Harrison - Gastroenterology and Hepatology, Notas de estudo de Farmácia

Baixe Harrison - Gastroenterology and Hepatology e outras Notas de estudo em PDF para Farmácia, somente na Docsity! HHARRISON'S * Gastroenterology and Hepatology DAN L. LONGO ANTHONY 5. FAUCI HARRISON’S Gastroenterology and Hepatology Copyright © 2010 by The McGraw-Hill Companies, Inc. 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: 978-0-07-166334-2 MHID: 0-07-166334-7 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-166333-5, MHID: 0-07-166333-9. All trademarks are trademarks of their respective owners. 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Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii SECTION I CARDINAL MANIFESTATIONS OF GASTROINTESTINAL DISEASE 1 Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . 2 William Silen 2 Oral Manifestations of Disease . . . . . . . . . . . . . . . 8 Samuel C. Durso 3 Atlas of Oral Manifestations of Disease . . . . . . . . 21 Samuel C. Durso, Janet A.Yellowitz, Jane C.Atkinson 4 Dysphagia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Raj K. Goyal 5 Nausea,Vomiting, and Indigestion . . . . . . . . . . . 33 William L. Hasler 6 Diarrhea and Constipation. . . . . . . . . . . . . . . . . 42 Michael Camilleri, Joseph A. Murray 7 Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Carol M. Reife 8 Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . 62 Loren Laine 9 Jaundice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Daniel S. Pratt, Marshall M. Kaplan 10 Abdominal Swelling and Ascites . . . . . . . . . . . . . 77 Robert M. Glickman, Roshini Rajapaksa SECTION II EVALUATION OF THE PATIENT WITH ALIMENTARY TRACT SYMPTOMS 11 Approach to the Patient with Gastrointestinal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 William L. Hasler, Chung Owyang 12 Gastrointestinal Endoscopy . . . . . . . . . . . . . . . . 94 Louis Michel Wong-Kee-Song, Mark Topazian SECTION III DISORDERS OF THE ALIMENTARY TRACT 13 Diseases of the Esophagus . . . . . . . . . . . . . . . . 112 Raj K. Goyal 14 Peptic Ulcer Disease and Related Disorders . . . 125 John Del Valle 15 Disorders of Absorption. . . . . . . . . . . . . . . . . . 152 Henry J. Binder 16 Inflammatory Bowel Disease . . . . . . . . . . . . . . 174 Sonia Friedman, Richard S. Blumberg 17 Irritable Bowel Syndrome . . . . . . . . . . . . . . . . 196 Chung Owyang 18 Diverticular Disease and Common Anorectal Disorders . . . . . . . . . . . . . . . . . . . . . 203 Susan L. Gearhart 19 Mesenteric Vascular Insufficiency . . . . . . . . . . . 213 Susan L. Gearhart 20 Acute Intestinal Obstruction . . . . . . . . . . . . . . 218 Susan L. Gearhart,William Silen 21 Acute Appendicitis and Peritonitis . . . . . . . . . . 222 Susan L. Gearhart,William Silen SECTION IV INFECTIONS OF THE ALIMENTARY TRACT 22 Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning. . . . . . . . . . . . . . 228 Joan R. Butterton, Stephen B. Calderwood 23 Clostridium Difficile–Associated Disease, Including Pseudomembranous Colitis. . . . . . . . 238 Dale N. Gerding, Stuart Johnson 24 Intraabdominal Infections and Abscesses . . . . . . 244 Miriam J. Baron, Dennis L. Kasper 25 Helicobacter Pylori Infections . . . . . . . . . . . . . . . 253 John C.Atherton, Martin J. Blaser 26 Salmonellosis. . . . . . . . . . . . . . . . . . . . . . . . . . 260 David A. Pegues, Samuel I. Miller v CONTENTS 27 Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 Philippe Sansonetti, Jean Bergounioux 28 Infections Due to Campylobacter and Related Species. . . . . . . . . . . . . . . . . . . . . 276 Martin J. Blaser 29 Cholera and Other Vibrioses . . . . . . . . . . . . . . 281 Matthew K.Waldor, Gerald T. Keusch 30 Viral Gastroenteritis. . . . . . . . . . . . . . . . . . . . . 289 Umesh D. Parashar, Roger I. Glass 31 Amebiasis and Infection with Free-Living Amebas. . . . . . . . . . . . . . . . . . . . . 296 Sharon L. Reed 32 Protozoal Intestinal Infections and Trichomoniasis . . . . . . . . . . . . . . . . . . . . . 304 Peter F. Weller 33 Intestinal Nematodes . . . . . . . . . . . . . . . . . . . . 312 Peter F. Weller,Thomas B. Nutman SECTION V EVALUATION OF THE PATIENT WITH LIVER DISEASE 34 Approach to the Patient with Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Marc Ghany, Jay H. Hoofnagle 35 Evaluation of Liver Function . . . . . . . . . . . . . . 332 Daniel S. Pratt, Marshall M. Kaplan SECTION VI DISORDERS OF THE LIVER AND BILIARY TREE 36 The Hyperbilirubinemias. . . . . . . . . . . . . . . . . 340 Allan W. Wolkoff 37 Acute Viral Hepatitis . . . . . . . . . . . . . . . . . . . . 349 Jules L. Dienstag 38 Toxic and Drug-Induced Hepatitis . . . . . . . . . . 378 Jules L. Dienstag 39 Chronic Hepatitis . . . . . . . . . . . . . . . . . . . . . . 390 Jules L. Dienstag 40 Alcoholic Liver Disease . . . . . . . . . . . . . . . . . . 415 Mark E. Mailliard, Michael F. Sorrell 41 Cirrhosis and Its Complications . . . . . . . . . . . . 419 Bruce R. Bacon 42 Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver . . . . . . . . . . . . . . . 434 Bruce R. Bacon 43 Diseases of the Gallbladder and Bile Ducts . . . . 439 Norton J. Greenberger, Gustav Paumgartner SECTION VII LIVER TRANSPLANTATION 44 Liver Transplantation . . . . . . . . . . . . . . . . . . . . 458 Jules L. Dienstag, Raymond T. Chung SECTION VIII DISORDERS OF THE PANCREAS 45 Approach to the Patient with Pancreatic Disease . . . . . . . . . . . . . . . . . . . . . . 472 Phillip P. Toskes, Norton J. Greenberger 46 Acute and Chronic Pancreatitis . . . . . . . . . . . . 479 Norton J. Greenberger, Phillip P. Toskes SECTION IX NEOPLASTIC DISEASES OF THE GASTROINTESTINAL SYSTEM 47 Gastrointestinal Tract Cancer . . . . . . . . . . . . . . 500 Robert J. Mayer 48 Tumors of the Liver and Biliary Tree . . . . . . . . 517 Brian I. Carr 49 Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . 528 Yu Jo Chua, David Cunningham 50 Endocrine Tumors of the Gastrointestinal Tract and Pancreas . . . . . . . . . . . . . . . . . . . . . . 533 Robert T. Jensen SECTION X NUTRITION 51 Nutritional Requirements and Dietary Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . 554 Johanna Dwyer 52 Vitamin and Trace Mineral Deficiency and Excess . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 Robert M. Russell, Paolo M. Suter 53 Malnutrition and Nutritional Assessment . . . . . 577 Douglas C. Heimburger 54 Enteral and Parenteral Nutrition Therapy . . . . . 586 Bruce R. Bistrian, David F. Driscoll vi Contents ix JOHN C.ATHERTON, MD Professor of Gastroenterology; Director,Wolfson Digestive Diseases Centre, University of Nottingham, United Kingdom [25] JANE C.ATKINSON, DDS Program Director, Clinical Trials Program, Center for Clinical Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda [3] BRUCE R. BACON, MD James F. King Endowed Chair in Gastroenterology; Professor of Internal Medicine, Division of Gastroenterology & Hepatology, St. Louis [41, 42] MIRIAM J. BARON, MD Instructor in Medicine, Harvard Medical School, Boston [24] JEAN BERGOUNIOUX, MD Medical Doctor of Pediatrics, Unité de Pathogénie Microbienne Moléculaire, Paris [27] HENRY J. BINDER, MD Professor of Medicine; Professor of Cellular & Molecular Physiology, Yale University, New Haven [15] BRUCE R. BISTRIAN, MD, PhD Chief, Clinical Nutrition, Beth Israel Deaconess Medical Center; Professor of Medicine, Harvard Medical School, Boston [54] MARTIN J. BLASER, MD Frederick H. King Professor of Internal Medicine; Chair, Department of Medicine; Professor of Microbiology, New York University School of Medicine, New York [25, 28] GERALD BLOOMFIELD, MD, MPH Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] RICHARD S. BLUMBERG, MD Professor of Medicine, Harvard Medical School; Chief, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston [16] CYNTHIA D. BROWN, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] JOAN R. BUTTERTON, MD Assistant Clinical Professor of Medicine, Harvard Medical School; Clinical Associate in Medicine, Massachusetts General Hospital, Boston [22] STEPHEN B. CALDERWOOD, MD Morton N. Swartz, MD Academy Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston [22] MICHAEL CAMILLERI, MD Atherton and Winifred W. Bean Professor; Professor of Medicine and Physiology, Mayo Clinic College of Medicine, Rochester [6] BRIAN I. CARR, MD, PhD Professor of Medicine,Thomas Jefferson University; Director of the Liver Tumor Program, Kimmel Cancer Center, Philadelphia [48] YU JO CHUA, MBBS Research Fellow (Medical Oncology), Royal Marsden Hospital, London [49] RAYMOND T. CHUNG, MD Associate Professor of Medicine, Harvard Medical School; Director of Hepatology, Massachusetts General Hospital; Medical Director, Liver Transplant Program, Massachusetts General Hospital, Boston [44] DAVID CUNNINGHAM, MD Professor of Cancer Medicine, Institute of Cancer Research; Consultant Medical Oncologist, Head of Gastrointestinal Unit, Royal Marsden Hospital, London [49] JOHN DEL VALLE, MD Professor and Senior Associate Chair of Graduate Medical Education, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Health System,Ann Arbor [14] JULES L. DIENSTAG, MD Carl W.Walter Professor of Medicine and Dean for Medical Education, Harvard Medical School; Physician, Gastrointestinal Unit, Massachusetts General Hospital, Boston [37–39, 44] DAVID F. DRISCOLL, PhD Assistant Professor of Medicine, Harvard Medical School, Boston [54] SAMUEL C. DURSO, MD, MBA Associate Professor of Medicine, Clinical Director, Division of Geriatric Medicine and Gerontology,The Johns Hopkins University School of Medicine, Baltimore [2, 3] JOHANNA DWYER, DSc, RD Professor of Medicine and Community Health,Tufts University School of Medicine and Friedman School of Nutrition Science and Policy; Senior Scientist Jean Mayer Human Nutrition Research Center on Aging at Tufts; Director of the Frances Stern Nutrition Center,Tufts-New England Medical Center Hospital, Boston [51] ROBERT H. ECKEL, MD Professor of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Cardiology; Professor of Physiology and Biophysics; Charles A. Boettcher II Chair in Atherosclerosis; Program Director,Adult General Clinical Research Center, University of Colorado at Denver and Health Sciences Center; Director Lipid Clinic, University Hospital,Aurora [58] DANIEL J. FINK,† MD, MPH Associate Professor of Clinical Pathology, College of Physicians and Surgeons, Columbia University, New York [Appendix] JEFFREY S. FLIER, MD Caroline Shields Walker Professor of Medicine, Harvard Medical School; Dean of the Faculty of Medicine, Harvard School of Medicine, Boston [55] CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or co-written by the contributor. †Deceased. x Contributors SONIA FRIEDMAN, MD Assistant Professor of Medicine, Harvard Medical School;Associate Physician, Brigham and Women’s Hospital, Boston [16] SUSAN L. GEARHART, MD Assistant Professor of Colorectal Surgery and Oncology,The Johns Hopkins University School of Medicine, Baltimore [18–21] DALE N. GERDING, MD Assistant Chief of Staff for Research, Hines VA Hospital, Hines; Professor, Stritch School of Medicine, Loyola University, Maywood [23] MARC GHANY, MD Staff Physician, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda [34] ROGER I. GLASS, MD, PhD Director, Fogarty International Center;Associate Director for International Research, National Institutes of Health, Bethesda [30] ROBERT M. GLICKMAN, MD Professor of Medicine, New York University School of Medicine, New York [10] RAJ K. GOYAL, MD Mallinckrodt Professor of Medicine, Harvard Medical School, Boston; Physician,VA Boston Healthcare and Beth Israel Deaconess Medical Center,West Roxbury [4, 13] NORTON J. GREENBERGER, MD Clinical Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital, Boston [43, 45, 46] WILLIAM L. HASLER, MD Professor of Medicine, Division of Gastroenterology, University of Michigan Health System,Ann Arbor [5, 11] DOUGLAS C. HEIMBURGER, MD, MS Professor of Nutrition Sciences; Professor of Medicine; Director, Clinical Nutrition Fellowship Program, University of Alabama at Birmingham, Birmingham [53] JAY H. HOOFNAGLE, MD Director, Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda [34] ROBERT T. JENSEN, MD Chief, Digestive Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda [50] STUART JOHNSON, MD Associate Professor, Stritch School of Medicine, Loyola University, Maywood; Staff Physician, Hines VA Hospital, Hines [23] MARSHALL M. KAPLAN, MD Professor of Medicine,Tufts University School of Medicine; Chief Emeritus, Division of Gastroenterology,Tufts-New England Medical Center, Boston [9, 35] DENNIS L. KASPER, MD, MA (Hon) William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston [24] GERALD T. KEUSCH, MD Associate Provost and Associate Dean for Global Health, Boston University School of Medicine, Boston [29] ALEXANDER KRATZ, MD, PhD, MPH Assistant Professor of Clinical Pathology, Columbia University College of Physicians and Surgeons;Associate Director, Core Laboratory, Columbia University Medical Center, New York-Presbyterian Hospital; Director,Allen Pavilion Laboratory, New York [Appendix] ROBERT F. KUSHNER, MD Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago [56] LOREN LAINE, MD Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles [8] MARK E. MALLIARD, MD Associate Professor and Chief, Division of Gastroenterology and Hepatology, Omaha [40] ELEFTHERIA MARATOS-FLIER, MD Associate Professor of Medicine, Harvard Medical School; Chief, Obesity Section, Joslin Diabetes Center, Boston [55] ROBERT J. MAYER, MD Stephen B. Kay Family Professor of Medicine, Harvard Medical School, Dana- Farber Cancer Institute, Boston [47] SAMUEL I. MILLER, MD Professor of Genome Sciences, Medicine, and Microbiology, University of Washington, Seattle [26] JOSEPH A. MURRAY, MD Professor of Medicine, Division of Gastroenterology and Hepatology, The Mayo Clinic, Rochester [6] THOMAS B. NUTMAN, MD Head, Helminth Immunology Section; Head, Clinical Parasitology Unit; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Insitutes of Health, Bethesda [33] CHUNG OWYANG, MD Professor of Internal Medicine, H. Marvin Pollard Collegiate Professor; Chief, Division of Gastroenterology, University of Michigan Health System,Ann Arbor [11, 17] UMESH D. PARASHAR, MBBS, MPH Lead, Enteric and Respiratory Viruses Team, Epidemiology Branch, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta [30] GUSTAV PAUMGARTNER, MD Professor of Medicine, University of Munich, Munich, Germany [43] DAVID A. PEGUES, MD Professor of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles [26] MICHAEL A. PESCE, PhD Clinical Professor of Pathology, Columbia University College of Physicians and Surgeons; Director of Specialty Laboratory, New York Presbyterian Hospital, Columbia University Medical Center, New York [Appendix] DANIEL S. PRATT, MD Assistant Professor of Medicine, Harvard Medical School; Director, Liver- Billary-Pancreas Center, Massachusetts General Hospital, Boston [9, 35] ROSHINI RAJAPAKSA, MD, BA Assistant Professor, Department of Medicine, Gastroenterology, New York University Medical Center School of Medicine and Hospitals Center, New York [10] SHARON L. REED, MD Professor of Pathology and Medicine; Director, Microbiology and Virology Laboratories, University of California, San Diego Medical Center, San Diego [31] CAROL M. REIFE, MD Clinical Associate Professor of Medicine, Jefferson Medical College, Philadelphia [7] ROBERT M. RUSSELL, MD Director, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University; Professor of Medicine and Nutrition,Tufts University, Boston [52] PHILIPPE SANSONETTI Professeur á l’Institut Pasteur, Paris, France [27] JOSHUA SCHIFFER, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] WILLIAM SILEN, MD Johnson and Johnson Distinguished Professor of Surgery, Emeritus, Harvard Medical School, Boston [1, 20, 21] MICHAEL F. SORRELL, MD Robert L. Grissom Professor of Medicine, University of Nebraska Medical Center, Omaha [40] ADAM SPIVAK, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] PAOLO M. SUTER, MD, MS Professor of Medicine, Medical Policlinic, Zurich, Switzerland [52] MARK TOPAZIAN, MD Associate Professor of Medicine, Mayo College of Medicine, Rochester [12] PHILLIP P.TOSKES, MD Professor of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine, Gainesville [45, 46] MATTHEW K.WALDOR, MD, PhD Professor of Medicine (Microbiology and Molecular Genetics), Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston [29] B.TIMOTHY WALSH, MD Professor of Psychiatry, College of Physicians & Surgeons, Columbia University; Director, Eating Disorders Research Unit, New York Psychiatric Institute, New York [57] PETER F.WELLER, MD Professor of Medicine, Harvard Medical School; Co-Chief, Infectious Diseases Division; Chief,Allergy and Inflammation Division;Vice-Chair for Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston [32, 33] CHARLES WIENER, MD Professor of Medicine and Physiology;Vice Chair, Department of Medicine; Director, Osler Medical Training Program, The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] ALLAN W.WOLKOFF, MD Professor of Medicine and Anatomy and Structural Biology; Director, Belfer Institute for Advanced Biomedical Studies; Associate Chair of Medicine for Research; Chief, Division of Hepatology, Albert Einstein College of Medicine, Bronx [36] LOUIS MICHEL WONG-KEE-SONG, MD Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo College of Medicine, Rochester [12] JANET A.YELLOWITZ, DMD, MPH Associate Professor; Director, Geriatric Dentistry,The Johns Hopkins University School of Medicine, Baltimore [3] Contributors xi xiv NOTICE Medicine is an ever-changing science. As new research and clinical experi- ence 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 publica- tion. However, in view of the possibility of human error or changes in med- ical 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 prod- uct information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accu- rate 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. The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine throughout the world. The genetic icons identify a clinical issue with an explicit genetic relationship. Review and self-assessment questions and answers were taken from Wiener C, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (editors) Bloomfield G, Brown CD, Schiffer J, Spivak A (contributing editors). Har- rison’s Principles of Internal Medicine Self-Assessment and Board Review, 17th ed. New York, McGraw-Hill, 2008, ISBN 978-0-07-149619-3. CARDINAL MANIFESTATIONS OF GASTROINTESTINAL DISEASE SECTION I William Silen 2 ■ Some Mechanisms of Pain Originating in the Abdomen . . . . . . 2 ■ Referred Pain in Abdominal Diseases . . . . . . . . . . . . . . . . . . . . 4 ■ Metabolic Abdominal Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 ■ Neurogenic Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 The correct interpretation of acute abdominal pain is challenging. Since proper therapy may require urgent action, the unhurried approach suitable for the study of other conditions is sometimes denied. Few other clinical situations demand greater judgment, because the most catastrophic of events may be forecast by the subtlest of symptoms and signs. A meticulously executed, detailed history and physical examination are of great impor- tance.The etiologic classification in Table 1-1, although not complete, forms a useful basis for the evaluation of patients with abdominal pain. The diagnosis of “acute or surgical abdomen” is not an acceptable one because of its often misleading and erroneous connotation. The most obvious of “acute abdomens” may not require operative intervention, and the mildest of abdominal pains may herald an urgently correctable lesion. Any patient with abdominal pain of recent onset requires early and thorough evaluation and accurate diagnosis. SOME MECHANISMS OF PAIN ORIGINATING IN THE ABDOMEN Inflammation of the Parietal Peritoneum The pain of parietal peritoneal inflammation is steady and aching in character and is located directly over the inflamed area, its exact reference being possible because it is transmitted by somatic nerves supplying the parietal peritoneum. The intensity of the pain is dependent on the type and amount of material to which the peritoneal surfaces are exposed in a given time period. For example, the sudden release into the peritoneal cavity of a small quantity of sterile acid gastric juice causes much more pain than the same amount of grossly contaminated neu- tral feces. Enzymatically active pancreatic juice incites more pain and inflammation than does the same amount of sterile bile containing no potent enzymes. Blood and urine are often so bland as to go undetected if their con- tact with the peritoneum has not been sudden and mas- sive. In the case of bacterial contamination, such as in pelvic inflammatory disease, the pain is frequently of low intensity early in the illness until bacterial multiplication has caused the elaboration of irritating substances. The rate at which the irritating material is applied to the peritoneum is important. Perforated peptic ulcer may be associated with entirely different clinical pictures dependent only on the rapidity with which the gastric juice enters the peritoneal cavity. The pain of peritoneal inflammation is invariably accentuated by pressure or changes in tension of the peritoneum, whether produced by palpation or by movement, as in coughing or sneezing. The patient with peritonitis lies quietly in bed, preferring to avoid motion, in contrast to the patient with colic, who may writhe incessantly. Another characteristic feature of peritoneal irritation is tonic reflex spasm of the abdominal musculature, local- ized to the involved body segment.The intensity of the tonic muscle spasm accompanying peritoneal inflamma- tion is dependent on the location of the inflammatory ABDOMINAL PAIN CHAPTER 1 respiratory phases if it is of abdominal origin. Palpation over the area of referred pain in the abdomen also does not usually accentuate the pain and in many instances actually seems to relieve it.Thoracic disease and abdom- inal disease frequently coexist and may be difficult or impossible to differentiate. For example, the patient with known biliary tract disease often has epigastric pain dur- ing myocardial infarction, or biliary colic may be referred to the precordium or left shoulder in a patient who has suffered previously from angina pectoris. Referred pain from the spine, which usually involves compression or irritation of nerve roots, is characteristi- cally intensified by certain motions such as cough, sneeze, or strain, and is associated with hyperesthesia over the involved dermatomes. Pain referred to the abdomen from the testes or seminal vesicles is generally accentuated by the slightest pressure on either of these organs.The abdominal discomfort is of dull aching char- acter and is poorly localized. METABOLIC ABDOMINAL CRISES Pain of metabolic origin may simulate almost any other type of intraabdominal disease. Several mechanisms may be at work. In certain instances, such as hyperlipidemia, the metabolic disease itself may be accompanied by an intraabdominal process such as pancreatitis, which can lead to unnecessary laparotomy unless recognized. C1- esterase deficiency associated with angioneurotic edema is often associated with episodes of severe abdominal pain.Whenever the cause of abdominal pain is obscure, a metabolic origin always must be considered. Abdominal pain is also the hallmark of familial Mediterranean fever. The problem of differential diagnosis is often not readily resolved.The pain of porphyria and of lead colic is usually difficult to distinguish from that of intestinal obstruction, because severe hyperperistalsis is a promi- nent feature of both. The pain of uremia or diabetes is nonspecific, and the pain and tenderness frequently shift in location and intensity. Diabetic acidosis may be pre- cipitated by acute appendicitis or intestinal obstruction, so if prompt resolution of the abdominal pain does not result from correction of the metabolic abnormalities, an underlying organic problem should be suspected. Black widow spider bites produce intense pain and rigidity of the abdominal muscles and back, an area infrequently involved in intraabdominal disease. NEUROGENIC CAUSES Causalgic pain may occur in diseases that injure sensory nerves. It has a burning character and is usually limited to the distribution of a given peripheral nerve. Normal stimuli such as touch or change in temperature may be transformed into this type of pain, which is frequently present in a patient at rest.The demonstration of irregu- larly spaced cutaneous pain spots may be the only indi- cation of an old nerve lesion underlying causalgic pain. Even though the pain may be precipitated by gentle pal- pation, rigidity of the abdominal muscles is absent, and the respirations are not disturbed. Distention of the abdomen is uncommon, and the pain has no relation- ship to the intake of food. Pain arising from spinal nerves or roots comes and goes suddenly and is of a lancinating type. It may be caused by herpes zoster, impingement by arthritis, tumors, herniated nucleus pulposus, diabetes, or syphilis. It is not associated with food intake, abdominal disten- tion, or changes in respiration. Severe muscle spasm, as in the gastric crises of tabes dorsalis, is common but is either relieved or is not accentuated by abdominal pal- pation. The pain is made worse by movement of the spine and is usually confined to a few dermatomes. Hyperesthesia is very common. Pain due to functional causes conforms to none of the aforementioned patterns. The mechanism is hard to define. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits. The diagnosis is made on the basis of clinical criteria (Chap. 17) and after exclusion of demonstrable structural abnormalities. The episodes of abdominal pain are often brought on by stress, and the pain varies considerably in type and location. Nausea and vomiting are rare. Localized tenderness and muscle spasm are inconsistent or absent. The causes of IBS or related functional disorders are not known. Approach to the Patient: ABDOMINAL PAIN Few abdominal conditions require such urgent oper- ative intervention that an orderly approach need be abandoned, no matter how ill the patient. Only those patients with exsanguinating intraabdominal hemor- rhage (e.g., ruptured aneurysm) must be rushed to the operating room immediately, but in such instances only a few minutes are required to assess the critical nature of the problem. Under these circum- stances, all obstacles must be swept aside, adequate venous access for fluid replacement obtained, and the operation begun. Many patients of this type have died in the radiology department or the emergency room while awaiting such unnecessary examinations as electrocardiograms or abdominal films. There are no contraindications to operation when massive intraabdominal hemorrhage is present. Fortunately, this situation is rela- tively rare.These comments do not pertain to gastroin- testinal hemorrhage, which can often be managed by other means (Chap. 8). Abdom inal Pain 5 CHAPTER 1 Nothing will supplant an orderly, painstakingly detailed history, which is far more valuable than any lab- oratory or radiographic examination.This kind of his- tory is laborious and time-consuming, making it not especially popular, even though a reasonably accurate diagnosis can be made on the basis of the history alone in the majority of cases. Computer-aided diagno- sis of abdominal pain provides no advantage over clinical assessment alone. In cases of acute abdominal pain, a diagnosis is readily established in most instances, whereas success is not so frequent in patients with chronic pain. IBS is one of the most common causes of abdominal pain and must always be kept in mind (Chap. 17).The location of the pain can assist in nar- rowing the differential diagnosis (see Table 1-2); however, the chronological sequence of events in the patient’s history is often more important than empha- sis on the location of pain. If the examiner is suffi- ciently open-minded and unhurried, asks the proper questions, and listens, the patient will usually provide the diagnosis. Careful attention should be paid to the extraabdominal regions that may be responsible for abdominal pain. An accurate menstrual history in a female patient is essential. Narcotics or analgesics should not be withheld until a definitive diagnosis or a definitive plan has been formulated; obfuscation of the diagnosis by adequate analgesia is unlikely. In the examination, simple critical inspection of the patient, e.g., of facies, position in bed, and respiratory activity, may provide valuable clues. The amount of information to be gleaned is directly proportional to the gentleness and thoroughness of the examiner. Once a patient with peritoneal inflammation has been examined brusquely, accurate assessment by the next examiner becomes almost impossible. Eliciting rebound tenderness by sudden release of a deeply pal- pating hand in a patient with suspected peritonitis is cruel and unnecessary. The same information can be obtained by gentle percussion of the abdomen (rebound tenderness on a miniature scale), a maneuver that can be far more precise and localizing.Asking the patient to cough will elicit true rebound tenderness without the need for placing a hand on the abdomen. Furthermore, the forceful demonstration of rebound tenderness will startle and induce protective spasm in a nervous or worried patient in whom true rebound tenderness is not present.A palpable gallbladder will be missed if palpation is so brusque that voluntary muscle spasm becomes superimposed on involuntary muscular rigidity. Cardinal M anifestations of Gastrointestinal Disease 6 SECTION I TABLE 1-2 DIFFERENTIAL DIAGNOSES OF ABDOMINAL PAIN BY LOCATION RIGHT UPPER QUADRANT EPIGASTRIC LEFT UPPER QUADRANT Cholecystitis Peptic ulcer disease Splenic infarct Cholangitis Gastritis Splenic rupture Pancreatitis GERD Splenic abscess Pneumonia/empyema Pancreatitis Gastritis Pleurisy/pleurodynia Myocardial infarction Gastric ulcer Subdiaphragmatic abscess Pericarditis Pancreatitis Hepatitis Ruptured aortic aneurysm Subdiaphragmatic abscess Budd-Chiari syndrome Esophagitis RIGHT LOWER QUADRANT PERIUMBILICAL LEFT LOWER QUADRANT Appendicitis Early appendicitis Diverticulitis Salpingitis Gastroenteritis Salpingitis Inguinal hernia Bowel obstruction Inguinal hernia Ectopic pregnancy Ruptured aortic aneurysm Ectopic pregnancy Nephrolithiasis Nephrolithiasis Inflammatory bowel disease Irritable bowel syndrome Mesenteric lymphadenitis Inflammatory bowel disease Typhlitis DIFFUSE NONLOCALIZED PAIN Gastroenteritis Diabetes Mesenteric ischemia Malaria Bowel obstruction Familial Mediterranean fever Irritable bowel syndrome Metabolic diseases Peritonitis Psychiatric disease As in history taking, sufficient time should be spent in the examination. Abdominal signs may be minimal but nevertheless, if accompanied by consistent symp- toms, may be exceptionally meaningful. Abdominal signs may be virtually or totally absent in cases of pelvic peritonitis, so careful pelvic and rectal examina- tions are mandatory in every patient with abdominal pain. Tenderness on pelvic or rectal examination in the absence of other abdominal signs can be caused by operative indications such as perforated appendicitis, diverticulitis, twisted ovarian cyst, and many others. Much attention has been paid to the presence or absence of peristaltic sounds, their quality, and their frequency. Auscultation of the abdomen is one of the least revealing aspects of the physical examination of a patient with abdominal pain. Catastrophes such as strangulating small intestinal obstruction or perforated appendicitis may occur in the presence of normal peristaltic sounds. Conversely, when the proximal part of the intestine above an obstruction becomes markedly distended and edematous, peristaltic sounds may lose the characteristics of borborygmi and become weak or absent, even when peritonitis is not present. It is usually the severe chemical peritonitis of sudden onset that is associated with the truly silent abdomen. Assessment of the patient’s state of hydration is important. Laboratory examinations may be of great value in assessment of the patient with abdominal pain, yet with few exceptions they rarely establish a diagnosis. Leukocytosis should never be the single deciding fac- tor as to whether or not operation is indicated. A white blood cell count >20,000/
L may be observed with perforation of a viscus, but pancreatitis, acute cholecystitis, pelvic inflammatory disease, and intestinal infarction may be associated with marked leukocytosis. A normal white blood cell count is not rare in cases of perforation of abdominal viscera.The diagnosis of ane- mia may be more helpful than the white blood cell count, especially when combined with the history. The urinalysis may reveal the state of hydration or rule out severe renal disease, diabetes, or urinary infection. Blood urea nitrogen, glucose, and serum bilirubin levels may be helpful. Serum amylase levels may be increased by many diseases other than pan- creatitis, e.g., perforated ulcer, strangulating intestinal obstruction, and acute cholecystitis; thus, elevations of serum amylase do not rule out the need for an opera- tion.The determination of the serum lipase may have greater accuracy than that of the serum amylase. Plain and upright or lateral decubitus radiographs of the abdomen may be of value in cases of intestinal obstruction, perforated ulcer, and a variety of other conditions. They are usually unnecessary in patients with acute appendicitis or strangulated external hernias. In rare instances, barium or water-soluble contrast study of the upper part of the gastrointestinal tract may demonstrate partial intestinal obstruction that may elude diagnosis by other means. If there is any question of obstruction of the colon, oral administration of bar- ium sulfate should be avoided. On the other hand, in cases of suspected colonic obstruction (without perfo- ration), contrast enema may be diagnostic. In the absence of trauma, peritoneal lavage has been replaced as a diagnostic tool by ultrasound, CT, and laparoscopy. Ultrasonography has proved to be useful in detecting an enlarged gallbladder or pan- creas, the presence of gallstones, an enlarged ovary, or a tubal pregnancy. Laparoscopy is especially help- ful in diagnosing pelvic conditions, such as ovarian cysts, tubal pregnancies, salpingitis, and acute appen- dicitis. Radioisotopic scans (HIDA) may help differ- entiate acute cholecystitis from acute pancreatitis. A CT scan may demonstrate an enlarged pancreas, rup- tured spleen, or thickened colonic or appendiceal wall and streaking of the mesocolon or mesoappen- dix characteristic of diverticulitis or appendicitis. Sometimes, even under the best circumstances with all available aids and with the greatest of clinical skill, a definitive diagnosis cannot be established at the time of the initial examination. Nevertheless, despite lack of a clear anatomic diagnosis, it may be abundantly clear to an experienced and thoughtful physician and surgeon that on clinical grounds alone operation is indicated. Should that decision be questionable, watch- ful waiting with repeated questioning and examination will often elucidate the true nature of the illness and indicate the proper course of action. FURTHER READINGS ASSAR AN, ZARINS CK: Ruptured abdominal aortic aneurysm: A surgical emergency with many clinical presentations. Postgrad Med J 85:268, 2009 CERVERO F, LAIRD JM: Visceral pain. Lancet 353:2145, 1999 FORD AC et al: Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: Systematic review and meta-analysis.Arch Intern Med 169:651, 2009 JAMES AW et al: Portomesenteric venous thrombosis after laparoscopic surgery:A systematic literature review.Arch Surg 144:520, 2009 JONES PF: Suspected acute appendicitis:Trends in management over 30 years. Br J Surg 88:1570, 2001 LYON C, CLARK DC: Diagnosis of acute abdominal pain in older patients.Am Fam Physician 74:1537, 2006 RICHARDSON WS et al: The role of diagnostic laparoscopy for chronic abdominal conditions: An evidence-based review. Surg Endosc 23:2073, 2009 SILEN W: Cope’s Early Diagnosis of the Acute Abdomen, 21st ed. New York and Oxford: Oxford University Press, 2005 SMITH JE, HALL EJ:The use of plain abdominal x-rays in the emer- gency department. Emerg Med J 26:160, 2009 TAIT IS et al: Do patients with abdominal pain wait unduly long for analgesia? J R Coll Surg Edinb 44:181, 1999 Abdom inal Pain 7 CHAPTER 1 Cardinal M anifestations of Gastrointestinal Disease 10 SECTION I Developmental and Systemic Disease Affecting the Teeth and Periodontium Malocclusion is the most common developmental prob- lem, which, in addition to a problem with cosmesis, can interfere with mastication unless corrected through orthodontic techniques. Impacted third molars are com- mon and occasionally become infected. Acquired prog- nathism due to acromegaly may also lead to malocclusion, as may deformity of the maxilla and mandible due to Paget’s disease of the bone. Delayed tooth eruption, receding chin, and a protruding tongue are occasional features of cretinism and hypopituitarism. Congenital syphilis produces tapering, notched (Hutchinson’s) incisors and finely nodular (mulberry) molar crowns. Enamel hypoplasia results in crown defects ranging from pits to deep fissures of primary or permanent teeth. Intrauterine infection (syphilis, rubella), vitamin deficiency (A, C, or D), disorders of calcium metabolism (malabsorp- tion, vitamin D–resistant rickets, hypoparathyroidism), pre- maturity, high fever, or rare inherited defects (amelogenesis imperfecta) are all causes. Tetracycline, given in sufficiently high doses during the first 8 years, may produce enamel hypoplasia and discoloration. Exposure to endogenous pigments can discolor developing teeth: erythroblastosis fetalis (green or bluish-black), congenital liver disease (green or yellow-brown), and porphyria (red or brown that fluoresces with ultraviolet light). Mottled enamel occurs if excessive fluoride is ingested during development.Worn enamel is seen with age, bruxism, or excessive acid expo- sure (e.g., chronic gastric reflux or bulimia). Premature tooth loss resulting from periodontitis is seen with cyclic neutropenia, Papillon-Lefèvre syn- drome, Chédiak-Higashi syndrome, and leukemia. Rapid focal tooth loosening is most often due to infec- tion, but rarer causes include histiocytosis X, Ewing’s sarcoma, osteosarcoma, or Burkitt’s lymphoma. Early loss of primary teeth is a feature of hypophosphatasia, a rare inborn error of metabolism. Pregnancy may produce severe gingivitis and local- ized pyogenic granulomas. Severe periodontal disease occurs with Down’s syndrome and diabetes mellitus. Gingival hyperplasia may be caused by phenytoin, calcium channel blockers (e.g., nifedipine), and cyclosporine. Idiopathic familial gingival fibromatosis and several syndrome- related disorders appear similar. Removal of the medica- tion often reverses the drug-induced form, though surgery may be needed to control both. Linear gingival erythema is variably seen in patients with advanced HIV infection and probably represents immune deficiency and decreased neutrophil activity. Diffuse or focal gingi- val swelling may be a feature of early or late acute myelomonocytic leukemia (AML) as well as of other lymphoproliferative disorders.A rare, but pathognomonic, sign of Wegener’s granulomatosis is a red-purplish, gran- ular gingivitis (strawberry gums). DISEASES OF THE ORAL MUCOSA Infection Most oral mucosal diseases involve microorganisms (Table 2-1). Pigmented Lesions See Table 2-2. Dermatologic Diseases See Tables 2-1, 2-2, and 2-3. Diseases of the Tongue See Table 2-4. HIV Disease and AIDS See Tables 2-1, 2-2, 2-3, and 2-5. Ulcers Ulceration is the most common oral mucosal lesion. Although there are many causes, the host and pattern of lesions, including the presence of systemic features, nar- row the differential diagnosis (Table 2-1). Most acute ulcers are painful and self-limited. Recurrent aphthous ulcers and herpes simplex infection constitute the majority. Persistent and deep aphthous ulcers can be idiopathic or seen with HIV/AIDS. Aphthous lesions are often the presenting symptom in Behçet’s syndrome. Similar-appearing, though less painful, lesions may occur with Reiter’s syndrome, and aphthous ulcers are occa- sionally present during phases of discoid or systemic lupus erythematosus. Aphthous-like ulcers are seen in Crohn’s disease (Chap. 16), but unlike the common aphthous variety, they may exhibit granulomatous inflammation histologically. Recurrent aphthae in some patients with celiac disease have been reported to remit with elimina- tion of gluten. Of major concern are chronic, relatively painless ulcers and mixed red/white patches (erythroplakia and leukoplakia) of more than 2 weeks’ duration. Squamous cell carcinoma and premalignant dysplasia should be considered early and a diagnostic biopsy obtained. The importance is underscored because early-stage malig- nancy is vastly more treatable than late-stage disease. High-risk sites include the lower lip, floor of the mouth, ventral and lateral tongue, and soft palate–tonsillar pillar complex. Significant risk factors for oral cancer in West- ern countries include sun exposure (lower lip) and tobacco and alcohol use. In India and some other Asian countries, smokeless tobacco mixed with betel nut, slaked lime, and spices is a common cause of oral cancer. Oral M anifestations of Disease 11 CHAPTER 2 TABLE 2-1 VESICULAR, BULLOUS, OR ULCERATIVE LESIONS OF THE ORAL MUCOSA CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Viral Diseases (Continued) Primary acute herpetic gingivostomatitis [herpes simplex virus (HSV) type 1, rarely type 2] Recurrent herpes labialis Recurrent intraoral herpes simplex Chickenpox (varicella-zoster virus) Herpes zoster (reactivation of varicella-zoster virus) Infectious mononucleosis (Epstein-Barr virus) Herpangina (coxsack- ievirus A; also possi- bly coxsackie B and echovirus) Hand, foot, and mouth disease (coxsack- ievirus A16 most common) Primary HIV infection Lip and oral mucosa (buccal, gingival, lingual mucosa) Mucocutaneous junction of lip, perioral skin Palate and gingiva Gingiva and oral mucosa Cheek, tongue, gingiva, or palate Oral mucosa Oral mucosa, pharynx, tongue Oral mucosa, pharynx, palms, and soles Gingiva, palate, and pharynx Labial vesicles that rupture and crust, and intraoral vesicles that quickly ulcerate; extremely painful; acute gingivitis, fever, malaise, foul odor, and cervical lymphadenopathy; occurs primarily in infants, children, and young adults Eruption of groups of vesicles that may coalesce, then rupture and crust; painful to pressure or spicy foods Small vesicles on keratinized epithelium that rupture and coalesce; painful Skin lesions may be accompanied by small vesicles on oral mucosa that rupture to form shallow ulcers; may coalesce to form large bullous lesions that ulcerate; mucosa may have generalized erythema Unilateral vesicular eruptions and ulceration in linear pattern following sensory distribution of trigeminal nerve or one of its branches Fatigue, sore throat, malaise, fever, and cervical lymphadenopathy; numerous small ulcers usually appear several days before lymphadenopathy; gingival bleeding and multiple petechiae at junction of hard and soft palates Sudden onset of fever, sore throat, and oropharyngeal vesicles, usually in children under 4 years, during summer months; diffuse pharyngeal congestion and vesicles (1–2 mm), grayish-white surrounded by red areola; vesicles enlarge and ulcerate Fever, malaise, headache with oropharyngeal vesicles that become painful, shallow ulcers; highly infectious; usually affects children under age 10 Acute gingivitis and oropharyngeal ulceration, associated with febrile illness resembling mononucleosis and including lymphadenopathy Heals spontaneously in 10–14 days. Unless secondarily infected, lesions lasting >3 weeks are not due to primary HSV infection Lasts about 1 week, but condition may be pro- longed if secondarily infected. If severe, topical or oral antiviral may reduce healing time Heals spontaneously in about 1 week. If severe, topical or oral antiviral may reduce healing time Lesions heal spontaneously within 2 weeks Gradual healing without scarring unless secondarily infected; postherpetic neuralgia is common. Oral acyclovir, famciclovir, or valacyclovir reduce healing time and postherpetic neuralgia Oral lesions disappear during convalescence; no treatment though gluco- corticoids indicated if tonsillar swelling compromises airway Incubation period 2–9 days; fever for 1–4 days; recovery uneventful Incubation period 2–18 days; lesions heal sponta- neously in 2–4 weeks Followed by HIV serocon- version, asymptomatic HIV infection, and usually ultimately by HIV disease Cardinal M anifestations of Gastrointestinal Disease 12 SECTION I TABLE 2-1 (CONTINUED) VESICULAR, BULLOUS, OR ULCERATIVE LESIONS OF THE ORAL MUCOSA CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Bacterial or Fungal Diseases Acute necrotizing ulcerative gingivitis (“trench mouth,” Vincent’s infection) Prenatal (congenital) syphilis Primary syphilis (chancre) Secondary syphilis Tertiary syphilis Gonorrhea Tuberculosis Cervicofacial actinomycosis Histoplasmosis Candidiasis (Table 2-3) Gingiva Palate, jaws, tongue, and teeth Lesion appears where organism enters body; may occur on lips, tongue, or tonsillar area Oral mucosa fre- quently involved with mucous patches, primarily on palate, also at commissures of mouth Palate and tongue Lesions may occur in mouth at site of inoculation or secondarily by hematogenous spread from a primary focus elsewhere Tongue, tonsillar area, soft palate Swellings in region of face, neck, and floor of mouth Any area of the mouth, particularly tongue, gingiva, or palate Painful, bleeding gingiva characterized by necrosis and ulceration of gingival papillae and margins plus lymphadenopathy and foul odor Gummatous involvement of palate, jaws, and facial bones; Hutchinson’s incisors, mulberry molars, glossitis, mucous patches, and fissures on corner of mouth Small papule developing rapidly into a large, painless ulcer with indurated border; unilateral lymphadenopathy; chancre and lymph nodes containing spirochetes; serologic tests positive by third to fourth weeks Maculopapular lesions of oral mucosa, 5–10 mm in diameter with central ulceration covered by grayish membrane; eruptions occurring on various mucosal surfaces and skin accompanied by fever, malaise, and sore throat Gummatous infiltration of palate or tongue followed by ulceration and fibrosis; atrophy of tongue papillae produces characteristic bald tongue and glossitis Most pharyngeal infection is asymptomatic; may produce burning or itching sensation; oropharynx and tonsils may be ulcerated and erythematous; saliva viscous and fetid A painless, solitary, 1–5 cm, irregular ulcer covered with a persistent exudate; ulcer has a firm undermined border Infection may be associated with an extraction, jaw fracture, or eruption of molar tooth; in acute form resembles an acute pyogenic abscess, but contains yellow “sulfur granules” (gram-positive mycelia and their hyphae) Nodular, verrucous, or granulomatous lesions; ulcers are indurated and painful; usual source hematogenous or pulmonary, but may be primary Debridement and diluted (1:3) peroxide lavage provide relief within 24 h; antibiotics in acutely ill patients; relapse may occur Tooth deformities in permanent dentition irreversible Healing of chancre in 1–2 months, followed by secondary syphilis in 6–8 weeks Lesions may persist from several weeks to a year Gumma may destroy palate, causing complete perforation More difficult to eradicate than urogenital infection, though pharyngitis usually resolves with appropriate antimicrobial treatment Autoinoculation from pulmonary infection usual; lesions resolve with appropriate antimicrobial therapy Typically swelling is hard and grows painlessly; multiple abscesses with draining tracks develop; penicillin first choice; surgery usually necessary Systemic antifungal therapy necessary to treat (Continued) Oral M anifestations of Disease 15 CHAPTER 2 TABLE 2-3 WHITE LESIONS OF ORAL MUCOSA CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Note: EBV, Epstein-Barr virus. Lichen planus White sponge nevus Smoker’s leuko- plakia and smoke- less tobacco lesions Erythroplakia with or without white patches Candidiasis Hairy leukoplakia Warts (papillomavirus) Buccal mucosa, tongue, gingiva, and lips; skin Oral mucosa, vagina, anal mucosa Any area of oral mucosa, sometimes related to location of habit Floor of mouth com- mon in men; tongue and buccal mucosa in women Any area in mouth Usually lateral tongue, rarely elsewhere on oral mucosa Anywhere on skin and oral mucosa Striae, white plaques, red areas, ulcers in mouth; purplish papules on skin; may be asymptomatic, sore, or painful; lichenoid drug reactions may look similar Painless white thickening of epithelium; adolescent/early adult onset; familial White patch that may become firm, rough, or red-fissured and ulcerated; may become sore and painful but usually painless Velvety, reddish plaque; occasionally mixed with white patches or smooth red areas Pseudomembranous type (“thrush”): creamy white curdlike patches that reveal a raw, bleeding surface when scraped; found in sick infants, debilitated elderly patients receiving high doses of glucocorticoids or broad-spectrum antibiotics, or in patients with AIDS Erythematous type: flat, red, sometimes sore areas in same groups of patients Candidal leukoplakia: nonremovable white thickening of epithelium due to Candida Angular cheilitis: sore fissures at corner of mouth White areas ranging from small and flat to extensive accentuation of vertical folds; found in HIV carriers in all risk groups for AIDS Single or multiple papillary lesions, with thick, white keratinized surfaces containing many pointed projections; cauliflower lesions covered with normal-colored mucosa or multiple pink or pale bumps (focal epithelial hyperplasia) Protracted; responds to topical glucocorticoids Benign and permanent May or may not resolve with cessation of habit; 2% develop squamous cell carcinoma; early biopsy essential High risk of squamous cell cancer; early biopsy essential Responds favorably to antifungal therapy and correction of predisposing causes where possible Course same as for pseudomembranous type Responds to prolonged antifungal therapy Responds to topical antifungal therapy Due to EBV; responds to high dose acyclovir but recurs; rarely causes discomfort unless secondarily infected with Candida Lesions grow rapidly and spread; consider squamous cell carcinoma and rule out with biopsy; excision or laser therapy; may regress in HIV infected patients on antiretroviral therapy Cardinal M anifestations of Gastrointestinal Disease 16 SECTION I TABLE 2-4 ALTERATIONS OF THE TONGUE TYPE OF CHANGE CLINICAL FEATURES Size or Morphology Changes Macroglossia Enlarged tongue that may be part of a syndrome found in developmental conditions such as Down syndrome, Simpson-Golabi-Behmel syndrome, or Beckwith-Wiedemann syndrome may be due to tumor (hemangioma or lymphangioma), metabolic disease (such as primary amyloidosis), or endocrine disturbance (such as acromegaly or cretinism) Fissured (“scrotal”) Dorsal surface and sides of tongue covered by painless shallow or deep fissures that tongue may collect debris and become irritated Median rhomboid Congenital abnormality of tongue with ovoid, denuded area in median posterior portion of the glossitis tongue; may be associated with candidiasis and may respond to antifungals Color Changes “Geographic” tongue Asymptomatic inflammatory condition of the tongue, with rapid loss and regrowth of filiform (benign migratory papillae, leading to appearance of denuded red patches “wandering” across the surface of the glossitis) tongue Hairy tongue Elongation of filiform papillae of the medial dorsal surface area due to failure of keratin layer of the papillae to desquamate normally; brownish-black coloration may be due to staining by tobacco, food, or chromogenic organisms “Strawberry” and Appearance of tongue during scarlet fever due to the hypertrophy of fungiform papillae plus “raspberry” tongue changes in the filiform papillae “Bald” tongue Atrophy may be associated with xerostomia, pernicious anemia, iron-deficiency anemia, pellagra, or syphilis; may be accompanied by painful burning sensation; may be an expression of erythematous candidiasis and respond to antifungals TABLE 2-5 ORAL LESIONS ASSOCIATED WITH HIV INFECTION LESION MORPHOLOGY ETIOLOGIES Papules, nodules, plaques Candidiasis (hyperplastic and pseudomembranous)a Condyloma acuminatum (human papillomavirus infection) Squamous cell carcinoma (preinvasive and invasive) Non-Hodgkin’s lymphomaa Hairy leukoplakiaa Ulcers Recurrent aphthous ulcersa Angular cheilitis Squamous cell carcinoma Acute necrotizing ulcerative gingivitisa Necrotizing ulcerative periodontitisa Necrotizing ulcerative stomatitis Non-Hodgkin’s lymphomaa Viral infection (herpes simplex, herpes zoster, cytomegalovirus) Mycobacterium tuberculosis, Mycobacterium avium-intracellulare Fungal infection (histoplasmosis, cryptococcosis, candidiasis, geotrichosis, aspergillosis) Bacterial infection (Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa) Drug reactions (single or multiple ulcers) Pigmented lesions Kaposi’s sarcomaa Bacillary angiomatosis (skin and visceral lesions more common than oral) Zidovudine pigmentation (skin, nails, and occasionally oral mucosa) Addison’s disease Miscellaneous Linear gingival erythemaa aStrongly associated with HIV infection. Oral M anifestations of Disease 17 CHAPTER 2 Less common etiologies include syphilis and Plummer- Vinson syndrome (iron deficiency). Rarer causes of chronic oral ulcer such as tuberculosis, fungal infection, Wegener’s granulomatosis, and midline granuloma may look identical to carcinoma. Making the correct diagnosis depends on recognizing other clinical features and biopsy of the lesion.The syphilitic chancre is typically painless and therefore easily missed. Regional lymphadenopathy is invariably present. Con- firmation is achieved using appropriate bacterial and serologic tests. Disorders of mucosal fragility often produce painful oral ulcers that fail to heal within 2 weeks. Mucous mem- brane pemphigoid and pemphigus vulgaris are the major acquired disorders. While clinical features are often dis- tinctive, immunohistochemical examination should be performed for diagnosis and to distinguish these entities from lichen planus and drug reactions. Hematologic and Nutritional Disease Internists are more likely to encounter patients with acquired, rather than congenital, bleeding disorders. Bleeding after minor trauma should stop after 15 min and within an hour of tooth extraction if local pressure is applied. More prolonged bleeding, if not due to contin- ued injury or rupture of a large vessel, should lead to investigation for a clotting abnormality. In addition to bleeding, petechiae and ecchymoses are prone to occur at the line of vibration between the soft and hard palates in patients with platelet dysfunction or thrombocytopenia. All forms of leukemia, but particularly acute myelomonocytic leukemia, can produce gingival bleed- ing, ulcers, and gingival enlargement. Oral ulcers are a feature of agranulocytosis, and ulcers and mucositis are often severe complications of chemotherapy and radia- tion therapy for hematologic and other malignancies. Plummer-Vinson syndrome (iron deficiency, angular stomatitis, glossitis, and dysphagia) raises the risk of oral squamous cell cancer and esophageal cancer at the post- cricoidal tissue web.Atrophic papillae and a red, burning tongue may occur with pernicious anemia. B-group vit- amin deficiencies produce many of these same symp- toms as well as oral ulceration and cheilosis. Cheilosis may also be seen in iron deficiency. Swollen, bleeding gums, ulcers, and loosening of the teeth are a conse- quence of scurvy. NONDENTAL CAUSES OF ORAL PAIN Most but not all oral pain emanates from inflamed or injured tooth pulp or periodontal tissues. Nonodonto- genic causes may be overlooked. In most instances toothache is predictable and proportional to the stimulus applied, and an identifiable condition (e.g., caries, abscess) is found. Local anesthesia eliminates pain originating from dental or periodontal structures, but not referred pain. The most common nondental origin is myofascial pain referred from muscles of mastication, which become tender and ache with increased use. Many suf- ferers exhibit bruxism (the grinding of teeth, often dur- ing sleep) that is secondary to stress and anxiety. Temporo- mandibular disorder is closely related. It predominantly affects females ages 15–45. Features include pain, limited mandibular movement, and temporomandibular joint sounds. The etiologies are complex, and malocclusion does not play the primary role once attributed to it. Osteoarthritis is a common cause of masticatory pain. Anti-inflammatory medication, jaw rest, soft foods, and heat provide relief. The temporomandibular joint is involved in 50% of patients with rheumatoid arthritis and is usually a late feature of severe disease. Bilateral preau- ricular pain, particularly in the morning, limits range of motion. Migrainous neuralgia may be localized to the mouth. Episodes of pain and remission without identifiable cause and absence of relief with local anesthesia are important clues. Trigeminal neuralgia (tic douloureux) may involve the entire branch or part of the mandibular or maxillary branches of the fifth cranial nerve and produce pain in one or a few teeth. Pain may occur spontaneously or may be triggered by touching the lip or gingiva, brushing the teeth, or chewing. Glossopharyngeal neuralgia produces similar acute neuropathic symptoms in the distribution of the ninth cranial nerve. Swallow- ing, sneezing, coughing, or pressure on the tragus of the ear triggers pain that is felt in the base of the tongue, pharynx, and soft palate and may be referred to the tem- poromandibular joint. Neuritis involving the maxillary and mandibular divisions of the trigeminal nerve (e.g., maxillary sinusitis, neuroma, and leukemic infiltrate) is distinguished from ordinary toothache by the neuro- pathic quality of the pain. Occasionally phantom pain fol- lows tooth extraction. Often the earliest symptom of Bell’s palsy in the day or so before facial weakness devel- ops is pain and hyperalgesia behind the ear and side of the face. Likewise, similar symptoms may precede visible lesions of herpes zoster infecting the seventh nerve (Ramsey-Hunt syndrome) or trigeminal nerve. Posther- petic neuralgia may follow either condition. Coronary ischemia may produce pain exclusively in the face and jaw and, like typical angina pectoris, is usually repro- ducible with increased myocardial demand. Aching in several upper molar or premolar teeth that is unrelieved by anesthetizing the teeth may point to maxillary sinusitis. Giant cell arteritis is notorious for producing headache, but it may also produce facial pain or sore throat without headache. Jaw and tongue claudication with chewing or talking is relatively common. Tongue infarction is rare. Patients with subacute thyroiditis often experience pain referred to the face or jaw before the Cardinal M anifestations of Gastrointestinal Disease 20 SECTION I ACKNOWLEDGMENT The author acknowledges the contribution to this chapter by the previous author, Dr. John S. Greenspan. FURTHER READINGS BAUM BJ et al:Aquaporin-1 gene transfer to correct radiation-induced salivary hypofunction. Handb Exp Pharmacol 190:403, 2009 DURSO SC: Interaction with other health team members in caring for elderly patients. Dent Clin North Am 49:377, 2005 GONSALVES WC et al: Common oral conditions in older persons.Am Fam Physician 78:845, 2008 GUEIROS LA et al: Impact of ageing and drug consumption on oral health. Gerodontology 26:297, 2009 LITTLE JW et al (eds): Dental Management of the Medically Compromised Patient, 6th ed. St. Louis, Mosby, 2002 REGEZI JA, SCIUBBA JJ: Oral Pathology: Clinical Pathologic Correlations, 4th ed. Philadelphia, Saunders, 2002 SPAHR A et al: Periodontal infection and coronary heart disease. Role of periodontal bacteria and importance of total pathogen burden in the coronary event and periodontal disease (CORODONT) study.Arch Intern Med 166:554, 2006 WOO SB et al: Systematic review: Bisphosphonates and osteonecrosis of the jaws.Ann Intern Med 144:753, 2006 Samuel C. Durso ■ Janet A. Yellowitz ■ Jane C. Atkinson 21 The health status of the oral cavity is linked to cardiovas- cular disease, diabetes, and other systemic illnesses.Thus, there is significant clinical value in examining the oral cavity for signs of disease.This chapter presents numerous outstanding clinical photographs illustrating many of the conditions discussed in Chap. 2, Oral Manifestations of Disease. Conditions affecting the teeth, periodontal tis- sues, and oral mucosa are all represented. ATLAS OF ORAL MANIFESTATIONS OF DISEASE CHAPTER 3 FIGURE 3-1 Gingival overgrowth secondary to calcium channel blocker use. FIGURE 3-2 Oral lichen planus. Cardinal M anifestations of Gastrointestinal Disease 22 SECTION I FIGURE 3-3 Erosive lichen planus. FIGURE 3-5 Inflamed palate. FIGURE 3-7 Angular cheilitis. FIGURE 3-4 Stevens-Johnson syndrome—reaction to nevirapine. FIGURE 3-6 Severe periodontitis. A B Atlas of Oral M anifestations of Disease 25 CHAPTER 3 FIGURE 3-19 Heavy plaque and gingival inflammation. FIGURE 3-20 Ulcer on lateral border of tongue—potential carcinoma. FIGURE 3-21 Osteonecrosis. FIGURE 3-22 Severe periodontal disease, missing tooth, very mobile teeth. FIGURE 3-23 Salivary stone. FIGURE 3-24 A. Calculus. B. Teeth cleaned. Cardinal M anifestations of Gastrointestinal Disease 26 SECTION I FIGURE 3-25 Traumatic ulcer. FIGURE 3-26 Fissured tongue. FIGURE 3-27 White coated tongue—likely candidiasis. Raj K. Goyal 27 Dysphagia is defined as a sensation of “sticking” or obstruction of the passage of food through the mouth, pharynx, or esophagus. However, it is often used as an umbrella term to include other symptoms related to swal- lowing difficulty. Aphagia signifies complete esophageal obstruction, which is usually due to bolus impaction and represents a medical emergency. Difficulty in initiating a swallow occurs in disorders of the voluntary phase of swal- lowing. However, once initiated, swallowing is completed normally. Odynophagia means painful swallowing. Fre- quently, odynophagia and dysphagia occur together. Globus pharyngeus is the sensation of a lump lodged in the throat. However, no difficulty is encountered when swal- lowing is performed. Misdirection of food, resulting in nasal regurgitation and laryngeal and pulmonary aspiration during swallowing, is characteristic of oropharyngeal dys- phagia. Phagophobia, meaning fear of swallowing, and refusal to swallow may occur in hysteria, rabies, tetanus, and pharyngeal paralysis due to fear of aspiration. Painful inflammatory lesions that cause odynophagia may also cause refusal to swallow. Some patients may feel the food as it goes down the esophagus.This esophageal sensitivity is not associated with either food sticking or obstruction. PHYSIOLOGY OF SWALLOWING The process of swallowing begins with a voluntary (oral) phase that includes a preparatory phase during which a food bolus suitable for swallowing is prepared and a transfer phase during which the bolus is pushed into the pharynx by contraction of the tongue. The bolus then activates oropharyngeal sensory receptors that initiate the deglutition reflex.The deglutition reflex is centrally mediated and involves a complex series of events. It serves both to propel food through the phar- ynx and the esophagus and to prevent its entry into the airway. When the bolus is propelled backward by the tongue, the larynx moves forward and the upper esophageal sphincter (UES) opens. As the bolus moves into the pharynx, contraction of the superior pharyngeal constrictor against the contracted soft palate initiates a peristaltic contraction that proceeds rapidly downward to move the bolus through the pharynx and the esophagus. The lower esophageal sphincter (LES) opens as the food enters the esophagus and remains open until the peri- staltic contraction has swept the bolus into the stomach. Peristaltic contraction in response to a swallow is called primary peristalsis. It involves inhibition followed by sequential contraction of muscles along the entire swal- lowing passage.The inhibition that precedes the peristaltic contraction is called deglutitive inhibition. Local distention of the esophagus from residual food activates secondary peristalsis. Muscles of the oral cavity, pharynx, UES, and cervical esophagus are striated and are directly innervated by the lower motor neurons carried in the cranial nerves. Oral cavity muscles are innervated by the Vth and the VIIth cranial nerves and the tongue muscles by the XIIth cra- nial nerve. Pharyngeal muscles are innervated by the IXth and the Xth cranial nerves. The UES consists of constrictor and dilator muscles. The constrictor muscles include the cricopharyngeus DYSPHAGIA CHAPTER 4 Physiology of Swallowing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Pathophysiology of Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . 28 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 the oropharyngeal muscles. Clinical manifestations of the cervical esophageal involvement are usually over- shadowed by those of the oropharyngeal dysphagia. Diseases of the smooth-muscle segment involve the thoracic part of the esophagus and the LES. Dysphagia occurs when the peristaltic contractions are weak or absent or when the contractions are nonperistaltic. Loss of peristalsis may be associated with failure of LES relax- ation.Weakness of contractile power occurs due to mus- cle weakness, as in scleroderma or impaired cholinergic effect. Nonperistaltic contractions and failure of LES relaxation occur due to impaired inhibitory innervation. In diffuse esophageal spasm (DES), inhibitory innervation only to the esophageal body is impaired, whereas in acha- lasia inhibitory innervation to both the esophageal body and LES is impaired. Dysphagia due to esophageal muscle weakness is often associated with symptoms of gastroe- sophageal reflux disease (GERD). Dysphagia due to loss of the inhibitory innervation is typically not associated with GERD but may be associated with chest pain. The causes of esophageal motor dysphagia are also listed in Table 4-2; they include scleroderma of the esophagus, achalasia, DES, and other motor disorders. Cardinal M anifestations of Gastrointestinal Disease 30 SECTION I TABLE 4-2 ESOPHAGEAL DYSPHAGIA ESOPHAGEAL MECHANICAL DYSPHAGIA I. Wall defects A. Congenital B. Tracheoesophageal fistula II. Intrinsic narrowing A. Inflammatory esophagitis 1. Viral (herpes simplex, varicella-zoster, cytomegalovirus) 2. Bacterial 3. Fungal (Candida) 4. Mucocutaneous bullous diseases 5. Caustic, chemical, thermal injury 6. Eosinophilic esophagitis B. Webs and rings 1. Esophageal (congenital, inflammatory) 2. Lower esophageal mucosal ring (Schatzki’s ring) 3. Eosinophilic esophagitis 4. Host-versus-graft disease, mucocutaneous disorders C. Benign strictures 1. Peptic 2. Caustic 3. Pill-induced 4. Inflammatory (Crohn’s disease, Candida, mucocutaneous lesions) 5. Ischemic 6. Postoperative 7. Post-radiation 8. Congenital D. Tumors 1. Benign 2. Malignant III. Extrinsic compression A. Vascular compression (dysphagia lusoria, aberrant right subclavian artery, right-sided aorta, left atrial enlargement, aortic aneurysm) B. Posterior mediastinal mass C. Postvagotomy hematoma and fibrosis I. Disorders of cervical esophagus (see oropharyngeal motor dysphagia, Table 4-1) II. Disorders of thoracic esophagus A. Diseases of smooth muscle or excitatory nerves 1. Weak muscle contraction or LES tone a. Idiopathic b. Scleroderma and related collagen vascular diseases c. Hollow visceral myopathy d. Myotonic dystrophy e. Metabolic neuromyopathy (amyloid, alcohol?, diabetes?) f. Drugs: anticholinergics, smooth muscle relaxants 2. Enhanced muscle contraction a. Hypertensive peristalsis (nutcracker esophagus) b. Hypertensive LES, hypercontracting LES B. Disorders of inhibitory innervation 1. Diffuse esophageal spasm 2. Achalasia a. Primary b. Secondary (Chagas’ disease, carcinoma, lymphoma, neuropathic intestinal pseudo- obstruction syndrome) 3. Contractile (muscular) lower esophageal ring ESOPHAGEAL MOTOR DYSPHAGIA Note: LES, lower esophageal sphincter. Approach to the Patient: DYSPHAGIA Figure 4-1 shows an algorithm of approach to a patient with dysphagia. HISTORY The history can provide a presumptive diagnosis in >80% of patients. The site of dysphagia described by the patient helps to determine the site of esophageal obstruction; the lesion is at or below the perceived location of dysphagia. Associated symptoms provide important diagnostic clues. Nasal regurgitation and tracheobronchial aspi- ration with swallowing are hallmarks of pharyngeal paralysis or a tracheoesophageal fistula. Tracheo- bronchial aspiration unrelated to swallowing may be due to achalasia, Zenker’s diverticulum, or gastroe- sophageal reflux. Association of laryngeal symptoms and dysphagia occurs in various neuromuscular disorders. The pres- ence of hoarseness may be an important diagnostic clue. When hoarseness precedes dysphagia, the pri- mary lesion is usually in the larynx; hoarseness fol- lowing dysphagia may suggest involvement of the recurrent laryngeal nerve by extension of esophageal carcinoma. Sometimes hoarseness may be due to laryngitis secondary to gastroesophageal reflux. Hiccups may rarely occur with a lesion in the distal portion of the esophagus. Unilateral wheezing with dysphagia may indicate a mediastinal mass involving the esophagus and a large bronchus. The type of food causing dysphagia provides useful information. Difficulty only with solids implies mechanical dysphagia with a lumen that is not severely narrowed. In advanced obstruction, dyspha- gia occurs with liquids as well as solids. In contrast, motor dysphagia due to achalasia and DES is equally affected by solids and liquids from the very onset. Patients with scleroderma have dysphagia to solids that is unrelated to posture and to liquids while recumbent but not upright. When peptic stricture develops in patients with scleroderma, dysphagia becomes more persistent. The duration and course of dysphagia are helpful in diagnosis. Transient dysphagia may be due to an inflammatory process. Progressive dysphagia lasting a few weeks to a few months is suggestive of carcinoma of the esophagus. Episodic dysphagia to solids lasting several years indicates a benign disease characteristic of a lower esophageal ring. Severe weight loss that is out of proportion to the degree of dysphagia is highly suggestive of carcinoma. Chest pain with dysphagia occurs in DES and related motor disorders. Chest pain resembling DES may occur in esophageal obstruction due to a large bolus. A prolonged history of heartburn and reflux preceding dysphagia indicates peptic stricture. A his- tory of prolonged nasogastric intubation, ingestion of Dysphagia 31 CHAPTER 4 Difficulty in initiating a swallow, misdirectional food causing coughing, choking, or nasal regurgitation (+ Localized to throat) (+ Localized to chest or throat) Oropharyngeal dysphagia Esophageal dysphagia Dysphagia to solids or liquids SOLIDS ONLYSOLIDS AND LIQUIDSNo No Yes Yes Oropharyngeal Motor dysphagia Mental status Oral phase abnormalities Pharyngeal phase abnormalities • ENT Evaluation • Barium swallow • Esophageal motility • Esophagoscopy • Esophagoscopy • Barium swallow Oropharyngeal Mechanical dysphagia Esophageal Motor dysphagia Esophageal Mechanical dysphagia NORMAL - VFSS + Prominent heartburnIMPAIRED Yes No Scleroderma Achalasia Episodic or progressive EPISODIC PROGRESSIVE Carcinoma Lower esophageal ring DYSPHAGIA Neuromuscular findings FIGURE 4-1 Approach to the patient with dysphagia. ENT, ear, nose, and throat; VFSS, videofluoroscopic swallow- ing study. caustic agents, ingestion of pills without water, previ- ous radiation therapy, or associated mucocutaneous diseases may provide the cause of esophageal stricture. If odynophagia is present, candidal, herpes, or pill- induced esophagitis should be suspected. In patients with AIDS or other immunocompro- mised states, esophagitis due to opportunistic infec- tions such as Candida, herpes simplex virus, or cytomegalovirus and to tumors such as Kaposi’s sar- coma and lymphoma should be considered. PHYSICAL EXAMINATION Physical examination is important in oral and pharyngeal motor dysphagia. Signs of bulbar or pseudobulbar palsy, including dysarthria, dysphonia, ptosis, tongue atrophy, and hyperactive jaw jerk, in addition to evidence of gener- alized neuromuscular disease, should be sought. The neck should be examined for thyromegaly or a spinal abnormality. A careful inspection of the mouth and pharynx should disclose lesions that may interfere with passage of food. Pulmonary complications such as acute or chronic aspiration pneumonia may be present. Physical examination is often unrevealing in esophageal dysphagia. Changes in the skin and extremities may suggest a diagnosis of scleroderma and other collagen vascular diseases or mucocuta- neous diseases such as pemphigoid or epidermolysis bullosa, which may involve the esophagus. Cancer spread to lymph nodes and liver may be evident. DIAGNOSTIC PROCEDURES Dysphagia is usually a symptom of organic disease rather than a functional complaint. If oral or pharyngeal dysphagia is suspected,VFSS by both a radiologist and a swallow therapist is the procedure of choice.Videoendoscopy is currently per- formed only in specialized centers. Otolaryngoscopic and neurologic evaluation are also usually required. If esophageal mechanical dysphagia is suspected on clinical history, barium swallow and esophagogas- troscopy with or without mucosal biopsies are the diagnostic procedures of choice. In some cases, CT examination and endoscopic ultrasound may be use- ful. For motor esophageal dysphagia, barium swallow, esophageal manometry, esophageal pH, and imped- ance testing are useful diagnostic tests. Esophagogas- troscopy is also often performed in patients with motor dysphagia to exclude an associated structural abnormality (Chap. 13). FURTHER READINGS ATKINS D et al: Eosinophilic esophagitis: the newest esophageal inflammatory disease. Nat Rev Gastroenterol Hepatol 6:267, 2009 BELHOCINE K, GALMICHE JP: Epidemiology of the complications of gastroesophageal reflux disease. Dig Dis 27:7, 2009 BHARDWAJ A et al: A meta-analysis of the diagnostic accuracy of esophageal capsule endoscopy for Barrett’s esophagus in patients with gastroesophageal reflux disease.Am J Gastroenterol 104:1533, 2009 MASSEY B, SHAKER R: Oral pharyngeal and upper esophageal sphinc- ter motility disorders.http://www.nature.com/gimo/index.html;doi:10.1038/ gimo19, 2006 MCCULLOUGH TM, JAFFE D: Head and neck disorders causing dys- phagia. www.GI motilityonline.com; doi:10.1038/gimo36, 2006 PATERSON WG et al: Esophageal motility disorders. www.GImotility online.com; doi:10.1038/gimo20, 2006 VELA MF: Non-acid reflux: detection by multichannel intraluminal impedance and pH, clinical significance, and management. Am J Gastroenterol 104:277, 2009 Cardinal M anifestations of Gastrointestinal Disease 32 SECTION I simplex virus induce emesis in immunocompromised individuals. Disordered gut sensorimotor function also commonly causes nausea and vomiting. Gastroparesis is defined as a delay in emptying of food from the stomach and occurs after vagotomy, with pancreatic adenocarcinoma, with mesenteric vascular insufficiency, or in systemic diseases such as diabetes, scleroderma, and amyloidosis. Idiopathic gastroparesis occurring in the absence of systemic illness may follow a viral prodrome, suggesting an infectious etiology. Intestinal pseudoobstruction is characterized by disrupted intestinal and colonic motor activity and leads to retention of food residue and secretions, bacter- ial overgrowth, nutrient malabsorption, and symptoms of nausea, vomiting, bloating, pain, and altered defeca- tion. Intestinal pseudoobstruction may be idiopathic or inherited as a familial visceral myopathy or neuropathy, or it may result from systemic disease or as a paraneo- plastic complication of a malignancy such as small cell lung carcinoma. Patients with gastroesophageal reflux may report nausea and vomiting, as do some individ- uals with functional dyspepsia and irritable bowel syndrome. Three other functional disorders without organic abnormalities have been characterized in adults. Chronic idiopathic nausea is defined as nausea without vomiting occurring several times weekly, whereas functional vomiting is defined as one or more vomiting episodes weekly in the absence of an eating disorder or psychiatric disease. Cyclic vomiting syndrome is a rare disorder of unknown etiology that produces periodic discrete episodes of relentless nausea and vomiting. The syndrome shows a strong association with migraine headaches, suggesting that some cases may be migraine variants. Cyclic vomit- ing is most common in children, although adult cases have been described in association with rapid gastric emptying and with chronic cannabis use. Extraperitoneal Disorders Myocardial infarction and congestive heart failure are cardiac causes of nausea and vomiting. Postoperative emesis occurs after 25% of surgeries, most commonly laparotomy and orthopedic surgery, and is more prevalent in women. Increased intracranial pressure from tumors, bleeding, abscess, or obstruction to cerebrospinal fluid outflow produces prominent vomiting with or without nausea. Motion sickness, labyrinthitis, and Ménière’s dis- ease evoke symptoms via labyrinthine pathways. Patients with psychiatric illnesses including anorexia nervosa, bulimia nervosa, anxiety, and depression may report sig- nificant nausea that may be associated with delayed gas- tric emptying. Medications and Metabolic Disorders Drugs evoke vomiting by action on the stomach (anal- gesics, erythromycin) or area postrema (digoxin, opiates, anti-Parkinsonian drugs). Emetogenic agents include antibiotics, cardiac antiarrhythmics, antihypertensives, oral hypoglycemics, and contraceptives. Cancer chemother- apy causes vomiting that is acute (within hours of administration), delayed (after 1 or more days), or antici- patory. Acute emesis resulting from highly emetogenic agents such as cisplatin is mediated by 5-HT3 pathways, whereas delayed emesis is 5-HT3-independent.Anticipa- tory nausea often responds better to anxiolytic therapy than to antiemetics. Several metabolic disorders elicit nausea and vomit- ing. Pregnancy is the most prevalent endocrinologic cause of nausea, occurring in 70% of women in the first trimester. Hyperemesis gravidarum is a severe form of nausea of pregnancy that can produce significant fluid loss and electrolyte disturbances. Uremia, ketoacidosis, and adrenal insufficiency, as well as parathyroid and thy- roid disease, are other metabolic causes of emesis. Circulating toxins evoke symptoms via effects on the area postrema. Endogenous toxins are generated in ful- minant liver failure, whereas exogenous enterotoxins may be produced by enteric bacterial infection. Ethanol intoxication is a common toxic etiology of nausea and vomiting. Approach to the Patient: NAUSEA AND VOMITING HISTORY AND PHYSICAL EXAMINATION The history helps define the etiology of unexplained nausea and vomiting. Drugs, toxins, and gastrointestinal infections commonly cause acute symptoms, whereas established illnesses evoke chronic complaints. Pyloric obstruction and gastroparesis produce vomiting within 1 h of eat- ing, whereas emesis from intestinal obstruction occurs later. In severe cases of gastroparesis, the vomitus may contain food residue ingested hours or days previously. Hematemesis raises suspicion of an ulcer, malignancy, or Mallory-Weiss tear, whereas feculent emesis is noted with distal intestinal or colonic obstruction. Bilious vomiting excludes gastric obstruction, while emesis of undigested food is consistent with a Zenker’s divertic- ulum or achalasia. Relief of abdominal pain by emesis characterizes small-bowel obstruction, whereas vomit- ing has no effect on pancreatitis or cholecystitis pain. Pronounced weight loss raises concern about malig- nancy or obstruction. Fevers suggest inflammation; an intracranial source is considered if there are headaches or visual field changes. Vertigo or tinnitus indicates labyrinthine disease. Nausea, Vom iting, and Indigestion 35 CHAPTER 5 The physical examination complements informa- tion obtained in the history. Demonstration of ortho- static hypotension and reduced skin turgor indicate intravascular fluid loss. Pulmonary abnormalities raise concern for aspiration of vomitus. Abdominal auscul- tation may reveal absent bowel sounds with ileus. High-pitched rushes suggest bowel obstruction, while a succussion splash upon abrupt lateral movement of the patient is found with gastroparesis or pyloric obstruction.Tenderness or involuntary guarding raises suspicion of inflammation, whereas fecal blood sug- gests mucosal injury from ulcer, ischemia, or tumor. Neurologic etiologies present with papilledema, visual field loss, or focal neural abnormalities. Neoplasm is suggested by palpation of masses or adenopathy. DIAGNOSTIC TESTING For intractable symptoms or an elusive diagnosis, selected diagnostic tests can direct clinical management. Electrolyte replenishment is indicated for hypokalemia or metabolic alkalosis. Detection of iron-deficiency anemia mandates a search for mucosal injury. Pancreaticobiliary disease is indicated by abnormal pancreatic enzymes or liver biochemistries, whereas endocrinologic, rheumato- logic, or paraneoplastic etiologies are suggested by specific hormone or serologic testing. If luminal obstruction is suspected, supine and upright abdomi- nal radiographs may show intestinal air-fluid levels with reduced colonic air. Ileus is characterized by dif- fusely dilated air-filled bowel loops. Anatomic studies may be indicated if initial testing is nondiagnostic. Upper endoscopy detects ulcers or malignancy, while small-bowel barium radiography diagnoses partial small-bowel obstruction. Colonoscopy or contrast enema radiography can detect colonic obstruction. Abdominal ultrasound or computed tomography (CT) defines intraperitoneal inflamma- tory processes, while CT or magnetic resonance imaging (MRI) of the head can delineate intracranial disease. Mesenteric angiography or MRI is useful when ischemia is considered. Gastrointestinal motility testing may detect a motor disorder that contributes to symptoms when anatomic abnormalities are absent. Gastroparesis com- monly is diagnosed using gastric scintigraphy, by which emptying of a radiolabeled meal is measured. Isotopic breath tests and telemetry capsule methods also have been validated. Electrogastrography, a non- invasive test of gastric slow-wave activity using cuta- neous electrodes placed over the stomach, has been proposed as an alternate means of diagnosing gastro- paresis. The diagnosis of intestinal pseudoobstruction often is suggested by abnormal barium transit and luminal dilation on small-bowel contrast radiogra- phy. Small-intestinal manometry can confirm the diagnosis and further characterize the motor abnor- mality as neuropathic or myopathic based on contrac- tile patterns. Such investigation can obviate the need for open intestinal biopsy to evaluate for smooth muscle or neuronal degeneration. Treatment: NAUSEA AND VOMITING GENERAL PRINCIPLES Therapy of vomiting is tai- lored to correction of medically or surgically remediable abnormalities if possible. Hospitalization is considered for severe dehydration especially if oral fluid replenishment cannot be sustained. Once oral intake is tolerated, nutri- ents are restarted with liquids that are low in fat, as lipids delay gastric emptying. Foods high in indigestible residues are avoided as these also prolong gastric retention. ANTIEMETIC MEDICATIONS The most com- monly used antiemetic agents act on sites within the central nervous system (Table 5-2). Antihistamines such as meclizine and dimenhydrinate and anticholinergic drugs like scopolamine act on labyrinthine-activated pathways and are useful in motion sickness and inner ear disorders. Dopamine D2 antagonists treat emesis evoked by area postrema stimuli and are useful for med- ication, toxic, and metabolic etiologies. Dopamine antagonists freely cross the blood-brain barrier and cause anxiety, dystonic reactions, hyperprolactinemic effects (galactorrhea and sexual dysfunction), and irre- versible tardive dyskinesia. Other drug classes exhibit antiemetic properties. Serotonin 5-HT3 antagonists such as ondansetron and granisetron exhibit utility in postoperative vomiting, after radiation therapy, and in the prevention of cancer chemotherapy–induced emesis. The usefulness of 5-HT3 antagonists for other causes of emesis is less well estab- lished. Low-dose tricyclic antidepressant agents provide symptomatic benefit in patients with chronic idiopathic nausea and functional vomiting as well as in diabetic patients with nausea and vomiting whose disease is long standing. GASTROINTESTINAL MOTOR STIMULANTS Drugs that stimulate gastric emptying are indicated for gastroparesis (Table 5-2). Metoclopramide, a combined 5-HT4 agonist and D2 antagonist, exhibits efficacy in gas- troparesis, but antidopaminergic side effects limit its use in 25% of patients. Erythromycin, a macrolide antibiotic, increases gastroduodenal motility by action on recep- tors for motilin, an endogenous stimulant of fasting motor activity. Intravenous erythromycin is useful for inpatients with refractory gastroparesis; however, oral forms also have some utility. Domperidone, a D2 antago- nist not available in the United States, exhibits proki- netic and antiemetic effects but does not cross into Cardinal M anifestations of Gastrointestinal Disease 36 SECTION I most other brain regions; thus, anxiety and dystonic reactions are rare. The main side effects of domperidone relate to induction of hyperprolactinemia via effects on pituitary regions served by a porous blood-brain barrier. The 5-HT4 agonist tegaserod potently stimulates gastric emptying in patients with gastroparesis; however, its effects on symptoms of gastric retention are unproven. Patients with refractory upper gut motility disorders pose significant challenges. Liquid suspensions of proki- netic drugs may be beneficial, as liquids empty from the stomach more rapidly than pills. Metoclopramide can be administered subcutaneously in patients unrespon- sive to oral drugs. Intestinal pseudoobstruction may respond to the somatostatin analogue octreotide, which induces propagative small intestinal motor com- plexes. Pyloric injections of botulinum toxin are reported in uncontrolled studies to benefit patients with gastroparesis. Placement of a feeding jejunostomy reduces hospitalizations and improves overall health in some patients with gastroparesis who do not respond to drug therapy. Surgical options are limited for refrac- tory cases, but postvagotomy gastroparesis may improve with near-total resection of the stomach. Implanted gastric electrical stimulators may reduce symptoms, enhance nutrition, improve quality of life, and decrease health care expenditures in patients with medication-refractory gastroparesis. SELECTED CLINICAL SETTINGS Cancer chemotherapeutic agents such as cisplatin are intensely emetogenic. Given prophylactically, 5-HT3 antagonists prevent chemotherapy-induced acute vomiting in most cases (Table 5-2). Optimal antiemetic effects often are obtained with a 5-HT3 antagonist combined with a glu- cocorticoid. High-dose metoclopramide also exhibits efficacy in chemotherapy-evoked emesis, while benzo- diazepines such as lorazepam are useful in reducing anticipatory nausea and vomiting. Therapy of delayed emesis 1–5 days after chemotherapy is less successful. Neurokinin NK1 antagonists (e.g., aprepitant) exhibit antiemetic and antinausea effects during both the acute and delayed periods after chemotherapy. Cannabinoids such as tetrahydrocannabinol, long advocated for cancer-associated emesis, produce significant side effects and exhibit no more efficacy than antidopaminergic agents. Most current drug regimens produce greater reductions in vomiting than in nausea. The clinician should exercise caution in managing the pregnant patient with nausea. Studies of the terato- genic effects of available antiemetic agents provide conflicting results. Few controlled trials have been per- formed in nausea of pregnancy, although antihista- mines such as meclizine and antidopaminergics such as prochlorperazine demonstrate efficacy greater than placebo. Some obstetricians offer alternative therapies such as pyridoxine, acupressure, or ginger. Controlling emesis in cyclic vomiting syndrome is a challenge. In many individuals, prophylactic treatment with tricyclic antidepressants, cyproheptadine, or -adrenoceptor antagonists can reduce the frequency of Nausea, Vom iting, and Indigestion 37 CHAPTER 5 TABLE 5-2 TREATMENT OF NAUSEA AND VOMITING TREATMENT MECHANISM EXAMPLES CLINICAL INDICATIONS Antiemetic agents Antihistaminergic Dimenhydrinate, meclizine Motion sickness, inner ear disease Anticholinergic Scopolamine Motion sickness, inner ear disease Antidopaminergic Prochlorperazine, Medication-, toxin-, or metabolic-induced thiethylperazine emesis 5-HT3 antagonist Ondansetron, granisetron Chemotherapy- and radiation-induced emesis, postoperative emesis NK1 antagonist Aprepitant Chemotherapy-induced nausea and vomiting Tricyclic antidepressant Amitriptyline, nortriptyline Chronic idiopathic nausea, functional vomiting, cyclic vomiting syndrome Prokinetic agents 5-HT4 agonist and Metoclopramide Gastroparesis antidopaminergic Motilin agonist Erythromycin Gastroparesis, ?intestinal pseudoobstruction Peripheral antidopaminergic Domperidone Gastroparesis 5-HT4 agonist Tegaserod ?Gastroparesis, ?intestinal pseudoobstruction Somatostatin analogue Octreotide Intestinal pseudoobstruction Special settings Benzodiazepines Lorazepam Anticipatory nausea and vomiting with chemotherapy Glucocorticoids Methylprednisolone, Chemotherapy-induced emesis dexamethasone Cannabinoids Tetrahydrocannabinol ?Chemotherapy-induced emesis failure of drug therapy and helps select patients who may require surgery. Demonstration of disordered esophageal body peristalsis may affect the decision to operate or modify the type of operation chosen. Manometry with provocative testing may clarify the diagnosis in patients with atypical symptoms. Blind perfusion of saline and then acid into the esophagus, known as the Bernstein test, can delineate whether unexplained chest discomfort results from acid reflux. Upper endoscopy is performed as the initial diag- nostic test in patients with unexplained dyspepsia who are >55 years old or have alarm factors because of the elevated risks of malignancy and ulcer in these groups. The management approach to patients <55 years old without alarm factors is dependent on the prevalence of H. pylori infection in the local pop- ulation. For individuals who reside in regions with low H. pylori prevalence (<10%), a 4-week trial of a potent acid-suppressing medication such as a proton pump inhibitor is recommended. If this fails, a “test and treat” approach is most commonly applied. H. pylori status is determined with urea breath test- ing, stool antigen measurement, or blood serology testing. Those who are H. pylori positive are given therapy to eradicate the infection. If symptoms resolve on either of these regimens, no further inter- vention is required. For patients in areas with high H. pylori prevalence (>10%), an initial test and treat approach is advocated, with a subsequent trial of an acid-suppressing regimen offered for those who fail H. pylori treatment or for those who are negative for the infection. In each of these patient subsets, upper endoscopy is reserved for those who fail to respond to therapy. Further testing is indicated if other factors are pre- sent. If bleeding is reported, a blood count is obtained to exclude anemia. Thyroid chemistries or calcium levels screen for metabolic disease, whereas specific serologies may suggest celiac disease. For suspected pancreaticobiliary causes, pancreatic and liver chemistries are obtained. If abnormalities are found, abdominal ultrasound or CT may give important information. Gastric emptying scintigraphy is considered to exclude gastroparesis in patients whose dyspeptic symptoms resemble postprandial distress when drug treatment fails. Gastric scintigraphy also assesses for gastroparesis in patients with GERD, especially if surgical inter- vention is being considered. Breath testing after car- bohydrate ingestion may detect lactase deficiency, intolerance to other dietary carbohydrates, or small- intestinal bacterial overgrowth. Treatment: INDIGESTION GENERAL PRINCIPLES For mild indigestion, reassurance that a careful evaluation revealed no seri- ous organic disease may be the only intervention needed. Drugs that cause acid reflux or dyspepsia should be stopped if possible. Patients with GERD should limit ethanol, caffeine, chocolate, and tobacco use because of their effects on the LES. Other measures in GERD include ingesting a low-fat diet, avoiding snacks before bedtime, and elevating the head of the bed. Specific therapies for organic disease should be offered when possible. Surgery is appropriate in disor- ders like biliary colic, while diet changes are indicated for lactase deficiency or celiac disease. Some illnesses such as peptic ulcer disease may be cured by specific medical regimens. However, as most indigestion is caused by GERD or functional dyspepsia, medications that reduce gastric acid, stimulate motility, or blunt gas- tric sensitivity are indicated. ACID-SUPPRESSING OR NEUTRALIZING MEDICATIONS Drugs that reduce or neutralize gas- tric acid are most often prescribed for GERD. Histamine H2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine are useful in mild to moderate GERD. For severe symptoms or many cases of erosive or ulcerative esophagitis, proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomepra- zole are needed. These drugs, which inhibit gastric H+-, K+-ATPase activity, are more potent than H2 antagonists. Acid suppressants may be taken continuously or on demand depending on symptom severity. Many patients initially started on a proton pump inhibitor can be stepped down to an H2 antagonist. Combination therapy with a proton pump inhibitor and an H2 antagonist has been proposed for some refractory cases. Acid-suppressing drugs are also effective in appro- priately selected patients with functional dyspepsia. Meta-analysis of eight controlled trials calculated a risk ratio of 0.86, with a 95% confidence interval of 0.78–0.95, favoring proton pump inhibitor therapy over placebo.The benefits of less potent acid-reducing thera- pies such as H2 antagonists are unproven. Cardinal M anifestations of Gastrointestinal Disease 40 SECTION I TABLE 5-3 ALARM SYMPTOMS IN GERD Odynophagia Unexplained weight loss Recurrent vomiting Occult or gross gastrointestinal bleeding Jaundice Palpable mass or adenopathy Family history of gastrointestinal malignancy Liquid antacids are useful for short-term control of mild GERD but are less effective for severe disease unless given at high doses that elicit side effects (diarrhea and constipation with magnesium- and aluminum-containing agents, respectively). Alginic acid in combination with antacids may form a floating barrier to acid reflux in indi- viduals with upright symptoms. Sucralfate is a salt of alu- minum hydroxide and sucrose octasulfate that buffers acid and binds pepsin and bile salts. Its efficacy in GERD is felt to be comparable to that of H2 antagonists. HELICOBACTER PYLORI ERADICATION H. pylori eradication is clearly indicated only for peptic ulcer and mucosa-associated lymphoid tissue gastric lymphoma. The utility of eradication therapy in func- tional dyspepsia is less well established, but <15% of cases relate to this infection. Meta-analysis of 13 con- trolled trials calculated a risk ratio of 0.91, with a 95% confidence interval of 0.87–0.96, favoring H. pylori eradi- cation therapy over placebo. Several drug combinations show efficacy in eliminating the infection (Chap. 14); most include 10–14 days of a proton pump inhibitor or bis- muth subsalicylate in concert with two antibiotics. H. pylori infection is associated with reduced prevalence of GERD, especially in the elderly. However, eradication of the infection does not worsen GERD symptoms. To date, no consensus recommendations regarding H. pylori eradication in GERD patients have been offered. GASTROINTESTINAL MOTOR STIMULANTS Motor stimulants (also known as prokinetics) such as metoclopramide, erythromycin, domperidone, and tegaserod have limited utility in GERD. The -aminobu- tyric acid B (GABA-B) agonist baclofen reduces esophageal acid exposure by inhibiting transient LES relaxations; the clinical benefits of this drug are yet to be defined in large trials. Several studies have evaluated the effectiveness of motor-stimulating drugs in functional dyspepsia; however, convincing evidence of their bene- fits has not been found. Some clinicians suggest that patients with symptoms resembling postprandial dis- tress may respond preferentially to prokinetic drugs. OTHER OPTIONS Antireflux surgery (fundoplica- tion) is offered to GERD patients who are young and may require lifelong therapy, have typical heartburn and regurgitation, and are responsive to proton pump inhibitors. Individuals who may respond less well to operative therapy include those with atypical symp- toms, those with poor response to proton pump inhibitors, and those who have esophageal motor dis- turbances. Fundoplications are performed laparoscopi- cally when possible and include the Nissen and Toupet procedures in which the proximal stomach is partly or completely wrapped around the distal esophagus to increase LES pressure. Dysphagia, gas-bloat syndrome, and gastroparesis may be long-term complications of these procedures. Endoscopic therapies for increasing the barrier function of the gastroesophageal junction, including radiofrequency energy delivery, suturing, biopolymer implantation, and gastroplication, have been investigated in patients with refractory GERD with variable results and some adverse consequences. Some patients with functional heartburn and func- tional dyspepsia refractory to standard therapies may respond to low-dose tricyclic antidepressants. Their mechanism of action is unknown but may involve blunting of visceral pain processing in the brain. Gas and bloating are among the most troubling symptoms in some patients with indigestion and can be difficult to treat. Dietary exclusion of gas-producing foods such as legumes and use of simethicone or activated charcoal provide symptom benefits in some patients. Therapies that modify gut flora, including antibiotics and probiotic preparations containing active bacterial cultures, are useful for cases of bacterial overgrowth and functional lower gastrointestinal disorders, but their utility in func- tional dyspepsia is unproven. Psychological treatments may be offered for refractory functional dyspepsia, but no convincing data suggest their efficacy. FURTHER READINGS ABELL TL et al:Treatment of gastroparesis:A multidisciplinary clinical review. Neurogastroenterol Motil 18:263, 2006 DEVAULT KR, CASTELL DO:American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroe- sophageal reflux disease.Am J Gastroenterol 100:190, 2005 GALMICHE JP et al: Functional esophageal disorders. Gastroenterol- ogy 130:1459, 2006 HASLER WL: Management of gastroparesis. Expert Rev Gastroenterol Hepatol 2:411, 2008 HASLER WL, CHEY WD: Nausea and vomiting. Gastroenterology 125:1860, 2003 KAHRILAS PJ, LEE TJ: Pathophysiology of gastroesophageal reflux dis- ease.Thorac Surg Clin 15:323, 2005 PARKMAN HP et al: American Gastroenterological Association tech- nical review on the diagnosis and treatment of gastroparesis. Gas- troenterology 127:1592, 2004 REDDYMASU SC, MCCALLUM RW: Pharmacotherapy of gastropare- sis. Expert Opin Pharmacother 10:469, 2009 SCHWARTZBERG LS:Chemotherapy-induced nausea and vomiting:Clini- cian and patient perspectives. J Support Oncol 5(suppl 1):5,2007 SZARKA LA, CAMILLERI M: Methods for measurement of gastric motility.Am J Physiol Liver Physiol 296:G461, 2009 TACK J et al: Functional gastroduodenal disorders. Gastroenterology 130:1466, 2006 TALLEY NJ: Green light from the FDA for new drug development in irritable bowel syndrome and functional dyspepsia. Am J Gas- troenterol 104:1339, 2009 TALLEY NJ et al: American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 129: 1756, 2005 TALLEY NJ et al: Guidelines for the management of dyspepsia. Am J Gastroenterol 100:2324, 2005 Nausea, Vom iting, and Indigestion 41 CHAPTER 5 Michael Camilleri ■ Joseph A. Murray 42 ■ Normal Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42 Neural Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43 Intestinal Fluid Absorption and Secretion . . . . . . . . . . . . . . . . .43 Small-Intestinal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43 Ileocolonic Storage and Salvage . . . . . . . . . . . . . . . . . . . . . . .43 Colonic Motility and Tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44 Colonic Motility after Meal Ingestion . . . . . . . . . . . . . . . . . . . . .44 Defecation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44 ■ Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44 Acute Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45 Chronic Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48 ■ Constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54 Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54 Investigation of Severe Constipation . . . . . . . . . . . . . . . . . . . .55 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57 Diarrhea and constipation are exceedingly common and together exact an enormous toll in terms of mortality, morbidity, social inconvenience, loss of work productivity, and consumption of medical resources. Worldwide, >1 billion individuals suffer one or more episodes of acute diarrhea each year. Among the 100 million persons affected annually by acute diarrhea in the United States, nearly half must restrict activities, 10% consult physicians, ~250,000 require hospitalization, and ~5000 die (primarily the elderly).The annual economic burden to society may exceed $20 billion. Acute infectious diarrhea remains one of the most common causes of mortality in developing countries, particularly among children, accounting for 2–3 million deaths per year. Constipation, by contrast, is rarely associated with mortality and is exceedingly common in developed countries, leading to frequent self-medication and, in a third of those, to medical consultation. Population statistics on chronic diarrhea and constipation are more uncertain, perhaps due to variable definitions and report- ing, but the frequency of these conditions is also high. United States population surveys put prevalence rates for chronic diarrhea at 2–7% and for chronic constipation at 12–19%, with women being affected twice as often as men. Diarrhea and constipation are among the most com- mon patient complaints faced by internists and primary care physicians, and they account for nearly 50% of refer- rals to gastroenterologists. Although diarrhea and constipation may present as mere nuisance symptoms at one extreme, they can be severe or life-threatening at the other. Even mild symp- toms may signal a serious underlying gastrointestinal lesion, such as colorectal cancer, or systemic disorder, such as thyroid disease. Given the heterogeneous causes and potential severity of these common complaints, it is imperative for clinicians to appreciate the pathophysiol- ogy, etiologic classification, diagnostic strategies, and principles of management of diarrhea and constipation, so that rational and cost-effective care can be delivered. NORMAL PHYSIOLOGY While the primary function of the small intestine is the digestion and assimilation of nutrients from food, the small intestine and colon together perform important functions that regulate the secretion and absorption of water and electrolytes, the storage and subsequent trans- port of intraluminal contents aborally, and the salvage of some nutrients after bacterial metabolism of carbohy- drate that are not absorbed in the small intestine. The main motor functions are summarized in Table 6-1. DIARRHEA AND CONSTIPATION CHAPTER 6 CHAPTER 6 Diarrhea and Constipation 45generally be considered diarrheal. Diarrhea may be further defined as acute if <2 weeks, persistent if 2–4 weeks, and chronic if >4 weeks in duration. Two common conditions, usually associated with the passage of stool totaling <200 g/d, must be distin- guished from diarrhea, as diagnostic and therapeutic algorithms differ. Pseudodiarrhea, or the frequent passage of small volumes of stool, is often associated with rectal urgency and accompanies IBS or proctitis. Fecal inconti- nence is the involuntary discharge of rectal contents and is most often caused by neuromuscular disorders or structural anorectal problems. Diarrhea and urgency, especially if severe, may aggravate or cause incontinence. Pseudodiarrhea and fecal incontinence occur at preva- lence rates comparable to or higher than that of chronic diarrhea and should always be considered in patients complaining of “diarrhea.” Overflow diarrhea may occur in nursing home patients due to fecal impaction that is readily detectable by rectal examination. A careful his- tory and physical examination generally allow these conditions to be discriminated from true diarrhea. ACUTE DIARRHEA More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medications, toxic ingestions, ischemia, and other conditions. Infectious Agents Most infectious diarrheas are acquired by fecal-oral trans- mission or, more commonly, via ingestion of food or water contaminated with pathogens from human or ani- mal feces. In the immunocompetent person, the resident fecal microflora, containing >500 taxonomically distinct species, are rarely the source of diarrhea and may actually play a role in suppressing the growth of ingested pathogens. Disturbances of flora by antibiotics can lead to diarrhea by reducing the digestive function or by allow- ing the overgrowth of pathogens, such as Clostridium diffi- cile (Chap. 23).Acute infection or injury occurs when the ingested agent overwhelms the host’s mucosal immune and nonimmune (gastric acid, digestive enzymes, mucus secretion, peristalsis, and suppressive resident flora) defenses. Established clinical associations with specific enteropathogens may offer diagnostic clues. In the United States, five high-risk groups are recognized: 1. Travelers. Nearly 40% of tourists to endemic regions of Latin America, Africa, and Asia develop so-called trav- eler’s diarrhea, most commonly due to enterotoxigenic or enteroaggregative Escherichia coli as well as to Campy- lobacter, Shigella, Aeromonas, norovirus, Coronavirus, and Salmonella.Visitors to Russia (especially St. Petersburg) may have increased risk of Giardia-associated diarrhea; visitors to Nepal may acquire Cyclospora. Campers, backpackers, and swimmers in wilderness areas may become infected with Giardia. Cruise ships may be affected by outbreaks of gastroenteritis caused by agents such as Norwalk virus. 2. Consumers of certain foods. Diarrhea closely following food consumption at a picnic, banquet, or restaurant may suggest infection with Salmonella, Campylobacter, or Shigella from chicken; enterohemorrhagic E. coli (O157:H7) from undercooked hamburger; Bacillus cereus from fried rice; Staphylococcus aureus or Salmo- nella from mayonnaise or creams; Salmonella from eggs; and Vibrio species, Salmonella, or acute hepatitis A from seafood, especially if raw. 3. Immunodeficient persons. Individuals at risk for diarrhea include those with either primary immunodeficiency (e.g., IgA deficiency, common variable hypogamma- globulinemia, chronic granulomatous disease) or the much more common secondary immunodeficiency states (e.g.,AIDS, senescence, pharmacologic suppres- sion). Common enteric pathogens often cause a more severe and protracted diarrheal illness, and, particularly in persons with AIDS, opportunistic infections, such as by Mycobacterium species, certain viruses (cytomegalovirus, adenovirus, and herpes sim- plex), and protozoa (Cryptosporidium, Isospora belli, Microsporida, and Blastocystis hominis) may also play a role. In patients with AIDS, agents transmitted vene- really per rectum (e.g., Neisseria gonorrhoeae, Treponema pallidum, Chlamydia) may contribute to proctocolitis. Persons with hemochromatosis are especially prone to invasive, even fatal, enteric infections with Vibrio species and Yersinia infections and should avoid raw fish. 4. Daycare attendees and their family members. Infections with Shigella, Giardia, Cryptosporidium, rotavirus, and other agents are very common and should be considered. 5. Institutionalized persons. Infectious diarrhea is one of the most frequent categories of nosocomial infec- tions in many hospitals and long-term care facilities; the causes are a variety of microorganisms but most commonly C. difficile. The pathophysiology underlying acute diarrhea by infectious agents produces specific clinical features that may also be helpful in diagnosis (Table 6-2). Profuse watery diarrhea secondary to small bowel hypersecre- tion occurs with ingestion of preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens. Diarrhea associated with marked vomiting and minimal or no fever may occur abruptly within a few hours after ingestion of the former two types; vom- iting is usually less, and abdominal cramping or bloating is greater; fever is higher with the latter. Cytotoxin-pro- ducing and invasive microorganisms all cause high fever SECTION I Cardinal M anifestations of Gastrointestinal Disease 46 and abdominal pain. Invasive bacteria and Entamoeba his- tolytica often cause bloody diarrhea (referred to as dysen- tery). Yersinia invades the terminal ileal and proximal colon mucosa and may cause especially severe abdomi- nal pain with tenderness mimicking acute appendicitis. Finally, infectious diarrhea may be associated with systemic manifestations. Reiter’s syndrome (arthritis, urethritis, and conjunctivitis) may accompany or follow infections by Salmonella, Campylobacter, Shigella, and Yersinia.Yersiniosis may also lead to an autoimmune-type thyroiditis, pericarditis, and glomerulonephritis. Both enterohemorrhagic E. coli (O157:H7) and Shigella can lead to the hemolytic-uremic syndrome with an attendant high mortality rate.The syndrome of postinfectious IBS has now been recognized as a complication of infectious diarrhea.Acute diarrhea can also be a major symptom of several systemic infections including viral hepatitis, listerio- sis, legionellosis, and toxic shock syndrome. Other Causes Side effects from medications are probably the most com- mon noninfectious cause of acute diarrhea, and etiology may be suggested by a temporal association between use and symptom onset. Although innumerable medications may produce diarrhea, some of the more frequently TABLE 6-2 ASSOCIATION BETWEEN PATHOBIOLOGY OF CAUSATIVE AGENTS AND CLINICAL FEATURES IN ACUTE INFECTIOUS DIARRHEA INCUBATION ABDOMINAL PATHOBIOLOGY/AGENTS PERIOD VOMITING PAIN FEVER DIARRHEA Toxin producers Preformed toxin Bacillus cereus, Staphylo- 1–8 h 3–4+ 1–2+ 0–1+ 3–4+, watery coccus aureus, Clostridium perfringens 8–24 h Enterotoxin Vibrio cholerae, enterotoxi- 8–72 h 2–4+ 1–2+ 0–1+ 3–4+, watery genic Escherichia coli, Klebsiella pneumoniae, Aeromonas species Enteroadherent Enteropathogenic and entero- 1–8 d 0–1+ 1–3+ 0–2+ 1–2+, watery, adherent E. coli, Giardia mushy organisms, cryptospori- diosis, helminths Cytotoxin-producers Clostridium difficile 1–3 d 0–1+ 3–4+ 1–2+ 1–3+, usually watery, occasion- ally bloody Hemorrhagic E. coli 12–72 h 0–1+ 3–4+ 1–2+ 1–3+, initially watery, quickly bloody Invasive organisms Minimal inflammation Rotavirus and Norwalk 1–3 d 1–3+ 2–3+ 3–4+ 1–3+, watery agent Variable inflammation Salmonella, Campylobacter, 12 h–11 d 0–3+ 2–4+ 3–4+ 1–4+, watery and Aeromonas species, or bloody Vibrio parahaemolyticus, Yersinia Severe inflammation Shigella species, enteroinvasive 12 h–8 d 0–1+ 3–4+ 3–4+ 1–2+, bloody E. coli, Entamoeba histolytica Source: Adapted from DW Powell, in T Yamada (ed): Textbook of Gastroenterology and Hepatology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003; and DR Syndman, in SL Gorbach (ed): Infectious Diarrhea. London, Blackwell, 1986. CHAPTER 6 Diarrhea and Constipation 47incriminated include antibiotics, cardiac antidysrhythmics, antihypertensives, nonsteroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, chemotherapeutic agents, bronchodilators, antacids, and laxatives. Occlusive or nonocclusive ischemic colitis typically occurs in persons >50 years; often presents as acute lower abdominal pain preceding watery, then bloody diarrhea; and generally results in acute inflammatory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versus-host disease. Acute diarrhea, often associated with systemic compro- mise, can follow ingestion of toxins including organophosphate insecticides, amanita and other mush- rooms, arsenic, and preformed environmental toxins in seafood, such as ciguatera and scombroid. Conditions causing chronic diarrhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease (IBD) and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection. Approach to the Patient: ACUTE DIARRHEA The decision to evaluate acute diarrhea depends on its severity and duration and on various host factors (Fig. 6-2). Most episodes of acute diarrhea are mild and self-limited and do not justify the cost and poten- tial morbidity of diagnostic or pharmacologic inter- ventions. Indications for evaluation include profuse diarrhea with dehydration, grossly bloody stools, fever 38.5°C, duration >48 h without improvement, recent antibiotic use, new community outbreaks, asso- ciated severe abdominal pain in patients >50 years, and elderly (70 years) or immunocompromised patients. In some cases of moderately severe febrile diarrhea associated with fecal leukocytes (or increased fecal levels of the leukocyte proteins) or with gross blood, a diagnostic evaluation might be avoided in favor of an empirical antibiotic trial (see below). The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool. Workup includes cultures for bacterial and viral pathogens, direct inspection for ova and parasites, and immunoassays for certain bac- terial toxins (C. difficile), viral antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica). The afore- mentioned clinical and epidemiologic associations may assist in focusing the evaluation. If a particular pathogen or set of possible pathogens is so impli- cated, then either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate as for enterohemor- rhagic and other types of E. coli, Vibrio species, and Yersinia. Molecular diagnosis of pathogens in stool can be made by identification of unique DNA sequences; and evolving microarray technologies could lead to a more rapid, sensitive, specific, and cost-effective diagnostic approach in the future. Persistent diarrhea is commonly due to Giardia (Chap. 31), but additional causative organisms that should be considered include C. difficile (especially if antibiotics had been administered), E. histolytica, Cryptosporidium, Campylobacter, and others. If stool studies are unrevealing, then flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated. Brainerd diarrhea is an increasingly recognized entity charac- terized by an abrupt-onset diarrhea that persists for at least 4 weeks, but may last 1–3 years, and is thought to be of infectious origin. It may be associ- ated with subtle inflammation of the distal small intestine or proximal colon. Structural examination by sigmoidoscopy, colonoscopy, or abdominal CT scanning (or other imaging approaches) may be appropriate in patients History and physical exam Moderate (activities altered) Mild (unrestricted) Observe Resolves Persists* Severe (incapacitated) Institute fluid and electrolyte replacement Fever ≥38.5°, bloody stools, fecal WBCs, immunocompromised or elderly host Antidiarrheal agents Resolves Persists* Stool microbiology studies Pathogen found Evaluate and treat accordingly Acute Diarrhea Likely noninfectious Likely infectious Yes†No Yes†No Select specific treatment Empirical treatment + further evaluation FIGURE 6-2 Algorithm for the management of acute diarrhea. Consider empirical Rx before evaluation with (*) metronidazole and with (†) quinolone. WBCs, white blood cells. SECTION I Cardinal M anifestations of Gastrointestinal Disease 50 may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison’s disease) that may be accompanied by skin hyperpigmentation. Osmotic Causes Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw enough fluid into the lumen to exceed the reabsorptive capacity of the colon. Fecal water output increases in proportion to such a solute load. Osmotic diarrhea characteristically ceases with fasting or with discontinuation of the causative agent. Osmotic Laxatives Ingestion of magnesium-containing antacids, health sup- plements, or laxatives may induce osmotic diarrhea typi- fied by a stool osmotic gap (>50 mosmol/L): serum osmolarity (typically 290 mosmol/kg)[2  (fecal sodium + potassium concentration)]. Measurement of fecal osmolarity is no longer recommended since, even when measured immediately after evacuation, it may be erro- neous, as carbohydrates are metabolized by colonic bac- teria, causing an increase in osmolarity. Carbohydrate Malabsorption Carbohydrate malabsorption due to acquired or con- genital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low pH. One of the most common causes of chronic diarrhea in adults is lactase deficiency, which affects three-fourths of non-Caucasians worldwide and 5–30% of persons in the United States; the total lactose load at any one time influences the symptoms experienced. Most patients learn to avoid milk products without requiring treat- ment with enzyme supplements. Some sugars, such as sorbitol, lactulose, or fructose, are frequently malab- sorbed, and diarrhea ensues with ingestion of medica- tions, gum, or candies sweetened with these poorly or incompletely absorbed sugars. Steatorrheal Causes Fat malabsorption may lead to greasy, foul-smelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the neutral fat. Quantitatively, steator- rhea is defined as stool fat exceeding the normal 7 g/d; rapid-transit diarrhea may result in fecal fat up to 14 g/d; daily fecal fat averages 15–25 g with small intestinal diseases and is often >32 g with pancreatic exocrine insufficiency. Intraluminal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea. Intraluminal Maldigestion This condition most commonly results from pancre- atic exocrine insufficiency, which occurs when >90% of pancreatic secretory function is lost. Chronic pancre- atitis, usually a sequel of ethanol abuse, most fre- quently causes pancreatic insufficiency. Other causes include cystic fibrosis, pancreatic duct obstruction, and rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle formation, impairing fat digestion; it occurs with stasis from a blind-loop, small bowel diverticulum or dysmotility and is especially likely in the elderly. Finally, cirrhosis or biliary obstruction may lead to mild steatorrhea due to deficient intraluminal bile acid concentration. Mucosal Malabsorption Mucosal malabsorption occurs from a variety of enteropathies, but most commonly from celiac disease. This gluten-sensitive enteropathy affects all ages and is characterized by villous atrophy and crypt hyperplasia in the proximal small bowel and can present with fatty diarrhea associated with multiple nutritional deficiencies of varying severity. Celiac disease is much more frequent than previously thought; it affects ~1% of the popula- tion, frequently presents without steatorrhea, can mimic IBS, and has many other GI and extraintestinal manifes- tations. Tropical sprue may produce a similar histologic and clinical syndrome but occurs in residents of or trav- elers to tropical climates; abrupt onset and response to antibiotics suggest an infectious etiology. Whipple’s dis- ease, due to the bacillus Tropheryma whipplei and histio- cytic infiltration of the small-bowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue and may affect the central nervous system and endocardium. A similar clinical and histologic picture results from Mycobacterium avium-intracellulare infection in patients with AIDS. Abetalipoproteinemia is a rare defect of chylomicron formation and fat malabsorption in chil- dren, associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause mucosal malabsorption including infections, espe- cially with protozoa such as Giardia, numerous medica- tions (e.g., colchicine, cholestyramine, neomycin), and chronic ischemia. Postmucosal Lymphatic Obstruction The pathophysiology of this condition, which is due to the rare congenital intestinal lymphangiectasia or to acquired lymphatic obstruction secondary to trauma, tumor, or infection, leads to the unique constellation of fat malab- sorption with enteric losses of protein (often causing edema) and lymphocytopenia. Carbohydrate and amino acid absorption are preserved. CHAPTER 6 Diarrhea and Constipation 51Inflammatory Causes Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflam- mation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/electrolyte absorption, and hypersecretion or hypermotility from release of cytokines and other inflammatory mediators.The unify- ing feature on stool analysis is the presence of leukocytes or leukocyte-derived proteins such as calprotectin. With severe inflammation, exudative protein loss can lead to anasarca (generalized edema). Any middle-aged or older person with chronic inflammatory-type diarrhea, espe- cially with blood, should be carefully evaluated to exclude a colorectal tumor. Idiopathic Inflammatory Bowel Disease The illnesses in this category, which include Crohn’s disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life-threatening.They may be associated with uveitis, polyarthralgias, cholesta- tic liver disease (primary sclerosing cholangitis), and skin lesions (erythema nodosum, pyoderma gangreno- sum). Microscopic colitis, including both lymphocytic and collagenous colitis, is an increasingly recognized cause of chronic watery diarrhea, especially in middle-aged women and those on NSAIDS; biopsy of a normal- appearing colon is required for histologic diagnosis. It may coexist with symptoms suggesting IBS or with celiac sprue. It typically responds well to anti-inflamma- tory drugs (e.g., bismuth), to the opioid agonist lop- eramide, or to budesonide. Primary or Secondary Forms of Immunodefi- ciency Immunodeficiency may lead to prolonged infectious diarrhea. With common variable hypogammaglobulinemia, diarrhea is particularly prevalent and often the result of giardiasis. Eosinophilic Gastroenteritis Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the GI tract may cause diarrhea, pain, vomiting, or ascites.Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspec- tion of stool, and peripheral eosinophilia is present in 50–75% of patients. While hypersensitivity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare. Other Causes Chronic inflammatory diarrhea may be caused by radia- tion enterocolitis, chronic graft-versus-host disease, Behçet’s syn- drome, and Cronkite-Canada syndrome, among others. Dysmotility Causes Rapid transit may accompany many diarrheas as a sec- ondary or contributing phenomenon, but primary dys- motility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea of up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prostaglandins, prokinetic agents) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopathies or idiopathic acquired intestinal pseudoobstruction may lead to stasis with secondary bacterial overgrowth caus- ing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility. The exceedingly common irritable bowel syndrome (10% point prevalence, 1–2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of stool frequency typically cease at night, alternate with periods of constipation, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss or true diarrhea. Factitial Causes Factitial diarrhea accounts for up to 15% of unexplained diarrheas referred to tertiary care centers. Either as a form of Munchausen syndrome (deception or self-injury for sec- ondary gain) or eating disorders, some patients covertly self- administer laxatives alone or in combination with other medications (e.g., diuretics) or surreptitiously add water or urine to stool sent for analysis. Such patients are more often female than male, often with histories of psychiatric illness, and disproportionately from careers in health care. Hypotension and hypokalemia are common co-present- ing features.The evaluation of such patients may be diffi- cult: contamination of the stool with water or urine is suggested by very low or high stool osmolarity, respec- tively. Such patients often deny this possibility when con- fronted, but they do benefit from psychiatric counseling when they acknowledge their behavior. Approach to the Patient: CHRONIC DIARRHEA The laboratory tools available to evaluate the very com- mon problem of chronic diarrhea are extensive, and many are costly and invasive. As such, the diagnostic evaluation must be rationally directed by a careful his- tory and physical examination (Fig. 6-3A).When this strategy is unrevealing, simple triage tests are often war- ranted to direct the choice of more complex investiga- tions (Fig. 6-3B). The history, physical examination SECTION I Cardinal M anifestations of Gastrointestinal Disease 52 (Table 6-4), and routine blood studies should attempt to characterize the mechanism of diarrhea, identify diagnostically helpful associations, and assess the patient’s fluid/electrolyte and nutritional status. Patients should be questioned about the onset, duration, pattern, aggravating (especially diet) and relieving factors, and stool characteristics of their diarrhea. The presence or absence of fecal incontinence, fever, weight loss, pain, certain exposures (travel, medications, contacts with diarrhea), and common extraintestinal manifestations (skin changes, arthralgias, oral aphthous ulcers) should be noted. A family history of IBD or sprue may indicate those possibilities. Physical findings may offer clues such as a thyroid mass, wheezing, heart murmurs, edema, hepatomegaly, abdominal masses, lymphadeno- pathy, mucocutaneous abnormalities, perianal fistulae, or anal sphincter laxity. Peripheral blood leukocytosis, elevated sedimentation rate, or C-reactive protein sug- gests inflammation; anemia reflects blood loss or nutri- tional deficiencies; or eosinophilia may occur with par- asitoses, neoplasia, collagen-vascular disease, allergy, or Exclude iatrogenic problem: medication, surgery Blood p.r. Colonoscopy + biopsy Features, e.g., stool, suggest malabsorption Small bowel: Imaging, biopsy, aspirate Pain aggravated before bm, relieved with bm, sense incomplete evacuation Suspect IBS Limited screen for organic disease No blood, features of malabsorption Consider functional diarrhea Dietary exclusion, e.g., lactose, sorbitol Chronic Diarrhea A Limited screen for organic disease Chronic Diarrhea B Stool vol, OSM, pH; Laxative screen; Hormonal screen Persistent chronic diarrhea Stool fat >20 g/day Pancreatic function Titrate Rx to speed of transit Opioid Rx + follow-up Low K + Screening tests all normal Colonoscopy + biopsy Normal and stool fat <14 g/day Full gut transit Low Hb, Alb; abnormal MCV, MCH; excess fat in stool Small bowel: X-ray, biopsy, aspirate; stool 48-h fat FIGURE 6-3 Chronic diarrhea. A. Initial management based on accompanying symptoms or fea- tures. B. Evaluation based on findings from a limited age appropriate screen for organic disease. p.r., per rectum; bm, bowel move- ment; IBS, irritable bowel syndrome; Hb, hemoglobin; Alb, albumin; MCV, mean cor- puscular volume; MCH, mean corpuscular hemoglobin; OSM, osmolality. (Reprinted from M Camilleri: Clin Gastroenterol Hepa- tol. 2:198, 2004.) TABLE 6-4 PHYSICAL EXAMINATION IN PATIENTS WITH CHRONIC DIARRHEA 1. Are there general features to suggest malabsorption or inflammatory bowel disease (IBD) such as anemia, der- matitis herpetiformis, edema, or clubbing? 2. Are there features to suggest underlying autonomic neuropathy or collagen-vascular 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? eosinophilic gastroenteritis. Blood chemistries may demonstrate electrolyte, hepatic, or other metabolic dis- turbances. Measuring tissue transglutaminase antibodies may help detect celiac disease. CHAPTER 6 Diarrhea and Constipation 55movements per week), consistency (lumpy/hard), excessive straining, prolonged defecation time, or need to support the perineum or digitate the anorectum. In the vast majority of cases (probably >90%), there is no underlying cause (e.g., cancer, depression, or hypothy- roidism), and constipation responds to ample hydra- tion, exercise, and supplementation of dietary fiber (15–25 g/d). A good diet and medication history and attention to psychosocial issues are key. Physical exami- nation and, particularly, a rectal examination should exclude fecal impaction and most of the important dis- eases that present with constipation and possibly indi- cate features suggesting an evacuation disorder (e.g., high anal sphincter tone). The presence of weight loss, rectal bleeding, or ane- mia with constipation mandates either flexible sig- moidoscopy plus barium enema or colonoscopy alone, particularly in patients >40 years, to exclude structural diseases such as cancer or strictures. Colonoscopy alone is most cost effective in this set- ting since it provides an opportunity to biopsy mucosal lesions, perform polypectomy, or dilate stric- tures. Barium enema has advantages over colonoscopy in the patient with isolated constipation, since it is less costly and identifies colonic dilatation and all signifi- cant mucosal lesions or strictures that are likely to present with constipation. Melanosis coli, or pigmen- tation of the colon mucosa, indicates the use of anthraquinone laxatives such as cascara or senna; how- ever, this is usually apparent from a careful history.An unexpected disorder such as megacolon or cathartic colon may also be detected by colonic radiographs. Measurement of serum calcium, potassium, and thy- roid-stimulating hormone levels will identify rare patients with metabolic disorders. Patients with more troublesome constipation may not respond to fiber alone and may be helped by a bowel training regimen: taking an osmotic laxative (lactulose, sorbitol, polyethylene glycol) and evacuat- ing with enema or glycerine suppository as needed. After breakfast, a distraction-free 15–20 min on the toilet without straining is encouraged. Excessive straining may lead to development of hemorrhoids, and, if there is weakness of the pelvic floor or injury to the pudendal nerve, may result in obstructed defecation from descending perineum syndrome several years later. Those few who do not benefit from the simple measures delineated above or require long-term treatment with potent laxatives with the attendant risk of developing laxative abuse syndrome are assumed to have severe or intractable constipation and should have further investigation (Fig. 6-4). Novel agents that induce secretion (e.g., lubiprostone, a chloride channel activator) are also available. INVESTIGATION OF SEVERE CONSTIPATION A small minority (probably <5%) of patients have severe or “intractable” constipation. These are the patients most likely to be seen by gastroenterologists or in referral cen- ters. Further observation of the patient may occasionally reveal a previously unrecognized cause, such as an evacua- tion disorder, laxative abuse, malingering, or psychological disorder. In these patients, evaluations of the physiologic function of the colon and pelvic floor and of psychologi- cal status aid in the rational choice of treatment. Even among these highly selected patients with severe consti- pation, a cause can be identified in only about two-thirds of tertiary referral patients (see later). Measurement of Colonic Transit Radiopaque marker transit tests are easy, repeatable, gen- erally safe, inexpensive, reliable, and highly applicable in evaluating constipated patients in clinical practice. Sev- eral validated methods are very simple. For example, radiopaque markers are ingested; an abdominal flat film taken 5 days later should indicate passage of 80% of the markers out of the colon without the use of laxatives or enemas. This test does not provide useful information about the transit profile of the stomach and small bowel. Radioscintigraphy with a delayed-release capsule con- taining radiolabeled particles has been used to noninva- sively characterize normal, accelerated, or delayed colonic function over 24–48 h with low radiation exposure.This Clinical and basic laboratory tests Bloods, chest and abd x-ray Exclude mechanical obstruction, e.g., colonoscopy Colonic transit Consider functional bowel disease Known disorder Rx No known underlying disorder Anorectal manometry and balloon expulsion Slow colonic transit Normal Rectoanal angle measurement, defecation proctography? Appropriate Rx: Rehabilitation program, surgery, or other Chronic Constipation Normal Abnormal FIGURE 6-4 Algorithm for the management of constipation. SECTION I Cardinal M anifestations of Gastrointestinal Disease 56 approach simultaneously assesses gastric, small bowel (which may be important in ~20% of patients with delayed colonic transit since they reflect a more general- ized GI motility disorder), and colonic transit.The disad- vantages are the greater cost and the need for specific materials prepared in a nuclear medicine laboratory. Anorectal and Pelvic Floor Tests Pelvic floor dysfunction is suggested by the inability to evacuate the rectum, a feeling of persistent rectal full- ness, rectal pain, the need to extract stool from the rec- tum digitally, application of pressure on the posterior wall of the vagina, support of the perineum during straining, and excessive straining.These significant symp- toms should be contrasted with the sense of incomplete rectal evacuation, which is common in IBS. Formal psychological evaluation may identify eating disorders, “control issues,” depression, or posttraumatic stress disorders that may respond to cognitive or other intervention and may be important in restoring quality of life to patients who might present with chronic constipation. A simple clinical test in the office to document a nonrelaxing puborectalis muscle is to have the patient strain to expel the index finger during a digital rectal examination. Motion of the puborectalis posteriorly during straining indicates proper coordination of the pelvic floor muscles. Measurement of perineal descent is relatively easy to gauge clinically by placing the patient in the left decubitus position and watching the perineum to detect inadequate descent (<1.5 cm, a sign of pelvic floor dysfunction) or perineal ballooning during straining relative to bony land- marks (>4 cm, suggesting excessive perineal descent). A useful overall test of evacuation is the balloon expul- sion test. A balloon-tipped urinary catheter is placed and inflated with 50 mL of water. Normally, a patient can expel it while seated on a toilet or in the left lateral decu- bitus position. In the lateral position, the weight needed to facilitate expulsion of the balloon is determined; nor- mally expulsion occurs with <200 g added. Anorectal manometry when used in the evaluation of patients with severe constipation may find an excessively high resting (>80 mmHg) or squeeze anal sphincter tone, suggesting anismus (anal sphincter spasm). This test also identifies rare syndromes, such as adult Hirschsprung’s disease, by the absence of the rectoanal inhibitory reflex. Defecography (a dynamic barium enema including lateral views obtained during barium expulsion) reveals “soft abnormalities” in many patients; the most relevant findings are the measured changes in rectoanal angle, anatomic defects of the rectum such as internal mucosal prolapse, and enteroceles or rectoceles. Surgically reme- diable conditions are identified in only a few patients. These include severe, whole-thickness intussusception with complete outlet obstruction due to funnel-shaped plugging at the anal canal or an extremely large recto- cele that fills preferentially during attempts at defecation instead of expulsion of the barium through the anus. In summary, defecography requires an interested and expe- rienced radiologist, and abnormalities are not pathogno- monic for pelvic floor dysfunction. The most common cause of outlet obstruction is failure of the puborectalis muscle to relax; this is not identified by defecography but requires a dynamic study such as proctography. MRI is being developed as an alternative and provides more information about the structure and function of the pelvic floor, distal colorectum, and anal sphincters. Dynamic imaging studies such as proctography dur- ing defecation or scintigraphic expulsion of artificial stool help measure perineal descent and the rectoanal angle during rest, squeezing, and straining, and scinti- graphic expulsion quantitates the amount of “artificial stool” emptied. Lack of straightening of the rectoanal angle by at least 15° during defecation confirms pelvic floor dysfunction. Neurologic testing (electromyography) is more helpful in the evaluation of patients with incontinence than of those with symptoms suggesting obstructed defecation. The absence of neurologic signs in the lower extremities suggests that any documented denervation of the pub- orectalis results from pelvic (e.g., obstetric) injury or from stretching of the pudendal nerve by chronic, long- standing straining. Constipation is common among patients with spinal cord injuries, neurologic diseases such as Parkinson’s disease, multiple sclerosis, and diabetic neuropathy. Spinal-evoked responses during electrical rectal stimula- tion or stimulation of external anal sphincter contraction by applying magnetic stimulation over the lumbosacral cord identify patients with limited sacral neuropathies with sufficient residual nerve conduction to attempt biofeed- back training. In summary, a balloon expulsion test is an important screening test for anorectal dysfunction. If positive, an anatomic evaluation of the rectum or anal sphincters and an assessment of pelvic floor relaxation are the tools for evaluating patients in whom obstructed defecation is suspected. Treatment: CONSTIPATION After the cause of constipation is characterized, a treat- ment decision can be made. Slow-transit constipation requires aggressive medical or surgical treatment; anis- mus or pelvic floor dysfunction usually responds to biofeedback management (Fig. 6-4). However, only ~60% of patients with severe constipation are found to have such a physiologic disorder (half with colonic transit CHAPTER 6 Diarrhea and Constipation 57 FURTHER READINGS ATIA AN, BUCHMAN AL: Oral rehydration solutions in non-cholera diarrhea:A review.Am J Gastroenterol 2009 epub ahead of print BARTLETT JG: Narrative review: The new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 145:758, 2006 CAMILLERI M: Chronic diarrhea: A review on pathophysiology and management for the clinical gastroenterologist. Clin Gastroen- terol Hepatol 2:198, 2004 CAMILLERI M: Serotonin in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 16:53, 2009 FARRELL RJ, KELLY CP: Celiac sprue. N Engl J Med 346:180, 2002 GADEWAR S, FASANO A: Current concepts in the evaluation, diagno- sis and management of acute infectious diarrhea. Curr Opin Pharmacol 5:559, 2005 LEMBO A, CAMILLERI M: Chronic constipation. N Engl J Med 349:1360, 2003 McCALLUM IJ et al: Chronic constipation in adults. BMJ 338:b831, 2009 MENNIGEN R, BRUEWER M: Effect of probiotics on intestinal barrier function.Ann NY Acad Sci 1165:183, 2009 MUSHER DM, MUSHER BL: Contagious acute gastrointestinal infec- tions. N Engl J Med 351:2417, 2004 WALD A: Clinical practice. Fecal incontinence in adults. N Engl J Med 356:1648, 2007 ———: Constipation in the primary care setting: Current concepts and misconceptions.Am J Med 119:736, 2006 delay and half with evacuation disorder). Patients with spinal cord injuries or other neurologic disorders require a dedicated bowel regime that often includes rectal stimulation, enema therapy, and carefully timed laxative therapy. Patients with slow-transit constipation are treated with bulk, osmotic, prokinetic, secretory, and stimulant laxatives including fiber, psyllium, milk of magnesia, lactu- lose, polyethylene glycol (colonic lavage solution), lubiprostone, and bisacodyl. Newer treatment aimed at enhancing motility and secretion may have application in circumstances such as constipation-predominant IBS in females or severe constipation. If a 3- to 6-month trial of medical therapy fails and patients continue to have docu- mented slow-transit constipation unassociated with obstructed defecation, the patients should be considered for laparoscopic colectomy with ileorectostomy; how- ever, this should not be undertaken if there is continued evidence of an evacuation disorder or a generalized GI dysmotility. Referral to a specialized center for further tests of colonic motor function is warranted. The decision to resort to surgery is facilitated in the presence of mega- colon and megarectum. The complications after surgery include small-bowel obstruction (11%) and fecal soiling, particularly at night during the first postoperative year. Frequency of defecation is 3–8 per day during the first year, dropping to 1–3 per day from the second year after surgery. Patients who have a combined (evacuation and transit/ motility) disorder should pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological coun- seling, and dietetic advice first, followed by colectomy and ileorectostomy if colonic transit studies do not normalize and symptoms are intractable despite biofeedback and optimized medical therapy. In patients with pelvic floor dysfunction alone, biofeedback training has a 70–80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) have achieved only mediocre success and have been largely abandoned. SECTION I Cardinal M anifestations of Gastrointestinal Disease 60 The review of systems should focus on signs or symptoms that are associated with disorders that commonly cause weight loss. These include fever, pain, shortness of breath or cough, palpitations, and evidence of neurologic disease. Gastrointestinal dis- turbances, including difficulty eating, dysphagia, anorexia, nausea, and change in bowel habits, should be sought.Travel history, use of cigarettes and alcohol, and all medications should be reviewed, and patients should be questioned about previous illness or surgery as well as diseases in family members. Risk factors for HIV infection should be assessed. Signs of depression, evidence of dementia, and social factors, including financial issues that might affect food intake, should be considered. Physical examination should begin with weight determination and documentation of vital signs. The skin should be examined for pallor, jaundice, turgor, scars from prior surgery, and stigmata of systemic dis- ease.The search for oral thrush or dental disease, thy- roid gland enlargement, adenopathy, and respiratory or cardiac abnormalities and a detailed examination of the abdomen often lead to clues for further evalua- tion. Rectal examination, including prostate examina- tion, should be performed in men; and all women should have a pelvic examination, even if they have had a hysterectomy. Neurologic examination should include mental status assessment and screening for depression. Laboratory testing should confirm or exclude possible diagnoses elicited from the history and physical examination (Table 7-2). An initial phase of testing should include a complete blood count with differential, serum chemistry tests including glucose, electrolytes, renal and liver tests, calcium, thyroid-stimulating hormone (TSH), urinalysis, and chest x-ray. Patients at risk for HIV infection should have HIV antibody testing. In all cases, recom- mended cancer screening tests appropriate for the Approach to the Patient: WEIGHT LOSS Before extensive evaluation is undertaken, it is important to confirm weight loss and to determine the time interval over which it has occurred. Almost half of patients who claim significant weight loss have no actual change when body weight is mea- sured objectively. In the absence of documentation, changes in belt notch position or the fit of clothing may be confirmatory. Not infrequently, patients who have actually sustained significant weight loss are unaware that it has occurred. Routine documenta- tion of weight during office visits is therefore important. Initial testing CBC Electrolytes, calcium, glucose Renal and liver function tests Urinalysis TSH Chest x-ray Recommended cancer screening Additional testing HIV test Upper and/or lower gastrointestinal endoscopy Abdominal CT scan or MRI Chest CT sca most common malignancies in patients presenting with weight loss. In younger individuals, diabetes mellitus, hyperthyroidism, psychiatric disturbances including eating disorders, and infection, especially with HIV, should be considered. The cause of involuntary weight loss is rarely occult. Careful history and physical examination, in association with directed diagnostic testing, will identify the cause of weight loss in 75% of patients.The etiology of weight loss may not be found in the remaining patients, despite extensive testing. Patients with negative evaluations tend to have lower mortality rates than those found to have organic disease. Patients with medical causes of weight loss usually have signs or symptoms that suggest involvement of a particular organ system. Gastrointestinal tumors, including those of the pancreas and liver, may affect food intake early in the course of illness, causing weight loss before other symptoms are apparent. Lung cancer may present with post-obstructive pneumonia, dyspnea, or cough and hemoptysis; however, it may be silent and should be considered even in those without a history of cigarette smoking. Depression and isolation can cause profound weight loss, especially in the elderly. Chronic pulmonary disease and congestive heart failure can produce anorexia, and they also increase resting energy expenditure.Weight loss may be the presenting sign of infectious diseases such as HIV infection, tuberculosis, endocarditis, and fungal or para- sitic infections. Hyperthyroidism or pheochromocy- toma increases metabolism. Elderly patients with apa- thetic hyperthyroidism may present with weight loss and weakness, with few other manifestations of thyro- toxicosis. New-onset diabetes mellitus is often accom- panied by weight loss, reflecting glucosuria and loss of the anabolic actions of insulin. Adrenal insufficiency may be suggested by increased pigmentation, hypona- tremia, and hyperkalemia. TABLE 7-2 SCREENING TESTS FOR EVALUATION OF INVOLUNTARY WEIGHT LOSS CHAPTER 7 W eight Loss 61gender and age group, such as mammograms and colonoscopies, should be updated. If gastrointestinal signs or symptoms are present, upper and/or lower endoscopy and abdominal imaging with either CT or MRI have a relatively high yield, consistent with the high prevalence of gastrointestinal disorders in patients with weight loss. If an etiology of weight loss is not found, careful clinical follow-up, rather than persistent undirected testing, is reasonable. HARRINGTON M et al: A review and meta-analysis of the effect of weight loss on all-cause mortality risk. Nutr Res Rev 22:93, 2009 HERNANDEZ JL, MATORRAS JA: Involuntary weight loss without specific symptoms:A clinical prediction score for malignant neo- plasm. Q J Med 96: 649, 2003 INUI A: Cancer anorexia-cachexia syndrome: Current issues in research and management. Cancer J Clinicians 52:72, 2002 NORA E, RAMAN A: Hypermetabolism, cachexia and wasting. Curr Opin Endocrinol Diabetes 12:326, 2005 SCHWARTZ MW: Brain pathways controlling food intake and body weight. Exp Biol Med 226:978, 2001 STRASSER F, BRUERA ED: Update on anorexia and cachexia. Hema- tol Oncol Clin North Am 16:589, 2002 TISDALE MJ: Mechanisms of cancer cachexia. Physiol Rev 89:381, 2009 WALLACE JI: Involuntary weight loss in elderly outpatients: Recogni- tion, etiologies, and treatment. Clin Geriatr Med 13:717, 1997 FURTHER READINGS ALIBHAI S: An approach to the management of unintentional weight loss in elderly people. CMAJ 172:773, 2005 BOURAS EP, LANGE SM: Rational approach to patients with uninten- tional weight loss. Mayo Clinic Proc 76:923, 2001 Loren Laine 62 Bleeding from the gastrointestinal (GI) tract may present in five ways. Hematemesis is vomitus of red blood or “coffee-grounds” material. Melena is black, tarry, foul- smelling stool. Hematochezia is the passage of bright red or maroon blood from the rectum. Occult GI bleeding (GIB) may be identified in the absence of overt bleeding by a fecal occult blood test or the presence of iron defi- ciency. Finally, patients may present only with symptoms of blood loss or anemia such as lightheadedness, syncope, angina, or dyspnea. SOURCES OF GASTROINTESTINAL BLEEDING Upper Gastrointestinal Sources of Bleeding (Table 8-1) The annual incidence of hospital admissions for upper GIB (UGIB) in the United States and Europe is ~0.1%, with a mortality rate of ~5–10%. Patients rarely die from exsanguination; rather, they die due to decompensation from other underlying illnesses. The mortality rate for patients <60 years in the absence of major concurrent illness is <1%. Independent predictors of rebleeding and death in patients hospitalized with UGIB include increasing age, comorbidities, and hemo- dynamic compromise (tachycardia or hypotension). Peptic ulcers are the most common cause of UGIB, accounting for up to ~50% of cases; an increasing pro- portion is due to nonsteroidal anti-inflammatory drugs (NSAIDs), with the prevalence of Helicobacter pylori decreasing. Mallory-Weiss tears account for ~5–10 or 15% of cases. The proportion of patients bleeding from varices varies widely from ~5 to 30%, depending on the population. Hemorrhagic or erosive gastropathy (e.g., due to NSAIDs or alcohol) and erosive esophagitis often cause mild UGIB, but major bleeding is rare. Peptic Ulcers In addition to clinical features, characteristics of an ulcer at endoscopy provide important prognostic information. One-third of patients with active bleeding or a non- bleeding visible vessel have further bleeding that requires urgent surgery if they are treated conservatively. These patients clearly benefit from endoscopic therapy with bipolar electrocoagulation, heater probe, injection ther- apy (e.g., absolute alcohol, 1:10,000 epinephrine), and/or clips with reductions in bleeding, hospital stay, mortality rate, and costs. In contrast, patients with clean-based ulcers have rates of recurrent bleeding approaching zero. If there is no other reason for hospitalization, such CHAPTER 8 GASTROINTESTINAL BLEEDING TABLE 8-1 SOURCES OF BLEEDING IN PATIENTS HOSPITALIZED FOR UPPER GI BLEEDING IN YEARS 2000–2002 SOURCES OF BLEEDING PROPORTION OF PATIENTS, % Ulcers 31–59 Varices 7–20 Mallory-Weiss tears 4–8 Gastroduodenal erosions 2–7 Erosive esophagitis 1–13 Neoplasm 2–7 Vascular ectasias 0–6 No source identified 8–14 Source: Data from M Van Leerdam et al: Am J Gastroenterol 98:1494, 2003; DM Jensen et al: Gastrointest Endosc 57:AB147, 2003; KC Thomopoulos et al: Eur J Gastroenterol Hepatol 16:177, 2004; F Di Fiore et al: Eur J Gastroenterol Hepatol 17:641, 2005. Sources of Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . .62 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67 Approach to the Patient: GASTROINTESTINAL BLEEDING Measurement of the heart rate and blood pressure is the best way to assess a patient with GIB. Clinically significant bleeding leads to postural changes in heart rate or blood pressure, tachycardia, and, finally, recum- bent hypotension. In contrast, the hemoglobin does not fall immediately with acute GIB, due to propor- tionate reductions in plasma and red cell volumes (i.e.,“people bleed whole blood”).Thus, hemoglobin may be normal or only minimally decreased at the initial presentation of a severe bleeding episode. As extravascular fluid enters the vascular space to restore volume, the hemoglobin falls, but this process may take up to 72 h. Patients with slow, chronic GIB may have very low hemoglobin values despite normal blood pressure and heart rate. With the development of iron-deficiency anemia, the mean corpuscular vol- ume will be low and red blood cell distribution width will be increased. DIFFERENTIATION OF UPPER FROM LOWER GIB Hematemesis an upper GI source of bleeding (above the ligament of Treitz). Melena indicates that blood has been present in the GI tract for at least 14 h. Thus, the more proximal the bleeding site, the more likely melena will occur. Hematochezia usually repre- sents a lower GI source of bleeding, although an upper GI lesion may bleed so briskly that blood does not remain in the bowel long enough for melena to develop.When hematochezia is the presenting symp- tom of UGIB, it is associated with hemodynamic CHAPTER 8 Gastrointestinal Bleeding 65instability and dropping hemoglobin. Bleeding lesions of the small bowel may present as melena or hema- tochezia. Other clues to UGIB include hyperactive bowel sounds and an elevated blood urea nitrogen level (due to volume depletion and blood proteins absorbed in the small intestine). A nonbloody nasogastric aspirate may be seen in up to 18% of patients with UGIB—usually from a duodenal source. Even a bile-stained appearance does not exclude a bleeding postpyloric lesion since reports of bile in the aspirate are incorrect in ~50% of cases. Testing of aspirates that are not grossly bloody for occult blood is not useful. DIAGNOSTIC EVALUATION OF THE PATIENT WITH GIB Upper GIB (Fig. 8-1) History and physical exami- nation are not usually diagnostic of the source of GIB. Upper endoscopy is the test of choice in patients with UGIB and should be performed urgently in patients with hemodynamic instability (hypotension, tachycardia, or postural changes in heart rate or blood pressure). Early endoscopy is also beneficial in cases of milder bleeding for man- agement decisions. Patients with major bleeding and high-risk endoscopic findings (e.g., varices, ulcers with active bleeding or a visible vessel) bene- fit from endoscopic hemostatic therapy, while patients with low-risk lesions (e.g., clean-based ulcers, nonbleeding Mallory-Weiss tears, erosive or hemorrhagic gastropathy) who have stable vital signs and hemoglobin, and no other medical prob- lems, can be discharged home. Acute Upper GI Bleeding ICU for 1–2 days; ward for 2–3 days Ligation (preferred) or sclerotherapy + IV octreotide Esophageal VaricesUlcer Mallory-Weiss Tear Clean base Discharge No IV PPI or endoscopic therapy Active bleeding or visible vessel ICU for 1 day; ward for 2 days IV PPI therapy + endoscopic therapy Adherent clot Ward for 3 days IV PPI therapy +/– endoscopic therapy Flat, pigmented spot No IV PPI or endoscopic therapy Ward for 3 days Active bleeding No active bleeding No endoscopic therapy Discharge Endoscopic therapy Ward for 1–2 days FIGURE 8-1 Suggested algorithm for patients with acute upper gastrointestinal bleeding. Recommendations on level of care and time of discharge assume patient is stabilized without further bleeding or other con- comitant medical problems. PPI, proton pump inhibitor; ICU, intensive care unit. Lower GIB (Fig. 8-2) Patients with hematochezia and hemodynamic instability should have upper endoscopy to rule out an upper GI source before evaluation of the lower GI tract. Patients with pre- sumed LGIB may undergo early sigmoidoscopy for the detection of obvious, low-lying lesions. However, the procedure is difficult with brisk bleeding, and it is usually not possible to identify the area of bleeding. Sigmoidoscopy is useful primarily in patients <40 years with minor bleeding. Colonoscopy after an oral lavage solution is the pro- cedure of choice in patients admitted with LGIB unless bleeding is too massive or unless sigmoidoscopy has dis- closed an obvious actively bleeding lesion. 99mTc- labeled red cell scan allows repeated imaging for up to 24 h and may identify the general location of bleeding. However, radionuclide scans should be interpreted with caution because results, especially from later images, are highly variable. In active LGIB, angiography can detect SECTION I Cardinal M anifestations of Gastrointestinal Disease 66 the site of bleeding (extravasation of contrast into the gut) and permits treatment with intraarterial infusion of vasopressin or embolization. Even after bleeding has stopped, angiography may identify lesions with abnor- mal vasculature, such as vascular ectasias or tumors. GIB of Obscure Origin Obscure GIB is defined as per- sistent or recurrent bleeding for which no source has been identified by routine endoscopic and contrast x-ray studies; it may be overt (e.g., melena, hema- tochezia) or occult. Push enteroscopy, with a specially designed enteroscope or a pediatric colonoscope to inspect the entire duodenum and part of the jejunum, is generally the next step. Push enteroscopy may iden- tify probable bleeding sites in 20–40% of patients with obscure GIB. Video capsule endoscopy, which allows endoscopic examination of the entire small intestine, increases diagnostic yield in obscure GIB: a systematic review of 14 trials comparing push enteroscopy to Acute Lower GI Bleeding No hemodynamic instability Age <40 years Flexible sigmoidoscopy (Colonoscopy if familial colon cancer, iron deficiency anemia, or copious bleeding)* Age >40 years Hemodynamic instability Bleeding stops Severe bleeding persists Upper endoscopy Mild to moderate bleeding persists Colonoscopy†Colonoscopy Angiography (Tc-RBC scan may be done first) Tc-RBC scan and/or angiography Consider intraoperative endoscopy Consider enteroscopy, video capsule, enteroclysis, angiography if major blood loss Enteroscopy Video capsule Intraoperative endoscopy Enteroscopy FIGURE 8-2 Suggested algorithm for patients with acute lower gastrointestinal bleeding. Sequential recommendations under “Hemodynamic instability” assume a test is found to be nondiagnostic before next test is performed. *Some suggest colonoscopy for any degree of rectal bleeding in patients <40 years as well. †If massive bleeding does not allow time for colonic lavage, proceed to angiography. Tc-RBC, 99mtechnetium-labeled red blood cell. CHAPTER 8 Gastrointestinal Bleeding 67capsule revealed “clinically significant findings” in 26% and 56% of patients, respectively. However, lack of con- trol of the capsule prevents its manipulation and full visualization of the intestine; in addition, tissue cannot be sampled and therapy cannot be applied. A new endoscopic technique, double-balloon enteroscopy, allows the endoscopist to potentially examine and pro- vide therapy to much or all of the small intestine. If enteroscopy and video capsule endoscopy are negative or unavailable, a specialized radiographic examination of the small bowel (e.g., enteroclysis) should be per- formed. Newer imaging techniques being investigated include CT and MR enterography. Patients with continued obscure GIB who require transfusions or repeated hospitalizations warrant further investigations. 99mTc-labeled red blood cell scintigraphy should be employed. Angiography is useful even if bleeding has subsided, since it may disclose vascular anomalies or tumor vessels. 99mTc-pertechnetate scintigraphy for diagnosis of Meckel’s diverticulum should be done, especially in the evaluation of young patients. When all tests are unrevealing, intraoperative endoscopy is indicated in patients with severe recurrent or persistent bleeding requiring repeated transfusions. Occult GIB Occult GIB is manifested by a positive test for fecal occult blood or iron-deficiency anemia. Eval- uation of a positive test for fecal occult blood gener- ally should begin with colonoscopy, particularly in patients >40 years. If evaluation of the colon is nega- tive, many perform upper endoscopy only if iron- deficiency anemia or upper GI symptoms are present, while others recommend upper endoscopy in all patients since up to 25–40% of these patients may have some abnormality noted on upper endoscopy. If standard endoscopic tests are unrevealing, enteroscopy, video capsule endoscopy, and/or enteroclysis may be considered in patients with iron-deficiency anemia. FURTHER READINGS CHAN FK et al: Proton pump inhibitor plus a COX-2 inhibitor for the prevention of recurrent ulcer bleeding in patients with arthritis: A double blinded, randomized trial. Gastroenterology 130:A-105, 2006 CHIU PW, NG EK: Predicting poor outcome from acute upper gas- trointestinal hemorrhage. Gastroenterol Clin North Am 38:215, 2009 CIPOLLETTA L et al: Outpatient management for low-risk nonvariceal upper GI bleeding: A randomized controlled trial. Gastrointest Endosc 55:1, 2002 CONRAD SA et al:Randomized, double-blind comparison of immediate- release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients. Crit Care Med 33:760, 2005 D’AMICO G et al: Pharmacological treatment of portal hypertension: An evidence-based approach. Semin Liver Dis 19:475, 1999 ELMUNZER BJ et al: Systematic review of the predictors of recurrent hemorrhage after endoscopic hemostatic therapy for bleeding peptic ulcers.Am J Gastroenterol 103:2625, 2008 HENDERSON JM et al: Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: A ran- domized trial. Gastroenterology 130:1643, 2006 LAINE L, COOK D: Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding: A meta-analysis. Ann Intern Med 123:280, 1995 LAU JYW et al: Effect of intravenous omeprazole on recurrent bleed- ing after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 343:310, 2000 LEONTIADIS GI, HOWDEN CW:The role of proton pump inhibitors in the management of upper gastrointestinal bleeding. Gastroen- terol Clin North Am 38:199, 2009 MARMO R et al: Dual therapy versus monotherapy in endoscopic treatment of high-risk bleeding ulcers: A meta-analysis of con- trolled trials.Am J Gastroenterol 102:279, 2007 ROCKALL TA et al: Risk assessment after acute upper gastrointestinal haemorrhage. Gut 38:316, 1996 SASS DA, CHOPRA KB: Portal hypertension and variceal hemorrhage. Med Clin North Am 93:837, 2009 TRIESTER SL et al: A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with obscure gastrointestinal bleeding. Am J Gastroenterol 100: 2407, 2005 SECTION I Cardinal M anifestations of Gastrointestinal Disease 70 The prolonged half-life of albumin-bound conju- gated bilirubin explains two previously unexplained enigmas in jaundiced patients with liver disease: (1) that some patients with conjugated hyperbilirubinemia do not exhibit bilirubinuria during the recovery phase of their disease because the bilirubin is covalently bound to albumin and therefore not filtered by the renal glomeruli, and (2) that the elevated serum bilirubin level declines more slowly than expected in some patients who otherwise appear to be recovering satisfactorily. Late in the recovery phase of hepatobiliary disorders, all the conjugated bilirubin may be in the albumin-linked form. Its value in serum falls slowly because of the long half-life of albumin. MEASUREMENT OF URINE BILIRUBIN Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not found in the urine. Conjugated bilirubin is filtered at the glomerulus and the majority is reabsorbed by the proxi- mal tubules; a small fraction is excreted in the urine. Any bilirubin found in the urine is conjugated bilirubin.The presence of bilirubinuria implies the presence of liver dis- ease. A urine dipstick test (Ictotest) gives the same infor- mation as fractionation of the serum bilirubin.This test is very accurate. A false-negative test is possible in patients with prolonged cholestasis due to the predominance of conjugated bilirubin covalently bound to albumin. ISOLATED ELEVATION OF SERUM BILIRUBIN Unconjugated Hyperbilirubinemia The differential diag- nosis of an isolated unconjugated hyperbilirubinemia is limited (Table 9-1). The critical determination is whether the patient is suffering from a hemolytic process resulting in an overproduction of bilirubin (hemolytic disorders and ineffective erythropoiesis) or from impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders). Hemolytic disorders that cause excessive heme production may be either inherited or acquired. Inherited disorders include spherocytosis, sickle cell anemia, thalassemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase. In these conditions, the serum biliru- bin rarely exceeds 86
mol/L (5 mg/dL). Higher levels may occur when there is coexistent renal or hepatocellular dysfunction or in acute hemolysis such as a sickle cell crisis. In evaluating jaundice in patients with chronic hemolysis, it is important to remember the high incidence of pigmented (calcium bilirubi- nate) gallstones found in these patients, which increases the likelihood of choledocholithiasis as an alternative explanation for hyperbilirubinemia. Acquired hemolytic disorders include microangio- pathic hemolytic anemia (e.g., hemolytic-uremic syndrome), paroxysmal nocturnal hemoglobinuria, spur cell anemia, and immune hemolysis. Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies. In the absence of hemolysis, the physician should consider a problem with the hepatic uptake or conju- gation of bilirubin. Certain drugs, including rifampicin and probenecid, may cause unconjugated hyperbilirubinemia by diminishing hepatic uptake of bilirubin. Impaired bilirubin conjugation occurs in three genetic conditions: Crigler-Najjar syndrome, types I and II, and Gilbert’s syndrome. Crigler-Najjar type I is an exceptionally rare condition found in neonates and characterized by severe jaundice [bilirubin > 342
mol/L (>20 mg/dL)] and neuro- logic impairment due to kernicterus, frequently lead- ing to death in infancy or childhood. These patients have a complete absence of bilirubin UDPGT activ- ity, usually due to mutations in the critical 3´ domain of the UDPGT gene, and are totally unable to conju- gate, hence cannot excrete bilirubin. The only effec- tive treatment is orthotopic liver transplantation. Use of gene therapy and allogeneic hepatocyte infusion are experimental approaches of future promise for this devastating disease. Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels that range from 103–428
mol/L (6–25 mg/dL). In these patients, mutations in the Approach to the Patient: BILIRUBIN The bilirubin present in serum represents a balance between input from production of bilirubin and hepatic/biliary removal of the pigment. Hyperbiliru- binemia may result from (1) overproduction of biliru- bin; (2) impaired uptake, conjugation, or excretion of bilirubin; or (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts. An increase in unconjugated bilirubin in serum results from either overproduction, impairment of uptake, or conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pig- ment. The initial steps in evaluating the patient with jaundice are to determine (1) whether the hyper- bilirubinemia is predominantly conjugated or uncon- jugated in nature, and (2) whether other biochemical liver tests are abnormal.The thoughtful interpretation of limited data will allow for a rational evaluation of the patient (Fig. 9-1).This discussion will focus solely on the evaluation of the adult patient with jaundice. bilirubin UDPGT gene cause reduced but not com- pletely absent activity of the enzyme. Bilirubin UDPGT activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients. Despite marked jaundice, these patients usually survive into adulthood, although they may be susceptible to kernicterus under the stress of intercurrent illness or surgery. Gilbert’s syndrome is also marked by the impaired con- jugation of bilirubin due to reduced bilirubin UDPGT activity. Patients with Gilbert’s syndrome have a mild unconjugated hyperbilirubinemia with serum levels almost always <103
mol/L (6 mg/dL). The serum levels may fluctuate, and jaundice is often identified only during periods of fasting. One molecular defect that has been identified in patients with Gilbert’s syn- drome is in the TATAA element in the 5´ promoter region of the bilirubin UDPGT gene upstream of exon 1.This defect alone is not necessarily sufficient for producing the clinical syndrome of Gilbert’s as there are patients who are homozygous for this defect yet do not have the levels of hyperbilirubinemia typically seen in History (focus on medication/drug exposure) Physical examination Lab tests: Bilirubin with fractionation, ALT, AST, alkaline phosphatase, prothrombin time, and albumin Isolated elevation of the bilirubin Indirect hyperbilirubinemia (direct < 15%) See Table 9-1 Direct hyperbilirubinemia (direct > 15%) See Table 9-1 Drugs Rifampicin Probenecid Inherited disorders Dubin-Johnson syndrome Rotor's syndrome 1. Viral serologies Hepatitis A IgM Hepatitis B surface antigen and core antibody (IgM) Hepatitis C RNA 2. Toxicology screen Acetaminophen level 3. Ceruloplasmin (if patient less than 40 years of age) 4. ANA, SMA, LKM, SPEP Inherited disorders Gilbert's syndrome Crigler-Najjar syndromes Hemolytic disorders Ineffective erythropoiesis Bilirubin and other liver tests elevated Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase See Table 9-2 Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST See Table 9-3 Dilated ducts Extrahepatic cholestasis CT/ERCP Liver biopsy Liver biopsy MRCP/Liver biopsy Results negativeResults negative Additional virologic testing CMV DNA, EBV capsid antigen Hepatitis D antibody (if indicated) Hepatitis E IgM (if indicated) Results negative AMA positive Serologic testing AMA Hepatitis serologies Hepatitis A, CMV, EBV Review drugs (see Table 9-3) Ultrasound Ducts not dilated Intrahepatic cholestasis ALGORITHM FOR PATIENT WITH JAUNDICE FIGURE 9-1 Evaluation of the patient with jaundice. MRCP, magnetic resonance cholangiopancreatog- raphy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SMA, smooth-muscle antibody; AMA, antimitochondrial antibody; LKM, liver-kidney microsomal antibody; SPEP, serum protein electrophoresis; CMV, cytomegalovirus; EBV, Epstein-Barr virus. C H A P T E R 9 CHAPTER 9 Jaundice 71 SECTION I Cardinal M anifestations of Gastrointestinal Disease 72 Gilbert’s syndrome. An enhancer polymorphism that lowers transcriptional activity has recently been identified. The decrease in transcription caused by both mutations together may be critical for producing the syndrome. Unlike both Crigler-Najjar syndromes, Gilbert’s syn- drome is very common.The reported incidence is 3–7% of the population with males predominating over females by a ratio of 2–7:1. Conjugated Hyperbilirubinemia Elevated conjugated hyperbilirubinemia is found in two rare inherited con- ditions: Dubin-Johnson syndrome and Rotor’s syndrome (Table 9-1). Patients with both conditions present with asymptomatic jaundice, typically in the second genera- tion of life. The defects in Dubin-Johnson syndrome are mutations in the gene for multiple drug resistance protein 2. These patients have altered excretion of bilirubin into the bile ducts. Rotor’s syndrome seems to be a problem with the hepatic storage of bilirubin. Dif- ferentiating between these syndromes is possible, but clinically unnecessary, due to their benign nature. ELEVATION OF SERUM BILIRUBIN WITH OTHER LIVER TEST ABNORMALITIES The remainder of this chapter will focus on the evaluation of the patient with a conju- gated hyperbilirubinemia in the setting of other liver test abnormalities.This group of patients can be divided into those with a primary hepatocellular process and those with intra- or extrahepatic cholestasis. Being able to make this differentiation will guide the physician’s evaluation (Fig. 9-1).This differentiation is made on the basis of the history and physical examination as well as the pattern of liver test abnormalities. History A complete medical history is perhaps the single most important part of the evaluation of the patient with unexplained jaundice. Important consid- erations include the use of or exposure to any chemi- cal or medication, either physician-prescribed, over- the-counter, complementary or alternative medicines such as herbal and vitamin preparations, or other drugs such as anabolic steroids.The patient should be carefully questioned about possible parenteral expo- sures, including transfusions, IV and intranasal drug use, tattoos, and sexual activity. Other important questions include recent travel history, exposure to people with jaundice, exposure to possibly contami- nated foods, occupational exposure to hepatotoxins, alcohol consumption, the duration of jaundice, and the presence of any accompanying symptoms such as arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool.While none of these latter symptoms are specific for any one condition, they can suggest a particular diagnosis.A history of arthralgias and myal- gias predating jaundice suggests hepatitis, either viral or drug-related. Jaundice associated with the sudden onset of severe right upper quadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis. Physical Examination The general assessment should include assessment of the patient’s nutritional status. Temporal and proximal muscle wasting suggests long- standing diseases such as pancreatic cancer or cirrho- sis. Stigmata of chronic liver disease, including spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren’s contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced alcoholic (Laennec’s) cirrhosis and occa- sionally in other types of cirrhosis. An enlarged left supraclavicular node (Virchow’s node) or periumbili- cal nodule (Sister Mary Joseph’s nodule) suggests an abdominal malignancy. Jugular venous distention, a sign of right-sided heart failure, suggests hepatic con- gestion. Right pleural effusion, in the absence of clin- ically apparent ascites, may be seen in advanced cirrhosis. The abdominal examination should focus on the size and consistency of the liver, whether the spleen is palpable and hence enlarged, and whether there is ascites present. Patients with cirrhosis may have an TABLE 9-1 CAUSES OF ISOLATED HYPERBILIRUBINEMIA I. Indirect hyperbilirubinemia A. Hemolytic disorders 1. Inherited a. Spherocytosis, elliptocytosis Glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies b. Sickle cell anemia 2. Acquired a. Microangiopathic hemolytic anemias b. Paroxysmal nocturnal hemoglobinuria c. Spur cell anemia d. Immune hemolysis B. Ineffective erythropoiesis 1. Cobalamin, folate, thalassemia, and severe iron deficiencies C. Drugs 1. Rifampicin, probenecid, ribavirin D. Inherited conditions 1. Crigler-Najjar types I and II 2. Gilbert’s syndrome II. Direct hyperbilirubinemia A. Inherited conditions 1. Dubin-Johnson syndrome 2. Rotor’s syndrome The vanishing bile duct syndrome and adult bile ductope- nia are rare conditions in which there are a decreased number of bile ducts seen in liver biopsy specimens. The histologic picture is similar to that found in pri- mary biliary cirrhosis. This picture is seen in patients who develop chronic rejection after liver transplanta- tion and in those who develop graft-versus-host disease after bone marrow transplantation. Vanishing bile duct syndrome also occurs in rare cases of sar- coidosis, in patients taking certain drugs including chlorpromazine, and idiopathically. There are also familial forms of intrahepatic cholestasis. The familial intrahepatic cholestatic syn- dromes include progressive familial intrahepatic cholestasis (PFIC) types 1–3, and benign recurrent cholestasis (BRC). PFIC1 and BRC are autosomal recessive dis- eases that result from mutations in the ATP8B1 gene that encodes a protein belonging to the subfamily of P-type ATPases; the exact function of this protein remains poorly defined.While PFIC1 is a progressive condition that manifests in childhood, BRC presents later than PFIC1 and is marked by recurrent episodes of jaundice and pruritus; the episodes are self-limited but can be debilitating. PFIC2 is caused by mutations in the ABCB11 gene, which encodes the bile salt export pump, and PFIC3 is caused by mutations in the multidrug-resistant P-glycoprotein 3. Cholestasis of pregnancy occurs in the second and third trimesters and resolves after delivery. Its cause is unknown, but the condition is probably inherited and cholestasis can be triggered by estrogen administration. Other causes of intrahepatic cholestasis include total parenteral nutrition (TPN), nonhepatobiliary sepsis, benign postoperative cholestasis, and a parane- oplastic syndrome associated with a number of differ- ent malignancies, including Hodgkin’s disease, medullary thyroid cancer, renal cell cancer, renal sar- coma, T cell lymphoma, prostate cancer, and several gastrointestinal malignancies. The term Stauffer’s syn- drome has been used for intrahepatic cholestasis specifically associated with renal cell cancer. In patients developing cholestasis in the intensive care unit, the major considerations should be sepsis, shock liver, and TPN jaundice. Jaundice occurring after bone marrow transplantation is most likely due to venoocclusive disease or graft-versus-host disease. Causes of extrahepatic cholestasis can be split into malignant and benign (Table 9-3). Malignant causes include pancreatic, gallbladder, ampullary, and cholan- giocarcinoma.The latter is most commonly associated with PSC and is exceptionally difficult to diagnose because its appearance is often identical to that of PSC. Pancreatic and gallbladder tumors, as well as cholangiocarcinoma, are rarely resectable and have poor prognoses. Ampullary carcinoma has the highest surgical cure rate of all the tumors that present as painless jaundice. Hilar lymphadenopathy due to metastases from other cancers may cause obstruction of the extrahepatic biliary tree. Choledocholithiasis is the most common cause of extrahepatic cholestasis. The clinical presentation can range from mild right upper quadrant discomfort TABLE 9-3 CHOLESTATIC CONDITIONS THAT MAY PRODUCE JAUNDICE I. Intrahepatic A. Viral hepatitis 1. Fibrosing cholestatic hepatitis—hepatitis B and C 2. Hepatitis A, Epstein-Barr virus, cytomegalovirus B. Alcoholic hepatitis C. Drug toxicity 1. Pure cholestasis—anabolic and contraceptive steroids 2. Cholestatic hepatitis—chlorpromazine, erythromycin estolate 3. Chronic cholestasis—chlorpromazine and prochlorperazine D. Primary biliary cirrhosis E. Primary sclerosing cholangitis F. Vanishing bile duct syndrome 1. Chronic rejection of liver transplants 2. Sarcoidosis 3. Drugs G. Inherited 1. Progressive familial intrahepatic cholestasis 2. Benign recurrent cholestasis H. Cholestasis of pregnancy I. Total parenteral nutrition J. Nonhepatobiliary sepsis K. Benign postoperative cholestasis L. Paraneoplastic syndrome M. Venoocclusive disease N. Graft-versus-host disease O. Infiltrative disease 1. TB 2. Lymphoma 3. Amyloid II. Extrahepatic A. Malignant 1. Cholangiocarcinoma 2. Pancreatic cancer 3. Gallbladder cancer 4. Ampullary cancer 5. Malignant involvement of the porta hepatis lymph nodes B. Benign 1. Choledocholithiasis 2. Postoperative biliary strictures 3. Primary sclerosing cholangitis 4. Chronic pancreatitis 5. AIDS cholangiopathy 6. Mirizzi syndrome 7. Parasitic disease (ascariasis) C H A P T E R 9 CHAPTER 9 Jaundice 75 SECTION I Cardinal M anifestations of Gastrointestinal Disease 76 with only minimal elevations of the enzyme tests to ascending cholangitis with jaundice, sepsis, and circu- latory collapse. PSC may occur with clinically impor- tant strictures limited to the extrahepatic biliary tree. In cases where there is a dominant stricture, patients can be effectively managed with serial endoscopic dilatations. Chronic pancreatitis rarely causes stric- tures of the distal common bile duct, where it passes through the head of the pancreas.AIDS cholangiopa- thy is a condition, usually due to infection of the bile duct epithelium with CMV or cryptosporidia, which has a cholangiographic appearance similar to that of PSC. These patients usually present with greatly ele- vated serum alkaline phosphatase levels (mean, 800 IU/L), but the bilirubin is often near normal. These patients do not typically present with jaundice. SUMMARY The goal of this chapter is not to provide an encyclope- dic review of all of the conditions that can cause jaun- dice. Rather, it is intended to provide a framework that helps a physician to evaluate the patient with jaundice in a logical way (Fig. 9-1). Simply stated, the initial step is to obtain appropriate blood tests to determine if the patient has an isolated elevation of serum bilirubin. If so, is the bilirubin eleva- tion due to an increased unconjugated or conjugated fraction? If the hyperbilirubinemia is accompanied by other liver test abnormalities, is the disorder hepatocel- lular or cholestatic? If cholestatic, is it intra- or extra- hepatic? All of these questions can be answered with a thoughtful history, physical examination, and interpreta- tion of laboratory and radiologic tests and procedures. FURTHER READINGS BOSMA PJ: Inherited disorders of bilirubin metabolism. J Hepatol 38:107, 2003 FERENCI P:Wilson’s disease. Clin Gastroenterol Hepatol 3:726, 2005 FOX IJ et al: Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338:1422, 1998 GLASOVA H, BEUERS U: Extrahepatic manifestations of cholestasis. J Gastroenterol Hepatol 9:938, 2002 PRATT DS, KAPLAN MM: Laboratory tests, in Schiff’s Diseases of the Liver, 9th ed, ER Schiff et al (eds). Philadelphia, Lippincott Williams & Wilkins, 2003 TRAUNER M et al: Molecular pathogenesis of cholestasis. N Engl J Med 339:1217, 1998 Robert M. Glickman ■ Roshini Rajapaksa 77 ■ Abdominal Swelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Clinical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 ■ Ascites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81 uncommon in cirrhosis with ascites, and when it is pre- sent, pancreatitis, hepatocellular carcinoma, or peritonitis should be considered.Tense ascites or abdominal tumors may produce increased intraabdominal pressure, resulting in indigestion and heartburn due to gastroesophageal reflux or dyspnea, abdominal wall hernias (inguinal and umbilical), orthopnea, and tachypnea from elevation of the diaphragm.A coexistent pleural effusion, more com- monly on the right, presumably due to leakage of ascitic fluid through lymphatic channels in the diaphragm, may also contribute to respiratory embarrassment. A large pleural effusion, obscuring most of the lung, is known as a hepatic hydrothorax.The patient with diffuse abdominal swelling should be questioned about increased alcohol intake, a prior episode of jaundice or hematuria, or a change in bowel habits. Such historic information may provide the clues that will lead one to suspect an occult cirrhosis, a colonic tumor with peritoneal seeding, con- gestive heart failure, or nephrosis. PHYSICAL EXAMINATION A carefully executed general physical examination can yield valuable clues concerning the etiology of abdomi- nal swelling.Thus palmar erythema and spider angiomas suggest an underlying cirrhosis, while supraclavicular adenopathy (Virchow’s node) should raise the question of an underlying gastrointestinal malignancy. Inspection of the abdomen is important. By noting the abdominal contour, one may be able to distinguish local- ized from generalized swelling. The tensely distended ABDOMINAL SWELLING Abdominal swelling or distention is a common problem in clinical medicine and may be the initial manifestation of a systemic disease or of otherwise unsuspected abdominal disease. Subjective abdominal enlargement, often described as a sensation of fullness or bloating, is usually transient and is often related to a functional gas- trointestinal disorder when it is not accompanied by objective physical findings of increased abdominal girth or local swelling. Obesity and lumbar lordosis, which may be associated with prominence of the abdomen, may usually be distinguished from true increases in the volume of the peritoneal cavity by history and careful physical examination. CLINICAL HISTORY Abdominal swelling may first be noticed by the patient because of a progressive increase in belt or clothing size, the appearance of abdominal or inguinal hernias, or the development of a localized swelling. Often, considerable abdominal enlargement has gone unnoticed for weeks or months, either because of coexistent obesity or because the ascites formation has been insidious, with- out pain or localizing symptoms. Progressive abdominal distention may be associated with a sensation of “pulling” or “stretching” of the flanks or groins and vague low back pain. Localized pain usually results from involvement of an abdominal organ (e.g., a passively congested liver, large spleen, or colonic tumor). Pain is CHAPTER 10 ABDOMINAL SWELLING AND ASCITES SECTION I Cardinal M anifestations of Gastrointestinal Disease 80 On occasion, ascites may develop as a seemingly iso- lated finding in the absence of a clinically evident underlying disease. Then, a careful analysis of ascitic fluid may indicate the direction the evaluation should take. A useful framework for the workup starts with an analysis of whether the fluid is classified as a high (tran- sudate) or low (exudate) gradient fluid. High-gradient (transudative) ascites of unclear etiology is most often due to occult cirrhosis, right-sided venous hypertension raising hepatic sinusoidal pressure, Budd-Chiari syn- drome, or massive hepatic metastases. Cirrhosis with well-preserved liver function (normal albumin) result- ing in ascites is invariably associated with significant portal hypertension (Chap. 40). Evaluation should include liver function tests and a hepatic imaging pro- cedure (i.e., CT or ultrasound) to detect nodular changes in the liver suggesting portal hypertension. On occasion, a wedged hepatic venous pressure can be use- ful to document portal hypertension. Finally, if clini- cally indicated, a liver biopsy will confirm the diagnosis of cirrhosis and perhaps suggest its etiology. Other eti- ologies may result in hepatic venous congestion and resultant ascites. Right-sided cardiac valvular disease and particularly constrictive pericarditis should raise a high index of suspicion and may require cardiac imag- ing and cardiac catheterization for definitive diagnosis. Hepatic vein thrombosis is evaluated by visualizing the hepatic veins with imaging techniques (Doppler ultra- sound, angiography, CT scans, MRI) to demonstrate obliteration, thrombosis, or obstruction by tumor. Uncommonly, transudative ascites may be associated with benign tumors of the ovary, particularly fibroma (Meigs’ syndrome) with ascites and hydrothorax. Low-gradient (exudative) ascites should initiate an evalua- tion for primary peritoneal processes, most importantly infection and tumor.Tuberculous peritonitis (Table 10-1) is best diagnosed by peritoneal biopsy, either percuta- neously or via laparoscopy. Histologic examination invariably shows granulomata that may contain acid-fast bacilli. Since cultures of peritoneal fluid and biopsies for tuberculosis may require 6 weeks, characteristic histol- ogy with appropriate stains allows antituberculosis ther- apy to be started promptly. Similarly, the diagnosis of peritoneal seeding by tumor can usually be made by cytologic analysis of peritoneal fluid or by peritoneal biopsy if cytology is negative. Appropriate diagnostic studies can then be undertaken to determine the nature and site of the primary tumor. Pancreatic ascites (Table 10-1) is invariably associated with an extravasation of pancreatic fluid from the pancreatic ductal system, most commonly from a leaking pseudocyst. Ultrasound or CT examination of the pancreas followed by visualiza- tion of the pancreatic duct by direct cannulation [viz., endoscopic retrograde cholangiopancreatography (ERCP)] usually discloses the site of leakage and per- mits resective surgery to be carried out. presents some of the disease states that produce high- SAAG and low-SAAG ascites. Although there is vari- ability of the ascitic fluid in any given disease state, some features are sufficiently characteristic to suggest certain diagnostic possibilities. For example, blood- stained fluid with >25 g/L protein is unusual in uncomplicated cirrhosis but is consistent with tubercu- lous peritonitis or neoplasm. Cloudy fluid with a pre- dominance of polymorphonuclear cells (>250/µL) and a positive Gram’s stain are characteristic of bacterial peritonitis, which requires antibiotic therapy; if most cells are lymphocytes, tuberculosis should be suspected. The complete examination of each fluid is most important, for occasionally only one finding may be abnormal. For example, if the fluid is a typical transu- date but contains >250 white blood cells per micro- liter, the finding should be recognized as atypical for cirrhosis and should warrant a search for tumor or infection. This is especially true in the evaluation of cirrhotic ascites where occult peritoneal infection may be present with only minor elevations in the white blood cell count of the peritoneal fluid (300–500/µL). Since Gram’s stain of the fluid may be negative in a high proportion of such cases, careful culture of the peritoneal fluid is mandatory. Bedside inoculation of blood culture flasks with ascitic fluid results in a dra- matically increased incidence of positive cultures when bacterial infection is present (90 vs 40% positivity with conventional cultures done by the laboratory). Direct visualization of the peritoneum (laparoscopy) may dis- close peritoneal deposits of tumor, tuberculosis, or metastatic disease of the liver. Biopsies are taken under direct vision, often adding to the diagnostic accuracy of the procedure. Chylous ascites refers to a turbid, milky, or creamy peri- toneal fluid due to the presence of thoracic or intestinal lymph. Such a fluid shows Sudan-staining fat globules microscopically and an increased triglyceride content by chemical examination. Opaque milky fluid usually has a triglyceride concentration of >11.3 mmol/L (>1000 mg/dL), but a triglyceride concentration of >2.3 mmol/L (>200 mg/dL) is sufficient for the diagnosis. A turbid fluid due to leukocytes or tumor cells may be confused with chylous fluid (pseudochylous), and it is often helpful to carry out alkalinization and ether extraction of the specimen. Alkali tend to dissolve cellular proteins and thereby reduce turbidity; ether extraction leads to clearing if the turbidity of the fluid is due to lipid. Chylous ascites is most often the result of lymphatic disruption or obstruction from cirrhosis, tumor, trauma, tuberculosis, filariasis, or congenital abnormalities. It may also be seen in the nephrotic syndrome. Rarely, ascitic fluid may be mucinous in character, suggesting either pseudomyxoma peritonei (Chap. 18) or rarely a colloid carcinoma of the stomach or colon with peritoneal implants. CHAPTER 10 Abdom inal Sw elling and Ascites 81An analysis of the physiologic and metabolic factors involved in the production of ascites (detailed in Chap. 40), coupled with a complete evaluation of the nature of the ascitic fluid, invariably discloses the eti- ology of the ascites and permits appropriate therapy to be instituted. ACKNOWLEDGMENT Dr. Kurt J. Isselbacher was the co-author of this chapter in pre- vious editions. FURTHER READINGS LIPSKY MS, STERNBACH MR: Evaluation and initial management of patients with ascites.Am Fam Physician 54:1327, 1996 MCHUTCHISON JG: Differential diagnosis of ascites. Semin Liver Dis 17:191, 1997 PARSONS SL et al: Malignant ascites. Br J Surg 83:6, 1996 PINTO PC et al: Large volume paracentesis in nonedematous patients with tense ascites: Its effect on intravascular volume. Hepatology 8:207, 1988 RUNYON BA: Management of adult patients with ascites due to cir- rhosis. Hepatology 39:841, 2004 This page intentionally left blank