CONTRIBUTORS

Edouard Vannier, PharmD, PhD xxxvii

Assistant Professor of Medicine, Division of Geographic Medicine and

Infectious Diseases, Department of Medicine, Tufts Medical Center and Tufts

University School of Medicine, Boston, Massachusetts [225]

Gauri R. Varadhachary, MD

Professor, GI Medical Oncology, The University of Texas MD Anderson

Cancer Center, Houston, Texas [92]

John Varga, MD

Frederick Huetwell Professor; Chief, Division of Rheumatology, University of

Michigan, Ann Arbor, Michigan [360]

David J. Vaughn, MD

Genitourinary Medical Oncology Professor, Perelman School of Medicine

at the University of Pennsylvania, Perelman Center for Advanced Medicine,

Philadelphia, Pennsylvania [88]

Birgitte Jyding Vennervald, MD, MSA

Professor, Section for Parasitology and Aquatic Pathobiology, Faculty

of Health and Medical Sciences, University of Copenhagen, Frederiksberg,

Denmark [234]

John T. Vetto, MD, FACS

Professor of Surgery, Division of Surgical Oncology; Director, Cutaneous

Oncology Program, Department of Surgery, Oregon Health & Science

University; Program Leader, Melanoma Disease Site Team, OHSU Knight

Cancer Institute, Portland, Oregon [76]

Luciano Villarinho, MD

Neuroradiologist, South County Hospital, Wakefield, Rhode Island [A16]

Bert Vogelstein, MD

Professor, Ludwig Center for Cancer Genetics and Therapeutics, Johns

Hopkins University School of Medicine; Investigator, Howard Hughes

Medical Institute, Baltimore, Maryland [71]

Everett E. Vokes, MD

John E. Ultmann Professor; Chairman, Department of Medicine; Physicianin-Chief, University of Chicago Medicine and Biological Sciences, Chicago,

Illinois [77]

Tamara J. Vokes, MD

Professor, Department of Medicine, Section of Endocrinology, University of

Chicago, Chicago, Illinois [412]

Nora D. Volkow, MD

Director, National Institute on Drug Abuse (NIDA), National Institutes of

Health, Rockville, Maryland [455]

Kevin G. Volpp, MD, PhD

Director, Penn Center for Health Incentives and Behavioral Economics;

Founders Presidential Distinguished Professor, Perelman School of

Medicine and the Wharton School, University of Pennsylvania, Philadelphia,

Pennsylvania [481]

Daniel D. Von Hoff, MD, FACP, FASCO, FAACR

Distinguished Professor, Translational Genomics Research Institute (TGEN),

Phoenix, Arizona; Virginia G. Piper Distinguished Chair for Innovative

Cancer Research and Chief Scientific Officer, Honor Health Research

Institute; Senior Consultant-Clinical Investigations, City of Hope; Professor

of Medicine, Mayo Clinic, Scottsdale, Arizona [83]

Martin H. Voss, MD

Clinical Director, Genitourinary Oncology Service, Memorial Sloan

Kettering Cancer Center, New York, New York [85]

Jiři F. P. Wagenaar, MD, PhD

Internist and Infectious Disease Specialist, Northwest Clinics, Alkmaar,

The Netherlands [184]

Jesse Waggoner, MD

Assistant Professor, Department of Medicine, Division of Infectious Diseases,

Emory University, Atlanta, Georgia [124]

Sushrut S. Waikar, MD, MPH

Chief, Section of Nephrology; Norman G. Lewinsky Professor of Medicine,

Boston University School of Medicine, Boston, Massachusetts [310]

Matthew K. Waldor, MD, PhD

Edward H. Kass Professor of Medicine, Harvard Medical School,

Division of Infectious Diseases, Brigham and Women’s Hospital, Boston,

Massachusetts [168]

David H. Walker, MD

The Carmage and Martha Walls Distinguished University Chair in Tropical

Diseases; Professor, Department of Pathology; Executive Director, Center for

Biodefense and Emerging Infectious Diseases, University of Texas Medical

Branch, Galveston, Texas [187]

Mark F. Walker, MD

Associate Professor, Neurology, Case Western Reserve University; Director,

Daroff-Dell’Osso Ocular Motility Laboratory, VA Northeast Ohio Healthcare

System, Cleveland, Ohio [22]

George R. Washko, MD, MMSc

Associate Professor of Medicine, Harvard Medical School; Associate

Physician, Division of Pulmonary and Critical Care Medicine, Department of

Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [286, A12]

Michael E. Wechsler, MD, MMSc

Professor of Medicine; Director, Asthma Program, Department of Medicine,

National Jewish Health, Denver, Colorado [288]

Anthony P. Weetman, MD, DSc

University of Sheffield, School of Medicine, Sheffield, United Kingdom

[382–385]

Robert A. Weinstein, MD

The C. Anderson Hedberg MD Professor of Internal Medicine, Rush

University Medical Center; Chairman of Medicine, Emeritus, Cook County

Health, Chicago, Illinois [142]

Jeffrey I. Weitz, MD, FRCP(C), FRSC, FACP

Professor of Medicine and Biochemistry and Biomedical Sciences, McMaster

University; Executive Director, Thrombosis and Atherosclerosis Research

Institute, Hamilton, Ontario, Canada [118]

Peter F. Weller, MD

William Bosworth Castle Professor of Medicine, Harvard Medical School;

Professor of Immunology and Infectious Diseases, Harvard T.H. Chan School

of Public Health; Chief Emeritus, Infectious Diseases Division and Vice Chair

of Research, Department of Medicine, Beth Israel Deaconess Medical Center,

Boston, Massachusetts [229–233, 235]

Andrew Wellman, MD, PhD

Associate Professor of Medicine, Harvard Medical School; Director,

Sleep Disordered Breathing Lab, Brigham and Women’s Hospital, Boston,

Massachusetts [297]

Patrick Y. Wen, MD

Professor of Neurology, Harvard Medical School; Director, Center for

Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of

Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital,

Boston, Massachusetts [90]

Michael R. Wessels, MD

John F. Enders Professor of Pediatrics and Professor of Medicine, Harvard

Medical School; Senior Physician, Division of Infectious Diseases, Boston

Children’s Hospital, Boston, Massachusetts [148]

L. Joseph Wheat, MD

Medical Director, MiraVista Diagnostics, Indianapolis, Indiana [212]

A. Clinton White, Jr., MD, FACP, FIDSA, FASTMH

Professor, Infectious Disease Division, Department of Internal Medicine,

University of Texas Medical Branch, Galveston, Texas [235]

Nicholas J. White, DSc, MD, FRCP, F Med Sci, FRS

Professor of Tropical Medicine, Mahidol and Oxford Universities, Bangkok,

Thailand [224, A2]

Richard J. Whitley, MD

Loeb Eminent Scholar in Pediatrics; Professor of Pediatrics, Microbiology

and Neurosurgery, The University of Alabama at Birmingham, Birmingham,

Alabama [193]

CONTRIBUTORS xxxviii Eleanor Wilson, MD, MHS

Associate Professor of Medicine, Associate Director of Clinical Research,

Division of Clinical Care and Research, Institute of Human Virology,

University of Maryland School of Medicine, Baltimore, Maryland [191]

Michael R. Wilson, MD, MAS

Rachleff Family Distinguished Associate Professor in Neurology, University

of California San Francisco Weill Institute for Neurosciences; Staff Physician,

University of California San Francisco Medical Center and Zuckerberg San

Francisco General Hospital, San Francisco, California [137, 139, S2]

Bruce U. Wintroub, MD

Professor and Chair, Department of Dermatology, University of California,

San Francisco, San Francisco, California [60]

Allan W. Wolkoff, MD

The Herman Lopata Chair in Liver Disease Research; Professor of Medicine

and Anatomy and Structural Biology; Associate Chair of Medicine for

Research; Chief, Division of Hepatology; Director, Marion Bessin Liver

Research Center, Albert Einstein College of Medicine and Montefiore

Medical Center, Bronx, New York [338]

Louis Michel Wong Kee Song, MD

Professor of Medicine, Division of Gastroenterology and Hepatology,

Mayo Clinic College of Medicine, Rochester, Minnesota [322, V5]

John B. Wong, MD

Professor of Medicine, Tufts University School of Medicine; Interim Chief

Scientific Officer, Tufts Medical Center, Boston, Massachusetts [4]

Thomas E. Wood, PhD

Research Fellow, Department of Medicine, Division of Infectious Diseases,

Massachusetts General Hospital; Department of Microbiology, Harvard

Medical School, Boston, Massachusetts [120]

Jennifer A. Woyach, MD

Professor of Medicine, Division of Hematology, The Ohio State University,

Columbus, Ohio [107]

Peter F. Wright, MD

Professor of Pediatrics, Geisel School of Medicine, Dartmouth College,

Hanover, New Hampshire [200]

Henry M. Wu, MD, DTM&H, FIDSA

Associate Professor of Medicine, Division of Infectious Diseases, Emory

University; Director, Emory TravelWell Center, Atlanta, Georgia [124]

Kim B. Yancey, MD

Professor and Chair, Department of Dermatology, University of Texas

Southwestern Medical Center in Dallas, Dallas, Texas [56, 59]

Lonny Yarmus, DO, MBA

Professor of Medicine, Division of Pulmonary and Critical Care Medicine,

Johns Hopkins University School of Medicine, Baltimore, Maryland [299]

Yusuf Yazici, MD

Clinical Associate Professor of Medicine, New York University Grossman

School of Medicine, New York, New York [364]

Baligh R. Yehia, MD, MPP, MSc

Ascension Health, St. Louis, Missouri [400]

Janet A. Yellowitz, DMD, MPH

Associate Professor; Director, Special Care and Geriatric Dentistry,

University of Maryland School of Dentistry, Baltimore, Maryland [A3]

Lam Minh Yen, MD

Senior Clinical Researcher, Oxford University Clinical Research Unit, Ho Chi

Minh City, Vietnam [152]

Neal S. Young, MD

Chief, Hematology Branch, National Heart, Lung, and Blood Institute,

National Institutes of Health, Bethesda, Maryland [102, 469]

Paul C. Zei, MD, PhD

Associate Professor of Medicine, Harvard Medical School; Director, Clinical

Atrial Fibrillation Program, Brigham and Women’s Hospital, Boston,

Massachusetts [243, 246–251]

Jing Zhou, MD, PhD, FASN

Professor of Medicine, Harvard Medical School; Director, Laboratory of

Molecular Genetics and Developmental Biology of Disease, Renal Division;

Director, Center for Polycystic Kidney Disease Research, Brigham and

Women’s Hospital; Boston, Massachusetts [315]

Werner Zimmerli, MD

Professor of Medicine, Basel University, Interdisciplinary Unit of

Orthopaedic Infections, Kantonsspital Baselland, Liestal, Switzerland [131]

Laura A. Zimmerman, MPH

Epidemiologist, Centers for Disease Control and Prevention, Atlanta,

Georgia [206]

Preface

The Editors are pleased to present the 21st edition of Harrison’s Principles of

Internal Medicine. This 21st edition is a true landmark in medicine, spanning

71 years and multiple generations of trainees and practicing clinicians. While

medicine and medical education have evolved, readers will appreciate how

this classic textbook has retained enduring features that have distinguished

it among medical texts—a sharp focus on the clinical presentation of disease,

expert in-depth summaries of pathophysiology and treatment, and highlights

of emerging frontiers of science and medicine. Indeed, Harrison’s retains its

conviction that, in the profession of medicine, we are all perpetual students

with lifelong learning as our common goal.

Harrison’s is intended for learners throughout their careers. For students,

Part 1, Chapter 1 begins with an overview of “The Practice of Medicine.” In

this introductory chapter, the editors continue the tradition of orienting clinicians to the science and the art of medicine, emphasizing the values of our

profession while incorporating new advances in technology, science, and clinical care. Part 2, “Cardinal Manifestations and Presentation of Diseases,” is a

signature feature of Harrison’s. These chapters eloquently describe how patients

present with common clinical conditions, such as headache, fever, cough, palpitations, or anemia, and provide an overview of typical symptoms, physical

findings, and differential diagnosis. Mastery of these topics prepares students

for subsequent chapters on specific diseases they will encounter in courses on

pathophysiology and in clinical clerkships. For residents and fellows caring for

patients and preparing for board examinations, Harrison’s remains a definitive

source of trusted content written by internationally renowned experts. Trainees

will be reassured by the depth of content, comprehensive tables, and illuminating figures and clinical algorithms. Many examination questions are based

on key testing points derived from Harrison’s chapters. A useful companion

book, Harrison’s Self-Assessment and Board Review, includes over 1000 questions, offers comprehensive explanations of the correct answer, and provides

links to the relevant chapters in the textbook. Practicing clinicians must keep

up with an ever-changing knowledge base and clinical guidelines as part of lifelong learning. Clinicians can trust that chapters are updated extensively with

each edition of Harrison’s. The text is an excellent point-of-care reference for

clinical questions, differential diagnosis, and patient management. In addition

to the expanded and detailed Treatment sections, Harrison’s continues its tradition of including “Approach to the Patient” sections, which provide an expert’s

overview of the practical management of common but often complex clinical

conditions.

This edition has been modified extensively in its structure as well as its content and offers a more consistently standardized format for each disease chapter.

The authors and editors have curated rigorously and synthesized the vast amount

of information that comprises general internal medicine—and each of the major

specialties—into a highly readable and informative two-volume book. Readers

will appreciate the concise writing style and substantive quality that have always

characterized Harrison’s. This book has a sharp focus on essential information

with a goal of providing clear and definitive answers to clinical questions.

In the 21st edition, examples of new chapters include “Precision Medicine

and Clinical Care,” focusing on the ever-growing pool of “big data” used to provide individualized genotype-phenotype correlations; “Mechanisms of Regulation and Dysregulation of the Immune System,” focusing on the extraordinary

advances made over the past 5 years in understanding the complex and subtle

mechanisms whereby the immune system is regulated and how perturbations

in this regulation lead to disease states as well as targets for therapeutic intervention; new chapters on Alzheimer’s disease and related conditions, with a

special focus on vascular dementia, a common and treatable cause of cognitive

loss; and a new chapter on marijuana and marijuana use disorders, as well as

updated management guidelines for multiple sclerosis and the expanding array

of other autoimmune nervous system diseases that can now be identified and

treated. 

Other new chapters include “Vaccine Opposition and Hesitancy,” “Precision

Medicine and Clinical Care,” “Diagnosis: Reducing Errors and Improving

Quality,” “Approach to the Patient with Renal or Urinary Tract Disease,” “Interventional Nephrology,” “Health Effects of Climate Change,” and “Circulating

Nucleic Acids as Liquid Biopsies and Noninvasive Disease Biomarkers.” In

addition, many chapters have new authors.

The chapter, “Vaccine Opposition and Hesitancy,” provides an overview of

the current antivaccination crisis, the issues involved, and specific strategies to

utilize within the clinical setting to address the lack of confidence that many

patients feel toward the health care system. The chapter, “Metabolomics,” outlines an emerging and important new and sensitive approach to measuring perturbations within a system or patient that will likely become a routine part of

the clinical armamentarium for diagnosing, monitoring, and treating disease.

In addition to these and other new topics, the 21st edition presents important updates in the established chapters, such as the microbiology and clinical

management of SARS-CoV-2 infection, the use of gene editing for sickle cell

anemia and thalassemia, gene therapy for hemophilia, new immunotherapies for autoimmune diseases and cancers, and novel approaches to vaccine

development, among many others. Our focus on forwarding-looking issues

of emerging clinical importance continues with the series of chapters entitled

“Frontiers,” which foreshadows cutting-edge science that will change medical

practice in the near term. Examples of new Frontier chapters include “Machine

Learning and Augmented Intelligence,” “Metabolomics,” “Protein Folding Disorders,” and “Novel Approaches to Disease of Unknown Etiology.”

Harrison’s content is available in a variety of print and digital formats,

including eBooks, apps, and a popular, widely used online platform available

at www.accessmedicine.com.

We have many people to thank for their efforts in producing this book. First,

the authors have done a superb job of producing authoritative chapters that

synthesize vast amounts of scientific and clinical data to create informative and

practical approaches to managing patients. In today’s information-rich, rapidly

evolving environment, they have ensured that this information is current. We

are most grateful to our colleagues who work closely with each editor to facilitate communication with the authors and help us keep Harrison’s content current. In particular, we wish to acknowledge the expert support of Lauren Bauer,

Patricia Conrad, Patricia L. Duffey, Gregory K. Folkers, Julie B. McCoy, Elizabeth Robbins, Marie Scurti, and Stephanie C. Tribuna. Scott Grillo and James

Shanahan, our long-standing partners at McGraw Hill’s Professional Publishing group, have inspired the creative and dynamic evolution of Harrison’s,

guiding the development of the book and its related products in new formats.

Kim Davis, as Managing Editor, has adeptly ensured that the complex production of this multi-authored textbook proceeded smoothly and efficiently.

Priscilla Beer oversaw the production of our videos and animations; Jeffrey

Herzich, Elleanore Waka, and Rachel Norton, along with other members of the

McGraw Hill staff; and Revathi Viswanathan of KnowledgeWorks Global Ltd.,

shepherded the production of this new edition.

We are privileged to have compiled this 21st edition and are enthusiastic

about all that it offers our readers. We learned much in the process of editing

Harrison’s and hope that you will find this edition uniquely valuable as a clinical

and educational resource.

The Editors

Related Harrison’s Resources

A complete collection to meet your educational, clinical, and board prep needs.

Harrison’s Online

The online edition of Harrison’s is available at www.accessmedicine.com. It requires an institutional or individual subscription separate from the purchase of the

print book. The online edition of Harrison’s features all the chapters from the print edition, plus more than two dozen supplementary chapters in print, atlas, and

video formats. Harrison’s Online includes numerous monthly updates, from the editors of Harrison’s, on important new developments in medical research and

practice. Easily search across the entire Harrison’s content set, download images and tables for presentations and lectures, view step-by-step videos on common

clinical procedures, access the text of the Harrison’s Manual of Medicine, set up a personalized test exam for board prep, get access to chapters from new editions

of Harrison’s months before book publication, and more.

The Harrison’s Manual of Medicine

The Harrison’s Manual of Medicine provides high-yield, rapid-access clinical summaries of Harrison’s content, suitable for use at the bedside. Chapters in the Manual reflect those likely to be encountered in both the inpatient and outpatient setting. The format is built for ease of use. The Manual is available in print, eBook,

and app. In addition, the full text of the Manual is available to subscribers at accessmedicine.com. This format provides flexibility of format to customers, who can

move back and forth between the full scope of Harrison’s Principles of Internal Medicine and the high-yield clinical essentials of the Manual.

The Manual includes more than 200 chapters in 17 sections and covers presenting signs and symptoms and major conditions seen in both inpatient and outpatient

settings. The full table of contents is available at www.accessmedicine.com.

The Harrison’s Self-Assessment and Board Review

This practical resource provides more than 1000 self-assessment questions, most in board-style clinical vignette format with multiple choice answers. The explanations for the questions are comprehensive and provide detailed guidance on correct and incorrect answers. Question-and-answer sets include references to related

chapters in Harrison’s Principles of Internal Medicine for more comprehensive understanding. Use this very handy resource for primary and recertification exam

prep, for rotational shelf exams, and for general assessment of understanding of the principles of clinical medicine. This resource is available as a print book, an

eBook, an app, and on accessmedicine.com, where users can create personalized testing experiences and receive instant scores on practice tests.

Harrison’s Podclass

Our podcast presents bi-weekly episodes covering clinical vignettes across internal medicine, with two expert discussants reviewing common and challenging

patient presentations and a series of self-assessment Q&A choices tied to each case. The hosts work through correct and incorrect answer choices and summarize

cases with practical pearls that all students and clinicians will find helpful and interesting. Harrison’s Podclass is available in most of the common podcast outlets

and on www.accessmedicine.com.

The Profession of Medicine PART 1

The Practice of Medicine

The Editors

1

ENDURING VALUES OF THE MEDICAL

PROFESSION

No greater opportunity, responsibility, or obligation can fall to the lot of a

human being than to become a physician. In the care of the suffering, [the

physician] needs technical skill, scientific knowledge, and human understanding. Tact, sympathy, and understanding are expected of the physician,

for the patient is no mere collection of symptoms, signs, disordered functions, damaged organs, and disturbed emotions. [The patient] is human,

fearful, and hopeful, seeking relief, help, and reassurance.

—Harrison’s Principles of Internal Medicine, 1950

The practice of medicine has changed in significant ways since the first

edition of this book was published in 1950. The advent of molecular

genetics, sophisticated new imaging techniques, robotics, and advances in

bioinformatics and information technology have contributed to an explosion of scientific information that has changed fundamentally the way

physicians define, diagnose, treat, and attempt to prevent disease. This

growth of scientific knowledge continues to evolve at an accelerated pace.

The widespread use of electronic medical records and the Internet

have altered the way physicians and other health care providers access

and exchange information as a routine part of medical education and

practice (Fig. 1-1). As today’s physicians strive to integrate an everexpanding body of scientific knowledge into everyday practice, it is

critically important to remember two key principles: first, the ultimate

goal of medicine is to prevent disease and, when it occurs, to diagnose

it early and provide effective treatment; and second, despite 70 years

of scientific advances since the first edition of this text, a trusting relationship between physician and patient still lies at the heart of effective

patient care.

■ THE SCIENCE AND ART OF MEDICINE

Deductive reasoning and applied technology form the foundation for

the approach and solution to many clinical problems. Extraordinary

advances in biochemistry, cell biology, immunology, and genomics,

coupled with newly developed imaging techniques, provide a window

into the most remote recesses of the body and allow access to the

innermost parts of the cell. Revelations about the nature of genes and

single cells have opened a portal for formulating a new molecular

basis for the physiology of systems. Researchers are deciphering the

complex mechanisms by which genes are regulated, and increasingly,

physicians are learning how subtle changes in many different genes,

acting in an integrative contextual way, can affect the function of cells

and organisms. Clinicians have developed a new appreciation of the

role of stem cells in normal tissue function, in the development of

cancer and other disorders, and in the treatment of certain diseases.

Entirely new areas of research, including studies of the human microbiome, epigenetics, and noncoding RNAs as regulatory features of

the genome, have become important for understanding both health

and disease. Information technology enables the interrogation of

medical records from millions of individuals, yielding new insights

into the etiology, characteristics, prognosis, and stratification of many

diseases. With the increasing availability of very large data sets (“big

data”) from omic analyses and the electronic medical record, there is

now a growing need for machine learning and artificial intelligence

for unbiased analyses that enhance clinical predictive accuracy. The

knowledge gleaned from the science of medicine continues to enhance

the understanding by physicians of complex pathologic processes

and to provide new approaches to disease prevention, diagnosis, and

treatment. With continued refinement of unique omic signatures

coupled with nuanced clinical pathophenotypes, the profession moves

ever closer to practical precision medicine. Yet, skill in the most

sophisticated applications of laboratory technology and in the use of

the latest therapeutic modality alone does not make a good physician.

Extraordinary advances in vaccine platform technology and the use

of cryo-electron microscopy for the structure-based design of vaccine

immunogens have transformed the field of vaccinology, resulting in

the unprecedented speed and success with which COVID-19 vaccines

were developed.

When a patient poses challenging clinical problems, an effective

physician must be able to identify the crucial elements in a complex

history and physical examination; order the appropriate laboratory,

imaging, and diagnostic tests; and extract the key results from densely

populated computer screens to determine whether to treat or to

“watch.” As the number of tests increases, so does the likelihood that

some incidental finding, completely unrelated to the clinical problem

at hand, will be uncovered. Deciding whether a clinical clue is worth

pursuing or should be dismissed as a “red herring” and weighing

whether a proposed test, preventive measure, or treatment entails a

greater risk than the disease itself are essential judgments that a skilled

clinician must make many times each day. This combination of medical knowledge, intuition, experience, and judgment defines the art of

medicine, which is as necessary to the practice of medicine and the precision medicine of the future as is a sound scientific base, and as important for contemporary medical practice as it has been in earlier eras.

■ CLINICAL SKILLS

History-Taking The recorded history of an illness should include

all the facts of medical significance in the life of the patient. Recent

events should be given the most attention. Patients should, at some

early point, have the opportunity to tell their own story of the illness

without frequent interruption and, when appropriate, should receive

expressions of interest, encouragement, and empathy from the physician. Any event related by a patient, however trivial or seemingly

irrelevant, may provide the key to solving the medical problem. A

methodical review of systems is important to elicit features of an

underlying disease that might not be mentioned in the patient’s narrative. In general, patients who feel comfortable with the physician

will offer more complete information; thus, putting the patient at ease

contributes substantially to obtaining an adequate history.

FIGURE 1-1 The Doctor by Luke Fildes depicts the caring relationship between

this Victorian physician and a very ill child. Painted in 1891, the painting reflects

the death of the painter’s young son from typhoid fever and was intended to reflect

the compassionate care provided by the physician even when his tools were not

able to influence the course of disease. (Source: History and Art Collection/Alamy

Stock Photo.)

2PART 1 The Profession of Medicine

An informative history is more than eliciting an orderly listing

of symptoms. By listening to patients and noting the ways in which

they describe their symptoms, physicians can gain valuable insight.

Inflections of voice, facial expression, gestures, and attitude (i.e., “body

language”) may offer important clues to patients’ perception of and

reaction to their symptoms. Because patients vary considerably in

their medical sophistication and ability to recall facts, the reported

medical history should be corroborated whenever possible. The social

history also can provide important insights into the types of diseases

that should be considered and can identify practical considerations for

subsequent management. The family history not only identifies rare

genetic disorders or common exposures, but often reveals risk factors

for common disorders, such as coronary heart disease, hypertension,

autoimmunity, and asthma. A thorough family history may require

input from multiple relatives to ensure completeness and accuracy.

An experienced clinician can usually formulate a relevant differential

diagnosis from the history alone, using the physical examination and

diagnostic tests to narrow the list or reveal unexpected findings that

lead to more focused inquiry.

The very act of eliciting the history provides the physician with an

opportunity to establish or enhance a unique bond that can form the

basis for a good patient–physician relationship. This process helps the

physician develop an appreciation of the patient’s view of the illness,

the patient’s expectations of the physician and the health care system,

and the financial and social implications of the illness for the patient.

Although current health care settings may impose time constraints

on patient visits, it is important not to rush the encounter. A hurried

approach may lead patients to believe that what they are relating is not

of importance to the physician, and, as a result, they may withhold

relevant information. The confidentiality of the patient–physician relationship cannot be overemphasized.

Physical Examination The purpose of the physical examination is

to identify physical signs of disease. The significance of these objective

indications of disease is enhanced when they confirm a functional or

structural change already suggested by the patient’s history. At times,

however, physical signs may be the only evidence of disease and may

not have been suggested by the history.

The physical examination should be methodical and thorough, with

consideration given to the patient’s comfort and modesty. Although

attention is often directed by the history to the diseased organ or part

of the body, the examination of a new patient must extend from head

to toe in an objective search for abnormalities. The results of the examination, like the details of the history, should be recorded at the time

they are elicited—not hours later, when they are subject to the distortions of memory. Physical examination skills should be learned under

direct observation of experienced clinicians. Even highly experienced

clinicians can benefit from ongoing coaching and feedback. Simulation

laboratories and standardized patients play an increasingly important

role in the development of clinical skills. Although the skills of physical

diagnosis are acquired with experience, it is not merely technique that

determines success in identifying signs of disease. The detection of a

few scattered petechiae, a faint diastolic murmur, or a small mass in the

abdomen is not a question of keener eyes and ears or more sensitive

fingers, but of a mind alert to those findings. Because physical findings

can change with time, the physical examination should be repeated as

frequently as the clinical situation warrants.

Given the many highly sensitive diagnostic tests now available

(particularly imaging techniques), it may be tempting to place less

emphasis on the physical examination. Some are critical of physical

diagnosis based on perceived low levels of specificity and sensitivity.

Indeed, many patients are seen by consultants only after a series of

diagnostic tests have been performed and the results are known. This

fact should not deter the physician from performing a thorough physical examination since important clinical findings may have escaped

detection by diagnostic tests. Especially important, a thorough and

thoughtful physical examination may render a laboratory finding

unimportant (i.e., certain echocardiographic regurgitant lesions). The

act of a hands-on examination of the patient also offers an opportunity

for communication and may have reassuring effects that foster the

patient–physician relationship.

Diagnostic Studies Physicians rely increasingly on a wide array

of laboratory and imaging tests to make diagnoses and ultimately to

solve clinical problems; however, such information does not relieve the

physician from the responsibility of carefully observing and examining

the patient. It is also essential to appreciate the limitations of diagnostic tests. By virtue of their apparent precision, these tests often gain

an aura of certainty regardless of the fallibility of the tests themselves,

the instruments used in the tests, and the individuals performing or

interpreting the tests. Physicians must weigh the expense involved in

laboratory procedures against the value of the information these procedures are likely to provide.

Single laboratory tests are rarely ordered. Instead, physicians generally request “batteries” of multiple tests, which often prove useful

and can be performed with a single specimen at relatively low cost.

For example, abnormalities of hepatic function may provide the clue

to nonspecific symptoms such as generalized weakness and increased

fatigability, suggesting a diagnosis of chronic liver disease. Sometimes

a single abnormality, such as an elevated serum calcium level, points to

a particular disease, such as hyperparathyroidism.

The thoughtful use of screening tests (e.g., measurement of lowdensity lipoprotein cholesterol) may allow early intervention to prevent

disease (Chap. 6). Screening tests are most informative when they

are directed toward common diseases and when their results indicate

whether other potentially useful—but often costly—tests or interventions are needed. On the one hand, biochemical measurements,

together with simple laboratory determinations such as routine serum

chemistries, blood counts, and urinalysis, often provide a major clue to

the presence of a pathologic process. On the other hand, the physician

must learn to evaluate occasional screening-test abnormalities that do

not necessarily connote significant disease. An in-depth workup after

the report of an isolated laboratory abnormality in a person who is

otherwise well is often wasteful and unproductive. Because so many

tests are performed routinely for screening purposes, it is not unusual

for one or two values to be slightly abnormal. Nevertheless, even if

there is no reason to suspect an underlying illness, tests yielding abnormal results ordinarily are repeated to rule out laboratory error. If an

abnormality is confirmed, it is important to consider its potential significance in the context of the patient’s condition and other test results.

There is almost continual development of technically improved

imaging studies with greater sensitivity and specificity. These tests

provide remarkably detailed anatomic information that can be pivotal

in informing medical decision-making. MRI, CT, ultrasonography, a

variety of isotopic scans, and positron emission tomography (PET)

have supplanted older, more invasive approaches and opened new

diagnostic vistas. In light of their capabilities and the rapidity with

which they can lead to a diagnosis, it is tempting to order a battery of

imaging studies. All physicians have had experiences in which imaging

studies revealed findings that led to an unexpected diagnosis. Nonetheless, patients must endure each of these tests, and the added cost

of unnecessary testing is substantial. Furthermore, investigation of an

unexpected abnormal finding may lead to an iatrogenic complication

or to the diagnosis of an irrelevant or incidental problem. A skilled

physician must learn to use these powerful diagnostic tools judiciously,

always considering whether the results will alter management and

benefit the patient.

■ MANAGEMENT OF PATIENT CARE

Team-Based Care Medical practice has long involved teams,

particularly physicians working with nurses and, more recently, with

physician assistants and nurse practitioners. Advances in medicine

have increased our ability to manage very complex clinical situations

(e.g., intensive care units [ICUs], bone marrow transplantation) and

have shifted the burden of disease toward chronic illnesses. Because an

individual patient may have multiple chronic diseases, he or she may

be cared for by several specialists as well as a primary care physician. In

the inpatient setting, care may involve multiple consultants along with