Harrison's Manual of Medicine [20 ed.] 9781260455359, 1260455351, 9781260455342, 1260455343

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EDITORS J. Larry Jameson, MD, PhD

Robert G. Dunlop Professor of Medicine Dean, Raymond and Ruth Perelman School of Medicine Executive Vice President, University of Pennsylvania for the   Health System Philadelphia, Pennsylvania

Anthony S. Fauci, MD

Chief, Laboratory of Immunoregulation Director, National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland

Dennis L. Kasper, MD

William Ellery Channing Professor of Medicine Professor of Immunology Department of Immunology Harvard Medical School Boston, Massachusetts

Stephen L. Hauser, MD

Robert A. Fishman Distinguished Professor Department of Neurology Director, UCSF Weill Institute for Neurosciences University of California, San Francisco San Francisco, California

Dan L. Longo, MD

Professor of Medicine Harvard Medical School Senior Physician, Brigham and Women’s Hospital Deputy Editor, New England Journal of Medicine Boston, Massachusetts

Joseph Loscalzo, MD, PhD

Hersey Professor of the Theory and Practice of Medicine Harvard Medical School Chairman, Department of Medicine Physician-in-Chief, Brigham and Women’s Hospital Boston, Massachusetts

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EDITORS J. Larry Jameson, MD, PhD Anthony S. Fauci, MD Dennis L. Kasper, MD Stephen L. Hauser, MD Dan L. Longo, MD Joseph Loscalzo, MD, PhD

New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

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Copyright © 2020, 2016, 2013, 2009, 2005, 2002, 1998, 1995, 1991, 1988 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-1-26-045535-9 MHID: 1-26-045535-1 The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-045534-2, MHID: 1-26-045534-3. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com. NOTE: Dr. Fauci’s work as editor and author was performed outside the scope of his employment as a U.S. government employee. This work represents his personal and professional views and not necessarily those of the U.S. government. TERMS OF USE This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

Contents

Contributors.............................................................................................................. xiii Preface..........................................................................................................................xv Acknowledgments................................................................................................... xvii

 SECTION 1   Care of the Hospitalized Patient

1 Electrolytes....................................................................................1 2 Acid-Base Disorders....................................................................16 3 Diagnostic Imaging in Internal Medicine.....................................22 4 Procedures Commonly Performed by Internists............................26 5 Principles of Critical Care Medicine.............................................32 6 Pain and Its Management............................................................35 7 Assessment of Nutritional Status.................................................40 8 Enteral and Parenteral Nutrition..................................................47 9 Transfusion and Pheresis Therapy................................................49 10 Palliative and End-of-Life Care...................................................51

 SECTION 2  Medical Emergencies

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

Cardiovascular Collapse and Sudden Death.................................59 Shock..........................................................................................62 Narcotic Overdose.......................................................................66 Sepsis and Septic Shock...............................................................68 Acute Pulmonary Edema.............................................................71 Acute Respiratory Distress Syndrome..........................................72 Respiratory Failure......................................................................75 Confusion, Stupor, and Coma......................................................76 Stroke..........................................................................................82 Subarachnoid Hemorrhage..........................................................91 Increased Intracranial Pressure and Head Trauma.........................93 Spinal Cord Compression............................................................98 Hypoxic-Ischemic Encephalopathy............................................100 Status Epilepticus......................................................................101 Diabetic Ketoacidosis and Hyperosmolar Coma.........................103 Hypoglycemia............................................................................106 Oncologic Emergencies.............................................................109 Anaphylaxis...............................................................................114 Bites, Venoms, Stings, and Marine Poisonings............................115

v

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CONTENTS

 SECTION 3   Common Patient Presentations

30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

Fever, Hyperthermia, and Rash..................................................127 Generalized Fatigue...................................................................131 Unintentional Weight Loss........................................................135 Chest Pain.................................................................................137 Palpitations...............................................................................141 Dyspnea....................................................................................141 Cyanosis....................................................................................144 Cough and Hemoptysis..............................................................146 Edema.......................................................................................149 Abdominal Pain.........................................................................153 Nausea, Vomiting, and Indigestion.............................................157 Dysphagia.................................................................................161 Diarrhea, Malabsorption, and Constipation...............................166 Gastrointestinal Bleeding...........................................................174 Jaundice and Evaluation of Liver Function.................................178 Ascites.......................................................................................186 Lymphadenopathy and Splenomegaly........................................189 Anemia and Polycythemia..........................................................194 Azotemia and Urinary Abnormalities.........................................197 Pain and Swelling of Joints.........................................................203 Back and Neck Pain...................................................................207 Headache..................................................................................215 Syncope.....................................................................................223 Dizziness and Vertigo................................................................227 Acute Visual Loss and Double Vision.........................................230 Weakness and Paralysis..............................................................234 Tremor and Movement Disorders..............................................237 Aphasia.....................................................................................240 Sleep Disorders..........................................................................242

 SECTION 4  Otolaryngology

59 Sore Throat, Earache, and Upper Respiratory Symptoms............247

 SECTION 5  Dermatology

60 General Examination of the Skin...............................................255 61 Common Skin Conditions.........................................................258

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CONTENTS

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 SECTION 6   Hematology and Oncology

62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79

Examination of Blood Smears and Bone Marrow.......................267 Red Blood Cell Disorders..........................................................269 Leukocytosis and Leukopenia....................................................275 Bleeding and Thrombotic Disorders...........................................278 Myeloid Leukemias, Myelodysplasia, and Myeloproliferative Syndromes....................................................285 Lymphoid Malignancies............................................................296 Skin Cancer...............................................................................309 Head and Neck Cancer..............................................................312 Lung Cancer..............................................................................314 Breast Cancer............................................................................320 Tumors of the Gastrointestinal Tract..........................................325 Genitourinary Tract Cancer.......................................................337 Gynecologic Cancer...................................................................343 Tumors of the Nervous System...................................................347 Prostate Hyperplasia and Carcinoma..........................................352 Cancer of Unknown Primary Site...............................................355 Paraneoplastic Endocrine Syndromes.........................................359 Neurologic Paraneoplastic Syndromes........................................362

 SECTION 7  Infectious Diseases

80 81 82 83 84 85 86 87 88 89 90

Growing Threats in Infectious Disease.......................................367 Infections Acquired in Health Care Facilities..............................371 Infections in the Immunocompromised Host.............................376 Infective Endocarditis................................................................387 Intraabdominal Infections..........................................................398 Infectious Diarrheas and Bacterial Food Poisoning.....................403 Sexually Transmitted and Reproductive Tract Infections.............417 Infections of the Skin, Soft Tissues, Joints, and Bones................433 Pneumococcal Infections...........................................................440 Staphylococcal Infections...........................................................444 Streptococcal/Enterococcal Infections, Diphtheria, and Infections Caused by Other Corynebacteria and Related Species..........................................................................453 91 Meningococcal and Listerial Infections......................................463 92 Infections Caused by Haemophilus, Bordetella, Moraxella, and HACEK Group Organisms.................................................467

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CONTENTS

93 Diseases Caused by Gram-Negative Enteric Bacteria and Pseudomonads....................................................................473 94 Infections Caused by Miscellaneous Gram-Negative Bacilli........483 95 Anaerobic Infections..................................................................490 96 Nocardiosis, Actinomycosis, and Whipple’s Disease...................498 97 Tuberculosis and Other Mycobacterial Infections.......................503 98 Lyme Disease and Other Nonsyphilitic Spirochetal Infections..................................................................................515 99 Rickettsial Diseases....................................................................521 100 Mycoplasma pneumoniae, Legionella Species, and Chlamydia pneumoniae....................................................................531 101 Chlamydia trachomatis and Chlamydia psittaci................................535 102 Infections with Herpes Simplex Virus, Varicella-Zoster Virus, Cytomegalovirus, Epstein-Barr Virus, and Human Herpesvirus Types 6, 7, and 8.........................................537 103 Influenza and Other Viral Respiratory Diseases.........................551 104 Rubeola, Rubella, Mumps, and Parvovirus Infections.................555 105 Enterovirus Infections...............................................................561 106 Insect- and Animal-Borne Viral Infections.................................564 107 HIV Infection and AIDS...........................................................572 108 Pneumocystis Pneumonia, Candidiasis, and Other Fungal Infections.............................................................588 109 Overview of Parasitic Infections.................................................606 110 Malaria, Toxoplasmosis, Babesiosis, and Other Protozoal Infections........................................................610 111 Helminthic Infections and Ectoparasite Infestations..................625

 SECTION 8  Cardiology

112 Physical Examination of the Heart.............................................639 113 Electrocardiography...................................................................644 114 Noninvasive Examination of the Heart.......................................648 115 Congenital Heart Disease in the Adult.......................................653 116 Valvular Heart Disease...............................................................658 117 Cardiomyopathies and Myocarditis............................................666 118 Pericardial Disease.....................................................................671 119 Hypertension.............................................................................676 120 Metabolic Syndrome..................................................................682 121 ST-Segment Elevation Myocardial Infarction............................684 122 Unstable Angina and Non-ST-Elevation Myocardial Infarction................................................................694

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CONTENTS

ix

123 Chronic Stable Angina...............................................................698 124 Bradyarrhythmias......................................................................703 125 Tachyarrhythmias......................................................................706 126 Heart Failure and Cor Pulmonale...............................................715 127 Diseases of the Aorta.................................................................721 128 Peripheral Vascular Disease........................................................724 129 Pulmonary Hypertension...........................................................727

 SECTION 9  Pulmonology

130 Diagnostic Procedures in Respiratory Disease............................731 131 Asthma......................................................................................734 132 Environmental Lung Diseases....................................................738 133 Chronic Obstructive Pulmonary Disease....................................741 134 Pneumonia, Bronchiectasis, and Lung Abscess...........................745 135 Pulmonary Thromboembolism and Deep-Vein Thrombosis.......754 136 Interstitial Lung Disease............................................................758 137 Diseases of the Pleura................................................................763 138 Diseases of the Mediastinum......................................................766 139 Disorders of Ventilation.............................................................767 140 Sleep Apnea...............................................................................768

SECTION 10    Nephrology

141 Acute Renal Failure...................................................................771 142 Chronic Kidney Disease and Uremia..........................................776 143 Dialysis......................................................................................778 144 Renal Transplantation................................................................781 145 Glomerular Diseases..................................................................784 146 Renal Tubular Disease...............................................................793 147 Dysuria, Urinary Tract Infections, Bladder Pain, and Interstitial Cystitis.....................................................................800 148 Nephrolithiasis..........................................................................805 149 Urinary Tract Obstruction.........................................................807

SECTION 11     Gastroenterology

150 Peptic Ulcer and Related Disorders............................................811 151 Inflammatory Bowel Diseases....................................................817 152 Colonic and Anorectal Diseases.................................................823 153 Cholelithiasis, Cholecystitis, and Cholangitis.............................828 154 Pancreatitis................................................................................835

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155 156 157 158

CONTENTS

Acute Hepatitis..........................................................................840 Chronic Hepatitis......................................................................847 Cirrhosis and Alcoholic Liver Disease........................................855 Portal Hypertension...................................................................860

SECTION 12     Allergy, Clinical Immunology,

and Rheumatology

159 Diseases of Immediate-Type Hypersensitivity.............................863 160 Primary Immune Deficiency Diseases........................................868 161 Systemic Lupus Erythematosus..................................................871 162 Rheumatoid Arthritis................................................................873 163 The Spondyloarthritides............................................................875 164 Other Connective Tissue Diseases.............................................882 165 Vasculitis...................................................................................885 166 Osteoarthritis............................................................................889 167 Gout, Pseudogout, and Related Diseases....................................891 168 Other Musculoskeletal Disorders...............................................896 169 Sarcoidosis.................................................................................899 170 Amyloidosis...............................................................................901

SECTION 13     Endocrinology and Metabolism

171 Disorders of the Anterior Pituitary and Hypothalamus...............905 172 Diabetes Insipidus and Syndrome of Inappropriate Antidiuretic Hormone.........................................912 173 Thyroid Gland Disorders...........................................................915 174 Adrenal Gland Disorders...........................................................924 175 Obesity......................................................................................930 176 Diabetes Mellitus......................................................................932 177 Disorders of the Male Reproductive System...............................941 178 Disorders of the Female Reproductive System............................946 179 Hypercalcemia and Hypocalcemia..............................................955 180 Osteoporosis and Osteomalacia..................................................961 181 Hypercholesterolemia and Hypertriglyceridemia........................966 182 Hemochromatosis, Porphyrias, and Wilson’s Disease..................972

SECTION 14     Neurology

183 The Neurologic Examination.....................................................979 184 Seizures and Epilepsy.................................................................987 185 Alzheimer’s Disease and Other Dementias.................................999

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CONTENTS

186 187 188 189 190 191 192 193 194 195 196 197 198

xi

Parkinson’s Disease.................................................................. 1007 Ataxic Disorders...................................................................... 1014 ALS and Other Motor Neuron Diseases.................................. 1017 Autonomic Nervous System Disorders..................................... 1020 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders................................................ 1027 Spinal Cord Diseases............................................................... 1034 Multiple Sclerosis.................................................................... 1040 Neuromyelitis Optica............................................................... 1048 Acute Meningitis and Encephalitis........................................... 1051 Chronic and Recurrent Meningitis........................................... 1063 Peripheral Neuropathies, Including Guillain-Barré Syndrome................................................................................ 1073 Myasthenia Gravis................................................................... 1083 Muscle Diseases....................................................................... 1086

SECTION 15     Psychiatry and Substance Abuse

199 200 201 202 203 204

Psychiatric Disorders............................................................... 1097 Psychiatric Medications........................................................... 1105 Eating Disorders...................................................................... 1114 Alcohol Use Disorder............................................................... 1116 Narcotic Abuse........................................................................ 1120 Cocaine and Other Commonly Used Drugs............................. 1122

SECTION 16     Disease Prevention and Health Maintenance

205 Routine Disease Screening....................................................... 1127 206 Vaccines................................................................................... 1131 207 Cardiovascular Disease Prevention........................................... 1133 208 Prevention and Early Detection of Cancer................................ 1137 209 Smoking Cessation.................................................................. 1144 210 Women’s Health...................................................................... 1147

SECTION 17     Adverse Drug Reactions

211 Adverse Drug Reactions.......................................................... 1151 Index 1153

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NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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Contributors

ASSOCIATE EDITORS S. Andrew Josephson, MD

Professor and Chair, Department of Neurology, University of California, San Francisco, San Francisco, California

Carol A. Langford, MD, MHS

Harold C. Schott Endowed Chair; Director, Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio

Leonard S. Lilly, MD

Professor of Medicine, Harvard Medical School; Chief, Brigham and Women’s/ Faulkner Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts

David B. Mount, MD

Assistant Professor of Medicine, Harvard Medical School; Renal Division, Brigham and Women’s Hospital, Renal Division, Boston VA Healthcare System, Boston, Massachusetts

Edwin K. Silverman, MD, PhD

Professor of Medicine, Harvard Medical School; Chief, Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

Neeraj K. Surana, MD, PhD

Assistant Professor in Pediatrics, Molecular Genetics and Microbiology, and Immunology, Duke University School of Medicine, Durham, North Carolina 

Numbers indicate the chapters written or co-written by the contributor.

Anthony S. Fauci, MD

Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 28, 44, 45, 49, 60, 61, 107, 153–170

Gregory K. Folkers, MPH

Chief of Staff, Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 107, 165

Stephen L. Hauser, MD

Robert A. Fishman Distinguished Professor, Department of Neurology; Director, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California 4, 6, 13, 18–24, 50–58, 75, 79, 183–204, 209

J. Larry Jameson, MD, PhD

Robert G. Dunlop Professor of Medicine; Dean, Raymond and Ruth Perelman School of Medicine; Executive Vice President, University of Pennsylvania for the Health System, Philadelphia, Pennsylvania 3, 4, 7, 8, 25, 26, 31, 32, 120, 171–182, 205, 210

xiii

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CONTRIBUTORS

S. Andrew Josephson, MD

Professor and Chair, Department of Neurology, University of California, San Francisco, San Francisco, California 18-21, 23, 51-54, 57, 183–184, 187, 189, 196–202, 209

Dennis L. Kasper, MD

William Ellery Channing Professor of Medicine; Professor of Immunology, Department of Immunology, Harvard Medical School, Boston, Massachusetts 14, 29, 30, 59, 80–106, 108–111, 134, 147, 206

Carol A. Langford, MD

Harold C. Schott Endowed Chair; Director, Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio 28, 44, 45, 49, 60, 61, 107, 153–170

Leonard S. Lilly, MD

Professor of Medicine, Harvard Medical School; Chief, Brigham and Women’s/ Faulkner Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts 11, 12, 15, 33, 34, 36, 112–119, 121–129, 207

Dan L. Longo, MD

Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts 9, 10, 27, 39–43, 46, 47, 62–74, 76–78, 150–152, 208

Joseph Loscalzo, MD, PhD

Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts 1, 2, 5, 11, 12, 15–17, 33–38, 48, 112–119, 121–146, 148, 149, 207, 211

David B. Mount, MD

Assistant Professor of Medicine, Harvard Medical School; Renal Division, Brigham and Women’s Hospital, Renal Division, Boston VA Healthcare System, Boston, Massachusetts 1, 2, 38, 48, 141–146, 148, 149

Edwin K. Silverman, MD, PhD

Professor of Medicine, Harvard Medical School; Chief, Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 5, 16, 17, 35, 37, 130–133, 135–140

Neeraj K. Surana, MD, PhD

Assistant Professor in Pediatrics, Molecular Genetics and Microbiology, and Immunology, Duke University School of Medicine, Durham, North Carolina  14, 29, 30, 59, 80–106, 108–111, 134, 147, 206

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Preface

Harrison’s Principles of Internal Medicine (HPIM), the premier medical textbook for students and clinicians, provides a comprehensive resource for understanding of the biological and clinical aspects of quality patient care. Harrison’s Manual of Medicine aims to fulfill a different need: As a concise, fact-rich resource for pointof-care, the Manual presents clinical information drawn from the 20th edition of HPIM, covering the key features of the diagnosis, clinical manifestations, and treatment of the major diseases that are likely to be encountered on a medical inpatient service and in the clinic. First published 30 years ago, the Manual is well established as a trusted resource for rapid access to clinically practical information. With each edition, it is updated by experts and has become ever more useful with the rapid expansion of medical knowledge and the increasing time constraints associated with heavy patient-care responsibilities in modern health care settings. The Manual’s popularity and value reflect its abbreviated format, which has proven extremely useful for initial diagnosis and management in time-restricted clinical settings. In particular, the book’s full-color format allows readers to locate and use information quickly. In addition, numerous tables and graphics facilitate decisions at the point of care. Although not a substitute for in-depth analysis of clinical problems, the Manual serves as a ready source of informative summaries that will be useful “on the spot” and that will prepare the reader for more in-depth analysis through more extensive reading at a later time. Of note, McGraw-Hill’s Access Medicine website (www.accessmedicine.com) provides online access to both the Manual and Harrison’s Principles of Internal Medicine, making it very easy to seek additional information when needed. The Manual is also available in a variety of eBook and app formats. Like previous editions, this latest edition of the Manual is intended to keep up with the continual evolution of internal medicine practices. To this end, every chapter from the prior edition has been closely reviewed and updated, with substantial revisions and new chapters provided where appropriate. The Editors learned much in the process of updating the Manual and we hope that you will find this edition uniquely valuable as a clinical and educational resource.

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Acknowledgments

The Editors and McGraw-Hill wish to thank their editorial staff, whose assistance and patience made this edition come out in a timely manner: From the Editors’ offices: Patricia Duffey; Gregory K. Folkers; Andrew Josephson, MD; H. Clifford Lane, MD; Carol A. Langford, MD; Julie B. McCoy; Anita Ortiz; Elizabeth Robbins, MD; Marie E. Scurti; and Stephanie Tribuna. From McGraw-Hill: James F. Shanahan, Kim J. Davis, and Catherine H. Saggese. The Editors also wish to acknowledge contributors to past editions of this Manual, whose work formed the basis for many of the chapters herein: Tamar F. Barlam, MD; Gerhard P. Baumann, MD; Eugene Braunwald, MD; Punit Chadha, MD; Joseph B. Martin, MD, PhD; Michael Sneller, MD; Kenneth Tyler, MD; Sophia Vinogradov, MD; and Jean Wilson, MD.

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GLOSSARY A2

aortic second sound

ABGs arterial blood gases ACE  angiotensin-converting  enzyme AF atrial fibrillation AIDS  acquired immunodeficiency   syndrome ALS  amyotrophic lateral  sclerosis ANA antinuclear antibody ARDS  acute respiratory distress  syndrome bid two times daily biw twice a week bp blood pressure BUN blood urea nitrogen CAPD  continuous ambulatory   peritoneal dialysis CBC complete blood count CF complement fixation CHF congestive heart failure CLL  chronic lymphocytic  leukemia CML chronic myeloid leukemia CMV cytomegalovirus CNS central nervous system CPK creatine phosphokinase CSF cerebrospinal fluid CT computed tomography CVP central venous pressure CXR chest x-ray DIC  disseminated intravascular  coagulation DVT deep-venous thrombosis

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EBV Epstein-Barr virus ECG electrocardiogram EEG electroencephalogram ELISA  enzyme-linked   immunosorbent assay EMG electromyogram ENT ear, nose, and throat EOM extraocular movement ESR  erythrocyte sedimentation  rate FDA  U.S. Food and Drug  Administration FEV1 forced expiratory volume in   first second GFR glomerular filtration rate GI gastrointestinal 

G6PD  glucose-6-phosphate  dehydrogenase Hb hemoglobin Hct hematocrit HDL high-density lipoprotein HIV  human immunodeficiency  virus hs at bedtime HSV herpes simplex virus ICU intensive care unit IFN interferon Ig immunoglobulin IL interleukin IM intramuscular IP intraperitoneal IV intravenous IVC inferior vena cava IVP intravenous pyelogram

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GLOSSARY JVP jugular venous pulse LA left atrium LAD left-axis deviation LBBB left bundle branch block LDH lactate dehydrogenase LDL low-density lipoprotein LFT liver function test LLQ left lower quadrant LP lumbar puncture LUQ left upper quadrant LV left ventricle MI myocardial infarction MIC minimal inhibitory  concentration MRI  magnetic resonance  imaging NPO nothing by mouth NSAIDs  nonsteroidal   anti-inflammatory drugs P2 pulmonic second sound PaO2  partial pressure of O2 in   arterial blood PAO2  partial pressure of O2 in   alveolar blood PCR polymerase chain reaction PFTs pulmonary function tests

PMNs  polymorphonuclear cells   or leukocytes PO by mouth PPD  purified protein   derivative, skin test for  tuberculosis prn as needed pt/pts patient/patients PT prothrombin time PTT  partial thromboplastin  time

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PVCs premature ventricular contractions QAM every morning qd every day qh every hour qhs every bedtime qid four times daily qod every other day RA rheumatoid arthritis RBBB right bundle branch block RBC red blood (cell) count RLQ right lower quadrant RR respiratory rate RUQ right upper quadrant RV right ventricle S1 . . . S4 heart sounds, 1st to 4th SARS  severe acute respiratory  syndrome SC subcutaneous SL sublingual SLE  systemic lupus  erythematosus SVC superior vena cava TIA transient ischemic attack tid three times daily tiw thrice a week TLC total lung capacity TNF tumor necrosis factor UA urinalysis URI  upper respiratory  infection UTI urinary tract infection UV ultraviolet VDRL test for syphilis VZV varicella-zoster virus WBC white blood (cell) count

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Care of the Hospitalized Patient

1

SECTION 1

Electrolytes

SODIUM Disturbances of sodium concentration [Na+] result in most cases from abnormalities of H2O homeostasis, which change the relative ratio of Na+ to H2O. Disorders of Na+ balance per se are, in contrast, associated with changes in extracellular fluid volume, either hypo- or hypervolemia. Maintenance of “arterial circulatory integrity” is achieved in large part by changes in urinary sodium excretion and vascular tone, whereas H2O balance is achieved by changes in both H2O intake and urinary H2O excretion (Table 1-1). Confusion can result from the coexistence of defects in both H2O and Na+ balance. For example, a hypovolemic pt may have an appropriately low urinary Na+ due to increased renal tubular reabsorption of filtered NaCl; a concomitant increase in circulating arginine vasopressin (AVP)—part of the defense of effective circulating volume (Table 1-1)—will cause the renal retention of ingested H2O and the development of hyponatremia. ■■HYPONATREMIA

This is defined as a serum [Na+] 180 mmHg) peristaltic contractions; particularly associated with chest pain or dysphagia, but correlation between symptoms and manometry is inconsistent. Condition may resolve over time or evolve into diffuse spasm; associated with increased frequency of depression, anxiety, and somatization. ■■EVALUATION

Barium swallow shows corkscrew esophagus, pseudodiverticula, and diffuse spasm. Manometry shows spasm with multiple simultaneous esophageal contractions of high amplitude and long duration. In nutcracker esophagus, the contractions are peristaltic and of high amplitude. If heart disease has been ruled out, edrophonium, ergonovine, or bethanechol can be used to provoke spasm. TREATMENT

Spastic Disorders Anticholinergics are usually of limited value; nitrates (isosorbide dinitrate, 5–10 mg PO ac) and calcium antagonists (nifedipine, 10–20 mg PO ac) are more effective. Those refractory to medical management may benefit from balloon dilation. Rare pts require surgical intervention: longitudinal myotomy of esophageal circular muscle. Treatment of concomitant depression or other psychological disturbance may help. ■■SCLERODERMA

Atrophy of the esophageal smooth muscle and fibrosis can make the esophagus aperistaltic and lead to an incompetent LES with attendant reflux esophagitis and stricture. Treatment of gastroesophageal reflux disease is discussed in Chap. 40.

ESOPHAGEAL INFLAMMATION ■■VIRAL ESOPHAGITIS

Herpesviruses I and II, varicella-zoster virus, and CMV can all cause esophagitis; particularly common in immunocompromised pts (e.g., AIDS). Odynophagia, dysphagia, fever, and bleeding are symptoms and signs. Diagnosis is made by endoscopy with biopsy, brush cytology, and culture. TREATMENT

Viral Esophagitis Disease is usually self-limited in the immunocompetent person; viscous lidocaine can relieve pain; in immunocompetent pts, herpes and varicella esophagitis are treated with acyclovir, 200 mg PO five times a day for 7−10 days;

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in prolonged cases and in immunocompromised hosts, treatment is with acyclovir, 400 mg PO five times a day for 14–21 days, famciclovir, 500 mg PO tid, or valacyclovir 1 g PO tid for 7 days. CMV is treated with ganciclovir, 5 mg/kg IV q12h, until healing occurs, which may take weeks. Oral valganciclovir (900 mg bid) is an effective alternative to parenteral treatment. In nonresponders, foscarnet, 90 mg/kg IV q12h for 21 days, may be effective. ■■CANDIDA ESOPHAGITIS

In immunocompromised hosts, or those with malignancy, diabetes, hypoparathyroidism, hemoglobinopathy, systemic lupus erythematosus, corrosive esophageal injury, candidal esophageal infection may present with odynophagia, dysphagia, and oral thrush (50%). Diagnosis is made on endoscopy by identifying yellow-white plaques or nodules on friable red mucosa. Characteristic hyphae are seen on KOH stain. In pts with AIDS, the development of symptoms may prompt an empirical therapeutic trial. TREATMENT

Candida Esophagitis In immunocompromised hosts, fluconazole, 200 mg PO on day 1 followed by 100 mg daily for 2–3 weeks, is treatment of choice; alternatives include itraconazole, 200 mg PO bid, or ketoconazole, 200–400 mg PO daily; long-term maintenance therapy is often required. Poorly responsive pts or those who cannot swallow may respond to caspofungin 50 mg IV qd for 7–21 days. ■■PILL-RELATED ESOPHAGITIS

Doxycycline, tetracycline, aspirin, nonsteroidal anti-inflammatory drugs, KCl, quinidine, ferrous sulfate, clindamycin, alprenolol, and alendronate can induce local inflammation in the esophagus. Predisposing factors include recumbency after swallowing pills with small sips of water and anatomic factors impinging on the esophagus and slowing transit. TREATMENT

Pill-Related Esophagitis Withdraw offending drug, use antacids, and dilate any resulting stricture.

■■EOSINOPHILIC ESOPHAGITIS

Mucosal inflammation with eosinophils with submucosal fibrosis can be seen especially in pts with food allergies. This diagnosis relies on the presence of symptoms of esophagitis with the appropriate findings on esophageal biopsy. Eotaxin 3, an eosinophil chemokine, has been implicated in its etiology. IL-5 and TARC (thymus and activation-related chemokine) levels may be elevated. Treatment involves a 12-week course of swallowed fluticasone (440 µg bid) using a metered-dose inhaler. In 30−50% of pts, proton pump inhibitors can reduce eosinophil infiltrates. ■■OTHER CAUSES OF ESOPHAGITIS IN AIDS

Mycobacteria, Cryptosporidium, Pneumocystis, idiopathic esophageal ulcers, and giant ulcers (possible cytopathic effect of HIV) can occur. Ulcers may respond to systemic glucocorticoids.

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Diarrhea, Malabsorption, and Constipation

NORMAL GASTROINTESTINAL FUNCTION ■■ABSORPTION OF FLUID AND ELECTROLYTES

Fluid delivery to the GI tract is 8–10 L/d, including 2 L/d ingested; most is absorbed in small bowel. About 2 L/d is delivered to the colon; about 0.2 L/d is excreted in the stool. Colonic absorption is normally 0.05–2 L/d, with capacity for 6 L/d if required. Intestinal water absorption passively follows active transport of Na+, Cl–, glucose, and bile salts. Additional transport mechanisms include Cl–/HCO3– exchange, Na+/H+ exchange, H+, K+, Cl–, and HCO3– secretion, Na+glucose cotransport, and active Na+ transport across the basolateral membrane by Na+,K+-ATPase. ■■NUTRIENT ABSORPTION

1. Proximal small intestine: iron, calcium, folate, fats (after hydrolysis of triglycerides to fatty acids by pancreatic lipase and colipase), proteins (after hydrolysis by pancreatic and intestinal peptidases), carbohydrates (after hydrolysis by amylases and disaccharidases); triglycerides absorbed as micelles after solubilization by bile salts; amino acids and dipeptides absorbed via specific carriers; sugars absorbed by active transport 2. Distal small intestine: vitamin B12, bile salts, water 3. Colon: water, electrolytes ■■INTESTINAL MOTILITY

Allows propulsion of intestinal contents from stomach to anus and separation of components to facilitate nutrient absorption. Propulsion is controlled by neural, myogenic, and hormonal mechanisms; mediated by migrating motor complex, an organized wave of neuromuscular activity that originates in the distal stomach during fasting and migrates slowly down the small intestine. Colonic motility is mediated by local peristalsis to propel feces. Defecation is effected by relaxation of internal anal sphincter in response to rectal distention, with voluntary control by contraction of external anal sphincter.

DIARRHEA ■■PHYSIOLOGY

Formally defined as fecal output >200 g/d on low-fiber (western) diet; also frequently used to connote loose or watery stools. Considered acute if 4 weeks. Mediated by one or more of the following mechanisms: ■■OSMOTIC DIARRHEA

Nonabsorbed solutes increase intraluminal oncotic pressure, causing outpouring of water; usually ceases with fasting; stool osmolal gap >40 (see below). Causes include disaccharidase (e.g., lactase) deficiencies, pancreatic insufficiency, bacterial overgrowth, lactulose or sorbitol ingestion, polyvalent laxative abuse, celiac or tropical sprue, and short bowel syndrome. Lactase deficiency can be either primary (more prevalent in blacks and Asians, usually presenting in early adulthood) or secondary (from viral, bacterial, or protozoal gastroenteritis, celiac or tropical sprue, or kwashiorkor).

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■■SECRETORY DIARRHEA

Active ion secretion causes obligatory water loss; diarrhea is usually watery, often profuse, unaffected by fasting; stool Na+ and K+ are elevated with osmolal gap 4 weeks), more insidious course suggests malabsorption, inflammatory bowel disease, metabolic or endocrine disturbance, pancreatic insufficiency, laxative abuse, ischemia, neoplasm (hypersecretory state or partial obstruction), or irritable bowel syndrome. Parasitic and certain forms of bacterial enteritis can

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also produce chronic symptoms. Particularly foul-smelling or oily stool suggests fat malabsorption. Fecal impaction may cause apparent diarrhea because only liquids pass partial obstruction. Several infectious causes of diarrhea are associated with an immunocompromised state. A pathophysiologic mechanism-based list of causes is shown in Table 42-1.

TABLE 42-1  Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism Secretory Causes   Exogenous stimulant laxatives   Chronic ethanol ingestion   Other drugs and toxins   Endogenous laxatives (dihydroxy bile acids)   Idiopathic secretory diarrhea or bile acid diarrhea   Certain bacterial infections   Bowel resection, disease, or fistula (↓ absorption)   Partial bowel obstruction or fecal impaction  Hormone-producing tumors (carcinoid, VIPoma, medullary cancer of thyroid, mastocytosis, gastrinoma, colorectal villous adenoma)   Addison’s disease   Congenital electrolyte absorption defects Osmotic Causes   Osmotic laxatives (Mg2+, PO4−3, SO4−2)   Lactase and other disaccharide deficiencies   Nonabsorbable carbohydrates (sorbitol, lactulose, polyethylene glycol)   Gluten and FODMAP intolerance Steatorrheal Causes  Intraluminal maldigestion (pancreatic exocrine insufficiency, bacterial overgrowth, bariatric surgery, liver disease)  Mucosal malabsorption (celiac sprue, Whipple’s disease, infections, abetalipoproteinemia, ischemia, drug-induced enteropathy)   Postmucosal obstruction (1° or 2° lymphatic obstruction) Inflammatory Causes   Idiopathic inflammatory bowel disease (Crohn’s, chronic ulcerative colitis)   Lymphocytic and collagenous colitis  Immune-related mucosal disease (1° or 2° immunodeficiencies, food allergy, eosinophilic gastroenteritis, graft-versus-host disease)   Infections (invasive bacteria, viruses, and parasites, Brainerd diarrhea)   Radiation injury   Gastrointestinal malignancies Dysmotile Causes   Irritable bowel syndrome (including postinfectious IBS)   Visceral neuromyopathies  Hyperthyroidism   Drugs (prokinetic agents)  Postvagotomy (Continued)

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TABLE 42-1  Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism (Continued) Factitial Causes  Munchausen   Eating disorders Iatrogenic Causes  Cholecystectomy   Ileal resection   Bariatric surgery   Vagotomy, fundoplication

Abbreviation: FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols.

■■PHYSICAL EXAMINATION

Signs of dehydration are often prominent in severe, acute diarrhea. Fever and abdominal tenderness suggest infection or inflammatory disease but are often absent in viral enteritis. Evidence of malnutrition suggests chronic course. Certain signs are frequently associated with specific deficiency states secondary to malabsorption (e.g., cheilosis with riboflavin or iron deficiency, glossitis with B12, folate deficiency). Questions to address in pts with chronic diarrhea are shown in Table 42-2. ■■STOOL EXAMINATION

Culture for bacterial pathogens, examination for leukocytes, measurement of C. difficile toxin, and examination for ova and parasites are important components of evaluation of pts with severe, protracted, or bloody diarrhea. Presence of blood (fecal occult blood test) or leukocytes (Wright’s stain) suggests inflammation (e.g., ulcerative colitis, Crohn’s disease, infection, or ischemia). Gram’s stain of stool can be diagnostic of Staphylococcus, Campylobacter, or Candida infection. Steatorrhea (determined with Sudan III stain of stool sample or 72-h quantitative fecal fat analysis) suggests malabsorption or pancreatic insufficiency. Measurement of Na+ and K+ levels in fecal water helps to distinguish osmotic from other types of diarrhea; osmotic diarrhea is implied by stool osmolal gap > 40, where stool osmolal gap = osmolserum [2 × (Na+ + K+)stool]. ■■LABORATORY STUDIES

Complete blood count may indicate anemia (acute or chronic blood loss or malabsorption of iron, folate, or B12), leukocytosis (inflammation), eosinophilia TABLE 42-2  Physical Examination in Pts with Chronic Diarrhea 1. Are there general features to suggest malabsorption or inflammatory bowel disease (IBD) such as anemia, dermatitis herpetiformis, edema, or clubbing? 2. Are there features to suggest underlying autonomic neuropathy or collagenvascular disease in the pupils, orthostasis, skin, hands, or joints? 3.  Is there an abdominal mass or tenderness? 4.  Are there any abnormalities of rectal mucosa, rectal defects, or altered anal sphincter functions? 5. Are there any mucocutaneous manifestations of systemic disease such as dermatitis herpetiformis (celiac disease), erythema nodosum (ulcerative colitis), flushing (carcinoid), or oral ulcers for IBD or celiac disease?

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(parasitic, neoplastic, and inflammatory bowel diseases). Serum levels of calcium, albumin, iron, cholesterol, folate, B12, vitamin D, and carotene; serum iron-binding capacity; and prothrombin time can provide evidence of intestinal malabsorption or maldigestion. ■■OTHER STUDIES

d-Xylose absorption test is a convenient screen for small-bowel absorptive function. Small-bowel biopsy is especially useful for evaluating intestinal malabsorption. Specialized studies include Schilling test (B12 malabsorption), lactose H2 breath test (carbohydrate malabsorption), [14C]xylose and lactulose H2 breath tests (bacterial overgrowth), glycocholic breath test (ileal malabsorption), triolein breath test (fat malabsorption), and bentiromide and secretin tests (pancreatic insufficiency). Sigmoidoscopy or colonoscopy with biopsy is useful in the diagnosis of colitis (esp. pseudomembranous, ischemic, microscopic); it may not allow distinction between infectious and noninfectious (esp. idiopathic ulcerative) colitis. Barium contrast x-ray studies may suggest malabsorption (thickened bowel folds), inflammatory bowel disease (ileitis or colitis), tuberculosis (ileocecal inflammation), neoplasm, intestinal fistula, or motility disorders. TREATMENT

Diarrhea An approach to the management of acute diarrheal illnesses is shown in Fig. 42-1. Symptomatic therapy includes vigorous rehydration (IV or with oral glucose-electrolyte solutions), electrolyte replacement, binders of osmotically active substances (e.g., kaolin-pectin), and opiates to decrease bowel motility (e.g., loperamide, diphenoxylate); opiates may be contraindicated in infectious or inflammatory causes of diarrhea. An approach to the management of chronic diarrhea is shown in Fig. 42-2.

MALABSORPTION SYNDROMES Intestinal malabsorption of ingested nutrients may produce osmotic diarrhea, steatorrhea, or specific deficiencies (e.g., iron; folate; B12; vitamins A, D, E, and K). Table 42-3 lists common causes of intestinal malabsorption. Protein-losing enteropathy may result from several causes of malabsorption; it is associated with hypoalbuminemia and can be detected by measuring stool α1-antitrypsin or radiolabeled albumin levels. Therapy is directed at the underlying disease.

CONSTIPATION Defined as decrease in frequency of stools to 20 g/day: pancreatic function

Stool fat 14–20 g/day: search for small bowel cause

Normal and stool fat 100-mL blood required for one melenic stool) usually indicates bleeding proximal to ligament of Treitz but may be as distal as ascending colon; pseudomelena may be caused by ingestion of iron, bismuth, licorice, beets, blueberries, and charcoal. 3. Hematochezia: Bright red or maroon rectal bleeding usually implies bleeding beyond ligament of Treitz but may be due to rapid upper GI bleeding (>1000 mL). 4. Positive fecal occult blood test with or without iron deficiency. 5. Symptoms of blood loss: e.g., light-headedness or shortness of breath. ■■HEMODYNAMIC CHANGES

Orthostatic drop in bp >10 mmHg usually indicates >20% reduction in blood volume (± syncope, light-headedness, nausea, sweating, thirst). ■■SHOCK

BP 90%; allows visualization of bleeding site and possibility of therapeutic intervention; mandatory for suspected varices, aortoenteric fistulas; permits identification of “visible vessel” (protruding artery in ulcer crater), which connotes high (∼50%) risk of rebleeding. • Upper GI barium radiography: Accuracy ∼80% in identifying a lesion, though does not confirm source of bleeding; acceptable alternative to endoscopy in resolved or chronic low-grade bleeding. • Selective mesenteric arteriography: When brisk bleeding precludes identification of source at endoscopy. • Radioisotope scanning (e.g., 99Tc tagged to red blood cells or albumin); used primarily as screening test to confirm bleeding is rapid enough for arteriography to be of value or when bleeding is intermittent and of unclear origin.

LOWER GI BLEEDING ■■CAUSES

Anal lesions (hemorrhoids, fissures), rectal trauma, proctitis, colitis (ulcerative colitis, Crohn’s disease, infectious colitis, ischemic colitis, radiation), colonic polyps, colonic carcinoma, angiodysplasia (vascular ectasia), diverticulosis, intussusception, solitary ulcer, blood dyscrasias, vasculitis, connective tissue disease, neurofibroma, amyloidosis, anticoagulation. ■■EVALUATION (SEE BELOW AND FIG. 43-2)

• History and physical examination. • In the presence of hemodynamic changes, perform upper endoscopy followed by colonoscopy. In the absence of hemodynamic changes, perform anoscopy and either flexible sigmoidoscopy or colonoscopy: Exclude hemorrhoids, fissure, ulcer, proctitis, neoplasm. • Colonoscopy: Often test of choice, but may be impossible if bleeding is massive. • Barium enema: No role in active bleeding. • Arteriography: When bleeding is severe (requires bleeding rate >0.5 mL/min; may require prestudy radioisotope bleeding scan as above); defines site of bleeding or abnormal vasculature. • Surgical exploration (last resort). ■■BLEEDING OF OBSCURE ORIGIN

Often small-bowel source. Consider small-bowel enteroclysis x-ray (careful barium radiography via peroral intubation of small bowel), Meckel’s scan, enteroscopy (small-bowel endoscopy), or exploratory laparotomy with intraoperative enteroscopy. TREATMENT

Upper and Lower GI Bleeding • Venous access with large-bore IV (14–18 gauge); central venous line for major bleed and pts with cardiac disease; monitor vital signs, urine output, Hct (fall may lag). Gastric lavage of unproven benefit but clears stomach before

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Hemodynamic Instability

No Hemodynamic Instability

Age