymphocytes sensitized to antigens along thyroid follicular cells and orbital fibroblasts that secrete cytokines.1 The ophthalmopathy of Graves disease can cause severe eye problems, including tethering of the extraocular muscles resulting in diplopia; involvement of the optic nerve, with some visual loss; and corneal ulceration because the lids do not close over the protruding eyeball (because of the exophthalmos). The ophthalmopathy usually tends to stabilize after treatment of the hyperthyroidism. However, ophthalmopathy can worsen acutely after radioiodine treatment. Some physicians prescribe glucocorticoids for several weeks surrounding the radioiodine treatment if the person had signs of ophthalmopathy. Ophthalmopathy can also be aggravated by smoking, which should be strongly discouraged.34 Figure 41-7 shows a woman with Graves disease.

Graves disease. A patient with Graves disease may show symptoms of an enlarged thyroid (goiter) and protrusion of one or both eyeballs (exophthalmos). (Asset provided by Anatomical Chart Co.) FIGURE 41-7

Thyroid Storm Thyroid storm, or thyrotoxic crisis, is an extreme and life-threatening form of thyrotoxicosis rarely seen today because of improved diagnosis and treatment methods. When it does occur, it is seen most often in undiagnosed cases or in people with hyperthyroidism who have not been adequately treated. It is often precipitated by stress, such as an infection, by physical or emotional trauma, or by manipulation of a hyperactive thyroid gland during thyroidectomy. Thyroid storm is manifested by a very high fever, extreme cardiovascular effects (i.e., tachycardia, congestive failure, and angina), and

severe CNS effects (i.e., agitation, restlessness, and delirium). The mortality rate is high.35-37 Thyroid storm requires rapid diagnosis and implementation of treatment. Initially, the person must be hemodynamically stabilized. The thyroid hormones can be removed by plasmapheresis, dialysis, or hemoperfusion adsorption. Peripheral cooling is initiated with cold packs and a cooling mattress. For cooling to be effective, the shivering response must be prevented. General supportive measures to replace fluids, glucose, and electrolytes are essential during the hypermetabolic state. A β-adrenergic blocking drug, such as propranolol, is given to block the undesirable effects of T4 on cardiovascular function. Glucocorticoids are used to correct the relative adrenal insufficiency resulting from the stress imposed by the hyperthyroid state and to inhibit the peripheral conversion of T4 to T3. Propylthiouracil or methimazole may be given to block thyroid synthesis. Aspirin increases the level of free thyroid hormones by displacing the hormones from their protein carriers and should not be used during thyroid storm.35-37 SUMMARY CONCEPTS Thyroid hormones play a role in the metabolic process of almost all body cells and are necessary for normal physical and mental growth in the infant and young child. Alterations in thyroid function can manifest as a hypothyroid or a hyperthyroid state. Hypothyroidism can occur as a congenital or an acquired defect. Congenital hypothyroidism leads to intellectual disability and impaired physical growth unless treatment is initiated during the first month of life. Acquired hypothyroidism leads to a decrease in metabolic rate and an accumulation of a mucopolysaccharide substance in the intercellular spaces; this substance attracts water and causes a mucous type of edema called myxedema. Hyperthyroidism causes an increase in metabolic rate and alterations in body function similar to those produced by enhanced sympathetic nervous system activity. Graves disease is characterized by the triad of hyperthyroidism, goiter, and ophthalmopathy. A life-threatening complication of hyperthyroidism is thyroid storm.

Disorders of Adrenal Cortical Function Control of Adrenal Cortical Function The adrenal glands are small, bilateral structures that weigh approximately 5 g each and lie retroperitoneally at the apex of each kidney (Fig. 41-8). The medulla or inner portion of the gland (which constitutes approximately 20% of each adrenal) secretes epinephrine and norepinephrine and is part of the sympathetic nervous system.4 The cortex forms the bulk of the adrenal gland (approximately 80%) and is responsible for secreting three types of hormones—the glucocorticoids, the mineralocorticoids, and the adrenal androgens.4 Because the sympathetic nervous system also secretes epinephrine and norepinephrine, adrenal medullary function is not essential for life, but adrenal cortical function is. The total loss of adrenal cortical function is fatal in a few days to a few weeks if untreated.4 This section of the chapter describes the synthesis and function of the adrenal cortical hormones and the effects of adrenal cortical insufficiency and excess.

(A) The adrenal gland showing the medulla and the three layers of the cortex. The outer layer of the cortex (zona glomerulosa) is primarily responsible for mineralocorticoid production and the middle layer (zona fasciculata) and the inner layer (zona reticularis) produce the glucocorticoids and the adrenal androgens. (B) Predominant biosynthetic pathways of the adrenal cortex. Critical enzymes in the biosynthetic process include 11-β-hydroxylase and 21-hydroxylase. A deficiency in one of these enzymes blocks the synthesis of hormones dependent on that enzyme and routes the precursors into alternative pathways. FIGURE 41-8

Biosynthesis, Transport, and Metabolism

More than 30 hormones are produced by the adrenal cortex. Of these hormones, aldosterone is the principal mineralocorticoid, cortisol (hydrocortisone) is the major glucocorticoid, and androgens are the chief sex hormones. All of the adrenal cortical hormones have a similar structure in which all are steroids and are synthesized from acetate and cholesterol. Each of the steps involved in the synthesis of the various hormones requires a specific enzyme (see Fig. 41-8). The ACTH secreted by the anterior pituitary gland controls the secretion of the glucocorticoids and the adrenal androgens.4,9 Cortisol, aldosterone, and the adrenal androgens are secreted in an unbound state and bind to plasma proteins for transport in the circulatory system.4,9 The main site for metabolism of the adrenal cortical hormones is the liver, where they undergo a number of metabolic conversions before being conjugated and made water-soluble. They are then eliminated in either the urine or the bile.4,9 KEY POINTS Adrenal Cortical Hormones The manifestations of primary adrenal cortical insufficiency are related mainly to mineralocorticoid deficiency (impaired ability to regulate salt and water elimination) and glucocorticoid deficiency (impaired ability to regulate blood glucose and control the effects of the immune and inflammatory responses). Adrenal cortical excess results in derangements in glucose metabolism, disorders of sodium and potassium regulation (increased sodium retention and potassium loss), impaired ability to respond to stress because of inhibition of inflammatory and immune responses, and signs of increased androgen levels such as hirsutism. Adrenal Androgens The adrenal androgens are synthesized primarily by the zona reticularis and the zona fasciculata of the cortex (see Fig. 41-8A).4 These sex hormones

probably exert little effect on normal sexual function. There is evidence, however, that the adrenal androgens (the most important of which is dehydroepiandrosterone and its dehydroepiandrosterone sulfate [DHEAS]) contribute to the pubertal growth of body hair, particularly pubic and axillary hair in women. They may also play a role in steroid hormone economy of the pregnant woman and the fetal–placental unit. The levels of DHEAS and other adrenal hormones decline with age, a process referred to as the adrenopause. DHEAS levels may represent another aging marker because it is involved with cardiovascular, immunologic, and endocrine systems and may be a trend indicator for prevention of specific problems with aging.38-40 Mineralocorticoids The mineralocorticoids play an essential role in regulating potassium and sodium levels and water balance. They are produced in the zona glomerulosa, the outer layer of cells of the adrenal cortex. Aldosterone secretion is regulated by the renin–angiotensin mechanism and by blood levels of potassium. Increased levels of aldosterone promote sodium retention by the distal tubules of the kidney while increasing urinary losses of potassium.4 Aldosterone is significant for balancing sodium, chloride, and potassium as well as maintaining the total body volume. To understand the importance of aldosterone, consider that both aldosterone and cortisone provide mineralocorticoid function; however, approximately 90% of mineralocorticoid function is provided through aldosterone. Although aldosterone is responsible for about 3000 times greater the amount of mineralocorticoid activity than cortisol, there is nearly 2000 times more serum cortisol than aldosterone.4 Because of the potency of aldosterone, it is crucial that the body does not have excess or deficiency of this potent steroid. The consequences of excess aldosterone are low potassium and muscle weakness, although low amounts of aldosterone cause high potassium and cardiac toxicity.4 Glucocorticoids The glucocorticoid hormones, mainly cortisol, are synthesized in the zona fasciculata and the zona reticularis of the adrenal gland.4 The blood levels

of these hormones are regulated by negative feedback mechanisms of the HPA system (Fig. 41-9). Just as other pituitary hormones are controlled by releasing factors from the hypothalamus, corticotropin-releasing hormone (CRH) is important in controlling the release of ACTH. Cortisol levels increase as ACTH levels rise and decrease as ACTH levels fall. There is considerable diurnal variation in ACTH levels, which reach their peak in the early morning (around 6 to 8 AM) and decline as the day progresses. This appears to be due to rhythmic activity in the CNS, which causes bursts of CRH secretion and, in turn, ACTH secretion. This diurnal pattern is reversed in people who work during the night and sleep during the day. The rhythm may also be changed by physical and psychological stresses, endogenous depression, manic-depressive psychosis, and liver disease or other conditions that affect cortisol metabolism.4

The HPA feedback system that regulates glucocorticoid (cortisol) levels. Cortisol release is regulated by ACTH. Stress exerts its effects on cortisol release through the HPA system and CRH, which controls the release of ACTH from the anterior pituitary gland. Increased cortisol levels incite a negative feedback inhibition of ACTH release. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamic–pituitary– adrenal. FIGURE 41-9

The glucocorticoids perform a necessary function in response to stress and are essential for survival. When produced as part of the stress response, these hormones aid in regulating the metabolic functions of the body and in controlling the inflammatory response. The actions of cortisol are

summarized in Table 41-4. Many of the anti-inflammatory actions attributed to cortisol result from the administration of pharmacologic levels of the hormone.4 TABLE 41-4 Actions of Cortisol

Major Influence Glucose metabolism Protein metabolism Fat metabolism

Effect on Body Stimulates gluconeogenesis Decreases glucose use by the tissues Increases breakdown of proteins Increases plasma protein levels Increases mobilization of fatty acids Increases use of fatty acids Anti-inflammatory Stabilizes lysosomal membranes of the inflammatory action cells, preventing the release of inflammatory mediators (pharmacologic Decreases capillary permeability to prevent levels) inflammatory edema Depresses phagocytosis by white blood cells to reduce the release of inflammatory mediators Suppresses the immune response Causes atrophy of lymphoid tissue Decreases eosinophils Decreases antibody formation Decreases the development of cell-mediated immunity Reduces fever Inhibits fibroblast activity Psychic effect May contribute to emotional instability Permissive effect Facilitates the response of the tissues to humoral and neural influences, such as that of the catecholamines, during trauma and extreme stress Metabolic Effects Cortisol stimulates glucose production by the liver, promotes protein breakdown, and causes mobilization of fatty acids. As body proteins are broken down, amino acids are mobilized and transported to the liver, where they are used in the production of glucose. Mobilization of fatty acids converts cell metabolism from the use of glucose for energy to the use of

fatty acids instead. As glucose production by the liver rises and peripheral glucose use falls, a moderate resistance to insulin develops. In people with diabetes and those who are diabetes prone, this has the effect of raising the blood glucose level.4,9 Psychological Effects The glucocorticoid hormones appear to be involved directly or indirectly in emotional behavior. Receptors for these hormones have been identified in brain tissue, which suggests that they play a role in the regulation of behavior. People treated with adrenal cortical hormones have been known to display behavior ranging from mildly aberrant to psychotic.41 Immunologic and Inflammatory Effects Cortisol influences multiple aspects of immunologic function and inflammatory responsiveness. Large quantities of cortisol are required for an effective anti-inflammatory action. This is achieved by the administration of pharmacologic rather than physiologic doses of synthetic cortisol. The increased cortisol blocks inflammation at an early stage by decreasing capillary permeability and stabilizing the lysosomal membranes, so that inflammatory mediators are not released. Cortisol suppresses the immune response by reducing humoral and cell-mediated immunity. With this lessened inflammatory response comes a reduction in fever. During the healing phase, cortisol suppresses fibroblast activity and thereby lessens scar formation. Cortisol also inhibits prostaglandin synthesis, which may account in large part for its anti-inflammatory actions.4 Pharmacologic Suppression of Adrenal Function A highly significant aspect of long-term therapy with pharmacologic preparations of the glucocorticoids is adrenal insufficiency on withdrawal of drugs. The deficiency results from suppression of the HPA system. Chronic suppression causes atrophy of the adrenal gland, and the abrupt withdrawal of drugs can cause acute adrenal insufficiency. Recovery to a state of normal adrenal function may be prolonged, requiring 6 to 12 months or more.42 Tests of Adrenal Function

Several diagnostic tests can be used to evaluate adrenal cortical function and the HPA system. Blood levels of cortisol, aldosterone, and ACTH can be measured using immunoassay methods. A 24-hour urine specimen measuring the excretion of various metabolic end products of adrenal hormones provides information about alterations in the biosynthesis of the adrenal cortical hormones. The 24-hour urinary free cortisol, late-night (between 11 PM and midnight) serum or salivary cortisol levels, and the overnight 1-mg dexamethasone suppression test are excellent screening tests for Cushing syndrome.39,43,44 Suppression and stimulation tests afford a means of assessing the state of the HPA feedback system. CRH tests can be used to diagnose a pituitary ACTH-secreting tumor (i.e., Cushing disease). Corticotropin (cosyntropin) stimulation testing is the most frequently used diagnostic test to assess testing responsiveness of the HPA axis.39,43,44 Congenital Adrenal Hyperplasia CAH, or the adrenogenital syndrome, describes a congenital disorder caused by an autosomal recessive trait in which a deficiency exists in any of the enzymes necessary for the synthesis of cortisol (see Fig. 41-8). A common characteristic of all types of CAH is a defect in the synthesis of cortisol that results in increased levels of ACTH and adrenal hyperplasia.1 The increased levels of ACTH overstimulate the pathways for production of adrenal androgens. Mineralocorticoids may be produced in excessive or insufficient amounts, depending on the precise enzyme deficiency. Infants of both sexes are affected. Boys are seldom diagnosed at birth unless they have enlarged genitalia or lose salt and manifest adrenal crisis.1 In female infants, an increase in androgens is responsible for creating the virilization syndrome of ambiguous genitalia with an enlarged clitoris, fused labia, and urogenital sinus (Fig. 41-10). In male and female children, other secondary sex characteristics are normal, and fertility is unaffected if appropriate therapy is instituted.1

(A) A female infant is markedly virilized with hypertrophy of the clitoris and partial fusion of labioscrotal folds with CAH demonstrating virilization of the genitalia with hypertrophy of the clitoris and partial fusion of labioscrotal folds. (B) A 7-week-old male died of severe salt-wasting CAH. At autopsy, both adrenal glands were markedly enlarged. (From Strayer D., Rubin E. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figure 27.31, p. 1203). Philadelphia, PA: Wolters Kluwer.). CAH, congenital adrenal hyperplasia. FIGURE 41-10

A spectrum of 21-hydroxylase deficiency state exists, ranging from simple virilizing CAH to a complete salt-losing enzyme deficiency. Simple virilizing CAH impairs the synthesis of cortisol, and steroid synthesis is shunted to androgen production. People with these deficiencies usually produce sufficient aldosterone or aldosterone intermediates to prevent signs

and symptoms of mineralocorticoid deficiency. The salt-losing form is accompanied by deficient production of aldosterone and its intermediates, resulting in fluid and electrolyte disorders (including hyponatremia, vomiting, dehydration, and shock). Hyperkalemia is not always present, so it should not be considered a major screening diagnostic parameter.1,45 The 11-β-hydroxylase deficiency is rare and manifests a spectrum of severity. Affected people have excessive androgen production and impaired conversion of 11-deoxycorticosterone to corticosterone. The overproduction of 11-deoxycorticosterone, which has mineralocorticoid activity, is responsible for the hypertension that accompanies this deficiency. Diagnosis of CAH depends on the precise biochemical evaluation of metabolites in the cortisol pathway and on clinical signs and symptoms. Genetic testing is also invaluable. However, correlation between the phenotype and genotype is not always straightforward.45 Medical treatment of CAH includes oral or parenteral glucocorticoid replacement. Fludrocortisone acetate, a mineralocorticoid, may also be given to children who are salt losers. Depending on the degree of virilization, reconstructive surgery during the first year of life may be indicated to reduce the size of the clitoris, separate the labia, and exteriorize the vagina. Women with CAH who are experiencing unwanted hair growth or androgenic hair loss may be prescribed antiandrogen drugs.45 Adrenal Cortical Insufficiency There are two forms of adrenal insufficiency—primary and secondary1 (see Table 41-5 for distinguishing features). Primary adrenal insufficiency, or Addison disease, is caused by destruction of the adrenal gland. Secondary adrenal insufficiency results from a disorder of the HPA system. TABLE 41-5 Clinical Findings of Adrenal Insufficiency

Finding Anorexia and weight loss

Primary Secondary/Tertiary Yes Yes (100%) (100%) Fatigue and weakness Yes Yes (100%) (100%) Gastrointestinal symptoms, nausea, diarrhea Yes Yes (50%) (50%)

Finding Myalgia, arthralgia, abdominal pain Orthostatic hypotension Hyponatremia Hyperkalemia Hyperpigmentation

Primary Secondary/Tertiary Yes Yes (10%) (10%) Yes Yes Yes Yes (60%) (85%– 90%) Yes No (60%– 65%) Yes No (>90%) No Yes

Secondary deficiencies of testosterone, growth hormone, thyroxine, and antidiuretic hormone Associated autoimmune conditions Yes

No

Primary Adrenal Cortical Insufficiency Addison disease is a primary adrenal insufficiency (i.e., originating in the adrenal glands) in which adrenal cortical hormones are deficient and ACTH levels are elevated because of lack of feedback inhibition. Etiology and Pathogenesis This disease is a relatively rare disorder in which all the layers of the adrenal cortex are destroyed. Autoimmune destruction is the most common cause of Addison disease in western societies, accounting for 75% of cases. Tuberculosis continues to be a major cause of the disease in countries where it is more prevalent.1 Rare causes include metastatic carcinoma, fungal infection (particularly histoplasmosis), cytomegalovirus infection, amyloid disease, CAH, Waterhouse–Friderichsen syndrome, and hemochromatosis. Bilateral adrenal hemorrhage may occur in people taking anticoagulants, during open-heart surgery and during birth or major trauma. Adrenal insufficiency can be caused by acquired immunodeficiency syndrome in which the adrenal gland is destroyed by a variety of opportunistic infectious agents. Drugs that inhibit synthesis or cause excessive breakdown of

glucocorticoids can ketoconazole).1,2,46,47

also

result

in

adrenal

insufficiency

(e.g.,

Clinical Manifestations The adrenal cortex has a large reserve capacity, and the manifestations of adrenal insufficiency usually do not become apparent until approximately 90% of the gland has been destroyed.4 These manifestations are related primarily to mineralocorticoid deficiency, glucocorticoid deficiency, and hyperpigmentation resulting from elevated ACTH levels. Although lack of the adrenal androgens (i.e., DHEAS) exerts few effects in men because the testes produce these hormones, women have sparse axillary and pubic hair.4,48 Mineralocorticoid deficiency causes increased urinary losses of sodium, chloride, and water, along with decreased excretion of potassium (Fig. 4111). The result is hyponatremia, loss of extracellular fluid, decreased cardiac output, and hyperkalemia. There may be an abnormal appetite for salt. Orthostatic hypotension is common. Dehydration, weakness, and fatigue are common early symptoms. If loss of sodium and water is extreme, cardiovascular collapse and shock ensue. Because of a lack of glucocorticoids, the person with Addison disease has poor tolerance to stress. This deficiency causes hypoglycemia, lethargy, weakness, fever, and gastrointestinal symptoms such as anorexia, nausea, vomiting, and weight loss.1,48

Clinical manifestations of primary (Addison disease) and secondary adrenal insufficiency. FIGURE 41-11

Hyperpigmentation results from elevated levels of ACTH. The skin looks bronzed or suntanned in exposed and unexposed areas, and the normal creases and pressure points tend to become especially dark. The gums and oral mucous membranes may become bluish black. The amino acid sequence of ACTH is strikingly similar to that of melanocyte-stimulating hormone; hyperpigmentation occurs in >90% of people with Addison

disease and is helpful in distinguishing the primary and secondary forms of adrenal insufficiency.1,48 Treatment Addison disease, like type 1 DM, is a chronic metabolic disorder that requires lifetime hormone replacement therapy. The daily regulation of the chronic phase of Addison disease is usually accomplished with oral replacement therapy, with higher doses being given during periods of stress. The pharmacologic agent that is used should have both glucocorticoid and mineralocorticoid activities. Mineralocorticoids are needed only in primary adrenal insufficiency. Hydrocortisone is usually the drug of choice. In mild cases, hydrocortisone alone may be adequate. Fludrocortisone (a mineralocorticoid) is used for people who do not obtain a sufficient saltretaining effect from hydrocortisone. DHEAS replacement may also be helpful in the female patient.1,48 Because people with the disorder are likely to have episodes of hyponatremia and hypoglycemia, they need to have a regular schedule for meals and exercise. People with Addison disease also have limited ability to respond to infections, trauma, and other stresses. Such situations require immediate medical attention and treatment. People with Addison disease should be advised to wear a medical alert bracelet or medallion/badge.1,48 Secondary Adrenal Cortical Insufficiency Secondary adrenal insufficiency can occur as the result of hypopituitarism or because the pituitary gland has been surgically removed. Tertiary adrenal insufficiency results from a hypothalamic defect. However, a far more common cause than either of these is the rapid withdrawal of glucocorticoids that have been administered therapeutically for asthma or an exacerbation of multiple sclerosis. These drugs suppress the HPA system, with resulting adrenal cortical atrophy and loss of cortisol production. This suppression continues long after drug therapy has been discontinued and can be critical during periods of stress or when surgery is performed.1,48 Acute Adrenal Crisis

Acute adrenal crisis is a life-threatening situation. If Addison disease is the underlying problem, exposure to even a minor illness or stress can precipitate nausea, vomiting, muscular weakness, hypotension, dehydration, and vascular collapse. The onset of adrenal crisis may be sudden, or it may progress over a period of several days. The symptoms may occur suddenly in children with salt-losing forms of CAH. Massive bilateral adrenal hemorrhage causes an acute fulminating form of adrenal insufficiency. Hemorrhage can be caused by meningococcal septicemia, adrenal trauma, anticoagulant therapy, adrenal vein thrombosis, or adrenal metastases.1,49 Adrenal insufficiency is treated with hormone replacement therapy that includes a combination of glucocorticoids and mineralocorticoids. For acute adrenal insufficiency, the five Ss of management should be followed: (1) Salt replacement, (2) Sugar (dextrose) replacement, (3) Steroid replacement, (4) Support of physiologic functioning, and (5) Search for and treat the underlying cause (e.g., infection). Extracellular fluid volume should be restored. Glucocorticoid replacement is accomplished through the intravenous administration of either dexamethasone or hydrocortisone.1,49 Glucocorticoid Hormone Excess (Cushing Syndrome) The term Cushing syndrome refers to the manifestations of hypercortisolism from any cause.1 Three important forms of Cushing syndrome result from excess glucocorticoid production by the body. Cushing disease is a pituitary form, which results from excessive production of ACTH by a tumor of the pituitary gland. The second form is the adrenal form, caused by a benign or malignant adrenal tumor. The third form is ectopic Cushing syndrome, caused by a nonpituitary ACTH-secreting tumor. Certain extrapituitary malignant tumors such as small cell carcinoma of the lung may secrete ACTH or, rarely, CRH and produce Cushing syndrome. Cushing syndrome can also result from long-term therapy with one of the potent pharmacologic preparations of glucocorticoids; this form is called iatrogenic Cushing syndrome.1 Clinical Manifestations The major manifestations of Cushing syndrome represent an exaggeration of the many actions of cortisol (see Table 41-4). Altered fat metabolism causes a peculiar deposition of fat characterized by a protruding abdomen;

subclavicular fat pads or “buffalo hump” on the back; and a round, plethoric “moon face” (Figs. 41-12 and 41-13). There is muscle weakness, and the extremities are thin because of protein breakdown and muscle wasting. In advanced cases, the skin over the forearms and legs becomes thin, having the appearance of parchment. Purple striae, or stretch marks, from stretching of the catabolically weakened skin and subcutaneous tissues are distributed over the breast, thighs, and abdomen. Osteoporosis may develop because of destruction of bone proteins and alterations in calcium metabolism, resulting in back pain, compression fractures of the vertebrae, and rib fractures. As calcium is mobilized from bone, renal calculi may develop.1,2,8

FIGURE 41-12

Clinical features of Cushing syndrome.

Cushing syndrome. A woman who had a pituitary adenoma that produced adrenocorticotropic hormone exhibits a moon face, buffalo hump, increased facial hair, and thinning of the scalp hair. (From Strayer D., Rubin E. (Eds.). (2015). Rubin’s FIGURE 41-13

pathology: Clinicopathologic foundations of medicine (7th ed., Figure 27-37, p. 1209). Philadelphia, PA: Wolters Kluwer.) The glucocorticoids possess mineralocorticoid properties. This causes hypokalemia, as a result of excessive potassium excretion, and hypertension, resulting from sodium retention. Inflammatory and immune responses are inhibited, resulting in increased susceptibility to infection. Cortisol increases gastric acid secretion, which may provoke gastric ulceration and bleeding. An accompanying increase in androgen levels causes hirsutism, mild acne, and menstrual irregularities in women. Excess levels of the glucocorticoids may give rise to extreme emotional lability, ranging from mild euphoria and absence of normal fatigue to grossly psychotic behavior.1,2,8 Diagnosis and Treatment Diagnosis of Cushing syndrome is a two-step process: the first step is the diagnosis of hypercortisolism and the second step is testing to determine the cause of the cortisol hypersecretion. The tests most commonly used for diagnosis are the 24-hour urinary free cortisol level, the midnight plasma and late-night salivary cortisol measurements, and the low-dose dexamethasone suppression test. After a diagnosis of Cushing syndrome has been made, the following tests can be used to help determine the cause: CRH stimulation test, high-dose dexamethasone suppression test, radiologic imaging of the pituitary and adrenal glands, and petrosal sinus sampling.50 Untreated, Cushing syndrome produces serious morbidity and even death. The choice of surgery, irradiation, or pharmacologic treatment is determined largely by the cause of the hypercortisolism. The goal of treatment for Cushing syndrome is to remove or correct the source of hypercortisolism without causing permanent pituitary or adrenal damage. Transsphenoidal removal of a pituitary adenoma or a hemihypophysectomy is the preferred method of treatment for Cushing disease. This allows removal of only the tumor rather than the entire pituitary gland.50,51 Incidental Adrenal Mass An incidentaloma is a mass found unexpectedly in an adrenal gland by an imaging procedure (done for other reasons), most commonly CT.

Incidentalomas can also occur in other organs, and it is important to determine if they are malignant or hormonally active. Primary adrenal carcinoma is quite rare, but other cancers, particularly lung cancers, commonly metastasize to the adrenal gland (other cancers include breast, stomach, pancreas, colon, kidney, melanomas, and lymphomas). The size and imaging characteristics of the mass may help determine whether the tumor is benign or malignant. Appropriate screening to exclude a hormonally active lesion includes tests to rule out pheochromocytoma, Cushing syndrome, and Conn syndrome (mineralocorticoid excess).1 SUMMARY CONCEPTS The adrenal cortex produces three types of hormones: mineralocorticoids, glucocorticoids, and adrenal androgens. The mineralocorticoids, along with the renin–angiotensin mechanism, aid in controlling body levels of sodium and potassium. The glucocorticoids have anti-inflammatory actions and aid in regulating glucose, protein, and fat metabolism during periods of stress. These hormones are under the control of the HPA system. The adrenal androgens exert little effect on daily control of body function, but they probably contribute to the development of body hair in women. CAH is caused by a genetic defect in the cortisol pathway resulting from a deficiency of one of the enzymes needed for its synthesis. Depending on the enzyme involved, the disorder causes virilization of female infants and, in some instances, fluid and electrolyte disturbances because of impaired mineralocorticoid synthesis. Chronic adrenal insufficiency can be caused by destruction of the adrenal gland (Addison disease) or by dysfunction of the HPA system. Adrenal insufficiency requires replacement therapy with adrenal cortical hormones. Acute adrenal insufficiency is a life-threatening situation. Cushing syndrome refers to the manifestations of excessive glucocorticoid levels. This syndrome may be a result of pharmacologic doses of glucocorticoids, a pituitary or adrenal tumor, or an ectopic tumor that produces ACTH. The clinical manifestations of Cushing syndrome reflect the very high level of glucocorticoid that is present. An incidental adrenal mass is a mass found unexpectedly in an adrenal gland by an imaging procedure done for other reasons. They are being

recognized with increasing frequency, emphasizing the need for correct diagnosis and treatment.

General Aspects of Altered Glucose Regulation Hormonal Control of Glucose, Fat, and Protein Metabolism The body uses glucose, fatty acids, and other substrates as fuel to satisfy its energy needs. Although the pulmonary and circulatory systems combine efforts to furnish the body with the oxygen needed for metabolic purposes, it is the liver, in response to hormones from the endocrine pancreas, which controls the body’s fuel supply (Fig. 41-14).

FIGURE 41-14

Hormonal and hepatic regulation of blood glucose.

Glucose Metabolism Glucose is a six-carbon molecule. It is an efficient fuel that, when metabolized in the presence of oxygen, breaks down to form carbon dioxide and water. Although many tissues and organ systems are able to use other forms of fuel (such as fatty acids and ketones), the brain relies almost exclusively on glucose as a fuel source. Because the brain can neither synthesize nor store more than a few minutes’ supply of glucose, normal cerebral function requires a continuous supply from the circulation. Severe and prolonged hypoglycemia can cause brain death, and even moderate hypoglycemia can result in substantial brain dysfunction.4 Body tissues obtain glucose from the blood. In people without diabetes, fasting blood glucose levels are usually tightly regulated between 80 and 90 mg/dL. After a meal, blood glucose levels rise from 100 to 120 mg/dL and the normal hormonal regulatory mechanisms return the blood levels to the control range within approximately 2 hours.4 Insulin is secreted in response to this rise in glucose. The hormone insulin facilitates the entry of glucose into body cells (to be discussed in greater depth later). Most of the glucose that is ingested with a meal is removed from the blood and stored in the liver as glycogen, with the remaining glucose used for cellular metabolic needs. Between meals, the liver releases glucose from the stored glycogen as a means of maintaining the blood glucose within its normal range. Some glycogen can also be stored within muscle for use within muscle cells by energy. The process of breaking down glycogen to release glucose is called glycogenolysis.4 In addition to mobilizing its glycogen stores, the liver can also synthesize new glucose from amino acids, glycerol, and lactic acid in a process called gluconeogenesis. This newly formed glucose may be released directly into the circulation or stored as glycogen.4 Fat Metabolism Fat is the most dense form of fuel storage, providing 9 kcal/g of stored energy, compared with the 4 kcal/g provided by carbohydrates and proteins. The metabolism of triglycerides from fats produces a glycerol molecule and three fatty acids. The glycerol molecule can enter the glycolytic pathway and be used along with glucose to produce energy, or it can be used to produce glucose. The fatty acids are transported to tissues where they may

also be used for energy by most body cells, with the previously noted exception of the brain.4 When fatty acids are used for energy, organic acid molecules called ketones are released into the bloodstream, creating a situation of ketosis. During periods of excessive use of fatty acids for fuels, the increased accumulation of these organic keto acids can produce a condition of metabolic acidosis called ketoacidosis. Conditions of decreased availability of either glucose or insulin create an increased risk of ketoacidosis.4 Protein Metabolism Proteins are essential for the formation of all body structures, including genes, enzymes, contractile structures in muscle, matrix of bone, and hemoglobin of red blood cells.4 Amino acids are the building blocks of proteins. Unlike glucose and fatty acids, excess amino acids can be stored in only a limited capacity in the body. Amino acids in excess of those needed for protein synthesis are converted to fatty acids, ketones, or glucose.4 Because fatty acids cannot be converted to glucose, the body must break down proteins and use the amino acids as a major substrate for gluconeogenesis during periods when the metabolic needs for glucose exceed glucose intake.4 Glucose-Regulating Hormones The hormonal control of blood glucose resides largely with the endocrine pancreas. The pancreas is made up of two major tissue types—the acini and the islets of Langerhans (Fig. 41-15). The acini secrete digestive juices into the duodenum; the islets of Langerhans secrete hormones into the blood.4 Each islet is composed of beta cells (which secrete insulin and amylin), alpha cells (which secrete glucagon), and a small number of delta cells (which secrete somatostatin).4

FIGURE 41-15

Islet of Langerhans in the pancreas.

Insulin Although several hormones increase blood glucose levels, insulin is the only hormone that acts to lower blood glucose levels. The active form of insulin is produced in the beta cells of the pancreas from a larger molecule called proinsulin (Fig. 41-16). Insulin is formed by cleaving away the Cpeptide of the proinsulin molecule, leaving the A and B polypeptide chains, which form the active insulin molecule.4 The insulin molecule itself has a short plasma half-life of approximately 6 minutes, with clearance from the body primarily through hepatic mechanisms and the action of the enzyme insulinase.4 However, circulating blood levels of the C-peptide molecule can be measured and are used as a proxy measure to reflect pancreatic insulin production.4,52

Structure of proinsulin. With removal of the connecting peptide (C-peptide), proinsulin is converted to insulin. FIGURE 41.16

The actions of insulin include: 1. Promoting glucose uptake by target cells and storage of glucose as glycogen (in liver and muscles) or fat (in adipose tissue) 2. Inhibiting fat and glycogen breakdown 3. Inhibiting gluconeogenesis and increasing protein synthesis1,2,4 (Table 41-6) TABLE 41-6 Actions of Insulin and Glucagon on Glucose, Fat, and Protein Metabolism

Insulin Glucose Glucose transport Glycogen synthesis

Glucagon

Increases glucose transport into skeletal muscle and adipose tissue Increases glycogen synthesis Promotes glycogen breakdown

Insulin Gluconeogenesis Decreases gluconeogenesis Fats Fatty acid and triglyceride synthesis Fat storage in adipose tissue

Proteins Amino acid transport

Glucagon Increases gluconeogenesis

Promotes fatty acid and triglyceride synthesis by the liver Increases the transport of fatty acids into adipose cells Increases conversion of fatty acids to triglycerides by increasing the availability of α-glycerol phosphate through increased transport of glucose in adipose cells Maintains fat storage by inhibiting Activates adipose cell breakdown of stored triglycerides lipase, making by adipose cell lipase increased amounts of fatty acids available to the body for use as energy Increases active transport of amino acids into cells

Protein synthesis Increases protein synthesis by increasing transcription of messenger RNA and accelerating protein synthesis by ribosomal RNA Protein Decreases protein breakdown by breakdown enhancing the use of glucose and fatty acids as fuel

Increases amino acid uptake by liver cells and their conversion to glucose by gluconeogenesis

Target cells for insulin include fat cells; therefore, insulin acts to promote fat storage by increasing the transport of glucose into fat cells. Within the fat cells, insulin facilitates the synthesis of triglycerides from glucose and inhibits the intracellular breakdown of stored triglycerides. Insulin increases protein synthesis and inhibits protein breakdown by increasing the active transport of amino acids into body cells. When sufficient glucose and insulin are present, protein breakdown is minimal because the body uses glucose and fatty acids for energy.4 Blood glucose levels regulate the release of insulin from the pancreatic beta cells. Insulin levels increase as blood glucose levels rise and decrease as blood glucose levels decline. Insulin binds to specific insulin receptor molecules embedded within the plasma membranes of the target cells for insulin. The insulin molecule itself does not enter the target cells; instead, the binding of insulin to its receptor causes several actions to occur within the cell, including the activation of the glucose transport proteins (described in the next paragraph). Other cellular actions triggered by the binding of insulin with its receptor include increasing the cellular permeability to amino acids and to potassium ions and phosphate ions, which increase the rate of transfer of these molecules into the cell.4 The binding of insulin with its cell surface receptors triggers the insertion into the cell membrane of specific glucose transporter proteins. The liver does most of the processing of glucose. When a glucose molecule enters hepatic cells through the glucose transporter protein, the glucose molecule is phosphorylated by the enzyme glucokinase, which creates a molecule that cannot diffuse through the cell membrane, thus effectively “trapping” the glucose inside the liver.4 Insulin also activates the enzyme glycogen synthase, which then catalyzes the intrahepatic process transformation of glucose into glycogen.4 Because cell membranes are impermeable to glucose, a family of glucose transporters mediates the movement of glucose from the blood into the cells. These glucose transporters (named GLUT-1, GLUT-2, etc.) each have their own unique tissue distribution. This process is shown in Figure 41-17.

Insulin-dependent glucose transporter (GLUT-4). (1) Binding of insulin-to-insulin receptor on the surface of the cell membrane, (2) generation of intracellular signal, (3) insertion of GLUT-4 receptor from its inactive site into the cell membrane, and (4) transport of glucose across the cell membrane. FIGURE 41-17

Glucagon Glucagon is a polypeptide molecule produced in the pancreas by the alpha cells of the islets of Langerhans in response to a decrease in blood glucose. The actions of glucagon maintain blood glucose levels between meals and during periods of fasting. Glucagon levels also increase during strenuous exercise to prevent a decrease in blood glucose. After release from the

pancreas, glucagon travels through the portal vein to the liver to initiate hepatic breakdown of glycogen (glycogenolysis), which rapidly raises blood glucose (see Table 41-6). Glucagon also increases the transport of amino acids into the liver and stimulates protein conversion into new glucose through the previously described process of gluconeogenesis. Because liver glycogen stores are limited, gluconeogenesis is important in maintaining blood glucose levels over time.4 Somatostatin, Amylin, and Gut-Derived Hormones Somatostatin is a pancreatic polypeptide hormone containing only 14 amino acids. It has an extremely short plasma half-life of 3 minutes; however, it acts locally in the islets of Langerhans to decrease secretion of insulin and also of glucagon. Somatostatin secretion is triggered by multiple characteristics related to the ingestion of food, including the release of certain gastrointestinal hormones as well as increased blood levels of glucose, fatty acids, and amino acids. In addition to the local pancreatic effects to reduce insulin and glucagon secretion, somatostatin also decreases gastrointestinal motility and slows the absorption of food. The overall role of somatostatin appears to be to increase the time in which nutrients are available in the bloodstream for use by the body cells.4 Islet amyloid polypeptide, or amylin, is another hormone secreted by the pancreatic beta cells. Plasma levels of amylin increase after a meal or a glucose infusion.3Amylin appears to work with insulin to regulate plasma glucose concentrations by suppressing postprandial secretion of glucagon and slowing gastric emptying.4,53 Several gut-derived hormones have been identified as having what is termed an incretin effect, meaning that they increase insulin release and decrease glucagon release when the plasma glucose is elevated.4 Counter-Regulatory Hormones Other hormones that can affect blood glucose include the catecholamines, GH, and the glucocorticoids. These hormones, along with glucagon, are sometimes called counter-regulatory hormones because they counteract the storage functions of insulin to regulate blood glucose levels during periods of fasting, exercise, and other situations that either limit glucose intake or deplete glucose stores.1,2,4

Epinephrine Epinephrine, a catecholamine from the adrenal medulla, helps to maintain blood glucose levels during periods of stress by stimulating glycogenolysis in the liver, thus causing large quantities of glucose to be released into the blood. Epinephrine also inhibits insulin release from pancreatic beta cells, which decreases movement of glucose into muscle cells and increases the breakdown of muscle glycogen stores. Although the glucose released from muscle glycogen does not enter the blood, the use of these internal energy stores by muscles conserves blood glucose for use by tissues such as the brain. Epinephrine also has a direct lipolytic effect on adipose cells, increasing the availability of fatty acids for use as an energy source. The blood glucose–elevating effect of epinephrine is also an important homeostatic mechanism during periods of hypoglycemia.1,2,4 Growth Hormone In addition to the previously described effects on growth, GH has metabolic effects, which include increasing cellular protein synthesis, stimulating release of fatty acids from adipose tissue, and antagonizing the effects of insulin. Secretion of GH is normally inhibited by insulin and by increased levels of blood glucose. During periods of fasting, when both blood glucose levels and insulin secretion fall, GH levels increase. Exercise, such as running and cycling, and various stresses, including anesthesia, fever, and trauma, increase GH levels. Chronic hypersecretion of GH, as occurs in acromegaly, can lead to glucose intolerance and the development of DM. The production of GH increases during childhood, peaks at puberty, and decreases with aging.1,2,4 Glucocorticoid Hormones The glucocorticoid hormones, synthesized in the adrenal cortex, are critical to survival during periods of fasting and starvation, with hypoglycemia a potent stimulus of glucocorticoid release. These hormones stimulate gluconeogenesis by the liver, thus increasing hepatic glucose production. Glucocorticoids also suppress the inflammatory phase of the immune response. The pharmacotherapeutic use of glucocorticoids is a common

treatment for inflammatory diseases, with hyperglycemia a potential side effect of these drugs.1,2,4 SUMMARY CONCEPTS The body can use glucose, fatty acids, and proteins as fuel to satisfy its energy needs; however, the brain neurons are exclusively dependent on glucose for energy. The liver stores excess glucose as glycogen and can convert amino acids, lactate, and glycerol into glucose through the process of gluconeogenesis during periods of fasting or when glucose intake does not keep pace with demand. Blood glucose levels reflect the difference between the amount of glucose released into the circulation by the liver and the amount of glucose removed from the blood by body tissues. Fats, which serve as an efficient source of fuel for the body, are stored in adipose tissue as triglycerides (which consist of three fatty acids linked to a glycerol molecule). In conditions that favor fat breakdown, such as fasting or DM, the triglycerides in adipose tissue are broken down through the process of lipolysis. The fatty acids that are produced through lipolysis are either used as energy by body tissues or converted to ketones by the liver. Proteins, composed of amino acids, are essential for the formation of all body structures. Unlike glucose and fatty acids, excess amino acids can be stored in only a limited capacity in the body. Because fatty acids cannot be converted to glucose, the body must break down proteins and use the amino acids for gluconeogenesis during conditions in which there is insufficient glucose available to support metabolic energy needs. A number of hormones, including insulin, glucagon, epinephrine, GH, and the glucocorticoids, control energy metabolism. Of these hormones, only insulin has the effect of lowering the blood glucose level. Insulin lowers blood glucose by increasing the transport of glucose into body cells and decreasing the hepatic production and release of glucose. Insulin also has the effect of decreasing the use of fats as an energy source by decreasing lipolysis. Other hormones— glucagon, epinephrine, GH, and the glucocorticoids—act to maintain or increase blood glucose concentrations; these hormones are referred to as counter-regulatory hormones. Glucagon and epinephrine

promote glycogenolysis (the breakdown of glycogen stores). Glucagon and the glucocorticoids increase gluconeogenesis (the production of new glucose from nonglucose substrates, primarily amino acids). GH decreases the peripheral use of glucose. Epinephrine and glucagon also increase the use of fat for energy by increasing the release of fatty acids from adipose cells.

Diabetes Mellitus and the Metabolic Syndrome Overview, Incidence, and Prevalence DM refers to a group of common metabolic disorders characterized by hyperglycemia resulting from imbalances between insulin secretion and cellular responsiveness to insulin. A person with uncontrolled diabetes is unable to transport glucose into cells. As a result, body cells are starved, and the breakdown of fat and protein is increased to generate cellular energy.1,2 DM is classified into four types, as described in Chart 41-3. CHART 41.3 CLASSIFICATIONS OF DM Prediabetes This classification is used when the blood glucose levels are elevated but do not meet the diagnostic criteria for diabetes. Type 1 DM Characterized by insufficient insulin production, typically because of autoimmune destruction of pancreatic beta cells and frequently leading to absolute insulin deficiency. There is also a subtype that is idiopathic in which no autoimmune antibodies are detected. Type 2 DM Characterized by a state of insulin resistance and progressive decline in pancreatic beta-cell secretion of insulin. Commonly accompanied by

co-occurring clinical manifestations called the “metabolic syndrome.” Gestational DM Abnormalities of glucose regulation presenting initially during pregnancy, primarily during the second or third trimester. Diabetes due to other causes Includes monogenic diabetic syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), as well as diabetes related to conditions such as cystic fibrosis and organ transplantation. Adapted from American Diabetes Association. (2018). Classification and diagnosis of diabetes: Standards of medical care in diabetes—2018. Diabetes Care 41(Suppl 1), S13–S27. DM is a chronic health problem, with the United States Centers for Disease Control and Prevention reporting 30.3 million people have diabetes (9.4% of the U.S. population).54 Of the total number of adults with diagnosed diabetes, only 5% had type 1 diabetes, with the majority of people having type 2 diabetes. In addition, another 84.1 million adults aged 18 years or older (33.9%) have been classified as having “prediabetes,” based on laboratory findings of elevations in either the fasting glucose or hemoglobin A1C levels (both to be discussed later in this chapter). Prediabetes and diabetes affect people across genders, ages, races, and ethnicity. Among U.S. adults, DM is more prevalent among American Indians/Alaska Natives (14.9% of men; 15.3% of women), non-Hispanic African Americans (12.2% of men; 13.2% of women), and Hispanic Americans (12.6% of men; 11.7% of women).54 Type 1 diabetes is the more prevalent form in children, with the childhood incidence of new cases of type 1 diabetes highest in non-Hispanic whites. The incidence of type 2 diabetes in children is also increasing, with the incidence of new childhood cases of type 2 diabetes highest in minority populations.54 DM, and the resulting impact of short-term and long-term blood glucose fluctuations, can lead to a variety of complications, ranging from acute medical emergencies to disability and death. DM is a significant risk factor in coronary heart disease and stroke, and it is the leading cause of blindness and chronic kidney disease as well as a common cause of lower extremity

amputations. Optimizing glycemic control, through a variety of interventions, minimizes the complications associated with diabetes.1,2 Testing for Diagnosis and Management The diagnosis of DM is confirmed through the use of laboratory tests that measure blood glucose levels. The diagnostic criteria for each type of DM are described in Chart 41-4. Both blood glucose measurements and tests for urinary glucose and ketones are useful in the management of diabetes. CHART 41.4 CRITERIA FOR THE DIAGNOSIS OF DIABETES Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours. OR 2-h PG ≥ 200 mg/dL (11.1 mmol/L) during OGTT. OR Hemoglobin A1C ≥ 6.5% (48 mmol/L) tested using a laboratory method that is NGSP certified (National Glycohemoglobin Standardization Program) and standardized to the Diabetes Control and Complications Trial (DCCT) assay. Repeat testing should be done to confirm the results in the absence of unequivocal hyperglycemia. OR A random plasma glucose of ≥200 mg/dL (11.1 mmol/L) in a person with classic symptoms of hyperglycemia or hyperglycemic crisis. Adapted from American Diabetes Association (2018). Classification and diagnosis of diabetes: Standards of medical care in diabetes—2018. Diabetes Care 41(Suppl 1), S15. Blood Tests Blood tests that are useful in the diagnosis and management of DM include the fasting blood glucose test, the random (or casual) blood glucose test, the oral glucose tolerance test (OGTT), capillary whole blood glucose testing, and glycated hemoglobin levels.

Fasting Plasma Glucose Test The fasting plasma glucose (FPG) test is a measure of plasma glucose after a period of at least 8 hours with no caloric intake.55 An FPG level below 100 mg/dL (5.6 mmol/L) is considered normal (see Table 50-2). A level between 100 and 125 mg/dL (5.6 and 6.9 mmol/L) is significant and is defined as IFG. The diagnostic FPG level for diabetes is 126 mg/dL (7.0 mmol/L) or higher.55 Random Blood Glucose Test A random (or casual) plasma glucose is one that is done without regard to the time of the last meal. A random plasma glucose concentration that is unequivocally elevated (≥200 mg/dL [11.1 mmol/L]) in a person with classic symptoms of diabetes (such as polydipsia, polyphagia, polyuria, and blurred vision) or in a person in hyperglycemic crisis is diagnostic of DM.55 Oral Glucose Tolerance Test The OGTT is an important screening test for diabetes, measuring the body’s ability to remove glucose from the blood. In both men and women, the test measures the plasma glucose response to 75 g of a concentrated glucose solution at selected intervals, usually 1 and 2 hours. In people with normal glucose tolerance, blood glucose levels return to normal within 2 to 3 hours after ingestion of a glucose load, in which case it can be assumed that sufficient insulin is present to allow glucose to leave the blood and enter body cells. Because a person with diabetes lacks the ability to respond to an increase in blood glucose by releasing adequate insulin to facilitate storage, blood glucose levels rise above those observed in people with normal glucose tolerance and remain elevated for longer periods. For diagnostic purposes, the 2-hour plasma glucose value during an OGTT is used as an indicator, with levels ≥200 mg/dL (11.1 mmol/L) serving as a threshold criteria for diagnosis of DM (see Table 41-7).55,56 TABLE 41-7 Correlation between Hemoglobin A1C Level and Mean Plasma Glucose Levels

Hemoglobin A1C (%) 6 7

Mean Plasma Glucose In mg/dL In mmol/L 126 (100–152) 7.0 (5.5–8.5) 154 (123–185) 8.6 (6.8–10.3)

Mean Plasma Glucose In mg/dL In mmol/L 8 183 (147–217) 10.2 (8.1–12.1) 9 212 (170–249) 11.8 (9.4–13.9) 10 240 (193–282) 13.4 (10.7–15.7) 11 269 (217–314) 14.9 (12.0–17.5) 12 298 (240–347) 16.5 (13.3–19.3) Adapted from American Diabetes Association. (2018). Glycemic targets: Standards of medical care in diabetes—2018. Diabetes Care 48 (Suppl 1), S55–S64. Hemoglobin A1C (%)

Capillary Whole Blood Glucose Monitoring Technologic advances have provided the means for monitoring blood glucose levels by using a drop of capillary blood.57,58 Continuous glucose monitoring systems are becoming available to finetune glucose management. The various systems have small catheters implanted in the subcutaneous tissue to provide frequent samples. Endocrine centers are increasingly using this technology in selected people to achieve optimal glycemic management. However, capillary glucose monitoring remains the standard of care.59 Glycated Hemoglobin Testing (Hemoglobin A1C) Hemoglobin A1C is a test that measures the quantity of a subtype of hemoglobin that has been glycated, meaning glucose molecules have become bound to the hemoglobin molecule.60 When red blood cells are released from the bone marrow, hemoglobin normally does not contain glucose; however, during the 120-day life span of the red blood cell, hemoglobin normally becomes glycated. Because glucose entry into red blood cells is not insulin-dependent, the rate at which glucose becomes attached to the hemoglobin molecule reflects blood glucose levels. Glycosylation is essentially irreversible; therefore, the level of A1C present in the blood provides an index of blood glucose levels over the approximate 120-day life span of red blood cells. In conditions of hyperglycemia, the A1C level is increased. Table 41-7 lists A1C values with correlations of mean plasma glucose levels.

Urine Tests Urine tests for glucose indicate that the renal threshold for reabsorption of glucose has been exceeded, which is typically accompanied by hyperglycemia. Renal tests for ketones indicate that the body is producing excessive ketone bodies, typically because of the use of nonglucose energy substrates for fuel.61,62 Classifications and Pathophysiology An overview of the classification scheme of DM is shown in Chart 41-3. The pathophysiologic characteristics and clinical manifestations of each type are described in the following sections. Prediabetes Prediabetes is the diagnostic term used when the blood glucose is elevated but does not yet meet the threshold criteria for the diagnosis of DM. Detection of the prediabetic state is more common in people at risk for type 2 DM. If prediabetes is detected, lifestyle modifications of diet, exercise, and weight loss can help to prevent the progression to type 2 DM.1,2,52 Type 1 Diabetes Mellitus Type 1 DM is characterized by destruction of the pancreatic beta cells. Approximately 5% of the cases of DM are type 1.55 Most instances of type 1 DM are immune mediated, as reflected by the detection of specific autoantibodies. A small minority of people with type 1 DM are considered to have an idiopathic form of type 1 DM in which no autoantibodies are detected. This idiopathic form is more likely in people of Asian or African ancestry.55 Immune-mediated type 1 DM was formerly called juvenile-onset diabetes or insulin-dependent diabetes.55 It occurs more commonly in young people but can occur at any age. The rate of beta-cell destruction is quite variable. The rapidly progressive form is not only commonly observed in children but also may occur in adults. Adults with type 2 DM sometimes also present with a slowly progressive form of insulin-dependent DM with autoimmune findings similar to type 1 DM. This slowly progressive adult

form is sometimes referred to as latent autoimmune diabetes in adults.52 Immune-mediated type 1 DM is often related to a genetic predisposition (i.e., diabetogenic genes). Susceptibility to type 1A DM involves multiple genes; however, the major susceptibility gene for type 1A DM is located in the human leukocyte antigen gene related to antigen presentation to T cells.63 Type 1 diabetes is a catabolic disorder characterized by an absolute lack of insulin, an elevation in blood glucose, and a breakdown of body fats and proteins. The absolute lack of insulin in people with type 1 DM means that they are particularly prone to the development of ketoacidosis. One of the actions of insulin is the inhibition of lipolysis (i.e., fat breakdown) and release of FFAs from fat cells. In the absence of insulin, ketosis develops when these fatty acids are released from fat cells and converted to ketones in the liver. Because of the loss of insulin response, all people with immunemediated type 1 diabetes require exogenous insulin replacement to reverse the catabolic state, control blood glucose levels, and prevent ketosis.1,2,52,55,63 Type 2 Diabetes Mellitus and the Metabolic Syndrome Type 2 DM accounts for the majority of cases of diabetes, approximately 90% to 95%.55 It is a heterogeneous condition that describes the presence of hyperglycemia in association with relative insulin deficiency. Many people with type 2 diabetes are adults and overweight; however, recent trends indicate that type 2 diabetes has become a more common occurrence in adolescents and children with obesity, a condition termed MODY.52 Although autoimmune destruction of the beta cells does not occur, people with type 2 diabetes eventually may require insulin. Therefore, the previous terms related to type 2 diabetes, such as adult-onset diabetes and non– insulin-dependent diabetes, can generate confusion and are thus obsolete.55 Type 2 diabetes has a strong genetic component. A number of genetic and acquired pathogenic factors have been implicated in the progressive impairment of beta-cell function in people with prediabetes and type 2 diabetes.52,63 The metabolic abnormalities associated with type 2 diabetes are illustrated in Figure 41-18. These abnormalities include:

FIGURE 41-18

Pathogenesis of type 2 diabetes mellitus.

1. Insulin resistance 2. Deranged secretion of insulin by the pancreatic beta cells 3. Increased glucose production by the liver52,55,63 In contrast to type 1 diabetes, where absolute insulin deficiency is present, people with type 2 diabetes can have high, normal, or low insulin levels. Insulin resistance is the decreased ability of insulin to act effectively on target tissues, especially muscle, liver, and fat. It is the predominate characteristic of type 2 diabetes and results from a combination of factors such as genetic susceptibility and obesity.52,55,63 Table 41-8 compares the characteristics of type 1 and type 2 DM. TABLE 41-8 Comparison of Type 1 and Type 2 DM

Type 1 Diabetes Age of onset Usually childhood Type of Abrupt; symptomatic onset (polyuria, polydipsia, dehydration) often with severe ketoacidosis Usual body Normal; recent weight weight loss is common Family Occurs, but less history common Human + leukocyte antigen associations Islet lesions Early—inflammation Late—atrophy and fibrosis Beta-cell Markedly reduced mass Circulating Markedly reduced insulin level Clinical Insulin absolutely management required

Type 2 Diabetes Usually adulthood Gradual; usually subtle; often asymptomatic Overweight Very common No

Late—fibrosis, amyloid

Normal or slightly reduced Elevated or normal

Insulin usually not needed initially; insulin supplementation may be needed at later stages; weight loss typically improves the condition Insulin resistance initially stimulates an increase in insulin secretion, often to a level of modest hyperinsulinemia, as the beta cells attempt to maintain a normal blood glucose level. In time, the increased demand for insulin secretion leads to beta-cell exhaustion and failure. This results in elevated postprandial blood glucose levels and an eventual increase in glucose production by the liver. Because people with type 2 DM do not have an absolute insulin deficiency, they are less prone to ketoacidosis compared to people with type 1 diabetes.52,55,63 In type 2 DM, the basal hepatic insulin resistance is manifested by a hepatic overproduction of glucose despite a fasting hyperinsulinemia, with

the rate of glucose production being the primary determinant of the elevated FPG in people with type 2 diabetes. Although the insulin resistance seen in people with type 2 diabetes can be caused by a number of factors, it is strongly associated with obesity and physical inactivity.1,2,52,55,63 Specific causes of beta-cell dysfunction in type 2 DM are unclear; however, it appears that in both type 1 DM and type 2 DM, there may be an increased apoptosis of pancreatic beta cells in response to the stress of hyperglycemia.63 Insulin Resistance and the Metabolic Syndrome Increasing evidence indicates that insulin resistance not only contributes to the hyperglycemia in people with type 2 diabetes, but it also may play a role in other metabolic abnormalities. These include obesity, high levels of plasma triglycerides and low levels of high-density lipoproteins (HDL), hypertension, systemic inflammation (as detected by CRP and other mediators), abnormal fibrinolysis, abnormal function of the vascular endothelium, and macrovascular disease (coronary artery, cerebrovascular, and peripheral arterial disease). This constellation of abnormalities is often referred to as the insulin resistance syndrome, syndrome X, or, the preferred term, metabolic syndrome.1,2,52,55,63 The clinical signs, laboratory abnormalities, and associated illnesses associated with this syndrome are described in Chart 41-5. CHART 41.5 FREQUENTLY OBSERVED CONCOMITANTS OF THE METABOLIC SYNDROME Clinical Signs Central (upper body) obesity with increased waist circumference Acanthosis nigricans (hypertrophic, hyperpigmented skin changes) Laboratory Abnormalities Elevated fasting and/or postprandial glucose Insulin resistance with hyperinsulinemia

Dyslipidemia characterized by increased triglycerides and low HDL cholesterol Abnormal thrombolysis Hyperuricemia Endothelial and vascular smooth muscle dysfunction Albuminuria Comorbid Illnesses Hypertension Atherosclerosis Hyperandrogenism with polycystic ovary syndrome Adapted from Rubin R., Strayer D. S. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Table 13-1, p. 521). Philadelphia, PA: Lippincott Williams & Wilkins. A major factor in people with metabolic syndrome that leads to type 2 diabetes is obesity. People with obesity have increased resistance to the action of insulin and impaired suppression of glucose production by the liver, resulting in both hyperglycemia and hyperinsulinemia. The type of obesity is an important consideration in the development of type 2 diabetes. People with upper body (or central) obesity are at greater risk for developing type 2 diabetes and metabolic disturbances than people with lower body (or peripheral) obesity. Waist circumference and waist–hip ratio, which are both surrogate measures of central obesity, have been shown to correlate well with insulin resistance. A loss of 5% to 10% of body weight has the potential to improve insulin resistance and lower blood glucose levels.1,2,55 The increased adipose tissue and/or dense distribution of central adiposity challenge the vascular perfusion of that tissue, leading to chronic underperfusion with areas of tissue hypoxia and necrosis in the adipose tissue. Tissue macrophages respond to the hypoxic–ischemic cellular damage that induces a condition of chronic inflammation. This inflammatory state begins in the adipose tissue and progresses to other areas of the body to foster a chronic systemic inflammatory response state with

oxidative stress that contributes to the development of atherosclerotic plaque and atherothrombosis.64 In type 2 DM, adipose tissues are among the tissues that demonstrate inadequate response to insulin, contributing to the pancreatic response of hyperinsulinemia to attempt to reduce the hyperglycemia. Overexpression of insulin receptors also may occur. Normally, cellular response to insulin binding stimulates two intracellular pathways—the phosphoinositide 3kinase (P13K) pathway and the mitogen-activated protein (MAP) pathway. In type 2 DM, the P13K pathway does not maintain its function; this P13K functional decline contributes to decreased nitric oxide production from endothelial cells and to a decrease in the translocation of the GLUT-4 proteins that facilitate glucose entry into cells.64 Nitric oxide is a powerful endothelial-derived relaxing factor, which promotes vasodilation.4 Therefore, the decline in nitric oxide production contributes to vasoconstriction and increased vascular resistance. In type 2 DM, the MAP pathway that is also stimulated by the binding of insulin to cellular insulin receptors continues to function. The actions of stimulation of the MAP pathway include stimulation of the vasoconstriction molecule endothelin-1, along with increased expression of adhesion molecules and smooth muscle stimulation, all of which further contribute to the increased risk of development of atherosclerosis in type 2 DM.64 Insulin also normally signals the inhibition of lipolysis; however, the insulin resistance in type 2 DM causes increased lipolysis with increased release of FFAs. The liver transforms these FFAs into triglycerides and very-low-density lipoproteins. The net results of the combined systemic inflammation, increased oxidative stress, endothelial dysfunction, and increased blood lipids all contribute to the constellation of metabolic alterations that are present in the metabolic syndrome—including dyslipidemia, hypertension, vascular pathology, and abnormal coagulation.64 KEY POINTS Diabetes Mellitus DM is a disorder of carbohydrate, fat, and protein metabolism brought about by impaired beta-cell synthesis or release of insulin,

or the inability of tissues to use insulin. Type 1 DM results from loss of beta-cell function and an absolute insulin deficiency. Type 2 DM results from impaired ability of the tissues to use insulin (insulin resistance) accompanied by a relative lack of insulin or impaired release of insulin in relation to blood glucose levels (beta-cell dysfunction). Gestational Diabetes Gestational diabetes mellitus (GDM) is any degree of glucose intolerance that occurs initially during pregnancy, particularly presenting during the second and third trimesters. Diagnosis and careful medical management are essential because women with GDM are at higher risk for complications of pregnancy, mortality, and fetal abnormalities. Fetal abnormalities include macrosomia (i.e., large body size), hypoglycemia, hypocalcemia, polycythemia, and hyperbilirubinemia. Women with GDM have an increased risk of developing type 2 DM; therefore, women in whom GDM is diagnosed should be followed after delivery to detect diabetes early in its course.55,65 Diabetes due to Other Causes A small percentage of the overall number of cases of diabetes consist of specific types of diabetes associated with certain other conditions and syndromes. Such diabetes can occur with pancreatic disease or the removal of pancreatic tissue and with endocrine diseases, such as acromegaly, Cushing syndrome, or pheochromocytoma. Endocrine disorders that produce hyperglycemia do so by increasing the hepatic production of glucose or decreasing the cellular use of glucose. Several specific types of diabetes are associated with monogenetic defects in beta-cell function. Other causes for diabetes can be genetic defects in beta-cell function or insulin secretion, drug treatment, or chemicals.1,2,52,55 Clinical Manifestations of Diabetes Mellitus In type 1 DM, signs and symptoms often arise suddenly. Type 2 DM usually develops more insidiously, often existing for years without detection until

diagnosed during a routine medical examination or care for other conditions. The most commonly identified signs and symptoms of diabetes are referred to as the three polys: 1. Polyuria (i.e., excessive urination) 2. Polydipsia (i.e., excessive thirst) 3. Polyphagia (i.e., excessive hunger) These three symptoms are closely related to the hyperglycemia and glycosuria of diabetes. Glucose is a small, osmotically active molecule. When blood glucose levels are sufficiently elevated, the amount of glucose filtered by the glomeruli of the kidney exceeds the amount that can be reabsorbed by the renal tubules. This results in glycosuria accompanied by osmotic large volume losses of water in the urine. Thirst results from the intracellular dehydration that occurs as blood glucose levels rise causing an osmotic movement of water out of body cells, including cells in the hypothalamic thirst center. This early symptom of increased thirst may be easily overlooked in people with type 2 DM, particularly in those who have had a gradual increase in blood glucose levels. Polyphagia is usually not present in people with type 2 diabetes. In type 1 diabetes, polyphagia probably results from cellular starvation and the depletion of cellular stores of carbohydrates, fats, and proteins.1,2,4,52,63 Weight loss despite normal or increased appetite is a common occurrence in people with uncontrolled type 1 diabetes. The cause of weight loss is twofold. First, loss of body fluids results from osmotic diuresis. Vomiting may exaggerate fluid loss in ketoacidosis. Second, body tissue is lost because the lack of insulin forces the body to use fat stores and cellular proteins for energy. Although weight loss is a frequent phenomenon in people with uncontrolled type 1 DM, type 2 DM is associated with obesity. However, some people with undiagnosed type 2 DM may experience unexplained weight loss as cellular resistance to circulating insulin reduces energy availability.1,2,4,52,63 Other signs and symptoms of hyperglycemia include recurrent blurred vision, fatigue, and skin infections. In type 2 DM, these are often the symptoms that prompt a person to seek medical treatment. Blurred vision develops as the lens and retina are exposed to hyperosmolar fluids.

Lowered plasma volume produces weakness and fatigue. Chronic skin infections often occur in people with type 2 DM. Hyperglycemia and glycosuria also favor the growth of yeast organisms. Candida infections are common initial complaints in women with diabetes.1,2,4,52,63 Treatment The desired management outcome in both type 1 and type 2 DM is normalization of blood glucose with the goal of preventing short-term and long-term complications. Treatment plans involve medical nutrition therapy, exercise, and antidiabetic agents. People with type 1 diabetes require insulin therapy from the time of diagnosis. Weight loss and dietary management may be sufficient to control blood glucose levels in some people with type 2 diabetes who adopt lifestyle changes long term. However, follow-up care is also important for type 2 diabetes because insulin secretion from the beta cells may decrease or insulin resistance may persist or worsen. If this is the case, medications to treat insulin resistance are prescribed. Pancreas transplantation methods are also increasingly being used as a method of diabetic control.1,2,55,65 SUMMARY CONCEPTS DM is a disorder of carbohydrate, protein, and fat metabolism resulting from an imbalance between insulin availability and insulin need. The disease can be classified as type 1 DM in which there is destruction of beta cells and an absolute insulin deficiency, or type 2 DM in which there is a lack of insulin availability or effectiveness. GDM develops during pregnancy, and although glucose tolerance often returns to normal after childbirth, it indicates an increased risk for the development of diabetes. The metabolic syndrome represents a constellation of metabolic abnormalities characterized by obesity, insulin resistance, high triglyceride levels and low HDL levels, hypertension, cardiovascular disease, insulin resistance, and increased risk for development of type 2 DM. The most commonly identified symptoms of type 1 DM are polyuria, polydipsia, polyphagia, and weight loss despite normal or increased appetite. Although people with type 2 DM may present

with one or more of these symptoms, they are often asymptomatic initially. The diagnosis of DM is based on clinical signs of the disease, fasting blood glucose levels, random plasma glucose measurements, and results of the glucose tolerance test. Glycation involves the irreversible attachment of glucose to the hemoglobin molecule; the measurement of A1C provides an index of blood glucose levels over several months. Self-monitoring provides a means of maintaining near-normal blood glucose levels through frequent testing of blood glucose and adjustment of insulin dosage.

Complications of Diabetes Mellitus Acute Complications of Diabetes The three major acute complications of diabetes are diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and hypoglycemia. All are life-threatening conditions that demand immediate recognition and treatment. These complications account for a significant number of hospitalizations and consumption of health care resources.1,2,4 Diabetic Ketoacidosis DKA most commonly occurs in a person with type 1 diabetes in whom the lack of insulin leads to increased release of fatty acids from adipose tissue because of the unsuppressed adipose cell lipase activity that breaks down triglycerides into fatty acids and glycerol. The increase in fatty acid levels leads to ketone production by the liver (Fig. 41-19). DKA can occur at the onset of the disease, often before diagnosis, and can occur as a complication during the course of the disease.

Mechanisms of diabetic ketoacidosis (DKA). DKA is associated with very low insulin levels and extremely high levels of glucagon, catecholamines, and other counter-regulatory hormones. Increased levels of glucagon and the catecholamines lead to mobilization of substrates for gluconeogenesis and ketogenesis by the liver. Gluconeogenesis in excess of that needed to supply glucose for the brain and other glucose-dependent tissues produces a rise in blood glucose levels. Mobilization of free fatty acid (FFA) FIGURE 41-19

from triglyceride stores in adipose tissue leads to accelerated ketone production and ketosis. CNS, central nervous system. Stress increases the release of gluconeogenic hormones and predisposes the person to the development of ketoacidosis. DKA is often preceded by physical or emotional stress, such as infection or inflammation, pregnancy, or extreme anxiety. Ketoacidosis also occurs with the omission or inadequate use of insulin.1,2,4 Etiology and Pathogenesis The three major metabolic derangements in DKA are hyperglycemia, ketosis, and metabolic acidosis. Hyperglycemia leads to osmotic diuresis, dehydration, and a critical loss of electrolytes. Hyperosmolality of extracellular fluid because of hyperglycemia leads to a shift of water from the intracellular to the extracellular compartment. Extracellular sodium concentration is frequently low or normal despite increased urinary water losses because of the intracellular–extracellular fluid shift. This dilutional effect is referred to as pseudohyponatremia. Serum potassium levels may be normal or elevated despite total potassium depletion resulting from protracted polyuria and vomiting. Metabolic acidosis is caused by the excess keto acids that require buffering by bicarbonate ions. This leads to a marked decrease in serum bicarbonate levels. The severity of DKA is classified on the severity of the metabolic acidosis.1,2,4 Clinical Manifestations A day or more of polyuria, polydipsia, nausea, vomiting, and marked fatigue, with eventual stupor that can progress to coma commonly precedes DKA. Abdominal pain and tenderness may be experienced without abdominal disease. The breath has a characteristic fruity smell because of the presence of the volatile keto acids. Hypotension and tachycardia may be present because of a decrease in blood volume. A number of the signs and symptoms that occur in DKA are related to compensatory mechanisms. The heart rate increases as the body compensates for a decrease in blood volume, and the rate and depth of respiration increase (i.e., Kussmaul respiration) as a compensatory mechanism to prevent further decrease in pH.1,2,4 Treatment

The goals in treating DKA are to improve circulatory volume and tissue perfusion, decrease blood glucose, correct the metabolic acidosis, and correct electrolyte imbalances. These objectives are usually accomplished through the administration of insulin along with intravenous fluid and electrolyte replacement solutions. Because insulin resistance accompanies severe acidosis, low-dose insulin therapy may be used.1,2,65 Hyperosmolar Hyperglycemic State HHS is characterized by hyperglycemia, hyperosmolarity with dehydration, the absence of ketoacidosis, and depression of the sensorium. HHS occurs frequently in people with type 2 diabetes.1,2,4 Etiology and Pathogenesis A partial or relative insulin deficiency may initiate HHS by reducing glucose utilization while increasing glucagon release and hepatic glucose output. The hyperglycemia leads to large volume water loss through osmotic diuresis. Dehydration is usually more severe in HHS than in DKA. As the plasma volume contracts, renal insufficiency develops. The resultant decrease in renal elimination of glucose further elevates blood glucose levels, which increases the severity of the hyperosmolar state. In hyperosmolar states, the increased serum osmolarity has the effect of pulling water out of body cells, including brain cells. HHS may also be complicated by thromboembolic events related to the contraction of plasma volume with increased coagulability because of stasis.1,2,4 Clinical Manifestations and Treatment The most prominent manifestations of HHS are weakness, dehydration, polyuria, neurologic alterations, and excessive thirst. Neurologic alterations include hemiparesis, seizures, and coma; these symptoms may be mistaken for a stroke. Successful treatment of HHS involves careful patient monitoring and correction of dehydration, hyperglycemia, and electrolyte imbalance. Close observation and care is particularly important as water moves back into brain cells, posing a threat of cerebral edema.1,2,65 Hypoglycemia

Hypoglycemia is generally defined as any blood glucose concentration of less than 70 mg/dL, with or without symptoms.65 It occurs most commonly in people treated with insulin injections, but prolonged hypoglycemia can also result from some oral antidiabetic agents.1,2,65 Etiology and Pathogenesis Many factors can precipitate hypoglycemia in a person with type 1 DM, including error in insulin dose, failure to eat, increased exercise, decreased insulin need after removal of a stress situation, medication changes, and a change in insulin injection site. Alcohol decreases liver gluconeogenesis; therefore, people with diabetes need to be cautioned about the potential for alcohol ingestion to cause hypoglycemia, particularly if consumed in large amounts or on an empty stomach.1,2,65 Clinical Manifestations Hypoglycemia usually has a rapid onset and progression of symptoms. The signs and symptoms of hypoglycemia can be divided into two categories: (a) those caused by altered brain function and (b) those related to activation of the autonomic nervous system. Because the brain relies on blood glucose as its main energy source, hypoglycemia produces behaviors related to altered brain function. Headache, difficulty in problem solving, disturbed or altered behavior, coma, and seizures may occur. At the onset of the hypoglycemic episode, activation of the parasympathetic nervous system often causes hunger. The initial parasympathetic response is followed by activation of the sympathetic nervous system; this causes anxiety, tachycardia, sweating, and constriction of the skin vessels (i.e., the skin is cool and clammy).1,2,4 The signs and symptoms of hypoglycemia are highly variable, and not everyone manifests all or even most of the symptoms. The signs and symptoms are particularly variable in children and in older adults. Older adults may not display the typical autonomic responses associated with hypoglycemia but frequently develop signs of impaired function of the CNS, including mental confusion. Some people develop hypoglycemic unawareness. Unawareness of hypoglycemia should be suspected in people who do not report symptoms when their blood glucose concentrations are 20 mIU/mL) is considered menopausal.2 Functional Changes Menopause represents the gradual cessation of ovarian function and resultant diminished levels of estrogen. Although estrogen from the adrenal cortex continues to circulate, it is not sufficient to maintain secondary sexual characteristics, and body hair, skin elasticity, and subcutaneous fat decrease. Breasts decrease in tissue mass, ovaries and uterus decrease in size, cervix and vagina are pale and friable,8 and vaginal pH increases (pH > 4.5 indicates estrogen deficiency).7 Problems resulting from urogenital atrophy include vaginal dryness, urinary stress incontinence, urgency, nocturia, vaginitis, and urinary tract infection.1 An individual may experience significant vasomotor instability secondary to the decrease in estrogens and relative increase in other hormones.9 This hormonal instability may give rise to “hot flashes,” palpitations, dizziness, and headaches as the blood vessels dilate. “Hot flashes,” which are a particularly frequent complaint, vary tremendously in their onset, frequency, severity, and duration. When they occur at night and are accompanied by significant perspiration, they can result in frequent awakenings, resulting in sleep deprivation. These uncontrollable and unpredictable events may cause irritability, anxiety, and depression. Despite the association with these biochemical changes, however, the underlying cause of hot flashes is unknown.9 The cessation of ovarian function also results in changes that can influence the health and well-being of postmenopausal individuals. Consequences of long-term estrogen deprivation include osteoporosis and an increased risk for cardiovascular disease, which is the leading cause of death after menopause.8 Other potential health threats are loss of vision and cognitive impairment. Hormone Therapy

Over the past four to five decades, hormone therapy (HT) has been prescribed with increasing frequency for postmenopausal individuals. Initially, HT was used only for symptom management and later to prevent osteoporosis. During the 1990s, it was used as a replacement for a vital hormone lost because of an endocrine organ failure (menopause). It was routinely offered to all postmenopausal individuals based on mounting evidence of its preventive benefits. Data from observational studies demonstrated a 50% reduction in coronary heart disease (CHD) and mortality among individuals using HT.7,10 Types of HT The type of HT prescribed was determined by the condition of the uterus. Females with an intact uterus received a combination of EPT, because estrogen monotherapy had been associated with a risk of endometrial cancer; those who had a hysterectomy received estrogen therapy (ET) only. When used cyclically (i.e., in continuous sequential estrogen–progesterone therapy [CSEPT]), progesterone is added to estrogen therapy for 12 to 14 days to induce the maturation of any endometrial tissue that developed in response to estrogen exposure. Progesterone withdrawal results in endometrial shedding. When used continuously, a small amount is added to the daily estrogen regimen. Continuous exposure to progesterone inhibits endometrial development and eventually results in the cessation of bleeding. However, it can result in irregular bleeding and spotting until the lining becomes atrophic. Prevention of endometrial hyperplasia, either by shedding excess endometrial tissue or by preventing its development in the first place, minimizes the risk of endometrial cancer. This protection must be considered when weighing the risks and benefits of HT. Avoiding Risks with Hormone Therapy: Cardiovascular, Carcinogenic, and Bone Integrity The Women’s Health Initiative (WHI) carried out several studies of the risks and benefits of various strategies for reducing the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal individuals. These strategies included estrogen plus progestin (CSEPT; for females with an intact uterus) and estrogen alone (ET; for females with prior hysterectomy). Both studies were terminated early because it was determined that the risk for breast cancer and cardiovascular events

outweighed the benefits.11 The study findings were later reevaluated and compared with those of other studies to fine-tune the actual risk. The WHI patients may have been at risk for cardiovascular disease on enrollment, given their average age (63.7 years) and time since menopause (18 years) before initiating HT. This suggests that there is a “critical window” of time after menopause during which HT may continue to confer the cardioprotection associated with estrogen before menopause.12,13 Time may also be a factor in treating females at risk for venous thromboembolism. This condition has also been associated with HT, but the absolute risk for this disorder is low, peaking during the first 2 years of HT and declining thereafter. However, females with a history of venous thromboembolism or who have a predisposition to clot formation as a result of coagulation defects are generally advised to avoid HT. Breast cancer cells can be present in the body for 8 to 10 years before the cancer is detected. Estrogen may accelerate the growth of these cells to the point that the cancer can be detected, possibly while it is still curable. It is still not clear whether females with a history of breast cancer and symptoms of menopause can take HT safely.14 Improved methods of identifying factors that predispose females to breast cancer may accelerate the path toward early detection. Estrogen inhibits bone resorption, which places patients taking estrogen at risk for hip fracture. Patients are usually advised to take calcium (1000 mg/day) plus vitamin D (200 IU/day). These dosages have been shown to result in a small but significant improvement in hip bone density but fail to reduce the risk of hip fractures.15 The Institute of Medicine (2010) recommends that all adults increase their vitamin D intake to 600 IU/day to maintain healthy bones16,17 Final Analysis: Current Recommendations for Hormone Therapy Although the average age of menopause has not changed substantially since 1900, increased life expectancy means the average female will live almost one third of her life after menopause. The need to replace the estrogen that is lost is highly controversial. The U.S. Preventive Services Task Force recommendations are against routine use of HT to prevent chronic conditions10; however, the North American Menopause Society,18 the American Society for Reproductive Medicine,19 the American College of Obstetricians and Gynecologists,20 and the National Institutes of Health

State-of-the-Science Conference Statement on Management of MenopauseRelated Symptoms21,22 all indicate that estrogen is the most consistently effective therapy for menopausal symptoms. HT for younger, recently menopausal females appears less likely to increase the risk of conditions reported in older, asymptomatic females on average 10 or more years beyond menopause. Current recommendations for HT are as follows: Avoid prescribing HT for primary or secondary prevention of CHD. Develop an individual risk profile and provide information regarding known risks. Prescribe HT only for individuals who require relief from menopausal symptoms that affect their quality of life. Consider lower-than-standard doses of HT and alternative routes of administration. Limit HT to the shortest duration that is consistent with the goals, benefits, and risks of treatment for each individual. Consider alternative therapies if the individual is not symptomatic to avoid the potential risks associated with HT products that are FDA approved for the prevention of postmenopausal osteoporosis.21 Other proposed methods of managing postmenopausal symptoms include the use of “natural” substances derived from plant oils that are similar in structure to human steroid hormones18 and “phytoestrogens” (naturally occurring substances that have estrogen-like properties, such as isoflavones [e.g., soy and red clover]). Selective serotonin receptor inhibitors, gabapentin, and clonidine have demonstrated improvements in the prevention of hot flashes compared with placebo.7 Botanicals and pharmaceuticals may provide another option for treating menopausal symptoms.23 Continued studies are needed to further evaluate efficacy. SUMMARY CONCEPTS Between menarche and menopause, the female reproductive system undergoes cyclic changes in the menstrual cycle. The normal menstrual cycle is a result of complex interactions among the hypothalamus (which produces GnRH), anterior pituitary gland (which synthesizes and releases FSH, LH, and prolactin), ovaries

(which synthesize and release estrogens, progesterone, and androgens), and associated target tissues (endometrium and vaginal mucosa). The ovarian hormones are largely responsible for controlling cyclic changes and length of the cycle. Estrogens are necessary for normal female physical maturation, for the growth of ovarian follicles, to generate a climate that is favorable to fertilization and implantation of the ovum, and to promote the development of the endometrium in case of pregnancy. Estrogens also prevent bone resorption and regulate the composition of lipoproteins (high-density lipoprotein and low-density lipoprotein) in the blood. Progesterone supports glandular development in the lobular and alveolar tissue of the breasts, and in the endometrium. Menopause is the cessation of menstrual cycles. It may be characterized systemically by significant vasomotor instability and “hot flashes” secondary to the decrease in estrogens and the relative increase in other hormones. The long-term effects of estrogen deprivation include osteoporosis because of an imbalance in bone remodeling (i.e., bone resorption occurs at a faster rate than does bone formation) and an increased risk of CVD, which is the leading cause of death in postmenopausal females. HT, which was regarded as hormone replacement therapy for postmenopausal females during the late 20th century, has come under scrutiny, given recent findings that CSEPT may increase the risk of CVD and breast cancer. It is now recommended that clinicians make a careful assessment of the patient history before completing a risk–benefit analysis for that individual. If the female selects hormone replacement therapy, the preferred approach is to prescribe a low dose for a short interval as early in menopause as possible.

Breasts Structure and Function The breasts are specialized glandular structures with an abundance of nervous, vascular, and lymphatic tissue (Fig. 44-7). Males and females are

born with rudimentary breast tissue, which includes ducts lined with epithelium. In females, estrogen stimulates the growth and proliferation of the ductile system; and progesterone, which is released with the onset of the ovulatory cycles, stimulates growth and development of ductile and alveolar secretory epithelium. By adolescence, the breasts develop characteristic patterns associated with fat deposition.

The breasts, showing the shared vascular and lymphatic supply as well as the pectoral muscles. FIGURE 44-7

The breasts are located on the anterior chest wall between the third and seventh ribs.4 The breast mass consists of fat, fibrous connective tissue, and glandular tissue.4 The superficial layer of fibrous connective tissue is attached to the skin, allowing the skin to move smoothly over the breast to facilitate visual observation of superficial structures, for example, during a breast self-examination. The breast mass is supported by the fascia of the pectoralis major and minor muscles and by the fibrous connective tissue within the breast. Fibrous tissue ligaments, called Cooper ligaments, extend radially from the outer boundaries of the breast to the nipple area (see Fig. 44-8) to provide further support for the breast tissue. In addition, they form septa that divide the breast into approximately 20 lobes,4 each of which contains grapelike clusters of alveoli or glands that are interconnected by

ducts. The alveoli are lined with secretory cells that can produce milk or fluid under specific hormonal conditions (Fig. 44-8). These breast secretions descend from the alveoli to a duct, to an intralobar duct, to a lactiferous duct and reservoir, and then to the nipple.4 Breast milk is produced secondary to complex hormonal changes associated with pregnancy. Fluid is produced and reabsorbed during the menstrual cycle. The breasts respond to cyclic changes in the menstrual cycle with fullness and discomfort.

The breast, showing the glandular tissue and ducts of the mammary glands. FIGURE 44-8

The nipple is made up of epithelial, glandular, erectile, and nervous tissue. The areola is the darker, smooth skin surrounding the nipple, and the surface is punctuated with small bumps known as Montgomery tubercles. These tubercles are sebaceous glands whose secretions keep the nipple area soft and elastic. At puberty and during pregnancy, increased levels of EPT cause the areola and nipple to become darker and more prominent and the Montgomery glands to become more active.7 The erectile tissue of the

nipple responds to psychological and tactile stimuli, contributing to the sexual aspect of the breast. The breast varies considerably in size and shape. Its shape and texture vary with hormonal, genetic, nutritional, and endocrine factors and with muscle tone, age, and pregnancy. The pectoralis muscles support the breast mass on the chest wall. Poor posture, significant weight loss, and lack of support may cause the breasts to droop. Changes during Pregnancy and Lactation During pregnancy, increased levels of EPT significantly alter the breasts. Estrogen stimulates increased vascularity of the breasts and the growth and extension of the ductile structures, causing “heaviness” of the breasts. Progesterone causes marked budding and growth of the alveolar structures. The alveolar epithelium assumes a secretory state in preparation for lactation. Cellular changes that occur in the alveolar lining are thought to change the susceptibility of these cells to estrogen-mediated changes later in life. During lactation, milk is secreted by alveolar cells, which are under the influence of the anterior pituitary hormone prolactin. Milk ejection from the ductile system occurs in response to the release of oxytocin from the posterior pituitary. The suckling of the infant provides the stimulus for milk ejection. Suckling produces feedback to the hypothalamus, stimulating the release of oxytocin from the posterior pituitary. Oxytocin causes contraction of the myoepithelial cells lining the alveoli and ejection of milk into the ductal system.4 KEY POINTS Breasts The structure and function of the breast are affected by hormonal changes throughout a person’s lifetime, such as during pregnancy and lactation. SUMMARY CONCEPTS

The breast is a complex structure that varies in size, consistency, and composition. Although anatomically distinct, breasts are functionally related to the female genitourinary system and change in shape, texture, and function in response to cyclic changes in sex hormones.

Review Exercises 1. Diabetes mellitus and treatment with broad-spectrum antibiotics increase the risk of vaginal infections. A. Explain how these two conditions change the vaginal ecology, making it more susceptible to infection. 2. Most oral contraceptive agents use low doses of estrogen and progestin to prevent conception. A. Use Figure 44-3 to explain how these oral agents prevent ovulation and pregnancy. REFERENCES 1. Ross M. H., Pawlina W. (2015). Histology: A text and atlas. Philadelphia, PA: Lippincott Williams & Wilkins. 2. Ricci S. (2017). Essentials of maternity, newborn, and women’s health nursing. Philadelphia, PA: Lippincott Williams & Wilkins. 3. Vaneechoutte M. (2017). The human vaginal microbial community. Research in Microbiology 168(9–10), 811–825. 4. Sillbert-Flagg J. (2018). Maternal and child health nursing: Care of the childbearing and childbearing family (8th ed.). Philadelphia, PA: Wolters Kluwer. 5. Gorroll A. H., Mulley A. G. (2014). Primary care medicine: Office evaluation and management of the adult patient. Philadelphia, PA: Lippincott Williams & Wilkins. 6. Singhal V., Maffazioli G. D., Ackerman K. E., et al. (2016). Effect of chronic athletic activity on brown fat in young women. PLoS One 11(5), e0156353. 7. Genazzani A., Brincat M. (2014). Frontiers in gynecological endocrinology—Vol. 1: From symptoms to therapies. New York, NY: Springer International Publishing. 8. Panay N., Hamoda H., Arya R., et al. (2013). The 2013 British Menopause Society & Women’s Health Concern recommendations on hormone replacement therapy. Menopause International 19(2), 59–68. 9. Takahashi T. A., Johnson K. M. (2015). Menopause. Medical Clinics of North America 99(3), 521–534. 10. Kreatsoulas C., Anand S. S. (2013). Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement. Polish Archives of Internal Medicine 123(3), 112–117.

11. Writing Group for the Women’s Health Initiative Investigators. (2002). Risks and benefits of estrogen and progestin in healthy postmenopausal women: Principal results from the WHI randomized controlled trial. Journal of the American Medical Association 288, 321–333. 12. Hall P. S., Nah G., Howard B. V., et al. (2017). Reproductive factors and incidence of heart failure hospitalization in the Women’s Health Initiative. Journal of the American College of Cardiology 69(20), 2517–2526. 13. Bassuk S. S., Manson J. E. (2016). The timing hypothesis: Do coronary risks of menopausal hormone therapy vary by age or time since menopause onset? Metabolism 65(5), 794–803. 14. Akram M., Iqbal M., Daniyal M., et al. (2017). Awareness and current knowledge of breast cancer. Biological Research 50(1), 33. 15. Garrido Oyarzún M. F., Castelo-Branco C. (2017). Use of hormone therapy for menopausal symptoms and quality of life in breast cancer survivors: Safe and ethical? Gynecological Endocrinology 33(1), 10–15. 16. Cauley J. A., Chlebowski R. T., Wactawski-Wende J., et al. (2013). Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: The Women’s Health Initiative. Journal of Women’s Health 22(11), 915–929. 17. Friedman P. A., Brunton L. L. (2018). Updated vitamin D and calcium recommendations. [Online]. Available: https://www.medscape.com/viewarticle/738275. Accessed March 12, 2018. 18. Moyer V. A.; U.S. Preventive Services Task Force. (2013). Medications for risk reduction of primary breast cancer in women: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine 159(10), 698–708. 19. North American Menopause Society 2017 Hormone Therapy Position Statement Advisory Panel. (2017). The 2017 hormone therapy position statement of the North American menopause society. Menopause 24(7), 728–753. 20. Committee on Gynecologic Practice and the American Society for the Reproductive Medicine Practice Committee. (2012). Committee opinion No. 532: Compounded bioidentical menopausal hormone therapy. Obstetrics & Gynecology 120(2 Pt 1), 411–415. 21. American College of Obstetricians and Gynecologists. (2014). ACOG Practice Bulletin No. 141: Management of menopausal symptoms. Obstetrics & Gynecology 123(1), 202–216. 22. National Institutes of Health State-of-the-Science Conference on Management of MenopauseRelated Symptoms. (2005). Available: http://consensus.nih.gov/2005/menopause.htm. Accessed August 15, 2011. 23. Chew F., Wu X. (2017). Sources of information influencing the state-of-the-science gap in hormone replacement therapy usage. PLoS One 12(2), e0171189.

CHAPTER 45 Disorders of the Female Reproductive System Disorders of the External Genitalia and Vagina Disorders of the External Genitalia Bartholin Gland Cyst and Abscess Nonneoplastic Epithelial Disorders Vulvodynia Cancer of the Vulva Disorders of the Vagina Vaginitis Cancer of the Vagina Disorders of the Cervix and Uterus Disorders of the Uterine Cervix Cervicitis and Cervical Polyps Cancer of the Cervix Disorders of the Uterus Endometritis Endometriosis Adenomyosis Endometrial Cancer

Leiomyomas Disorders of the Fallopian Tubes and Ovaries Pelvic Inflammatory Disease Clinical Manifestations Diagnosis and Treatment Ectopic Pregnancy Clinical Manifestations Diagnosis and Treatment Cancer of the Fallopian Tube Ovarian Cysts and Tumors Ovarian Cysts Polycystic Ovary Syndrome Benign and Functioning/Endocrine Active Ovarian Tumors Ovarian Cancer Disorders of Pelvic Support and Uterine Position Disorders of Pelvic Support Cystocele Rectocele and Enterocele Uterine Prolapse Treatment of Pelvic Support Disorders Variations in Uterine Position Menstrual Disorders Dysfunctional Menstrual Cycles Etiology and Pathogenesis Treatment Amenorrhea Etiology Diagnosis and Treatment Dysmenorrhea Premenstrual Symptom Disorders Etiology Clinical Manifestations Diagnosis Treatment Disorders of the Breast

Galactorrhea Mastitis Ductal Disorders Fibroadenoma and Fibrocystic Changes Breast Cancer Risk Factors Detection Diagnosis and Classification Treatment Paget Disease Infertility Male Factors Female Factors Diminished Ovarian Reserve Ovulatory Dysfunction Cervical Mucus Problems Uterine Cavity Abnormalities Tubal Factors Assisted Reproductive Technology Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Discuss the abnormalities associated with Bartholin cysts, nonneoplastic epithelial disorders, vulvodynia, and cancer of the vulva. 2. Describe the conditions that predispose to vaginal infections and the methods used to prevent and treat these infections. 3. Describe the importance of the cervical transformation zone in cervical cancer. 4. Describe the development of cervical cancer from the appearance of atypical cells to the development of invasive cervical cancer and relate to the importance of the Pap smear in early detection of cervical cancer.

5. Compare the pathology and manifestations of endometriosis and adenomyosis. 6. List the common causes and symptoms of pelvic inflammatory disease (PID). 7. Describe the risk factors and symptoms of ectopic pregnancy. 8. List the hormones produced by the three types of functioning ovarian tumors. 9. Characterize the function of the supporting ligaments and pelvic floor muscles in maintaining the position of the pelvic organs, including the uterus, bladder, and rectum. 10. Describe the cause of cystocele, rectocele, enterocele, and uterine prolapse. 11. Define the terms amenorrhea, hypomenorrhea, oligomenorrhea, menorrhagia, metrorrhagia, and menometrorrhagia in relation to the Federation of Gynecology and Obstetrics (FIGO) classification. 12. Relate the alteration in estrogen and progesterone levels to the development of dysfunctional menstrual cycles. 13. Differentiate between primary dysmenorrhea and secondary dysmenorrhea. 14. Describe changes in breast function that occur with galactorrhea, mastitis, and ductal ectasia. 15. Describe the methods used in the diagnosis and treatment of breast cancer. 16. Provide a definition of infertility. 17. List male and female factors that contribute to infertility. 18. List basic treatments of infertility.

Disorders of the female genitourinary system have widespread effects on physical and psychological function, including general health status, sexuality, and reproductive potential. The reproductive structures are located near other pelvic structures, and disorders of the reproductive system may affect urinary function. This chapter focuses on infection and inflammation, benign conditions, and neoplasms of the female reproductive structures; disorders of pelvic support and uterine position; and alterations in menstruation. An overview of infertility is included.

Disorders of the External Genitalia and Vagina Disorders of the External Genitalia Most skin cysts, nevi, and malignant neoplasms can occur on all hairbearing skin. The vulva (mons pubis, labia majora and minora, clitoris, and vestibule) is prone to skin infections because it is constantly exposed to secretions and moisture. Nonspecific vulvitis is common in diabetes, chronic kidney disease, blood dyscrasias, and malnutrition. Bartholin Gland Cyst and Abscess A Bartholin gland cyst is a fluid-filled sac that results from occlusion of the duct system in the Bartholin gland (Fig. 45-1).1 If the cyst becomes infected, an abscess may develop in the gland and is commonly caused by staphylococcal, chlamydial, and anaerobic infections.1–3

Bartholin gland cyst. The 4-cm lesion (arrows) is posterior to the vaginal introitus. (From Strayer D., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 24-3, p. 1001). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-1

Acute symptoms are usually the result of infection and include pain, tenderness, and dyspareunia (pain with intercourse). Treatment of symptomatic cysts consists of appropriate antibiotics, local application of moist heat, and incision and drainage. A Word catheter may be used to drain the cyst for a few weeks. Reoccurring cysts may require surgical

intervention. Bartholin glands shrink during menopause, so a growth postmenopause should be evaluated for malignancy.4 Nonneoplastic Epithelial Disorders Nonneoplastic epithelial disorders are nonmalignant atrophic and hyperplastic changes of the vulvar skin and mucosa that can develop at any age and can progress to malignancy. Lesions can be categorized as lichen simplex chronicus, sclerosus, or planus.5,6 These can progress to vulvar intraepithelial neoplasia (VIN) or VIN simplex.1 Vulvar carcinoma is rare.1 Lichen simplex chronicus presents as thickened, gray-white plaques with an irregular surface. This diagnosis is made when human papillomavirus (HPV) infection, fungal infections, or other known causative conditions have been ruled out. Vulvar pruritus is the most common presenting complaint. Treatment is aimed at reducing itching and preventing further irritation to the skin. Lichen sclerosus is an inflammatory disease of the vulva characterized by plaquelike areas that may progress to parchment-thin epithelium with focal areas of ecchymosis and superficial ulceration secondary to scratching.4 Atrophy and contracture of vulvar tissues with eventual stenosis of the introitus are common when this disease is chronic. Itching and dyspareunia are common. Lichen sclerosus develops insidiously and is highly associated with developing vulvar malignancy.1 It is also seen with autoimmune disorders such as thyroiditis and vitiligo.1 Current treatments favor use of potent topical corticosteroids.6,7 Lichen sclerosus frequently recurs, and lifetime maintenance therapy may be required. Hyperplastic areas in the field of lichen sclerosus may be sites of malignant change and warrant follow-ups and possible biopsy. Lichen planus likely has an autoimmune component and is rare. The three types are erosive (the most common), papulosquamous, and hypertrophic.4 Treatment is usually a mild topical steroid. Vulvodynia Vulvodynia is a multifactorial chronic vulvar pain disorder of at least 3 months’ duration.8,9 The International Society for the Study of Vulvovaginal Disorders defines it as a condition characterized by vulvar pain in the absence of relevant visible findings or a clinically identifiable disorder.9 It

may be primary or secondary. Vulvodynia is further classified as localized or generalized, and as to whether it is provoked, unprovoked, or of mixed origin.9 Localized Vulvodynia Localized vulvodynia or vestibulodynia is characterized by often stinging, burning, or cutting pain at onset of intercourse (i.e., insertional dyspareunia), localized point tenderness near the vaginal opening, and sensitivity to tampon placement.10,11 Pain can be primary (present from first contact) or secondary (developing after a period of comfortable sexual relations). The etiology is unknown but may involve brain and spinal cord pain circuit sensitization.10 Women who have anxiety and mood disorders may be predisposed to developing vestibulodynia.10 Surgical vestibulectomy may provide symptom relief when medical management fails. Because there is no known specific etiology, treatment must be individualized. Biofeedback, sexual counseling, and psychological and emotional support may also be beneficial.11 Generalized Vulvodynia Generalized vulvodynia involves severe, constant, widespread pain or burning that interferes with daily activities.8,12 No abnormalities are found on examination, but there is diffuse and variable hypersensitivity and altered sensation to light touch. This unprovoked pain shares many features of other neuropathic pain disorders. The cause of the pain is unknown but may be due to myofascial restrictions affecting the sacral and pelvic floor nerves. Surface electromyography-assisted pelvic floor muscle rehabilitation has been an effective primary therapy or adjunct to medical or surgical therapy for generalized vulvodynia.8,9 Proposed triggers include chronic recurrent vaginal infections; chemical irritation or drug effects, especially prolonged use of topical steroid creams; irritating effects of elevated urinary levels of calcium oxalate; and immunoglobulin A deficiency or other immune regulation disorders.8,9 Careful history and physical assessment are essential. Vulvodynia is a diagnosis of exclusion after ruling out infections, such as candidiasis and genital herpes; inflammatory conditions, such as lichen simplex chronicus and lichen sclerosus; vulvar cancer; or neurologic disorders, such as herpes neuralgia or spinal nerve compression, as causes for the pain.

Treatment aims for symptom relief, is often long term, and is managed with a multidimensional, chronic pain perspective.8,9 Regimens include long-term vaginal or oral antifungal therapy, avoidance of irritants, sitz baths with baking soda, emollients (vitamin E or vegetable oil for lubrication), anesthetic or steroid ointments, capsaicin cream, physical therapy, and surgery. Oral medications, including tricyclic antidepressants, other antidepressants, or gabapentin, are often used to treat neuropathic pain associated with vulvodynia.11 Because it can cause strain in sexual, family, and work relationships, psychosocial support often is needed. Cancer of the Vulva Estimates of carcinoma of the vulva for 2019 in the United States are approximately 6070 new cases per year with 1280 predicted deaths.13 There is a lifetime risk of 0.3%,13 and it accounts for 3% of all of female genital malignancies occurring in females over 60 years of age.1 Vulvar carcinoma can be divided into two groups: HPV-associated usual vulvar intraepithelial neoplasm (uVIN) and HPV-independent VIN (dVIN). uVIN is commonly found in younger women. By contrast, dVIN more commonly occurs in postmenopausal women with a history of lichen sclerosus or lichen simplex chronicus.14 One third to one half of uVIN cases appear to be caused by the cancerpromoting potential of certain strains (subtype 16) of HPV that are sexually transmitted.1 VIN lesions may be singular or multicentric, macular or papular, red or white, and plaquelike. Microscopically, uVIN presents as a proliferative process and is characterized by epithelial cells with hyperchromatic nuclei, increased mitosis, and a larger nucleus-to-cytoplasm ratio. The risk of progression to invasive cancer increases in older females and in females with suppressed immune function.14 The dVIN form of vulvar cancer is generally preceded by vulvar nonneoplastic disorders such as chronic vulvar irritation or lichen sclerosus. The etiology is unclear. Neoplastic changes may arise from lichen sclerosus lesions or hyperplasia, leading directly to malignancy.14 The initial lesion of squamous cell vulvar carcinoma may appear as an inconspicuous thickening of skin, a small raised area, or an ulceration that fails to heal. It may be single or multiple and vary from white to velvety red or black.15 Lesions may resemble eczema or dermatitis and may produce

few symptoms other than pruritus, local discomfort, and exudation. It may become secondarily infected, causing pain and discomfort. The malignant lesion gradually spreads superficially or as a deep furrow involving all of one labial side. Because there are many lymph channels around the vulva, the cancer metastasizes freely to the regional lymph nodes. The most common extension is to the superficial inguinal, and then to deep femoral, inguinal, and pelvic lymph nodes.16 The system developed by the 2009 International FIGO grades vulvar cancer using four stages depending on where it has spread.17 Early diagnosis is important. Because lesions are commonly mistaken for other conditions, biopsy and treatment often are delayed. Treatment is primarily wide surgical excision of the lesion for noninvasive cancer and radical excision or vulvectomy with node resection for invasive cancer. Postoperative groin and pelvic radiation is recommended if groin lymph nodes are involved.18 Disorders of the Vagina Vaginal ecology depends on a balance of hormones and bacterial flora. Normal estrogen levels maintain a thick, protective squamous epithelium that contains glycogen. Vaginal flora consists of bacteria mostly from the Lactobacillus genus that metabolizes glycogen and produces the lactic acid that normally maintains vaginal pH of 4.0 to 4.5.19 Disruptions in these conditions, such as changes in the normal flora by antibiotic use, predispose to infection. Vaginitis Vaginitis is an inflammation of the vagina characterized by discharge and burning, itching, redness, and swelling of vaginal tissues. Pain often occurs with urination and sexual intercourse. Chemical irritants, foreign bodies, or infectious agents may be the cause. Most vaginal infections premenarche have nonspecific causes, such as poor hygiene, intestinal parasites, or the presence of foreign bodies. Candida albicans, Trichomonas vaginalis, and bacterial vaginosis are the most common causes of vaginitis postmenarche and premenopause.1 In postmenopausal women, atrophic vaginitis is the most common form. This is an inflammation of the vagina that occurs after menopause or

removal of ovaries (causing estrogen deficiency). Estrogen deficiency results in a lack of regenerative growth of the vaginal epithelium, rendering these tissues more susceptible to infection and irritation. This leads to a decrease in the vaginal flora, causing vaginal secretions to become less acidic. Symptoms include itching, burning, and painful intercourse. Extreme symptoms may be reversed by local application of estrogen cream. Vaginal discharge that causes burning, itching, or has an unpleasant odor suggests inflammation or infection. Because these symptoms are common to the different types of vaginitis, precise identification of the organism is essential for treatment. A history should include information about systemic disease conditions, use of drugs such as antibiotics, dietary habits, stress, and other factors that alter the resistance of vaginal tissue to infections. A physical examination can evaluate the nature of the discharge and its effects on genital structures. A saline wet-mount smear (prepared by placing a sample of vaginal mucus in one or two drops of normal saline) is the primary means of identifying the organism responsible. To identify candidiasis, potassium hydroxide is used with the wet mount instead of saline.19 The prevention and treatment depend on health habits and accurate diagnosis and treatment of infections. An earlier diagnosis may lead to more effective treatment. Cancer of the Vagina Primary cancers of the vagina are rare: Approximately 1% of women will develop vaginal cancer in their lifetime.20 Most females are over 60 years at the time of diagnosis, with the exception being the clear cell adenocarcinoma associated with diethylstilbestrol (DES) exposure in utero.1 Vaginal cancers may result from local extension of cervical cancer, from exposure to sexually transmitted HPV, or, rarely, from local irritation (e.g., from prolonged use of a pessary). Squamous cell carcinomas begin in the epithelium and progress over years from precancerous lesions called vaginal intraepithelial neoplasia, 65% to 80% of which contain HPV.21 The most common symptom is abnormal bleeding. Other symptoms include abnormal vaginal discharge, a palpable mass, or dyspareunia. Most females with preinvasive vaginal carcinoma are asymptomatic, with the cancer discovered during a routine

pelvic examination. The proximity of the vagina to other pelvic structures (urethra, bladder, and rectum) permits early spread to these areas. Therefore, about 80%, of vaginal cancer is due to metastasis.1 Treatment considers the type of cancer; the size, location, and spread of the lesion; and age. Local excision, laser vaporization, or a loop electrosurgical excision procedure (LEEP) can be used with stage 0 squamous cell cancers. Radical surgery and radiation therapy are both curative with more advanced cancers. When there is upper vaginal involvement, radical surgery may be required, including a total hysterectomy, pelvic lymph node dissection, and partial vaginectomy. Ovaries usually are preserved unless they are diseased. Extensive lesions and those located in the middle or lower vaginal area usually are treated by radiation therapy. Prognosis depends on stage of the disease, involvement of lymph nodes, and degree of mitotic activity of the tumor.22 SUMMARY CONCEPTS The surface of the vulva is affected by disorders that affect the skin on other parts of the body. Bartholin cysts are the result of occluded ducts in Bartholin glands. They often are painful and can become infected. Nonneoplastic epithelial disorders are characterized by thinning or hyperplastic thickening of vulvar tissues. Vulvodynia is a chronic vulvar pain syndrome with several classifications and variable treatment results. Cancer of the vulva is associated with HPV infections in younger women and lichen sclerosus in older females. Normal vaginal ecology depends on the balance of hormones and bacterial flora. Disruptions predispose to vaginal infections. Vaginitis is characterized by vaginal discharge and burning, itching, redness, and swelling of vaginal tissues. It may be caused by chemical irritants, foreign bodies, or infectious agents. Primary cancers of the vagina account for about 1% of all cancers of the female reproductive system. Daughters of females treated with DES to prevent miscarriage are at increased risk for development of adenocarcinoma of the vagina.

Disorders of the Cervix and Uterus Disorders of the Uterine Cervix The cervix is composed of two types of tissue. The exocervix, the visible portion, has stratified squamous epithelium, which also lines the vagina.1 The endocervix, the canal that leads to the endometrial cavity, is lined with columnar epithelium that has large, branched mucus-secreting glands.1 During a menstrual cycle, cervical glands undergo functional changes. The mucus secreted by the gland cells vary under the influence of ovarian hormones, and blockage of the glands results in trapping of mucus in the deeper glands, leading to formation of dilated benign cysts in the cervix (nabothian cysts). These may grow to one centimeter or more.6 The junction of squamous and mucus-secreting columnar epithelium (squamocolumnar junction) appears at various locations over a lifetime (Fig. 45-2).6 During the reproductive years, the cervix everts or turns outward, exposing the columnar epithelium to the vaginal environment. The combination of hormonal and pH changes, long-term inflammation, and mechanical irritation lead to a gradual transformation from columnar to squamous epithelium—a process called metaplasia. This area of continuous change is called the transformation zone.6

Location of the squamocolumnar junction (transformation zone) in menarchial, menstruating, menopausal, and postmenopausal women. (A, menarchial; B, menstruating; C, menopausal; D, postmenopausal.) FIGURE 45-2

The transformation zone is a critical area in the development of cervical cancer. During metaplasia, newly developed squamous epithelial cells are vulnerable to development of dysplasia (disordered growth or development of cells) and genetic changes if exposed to cancer-producing agents. Although initially reversible, untreated dysplasia can develop into carcinoma. The transformation zone is sampled in a Pap smear. If the Pap smear is abnormal, the transformation zone is carefully examined during colposcopy, a vaginal examination using a colposcope.6 Cervicitis and Cervical Polyps Acute cervicitis may result from direct infection of the cervix or may be secondary to a vaginal or uterine infection. It may be caused by infective agents including Streptococcus, Staphylococcus, Enterococcus, C. albicans, T. vaginalis, Neisseria gonorrhoeae, Gardnerella vaginalis, Chlamydia trachomatis, Ureaplasma urealyticum, and herpes simplex virus type 2.1 C. trachomatis is most commonly associated with mucopurulent cervicitis.

With acute cervicitis, the cervix becomes reddened and edematous. Irritation from infection results in mucopurulent drainage and leukorrhea.1 Depending on the cause, acute cervicitis is treated with appropriate antibiotic therapy. Untreated cervicitis may extend to include the development of pelvic cellulitis, dyspareunia, cervical stenosis, and ascending infection of the uterus or fallopian tubes. Polyps are the most common lesions of the cervix. Incidence is higher during reproductive years.1 They are soft, velvety, red lesions, usually pedunculated and found protruding through the cervical os. They usually develop due to inflammatory hyperplasia of endocervical mucosa. They typically are asymptomatic but may be associated with postcoital bleeding. Most are benign but should be removed and examined to exclude possibility of malignant change.23 Cancer of the Cervix Cervical cancer is readily detected and, if detected early, is the most easily cured of all female reproductive system cancers. Approximately 13,170 new cases of invasive cervical cancer will be diagnosed in the United States in 2019, with 4250 predicted deaths.24 In the past 40 years, cervical cancer deaths have decreased by 50%, indicating the importance of early detection and treatment.24 Risk Factors Risk factors include early age at first intercourse, multiple sexual partners, smoking, and a history of sexually transmitted infections (STIs). Homosexual and heterosexual females should follow the same guidelines for Pap smear screening.23 HPV is an STI passed through genital or skin-toskin contact. At least 50% of people contract HPV in their lifetime.24 HPV type 16 and HPV type 18 have been associated with cervical cancer.1 Other HPV types linked with cervical cancer include HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.1 Other factors such as smoking, nutrition, and coexisting sexual infections such as C. trachomatis, herpes simplex virus type 2, and HIV may contribute to whether an HPV infection develops into cervical cancer.24 Preventing Cervical Cancer

The HPV vaccine has decreased the risk of cervical cancer by 97%.1 Gardasil is an HPV vaccine that prevents infection with HPV subtypes 16, 18, 6, and 11. It is approved for females and males between 9 and 26 years of age (before sexual activity) to prevent HPV 6 and HPV 11 genital warts. HPV 16 and 18 are responsible for 70% of cervical cancer, and the two most common benign strains (HPV 6 and 11) account for up to 90% of genital warts. The vaccine is safe and effective in inducing a sustained immunity response to HPV.24,25 Gardasil 9 vaccine offers the same protection as Gardasil and protects against HPV types 31, 33, 45, 52, and 58. These nine strains contribute to 90% of cervical cancers.24 The other U.S. Food and Drug Administrationapproved HPV vaccine is Cervarix, which is recommended for females between 9 and 25 years of age, before becoming sexually active. Cervarix protects against HPV 16 and 18.26 Pathogenesis Pap smear cytological screening allows precancerous lesions to be detected and treated before cancer develops. Atypical cells may display changes in the nuclear and cytoplasmic parts of the cell and variation in cell size and shape (i.e., dysplasia). These precancerous changes represent a continuum of changes with indistinct boundaries that may gradually progress to cancer in situ and then to invasive cancer or may spontaneously regress.1 A system of grading to describe the histopathologic findings of dysplastic changes of cancer precursors uses the term cervical intraepithelial neoplasia (CIN),18 which describes premalignant changes in the epithelial tissue. CIN I is defined as dysplasia or atypical changes in the cervical epithelium, CIN II is moderate dysplasia, and CIN III is severe dysplasia.25 Diagnosis Abnormal Pap smear results will return as atypical squamous cells of undetermined origin (ASC-US); atypical squamous cells of undetermined origin that cannot exclude high-grade squamous intraepithelial lesion (ASC-H); low-grade squamous intraepithelial lesion (LGSIL); high-grade squamous intraepithelial lesion (HGSIL); or squamous cell cancer. If abnormal results are detected, a colposcopy may be done. Biopsies are taken of potential abnormal lesions or areas of increased vascularity, as well as a curettage of the endocervical canal that may not be fully seen on

colposcopy. The abnormal Pap smear finding of LGSIL is often CIN I on biopsy, whereas HGSIL on a Pap smear is likely CIN II or CIN III on a biopsy27 (Fig. 45-3).

The Bethesda system for designation of premalignant cervical disease as squamous intraepithelial lesions (SILs). This chart integrates multiple aspects across the normal–LGSIL (lowgrade squamous intraepithelial lesion), and LSIL–HSIL (high-grade squamous intraepithelial lesion) interfaces, which correspond to therapeutic thresholds. It lists the qualitative and quantitative features that distinguish low-cancer-risk (LSIL) from high-cancer-risk (HSIL) lesions, which are generally caused by different subtypes of HPV. It also illustrates approximate counterparts for the legacy cervical intraepithelial neoplasia (CIN) system, which was based on a model of continuous progression rather than on dichotomous viral subtypes. Finally, the scheme illustrates the corresponding cytologic smear resulting from exfoliation of the most superficial cells, indicating that even in the mildest disease state, abnormal cells FIGURE 45-3

reach the surface and are shed. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 24-18, p. 1012). Philadelphia, PA: Lippincott Williams & Wilkins.) Recommendations for screening include HPV testing and cytology in females over 30 years of age. Results dictate the next steps in disease management. Cytology (Pap smear) alone is recommended beginning at 21 years of age and then every 3 years until age 29. For females over 30, a Pap smear alone should be performed every 3 years or cotesting every 5 years.25 False-negative Pap smears occur,28 and care must be taken to obtain a smear from the transformation zone that includes endocervical cells. The presence of normal endometrial cells in a cervical cytologic sample during the luteal phase or during the postmenopausal period is associated with endometrial disease and warrants evaluation with endometrial biopsy. This demonstrates that shedding of normal cells at an inappropriate time may indicate disease. Because adenocarcinoma of the cervix is detected more frequently, a Pap smear result of atypical glandular cells warrants evaluation by endocervical or endometrial curettage, hysteroscopy, or, ultimately, a cone biopsy if the abnormality cannot be identified through other means.21 Cone biopsy involves removal of a cone-shaped wedge of cervix, including the entire transformation zone and at least 50% of the endocervical canal. Postoperative hemorrhage, infection, cervical stenosis, infertility, and incompetent cervix are possible, and this procedure should be avoided unless necessary. LEEP is the first-line management for CIN II/III.21 This outpatient procedure allows for simultaneous diagnosis and treatment of dysplastic lesions found on colposcopy. It uses a thin, rigid, wire loop electrode attached to a generator that blends high-frequency, lowvoltage current for cutting and a modulated higher voltage for coagulation. It can remove the entire transformation zone, providing adequate treatment for the lesion and obtaining a specimen for histologic evaluation. Clinical Manifestations and Treatment In its early stages, cervical cancer is often a poorly defined lesion of the endocervix. Frequently, females will present with abnormal vaginal bleeding, spotting, and discharge. Bleeding is reported most frequently after

intercourse. More advanced disease may present with pelvic or back pain that may radiate down the leg, hematuria, fistulas (rectovaginal or vesicovaginal), or evidence of metastatic disease to supraclavicular or inguinal lymph node areas. Early treatment involves removal of the lesion. Biopsy or local cautery may be therapeutic in and of itself. Electrocautery, cryosurgery, or carbon dioxide laser therapy may treat moderate to severe dysplasia that is limited to the exocervix (i.e., squamocolumnar junction clearly visible). Therapeutic conization is necessary if the lesion extends into the endocervical canal and can be done surgically or with LEEP in the physician’s office. Invasive cancer is treated with radiation therapy, surgery, or both. External-beam irradiation and intracavitary irradiation or brachytherapy (i.e., insertion of radioactive materials into the body) can be used.29,30 Intracavitary radiation provides direct access to the central lesion and increases the tolerance of the cervix and surrounding tissues, permitting curative levels of radiation. External-beam radiation eliminates metastatic disease in pelvic lymph nodes and other structures, and shrinks the cervical lesion to optimize the effects of intracavitary radiation. Surgery can include trachelectomy (removal of cervix) in females with early-stage cancer desiring fertility, radical hysterectomy (includes uterus, cervix, parametria, and upper portion of the vagina) with pelvic lymph node dissection,29 or pelvic exenteration (removal of all pelvic organs, including the bladder, rectum, vulva, and vagina). Disorders of the Uterus Disorders of the uterus include endometritis, endometriosis, and endometrial cancer. There is also a high frequency of leiomyomas, including uterine fibroid tumors that are benign neoplasms, and adenomyosis, which is uterine thickening due to tissue from the endometrium being displaced in the outer muscular wall of the uterus. Endometritis The endometrium and myometrium are resistant to infections primarily because the endocervix forms a barrier to ascending infections. Endometritis is inflammation of the endometrium. Acute endometritis can

occur after an abortion or delivery of a newborn when the cervical barrier is compromised.1 Thus, prophylactic antibiotics are given before and after an abortion. There is an increased risk of endometritis after delivery if the female had chorioamnionitis during labor, a cesarean section, or needed manual or instrumented removal of the placenta. Treatment includes antibiotics, and a curettage if there are retained products of conception or placenta.1 Chronic endometritis can occur with PID, after instrumentation of the uterus (e.g., after endometrial biopsy or intrauterine device [IUD] insertion), and with unrecognized retained products of conception after delivery or abortion. The presence of plasma cells is required for diagnosis.1 The clinical picture is variable, but often includes mild to severe uterine tenderness, fever, malaise, and foul-smelling discharge. Treatment involves oral or intravenous antibiotic therapy, depending on severity. Endometriosis In endometriosis, functional endometrial tissue is found in ectopic sites outside the uterus. It is estrogen dependent. It is unclear whether it is an inflammatory disease or an immune disorder. Implants of endometriosis are functional and can lead to scarring, adhesions, and ovarian cysts (endometriomas).31 Sites may include ovaries, posterior broad ligaments, uterosacral ligaments, pouch of Douglas, pelvis, vagina, vulva, perineum, or intestines32 (Fig. 45-4).

FIGURE 45-4

Common locations of endometriosis in the pelvis and

abdomen. Etiology and Pathogenesis The cause is unknown. Its incidence has increased in Western countries in the past five decades. Approximately 10% of premenopausal women have some degree of endometriosis, causing infertility and chronic pain, and 24% to 50% of infertile women have some degree of endometriosis.33 Clinical Manifestations Endometriosis usually becomes apparent in the reproductive years when ovarian hormones stimulate both the lesions and normal endometrium. Lesions become proliferative, secretory, and undergo menstrual breakdown. Bleeding into surrounding structures can cause pain and development of pelvic adhesions. Symptoms tend to be strongest premenstrually, subsiding after menstruation. Pelvic pain is the most common symptom. Others include back pain, dyspareunia, and pain on defecation and micturition. Endometriosis is associated with infertility because of adhesions that distort the pelvic anatomy and cause impaired ovum release and transport.33

Gross pathologic changes differ with location and duration. In the ovary, endometrial tissue may form endometriomas. Rupture of these cysts, which are filled with old blood, can cause peritonitis and adhesions. Elsewhere in the pelvis, the tissue may be small hemorrhagic lesions, usually appearing as red-blue nodules (Fig. 45-5). Lesions may be surrounded by scar tissue.31,33 Diagnosis and Treatment Endometriosis may be difficult to diagnose: its symptoms mimic other pelvic disorders, and the symptoms do not always reflect the extent of the disease. Treatment may be initiated on the basis of clinical presentation because definitive diagnosis can be accomplished only through laparoscopy and confirmed with histology.34,35 This minimally invasive surgery allows visualization of pelvic organs to determine presence and extent of endometrial lesions. Imaging, including ultrasonography and magnetic resonance imaging (MRI), is useful in evaluating endometriomas and deep endometriosis.33 Treatments are pain relief, endometrial suppression, and surgery. In young females, observation and analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs]) may be sufficient. Use of hormones to induce physiologic amenorrhea is based on the observation that pregnancy and menopause relieve pain by inducing atrophy of endometrial tissue. This can be accomplished via oral contraceptive pills (OCPs) or continuous progestogen agents. In severe endometriosis, long-acting gonadotropin-releasing hormone (GnRH) analogs that inhibit the pituitary gonadotropins and suppress ovulation may be used short term, but is limited in its time course because of the side effects of prolonged artificial menopause (decreased bone density).36 Surgery may offer definitive therapy with large or symptomatic endometriomas, or individuals who have failed medical therapy for endometriosis. The goal is to restore normal anatomy, remove visible lesions, and slow progression of the disease in a way that minimizes development of pelvic adhesions and avoids injury to surrounding structures. Laparoscopy is the preferred surgical approach aimed at repairing adhesions and ablation of lesions. Even with extensive surgery, the risk of continued symptoms and disease recurrence is great. Hormone suppression with OCPs or other suppressive therapy before and after

surgery can aid in suppression of the disease.36 Definitive treatment involves total hysterectomy and bilateral salpingo-oophorectomy when the symptoms are unbearable or the woman’s childbearing is completed. Adenomyosis In adenomyosis, endometrial glands and stroma are found within the myometrium, interspersed between smooth muscle fibers.1 It is typically found in multiparous females, perhaps due to repeated pregnancies, deliveries, and uterine involution causing endometrium displacement throughout the myometrium.1 Adenomyosis frequently coexists with uterine myomas or endometrial hyperplasia. Diagnosis often occurs as an incidental finding in a uterus removed for symptoms of myoma or hyperplasia. Heavy, painful periods (with clots) and painful intercourse are common. MRI is the diagnostic tool. Conservative medical therapy with OCPs and NSAIDs is the first choice for treatment. Severe adenomyosis will ultimately require a hysterectomy (with preservation of the ovaries in premenopausal females) for full resolution. Endometrial Cancer Endometrial cancer is the most common cancer in the female pelvis, occurring over twice as often as cervical cancer. Most cases are adenocarcinomas, and fewer than 1% are sarcomas.37 The American Cancer Society estimates that in 2019 approximately 61,880 females will be diagnosed with endometrial cancer and 12,170 will die. The average age for endometrial cancer is older than 60 years, and it is less common in females younger than 45.38 Approximately 5% of endometrial cancer can develop as part of a hereditary cancer syndrome.39 Females with a family history of hereditary nonpolyposis colorectal cancer may have an inherited disorder in deoxyribonucleic acid (DNA) mismatch repair genes that predisposes to cancers, including colorectal and endometrial. Pathogenesis Two general groups of endometrial cancer can be identified. The first develops on a background of prolonged estrogen stimulation and

endometrial hyperplasia, whereas the second is less commonly associated with hyperestrogenism and endometrial hyperplasia. About 85% of endometrial cancers are moderately well-differentiated adenocarcinomas that develop on a background of endometrial hyperplasia. These tumors, type 1 endometrial cancers, are typically hormone sensitive, low grade, and have a favorable prognosis.1 They are associated with longduration unopposed estrogen stimulation and tend to be well differentiated, mimicking normal endometrial glands in histologic appearance, or display altered differentiation. The endometrium undergoes structural modification and cellular changes during the menstrual cycle. Prolonged unopposed estrogen leads to endometrial hyperplasia, which increases the chance of atypical hyperplasia and type 1 endometrial cancer. Although the molecular basis for this is still unknown, anovulatory cycles, disorders of estrogen metabolism, unopposed estrogen therapy, estrogen-secreting granulosa cell tumor, and obesity increase risk of endometrial cancer. Ovulatory dysfunction that causes infertility or occurs with declining ovarian function in perimenopausal females can result in unopposed estrogen and increase the risk of endometrial cancer. In the 1970s, a sharp rise in endometrial cancer was seen in middle-aged females who had received unopposed estrogen therapy (estrogen without progesterone) for menopausal symptoms. Progesterone in the second half of the menstrual cycle matures the endometrium, and withdrawal of progesterone results in endometrial sloughing. Long-term unopposed estrogen without progesterone allows for continued endometrial growth and hyperplasia, which increases the chance of development of atypical cells. Hyperplasia usually regresses after treatment with cyclic progesterone. Combination oral contraceptives (estrogen and progestin in each pill) prevent hyperplasia and decrease the risk of cancer by 50%.21 Tamoxifen, a drug that blocks estrogen receptor sites and is used in treatment of breast cancer, exerts a weak estrogenic effect on the endometrium and represents another exogenous risk factor for endometrial cancer.

Endometriosis. Implants of endometrium on the ovary appear as red-blue nodules. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 24-73A, p. 1049). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-5

Diabetes mellitus, hypertension, and polycystic ovary syndrome (PCOS) are conditions that alter estrogen metabolism and elevate estrogen levels. Excessive fat consumption and being overweight are important risk factors. In premenopausal females, overweight causes insulin resistance, ovarian androgen excess, anovulation, and chronic progesterone deficiency. In postmenopausal females, estrogens are synthesized in body fats from adrenal and ovarian androgen precursors. Because of its effect on insulinlike growth factor-1 (IGF-1) and its binding protein, obesity can be a risk factor even when circulating estrogen levels are normal. Estrogen receptor transcriptional activity can be induced by IGF-1 signaling even without estrogen. A second subset of endometrial cancers (about 10%) is high-grade tumors with high recurrence, even in early stages. These type 2 endometrial cancers are not estrogen driven, typically occur in females who acquire the disease at older ages, and are mostly associated with endometrial atrophy

rather than with hyperplasia.40 Type 2 endometrial cancers usually have a poorer prognosis than that associated with prolonged estrogen stimulation and endometrial hyperplasia. Clinical Manifestations The major symptom of endometrial hyperplasia or overt endometrial cancer is abnormal, painless bleeding. In menstruating females, this is bleeding between periods or excessive, prolonged menstrual flow. In postmenopausal females, any bleeding is abnormal and is an early warning sign of the disease. Because it tends to grow slowly in the early stages, the chances of cure are good if prompt medical care is sought. Later signs may include cramping, pelvic discomfort, postcoital bleeding, lower abdominal pressure, and enlarged lymph nodes. Diagnosis and Treatment Endometrial biopsy (tissue sample obtained by direct aspiration of the endometrial cavity) is far more accurate than a Pap smear. Dilation and curettage (D&C), which consists of dilating the cervix and scraping the uterine cavity, is the definitive procedure for diagnosis because it provides a more thorough evaluation. Prognosis depends on the clinical stage when it is discovered and its histologic grade and type. Surgery and radiation therapy are the most successful methods of treatment. When used alone, radiation therapy has a 20% lower cure rate than does surgery for stage I disease. It may be the best option in females who are not good surgical candidates. Total abdominal hysterectomy with bilateral salpingo-oophorectomy plus sampling of regional lymph nodes and peritoneal washings for cytologic evaluation of occult disease is the treatment of choice when possible. The 5-year relative survival rates of early-diagnosed endometrial cancers are 96%. The survival rate for all endometrial cancers (diagnosed early and late stage) is 83%.37 Leiomyomas Uterine leiomyomas (or fibroids) are benign neoplasms of smooth muscle origin. These are the most common form of pelvic tumor and occur in one of every four or five females over 35 years of age. Leiomyomas usually develop as submucosal, subserosal, or intramural tumors in the corpus of the uterus (Fig. 45-6). Intramural fibroids are embedded in the

myometrium. They are the most common type of fibroid and present as a symmetric enlargement of the nonpregnant uterus. Subserosal tumors are located beneath the perimetrium of the uterus. These tumors are irregular projections on the uterine surface. They may become pedunculated, displacing or impinging on other genitourinary structures and causing hydroureter or bladder problems. Submucosal fibroids displace endometrial tissue and are more likely to cause bleeding, necrosis, and infection.

Leiomyoma of the uterus. (A) The leiomyomas are intramural, submucosal (a pedunculated one appearing in the form of an endometrial polyp), and subserosal (one compressing the bladder and the other the rectum). (B) Bisected uterus displays a prominent, circumscribed, fleshy tumor. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Figs. 24-41 and 24-42A, p. 1029). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-6

Leiomyomas are asymptomatic approximately half of the time and may be discovered during a routine pelvic examination, or may cause menorrhagia, anemia, urinary frequency, rectal pressure/constipation, abdominal distension, and, infrequently pain. Rate of growth is variable, but they may increase in size during pregnancy or with exogenous estrogen stimulation (i.e., OCPs or menopausal estrogen replacement therapy). Interference with pregnancy is rare unless the tumor is submucosal and interferes with implantation or obstructs the cervical outlet. Tumors may outgrow their blood supply, become infarcted, and undergo degenerative changes. Most leiomyomas regress with menopause, but if bleeding, pressure on the bladder, pain, or other problems persist, hysterectomy may be required. Myomectomy (removal of the tumors) can preserve the uterus for future

childbearing. Cesarean section is recommended if the uterine cavity is entered during myomectomy. Hypothalamic GnRH agonists may be used to suppress leiomyoma growth before surgery.41 SUMMARY CONCEPTS Disorders of the cervix and uterus include inflammatory conditions, cancer, endometriosis, and leiomyomas. Cervicitis is an acute or chronic inflammation of the cervix. Acute cervicitis may result from the direct infection of the cervix or may be secondary to a vaginal or uterine infection. It may be caused by a variety of infectious agents. Chronic cervicitis represents a low-grade inflammatory process resulting from trauma or nonspecific infectious agents. Cervical cancer arises from precursor lesions that can be detected on a Pap smear, and, if detected early, is the most easily cured of all the cancers of the female reproductive system. Evidence suggests a causal link between HPV infection and cervical cancer. Vaccines against several strains of the HPV are available and show promise for the prevention of cervical cancer. Endometritis is an ill-defined inflammation or infection of the endometrium. Endometriosis is the condition in which functional endometrial tissue is found in ectopic sites outside the uterus, particularly in dependent parts of the pelvis and the ovaries, causing dysmenorrhea, dyspareunia, and infertility. Adenomyosis is the condition in which endometrial glands and stroma are found in the myometrium, interspersed between smooth muscle fibers. Endometrial cancer is the most common cancer in the female pelvis, occurring over twice as often as cervical cancer. Prolonged estrogen stimulation with hyperplasia of the endometrium is a major risk factor. Leiomyomas are benign uterine wall neoplasms of smooth muscle origin. They can develop in the corpus of the uterus and can be submucosal, subserosal, or intramural. Submucosal fibroids displace endometrial tissue and are more likely to cause bleeding, necrosis, and infection.

Disorders of the Fallopian Tubes and Ovaries Pelvic Inflammatory Disease PID is a polymicrobial infection of the upper reproductive tract (uterus, fallopian tubes, ovaries) associated with sexually transmitted organisms such as N. gonorrhoeae or C. trachomatis and endogenous organisms including anaerobes such as Haemophilus influenzae, enteric gram-negative rods, and streptococci.1,42 Organisms ascend through the endocervical canal to the endometrial cavity, and then to the tubes and ovaries. The endocervical canal is slightly dilated during menstruation, allowing bacteria to gain entrance to the uterus and other pelvic structures. After entering the upper reproductive tract, the organisms multiply rapidly in the favorable environment of the sloughing endometrium and ascend to the fallopian tube (Fig. 45-7).

Pelvic inflammatory disease. Microbial agents enter through the vagina and ascend to involve the uterus, fallopian tubes, and pelvic structures. FIGURE 45-7

Factors that predispose the development of PID include an age of 16 to 24 years, nulliparity, history of multiple sexual partners, and previous history of PID.42 IUD use is associated with a three- to fivefold increased risk for PID development, but females with one sexual partner and at low risk of acquiring STIs have no significant risk for development of PID from using an IUD. Clinical Manifestations Symptoms include lower abdominal pain, dyspareunia, back pain, purulent cervical discharge, adnexal tenderness, and painful cervix on bimanual pelvic examination. Fever (>101°F), increased erythrocyte sedimentation

rate, multiple leukocytes on wet-mount vaginal microscopy, and coinfection with chlamydia and/or gonorrhea further support diagnosis of PID. Elevated C-reactive protein levels equate with inflammation and can be used as another diagnostic tool.42 Diagnosis and Treatment Laparoscopy can diagnose PID but is costly and carries the inherent risks of surgery.12 Minimal criteria for a presumptive diagnosis are lower abdominal pain, adnexal tenderness, and cervical motion tenderness on bimanual examination with no other apparent cause.43 Outpatient antibiotic therapy is usually sufficient. Treatment may involve hospitalization with intravenous administration of antibiotics. Antibiotic regimens should be selected according to STI treatment guidelines published by the Centers for Disease Control and Prevention (CDC). Treatment is aimed at preventing complications, which can include pelvic adhesions, infertility, ectopic pregnancy, chronic abdominal pain, and tuboovarian abscesses. Accurate diagnosis and appropriate antibiotic therapy may decrease the severity and frequency of PID sequelae. The CDC recommends empiric treatment with a presumptive diagnosis of PID, while waiting for confirmation by culture or other definitive test results.42 Ectopic Pregnancy Ectopic pregnancy represents a true gynecologic emergency and should be considered when a female of reproductive age presents with pelvic pain. It occurs when a fertilized ovum implants outside the uterine cavity, commonly in the fallopian tube (Fig. 45-8). Ectopic pregnancy is the leading cause of maternal mortality in the first trimester, but the death rate has steadily declined with improved diagnostic methods.

Ectopic pregnancy. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 778). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-8

The cause of ectopic pregnancy is delayed ovum transport, which may result from decreased tubal motility or distorted tubal anatomy (i.e., narrowed lumen, convolutions, or diverticula). Risk factors include tubal surgery, tubal ligation or reversal, previous ectopic pregnancy, and a tubal lesion or abnormality.44 Smoking, current IUD, history of PID or therapeutic abortion, and use of fertility drugs to induce ovulation have also been associated with an increased risk. Clinical Manifestations The site of implantation may determine onset of symptoms and timing of diagnosis. As the tubal pregnancy progresses, surrounding tissue is stretched. The pregnancy eventually outgrows its blood supply, at which point the pregnancy terminates or the tube ruptures. Symptoms include lower abdominal discomfort—diffuse or localized to one side—that progresses to severe pain caused by rupture, spotting, syncope, referred shoulder pain from bleeding into the abdominal cavity,

and amenorrhea. Physical examination usually reveals adnexal tenderness; an adnexal mass is found in about half of cases. Diagnosis and Treatment Diagnostic tests include a urine pregnancy test, ultrasonography, and βhuman chorionic gonadotropin (hCG; a hormone produced by placental cells) levels. Serial hCG tests may detect lower than expected hCG rise. Transvaginal ultrasonographic studies after 5 weeks of gestation may reveal an empty uterine cavity or presence of the gestational sac outside the uterus.44 Definitive diagnosis may require laparoscopy. Differential diagnosis for this pelvic pain includes ruptured ovarian cyst, threatened/incomplete abortion, PID, acute appendicitis, and degenerating fibroid. Treatment aims to resolve the problem with minimal morbidity and protecting future fertility. Early ectopic pregnancies can be treated medically with methotrexate to stop the pregnancy followed by serial hCG to ensure that it has been effectively treated. Surgical removal of the pregnancy is required when it is unlikely that medical management will be effective (large ectopic pregnancy, presence of a fetal heartbeat, noncompliance), rupture is imminent or has already occurred, or when the patient is hemodynamically unstable.12,44,45 Laparoscopic treatment is well tolerated and more cost-effective than is laparotomy because of shorter convalescence and the reduced need for postoperative analgesia. Laparotomy, which involves an open incision into the abdominopelvic cavity, is necessary when there is uncontrolled internal bleeding or when the ectopic site cannot be visualized through the laparoscope. Methotrexate (an antimetabolite used in treatment of chronic inflammatory diseases and cancer) eliminates residual ectopic pregnancy tissue after laparoscopy. It is a primary treatment in cases where the pregnancy is diagnosed early and tubal rupture has not occurred, or when the pregnancy is not in a common location, such as when the pregnancy occurs in the cornua of the uterus or in the cervix. This folic acid antagonist interferes with DNA and ribonucleic acid synthesis, thus inhibiting growth of trophoblastic cells at the placental implantation site. Adverse effects include bone marrow depression, transient elevation of liver enzymes, anemia, and stomatitis.44

Cancer of the Fallopian Tube The fallopian tube is the primary site of cancer in a large majority of ovarian cancer cases.1,46 Metastasis from the uterus and/or ovaries is also observed. When primary fallopian tube cancer is diagnosed, it is usually an adenocarcinoma.1 Symptoms are uncommon, but intermittent serosanguineous vaginal discharge, abnormal vaginal bleeding, and colicky low abdominal pain have been reported. Management usually includes total hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, and chemotherapy, depending on the type of cancer cells. The staging of ovarian, fallopian tube, and peritoneal cancer has been integrated, potentially allowing for better treatment options.1,46 Ovarian Cysts and Tumors Ovaries produce germ cells (ova) and synthesize female sex hormones. Disorders often cause menstrual and fertility problems. Benign conditions can present as primary lesions of ovarian structures or as secondary disorders related to hypothalamic, pituitary, or adrenal dysfunction. Ovarian Cysts Cysts are the most common form of ovarian tumor. Many are benign. A follicular cyst results from occlusion of the duct of the follicle. Each month, several follicles develop. The dominant follicle normally ruptures to release the egg (ovulation), but occasionally persists and continues growing. A luteal cyst is a persistent cystic enlargement of the corpus luteum formed after ovulation and does not regress in the absence of pregnancy. Functional cysts are asymptomatic unless there is substantial enlargement or bleeding into the cyst. This can cause discomfort or a dull, aching sensation on the affected side. These cysts usually regress spontaneously. Occasionally, a cyst may become twisted or may rupture into the intra-abdominal cavity (Fig. 45-9).

Follicular cyst of the ovary. The rupture of this thin-walled follicular cyst (dowel stick) led to intra-abdominal hemorrhage. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 24-44, p. 1033). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-9

Polycystic Ovary Syndrome PCOS is a common endocrine disorder affecting 6% to 15% of females of reproductive age and is a frequent source of chronic anovulation. Diagnosis is made after other endocrine diseases are ruled out and the person has oligomenorrhea (irregular infrequent periods), signs of hyperandrogenism (acne and excess body hair [hirsutism]), elevated testosterone levels on blood testing, or polycystic-appearing ovaries in which there are numerous small cysts at the periphery of the ovary.47 Etiology and Pathogenesis

About 50% of females diagnosed with PCOS are obese. People with PCOS will have irregular menses due to anovulation that can lead to infertility. Because of the hyperandrogenism associated with PCOS, many individuals with PCOS suffer from hirsutism and acne.47 The etiology of PCOS is probably multifactorial. A genetic basis has been suggested, with an autosomal dominant mode of inheritance. The disorder may begin before adolescence.48 Because many of the symptoms, such as excess hair, acne, and obesity, can be detrimental to a teenage girl’s health and self-esteem, early detection and treatment in adolescents are essential. The underlying mechanisms of PCOS remain unclear. Chronic anovulation may underlie the amenorrhea or irregular menses, and the enlarged, “polycystic” ovaries. Most individuals with PCOS have elevated luteinizing hormone (LH) levels with normal estrogen and folliclestimulating hormone (FSH) levels. Elevated circulating total testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEAS) are not uncommon, along with occasional hyperprolactinemia or hypothyroidism. Persistent anovulation results in an estrogen environment that alters hypothalamic release of GnRH, causing increased LH secretion and suppression of FSH release. This altered LH/FSH ratio often is used as a diagnostic criterion, but it is not universally present. Although the presence of FSH allows for new follicular development, full maturation is not attained, and ovulation does not occur. An elevated LH level results in increased androgen production, which prevents follicular development and contributes to anovulation.49 There is an association between hyperandrogenism and hyperinsulinemia. The frequency and degree of hyperinsulinemia in PCOS are often amplified by obesity. Insulin may cause hyperandrogenism in several ways. The ovary possesses insulin receptors, and there is evidence that insulin may act directly on the ovary.50 Long-term health problems including cardiovascular disease and diabetes are linked to PCOS. There is concern that females with PCOS who are anovulatory do not produce progesterone. Although there is a reported association with breast, endometrial, and ovarian cancer, PCOS has not been conclusively shown to be an independent risk factor for these malignancies.47

Diagnosis and Treatment Diagnosis can be suspected from clinical presentation. Commonly, laboratory evaluation is used to exclude hyperprolactinemia, late-onset adrenal hyperplasia, and androgen-secreting tumors of the ovary and adrenal gland. Although a fasting blood glucose, 2-hour oral glucose tolerance test, and insulin levels are often measured to evaluate for hyperinsulinemia, this testing is not required before treatment because insulin resistance is almost universal in women with PCOS. Confirmation with ultrasonography of the ovaries is often done, but not required.51 The overall goal of treatment is directed toward symptom relief, prevention of potential malignant endometrial sequelae, and reduction in risk for development of diabetes and cardiovascular disease. The most effective treatment for PCOS is lifestyle modification. Weight loss may be beneficial in restoring normal ovulation when obesity is present. Treatment choice depends on the most bothersome manifestations and the individual’s goals. Combined oral contraceptive agents ameliorate menstrual irregularities and improve hirsutism and acne. Metformin, an insulin-sensitizing drug, is an important component of PCOS treatment.51 In addition to improvements in insulin sensitivity and glucose metabolism, it is associated with reduced androgen and LH levels, and restoring normal menstrual regularity and ovulatory cycles. When fertility is desired, PCOS usually is treated by the administration of the hypothalamic-pituitary–stimulating drug clomiphene citrate or injectable gonadotropins to induce ovulation. These drugs must be used carefully because they can induce extreme enlargement of the ovaries. Benign and Functioning/Endocrine Active Ovarian Tumors Ovarian tumors are common, and most are benign. They can arise from any of the ovarian tissue types—serosal epithelium, germ cell layers, or gonadal stroma tissue21 (Fig. 45-10).

Classification of ovarian neoplasms based on cell of origin. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 24-48, p. 1035). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-10

Serous and mucinous cystadenomas are common benign ovarian neoplasms. Endometriomas develop secondary to ovarian endometriosis. Ovarian fibromas are connective tissue tumors composed of collagen, ranging in size from 15 to 30 cm. Cystic teratomas, or dermoid cysts, are derived from primordial germ cells and composed of well-differentiated ectodermal, mesodermal, and endodermal elements. They can contain sebaceous material, hair, or teeth.1 Hormonally active tumors can impact the body either with an excess or a decrease in reproductive hormone excretion. The granulosa cell tumor is associated with excess estrogen production. Most granulosa cell tumors occur after menopause. When they develop during the reproductive period, uncontrolled production of estrogen interferes with the normal menstrual

cycle. In addition, when present in young females, early puberty and an associated loss of oocytes occur.1 Androgen-secreting tumors (Sertoli– Leydig cell tumor or androblastoma) inhibit ovulation and estrogen production. They may cause hirsutism and development of masculine characteristics, such as baldness, acne, oily skin, breast atrophy, and deepening of the voice.1 Treatment for ovarian tumors includes surgical excision, chemotherapy, and/or radiation. Tissue, lymph nodes, and fluid are analyzed. If metastasis has occurred, the goal is to remove as much of the cancer as possible and, when combined with chemotherapy, provides the best results.46 Ovarian Cancer Ovarian cancer is often lethal. It is the fifth leading cause of female cancer deaths. The rate of ovarian cancer has declined slowly over the past 20 years. In 2019, there will be an estimated 22,530 new cases of ovarian cancer in the United States, and 13,980 deaths.52 It is difficult to diagnose because symptoms mimic other benign health issues. Because of this, the disease often spreads before the time of discovery.53 Risk Factors The most significant risk factor appears to be ovulatory age: the length of time during a female’s life when her ovarian cycle is not suppressed by pregnancy, lactation, or oral contraceptive use. The incidence is much lower in parous versus nulliparous women.54 Family history also is a significant risk factor. A female with two or more first- or second-degree relatives who have had site-specific ovarian cancer have up to a 50% risk for development of the disease. There are two other types of inherited risk for ovarian cancer: breast–ovarian cancer syndrome, where both breast and ovarian cancer occur among first- and second-degree relatives, and family cancer syndrome or Lynch syndrome II, in which male or female relatives have a history of colorectal, endometrial, ovarian, pancreatic, or other types of cancer.21 The breast cancer susceptibility genes, BRCA1 and BRCA2, which are tumor suppressor genes, are linked to approximately 10% of hereditary ovarian cancers.29 Susceptibility to ovarian cancer is transmitted as an autosomal dominant characteristic. A high-fat Western diet and use of

powders containing talc in the genital area are other factors that have been linked to the development of ovarian cancer. Prevention Chemoprevention strategies include long-term oral contraceptive use, acetaminophen, and aspirin. Additional clinical trials are needed to support the effectiveness of these agents. Surgical strategies that reduce the risk of developing ovarian cancer include prophylactic removal of both fallopian tubes and ovaries.55 Types of Ovarian Cancer Cancer of the ovary is a complex neoplasm because of the diversity of tissue types that originate in the ovary. As a result, there are several types of ovarian cancers. Malignant neoplasms of the ovary can be divided into epithelial tumors, germ cell tumors, and gonadal stromal tumors (Fig. 4510). Epithelial tumors account for approximately 90% of cases.21 Clinical Manifestations Different types of ovarian cancers display various degrees of virulence, depending on the type of tumor and degree of differentiation involved. A well-differentiated cancer may produce symptoms for many months and still be operable at the time of surgery. A poorly differentiated tumor may have been clinically evident for only a few days but be found to be widespread and inoperable. Often, no correlation exists between duration of symptoms and extent of the disease. Ovarian cancer is often diagnosed at an advanced stage because many symptoms are nonspecific and therefore difficult to distinguish from other problems. Symptoms believed to have a strong correlation to ovarian cancer include abdominal or pelvic pain, increased abdominal size or bloating, and difficulty eating or feeling full quickly after ingesting food. Many self-treat with antacids and other remedies for a time before seeking treatment, and health care providers may dismiss the complaints as being caused by other conditions. Recent onset (12 times per month) of these symptoms suggest the need for further evaluation.21 It is not fully understood why initial symptoms of ovarian cancer are manifested as gastrointestinal disturbances. It is thought that biochemical changes in peritoneal fluids may irritate the bowel, or pain originating in the ovary may

be referred to the abdomen and be interpreted as a gastrointestinal disturbance. Clinically evident ascites is seen in approximately one fourth of females with malignant ovarian tumors and is associated with a worse prognosis. Diagnosis and Treatment There are no good screening tests or early methods of detection. Transvaginal sonography (TVS) can evaluate ovarian masses for malignant potential, but its cost precludes its use as a universal screening method. The serum tumor marker CA-125 is a cell surface antigen and is detectable in the serum of about half of epithelial tumors confined to the ovary and 90% of those that have spread. The specificity of this is highest when combined with TVS.1 Screening with CA-125 is not recommended for asymptomatic women. It can be used in monitoring therapy and recurrences when preoperative levels have been elevated. Despite its role in diagnostic evaluation and follow-up, CA-125 is not cancer or tissue specific for ovarian cancer. Levels also are elevated in other cancers and some benign conditions.56 When ovarian cancer is suspected, surgical evaluation is required for diagnosis, complete and accurate staging, and cytoreduction and debulking procedures to reduce the size of the tumor. The most common surgery involves removal of uterus, fallopian tubes, ovaries, and omentum. The liver, diaphragm, retroperitoneal and aortic lymph nodes, and peritoneal surface are examined and biopsies are taken as needed. Cytologic washings test for cancerous cells in the peritoneal fluid. Individuals with early cancer who may wish to become pregnant may have only the affected ovary removed. Recommendations for treatment beyond surgery and prognosis depend on the stage of the disease.21 The lack of accurate screening tools and the resistant nature of ovarian cancers significantly affect the success of treatment and survival. SUMMARY CONCEPTS PID is an inflammation of the upper reproductive tract that involves the uterus (endometritis), fallopian tubes (salpingitis), or ovaries (oophoritis). It is commonly caused by N. gonorrhoeae or C. trachomatis. Accurate diagnosis and therapy aim to prevent

complications such as pelvic adhesions, infertility, ectopic pregnancy, chronic abdominal pain, and tubo-ovarian abscesses. Ectopic pregnancy occurs when a fertilized ovum implants outside the uterine cavity; the most common site is the fallopian tube. Causes of ectopic pregnancy are delayed ovum transport resulting from complications of PID, therapeutic abortion, tubal ligation or tubal reversal, previous ectopic pregnancy, or other conditions such as use of fertility drugs to induce ovulation. It represents a true gynecologic emergency, often necessitating surgical intervention. Cancer of the fallopian tube is rare; diagnosis is difficult and the condition usually is advanced at diagnosis. Disorders of the ovaries include benign cysts, functioning ovarian tumors, and cancer of the ovary; they usually are asymptomatic unless there is substantial enlargement or bleeding into the cyst, or the cyst becomes twisted or ruptured. PCOS is characterized by anovulation with varying degrees of menstrual irregularity and infertility; hyperandrogenism with hirsutism, acne, male pattern of hair loss, and obesity; polycystic ovaries; and hyperinsulinemia with insulin resistance. Benign ovarian tumors consist of endometriomas (chocolate cysts that develop secondary to ovarian endometriosis), ovarian fibromas (connective tissue tumors composed of fibrocytes and collagen), and cystic teratomas or dermoid cysts (germ cell tumors composed of various combinations of ectodermal, mesodermal, and endodermal elements). Functioning ovarian tumors may be benign or malignant and are of three types: estrogen secreting, androgen secreting, and mixed estrogen–androgen secreting. Because ovarian cancer has vague symptoms until the disease has progressed, it is among the most lethal of female cancers. It can be divided into epithelial tumors, germ cell tumors, and gonadal stromal tumors. There are no effective screening methods for ovarian cancer, and often the disease is well advanced at diagnosis.

KEY POINTS Gynecologic Cancers

Cancers of the vulva, cervix, endometrium, and ovaries are a spectrum of malignancies. Ovarian cancer often goes undiagnosed until in advanced stages; therefore, it is often lethal. The most significant risk factors for ovarian cancer are the length of time that ovarian cycles are not suppressed by pregnancy, lactation, or oral contraceptive use, and family history.

Disorders of Pelvic Support and Uterine Position Disorders of Pelvic Support The uterus and the pelvic structures are maintained in position by the uterosacral ligaments, round ligaments, broad ligaments, and cardinal ligaments. The two cardinal ligaments maintain the cervix in position. The uterosacral ligaments hold the uterus in a forward position and the broad ligaments suspend the uterus, fallopian tubes, and ovaries. The vagina is encased in the semirigid structure of strong supporting fascia (Fig. 45-11A). The muscular floor of the pelvis is a strong, slinglike structure that supports the uterus, vagina, urinary bladder, and rectum (Fig. 45-12). The pelvic viscera must be supported against the force of gravity and increases in intraabdominal pressure associated with coughing, sneezing, defecation, and laughing while allowing for urination, defecation, and reproductive tract function. The bony pelvis provides support and protection for parts of the digestive tract and genitourinary structures, and the peritoneum holds the pelvic viscera in place. The main support for the viscera is the pelvic diaphragm, made up of muscles and connective tissue that stretch across the bones of the pelvic outlet. Openings for the urethra, rectum, and vagina cause an inherent weakness in the pelvic diaphragm. Congenital or acquired weakness of the pelvic diaphragm results in widening of these openings, particularly the vagina, with the possible herniation of pelvic viscera through the pelvic floor (i.e., prolapse).57

(A) Normal support of the uterus and vagina, (B) cystocele, (C) rectocele, and (D) uterine prolapse. FIGURE 45-11

FIGURE 45-12

Muscles of the pelvic floor (female perineum).

Relaxation of the pelvic outlet is usually due to overstretching of perineal supporting tissues during pregnancy and childbirth. Although the tissues are stretched only during these times, there may be no difficulty until the fifth or sixth decade, when further loss of elasticity and muscle tone occurs. The combination of aging and postmenopausal changes may give rise to problems related to relaxation of the pelvic support structures regardless of a history of pregnancy. The most common conditions associated with this relaxation are cystocele, rectocele, and uterine prolapse. These may occur separately or together.58,59 Cystocele Cystocele is a herniation of the bladder into the vagina. It occurs when muscle support for the bladder is weakened, and the bladder sags below the uterus. This causes the anterior vaginal wall to stretch and bulge downward,

allowing the bladder to herniate into the vagina due to gravity and pressures from coughing, lifting, or straining (Fig. 45-11B). The symptoms of cystocele include a bearing-down sensation, difficulty in emptying the bladder, frequency and urgency of urination, and cystitis. Stress incontinence may occur at times of increased abdominal pressure, such as during squatting, straining, coughing, sneezing, laughing, or lifting.57–59 Rectocele and Enterocele Rectocele is the herniation of the rectum into the vagina. It occurs when the posterior vaginal wall and underlying rectum bulge forward, protruding through the introitus because the pelvic floor and perineal muscles are weakened. Symptoms include discomfort because of the protrusion of the rectum and difficulty in defecation (Fig. 45-11C). Digital pressure (i.e., splinting) on the bulging posterior wall of the vagina may be necessary for defecation. The area between the uterosacral ligaments posterior to the cervix may weaken and form a hernial sac into which the small bowel protrudes when standing. This defect, an enterocele, may extend into the rectovaginal septum. It may be congenital or acquired through birth trauma. Enterocele can be asymptomatic or cause a dull, dragging sensation and, occasionally, low backache.57–59 Uterine Prolapse Uterine prolapse is bulging of the uterus into the vagina that occurs when the primary supportive ligaments (i.e., cardinal ligaments) are stretched (Fig. 45-11D). Prolapse is ranked as first, second, or third degree, depending on uterus protrusion through the introitus. First-degree prolapse shows some descent, but the cervix has not reached the introitus. In seconddegree prolapse, the cervix or part of the uterus has passed through the introitus. The entire uterus protrudes through the vaginal opening in thirddegree prolapse (i.e., procidentia).57,59 Symptoms associated with uterine prolapse result from irritation of exposed mucous membranes of the cervix and vagina and discomfort of the protruding mass.56 There may be incontinence along with discomfort from the pelvic floor prolapse. Prolapse often is accompanied by perineal relaxation, cystocele, or rectocele. Like cystocele, rectocele, and enterocele, it occurs most commonly in multiparous females because childbearing is

accompanied by injuries to pelvic structures and uterine ligaments. It also may result from pelvic tumors and neurologic conditions, which interrupt the innervation of pelvic muscles. Generally, it is a benign condition, but problems can arise with infection, obstruction, and skin irritation, leading to skin breakdown.59 A pessary may be inserted to hold the uterus in place and may stave off surgical intervention in females who want to have children or in older females for whom surgery may pose a significant risk. Pelvic floor physical therapy is suitable for females who wish to preserve their uterus.60 Treatment of Pelvic Support Disorders Kegel exercises, which strengthen the pubococcygeus muscle, may be helpful in cases of mild cystocele or rectocele (or after surgical repair to help maintain the improved function).58 Most disorders of pelvic relaxation eventually require surgical correction. Surgery is usually elective and deferred until after childbearing years, so only one repair will be necessary. Symptoms often are not severe enough to warrant surgical correction. Stress of surgery may be contraindicated because of other physical disorders. This is particularly true of older individuals, in whom many of these disorders occur and other nonsurgical interventions may be successful.58 There are many surgical procedures for conditions that result from relaxation of pelvic support structures. Removal of the uterus through the vagina (vaginal hysterectomy) with repair of the vaginal wall (colporrhaphy) often is done when uterine prolapse is accompanied by cystocele or rectocele. A vesicourethral suspension may alleviate the symptoms of stress incontinence. Repair may involve abdominal hysterectomy along with anteroposterior repair.58,59 Variations in Uterine Position Variations in the position of the uterus are common. Some variations are innocuous. Others, which may be the result of weakness and relaxation of the perineum, give rise to problems that compromise the structural integrity of the pelvic floor, particularly after childbirth. The uterus is flexed about 45 degrees anteriorly, with the cervix in the anteverted position. If standing, the angle of the uterus is such that it lies horizontal, resting lightly on the bladder.

Asymptomatic, normal variations of the uterus in relation to the cervix and physiologic displacements that arise after pregnancy or with pathology of the cul-de-sac include anteflexion, retroflexion, and retroversion (Fig. 45-13). An anteflexed uterus is flexed forward on itself. Retroflexion is flexion backward at the isthmus. Retroversion is the condition in which the uterus inclines posteriorly while the cervix remains tilted forward. Simple retroversion of the uterus is the most common displacement, found in 30% of females. It usually is a congenital condition caused by a short anterior vaginal wall and relaxed uterosacral ligaments, forcing the uterus to fall back into the cul-de-sac.61 Retroversion also can follow diseases such as endometriosis and PID, which produce fibrous tissue adherence with retraction of the fundus posteriorly. Large leiomyomas may cause the uterus to move into a posterior position. Dyspareunia with deep penetration or low back pain with menses can also be associated with retroversion.

FIGURE 45.13

Variations in uterine position.

SUMMARY CONCEPTS Alterations in pelvic support frequently occur because of weaknesses and relaxation of the pelvic floor and perineum. Cystocele and rectocele involve herniation of the bladder or rectum into the vagina. In uterine prolapse, the uterus bulges into the vagina. Pelvic relaxation disorders often result from overstretching of perineal supporting muscles during pregnancy and childbirth, or loss of elasticity with aging. Variations in uterine position include anteflexion, retroflexion, and retroversion, and can be due to congenital shortness of the vaginal wall, fibrous adhesions secondary to endometriosis or PID, or displacement caused by large uterine leiomyomas.

Menstrual Disorders Dysfunctional Menstrual Cycles Unexplained uterine bleeding can occur for many reasons, such as pregnancy, abortion, bleeding disorders, hormone imbalances, and neoplasms. Abnormal uterine bleeding (AUB) refers to any bleeding outside of normal menstruation. AUB classification is based on pattern and etiology: Heavy menstrual bleeding—regular menses, lasting a week or more, or bleeding greater than 80 mL per cycle Light menstrual bleeding—a regular period, but flow is light. Intermenstrual bleeding—any bleeding between periods. Flow is usually light. Heavy irregular bleeding—prolonged or heavy bleeding that occurs at irregular times Infrequent cycles—cycles that are irregular and occur greater than 35 days apart

Polymenorrhea—cycles that occur on a regular basis less than 21 days apart Primary amenorrhea—no menses and no secondary sexual characteristics by age 14 or no menses by age 16 with secondary sexual characteristics evident Secondary amenorrhea—the individual has had menstrual cycles and then no cycle for a period of at least 6 months. To classify by etiology, FIGO coined the phrase “PALM-COEIN”— PALM outlining mechanical causes of bleeding and COEIN outlining other causes: P polyps A adenomyosis L leiomyomas M malignancy and hyperplasia C coagulopathy O ovulatory dysfunction E endometrial I iatrogenic causes N not yet classified Once the etiology is determined, documentation of AUB is written accordingly (e.g., AUB-P is bleeding related to polyps). Treatment is then based on the underlying cause.62 Etiology and Pathogenesis Dysfunctional menstrual cycles are related to alterations in the hormones that support normal cyclic endometrial changes. Estrogen deprivation causes retrogression of a previously built-up endometrium and bleeding. Such bleeding often is irregular in amount and duration, with the flow varying with the time and degree of estrogen stimulation and with the degree of estrogen withdrawal. A lack of progesterone can cause abnormal menstrual bleeding. In its absence, estrogen induces development of a thicker endometrial layer with a richer blood supply. The absence of progesterone results from the failure of any developing ovarian follicles to mature to ovulation, which normally forms the corpus luteum and produces and secretes progesterone.

Periodic bleeding episodes alternating with amenorrhea are caused by variations in the number of functioning ovarian follicles present. If sufficient follicles are present and active and if new follicles assume functional capacity, high levels of estrogen develop, causing the endometrium to proliferate for weeks or months. Estrogen withdrawal and bleeding develop for two reasons: absolute estrogen deficiency when several follicles simultaneously degenerate or a relative deficiency because the needs of enlarged endometrial tissue mass exceed the capabilities of existing follicles. Estrogen and progesterone deficiencies are associated with absence of ovulation (anovulatory bleeding). Because the vasoconstriction and myometrial contractions that normally accompany menstruation are caused by progesterone, anovulatory bleeding seldom is accompanied by cramps, and flow frequently is heavy. Anovulatory cycles are common among adolescents during the first years after menarche, when ovarian function is becoming established, among perimenopausal women whose ovarian function is beginning to decline, and, commonly, in obese women with PCOS. Dysfunctional menstrual cycles can originate as a primary disorder of the ovaries or as a secondary defect in ovarian function related to hypothalamic–pituitary stimulation. The latter can be initiated by emotional stress, marked variation in weight (i.e., sudden gain or loss), or nonspecific endocrine or metabolic disturbances. Nonhormonal causes of irregular menstrual bleeding include endometrial polyps, submucosal myoma (i.e., fibroid), bleeding disorder (e.g., von Willebrand disease, platelet dysfunction), infection, endometrial cancer, and pregnancy.62 Treatment Treatment is based on the probable cause. Evaluation should include a history with emphasis on bleeding pattern and physical examination. Endocrine studies (e.g., FSH/LH ratio, prolactin, testosterone, DHEAS levels), β-hCG pregnancy test, endometrium ultrasonography, endometrial biopsy, D&C with or without hysteroscopy, and progesterone withdrawal tests may be needed for diagnosis. Nonhormonal causes may require surgical intervention. D&C can be therapeutic and diagnostic. Endometrial ablation (thinning or elimination of the basal layer of endometrium from which the monthly buildup generates) is a primary treatment for heavy

bleeding.55 If alterations in hormone levels are the primary cause, treatment may include oral contraceptives, cyclic progesterone therapy, or long-acting progesterone via injection or IUD. Amenorrhea Primary amenorrhea is failure to menstruate by 15 years of age, or by 13 years of age if accompanied by absence of secondary sex characteristics. Secondary amenorrhea is the cessation of menses for at least 6 months in an individual with established normal menstrual cycles.62 Etiology Primary amenorrhea usually is caused by gonadal dysgenesis, congenital müllerian agenesis, testicular feminization, or a hypothalamic–pituitary– ovarian axis disorder. Causes of secondary amenorrhea include pregnancy; ovarian, pituitary, or hypothalamic dysfunction; intrauterine adhesions; chronic conditions or infections; pituitary tumor; anorexia nervosa; or strenuous physical exercise, which can alter the body fat–muscle ratio needed for menses to occur.63 Diagnosis and Treatment Diagnosis resembles that for AUB, with the possible addition of a computed tomographic scan or an MRI to exclude a pituitary tumor. Treatment is based on correcting the underlying cause and inducing menstruation with cyclic progesterone or combined estrogen– progesterone.62 KEY POINTS Dysfunctional Menstrual Cycles The pattern of menstrual bleeding tends to be fairly consistent in most healthy women with regard to frequency, duration, and amount of flow. AUB in postpubertal women can take the form of absent or scanty periods, infrequent periods, excessive and irregular periods,

excessive bleeding during periods, and bleeding between periods. Dysmenorrhea Dysmenorrhea is pain or discomfort with menstruation that causes some degree of monthly disability for a significant number of individuals. Primary dysmenorrhea is menstrual pain not associated with physical abnormality or pathology.64 It occurs with ovulatory menstruation beginning 6 months to 2 years after menarche. Symptoms begin 1 to 2 days before menses, peak on the first day of flow, and subside within several hours to days. Severe dysmenorrhea may be associated with systemic symptoms such as headache, nausea, vomiting, diarrhea, fatigue, irritability, dizziness, and syncope.65 The pain is dull, lower abdominal aching or cramping, spasmodic or colicky in nature, often radiating to the lower back, labia majora, or upper thighs. Secondary dysmenorrhea is menstrual pain caused by specific organic conditions, such as endometriosis, uterine fibroids, adenomyosis, pelvic adhesions, IUDs, or PID. Laparoscopy often is required for diagnosis if medication for primary dysmenorrhea is ineffective. Treatment for primary dysmenorrhea aims for symptom control. Although analgesic agents (aspirin, acetaminophen) may relieve minor uterine cramping or low back pain, prostaglandin synthetase inhibitors (ibuprofen, naproxen, mefenamic acid, and indomethacin) are specific for dysmenorrhea and treatment of choice if contraception is not desired. Ovulation suppression and symptomatic relief of dysmenorrhea can be used simultaneously with oral contraceptives. Relief of secondary dysmenorrhea depends on the cause, and medical or surgical intervention may be needed.57 Premenstrual Symptom Disorders Approximately 80% of females experience some type of premenstrual emotional or physical changes, and 20% indicate that these mild to moderate monthly symptoms cause some difficulty, sometimes enough to present for medical assistance.66 How many have symptoms that are severe enough to warrant treatment is unknown because of the multiple symptoms associated with premenstrual syndrome (PMS).61 The spectrum of premenstrual symptom disorders ranges from mild to severe and includes the following:

PMS: mild to moderate physical and psychological symptoms limited to within 14 days preceding menstruation and relieved by onset of the menses Premenstrual dysphoric disorder (PMDD): the most severe form of premenstrual distress and generally is associated with mood disorders The incidence of PMS seems to increase with age. It is less common in teens and those in the 20s, and most individuals seeking help are in their mid-30s. The disorder is not culturally distinct.62 Etiology The causes of PMS and PMDD are unknown but likely multifactorial. Previously, they were linked to endocrine imbalances such as hyperprolactinemia, estrogen excess, and alteration in estrogen– progesterone ratios. Recent studies suggest females may have normal hormone levels but react abnormally to changes in levels. Other hypotheses suggest alterations in the renin–angiotensin–aldosterone system and/or prostaglandin excess may contribute to symptoms.62 One theory suggests a relationship between normal gonadal fluctuations and central neurotransmitter activity, particularly serotonin. It is unclear as to whether decreased levels of serotonin are present during the luteal phase, and only susceptible women respond with varying degrees of PMS, or if women with PMDD have a neurotransmitter abnormality.67–69 Clinical Manifestations Physical symptoms of PMS include painful and swollen breasts, bloating, abdominal pain, headache, and backache. Psychologically, there may be depression, anxiety, irritability, and behavioral changes. Females with PMS may report one or several symptoms, and symptoms vary between and within individuals67,68 (Table 45-1). It can affect normal daily performance. TABLE 45-1 Symptoms of Premenstrual Syndrome by System

Body System Symptoms Cerebral Irritability, anxiety, nervousness, fatigue, exhaustion, increased physical and mental activity, lability, crying spells, depression, inability to concentrate

Body System Symptoms Gastrointestinal Craving for sweets or salt, lower abdominal pain, bloating, nausea, vomiting, diarrhea, constipation Vascular Headache, edema, weakness, fainting Reproductive Swelling and tenderness of the breasts, pelvic congestion, ovarian pain, altered libido Neuromuscular Trembling of the extremities, changes in coordination, clumsiness, backache, leg aches General Weight gain, insomnia, dizziness, acne Diagnosis A history and physical examination are necessary to exclude other causes. Blood studies, including thyroid hormones, glucose, and prolactin assays, may be done. Psychosocial evaluation is helpful to exclude mental illness that is exacerbated premenstrually. The American College of Obstetricians and Gynecologists (ACOG) has clinical management guidelines for PMS that include diagnostic criteria similar to what the American Psychiatric Association did for PMDD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).61 Diagnosis focuses on identification of symptoms by a daily calendar on which symptoms are recorded for 2 to 3 consecutive months. PMDD is a psychiatric diagnosis that distinguishes those whose symptoms are severe enough to interfere significantly with daily activities. It requires prospective symptom charting, and a minimum of 5 of the 11 symptom groups as described in the DSM. Presence of one symptom is sufficient for PMS diagnosis.66 Treatment Management of PMS/PMDD has been largely symptomatic and includes education and support directed toward lifestyle changes for females with mild symptoms. Treatment includes diuretics to reduce fluid retention, analgesics for pain, and anxiolytic drugs to treat mood changes. An integrated program of personal assessment by diary, regular exercise, avoidance of caffeine, and a diet low in simple sugars and high in lean proteins is often beneficial. Additional therapeutic regimens include vitamin or mineral supplements (particularly pyridoxine, vitamin E, and

magnesium), evening primrose oil (which contains linoleic acid, a precursor of prostaglandin E1), natural progesterone supplements, low-dose oral monophasic contraceptives, GnRH agonists, bromocriptine for prolactin suppression, danazol (a synthetic androgen), and spironolactone (an aldosterone antagonist and inhibitor of adrenal androgen synthesis).66 Although a variety of therapeutic choices exist, few treatments have been adequately evaluated in randomized, controlled clinical trials. Selective serotonin reuptake inhibitor antidepressants demonstrate significant improvement in overall symptoms compared with placebo, whether used continuously or only in the luteal phase, and are recommended by ACOG as first-line therapy for severe PMS or PMDD.61,68 SUMMARY CONCEPTS Menstrual disorders include dysfunctional menstrual cycles, dysmenorrhea, and PMS. Dysfunctional menstrual cycles, which involve amenorrhea, oligomenorrhea, metrorrhagia, or menorrhagia, occur when hormonal support of the endometrium is altered. Estrogen deprivation causes retrogression of a previously built-up endometrium and bleeding. A lack of progesterone can cause abnormal menstrual bleeding; in its absence, estrogen induces development of a much thicker endometrial layer with a richer blood supply. The absence of progesterone results from the failure of any of the developing ovarian follicles to mature to the point of ovulation, with subsequent formation of the corpus luteum and production of progesterone. Dysmenorrhea is characterized by pain or discomfort during menses. Primary dysmenorrhea is not associated with other disorders and begins soon after menarche. Secondary dysmenorrhea is caused by a specific organic condition. It occurs in individuals with previously painless menses. Premenstrual symptom disorders represent a spectrum from molimina, which is present to some degree in most ovulatory females, to PMS and PMDD. PMS represents a cluster of physical and psychological symptoms that precede menstruation by 1 to 2

weeks. PMDD is the most severe, disabling form of PMS. The cause and methods for treatment of PMS are still under study.

Disorders of the Breast Breast tissue is never static; it is constantly responding to changes in hormonal, nutritional, psychological, and environmental stimuli that cause continual cellular changes. Benign breast conditions are nonprogressive, but some forms of benign disease increase the risk of malignant disease. Thus, strict adherence to a dichotomy of benign versus malignant disease may not always be appropriate but is useful for the sake of simplicity and clarity. Galactorrhea Galactorrhea is secretion of breast milk in a nonlactating breast. It may result from vigorous nipple stimulation, exogenous hormones, internal hormonal imbalance, or local chest infection or trauma. A pituitary tumor, such as a prolactinoma, may produce large amounts of prolactin and cause galactorrhea. It occurs in males and females and usually is benign. Observation may be continued for several months before diagnostic hormonal screening. Spontaneous leaking from the breast (without any type of stimulation) is pathologic and warrants a full workup.70,71 Mastitis Mastitis is breast inflammation and frequently occurs during lactation.72 Inflammation results from ascending infection (commonly Staphylococcus) traveling from nipple to ductile structures.70 Offending organisms originate from an infant’s nasopharynx or mother’s hands. In the early weeks of nursing, the breast is more vulnerable to infection because of minor cracks and fissures. Infection and inflammation obstruct the ductile system. The area becomes hard, inflamed, and tender if not treated early, and the area becomes walled off and may abscess, requiring drainage. The mother should continue breastfeeding during antibiotic therapy to prevent this.72 Mastitis is not confined to the postpartum period; it can occur due to hormonal fluctuations, tumors, trauma, or skin infection. Cyclic

inflammation of the breast occurs most frequently in adolescents, who may have fluctuating hormone levels. Tumors may cause mastitis secondary to skin involvement or lymphatic obstruction. Local trauma or infection may develop into mastitis because of ductal blockage of trapped blood, cellular debris, or the extension of superficial inflammation.1 Treatment for mastitis symptoms includes application of heat or cold, excision, aspiration, mild analgesics, antibiotics, and a supportive brassiere or breast binder. Ductal Disorders Ductal ectasia manifests in older females as a spontaneous, intermittent, often unilateral, grayish-green nipple discharge. Breast palpation increases discharge. It occurs during or after menopause and is associated with burning, itching, pain, and pulling sensation of nipple and areola. It results in duct inflammation and thickening. Treatment requires removal of involved ductal mass.73 Intraductal papillomas are benign epithelial tissue tumors that range from 2 mm to 5 cm. A small number of lesions will have atypical cells that progress to cancer, and excision is recommended. Papillomas usually cause bloody nipple discharge.71 The tumor may be palpated in the areolar area. Galactography (radiograph after dye is injected into the affected duct) is used for diagnosis. The papilloma is probed through the nipple and the involved duct removed. MRI may also be effective in identifying disease.71,74 Fibroadenoma and Fibrocystic Changes Fibroadenomas are most commonly seen in 30- to 40-year-old females. Clinical findings include a firm, rubbery, sharply defined round mass. On palpation, a mass “slides” between fingers and is easily movable. Masses are often singular; 15% are multiple or bilateral. They are asymptomatic, not precancerous, and are often found by accident. Treatment involves simple excision.75 Fibrocystic changes are the most frequent breast lesion and are most common in between 20 and 50 years of age. They are rare in postmenopausal females not receiving hormone replacement.1 They usually present as nodular (i.e., “shotty”), granular breast masses that are more prominent and painful during the luteal portion of the menstrual cycle.

Discomfort ranges from heaviness to tenderness, depending on degree of vascular engorgement and cystic distension. Fibrocystic changes encompass a variety of lesions and breast changes. Microscopically, they refer to morphologic changes manifested by (a) microscopic cysts, (b) apocrine metaplasia, (c) mild epithelial hyperplasia, and (d) increase in fibrous stroma.1 Only certain variants in which proliferation of epithelial components is demonstrated increase the risk of breast cancer. Presence of large cysts and proliferative epithelial lesions with atypia are more common in females at increased risk for invasive breast cancer. The nonproliferative form of fibrocystic changes is more common. Diagnosis of fibrocystic changes is made by examination, mammography, ultrasonography, and biopsy. Routine mammography in high-risk groups of those younger than 35 years of age is controversial. Mammography may be helpful in establishing diagnosis, but increased breast tissue density with fibrocystic changes may make an abnormal mass difficult to discern and requires MRI. Ultrasonography can differentiate a cystic from a solid mass. Because a mass caused by fibrocystic changes may be indistinguishable from carcinoma depending on clinical findings, suspect lesions should undergo biopsy. Fine-needle aspiration may be used. If a suspect mass that was nonmalignant on cytologic examination does not resolve in several months, it should be removed surgically. Any discrete breast mass or lump should be viewed as possible carcinoma, and cancer should be excluded before instituting the conservative measures used to treat fibrocystic changes. Treatment for fibrocystic changes is usually symptomatic. Mild analgesics (e.g., aspirin, acetaminophen, or NSAIDs) and local application of heat or cold may be used for pain relief. Prominent or persistent cysts may be aspirated and fluid sent for cytologic analysis.76 Breast Cancer Cancer of the breast is the most common female cancer after skin cancer. One in eight females in the United States will have breast cancer in her lifetime. In 2019, invasive breast cancer will affect an estimated 268,600 American and kill an estimated 41,760 females. Although breast cancer mortality rate has shown a slight decline, it is second to lung cancer as a cause of cancer-related deaths in females. Approximately 62,930 U.S.

females will be diagnosed with cancer in situ or precancer in 2019.77 Incidence rates for carcinoma in situ have increased since the mid-1970s because of mammography screening recommendations. Death rates have decreased, particularly in those younger than 50 years of age, which can be attributed to earlier diagnosis and increased awareness, as well as improvements in cancer treatments.78 Risk Factors Risk factors for breast cancer include sex, increasing age, personal or family history of breast cancer, history of benign breast disease, and hormonal influences that promote breast maturation and may increase the chance of mutation (i.e., early menarche, late menopause, no term pregnancies or first child after 30 years of age, and no breastfeeding). Modifiable risk factors include obesity (particularly after menopause), physical inactivity, and alcohol intake over one drink per day.78 However, most with breast cancer have no identifiable risk factors. Approximately 5% to 10% of breast cancers are hereditary; genetic mutations cause up to 80% of breast cancers in females younger than 50 years of age.79 Two breast cancer susceptibility genes may account for most inherited forms of breast cancer. BRCA1 is involved in tumor suppression. A female with known mutations in BRCA1 has a lifetime risk of 60% to 85% for breast cancer and increased risk of ovarian cancer. BRCA2 carries an elevated cancer risk similar to BRCA1.22,79 Guidelines are established for when genetic counseling and testing should be offered.80 Risk reduction options include surveillance, chemoprevention, and surgery. Breast evaluation using MRI is preferred over standard mammography because of its enhanced sensitivity and lack of radiation exposure. Prophylactic surgery (bilateral mastectomy, bilateral oophorectomy, or both) decreases risk of developing cancer. These surgeries can have physical and psychological side effects that warrant careful consideration. Use of aromatase inhibitors for prevention of breast cancer in those with + BRCA1 and/or 2 gene mutations depends on the type of breast cancer. Detection Breast cancer may manifest as a mass, a puckering, nipple retraction, or unusual discharge. The variety of symptoms and potential for self-discovery

stress the need for females to know their normal breast appearance and texture. Those who discover their own cancer do so outside of a scheduled breast self-examination (BSE). American Cancer Society screening guidelines emphasize breast cancer diagnosis on mammography and encourage females to be self-aware.81 Premenopausal females should perform BSE right after menses. Postmenopausal females and those with a hysterectomy can perform BSE at any time. Most important is a systematic, convenient, and consistent method of examination. Females should have a clinical examination every 3 years between 20 and 40 years of age, and annually after 40 years of age. Mammography is the effective screening technique for early detection of clinically unapparent lesions. Breast cancer is generally slow growing and may be present for 2 to 9 years before it reaches 1 cm, the smallest mass normally detected by palpation. Mammography can disclose 1-mm lesions and clustering of calcifications that may warrant biopsy. Mammography has a sensitivity of 80% to 90% for breast cancer detection, so, even if the mammogram is negative, a palpable mass requires further evaluation. Approximately 40% of breast cancers can be detected only by palpation and another 40% only by mammography.22 Comprehensive screening requires self-awareness, clinical breast evaluation by a health professional, and mammography. Diagnosis and Classification Procedures used in diagnosis include physical examination, mammography, ultrasonography, percutaneous needle aspiration, stereotactic needle biopsy (i.e., core biopsy), and excisional biopsy (Fig. 45-14). Breast cancer is often a solitary, painless, firm, fixed lesion with poorly defined borders. It can be found anywhere in the breast, but it is most common in the upper outer quadrant. Because of the variability, any suspect change in breast tissue warrants investigation. The diagnostic use of mammography enables additional definition of the clinically suspect area and may lead to early detection. A wire marker under radiographic guidance can ensure accurate surgical biopsy of nonpalpable suspect areas. Ultrasonography is useful as a diagnostic adjunct to differentiate cystic from solid tissue in females with nonspecific thickening.82

Carcinoma of the breast. (A) Mammogram. An irregularly shaped, dense mass (arrows) is seen in this otherwise fatty breast. (B) Mastectomy specimen. The irregular white, firm mass in the center is surrounded by fatty tissue. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 25-35A and B, p. 1071). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45.14

Fine-needle aspiration is an in-office procedure that can be performed repeatedly in multiple sites and with minimal discomfort. A palpable mass is stabilized between two fingers or in conjunction with handheld sonography to define cystic masses or fibrocystic changes. Fine-needle aspiration can identify malignant cells but cannot differentiate in situ from infiltrating cancers. Stereotactic needle biopsy is an outpatient procedure done with the guidance of a mammography machine. After the lesion is localized, a large-bore needle is inserted quickly, removing a core of tissue. Discomfort is mild, and healing occurs rapidly. Histologic evaluation provides 96% accuracy in detecting cancer. This procedure is less costly than is excisional biopsy. However, excisional biopsy to remove the entire lump provides the only definitive diagnosis of breast cancer, and often is therapeutic without additional surgery. MRI, positron emission tomography, and computer-based or digital mammography are additional diagnostic modalities for breast cancer, and may supplement conventional mammography in females with radiographically dense breasts or a strong family history of cancer, or who are known carriers of BRCA1 or BRCA2.83

Tumors are classified according to tissue characteristics and staged clinically according to size, nodal involvement, and metastasis. Estrogen and progesterone receptor analysis should be performed on surgical specimens, because the presence or absence of these receptors can predict tumor responsiveness to hormonal manipulation. High levels of both receptors improve prognosis and increase likelihood of remission. Treatment Treatment methods include surgery, chemotherapy, radiation, and hormonal manipulation. Radical mastectomy (i.e., removal of the entire breast, underlying muscles, and all axillary nodes) is rarely the primary surgical therapy unless cancer is advanced at diagnosis. Modified surgical techniques (mastectomy plus axillary dissection or lumpectomy for breast conservation) plus chemotherapy or radiation therapy have comparable outcomes and are preferred. Prognosis is related more to the extent of nodal involvement than to breast involvement. Greater nodal involvement requires more aggressive postsurgical treatment, and a diagnosis is not complete until dissection and testing of axillary lymph nodes. Evaluating lymph node involvement can be done via sentinel lymph node (SLN) biopsy. If the SLN biopsy is positive, more nodes are removed. If it is negative, further lymph node evaluation may not be needed. Systemic therapy is administration of chemotherapy, biologic therapy, or hormonal therapy. Neoadjuvant therapy is given before surgery to shrink the tumor and make surgical removal more effective. Adjuvant therapy is given after surgery to females with and without detectable metastatic disease. The goal of this therapy depends on nodal involvement, menopausal status, and hormone receptor status. Systemic adjuvant therapy has benefits in reducing rates of recurrence and death from breast cancer.83 Biologic therapy, using trastuzumab, is used to stop growth of breast tumors that express the HER2/neu receptor on the cell surface. The HER2/neu receptor binds an epidermal growth factor that contributes to cancer cell growth. Hormone therapy can block the effects of estrogen on breast cancer cell growth. Tamoxifen is a nonsteroidal antiestrogen that binds to estrogen receptors and blocks the effects of estrogens on growth of malignant breast

cells. Decreased cancer recurrence and mortality rates, and increased 5-year survival rates, have been found in females with estrogen receptor–positive tissue samples treated with tamoxifen. Aromatase inhibitors block the enzyme that converts androstenedione and testosterone to estrogen in peripheral tissues. This reduces circulating estrogen levels in postmenopausal females and is an effective adjuvant therapy for early-stage breast cancer.84 Paget Disease Paget disease accounts for 1% of all breast cancers. It presents as an eczematoid lesion of nipple and areola (Fig. 45-15). It usually is associated with infiltrating, intraductal carcinoma. Complete examination includes a mammogram and biopsy. Treatment depends on the extent of spread.85

Paget disease of the nipple. (From Strayer D. S., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 25-30A, p. 1069). Philadelphia, PA: Lippincott Williams & Wilkins.) FIGURE 45-15

SUMMARY CONCEPTS The breasts are subject to benign and malignant diseases. Mastitis is inflammation of the breast, occurring most frequently during lactation. Galactorrhea is an abnormal secretion of milk that may occur as a symptom of increased prolactin secretion. Ductal ectasia and intraductal papilloma cause abnormal drainage from the nipple. Fibroadenoma and fibrocystic changes are abnormal masses in the

breast that are benign. Breast cancer is a significant cause of death of females. Clinical breast examination and mammography afford the best protection against breast cancer. They provide the means for early detection and allow early treatment and cure.

Infertility Infertility is the inability to conceive a child after 1 year of unprotected intercourse. Primary infertility refers to situations in which there has been no prior conception. Secondary infertility occurs after one or more previous pregnancies. Sterility is the inability to father a child or to become pregnant because of congenital anomalies, disease, or surgical intervention. In the United States, approximately 6% to 12% of females ages 15 to 44 are affected by infertility.86 For pregnancy to occur, three things must be available: (a) oocytes or eggs, (b) spermatozoa or sperm, and (c) a place for oocytes and spermatozoa to fertilize and implant. There are several contributing factors to infertility. Male and female factors each make up about one third. Approximately 20% of couples suffer from unexplained infertility. Roughly 10% of infertility is caused by a combination of both male and female factors.87 Although a full discussion of the diagnosis and treatment of infertility is beyond the scope of this book, an overview is presented. Male Factors For pregnancy to occur, the man must provide sperm in sufficient quantity, delivered to the upper end of the vagina, with adequate motility. This is assessed by a semen analysis, which evaluates volume (normally 1.5 mL), sperm density (15 to 39 million/mL), motility (>32% good progressive), viability (58%), morphology (4% normal), and viscosity (full liquefaction within 20 minutes).88 The specimen is best collected by masturbation into a sterile container after 3 days of abstinence. Because of variability, abnormal results should lead to a repeat test before the need for treatment is presumed. Azoospermia is the absence of sperm, oligospermia refers to

decreased numbers of sperm, and asthenospermia refers to poor motility of sperm.89 Causes include varicocele, ejaculatory dysfunction, hyperprolactinemia, hypogonadotropic hypogonadism, infection, immunologic problems, obstruction, and congenital anomalies. Risk factors include a history of mumps orchitis, cryptorchidism, testicular torsion, hypospadias, previous urologic surgery, and history of STIs. Treatment may include surgery, medication, or artificial insemination to deliver a concentrated specimen to the cervical canal or uterine fundus.87 Female Factors Female factors for pregnancy require production and release of a mature ovum capable of being fertilized, cervical mucus for sperm transport and sperm viability in the female reproductive tract, patent fallopian tubes with the motility to pick up and transfer the ovum to the uterine cavity, an endometrium suitable for implantation and nourishment of a fertilized ovum, and a uterine cavity that allows for growth and development of a fetus. Diminished Ovarian Reserve Oocyte quality, ability for fertilization, and ovulation are important for pregnancy. Females are born with a lifetime cache of oocytes. Oocyte quality and quantity decline (diminished ovarian reserve, DOR) with age. Females with DOR have a higher rate of miscarriage if they do conceive, perhaps related to oocyte quality. DOR assessment is generally done early in the menstrual cycle. FSH, LH, and estradiol levels should be lowest days 1 to 3 when they are measured. FSH levels >10, estradiol >80, and/or anti-müllerian hormone levels under 1 and 3.5 are indicative of DOR. Ultrasound of the number of antral (primordial) ovarian follicles on day 3 of the menstrual cycle can detect DOR. Antral follicle count of 3 to 10 on both ovaries and low ovarian volume may indicate DOR.90 DOR is only predictive of chances of successful treatment using the woman’s own oocytes. Ovulatory Dysfunction

Ovulatory dysfunction is a common cause of infertility. It can be due to primary problems of the ovary or secondary problems related to endocrine dysfunction. When disturbances in ovulation are confirmed, other endocrine system problems should be ruled out before initiating treatment. If results for pituitary hormones, thyroid studies, and adrenal function are normal, dysfunction is primary and should respond to treatment. Other endocrine areas should be assessed. Hyperprolactinemia requires workup for pituitary lesions or associated endocrinopathies. Continued hyperprolactinemia can be treated with bromocriptine or cabergoline. Hypothyroidism requires thyroid replacement, and hyperthyroidism requires suppressive therapy and, sometimes, surgical intervention with thyroid replacement later. Adrenal suppression can be instituted with dexamethasone, a glucocorticoid analog. If normal ovulatory function does not resume, treatment can be concurrent with management of other endocrine problems.90 It is important to determine whether ovulation is occurring. Progesterone after ovulation increases basal body temperature (BBT). Females should be able to detect at least a 0.4°F rise in BBT at rest after ovulation, maintained throughout the luteal phase. This shows ovulation has taken place, when it occurred, and the length of the luteal phase. BBT can be influenced by factors including restless sleep, alcohol intake, drug use, fever due to illness, and change in usual rising time. LH predictor kits test for LH in the urine after the LH surge, which indicates ovulation. Serum progesterone can also be measured after expected ovulation to confirm whether ovulation occurred. Cervical Mucus Problems High preovulatory levels of estradiol stimulate production of clear, stretchy cervical mucus that aids transport of sperm into the uterine cavity and helps maintain an environment that keeps sperm viable for up to 72 hours. Insufficient estrogen production (i.e., inherent or secondary to treatment with clomiphene citrate), cervical abnormalities from disease or invasive procedures (e.g., DES exposure, stenosis, conization), and cervical infection (e.g., chlamydial infection, mycoplasmal infection, and gonorrhea) can adversely affect production of healthy cervical mucus. A postcoital test evaluates cervical mucus 1 to 8 hours after intercourse and in the 48 hours before ovulation. A sample is evaluated for amount,

clarity, stretch, cellularity, number and quality of motile sperm, and ferning after the sample has air dried on the slide. Intrauterine insemination with sperm can bypass the cervical mucus. Cervical cultures for gonorrhea, chlamydial infection, and mycoplasmal infection should be obtained and treatment instituted as needed. Uterine Cavity Abnormalities Alterations in the uterine cavity can occur due to DES exposure, submucosal fibroids, cervical polyps, bands of scar tissue, or congenital anomalies (e.g., bicornuate uterus, uterine septum, single horn). Defects may be suspected from a person’s history or pelvic examination but require hysterosalpingography or hysteroscopy for confirmation. Treatment is surgical when possible. Tubal Factors Tubal patency is required for fertilization and can be disrupted secondary to PID, ectopic pregnancy, large myomas, endometriosis, pelvic adhesions, and previous tubal ligation. Hysterosalpingography can reveal the location and type of any blockage, such as fimbrial, cornual, or hydrosalpinx. Microsurgical repair sometimes is possible.90 Tubal disease may make ovum pickup impossible. The tube must be free to move to engulf the ovum after release. Pelvic adhesions from previous infection, surgery, or endometriosis can interfere with the tube’s mobility. Laparoscopic evaluation is needed for diagnosis. Laser ablation or cautery can lyse adhesions and remove endometriosis through the laparoscope or, if severe, by means of laparotomy. Assisted Reproductive Technology Assisted reproductive technology (ART) includes in vitro fertilization (IVF) using nondonor and donor oocytes, oocyte and embryo cryopreservation, and donor and nondonor frozen embryo transfers. Developed in 1978, IVF involves stimulation of the ovaries to produce multiple follicles. To do so, the female injects FSH and LH daily and is monitored with ultrasounds and blood tests to avoid overstimulation of the ovaries. When the follicles are mature, transvaginal oocyte retrieval is

performed. The patient is sedated, and a needle (guided by ultrasound) is placed through the vaginal wall into each ovary to remove the oocytes. Sperm is provided by a male partner or a donor. Oocytes and sperm are mixed together in a Petri dish. In some instances, a single sperm may be injected into each oocyte (intracytoplasmic sperm injection). Once fertilization occurs, the embryo(s) is/are allowed to grow in the dish over 3 to 5 days. Embryos are then transferred to the female by passing the catheter into the uterus and injecting the embryo(s). Success depends on many factors. About 23% of fresh nondonor cycles will result in a live birth. Success with donor oocytes is higher: 55.6% of cycles will result in a live birth.86 Indications for IVF have been expanded to include male factors, ovulatory dysfunction, uterine factors, endometriosis, and idiopathic infertility. As more is learned about implantation, the risk of a multiple pregnancy via IVF is decreasing. Cryopreservation of excess embryos allows for multiple attempts, which provide confidence to transfer fewer embryos. The use of donor gametes (eggs, sperm, and embryos) provides an alternative for achieving pregnancy for couples who are unable to use their own gametes and are comfortable raising a child not genetically related to them. Donor eggs provide a much higher likelihood of success for women older than 40 years of age, when both egg numbers and egg quality decline. SUMMARY CONCEPTS Infertility is the inability to conceive a child after 1 year of unprotected intercourse. Male factors are related to number and motility of sperm and ability to penetrate cervical mucus or ovum. Causes include varicocele, ejaculatory dysfunction, hyperprolactinemia, hypogonadotropic hypogonadism, infection, immunologic problems, obstruction, and congenital anomalies. Risk factors include a history of mumps orchitis, cryptorchidism, testicular torsion, hypospadias, previous urologic surgery, infection, and exposure to known gonadotoxins. The female contribution to pregnancy is complex, requiring production and release of an ovum capable of being fertilized, cervical mucus that assists in sperm transport and maintains sperm

viability, patent fallopian tubes with mobility to pick up and transfer the ovum to the uterine cavity, development of an endometrium that is suitable for the implantation and nourishment of a fertilized ovum, and a uterine cavity that allows for growth and development. Evaluation and treatment of infertility can be lengthy and highly stressful. Options continue to expand, but newer ART modalities are expensive, and financial resources can be strained while individuals seek to fulfill their, sometimes elusive, dream of having a child.

Review Exercises 1. A 32-year-old woman has been told that the report of her annual Pap test revealed the presence of mild dysplasia. A. What questions should this woman ask as a means of becoming informed about the significance of these findings? B. In obtaining additional information about the results of her Pap test, the woman is informed that dysplastic changes are consistent with a CIN 1 classification. 1. Does this mean that the woman has cervical cancer? 2. Cervical cancer is often referred to as an STI. Explain. 3. What type of follow-up care would be indicated? 2. A 30-year-old woman consults her gynecologist because of amenorrhea and an inability to become pregnant. Physical examination reveals an obese woman with hirsutism. The physician tells the woman that she might have a condition known as polycystic ovary syndrome and that further laboratory tests are indicated. A. Among the tests ordered were fasting blood glucose, LH, FSH, and DHEAS levels. What information can these tests provide that would help in establishing a diagnosis of PCOS? B. What is the probable cause of this woman’s amenorrhea, hirsutism, and failure to become pregnant?

C. What type of treatment might be used to help this woman become pregnant? 3. A 45-year-old woman makes an appointment to see her physician because of a painless lump in her breast that she discovered while doing her routine monthly BSE. A. What tests should be done to confirm the presence or absence of breast cancer? B. During the removal of breast cancer, an SLN biopsy is often done to determine whether the cancer has spread to the lymph nodes. Explain how this procedure is done and its value in determining lymph node spread. C. After surgical removal of breast cancer, an aromatase inhibitor may be used as an adjuvant systemic therapy for women without detectable metastatic disease. The presence or absence of estrogen receptors in the cytoplasm of tumor cells is important in determining the selection of an agent for use in adjuvant therapy. Explain. REFERENCES 1. Strayer D., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2. Gorrol A. H., Mulley A. G. (2014). Primary care medicine: Office evaluation and management of the adult patient (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 3. Krissi H., Shmuely A., Aviram A., et al. (2016). Acute Bartholin’s abscess: Microbial spectrum, patient characteristics, clinical manifestation, and surgical outcomes. European Journal Clinical Microbial Infectious Disease 35, 443–446. 4. Cash J. C., Glass C. A. (2014). Family practice guidelines (3rd ed.). New York, NY: Springer Publishing Company, LLC. 5. Chan M. P., Zimarowski M. J. (2015). Vulvar dermatoses: A histopathologic review and classification of 183 cases. Journal of Cutaneous Pathology 42, 510–518. 6. Girardi F., Reich O., Tamussino K., et al. (2015). Burghardt’s colposcopy and cervical pathology: Textbook and atlas (4th ed.). Stuttgart, New York, Delhi, Rio de Janeiro: Thieme. 7. Lee A., Bradford J., Fischer G. (2015). Long-term management of adult vulvar lichen sclerosus a prospective cohort study of 507 women. Journal of American Medical Association Dermatology 151(10), 1061–1067. 8. De Andres J., Sanchis-Lopez N., Marcos Ansensio-Samper J. M., et al. (2016). Vulvodynia—an evidence-based literature review and proposed treatment algorithm. World Institute of Pain 16(2), 204–236. 9. International Society for the Study of Vulvovaginal Disorders. (2015). Vulvovaginal disorders. [Online]. Available: https://www.issvd.org/issvd-terminology-classification-of-vulvar-diseases/. Accessed October 26, 2017.

10. Basson R., Driscoll M., Correia S. (2016). When sex is always painful: Provoked vestibulodynia. British Columbia Medical Journal 58(2), 77–81. 11. CerVigni M., Natale F. (2014). Gynecological disorders in bladder pain syndrome/interstitial cystitis patients. International Journal of Urology 21(suppl 1), 85–88. 12. IsHak W. W. (Ed.). (2017). The textbook of clinical sexual medicine (1st ed.). New York, NY: Springer Publishing Company, LLC. 13. National Cancer Institute. (2019). Surveillance, epidemiology, and end results cancer statistics review: Vulva cancer. [Online]. Available: http://seer.cancer.gov/statfacts/html/vulva.html. Accessed May 11, 2019. 14. Reyes M. C., Cooper K. (2014). An update on vulvar intraepithelial neoplasia: Terminology and a practical approach to diagnosis. [abstract] Journal of Clinical Pathology 67(4), 290–294. 15. American College of Obstetrics and Gynecology and American Society for Colposcopy and Cervical Pathology. (2017). Management of vulvar intraepithelial lesions. Committee opinion. [Online]. Available: https://www.acog.org/-/media/Committee-Opinions/Committee-onGynecologic-Practice/co675.pdf?dmc=1&ts=20180312T0238240039. Accessed March 11, 2018. 16. Ramirez P. D., Gershenson D. M., Salvo G. (2018). Vulvar cancer. Merck Manual Professional. [Online]. Available: https://www.merckmanuals.com/professional/gynecology-andobstetrics/gynecologic-tumors/vulvar-cancer. Accessed March 4, 2018. 17. International Federation of Gynecology and Obstetrics. (2009). Vulvar cancer. [Online]. Available: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757555/. Accessed November 6, 2017. 18. Khanna N., Raug L. A., Lachiewicz M. P., et al. (2016). Margins for cervical and vulvar cancer. Journal of Surgical Oncology 113, 304–309. 19. Rhoads J., Murphy M. (2014). Differential diagnosis for the advanced practice nurse. New York, NY: Springer Publishing Company, LLC. 20. American Cancer Society. (2017). What are the key statistics about vaginal cancer? [Online]. Available: https://www.cancer.org/cancer/vaginal-cancer/about/key-statistics.html. Accessed June 22, 2019. 21. Yarbro C. H., Wujcik D., Gobel B. H. (2018). Cancer nursing: Principles and practice (8th ed.). Burlington, MA: Jones & Bartlett. 22. Jentschke M., Hoffmeister V., Soergel P., et al. (2016). Clinical presentation, treatment and outcome of vaginal intraepithelial neoplasia. Archives of Gynecology and Obstetrics 293, 415– 419. doi:10:1007/s0040-015-3835-6. 23. Carcio H. N., Secor M. (2015). Advanced health assessment of women: Clinical skills and procedures (3rd ed). New York, NY: Springer Publishing Company, LLC. 24. American Cancer Society. (2018). Cervical cancer. [Online]. Available: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annualcancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed May 5, 2018. 25. American Cancer Society. (2016). Tests for cervical cancer. [Online]. Available: https://www.cancer.org/cancer/cervical-cancer/detection-diagnosis-staging/how-diagnosed.html. Accessed October 29, 2017. 26. United States Federal Drug Administration. (2017). Cervarix. [Online]. Available: https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm186957.htm. Accessed October 29, 2017. 27. Nayar R., Wilbur D. C. (2015). The pap test and Bethesda 2014. Acta Cytologica 59, 121–132. doi:10.1159/000381842. 28. Baker E. (2013). HPV and Pap: Shifting roles in cervical cancer screening. Medical Laboratory Observer. [Online]. Available: https://www.mlo-online.com/hpv-and-pap-shifting-roles-incervical-screening.php. Accessed October 29, 2017.

29. Medlin E. E., Kushner D. M., Barroilhet L. (2016). Robotic surgery for early stage cervical cancer: Evolution and current trends. Journal of Surgical Oncology 112, 772–781. 30. Marnitz S., Budach V., Weiber F., et al. (2012). Rectum separation in patients with cervical cancer for treatment planning in primary chemo-radiation. Radiation Oncology 7, 109. 31. Ahn S. H., Monsanto S. P., Miller C., et al. (2015). Pathophysiology and Immune dysfunction in endometriosis. Biomed Research International 2015, 795–976. doi:10.1155/2015/795976. 32. Morotti M., Vincent K., Brawn J., et al. (2014). Peripheral changes in endometriosis-associated pain. Human Reproduction Update 20(5), 717–736. 33. American Society for Reproductive Medicine. (2012). Endometriosis a guide for patients [pamphlet]. Birmingham, AL: American Society for Reproductive Medicine under the direction of the Patient Education Committee and the Publications Committee. 34. Sinervo K. R. (2015). The case for surgery for endometriosis. Contemporary OB/GYN 60(10), 51–54. 35. Mishra V. V., Gaddagi R. A., Aggarwal R., et al. (2015). Prevalence; characteristics and management of endometriosis amongst infertile women: A one year retrospective study. Journal of Clinical and Diagnostic Research 9(6), 1–3. 36. Fraser I. (2016). Current trends in the medical management of endometriosis “available therapies in perspective”. Indian Obstetrics and Gynaecology 6(1), 8–17. 37. American Cancer Society. (2017). Endometrial cancer. [Online]. Available: https://www.cancer.org/cancer/endometrial-cancer/about/key-statistics.html. Accessed October 29, 2017. 38. American Cancer Society. (2017). What are key statistics about uterine sarcoma? [Online]. Available: https://www.cancer.org/cancer/uterine-sarcoma/about/key-statistics.html. Accessed October 31, 2017. 39. Folkins A. K., Longmore T. A. (2013). Hereditary gynaecological malignancies: Advances in screening and treatment. Histopathology 62(2), 2–30. 40. American Cancer Society. (2017). What is endometrial cancer. [Online]. Available: https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html. Accessed October 29, 2017. 41. Tang Y., Chen C., Duan H., et al. (2015). Low vascularity predicts favourable outcomes in leiomyoma patients treated with uterine artery embolization. European Radiology 26, 3571–3579. 42. Centers for Disease Control and Prevention. (2015). STI pelvic inflammatory disease. [Online]. Available: https://www.cdc.gov/std/tg2015/pid.htm. Accessed November 1, 2017. 43. Gradison M. (2012). Pelvic inflammatory disease. American Family Physician. 85(8), 791–796. 44. Taran F. A., Kagan K. O., Hubner M., et al. (2015). The diagnosis and treatment of ectopic pregnancy. Deutsches Aerzteblatt International 112, 693–704. 45. Epee-Bekima M., Overton C. (2013). Diagnosis and treatment of ectopic pregnancy. The Practitioner 257(1759), 15–17. 46. American Society of Clinical Oncology. (2017). Ovarian, fallopian tube, and peritoneal cancer: Statistics. [Online]. Available: https://www.cancer.net/cancer-types/ovarian-fallopian-tube-andperitoneal-cancer/statistics. Accessed April 17, 2018. 47. Fauser B. C., Tarlatzis B. C., Rebar R. W., et al. (2012). Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-sponsored 3rd PCOS consensus workshop group. Fertility and Sterility 97(1), 28.e25–36.e25. doi:10.1016/j.fertnstert.2011.09.024. 48. Franks S., Berga S. L. (2012). Does PCOS have developmental origins? Fertility and Sterility 97(1), 1–6. 49. Tsai Y., Wang T., Wei H., et al. (2013). Dietary intake, glucose metabolism and sex hormones in women with polycystic ovary syndrome (PCOS) compared with women with non-PCOS-related infertility. British Journal of Nutrition 109(12), 2190–2198.

50. Dumitrescu R., Mehedintu C., Briceag I., et al. (2015). The polycystic ovary syndrome: An update on metabolic and hormonal mechanisms. Journal of Medicine and Life 8(2), 142–145. 51. Legro R. S., Arsianian S. A., Ehrmann D. A., et al. (2013). Diagnosis and treatment of polycystic ovary syndrome: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism 98(12), 4565–4592. 52. American Cancer Society. (2017). Ovarian cancer. [Online]. Available: https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html. Accessed October 31, 2017. 53. American Cancer Society. (2016). Can ovarian cancer be found early? [Online]. Available: https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/detection.html. Accessed October 31, 2017. 54. Wentzensen N., Poole E. M., Trabert B., et al. (2016). Ovarian cancer risk factors by histologic subtype: An analysis from the ovarian cancer cohort consortium. Journal of Clinical Oncology 34(24), 2888–2897. 55. American Cancer Society. (2018). What are the risk factors for ovarian cancer? [Online]. Available: https://www.cancer.org/cancer/ovarian-cancer/causes-risks-prevention/riskfactors.html. Accessed April 17, 2018. 56. King G. G. T., Leighton J. C. (2015). CA 125. Medscape Drugs and Diseases/Laboratory Medicine. [Online]. Available: https://emedicine.medscape.com/article/2087557-overview#a2. Accessed March 5, 2018. 57. Hacker N. F., Gambone J. C., Moore C. J. (2016). Hacker and Moore’s essentials of obstetrics and gynecology (6th ed.). Philadelphia, PA: Elsevier. 58. McNeely S. G. (2017). Cystoceles, urethroceles, enteroceles, and rectoceles. Merck Manual Professional version. [Online]. Available: https://www.merckmanuals.com/professional/gynecology-and-obstetrice/pelvic-relaxationsyndromes/cystoceles-urethroceles-enteroceles-and-rectoceles. Accessed March 5, 2018. 59. McNeely S. G. (2018). Uterine and vaginal prolapse. Merck manual professional version. [Online]. Available: https://www.merckmanuals.com/professional/gynecology-andobstetrics/pelvic-relaxation-syndromes/uterine-and-vaginal-prolapse#v1064484. Accessed March 17, 2018. 60. Kow N., Goldman H. B., Ridgeway B. (2013). Management options for women with uterine prolapse interested in uterine preservation. Current Urology Reports 14, 395–402. 61. U.S. National Library of Medicine. (2017). Premenstrual syndrome: Overview. PubMed Health. [Online]. Available: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072449/. Accessed March 4, 2018. 62. Callahan T. (2018). Blueprints obstetrics gynecology (7th ed.) Philadelphia, PA: Wolters Kluwer. 63. Fothergill D. (2012). Causes of primary and secondary amenorrhea. Practice Nursing 23(9), 465– 469. 64. American Congress of Obstetrics and Gynecology. (2015). Dysmenorrhea, painful periods. [Online]. Available: https://www.acog.org/Patients/FAQs/Dysmenorrhea-Painful-Periods#are. Accessed November 1, 2017. 65. Hawkins J. W., Roberto-Nichols D. M., Stanley-Haney J. L. (2016). Guidelines for nurse practitioners in gynecological settings (11th ed.). New York, NY: Springer Publishing Company, LLC. 66. Hantsoo L., Epperson C. N. (2015). Premenstrual dysphoric disorder: Epidemiology and treatment. Current Psychiatry 17, 87. doi:10.1007/s11920-015-0628-3. 67. Patient education: Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) (beyond the basics). [Online]. Available: https://www.uptodate.com/contents/premenstrualsyndrome-pms-and-premenstrual-dysphoric-disorder-pmdd-beyond-the-basics. Accessed June 22, 2019.

68. American College of Obstetrics and Gynecology. (2015). Frequently asked questions gynecological problems premenstrual syndrome. [Online]. Available: https://www.acog.org/Patients/FAQs/Premenstrual-Syndrome-PMS. Accessed March 11, 2018. 69. Benjamin I. J., Griggs R. C., Wing E. J., et al. (2016). Andreoli and Carpenter’s Cecil essentials of medicine (9th ed.). Philadelphia, PA: Saunders. 70. Cullinane M., Amor L. H., Donath S. M., et al. (2015). Determinants of mastitis in women in the CASTLE study: A cohort study. BMC Family Practice 16, 181. doi:10.1186/s12875-015-0396-5. 71. Yi W., Xu F., Zou Q., et al. (2013). Completely removing solitary intraductal papillomas using the mammotome system guided by ultrasonography is feasible and safe. World Journal of Surgery 37, 2613–2617. 72. American Cancer Society. (2017). Non-cancerous breast conditions mastitis. [Online]. Available: https://www.cancer.org/cancer/breast-cancer/non-cancerous-breast-conditions/mastitis.html. Accessed April 18, 2018. 73. American Cancer Society. (2018). Non-cancerous breast conditions duct ectasia. [Online]. Available: https://www.cancer.org/cancer/breast-cancer/non-cancerous-breast-conditions/ductectasia.html. Accessed April 17, 2018. 74. Manganaro L., D’Ambrosio I., Gigli S., et al. (2015). Breast MRI in patients with unilateral bloody and serous-bloody nipple discharge: A comparison with galactography. BioMed Research International. [Online]. Available: http://dx.doi.org/10.1155/2015/806368. Accessed November 2, 2017. 75. American Cancer Society. (2018). Non-cancerous breast conditions. [Online]. Available: https://www.cancer.org/cancer/breast-cancer/non-cancerous-breast-conditions.html. Accessed April 17, 2018. 76. American Cancer Society. (2017). Fibrosis and simple cysts in the breast. [Online]. Available: https://www.cancer.org/cancer/breast-cancer/non-cancerous-breast-conditions/fibrosis-andsimple-cysts-in-the-breast.html. Accessed: March 17, 2018. 77. American Cancer Society. (2017). Breast cancer. [Online]. Available: https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html. Accessed October 31, 2017. 78. NIH National Cancer Institute. (2012). Breast cancer risk in American women. [Online]. Available: https://www.cancer.gov/types/breast/risk-fact-sheet. Accessed March 18, 2018. 79. Breastcancer.org. (2018). U.S. breast cancer statistics. [Online]. Available: http://www.breastcancer.org/symptoms/understand_bc/statistics. Accessed: March 18, 2018. 80. NIH National Cancer Institute. (2018). BRCA mutations: Cancer risk and genetic counseling. [Online]. Available: https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-factsheet. Accessed March 9, 2018. 81. Oeffinger K. C., Fontham E. T., Etzioni R., et al. (2015). Breast cancer screening for women at average risk 2015 guideline update from the American cancer society. Journal of the American Medical Academy 314(15), 1599–1614. doi:10.1001/jama.2015.12783. 82. Breastcancer.org. (2014). What can you tell me about sentinel node biopsy? [Online]. Available: http://www.breastcancer.org/questions/sentinel_node. Accessed March 11, 2018. 83. Odle T. G. (2017). Precision medicine in breast cancer. Radiologic Technology 88(40), 401–424. 84. Breastcancer.org. (2016). Aromatase inhibitors. [Online]. Available: http://www.breastcancer.org/treatment/hormonal/aromatase_inhibitors. Accessed November 1, 2017. 85. American Cancer Society. (2018). Types of breast cancer. [Online]. Available: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/types-ofbreast-cancer.html. Accessed April 17, 2018. 86. Center for Disease Control. (2017). 2015 Assisted reproductive technology national summary report. [Online]. Available: https://www.cdc.gov/art/pdf/2015-report/ART-2015-National-

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CHAPTER 46 Sexually Transmitted Infections Infections of the External Genitalia Condylomata Acuminata (Genital Warts) Types of Human Papillomavirus Pathogenesis and Clinical Manifestations Diagnosis Prevention and Treatment Genital Herpes Pathogenesis Clinical Manifestations Diagnosis Treatment Molluscum Contagiosum Chancroid Granuloma Inguinale Lymphogranuloma Venereum Vaginal Infections Candidiasis Etiology and Clinical Manifestations Diagnosis and Treatment Trichomoniasis

Clinical Manifestations and Complications Diagnosis and Treatment Bacterial Vaginosis Pathogenesis Clinical Manifestations Diagnosis and Treatment Vaginal–Urogenital–Systemic Infections Chlamydial Infections Clinical Manifestations Diagnosis and Treatment Gonorrhea Clinical Manifestations Diagnosis Treatment Syphilis Clinical Manifestations Diagnosis Treatment Other Infections Zika Clinical Manifestations Risk Diagnosis Treatment Prevention Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Name the organisms responsible for condylomata acuminata, genital herpes, molluscum contagiosum, chancroid, granuloma inguinale, and lymphogranuloma venereum. 2. State the significance of being infected with high-risk strains of the human papillomavirus.

3. Explain the pathogenesis of recurrent genital herpes infections. 4. Differentiate between wet-mount slide and culture methods of diagnosis of sexually transmitted infections. 5. Compare the signs and symptoms of infections caused by Candida albicans, Trichomonas vaginalis, and bacterial vaginosis. 6. Explain the genital and nongenital complications that can occur with chlamydial infections, gonorrhea, and syphilis. 7. Describe the three stages of syphilis. 8. Describe the complications that can occur with infection of the Zika virus. 9. Describe the spread of Zika virus. 10. Describe the symptoms of Zika infection.

Sexually transmitted infections (STIs) encompass a broad range of infectious diseases that are spread by sexual contact. The incidence of STIs is increasing as is the technology’s ability to screen STIs.1 The Centers for Disease Control and Prevention (CDC; 2014) requires reporting of chlamydia, syphilis, and gonorrhea and, therefore, tracks these three STIs most specifically.1 However, the actual figures of total STIs are probably much higher because many STIs are not reportable or not reported. There are many factors that contribute to the increased prevalence and the continued spread of STIs. One key factor is that STIs are frequently asymptomatic, which promotes the spread of infection by people who are unaware they are carrying the infection.2 Furthermore, partners of infected people are often difficult to notify and treat. In addition, there currently are no cures for viral STIs (e.g., human immunodeficiency virus [HIV], herpes simplex virus [HSV]). Although there are drugs available that may help to manage the infections, they do not entirely control the spread.3 Also, drugresistant microorganisms are rapidly emerging, making treatment of many STIs more difficult. Sexual contact transmission has been identified in over 30 bacteria.2 There are currently four curable infections: trichomoniasis, syphilis, gonorrhea, and chlamydia. Four of the infections are viral and considered incurable: hepatitis B, HSV, HIV, and human papillomavirus (HPV).2 Portals of entry include the mouth, genitalia, urinary meatus, rectum, and skin. The rates of many STIs are highest among adolescents. All STIs are

more common in people who have more than one sexual partner. Furthermore, it is not uncommon for a person to be concurrently infected with more than one type of STI.2 STIs can result in stillbirth, death of the neonate, prematurity and low-birth weight, sepsis, pneumonia, and congenital deformities.2 This chapter discusses the manifestations of STIs in men and women in terms of infections of the external genitalia, vaginal infections, and infections that have genitourinary as well as systemic manifestations.

Infections of the External Genitalia STIs can selectively infect the mucocutaneous tissues of the external genitalia, cause vaginitis in women, or produce both genitourinary and systemic effects. Some STIs may be transmitted by an infected mother to the fetus, causing congenital defects or death of the child or the newborn.2 The discussion in this section of the chapter focuses on STIs that affect the mucocutaneous tissues of the oropharynx and external genitalia and anorectal tissues. These infections include condylomata acuminata, genital herpes, molluscum contagiosum, chancroid, granuloma inguinale, and lymphogranuloma venereum. Condylomata Acuminata (Genital Warts) Condylomata acuminata, or genital warts, are caused by the HPV (Fig. 461). Although recognized for centuries, HPV-induced genital warts have become the most common STI, and there are over 40 different types of the HPV virus. The CDC estimates that 20 million Americans carry the virus and up to 6 million new cases are diagnosed each year.4 Risk factors for acquiring HPV include young age (80 IU/mL) and a positive anti-CCP antibody. A. Describe the immunopathogenesis of the joint changes that occur with RA. B. How do these changes relate to this woman’s symptoms? C. What is the significance of her RF test results? D. What is the significance of her positive anti-CCP antibody test? E. How do her complaints of general fatigue and weight loss relate to the RA disease process? 2. A 65-year-old obese woman with a diagnosis of OA has been having increasing pain in her right knee that worsens with movement and weight-bearing and is relieved by rest. Physical examination reveals an enlarged joint with a varus deformity; coarse crepitus is felt over the joint on passive movement. A. Compare the pathogenesis and articular structures involved in OA with those of RA. B. What is the origin of the enlargement of the affected joint, the varus deformity, and the crepitus that is felt on movement of the affected knee? C. Explain the predilection for involvement of the knee in people such as this woman. 3. A 75-year-old woman is seen by her health care provider because of complaints of fever, malaise, and weight loss. She is having trouble combing her hair, putting on a coat, and getting out of chairs because of the stiffness and pain in her shoulders, hip, and lower back. Because of her symptoms, the health care provider suspects the woman has polymyalgia rheumatica. A. What laboratory test can be used to substantiate the diagnosis? B. What other diagnostic strategies are used to confirm the diagnosis? REFERENCES

1. Arthritis Foundation. (2018). Exercise benefits for hip osteoarthritis. [Online]. Available: https://www.arthritis.org/about-arthritis/types/osteoarthritis/articles/hip-oa-exercises.php. Accessed March 14, 2018. 2. Strayer D., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 3. Arnold M. B., Bykerk V. P., Boire G., et al. (2014). Are there differences between young-and older-onset early inflammatory arthritis and do these impact outcomes? An analysis from the CATCH cohort. Rheumatology 53, 1075–1086. 4. Dunphy L. M., Windland-Brown J. E., Porter B. O., et al. (2015). Primary care: The art and science of advanced practice nursing (4th ed.). Philadelphia, PA: FA Davis. 5. Schulte-Pelkum J. S., Schulz-Knappe P. S. (2015). A multi-marker approach to diagnosing autoimmune diseases. MLO: Medical Laboratory Observer 47(10), 44–46. 6. Liu Q., Zhao J., Zhou H., et al. (2015). Parthenolide inhibits pro-inflammatory cytokine production and exhibits protective effects on progression of collagen-induced arthritis in a rat model. Scandinavian Journal of Rheumatology 44(3), 182–191. 7. JÄmsen E., Virta L. J., Hakala M., et al. (2013). The decline in joint replacement surgery in RA is associated with a concomitant increase in the intensity of anti-rheumatic therapy: A nationwide register-based study from 1995–2010. Acta Orthopaedica 84(4), 331–337. 8. Jensen S. (2014). Nursing health assessment: A best practice approach (2nd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 9. American Academy of Orthopaedic Surgeons; Armstrong A. D., Hubbard M. C. (Eds.) (2016). Essentials of musculoskeletal care (5th ed.). Rosemont, IL: American Academy of Orthopaedic Surgeons. 10. Woolston W., Connelly L. M. (2017). Felty’s syndrome: A qualitative case study. Medsurg Nursing 26(2), 105–118. 11. Schuler S., Brunner M., Bernauer W. (2016). Rituximab and acute retinal necrosis in a patient with scleromalacia and rheumatoid arthritis. Ocular Immunology and Inflammation 24(1), 96–98. 12. American College of Rheumatology and European League against Rheumatism Association. (2010). 2010 ACR–EULAR classification criteria of rheumatoid arthritis. [Online]. Available: https://www.rheumatology.org/Portals/0/Files/2010%20Rheumatoid%20Arthritis%20Classificati on_EXCERPT%202010.pdf. Accessed March 16, 2018. 13. Aletaha D., Neogi T., Silman A. J., et al. (2010). 2010 Rheumatoid arthritis classification criteria: An American college of rheumatology/European league against rheumatism collaborative initiative. Arthritis and Rheumatism 62(9), 2569–2581. 14. Mastrangelo A., Colasanti T., Barbati C., et al. (2015). The role of posttranslational protein modifications in rheumatological diseases: Focus on rheumatoid arthritis. Journal of Immunology Research 2015, 1–10. 15. Scally S.W., Petersen J., Law S. C., et al. (2013). A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. Journal of Experimental Medicine 210(12), 2569–2582. 16. Arthritis Foundation. (2018). Rheumatoid arthritis treatment. [Online]. Available: https://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php. Accessed March 17, 2018. 17. National Rheumatoid Arthritis Society. (2018). Anti-TNFα treatment in rheumatoid arthritis. [Online]. Available: https://www.nras.org.uk/anti-tnfa-treatment-in-rheumatoid-arthritis. Accessed March 17, 2018. 18. American College of Rheumatology. Lupus. [Online]. Available: https://www.rheumatology.org/IAm-A/Patient-Caregiver/Diseases-Conditions/Lupus. Accessed March 17, 2018 19. Lupus Foundation of America. What is lupus? [Online]. Available: https://resources.lupus.org/entry/what-is-lupus?

utm_source=lupusorg&utm_medium=answersFAQ. Accessed March 17, 2018. 20. The Johns Hopkins Lupus Center. Lupus primer: Types of lupus. [Online]. Available: https://www.hopkinslupus.org/lupus-info/types-lupus/. Accessed March 17, 2018. 21. American College of Rheumatology. (2011). Systemic lupus erythematosus. [Online]. Available: https://www.rheumatology.org/Portals/0/Files/1997%20Update%20of%201982%20Revised.pdf. Accessed March 17, 2018. 22. Singh J. A., Solomon D. H., Dougados M., et al.; Classification and Response Criteria Subcommittee of the American College of Rheumatology Committee on Quality Measures. (2006). Development of classification and response criteria for rheumatic diseases. Arthritis and Rheumatism (Arthritis Care and Research) 55(2), 348–352. 23. Oldroyd A., Lilleker J., Chinoy H. (2017). Idiopathic inflammatory myopathies: A guide to subtypes, diagnostic approach and treatment. Clinical Medicine 17(4), 322–328. 24. Bohan A., Peter J. B. (1975). Polymyositis and dermatomyositis (first of two parts). New England Journal of Medicine 292, 344–347. 25. Bohan A., Peter J. B. (1975). Polymyositis and dermatomyositis (second of two parts). New England Journal of Medicine 292, 403–407. 26. Bond D. (2013). Ankylosing spondylitis: Diagnosis and treatment. Nursing Standard 28(16–18), 52–59. 27. Montilla C., Del Pino-Montes J., Collantes-Estevez E., et al. (2012). Clinical features of lateonset ankylosing spondylitis: Comparison with early-onset disease. Journal of Rheumatology 39(5), 1008–1012. 28. Calvo-Gutiérrez J., Garrido-Castro J. L., González-Navas C., et al. (2016). Inter-rater reliability of clinical mobility measures in ankylosing spondylitis. BMC Musculoskeletal Disorders 17, 1–6. 29. Rudwaleit M., van der Heijde D., Landewé R., et al. (2009). The development of Assessment of Spondylo Arthritis International Society classification criteria for axial spondyloarthritis (part II): Validation and final selection. Annals of the Rheumatic Diseases 68(6), 777–783. 30. Van der Heijde D., Ramiro S., Landew R., et al. 2016 Update of the ASAS-EULAR managements recommendations for axial spondyloarthritis. Annals of the Rheumatic Diseases 76, 978–991. 31. Arthritis Foundation. (2018). What is psoriatic arthritis? [Online]. Available: https://www.arthritis.org/about-arthritis/types/psoriatic-arthritis/what-is-psoriatic-arthritis.php. Accessed March 18, 2018. 32. Glyn-Jones S., Palmer A. J. R., Agricola R., et al. (2015). Osteoarthritis. Lancet 386, 376–387. 33. American College of Rheumatology. (2018). Osteoarthritis. [Online]. Available: https://www.rheumatology.org/Practice-Quality/Clinical-Support/Clinical-PracticeGuidelines/Osteoarthritis. Accessed March 18, 2018. 34. Abhishek A., Roddy E., Doherty M. (2017). Gout: A guide for the general and acute physicians. Clinical Medicine 17(1), 54–59. 35. American College of Rheumatology. (2011). 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care and Research 63(4), 465–482. 36. Khanna D., Fitzgerald J. D., Khanna P. P., et al. (2012). 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systemic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care and Research 64(10), 1431–1446. 37. Arthritis Foundation. (2018). What is juvenile idiopathic arthritis? [Online]. Available: https://www.arthritis.org/about-arthritis/types/juvenile-idiopathic-arthritis-jia/what-is-juvenileidiopathic-arthritis.php. Accessed March 18, 2018 38. Klein-Gitelman M. S. (2015). Pediatric systemic lupus erythematosus. [Online]. Medscape. Available: http://emedicine.medscape.com/article/1008066-overview#showall. Accessed March 18, 2018.

39. Rider, L. G., Katz, J. D., Jones, O. Y. (2013). Developments in the classification and treatment of juvenile idiopathic inflammatory myopathies. Rheumatic Diseases Clinics of North America 39(4), 877–904. 40. Kennedy S. (2012). Polymyalgia rheumatica and giant cell arteritis: An in-depth look at diagnosis and treatment. Journal of the American Academy of Nurse Practitioners 24(5), 277–285. 41. Werner R. (2017) Polymyalgia rheumatica and giant cell arteritis: Common, dangerous, treatable. Massage & Bodywork 32(6), 36–39.

UNIT 15

Disorders of Integumentary Function

CHAPTER 51 Structure and Function of the Skin Structure and Function of the Skin Skin Structures Epidermis Basement Membrane Dermis Subcutaneous Tissue Skin Appendages Sweat Glands Sebaceous Glands Hair Nails Functions of the Skin Learning Objectives After completing this chapter, the learner will be able to meet the following objectives:

1. Characterize the changes in a keratinocyte from its inception in the basal lamina to its arrival on the outer surface of the skin. 2. Describe the following skin appendages and their functions: sebaceous gland, eccrine gland, apocrine gland, nails, and hair. 3. Characterize the skin in terms of sensory and immune functions.

The skin, also called the integumentum, is one of most versatile organs of the body, accounting for roughly 16% of the body’s weight. It forms the major interface between the internal organs and the external environment. The thickness of the skin can range from less than 1 to greater than 5 mm.1 As the body’s first line of defense, the skin is continuously subjected to potentially harmful environmental agents, including solid matter, liquids, gases, sunlight, and microorganisms. Although it may become bruised, lacerated, burned, or infected, it has remarkable properties that allow for a continuous cycle of shedding, healing, and cell regeneration. As the outer covering of the body, the skin may demonstrate outwardly what occurs inside the body. A number of systemic diseases are manifested by skin disorders (e.g., malar rash associated with systemic lupus erythematosus, bronze skin with Addison disease, and jaundice with liver disease). Thus, it is important to recognize that although skin eruptions are frequently caused by primary disorders of the skin, they may also represent manifestations of systemic disease.

Structure and Function of the Skin Skin Structures There are great variations in skin structure on different parts of the body. Therefore, “normal skin” on any one surface of the body is difficult to describe. Variations are found in the properties of the skin, such as the thickness of skin layers, the distribution of sweat glands, and the number and size of hair follicles. For example, the epidermis is thicker on the palms of the hands and soles of the feet than it is elsewhere on the body. The dermis, on the other hand, is thickest on the back, whereas the subcutaneous fat layer is thickest on the abdomen and buttocks. Hair follicles are densely

distributed on the scalp, axillae, and genitalia, but they are sparse on the inner arms and abdomen. The apocrine sweat glands are confined to the axillae and the anogenital area. Nevertheless, certain structural properties are common to the skin on all areas of the body. The skin is composed of the following three layers: 1. Epidermis (outer layer) 2. Dermis (inner layer) 3. Subcutaneous fat layer The basement membrane divides the first two layers. The subcutaneous tissue, a layer of loose connective and adipose connective tissues, binds the dermis to the underlying tissues of the body (Fig. 51-1).

FIGURE 51-1

Three-dimensional view of the skin.

KEY POINTS Organization of Skin Structures The epidermis, which is avascular, is composed of four to five layers of stratified squamous keratinized epithelial cells that are

formed in the deepest layer of the epidermis and migrate to the skin surface to replace cells that are lost during normal skin shedding. The basement membrane is a thin adhesive layer that cements the epidermis to the dermis. The dermis is a connective tissue layer that separates the epidermis from the underlying subcutaneous fat layer. It contains the blood vessels and nerve fibers that supply the epidermis. Epidermis The functions of the skin depend on the properties of its outermost layer, the epidermis. The epidermis covers the body. It is specialized to form the various skin appendages, which include the hair, nails, and glandular structures.2 The keratinocytes of the epidermis produce a fibrous protein called keratin, which is essential for the protective function of the skin. The epidermis also has three other types of cells that arise from its basal layer— melanocytes, Merkel cells, and Langerhans cells. Melanocytes produce a pigment called melanin, which is responsible for skin color, tanning, and protection against ultraviolet radiation. Merkel cells provide sensory information and Langerhans cells link the epidermis to the immune system. The epidermis contains openings for two types of glands—sweat glands, which produce watery secretions, and sebaceous glands, which produce an oily secretion called sebum. Keratinocytes The keratinocyte is the major cell of the epidermis, comprising approximately 85% of the cells of this layer. The epidermis is composed of stratified squamous keratinized epithelium, which, when viewed under the microscope, is seen to consist of five distinct layers, or strata, that represent a progressive differentiation or maturation of the keratinocytes: 1. Stratum germinativum or stratum basale 2. Stratum spinosum 3. Stratum granulosum 4. Stratum lucidum 5. Stratum corneum

The deepest layer, the stratum germinativum or stratum basale, consists of a single layer of basal cells that are attached to the basal lamina. The basal cells, which are columnar, undergo mitosis to produce new keratinocytes that move toward the skin surface to replace cells lost during normal skin shedding. The next layer, the stratum spinosum, is formed as a result of the cell division in the stratum basale. The stratum spinosum is two to four layers thick, and its cells become differentiated as they migrate toward the surface of the epidermis. Because they develop a spiny appearance where their cell borders interconnect, the cells of this layer are commonly referred to as prickle cells.1 The stratum granulosum is only a few cells thick (thickness varies between one and three cells).1 It consists of granular cells that are the most differentiated cells of the living skin. The cells in this layer are unique in that two opposing functions occur simultaneously. Although some cells lose cytoplasm and nuclear structures, others continue to synthesize keratin. Keratinocytes in this layer secrete lamellar bodies into the next layer of the epidermis, the stratum lucidum, providing the skin with its important waterimpermeable properties. The stratum lucidum, which lies just superficial to the stratum granulosum, is a thin, transparent layer found primarily on the thick skin such as over the palms of the hands and soles of the feet.1 It consists of transitional cells that retain some of the functions of living skin cells from the layers below and provide a barrier to water. The most superficial layer, the stratum corneum, consists of dead, keratinized cells, which shed intermittently. This layer contains the most cell layers and the largest cells of the epidermis. This layer blocks microbes from entering the skin and prevents dehydration of tissues. The keratinocytes that originate in the basal layer change morphologically as they are pushed toward the outer layer of the epidermis. In the basal layer, keratinocytes are cuboidal to low columnar. As it is pushed into the stratum spinosum, the keratinocyte becomes multisided. It becomes flatter in the granular layer and is flattened and elongated in the stratum corneum (Fig. 51-2). Keratinocytes also change cytoplasmic structure and composition as they are pushed toward the surface of the epidermis. This transformation from viable cells to the dead cells of the stratum corneum is called keratinization. The migration time of a

keratinocyte from the basal layer to the stratum corneum is 20 to 30 days. The rate of production of new keratinocytes needs to be consistent with the rate of shedding old keratinocytes. When these rates are not in balance, skin anomalies occur.

Epidermal cells. The basal cells undergo mitosis, producing keratinocytes that change their size and shape as they move upward, replacing cells that are lost during normal cell shedding. FIGURE 51-2

Keratinocytes are connected by minute points of attachment called desmosomes. They are terminal end points on the cell walls of keratinocytes, made up of fibrous material that is bound into bundles, called tonofilaments. Desmosomes keep the cells from detaching and provide some structure to the skin while it is in perpetual motion. The basal layer provides the underlying structure and stability for the epidermis. Besides desmosomes, there are three other types of cellular junctions that bind keratinocytes—adherens junctions, gap junctions, and tight junctions. Adherens junctions are specialized structures that provide strong

mechanical connections between cells. They are responsible for adhesion between cells, communicate about the presence of neighboring cells, and anchor the skin cells. Gap junctions are cylindrical channels that permit ions and small molecules to pass between cells. They are composed of proteins called connexins. Tight junctions are made of transmembrane proteins that function to prevent substances passing between cells. Keratinocytes are active secretory cells that play an important role in the immunobiology of the skin by communicating and regulating cells of the immune response and secreting cytokines and inflammatory mediators. Melanocytes Melanocytes are pigment-synthesizing cells that are scattered in the basal layer and are responsible for skin color.1,3 They function to produce pigment granules called melanin, the substance that gives the skin its color. There are two major forms of melanin—eumelanin and pheomelanin. The two forms of eumelanin are brown and black; pheomelanin is yellow to red. The type of melanin produced depends on the stimulation of specific hormones or proteins and the binding of these substances to receptors on the melanocyte. Eumelanin is the most abundant in humans. Exposure to the sun’s ultraviolet rays increases the production of eumelanin, causing tanning to occur. The primary function of such melanin is to protect the skin by absorbing and scattering harmful ultraviolet rays, which are associated with skin cancers. Localized concentrations of eumelanin are also responsible for the formation of freckles and moles. Pheomelanin, the yellow to red pigment, is found in all humans. It is particularly concentrated in the lips, nipples, glans penis, and vagina. Besides the skin, it is found in the hair, particularly red hair. The ability to synthesize melanin depends on the ability of the melanocytes to produce an enzyme called tyrosinase, which converts the amino acid tyrosine to a precursor of melanin. A genetic lack of this enzyme results in a clinical condition called albinism, or lack of pigmentation in the skin, hair, and the iris of the eye. Tyrosinase is synthesized in the rough endoplasmic reticulum of the melanocytes and then routed to membranous vesicles in the Golgi complex called melanosomes. Melanin is subsequently synthesized in the melanosomes. Melanocytes have long, cytoplasm-filled dendritic processes that contain accumulated melanosomes and extend between the keratinocytes. Although the melanocytes remain in the basal layer, the

melanosomes are transferred to the keratinocytes through their dendritic processes. The dendrite tip containing the melanosome is engulfed by a nearby keratinocyte, and the melanin is transferred (Fig. 51-3).

The melanocytes, which are located in the basal layer of the skin, produce melanin pigment granules that give the skin its color. The melanocytes have threadlike, cytoplasm-filled extensions that are used in passing the pigment granules to the keratinocytes. FIGURE 51-3

The amount of melanin in the keratinocytes determines a person’s skin color.3 Dark-skinned and light-skinned people have approximately the same number of melanocytes, but the production and packaging of pigment are different. In dark-skinned people, larger melanin-containing melanosomes are produced and transferred individually to the keratinocyte. In lightskinned people, smaller melanosomes are produced and then packaged together in a membrane before being transferred to the keratinocyte. All people, regardless of skin color, have relatively few or no melanocytes in the epidermis of the palms of the hands or the soles of the feet. In light-

skinned people, the number of melanocytes decreases with age, and the skin becomes lighter and is more susceptible to skin cancer when exposed to ultraviolet light. However, people with vitiligo, a skin problem where the melanocytes are destroyed, have a significantly reduced risk of developing nonmelanoma skin cancers, whereas people with albinism have a significantly increased risk.4 Merkel Cells Merkel cells are clear cells found in the stratum basale of the epidermis. They are connected to other skin cells by desmosomes. Each Merkel cell is connected to an afferent nerve terminal, forming a structure known as a Merkel disk. They are the sparsest cells of the epidermis and are found over the entire body, but are most plentiful in the basal layer of the fingers, toes, lips, and oral cavity, and in the outermost sheath of hair follicles (i.e., the touch areas). All functions of Merkel cells are unclear, but they serve as sensory touch receptors and are believed to be neuroendocrine cells (i.e., they release hormones into the blood in response to neural stimuli).1 Langerhans Cells Langerhans cells are scattered in the suprabasal layers of the epidermis among the keratinocytes. They are less numerous (3% to 5% of epidermal cells) than are the keratinocytes. They are derived from precursor cells originating in the bone marrow and continuously repopulate the epidermis. Like melanocytes, they have a dendritic shape and clear cytoplasm. Birbeck granules that often resemble tennis racquets are their most distinguishing characteristic microscopically.1 Langerhans cells are the immunologic cells responsible for recognizing foreign antigens harmful to the body (Fig. 51-4). As such, Langerhans cells play an important role in defending the body against foreign antigens. Langerhans cells bind antigen to their surface and process it, and, bearing the processed antigen, migrate from the epidermis into lymphatic vessels and then into regional lymph nodes, where they are known as dendritic cells. During their migration in the lymph system, the Langerhans cells become potent antigen-presenting cells.1 Langerhans cells are innervated by sympathetic nerve fibers, which may explain why the skin’s immune system is altered under stress. An example of this is the exacerbations of acne seen in people under stress. Langerhans cells and the keratinocytes produce a

number of cytokines that stimulate maturation of skin-localizing T lymphocytes.

FIGURE 51-4

Langerhans cells.

Basement Membrane The terms basement membrane and basal lamina are often used interchangeably. Technically, however, the basal lamina is a component of the basement membrane. The basement membrane is a layer of intercellular and extracellular matrices that serves as an interface between the dermis and the epidermis (Fig. 51-5). It separates the epithelium from the underlying connective tissue, it anchors the epithelium to the loose connective tissue underneath, and it serves as a selective filter for molecules moving between the two layers. It is also a major site of immunoglobulin and complement deposition in skin disease. The basement membrane is involved in skin disorders that cause bullae or blister formation.1

The dermal–epidermal interface and basement membrane zone. The epithelial–mesenchymal interface comprises the basement membrane zone. This structure is mostly synthesized by the basal cells of the epidermis. This is the site of change in most diseases, from tonofilaments and attachment plaques of basal cells to microfibrils and fibrils. (From Strayer D. E., Rubin R. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 28-7, p. 1224). Philadelphia, PA: Wolters Kluwer.) FIGURE 51-5

The basement membrane consists of three distinct zones or layers— lamina lucida, lamina densa, and lamina fibroreticularis—all of which contribute to the adhesion of the two skin layers. The lamina lucida is an electron-lucent layer where adherence proteins are located. It consists of fine anchoring filaments and a cell adhesion glycoprotein, called laminin, which plays a role in the organization of the macromolecules in the basement membrane zone and promotes attachment of cells to the extracellular matrix. The lamina densa contains an adhesive called type IV collagen as well as laminin. It is important in dermal–epidermal attachment. Combined, the lamina lucida and the lamina densa comprise what is known as the basal lamina. The lamina fibroreticularis then completes the basement membrane. This layer contains many anchoring microfibrils. These are short, curved structures that insert into the lamina densa and the superficial dermis, where they are known as anchoring fibrils. Type VII collagen, another adherent substance, has been found in the anchoring fibrils and plaques. Another component of the lamina fibroreticularis are elastic fiber bundles that extend to the dermis.2 Hemidesmosomes are like half desmosomes in both structure and function. They lie immediately at the basal plasma membrane and form the site or source of tonofilaments, which attach the dermis and epidermis (see Fig. 51-5).2 Because they form a continuous link between the intracellular keratin filament network and the extracellular basement membrane, they are also involved in relaying signals between the skin layers. Dermis The dermis is the connective tissue layer that separates the epidermis from the subcutaneous fat layer (see Fig. 51-1). It supports the epidermis and

serves as its primary source of nutrition. The two layers of the dermis, the papillary dermis and the reticular dermis, are composed of cells, fibers, ground substances, nerves, and blood vessels. The main component of the dermis is collagen, a group of fibrous proteins. The collagen is enmeshed in a ground substance called hyaluronic acid.2 Collagen fibers are loosely arranged in the papillary dermis, but are tightly bundled in the reticular dermis. The pilar (hair) and glandular structures are embedded in this layer and continue through the epidermis. In general, a dark dermis is more compact than is a white dermis, and consequently darker skinned people show less wrinkling. Papillary Dermis The papillary dermis (pars papillaris) is a thin, superficial layer that lies adjacent to the epidermis. It consists of collagen fibers and ground substance. This layer is densely covered with conical projections called dermal papillae (see Fig. 51-1). The basal cells of the epidermis project into the papillary dermis, forming rete ridges. Microscopically, the junction between the epidermis and the dermis appears like undulating ridges and valleys. It is believed that the dense structure of the dermal papillae serves to minimize the separation of the dermis and the epidermis. Dermal papillae contain capillaries, end arterioles, and venules that nourish the epidermal layers of the skin. This layer of the dermis is richly vascularized. Lymph vessels and nerve tissue also are found in this layer. Reticular Dermis The reticular dermis (pars reticularis) is the thicker area of the dermis and forms the bulk of the dermal layer. The reticular dermis is characterized by a complex meshwork of three-dimensional collagen bundles interconnected with large elastic fibers and ground substance, a viscid gel that is rich in mucopolysaccharides. The collagen fibers are oriented parallel to the body’s surface in any given area. Collagen bundles may be organized lengthwise, as on the abdomen, or in round clusters, as on the heel. The direction of surgical incisions is often determined by this organizational pattern. Immune Cells.

Dermal dendrocytes are spindle-shaped cells that have both phagocytic and dendritic properties. They are believed to possess antigen-presenting functions and play an important part in the immunobiology of the dermis. In addition, it is possible that dermal dendrocytes may be able either to initiate or to respond to immunologic events in the epidermis. Dermal dendrocytes are also thought to be involved in processes such as wound healing, blood clotting, and inflammation. Immune cells found in the dermis include macrophages, T cells, mast cells, and fibroblasts. Dermal macrophages may present antigens to T cells in the dermis. Most of these T cells are previously activated or memory T cells. T-cell responses to macrophage- or endothelium-associated antigens in the dermis are probably more important in generating an immune response to antigen challenge in previously exposed people than in initiating a response to a new antigen. The major type of T-cell–mediated immune response in the skin is delayed-type hypersensitivity. Mast cells, which have a prominent role in immunoglobulin E–mediated immediate hypersensitivity, also are present in the dermis. These cells are strategically located at body interfaces such as the skin and mucous membranes and are thought to interact with antigens that come in contact with the skin. Blood Vessels. The arterial vessels that nourish the skin form two plexuses (i.e., collections of blood vessels), one located between the dermis and the subcutaneous tissue and the other between the papillary and reticular layers of the dermis. The pink color of light skin results primarily from blood in the vessels of this latter plexus. Capillary flow that arises from vessels in this plexus also extends up and nourishes the overlaying epidermis by diffusion. Blood leaves the skin through small veins that accompany the subcutaneous arteries. The lymphatic system of the skin, which aids in combating certain skin infections, also is limited to the dermis. The skin is richly supplied with arteriovenous anastomoses in which blood flows directly between an artery and a vein, bypassing the capillary circulation. These anastomoses are important for temperature regulation. They can open up, letting blood flow through the skin vessels when there is a need to dissipate body heat, and close off, conserving body heat if the environmental temperature is cold.

Innervation. The innervation of the skin is complex. The skin, with its accessory structures, serves as an organ for receiving sensory information from the environment. The dermis is well supplied with sensory neurons as well as nerves that supply the blood vessels, sweat glands, and arrector pili muscles. The arrector pili muscles connect the dermis to the hair follicles.1 The receptors for touch, pressure, heat, cold, and pain are widely distributed in the dermis. The papillary layer of the dermis is supplied with free nerve endings that serve as nociceptors (i.e., pain receptors) and thermoreceptors. The dermis also contains encapsulated pressure-sensitive receptors that detect pressure and touch. The largest of these are the pacinian corpuscles, which are widely distributed in the dermis and subcutaneous tissue. The afferent nerve endings of the pacinian corpuscle are surrounded by concentric layers of modified Schwann cells. Pacinian corpuscles are responsible for detecting gross pressure changes and vibrations. Pressure causes the pacinian corpuscle to change its shape, thereby triggering nerve impulses. Pacinian corpuscles are adaptive and they respond more to changes than to steady pressure or vibration. Flat, encapsulated nerve endings found on the palmar surfaces of the fingers and hands and planter surfaces of the feet are called Meissner corpuscles and serve as touch receptors.1 They are concentrated on the fingertips, palms, soles, lips, tongue, face, and genitalia. They are thick, laminated, ovoid capsules each containing up to six nerve endings. When the corpuscle is deformed by pressure, the nerve endings are stimulated, signaling the somatosensory portion of the cerebral cortex and informing the person about the location and strength of the stimulus. They are rapidly adapting and do not react to constant, steady stimulation. Ruffini corpuscles are small, oval mechanoreceptors located in the deep dermal tissue. Several expanded nerve endings branch from a single, myelinated afferent fiber.1 They are slowly adapting receptors, responding to heavy pressure and joint movement. They are also believed to detect cold. Most of the skin’s blood vessels are under the control of the sympathetic nervous system. The sweat glands are innervated by cholinergic fibers but controlled by the sympathetic nervous system. Likewise, the sympathetic nervous system controls the arrector pili (pilomotor) muscles that cause

elevation of hairs on the skin. Contraction of these muscles tends to cause the skin to dimple, producing “goose bumps or goose flesh.”1 Subcutaneous Tissue The subcutaneous tissue layer is the third layer of the skin and consists primarily of fat cells and connective tissues that lend support to the vascular and neural structures supplying the superficial layers of the skin. There is controversy about whether the subcutaneous tissue should be considered an actual layer of the skin. Because the eccrine glands and deep hair follicles extend to this layer and several skin diseases involve the subcutaneous tissue, the subcutaneous tissue may be considered part of the skin. The subcutaneous layer has varying levels of thickness depending on its location. The fascia may be thinner over a bony prominence and thicker when covering other organs. Therefore, if there is a break in the skin, which is more likely to occur over a bony prominence, and infection occurs in the subcutaneous tissue, the macrophages will proliferate to fight the infectious agents.1,2 Hence, the subcutaneous layer of the skin does contribute to the skin’s immunologic function. Skin Appendages The skin houses a variety of appendages, including sweat glands, sebaceous glands, hair, and nails. The distribution and functions of the appendages vary. Sweat Glands There are two types of sweat glands—eccrine and apocrine. Eccrine sweat glands are simple tubular structures that originate in the dermis and open directly to the skin surface. They are numerous (several million), vary in density, and are located over the entire body surface except the lips and part of the external genitalia.1 Their purpose is to transport sweat to the outer skin surface to regulate body temperature. Apocrine sweat glands are less numerous than are eccrine sweat glands. They are larger and located deep in the dermal layer. They open through a hair follicle, even though a hair may not be present, and are found primarily in the axillae and groin. The major difference between these glands and the eccrine glands is that apocrine

glands secrete an oily substance. Apocrine secretions are sterile until mixed with the bacteria on the skin surface. They then produce what is commonly known as “body odor.” Sebaceous Glands The sebaceous glands are located over the entire skin surface except for the palms, soles, and sides of the feet. They are part of the pilosebaceous unit. They secrete a mixture of lipids, including triglycerides, cholesterol, and wax. This mixture is called sebum, and it lubricates the hair and skin.1 Sebum is not the same as the surface lipid film. Sebum prevents undue evaporation of moisture from the stratum corneum during cold weather and helps conserve body heat. Sebum production is under the control of genetic and hormonal influences. Sebaceous glands are relatively small and inactive until people approach adolescence. The glands then enlarge, stimulated by the rise in sex hormones. Gland size directly influences the amount of sebum produced, and the level of androgens influences gland size. The sebaceous glands are the structures that become inflamed in acne. Hair The hair is a structure that originates from hair follicles in the dermis. Most hair follicles are associated with sebaceous glands, and these structures combine to form the pilosebaceous unit. The entire hair structure consists of the hair follicle, sebaceous gland, hair muscle (arrector pili), and, in some instances, the apocrine gland (Fig. 51-6). The hair is a keratinized structure that is pushed upward from the hair follicle. Growth of the hair is centered in the bulb (i.e., base) of the hair follicle, and the hair undergoes changes as it is pushed outward. The hair goes through three cyclic phases identified as anagen (the growth phase), catagen (the atrophy phase), and telogen (the resting phase, or no growth). Human beings shed hair cyclically and independently, causing the hair to be shed asynchronously.

FIGURE 51-6

Parts of a hair follicle.

A vascular network at the site of the follicular bulb nourishes and maintains the hair follicle. Melanocytes in the bulb transfer melanosomes to the cells of the bulb matrix in much the same way as in the skin and are therefore responsible for the color of the hair. Similar to the skin, large melanosomes are found in the hair of darker skinned people. Aggregated and encapsulated melanosomes are found in people with light skin. Red hair has spherical melanosomes, whereas gray hair is the result of a decreased number of melanosome-producing melanocytes. The arrector pili muscle, located deep to the sebaceous gland, provides a thermoregulatory function by contracting the skin to cause goose bumps, thereby reducing the skin surface area that is available for the dissipation of body heat. Nails The nails are hardened keratinized plates, called fingernails and toenails, which protect the fingers and toes and enhance dexterity. The nails grow out

from a curved transverse groove called the nail groove. The floor of this groove, called the nail matrix, is the germinal region of the nail plate (Fig. 51-7). The underlying epidermis, attached to the nail plate, is called the nail bed. Like hair, nails are the end product of dead matrix cells that are pushed outward from the nail matrix. Unlike hair, nails grow continuously rather than cyclically, unless permanently damaged or diseased. The epithelium of the fold of the skin that surrounds the nail consists of the usual layers of the skin. The stratum corneum forms the eponychium or cuticle. The nearly transparent nail plate provides a useful window for viewing the amount of oxygen in the blood, providing a view of the color of the blood in the dermal vessels. Changes or abnormalities of the nail can also serve to help diagnose skin or systemic diseases.

FIGURE 51-7

Parts of a fingernail.

Functions of the Skin The skin and its derivatives constitute a complex organ with many cell types. The diversity of cell types and their ability to work together provide a number of ways of protecting a person from the elements in the external environment. Microorganisms find it almost impossible to penetrate the skin from the outside, and water loss is limited from the inside. The skin surface is covered with a thin lipid film containing bactericidal fatty acids

that protect against the entry of harmful microorganisms, and it harbors a constant flora of relatively harmless strains of microorganisms that protect against other, more virulent strains. The skin also plays an important role in immune regulation through skin-associated lymphoid tissues, including Langerhans cells, mast cells, and lymphocytes. Langerhans cells, the antigen-presenting cells of the epidermal skin, not only protect against harmful pathogens but also play an important role in the development of allergic skin conditions. As the antigen is phagocytized, it is evident on the Langerhans cell surface, and the cell moves to a regional lymph node where it interacts with T lymphoctyes.1 KEY POINTS Functions of the Skin The skin prevents body fluids from leaving the body, protects the body from potentially damaging environmental agents, and serves as an area for heat exchange. In addition, cells of the skin immune system provide protection against invading microorganisms. Receptors in the skin relay touch, pressure, temperature, and pain sensation to the central nervous system for localization and discrimination. The skin serves several other vital functions, including somatosensory function, temperature regulation, and vitamin D synthesis. The skin is richly innervated with pain, temperature, and touch receptors. Skin receptors relay the numerous qualities of touch, such as pressure, sharpness, dullness, and pleasure to the central nervous system for localization and fine discrimination. Most of the heat produced in the body is generated by deep organs, such as the liver, heart, and skeletal muscles, and then transferred to the skin, where it is lost to the surrounding environment. The rate at which heat is dissipated from the body is determined by constriction or dilation of the arterioles that supply blood to the skin and through evaporation of moisture and sweat from the skin surface. The skin also functions as an endocrine organ, in which 7-dehydrocholesterol, a substance normally found in epidermal cells, is converted to cholecalciferol (an inactive form of

vitamin D), by ultraviolet rays from the sun. The skin is increasingly being understood as a complex and dynamic system involving neuroendocrine, immunologic, and cutaneous interactions. SUMMARY CONCEPTS The skin is primarily an organ of protection. It is the largest organ of the body and forms the major barrier between the internal organs and the external environment. The pigment melanin absorbs harmful ultraviolet light. The skin is richly innervated with pain, temperature, and touch receptors. It synthesizes vitamin D and plays an essential role in fluid and electrolyte balance. It contributes to glucose metabolism through its glycogen stores. Sweat is a means of excreting salt, carbon dioxide, ammonia, and urea. The skin absorbs lipid-soluble materials, toxic substances (such as mercury and lead, and substances in poison ivy and poison oak), fat-soluble vitamins, and certain drugs administered through transdermal patches. The skin is composed of two layers, the epidermis and the dermis, separated by a basement membrane. A layer of subcutaneous tissue binds the dermis to the underlying organs and tissues of the body. The epidermis, the outermost layer of the skin, contains four to five layers, or strata. The major cells of the epidermis are the keratinocytes, melanocytes, Langerhans cells, and Merkel cells. The stratum germinativum, or basal layer, is the source of the cells in all five layers of the epidermis. The keratinocytes, which are the major cells of the epidermis, are transformed from viable keratinocytes to dead keratin as they move from the innermost layer of the epidermis (i.e., stratum germinativum) to the outermost layer (i.e., stratum corneum). The melanocytes are pigment-synthesizing cells that give the skin its color. The dermis provides the epidermis with support and nutrition and is the source of blood vessels, nerves, and skin appendages (i.e., hair follicles, sebaceous glands, nails, and sweat glands). Sensory receptors for touch, pressure, heat, cold, and pain are widely distributed in the dermis. The skin serves as a first line of defense against microorganisms and other harmful agents. The epidermis contains Langerhans cells, which process foreign antigens for presentation to T cells, and the dermis contains macrophages, T

cells, mast cells, and fibroblasts, all contributing to the body’s immune defenses.

Review Exercises 1. Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies to constituents of the dermal– epidermal junction. A. Explain how antibodies, which attack glycoproteins in the lamina lucida and their attachment to the hemidesmosomes, can cause blisters to form (hint: see Fig. 51-5). 2. “Allergy tests” involve the application of an antigen to the skin, either through a small scratch or by intradermal injection. A. Explain how the body’s immune system is able to detect and react to these antigens REFERENCES 1. Pawlina W. (2016). Histology: A text and atlas (7th ed.). Philadelphia, PA: Wolters Kluwer Health. 2. Rubin R., Strayer D. E. (Eds.). (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed.). Philadelphia, PA: Wolters Kluwer Health. 3. Habif T. P. (2016). Clinical dermatology: A color guide to diagnosis and therapy (6th ed.). St. Louis, MO: Elsevier. 4. Paradisi A., Tabolli S., Didona B., et al. (2014). Marked by reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo. Journal of American Academy of Dermatology 71(6), 1110–1116.

CHAPTER 52 Disorders of Skin Integrity and Function Manifestations of Skin Disorders Lesions and Rashes Pruritus Dry Skin Skin Variations Primary Disorders of the Skin Pigmentary Skin Disorders Vitiligo Albinism Melasma Infectious Processes Superficial Fungal Infections Bacterial Infections Viral Infections Acne and Rosacea Acne Vulgaris Acne Conglobata Rosacea Allergic and Hypersensitivity Dermatoses

Contact and Allergic Dermatitis Atopic Dermatitis and Nummular Eczema Urticaria Drug-Induced Skin Eruptions Papulosquamous Dermatoses Psoriasis Pityriasis Rosea Lichen Planus Lichen Simplex Chronicus Arthropod Infestations Scabies Pediculosis Ultraviolet Radiation and Thermal and Pressure Injuries Skin Damage Caused by Ultraviolet Radiation Drug-Induced Photosensitivity Sunburn Preventing Skin Damage Caused by Ultraviolet Radiation Thermal Injury Classification of Burns Systemic Complications Emergency and Long-Term Treatment Pressure Ulcers Mechanisms of Development Prevention Staging and Treatment Nevi and Skin Cancers Nevi Skin Cancer Malignant Melanoma Basal Cell Carcinoma Squamous Cell Carcinoma Age-Related Skin Manifestations Skin Manifestations of Infancy and Childhood Skin Disorders of Infancy Skin Manifestations of Common Infectious Diseases

Skin Manifestations and Disorders in Older Adults Normal Age-Related Changes Skin Lesions Common among Older Adults Learning Objectives After completing this chapter, the learner will be able to meet the following objectives: 1. Describe the following skin rashes and lesions—macule, patch, papule, plaque, nodule, tumor, wheal, vesicle, bulla, and pustule. 2. Cite two physiologic explanations for pruritus. 3. Describe the causes and treatment of dry skin. 4. Describe the pathogenesis of acne vulgaris. 5. Differentiate allergic and contact dermatitis and atopic and nummular eczema. 6. Define the term papulosquamous and use the term to describe the lesions associated with psoriasis, pityriasis rosea, and lichen planus. 7. Compare the tissue involvement in first- and second-degree fullthickness and in third-degree burns. 8. Describe the systemic complications of burns. 9. Describe two causes of pressure ulcers. 10. Describe the origin of nevi and their relationship to skin cancers. 11. Compare the appearance and outcome of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. 12. Describe the distinguishing features of rashes associated with the following infectious childhood diseases: roseola infantum, rubeola, rubella, and varicella. 13. Characterize the physiologic changes of aging skin.

The skin is a unique organ in that numerous signs of disease or injury are immediately observable on the skin. The skin serves as the interface between the body’s internal organs and the external environment. Therefore, skin disorders represent the culmination of environmental forces and the internal functioning of the body. Sunlight, insects, other arthropods, infectious organisms, chemicals, and physical agents all play a role in the

pathogenesis of skin diseases. Although most disorders are intrinsic to skin, many are external manifestations of systemic disease. It is through the skin that warmth and other responses are given and received. The skin conveys a sense of health, beauty, integrity, and even emotion.

Manifestations of Skin Disorders No two skin disorders look exactly alike, nor do the same agents necessarily cause them. Excessive itching, infection, or the effects of self-treatment may further influence the appearance of many skin disorders. Skin color also may influence the appearance. Nevertheless, most skin disorders have some common characteristics that can be used to describe them. This section of the chapter covers lesions and rashes, dry skin, pruritus, skin disorders because of mechanical forces, and variations in dark skin. Lesions and Rashes Rashes are temporary eruptions of the skin, such as those associated with childhood diseases, heat, diaper irritation, or drug-induced reactions. The term lesion refers to a traumatic or pathologic loss of normal tissue continuity, structure, or function. The components of a rash often are referred to as lesions. Rashes and lesions may range in size from a fraction of a millimeter (e.g., the pinpoint spots of petechiae) to many centimeters (e.g., pressure ulcer). They may be blanched (white), erythematous (reddened), hemorrhagic or purpuric (containing blood), or pigmented (colored). Repeated rubbing and scratching can lead to lichenification (thickened, leathery, and roughened skin characterized by prominent markings) or excoriation (a raw, denuded area caused by breakage of the epidermis). Skin lesions may occur as primary lesions arising in previously normal skin, or they may develop as secondary lesions resulting from other disease conditions. Table 52-1 illustrates various types of skin lesions. TABLE 52-1 Primary and Secondary Skin Lesions

Lesion Description Primary Lesions

Examples

Lesion

Description Flat, nonpalpable skin color change Macule, patch (color may be brown, white, tan, purple, red) Macule: 1 cm; may have irregular border

Examples Freckles, flat moles, petechiae, rubella, vitiligo, port-wine stains, ecchymosis

Papule, plaque Elevated, palpable, solid mass with a Papules: Elevated circumscribed border nevi, warts, lichen Plaque may be coalesced papules planus with flat top. Plaques: Psoriasis, Papule: 0.5 cm Nodule, tumor

Vesicle, bulla

Nodules: Lipoma, squamous cell carcinoma, poorly absorbed injection, Nodule: 0.5–2 cm; circumscribed dermatofibroma Tumor: >1–2 cm; tumors do not Tumors: Larger always have sharp borders lipoma, carcinoma

Elevated, palpable, solid mass that extends deeper into the dermis than does a papule

Circumscribed, elevated, palpable mass containing serous fluid Vesicle: 0.5 cm

Vesicles: Herpes simplex/zoster, varicella, poison ivy, second-degree burn (blister) Bulla: Pemphigus, contact dermatitis, large burn blisters, poison ivy, bullous impetigo

Lesion Wheal

Description

Examples

Elevated mass with transient borders; often irregular; size and color vary Caused by movement of serous fluid Urticaria (hives), into the dermis; does not contain free insect bites fluid in a cavity (e.g., as a vesicle does) Pustule

Pus-filled vesicle or bulla

Acne, impetigo, furuncles, carbuncles

Cyst Encapsulated fluid-filled or semisolid Sebaceous cyst, mass in the subcutaneous tissue or epidermoid cysts dermis

Secondary Lesions Erosion Loss of superficial epidermis that Ruptured vesicles, does not extend to dermis; depressed, scratch marks moist area

Lesion Ulcer

Description

Examples

Skin loss extending past epidermis; necrotic tissue loss; bleeding and scarring possible

Stasis ulcer of venous insufficiency, pressure ulcer

Linear crack in the skin that may extend to dermis

Chapped lips or hands, tinea pedis

Flakes secondary to desquamated, dead epithelium that may adhere to skin surface; color varies (silvery, white); texture varies (thick, fine)

Dandruff, psoriasis, dry skin, pityriasis rosea

Fissure

Scales

Crust Residue left after Dried residue of serum, blood, or pus vesicle rupture: on skin surface impetigo, herpes, Large, adherent crust is a scab eczema

Lesion Description Scar (cicatrix) Skin mark left after healing of a wound or lesion; represents replacement by connective tissue of the injured tissue

Examples

Healed wound or surgical incision

Young scars: Red or purple Mature scars: White or glistening Keloid Hypertrophied scar tissue secondary to excessive collagen formation Keloid of ear during healing; elevated, irregular, piercing or surgical red incision Greater incidence among African Americans Atrophy Thin, dry, transparent appearance of the epidermis; loss of surface Aged skin, arterial markings; secondary to loss of insufficiency collagen and elastin; underlying vessels may be visible Lichenification Thickening and roughening of the skin or accentuated skin markings that may be secondary to repeated rubbing, irritation, scratching

Contact dermatitis

Reprinted from Hinkle J. L., Cheever K. H. (2018). Brunner and Suddarth’s textbook of medical-surgical nursing (14th ed., pp. 1798–1799).

Philadelphia, PA: Wolters Kluwer, with permission; Adapted from Bickley L. S. (2013). Bates’ guide to physical examination and history taking (11th ed.). Philadelphia, PA: Lippincott Williams & Wilkins; Weber J. W., Kelley J. (2014). Health assessment in nursing (5th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. A blister is a vesicle or fluid-filled papule. Blisters of mechanical origin are caused by friction from repeated rubbing on a single area of the skin. Friction blisters most commonly occur on the palmar and plantar surfaces of the hands and feet where the skin is constantly exposed to mechanical trauma, such as from shoes and household tools and appliances. Blisters also develop in bullous skin disorders and from burns. Histologically, there is degeneration of the epidermal cells and a disruption of the intercellular junctions, causing the layers of the skin to separate. As a result, fluid accumulates and a noticeable bleb forms on the skin surface. Adhesive bandages and gauze can be used to protect friction blisters and prevent further irritation and rubbing. A callus is a hyperkeratotic plaque of the skin because of chronic pressure or friction. It represents hyperplasia of the dead, keratinized cells that make up the cornified or horny layer of the skin. Increased cohesion between cells results in hyperkeratosis and decreased skin shedding. Corns (helomas) are small, well-circumscribed, conical, keratinous thickenings of the skin. They usually appear on the toes from rubbing or ill-fitting shoes. The corn may be either hard (heloma durum) with a central hard, horny core or soft (heloma molle), as commonly seen between the toes. They may appear on the hands as an occupational hazard. The hard tissue at the center of the corn looks like a funnel with a broad top and a pointed bottom, hence the name “corn.” Corns on the feet often are painful, whereas corns on the hands may be asymptomatic. Corns may be abraded or surgically removed, but they recur if the causative agent is not removed. Pruritus Pruritus, or the sensation of itch, is a common symptom of skin disorders ranging from mild to severe. In some people, the condition may be so severe that it interrupts sleep and the general quality of life. Although itching commonly occurs with skin disorders, it can also provide a valuable

clue to internal disorders, such as chronic renal disease, diabetes, or biliary disease. It is generally agreed that itch is a sensation that originates in free nerve endings in the skin, is carried by small myelinated type C nerve fibers to the dorsal horn of the spinal cord, and is then transmitted to the somatosensory cortex through the spinothalamic tract. There are itch-specific neuronal pathways in the spinothalamic tract and central nervous system that process peripheral itch stimuli.1,2 Advances have also been made in understanding peripheral mediators (i.e., substances that cause itch) other than histamine. Tryptase, an enzyme released by mast cells, may be an important itch mediator because it activates a specific receptor in the sensory nerves. Opioids operate centrally and peripherally in producing itch, whereas neuropeptides, such as substance P, induce itch by their effect on mast cells. Substances such as bradykinin and bile salts act locally to stimulate the itch sensation. Prostaglandins are modulators of the itch response, lowering the threshold for other mediators. Scratching, the well-known response to itch, is a spinal reflex response that to varying degrees can be controlled by the person. Many types of itch are not easily localized or relieved by scratching. Excoriations and thickened papular areas develop at the site of repeated scratching or rubbing, and in some skin conditions, such as dry skin, scratching further activates itch sensations. Chronic forms of pruritus can severely affect the quality of a person’s life. Most treatment measures for pruritus are nonspecific. Measures such as using the entire hand to rub over large areas and keeping the fingernails trimmed often can relieve itch and prevent skin damage. Self-limited or seasonal cases of pruritus may respond to treatment measures such as moisturizing lotions, bath oils, and the use of humidifiers. Because vasodilation tends to increase itching, cold applications may provide relief. Topical corticosteroids may be helpful in some cases, such as itch related to allergy-mediated urticaria. Given the recent advances in the science of pruritus, health care professionals have new, effective, and disease-specific antipruritic drugs available. The International Forum for the Study of Itch has developed a classification system dividing chronic pruritus into six major groups depending on its underlying cause: dermatologic, systemic, neurologic,

psychiatric, multifactorial, or unknown origin.3 Similar to pain scales, visual analog scales are being developed and used in the diagnosis and treatment of pruritus.4 Dry Skin Dry skin, also called xerosis, may be a natural occurrence, as in the drying of the skin associated with aging, or it may be symptomatic of an underlying systemic disease or skin disorder such as contact dermatitis or diabetes mellitus. People with diabetes mellitus often experience xerosis especially on the extremities.5 Most cases of dry skin are caused by dehydration of the stratum corneum. The effects of aging on skin dryness include a change in the composition of sebaceous gland secretions and a decrease in the secretion of moisture from the sweat glands. Aging is also accompanied by a decrease in skin capillaries as well as a flattening of the dermal rete ridges, resulting in less surface area for exchange of fluids between the dermis, epidermis, and skin surface.6 People with dry skin often experience severe pruritus and discomfort, most commonly of the extremities. Other commonly involved areas include the back, abdomen, and waist. Dry skin appears rough and scaly and there may be increased wrinkles or lines. Skin drying also predisposes the skin to scratching, resulting in cracking, fissuring, and a number of other skin maladies. Moisturizing agents are the cornerstone of treatment for dry skin. These agents exert their effects by repairing the skin barrier, increasing the water content of the skin, reducing transepidermal water loss, and restoring the lipid barrier’s ability to attract, hold, and redistribute water. Lotion or cream additives can include corticosteroids or mild anesthetics, such as camphor, menthol, lidocaine, or benzocaine. These agents work by suppressing itching while moisturizing the skin. Using room humidifiers and keeping room temperatures as low as possible to prevent water loss from the skin also may be helpful. Skin Variations A condition common in people with dark skin is increased or reduced color. Areas of the skin may darken after injury, such as a cut or scrape, or after disease conditions such as acne. These darkened areas may take many

months or years to fade. Areas of the skin may lighten because of decreased pigment or melanin, resulting in vitiligo. Normal variations in skin structure and skin tones often make evaluation of dark skin difficult. The darker pigmentation can make skin pallor, cyanosis, and erythema more difficult to observe. Therefore, verbal histories must be relied on to assess skin changes. The verbal history should include the person’s description of her or his normal skin tones. Changes in skin color, in particular hypopigmentation and hyperpigmentation, often accompany disorders of dark skin and are very important signs to observe when diagnosing skin conditions. SUMMARY CONCEPTS Skin lesions and rashes are the most common manifestations of skin disorders. Rashes are temporary skin eruptions. Lesions result from traumatic or pathologic loss of the normal continuity, structure, or function of the skin. Lesions may be vascular in origin. They may occur as primary lesions in previously normal skin or they may develop as secondary lesions resulting from primary lesions. Blisters, calluses, and corns result from rubbing, pressure, and frictional forces applied to the skin. Pruritus and dry skin are symptoms common to many skin disorders. Scratching because of pruritus can lead to excoriation, infection, and other complications. Normal variations in dark skin often make evaluation difficult and result in some disorders being overlooked. Changes in color, especially hypopigmentation or hyperpigmentation, often accompany the skin disorders of darkskinned people.

Primary Disorders of the Skin Primary skin disorders originate in the skin and describe the appearance of skin tags, keratoses, lentigines, and vascular lesions that are commonly seen in older adults. They include pigmentary skin disorders, infectious processes, acne, rosacea, papulosquamous dermatoses, allergic disorders

and drug reactions, and arthropod infestations. Although most of these disorders are not life-threatening, they can affect the quality of life. KEY POINTS Primary Skin Disorders Infectious skin disorders are caused by viruses, bacteria, and fungi that invade the skin, incite inflammatory responses, and otherwise cause rashes and lesions that disrupt the skin surface. Allergic and hypersensitivity responses are caused by antigen– antibody responses resulting from sensitization to topical or systemic antigens. Pigmentary Skin Disorders Pigmentary skin disorders involve the melanocytes. In some cases, there is an absence of melanin production, as in vitiligo or albinism. In other cases, there is an increase in melanin or some other pigment, as in mongolian spots or melasma. In either case, the emotional impact can cause much worry and anxiety. Vitiligo Vitiligo is a pigmentary problem of concern to darkly pigmented people of all races. It also affects white-skinned people, but not as often, and the effects usually are not as socially problematic. Vitiligo appears at any age. However, roughly half of the cases begin before the age of 20 years.7 Worldwide, it affects people of all races regardless of gender. Etiology The cause of vitiligo is not known. However, there are many possible rationales for its etiology including genetics and autoimmunity.7 In some cases, vitiligo has been reportedly precipitated by emotional stress or physical trauma, such as sunburn. Oxidative stress is responsible for initiating melanocyte destruction and the development of vitiligo.8 In addition, vitiligo is associated with concurrent disease such as

hypothyroidism, Graves disease, Addison disease, pernicious anemia, type 2 diabetes mellitus, and melanoma.1,9,10 Clinical Manifestations The classic manifestation of vitiligo is the sudden appearance of white patches on the skin.7 The lesion is a depigmented macule with definite smooth borders on the face, axillae, neck, or extremities. The patches vary in size from small macules to ones involving large skin surfaces. The large macular type is more common. Depigmented areas appear white, pale colored, or sometimes grayish-blue. The depigmented sites may have melanocytes that no longer produce melanin or may not have any functioning melanocytes or have very few.7 These areas sunburn easily, and they enlarge over time. Vitiligo often is asymptomatic, although pruritus may occur. There are two types of vitiligo: vitiligo A and vitiligo B. Vitiligo A is seen more frequently, and the white patches are symmetrical with discrete borders.10 Vitiligo A progresses slowly over years to cover first the back of the hands, the face, and body folds.10 Vitiligo B is the segmental type, which means that the white patches are not symmetrical but are rather randomly disseminated anywhere on the body. The onset of vitiligo B occurs earlier in life than does vitiligo A.10 Treatment Although there are many treatment regimens for vitiligo, none is curative. Self-tanning lotions, skin stains, and cosmetics are used for camouflage. Corticosteroids administered topically, intralesionally, and orally have been used successfully. Broadband (large area) and narrowband (focused) ultraviolet B (UVB) irradiation has also been used successfully in the treatment of vitiligo. A variety of skin grafting techniques have been used in people unresponsive to other therapies. If extensive skin surfaces are involved, the treatment may be reversed and the pigmented areas bleached to match the remainder of the skin color. A melanocytotoxic agent is used to remove the remaining melanocytes from skin areas. This process, which is called depigmentation, is permanent and irreversible. Albinism

Albinism, a genetic disorder in which there is complete or partial congenital absence of pigment in the skin, hair, and eyes, is found in all races. Although there are over 10 different types of albinism, the most common type is recessively inherited oculocutaneous albinism, in which there is a normal number of melanocytes, but they have little to no tyrosinase, the enzyme needed for synthesis of melanin.1 It affects the skin, hair, and eyes. People have pale or pink skin, white or yellow hair, and light-colored or sometimes pink eyes. People with albinism have ocular problems, such as extreme sensitivity to light, refractive errors, foveal hypoplasia, and nystagmus.1 The most severe form is OCA1A, which is tyrosinase negative because these people have a complete lack of tyrosinase.1 There is no cure for albinism. Treatment efforts for people with albinism are aimed at reducing their risk of skin cancer through protection from solar radiation and screening for malignant skin changes. Melasma Melasma is characterized by darkened facial macules.2,3 It is common in all skin types but most prominent in brown-skinned people from Asia, India, and South America. It occurs in men but is more common in women, particularly during pregnancy or while using oral contraceptives.2,4 It may or may not resolve after giving birth or discontinuing hormonal birth control. Melasma is exacerbated by sun exposure.2–4 Treatment measures are palliative, mostly consisting of limiting exposure to the sun and using sunscreens. Bleaching agents, containing 2% to 4% hydroquinone, are standard treatments. Tretinoin cream and azelaic acid have been useful in treating severe cases. Infectious Processes The skin is subject to invasion by a number of microorganisms, including fungi, bacteria, and viruses. Normally, the skin flora, sebum, immune responses, and other protective mechanisms guard the skin against infection. Depending on the virulence of the infecting agent and the competence of the host’s resistance, infections may result. Superficial Fungal Infections

Fungi are free-living, saprophytic plantlike organisms, certain strains of which are considered part of the normal skin flora. Some fungi cause deep infections and others are superficial. There are two types of fungi, yeasts, and molds. Yeasts, such as Candida albicans, grow as single cells and reproduce asexually5 (see Fig. 52-1). Molds grow in long filaments, called hyphae.5 There are thousands of known species of yeasts and molds, but only about 100 of them cause disease in humans and animals.5 Fungal or mycotic infections of the skin are traditionally classified as superficial or deep. The superficial mycoses, more commonly known as tinea or ringworm, invade only the superficial keratinized tissue (skin, hair, and nails). Deep fungal infections involve the epidermis, dermis, and subcutaneous tissue. Infections that typically are superficial may exhibit deep involvement in people who are immunosuppressed.1

Superficial fungal infection. Candida in skin fold. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 275). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-1

Most of the superficial mycoses, also called dermatophytoses, are caused by the dermatophytes, a group of closely related fungi. These fungi are classified into three genera: Microsporum (M. audouinii, M. canis, and M. gypseum) Epidermophyton (E. floccosum) Trichophyton (T. schoenleinii, T. violaceum, and T. tonsurans)1 Two of these, Microsporum and Trichophyton, affect the hair.1

Another way of classifying the dermatophytes is according to their ecologic origin—human, animal, or soil. Anthropophilic species (M. audouinii, T. tonsurans, and T. violaceum) are parasitic on humans and are spread by other infected humans. Zoophilic species (M. canis and Trichophyton mentagrophytes) cause parasitic infections in animals, some of which can be spread to humans. Geophilic species originate in the soil but may infect animals, which in turn serve to infect humans. Pathogenesis and Clinical Manifestations The fungi that cause superficial mycoses live on the dead keratinized cells of the epidermis. They emit an enzyme that enables them to digest keratin, which results in superficial skin scaling, nail disintegration, or hair breakage, depending on the location of the infection.1 An exception to this is the invading fungus of tinea versicolor, which does not produce a keratolytic enzyme. Deeper reactions involving vesicles, erythema, and infiltration are caused by the inflammation that results from exotoxins liberated by the fungus. Fungi also are capable of producing an allergic or immune response.1 Superficial fungal infections affect various parts of the body, with the lesions varying according to site and fungal species. Tinea can affect the body (tinea corporis), face and neck (tinea faciale), scalp (tinea capitis), hands (tinea manus), feet (tinea pedis), nails (tinea unguium), or genitalia (tinea cruris).1 Diagnosis and Treatment Diagnosis of superficial fungal infections is primarily done by microscopic examination of skin scrapings for fungal spores, the reproducing bodies of fungi. Potassium hydroxide (KOH) preparations are used to prepare slides of skin scrapings. KOH disintegrates human tissue and leaves behind the threadlike filaments or hyphae that grow from the fungal spores. Cultures also may be done using a dermatophyte test medium or a microculture slide that produces color changes and allows for direct microscopic identification. The Wood light (ultraviolet [UV] light) is another method that can assist with the diagnosis of tinea. Some types of fungi (e.g., M. canis and M. audouinii) fluoresce yellow-green when the light is directed onto the affected area.1 Superficial fungal infections may be treated with topical or systemic antifungal agents. Treatment usually follows diagnosis confirmed by KOH

preparation or culture, particularly if a systemic agent is to be used. Topical agents, both prescription and over-the-counter preparations, are commonly used in the treatment of tinea infections. However, success often is limited because of the lengthy duration of treatment, poor compliance, and high rates of relapse at specific body sites. The oral systemic antifungal agents include griseofulvin, the azoles, and the allylamines. Griseofulvin is a fungicidal agent derived from a species of Penicillium that is used only in the treatment of dermatophytoses. It acts by binding to the keratin of newly forming skin, protecting the skin from new infection. The azoles are a group of synthetic antifungal drugs that act by inhibiting the fungal enzymes needed for the synthesis of ergosterol, which is an essential part of fungal cell membranes. The triazoles are used for the systemic treatment of fungal infections. Topical corticosteroids may be used in conjunction with antifungal agents to relieve itching and erythema secondary to inflammation. Tinea of the Body or Face Tinea corporis (ringworm of the body) can be caused by any of the fungi but is most frequently caused by M. canis in the United States and by Trichophyton rubrum worldwide (Fig. 52-2). There has been an increase in T. tonsurans as the causative agent of tinea corporis as well. Although tinea corporis affects all ages, children seem most prone to infection. Transmission is most commonly from kittens, puppies, and other children who have infections.

Dermatophytosis—this fungal infection is superficial. Tinea corporis. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 846). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-2

The lesions vary, depending on the fungal agent. The most common types of lesions are oval or circular patches on exposed skin surfaces and the trunk, back, or buttocks. Less common are foot and groin infections. The lesion begins as a red papule and enlarges, often with a central clearing. Patches have raised red borders consisting of vesicles, papules, or pustules. The borders are sharply defined, but lesions may coalesce (see Fig. 52-3). Pruritus, a mild burning sensation, and erythema frequently accompany the skin lesion.

Tinea corporis (ringworm) is a dermatophyte skin infection that is depicted as an annular lesion with a raised border and a central clearing. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 276). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-3

Tinea faciale, or ringworm of the face, is an infection caused by T. mentagrophytes or T. rubrum. Tinea faciale may mimic the annular, erythematous, scaling, pruritic lesions characteristic of tinea corporis. It also may appear as flat erythematous patches. Topical antifungal agents usually are effective in treating tinea corporis and tinea faciale. Oral antifungal agents may be used in resistant cases. Tinea of the Scalp There are two common types of tinea capitis (ringworm of the scalp): primary (noninflammatory) and secondary (inflammatory). In the United States, most of the cases of noninflammatory tinea capitis are caused by T. tonsurans, which does not turn fluorescent green with a Wood lamp. The infection is spread most often among household members who share combs and brushes on which the spores are shed and remain viable for long periods. Depending on the invading fungus, the lesions of the noninflammatory type can vary from grayish, round, hairless patches to balding spots, with or without black dots on the head. The lesions vary in size and are most commonly seen on the back of the head. Mild erythema, crust, or scale may be present. The individual usually is asymptomatic, although pruritus may exist.

The inflammatory type of tinea capitis is caused by virulent strains of T. mentagrophytes, T. verrucosum, and M. gypseum. The onset is rapid, and inflamed lesions usually are localized to one area of the head. The inflammation is believed to be a delayed hypersensitivity reaction to the invading fungus. The initial lesion consists of a pustular, scaly, round patch with broken hairs. A secondary bacterial infection is common and may lead to a painful, circumscribed, boggy, and indurated lesion called a kerion. The treatment for both noninflammatory and inflammatory forms of tinea capitis is oral griseofulvin or synthetic antifungals. Tinea of the Foot and Hand Tinea pedis (athlete’s foot) is the most common fungal dermatosis, primarily affecting the spaces between the toes, the soles, or sides of the feet. It is caused by T. mentagrophytes and T. rubrum. The lesions vary from a mildly scaling lesion to a painful, exudative, erosive, inflamed lesion with fissuring. Lesions often are accompanied by pruritus, pain, and foul odor. Some people are prone to chronic tinea pedis. Mild forms are more common during dry environmental conditions. Tinea manus usually is a secondary infection with tinea pedis as the primary infection. In contrast to other skin disorders, such as contact dermatitis and psoriasis, which affect both hands, tinea manus usually occurs only on one hand. The characteristic lesion is a blister on the palm or finger surrounded by erythema. Chronic lesions are scaly and dry. Cracking and fissuring may occur. The lesions may spread to the plantar surfaces of the hand. If chronic, tinea manus may lead to tinea of the fingernails. Simple forms of tinea pedis and tinea manus are treated with topical applications of antifungals. Tinea of the Nail Tinea unguium is a dermatophyte infection of the nails. It is a subset of onychomycosis, which includes dermatophyte, nondermatophyte, and candidal infections of the nails. There is an increased incidence of fungal nail infections in recent years, probably reflecting better diagnostics, increased numbers of immunocompromised people who have greater susceptibility, increased use of immunosuppressive drugs, increasing numbers of older adults, worldwide travel, and increased use of communal bathing facilities.

Distal and lateral subungual onychomycosis, the most common form of Tinea unguium, usually is caused by T. rubrum or T. mentagrophytes. Toenails are involved more commonly than are fingernails because fingernails are more exposed to air. The infection often begins at the tip of the nail, where the fungus digests the nail keratin. In some cases, the infection may begin from a crushing injury to a toenail or from the spread of tinea pedis. Initially, the nail appears opaque, white, or silver. The nail then turns yellow or brown. The condition often remains unchanged for years. During this time, it may involve only one or two nails and may produce little or no discomfort. Gradually, the nail thickens and cracks as the infection spreads and includes the nail plate. Permanent discoloration and distortion result as the nail plate separates from the nail bed. Less common forms of tinea unguium are superficial white onychomycosis, in which areas of the nails become powdery white and erode, and proximal subungual onychomycosis, in which there is rapid invasion of the nail, leaving it white with no additional thickening of the nail. Although it is one of the less common forms of tinea unguium, proximal subungual onychomycosis has increased among people with human immunodeficiency virus (HIV) infection. Treatment of tinea unguium usually requires oral antifungal therapy. Fingernail infections are more easily treated, in part because the fingernails are more exposed to air. A new nail may require 3 to 12 months to grow. Tinea Versicolor Tinea versicolor is a fungal infection involving the upper chest, the back, and sometimes the arms. It is caused by the dimorphic–lipophilic yeasts Pityrosporum orbiculare (round form) and Pityrosporum ovale (oval form).10 The yeast lives within the stratum corneum and hair follicles in areas with sebaceous glands, where it is easy to obtain triglycerides and free fatty acids.10 The characteristic lesion is a yellow, pink, or brown sheet of scaling skin (see Fig. 52-4). The name versicolor is derived from the multicolored variations of the lesion. The patches are depigmented and do not tan when exposed to UV light.

Tinea versicolor. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 276). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-4

Selenium sulfide, found in several shampoo preparations, has been an effective fungistatic treatment measure. Miconazole or ketoconazole creams or shampoos, because of their fungicidal properties, have become the drugs of choice. Oral antifungals are used for extensive cases. The infection may recur after drug therapy. Tinea Incognito Tinea incognito is a form of dermatophyte infection that developed with the widespread use of topical corticosteroids. It often is seen in cases where tinea infections are misdiagnosed as eczema and treated with corticosteroids. Because corticosteroids suppress inflammation, scaling and erythema may not be present or it may not resemble a fungal infection at all after several rounds of cortisone therapy. There has been an increased incidence of tinea incognito in people with HIV infection. People with the disorder often present with thickened plaques with lichenification, papules, pustules, and nodules. Telangiectases, atrophy, and striae may be present. Tinea incognito is seen most often on the groin, the palms, or the dorsal aspect of the hand. Treatment measures include discontinuing topical corticosteroids while using low-dose oral corticosteroids to prevent the flare-up associated with discontinuing potent topical steroids. Topical or oral antifungal agents are used, depending on the severity of the infection.

Dermatophytid Reaction A secondary skin eruption may occur in people allergic to the fungus responsible for the dermatophytosis. This dermatophytid or allergic reaction may occur during an acute episode of a fungal infection. The most common reaction occurs on the hands in response to tinea pedis. The lesions are vesicles with erythema extending over the palms and fingers, sometimes extending to other areas. Less commonly, a more generalized reaction occurs, in which papules or vesicles erupt on the trunk or extremities. These eruptions may resemble tinea corporis. Lesions may become excoriated and infected with bacteria. Treatment is directed at the primary site of infection. The intradermal reaction resolves in most cases without intervention if the primary site is cleared. Candidal Infections Candidiasis (moniliasis) is a fungal infection caused by C. albicans and occasionally by a few other Candida species. This yeastlike fungus is a normal inhabitant of the gastrointestinal tract, mouth, and vagina. The skin problems result from the release of irritating toxins on the skin surface. C. albicans is found almost always on the surface of the skin. It rarely penetrates to the deeper layers of the skin. Some people are predisposed to candidal infections by conditions such as diabetes mellitus, antibiotic therapy, pregnancy, oral contraceptive use, poor nutrition, and immunosuppressive diseases. Oral candidiasis may be the first sign of infection with HIV. C. albicans thrives on warm, moist, intertriginous areas of the body. The rash is red with well-defined borders. Patches erode the epidermis, and there is scaling. Mild to severe itching and burning often accompany the infection. Severe forms of infection may involve pustules or vesiculopustules. In addition to microscopy, a candidal infection often can be differentiated from a tinea infection by the presence of satellite lesions. These satellite lesions are maculopapular and are found outside the clearly demarcated borders of the candidal infection. Satellite lesions often are diagnostic of diaper rash complicated by Candida. The appearance of candidal infections varies according to the site. Diagnosis usually is based on microscopic examination of the skin or mucous membrane scrapings placed in a KOH solution. Treatment measures vary according to the location. Preventive measures such as

wearing rubber gloves are encouraged for people with infections of the hands. Intertriginous areas often are separated with clean cotton cloth and allowed to air dry as a means of decreasing the macerating effects of heat and moisture. Topical and oral antifungal agents are used in treatment depending on the site and extent of involvement. Bacterial Infections Bacteria are considered normal flora of the skin. Most bacteria are not pathogenic, but when pathogenic bacteria invade the skin, superficial or systemic infections may develop. Bacterial skin infections are commonly classified as primary or secondary infections. Primary infections are superficial skin infections such as impetigo or ecthyma. Secondary infections consist of deeper cutaneous infections, such as infected ulcers. Diagnosis usually is based on cultures taken from the infected site. Treatment measures include antibiotic therapy and measures to promote comfort and prevent the spread of infection. Impetigo Impetigo is a common, superficial bacterial infection caused by staphylococci or group A beta-hemolytic streptococci, or both.10 Impetigo is common among infants and young children, although older children and adults occasionally contract the disease. Its occurrence is highest during warm summer months or in warm, moist climates. Impetigo initially appears as a small vesicle or pustule or as a large bulla on the face or elsewhere on the body. As the primary lesion ruptures, it leaves a denuded area that discharges a honey-colored serous liquid that hardens on the skin surface and dries as a honey-colored crust (Fig. 52-5). New vesicles erupt within hours. Pruritus often accompanies the lesions, and skin excoriations that result from scratching multiply the infection sites. Although a very low risk, a possible complication of untreated streptococcal impetigo is poststreptococcal glomerulonephritis. Topical mupirocin is effective in treating impetigo. If a larger area is involved, then a systemic antibiotic may be necessary.6

Impetigo. This highly contagious superficial skin infection commonly results from Staphylococcus aureus or group A betahemolytic streptococci. It is characterized by vesicles or bullae that eventually rupture and ooze serous fluid that forms the classic honey-colored crust. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 274). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-5

Another form of impetigo exists, bullous impetigo, which is usually caused by Staphylococcus aureus.10 Bullous impetigo is common among children. It is due to the epidermolytic toxin and is not generally contaminated by streptococci.10,11 Thin bullae that appear clear to cloudy erupt and coalesce. The bullae open, leaving the original bullous rim with central thin, flat, honey-colored crusts, or in some cases denuded areas. The face is often affected, but bullous impetigo may occur anywhere on the body. The treatment measures are the same as for nonbullous impetigo. Ecthyma is an ulcerative form of impetigo, usually secondary to minor trauma. It is caused by group A beta-hemolytic streptococci, S. aureus, or Pseudomonas species. It frequently occurs on the buttocks and thighs of children. The lesions are similar to those of impetigo. A vesicle or pustule ruptures, leaving a skin erosion or ulcer that weeps and dries to a crusted patch, often resulting in scar formation. With extensive ecthyma, there is a low-grade fever and extension of the infection to other organs. Treatment usually involves the use of systemic antibiotics. A less common form of S. aureus infection, called Ritter disease, manifests with a diffuse, scarlet fever–like rash, followed by skin separation

and sloughing. It is also called staphylococcal scalded skin syndrome because the skin looks scalded (Fig. 52-6). Ritter disease usually affects children younger than 5 years of age. However, immunosuppressed adults also are at risk. The disorder, which is considered a deeper skin infection because the superficial layers of the epidermis are separated and shed in sheets, is caused by the hematologic spread of toxins from a focal infection, such as the nasopharynx or a superficial skin abrasion. The onset of the rash may be preceded by malaise, fever, irritability, and extreme tenderness over the skin. The conjunctiva often is inflamed, with purulent drainage. Although the fluid in the unbroken bullae is sterile, cultures usually are obtained from suspected sites of local infection and from the blood. Systemic antibiotics, either oral or parenteral, are used to treat the disorder. Healing usually occurs in 10 to 14 days without scarring.

Staphylococcal scalded skin syndrome. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 846). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-6

Cellulitis is a deeper infection affecting the dermis and subcutaneous tissues. It is usually caused by group A beta-hemolytic streptococci or S. aureus but can be caused by bacteria specific to certain activities, such as fish handling, swimming in fresh or salt water, or from animal bites or scratches. Preexisting wounds (e.g., ulcers, erosions) and tinea pedis are

often portals of entry. Legs are the most common sites, followed by the hands and pinnae of the ears, but cellulitis may be seen on many body parts. The lesion consists of an expanding red, swollen, tender plaque with an indefinite border (Fig. 52-7). Cellulitis is frequently accompanied by fever, erythema, heat, edema, and pain. Cellulitis often involves the lymph system, and, once compromised, repeat infections may impair lymphatic drainage, leading to chronically swollen legs, and eventually dermal fibrosis and lymphedema. Incorrectly treated, it may result in septicemia, nephritis, or death. Antibiotics are aimed at the invasive organisms and the extent of the infection.

Cellulitis on leg infected with Staphylococcus aureus and Pseudomonas. FIGURE 52-7

Viral Infections Viruses are intracellular pathogens that rely on live cells of the host for reproduction. They have no organized cell structure but consist of a deoxyribonucleic acid (DNA) or ribonucleic acid core surrounded by a protein coat. The viruses seen in skin lesion disorders tend to be DNAcontaining viruses. Viruses invade the keratinocyte, begin to reproduce, and cause cellular proliferation or cellular death. The rapid increase in viral skin diseases has been attributed to the use of corticosteroid drugs, which have

immunosuppressive qualities, and the use of antibiotics, which alter the bacterial flora of the skin. As the number of bacterial infections has decreased, there has been a proportional rise in viral skin diseases. Verrucae Verrucae, or warts, are common benign papillomas caused by the DNAcontaining human papillomavirus (HPV). Transmission of HPV infection is largely by direct contact between people or by autoinoculation. Benign papillomas, warts represent an exaggeration of the normal skin structures with an irregular thickening of the stratum spinosum and greatly increased thickening of the stratum corneum. The classification of warts is based largely on morphology and location. Although warts vary in appearance depending on their location, it is now recognized that the clinically distinct types of warts result not simply because of the anatomic sites in which they arise but also because of the distinct types of HPV. There are almost 90 types of HPV found on humans that cause several different kinds of warts, including skin warts and genital warts.10 Many of the HPV types that cause genital warts are sexually transmitted, some of which (types 6, 11, 16, and 18) may increase the risk of cervical cancer.10,12,13 Nongenital warts often occur on the hands and feet. They are commonly caused by HPV types 1, 2, 3, 4, 27, and 57 and are not considered precancerous lesions. They are classified as common warts, flat warts, and plantar or palmar warts. Common warts, or verrucae vulgaris, are the most common type. The lesions can occur anywhere but most frequently occur on dorsal surfaces of the hands, especially the periungual area, where they appear as small, grayish-white to tan, flat to convex papules with a rough, pebble-like surface. Verrucae plana, or flat warts, are common on the face or dorsal surfaces of the hands. The warts are slightly elevated, flat, smooth, tan papules that are slightly larger than verrucae vulgaris (Fig. 52-8). Verrucae plantaris and verrucae palmaris (i.e., plantar and palmar warts, respectively) occur on the soles of the feet and palms of the hands, respectively. They appear as rough, scaly lesions that may reach 1 to 2 cm in diameter, coalesce, and be confused with ordinary calluses. HPV transmission usually occurs through breaks in skin integrity.

Common warts. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 273). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-8

Treatment is usually directed at inducing a “wart-free” period without producing scarring. Warts resolve spontaneously when immunity to the virus develops. The immune response, however, may be delayed for years. Because of their appearance or discomfort, people usually desire their removal, rather than waiting for immunity to develop. Removal is usually done by applying a keratolytic agent, such as salicylic acid gel or plaster that breaks down the wart tissue, or by freezing with liquid nitrogen. Various types of laser surgery, electrosurgery, cryotherapy, immunotherapy, and antiviral therapy also have been successful in wart eradication. Herpes Simplex Herpes simplex virus (HSV) infections of the skin and mucous membrane (i.e., cold sore or fever blister) are common. Two types of HSV infect humans: type 1 and type 2. HSV-1 is usually associated with oropharynx infections, and the organism is spread by respiratory droplets or by direct

contact with infected saliva. HSV-1 may also be transmitted to other parts of the body through occupational hazards, such as skin contact athletics, dentistry, and medicine. Genital herpes usually is caused by HSV-2. HSV-1 genital infections and HSV-2 oral infections are becoming more common. Infection with HSV-1 may present as a primary or recurrent infection. Primary HSV-1 symptoms include fever; sore throat; painful vesicles; and ulcers of the tongue, palate, gingiva, buccal mucosa, and lips. Primary infection results in the production of antibodies to the virus so that recurrent infections are more localized and less severe. After an initial infection, the herpesvirus persists in the trigeminal and other dorsal root ganglia in the latent state, periodically reactivating in recurrent infections. It may be that reactivation of a herpes infection occurs both in the dorsal root ganglion and locally, where it has been found to exist in the epidermis and other organs. The symptoms of a primary HSV-1 infection most often occur in young children (1 to 5 years of age). It is likely that many adults were exposed to HSV-1 during childhood and therefore have antibodies to the virus. The recurrent lesions of HSV-1 usually begin with a burning or tingling sensation. Umbilicated vesicles and erythema follow and progress to pustules, ulcers, and crusts before healing (Fig. 52-9). Lesions are most common on the lips, face, mouth, nasal septum, and nose. When a lesion is active, HSV-1 is shed, and there is risk of transmitting the virus to others. Pain is common, and healing takes place within 10 to 14 days. Precipitating factors may be stress, menses, or injury. In particular, UVB exposure seems to be a frequent trigger for recurrence. There is no cure for oropharyngeal herpes. Most treatment measures are palliative.

Herpes simplex 1 of the oral mucosa. (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 407). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-9

Herpes Zoster Herpes zoster (shingles) is an acute, localized vesicular eruption distributed over a dermatomal segment of the skin. It is caused by the same herpesvirus, varicella–zoster, which causes chickenpox. It is believed to be the result of reactivation of a latent varicella–zoster virus infection that was dormant in the sensory dorsal root ganglia since a primary childhood infection. During an episode of herpes zoster, the reactivated virus travels from the ganglia to the skin of the corresponding dermatome. Although herpes zoster is not as contagious as chickenpox, the reactivated virus can be transmitted to nonimmune contacts. Herpes zoster occurs in 10% to 20% of all people.10 It can occur at any time during the life span but tends to happen in older adults more frequently. The incidence is much less among African Americans. Other people at risk because of impaired T-cell–mediated immunity are those with conditions such as HIV infection and certain malignancies, chronic corticosteroid users, and those undergoing chemotherapy and radiation therapy.

The lesions of herpes zoster typically are preceded by a prodrome consisting of a burning pain, a tingling sensation, extreme sensitivity of the skin to touch, and pruritus along the affected dermatome. Among the dermatomes, the most frequently involved are the thoracic, cervical, trigeminal, and the lumbosacral. Prodromal symptoms may be present for 1 to 3 days or longer before the appearance of the rash. During this time, the pain may be mistaken for a number of other conditions, such as heart disease, pleurisy, musculoskeletal disorders, or gastrointestinal disorders. The lesions appear as an eruption of vesicles with erythematous bases that are restricted to skin areas supplied by sensory neurons of a single or an associated group of dorsal root ganglia. In immunosuppressed people, the lesions may extend beyond the dermatome. Eruptions usually are unilateral in the thoracic region, trunk, or face. New groups of vesicles erupt for 3 to 5 days along the nerve pathway. The vesicles dry, form crusts, and eventually fall off. The lesions usually clear in 2 to 3 weeks, although they can persist up to 6 weeks in some older adults. Serious complications can accompany eruptions. Eye involvement can result in permanent blindness and occurs in a large percentage of cases involving the ophthalmic division of the trigeminal nerve (Fig. 52-10). Postherpetic neuralgia, which is pain that persists longer than 1 to 3 months after the resolution of the rash, is an important complication of herpes zoster. It is seen most commonly in people older than 60 years of age, increasing age being the greatest risk factor. Given the aging population in the United States, the incidence of herpes zoster is expected to increase dramatically over the next two decades. Affected people complain of a sharp, burning pain that often occurs in response to nonnoxious stimuli. Even the slightest pressure of clothing and bedsheets may elicit pain. It usually is a self-limited condition that persists for months, with symptoms abating over time.

Dermatomal distribution of herpes zoster rash due to varicella–zoster virus. (From Hinkle J. L., Cheever K. H. (2018). Brunner & Suddarth’s textbook of medical–surgical nursing (14th ed., p. 1819). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-10

The treatment of choice for herpes zoster is the administration of an antiviral agent. The treatment is most effective when started within 72 hours of rash development. Narcotic analgesics, tricyclic antidepressants, gabapentin, anticonvulsant drugs, and nerve blocks have been used for management of postherpetic neuralgia. Local application of capsaicin cream or lidocaine patches may be used in selected cases. Zoster vaccine (Zostavax) is effective in either preventing or lessening the severity of herpes zoster.14 This vaccine is highly recommended for people older than 50 years of age and anyone with high risk for herpes zoster.15 Acne and Rosacea

Acne is a disorder of the pilosebaceous unit, which comprises a tiny vellus hair, hair follicle, and sebaceous gland.16,17 The hair follicle is a tubular invagination of the epidermis in which hair is produced. The sebaceous glands empty into the hair follicle, and the pilosebaceous unit opens to the skin surface through a widely dilated opening called a pore. The sebaceous glands produce a complex lipid mixture called sebum. Sebum consists of a mixture of free fatty acids, triglycerides, diglycerides, monoglycerides, sterol esters, wax esters, and squalene. Sebum production occurs through what is called a holocrine process, in which the sebaceous gland cells that produce the sebum are completely broken down and their lipid contents emptied through the sebaceous duct into the hair follicle. The amount of sebum produced depends on two factors: the size of the sebaceous gland and the rate of sebaceous cell proliferation. The sebaceous glands are largest on the face, scalp, and scrotum but are present in all areas of the skin except for the soles and palms. Sebaceous cell proliferation and sebum production are uniquely responsive to direct hormonal stimulation by androgens. In men, testicular androgens are the main stimulus for sebaceous activity; in women, adrenal and ovarian androgens maintain sebaceous activity. Acne lesions are divided into noninflammatory and inflammatory lesions.18 Noninflammatory lesions consist of comedones (whiteheads and blackheads). Blackheads are plugs of material that accumulate in sebaceous glands that open to the skin surface. The color of blackheads results from melanin that has moved into the sebaceous glands from adjoining epidermal cells. Whiteheads are pale, slightly elevated papules with no visible orifice. Inflammatory lesions consist of papules, pustules, nodules, and, in severe cases, cysts.18 Papules are raised areas less than 5 mm in diameter. Pustules have a central core of purulent material. Nodules are larger than 5 mm in diameter and may become suppurative or hemorrhagic. Suppurative nodules often are referred to as cysts because of their resemblance to inflamed epidermal cysts. The inflammatory lesions are believed to develop from the escape of sebum into the dermis and the irritating effects of the fatty acids contained in the sebum. Two types of acne occur during different stages of the life cycle: acne vulgaris, which is the most common form among adolescents and young adults, and acne conglobata, which develops later in life. Other types of

acne occur in association with various etiologic agents such as drugs, occupational compounds, cosmetics, and other irritating agents. Treatment measures for these acnes depend on the precipitating agent and the extent of the lesions. Acne Vulgaris Acne vulgaris is considered a chronic inflammatory disease of the pilosebaceous unit. It is a disorder of adolescents and young adults, affecting over 80% of people between the ages of 11 and 30 years in Westernized countries.19 In women, acne may begin earlier and persist longer. However, overall, the incidence and severity of acne vulgaris is greater in men. Acne vulgaris lesions form primarily on the face and neck and, to a lesser extent, on the back, chest, and shoulders (Fig. 52-11). The lesions may consist of comedones (whiteheads and blackheads) or inflammatory lesions (pustules, nodules, and cysts).

Pustular acne (A) and cystic acne (B). (From Jensen S. (2015). Nursing health assessment: A best practice approach (2nd ed., p. 273). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-11

Etiology The cause of acne vulgaris remains unknown. However, there is a genetic factor. Multiple generations of family members often experience the disease. Several factors are believed to contribute to acne, including the following: Increased sebum production Increased proliferation of the keratinizing epidermal cells that form the sebaceous cells The colonization and proliferation of Propionibacterium acnes Inflammation These factors are probably interrelated. Increased androgen production results in increased sebaceous cell activity, with resultant plugging of the pilosebaceous ducts. The excessive sebum provides a medium for the growth of P. acnes. The P. acnes organism contains lipases that break down the free fatty acids that produce the acne inflammation. In addition, there have been new findings regarding the physiology of acne (Fig. 52-12). One example is that P. acnes form a biofilm (an extracellular polysaccharide lining in which the bacteria are encased) that prevents antibiotic treatment.

Acne vulgaris. The pathogenesis of follicular distension, rupture, and inflammation is illustrated. Microcomedones (A) and closed (B) and open (C) comedones form. Excessive sebum can be secreted, and the Propionibacterium acnes proliferates. Neutrophilic enzymes are released, and the comedone ruptures causing a cycle of intense inflammation (D and E). (From Strayer D., Rubin R. (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., p. 1250). Philadelphia, PA: Wolters Kluwer.) FIGURE 52-12

Although general hygienic measures are important, obsessive scrubbing can traumatize the skin and worsen the condition. Instead, it is recommended that the affected areas be washed gently and patted dry.

Diagnosis The diagnosis of acne is based on history and physical examination. Generally, the type and amount of lesions assists in determining the severity of the acne (mild, moderate, and moderately severe).16,19–21 Mild acne is usually characterized by the presence of a small number (generally 2 mEq/L Base deficit < −2 mEq/L HCO3 22–26 mEq/L Males: 0.23–0.33 Aspartase aminotransferase Males: 14–20 U/L μkat/L† (AST) Females: 10–36 U/L† Females: 0.17–0.60 μkat/L† Bilirubin (total) 0.3–1.0 mg/dL 5–17 μmol/L Bilirubin (direct or 0.0–0.2 mg/dL 0.0–3.4 μmol/L conjugated) Blood urea nitrogen (BUN) 6–20 mg/dL 2.1–7.1 mmol/L 2+ Calcium (Ca ) (total) 8.8–10.4 mg/dL 2.20–2.60 mmol/L Chloride 96–106 mEq/L 96–106 mmol/L

Test

Conventional Units

SI Units Males: 0.63–2.90 Males: 38–174 units/L† Creatine kinase (CK, CPK) μkat/L† Females: 26–140 U/L Females: 0.46–2.38 Creatine kinase isoenzymes: MB (CK2) 0%–6% 0.00–0.06 MM (CK3) 96% or 100% 0.96–1.0 0% 0.00 BB (CK1) Creatinine (serum)

Males: 0.6–1.2 Females: 0.4–1.0 mg/dL‡

Gamma-glutamyltranspeptidase (GGT)

Males: 7–47 U/L Females: 5–25 U/L

Glucose (plasma, fasting) Glycosylated hemoglobin (HbA1c) Lactate dehydrogenase (LDH) Lipids