Ddsep 7 2013

Syllabus
DDSEP7
®
Digestive Disease Self-Education Program

®
A Core Curriculum and Self-Assessment in Gastroenterology and Hepatology
EDITOR
Arthur J. DeCross, MD, AGAF
ASSOCIATE EDITORS
Carl L. Berg, MD
Anil B. Nagar, MD
CMYK
DDSEP®7 ®
Digestive Diseases Self-Education Program
BOOK 1
Syllabus
A Core Curriculum and Self-Assessment in Gastroenterology and Hepatology
EDITOR
ASSOCIATE EDITORS
Carl L. Berg, MD
Anil B. Nagar, MD
AGA Institute Education

Lori N. Marks, PhD Vice President, Education
Maura H. Davis Director, Education
Kelley M. Blanchard Senior Coordinator, Education
Brenda Helmandollar Design and Composition
PROforma Printing
Disclaimer
This publication provides accurate information on the subject matter covered. The publisher is not providing
or services by trade name, trademark, manufacturer, or otherwise does not constitute or imply endorsement,
recommendation, or favored status by the AGA Institute. The views and opinions of the author(s) expressed
advertise or endorse a product.
©2013 by AGA. All rights reserved. No part of this book may be reproduced or utilized in any form or by any
means, electronic or mechanical, including photocopying and recording or by any information storage and
retrieval system without permission in writing from the publisher.
Printed in the United States of America
14 13 12 11 1 2 3 4 5 6
ISBN: 978-1-60356-018-4
For additional copies or information on licensing or translating this content, please contact:
AGA
4930 Del Ray Avenue
Bethesda, MD 20814-2513
www.gastro.org
Foreword
he Digestive Diseases Self-Education Program (DDSEP®) has been a high quality update and re-
by the Education and Training Committee of the American Gastroenterological Association (AGA) Institute,
the core philosophy of this program has been to maintain an informed conversation between expert medical
educators and the learner, including our fellowship trainees and practicing clinicians.
While preserving this guiding principle, each edition of the program has sought to build upon prior suc-
cess with improvements that allow the DDSEP® project to remain relevant to the needs of the physician
learner in a rapidly changing landscape of medical innovation, regulation, licensure, and maintenance of cer-
the organization of the educational objectives in parallel with the national core curriculum in gastroenterol-
ogy and hepatology, and the expansion into online access, while maintaining the availability of high quality
AMA category 1 CME credits for the completion of program participation.
A continuously increasing proportion of our professional work force and AGA membership has time-lim-
-
grams are being measured against the outcomes of their trainees, and our gastroenterology fellows have
made clear demands for rigorous board exam review and preparation tools. In response to all these needs,
we are excited to enhance the DDSEP® platform in the seventh edition with a number of innovations and
adaptations that we anticipate will make DDSEP® 7 an even more robust board exam preparation program.
DDSEP® 7 features a special preface chapter on “How to Prepare for the Gastroenterology Boards”, writ-
ten by education experts. Program content has been expanded to include a new chapter on small bowel dis-
eases. In addition, each chapter now includes a special section identifying “Pearls and Pitfalls for the Board
Exam”, highlighting the most important, highly testable contents of that chapter in bullet point format. Each
chapter will also contain a list of “ ”, in order to guide
matter. In addition, DDSEP® 7 has doubled the number of available questions per chapter, so that the entire
program contains more than 800 board exam style questions with available answers and rationales. While
the chapter content is written by subject matter experts, our questions have been written separately by medi-
cal educators drawn for their expertise and training in writing questions in the board exam format. Chapter
content, questions and critiques have each been peer reviewed by an independent subject matter expert as
well as two editors.
Whether you use this program to review and stay current or use it for your board exam preparation, I
quality of your care for patients with digestive and liver diseases. Nonetheless, the foundation of success for
this program is the willingness to adapt and improve so that we can meet your needs as a physician learner.
For this reason, I welcome your suggestions and guidance for our future editions, and ask that you please
complete the program evaluation of DDSEP®
I am grateful to the AGA Institute for the opportunity to have served in guiding the development of the
seventh edition of DDSEP®, and for the support of the Education and Training Committee in this endeavor.
I wish to additionally acknowledge our many contributing authors, educators, peer reviewers, and ques-
iv Digestive Diseases Self-Education Program®
have been fortunate to meet and be inspired by many exceptional educators through the AGA Institute, too
numerous to mention all, but in particular I would like to acknowledge some outstanding teachers for their
inspiration, guidance, and mentorship, including Helen Shields MD, Suzanne Rose MD, Deborah Proctor MD,
and Richard Farmer MD. A special acknowledgement must be extended to my fellowship program director,
David Peura MD, for his life-long mentorship. With respect to this immediate project, special thanks and
recognition to the editor of DDSEP® 6, John Kuemmerle MD, for advice, training, and guidance, and special
Nagar MD. I acknowledge the many individuals of the AGA Institute who brought this project successfully to
completion, particularly Maura Davis, Kelley Blanchard, Lori Marks PhD, and Thomas Serena, for their sup-
port, encouragement, and enthusiasm. I am grateful for the support and patience of my family as I labored
on this project, especially my wife Karen, as well as the support and warm, collegial atmosphere of my profes-
sional colleagues in the Gastroenterology and Hepatology division of the University of Rochester. Last but
certainly not least, I owe my sincere appreciation to my GI fellows, who keep me fresh, challenged, motivated,
and inspired!

Editor
Acknowledgements
he American Gastroenterological Association (AGA) Institute expresses appreciation to the Gov-

erning Board and the Education and Training Committee for their ongoing support and commit-
ment to bringing innovative educational programs such as DDSEP® 7 to those who practice gastroenterol-
ogy and hepatology.
The AGA Institute is grateful to all the chapter content authors, educators, questions writers, and peer
-
tors are listed individually in our preface. For their vision, commitment, oversight, and guidance, we thank
our Editor, Arthur J. DeCross MD AGAF, and Associate Editors Carl L. Berg MD and Anil B. Nagar MD.
-
tivity in bringing the DDSEP® 7 program to completion: Maura Davis, Director of Education; Lori Marks,
Vice President, Education; Kelley Blanchard, Senior Coordinator, Education; and Mark Goetz, e-Learning
Manager.
vi Digestive Diseases Self-Education Program®
Contributing Educators
Content Authors
Carl L. Berg, MD Jeanette Keith, MD

Professor of Medicine Gastroenterologist/ Physician Nutrition Specialist
Chief, Division of Gastroenterology and Hepatology Decatur Gastroenterology Associates
Medical Director, Liver Transplantation Decatur, AL
University of Virginia Health System
Caroline Kerner, MD, MSCE
Steve S. Choi, MD Gastroenterology Division, Department of Medicine
Assistant Professor of Medicine University of Pennsylvania
Duke University Medical Center
Thomas O.G. Kovacs, MD
Guadalupe Garcia-Tsao, MD Professor of Medicine
Professor of Medicine UCLA David Geffen School of Medicine
Yale University School of Medicine
VA-Connecticut Healthcare System Rahul Kuver, MD
Associate Professor of Medicine
Fred S. Gorelick, MD University of Washington School of Medicine
Professor of Medicine and Cell Biology
Deputy Director, Yale MD, PhD Program
Yale University School of Medicine Director of Clinical Research, The Celiac Center at
BIDMC
Adam D. Harris, MD Director of Quality Assurance, Division of Gastroen-
Assistant Professor terology
Warren Alpert Medical School of Brown University Beth Israel Deaconess Medical Center
Douglas M. Heuman, MD, AGAF, FACP, FACG Gary R. Lichtenstein, MD, AGAF
Professor of Medicine Professor of Medicine
Virginia Commonwealth University University of Pennsylvania School of Medicine
Dennis Jensen, MD Hospital of the University of Pennsylvania

Professor of Medicine -David Geffen School of Medi-
cine at UCLA Benson T. Massey, MD, FACP
Divisions of Digestive Diseases at UCLA and VA West Professor of Medicine
Los Angeles Medical Centers Director, GI Manometry Laboratory
Division of Gastroenterology & Hepatology
Barbara H. Jung, MD Medical College of Wisconsin
Associate Professor of Medicine
Northwestern University Feinberg School of Medi- Steven F. Moss, MD, AGAF
cine Professor of Medicine
Division of Gastroenterology Brown University
Robert H. Lurie Comprehensive Cancer Center Providence, RI
viii Digestive Diseases Self-Education Program®
Rupa Mukherjee, MD Sidney Barritt, IV, MD

Division of Gastroenterology Assistant Professor of Medicine
Beth Israel Deaconess Medical Center The University of North Carolina at Chapel Hill
Karthik Ravi, MD C. Richard Boland, MD, AGAF

Mayo Clinic Rochester Chief, Division of Gastroenterology
Baylor University Medical Center
Suzanne Rose, MD, MSEd, AGAF
Professor of Medicine Stephen M. Borowitz, MD
University of Connecticut School of Medicine Professor of Pediatrics and Public Health Sciences
Senior Associate Dean for Education Chief, Division of Pediatric Gastroenterology and
Nutrition
Joel R. Rosh, MD, AGAF University of Virginia Health System
Director, Pediatric Gastroenterology
Goryeb Children’s Hospital/Atlantic Health Kyle E. Brown, MD
Associate Professor of Pediatrics, NJ Medical School Associate Professor Internal Medicine
University of Iowa Hospitals and Clinics
Norma Saks, EdD
Associate Professor, Department of Psychiatry Rebecca A. Burbridge, MD
Assistant Dean for Educational Programs & Director Assistant Professor of Medicine
of the Cognitive Skills Program Duke University Medical Center
Robert Wood Johnson Medical School
Walter W. Chan, MD, MPH
Lawrence R. Schiller, MD Director, Center for Gastrointestinal Motility
Program Director, Gastroenterology Fellowship Brigham and Women's Hospital, Harvard Medical
Baylor University Medical Center, Dallas School
Reza Shaker, MD Jennifer Christie, MD

Joseph E. Geenen Professor and Chief, Associate Professor of Medicine
Division of Gastroenterology and Hepatology Emory University School of Medicine
Senior Associate Dean and Director, Director of Gastrointestinal Motility
Clinical and Translational Science Institute
Medical College of Wisconsin Svetang V. Desai, MD
Department of Gastroenterology
Christina M. Surawicz, MD Duke University Hospital
Professor of Medicine
Department of Gastroenterology Amar R. Deshpande, MD
University of Washington School of Medicine Assistant Professor of Medicine
University of Miami
Seth R. Sweetser, MD
Assistant Professor of Medicine Ronnie Fass, MD
Mayo Clinic College of Medicine Director, GI Motility Laboratory
Southern Arizona VA Health Care System
Peer Reviewers and Question Writers
Lisa Gangarosa, MD, AGAF
David H. Alpers, MD Professor of Medicine
William B. Kountz Professor of Medicine University of North Carolina
Washington University School of Medicine
Shilpa Grover, MD, MPH
Kiran Bambha, MD, MSc Associate Physician, Division of Gastroenterology,
Assistant Professor of Med, Hep & Liver Transplan- Brigham and Women's Hospital
tation Clinical Instructor in Medicine, Harvard Medical
University of Colorado Denver School
ix
C. Prakash Gyawali, MD, MRCP, AGAF Ioannis Oikonomou, MD

Professor of Medicine Assistant Professor of Medicine
Washington University School of Medicine Yale School of Medicine
Jane E. Onken, MD, MHS, AGAF
Christina Ha, MD Associate Professor of Medicine, Division of Gastro-
Assistant Professor of Medicine enterology
The Johns Hopkins School of Medicine Duke University Medical Center
Charles Halsted, MD, AGAF Amy S. Oxentenko, MD

Professor of Internal Medicine Fellowship Director, Gastroenterology & Hepatology
School of Medicine Associate Professor of Medicine
University of California Davis Mayo Clinic, Rochester
Jonathan Huang, DO Henry P. Parkman, MD

Assistant Professor of Medicine Professor of Medicine
University of Rochester Medical Center GI Section, Department of Medicine
Temple University School of Medicine
Kim Isaacs, MD, PhD, AGAF
Professor of Medicine George Philips, MD, BS
University of North Carolina at Chapel Hill Senior Instructor of Medicine
University of Rochester
Christian Jackson, MD
Chief, Section of Gastroenterology Anamika Reed, MD
Loma Linda VA Healthcare System Assistant Professor of Medicine, Digestive Diseases
Yale School of Medicine
Sunanda V. Kane, MD, MSPH, AGAF
Professor of Medicine Joel R. Rosh, MD, AGAF
Mayo Clinic Director, Pediatric Gastroenterology
Goryeb Children’s Hospital/Atlantic Health
Joseph K. Lim, MD Associate Professor of Pediatrics, NJ Medical School
Associate Professor of Medicine; Director, Yale Viral
Hepatitis Program Bimaljit Sandhu, MD
Yale University School of Medicine Associate Professor of Medicine
VCU Medical Center
Anna Suk-Fong Lok, MD
Professor of Internal Medicine Robert S. Sandler, MD, MPH, AGAF
University of Michigan Chief, Division of GI & Hepatology
University of NC at Chapel Hill
Millie D. Long, MD, MPH
Assistant Professor of Medicine Gregory S. Sayuk, MD, MPH
University of North Carolina Gastroenterology Assistant Professor of Medicine
Associate Director, Fellowship Training Program
Mark Lowe, MD, PhD Washington University School Medicine
Professor and Vice-Chairman of Pediatrics
Director, Pediatric Gastroenterology, Hepatology and Mitchell L. Schubert, MD, FASGE
Nutrition Professor of Medicine & Physiology, Virginia Com-
monwealth University
Ryan D. Madanick, MD Chief of Gastroenterology, McGuire VAMC
Assistant Professor of Medicine
University of North Carolina at Chapel Hill Neeral L. Shah, MD
Assistant Professor
Anil B. Nagar, MD University of Virginia
Associate Professor of Medicine, Digestive Diseases
Endoscopy Director
Yale School of Medicine
x Digestive Diseases Self-Education Program®
Pratima Sharma, MD
Assistant Professor, Hepatology
University of Michigan
Melissa Teitelman, MD, MSCE

Duke University School of Medicine
Anne C. Travis, MD, MSC

Clinical Instructor
Harvard Medical School
Jamile Wakim-Fleming, MD, FACG

Hepatology
Digestive Disease Institute
Cleveland Clinic Foundation
Arnold Wald, MD, AGAF

University of Wisconsin School of Medicine
C. Mel Wilcox, MD, FASGE

Program Director, Chief of GI
University of Alabama at Birmingham
Daniel M. Wild, MD
Duke University Medical Center
Richard K. Wood Jr., MD

Assistant Professor
Duke University
Sonia Yoon, MD
Advanced Fellow in GI Motility and
Functional GI Disease
Massachusetts General Hospital
Program Guidelines
Using DDSEP® 7
You can use DDSEP® 7 for self-assessment in two ways: you can take the test without studying the syllabus,
which assesses your current knowledge, or you can review the syllabus and critiques to refresh your knowl-
edge and then take the test. Either way, the validity of your test results relies on the honor system.
The test is printed in Book 2, which contains all the questions by chapter. Book 3 provides you with the
questions and the answers by chapter, as well as critiques (explanations) of each answer.
The test resides in an online learning environment that you access by logging into http://www.gastro.
org/absorb/login. You must use the online test if you want to claim continuing education credits (CME). Use
your email address and AGA password to login. If you forgot your AGA provided password, please contact
member services at: 301-941-2651 or member@gastro.org. When you have completed each chapter, you
will have the opportunity to claim CME.
Accreditation and CME Credits

The American Gastroenterological Association (AGA) Institute is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for physicians.
Each chapter offers you the opportunity to claim up to 6 . You must sup-
ply the number of hours you required to complete each chapter, including the time you spent reading the
text, completing the questions, and reviewing the critiques. This is the basis for the number of CME credits
awarded.
The AGA Institute designates this educational activity for a maximum of 102 .
Physicians should claim only the credit commensurate with the extent of their participation in the activity.
To obtain CME credit, you are required to complete and submit the online test and additional questions
that will help us evaluate the DDSEP® 7 product. The expire May 1, 2016.
xii Digestive Diseases Self-Education Program®
How to Prepare for the
Gastroenterology Boards
Test Taking Tips from the Experts
Suzanne Rose, MD, MSEd

Professor of Medicine, University of Connecticut School of Medicine
Senior Associate Dean for Education
Norma Saks, EdD

Associate Professor, Department of Psychiatry
Assistant Dean for Educational Programs & Director of the Cognitive Skills Program
Robert Wood Johnson Medical School
Planning for the Examination

It is important to know the “rules” of any test you are going to take. These include test content, scheduling,
testing centers. You should be familiar with the processes and the rules, and comfortable navigating the
examination before you take the actual test.
examination can be found on the ABIM website: http://www.abim.org/specialty/gastroenterology.aspx

This website includes information about the examination content, and includes an examination tutorial in
addition to information related to the logistics of examination scheduling. The exam blueprint may be found
here: http://www.abim.org/pdf/blueprint/gastro_moc.pdf You should review this carefully and make sure
you have had adequate time to prepare for the examination in all of the areas that are tested.
Studying for the Examination

Be prepared. It is important to organize and manage your study time to maximize your mastery of the ma-
terial, particularly in those areas where you may be least knowledgeable. Make yourself familiar with the
content areas on this exam. Remember that in general, very new information will not be on the examination.
In your review, you should try to include key review articles in the literature from 2-4 years prior to your
examination date, among your other study sources.
Identify your knowledge strengths and weaknessesUse self-assessment tools and practice tests. The
(MOC) modules.
-
ness, but it is valuable to consider that personal areas of strength and expertise may also represent special
xiv Digestive Diseases Self-Education Program®
equally hazardous trap while answering questions in your areas of special strength can be “over-thinking”
the question. This happens when you know so many details, nuances, and exceptions to the rules that you
over-complicate your answer, and lose focus on the direct, simple objective of the question. For example, if
you were asked what part of the GI tract was affected by ulcerative colitis, the correct answer would be the
colon; however, an IBD expert might over-complicate their answer and include the ileum as well as the colon,
because they were thinking additionally about backwash ileitis. Remember to think of the question as pos-
sessing a simple and direct learning objective. During your preparation, certainly focus more time and effort
on your weak areas of knowledge, but remember to do a refresher on your strengths.
Do not waste time and effort trying to memorize normal ranges and units for lab test values. A list of such
values is provided to you for the exam.
Make a study schedule

Allow yourself enough time before the test to read material and do practice questions. Set aside a time each
week or a couple of times a week and then stick to that plan. Short and frequent periods of study are recom-
mended rather than intense cramming just before the exam. Keep track of your study schedule and your com-
or two before it is actually required. This does not -

tage. If you are not compliant with your study schedule, you can have a back up plan to delay the examination.
The major cause of situational test anxiety is under-preparation – do not “cram” for this test directly be-
Facts that you have
down cold may be forgotten if you are feeling nervous and ill prepared.
Cramming is not the same as refreshing your memory prior to an exam, though, so consider keeping
cards or electronic notes of material you wish to review just prior to taking the exam, e.g. How to calculate
the Serum-Ascites Albumin Gradient. This will help you learn more subject matter and review relevant facts
that you have previously studied.
Remember: Taking any examination poorly

prepared is never a good strategy.
Take practice tests

Practice tests are a great way to assess your knowledge. The following tips will help you get the most of this
assessment:
Analyze each question: What is the question asking?

Analyze the distractors: What are the subtle differences?
Analyze why you are getting a question right or wrong.
Ask yourself: Am I prepared in the content area?
Ask yourself: Do I understand what the question is asking?
Remember to practice pacing yourself, to complete the appropriate number of questions in the allotted
time.
Test Error Analysis

There is a strategy known as test error analysis. For each practice test, note your answers and make a nota-
tion whether you were sure of the answer, whether you made a guess between two answers or if you had no
inkling of the answer. If you are not doing well on the practice examinations, you should make yourself a grid
with the following components in order to analyze the reasons for your poor performance:
xv
List all Questions you Got List Topic of Did you? Regarding your studying: Your answer:
Wrong: Question:
Question # Esophagus 1. Know the answer 1. Material was not 1. Deliberate
Stomach/Duodenum 2. Predict the answer, studied 2. Misinterpreted
Liver i.e. make an 2. Material studied but 3. Impulsive
Biliary Tract intelligent guess learned incorrectly
Pancreas 3. Not know the 3. Material studied
Small intestine answer at all but could not recall
Colon information
General
Look for any patterns in the above grid. Which topics are you still weak in? Do you need to clarify informa-
tion? Review more? Read the questions more carefully? It will then be helpful to make adjustments in your
study approaches and/or test taking strategies.
Consider working in a group or with a partner

Teaching someone else is a good way to learn, so consider partnering with another individual and tutoring
each other. This divide-and-conquer type of approach is a good way to manage your study time and master
material through teaching. It may not be practical but with web-based conferencing and electronic modali-
ties it might be a good option to keep on track with your study schedule and have some fun. All group/part-
ner interactions will increase the learning/retention experience.
Taking the Actual Examination

The following tips will help you directly before the examination to put forth your best effort:
Review in advance what to expect the day of the exam by visiting the ABIM website: http://www.abim.
org/exam/exam-day.aspx
Certainly get a good night’s sleep just prior to the exam, but in general, it would be a good idea to attend
to good sleep hygiene for at least a week prior to the exam. You should be well rested, with neither too
little nor too much sleep. It is worthwhile to plan ahead and minimize your call and service obligations
the week prior to the exam.
Avoid alcohol in the week before the exam.
Do not abruptly change your usual caffeine intake the week before the exam.
While in general a “good breakfast” is often advocated to assist alertness and ward off fatigue, the morning
of the exam is not the right time to risk gastrointestinal distress with severe changes in your usual dietary
habits.
Get in the mind set: Don’t be mad that you have to take an exam; just be proud of your accomplishments
and go in with a positive attitude to conquer the test.
Logistics
Make sure you have the correct documentation to be allowed to sit for the exam.
Be clear about what you can or cannot have with you at the examination.
The examination takes a full day. Plan for breaks and snacks.
xvi Digestive Diseases Self-Education Program®
Familiarize yourself with the location of the restroom facilities, and the proper procedure for taking a break to use the
restroom at that testing facility.
Some test-takers prefer to stay in a local hotel rather than brave traffic on the morning of a high stakes examination.
Consider what is best for you.
Classifying Questions and Time Management

Test questions tend to fall in three categories:
The answer is readily known: your response is immediate and you can go on to the next question.
The content is familiar but it will take some time to sort out the answer.
The material is familiar; you just don’t know the answer and will need to make an intelligent guess.
By the time you take the test, it should be rare to have a question that is totally unfamiliar to you. It is im-
portant for you to manage your examination time wisely. Answer the questions in sequence. You should
provide an answer for every question as you proceed through the examination, but mark the questions that
you would like to return to, if you have the time. These might include questions that have familiar content
but will take a little longer to work through, or questions for which you simply don’t know the answer. In the
latter case, learn to guess intelligently by methodically using whatever knowledge you have to eliminate at
least some of the possible answer choices.
Choosing Answers
Read carefully. All questions are single best answer, so there is no opportunity to employ test taking logic
skills to eliminate combination answers. It is important to read all the answer options. Even though you
to be certain the answer you selected is the best one. Examination writers use subtle differences or nuances
when writing the incorrect or “distracting” answer choices.
Always read through the case description or “stem” of a question first
to simple recall information. Others like to think of each answer choice as a true/false statement and elimi-
nate answers. Regardless of the method you prefer, it is essential to carefully read all of the possible answer
choices before making your selection. There may be a subtle nuance or phrasing that would alter your choice.
Guessing
Make sure you pace yourself during the examination. You don’t want to move too slowly in the beginning and
have to rush at the end of your examination time. One common mistake is to spend too much time on a ques-
tion that is challenging. It can lead to rushing later during the examination, which in turn can lead to careless
errors. A better strategy is to mark down an answer for the challenging question, and make note to return to
it at the end of your test if there is time.
There are two reasons why a test taker may have unanswered questions. Either they have left an answer
blank because they don’t know the answer, or they run out of time and are unable to complete all the ques-
tions. The Gastroenterology Board examinations do not penalize for wrong answers. Since that is the case,
One recommendation suggests that the test taker pick a letter such as “b” or “d” and consistently use this let-
ter if you have absolutely no clue as to the answer. Education experts contest this strategy, pointing out that if
you are prepared for the test by mastering content, you should do your best to at least eliminate some of the
wrong choices. Whatever you do, focus on completing all questions. So make an educated guess—eliminate
xvii
all answer choices that you know are wrong and apply what you know to choose the best possible choice. It
If you have read about the subject and do not recognize one of the answers, it is very likely a distractor and the wrong
answer.
Caveat: Test item writers usually pick distractors that are subtly written and appear to be reasonable considerations. It is
important to read all the choices carefully.
Your test questions are created by content experts and experts in psychometrics who use statistical analysis and data-
driven processes. Don’t assume the test is flawed. That is unlikely. Consider the content carefully and don’t be concerned
about being “tricked.”
Pay attention to race, gender, geography, occupation and age in determining your answer. As an example, women have a
higher incidence of connective tissue disease than men.
Difficult Questions
Do not get caught up in trying to conquer a single question. Note your initial impression; there is a mechanism
for you to make notations on the examination via a Notes window. You will also be provided with an erasable
note board at the testing station so that you may record notes by hand. Mark an answer and proceed to the next
question. You can mark questions that you want to return to. There will be a button to mark for review but
If you are presented with a case scenario, approach it as you would your clinical patient. Identify the various
If the question has no sign of familiarity to it, narrow the choices and move on to the next one.
Additional Tips
Visual cues: It will probably be helpful to make notations using the electronic notes option or the erasable board that will
be provided. This will help you synthesize and recall information.
Pace yourself. You can determine how much time you have per question; in general you want to have 15 minutes at the end
to review your answers.
Material that may be controversial is sometimes on an examination, perhaps as an experimental question. Do not get
bogged down on these. Just mark an answer and move on.
Remember in your preparation that there is a substantial amount of hepatology on the examination.
As noted above, it is a good idea to read the reviews in major journals published over the 2 to 4 years preceding the
examinations. Since tests are designed a year or more in advance, information from a recent study published within the
past few weeks or even months will not be on the exam.
Statistics: Most examinations will expect you to be able to interpret a proposed study and to know sensitivity, specificity,
positive predictive value, and negative predictive value.
If you experience a lapse in memory, do not panic. It is a normal occurrence: just make your best guess and mark the
question to return to it later. Do not linger on a single question for a long period of time.
Always give an answer for a question, even the ones you do not know. Important point again: A blank answer is a WRONG
answer.
It is a good idea to use any extra time to check your work. Use the time to avoid careless errors.
Do not spend the last minutes of the exam changing answers. Your first “guess” is more likely to be correct. Make sure you
have a rationale for changing an answer.
Do not cram the night before. Long-term knowledge could be replaced by short-term memory (a phenomenon known as
retroactive inhibition).
Do not think about or check your answers during breaks. This could break your confidence!
Check the ABIM website for any new updates on the Board examination.
xviii Digestive Diseases Self-Education Program®
Preparing for and taking an examination should be a positive experience. This is a commitment to lifelong learning and
continuous quality improvement in your knowledge and practice, which can benefit you, any students or residents you
supervise, your peers, and your patients.
Finally, keep in mind that while it is very easy to get wrapped up in achieving a grade or completing a test, this
is really about assessing what you know in order to improve your skills as a clinician. It is good to achieve a
high score but it is more important to understand what you know, uncover what you don’t know, learn some-
We wish you great success!

Contents
Foreword ..................................................................................................................... iii

Acknowledgements ..................................................................................................... v
Contributing Educators .............................................................................................. vii
Program Guidelines .................................................................................................... xi
How to Prepare for the Gastroenterology Boards.................................................... xiii
Contents ....................................................................................................................xix
Disclosures ........................................................................................................... xxxvii
CHAPTER 1
Esophageal Disorders .................................................................................................. 1
Reza Shaker, MD, and Benson T. Massey, MD, FACP
Introduction ................................................................................................................................................................ 1
Gastroesophageal Reflux Disease ............................................................................................................................. 1
Pathophysiology of GERD .................................................................................................................................. 2
Epidemiology, Risk Factors, and Natural History ...................................................................................................... 4
GERD-Related Syndromes ................................................................................................................................. 5
Complications of GERD...................................................................................................................................... 5
Therapy for GERD .............................................................................................................................................. 8
Extraesophageal Syndromes ............................................................................................................................. 9
Eosinophilic Esophagitis .................................................................................................................................... 9
Other Intrinsic Structural Disorders of the Esophagus............................................................................................ 12
Congenital Esophageal Stenosis, Atresia, and Tracheoesophageal Fistula ................................................... 12
Inlet Patch (Gastric Heterotopia) ..................................................................................................................... 13
Esophageal Manifestations of Systemic Disorders ................................................................................................ 13
Diabetes........................................................................................................................................................... 13
Connective Tissue Disorders ........................................................................................................................... 13
Dermatologic Disorders ................................................................................................................................... 13
Infection ........................................................................................................................................................... 14
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Cardiovascular Disorders................................................................................................................................. 14
Accidental and Iatrogenic Esophageal Disorders ................................................................................................... 14
Esophageal Pill Injury, Caustic Ingestion, and Foreign Bodies........................................................................ 14
Medication and Radiation Effects ................................................................................................................... 15
Consequences of Instrumental and Surgical Procedures................................................................................ 15
Motor, Neoplastic, and Portal Hypertensive Disorders of the Esophagus .............................................................. 15
Approach to the Patient with Suspected Esophageal Disorders ............................................................................ 15
Diagnostic Strategies and Options for Testing .............................................................................................. 17
Illustrative Clinical Case .......................................................................................................................................... 20
Pearls and Pitfalls for the Board Exam .................................................................................................................... 21
Most Efficient Source Reviews for Examination Preparation ................................................................................. 21
References ............................................................................................................................................................... 21
CHAPTER 2
Acid Diseases of the Stomach .................................................................................. 29
Steven F. Moss, MD, AGAF, and Adam D. Harris, MD
Review of Gastric Acid Secretory Physiology ......................................................................................................... 29
Parietal Cell Stimulation and Inhibition .......................................................................................................... 31
Physiology of Gastric Acid Secretion .............................................................................................................. 32
Mucosal Defense Factors (Bicarbonate and Mucus Secretion, Blood Flow, Prostaglandins) 32
Pepsinogen Secretion ...................................................................................................................................... 33
Vitamin B12 Physiology ..................................................................................................................................... 33
Peptic Ulcer Disease ................................................................................................................................................ 34
Patient Presentation ........................................................................................................................................ 35
Evaluation and Management of Patients with Dyspepsia ............................................................................. 36
H. pylori–Induced Peptic Ulcer Disease ........................................................................................................ 36
Nonsteroidal Anti-Inflammatory Drug–Induced Injury .................................................................................... 41
Stress-Induced Ulcer Disease ......................................................................................................................... 44
Gastric Bypass and Peptic Ulcer Disease........................................................................................................ 44
Other Causes of Peptic Ulcer Disease............................................................................................................. 44
Acid Hypersecretory States ............................................................................................................................. 45
Zollinger-Ellison Syndrome .............................................................................................................................. 45
Other Diseases Associated with Gastric Acid Hypersecretion ....................................................................... 48
Nonulcer Dyspepsia ................................................................................................................................................. 48
References ............................................................................................................................................................... 50
CHAPTER 3
Gastrointestinal Motility ........................................................................................... 53
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Seth Sweetser, MD and Karthik Ravi, MD

Neuroenteric Control of Gastrointestinal Motor Function ...................................................................................... 53
Esophageal Motility ................................................................................................................................................. 54
Specialized Anatomy of the Esophagus and Its Sphincters ............................................................................ 54
Innervation of the Esophagus .......................................................................................................................... 55
Motor Physiology of the Esophagus and Its Sphincters.................................................................................. 55
Esophageal Motility Disorders and Chest Pain ....................................................................................................... 56
Cricopharyngeal Dysfunction ................................................................................................................................... 58
Achalasia ................................................................................................................................................................. 60
Pathophysiology............................................................................................................................................... 60
Clinical Manifestations ................................................................................................................................... 60
Other Esophageal Motility Disorders ...................................................................................................................... 65
Gastric and Small Intestinal Motility ...................................................................................................................... 66
Normal Gastric and Small Intestinal Motility ................................................................................................. 66
Gastric Emptying.............................................................................................................................................. 66
Small Intestinal Motility .................................................................................................................................. 68
Gastric Motility Disorders ............................................................................................................................... 68
Investigation of Patients with Suspected Chronic Intestinal Pseudo-Obstruction ......................................... 74
Colonic Motility ....................................................................................................................................................... 75
Normal Colonic Motility .................................................................................................................................. 75
Acute Colonic Pseudo-Obstruction (Ogilvie’s Syndrome) ................................................................................ 77
Irritable Bowel Syndrome ................................................................................................................................ 77
Slow Transit Constipation and Colonic Inertia ................................................................................................ 79
Anorectal Motility............................................................................................................................................ 79
Defecation and Continence ............................................................................................................................. 80
Obstructed Defecation..................................................................................................................................... 81
Fecal Incontinence ........................................................................................................................................... 81
Hirschsprung’s Disease ................................................................................................................................... 81
Multiple Endocrine Neoplasia IIB.................................................................................................................... 82
References ............................................................................................................................................................... 83
CHAPTER 4
Diarrhea and Constipation ........................................................................................ 87
Lawrence R. Schiller, MD
Definition of Diarrhea .............................................................................................................................................. 87
Pathophysiology of Diarrhea ................................................................................................................................... 87
Infections ......................................................................................................................................................... 88
Reduction of Mucosal Surface Area ............................................................................................................... 90
Absence of an Ion Transport Mechanism........................................................................................................ 90
Inflammation .................................................................................................................................................... 90
Dysregulation................................................................................................................................................... 91
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Circulating Secretagogues .............................................................................................................................. 91

Clinical Classification of Diarrhea ................................................................................................................... 91
Evaluation of the Patient with Diarrhea .................................................................................................................. 91
History.............................................................................................................................................................. 91
Physical Examination ....................................................................................................................................... 92
Further Evaluation of Acute Diarrhea .............................................................................................................. 94
Further Evaluation of Chronic Diarrhea ........................................................................................................... 95
Evaluation of Chronic Watery Diarrhea........................................................................................................... 99
Evaluation of Chronic Inflammatory Diarrhea ............................................................................................... 102
Evaluation of Chronic Fatty Diarrhea............................................................................................................. 102
Treatment of Diarrhea............................................................................................................................................ 103
Empirical Therapy of Acute Diarrhea ............................................................................................................ 104
Empirical Therapy of Chronic Diarrhea.......................................................................................................... 104
Definition of Constipation ...................................................................................................................................... 105
Pathophysiology of Constipation ........................................................................................................................... 105
Evaluation of Constipation .................................................................................................................................... 106
Treatment ............................................................................................................................................................... 108
Diet and Lifestyle........................................................................................................................................... 108
Habit and Biofeedback Training .................................................................................................................... 110
Laxatives ........................................................................................................................................................ 110
Chloride Secretagogues ................................................................................................................................ 110
Systemic Agents ............................................................................................................................................ 110
Surgery........................................................................................................................................................... 111
Pearls and Pitfalls for the Board Exam .................................................................................................................. 112
Most Efficient Source Reviews for Examination Preparation ............................................................................... 113
References ............................................................................................................................................................. 113
CHAPTER 5
Inflammatory Bowel Disease .................................................................................. 115
Caroline Kerner, MD, MSCE and Gary R. Lichtenstein, MD, AGAF
Intestinal Immunology ........................................................................................................................................... 115
Intestinal Mucosal Immune Elements ........................................................................................................... 117
Antigen Presentation in the Intestine ........................................................................................................... 119
Oral Immunization and Tolerance .................................................................................................................. 119
Overview ................................................................................................................................................................ 120
Definitions...................................................................................................................................................... 120
Epidemiology ................................................................................................................................................. 120
Genetics ......................................................................................................................................................... 120
Intestinal Microbiome ................................................................................................................................... 122
Disease Modifiers.......................................................................................................................................... 123
Mucosal Inflammatory Mechanisms ............................................................................................................. 124
Differential Diagnosis.................................................................................................................................... 124
Features of Ulcerative Colitis ................................................................................................................................ 126
Pathologic Features ....................................................................................................................................... 126
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Endoscopic Features ...................................................................................................................................... 127

Radiologic Features ....................................................................................................................................... 128
Clinical Features ............................................................................................................................................ 129
Features of Crohn’s Disease .................................................................................................................................. 130
Pathologic Features ....................................................................................................................................... 130
Endoscopic Features ...................................................................................................................................... 131
Radiologic Features ....................................................................................................................................... 131
Extraintestinal Manifestations of Inflammatory Bowel Disease .......................................................................... 133
Dermatologic Manifestations........................................................................................................................ 133
Ocular Manifestations ................................................................................................................................... 133
Musculoskeletal Manifestations................................................................................................................... 133
Other Extraintestinal Manifestations ............................................................................................................ 135
Complications of IBD ............................................................................................................................................. 135
Decreased Bone Mineral Density.................................................................................................................. 135
Nephrolithiasis .............................................................................................................................................. 135
Other Genitourinary Complications ............................................................................................................... 135
Cholecystolithiasis......................................................................................................................................... 136
Amyloidosis ................................................................................................................................................... 136
Anemia........................................................................................................................................................... 136
Pregnancy and IBD......................................................................................................................................... 136
Colorectal Cancer in IBD................................................................................................................................ 137
Medical Therapy .................................................................................................................................................... 139
Aminosalicylates ........................................................................................................................................... 139
Mesalamine and Sulfasalazine Side Effects................................................................................................. 143
Corticosteroids............................................................................................................................................... 143
Immune-Modifier Drugs................................................................................................................................. 144
Biologic Agents.............................................................................................................................................. 146
Antibiotics...................................................................................................................................................... 147
Probiotics ....................................................................................................................................................... 147
Nicotine ......................................................................................................................................................... 148
Nutritional Therapy........................................................................................................................................ 148
Surgery........................................................................................................................................................... 148
References ............................................................................................................................................................. 150
CHAPTER 6
Small Bowel Disease .............................................................................................. 159
Rupa Mukherjee, MD, and Daniel A. Leffler, MD, MS
Introduction ............................................................................................................................................................ 159
Celiac Disease ....................................................................................................................................................... 159
Introduction.................................................................................................................................................... 159
Epidemiology ................................................................................................................................................. 159
Genetics ......................................................................................................................................................... 160
Pathogenesis ................................................................................................................................................. 160
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Clinical Categories......................................................................................................................................... 160

Clinical Manifestations ................................................................................................................................. 161
Diagnosis ....................................................................................................................................................... 161
Treatment ....................................................................................................................................................... 163
Medication-Induced Enteropathy .................................................................................................................. 164
Autoimmune Enteropathy (AIE) ............................................................................................................................. 165
Introduction.................................................................................................................................................... 165
Epidemiology ................................................................................................................................................. 165
Pathogenesis ................................................................................................................................................. 165
Clinical ........................................................................................................................................................... 166
Diagnosis ....................................................................................................................................................... 166
Treatment ...................................................................................................................................................... 166
Collagenous Sprue ................................................................................................................................................. 167
Introduction.................................................................................................................................................... 167
Epidemiology ................................................................................................................................................. 167
Pathogenesis ................................................................................................................................................. 167
Clinical ........................................................................................................................................................... 168
Diagnosis ....................................................................................................................................................... 168
Treatment ....................................................................................................................................................... 168
Tropical Sprue ........................................................................................................................................................ 169
Introduction.................................................................................................................................................... 169
Epidemiology ................................................................................................................................................. 169
Pathogenesis ................................................................................................................................................. 169
Clinical ........................................................................................................................................................... 169
Diagnosis ....................................................................................................................................................... 170
Treatment ...................................................................................................................................................... 170
Whipple’s Disease ................................................................................................................................................. 170
Introduction.................................................................................................................................................... 170
Epidemiology ................................................................................................................................................. 170
Pathogenesis ................................................................................................................................................. 171
Clinical ........................................................................................................................................................... 171
Diagnosis ...................................................................................................................................................... 171
Treatment ....................................................................................................................................................... 172
Small Intestinal Bacterial Overgrowth (SIBO)....................................................................................................... 173
Introduction.................................................................................................................................................... 173
Clinical ........................................................................................................................................................... 173
Diagnosis ....................................................................................................................................................... 173
Treatment ....................................................................................................................................................... 173
Infiltrative Diseases ............................................................................................................................................... 174
Eosinophilic Enteritis ............................................................................................................................................. 174
Introduction.................................................................................................................................................... 174
Epidemiology ................................................................................................................................................. 174
Pathogenesis ................................................................................................................................................. 174
Clinical .......................................................................................................................................................... 174
Diagnosis ....................................................................................................................................................... 174
Treatment ....................................................................................................................................................... 175
Mastocytosis ......................................................................................................................................................... 175
Introduction.................................................................................................................................................... 175
Epidemiology ................................................................................................................................................. 175
Pathogenesis ................................................................................................................................................. 176
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Clinical ........................................................................................................................................................... 176

Diagnosis ....................................................................................................................................................... 176
Treatment ....................................................................................................................................................... 177
Amyloidosis ........................................................................................................................................................... 177
Introduction.................................................................................................................................................... 177
Epidemiology ................................................................................................................................................. 177
Pathogenesis ................................................................................................................................................. 177
Clinical ........................................................................................................................................................... 178
Diagnosis ....................................................................................................................................................... 178
Treatment ....................................................................................................................................................... 179
Lymphangiectasia .................................................................................................................................................. 179
Introduction.................................................................................................................................................... 179
Epidemiology ................................................................................................................................................. 180
Pathogenesis ................................................................................................................................................. 180
Clinical ........................................................................................................................................................... 180
Diagnosis ....................................................................................................................................................... 180
Treatment ....................................................................................................................................................... 180
Radiation Enteritis ................................................................................................................................................. 181
Introduction.................................................................................................................................................... 181
Pathogenesis ................................................................................................................................................. 181
Clinical ........................................................................................................................................................... 181
Diagnosis ....................................................................................................................................................... 182
Treatment ....................................................................................................................................................... 182
Gastrointestinal Vasculitis..................................................................................................................................... 182
Introduction.................................................................................................................................................... 182
Specific Disorders .......................................................................................................................................... 182
Ischemic Disorders of the Small Intestine ............................................................................................................ 184
Introduction.................................................................................................................................................... 184
Pathogenesis of Ischemic Injury 165 ................................................................................................................................................................................................. 184
Acute Mesenteric Ischemia (AMI)................................................................................................................. 184
Clinical ........................................................................................................................................................... 184
Diagnosis ....................................................................................................................................................... 184
Treatment ....................................................................................................................................................... 185
Chronic Mesenteric Ischemia (CMI) ...................................................................................................................... 185
Clinical ........................................................................................................................................................... 185
Diagnosis ....................................................................................................................................................... 185
Treatment ....................................................................................................................................................... 185
Small Bowel Transplant................................................................................................................................. 186
References ............................................................................................................................................................. 188
CHAPTER 7
Gastrointestinal Infections of the Small Intestine and Colon................................. 195
Christina M. Surawicz, MD
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Introduction ............................................................................................................................................................ 195

Pathophysiology ..................................................................................................................................................... 195
Clinical Presentation .............................................................................................................................................. 196
Specific Infections – Small Intestinal Pathogens.................................................................................................. 196
Specific Infections – Ileocolonic Pathogens .......................................................................................................... 201
Special Syndromes ................................................................................................................................................ 207
Food Poisoning............................................................................................................................................... 207
Traveler’s Diarrhea ......................................................................................................................................... 207
Infections and IBD ......................................................................................................................................... 208
Evaluation of Acute Diarrhea ................................................................................................................................ 208
Therapy of Acute Diarrhea .................................................................................................................................... 209
Infectious Causes of Persistent or Chronic Diarrhea ............................................................................................ 210
Diarrhea Due to Non-GI Infections ................................................................................................................ 210
References ............................................................................................................................................................. 212
CHAPTER 8
Gastrointestinal Bleeding ........................................................................................ 215
Thomas O.G. Kovacs, MD, and Dennis M. Jensen, MD
UGI Bleed Etiology ............................................................................................................................................... 216
Risk Factors ............................................................................................................................................................ 216
Presentation ........................................................................................................................................................... 217
Initial Resuscitation and Medical Management ................................................................................................... 217
Medical Therapy .................................................................................................................................................... 218
Endoscopic Stigmata of Ulcer Hemorrhage .......................................................................................................... 220
Endoscopic Therapy .............................................................................................................................................. 223
Injection Treatment........................................................................................................................................ 223
Electrocoagulation ......................................................................................................................................... 224
Heater Probe .................................................................................................................................................. 225
Endoclips........................................................................................................................................................ 225
Combination Therapy ............................................................................................................................................. 226
Recommendations for endoscopic therapy based on stigmata of hemorrhage ........................................... 227
Second Look Endoscopy ................................................................................................................................ 228
Re-treatment.................................................................................................................................................. 229
Complications of endoscopic hemostasis ..................................................................................................... 229
Surgical Therapy .................................................................................................................................................... 229
Angiographic Therapy ............................................................................................................................................ 230
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Follow-Up Medical Management .......................................................................................................................... 231

Summary For UGI Bleeding............................................................................................................................ 231
Severe Hematochezia (AKA Lower Gastrointestinal Bleeding) ............................................................................ 232
Introduction And Epidemiology ..................................................................................................................... 232
General Measures And Diagnosis................................................................................................................. 238
Colonoscopy................................................................................................................................................... 239
Scintigraphy ................................................................................................................................................... 240
Angiography, Magnetic Resonance Imaging (Mri), Computed Tomography (Ct) and Barium X-Rays 240
Small Bowel Evaluation................................................................................................................................. 241
Emergency Surgery ........................................................................................................................................ 241
Summary For LGI Bleeding ............................................................................................................................ 241
Pearls and Pitfalls for the Board Exam: ................................................................................................................. 241
References ............................................................................................................................................................. 242
CHAPTER 9
Gastrointestinal Cancers ......................................................................................... 245
Barbara H. Jung, MD
Cancer of the Esophagus ....................................................................................................................................... 245
Epidemiology ................................................................................................................................................. 245
Etiology/Pathogenesis ................................................................................................................................... 246
Symptoms/Clinical Signs............................................................................................................................... 246
Diagnosis ....................................................................................................................................................... 246
Staging........................................................................................................................................................... 246
Treatment ....................................................................................................................................................... 247
Prognosis ....................................................................................................................................................... 247
Screening, Surveillance, Prevention.............................................................................................................. 247
Cancer of the Stomach .......................................................................................................................................... 248
Epidemiology ................................................................................................................................................. 248
Diagnosis ....................................................................................................................................................... 249
Histological Classification/Molecular Genetics ............................................................................................ 249
Treatment ....................................................................................................................................................... 249
Prognosis ....................................................................................................................................................... 250
Lymphoma of the Stomach ............................................................................................................................ 250
Cancer of the Small Intestine ................................................................................................................................ 250
Epidemiology ................................................................................................................................................. 250
Diagnosis ....................................................................................................................................................... 251
Treatment ....................................................................................................................................................... 251
Prognosis ....................................................................................................................................................... 251
Carcinoid Tumors of the Small Intestine ....................................................................................................... 251
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Pancreatic Cancer .................................................................................................................................................. 251

Epidemiology ................................................................................................................................................. 251
Diagnosis ....................................................................................................................................................... 252
Treatment ....................................................................................................................................................... 253
Prognosis ....................................................................................................................................................... 253
Cancer of the Gallbladder and Bile Ducts ............................................................................................................. 255
Epidemiology ................................................................................................................................................. 255
Diagnosis ....................................................................................................................................................... 256
Histological Classification ............................................................................................................................. 256
Treatment ....................................................................................................................................................... 256
Prognosis ....................................................................................................................................................... 257
Ampullary Cancer .......................................................................................................................................... 257
Hepatocellular Cancer ........................................................................................................................................... 257
Epidemiology ................................................................................................................................................. 257
Diagnosis ....................................................................................................................................................... 258
Treatment ....................................................................................................................................................... 259
Prognosis ....................................................................................................................................................... 259
Colorectal Cancer .................................................................................................................................................. 260
Epidemiology ................................................................................................................................................. 260
Diagnosis ....................................................................................................................................................... 263
Treatment ....................................................................................................................................................... 264
Prognosis ....................................................................................................................................................... 265
Follow-Up....................................................................................................................................................... 265
Hereditary Colorectal Cancer Syndromes ................................................................................................... 267
Most Efficient Source Review for Examination Preparation ................................................................................. 272
References ............................................................................................................................................................. 272
CHAPTER 10
Pancreatic Physiology and Disease ......................................................................... 275
Fred S. Gorelick, MD and Anil B. Nagar, MD
Introduction ............................................................................................................................................................ 275
Normal Pancreatic Function .................................................................................................................................. 276
Pancreatic Organization................................................................................................................................. 276
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Secretion of Water and Electrolytes ..................................................................................................................... 277

Secretion of Protein ....................................................................................................................................... 279
Regulation of Pancreatic Secretion ............................................................................................................... 282
Endocrine Hormones Secreted by the Pancreas ........................................................................................... 284
Acute Pancreatitis ................................................................................................................................................. 284
Pathophysiology............................................................................................................................................. 285
Pathogenesis and Etiological Factors............................................................................................................ 286
Pathology ....................................................................................................................................................... 290
Diagnosis ....................................................................................................................................................... 291
Estimating Severity........................................................................................................................................ 293
Management ................................................................................................................................................. 294
Management after Recovery ......................................................................................................................... 300
Chronic Pancreatitis ............................................................................................................................................... 300
Pathogenesis and Etiologic Factors............................................................................................................... 301
Pathology ....................................................................................................................................................... 303
Diagnosis ....................................................................................................................................................... 303
Management ................................................................................................................................................. 307
Pancreatic Neoplasms ........................................................................................................................................... 310
Risk Factors.................................................................................................................................................... 311
Morphologic and Genetic Features ............................................................................................................... 311
Diagnosis ....................................................................................................................................................... 311
Treatment ....................................................................................................................................................... 312
Uncommon Pancreatic Tumors ...................................................................................................................... 313
Cystic Neoplasms of the Pancreas ................................................................................................................ 314
Pancreatic Endocrine Tumors ........................................................................................................................ 315
Most Efficient Source Review For Exam Preparation............................................................................................ 317
References ............................................................................................................................................................. 318
CHAPTER 11
Diseases of the Biliary Tract.................................................................................... 321
Rahul Kuver, MD
Biliary System Anatomy and Physiology ............................................................................................................... 321
Biliary Tract Embryology ................................................................................................................................ 321
Biliary Tract Anatomy .................................................................................................................................... 321
Gallbladder Motility....................................................................................................................................... 322
Sphincter of Oddi Function ............................................................................................................................ 322
Hepatic Cholesterol Metabolism................................................................................................................... 322
Bile Acid Synthesis ........................................................................................................................................ 323
Bile Secretion ................................................................................................................................................ 324
Enterohepatic Circulation .............................................................................................................................. 325
Gallstones .............................................................................................................................................................. 325
Cholesterol Gallstone Pathogenesis ............................................................................................................. 326
Risk Factors for Gallstones ............................................................................................................................ 327
Clinical Course and Complications ................................................................................................................ 329
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Biliary Colic .................................................................................................................................................... 329

Diagnostic Studies......................................................................................................................................... 332
Treatment for Gallstone-Related Disorders .................................................................................................. 335
Optimal Management.................................................................................................................................... 336
Rare Complications of Gallstones ................................................................................................................. 337
Primary Intrahepatic Stones (Recurrent Pyogenic Cholangitis)..................................................................... 338
Salmonella typhi, Gallstones, and the Gallbladder....................................................................................... 338
Acalculous Disorders of the Biliary Tract .............................................................................................................. 339
Sphincter of Oddi Dysfunction....................................................................................................................... 339
Gallbladder Dysmotility ................................................................................................................................. 339
Acute Acalculous Cholecystitis ..................................................................................................................... 340
Gallbladder Polyps ......................................................................................................................................... 340
Biliary Cysts ................................................................................................................................................... 340
Biliary Ductopenic Disorders ......................................................................................................................... 343
HIV Cholangiopathy ....................................................................................................................................... 344
Neoplastic Disorders of the Biliary Tract............................................................................................................... 344
Gallbladder Carcinoma .................................................................................................................................. 344
Cholangiocarcinoma ...................................................................................................................................... 345
Ampullary Carcinoma .................................................................................................................................... 345
References ............................................................................................................................................................. 347
CHAPTER 12
Viral Hepatitis .......................................................................................................... 353
Steve S. Choi, MD, and Carl L. Berg, MD
Introduction ............................................................................................................................................................ 353
Natural History of Viral Hepatitis .......................................................................................................................... 353
Acute Viral Hepatitis ..................................................................................................................................... 353
Chronic Viral Hepatitis................................................................................................................................... 355
Extrahepatic Manifestations of Viral Hepatitis..................................................................................................... 356
Hepatocellular Carcinoma and Viral Hepatitis ...................................................................................................... 357
Hepatitis A ............................................................................................................................................................. 358
Epidemiology ................................................................................................................................................. 358
Clinical Course ............................................................................................................................................... 359
Hepatitis B ............................................................................................................................................................. 359
Hepatitis B Serology ...................................................................................................................................... 361
Epidemiology ................................................................................................................................................. 361
Clinical Course ............................................................................................................................................... 362
Variant Forms of HBV .................................................................................................................................... 364
Hepatitis C ............................................................................................................................................................. 365
Epidemiology ................................................................................................................................................. 366
Clinical Course ............................................................................................................................................... 366
Hepatitis D ............................................................................................................................................................. 368
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Epidemiology ................................................................................................................................................. 368

Clinical Course ............................................................................................................................................... 368
Hepatitis E ............................................................................................................................................................. 369
Epidemiology ................................................................................................................................................. 370
Clinical Course ............................................................................................................................................... 370
Prophylaxis against Viral Hepatitis ....................................................................................................................... 371
Passive Prophylaxis ....................................................................................................................................... 371
Active Prophylaxis ......................................................................................................................................... 371
Treatment ............................................................................................................................................................... 372
Treatment of Acute Infection......................................................................................................................... 372
Treatment of Chronic Infection ...................................................................................................................... 373
References ............................................................................................................................................................. 386
CHAPTER 13
Cirrhosis and Liver Transplantation ......................................................................... 389
Guadalupe Garcia-Tsao, MD
Introduction ............................................................................................................................................................ 389
Portal Hypertensive Hemorrhage .......................................................................................................................... 391
Prevention of First Variceal Bleeding ............................................................................................................ 393
Management of Acute Variceal Bleeding ..................................................................................................... 395
Prevention of Recurrent Variceal Hemorrhage .............................................................................................. 398
Treatment of Portal Hypertensive Gastropathy and Gastric Antral Vascular Ectasia ........................................... 398
Ascites ................................................................................................................................................................... 398
Spontaneous Bacterial Peritonitis........................................................................................................................400
Hepatorenal Syndrome .......................................................................................................................................... 402
Hepatic Encephalopathy ........................................................................................................................................ 404
Hepatopulmonary Syndrome ................................................................................................................................. 405
Portopulmonary Hypertension ............................................................................................................................... 405
Hepatocellular Carcinoma ..................................................................................................................................... 405
Liver Transplantation ............................................................................................................................................. 407
Indications ..................................................................................................................................................... 407
Contraindications........................................................................................................................................... 409
Selection ........................................................................................................................................................ 409
Complications ................................................................................................................................................ 410
References ............................................................................................................................................................. 414
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CHAPTER 14
Metabolic, Hereditary, Inflammatory and Vascular Diseases of the Liver.............. 417
Douglas M. Heuman, MD, FACP, AGAF, FACG
Hepatic Disorders Associated with Steatosis....................................................................................................... 417
Alcohol induced liver disease 2, 3....................................................................................................................................................................................................... 418
Nonalcoholic fatty liver disease (NAFLD)17 ........................................................................................................... 421
Epidemiology and pathogenesis:................................................................................................................... 421
Clinical features and diagnosis ..................................................................................................................... 422
Treatment and prognosis: .............................................................................................................................. 423
Microvesicular steatosis syndromes ............................................................................................................. 423
Hereditary hyperbilirubinemias ..................................................................................................................... 424
Hereditary cholestatic disorders .................................................................................................................. 425
Storage diseases affecting the liver ............................................................................................................. 425
Hereditary hemochromatosis43, 44...................................................................................................................................................................................................... 426
Treatment and prognosis ............................................................................................................................... 428
Wilson’s Disease52, 53 ...................................................................................................................................................................................................................................... 429
Alpha-1-Antitrypsin Deficiency57 ....................................................................................................................................................................................................... 432
Epidemiology and pathogenesis.................................................................................................................... 432
Inflammatory Liver Diseases ................................................................................................................................. 433
Primary biliary cirrhosis59........................................................................................................................................................................................................................... 433
Epidemiology and pathogenesis.................................................................................................................... 433
Autoimmune hepatitis67 .............................................................................................................................................................................................................................. 435
Epidemiology and pathogenesis. .................................................................................................................. 435
Primary sclerosing cholangitis76......................................................................................................................................................................................................... 436
IgG4 Related Disease77 ................................................................................................................................................................................................................................ 436
Hepatic sarcoidosis79 ..................................................................................................................................................................................................................................... 436
Liver allograft rejection ................................................................................................................................. 437
Graft versus host disease .............................................................................................................................. 437
Hepatic vascular diseases86, 87 ........................................................................................................................................................................................................................... 437
Diseases of liver perfusion ............................................................................................................................ 437
Disorders of hepatic venous outflow............................................................................................................. 439
References ............................................................................................................................................................. 441
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CHAPTER 15
Digestive Health and Disease In Women ............................................................... 445
Sex Differences in Gastrointestinal Physiology ................................................................................................... 445
Functional Disorders .............................................................................................................................................. 447
GERD ............................................................................................................................................................ 447
Functional Disorders .............................................................................................................................................. 448
Dyspepsia ...................................................................................................................................................... 449
Irritable Bowel Syndrome ............................................................................................................................. 449
Constipation and Pelvic Floor Dysfunction ................................................................................................... 453
Fecal Incontinence ......................................................................................................................................... 457
Chronic Pelvic Pain and Endometriosis ......................................................................................................... 461
Inflammatory Bowel Disease (IBD) ........................................................................................................................ 462
Liver Diseases and Gallstones ..................................................................................................................... 465
Pregnancy and Hepatobiliary Diseases ................................................................................................................ 470
Coincident Liver Disease During Pregnancy ................................................................................................. 470
Liver Diseases Likely Related to Pregnancy ................................................................................................. 472
Liver Diseases Unique to Pregnancy ............................................................................................................. 473
Colon Cancer Screening in Women ....................................................................................................................... 475
Abuse and GI Disorders ......................................................................................................................................... 477
Summary ................................................................................................................................................................ 478
References ............................................................................................................................................................. 480
CHAPTER 16
Nutrition, Obesity and Eating Disorders ................................................................. 487
Jeanette Keith, MD
Basic Nutritional Requirements ............................................................................................................................ 487
Macronutrients .............................................................................................................................................. 487
Micronutrients ............................................................................................................................................... 488
Nutritional Assessment ......................................................................................................................................... 489
Mechanisms of Malnutrition in Gastrointestinal Disease .................................................................................... 492
Nutritional Support ................................................................................................................................................ 492
Enteral Nutrition ............................................................................................................................................ 493
Parenteral Nutrition ....................................................................................................................................... 494
Specific Disorders .................................................................................................................................................. 496
Protein-Losing Gastroenteropathy................................................................................................................. 498
Food Allergies ................................................................................................................................................ 499
Nutrition and Inflammatory Bowel Disease (IBD) ......................................................................................... 500
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Obesity ................................................................................................................................................................... 501

Definition and Risk Stratification................................................................................................................... 502
Pathogenesis ................................................................................................................................................. 502
Treatment ....................................................................................................................................................... 504
Eating Disorders .................................................................................................................................................... 505
Anorexia Nervosa .......................................................................................................................................... 506
Bulimia Nervosa ............................................................................................................................................ 507
Eating Disorders Not Otherwise Specified.................................................................................................... 508
Editor’s pick ................................................................................................................................................... 509
References: ............................................................................................................................................................ 510
CHAPTER 17
Issues in Pediatric Gastroenterology ...................................................................... 513
Joel R. Rosh, MD, AGAF
Introduction ............................................................................................................................................................ 513
Recurrent Abdominal Pain of Childhood ............................................................................................................... 513
Investigation .................................................................................................................................................. 514
Treatment ....................................................................................................................................................... 515
Functional Defecation Disorders ........................................................................................................................... 515
Functional Constipation and Encopresis ....................................................................................................... 515
Functional Nonretentive Fecal Soiling .......................................................................................................... 516
Evaluation of Disorders of Defecation .......................................................................................................... 516
Treatment of Constipation and Encopresis ................................................................................................... 517
Hirschsprung’s Disease.......................................................................................................................................... 518
Clinical Presentation...................................................................................................................................... 518
Diagnosis ....................................................................................................................................................... 519
Treatment and Follow-Up .............................................................................................................................. 519
Gastroesophageal Reflux Disease ......................................................................................................................... 520
Diagnostic Evaluation .................................................................................................................................... 521
Treatment ....................................................................................................................................................... 522
Acute Diarrhea ....................................................................................................................................................... 523
Management ................................................................................................................................................. 526
Food Allergy ........................................................................................................................................................... 527
Epidemiology in Industrialized Countries ...................................................................................................... 527
Clinical Presentation...................................................................................................................................... 527
Management of Food Allergy ........................................................................................................................ 528
Chronic Diarrhea .................................................................................................................................................... 529
Cow’s Milk Protein Allergy ............................................................................................................................ 529
Chronic Nonspecific Diarrhea ........................................................................................................................ 529
Protracted Post-infectious Diarrhea .............................................................................................................. 530
Celiac Disease ............................................................................................................................................... 530
xxxv
Cystic Fibrosis ................................................................................................................................................ 531

Giardiasis ....................................................................................................................................................... 532
Small Bowel Bacterial Overgrowth ............................................................................................................... 532
Inflammatory Bowel Disease ................................................................................................................................. 532
Hepatobiliary Disease in Infants and Young Children........................................................................................... 535
Evaluation and Management ........................................................................................................................ 536
Most Efficient Source Reviews for Board Preparation.......................................................................................... 538
References ............................................................................................................................................................. 539
xxxvi Digestive Diseases Self-Education Program®
Disclosures
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CHAPTER 1
Esophageal Disorders
Reza Shaker, MD, and Benson T. Massey, MD, FACP
Learning Objectives
AFTER COMPLETING THIS CHAPTER, THE LEARNER SHOULD BE ABLE TO:
1. Recognize the typical and atypical presentations of esophageal disorders.
2. Review the pathophysiology of gastroesophageal reflux disease (GERD).
3. List the risk factors associated with GERD.
4. Identify the typical endoscopic and pathologic findings of eosinophilic esophagitis.
5. Know the differential diagnosis for esophageal eosinophilia.
6. Know the treatment options for eosinophilic esophagitis.
7. Review the advantages and limitations of the different diagnostic tests available to diagnose esophageal disorders.
8. Learn the natural history of esophageal disorders as patients move from pediatric to adult care, and the differences in childhood and adult
presentations.
9. Know the appropriate use and limitations of proton pump inhibitors in treating different patient groups.
Introduction
The list of symptoms that strongly suggest the presence of an esophageal disorder is relatively small (Table
variety of symptoms or signs that (1) are infrequent, atypical manifestations of esophageal disorders, (2)
are more commonly seen with nonesophageal disorders, (3) represent extraesophageal complications of the
underlying esophageal disorder, or (4) have an inconsistent or unproven relationship to esophageal disor-
ders (Table 1.2). Symptoms may arise from disorders intrinsic to the esophagus or conditions that affect the
esophagus secondarily.
Gastroesophageal Reflux Disease
and those diagnosed with GERD. This overlap and the fact that otherwise healthy individuals may occasion-
or complications.”1
1
2 Digestive Diseases Self-Education Program®
Table 1.1
pressure in the abdomen to the lower intraluminal
Cardinal Symptoms of Esophageal Disorders
pressure of the thoracic esophagus. TLESRs may be
accompanied by relaxation or contraction of the up-
Heartburn per esophageal sphincter (UES).7–9 Relaxation of the
Bland or sour regurgitation
Chest pain
Dysphagia (solid/liquid/mixed)
Odynophagia will block orad movement of esophageal contents
Eructation/hiccup into the upper aerodigestive tract.
TLESRs require an intact vagal innervation. Neu-
rotransmission between the afferent and efferent
Table 1.2 limbs of the TLESR response are mediated or mod-
Atypical Symptoms of Esophageal Disorders ulated by nitric oxide as well as cholecystokinin A,
gamma-aminobutyric acid B, and metabotropic glu-
Dyspepsia (epigastric burning/fullness)
tamate receptors.10–13 TLESRs are triggered by disten-
Nausea with or without vomiting
sion of the stomach; are more common in the awake,
Hematemesis
postprandial state; and are reduced in frequency
Globus
during recumbency and deep sleep.2,14,15 TLESRs are
Coughing
a normal physiologic process that facilitates the vent-
Throat clearing
ing of swallowed air from the upper digestive tract.
Throat pain
Throat burning
of this process.
Hoarseness
TLESRs occur with similar frequency in healthy
Wheezing/stridor
subjects and patients with GERD.16 Where patients
Dyspnea
with GERD differ from healthy subjects is in the na-
Apnea
Movement disorder (Sandifer syndrome)
Halitosis
Sleep disturbance
ate into the esophageal lumen.16,17 While TLESRs are
Anorexia/weight loss/failure to thrive
Sudden infant death
GERD, those who have lost tonic function of the LES
or developed abnormalities in the normal valvular
Pathophysiology of GERD anatomy of the gastroesophageal junction exhibit
additional processes for displacement of gastric
The most common mechanism by which gastric con-
contents into the esophageal lumen, including con-
esophageal sphincter relaxation (TLESR). TLESRs 3,17–20
are characterized by brief (<1 minute) inhibition of

Pediatric patients show similar mechanisms for re-
the tone of the lower esophageal sphincter (LES), 21,22
Hiatal hernia is a risk factor for the presence
cessation of the phasic respiratory contractions of
of erosive esophagitis in both adult and pediatric pa-
the diaphragmatic crura, and reduction in the con-
tients with GERD.23–26
tractility of the circular muscle of the esophageal
Conditions that increase the pressure differen-
body.2–4 In addition, contraction of the esophageal
tial between the abdominal and thoracic cavities or
longitudinal muscle during a TLESR can be strong
cause retention of gastric contents will promote re-
enough to pull the gastroesophageal junction into the
thoracic cavity.5,6 These actions allow movement of
inal pressures,27 have greater TLESR responses to
gastric contents from a region of higher intraluminal
Chapter 1 — Esophageal Disorders 3
gastric distension following a meal,28 more acid rein heartburn,34 and the healing of esophagitis by
29
and more proton pump inhibitors (PPIs) is associated with
30
.
Conversely, in patients with lung disease, such as cys-
events.39 Exposure to bile acids and pancreatic
. Some patients with
31
enzymes induces esophageal mucosal injury in
GERD have delayed emptying of the proximal stom- animal models,40 and the duration of esophageal
ach.32 Consumption of high-fat meals, which empty
more slowly from the stomach, are associated with is higher in patients with erosive esophagitis and
GERD.33 Barrett’s esophagus.41 Patients with GERD overall do
not have abnormal levels of gastric acid secretion.
duration and distribution of esophageal exposure to However, patients with acid hypersecretory states
such as Zollenger-Ellison Syndrome are at risk to
esophagus is more likely to be symptomatic,34 and 42
migration past the UES into the pharynx predisposes Patients infected with Helicobacter pylori
the patient to oral and upper airway injury from the
esophagitis, Barrett’s esophagus, and esophageal
recording during ambulatory pH monitoring adenocarcinoma, an effect that may in part be
correlates with the severity of esophagitis,35 and mediated through gastric mucosal atrophy and the
associated reduction in acid secretion that result from
long-standing infection.43 Men without HP infection
times than those without these complications.36 The actually show increasing gastric acid secretion
duration of acid exposure depends on the interplay with age.44 While the presence of HP infection is
between the factors previously discussed that associated with an improved response to therapy for
GERD,45,46 eradication of HP does not seem to induce
47
clearance of acid depends on intact motor function or increase the dose of acid suppression therapy
is cleared by primary or secondary peristalsis. esophagitis.48

Patients with severe peptic esophagitis have a high Recent evidence suggests that the development
incidence of esophageal peristaltic dysfunction.37 of esophageal mucosal lesions in response to the
Restoration of the normal intraluminal esophageal
pH also requires neutralization of acid retained in direct chemical injury to the mucosa. Animal studies
the esophageal mucous layer by the bicarbonate indicate the initial response is induction of an
in swallowed saliva.38 Esophageal acid exposure to
the point of inducing heartburn stimulates saliva 49
and the recruitment of
production (water brash). Conditions that impair 50
Injury to the esophageal
mucosa results in dilated intracellular spaces and
increased mucosal permeability51. These changes in
awakenings often leads to prolonged episodes of mucosal permeability are associated with reductions
acid exposure because swallowing and salivation are in esophageal intraluminal and mucosal electrical
inhibited following return to sleep. impedance.52-54
The development of symptoms such as
severity of symptoms and esophageal mucosal heartburn or chest pain requires activation of
esophageal nociceptors, with transmission of
intraluminal esophageal pH are more likely to result afferent pain signals via spinal afferent pathways to
brainstem and higher cortical centers. The receptive

mucosal lesions persist over 1 year, even if symptoms
overlap among different thoracic dermatomes. This resolve.69 A substantial fraction of children diagnosed
symptoms. Moreover, spinal afferent neurons can esophagitis into adolescence and early adulthood.70
receive input from multiple thoracic structures, The estimates on prevalence of GERD among
adults vary among studies, depending on the
between esophageal and, for example, cardiac criteria for ascertaining the diagnosis. Studies on
sources for pain. Esophageal pain pathways may the prevalence of typical symptoms as an indi-rect
develop both peripheral and central sensitization, marker for the presence of GERD indicate that about
wherein prior exposure to noxious stimuli lowers half of adults report such symptoms at some time,
the threshold for subsequent noxious stimuli to 71-73
initiate symptoms, as well as induce hyperalgesia Findings from population-based endoscopic

and allodynia in adjacent structures.55 Thus a major screening studies indicate a lower prevalence of
esophagitis (12–16%) of whom about one-third
induces symptoms is the cumulative acid exposure 72,73
GERD is present
during preceding time periods.34 around the globe and the pre-valence appears to be
increasing over time.74 While symptoms of GERD are
symptoms is lowered by acute auditory stress,56 and seen frequently in both genders and ethnic groups,
the burden of chronic life stress events is a major
in women and blacks.75-79 The prevalence of GERD
over longer time periods.57 Sleep deprivation lowers symptoms and complicated disease tends to increase
the threshold for esophageal acid exposure to cause with age.78,80-82
symptoms;58 this effect is likely compounded by
the fact that GERD has a great effect on the quality factors associated with the presence of GERD (Table
of sleep.59,60 On the other hand, loss of normal 1.3). Obesity and presence of a hiatal hernia are the
nociceptive pathways may predispose the esophagus
to injury. Patients with Barrett’s esophagus have symptoms and esophagitis in studies throughout
been shown to have reduced sensitivity to acid the world. Both the presence of infection with HP
infusion61 and esophageal distension,62 and have and the subsequent development of chronic atrophic
63
gastritis have been associated with a reduced risk for
Table 1.3
Epidemiology, Risk Factors, and Risk Factors Associated with GERD
Natural History
GERD is the most commonly diagnosed Obesity
gastrointestinal disorder, accounting for nearly Hiatal hernia
9 million outpatient visits annually in the United Smoking
States64. GERD occurs among all age cohorts, from Nonsteroidal anti-inflammatory drugs (NSAIDs)
Chronic atrophic gastritis/Helicobacter pylori infection
as regurgitation occur in the majority of healthy (inverse association)
infants, with the prevalence of such symptoms Aging
Irritable bowel syndrome
of life.65,66 GERD symptoms are present in <10% Anxiety/depression
of young children and adolescents.67,68 However, Family history of GERD
Complications of GERD
has the most consistently positive association with
Esophagitis and ulceration
other dietary components show either inconsistent
GERD-related mucosal erosions typically have their
or no such associations.83 Among medications,
base on the squamocolumnar junction and extend
are associated with GERD symptoms, ulceration, and

extend to involve nearly the entire esophageal mucosa.
stricturing.84-87 The rate of co-occurrence of GERD and
irritable bowel syndrome in the community is more
has been demonstrated to have good intra- and
than would be expected by chance.88 Both anxiety
interobserver agreement (Table 1.4). Validity of
and depression are risk factors for the presence of
GERD symptoms.89 Family and twin studies have
association of higher grades with more esophageal
indicated a familial risk for GERD.90-92 The interplay
between common environmental and genetic risks
frequent complete healing of esophagitis on therapy,
is not currently completely understood, although
and greater frequency of symptom relapse after a
a recent genome-wide screening of patients with
course of therapy.35
GERD implicates mutations involving the regulation
Esophageal ulcers are more severe mucosal
of the gene for type III collagen in the development of
breaks, completely through the esophageal mucosa.
hiatal hernia in men and GERD in both sexes.93
The major complication from peptic esophagitis is
Longitudinal studies of patients with GERD
in clinical care show that many either acquire or
endoscopic evaluation for upper gastrointestinal
94
hemorrhage are found to have erosive esophagitis.98
Overall, the incidence of new GERD symptoms
In certain patient groups, such as the elderly and
exceeds the rate of loss, resulting in a net increase
those with developmental abnormalities and/or
in GERD prevalence of 30% over 11 years in one
study.95 Follow-up endoscopy in patients with GERD
the most common cause for upper gastrointestinal
with initially normal mucosa shows a low (1-5%)
hemorrhage.99,100
likelihood for interval development of Barrett’s 101,102
esophagus, whereas patients with esophagitis at

initial endoscopy have up to a 5-fold higher risk to
develop Barrett’s esophagus.94,96,97 Table 1.4
Los Angeles Classification for Erosive Esophagitis
GERD-Related Syndromes
One (or more) mucosal break, ≤5 mm long, that
Grade
does not extend between the tops of two muco-
(Figure 1.1) incorporates research showing that for A
sal folds
many patients the manifestations are symptomatic One (or more) mucosal break, >5 mm long, that
only, without evidence for overt damage to the Grade
does not extend between the tops of two muco-
esophagus or extraesophageal structures. It B
sal folds
also takes into account those patients who have
One (or more) mucosal break that is continuous
complications of GERD without manifesting typical Grade
between the tops of two or more mucosal folds,
GERD symptoms. Finally, it acknowledges the C
but that involves <75% of the circumference
potential for extraesophageal complications of GERD,
based on the strength of evidence for association and Grade
One (or more) mucosal break that involves at
causality. D
least 75% of the esophageal circumference
Figure 1.1
Montreal Classification of Syndromes Resulting from GERD
1. 1. 1. 1.
2.
2. 2. 2. 3.
3.
3.
4. 4.
4.
From Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-
based consensus. Am J Gastroenterol 2006; 101(8):1900–20.
Strictures determines the degree of reported dysphagia.103

Peptic strictures may be ringlike or involve longer Additional symptoms associated with strictures are
segments of the esophagus with diffuse narrowing. hiccups and retching.
Peptic strictures usually have a distal location near
Barrett’s esophagus
the squamocolumnar junction and are commonly
Barrett’s esophagus is the term used for the
accompanied by other mucosal changes from peptic
replacement of the normal squamous epithelium
injury, such as erosions, ulcerations, and Barrett’s
lining the esophagus with a columnar epithelium
mucosa. For strictures separated by more than a
characterized by intestinal metaplasia containing
few cm from the squamocolumnar junction and
goblet cells. The presence of Barrett’s esophagus is
intervening normal mucosa, other etiologies for
suspected when the squamocolumnar junction is
the stricture must be considered, including pill
displaced proximal to the anatomic gastroesophageal
injury, neoplasia, and eosinophilic esophagitis.
junction. The suspected diagnosis requires pathologic
The diameter of the narrowest part of the stricture
determines the risk for dysphagia, and nearly all
appearing mucosa. Barrett’s mucosa may range in
patients having strictures < 12 mm in diameter
length from the appearance of an irregular z-line to
nearly complete replacement of the entire squamous
of esophagitis accompanying the stricture also
mucosa in the esophageal body. The Prague C & M
criteria for assessing the extent of the esophageal above the esophagus are not normally exposed
lumen involvement by Barrett’s epithelium have
shown good interobserver agreement (Figure 1.2).104 available for acid neutralization and clearance.
Barrett’s esophagus can be seen at any age, Even brief episodes of relatively minor exposure
but becomes more prevalent with increasing age.
Endoscopic screening studies of adult populations and symptomatic consequences. Extraesophageal
have suggested an overall prevalence of 1–2%, with symptoms are present in about a third of patients
with GERD.106
typical GERD symptoms.72, 105 The risk factors
associated with Barrett’s esophagus are similar to individual patient’s extraesophageal symptoms and
those for uncomplicated GERD, but severe erosive
esophagitis is an additional risk factor, as are male
sex, white race, and heavy alcohol (not wine) of co-occurrence of the two conditions by unclear
consumption. As in patients with erosive esophagitis, mechanisms. Second, the patient’s symptoms and
hiatal hernia, reduced LES pressure, and esophageal
peristaltic dysfunction are commonly present and unrecognized disorder. For example, chronic cough
contribute to the excess esophageal acid exposure.
disease, bronchiectasis, allergic laryngitis, or sinus
also common in patients with Barrett’s esophagus. disease. Third, initial descriptions of the association
The major clinical concern for patients with Barrett’s of severe extraesophageal manifestations with
esophagus is their greater risk for developing
adenocarcinoma of the esophagus. Screening and replicated with milder forms of these conditions.
surveillance for adenocarcinoma are covered in For example, the initial descriptions of severe
Chapter 9, Gastrointestinal Cancers. ulcerative laryngitis and tracheal stenosis were
Extraesophageal manifestations disease, and brought to clinical awareness the
the esophagus, either through the direct exposure of However, attempts to ascribe less severe laryngeal
by poor intra- and inter-observer agreement on
implicated are listed in Table 1.5. Structures located 107

Furthermore, the majority
Figure 1.2
no evidence for esophagitis or hiatal hernia. Finally,
Prague Classification of Barrett’s Esophagus
Table 1.5
Extraesophageal Manifestations
and Associations of GERD
Asthma
Aspiration pneumonitis/pulmonary fibrosis
Laryngitis/vocal cord lesions
Laryngeal cancer
Chronic cough
Dental erosions
Sinusitis
Otitis media
seen in normal subjects,108 as can the laryngoscopic respond equally well to PPI therapy.112 Many NERD
109
The natural patients can use short-course therapy for symptom
history of laryngeal symptoms in patients with GERD recurrence, rather than continuous daily PPI therapy.
is that these tend to resolve with time, in a course The current concerns for long-term PPI therapy
include increased risk for hip fractures, infections
disease or treatment for same.110 such as
clopidogrel therapy; none of these concerns to date
has been substantiated in a prospective, placebo-
Therapy for GERD controlled trial.
For patients who have intolerance to or
Lifestyle modifications contraindications for PPI therapy, the histamine2-
receptor antagonists and sucralfate have some
of such triggers as large meals, eating shortly before
sleeping, and consuming foods and beverages that
predictably cause symptoms. Patients with night- is not recommended as a primary or adjunct therapy
time symptoms should elevate the head of the bed.
Patients should be cautioned regarding the hazards anti-secretory therapies is greater for symptoms
of obesity, smoking, and use of nonsteroidal drugs, of heartburn than for regurgitation,113 and many
and encouraged to modify these risk factors. While patients with GERD continue to report incomplete
the currently available evidence to support these symptom control on PPI therapy.114
suggested lifestyle changes is weak, their lack of ex-
Surgery
reasonable interventions. However, these will be
similar to PPI therapy in long-term follow-up.115 For
inadequate by themselves for most patients with
surgery, a somewhat higher improvement in primary
GERD.
GERD symptoms is offset by more symptoms of
Medical Therapy dysphagia and gas-bloat116. About half of patients
The mainstay for medical treatment of GERD in undergoing surgery require surgical revision or
medical therapy over time. This, plus the risk of
(PPI) therapy.111 Most patients with GERD respond postoperative complications and the small risk of
adequately to a single daily PPI dose, taken before the operative mortality, indicate that surgery should
be reserved for those patients whose GERD-related
daily before meals when needed, the vast majority symptoms and complications cannot be controlled
adequately by medical therapy. For patients
their symptoms will resolve on PPI therapy. There is with morbid obesity complications warranting
no evidence to support more frequent dosing. The bariatric surgery, Roux-en-Y gastric bypass can
different available PPI agents are similar in their
117
However,
vertical-banded gastroplasty is associated with
for any particular patient is increasingly driven a high rate of postoperative GERD. A variety of
by formulary decisions of the patient’s insurance endoscopically delivered approaches to create an
plan. Maintenance therapy at the dose needed
for healing has the highest chance of maintaining
remission, but patients may be titrated down to the currently recommended.
lowest daily dose that permits control of symptoms.
Extraesophageal Syndromes in patients with Barrett’s esophagus. Techniques

for endoscopic mucosal ablation are not currently
Placebo-controlled trials of acid suppressive therapy
recommended for Barrett’s mucosa without high-
grade dysplasia. Chemoprevention with agents such
118
or in the treat-
as COX-2 inhibitors is not recommended solely to
treat Barrett’s esophagus. Surveillance of Barrett’s
if abnormal esophageal acid exposure is present.119
esophagus and treatment of associated high-grade
dysplasia and adenocarcinoma are reviewed in
for extra-esophageal symptoms in the patient with-
Chapter 9 on Gastrointestinal Cancers. Smoking
out concomitant heartburn and excessive (>12%)
cessation should be recommended to all patients
esophageal acid exposure.120 When therapy controls
with known Barrett’s esophagus.
the cardinal symptoms of GERD, but atypical symp-
toms persist, the patient should be investigated for
the presence of other disorders that could cause the
Eosinophilic Esophagitis
latter.
Eosinophilic esophagitis (EoE) is a clinicopathologic
Peptic stricture disease characterized by symptoms resulting from
Dilation of peptic strictures improves symptoms esophageal dysfunction accompanied by pathologic
-
subtle, asymptomatic strictures that are found -
incidentally. If dysphagia is the dominant symptom sensus, in untreated patients the accepted density of
and the stricture diameter is < 12 mm diameter, then 123
initial treatment with dilation will produce immediate Other conditions can cause esophageal eosinophilia,
and these need to be excluded (see Table 1.6) before
strictures, the option exists for an initial trial of PPI a diagnosis of primary EoE can be established. The
therapy. Control of GERD with PPI therapy reduces entity of proton pump inhibitor-responsive esopha-
the need for repeat stricture dilation;121 this therapy
this diagnostic scheme. This entity may represent
diagnosed strictures, if there is concern about the
peptic etiology, obtaining mucosal biopsy specimens that responds to further reduction of normal levels
is prudent; (re)biopsy should also be considered
if a presumed peptic stricture fails to respond to effects of PPI therapy), or co-occurrence of GERD
intervention. Patients with strictures should be
cautioned to avoid medications with a high risk for Table 1.6
esophageal injury, such as bisphosphonates. Conditions Associated with Esophageal Eosinophilia
Barrett’s esophagus GERD

Therapy in patients with Barrett’s esophagus is EoE
to control the symptoms of GERD, since neither Eosinophilic gastritis/gastroenteritis/enteritis
medical nor surgical treatment results in clinically Celiac disease
meaningful regression of Barrett’s mucosa. The Inflammatory bowel disease
current consensus recommendation is to control Drug reactions
symptoms, not normalize esophageal acid exposure. Hypereosinophilic syndrome
Ongoing PPI therapy may inhibit the development of Infections
dysplasia in Barrett’s esophagus.122 However, neither Autoimmune disorders
medical nor surgical treatment of GERD has yet been Esophageal motor disorders
shown to reduce the incidence of adenocarcinoma Graft-versus-host disease
Figure 1.3 and EoE, where treatment of GERD secondarily improves

Endoscopic Findings in Eosinophilic Esophagitis the EoE.
Pathophysiology
concordance for the disease among family members.124 Ge-
thymic stromal lymphopoetin ( ), involved in TH2 cell de-

termination, is a susceptibility locus for EoE, as is a variant in
the receptor gene (located on the X-chromosome) for
male patients.125
with atopic dermatitis) is more prevalent In EoE.126 Variants
in the gene appear to determine response to topical
steroid therapy.127 The esophageal mucosa in EoE shows
over-expression of eotaxin-3128 and upregulation of interleu-
kin-13.129 The majority of pediatric and adult patients exhibit
allergic responses to food and/or aeroallergens,130 and most
patients have other atopic disorders. Taken together, these
in the genetic control of the immune response to antigenic
Epidemiology and Natural History

Epidemiologic studies suggest a population based
prevalence of < 1 per 1000, while among unselected
adult patients undergoing clinical endoscopic evaluation
esophageal eosinophilia may be found in up to 6.5%.131
Studies of pathology databases suggest a true increase
in the incidence and prevalence of EoE over the past few
decades.132,133 In adults, the diagnosis is less frequently
made in winter months. EoE is more prevalent in male and
non-Hispanic white patients.134 EoE occurs in all age groups.
Clinical Presentation and Evaluation

The most common clinical presentation is solid food dys-
phagia, and EoE has become the most common diagnosis in
young patients presenting with food impactions. Pediatric
patients are more likely to present with recurrent vomiting
or food intolerance, but other esophageal symptoms, such
as heartburn and chest pain, may be seen in all age groups.
Pediatric patients may fall off the normal growth curve.
No constellation of symptoms is pathognomonic for EoE.
A. Food impaction B. Corrugated appearance and mucosal white spots. C. Corrugations Most patients will have a history of other atopic (asthma,
and longitudinal creases D. “Felinization” from muscularis mucosae contraction.
eczema, allergic rhinitis, food allergy) conditions.
The characteristic endoscopic features (Figure 1.3) of Table 1.7

EoE are listed in Table 1.7, but it is important to recognize that Endoscopic Findings in Eosinophilic Esophagitis
some patients may have a normal endoscopic appearance.135
Corrugated mucosa
esophageal mucosal biopsy specimens is required to make Longitudinal mucosal furrows
the diagnosis (Figure 1.4) By current consensus, eosinophil Mucosal white spots/plaques
counts of Focal rings and strictures
the diagnosis.123,136 Diagnostic eosinophil counts may not Diffusely small-caliber esophageal lumen
be present during seasons with low levels of aeroallergins Fragile (“crepe paper”) mucosa
in some patients.137 Biopsies obtained when patients are
treated can produce false negative results. Additional
Figure 1.4
Photomicrographs of the Pathologic Changes Seen in Eosino-
philic Esophagitis
layering of eosinophils, extracellular eosinophile granules,
can be seen throughout the esophagus, but are often patchy

in distribution, requiring multiple biopsies from different
levels of the esophagus for adequate diagnostic sensitivity.
An allergist should evaluate EoE patients with comor-
bid atopic illnesses or history of food allergies. However,
routine allergy testing for food and aeroallergens is not oth-
erwise recommended.
Therapy for EoE
setting and allows diagnosis of the underlying condition.138

Dilation of rings and strictures is safe and effective therapy
for improving dysphagia, but the need for repeat dilations
with time is common.139 The mucosa in untreated EoE
can tear easily, and dilation can produce deep rents into
the mucosa the cause chest pain and odynophagia severe
enough to require brief hospitalization for pain control and
hydration. If care is taken to avoid excessive dilation in any
one treatment session, risk of perforation is < 1%.123 The
passage of single large-caliber (54–60 French) bougies to
treat a seemingly isolated distal ring in EoE can be hazardous
because endoscopically unrecognized stenoses may coexist
proximally; dilation with graduated balloon catheters may
be safer in this instance. Dilation therapy does not alter the
140
Top: Basal cell hyperplasia and elongation of the connective tissue
Unless there is a dominant stricture that is likely driving papillae are present. Bottom: The stratified squamous epithelium
of the esophagus has numerous (>15/HPF) eosinophils between
dysphagic symptoms, the current trend in EoE management
epithelial cells (arrows). Also noted is basal cell hyperplasia
is to defer dilation until the response to dietary and/or (bracket). (Courtesy of Richard Komorowski, MD, Medical College
medical therapy is known (See Table 1.8). PPI therapy is of Wisconsin.)
Table 1.8
Medical and Dietary Therapies for Eosinophilic Esophagitis
Modality Comments
Proton Pump Inhibitor Consider as initial treatment to exclude PPI-REE. Use to treat coexistent
20-40 mg qd to bid GERD.
Systemic corticosteroids For severe symptoms; 4 week course, then taper off.
2 mg/kg/d (60 mg/d maximum) Requires other therapy for maintenance.
Fluticasone 880-1760 mcg/d Better esophageal coating with viscous liquid formulations. Resolution of
Budesonide 1-2 mg/d eosinophilia > symptom improvement. Risk for candida esophagitis
Most effective therapy in pediatric population. Expensive.
Elemental diet
Poorly tolerated (most require feeding tube).
Six food elimination diet (wheat, milk, eggs, Consultation with dietician to assure appropriate elimination/nutritional bal-
soy, peanuts/tree nuts, fish/shellfish). ance. May be able to re-introduce some foods.
Targeted elimination diet based on allergy Current testing poorly predicts response in adults.
test findings Lower response than elemental diet in children. Added cost of testing.
suspected EoE because 1) this may uncover a case of pathologic changes and symptoms,153 and the effect of
PPI-REE141 and 2) this can address concomitant GERD therapy on the long-term need for stricture dilation
in patients with EoE. Topical corticosteroid therapy, frequency is unclear. Comorbid atopic conditions,
such as allergic rhinitis and asthma, should also be
treated.154
proliferative responses and inconsistently improve
symptoms in both pediatric and adult patients.142-6
Chronic therapy carries some risk of (typically Other Intrinsic Structural
mild or asymptomatic) esophageal candidiasis.
Montelukast at high doses may improve symptoms, Disorders of the Esophagus
but without resolution of the mucosal eosinophilic
147
Cromolyn sodium has not been shown to
Congenital Esophageal Stenosis, Atresia,
and Tracheoesophageal Fistula
antibody mepolizumab was shown to reduce tissue Abnormal embryonic development arising in
the esophageal and tracheal anlagen can result
resolution.148 in incomplete separation of the esophagus from
Elemental and elimination diets to reduce the trachea and incomplete development of the
esophagus. The resulting defects range in severity
children,149,150 while a six food elimination diet has from esophageal stenosis to tracheoesophageal
been shown to improve symptoms and resolve
151
In this last
study and in a pediatric study, the results of food
152
vomiting, cough productive of feedings, and
allergy (skin prick) testing have not been shown pneumonia. Patients with more subtle stenoses
to be reliable in predicting the causative foods on may not present with dysphagic symptoms until
rechallenge. adulthood. The defects can often be bridged using
Cessation of therapy for EoE results in relapse of a gastric tube reconstruction, but with the obligate
absence of a lower esophageal sphincter and normal Connective Tissue Disorders

esophageal motility, these patients are at high risk
In patients with progressive systemic sclerosis or
for subsequent complications of GERD.155
mixed connective tissue disease, the reduction in
LES pressure and peristaltic function from atrophy
of the smooth muscle predisposes these patients
Inlet Patch (Gastric Heterotopia)
About 1–5% of individuals have an inlet patch of gastric emptying that is also frequently present.
columnar mucosa located at or below the distal aspect
of the UES. Whether the origins are congenital or
Patients with Sjögren’s (sicca) syndrome have
and Barrett’s esophagus are common associated
of the lubricating properties of saliva also causes
some larger patches appear capable of secreting dysphagia for solids. Patients with connective tissue
acid and may be complicated by symptoms of globus disorders are at risk for iatrogenic complications
and dysphagia. Complications include esophageal from immunosuppression (infectious esophagitis)
strictures, ulcers, and rare neoplastic degeneration.
and bisphosphonates for arthritis and osteoporosis).
Esophageal Manifestations of
Dermatologic Disorders
Systemic Disorders
Many systemic conditions can affect the esophagus Due to its squamous epithelium, the esophagus
secondarily. In some cases, esophageal complications is subject to several systemic diseases typically
affecting the skin (Table 1.9). These immune-
the most problematic manifestation for some patients. mediated disorders can manifest on endoscopy as
blisters, a positive Nikolsky’s sign, erosions, plaques,
ulcers, and strictures. Nikolsky’s sign is present
Diabetes when gentle friction on the epidermal surface results
in exfoliation, followed by blister formation over
Several factors predispose diabetic patients to develop minutes; the sign is associated with pemphigus
GERD and its complications. The majority of patients vulgaris, but is absent in bullous pemphigoid. The
with type 2 diabetes are obese. Hyperglycemia presence of skin and oral lesions usually provides
increases the rate of TLESR response to gastric clues to the diagnosis, although esophageal
distension in healthy subjects,156 and diabetic involvement is rarely the presenting manifestation.
patients with higher glycosylated hemoglobin
values are more likely report GERD symptoms.157,158
Many patients with diabetes have delayed gastric
diabetes may also be less sensitive to the presence Table 1.9

159
and thus may not Primary Dermatologic Disorders Affecting the Esophagus
come to clinical attention until they develop more

Epidermolysis bullosa
Bullous phemphigoid
with diabetic ketoacidosis and upper gastrointestinal
Pemphigus vulgaris
hemorrhage.160 Diabetes is a risk factor for developing
Stevens-Johnson syndrome
esophagitis.
Lichen planus
Infection Accidental and Iatrogenic

The major clinical infections of the esophagus are
Esophageal Disorders
, herpes, and cytomegalovirus. The most
common symptom of infectious esophagitis is Esophageal Pill Injury, Caustic Ingestion,
odynophagia. Risk factors for all infections include
and Foreign Bodies
profound suppression of the immune system, as can
Well over 100 medications have been reported to
syndrome or in patients on immunosuppressive cause pill-induced esophageal injury.166-168 The most
therapy for transplants. Poorly controlled HIV common agents in clinical practice are listed in Table
infection itself can be associated with large ulcers 1.10. Doxycycline is notorious for causing severe
that are negative for other infectious agents. odynophagia, but this symptom is seen with many
Additional risk factors for fungal infections include other agents, as well as symptoms of heartburn,
diabetes, recent antibiotic exposure, and swallowed chest pain, and dysphagia. Injury can range from
topical corticosteroid therapy.161 Fungal infections erosions to deep ulcers to perforation, and the initial
usually have an endoscopic appearance of a whitish lesion may evolve into a refractory stricture. A clue
exudate (“cottage cheese”), while viral infections to the etiology of these lesions is their common
typically cause esophageal ulceration. locations above the level of the lower esophageal
sphincter and above the aortic arch, unlike lesions
from GERD, which are usually based on or just above
Cardiovascular Disorders the squamocolumnar junction. A common history
preceding such injury is that the patient swallowed
The major clinical issue regarding cardiovascular
the pill dry and/or while recumbent. Risk factors
disorders and the esophagus is the need to avoid
for pill injury are old age and sustained release
ascribing symptoms from cardiac disease to the
preparations.
esophagus. While GERD may cause chest pain in
Extremely acid (pH <2) or alkaline (pH >12)
patients with known coronary artery disease,162 the
solutions can cause severe esophageal injury. A full
obverse is also true. Patients with coronary artery
thickness injury may result in perforation acutely
disease may present with vague chest symptoms
and chronic stricture formation, requiring repeated
ascribed to heartburn, or atypical gastrointestinal
courses of dilation. Some patients will require
symptoms such as nausea or eructation, and
esophageal replacement. Early endoscopy (within 24
there is some evidence in population studies that
hours) is safe and warranted to assess the severity of
misdiagnosis of myocardial infarction as GERD is an
injury in patients who have symptoms after reported
important problem.163 Complicating matters further
ingestion. A lack of oral lesions does not exclude
is that fact that GERD is a common comorbidity
severe injury more distally in the esophagus.
in patients with coronary artery disease,164 and
esophageal acid exposure can reduce coronary blood
165 Table 1.10
Congenital or acquired abnormalities of the Common Medications for Pill-Induced Esophageal Injury
cardiovascular system can obstruct the esophagus
via extrinsic compression (dysphagia lusoria). Aspirin and other nonsteroidal anti-inflammatory drugs
Dissection of the thoracic aortic may cause acute (NSAIDs)
esophageal necrosis. Rupture of an aortic aneurysm Bisphosphonates
into the esophagus is usually a fatal event, presenting Potassium chloride
as massive hematemesis. Doxycycline/tetracycline
Ascorbic acid
Ferrous sulfate
Inadvertent or intentional ingestion of recognized at the time of endoscopy. Perforation is

sharp or pointed foreign bodies, such as bones, the dreaded complication of stricture dilation; the
pins, and razor blades, places the patient at risk time-honored dictum is to pass no more than three
for esophageal laceration or perforation, with successively larger dilators, once resistance to dilator
passage is present, in any one session. Treatments
into the cardiovascular system. Retained button to eradicate abnormal mucosa and vessels in the
batteries can produce a deep tissue injury. Retained esophagus may produce strictures.
esophageal foreign bodies constitute an endoscopic Immediate iatrogenic injuries from esophageal
emergency. surgery include mucosal tears, frank perforations,
intramural hematomas, ischemic necrosis, and
anastomotic strictures and leaks. Patients undergoing
Medication and Radiation Effects
symptoms from overly tight or long wraps, slipped
Medications that inhibit smooth-muscle tone or
wraps, or development of a paraesophageal hernia.
contractility can theoretically place patients at
About half of patients following a myotomy for
Patients undergoing radiofrequency ablation cardiac

channel blockers, theophylline, and beta-agonists,
arrhythmias are at risk to develop thermal injury to
the latter two being used frequently in asthmatics,
the adjacent esophagus. Such lesions are not always
who commonly have coexisting GERD. Agents with
symptomatic, but the concern is for the rare develop-
anticholinergic properties can also decrease salivary
-
secretion, resulting in impaired neutralization of
lowing such transmural esophageal injury.
Ionizing radiation has both early and delayed
response may cause dysphagia and odynophagia Motor, Neoplastic, and Portal
severe enough to require alternate means of Hypertensive Disorders of the
alimentation. More severe injury can lead to
extensive transmural necrosis, with hemorrhage and Esophagus
perforation. Later effects tend to be from stenosis, These topics are covered in separate chapters. The
which may extend to complete luminal occlusion. clinician must remain aware that these can coexist
Concurrent chemotherapy increases the risk of injury with other esophageal disorders. For example,
for any given course of radiation therapy. Patients patients with esophageal achalasia may suffer
with radiation-induced xerostomia have a higher from pill injury,
frequency of abnormal esophageal acid exposure (following surgical myotomy), or esophageal cancer.
169 Patients with GERD and Barrett’s esophagus may
develop adenocarcinoma of the esophagus. Patients
may develop esophageal strictures from efforts to
Consequences of Instrumental and eradicate varices. Patients with motor disorders can
Surgical Procedures develop Zenker’s and other pulsion diverticula.
Passage of instrumentation into the esophageal

lumen carries a small risk of abrasion, laceration,
hematoma, or frank perforation of the esophagus.
Approach to the Patient with
This risk becomes much greater in the presence of Suspected Esophageal Disorders
structural disorders, such as rings and strictures, The patient history remains the cornerstone of
particularly since subtle strictures may not be easily evaluation when esophageal disorders are suspected,
Figure 1.5
Flow Charts for the Evaluation of the Patient with Symptoms Suggesting the Presence of an Esophageal Disorder.
5A
INITIAL DIAGNOSTIC APPROACH FOR SUSPECTED ESOPHAGEAL DISORDER
Heartburn/ Chest Pain Atypical/Alarm

Regurgitation Syndrome Symptoms
PPI + GERD CAD?

+ EGD +/- +
DX DX
trial biopsy
- - -
EGD +/- + PPI
+ PPI +
DX GERD GERD
biopsy trial trial
- - -
EGD +/- +
DX
biopsy
5B
APPROACH AFTER PPI TRIAL & EGD ARE NEGATIVE
Functional
disorder
Solid dysphagia - Esophageal - Ambulatory reflux - Non-esophageal
only manometry testing off therapy disorder
Prior testing
+ + +
- falsely negative
Esophagram
DX DX
with solid bolus
DX
5a shows the initial approach, depending on the nature of the presenting symptoms. 5b shows the additional work-up to perform if the patient
fails to respond to a PPI trial and/or EGD testing is nondiagnostic. DX, diagnosis made; CAD, coronary artery disease; PPI, proton pump inhibitor
therapy; EGD, upper endoscopy.
with emphasis on the presence, severity, time course, dysphagia should include random biopsies from
and associations of cardinal and atypical symptoms. the proximal and distal esophagus (if no other
History-taking should also address the presence of explanation for dysphagia is seen), to identify
conditions that secondarily affect the esophagus, otherwise unsuspected EoE. Early endoscopy should
as should the physical examination (which is also be performed in patients with additional alarm
typically normal for primary esophageal disorders). symptoms, such as weight loss, failure to thrive,
Additional testing is usually necessary to obtain an repetitive vomiting, or hematemesis. Patients with a
accurate diagnosis of esophageal disorders, with combination of cardinal and atypical symptoms are
also candidates for early endoscopy, which can help
determine whether any explanatory esophageal
in conjunction with knowledge regarding the disorder is present and may detect another source
background prevalence and clinical associations of for the atypical symptoms.
the different esophageal disorders. Careful consideration has to be given to the
patient presenting only with chest discomfort
atypical for GERD. The concern is that the patient
Diagnostic Strategies and has undiagnosed coronary artery disease (CAD).
Options for Testing CAD and GERD share many of the same risk factors
and commonly occur together. Such patients warrant
Rational and cost-effective testing and treatment in
rigorous evaluation to exclude a cardiac source
of pain before evaluation of possible esophageal
that the most prevalent esophageal disorder by far
sources. For patients with these atypical coronary
is GERD. Even patients presenting with atypical
syndromes, resting EKG and routine exercise stress
symptoms are more likely to have GERD than another
testing alone may not be adequately sensitive.
esophageal disorder. This high prior probability of
Following a negative cardiac evaluation for
GERD drives the diagnostic algorithm outlined in
patients with only chest pain, and a negative
Figure 1.5.
endoscopy in patients with other cardinal
For patients presenting only with the classical
esophageal symptoms, the next reasonable step is
symptoms of heartburn (typically postprandial
a diagnostic/therapeutic trial of PPI therapy (once
substernal burning with upward radiation) and
daily, followed by twice daily if no response, each for
sour regurgitation, the likelihood that they have
at least 8 weeks), since in this setting the most likely
GERD as the etiology is so great that a trial of PPI
remaining diagnosis is still GERD. Patients who fail a
therapy can be both diagnostic and therapeutic. If
PPI trial should proceed to endoscopy, if this has not
the patient responds appropriately, no other testing
esophageal disorders or complications of GERD on

utility of evaluating such patients for asymptomatic
such testing become greater in this setting.
complications of GERD, such as Barrett’s esophagus,
After a negative endoscopy, if the patient’s
is controversial. Any such testing should be guided
dominant symptom is solid food dysphagia, the next
by the presence of known risk factors for Barrett’s
test should be a barium pharyngoesophagram that
esophagus.
incorporates a solid bolus challenge, to assess for
On the other hand, patients who have other
previously missed subtle rings, webs, and stenoses.
cardinal symptoms, such as odynophagia and
Otherwise (and if the esophagram is negative), the
troublesome dysphagia (not mild, brief, and
next test should be an esophageal manometry to
infrequent bolus hesitancy or sticking sensations)
detect the presence of rarer major esophageal motor
should undergo early endoscopic evaluation,
disorders, such as achalasia or distal esophageal
because of the greater likelihood of GERD
spasm.
complications or the presence of another serious
At this point, the patient in whom preceding
esophageal disorder. Endoscopic evaluation of
testing was non-diagnostic and whose cardinal insurance. Patients are often not instructed as to
symptoms failed to respond to a PPI trial should the appropriate timing of PPI therapy, which should
undergo ambulatory esophageal pH testing, possibly be taken before meals. Unrecognized conditions
combined with impedance for assessing nonacid that could be impairing the response to therapy
at this point include celiac disease, surreptitious
respond to therapy and is temporally associated with abuse, and systemic sclerosis. The most common
the patient’s symptoms. The preceding manometric causes for false-positive endoscopic diagnoses of
evaluation will aid in probe placement. Ambulatory GERD are erosions from pill injury and strictures
from EoE. Repeat ambulatory pH/impedance testing
should be performed on therapy in this setting, as it
indeed present. For patients with GERD documented may help identify those patients whose therapy is
previously but poor response to therapy, a case can 171
PPI therapy to document failure of such therapy, but surgery, or relapses after initial success, endoscopy
with an expected yield of less than one in ten.170
In patients whose diagnostic evaluation remains of the surgical repair and such complications as
inconclusive after the above sequence, the most likely the development of a paraesophageal hernia.172
etiology for symptoms is a sensory disturbance, such Endoscopy can also detect whether the patient has
as functional heartburn, which may not necessarily a new, or previously missed, esophageal disorder.
have its origins in the esophagus. Alternatively, the If endoscopy is unrevealing, the next test should
chances are greater at this point that the symptoms be esophageal manometry, especially if this was
come from a nonesophageal disorder. Finally, a not performed preoperatively. If these tests are
careful review of prior testing should be undertaken, negative and the patient fails a PPI test, ambulatory
to assess for test quality concerns and other reasons pH monitoring is likely to be normal. Such patients
for false-negative testing. are likely to have functional disorders as the cause of
For some patients without cardinal esophageal their symptoms.
symptoms, the issue is whether their atypical The capabilities and caveats for the major tests
symptoms might be from an esophageal disorder. In to evaluate esophageal disorders are described
these cases, the prior probability of an underlying
esophageal disorder is so low that the patient would of these tests must be considered when they are used
to evaluate patients with a low pretest likelihood
that are more likely to be the source of symptoms. of an esophageal disorder, such as those with only
Once other causes are excluded, evaluation can atypical symptoms. In this setting, negative test
proceed along the lines described for patients with results are often the most helpful, because the post-
cardinal esophageal symptoms, with the proviso that
patients with candidate supraesophageal symptoms etiologies can be removed from further consideration.
are unlikely to respond to PPI trials when typical
GERD symptoms are absent. Proton Pump Inhibitor Test
Unfortunately, a common clinical scenario is the The virtue of the PPI test for GERD, which is simply
patient whose test results support the diagnosis of assessing whether the patient’s symptoms respond
GERD but who fails to respond to GERD-directed to a short course of PPI therapy, is its simplicity and
therapy. The most plausible reasons for this failure
are in Table 1.11. Compliance has become a greater duration are not standardized, and a meta-analysis
issue, as expensive PPI agents have become available of trials of the PPI test indicate a sensitivity of 78%
over the counter and are no longer covered by
173
Thus the test is useful
only in cases where the pretest probability of GERD is Manometry

already large (typical GERD symptoms only, or prior Manometry has no role in the diagnosis of GERD.
testing excludes other candidate disorders). The Manometry is used to diagnose symptomatic
recent recognition of the entity of PPI-responsive major esophageal motor disorders and to exclude
esophageal eosinophilia has further complicated the
interpretation of the PPI test. An additional concern surgery. Manometry may be helpful in identifying
regarding the PPI test is the risk of development of symptomatically tight fundoplication wraps when
symptoms from rebound acid hypersecretion upon endoscopic and radiologic testing is inconclusive.
PPI withdrawal.174 Manometry is also used for locating the position of
the LES for placement of pH probes.
Endoscopy
pH/impedance monitoring
and structural abnormalities in the esophagus and
affords the opportunity to obtain diagnostic mucosal of the degree of esophageal acid exposure and the
biopsies. Treatment of some disorders (stricture
dilation, control of bleeding) can also be performed problem with such testing is that no cutoff value for
at the time of testing. False-positive results from acid exposure completely separates normal subjects
endoscopy are usually related to misinterpretation from those with GERD. The accuracy of pH testing is at
best about 90% in patients with GERD.175 Testing can
for candidiasis, or ulcers from viruses or pill injury be performed with either catheter-based or mucosal-
for GERD, or EoE strictures for peptic stictures).
Preventable causes for false-negative endoscopies
include failure to (1) examine the esophageal inlet Table 1.11
carefully for webs and inlet patches, (2) recognize Reasons for Therapeutic Failure in Patients
the characteristic features of EoE, and (3) obtain Diagnosed with GERD
mucosal biopsy specimens to diagnose EoE.
Noncompliance
However, despite careful technique, subtle webs and
Improper timing
stenoses may remain undetected. In addition, nearly
Inadequate dosage
half of patients with GERD do not have detectable
Inadequate delivery/bioavailability
endoscopic abnormalities, especially in an era when
Rapid medication metabolizer; true PPI resistance
many patients are already on a PPI at the time of
Nocturnal acid breakthrough
endoscopy.
Nonacid/weakly acid/duodenogastric reflux
Radiology Patient does not have GERD (prior test false-positive)
Patient has another esophageal disorder (e.g., achalasia, EoE)
Patient has a functional disorder (functional heartburn, hypersensitive
during these studies do not reliably predict the esophagus, rumination)
presence of GERD. These studies are useful in Patient has a nonesophageal disorder (cardiac disease, asthma)
identifying subtle webs, rings, and stenoses that Patient has GERD plus another disorder
are not detectable by endoscopy, but this requires Zollinger-Ellison syndrome
the additional use of an adequate-sized solid bolus EoE
challenge. Barium studies can also assess the detail Connective tissue disease (e.g., scleroderma)
of strictures too tight to allow endoscope passage and Celiac disease
Medication injury
(CT) imaging can detect pathologic thickening of the Infection
esophageal wall and extrinsic pathologic processes Delayed gastric emptying
that compress or invade the esophagus.
attached sensors. The latter have the advantage a blood pressure (BP) of 134/80 and a body mass
of better tolerability by the patient and longer index (BMI) of 32, but is otherwise unremarkable.
recording times; disadvantages include the cost of Because of the new-onset solid-food dysphagia,
a second endoscopy often used to place the probe
(and occasionally a third to remove probes causing of Los Angeles class B erosive esophagitis at the
intolerable pain), and premature dislodgement and gastroesophageal junction, a 13-mm diameter ring-
migration of the sensor distally. This latter event can type stricture at the gastroesophageal junction, and
give the false appearance of prolonged esophageal
acid exposure time. a 16-mm diameter balloon dilator, and the patient is
Probes are also available that record intraluminal switched to a PPI before breakfast and advised to use
pH and impedance changes, the latter being used to acetaminophen instead of ibuprofen for joint pain. On
follow-up one month later, dysphagia has resolved,
used to prevent mistaking undocumented ingestion but she is having heartburn 3 nights per week.
Addition of a second dose of PPI before the evening
single-point pH sensors.176 meal results in essentially complete resolution of her
Ambulatory studies can be performed off or on symptoms after 2 additional months.
acid suppressive therapy, depending on whether the She does well until 2 years later, when she
goal is to help make the initial diagnosis of GERD develops burning substernal pain that can last for
or to try to determine if persistent symptoms while hours and can awaken her, even though she continues
on therapy result from GERD that is not adequately
treated under the current regimen. These studies can when swallowing her pills. Interval history is of a
also assess the temporal association of the patient’s new diagnosis of osteoporosis, which is being treated
with alendronate. She undergoes repeat endoscopy,
events. Limitations are failure to have a symptom showing erosions at 25 cm from the incisors and at
event reported during the recording period. 4 cm above the gastroesophageal junction. Biopsies
Symptom associations on studies with few events are negative for EE or infection, and she is advised to
are unreliable.177 For cough, it is often not possible to discontinue the alendronate, with resolution of her
symptoms over the next week.
and vice versa.178 She again does well until 2 years later, when she
develops substernal chest discomfort at mealtime
or when walking her dog. An associated symptom
Illustrative Clinical Case is nausea, and additional over-the-counter antacid
tablets do not help. Examination is unchanged except
A 53-year-old woman presents with a 3-month
for BMI of 34 and BP of 148/92. She is referred to
history of worsening heartburn and a 1-month
a cardiologist who performs a coronary angiogram,
history of persistent dysphagia for breads and meats.
showing a 90% occlusion in the right coronary artery.
She has had occasional heartburn for years that she
A drug eluting stent is placed, and she is begun on
treated with over-the-counter antacids. However,
clopidogrel and low-dose aspirin, with resolution of
she has been having more heartburn in the evening
these symptoms.
and night, and started taking an over-the-counter
This case illustrates several important concepts
histamine2-receptor antagonists at bedtime last
in the evaluation and management of esophageal
month without much improvement. Her medical
disorders. The patient had several risk factors for
history is pertinent for asthma, hypertension,
her primary esophageal disorder of GERD. She
hyperlipidemia, obesity, and degenerative joint
had symptoms that should prompt endoscopic
disease. Her other medications are albuterol and
evaluation (and treatment). She required medication
adjustments to provide adequate symptom relief.
the-counter ibuprofen. Physical examination shows
While her condition is a chronic one, she required

eosinophilic esophagitis. Clin Gastroenterol Hepatol
careful reevaluation when she later experienced
2012; 10:1066-78.
new symptoms while on effective therapy, due to
Guideline. Role of endoscopy in the management of
the subsequent development of a new esophageal
GERD. Gastrointest Endosc 2007;66:219-224.
disorder and coronary artery disease.
American Gastroenterological Association medical
position statement on the management of Barrett’s
Pearls and Pitfalls for the esophagus. Gastroenterology 2011;140:1084-91.
Kahrilas PJ, Shaheen NJ, Vaezi MF. American
Board Exam Gastroenterological Association medical position
Beware “white spots” in the esophagus: these could statement on the management of gastroesophageal
be from Candida or EoE! reflux disease. Gastroenterology 2008;135:1383-
Be able to recognize reflux events on pH/impedance 1391.
tracings
Know that no treatment is approved or has
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CHAPTER 2
Acid Diseases of the Stomach
Steven F. Moss, MD, AGAF, and Adam D. Harris, MD
Learning Objectives
1. Review the normal physiology of the stomach as it relates to acid secretion.
2. Review the pathophysiological mechanisms underlying mucosal injury and ulcer formation caused by Helicobacter pylori infection and nonste-
roidal anti-inflammatory drugs.
3. Review the pathophysiology of stress-induced ulcer disease and the indications for prophylaxis in patients in the intensive care unit.
4. Review the pathophysiology and risk factors for peptic ulcer disease in the postsurgical stomach.
5. Review approaches to diagnosis and treatment of Zollinger-Ellison syndrome and other diseases associated with acid hypersecretion.
Review of Gastric Acid Secretory Physiology

Gastric juice is a combination of parietal (acid) and nonparietal secretions. Parietal cells secrete pure hydro-
chloric acid at a concentration of 160 mmol/L (equivalent to a pH of 0.8), in a volume determined by the num-
ber of actively secreting cells;lnonparietal secretions include water, electrolytes, and mucus.1 The parietal cell
alone is responsible for gastric acid secretion (Table 2.1). Parietal cells possess basolateral membrane recep-
tors for three stimulants: a histamine (H2)-receptor, a muscarinic (M3) cholinergic receptor for acetylcholine
released from preganglionic neurons, and a cholecystokinin (CCKB) receptor for gastrin released from pyloric
G cells (Figure 2.1). The parietal cell also has basolateral receptors for inhibitors of its function, which include
somatostatin and prostaglandins.
cells and possibly mast cells in the lamina propria, and interacts with H2-receptors (Figures 2.1 and 2.2).
There is evidence that histamine also acts through an H3-receptor to suppress the release of somatostatin
from D cells. H2-receptor antagonists (H2RAs) inhibit gastric acid secretion by blocking H2 receptors on the
parietal cell. Acetylcholine (Ach) released from nerve endings following vagal nerve stimulation interacts
directly with M3 receptors on ECL cells to release histamine, and on D cells to suppress the release of soma-
tostatin, an inhibitory peptide (Figure 2.2). All 3 mechanisms serve to promote acid secretion.
Gastrin is released from G cells in the gastric antrum. Stimulation occurs via food (particularly proteins)
in the gastric lumen and by neural release of gastrin-releasing peptide (GRP). Gastrin binds directly to CCKB/
gastrin receptors on canine parietal cells; however, studies in humans suggest that the gastrin receptor on
the parietal cell may not be involved in acid secretion, and CCKB/gastrin receptors are present on ECL cells.
Thus gastrin’s effect on parietal cells in humans is mostly or entirely mediated through histamine released
from ECL cells (Figure 2.2).
29
Table 2.1 Somatostatin is an inhibitor of parietal cell func-

Secretory Cells of the Stomach tion (Figures 2.1 and 2.2) and plays an important role
in modulating gastrin release. D cells and G cells are
Cell type Product Function in close proximity, allowing somatostatin to function
Kill enteric pathogens in a paracrine manner to inhibit gastrin release. H+
HCl
Parietal cell Cobalamin (vitamin B12) ions in the gastric lumen stimulate D cells to inhibit
Intrinsic factor
absorption gastrin release by G cells. However, acetylcholine, re-
Chief cell Pepsinogen I Digest protein leased via vagal stimulation, inhibits D cells, thereby
Pepsinogen II Digest protein enhancing gastrin release and providing another
Mucous cell means through which acetylcholine promotes acid
Mucus and bicarbonate Gastroprotection
secretion.
Stimulate parietal cell by
Virtually every epithelial and non-epithelial cell
G cell Gastrin releasing histamine from
in the stomach secretes prostaglandins. The major
ECL cell
prostaglandins produced by the human stomach are
Inhibit parietal cell and G
D cell Somatostatin PGE2, PGF2, and PGI2 (prostacyclin). Activation of
cell secretion
PGE2 receptors on parietal cells inhibits adenylate
ECL cell Histamine Stimulate parietal cell
cyclase activity, intracellular cyclic AMP (cAMP) gen-
Figure 2.1
Model of Gastric Acid Secretion by the Parietal Cell
Parietal cells possess basolateral membrane receptors for 3 stimulants: histamine, acetylcholine (Ach), and gastrin. Hydrogen ions are secreted into the gastric
lumen in exchange for potassium ions via action of the hydrogen/potassium ATPase proton pump. This pump is the pharmacologic target of proton pump
inhibitors. Gastrin stimulates hydrogen ion (acid) secretion mainly through the release of histamine from ECL cells. From Schubert ML, Peura DA. Gastric acid
secretion in health and disease. Gastroenterology 2008;134:1842-60.
Chapter 2 — Acid Diseases of the Stomach 31
Figure 2.2
Cellular Physiology of Acid Secretion
Acid secretion from parietal cells in the gastric body is regulated at multiple levels. The principal stimulant for acid secretion is from gastrin
released by antral cells. Gastrin release is stimulated by vagal nerve endings via acetyl choline (Ach) and gastrin-releasing peptide (GRP)
neurotransmission, and gastrin release is inhibited by somatostatin released by antral D cells. Gastrin stimulates acid secretion via histamine
release from ECL cells of the gastric body and, less importantly, through interactions with CCK2 receptors on parietal cells. Gastric body D cells
inhibit acid secretion from parietal cells. Acetylcholine from vagal nerve endings stimulates acid secretion.
eration, and protein kinase A activation (Figure 2.2). etal cell and acid secretion. In its resting state, the pa-
Prostaglandin E analogs such as misoprostol reduce
acid secretion to approximately the same extent as upon activation, open up into intracellular canaliculi
H2RAs, although they induce more side effects. with multiple microvilli. These changes markedly in-
crease the apical surface area from which acid can be
secreted.
Parietal Cell Stimulation and Inhibition Hydrogen ions are secreted into the gastric lumen in
exchange for potassium ions through the action of
Following the binding of a ligand to its cognate pari-
the H+/K+-ATPase proton pump.2 This enzyme is con-
etal cell receptor, a second messenger is elaborated
stitutively active, but cannot pump hydrogen from
(Figure 2.2). For acetylcholine, this is calcium, al-
the cell unless potassium is present in the lumen. Ac-
though precisely how this occurs is not known. For
tivation of the parietal cell occurs when transcellu-
histamine, the second messenger is cAMP. When his-
lar pathways for potassium and chloride are opened,
tamine binds to its H2 receptor, a stimulatory G pro-
thereby providing the potassium needed to exchange
tein activates adenylate cyclase and generates cAMP.
with hydrogen (Figure 2.1). The proton pump is the
Calcium and cAMP subsequently activate protein ki-
pharmacologic target of proton pump inhibitors
nases, leading to physical transformation of the pari-
(PPIs), drugs that markedly reduce gastric acid se- release during the cephalic phase.
cretion and are consequently used to treat a variety The gastric phase of acid secre-
of acid-peptic diseases. tion, which occurs when food reaches the stomach,
Several substances, including prostaglandins and is mediated by gastric distention and by the action of
peptides such as secretin, gastric inhibitory polypep- food itself on gastrin release. Distention stimulates
tide, peptide YY, and somatostatin, inhibit parietal cell modest levels of acid secretion directly and through
function and suppress acid secretion. Prostaglandins
and somatostatin act through inhibitory G proteins, food (primarily amines and other protein digestion
which inhibit adenylate cyclase and cAMP (Figure products) is the most important stimulant prompting
2.2). Somatostatin also inhibits ECL cells, thereby sup- G cells to release gastrin. Gastrin release accounts for
pressing histamine release. Finally, it has been postu- up to 90% of the gastric phase of acid secretion, and
lated that histamine itself, through a feedback loop, gastrin release is inhibited at low pH levels.
may inhibit further release of histamine from ECL cells Digested protein in the small in-
via H3 receptors on fundic D cells. testine results in modest stimulation of acid secretion.
Under normal circumstances, the intestinal phase ac-
counts for only a small proportion of the acid secretory
Physiology of Gastric Acid Secretion response to a meal. Indeed, gastric contents and food
in the duodenum, particularly fat, inhibit acid secretion,
Basal Acid Secretion primarily via the release of secretin and other small in-
Acid secretion in the fasting stomach has a diurnal testinal peptides that stimulate gastric somatostatin.
pattern and varies widely among normal subjects.2
The main determinant of basal acid output is vagal
tone. High vagal tone may lead to sustained basal Mucosal Defense Factors (Bicarbonate
acid hypersecretion in some subjects and temporary and Mucus Secretion, Blood Flow,
hypersecretion during periods of stress in others. Prostaglandins)
Women secrete less acid in the basal state than do Because of their constant exposure to high
men. This is likely due to women having fewer pa- concentrations of hydrochloric acid, gastroduodenal
rietal cells and decreased sensitivity to acid secreta- epithelial cells would appear to be at risk of
gogues. autodigestion. However, mucosal protective factors
(the mucosal barrier) prevent such self-destruction
Stimulated Acid Secretion
by preventing acid (H+) accumulation at or inside
Different stimulants of gastric acid secretion may be
epithelial cells (Figure 2.3).2 The mucosal barrier is a
additive. The acid secretory response to food is di-
thick, alkaline, unstirred, aqueous layer of dissolved
vided into 3 phases: the cephalic phase, the gastric
bicarbonate (HCO3) and mucus, which neutralizes
phase, and the intestinal phase.
the effects of gastric juice H+. The next layer of
Acid secretion that occurs in re-
defense is the gastric surface mucus cells or, in the
sponse to the sight, smell, taste, or thought of food
duodenum, enterocytes and goblet cells. The lipid
is mediated by the vagus nerve. Vagal stimulation,
bilayer of the epithelial cell apical membranes poses
which can be elicited by sham feeding, results in re-
a fairly impermeable barrier to H+, and tight junctions
lease of histamine from ECL cells, activation of the
between adjacent cells maintain physical integrity.
parietal cell, and stimulation of the G cells through
gastrin-releasing peptide, eliciting a modest release
mucosal barrier, and this circulation drains H+ away
of gastrin. Vagal stimulation may also inhibit soma-
from the mucosa and buffers H+ with plasma HCO3 and
tostatin release, thereby permitting unrestrained
proteins. The effectiveness of the mucosal barrier in
activation of parietal and G cell function. Truncal
neutralizing acid is depicted as a pH gradient in Figure
vagotomy abolishes both acid secretion and gastrin
2.3, where the gastric lumen pH is 2.0, the mucosal
Figure 2.3
Pepsinogen Secretion
Gastric Mucosal Barrier to Injury Induced by Hydrogen Ions Seven different isoenzymes of pepsinogen exist and
are grouped based on immunologic reactivity into
pepsinogen I (pepsinogens 1–5) and pepsinogen II
(pepsinogens 6 and 7). Mucous cells throughout the
stomach secrete pepsinogen II, while chief cells and
perhaps mucous neck cells of oxyntic glands secrete
pepsinogen (Table 2.1). Pepsinogen is converted
in the gastric lumen to pepsin, the active enzyme, by
gastric acid. While pepsin is important early in life for
the digestion of milk, the major substrates for pepsin
later in life are proteins. Relatively little digestion
takes place in the stomach, but release of peptides
and amino acids by pepsin triggers the release
The gastric mucosal barrier is comprised of a thin, alkaline layer of of other digestive hormones such as gastrin and
dissolved bicarbonate (HCO3–) and mucus, which neutralizes gastric
CCK. There are both cephalic and gastric phases of
juice H+. Surface epithelial cells in the stomach or duodenum secrete
mucus and bicarbonate. The effectiveness of the mucosal barrier in pepsinogen secretion, with the major stimulus being
neutralizing gastric acid is depicted as a pH gradient that ranges from cholinergic.
2 in the gastric lumen to 7 at the epithelial surface.
Vitamin B12 Physiology

cell surface pH is 7.0, the mucosal cell interior pH is
7.0, and the circulating blood pH is 7.4. When HCO3- Intrinsic factor is a glycoprotein whose primary role
secretion is suppressed, when proteolysis of mucus is the facilitation of cobalamin (vitamin B12) absorp-
tion. Intrinsic factor is secreted by the parietal cell
under the same stimulatory conditions as is acid.
Cobalamin, when liberated from protein by acid and
occurs, leading to cell necrosis. pepsin, initially combines with R proteins present
Prostaglandins play a critical role in mucosal in saliva. In the alkaline environment of the duode-
defense, as evidenced by animal studies in which num, R proteins are hydrolyzed by pancreatic en-
pretreatment with prostaglandins can prevent zymes, freeing cobalamin to bind to intrinsic factor.
gross gastric damage from injurious agents such as The intrinsic factor–cobalamin complex then passes
ethanol or boiling water. While grossly visible injury through the intestine to the ileum, where the vita-
min is actively absorbed. Failure to absorb cobala-
not. In humans, evidence for the role of prostaglandins -
in mucosal protection is indirect. NSAIDs, which
block the synthesis of prostaglandins, predispose overgrowth, or diseases affecting the ileum, such as
to mucosal injury and peptic ulceration. The means Crohn’s disease.
by which prostaglandins protect gastroduodenal The Schilling test is used to measure uptake and
mucosa include the secretion of mucus, stimulation of urinary excretion of radiolabeled vitamin B12 under
various conditions. This test is performed in patients
during periods of potential injury. with documented low serum levels of vitamin B12 af-
Mucosal peptides and growth factors, including ter adequate repletion of the vitamin by parenteral
trefoil-family peptides and transforming growth-
factor alpha, also participate to ensure normal vitamin B12 alone. If 24-hour urinary excretion is low,
epithelial function by regulating responses to injury. the test is then repeated with concomitant intrinsic
factor. Normalization of urinary excretion indicates Gastric acid and pepsin secretion are impor-
that the cause of serum vitamin B12 - tant components in the pathogenesis of gastric and
duodenal ulcers.3 However, while some persons with
a course of antibiotics is given and the test repeated. DUs secrete excessive amounts of gastric acid, most
Normalization of the results suggests that bacterial DU patients are not hypersecretors of acid, and most
overgrowth was responsible for malabsorption of gastric ulcer patients have normal-to-low secretion
vitamin B12. If the test remains abnormal after anti- (Figure 2.4). Gastric acid is required for peptic ulcer
- formation, but acid alone does not commonly cause
minal ileum is implicated. ulcers. The most common causes of PUD are infec-
tion with the bacterium Helicobacter pylori (HP) or
the use of NSAIDs. Approximately 90% of patients
Peptic Ulcer Disease with PUD will be infected with HP or will be taking an
NSAID, or both; the risk for PUD increases synergisti-
A peptic ulcer is a mucosal breach of the stomach
cally in HP-infected persons who ingest NSAIDs.
or duodenum that penetrates the muscularis mu-
pylori and NSAIDs each increase susceptibility to ul-
ceration by compromising mucosal defense mecha-
the muscularis mucosa.3 Peptic ulcer disease (PUD)
nisms, each by a separate mechanism to be described
is common and in the United States; the lifetime
later.
prevalence is about 5–10%, although many cases are
Epidemiologic studies indicate that smokers are
asymptomatic. At any point in time, the prevalence
at moderately increased risk for both DU and GU,
of symptomatic PUD is about 2%. The incidence of
and this risk is proportional to the amount smoked.
both gastric ulcers (GU) and duodenal ulcers (DU)
Smoking impairs ulcer healing, promotes recur-
increases with advancing age.3
rences, and is associated with higher death rates
from ulcer disease.4 In human studies of volunteers
Figure 2.4
experimentally administered high concentrations of
Comparison of Resting and Stimulated Acid Secretion in
alcohol, acute hemorrhage and erosions can be ob-
Normal Subjects Versus Patients with Different Acid-Peptic
served, but there are no convincing data to suggest
Diseases
that chronic alcohol use causes PUD.
Corticosteroids alone do not increase the risk
of PUD; however, when they are taken in high dos-
es in combination with NSAIDs, the risk of PUD is
greatly increased and is higher than the risk of PUD
with NSAIDs alone. Although many foods, beverages,
and spices cause dyspepsia, there is no evidence that
dairy-rich diet is useful in the therapy of the ulcer pa-

tient. Certain extraintestinal illnesses are associated
with increased risk of developing peptic lesions in
the stomach and duodenum. These include chronic
While there is considerable overlap between acid secretory levels obstructive lung disease, cirrhosis, systemic masto-
at rest or following stimulation between normal subjects and gastric cytosis and uremia. In cirrhosis and uremia, there is
ulcer or duodenal ulcer patients, gastric ulcer patients tend to have a loss of the normal pH gradient from the gastric lu-
normal–low acid secretion, and duodenal ulcer patients tend to
have higher secretion than normal. However, in Zollinger-Ellison (ZE)
men to the epithelial cell surface, with increased back-
syndrome, resting acid secretion is strikingly higher than in the other diffusion of acid into the surface cells. Other causes
conditions. of peptic ulcer disease will be discussed later in this
chapter.
Patient Presentation -
suscitation (with possible need for transfusion)
Uncomplicated peptic ulcer disease most commonly
with upper endoscopy once the patient is stabilized.
presents as upper abdominal pain that is often de-
Intravenous proton pump inhibitors should be used
scribed as burning, sharp, or gnawing and typically
does not radiate. However, it may also be character-
ulcer bleeding. The subsequent management of pa-
ized as vague abdominal discomfort, nausea, aching,
tients with a bleeding ulcer depends on the charac-
or be perceived as an abdominal pressure, fullness,
teristics of the ulcer at the time of endoscopy. Ulcers
or hunger sensation. The pain of duodenal ulceration
that display active arterial bleeding, visible vessels,
typically occurs 2–3 hours after meals, at night or
or adherent clots have a high rate of rebleeding when
when the stomach is empty, and can awaken the pa-
treated with medical therapy alone. Randomized
tient from sleep. Food and antacids relieve the pain
controlled trials have found that multipolar probe
for a short time; however, discomfort usually returns
electrocoagulation, heater probe, and hemostatic
in 30–60 minutes. Symptoms may persist for several
days, weeks, or months, and patients frequently have
alone for treating such ulcers with regard to the need
a history of self-treatment with antacids or antisecre-
for fewer transfusions, shorter hospital stays, and
tory therapy. Patients may even describe weight gain
less frequent need for emergency surgery. A meta-
due to their hyperphagia in attempting to prevent the
analysis concluded that the independent predictors
pain from duodenal ulceration.
of recurrent hemorrhage after endoscopic therapy
Classically, DU symptoms occur in the setting of
include active bleeding at original endoscopy, large
low pH without a food buffer, whereas gastric ulcer
ulcer size (>1–2 cm), posterior DU, and lesser gastric
symptoms typically worsen after food. Anorexia and
curvature ulcer.5
weight loss may occur in these patients. Symptoms
Perforation is the second most common compli-
tend to be recurrent and episodic, and ulcer disease
cation, and severe, sudden abdominal pain associated
can recur in the absence of pain. In some patients, the
with shock suggests acute perforation of an ulcer com-
disease is more aggressive, with frequent and per-
plicated by peritonitis. The initial pain is due to caustic
sistent symptoms or development of complications.
gastric juice in the peritoneal cavity; subsequently the
Dyspeptic symptoms alone, though, are not sensitive
patient may begin to feel better once this caustic gastric
juice becomes buffered. The physician should be aware
physical examination, epigastric tenderness is the
of this potential change in symptoms and realize that
frank peritonitis and sepsis will likely follow. On exami-
classic manifestations of PUD, there is wide variation
nation, a rigid, board-like abdomen with generalized
in the clinical presentation. In many individuals, pep-
rebound tenderness is typically present. Auscultation
-
of the abdomen may initially reveal hyperactive bowel
tation will be a complication, particularly in elderly
sounds that with clinical progression, may diminish or
patients taking NSAIDs.
disappear. The presence of free air on imaging can con-
The most common ulcer complications are
bleeding, perforation, penetration, and obstruction.
should be avoided if perforation is suspected.
Bleeding is the most frequent complication, occur-
Immediate surgery is often required to repair the
ring in 15–20% of patients, and is commonly mani-
perforation; however, while surgical exploration is the
fested by melena and/or hematemesis or coffee-
preferred approach for most patients with perfora-
ground emesis. A brisk upper gastrointestinal (UGI)
tions, some patients may be poor surgical candidates
bleed can also manifest as hematochezia. Ulcers can
because of comorbid disease. In such patients, medi-
cal therapy may be successful, especially those with
anemia or occult blood in the stool.
a perforation of >24 hours in whom a water-soluble
Initial management of the acute upper gastro-
contrast study demonstrates a contained perfora-
intestinal bleed due to peptic ulcer disease includes
tion. Medical therapy consists of nasogastric suction, gested by classic symptoms of substernal heartburn
are required and should cover gram negative rods, alarm symptoms suggestive of upper gastrointesti-
- nal tract cancer are present, initial management in-
tential pathogens as well. cludes empiric treatment with antisecretory therapy
Penetrating ulcers usually extend into adjacent (Figure 2.5). If biliary tract or pancreatic disease is
organs (most commonly the pancreas, though the
liver, bile duct, and colon can all be involved) without and pancreatic blood tests and abdominal imaging.
free perforation and leakage of luminal contents into The next decision is whether early endoscopy
the peritoneum. Initial management of penetrating
ulcers employs nasogastric suction and intravenous suggestive of gastric malignancy or an ulcer complica-
antisecretory therapy. Obstruction is another com- tion are present.6 If alarm features are present (such
plication of peptic ulcer disease and can result in as gastrointestinal bleeding, unintended weight loss,
nausea, vomiting, and early satiety. Bloating, weight family history of upper GI malignancy, odynophagia
loss, and indigestion can also be present. Vomiting
tends to occur 30–60 minutes following meals, and the development of new upper gastrointestinal symp-
patients will frequently remain satiated for hours toms after the age of about 55) are present in the dys-
following a meal. Dehydration and electrolyte dis- peptic patient, endoscopy is advisable. If not NSAIDs
turbances may occur. Ulcers that present with ob- should be stopped if they are being taken, and the
struction usually are located in the pyloric channel possibility of HP infection should be evaluated by a
or duodenal bulb, where the GI lumen naturally nar- stool or breath test, and if positive, treated. The latter
rows. On examination, patients with gastric outlet recommendation is based on the premise that treat-
obstruction may have a succussion splash produced ing an underlying HP infection will reduce the risk of
PUD and gastric cancer in the future, and outcomes
Endoscopy with biopsies and abdominal CT imaging studies indicating that this approach is the most cost-
should be performed to rule out malignancy or HP. effective.6 Endoscopy is warranted for persistent
Antisecretory therapy should be the initial medica- symptoms following HP treatment. If HP infection is
tion of choice, along with nasogastric suction (in the not present after initial testing, empiric therapy for
acute case of gastric outlet obstruction). As acute NUD should be given (usually a PPI), and persistent
ulceration is treated, swelling resolves and obstruc- symptoms after empiric therapy should be evaluated
tive symptoms will generally subside. Endoscopic by endoscopy (Figure 2.5).
balloon dilation can be helpful in those patients who
do not experience relief with medical therapy alone.
Surgical therapy may be necessary if these modali- H. pylori–Induced Peptic Ulcer Disease
ties do not succeed.
The most common causes of peptic ulceration are
infection with HP and use of NSAIDs, which account
for >90% of all ulcers. colonizes the stom-
Evaluation and Management of Patients achs of at least half of the world’s population and
with Dyspepsia is a strong risk factor for both PUD and gastric ma-
Uncomplicated PUD presents with dyspepsia or oth- lignancy (adenocarcinoma and mucosa-associated
er upper GI symptoms in most patients. Dyspepsia 7
Infection is
describes epigastric pain or burning, postprandial usually acquired in childhood and persists for the
fullness, or early satiety. The differential diagno- lifetime of the host. The prevalence of HP is higher
in developing than developed countries, and in the
(GERD), nonulcer dyspepsia (NUD), biliary tract dis- United States, HP is present in 10–15% of children
ease, pancreatitis, and cancer. GERD is usually sug- under age 12 compared with 50–60% of people over
age 60. After early childhood, the rate of acquisition Figure 2.5
of new HP infection in developed countries is <1% Algorithm to Guide Management of Patients with Dyspepsia
per year. Over the past half-century, however, there
has been a progressive decline in the prevalence of
pylori in the United States at all ages. Risk factors for
HP acquisition include lower socioeconomic status
country of origin and ethnicity; for example, within

the United States, HP infection rates are over 60%
in Mexican-Americans versus fewer than 30% in the
non-Hispanic white population.8
sists of neutrophils, lymphocytes, plasma cells, and

macrophages, along with varying degrees of epi-
thelial cell degeneration and injury (referred to as
chronic active gastritis); the most distinctive feature
(Figure 2.6). colonization also induces an

exuberant systemic and mucosal humoral response;
however, antibody production does not result in
eradication. In the majority of infected persons resid-
ing in developed countries, gastritis is most severe Based on Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association
technical review on the evaluation of dyspepsia. Gastro-enterology 2005;129:1756-80.
gastric body. Persons with such corpus-sparing in-
increased acid output. This is due to the depletion of

antral somatostatin secretion induced by HP, with re-
Figure 2.6
sultant exaggerated gastrin release.1 In contrast, per-
Inflammatory Components Within H. pylori–Colonized Mucosa
sons who progress to gastric ulcer disease and gastric
adenocarcinoma have a different pattern of gastritis
that not only involves the antrum but also the acid-
secreting corpus. These patients tend to have reduced
acid outputs, despite elevated gastrin levels, because
can lead to parietal cell loss (Figure 2.7). Corpus gas-

tritis is often accompanied by gastric atrophy and in-
testinal metaplasia (Figure 2.8); this pattern of gas-
persons residing in Southeast Asia, South America,

and certain regions of Central, Eastern, and Southern
Europe. This divergent pathophysiological outcome
of infection is related to heterogeneity in
pylori strains and genetically determined differences
The lamina propria contains a mixed inflammatory infiltrate of plasma cells,
lymphocytes, and neutrophils, the latter of which can infiltrate the lamina
Although a strong risk factor for peptic ulcer-
propria and foveolar epithelium and form pit abscesses.
ation and distal gastric cancer, gastritis has no ad-
Figure 2.7 verse consequences for most hosts. The prevalence

Differing Effects of H. pylori on Acid Secretion, Depending on the Extent and of HP is inversely related to esophageal adenocar-
Intensity of Gastric Inflammation cinoma,9 suggesting that HP may “protect” against
the majority of published intervention trials indicate
disease nor leads to the development of clinically sig-
-
plications.
Diagnosis of H. pylori
The presence of should only be sought if
such results will affect clinical decisions.1 Currently,
testing exists are those with PUD, patients with unin-

vestigated dyspepsia without alarm symptoms, after
mucosal resection of an early gastric cancer, and in
SST, somatostatin. From Schubert ML, Peura DA. Gastric acid secretion in patients who have developed a low-grade MALT lym-
health and disease. Gastroenterology 2008;134:1842-60. phoma. Up to 80% of these lymphomas will regress
with anti-HP therapy alone. Testing for and treating
Figure 2.8
Histology of H. pylori–Induced Atrophy and Metaplasia dyspepsia, persons at high risk for NSAID complica-
tions, subjects with a family history of gastric cancer,
-
pathic thrombocytopenic purpura. 10
either invasive or noninvasive.11 Invasive methods

require endoscopy with biopsy and include histol-
ogy, rapid urease tests, or culture. Noninvasive tests
include urea breath tests, serology, and stool anti-
gen testing. The choice of test will depend upon the
clinical situation and available local resources, but
serology is now recognized to be less accurate than
breath or stool tests. 11 The use of proton pump in-
hibitors, antibiotics, and bismuth compounds re-
duces the sensitivity of all these tests except serology
(Table 2.2).
The presence of HP within biopsy specimens can
be determined histologically with or without the use
of special stains that enhance bacterial visibility (Fig-
ure 2.9).11 Advantages of histologic diagnosis include
direct visualization of the organism, simultaneous
Multifocal atrophic gastritis involving the gastric corpus, showing patchy loss assessment of the gastric mucosa (thus, evaluating
of oxyntic glands and intestinal metaplasia (arrow). the severity of gastritis and any associated lesions
such as intestinal metaplasia, adenocarcinoma, or Figure 2.9

lymphoproliferative disease), and accuracy for both H. pylori Immunohistochemistry
-
tion of multiple biopsy specimens obtained from the
antrum, corpus, and incisura reliably distinguishes
stains such as immunohistochemistry (Figure 2.9),

Warthin-Starry, Giemsa, and Genta stains enhances
detection rates, especially in patients taking proton
pump inhibitors, since these drugs reduce the num-
ber of viable HP bacteria. Chronic active gastritis is
the sine qua non histology for HP infection; even if
HP is not seen histologically by staining, the presence
of chronic active gastritis is strongly suggestive of ac-
tive infection.
Rapid urease tests take advantage of urease pro-
duction by HP Most detect a pH change in the test H. pylori organisms identified by immunohistochemistry (black) are found in
matrix within minutes to hours, resulting from the the surface mucous layer and extending into the lumen of the gastric pits.
conversion of urea to ammonia by the urease pro-
duced by viable organisms. Advantages of rapid ure-
ase testing include ease of use, cost-effectiveness, and
detected in breath samples. Urea breath tests accu-
rapid acquisition of results, and these tests can be uti-
rately ascertain the presence of active infection, and
lized for both initial diagnosis and follow-up of thera-
allow a more global assessment of HP than can be
provided by biopsy-based techniques. Breath tests
sensitivity may exceed 90% but is reduced by the use
also are effective for detection of HP post-therapy,
of proton pump inhibitors, antibiotics, and bismuth
-
HP eradication, it is recommended to wait at least 4
high—approximately 95%. Proton pump inhibitors
weeks following completion of anti-HP therapy and
at least two weeks after discontinuing proton pump
Table 2.2
inhibitors.11
H. pylori Diagnostic Tests
can be cultured directly from gastric tis-
sue, although antibiotics or acid-suppressive drugs
that alter bacterial colonization patterns may affect Clinical utility for:
sensitivity. Culture is rarely performed in the United Primary Confirmation Detects viable
Test
States, primarily due to cost, special conditions re- diagnosis of cure bacteria
quired for specimen transport and growth, and the Invasive
long interval between specimen harvest and test re-
Histology + + -
sults, which delays treatment decisions. Potentially,
culture results could guide therapy in infec- Rapid urease testing + + +
tions that appear refractory to conventional antibiotic Culture ± ± +
eradication regimens.
Noninvasive
When a patient with HP infection ingests urea la-
beled either with 13C or 14C, gastric urease hydrolyzes Urea breath testing + + +
the labeled urea to ammonia and labeled CO2, which Serology + - -
is quickly absorbed into the bloodstream and can be Stool antigen tests + + -
should be withheld for at least one week prior to Treatment of H. pylori Infection
urea breath testing to avoid false-negative results.
Stool testing can detect HP antigens by immuno- for -
assay. As for the urea breath test, stool testing may apy. First-line regimens consist of a proton pump in-
- hibitor (PPI) in combination with clarithromycin and
- either amoxicillin or metronidazole (triple therapy),
centage points below that of the breath test, and there for at least 7 but preferably 14 days (Table 2.3). An
are similar concerns regarding false-negative testing alternative regimen is a proton pump inhibitor with
in patients taking proton pump inhibitors. Because bismuth, tetracycline, and metronidazole (bismuth-
the stool test detects antigens rather than viable or- based quadruple therapy) for 14 days. Success rates
ganisms, it may take several weeks after successful of 75–80% are reported in clinical trials, most likely
eradication for the test results to be negative—wait- much less in practice.12 There are no consistent ad-
ing a month after the end of treatment is advisable. vantages to using a particular PPI for HP eradication;
Serology used to be widely used but is no lon- therefore, any agent in this class can be used.
ger advisable, as it is considerably less sensitive than A second-line course of therapy should be used
detecting HP by breath or stool testing.11 The most
- course should not include repeating metronidazole
or clarithromycin, since resistance to these drugs
levels decline slowly following treatment. is common after initial treatment failure. Any of the
Table 2.3
Treatment Regimens for H. pylori
Duration
Therapy Drug Dosage
(days)
Triple Proton pump inhibitor (PPI)* Twice a day† 7–10
and
Clarithromycin 500 mg twice a day 7–10
and
Amoxicillin 1000 mg twice a day 7–10
or
Metronidazole 500 mg twice a day 7–10
Bismuth-based PPI Twice a day† 14

Quadruple and
Bismuth subsalicylate 120 mg four times a day 14
and
Tetracycline 500 mg four times a day 14
and
Metronidazole 500 mg three times a day 14
*PPIs can be used interchangeably.

Dose depends on individual PPI.
†
second course. Declining eradication rates related (releases its H+), cannot cross lipid membranes, and
to antibiotic resistance have recently led to interest becomes trapped. There can be uncoupling of oxida-
in novel approaches. Sequential therapy (typically tive phophorylation leading to decreased mitochon-
consisting of a PPI plus amoxicillin for 5 days, fol- drial energy production, reduced cellular integrity,
lowed by a PPI with tinidazole and clarithromycin and increased cellular permeability.16 This can result
for the next 5 days) appeared initially promising 13 in a topical injury and rapid epithelial cell death, su-
but enthusiasm has been tempered by experience
in Central America 14, and it has not been formally The more important mechanism of NSAID-in-
evaluated in the United States. Other “salvage” ther- duced injury is systemic in nature and is related to in-
- hibition of cyclooxygenase-1 (COX-1), the enzyme re-
fabutin-based regimens,11 though myelotoxicity from sponsible for prostaglandin synthesis. Prostaglandins
rifabutin necessitates some caution. Unfortunately, a increase secretion of bicarbonate and mucus, increase
paucity of information regarding antibiotic sensitivity +
, and
rates and a lack of clinical trials for infection accelerate epithelial restitution and turnover after
in the United States over the past decade has limited injury. Aspirin acetylates cyclooxygenase, which irre-
- versibly inhibits the enzyme, whereas NSAIDs inhibit
rent eradication failures. the enzyme in a reversible, concentration-dependent
manner. NSAIDs, by decreasing prostaglandin levels,
impair these protective mechanisms, thus allowing
Nonsteroidal Anti-Inflammatory Drug–In- unopposed injury from aggressive factors such as
duced Injury acid and pepsin. Among these pathophysiologic re-
NSAIDs are valuable agents in the treatment of ar-

primary mechanism responsible for NSAID-induced
injury.
they are somewhat limited by their side-effect pro-
Two isoforms of COX exist: COX-1 is primarily re-
sponsible for PG synthesis in the GI tract, and COX-2
tract. Gastrointestinal side effects from NSAIDs re-
is primarily responsible for PG synthesis at sites of in-
sult in over 100,000 hospital admissions annually.
Approximately 25% of chronic NSAID users will
COX-2 requires induction by cytokines, hormones, or
develop peptic ulcer disease, and 2–4% will bleed or
other stimulants. Many traditional NSAIDs such as
perforate.15
ibuprofen, naproxen, aspirin, and indomethacin in-
mucosal hemorrhages and erosions) are common af-
-
ter exposure to traditional NSAIDs such as indometh-
acin, aspirin, ibuprofen, and naproxen. This form of
or rofecoxib, inhibit COX-2 without inhibiting COX-1,
topical injury, termed NSAID gastropathy, is charac-
making them potentially safer in the GI tract. How-
terized by multiple small erosions located primarily
ever, COX-2-selective NSAIDs incur an increased risk
in the antrum, but also seen in the gastric body and
of cardiac disease, which has led to the withdrawal of
the duodenum. NSAID gastropathy is usually asymp-
several of these drugs from the marketplace.
tomatic, with no long-term consequences; however,
it can be observed endoscopically in up to 50% of Therapy of NSAID-Induced Injury
NSAID users. Before prescribing NSAIDs, a practitioner should as-
sess whether the patient is at high risk for gastrointes-
Mechanisms of NSAID-Induced Injury
tinal complications. Those at highest risk for NSAID-
Most NSAIDs are weak acids and when exposed to
induced gastrointestinal complications have a history
acidic gastric juice (pH 2), they become protonated
of ulcer or GI hemorrhage in the past. Other high-risk
and cross lipid membranes to enter epithelial cells.
patients include those over the age of 65, those on
Within the epithelial cell (pH 7.4) the NSAID ionizes
higher doses of NSAIDs and those on concomitant cor- Table 2.4

ticosteroids or anticoagulants.15 infection Patients at High Risk for NSAID-Induced Ulcer
increases the risk of NSAID-related GI complications.
History of peptic ulcer or hemorrhage
Patients with a history of ulcer disease should have
Concomitant corticosteroids
HP testing and eradication before starting NSAIDs.
Concomitant anticoagulants
Some studies have indicated that even patients who
Older age (>65)
Patients taking high doses of NSAIDs or combinations of
testing and eradication before embarking on long-
more than one NSAID (including low-dose aspirin)
term NSAID use.
Therapy for NSAID-induced peptic ulcer dis-
ease includes three modalities: primary prevention
of GI side effects, treatment of an NSAID-induced direct comparison of misoprostol and ranitidine, the
ulcer, and secondary prevention of peptic ulcer dis-
ease. Reduction in NSAID-induced GI toxicity can NSAID-induced DUs, whereas misoprostol was sig-
be accomplished by prescribing drugs that, when -
co-administered with NSAIDs, protect against mu- tion of endoscopically diagnosed gastric ulcers.
cosal ulceration. Because the majority of patients Sucralfate has been shown to
who chronically ingest NSAIDs never develop clini- form an ulcer-adherent complex at the ulcer site and
-
co-therapy are those considered to be at high risk fate is effective in the treatment of NSAID-induced
for NSAID-induced ulcers (Table 2.4). Cotherapy op- DUs (particularly when the NSAID is stopped), but
tions include the following: it is not effective in the treatment or prevention of
H2 H2RAs do not prevent NSAID-associated NSAID-related gastric ulcers.
gastric ulcers when prescribed at their usual ulcer- Use of PPIs (omepra-
healing doses.17 Because most NSAID-induced ulcers zole, lansoprazole, rabeprazole, pantoprazole and
are gastric rather than duodenal, and becuase one esomeprazole) as primary prophylaxis for NSAID-
cannot predict which type of NSAID-induced ulcer induced ulcers has become an attractive strategy for
will develop, H2RAs have not been ideal drugs for many clinicians. Support for this comes from studies
NSAID-induced ulcer prophylaxis. While famotidine, demonstrating omeprazole to be more effective than
when administered at a “high” dose (40 mg twice ranitidine (150 mg BID) or than misoprostol (200
daily), has been shown to reduce NSAID-induced mcg twice daily) for the prevention of NSAID-in-
duodenal and gastric ulcers in one report,18 other duced gastric and DUs. PPIs are currently the drug of
studies of high-dose H2RA have not demonstrated choice to prevent NSAID- or aspirin-induced ulcers.
Treatment of NSAID-induced ulcers is more
straightforward than prophylaxis. When attempt-
approved for the prevention of NSAID-related ulcer-
ation. It is a synthetic prostaglandin analogue that NSAID if medically feasible. Then rapid ulcer healing
reduces both endoscopic NSAID-induced gastric and can be achieved by treatment with standard doses
duodenal ulceration when given at full dose (800 of H2RA, PPIs, sucralfate, or misoprostol. For those
mcg/day). The disadvantages to using misopro- patients who develop gastroduodenal toxicity from
stol are that it frequently causes diarrhea and it is NSAIDs (including aspirin) and yet must continue
not effective in treating dyspepsia associated with with these medications due to their ongoing medical
NSAIDs. The development of a combination tablet problems, secondary prophylaxis of further peptic
of misoprostol and the NSAID diclofenac is associ- ulcer disease is necessary. Proton pump inhibitors
ated with a reduction in side effects, such as diar- are superior to H2RA, misoprostol, and placebo in
rhea, and has a favorably low ulceration rate. In a preventing further GI bleeding in those patients who
must continue NSAID or aspirin therapy. were monitored throughout the study. Patients tak-
status should be determined, and the bacteria should
be eradicated if present. If patients must resume decrease in peptic ulcer disease compared to those
NSAIDs, a COX-2 selective NSAID at the lowest effec- taking placebo.20 A small study assessed famotidine
tive dose plus daily PPI is recommended if medically 20 mg twice daily compared with placebo in patients
feasible. 19 More studies are necessary and the health taking aspirin for vascular prevention. The study did
risks from COX-2 inhibitors must also be considered not control for dose of aspirin or other cardioprotec-
in these situations. tive drugs, and approximately 20% of study patients
did not have their end-of-study endoscopy. However,
Specific Situations
Endoscopic studies of peptic ulcer disease in those patients taking placebo
- compared with famotidine.21 Further randomized
onstrated incidences of ulceration of approximately RAs can
2
3–5% (similar to placebo) when compared to tradi- reduce GI bleeding in the setting of aspirin use. The
tional NSAIDs, which have a 20–40% incidence of need for aspirin in patients with low-dose aspirin-
endoscopic ulcers. However, endoscopic ulceration associated bleeding ulcers should be re-assessed.
is generally asymptomatic; thus, the more clinically If given for secondary prevention, then the aspirin
meaningful data are those that report incidences of should be continued shortly after the bleeding event
serious GI adverse events such as perforation, pain, has ceased and daily PPI should be given as well. If
or bleeding. Prospective randomized controlled tri- the aspirin is for primary prevention, antiplatelet
als have reported that COX-2 inhibitors are associated therapy should likely be discontinued. 19
with reductions in upper GI complications when com- Aspirin and clopidogrel
pared to nonselective NSAIDs. However, concomitant are used as dual therapy after cardiac catheterization
use of low-dose aspirin may reduce or eliminate any with stent placement, in patients with unstable an-
- gina, after a non-ST elevation myocardial infarction,
more, although COX-2 inhibitors are associated with or after a cerebrovascular event. Given the increased
reduced GI toxicity, increased adverse events in other risk of gastrointestinal hemorrhage, these patients
systems (particularly cardiovascular events) reduce were generally prescribed proton pump inhibitors
- to help reduce potential side-effects. Recently, it has
pared to traditional NSAIDs, particularly in older pa- been suggested that PPIs might interfere with clopi-
tients who may be at risk for cardiovascular disease.
Low-dose aspirin is used routinely for events, owing to both PPI and clopidogrel metabo-
primary and secondary prevention of cardiovascular lism by CYP2C19. Theoretically, PPI may limit the
and cerebrovascular events. The distribution of pa-
tients using aspirin is skewed toward an older pop- omeprazole, the most potent inhibitors of CYP2C19
ulation; this same population is more at risk for GI in studies. Bhatt et al 22 in a randomized dou-
complications of aspirin use. Aspirin has been found ble-blind trial showed less bleeding in the PPI group
to be associated with a 2- to 4-fold increase in upper and no evidence of a cardiovascular interaction be-
gastrointestinal events. Enteric-coated aspirin theo- tween Omeprazole and Clopidogrel. However, the
retically could help lessen these side effects; however,
the data do not support this. One study assessed pa-
tients over the age of 60 on low-dose aspirin therapy out an effect. 23 A systematic review of the multiple
without gastroduodenal ulcer at baseline. These pa- trials involving proton pump inhibitors and clopido-
tients were randomized to receive esomeprazole 20 grel concluded that an adverse effect of PPI use on
mg or placebo along with their aspirin over 26 weeks. clinical outcome in patients on clopidogrel cannot be
Endoscopic appearances and clinical symptoms substantiated. 24
ing to endobronchial colonization. Sucralfate is less

- effective at preventing stress-induced ulceration,
sion. Serotonin itself is thought to be crucial for the though it is less likely to cause nosocomial pneu-
promotion of platelet aggregation; blocking uptake -
of serotonin into platelets may impair hemostatic phylaxis should be examined for each patient on an
mechanisms. A population-based case-control study individual basis.28
determined that there is a modest increase in up-
per GI bleeding in those patients who use SSRIs.25
The addition of a SSRI to an NSAID did not increase Gastric Bypass and Peptic Ulcer Disease
bleeding risk more than NSAID use alone, but PPI co- Given the increasing prevalence of obesity, gastric
bypass surgeries have markedly increased in recent
of GI bleeding. years and will likely continue to do so. There are
now multiple types of surgeries including Roux en
Y gastric bypass, sleeve gastrectomy, and lap band
Stress-Induced Ulcer Disease surgery. Complications of these operations are com-
Stress ulcers are usually located in the gastric fundus mon and include peptic ulcer disease. Data are lack-
and body, and occur in critically ill patients in inten- ing to support the common practice of preoperative
sive care units (ICUs) (particularly patients with ex-
tensive burns or cranial trauma). They are typically and eradicating HP prior to surgery. Postoperatively,
multiple and shallow and have a tendency to present patients presenting with persistent upper abdominal
with hematemesis or melena. The etiology of stress symptoms including nausea, vomiting, and abdomi-
ulcers is multifactorial, though they originate from nal pain should be evaluated with upper endoscopy.
mucosal ischemia secondary to reduced mesenteric In Roux en Y gastric bypass, marginal ulcers are typi-
vascular perfusion associated with severe illness. Im- cally seen 1–6 months after surgery and occur at the
paired mucosal protection and oxidative stress also gastrojejunal anastomosis (usually on the intestinal
contribute to the ongoing process of epithelial necro- side). The etiology of these ulcers is thought to be
sis and mucosal ulceration.26 due to local ischemia, staple-line disruption, the ef-
Not all patients in ICUs require stress ulcer fects of gastric acid on exposed intestinal mucosa,
prophylaxis, however. One large study of 2252 ICU and the presence of staples or suture material.29 HP
is also a risk for marginal ulceration. Smoking and
stress ulcer bleeding: mechanical ventilation for NSAID use were both found to be independent pre-
>48 hours, and coagulopathy (platelets <50,000 or dictors of marginal ulcer occurrence; PPI use was
INR >1.5).27 found to be protective.30
other studies include previous history of peptic ul-
failure, sepsis, burns over 35% of the body, gluco- Other Causes of Peptic Ulcer Disease
corticoid therapy (>250 mg hydrocortisone or the When testing is negative and there is no his-
equivalent), and severe head or spinal cord injury. tory of NSAID use, other etiologies of PUD should be
Both oral and intravenous H2RAs and PPIs effec- considered (Table 2.5). The possibility of malignancy
tively raise gastric pH and reduce the frequency of should always be entertained, especially for gastric
GI bleeding in ICU patients. H2 ulcers that fail to heal after antisecretory therapy,
are limited by the development of patient tolerance. and all gastric ulcers should be biopsied.
Both medications might increase the risk of noso- Viral etiologies from Herpes simplex type I or cy-
comial pneumonia through increased gastric pH tomegalovirus ( ) should be suspected in immu-
promoting the growth of bacteria (especially gram nocompromised or post-transplant patients. However,
negative bacilli) along the endotracheal tube, lead-
has been reported in association with PUD in Table 2.5

nonimmunocompromised hosts after blood transfu- Etiologies of Gastric or Duodenal Ulcers
sions or even with no known predisposing factors.
Very common
Gastric, duodenal, and more distal intestinal ul-
Helicobacter pylori
cers have been reported with the use of crack and
Nonsteroidal anti-inflammatory drugs
intranasal cocaine, and mesenteric ischemia is the
Less common
suspected pathophysiologic basis in these cases.
Gastric malignancy (adenocarcinoma or lymphoma)*
Crohn’s disease can be associated with ulcers in any
Stress ulceration
location from the mouth to the anus; however, gas-
Viral infections (Herpes simplex type I or cytomegalovirus)*
troduodenal ulceration secondary to Crohn’s disease
Uncommon or rare
is uncommon. When Crohn’s disease does involve the
Zollinger-Ellison syndrome
stomach and duodenum, it almost always is associat-
Cocaine-induced ulcers*
ed with concurrent terminal ileal disease; therefore,
Crohn’s disease*
the small intestine and colon should also be evalu-
Treponema pallidum*
ated for evidence of disease in such cases.
Systemic mastocytosis
Localized radiation therapy, sarcoidosis, and
Myeloproliferative disorders with basophilia
medications (including oral iron tablets, bisphos-
Idiopathic (non–H. pylori) hypersecretory duodenal ulcer
phonates, sirolimus, and other chemotherapeutic
Abdominal radiotherapy*
medications) have been associated with PUD and
Hepatic artery infusion of 5-fluorouracil*
gastropathy.
*These etiologies are likely not related to acid-peptic processes.
Overproduction of histamine leading to acid
hypersecretion can occur in systemic mastocytosis,
basophilic leukemia, or with carcinoid tumors. Other for women is up to 5.6 mmol/hour. Normal ranges
less common causes of acid hypersecretion include for PAO in men and women are 11.6–60 mmol/hour
increased intracranial pressure (related to increased and 8.0–40 mmol/hour, respectively. Acid hyper-
vagal stimulation) and extensive small bowel resec-
tion. Following gastric acid reductive surgery such as va-
Despite extensive investigation, a small propor- gotomy or parietal gastrectomy, a BAO of >5 mmol/
tion of cases of peptic ulcer appear truly idiopathic; hour is consistent with a hypersecretory state. Most
prolonged high-dose PPI therapy may be advisable disease states associated with acid hypersecretion
for such cases.31 will have elevated levels of one of the hormones
that drive parietal cell secretion, most commonly
gastrin or histamine, which can lead to increased
Acid Hypersecretory States parietal cell secretion and, over time, to increased
Most patients with ulcers related to NSAIDs or HP parietal cell mass.
will have normal ranges of gastric acid secretion.
Though rarely measured now in clinical practice,
gastric acid secretion may be expressed either (1) Zollinger-Ellison Syndrome
as acid secretion in the unstimulated or fasting state Patients with Zollinger-Ellison syndrome (ZES) have
(basal acid output or BAO), or (2) as acid secretion elevated serum gastrin concentrations and basal acid
after stimulation by intravenous pentagastrin (ei- hypersecretion that is caused by a gastrinoma, a tu-
mor of gastrin-secreting G cells.32 The tumor is usu-
sum of the two highest 15-minute outputs of gastric ally located in the pancreas or duodenum, and exces-
sive secretion of gastrin is responsible for the clinical
measured continually for 1 hour). The normal range features of ZES. Approximately 75% of ZES patients
of BAO in men is up to 10 mmol of H+ ions/hour, and will have the sporadic syndrome; however, 25% of
patients will have ZES in association with the mul- diarrhea by (1) overwhelming enterocyte reabsorp-
tiple endocrine neoplasia type 1 (MEN-1) syndrome. tion capacity, (2) decreasing lipase activity (by acidi-
MEN-1 is an autosomal dominant condition due usu- fying the distal duodenum and jejunum, thus inter-
ally to a mutation in the gene encoding menin. Clinical fering with the alkaline pH environment optimum
features include hyperparathyroidism, gastrinoma or for effective pancreatic enzyme function), and/or
other islet cell tumors, and anterior pituitary tumors. (3) interfering with micelle formation. ZES-induced
The true incidence and prevalence of gastrinomas are diarrhea can cause hypokalemia that may become
unknown, although ZES may be present in up to 1% of life threatening due to cardiac arrhythmias or renal
all DU patients in the United States. The average age tubular damage. The continual attenuation of pan-
range at diagnosis is 45–50, and there is a slight male creatic lipase activity may lead to steatorrhea and
predominance. weight loss.
ZES may present with severe, multiple or refrac-
tory DUs, ulcers in unusual sites (such as the distal Diagnosis of Zollinger-Ellison Syndrome
duodenum and jejunum), ulcer complications, severe The clinical presentation of a patient with multiple,
esophagitis, and/or unexplained diarrhea (see be- refractory, and/or recurrent PUD, especially if ac-
low). infection usually is not present. The companied by diarrhea, should prompt measure-
diagnosis should be considered in patients with ul- ment of the fasting plasma gastrin. In the absence of
cers that recur frequently, ulcers that require large ZES, patients with PUD usually have a fasting serum
doses of medication for healing, HP-negative DUs, ul- gastrin concentration of <100 pg/ml (or <150 pg/ml
cers that occur in the absence of NSAIDs, and always if infected by HP). The diagnosis of ZES is strongly
in patients with both DUs and diarrhea. suggested by elevated serum gastrin concentration
of >1000 pg/ml in a patient who is not achlorhydric
Pathophysiology of Zollinger-Ellison (gastric pH check at endoscopy of <3).32 Conversely,
Syndrome ZES can be ruled out as a cause of hypergastrinemia
The essential pathophysiological feature of ZES is an if the gastric pH is not acidic.
extremely elevated level of circulating gastrin with In patients with ZES, the gastrin level is almost
the primary target being parietal cells.33 Since gas- always >150 pg/ml and some patients may have
trin is also a trophic hormone for the oxyntic (acid levels >100,000 pg/ml. It is important that serum
secreting) mucosa of the gastric corpus, large gastric gastrin be determined in a fasting state and that
folds may be evident at endoscopy, and gastric acid the patient not be taking antisecretory drugs, since
hypersecretion is characteristic. Unlike normal G cell treatment with a PPI may elevate fasting gastrin lev-
secretion of gastrin that is subject to negative feed-
back, the excess and autonomous secretion of gastrin withdrawal to distinguish appropriate from inap-
by a gastrinoma is not inhibited by meals or by soma- propriate hypergastrinemia in patients with ZE can
tostatin release. Hence, ZES patients typically have be potentially dangerous and should be performed
markedly and consistently elevated serum gastrin carefully. Acid inhibition (either therapeutic, or due
levels, and the BAO is usually 10 times higher than in to diseases such as atrophic gastritis from pernicious
normal adults (Figure 2.4). anemia) causes high gastrin levels by abolishing the
The increased acidic burden on the stomach and normal negative inhibition of gastrin secretion on
small bowel eventually causes severe complications acid release. Indeed, patients with pernicious anemia
in most ZES patients. Approximately 90% develop associated with achlorhydria may have serum gas-
ulcers, usually in the duodenal bulb, but also in the trin levels of 1000 pg/ml or greater, and hypergas-
- trinemia may be due to multiple other causes (Table
cult to heal and may require high doses of PPIs to 2.6). Therefore, it is necessary to document gastric
reduce acid secretion. The sheer volume of acidic acid hypersecretion for the diagnosis of ZES by mea-
surement of basal acid output (BAO) and peak acid
output (PAO) following pentagastrin stimulation. Treatment of ZES

Both BAO and PAO are typically increased in ZES, The main objective of treatment is to control acid hy-
and the ratio of BAO:PAO is also increased. A BAO of persecretion, which can be effectively achieved by PPI
greater than 15 mEq/h in this setting is very sugges- therapy. These drugs are often required in high dos-
tive of ZES. Since gastric secretory studies are now es and should be given twice daily.33 The dose of PPI
rarely performed, referring atypical cases to centers should be titrated until the BAO immediately before
capable of these analyses should be considered, es- the next scheduled dose is <10 mmol/hour daily. Va-
pecially for atypical cases. gotomy may help to control acid hypersecretion, but is
- generally unnecessary in patients treated with a PPI. If
tients with equivocal or otherwise undiagnosed possible, the primary tumor should be resected since
hypergastrinemia. In this test, serum gastrin is surgery provides a survival advantage over medi-
measured before and after injection of intravenous cal therapies, based upon a retrospective analysis.34
secretin. The normal response is a fall in serum gas- However, this may not be possible due to inadequate
trin; however, patients with ZES display a paradoxi- tumor localization or the presence of distant metas-
cal increase of >200 pg/ml after a bolus infection of tases (seen in up to 50% of patients at the time of di-
secretin at a dose of 2 U/kg. False-positive tests can agnosis). Gastric carcinoid tumors of ECL cells may
occur, in patients with achlorhydria, G-cell hyperpla- complicate ZES that is part of the MEN-1 syndrome.
sia, infection, gastric atrophy and chronic These gastric carcinoids develop secondary to pro-
PPI exposure. longed and extreme gastrin hypersecretion, do not se-
Once the diagnosis of ZES is established bio- crete peptides to cause a carcinoid syndrome, and are
chemically, it is important to consider whether the rarely malignant. Nevertheless, the presence of mul-
patient has MEN1 (through measuring calcium and tiple pancreatic gastrinomas and the frequent occur-
rence of lymph node metastases at diagnosis usually
analysis) and then to try and localize the neoplasm. precludes curative surgery in MEN-1 cases.
Since the primary tumor may be tiny, detailed radio-
logic studies are often necessary. Diagnostic tech- Table 2.6
niques that have been used for preoperative local- Differential Diagnosis of Hypergastrinemia
ization of gastrinomas include CT scans, abdominal
ultrasonography, endoscopic ultrasonography, mag- Appropriate (pH >2)
netic resonance imaging (MRI), abdominal arteriog- Antisecretory therapy/vagotomy
raphy, selective portal venous sampling for gastrin, Atrophic gastritis (autoimmune pernicious anemia)
selective arterial stimulation of secretion, and scan- H. pylori pangastritis
ning with radiolabelled octreotide, a somatostatin Vagotomy
Inappropriate (pH <2)
analog (Table 2.7). Since gastrinomas express a high
Zollinger-Ellison syndrome
density of somatostatin receptors, nuclear scanning
Retained antrum
following injection of radiolabeled octreotide pro-
Antral G cell hyperfunction (antral-predominant H. pylori
vides a noninvasive means to localize gastrinomas, infection)
with a sensitivity of approximately 65%. The sen- Gastric outlet obstruction
sitivities of various diagnostic modalities in localiz- Massive intestinal resection
ing gastrinomas are shown in Table 2.7. Since many Chronic renal failure
gastrinomas will be located in the duodenal mucosa
or the pancreatic head, upper endoscopy with endo- Adapted from Murugesan SV, Varro A, Pritchard DM. Review ar-
scopic ultrasound is often valuable in the diagnostic ticle: Strategies to determine whether hypergastrinaemia is due to
evaluation. Despite all attempts to image the primary Zollinger-Ellison syndrome rather than a more common benign cause.
lesion, diagnostic laparotomy may still sometimes be Aliment Pharmacol Ther 2009;29:1055–68.
necessary.
Table 2.7 concentrations and acid secretion due to a concomi-

Prospective Studies of Gastrinoma Detection tant gastrinoma. However, in patients with hyper-
parathyroidism without the MEN-1 syndrome, or in
Method Detection rate
those with hypercalcemia from other causes, there
CT/MRI 10–40% (much higher % if metastatic) is no clear association with gastric acid hypersecre-
Angiography 20–50% tion. In patients with antral G cell hyperplasia, there
is basal hypergastrinemia that is markedly increased
Octreotide scan 60–70%*
by eating. Since hyperplasia of G cells can only be ac-
EUS up to 80%† curately determined by evaluation of the stomach
NOTES after total gastrectomy, a preferred terminology for
this syndrome is antral G cell hyperfunction.
*Changes management in 15–45%.
†Pancreas>duodenum; highly operator dependent.
From Jensen RT, Niederle B, Mitry E, et al. Frascati Consensus Conference;
European Neuroendocrine Tumor Society. Gastrinoma (duodenal and pancreatic).
Neuroendocrinology 2006;84:173–82.
Nonulcer Dyspepsia
Dyspepsia constitutes a heterogeneous group of up-
per GI symptoms including epigastric fullness, pain,
discomfort, belching, bloating, nausea, and food in-
Other Diseases Associated with Gastric tolerance. Nonulcer dyspepsia and functional dys-
Acid Hypersecretion pepsia are terms commonly used after negative rou-
tine evaluations of dyspeptic patients (for example,
The retained antrum syndrome is a rare complica-
with endoscopy, ultrasound, and CT scans). The en-
tion that can follow antrectomy and Billroth II gas-
tity described as NUD probably includes a variety of
trojejunostomy in which a small portion of the an-
distinct gastric pathophysiologic abnormalities, in-
trum (with its pyloric glands and gastrin producing
cluding gastric dysmotility, gastroparesis, impaired
G cells) is not resected and is consequently left at-
postprandial fundic accommodation, delayed gas-
tached to the duodenal bulb (afferent loop). In the in-
tric emptying, and visceral hypersensitivity, as well
tact stomach, G cell function is normally inhibited by
as truly idiopathic symptomatology. The relationship
H+ ions in the gastric lumen; however, in the retained
of gastric abnormalities to symptoms is usually un-
antrum syndrome, G cells have been surgically dis-
clear, and psychosocial factors may also play a role.
placed from the stomach and are no longer exposed
Testing for most pathophysiologic defects requires
to the inhibitory effects of gastric acid. Therefore,
relatively invasive tests such as gastric scintigraphy
there is no negative feedback on gastrin production
or electrogastrography, which are not widely avail-
from G cells in the afferent limb, leading to continu-
able. Testing for these abnormalities, beyond the
ally high serum gastrin concentrations that stimulate
routine diagnostic tests mentioned above, is not war-
excessive amounts of gastric acid secretion in the re-
ranted in routine clinical practice.
maining stomach. These patients can develop post-
Currently there is no proven effective therapy
operative ulcer recurrence and hypergastrinemia ac-
for NUD. Acid inhibitory therapy with PPIs may lead
companied by a negative secretin test.
to complete symptom relief in 25–50%.35 The proki-
Patients with chronic gastric outlet obstruction
netic agents cisapride and domperidone are effective
can develop hypergastrinemia and increased gas-
in a small number of patients, but are not available in
tric acid secretion. It is likely that either the chronic
gastric distention or the persistent stimulation by
(alosetron, granisetron, and ondansetron) in NUD
food retained within the stomach leads to increases
has not been conclusively demonstrated. Tricyclic
in gastrin and acid secretion. Patients with hyper-
antidepressants are widely used in the treatment of
parathyroidism may have the MEN-1 syndrome and
functional gastrointestinal disorders despite a lack
can therefore present with increased serum gastrin
of large, controlled studies. Psychological therapies,
such as cognitive-behavioral therapy, may be helpful

PPIs are currently the drug of choice to prevent
in selected patients.36
NSAID- or aspirin-induced ulcers
In any particular NUD patient, treatment is em-
If aspirin is given for secondary prevention but leads
pirically directed toward the principal symptoms. If
to low-dose aspirin-associated gastrointestinal
the principal manifestation is dyspepsia, antisecre-
bleeding, then the aspirin should be continued
tory therapy should be given; simethicone may help
shortly after the bleeding event has ceased and daily
belching and gas; and prokinetic agents should be
PPI should be given as well.
considered for symptoms suggestive of gastropare-
If the aspirin is for primary prevention and low-
sis. Patients with NUD that is refractory to empiric
dose aspirin-associated bleeding has occurred,
therapy should be tested for HP and treated if infect-
antiplatelet therapy should likely be discontinued.
ed. However, the majority of well-designed interpre-
While there is a theoretical interaction between PPI
and Clopidogrel, recent studies have not supported
associated with nonulcer dyspepsia will be low.
a worsened clinical outcome. More studies are
necessary.
Not all patients in the ICU require stress-ulcer
Pearls and Pitfalls prophylaxis. Major risks include mechanical
ventilation for >48 hours, and coagulopathy
for the Board Exam (platelets <50,000 or INR >1.5)
Somatostatin inhibits gastrin and gastric acid
Roux en Y gastric bypass can lead to marginal ulcers.
secretion.
Modifiable risk factors include H. pylori, NSAID use,
Vitamin B12 malabsorption may result from each
and smoking.
of the following: autoimmune gastritis, PPI
Hypergastrinemia may be due to a gastrinoma
use, pancreatic exocrine insufficiency, bacterial
(Zollinger-Ellison syndrome) - usually sporadic but
overgrowth, and terminal ileal resection.
occasionally (25% of cases) in MEN1 syndrome.
H. pylori is associated with PUD, chronic gastritis,
Acid secretion is greatly increased. Other causes
gastric cancer and MALT lymphoma, but is inversely
of hypergastrinemia are secondary to achlorhydria/
related to (“protective against”) esophageal
hypochlorhydria from PPI use or autoimmune
adenocarcinoma.
gastritis. Rare causes: retained antrum syndrome
Testing for H. pylori: sensitivity of tests of active
(with high acid output), pyloric obstruction.
infection are decreased by PPI use.
Non-ulcer dyspepsia treatment should be symptom-
Testing for H. pylori: serology significantly less
sensitive/specific/accurate than biopsy urease/ based.
histology/breath test/stool tests. Serology is
unreliable as a test of cure.
NSAIDs inhibit cyclooxygenase, thereby decreasing
prostaglandin synthesis. Protective mechanisms are Most Efficient Source Reviews
impaired (secretion of mucus and bicarbonate) and for Examination Preparation
there is a reduction in blood flow, leading to injury.
Lanza F, Chan F, Quigley E et al. Guidelines for
Those at highest risk for NSAID-induced
prevention of NSAID-related ulcer complications.
gastrointestinal complications have a history of
Am J Gastroenterol 2009;104:728–738.
ulcer or GI hemorrhage in the past.
Quenot J, Thiery N, Barbar S. When should stress
Other high-risk patients for NSAID-induced bleeding
ulcer prophylaxis be used in the ICU? Curr Opin Crit
include those over the age of 65, those on higher doses
Care 2009;15:139–143.
of NSAIDs, and those on concomitant corticosteroids
Talley NJ, American Gastroenterological Association.
or anticoagulants. H. pylori infection increases the risk
American Gastroenterological Association medical
of NSAID-related GI complications.
ple vs. triple therapy for primary treatment of Helicobacter

position statement: Evaluation of dyspepsia. Gastro- pylori infection: Systematic review and meta-analysis of
enterology 2005;129:1753-80. efficacy and tolerability. Am J Gastroenterol 2010;105:65–
Chey WD, Wong BC, Practice Parameters Committee 73.
of the American College of Gastroenterology. 13. Gatta L, Vakil N, Leandro G, et al. Sequential therapy
American College of Gastroenterology guideline on or triple therapy for Helicobacter pylori infection: sys-
tematic review and meta-analysis of randomized con-
the management of Helicobacter pylori infection.
trolled trials in adults and children. Am J Gastroenterol
Am J Gastroenterol. 2007;102:1808-25. 2009;104:3069–79.
Bhatt, DL. ACCF/ACG/AHA 2008 Expert Consensus 14. Greenberg ER, Anderson GL, Morgan DR et al. 14-day tri-
Document on Reducing the Gastrointestinal Risks ple, 5-day concomitant, and 10-day sequential therapies
of Antiplatelet Therapy and NSAID Use. Am J for Helicobacter pylori infection in seven Latin American
Gastroenterol 2008;103:2890-2907. sites: a randomized trial. Lancet 2011;378:507-14.
15. Lanza F, Chan F, Quigley E et al. Guidelines for prevention
of NSAID-related ulcer complications. Am J Gastroenterol
2009;104:728–738.
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CHAPTER 3
Gastrointestinal Motility
Seth Sweetser, MD and Karthik Ravi, MD
Learning Objectives
1. Review the essential features of the neuromuscular control of motility.
2. Review the normal anatomy, innervations, and physiology of esophageal peristalsis, gastric emptying, small intestinal transit, and colonic
emptying.
3. Describe the spectrum of symptoms, diagnostic criteria, manometric subtypes, complications, and treatments for achalasia.
4. Review the diagnostic criteria and treatment for gastroparesis.
5. Recognize important neuropathic and myopathic causes of chronic intestinal pseudo-obstruction.
6. Highlight pathophysiological abnormalities in selected colonic motility disorders, including Ogilvie’s syndrome, Hirschsprung’s disease, and
irritable bowel syndrome.
Neuroenteric Control of Gastrointestinal Motor Function

Motor function of the gastrointestinal (GI) tract depends on the contraction of smooth muscle cells and their
integration and modulation by enteric and extrinsic nerves.1 Neurogenic modulators of gastrointestinal mo-
tility include the central nervous system, autonomic nerves, and enteric nervous system.
Extrinsic neural control of gastrointestinal motor function consists of the cranial and sacral parasympa-
to the stomach and small bowel arise from T5 to T10 of the intermediolateral column of the thoracic spinal
cord. Although the vagus nerve projects from the esophagus to the proximal colon, the principal motility
effects are on the foregut, namely the esophagus and stomach. Projections of the vagus nerve directly in-
nervate the pharynx and striated muscle segment of the esophagus. Vagal innervation of the smooth muscle
regions of the GI tract is indirect and via the enteric nervous system (ENS). The vagus nerve is also involved
in secretomotor activity of the stomach and gallbladder. Preganglionic neurons in the sacral (S1–S5) region
Sympathetic neural control originates from preganglionic, cholinergic neurons in the spinal cord that
synapse with postganglionic, noradrenergic neurons in the celiac, superior mesenteric, inferior mesenteric,
and pelvic ganglia. Sympathetic efferent stimulation generally leads to inhibition of GI motor and secretory
function by inhibiting the release of acetylcholine from enteric neurons. These effects are more prominent in
53
the stomach, small, and large bowel. The preverte- The enteric nervous system or “second brain” is
bral ganglia play an important role in the integration comprised of over 100 million neurons that provide
of afferent impulses between the gut and the central local neural control of many functions of the GI tract
- (Figure 3.1). The ENS extends from the esophagus
nal viscera. Visceral afferent nerves course along the to the internal anal sphincter and is organized in two
- major ganglionated structures: one between circular
tion (nociception). There is a chain of three neurons and longitudinal muscle layers, named the myenteric
that conveys afferent information to the visceral cor- plexus or Auerbach’s plexus, and the other between
tex in the insula and to centers involved in conscious muscularis mucosa and circular muscle, named the
sensation, appetite, and emotional response in the submucous or Meissner’s plexus.
brain. The ENS has important roles in normal physi-
ologic states including motility, secretion, microcir-
culation, and immunologic function. More than 20
Figure 3.1
neurotransmitters have been localized to the ENS
Enteric Nervous System
and are involved in these functions. Acetylcholine and
tachykinins are the major excitatory transmitters, and
the inhibitory transmitters, nitric oxide and vasoactive
intestinal peptide (VIP), are co-localized and act syn-
ergistically.
The ENS is connected to the CNS by the parasym-
pathetic and sympathetic nervous systems (Figure
-
Myogenic factors regulate the electrical activ-

ity generated by gastrointestinal smooth muscle cells.
Interstitial cells of Cajal form a nonneural pacemaker
system located at the interface of the circular and lon-
gitudinal muscle layers of the intestine, and function
as intermediaries between the neurogenic enteric ner-
vous system and myogenic control system. Electrical
control activity spreads through the contiguous seg-
ments of the gut through neurochemical activation by
excitatory (e.g., acetylcholine, substance P) and inhibi-
tory (e.g., nitric oxide, VIP, somatostatin) transmitters.
The neural plexuses in the gut represent an independently functioning

network known as the enteric nervous system, which is connected to Esophageal Motility
the central autonomic neural network in the central nervous system
by parasympathetic and sympathetic nerves. The enteric nervous
system may influence the effector systems in the gut that include
smooth muscle directly, or may do so indirectly through its action Specialized Anatomy of the Esophagus
on intermediate cells, which include endocrine cells, the interstitial and Its Sphincters
cells of Cajal, and cells of the immune system, such as mast cells.
The cell bodies of the primary vagal and primary splanchnic afferent The upper esophageal sphincter (UES) is an integral
neurons are located in the nodose ganglia and the dorsal root part of both the esophagus and the pharynx. The
ganglia, respectively; each carries distinct information from the gut
to the central nervous system. muscular elements of the UES are striated muscle,
with the cricopharyngeus, as well as adjacent por-
Chapter 3 — Gastrointestinal Motility 55
tions of the cervical esophagus and the inferior pha- the superior aspect of the ring to the distal aspect of
ryngeal constrictor, contributing to sphincteric func-
tion. The cricopharyngeus muscle receives its motor
nerve supply from the vagus. The two major func-
tions of the UES are to prevent air from entering the Innervation of the Esophagus
esophagus during inspiration and to act as a second-
The proximal (striated muscle) esophagus receives
only excitatory vagal innervation; peristaltic con-
UES pressure can lead to the formation of a cricopha-
traction of this segment and the oropharyngeal mus-
ryngeal bar or Zenker’s diverticulum.
culature results from the sequential activation of mo-
The esophagus is a 20-cm muscular tube with a
tor units by the swallowing center of the medulla.
wall composed of skeletal and smooth muscle. The
In the distal (smooth muscle) esophagus and
proportion of each muscle type is species dependent,
-
but in humans, the proximal 5% including the UES is
rons rather than directly at neuromuscular junctions
striated, the middle 35–40% is mixed with increas-
as in other segments of the gut. Excitatory neurons
ing proportion of smooth muscle distally, and the dis-
mediate contraction of both longitudinal and circu-
tal 50–60% is entirely smooth muscle. The adjacent,
lar muscle layers via nicotinic cholinergic receptors.
inner muscularis propria layer is formed of circular
Inhibitory neurons affect predominantly the circu-
muscle, also forming a sheath throughout the length
lar muscle layer via nitric oxide nerves that, in turn,
of the esophageal body. Unlike the distal GI tract,
inhibit muscarinic cholinergic neurons. There is
there is no serosal layer to the esophagus.
progressively prolonged inhibition with more distal
Both the striated and smooth muscle portions of
esophageal locations, and the same process results
the esophagus contain the myenteric plexus between
in LES relaxation, which is associated with more
the longitudinal and circular muscle. In the smooth
prolonged inhibition. Although facilitated by vagal
muscle portion, these enteric neurons are the relay
-
neurons between the vagus and the smooth muscle;
nize peristalsis, as evidenced by the absence of vagal
their function in the striated muscle esophagus is ob-
activity during secondary peristalsis. A unique fea-
scure. The ganglia of the myenteric plexus are more
ture of the LES is that it maintains a tonic contraction
numerous in the smooth muscle region than in the
at rest by a myogenic mechanism.
striated muscle region of the esophagus. However,
throughout they are far less dense and smaller than
in other regions of the gut. A sparse submucous plex-
Motor Physiology of the Esophagus and Its
us is situated between the muscularis mucosae and
Sphincters
the circular muscle layer of the human esophagus.
The lower esophageal sphincter (LES) is com- Through peristalsis and the actions of the UES and
prised of a circular muscle band contiguous with the LES, esophageal motility facilitates the pharyngogas-
circular muscle of the esophageal body.2 It angles tric transit of food, permits the occasional gastric-pha-
obliquely upward from the lesser to the greater cur- ryngeal transit of gas or food, and keeps the esopha-
vature of the stomach and its maximal thickness is at gus empty at all other times.3 Esophageal peristalsis
the greater curvature. Moving away from this ring, begins at the pharynx; contraction traverses the UES,
muscle thickness decreases. Toward the stomach, progressing at 2–4 cm/sec. The longitudinal muscle
the ring splits into two segments, one forming short also contracts sequentially during peristalsis, tran-
transverse muscle clasps around the esophagus and siently shortening the esophagus by 2.0–2.5 cm.
the other forming long oblique loops to the stomach, Primary peristalsis is initiated by a swallow (Fig-
positioned in such a way as to maintain the angle of ure 3.2), whereas secondary peristalsis is elicited in
His or the angle of entry of the esophagus into the response to esophageal distension. The propagation
stomach. The LES high-pressure zone extends from -
sponds with the manometric contraction such that -

- where in this syllabus. This section will focus on less
oroscopically occurs with the upstroke of the pres- common presentations of sphincter and peristaltic
sure wave. Immediately prior to luminal closure, dysfunction.
an intrabolus pressure is recorded manometrically. Processes of esophageal dysmotility may be ei-
The magnitude of the intrabolus pressure depends ther dysfunctions of deglutitive relaxation (including
failure of sphincter relaxation) and/or of propagated
excitation. Esophageal motor disorders are not di-
intrabolus pressure prior to luminal closure. agnosed on histopathological grounds; diagnosis de-
Recent topographic analyses of the vigor and
propagation of esophageal peristalsis reveal a dis- A possible exception is achalasia in which tissue may
tinct transition zone between the striated and be available, and the condition is characterized by
smooth muscle esophagus. This is characterized by
low peristaltic amplitude, slight delay in progres- cells in the myenteric plexus. Hence, esophageal ma-
sion, and an increased likelihood of failed propaga-
tion distally. The smooth muscle esophagus presents typically used to evaluate peristaltic function. Fig-
two distinct contractile segments that correspond to ure 3.2 is an example of a normal peristaltic wave
double-peaked contractile waves sometimes seen in on esophageal manometry. With the advent of high
manometric recording if the segments are not syn- -
chronized precisely, followed by the LES that con- -
tracts with vigor and persistence quite dissimilar to
the adjacent esophagus.
Another property of peristalsis is deglutitive in- (Table 3.1, Figure 3.3) attempts to address this by
hibition. A second swallow, initiated while an earlier providing a new system in which to group esopha-
peristaltic contraction is still progressing in the stri-
ated muscle segment of the esophagus, inhibits the manometry.4 However, further clinical experience is
needed to determine how high resolution manom-
last swallow in a series, a normal peristaltic con- etry and the abnormalities detected by it will impact
traction occurs. Basal LES tone is inhibited with the evaluation and clinical management of patients
swallowing concurrently with deglutitive inhibition. with esophageal motility disorders.
Inhibition occurs distal to the oncoming peristaltic A common reason for patient referral to the
contraction in the tubular esophagus and the duration esophageal motility lab is chest pain. However, it is
important to remember that cardiac related chest
and excitatory myenteric plexus neurons at each lev- pain is the most important consideration in these
el, and hence it determines the propagation velocity patients. In fact for patients with new onset chest
of esophageal peristalsis. If the effects of inhibitory pain, the odds ratio for ischemic heart disease is
nerves are blocked, simultaneous esophageal contrac- -
tion occurs. tic ulcer disease. In patients with noncardiac chest
5
pain, esophageal acid exposure is the most likely eti-

ology. Consequently a four week trial of maximum
Esophageal Motility Disorders strength proton pump inhibitors (PPI) is warranted.
However, in patients without clinical response to PPI,
and Chest Pain extending the medication trial beyond this has not
Retained material within the esophagus or excessive 6
disorders are in fact a rare cause of noncardiac chest

of peristalsis or of sphincter competence.3 LES in- pain. Consequently esophageal manometry should
Figure 3.2
Normal Manometric Recording of Esophageal Peristaltic Contraction
As shown to the left, low pressure is shown in blue while high pressure in yellow and red. The proximal sensors are positioned at the UES while the distal sensors
below the LES in the gastric body. Note that LES relaxation commences early in the swallow, prior to the onset of contraction above the LES and nearly concurrently
with relaxation of the upper esophageal sphincter. Note that propagation of the peristaltic contraction is demonstrated as an isobaric pressure contour from the
proximal to distal esophagus.
be reserved for patients who do not have pathologic phagia, or intermittent esophageal obstruction. The
ability of the dysphagic patient to localize esophageal
major motor abnormality such as achalasia. obstruction is inaccurate because 30% of patients
In contrast, dysphagia is a fundamental symp- with a distal esophageal obstruction will perceive
tom of esophageal motility disorders. The two basic it at the level of the suprasternal notch. Thus, the
types of dysphagia are oropharyngeal and esopha- entire esophagus should be evaluated regardless of
geal.7 Oropharyngeal dysphagia is suggested by the where the patient localizes the dysphagia. The his-
presence of associated coughing, choking, or nasal tory is suggestive of a motor disorder when there is
regurgitation of oral residue upon initiation of swal-
lowing. Esophageal dysphagia is suggested by asso- only solids, which is more indicative of mechanical
ciated heartburn, regurgitation, chest pain, odyno- obstruction.
Figure 3.3
Chicago Classification
Flow diagram for the diagnosis of esophageal motility disorders using the Chicago classification. The first step is assessment for achalasia or
outflow obstruction, defined by elevated IRP with or without peristalsis. Minor motor abnormalities are the final branch point and are defined
by normal lower esophageal relaxation with weak or hypertensive peristalsis. Adapted from Breenoord AJ. Neurogastroenterol Motil 2012;
24: 57-65
of which is the cricopharyngeus. In some patients,

Cricopharyngeal Dysfunction the cricopharyngeus muscle can become prominent,
Dysfunction of the upper esophageal sphincter demonstrating posterior indentation at the level of
- the cricoid cartilage on an esophagram and resulting
gia. The UES itself is best characterized as a complex in dysphagia. Despite its potential etiologic role, it
consisting of multiple muscles, the most prominent is important to note that cricopharyngeal bars are
Table 3.1
Definitions of Esophageal manometric metrics in the Chicago classification scheme
Manometric metric Definition
Integrated Relaxation pressure Mean pressure of the esophagogastric junction for 4 contiguous or noncontiguous
(mm Hg) seconds of lowest pressure during a 10 second window following UES relaxation.
Distal contractile Integral
Product of amplitude, duration, and length of distal esophageal contraction
(mm Hg x s x cm)
Contractile front velocity
slope of the 30mmHg isobaric contour defining distal esophageal peristalsis
(cm/s)
Time from UES relaxation to point in the distal esophagus where the slope of the
Distal latency (s)
isobaric contour changes, indicative of the phrenic ampulla
Peristalsis breaks (cm) Distance of breaks in the 20mmHg isobaric contour of peristalsis
(Adapted from Bredenoord AJ. Neurogastroenterol Motil 2012; 24: 57-65)
often found in asymptomatic patients. In fact, a cri-

copharyngeal bar is seen in the majority of patients
- structural changes that would decrease UES com-
tients undergoing a routine esophagram.7, 8 Conse-
quently, prior to pursuing treatment it is imperative pressure or tension). Thus, although the muscle re-
to rule out other potential causes of dysphagia. Sur- laxes normally during a swallow, it cannot distend
gical myotomy is the traditional treatment approach, normally, resulting in reduced UES opening and the
although aggressive endoscopic dilation has been appearance of a cricopharyngeal bar (Figure 3.4, left)
shown to be effective as well.9 on a barium swallow with increased intrabolus pres-
The most common manifestation of cricopharyn- sure above the cricopharyngeus during swallowing.
geal dysfunction is the development of a hypopha- The elevated intrabolus pressures result in increased
ryngeal (Zenker’s) diverticulum, with an estimated hypopharyngeal wall stress (Figure 3.4, right).
prevalence of 0.01 to 0.11%.10,11 Zenker’s diverticula The treatment of hypopharyngeal diverticula is
are hypopharyngeal pouches composed of mucosa, cricopharyngeal myotomy with a diverticulectomy.
submucosa, and connective tissue. They are more Diverticulectomy alone may be followed by recur-
common in men and typically occur in the seventh rence, because the underlying resistance at the level
or eighth decades of life. Patients typically present of the cricopharyngeus is not remedied; myotomy
with dysphagia, although symptoms such as halito- alone does not resolve the problem of food accu-
sis, regurgitation, and cervical borborygmi may also mulation within the diverticulum, with attendant
be present. The most frequent site of herniation is in risks of regurgitation and aspiration. The criteria
a midline area of pharyngoesophageal wall between for performing a myotomy should be the presence
-
tor and the cricopharyngeus muscle, referred to as -
the triangle of Killian, where a dehiscence can occur function by videoradiography, preferably with con-
and lead to the formation of a diverticulum. While current manometry; and the absence of clinically
Zenker’s diverticula result from increased intrap-
haryngeal pressure, the precise etiology is unclear. Although myotomy is a relatively safe procedure and
One proposed mechanism is restrictive myopathy can be performed with only local anesthesia, sudden
of the cricopharyngeus. Surgical specimens of cri- death from aspiration is a reported complication,
copharyngeus muscle strips from patients treated emphasizing the need to assess LES competence pre-
Figure 3.4 the smooth muscle esophagus (Figure 3.5). While

Cricopharyngeal Dysfunction classically described as elevated, it is important to
note that resting LES pressure is normal in up to 50%
of patients with achalasia.
Achalasia occurs as a result of degeneration of
ganglion cells in the myenteric plexus of the distal
esophageal body and LES. While the exact etiology
of this degeneration is unknown, the co-existent in-
including autoimmune, viral immune, or neurode-

generative mechanisms. Regardless of the etiology,
this degeneration leads to a disproportionate loss
of inhibitory input via nitric oxide (NO) compared
to excitatory input via acetylcholine. As a result, the
timed release of NO, which is responsible for peri-
Left: Appearance of a cricopharyngeal bar during a barium swallow due to inability of stalsis in the esophageal body, and NO mediated LES
the upper esophageal sphincter to distend normally. Right: Development of Zenker’s relaxation are both lost leading to the characteristic
diverticulum as an eventual consequence of increased pressure on the hypopharynx.
operatively. If the myotomy is essential in this cir- cause. In Chagas disease, ganglion degeneration
results from Trypanasoma cruzi infection. This re-
addition, such an approach may be problematic in sults in achalasia as well as associated conditions
elderly patients in whom the need for neck hyperex- such as megacolon, cardiomyopathy, and neurologic
tension may preclude repair. For such patients, an disorders. The most common cause of secondary or
endoscopic approach with division of the septum be- pseudoachalasia is the result of direct tumor inva-
tween the esophagus and diverticulum as well as the sion of the gastroesophageal junction. This typically
cricopharyngeus contained within it has proven ef- is related to adenocarcinoma of the proximal stom-
fective.12 Patients with minimal or no symptoms may ach or gastroesophageal junction. Inhibitory nitric
be followed, and intervention is only indicated when oxide–containing neurons are functionally impaired,
there is evidence for clinical progression. preventing the process of LES relaxation. Addition-
ally pseudoachalasia can occur as a result of an anti-
neuronal antibody mediated paraneoplastic process,
most often associated with lung cancer.
Achalasia
esophagus.13 It is uncommon, with an estimated in- Clinical Manifestations
cidence of about 1 in 100,000 and a prevalence of
about 1 in 10,000. There is no gender predominance Dysphagia is a nearly universal symptom in patients
but incidence does increase with age, with the high- with achalasia. Many patients learn adaptive be-
est incidence in the eight decade of life and a smaller haviors such as such as drinking carbonated bever-
ages while eating, straightening the back, raising
14,15
.
their arms over their heads, or standing to increase
intraesophageal pressure which often leads to a di-
agnostic delay. As a result, the majority of patients
Pathophysiology
experience dysphagia for solids and liquids at the
Achalasia is characterized by failure of the LES to re- time of diagnosis, although dysphagia may initially
lax completely with swallowing and aperistalsis in be more prominent for solids alone. Weight loss
Figure 3.5
Esophageal Manometric Recording in Patient with Achalasia
High resolution manometry of a patient with achalasia. Note the lack of peristalsis following initiation of the swallow, illustrated by UES relaxation. In addition,
note the lack of LES relaxation.
often accompanies dysphagia in patients with acha- duration is variable, lasting anywhere from minutes
lasia. However, weight loss is gradual and modest. to hours. Notably, chest pain is typically more prom-
inent early in the course of achalasia and becomes
dysphagia should raise suspicion for gastroesopha- less prominent later as the esophagus becomes di-
geal junction malignancy. Regurgitation is another lated. Perhaps most vexing, no therapy is reliably ef-
prominent symptom. The regurgitant material is of- fective. Medications such as nitrates and PPIs have
ten described as acidic and consisting of food eaten variable success and while dilation and myotomy
several hours earlier. In addition, patients may de- are effective for dysphagia and regurgitation (see
below), they do not consistently improve chest pain.
of regurgitated saliva. Nocturnal regurgitation can
be particularly problematic. Patients may describe complain of heartburn. This symptom often con-
tributes to diagnostic delay, as conditions such as
Most notably, regurgitation can lead to aspiration -
pneumonitis or even lung abscess. sidered. While impaired LES relaxation diminishes
Chest pain is seen in nearly half of patients with
achalasia. The pain can be severe and may radiate to occur via other means. One proposed mechanism is
the neck, jaw, and back even mimicking angina. The that stasis of food within the esophagus undergoes
bacterial fermentation leading to acid production.16 veillance is currently not advocated by any national
Alternatively, esophageal dilation and stretch sec- gastroenterology societies.
ondary to retained food may precipitate heartburn.17
A potential complication of achalasia is the de- Diagnosis
velopment of esophageal squamous cell carcinoma, The diagnosis of achalasia relies on the combination
the estimated risk of which ranges from 0 to 33-fold. of several modalities. Barium esophagram is often
The only population-based study found a 16-fold risk the initial test in patients with a history suggestive
among 1062 achalasia patients with 9864 years of of achalasia. Findings include a dilated intrathoracic
follow-up. Treatment of the achalasia does not elimi-
nate the cancer risk. Esophageal cancer typically
occurs in patients many years after onset of symp- of the LES to a point, giving the distal esophagus a
“bird’s beak” appearance. (Figure 3.6) However, the
esophagus. This has led to some groups advocating
surveillance programs in patients with long standing
disease and esophageal dilation. However, despite Esophageal manometry is considered the gold
the 16-fold relative risk, the absolute risk of cancer
remains slight. As a result, the diagnostic yield of features are aperistalsis and incomplete LES relax-
surveillance endoscopy is limited, requiring an esti- ation. While a hypertensive LES is often described,
mated 681 annual surveillance endoscopies to detect this is not a requirement for the diagnosis and resting
only one cancer among achalasia patients. Thus, sur- LES pressure may be normal in up to 50% of patients.
In addition, more sophisticated investigations with
-
Figure 3.6
ance measurement may facilitate the diagnosis. 18
Barium esophagram of a patient with achalasia
The recent use of high-resolution manometry
(HRM) with pressure topography plotting has de-
treatment outcomes, which are shown in Figure 3.7.19

The type I achalasia variant (classic achalasia) is
characterized by the presence of minimal esophageal
pressurization. Type II has absent peristalsis with
esophageal pressurization and likely represents an
earlier form of achalasia. The type III variant (spas-
tic achalasia) has lumen obliterating spasm on HRM.
the likelihood of clinical response to treatment, with

greater than 80% response in type II compared to
only 44% and 9% in types I and III respectively.19
EGD is an essential part of the diagnostic evalu-
-
ings are consistent with achalasia. During endoscopy,
slight resistance to passage of the endoscope across
the gastroesophageal junction suggests achalasia.
However, it is important to note that EGD may be nor-
mal in up to 40% of patients with achalasia. None-
The esophagram demonstrates a diffusely dilated esophagus. In addition, the distal theless, tumor-related pseudoachalasia accounts for
esophagus tapers to a point, giving the characteristic “bird’s beak” appearance. up to 5% of cases which meet manometric criteria for
achalasia. Consequently a thorough anatomic evalu- The aim of pneumatic dilation in achalasia is to
ation including endoscopy is essential. Further, in fracture the muscularis propria. Pneumatic dilation
some cases further testing such as computed tomog- is performed by positioning a rigid balloon across the
raphy (CT), magnetic resonance imaging (MRI), or LES, traditionally with the assistance of a guidewire
endoscopic ultrasound may also be employed if the -
suspicion for malignancy is high.
-
Treatment: roscopy, indicative of appropriate fracturing of the
The goal of treatment is to reduce the LES pressure, muscularis propria. There is no evidence that “hold-
allowing gravity to facilitate esophageal emptying,
reducing esophageal symptoms from retention and, the effect is from the fracturing of the muscularis pro-
hopefully, preventing complications. However, there pria which is achieved with obliteration of the waist.
are no data on the prevention of complications, and -
- lation under direct visualization has been shown to be
tomatic or functional improvement. 20
An analysis
of pneumatic dilation found that a post dilation LES the need for radiation exposure. If the clinical result
pressure <10 mm Hg was the best predictor of pro- is unsatisfactory, pneumatic dilation can be repeated
longed remission, while patients with values >20 mm at later sessions with larger balloons of 35mm and
21
Esophageal emptying can be 40mm available. While pneumatic dilation is highly
assessed with timed barium swallow or scintigraphy. effective, its durability has been debated. A recent
Proposed treatments include oral or intrasphinc- -
teric medications, mechanical dilation, or surgery. tion and myotomy, with 86% of patients reporting
Oral medications such as isosorbide dinitrate or nife- durable treatment success two years after pneumatic
dipine may be administered orally or sublingually dilation.24 However, long term data on the durability
of pneumatic dilation is lacking. Further, predictors
Most of the literature on achalasia treatment of poor response include young age and male gender,
consists of uncontrolled case series with a variety
dilation in these groups.25
Treatments include pharmacological therapy, botu- The major complication of pneumatic dilation is
linum toxin injection, pneumatic dilation, and Heller esophageal perforation, with an overall perforation
rate of approximately 2%.26 Perforation should be
pneumatic dilation and Heller myotomy. Pharmaco- suspected with post procedure pain or subcutane-
logical therapy with smooth muscle relaxants such as ous emphysema. A contrast esophagram should be
nitrates or calcium channel blockers can reduce LES obtained if perforation is suspected. Any substantial
pressure and alleviate dysphagia, however as men- perforation requires surgical repair. Patients with
perforations that are promptly recognized and treat-
often limit their use. Intrasphincteric injection of ed surgically within 6–8 hours have outcomes com-
botulinum toxin inhibits acetylcholine release from parable to patients undergoing elective thoracotomy
nerve endings, reducing the LES pressure. Botu- and Heller myotomy.
linum toxin is a highly effective treatment, with a Surgery for achalasia disrupts the LES (Heller’s
symptomatic response in the majority of patients. myotomy) enough to eliminate dysphagia without
However, the main limitation of botulinum toxin is its
durability with the effect typically dissipating within approach requires division of the phrenoesophageal
6 months to 1 year. Further, repeat treatments are membrane and partial mobilization of the esophagus.
progressively less effective and often treatment effect With this approach, at least a partial anterior or pos-
is lost all together.22,23 terior fundoplication is required with or without long-
Figure 3.7
Achalasia Subtypes
The subtypes are distinguished by 3 distinct manometric patterns of esophageal body contractility. Type I is illustrated in both a color pressure topography plot
(panel A) and as a 3-dimensional plot to illustrate the pressure gradients spanning the esophagus and proximal stomach (panel B). In panel A, there is no significant
pressurization within the body of the esophagus, and this would be classified as failed peristalsis with an IRP of 42 mm Hg. The 3-dimensional rendering of these
pressure data in panel B clearly illustrates that esophagogastric flow cannot occur because the esophageal pressure is too low to overcome the esophagogastric
junction (EGJ) high-pressure zone. Panel C represents a swallow from a type II achalasia patient with compartmentalized pressurization spanning the entire length
of the esophagus. The 3-dimensional rendering of these pressure data (panel D) illustrates that the isobaric column within the esophagus equals the EGJ pressure
and would likely be associated with esophagogastric flow. Panel E illustrates a pressure topography plot of a spastic contraction in a type III achalasia patient.
Although this swallow is also associated with rapidly propagated pressurization, the pressurization is attributable to an abnormal lumen obliterating contraction.
The 3-dimensional rendering of these pressure data (panel F) illustrates the peaks and valleys of that spastic contraction, and this swallow would likely appear as a
rosary-bead pattern on fluoroscopy. From Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new clinically relevant classification by high-resolution manometry.
Gastroenterology 2008;135:1526–33.
term acid suppression with a proton pump inhibitor.27 -

Post myotomy dysphagia may result from in- late to the loss of inhibitory innervation. Inhibitory
innervation is progressively increased in the distal
- esophagus and is responsible for the latency be-
tis to Barrett’s metaplasia to adenocarcinoma as a tween upper esophageal relaxation and distal esoph-
ageal contraction following initiation of a swallow. In
DES, this loss of inhibition leads to a short contractile
treated with partial fundoplication and proton pump latency, less than 4.5 seconds, and simultaneous con-
inhibitors. tractions.28
In extremely advanced or refractory cases of by dysphagia, chest pain, and heartburn. However
achalasia, esophageal resection with gastric pull-up
or interposition of a segment of transverse colon may Pathologic esophageal acid exposure may also result
be the only surgical options. Patients with daily dys- -
phagia, a “sigmoid” or tortuous esophagus with poor
emptying, or regurgitation despite multiple previous with a PPI treatment trial or ambulatory pH testing,
procedures are likely candidates. This technique is is important. Treatment otherwise is largely based
necessary in <1% of patients with achalasia. on anecdotal evidence. Medical therapy includes
nitrates, calcium channel blockers, low dose antide-
pressants, PPI, and peppermint oil. Some reports of
Other Esophageal Motility success with endoscopic dilation, botulinum toxin
injection, and even long surgical myotomy extending
Disorders into the esophageal body have also been reported.29
Scleroderma Minor Esophageal Motility Disorders

Scleroderma is a generalized systemic disorder of The clinical relevance of minor esophageal motor ab-
normalities is not clear. This is largely because the
and multiple internal organs. Approximately 90%
of patients will have gastrointestinal involvement,
with esophageal symptoms in up to 80%. Most pa- endoscopic, or surgical treatment is lacking.
tients will have manometric abnormalities. The ear- Hypertensive peristalsis, often referred to nut-
cracker esophagus, is the most common motility ab-
muscle esophagus. This may progress to aperistalsis normality detected in individuals with noncardiac
with a hypotonic lower esophageal sphincter. Be- chest pain and may be triggered by gastroesopha-
30
In fact, Barrett’s esophagus occurs in 5 to 35% of esophagus is unknown and it may be only a mano-
patients, although the development of esophageal metric phenomenon. It is characterized by hyperten-
adenocarcinoma is rare. Dysphagia may also result, -
either from aperistalsis or secondary to peptic stric-
ture formation. Treatment consists of aggressive PPI and normal LES relaxation. Weak esophageal peri-
therapy. While a partial fundoplication for refrac- -
tory GERD symptoms may be helpful, it is typically ic contour, or in other words areas of weak peristal-
contraindicated due to high rates of dysphagia and
symptom recurrence.
Distal Esophageal Spasm:
characterized in Figure 3.3. While the pathophysi-

and small intestine contract in a coordinated man-

Gastric and Small ner at the highest frequencies for each site (3/min-
Intestinal Motility ute in the stomach, 12/minute in the duodenum,
8/minute in the ileum; Figure 3.8). The hormonal
control of the MMC is still incompletely understood;
Normal Gastric and Small
Intestinal Motility contractions passing through the duodenum. This
propagates from the stomach to the ileum and pro-
pels residual contents across an open pylorus into
Functional regional differentiation
the duodenum and through the small intestine into
and relationship to meals
the colon. The MMC has been called the intestinal
The stomach can be divided into different functional
housekeeper. The MMC is inhibited by meals but
areas. The gastric body and fundus and, to a lesser
cycles throughout the day and night in the fasting
extent, the antrum actively relax in response to a
state. At the end of phase II and during phase III of
-
the MMC, there is pancreaticobiliary secretion and
ated event that allows ingested food to accumulate
gallbladder emptying.
in the stomach, where it can be acted upon by gastric
The frequency of antral contractions is regulated
acid and pepsin. The gastric fundus also generates
by gastric pacesetter potentials known as .
both tonic (sustained) and phasic (short duration)
In the human antrum, slow waves occur with a fre-
contractions that act to gradually transfer ingested
quency of 3 cycles per minute. Slow wave activity in
solid food to the antrum. These contractions increase
the stomach originates from a pacemaker region sit-
intragastric pressure, which creates a gradient from
uated along the greater curvature between the gastric
the stomach to the duodenum, thus promoting gas-
fundus and body. Pacing is generated by the intersti-
tric emptying.31
tial cells of Cajal (ICC), which are found throughout the
The gastric antrum and pylorus function in con-
GI tract from the esophagus to the colon and possess
cert to mechanically triturate ingested food, i.e., to re-
spontaneous rhythmic electrical activity. In addition to
duce it to a small particle size. The antrum generates
serving as pacemaker cells for the GI tract, ICCs may
high amplitude, phasic contractions that forcefully
also facilitate neurotransmission.
propel ingested contents against a closed pylorus
The autonomic nervous system has an impor-
grinding solid material to particle sizes of 1–2 mm.
tant role in the regulation of gastric motor function.
The pylorus acts as a sieve by preventing the passage
Receptive relaxation and accommodation of the
of materials larger than 1–2 mm in diameter and al-
gastric fundus and body are mediated by the vagus
lowing only small aliquots of ingested nutrients to
-
pass to the duodenum in a suspension referred to
tients who have undergone vagotomy is responsible
as The small particle size maximizes the sur-
for accelerated emptying of liquids. Vagotomy also in-
face-area-to-volume ratio to facilitate digestion by
terferes with antral contractile activity, which results
enzymes in the small bowel. Following completion
in reduced mechanical breakdown and, therefore, de-
of the fed state, larger, nondigestible contents (e.g.,
layed emptying of solids. This effect of vagotomy neces-
cellulose-based foods) that remain in the stomach
sitates the addition of a pyloroplasty in patients under-
are emptied during phase III of the migrating motor
going surgical procedures during which a vagotomy is
complex (MMC).
performed.
The MMC cycles approximately every 60–90
minutes. The complex has three phases: a period of
quiescence (phase I, which lasts 15–30 minutes), a
Gastric Emptying
period of intermittent pressure activity (phase II,
lasting ~60 minutes), and an activity front (phase The kinetics of gastric emptying are determined by
III, lasting ~6 minutes) during which the stomach the physical state (solid versus liquid) and calorie
Figure 3.8
Phase III of the Migrating Motor Complex (MMC)
Phase I consists of a period of motor quiescence of the small intestine and lasts 15–30 minutes. Phase II consists of irregular, phasic contractions that last
approximately 1 hour. Phase III is depicted and consists of a series of clustered phasic contractions that propagate in an aboral direction and serve to remove
residual chime from the small intestine over a period of 4–7 minutes. The MMC cycles every 90–120 minutes in the fasting state.
content of the ingested material. Liquids empty the the normal gastric emptying of liquids and solids.
fastest, in an exponential pattern, with a half-life of The chemical composition of ingested material
approximately 20–30 minutes. The higher the nutri- also affects the rate of emptying. Chemoreceptors in
ent content of the liquid phase of the meal, the slow- -
er it empties, but it is still faster than solid emptying. ids, and chemoreceptors along the full length of the
Solids empty with a half-life on the order of 90 min- small intestine, sensitive to fat, delay gastric empty-
utes, depending on the size of the meal. The slower ing through the release of cholecystokinin, secre-
- tin, gastric inhibitory (or glucose-stimulated insu-
ing: an initial lag phase during which food is mechani- linotropic) peptide, and peptide YY. This provides
cally digested into smaller particles (trituration), fol- an important mechanism for feedback inhibition.
lowed by a generally linear phase when the triturated Several hormones mediate and integrate the motor
particles are emptied. Large, indigestible solids are and digestive processes after food ingestion. These
not removed from the stomach in the postprandial include gastrin (e.g., acid secretion), cholecystokinin
period, but they are “swept” by the “housekeeping” (e.g., gallbladder contraction, bile and pancreatic se-
effect of phase III of the MMC. The MMC is inhibited cretion), and glucose-regulating hormones (e.g., insu-
usually for >2 hours after the fed state, typically for lin, glucagon, incretins such as glucagon-like-peptide
1 hour for each 200 kcal ingested. Figure 3.9 depicts I). Secretion of these hormones is integrated with the
arrival of chyme (i.e., food) in different levels of the boluses. In addition to controlling the delivery of a
gut to ensure optimal digestion. meal into the small intestine via regulation of gastric
emptying, the jejunal brake and ileal brake slow tran-
sit of the meal through the small intestine.
Small Intestinal Motility
The motor function of the small intestine serves to
mix digested contents with pancreatic enzymes, bile,
Gastric Motility Disorders
and intestinal secretions, and then to propel the re- Disorders of gastric motility can result from a wide
sulting mixture over the intestinal mucosa where variety of causes (Table 3.2); these include disorders
it can be further digested and absorbed. The small affecting the autonomic nervous system (diabetes, va-
intestine has two distinct motility patterns: the fed gotomy), ENS (visceral neuropathy), smooth muscle
pattern and the fasting pattern. The fed pattern is (scleroderma, amyloidosis, mitochondrial cytopathy),
characterized by segmentation: nonpropagated focal and, possibly, abnormalities of the ICCs. During upper
contractions of intestine that occur simultaneously at endoscopy, the presence of food in the stomach sever-
multiple levels along the intestine. This pattern typi- al hours after ingestion, in the absence of gastric out-
cally lasts for 4–6 hours following a meal and is re- let obstruction, provides strong evidence for delayed
placed by the fasting MMC pattern (see Figure 3.8). gastric emptying.
Another characteristic interdigestive motor pattern In patients with suspected gastroparesis, re-
seen in the distal small intestine is the giant migrating -
complex, or power contraction, which empties resi- explained recurrent vomiting, a careful history to
due from the ileum into the colon in bolus transfers. identify features of rumination syndrome is very
The local provides an example useful. Typically, patients have recurrent regurgita-
of one of the better understood small bowel motor
30 minutes after a meal, with effortless, belch-like
GI tract stimulates mucosal afferent nerves. Through return of material to the mouth. Depending on the
a series of interneurons, motor neurons containing social circumstance, patients spit out or re-swallow
excitatory transmitters such as acetylcholine and
substance P are activated above the bolus, and mo- behavioral and is summarized as a “day-in, day-out,
tor neurons containing inhibitory transmitters such meal-in, meal-out” behavior.
as nitric oxide and VIP are activated below the bolus. In patients with suspected gastric dysmotility, the
The net result is contraction above and relaxation test most commonly employed in clinical practice is
below the bolus and aboral propagation. Chemore- measurement of gastric emptying by scintigraphy.
ceptors throughout the small bowel help to regulate Scrambled eggs that are radiolabeled with techne-
gastric emptying and, thus, control the rate of nutri- tium-99m are ingested, with periodic imaging of the
ent delivery to the small bowel. An example of this is activity remaining in the stomach. Information pro-
known as the “ileal brake.” Fat content in the ileum vided includes the percentage of the meal emptied at
delays gastric emptying. Proposed mediators of this 1, 2, and 4 hours, the time for 50% emptying of the
response include peptide YY, enteroglucagon, GLP-1, test meal, and duration of the lag phase of solid food
and neurotensin. emptying.13 C-labeled octanoic acid (a medium-chain
triglyceride), spirulina (a protein), and acetate (for
Small bowel transit liquid emptying) breath tests have been recently de-
The small intestine transports solids and liquids at veloped to measure gastric emptying. These have the
approximately the same rate. As a result of the lag potential to be used in children and pregnant women,
phase for the transport of solids from the stomach, in view of the use of the stable isotope, and can also
liquids typically arrive in the colon before solids. be performed at the point of service where the meal is
Chyme moves from ileum to colon intermittently in ingested and the breath samples are collected.
Figure 3.9
Kinetics of Gastric Emptying
Liquids empty in an exponential manner from the stomach, whereas solids require mechanical digestion or trituration that occurs in the gastric
antrum. The lag phase of solid gastric emptying corresponds to this period of trituration and is dependent upon the sieve-like effect of the closed
pyloric sphincter that allows only small particle sizes to exit into the duodenum. Additional factors that regulate the rate of gastric emptying include
the chemical composition of the ingested food. Residual indigestible substances are removed from the stomach during phase III of the migrating
motor complex (MMC).
Hydrogen breath tests and scintigraphy have been and bradygastria (1–2.5 cpm). While the noninvasive
used to measure orocecal transit time, but these are nature of the EGG makes it quite attractive, the clinical
less accurate than gastric emptying tests, and breath and therapeutic implications of the dysrhythmias are
tests do not allow differential estimates of gastric and still being investigated.
small bowel transit. Additional methods for examin-
ing gastric motility that are primarily being used for Diabetic gastroparesis
investigational purposes include gastroduodenal Diabetic gastroparesis is the classic example of a
manometry, ultrasonography, or electrogastrography motility disorder affecting the stomach that can oc-
(EGG) to measure motor function and volume-based cur with both type 1 and type 2 diabetes, usually of
methods (e.g., ultrasonography, MRI, or single photon at least 5 years’ duration.32 Patients at risk for this
emission CT imaging) to noninvasively assess gastric complication commonly have long-standing diabe-
accommodation. Of these, the most widely available tes with other diabetic complications, including pe-
is electrogastrography, which is capable of recording ripheral neuropathy, nephropathy, and retinopathy.
gastric myoelectrical activity using cutaneous elec- Diabetic gastroparesis is a complex disorder involv-
trodes similar to an EKG. Deviations from the normal ing abnormalities in multiple interacting cell types
myoelectric activity of the stomach of 3 cycles per including extrinsic nervous system, enteric nervous
minute have been termed tachygastria (3.7–10 cpm) system, ICCs, smooth muscle cells, and immune cells.
Table 3.2 apride, reports of cardiac dysrhythmias due to QTc

Gastric Motility Disorders prolongation led to the withdrawal of cisapride from
the market and availability only through a carefully
Diabetic gastroparesis monitored, limited access program.
Postoperative vagotomy Metoclopramide is a central and peripheral do-
Dumping syndrome pamine antagonist as well as being a 5-HT3 antagonist
Infantile hypertrophic pyloric stenosis and 5-HT4 agonist. In addition to peripherally stimu-
Parkinson’s disease lating gastric emptying, metoclopramide also has cen-
Scleroderma tral antiemetic effects. Its use is limited by side effects
Visceral myopathy that include tardive dyskinesia, dystonia, and hyper-
Viral or postviral gastroparesis prolactinemia. There is a Food and Drug Administra-
Paraneoplastic syndrome tion (FDA) black-box warning regarding long-term
Hyper- or hypothyroidism or high-dose use of metoclopramide because of the
Amyloidosis risk of the patient’s developing tardive dyskinesia. In
Idiopathic general, these side effects are rare below a total daily
dose of 40 mg and with short-term use of <3 months.
Patients who are at increased risk of developing side
Acute hyperglycemia itself can delay gastric empty- effects with metoclopramide use include the elderly,
ing, although this is not thought to be a central factor women, cirrhotics, uremics, alcoholics, schizophren-
in the pathogenesis of diabetic gastroparesis unless ics, individuals with a preexisting movement dis-
the blood glucose is >250 mg/dl. Medications used to order, and those taking concomitant neuroleptics.
enhance control of postprandial hyperglycemia such Because these side effects can be irreversible, risk-
as exenatide (GLP-1) retard gastric emptying of sol- -
ids and may cause nausea in about 50% of patients. tion of this medication. Metoclopramide is available
33
Symptoms of gastroparesis include nausea, as sublingual, liquid, and injectable formulations; fa-
vomiting, regurgitation, early satiety, and abdomi- cilitating its use in patients with severe delay in gas-
nal pain. Gastric body and antral hypomotility and tric emptying of solids.
pylorospasm have been demonstrated. This results Domperidone also acts as a dopamine antago-
in prolongation of the emptying of solids and in a nist but is devoid of CNS side effects, as it does not
minority of patients also liquids. Dysfunction of the cross the blood-brain barrier. However, it also can
gastric component of the MMC results in the frequent lead to hyperprolactinemia (because the posterior
failure to empty nondigestible residue and formation pituitary is outside the blood brain barrier) and is
of gastric bezoars. only available in the United States through a restrict-
The mainstay of treatment is - ed program.
cation consisting of smaller meals with low fat and Erythromycin acts as a motilin agonist and
stimulates antral contractions as well as phase III of
be necessary to homogenize solid foods, avoid non- the MMC. Antibiotic side effects, abdominal cramp-
digestible solids (e.g., uncooked vegetables), and ing, and development of tolerance limit the long-term
supplement nutrition with liquid foods. utility of this agent at high dosage. At a lower dose
Prokinetic agents, in general, have limited ef- of approximately 50 mg 3 times per day, there is no
-
tomatic gastroparesis. Cisapride is a mixed 5-HT4 activity may be induced.
agonist and 5-HT3 antagonist that enhances release The use of gastric electrical stimulation (En-
of acetylcholine from postganglionic neurons in the terra) is approved by the FDA through a Humanitar-
myenteric plexus. While stimulation of gastric and ian Device Exemption for patients with diabetic and
duodenal motor activity was demonstrated with cis- idiopathic gastroparesis. Studies with this technol-
ogy demonstrate symptomatic improvement in the at upper endoscopy), and no evidence that the dys-
absence of objective improvement in gastric empty- pepsia is exclusively relieved by defecation or asso-
ing. Proposed mechanisms of action of gastric elec- ciated with the onset of change in stool frequency or
trical stimulation (GES) include activation of central form.36,37
mechanisms for controlling nausea and vomiting, en- The majority of patients presenting to a gas-
hanced relaxation of the fundus that increases gastric troenterologist with dyspepsia will have negative
accommodation and decreased sensitivity to disten- endoscopy. Potential pathophysiological mechanisms
sion, augmentation of the postprandial gastric slow include delayed or accelerated gastric emptying, re-
wave amplitude, and enhanced vagal function. The duced fasting gastric volume, impaired gastric accom-
intended response for the GES device is improvement modation, abnormal gastric myoelectrical activity,
in nausea, vomiting, quality of life, and elimination of gastric visceral hypersensitivity, Helicobacter pylori
the need for enteral and parenteral nutrition. Predic- gastritis, duodenal hypersensitivity to lipids or gas-
tors for suboptimal response to GES include: chronic tric acid, and psychological factors. Accelerated gastric
use of narcotic analgesics, predominance of abdomi- emptying may be associated with postprandial symp-
nal pain, and history of migraines.34 GES has some- toms38 including intolerance of dietary fat.39
- It is not yet proven that physiological tests en-
tients than in those with idiopathic gastroparesis. hance management, probably because the spectrum
Some patients with severe gastroparesis may of therapies available is not effective. However, there
enteral feeding via a tube, which can is evidence that prokinetic therapy and proton pump
be placed either laparoscopically or via percutane-
ous endoscopic jejunostomy, and may require a vent- with the PDS subtype more likely to respond to a
ing gastrostomy. prokinetic agent, and the EPS subtype to acid-sup-
pressive therapy.40,41
Nonulcer or functional dyspepsia
Nonulcer or functional dyspepsia refers to the symp- Small bowel motility disorders, pseudo-
toms centered in the upper abdomen that occur af- obstruction, and chronic intestinal dysmotility
- Chronic intestinal pseudo-obstruction (CIPO) is a
tion). Functional dyspepsia is common, affecting up -
to 15% of the general population. The most frequent testinal dilatation and dysmotility in the absence of
dyspeptic symptoms are postprandial fullness, early mechanical obstruction. It is a syndrome with many
satiation, upper abdominal pain, and nausea. There causes (Tables 3.3 and 3.4). Etiologies include dis-
ease processes localized to the small intestine and
complex. After an epidemiological study showed that generalized motility disorders that affect multiple
in about 60% of patients with upper gastrointestinal regions of the GI tract. The pathogenesis varies from
symptoms, those symptoms were related to meal primary involvement of the ENS and smooth muscle
ingestion,35 and in an attempt to identify clinically of the gut to CNS disorders to systemic processes that
meaningful dyspepsia subgroups, the Rome III com- secondarily affect the GI tract.
mittee proposed dividing dyspeptic patients based
on meal-related versus meal-unrelated symptoms. applied to the disorders that cause CIPO. Chronic in-
Thus the Rome III criteria subdivide functional -
dyspepsia into postprandial distress syndrome (PDS) ologically into disorders that affect the smooth mus-
and the epigastric pain syndrome (EPS). PDS is char- cle of the intestine (myopathic disorders) and those
acterized by meal-related symptoms of postprandial that affect the central, autonomic or ENS (neuropathic
fullness and early satiation, whereas EPS has meal- disorders). This categorization is based upon histo-
unrelated symptoms of epigastric pain and burning. -
There should be no evidence of organic disease (e.g., pathic causes, intestinal contractions are of normal
amplitude but occur in an uncoordinated manner, pria or myenteric neurons and are not diagnostically
whereas in myopathic causes, the contractions are helpful.
either absent or of low average amplitude (<10 mm
Hg in the small bowel and <40 mm Hg in the antrum). Familial visceral neuropathy and myopathy
There is some overlap between the manometric The familial visceral neuropathies and myopathies
are a group of rare disorders with different modes
disorders, and a number of disorders—including of inheritance that affect the ENS. Familial visceral
amyloidosis, scleroderma, and mitochondrial neuro- neuropathy (FVN) is characterized by degeneration
gastrointestinal encephalomyopathy (MNGIE)—have of the myenteric plexus and has two distinct pheno-
both myopathic and neuropathic features. types. Type 1 FVN is inherited in an autosomal domi-
nant fashion and may have its onset at any age. The
CIPO disorders on the basis of their pathology such degree of gastrointestinal involvement is variable.
as neuronal intestinal dysplasia or intranuclear in- Type 2 FVN is inherited in an autosomal recessive
fashion with onset in infancy.
The familial visceral myopathies (FVM) are char-
-
ICCs, or smooth muscle involvement. In most cases testinal smooth muscle and there are at least three
of suspected CIPO, histopathological data are not types of FVM. Type 1 FVM is inherited in an autoso-
available. Endoscopic biopsies sample only the mu-
cosa and submucosa rather than the muscularis pro- decade of life with pseudoobstruction. Extra-gastro-
intestinal features of type 1 FVM include megacystis,
Table 3.3 uterine inertia, and mydriasis.
Classification of Congenital or Familial Chronic Intestinal Type 2 FVM (MNGIE) is an autosomal recessive
Pseudo-Obstruction disorder characterized clinically by the presence of se-
Congenital vere GI dysmotility, ptosis, external ophthalmoparesis,
Hirschsprung’s disease peripheral neuropathy, skeletal muscle weakness, and
Waardenburg syndrome acidosis. Essentially any tissue having mitochondria
Santos syndrome is vulnerable. Pathologically, hypertrophy of the cir-
Maturational arrest
Neuronal intestinal dysplasia longitudinal muscle of the muscularis propria is seen
Multiple endocrine neoplasia IIB in type 2 FVM. Mutations in the gene encoding thymi-
dine phosphorylase are responsible for the defects
Familial Visceral Neuropathy in mitochondrial DNA that characterize this disor-
Neuronal intranuclear inclusion disease der. Skeletal muscle biopsy shows the classic “ragged
Familial steatorrhea with calcification of the basal ganglia
and mental retardation Cytochemical stains are useful to identify the enzyme
Familial visceral neuropathy with autosomal dominant defect in the oxidative phosphorylation chain of the
transmission mitochondria.
Infantile short bowel, malrotation, and pyloric hypertrophy Type 3 FVM is an autosomal-recessive disorder
that has its onset in middle age with intestinal pseu-
Familial Visceral Myopathy do-obstruction. Unlike the other two FVMs, type 3
Type I: autosomal dominant has no extra-gastrointestinal features.
Type II: autosomal recessive (mitochondrial neurogastrointes-
Scleroderma
tinal encephalomyopathy)
Scleroderma is an example of an acquired myopathic
Type III: autosomal recessive
motility disorder. Esophageal dysmotility is the most
Familial Autonomic Dysfunction
common GI manifestation and is seen in up to 90%
Table 3.4
Classification of Acquired Gastroparesis and Pseudo-Obstruction
Type Neuropathic Myopathic

Infiltrative Progressive systemic sclerosis Progressive systemic sclerosis
Mixed connective tissue disease
Amyloidosis Amyloidosis
Systemic lupus erythematosus
Ehlers-Danlos syndrome
Eosinophilic enteritis
Dermatomyositis
Familial Familial visceral neuropathies Familial visceral myopathies
Metabolic myopathies
Idiopathic Sporadic hollow visceral myopathy Idiopathic intestinal pseudo-obstruction
Neurologic Porphyria Myotonic dystrophy
Heavy metal poisoning Muscular dystrophy
Brainstem tumor
Parkinson disease
Multiple sclerosis
Neurofibromatosis
Spinal cord injury
Infectious Chagas’ disease
Cytomegalovirus
Norwalk virus
Epstein-Barr virus
Drug-induced Vincristine
Paraneoplastic Small cell lung cancer
Carcinoid syndrome
Postsurgical Postvagotomy with or without pyloroplasty/gastric
resection
Post-Nissen fundoplication
Endocrine Diabetes mellitus
Hypo- or hyperthyroidism
Hypoparathyroidism
Medications Tricyclic antidepressants Calcium channel antagonists
Anticholinergic agents
Calcium channel antagonists
Narcotics
Laxative abuse
Isoniazid
Dopaminergic agents
Antihypertensives
of cases. The small bowel is the second most often patients having cardiac abnormalities or GI involve-
involved gastrointestinal organ in scleroderma, after ment. Gastrointestinal complications of chronic Cha-
the esophagus. The primary manifestation of small gas’ disease result in achalasia, gastroparesis, small
intestinal involvement by scleroderma is pseudo- bowel dysmotility, or megacolon. Pathologically,
there is degeneration and loss of enteric neurons;
are characteristically seen in scleroderma include the parasite itself is absent from affected GI tissues.
megaduodenum with packed valvulae conniventes, Autoimmune and neurotoxin-mediated destruction
wide-mouth diverticula, and pneumatosis cystoides have been proposed as the cause of this enteric neu-
intestinalis.
Other parts of the GI tract can be involved, with available pharmacologic therapy makes the treatment
delayed gastric emptying, colonic inertia, and fecal directed at the parasitic infection itself controversial.
incontinence. Nocturnal fecal incontinence occurs
because of weakness of the internal anal sphincter Paraneoplastic visceral neuropathy
Patients with malignancies may develop an intestinal
of the muscularis propria are found. The small bowel -
motility pattern in scleroderma is characterized by
markedly diminished amplitude of contractions (<10 to cause this immune paraneoplastic process include
mm Hg average) or even completely absent pressure small-cell carcinoma (most common), carcinoids,
waves. Radiographically, small bowel dilatation and Hodgkin’s lymphoma, ovarian carcinoma, and renal
wide-mouthed intestinal diverticula are seen. cell carcinoma. More than 90% of individuals whose
Complications of scleroderma include dyspha- GI motility disorders are proven to be paraneoplastic
have small-cell lung cancer. Esophageal, gastric, and
formation, diarrhea, and small bowel bacterial over- large bowel involvement have been reported.
growth with steatorrhea. Octreotide treatment stimu- The syndrome is due to circulating IgG antibod-
lates MMC-like activity and may ameliorate bacterial ies that cross-react with neurons of the ENS and
overgrowth. However, octreotide may further delay tumor antigens. The most commonly detected anti-
transit through the stomach and small bowel. Judi- body detected is the anti-Hu or antineuronal nuclear
cious use of low-dose octreotide (e.g., 25–50 µg night- antibody 1 (ANNA-1). Most patients presenting with
ly) may help reduce bacterial overgrowth by clearing this syndrome have advanced disease and a poor
residue from the small bowel with induced MMC-like prognosis, although a subset of individuals present
activity. If octreotide is given with meals during the at an early stage when the malignancy is not clinical-
day, it may also induce MMC activity, but it retards ly apparent. If there is a high suspicion for this syn-
gastric emptying and small bowel transit42 and may drome and the chest X-ray (for small cell lung cancer)
actually aggravate the gastrointestinal stasis. is negative, a chest CT scan is indicated. A paraneo-
plastic visceral neuropathy should be suspected in
Chagas’ disease a middle-aged smoker with recent onset of nausea,
Chagas’ disease is endemic to certain regions of Cen- vomiting, or feeding intolerance.
tral and South America and is caused by infection with
the parasite The incidence of the
disease is on the rise in the United States due to the im- Investigation of Patients with Suspected
migration of chronically infected individuals. is Chronic Intestinal Pseudo-Obstruction
transmitted by the reduviid bug that carries the para-
After exclusion of mechanical obstruction (e.g., CT
site in its feces. Only 10–30% of acutely infected indi-
enterography, barium follow-through), patients
viduals develop symptomatic chronic Chagas’ disease.
should be evaluated by measurement of GI and colon-
The clinical presentation of the chronic infection is
ic transit, manometry (if underlying disease is unclear
dependent on the organ affected, with the majority of
and if there is bowel dilatation on X-rays), blood tests
to identify associated disease (ANA, Scl-70, ANNA-1, attempt to sweep residue down to the colon with the
thyroid-stimulating hormone, lactate dehydrogenase, MMC-like activity.
creatine phosphokinase) and, if indicated, an auto- Antibiotic therapy is often necessary for patients
with small-bowel bacterial overgrowth; every 2–4
weeks, 7-day courses of antibiotics with activity
Treatment of chronic intestinal pseudo-
obstruction
Effective treatment is lacking for most forms of CIPO. rifaximin, and cephalosporins. Repeated courses of
For these disorders, treatment focuses on main- therapy are often required; this may result in the
tenance of nutrition, facilitating bowel clearance emergence of antibiotic-resistant strains; therefore it
and avoidance of surgery, if possible. Many patients is useful to rotate the antibiotic selected each month.
are mistakenly diagnosed with mechanical bowel
obstructions and undergo repeated surgeries. Os- and vitamins and long-term total enteral or paren-
teral nutrition can be required in some patients.
If patients do not respond to medical manage-
predominant slow colonic transit. Available promo- ment, surgery may be required. The operation is
based on the underlying cause of the pseudo-ob-
pseudo-obstruction. Metoclopramide and domperi- struction and can range from simple decompression
done are ineffective. In the small intestine, acute to resection of the diseased area with re-anastomo-
administration of cisapride increased contractility sis. In patients with extensive small bowel involve-
and decreased transit time of chyme. Controlled tri- ment and contraindications to total parenteral nu-
als showed improvement in symptoms with medium trition, a limited number of centers have reported
term administration. Symptomatic improvement de- successful small bowel transplantation. Success is
creased with long-term administration in open trials. greatest with isolated intestinal transplantation
Tegaserod, a selective 5-HT4 receptor partial agonist, rather than multivisceral transplants, which are as-
has never been formally tested in patients with CIPO. sociated with greater risk of rejections, more need
Erythromycin is a motilin agonist that increases for immunosuppressives, and, as a consequence,
contractility by inducing activity of MMC. The concen- greater risk of infections and lymphoproliferative
tration of motilin receptors is highest in the upper GI diseases.
tract with a lower concentration in the terminal ile-
um and colon. This probably explains the negative re- Accelerated small bowel transit in
sults of many studies on small intestinal and colonic dysmotilities
In patients with dumping syndrome or accelerated
patients over a 4-week study. transit secondary to small bowel resection, there
Octreotide has been shown to induce MMC-like may be cramping and diarrhea, which may respond
small bowel motility, but it retards transit through to dietary maneuvers (e.g., fatty acids in the diet)
the stomach and small bowel. Breath tests suggest or subcutaneous octreotide (25–100 µg) 5 minutes
that octreotide reduces hydrogen excretion in pa- before each meal.
tients with connective tissue disorders; however it is
unclear whether this is associated with reduction in
the malabsorptive effects of bacterial overgrowth. Oc- Colonic Motility
treotide may worsen antral contractility and should
be avoided in patients with severe gastroparesis; in
patients with pseudo-obstruction, it should be used
Normal Colonic Motility
before bedtime, at least 2 hours after the last meal, in
order to avoid further delay in gastric emptying and to The colon functions as a reservoir to store fecal ma-
terial as well to allow time for maximal absorption
of water as well as electrolytes, short-chain fatty ac- by the presence of the mass movement. Mass move-
ids, and bacterial metabolites.43,44 Considering that ments represent lumen-obliterating, intermittent
material is constantly being delivered to the colon contractions of the colonic circular muscle layer
during the fed state and by the MMC during fasting, that serve to propel fecal material short distances
the colon must also be capable of retaining feces un- along the colon. Through the mass movement, fe-
til a “socially acceptable” time. Scintigraphic studies cal material gradually works its way from the right
have shown that the ascending and transverse co- colon to the sigmoid and rectum. The mass move-
lonic regions function as the “reservoirs” of the co- ment represents an example of a motility pattern
that is not regulated by the intrinsic slow-wave ac-
can be conserved. Each day, the colon receives 1–1.5 tivity. Instead, it has been proposed that the mass
L of material from the ileum; since stool weight is movements are under the control of the autonomic
typically <0.2 kg, it follows that the colon reabsorbs nervous system. This motor activity can be initi-
- ated by stimulation of the parasympathetic sacral
tility, like gastric and small bowel motility, is under
the involuntary control of the ENS, defecation itself with giant migrating or high amplitude peristaltic
is generally under voluntary control. Colonic motil- contractions (HAPCs), described above. HAPCs can
ity, therefore, can be divided into the function of the be found more frequently after meals in some pa-
colon and that of the anorectum. tients with diarrhea-predominant irritable bowel
The normal colon displays short-duration (pha- syndrome (IBS). The electrical correlate is known
sic) contractions and a background contractility, as the migrating action potential complex.
or tone. Non-propagated phasic contractions have
a role in segmenting the colon into haustra, which
compartmentalize the colon and facilitate mixing, represents an example of a motility pattern that oc-
retention of residue, and formation of solid stool.
High-amplitude propagated contractions, which are
characterized by amplitude greater than 75 mm Hg,
propagation over a distance of at least 15 cm, and a stimulated by the presence of food in the duodenum
propagation velocity of 0.15–2.2 cm/sec, contribute and appears to be a neurally mediated response in-
to the mass movements in the colon. In health, these volving cholecystokinin release.
Colonic transit is a discontinuous process, slow
day, most often postprandially and between 6 a.m. most of the time and rapid at other times. Residue
and 2 p.m. may be retained for prolonged periods in the right
Motor function of the ascending colon is char- colon, and a mass movement may deliver the con-
acterized by ring contractions that migrate from tents to the sigmoid colon in seconds. Movement of
colonic content is stimulated by feeding (gastroco-
the reverse direction of normal intestinal transit al- lonic response). In health, the average mouth-to-ce-
lows for the retention and storage of fecal material. cum transit time is about 6 hours, and transit times
Slow waves are present in the colon, as they are in through the right colon, left colon, and sigmoid co-
the small bowel, and migrate toward the cecum in -
the proximal colon. Tonic contraction of the taenia creased, mean colonic transit time decreases, stool
frequency increases, and stool consistency becomes
is responsible for the haustral folds throughout the softer. Decreased caloric intake slows colonic tran-
colon that increase the surface area for water and
nutrient absorption and also retard fecal egress. dysfunction or voluntary suppression of defecation
Movement in the transverse and descending co- often is associated with slow colonic transit and de-
lon is generally toward the anus and characterized creased motor response to feeding.
neostigmine (0.5–2.0 mg), an acetylcholinesterase

inhibitor, in the short-term treatment of acute in-
from oral intake and endogenous secretions. The testinal pseudo-obstruction.45 Patients’ heart rates
and blood pressure should be monitored closely, and
colon, where most is reabsorbed, leaving a maxi- atropine should be available to reverse the effects if
mum of 200 ml of water excreted in normal stool. there is cardiovascular compromise. Contraindica-
tions to use of neostigmine include known hypersen-
in a 24-hour period, unless the rate of ileocolonic sitivity and mechanical intestinal obstruction. Recent
- myocardial infarction, acidosis, asthma, bradycardia,
pacity and/or reabsorptive ability. Electrolytes and peptic ulcer disease, and therapy with beta-blockers
water are absorbed in part under mineralocorticoid are relative contraindications.
control, and this leads to a balance of anions (e.g.,
chloride, bicarbonate) and cations (e.g., sodium, po-
tassium) being excreted, and usually similar sodium Irritable Bowel Syndrome
and potassium concentrations.
IBS is common affecting 20% of the population in
developed countries. In the United States, prevalence
decreases with age, and two-thirds of patients are
Acute Colonic Pseudo-Obstruction women.46 -
(Ogilvie’s Syndrome)
Acute colonic pseudo-obstruction presents with the disorder rely upon clinical criteria. The most com-
- monly used criteria are the Rome III criteria (Table
chanical obstruction. It is most commonly recog- 3.5). An important caveat to all symptom-based crite-
nized in hospitalized patients in the postoperative ria is adequate exclusion of organic disease; however,
setting and can occur even with operations that do IBS should not be considered a “diagnosis of exclusion.”
not involve manipulation of the bowel, such as or- Invasive and costly testing can be avoided in most pa-
thopedic or cardiac procedures. The pathogenesis tients who meet Rome criteria. Positive symptom
of the disorder is still unclear but increased inhibi- based diagnosis is generally safe in the absence of “red
tory sympathetic and/or decreased stimulatory,
parasympathetic innervation of the distal colon has -
been incriminated. -
Medications that produce smooth muscle relax- -
ation (calcium channel antagonists, narcotics, and an- ings. Most patients with IBS have symptom onset at a
ticholinergics) and metabolic derangements (hypo- young age; therefore, age >50 years at presentation is
calcemia, hypokalemia) should be corrected but have generally considered an indication for additional test-
a secondary role in the pathogenesis. Experimental ing, including colonoscopy.
The understanding of the pathophysiological ba-
also derange neuromuscular function. Management sis of IBS has continued to evolve. IBS is no longer
involves nasogastric and rectal tube decompression, considered a condition that originates exclusively
correction of electrolyte imbalance, cessation of med- from psychological stress and brain dysfunction.
ications listed above, and monitoring for potential -
complications of perforation with daily abdominal ra- toms of IBS include abnormal colonic transit and rec-
diographs. Colonoscopic decompression with place- tal evacuation; intraluminal intestinal irritants, such
ment of a decompression catheter can produce some, as maldigested carbohydrates (producing short-
chain fatty acids) or fats, an excess of bile acids, and
A placebo-controlled trial reported on the fa- gluten intolerance; alterations in the microbiome;
enteroendocrine-cell products; and genetic suscepti-
47
toms.51 These food-related gut stimuli may include
Symptoms of constipation-predominant IBS are poorly absorbed short-chain carbohydrates that are
similar to chronic constipation; however, associated rapidly fermented resulting in luminal distension by
abdominal discomfort and pain are more prominent. gas and liquid. Culprit short-chain carbohydrates
About 25% of patients with constipation-predominant that are readily fermentable include the FODMAPs
IBS have slow colonic transit.48 Disorders of rectal (fermentable oligo-, di-, and mono-saccharides and
evacuation (e.g., dyssynergic defecation) cause symp- polyols). Restricting dietary intake of FODMAPs can
toms that mimic constipation-predominant IBS49 with
constipation, straining, a sense of incomplete evacua- IBS.52 In addition, gluten causes GI symptoms in IBS
tion, bloating, and abdominal discomfort. Treatment patients without celiac disease providing support for
of the evacuation disorder relieves the symptoms of the existence of non-celiac gluten intolerance.53 Fur-
constipation-predominant IBS.50 thermore, diarrhea-predominant IBS patients have a
In addition, diarrhea-predominant IBS is asso- defect in bile acid absorption leading to cholerheic
ciated with acceleration of colonic transit in up to diarrhea.47
45% of patients.48 There are several disorders that The precise role of the microbiome in IBS is un-
mimic diarrhea-predominant IBS or cause accelerat- clear. Small intestinal bacterial overgrowth (SIBO)
ed bowel transit and should be considered including has been proposed as an etiologic factor in IBS, but
- 54
The prevalence of SIBO
cies, celiac disease, gluten intolerance without celiac in individuals meeting diagnostic criteria for IBS is
disease, microscopic colitis, and idiopathic bile acid highest with breath testing and the role of testing
malabsorption.47 for SIBO in individuals with suspected IBS remains
It is recognized that luminal factors such as mal- unclear. The role of the microbiome in the causa-
absorbed sugars, gluten intolerance, and bile acids tion of IBS symptoms is supported by randomized,
may contribute to gastrointestinal symptoms in IBS -
patients either directly or indirectly by stimulating lief of IBS symptoms, bloating, abdominal pain, and
- diarrhea.55 The therapeutic gain over placebo with
ing food-related stimuli may provide a key manage- rifaximin was approximately 10% and studies aimed
ment strategy for alleviating functional gut symp- at identifying the patients with IBS who are likely to
respond to rifaximin are needed. Until this informa-
Table 3.5 tion is available, rifaximin use should be limited to
Rome III Criteria for Irritable Bowel Syndrome
A number of abnormal motility patterns have
Irritable Bowel Syndrome been described in IBS patients, including increased
Recurrent abdominal pain or discomfort at least 3 days per high amplitude peristaltic contractions in patients
month for the past 3 months, associated with two or more of with diarrhea and urgency, and prolonged propa-
the following: gated contractions associated with pain. No motility
Improvement with defecation
Onset associated with a change in frequency of stool appears that the motor abnormalities may be sec-
Onset associated with a change in stool form or ondary rather than the primary defect in IBS patho-
appearance genesis. The current concept is that IBS represents
Criteria must have been fulfilled for the past 3 months, dysfunction at the level of enteric, autonomic, or CNS
with symptom onset at least 6 months before diagnosis. processing of physiological and noxious stimulation
of the gut.
From Longstreth GF, Thompson WG, Chey WD, et al. Functional A subset of patients with IBS report discomfort
bowel disorders. In Rome III: The Functional Gastrointestinal
Disorders, 3rd ed. Drossman DA, Corazziari E, Devaux M, et al., Eds. or pain at a lower threshold of balloon distention of
McLean, VA: Degnon, 2006, p. 487–555. the rectum compared with controls. In some studies,
sensory thresholds for painful stimulation of the colitis. Other nontraditional approaches that have
skin are similar between IBS patients and controls, been shown to be effective include hypnotherapy and
demonstrating that the increased sensitivity is spe- behavioral therapy.
cerebral activation in response to rectal distension in Slow Transit Constipation

patients with IBS is unclear. The biologic and psycho- and Colonic Inertia
logical basis of the brain-gut dysfunction is an area of
Although normal transit typically characterizes the
active research in IBS. Irritable bowel syndrome has
majority of patients presenting with constipation,
been reported in 7–25% of patients following an
with or without irritable bowel syndrome, there
acute episode of gastroenteritis. Female gender, un-
is a minority of patients who have delayed colonic
derlying psychopathology, and severity of the acute
transit. This is most easily assessed by retention of
infectious diarrhea are predictors for the develop-
-
ment of IBS following acute infection. The pattern of
diograph several days after ingestion (e.g., 5 of 20
bowel dysfunction is typically diarrhea-predominant.
markers retained after 5 days). Alternatively, one can
Increased mucosal permeability and increased num-
count the number of markers retained on day 4 af-
bers of enteroendocrine cells containing serotonin
ter ingestion of 24 markers per day on days 1 to 3,
have been found in such patients. The role of abnor-
and this number provides an estimate of the mean co-
mal serotonin metabolism and reuptake in IBS pa-
lonic transit time. It is essential to exclude dyssynergic
tients is the subject of ongoing research.
defecation (see below) in any patient with suspected
Therapy of IBS focuses not only on the patient’s
slow colonic transit.
symptoms but also on potential triggers of the symp-
An extreme form of slow transit constipation is
colonic inertia, in which there is absence of a motor
lifestyle factors such as diet (e.g., poorly absorbed
response of the colon to pharmacological stimula-
tion. Some centers apply this diagnosis based on a
or fears regarding their symptoms, and psychosocial
failed trial of medical therapy. Others require colonic
stressors. Pharmacologic therapy is directed at pa-
intraluminal measurement of tone and phasic pres-
tient’s predominant complaints (i.e., abdominal pain,
sure activity with standardized meal (100 kcal) and
diarrhea, and/or constipation). Pain can be transient-
pharmacological stimulation (e.g., 1 mg neostigmine
ly improved with anticholinergic agents or inhibited
by slow intravenous injection over 5 minutes).
with low-dose tricyclic antidepressants. Diarrhea may
Colonic inertia or severe slow transit constipa-
tion is associated with loss of myenteric neurons or
or diphenoxylate. Constipation management strate-
ICCs. If there is no response to medical therapy, pa-
tients are good candidates for colectomy (e.g., lapa-
with addition of osmotic, bulk-forming, or stimulant
roscopic) and ileorectal anastomosis, provided there
laxatives.56 Lubiprostone, a chloride channel activator,
is no evidence of evacuation disorder (see below) or
a severe generalized motility disorder on upper gas-
for women with constipation-predominant IBS at a
trointestinal transit or manometry.
dose of 8 µg twice daily. Linaclotide is a synthetic gua-
constipation-predominant IBS at a dose of 290 mcg

Anorectal Motility
once daily. Alosetron, a 5-HT3 antagonist, is effec-
tive for the treatment of diarrhea, urgency and pain; The anorectum consists of both smooth and skel-
the drug is available under a restricted prescription etal muscle components that allow continence of
program because of the potential association with sig- feces and the voluntary control of defecation.57 The
components include the striated muscle of the ex-
Figure 3.10
Anorectum at Rest and Straining to Defecate
Sagittal view of the anorectum at rest (panel A) and during straining to defecate (panel B). Continence is maintained by normal rectal sensation
and tonic contraction of the internal anal sphincter and the puborectalis muscle, which wraps around the anorectum, maintaining an anorectal
angle between 80 and 110 degrees. During defecation, the pelvic floor muscles (including the puborectalis) relax, allowing the anorectal angle
to straighten by at least 15 degrees, and the perineum descends by 1.0–3.5 cm. The external anal sphincter also relaxes and reduces pressure
on the anal canal.
ternal anal sphincter and puborectalis muscle and anal sphincter remains tonically contracted in the
the smooth muscle of the internal anal sphinc- absence of neural inhibition. In response to rectal
ter. The external anal sphincter contributes to the distention with feces or a balloon, the internal anal
preservation of fecal continence primarily through
phasic contractions that are important during peri-
ods of increased intra-abdominal pressure that oc-
curs with coughing, changes in posture, and lifting Defecation and Continence
of heavy objects. Innervation to the external anal
Normal defecation requires a series of coordinated
sphincter is via the pudendal nerves arising from
S2–S4. In addition, the puborectalis muscle (in-
sphincter muscles (Figure 3.10). Filling of the rec-
nervated by S3–S5) forms a posterior “sling” that
tum by a volume of 10 ml may be sensed, although
creates an acute angulation in the rectum that ob-
the rectum can accommodate 300 ml before a sense
structs the passage of the rectal contents. The inter-
of fullness and urge to defecate develop. Disten-
nal anal sphincter maintains resting tone and is the
tion of the rectum results in the relaxation of the
major determinant of resting pressure of the anal
canal and the primary deterrent for the involuntary
and simultaneous contraction of the external anal
egress of stool especially at nighttime. The internal
sphincter to maintain continence. The anal transi-
tion zone can sense the difference between solid or reduced sensation or external sphincter pressure
liquid stool compared with gas. can be treated respectively with surgery (overlap
sphincteroplasty) and biofeedback. For further discus-
sion on treatment of fecal incontinence see Chapter 15
Obstructed Defecation on Digestive Health and Disease in Women.
Functional obstruction of the anal canal can be

an important cause of constipation.58 This may be
manifest on a colonic transit test, with most radi-
Hirschsprung’s Disease
opaque markers being retained in the descending Hirschsprung’s disease (HD) is synonymous with
or sigmoid colon. However, markers may be re- congenital megacolon. Several other developmental
tained throughout the colon, as there is evidence of abnormalities of the myenteric plexus including mat-
urational defects are related to or are variants of HD.
patients are at risk for descending perineum syn- The disease occurs in 1 in 5000 live births with a male
drome or rectal prolapse, in which intussusception predominance (5:1), and has a high concordance in
of the rectum through the anal canal can transiently monozygotes. Approximately 10% of babies with
produce a mechanical obstruction. Dyssynergic Down syndrome have HD. Patients typically present
defecation refers to inappropriate contraction of in infancy with symptoms of large bowel obstruction.
the puborectalis muscle or external anal sphincter, Nausea, vomiting, abdominal distention, and consti-
preventing the normal egress of stool. In such cases, pation are common symptoms. HD is reputed to occur
anorectal manometry demonstrates paradoxical later in life with a less dramatic presentation consisting
contraction and electromyographic activity of the of chronic constipation and recurrent fecal impaction;
external anal sphincter in response to straining. however, underappreciation of the evacuation disor-
This may manifest as an increase in “resting” anal ders may have led to misdiagnosis in the past.
sphincter pressure as the external sphincter does The megacolon in HD is caused by a functional
not relax. Prolongation of the time or increase in the obstruction secondary to the absence of the myen-
weight (>200 g) required to expel a rectal balloon teric ganglion cells in the affected portion of the dis-
can be an important diagnostic clue to obstructive tal colon. Variable lengths of the distal colon can be
defecation. Defecography can assess the anorectal affected (long, short, and ultrashort segments). The
angle as a marker of puborectalis contractile activity aganglionic segment fails to relax and remains con-
and detect the presence of internal rectal prolapse tracted, resulting in dilation of the more proximal
and a rectocele. Biofeedback has been effective in colon. The failure of relaxation is attributed to the
improving symptoms of dyssynergic defecation. absence of inhibitory neurons containing the inhibi-
tory neurotransmitters nitric oxide and vasoactive
intestinal peptide.
Fecal Incontinence The aganglionosis observed in HD is due to im-
paired neural crest cell migration during gestation. Re-
There are three factors that clinically contribute to
cent evidence suggests that an autosomal dominant
fecal incontinence: weakness of the anal sphincters,
form of this developmental abnormality is related to
lack of rectal sensation or reduced rectal capaci-
mutations in the RET proto-oncogene. Mutations of
tance, and rapid distal colonic motility that aggra-
-
vates the urge to have a bowel movement and may
ial and 15–20% of sporadic cases of HD. Alterations in
overwhelm the continence mechanism. Investiga-
several other genes have also been implicated in HD.
tion includes anorectal manometry, sensation, com-
The evaluation of suspected HD generally includes con-
pliance, and ultrasound or MRI of the sphincter and
trast enema, rectal biopsy, and anorectal manometry.
Contrast enema may reveal dilated colon proximal to
cause. The typical causes of sphincter damage and
a constricted distal colon and anorectum. However, HD
may involve only a very short segment of rectum that mon GI manifestations and typically present during
can easily be missed on barium enema. In these cases, early childhood.
anorectal manometry is very useful. The aganglionic -
segment always extends from the internal anal sphinc- ease is another example of a disease associated with
ter (IAS) for a variable distance proximally. The nor- intestinal neuronal dysplasia that is often congenital
mal physiologic response to distention of the rectum and associated with megacolon, as well as other mo-
is relaxation of the smooth muscle IAS. With IAS in- tility abnormalities of the GI tract. It is particularly
volvement in HD, there will be failure of IAS relaxation important to exclude a mechanical bowel obstruc-
with rectal distention (absence of rectoanal inhibitory
manometry is the best method by which to make the

diagnosis of ultrashort-segment HD. It is important to
know that false-positive results can be caused by a ca-
pacious rectum resulting from megacolon or chronic
Pearls and Pitfalls
fecal retention, in which case balloon distention may for the Board Exam
The most important consideration in evaluation of
rectal mucosa is the most reliable method to diagnose chest pain is a cardiac cause. Gastroesophageal re-
HD, except in patients with ultrashort-segment dis- flux is the most common cause of non cardiac chest
ease.59 Rectal biopsy will show absence of ganglion pain, while a primary esophageal motility disorder
is rare.
ganglion cells 1–2 cm proximal to the anus rules out Patients with achalasia may present with long
Hirschsprung’s disease. standing symptoms. Heartburn may be a prominent
Treatment is dependent on symptoms. In the symptom despite incomplete LES relaxation.
majority of patients, symptoms begin during infancy The diagnosis of achalasia depends on radiographic,
and can be life threatening with the development of manometric, and endoscopic evaluation in combina-
ischemic enterocolitis from colonic distention proxi- tion. While defined by incomplete LES relaxation
and aperistalsis, resting LES pressure may be nor-
(pull-through operations) is the treatment of choice. mal in some patients.
Patients who present later in life will have less severe Gastroesophageal junction malignancy is an impor-
complications, such as colonic constipation and re- tant consideration in patients meeting manometric
current fecal impaction. Evacuation disorder second- criteria for achalasia.
Surgical myotomy with partial fundoplication and
pneumatic dilation are the most effective treatment
options in achalasia. Botulinum toxin injection is ef-
Multiple Endocrine Neoplasia IIB fective, but lacks durability and loses efficacy with
In contrast to the aganglionosis seen in HD, neuronal repeat injections.
intestinal dysplasia is characterized by hypergangli- Esophageal involvement in scleroderma is common.
onosis. The best understood example of neuronal The earliest manometric findings are weak peristal-
intestinal dysplasia syndrome is multiple endocrine sis, which may progress to aperistalsis and a hypo-
neoplasia type IIB (MEN IIB). Gastrointestinal com- tensive LES.
plications occur in almost all patients with MEN IIB The initial treatment for gastroparesis is dietary
and can often precede the appearance of the other modification (small frequent meals that are low in
associated neoplasms (100% medullary carcinoma fat and fiber).
of the thyroid, ~60% phaeochromocytoma) by many A paraneoplastic visceral neuropathy causing pseu-
years. Although MEN IIB may involve the entire GI do-obstruction should be suspected in a middle-age
tract, megacolon and constipation are the most com-
smoker with recent onset of nausea, vomiting, and References

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CHAPTER 4
Diarrhea and Constipation
Lawrence R. Schiller, MD
Learning Objectives
1. Review current clinical definitions of diarrhea and constipation.
2. Comprehend the normal physiology of water absorption and transit in the gut and disruptions found in patients with diarrhea and constipa-
tion.
3. Define clinically useful classification schemes for diarrhea and constipation.
4. Describe a practical approach to the evaluation of patients with diarrhea or constipation.
5. Identify appropriate therapies for diarrhea or constipation.
Definition of Diarrhea
-
diarrhea.1 Three or more bowel movements per day are abnormal and the upper limit of stool weight in the
United States is generally agreed to be 200 grams per day. These quantitative criteria should not be applied
but do not complain of diarrhea since their stool consistency is normal. Other patients have normal stool
weight, but complain of diarrhea because their stools are loose or watery. A further complicating feature is
fecal incontinence. This symptom is usually caused by abnormalities in the mechanisms of continence, not
caused by especially severe diarrhea. Incontinence needs to be evaluated separately from diarrhea.
Pathophysiology of Diarrhea
2–4
ml/24 hours); leaving approximately 80–100 ml excreted each day in feces. If a disease process in the small
to 3000–4000 ml/24 hours.
87
Loosening of the stool may occur when daily fecal ions to account for the anions that accompany these
water output increases by 50–60 ml and an increase cations. The concentration of unmeasured osmoles is
- calculated as the difference between 290 mosm/kg
cient to increase stool weight above 200 g/24 hours, and the contribution of fecal electrolytes. Since fecal
the upper limit of normal. Thus a decrease in overall electrolyte concentrations are low in osmotic diar-
rhea, the fecal osmotic gap is large. A fecal osmotic
to cause diarrhea. Many disorders are capable of dis- gap of >50 mosm/kg is suggestive of an osmotic di-
at least this amount. This accounts for the frequency When the osmotic gap is small, electrolytes ac-
of diarrhea as a symptom and also for the extensive count for most of the luminal osmolality and a secre-
differential diagnosis that confronts the physician at- tory diarrhea is said to be present. To some extent
tempting to treat a patient with diarrhea. secretory diarrhea is a misnomer: most patients with
Excess stool water can result from ingestion of
poorly absorbed substances that remain in the lumen
of the intestine and obligate retention of water with- jejunum each day—they just do not absorb almost all
in the lumen by virtue of their osmotic effects.2–4 This of it as under normal circumstances.2–4
is so-called osmotic diarrhea. Examples of osmotic Many conditions can lead to secretory diarrhea
diarrhea include lactose malabsorption and diarrhea (Table 4.2). These include small bowel disorders, such
due to ingestion of magnesium laxatives (Table 4.1). as bacterial infections, Crohn’s disease, and mucosal
Electrolyte absorption is unaffected by these osmoti- diseases, such as celiac disease or Whipple’s disease.
cally active substances and stool water contains very In addition, several diseases affecting the colon exclu-
little unabsorbed sodium or potassium with osmotic sively can produce secretory diarrhea, such as ulcer-
diarrhea. This is the basis for the calculation of the ative colitis or microscopic colitis.
“fecal osmotic gap,” an estimate of the concentration
of the osmotically active substance driving diarrhea.
In this calculation, the osmolality of intraluminal Infections
Bacterial and viral infections account for the vast ma-
jority of acute diarrheas and for some chronic diar-
osmotic gradient against plasma). The contribution
rheas. Microorganisms produce diarrhea by several
of fecal electrolytes to intraluminal osmolality is es-
mechanisms: secretion of enterotoxins, invasion of
timated as twice the sum of sodium and potassium
the mucosa, bacterial adhesion to the enterocytes,
Table 4.1 and production of cytotoxins that destroy entero-
Causes of Osmotic Diarrhea cytes.5 Pathogenic bacteria often adhere to or pen-
etrate the apical membrane of the enterocyte to cause
disease. For example, enterotoxigenic adhere
Ingestion of poorly absorbed carbohydrates
-
and sugar alcohols
crovillus membrane by means of pili. Conversely, en-
Lactose (in individuals with lactase deficiency)
teropathogenic obliterate microvilli, producing
Fructose
“pedestals” to which they adhere. and -
Mannitol
gella invade the mucosa to produce disease.
Sorbitol
is internalized by endocytosis and spreads laterally
Lactulose
from cell to cell. penetrates the brush bor-
Ingestion of poorly absorbed ions
der and tight junction to gain access not only to the
Magnesium
mucosa, but also to the bloodstream.
Phosphate
Toxins co-opt the regulatory machinery of the in-
Sulfate
testine both at a cellular level and at the organ level.
Chapter 4 — Diarrhea and Constipation 89
Table 4.2
Mechanisms of Secretory Diarrhea
Mechanism Examples
Infection E. coli, cholera, Campylobacter jejuni, Clostridium difficile
Reduction of mucosal surface area Intestinal resection, diffuse mucosal disease
Absence of an ion-transport mechanism Congenital chloridorrhea, congenital sodium diarrhea
Inflammation Crohn’s disease, microscopic colitis
Dysregulation Diabetes, postvagotomy diarrhea
Circulating secretagogues Neuroendocrine tumors
For example, cholera toxin binds to the apical mem- remains a common cause
brane of the enterocyte and is internalized, making of acute community-acquired diarrhea. Tissue inva-
its way to adenylate cyclase located on the basolateral sion occurs frequently and severe colitis mimicking
membrane. There it binds to and activates the cata- idiopathic ulcerative colitis can occur. Studies suggest
lytic unit of this G protein, causing the unregulated an association between infection and Guil-
intracellular production of cyclic adenosine mono- lain-Barré syndrome.
phosphate. This, in turn, blocks sodium absorption Because of its morbidity and relatively high case
and stimulates chloride secretion by the entero- fatality rate, acute diarrhea caused by O157:H7
cyte. For many years this was thought to be the sole has received much attention. This organism pro-
mechanism of action of cholera toxin. It is now clear duces a hemorrhagic segmental colitis and is associ-
that cholera toxin also interacts with enteroendo- ated with hemolytic-uremic syndrome. Infection has
crine cells, stimulating the release of endogenous been associated with eating undercooked hamburger
secretagogues, and with the enteric nervous sys- or other foods, and outbreaks are distressingly fre-
tem, altering both electrolyte transport and motil- quent. Stool electrolyte analysis suggests a secretory
ity. Another example is STa toxin, which is a diarrhea, but frankly bloody diarrhea or a strongly
ligand for a brush-border receptor for guanylin, an positive fecal occult blood test is typical. Antibiotic
endogenous regulatory peptide that is distributed therapy may predispose to the development of hemo-
intraluminally to the enterocyte. Binding of guanyl- lytic-uremic syndrome.
in or STa to this receptor results in activation of gua- -associated colitis is the most
nylate cyclase C and production of cyclic guanylate common cause of infectious diarrhea in hospitalized
monophosphate, which causes chloride secretion patients, but may also occur in outpatients. It usually
by the enterocyte. (The drug, linaclotide, is a gua- follows broad-spectrum antibiotic therapy that inhib-
nylin analog that induces chloride secretion and is
approved for treatment of constipation.) of The organism produces spores that are
relatively resistant to disinfection, thus promoting and electrolyte absorption are reduced, the colon can
spread among patients and reinfection in individu- compensate, but only to a certain extent. In contrast,
als. Inadequate hand washing by healthcare workers there is no more distal segment to compensate when
and ingestion of gastric antisecretory drugs, such as colonic absorptive function is disrupted.
proton pump inhibitors, by patients are associated These theoretical considerations are exempli-
with higher rates of infection in hospitalized patients.
toxins A and B are cytotoxins that These patients not only have problems with bile acid
kill enterocytes, producing a pseudomembranous and vitamin B12 absorption, but also develop a wa-
colitis. Some strains hyperproduce these toxins and tery diarrhea that may be resistant to therapy with
cause more severe illness with increased mortality. bile acid sequestrants. Refractory diarrhea in this
Abdominal tenderness and leukocytosis with a “left setting is caused by compromise of the unique abil-
shift” may be dramatic and fecal leukocytes are easy ity of the missing segment of the bowel to absorb
sodium against a large concentration gradient and
-
cile toxin in stool samples. Not all assays detect all sodium to fully compensate for this defect. Fatty acid
forms of the toxin and so “toxin-negative” -
diarrhea can occur. Symptomatic improvement with ids also may contribute to post-resection diarrheas
metronidazole or vancomycin usually is rapid, but re- by stimulating secretion by the colonic epithelium.
lapse of diarrhea occurs in >20% of patients when
antibiotic therapy is discontinued. Patients who re-
lapse have failed to develop appropriate immunity Absence of an Ion Transport Mechanism
to the toxin. Prolonged or pulse-dosed vancomycin
Secretory diarrhea can result from congenital ab-
has been suggested for relapses. Refractory patients
sence of an ion transport mechanism.2–4 This occurs
have been treated with immunoglobulin infusions
in congenital chloridorrhea, an absence of the chlo-
and “stool transplants.” These therapies are not yet
ride-bicarbonate exchanger in the intestinal mucosa
standard-of-care, but the reported response rate to
(the product of the gene, DRA, down-regulated in ad-
stool transplant in case series of patients with re-
enoma). Chloride cannot be removed from the lumen
current infection has been 90—
against a concentration gradient and accumulates,
95%. Toxin-binding resins, such as cholestyramine,
-
and probiotic bacteria or yeast may reduce the risk of
men. Reducing the chloride load to the intestine by in-
relapse.
hibiting gastric chloride secretion with proton-pump
inhibitors can reduce stool weight. Therapy with bu-
tyrate may mitigate diarrhea caused by the effects of
Reduction of Mucosal Surface Area short-chain fatty acid absorption on sodium, potas-
The intestine has a reserve absorptive capacity to sium, and chloride absorption in the colon.
compensate for variation in daily intake and minor Another similar mechanism of diarrhea is con-
abnormalities in absorptive function, but this re- genital sodium diarrhea caused by absence of func-
serve has some limitations.2–4 First, because absorp- tional Na+-H+ antiporter in the brush border of the
tive function in different parts of the intestine is spe- intestine.
cialized, some segments cannot compensate for the
missing functions of other segments. For example, if
the terminal ileum is resected or diseased, the colon Inflammation
cannot compensate by absorbing bile acids or vitamin
The immune system in the intestine modulates elec-
B12 -
trolyte absorption by release of cytokines and by
ity more distally to be able to compensate for missing
effects on the enteric nervous system. These inter-
actions have been studied best in animal models of problem. For practical purposes, duration of illness
infection and hypersensitivity. It is likely that similar and stool characteristics can be used to sort through
interactions occur in humans. Sellin has coined the the differential diagnosis and to direct the evaluation
acronym “PINES” to identify the interaction of para- of patients with diarrhea (Table 4.3).1, 2
crine, immune, neural, and endocrine systems in the
regulation of ion transport by the mucosa.3 Efforts to
modulate this system with drugs may produce new Evaluation of the Patient with
classes of antidiarrheal agents in the future.
Diarrhea
Dysregulation
History
Secretory diarrhea may occur as a complication of
diabetic autonomic neuropathy. Abnormal function Medical history is the key to the evaluation of pa-
of the enteric nervous system may alter the dynamics tients presenting with diarrhea.2 Duration of symp-
- toms can be an important clue. Patients who present
with acute diarrhea (<4 weeks’ duration) are more
develop diarrhea after vagotomy, sympathectomy, or likely to have an infectious cause for their problem. In
celiac plexus neurolysis. contrast, patients with chronic diarrhea have a much
broader group of diagnoses to consider, including not
only infectious problems but also a variety of other
Circulating Secretagogues conditions (Table 4.3). Some idea of the severity of
the symptoms should also be gathered. Frequency is
Tumors of endocrine cells in the gut, pancreas, and
elsewhere can produce high enough circulating levels
not necessarily correlate with stool weight. Some in-
of secretagogues in the blood to inhibit absorption or
dividuals may pass small amounts of stool frequently,
to produce secretion by the intestine. Although gas-
whereas others may have less frequent but more vo-
troenterologists and internists often consider these
luminous evacuations. Patients generally have little
tumors when caring for patients with secretory di-
idea of the volume of stool that they are passing. The
arrhea, they are quite rare. Estimates of prevalence
presence of symptoms of dehydration or volume de-
range from 1 per 1000 to 1 per 10,000 patients with
pletion, such as orthostasis, thirst, decreased urine
output, and weakness, suggests higher stool output.
these tumors is quite low when evaluating a given pa-
Acute weight loss also can be a guide to the sever-
tient with chronic diarrhea.2–4
ity of diarrhea, with large stool outputs causing more
substantial weight loss if rehydration efforts are sub-
optimal.
Clinical Classification of Diarrhea Stool characteristics such as the presence of
blood, mucus, pus, oil droplets, or food particles can
for diarrhea based on factors such as duration of also shed some light on the cause or mechanism of
illness (acute vs. chronic), population at risk (i.e., pa- diarrhea. For example, the presence of oil or food
particles may suggest malabsorption, maldigestion,
(AIDS) or international travelers), severity (large vs. or rapid intestinal transit. Blood in the stool should
small volume), pathophysiologic mechanism (osmot- alert the physician to the possibility of malignancy
ic vs. secretory), or by stool characteristics (watery,
suggest either an osmotic or secretory process.
has some merit and the wise clinician considers each These clues should not be over interpreted, however.
of these when trying to sort out an individual patient’s For example, blood can be present in stool from hem-
orrhoidal bleeding aggravated by diarrhea and not complaining of diarrhea is the need to differentiate
necessarily tumor or colitis. patients who have irritable bowel syndrome (IBS)
Other points of interest in the medical history in- from those with other functional disorders and or-
clude the relationship of defecation to meals or fast- ganic conditions causing diarrhea. Irritable bowel
ing, passage of stool during the day versus the night, syndrome is characterized by the presence of ab-
and the presence of fecal urgency or incontinence. dominal pain associated with defecation. Variable
Urgency and incontinence do not necessarily indi- stool consistency and periods of constipation also
cate voluminous diarrhea; instead these symptoms are common in patients with IBS. It is no longer be-
suggest problems with rectal compliance or with the lieved that painless diarrhea should be included as
muscles regulating continence and should direct at- a category of IBS. In patients with painless diarrhea,
tention to disorders that might affect the rectum or other causes of diarrhea such as those discussed in
pelvic structures. Diarrhea occurring at night that this section should be considered. Additional fac-
awakens the patient from sleep strongly suggests tors that suggest a diagnosis of IBS include a long
an organic cause rather than a functional problem. history, usually beginning in adolescence or young
- adulthood, passage of mucus, and exacerbation of
lence, bloating, or gaseous distention, cramps, fever, symptoms by stress. Factors that argue against a di-
and weight loss should also be elicited. agnosis of IBS include recent onset of diarrhea, espe-
Because iatrogenic causes of diarrhea such as cially in older individuals, nocturnal diarrhea, weight
previous surgery, medications, or radiation therapy loss, the presence of blood in the stool, stool weights
are common, the physician should also explore previ- greater than 400 to 500 grams per day, and abnor-
ous medical problems and surgeries, and compile a mal blood tests such as a low hemoglobin level, low
comprehensive list of current medications compris- serum albumin concentration, or high erythrocyte
ing both prescription drugs and over-the-counter sedimentation rate.
remedies, including nutritional and herbal thera-
pies (Table 4.4). The patient’s diet also should be
scrutinized. Some patients ingest large quantities Physical Examination
of relatively poorly absorbable carbohydrates such
Physical signs are more helpful in determining the
-
severity of diarrhea than its cause.1,2 Assessment of
tose (present in high fructose corn syrup, a common
volume status by looking for orthostatic changes in
sweetener in processed foods), or sugar alcohols
blood pressure and pulse, assessment of body tem-
such as sorbitol and mannitol. These substances can
perature, and signs of toxicity should be noted. Care-
cause osmotic diarrhea, usually associated with ex-
ful abdominal examination is also important. The
presence and quality of bowel sounds and the pres-
Epidemiological clues may also be useful (Table
ence or absence of abdominal distention and tender-
4.5).1,2 For example, in a person with acute diarrhea
ness may provide clues to the cause of the problem.
a history of recent foreign travel, particularly to third
On rare occasions, the physical examination may
world countries, makes a diagnosis of traveler’s diar-
provide more direct evidence of the cause of diarrhea.
rhea likely. Attention should be paid to whether the
Characteristic skin changes can be seen in mastocy-
patient lives in a rural setting or in the city, his or her
tosis, glucagonoma, Addison’s disease, amyloidosis,
source of drinking water, exposure to domestic pets
carcinoid syndrome, Degos disease and celiac dis-
or livestock, the patient’s occupation, sexual prefer-
ease. Hepatosplenomegaly and orthostatic hypoten-
ence and activity, and use of illicit drugs or alcohol.
sion may be the only clues to a diagnosis of amyloido-
Potential secondary gains from illness or a history
may be the only clues to a diagnosis of medullary

should raise the possibility of laxative abuse.
carcinoma of the thyroid or thyroid adenoma causing
A very practical issue in dealing with patients
hyperthyroidism. A right-sided heart murmur may
Table 4.3
Differential Diagnosis of Diarrhea by Duration and Stool by Characteristics
Acute diarrhea
Infection
Bacteria
Virus
Protozoa
Multicellular parasites
Food poisoning
Food allergies
Medication
Initial presentation of chronic diarrhea
Chronic diarrhea
Watery diarrhea
Osmotic diarrhea
Osmotic laxatives (e.g., Mg+2, PO4-3, SO4-2)
Carbohydrate malabsorption
Secretory diarrhea
Congenital syndromes (e.g., congenital chloridorrhea)
Bacterial toxins
Ileal bile acid malabsorption
Inflammatory bowel disease
Ulcerative colitis
Crohn’s disease
Microscopic colitis
Lymphocytic colitis
Collagenous colitis
Diverticulitis
Vasculitis
Drugs and poisons
Laxative abuse (stimulant laxatives)
Disordered motility/regulation
Postvagotomy diarrhea
Postsympathectomy diarrhea
Diabetic autonomic neuropathy
Endocrine diarrhea
Hyperthyroidism
Addison’s disease
Gastrinoma
VIPoma
Somatostatinoma
Carcinoid syndrome
Medullary carcinoma of the thyroid
Mastocytosis
Pheochromocytoma
Other tumors
Colon carcinoma
Lymphoma
Villous adenoma
Idiopathic secretory diarrhea
Epidemic secretory (Brainerd) diarrhea
Sporadic idiopathic secretory diarrhea
Inflammatory diarrhea
Ulcerative colitis
Crohn’s disease
Diverticulitis
Ulcerative jejunoileitis
Infectious diseases
Pseudomembranous colitis
Invasive bacterial infections (e.g., tuberculosis, yersiniosis)
Ulcerating viral infections (e.g., cytomegalovirus, Herpes simplex)
Invasive parasitic infections (e.g., amebiasis, strongyloides)
Ischemic colitis
Radiation colitis
Neoplasia
Colon cancer
Lymphoma
Fatty diarrhea
Malabsorption syndromes
Mucosal diseases (e.g., celiac disease, Whipple’s disease)
Short bowel syndrome
Small bowel bacterial overgrowth
Mesenteric ischemia
Maldigestion
Pancreatic exocrine insufficiency
Inadequate luminal bile acid concentration
be present with carcinoid syndrome. Arthritis may

Table 4.4
occur with IBD, Whipple’s disease, and some enteric
Drugs and Poisons Associated with Diarrhea
infections. Lymphadenopathy might suggest AIDS or
lymphoma. Signs of peripheral vascular disease with
Antibiotics (most) or without an abdominal bruit may suggest vascular
Antineoplastic agents (many) disease of the mesenteric system. Finally, careful at-
Anti-inflammatory agents (e.g., NSAIDs, gold, 5-aminosalicy-
tention to the rectal examination may disclose defec-
lates)
Anti-arrhythmics (e.g., quinidine)
Antihypertensives (e.g., beta-adrenergic receptor–blocking that may produce fecal incontinence.
drugs)
Antacids (e.g., those containing magnesium)
Acid-reducing agents (e.g., H2-receptor antagonists, proton
pump inhibitors) Further Evaluation of Acute Diarrhea
Colchicine
Prostaglandin (e.g., misoprostol)
Selective serotonin-reuptake inhibitors (e.g., antidepressants) weeks. Infectious diseases that run their courses
Theophylline during this time frame predominantly cause these.
Vitamin/mineral supplements
Herbal products Most are self-limited and do not require medication
Heavy metals for cure unless the patient’s immune system is com-
promised in some fashion. Patients with these infec-
tions may require a physician’s attention if they de- Table 4.5

velop volume depletion or severe toxicity.1,2 Likely Causes of Diarrhea in Patients with Certain Epidemiological
When these complications are present, or when Characteristics
diarrhea has persisted for more than a few days, a
more detailed evaluation is warranted. In these pa- Travelers
tients, a complete blood count should be done to look Bacterial infection (mostly acute)
for anemia, hemoconcentration, or an abnormal white Viral infection (e.g., Norovirus)
blood cell count or differential. Patients with viral di- Protozoal infections (e.g., amebiasis, giardiasis)
arrhea usually have a normal white blood cell count Tropical sprue
and differential or a lymphocytosis. Patients with bac- Epidemics/outbreaks
terial infections, particularly those involving invasion Bacterial infection
of the mucosa, typically have a leukocytosis with an Viral infection (e.g., rotavirus)
excess of immature white blood cells. Neutropenia Protozoal infections (e.g., cryptosporidiosis)
can occur in salmonellosis, however. Measurement of Epidemic idiopathic secretory diarrhea (Brainerd diarrhea)
serum electrolyte concentrations, blood urea nitro- Diabetics
gen, and serum creatinine level should be obtained to Altered motility (increased or decreased)
look for evidence of mineral and volume depletion. A Drugs (especially acarbose, metformin)
stool sample should be examined for the presence of Associated diseases
white blood cells by either microscopy or, more sen- Celiac disease
sitively, by analysis of fecal lactoferrin or calprotectin Pancreatic exocrine insufficiency
levels. Studies have suggested that stool cultures are Small bowel bacterial overgrowth
unlikely to grow pathogenic organisms in the absence AIDS patients
of fecal leukocytes, so this relatively simple and inex- Opportunistic infections (e.g., cryptosporidiosis, cytomegalovirus, her-
pensive test or a surrogate test for fecal leukocytes pes, mycobacterium avium complex)
can be used to decide which stool samples should be Drug side effect
sent for bacterial culture. Examination of stool for ova Lymphoma
and parasites has variable utility depending on the Institutionalized patients
pretest probability of these infections. ELISA testing Drug side effect
for giardiasis and serological testing for amebiasis Clostridium difficile toxin–mediated colitis
Tube feeding
most settings but may be false-negative in as many as Ischemia
15% of patients. Patients who have been treated with Fecal impaction with overflow diarrhea
antibiotics in the preceding 3 months, patients with
-
oping diarrhea in institutional settings should have a pathologist can distinguish self-limited colitis from
stool sample sent for measurement of toxin. chronic ulcerative colitis with good precision. Plain
abdominal X-rays should be obtained in toxic pa-
be considered in toxic patients, patients with blood or
pus in the stool, or those with persistent acute diar- evidence of ileus or megacolon. An algorithm for the
rhea. In the average patient, sigmoidoscopy is prob- evaluation of patients with acute diarrhea is shown in
ably adequate as an initial investigation. In patients Figure 4.1.
with AIDS who have diarrhea, colonoscopy is prefer-
able because a substantial proportion of infections
and lymphomas may be present only in the right Further Evaluation of Chronic Diarrhea
colon, although this has been called into question.2
Mucosal biopsies should be obtained, particularly if Because of the larger differential diagnosis for chron-
ic diarrhea, the initial evaluation of these patients is
more complex (Figure 4.2). When the history, physi- The pH of stool water can give useful informa-
cal examination, and the routine laboratory tests tion about the presence of carbohydrate malabsorp-
already mentioned strongly suggest a particular dition. When carbohydrate reaches the bacteria in
the colon, it is fermented and produces short chain
focused empiric trial of therapy can be used to con- fatty acids, most of which are absorbed. As a result
of fermentation, however, the pH drops (usually <6)
is suggested by the initial evaluation, a stool analysis and thus the presence of acidic stool is an indirect
is useful in an effort to categorize these patients and assessment of excess carbohydrate fermentation in
thus limit the number of conditions to be considered the colon.
in the differential diagnosis.1,2 The stool analysis can Fecal occult blood testing and examination for
be obtained on either a random sample or a timed
collection. The value of a timed collection is that it
allows the physician to accurately quantitate stool the presence of a malignancy in the gastrointestinal
output. In the absence of a timed collection, how- tract. Recent work suggests that surrogate measures
ever, measurement of other stool characteristics on for stool white cells such as fecal lactoferrin or cal-
a random stool sample still provides many clues to protectin, are less operator-dependent and perhaps
the correct diagnosis. Characteristics that should be more accurate in making this assessment.
measured include stool sodium and potassium con- Estimation of fat output, either by quantitative
centrations, stool osmolality, stool pH, fecal occult measure of fat content or by qualitative estimation
blood testing, and assessment for stool white cells or by Sudan stain, can yield important information.
a surrogate marker such as fecal lactoferrin or cal- The presence of steatorrhea implies some dysfunc-
protectin. Stool fat output should be assessed either tion of fat digestion or mucosal absorption by the
quantitatively or qualitatively with a Sudan stain. In small intestine. A Sudan stain of a fecal smear can
appropriate circumstances, a laxative screen should yield a reliable estimate of steatorrhea if the speci-
be obtained.
Measurement of stool electrolytes allows the absorbed fat substitutes such as olestra or use of a
physician to calculate an osmotic gap in stool wa- lipase inhibitor such as orlistat can confound tests
ter (see above). When the osmotic gap is small (<50 for steatorrhea.
mosm/kg), the osmolality of stool water is mostly Finally, in patients who are suspected of surrep-
due to electrolytes (mainly sodium and potassium titious laxative ingestion, analysis of stool water for
and their accompanying anions), suggesting that laxatives by chemical or chromatographic methods
excess water is retained in the stool because of in- can detect laxative ingestion. If positive, tests for
complete absorption of electrolytes. This indicates laxatives should be repeated on another stool sam-
the presence of a secretory diarrhea. When a large
osmotic gap is present, most of the stool osmolality is patient with this discovery. (The presence of mela-
contributed by nonelectrolytes, indicating the pres-
ence of an osmotic diarrhea caused by ingestion of has ingested anthraquinone laxatives chronically.)
some poorly absorbed substance. Measurement of The utility of this approach was investigated by
actual stool osmolality is only of value in detecting Steffer et al in a series of patients seen for chronic
samples that have been contaminated by the addi- diarrhea at a tertiary referral center. Six patterns of
tion of water or dilute urine and, therefore, have an results were evident: a) stool weights <200 g/24h,
osmolality <290 mosm/kg. Stool osmolality tends to b) secretory diarrhea without steatorrhea, c) carbo-
rise once the stool has been collected because of con- hydrate malabsorption without steatorrhea, d) ste-
tinuing bacterial fermentation , so this value atorrhea with or without carbohydrate malabsorp-
should not be used in the calculation of the osmotic tion, e) osmotic diarrhea due to laxative ingestion,
gap.
Figure 4.1
Algorithm for Evaluation of Acute Diarrhea
WBCs, white blood cells. From Schiller LR. Diarrhea. Med Clin N Amer 2000;84:1259–74; used with permission.
Figure 4.2
Initial Evaluation Scheme for Chronic Diarrhea
AIDS, acquired immunodeficiency syndrome; OTC, over the counter; WBCs, white blood cells. From Schiller LR, Sellin JH. Diarrhea. In: Sleisenger and Fordtran’s
Gastrointestinal and Liver Diseases. Pathophysiology, Diagnosis, Treatment. 9th ed. Feldman M, Friedman L, Brandt LJ, Eds. Philadelphia, PA: Elsevier, 2010, p.
211–3; used with permission.
including lymphomas should be sought by means

diarrhea” patients with stool weights <200 g/24h of radiographic and endoscopic techniques. Small-
had formed stools. Of these patients 9 had normal bowel radiographs remain an important method for
stool characteristics, suggesting intermittency of detecting structural small-bowel problems but CT
symptoms or incontinence as the primary problem, enterography is said to be more accurate. Comput-
4 had steatorrhea, and 1 had high fecal magnesium erized tomography is of value in detecting not only
content. Discovery of formed stool in a patient com- small-bowel and colonic disease, but also problems
plaining of “chronic diarrhea” should prompt a re- extrinsic to the bowel that can cause diarrhea, such
consideration of the patient’s symptoms and per- as pancreatic tumors. Visualization of the mucosa
haps a repeat stool collection when stools are loose. by sigmoidoscopy or colonoscopy is valuable in the
When stools are loose, stool analysis allows diagnosis of IBD and tumors and permits directed
chronic diarrhea to be categorized as being watery biopsy. In most patients with chronic secretory di-
with the subheadings of secretory or osmotic diar- arrhea, sigmoidoscopy is adequate for this purpose.
rhea, or - Colonoscopy should be used if blood is present in the
lows a focused evaluation of the cause of diarrhea. stool or if there is a strong suspicion of right-colon
or ileal disease.6 It is important to emphasize that all
patients with chronic secretory diarrhea should have
Evaluation of Chronic Watery Diarrhea biopsies obtained from the colon even when the mu-
cosa looks normal, because of the prevalence of mi-
has a broad differential diagnosis
croscopic colitis. Although small-bowel mucosal dis-
(Table 4.3). The common thread among these condi-
ease often is a cause of steatorrhea, it may produce
tions is that salt and water absorption is impaired.
a watery diarrhea without steatorrhea. Wireless
This can be caused by several mechanisms: bacterial
capsule endoscopy can be used to survey the entire
toxins, abnormal neural regulation, circulating secre-
small-bowel surface for visual evidence of disease,
tagogues, local release of immune mediators, or con-
particularly ulcerations suggesting Crohn’s disease.
genital defects in transport proteins. To make a diagno-
Small-bowel biopsy may add useful information to
sis, a broad net must be cast (Figure 4.3).
the evaluation of chronic watery diarrhea if other
Infection should be excluded by looking for bac-
diagnostic tests are inconclusive. Double balloon or
teria by stool culture and for other organisms by spe-
spiral overtube-assisted enteroscopy can be used to
cial tests. Whereas most bacterial pathogens will be
reach lesions beyond the reach of push enteroscopes.
cleared spontaneously within 4 weeks, some organ-
Endocrine diarrhea is an intellectually interest-
isms such as Aeromonas and Pleisiomonas may pro-
ing form of chronic diarrhea, but is quite rare. Ac-
duce chronic diarrhea. Special cultures may be need-
cordingly, the pretest probability of having a peptide-
secreting tumor is very low even in patients with
chronic diarrhea, and screening all chronic diarrhea
the stool. Small bowel biopsies may need examina-
patients with a panel of serum peptide levels is likely
to produce far more false-positive than true-positive
the pathogens. Small bowel aspirate for quantitative
results. Limiting testing to patients who have chron-
culture of both aerobes and anaerobes can be used
ic diarrhea with symptoms consistent with tumor
to detect small bowel bacterial overgrowth. Glucose
breath hydrogen testing may be used as a fairly accu-
rate alternative test. Giardiasis and cryptosporidiosis
syndrome) or who have computerized tomography
that demonstrates tumors can enhance test perfor-
mance. More common endocrine diseases that may
has made diagnosis more accurate.
have diarrhea as a symptom include diabetes melli-
such as short-bowel syn-
tus, hyperthyroidism, and Addison’s disease. In most
Figure 4.3
Further Evaluation of Chronic Secretory Diarrhea
CT, computed tomography; 5-HIAA, 5-hydroxyindoleacetic acid; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; VIP, vasoactive intesti-
nal peptide. From Schiller LR, Sellin JH. Diarrhea. In Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases. Pathophysiology, Diagnosis, Treatment. 9th
ed. Feldman M, Friedman L, Brandt LJ, Eds. Philadelphia, PA: Elsevier, 2010, p. 211–32; used with permission.
cases, other signs and symptoms of these diseases will chronic diarrhea. Everyone agrees that ileal disease
be present, but one could argue for measurement of or resection allows excessive amounts of conjugated
blood sugar, thyroid-stimulating hormone, and serum bile acid to enter the colon. If the concentration of
cortisol before and after injection of an adrenal stimu- bile acid in colon contents exceeds 3–5 mmol/L, elec-
lant in patients who might have these disorders. trolyte absorption by the colon mucosa is inhibited
One controversial issue is the importance of bile and a secretory diarrhea may result. The controversy
acid malabsorption as a mechanism for producing is how often this mechanism produces chronic diar-
rhea when there is not overt ileal disease or resec- of settings. Usually it is caused by ingestion of poorly
tion. Studies from both Europe and the United States absorbable carbohydrates such as lactose in some-
indicate that bile acid malabsorption is common in
patients with idiopathic chronic diarrhea. Investiga- include ingestion of poorly absorbed sugar alcohols
tors differ in their assessments of the effect of bile -
acid sequestering resins in this setting, however. Eu- eners, or excessive ingestion of sugars with limited
ropean studies have shown that a high proportion of absorption capacity such as fructose. A new cause
patients with otherwise idiopathic diarrhea respond is therapeutic use of inhibitors of carbohydrate ab-
to therapeutic doses of bile acid sequestrants, where- sorption such as acarbose. Because carbohydrate
as American studies have shown no consistent effect. delivered to the colon is rapidly fermented to short
The reasons for this discrepancy are not known. The chain fatty acids, carbon dioxide, and hydrogen by
the colonic bacteria, acid stools, gas, and bloating
pay to do a sophisticated test for bile acid malabsorp- are frequently present in patients with carbohydrate
tion; the test is likely to be abnormal and may not be malabsorption. Diagnosis depends on measuring fe-
predictive of successful therapy with bile acid se- cal osmotic gap (typically >50 mosm/kg), stool pH
questrants. It makes more sense to try patients with (often <6), and obtaining a thorough dietary history.
idiopathic chronic secretory diarrhea on an empiric Breath hydrogen testing with various carbohydrates
trial of bile acid-sequestering resins. If diarrhea is may yield misleading results and should not be re-
controlled, bile acid malabsorption may be playing a lied on for diagnosis.
role in that patient. Osmotic diarrhea should disappear with fasting
some pa- or elimination of the offending agent from the diet,
tients with chronic secretory diarrhea have no cause but diarrhea may not disappear completely in some
individuals with magnesium ingestion or carbohy-
occur in two patterns: epidemic idiopathic secre- drate malabsorption who have other mechanisms
tory diarrhea (Brainerd diarrhea) and sporadic idio- of diarrhea still operative (e.g., some patients with
pathic secretory diarrhea. Whereas the occurrence of short bowel syndrome).
chronic diarrhea in outbreaks suggests an infectious
Figure 4.4
Both forms of idiopathic secretory diarrhea resolve Further Evaluation of Chronic Osmotic Diarrhea
spontaneously, usually within 3 years of onset.
Osmotic diarrhea has a more limited differential
diagnosis. If stool water has low electrolyte concen-
trations (and therefore a high osmotic gap), some
nonelectrolyte is holding water within the colonic lu-
men. Practically, this is because of one of two condi-
tions: magnesium ingestion or carbohydrate malab-
sorption (Figure 4.4).
Magnesium is relatively easy to measure accu-
rately in stool water. Excretion of more than 15 mmol
(30 mEq) of magnesium daily or concentrations in
stool water of >45 mmol/L (90 mEq/L) strongly
suggests magnesium-induced diarrhea. This can
be intentional (surreptitious laxative ingestion) or From Schiller LR, Sellin JH. Diarrhea. In Sleisenger and Fordtran’s
accidental (from therapeutic use of magnesium-con- Gastrointestinal and Liver Diseases. Pathophysiology, Diagnosis,
taining antacids or mineral supplements). Treatment. 9th ed. Feldman M, Friedman L, Brandt LJ, Eds. Philadel-
Carbohydrate malabsorption occurs in a variety phia, PA: Elsevier, 2010, p. 211–32; used with permission. Figure 9.5
Evaluation of Chronic Inflammatory diarrhea produced mild “steatorrhea” in 35% of nor-

Diarrhea mal subjects. In patients with diarrhea, fat excretion
-
Patients with chronic diarrhea who have evidence of
nosis of defective fat absorption. Conversely, excre-
tion of >14 g/24 hours strongly suggests a problem
-
with fat absorption. These limits need to be adjusted
matory diarrhea. Diagnostic considerations include
for fat intake; patients with diarrhea frequently have
IBD, infections, ischemia, radiation enteritis, and neo-
anorexia or early satiety that substantially reduces
plasia (Table 4.3). In some cases, these conditions
their fat intake. When possible, diet diaries should
produce a secretory diarrhea without markers of
be maintained during the collection period and fat
intake estimated from them. Measurement of fat ex-
in the evaluation of secretory diarrhea. When white
cretion can be compromised by ingestion of the fat
-
substitute, Olestra.
eases need to be strongly considered.
When a quantitative collection is not possible,
Evaluation of these patients should start with
qualitative estimation of fat excretion can be made
looking for structural problems by means of radio-
by means of a Sudan stain of a fecal smear. Semiquan-
graphic and endoscopic techniques (Figure 4.5). Sig-
titative methods can be applied to measure the num-
moidoscopy or colonoscopy should be considered
ber and size of fat globules and these produce results
that correlate well with quantitative collections.
of diarrhea.6 Selection of the most appropriate endo-
Fecal fat concentration can provide a clue to the
etiology of steatorrhea. The major causes of steator-
argue that sigmoidoscopy can detect most causes of
rhea are mucosal disease (e.g., celiac disease), pan-
-
is simpler than that for colonoscopy. Others prefer to
atitis), and lack of bile (e.g., advanced primary biliary
examine the entire colon and terminal ileum when
cirrhosis). Mucosal disease often is associated with
-
The proper test should be selected according to the
luted by unabsorbed water. In addition, fat digestion
circumstances of the individual patient. Whichever
usually is intact in mucosal disease, producing fatty
method is selected, the important point is to obtain
acids that can inhibit water absorption in the colon,
-
further diluting the fat content of stool. In contrast,
tion that is present.
pancreatic and biliary diarrheas typically do not af-
Infection needs to be considered as a cause of in-
-
-
absorbed fat is dispersed in a smaller stool volume.
-
A fecal fat concentration >9.5 g/100 g strongly sug-
rhea are cytomegalovirus, amebiasis, and
gests the presence of pancreatic or biliary steator-
tuberculosis. Appropriate cultures and serological
rhea.
tests need to be obtained.
Evaluation of patients with chronic fatty diar-
rhea should begin with an assessment of fecal fat
excretion and concentration (Figure 4.6).1,2 Often,
Evaluation of Chronic Fatty Diarrhea the cause of steatorrhea will be obvious from the
The presence of steatorrhea implies a disruption of patient’s history but when it is not, evaluation of the
fat solubilization, digestion, or absorption in the small absorptive surface of the small bowel with radiogra-
phy and endoscopy with biopsy should be the initial
fat in the stool, usually >7 g or 9% of intake per 24 steps. During endoscopy, an aspirate of duodenal or
hours, but these criteria probably are not valid in pa- jejunal contents can be cultured quantitatively, both
tients with diarrhea.1,2 In one study, laxative-induced aerobically and anaerobically, to evaluate the patient
for small-bowel bacterial overgrowth. At present, in- Figure 4.5

direct testing for the diagnosis of celiac disease, such Further Evaluation of Chronic Inflammatory Diarrhea
as measuring anti-endomysial or anti-tissue trans-
glutaminase antibodies, is good for screening but is
not accurate enough to displace endoscopic biopsy
-
doscopy can assess areas beyond the reach of push
enteroscopy but inability to biopsy is a limitation in
its use. Deep enteroscopy (e.g., double-balloon or
spiral overtube- assisted enteroscopy) is good for ex-
amining more distal regions, but is usually not neces-
sary for the evaluation of steatorrhea. Computerized
tomography of the abdomen can be used to complete
the structural assessment by imaging the liver, pan-
creas, and abdominal lymphatic system.
If the absorptive surface is normal, abnormal pan-
creatic exocrine function should be considered. Avail-
able tests all have limitations. The secretin test is the
CT, computed tomography. From Schiller LR, Sellin JH. Diarrhea. In Sleisenger and
most time-honored of these tests, but involves duo-
Fordtran’s Gastrointestinal and Liver Diseases. Pathophysiology, Diagnosis, Treat-
denal intubation and is rarely done, even in academic
ment. 9th ed. Feldman M, Friedman L, Brandt LJ, Eds. Philadelphia, PA: Elsevier, 2010,
centers. Measurement of stool chymotrypsin or elas-
p. 211–32; used with permission.
tase activity has been used for screening, especially in
in patients with chronic diarrhea. While not diag- food stores or from Internet sources; 1 g with each
nostic of impaired pancreatic function per se, dem-
onstration of abnormal pancreatic duct anatomy by enough by patients.
computed tomography (CT), magnetic resonance
cholangiopancreatography, endoscopic ultrasound,
or endoscopic retrograde cholangiopancreatogra-
Treatment of Diarrhea
phy provides support for a diagnosis of pancreatic
The most important therapy for diarrhea is to in-
-
-
paired.2,7
peutic trial of pancreatic enzyme supplementation.
-
If a therapeutic trial is conducted, high doses of en-
ids are based on the concept that nutrient absorp-
zymes should be used and some objective measure-
ment (e.g., fecal fat excretion) should be monitored to
jejunum. Recent work has shown that cereal-based
assess response.
oral rehydration solutions can be as effective as
Testing rarely is used to evaluate the adequacy
glucose-based solutions. Although oral rehydration
of bile salt solubilization of dietary fat. The diagnosis
-
they are not designed to reduce stool output and so
tory or physical examination. If proof of mechanism
stool weight may actually increase. They also are not
is necessary, duodenal bile salt concentration can be
of use when vomiting precludes ingestion of the so-
measured or an empiric trial of bile acid supplemen-
lution. Most sports drinks (e.g., Gatorade®) are de-
tation can be tried. Ox bile extract used to be avail-
able through standard pharmaceutical channels, but
exercise (mostly free water and sweat); they do not
now is available as a dietary supplement from health
have enough sodium to replace stool losses in diar-
rhea effectively. These solutions or just plain water return. Empiric antiprotozoal therapy makes some
can be used if additional sources of sodium and ab- sense in patients with more than a week or two of
sorbable nutrients (e.g., pretzels or crackers) are acute diarrhea (“persistent acute diarrhea”) in which
ingested concomitantly. Solutions that more closely the probability of giardiasis or cryptosporidiosis is
approximate World Health Organization rehydration increased.
solution are now commercially available (e.g., Rehy-
dralyte®, Resol®, Ricalyte®). frequency and stool weight and also can reduce coex-
isting symptoms, such as abdominal cramps.2,7 Opiates,
such as loperamide or diphenoxylate with atropine,
Empirical Therapy of Acute Diarrhea frequently are employed. Concerns about slowing the
clearance of pathogens from the intestine with these
Physicians confronted with patients with acute di-
antiperistaltic agents largely have not been borne out.
arrhea often consider empirical trials of antibiotic
Intraluminal agents, such as bismuth subsalicylate
therapy. If the prevalence of bacterial or protozoal
and adsorbents (e.g., kaolin) also can be of use.
infection is high in a given community or in a spe-
would make sense. For example, travelers’ diarrhea

Empirical Therapy of Chronic Diarrhea
without bacteriological proof of infection. Empirical Empirical therapy is used in patients with chronic
antibiotic therapy also is used for more than mildly diarrhea in three situations: (1) as a temporizing or
initial treatment before diagnostic testing, (2) after
Figure 4.6
and (3) when a diagnosis has been made, but no spe-
Further Evaluation of Chronic Fatty Diarrhea
to produce a cure.
Empirical antibiotic therapy generally is less use-
ful than in acute diarrhea, since bacterial infection is
a less likely cause of chronic diarrhea. Nevertheless,
some clinicians try an empirical course of metroni-
-
this approach has not been assessed by clinical trials.

Therapeutic trials of bile acid-binding resins in
idiopathic secretory diarrhea and pancreatic enzyme
replacement in unexplained steatorrhea have been
discussed previously.
Symptomatic treatment with opiates and other
agents often is necessary after evaluation in patients
not be available (Table 4.6). Potent opiates, such as

codeine, opium, or morphine, probably are underuti-
lized in the management of these patients. Because
of the abuse potential of these agents, they are con-
CT, computed tomography. From Schiller LR, Sellin JH. Diarrhea. In Sleisenger and
trolled substances in the United States. Nevertheless
Fordtran’s Gastrointestinal and Liver Diseases. Pathophysiology, Diagnosis, Treat-
patients with chronic diarrhea rarely abuse them if
ment. 9th ed. Feldman M, Friedman L, Brandt LJ, Eds. Philadelphia, PA: Elsevier, 2010,
a few simple measures are taken. First, the patient
p. 211–32; used with permission.
needs to be informed about the abuse potential of the
medication and should be warned about increasing

the dose without consulting with his or her physician.
Pathophysiology of Constipation
Second, dosing should be started at a low level (e.g., -
codeine 30 mg QID, deodorized tincture of opium 3 cum from the terminal ileum. 3
drops QID, or morphine 2 mg QID) and titrated up to of the residues of the digestive process, mostly salt,
an effective dose. Third, use of the opiate should be
monitored closely and the prescription should not be through the colon is sluggish, taking 24–30 hours for
material to pass from the cecum to the rectum. Dur-
amount of medication dispensed has passed. ing this time 90% of the salt and water is reabsorbed
Octreotide, a somatostatin analog, is of proven
value in the treatment of diarrhea due to dumping syn- chain fatty acids by colonic bacteria. These products
drome and due to peptide-secreting tumors. It is some- are absorbed by the colonic mucosa and the amount
times employed in the treatment of idiopathic diar- of feces produced is only a small fraction of what en-
tered the colon (about 80–120 g/24 hours). The pro-
Stool modifying agents, such as psyllium, can al- cess of defecation involves the sequential removal of
ter stool consistency, but do not reduce stool weight.
They can be of use in patients with coexisting fecal sphincters that are meant to promote continence.
incontinence and many patients with relatively low Constipation can be idiopathic or secondary. Dis-
stool weights.7,8 orders causing constipation include endocrine and
metabolic conditions, neurological diseases and/or
organic anorectal and colonic disorders (Table 4.7).
Many drugs can also cause constipation as a side ef-
Definition of Constipation fect (Table 4.8).
Idiopathic constipation is attributed to two
Patients also com-
9–11
pathophysiological mechanisms that may overlap in
plain about constipation when they pass what they some individuals.12,13 slow-transit constipa-
perceive as “hard” stools. Normal stool frequency the failure of propulsion through the colon, which
ranges from three times weekly to twice daily. Infre- probably results from dysfunction of enteric nerves or
smooth muscle in the colon. Of late, some investigators
have proposed that excess methane production by co-
and is often described by patients as inability to ini- lonic bacteria may be responsible for slow transit in
tiate defecation, excess straining to initiate or com- some patients. Slow transit is a common mechanism
plete evacuation, or a feeling of incomplete evacua- of idiopathic constipation, particularly in patients pre-
tion. Objective measurement of stool texture shows senting with longstanding constipation. When people
no difference between stools from patients with develop slow transit through the colon, luminal con-
constipation and those without constipation, raising tents are exposed to the mucosa and to colonic bac-
the issue of whether patients complaining of “hard teria for a longer period of time and more water and
stools” really have stools that are physically hard or solid residue are removed. Thus the total amount of
are just hard to pass. feces produced per week is decreased, but curiously
Patients also may complain about constipa- the amount produced with each bowel movement
(“stroke volume”) is about the same as in normal in-
evacuation and also have subsidiary problems such dividuals.
as abdominal pain, bloating, or rectal bleeding. Ab- The other mechanism for idiopathic constipation
dominal pain is a particularly confusing problem to is which is due to inef-
assess in these patients because the combination of fective opening or blockage of the anal canal during
abdominal pain and irregular bowel habits may be defecation or by failure of the rectum to expel feces.14
diagnosed as constipation-predominant IBS. Patients with functional outlet obstruction typically
Table 4.6
Nonspecific Therapy for Chronic Diarrhea
Drug class Agent Dose

Opiates
Diphenoxylate 2.5–5 mg QID
Loperamide 2–4 mg QID
µ-opiate receptor selective Codeine 15–60 mg QID
Morphine 2–20 mg QID
Opium tincture 2–20 drops QID
-opiate receptor active Racecadotril (acetorphan) 1.5 mg/kg TID*
Adrenergic agonist Clonidine 0.1–0.3 mg TID
Somatostatin analogue Octreotide 50–250 mg TID (subcutaneously)
Bile acid–binding resin Cholestyramine 4 g daily–QID
Psyllium 10–20 g daily

Fiber supplements
Calcium polycarbophil 5–10 g daily
*Not yet approved in the United States.
-
tional outlet obstruction is most often attributed to
Evaluation of Constipation
dyssynergia (anismus), paradoxical contraction of the Every patient with constipation should have a thor-
ough history and physical examination in order
attempting defecation. It also may occur with intus- to understand the patient’s symptoms, to exclude
susception of the rectal mucosa into the anal canal that causes of secondary constipation, and to plan an ap-
typically produces the sensation of incomplete evacu- propriate strategy for further diagnostic testing and
ation. Functional outlet obstruction coexists with slow therapy (Figure 4.7).
transit in approximately 20% of patients presenting The history should highlight the duration of
- symptoms, any recent changes in symptoms, the fre-
stipation. It is the sole mechanism of constipation in quency of defecation, stool characteristics, such as
approximately 25% of such patients. bulk, size, consistency or the presence of blood, and
16
The pathophysiology of idiopathic constipation
in patients with normal transit and no demonstrable Measures that the patient has taken to relieve them-
outlet problem is unknown. In some reported series selves should be documented including all prescrip-
this combination is quite common. For now it is best tion and the over-the-counter medications.
recognized as a part of “functional constipation.” In Physical examination should concentrate on the
this syndrome, various problems with the defecation abdomen and rectum. The abdomen should be exam-
process may be reported to physicians by patients as ined for evidence of distention, tympany, fecal load-
“constipation.” ing, and tenderness. Rectal examination should in-
Painful constipation is a newly described subtype clude assessment of the perineum, the cutaneo-anal
of chronic constipation. The relationship of this syn-
15 presence of stool in the rectum, strictures, masses
or tenderness. Particular attention should be made
evaluation of these patients.

asked to strain as if simulating defecation. Paradoxi- Anoscopy and sigmoidoscopy should be consid-
cal contraction of the puborectalis muscle and pelvic ered in patients who present with bright red rectal
bleeding or obstructive symptoms and should always
presence of functional outlet obstruction. The exam- be done to exclude malignancy in patients 40 years
iner be able to appreciate perineal descent, weak or of age or older who present with constipation for the
ineffectual push, rectal intussusception or prolapse,
and the presence of a rectocele. A careful neurologic evaluation of constipation unless there is evidence of
examination should also be done in every patient with
constipation.9,10,17 should be performed for colon cancer screening when
Clinical laboratory tests often include a complete
blood count to exclude anemia, serum chemistry Radiographic studies should include a plain
screen to look for hypokalemia, hypercalcemia, and
diabetes, and measurement of serum thyroid-stim- gaseous distention, particularly in those patients
ulating hormone to exclude hypothyroidism. There complaining of abdominal pain and bloating. Bari-
is no evidence that these tests are more likely to be um or Hypaque™ enema is useful in excluding ana-
abnormal in patients with chronic constipation and tomic problems in the colon, such as megacolon and
experts advise against their routine use in the initial diverticulosis, especially in patients with abdominal
Table 4.7
Secondary Causes of Constipation
Metabolic conditions Central nervous system Stenotic or obstructive lesions

Diabetes mellitus Spinal cord lesions or injuries Tumors
Hypercalcemia Cauda equina tumor Diverticulitis
Hypokalemia Lumbar disc disease Inflammatory strictures
Porphyria Tabes dorsalis Ischemia
Multiple sclerosis Volvulus
Parkinson’s disease Endometriosis
Stroke Postoperative strictures
Brain tumor
Endocrine conditions Peripheral nervous system conditions Painful anorectal lesions
Hypothyroidism Autonomic neuropathy Anal fissure

Panhypopituitarism Diabetes mellitus Thrombosed hemorrhoids
Hyperparathyroidism Amyloidosis Mucosal prolapse
Pseudohypoparathyroidism Paraneoplastic disease Ulcerative proctitis
Pheochromocytoma Chagas’ disease
Glucagonoma Neurofibromatosis
Ganglioneuromatosis
Hirschsprung’s disease and variants
Smooth muscle disorders

Myotonic dystrophy
Dermatomyositis
Systemic sclerosis
Table 4.8 who do not respond to conservative therapy should

Some Drugs Associated with Constipation be evaluated further with functional studies to bet-
Analgesics These functional studies include colon transit studies

Nonsteroidal anti-inflammatory agents using radio-opaque markers or a telemetry capsule,
Opiates and related agents anorectal manometry, balloon expulsion test, and bar-
Anticholinergic drugs ium defecography.
Atropine and related antispasmodics Colon transit studies are simple to do and can
Antidepressants provide useful information about the mechanism of
Neuroleptic drugs (antipsychotics, antiemetics) constipation. Several protocols have been described,
Some agents used for Parkinson’s disease the easiest of which is to administer a capsule con-
Anticonvulsants taining 24 radio-opaque rings (Sitzmarks®) and then
Antihistamines to obtain X-rays of the abdomen over time to see the
Antihypertensives progress of these rings through the colon. Retention
Calcium channel antagonists of more than 5 rings 5 days after ingestion is abnor-
Clonidine mal. A telemetry capsule that reports pH, pressure,
Hydralazine and temperature has been used to measure gastric,
Monoamine oxidase inhibitors small bowel, and colonic transit time. Anorectal ma-
Methyldopa
Chemotherapeutic agents responses to rectal distention, and rectal sensation,
Vinca derivatives as well as detecting dyssynergia and Hirschsprung’s
Diuretics disease. In the balloon expulsion test a small balloon
Metal ions
Aluminum (antacids, sucralfate) within the rectum and the patient is asked to expel
Barium sulfate it; failure to expel the balloon within 60 seconds is
Bismuth abnormal. Defecography is a radiographic technique
Calcium (antacids, supplements) in which a small amount of barium is placed in the
Iron supplements -
Poisonous heavy metals (arsenic, lead, mercury)
Resins evidence of intussusception or prolapse. Other stud-
Cholestyramine ies, such as electromyography and colonic motility
Sodium polystyrene sulfonate studies, can be used to examine anorectal and colonic
function, but their role in clinical management is still
pain or obstructive symptoms. Young patients, es-

-
pecially those with a brief history of constipation,
sit, and slow-transit constipation (Figure 4.7).9,10
At this point it is useful to stratify patients by

duration of symptoms and severity. Patients with
acute constipation, who have had secondary causes Treatment
excluded, should probably receive laxative therapy
in the hope of eventually regularizing their bowel
habits. Those with chronic constipation of mild se- Diet and Lifestyle
-
plementation. Those who have severe chronic con- main goal of diet therapy for constipation. This can
Figure 4.7
Evaluation of Constipation
IBS, irritable bowel syndrome; STT, slow transit time; R/O, rule out. From Locke GR 3rd, Pemberton JH, Phillips SF. AGA technical review on constipation. From
Whitehead WE, Di Lorenzo C, Leroi AM, et al. Conservative and behavioural management of constipation. Neurogastroenterol Motil 2009;21(Suppl 2): 55–61;
used with permission.
be achieved by modifying the composition of the diet -

or by supplementing the usual diet with psyllium, or
and abdominal distention may be made worse be- symptoms, a low residue diet may improve matters by
reducing the amount of stool that needs to be evacuat- Chloride Secretagogues

ed and by reducing colonic gas formation.18 Laxatives
Lubiprostone is an agent that opens ClC-2 chloride
may need to be used to produce stool.
channels on the apical surface of enterocytes by a
Although many experts recommend increasing
direct effect. It improves stool frequency in patients
with constipation and reduces symptoms of IBS with
that these maneuvers are of any value in the manage-
constipation.20
ment of constipation.
secretion, affect epithelial permeability, or modify
the regulatory function of the gut to produce these
effects. Linaclotide, a guanylin analog, works by stim-
Habit and Biofeedback Training
ulating the guanylyl cyclase-C receptor on the apical
Patients with functional outlet obstruction constipa- surface of enterocytes, increasing intracellular cyclic
guanylyl monophosphate (cGMP) concentrations.
helped by attempts to teach proper defecation tech- -
niques.18 This can be accomplished by having the lator (CFTR) channel, thereby stimulating enterocyte
patient attempt defecation on a regular schedule, chloride secretion.21 Linaclotide is FDA-approved for
inducing defecation with suppositories or enemas, use in chronic constipation and IBS with constipa-
and rewarding success (so-called “habit training”). tion.
Biofeedback techniques, in which manometric or
activity is used to guide relaxation of the paradoxi- Systemic Agents

Patients with chronic constipation sometimes re-
more successful with improvement in up to 70% of
spond to systemic agents that may affect enteric
nerve or muscle function. Trials have had mixed re-
trials show that biofeedback is of use only in pa-
sults and new agents are being developed. Currently
tients with dyssynergia; patients with slow-transit
bethanechol (Urecholine), misoprostol (Cytotec), and
constipation do not respond.19 Conversely, patients
colchicine have produced results in some patients
with dyssynergia do not respond well to tradition-
(Table 4.10).
al therapies for constipation, making biofeedback
Prucalopride is a full agonist at 5-HT4 receptors
training their best option. Such techniques should
and has effects similar to cisapride and tegaserod.22
only be attempted in centers that are experienced
It speeds peristalsis and reduces visceral pain, but
with the biofeedback process and have good success
does not interact with the cardiac K+ channel that
rates with it.
occasionally caused cardiac arrhythmias with cis-
apride. It has been approved for laxative-refractory
constipation in Canada and Europe and is under
Laxatives
development in the United States for use in chronic
Most patients with constipation require the use of constipation and IBS with constipation.
laxatives at some point in their course. A variety of Opiate-induced constipation is a common prob-
agents are available (Table 4.9).9,10 For chronic use, lem. Methylnaltrexone, a peripheral-only µ-receptor
bulk laxatives and osmotic agents, such as magne- antagonist, is approved for this indication and is giv-
sium salts and polyethylene glycol, are tolerated best. en by subcutaneous injection, typically every other
Stimulant laxatives may produce excessive cramping day.23 Alvimopam, another new agent which blocks
and lose effectiveness in some patients with pro- µ-opiate receptors in the enteric nervous system but
longed daily use. Available stimulant laxatives seem not in the central nervous system, is available only
to be safe and effective for short-term or intermittent for management of postoperative ileus.
chronic use, however.
Table 4.9
Laxatives Used to Treat Constipation
Laxative Typical adult daily dosage
Bulk laxatives
Psyllium preparations (Metamucil) 20 g
Polycarbophil (Equilactin) 4g
Methylcellulose (Citrusel) 4g
Emollients
Docusates (sodium or calcium) (Colace) 200 mg
Mineral oil 15–30 ml
Osmotic agents
Magnesium hydroxide (milk of magnesia) 15–60 ml
Phosphate salts (Phospho-soda) 30–45 ml
Lactulose (Chronulac) 15–60 ml
Sorbitol 15–60 ml
Polyethylene glycol (Miralax) 17 g
Glycerin suppositories 1–2 suppositories
Stimulant laxatives
Castor oil 30–60 ml
Cascara fluid extract 5 ml
Senna (Senokot) 15–60 ml
Bisacodyl (Dulcolax) 10–20 mg
Surgery Table 4.10

Chloride Secretagogues and Systemic Agents
Surgical approaches to constipation should be re-
Used to Treat Constipation
served for patients who have failed medical manage-
ment. Patients should have a complete evaluation
Agent Typical dosage in adults
with physiologic tests to exclude functional outlet
obstruction when subtotal colectomy with ileorectal Chloride secretagogues
anastomosis is being considered for severe and in- Lubiprostone 24 µg BID (constipation)
tractable slow transit constipation, since this surgery 8 µg BID (IBS-C)
will not necessarily improve symptoms if co-existing Linaclotide 145 or 290 µg daily
functional outlet obstruction is not treated.9,10 Subto-
tal colectomy may not help patients with severe ab- Systemically-acting drugs
dominal pain or diffuse motility disorders affecting Bethanechol 25 mg QID
other parts of the gastrointestinal tract, those with Misoprostol 200 µg QID
bloating and those with decompensated psychologi- Colchicine 0.6 mg BID
cal problems. Ileostomy may be a reasonable (and
reversible) method for dealing with some patients.
Before surgical correction of any outlet problem is un-
dertaken, assessment of outlet function is mandatory
in order to avoid problems with fecal incontinence.

the differential diagnosis of each category (see
Sacral nerve stimulation is a novel technique that has
Figures).
produced encouraging initial results, but further stud-
Constipation can be defined as infrequent or
ies are needed.24
difficult passage of stool. The normal range of stool
frequency is as low as three times a week.
The pathophysiology of idiopathic constipation
Pearls and Pitfalls often remains undefined, but may be characterized
as slow transit constipation (prolonged passage
for the Board Exam from the cecum to the rectum) or as functional outlet
Although patients may define diarrhea as defecation
obstruction (due to failure to open the rectal outlet).
of loose consistency or increased frequency,
However, both conditions may coexist or be absent
physicians define diarrhea by stool weight >200
in patients complaining of constipation.
gm/24 hours.
Slow transit constipation is characterized by
Watery diarrhea, due to excess stool water content,
infrequency of the urge to defecate and often occurs
can be due to even small reductions in the net rate
when constipation has been longstanding. It may
of absorption of electrolytes by the gut (“secretory
be due to the alteration of enteric nerve or colonic
diarrhea”) or to osmotic retention of water by
muscle function, or possibly to the presence of
poorly absorbed substances in the lumen (“osmotic
methanogenic bacteria.
diarrhea”).
Functional outlet obstruction is characterized by
Analysis of the fecal osmotic gap in stool electrolyte
difficulty with evacuating stool from the rectum,
concentrations can differentiate secretory from
due to a failure to relax or coordinate pelvic floor or
osmotic diarrhea. The fecal osmotic gap is calculated
sphincteric muscles. Acute constipation may be due
as 290 mosm/kg – 2(fecal sodium concentration in
to painful anorectal, abdominal or pelvic conditions,
mosm/kg + fecal potassium concentration in mosm/
medications, trauma or alterations in diet. It is
kg). Impaired electrolyte absorption results in
best managed with laxatives and attention to any
high concentrations of electrolytes in stool water.
causative condition.
Therefore, the fecal osmotic gap is low (<50 mosm/
Chronic constipation typically is idiopathic.
kg) in secretory diarrhea. On the other hand, the
Patients with chronic idiopathic constipation that
osmotic retention of water by poorly absorbed
does not respond to initial attempts at empiric
substances does not reduce electrolyte absorption
therapy may benefit from additional evaluation with
and so stool electrolyte concentrations are low.
physiological tests of colon transit (e.g., radio-opaque
Accordingly, since fecal electrolyte concentrations
markers or wireless motility capsule) and outlet
are low in osmotic diarrhea, the fecal osmotic gap
function (e.g., balloon expulsion testing, anorectal
is large. A fecal osmotic gap of >50 mosm/kg is
manometry, and defecography). Diet and lifestyle
suggestive of an osmotic diarrhea and a gap of >100
changes often are recommended for management
mosm/kg is more specific.
of constipation, but with little supportive evidence.
Acute diarrhea episodes are usually due to
Dietary fiber intake should be assessed using a diet
infections, food poisoning, or drugs.
diary; optimal intake is 20—30 g/24h. If a patient
Chronic diarrhea is defined as loose stools lasting
is already consuming that much fiber, increasing
more than 3-4 weeks, and has a broad differential
fiber intake is unlikely to be helpful and may
diagnosis.
accentuate secondary symptoms, such as bloating.
When no specific cause is likely, evaluation of
Increasing water intake will increase urination,
chronic diarrhea can be expedited by categorizing
but not necessarily defecation. Being bedbound or
diarrhea as watery, inflammatory or fatty.
sedentary may promote constipation, but the benefit
Algorithmic approaches can be used to work through
of exercise above a minimum threshold is uncertain.
2010, p. 211–32.
Biofeedback training is of proven value, but only 3. Venkatasubramanian J, Rao MC, Sellin JH. Intestinal
in patients with dyssynergic functional outlet electrolyte absorption and secretion. In Sleisenger and
obstruction. Fordtran’s Gastrointestinal and Liver Diseases. Patho-
Drugs available to treat constipation include osmotic physiology, Diagnosis, Treatment. 9th ed. Feldman M,
and stimulant laxatives, chloride secretagogues Friedman L, Brandt LJ, Eds. Philadelphia, PA: Elsevier,
2010, p. 1675–94.
(e.g., lubiprostone, linaclotide), and systematic
4. Field M. Intestinal ion transport and the pathophysiology
“motility” agents (e.g., bethanechol, misoprostol, of diarrhea. J Clin Invest 2003;111: 931–43.
cochicine, and in some countries, prucalopride). For 5. Dupont HL. Clinical practice. Bacterial diarrhea. N Engl J
opiate-induced constipation, methylnaltrexone is Med 2009;361:1560–69.
of some value. Surgery should be discouraged as a 6. Lasson A, Kilander A, Stotzer PO. Diagnostic yield of
treatment for constipation. colonoscopy based on symptoms. Scand J Gastroenterol
2008;43:356–62.
7. Schiller LR. Review article: anti-diarrhoeal pharmacology
and therapeutics. Aliment Pharmacol Ther 1995;9:87–106.
Most Efficient Source Reviews 8. Schiller LR. Diarrhea and malabsorption in the elderly.
Gastroenterol Clin North Amer 2009; 38:481–502.
for Examination Preparation 9. Locke GR 3rd, Pemberton JH, Phillips SF. AGA technical
review on constipation. Gastroenterology 2000;119:1766–
Fine KD, Schiller LR. AGA technical review on the
78.
evaluation and management of chronic diarrhea. 10. Brandt LJ, Prather CM, Quigley EM, et al. Systematic re-
Gastroenterology 1999;116:1464–86. view on the management of chronic constipation in North
Schiller LR, Sellin JH. Diarrhea. In Sleisenger and America. Am J Gastroenterol 2005;100(Suppl 1):S1–S21.
Fordtran’s Gastrointestinal and Liver Diseases. 11. McCallum IJ, Ong S, Mercer-Jones M. Chronic constipa-
Pathophysiology, Diagnosis, Treatment. 9th ed. tion in adults. BMJ 2009;338:b831.
12. Quigley EM. What have we learned about colonic mo-
Feldman M, Friedman L, Brandt LJ, Eds. Philadelphia,
tility: normal and disturbed. Curr Opin Gastroenterol
PA: Elsevier, 2010, p. 211–32. 2010;26:53–60.
Steffer KJ, Santa Ana CA, Cole JA, Fordtran JS. The 13. Ravi K, Bharucha AE, Camilleri M, et al. Phenotypic varia-
practical value of comprehensive stool analysis in tion of colonic motor functions in chronic constipation.
detecting the cause of idiopathic chronic diarrhea. Gastroenterology 2010; 138:89–97.
Gastroenterol Clin North Am 2012;41:539-60. 14. Lunniss PJ, Gladman MA, Bennings MA, Rao SS. Patho-
physiology of evacuation disorders. Neurogastroenterol
Locke GR 3rd, Pemberton JH, Phillips SF. AGA
Motil 2009;21(Suppl 2):31–40.
technical review on constipation. Gastroenterology 15. Drossman DA, Morris C, Hu Y, et al. Further character-
2000;119:1766–78. ization of painful constipation (PC): clinical features over
Brandt LJ, Prather CM, Quigley EM, et al. Systematic one year and comparison with IBS. J Clin Gastroenterol
review on the management of chronic constipation in 2008;42:1080–88.
North America. Am J Gastroenterol 2005;100(Suppl 16. Saad RJ, Rao SS, Koch KL, et al. Do stool form and fre-
quency correlate with whole-gut and colonic transit?
1):S1–S21.
Results from a multicenter study in constipated indi-
McCallum IJ, Ong S, Mercer-Jones M. Chronic viduals and healthy controls. Am J Gastroenterol Clin
constipation in adults. BMJ 2009;338:b831. 2010;105:403–11.
17. Bouras EP, Tangalos EG. Chronic constipation in the el-
derly. Gastroenterol Clin North Am 2009; 38:463–80.
References 18. Whitehead WE, Di Lorenzo C, Leroi AM, et al. Conserva-
1. Fine KD, Schiller LR. AGA technical review on the evalua- tive and behavioural management of constipation. Neu-
tion and management of chronic diarrhea. Gastroenterol- rogastroenterol Motil 2009;21(Suppl 2):55–61.
ogy 1999;116:1464–86. 19. Rao SS, Valestin J, Brown CK, et al. Long-term efficacy of
2. Schiller LR, Sellin JH. Diarrhea. In Sleisenger and biofeedback therapy for dyssynergic defecation: random-
Fordtran’s Gastrointestinal and Liver Diseases. Patho- ized controlled trial. Am J Gastroenterol 2010;105:890–96.
physiology, Diagnosis, Treatment. 9th ed. Feldman M, 20. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial:
Friedman L, Brandt LJ, Eds. Philadelphia, PA: Elsevier, lubiprostone in patients with constipation-associated ir-
ritable bowel syndrome—results of two randomized,

placebo-controlled studies. Aliment Pharmacol Ther
2009;29:329–41.
21. Andresen V, Camilleri M, Busciglio IA, et al. Effect of 5
days linaclotide on transit and bowel function in females
with constipation-predominant irritable bowel syndrome.
Gastroenterology 2007;133:761–8.
22. Camilleri M, Deiteren A. Prucalopride for constipation.
Expert Opin Pharmacother 2010;11: 451–61.
23. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone
for opioid-induced constipation in advanced illness. N
Engl J Med 2008;358:2332–43.
24. Kamm MA, Dudding TC, Melenhorst J, et al. Sacral nerve
stimulation for intractable constipation. Gut 2010;59:333–
40.
CHAPTER 5
Inflammatory Bowel Disease
Caroline Kerner, MD, MSCE and Gary R. Lichtenstein, MD, AGAF
Learning Objectives
1. Review normal intestinal mucosal immunology and abnormalities of the mucosal immune system that are present in individuals with inflam-
matory bowel disease (IBD).
2. Recognize and differentiate the mimickers of chronic idiopathic IBD from other causes of enterocolitis.
3. Compare and contrast the pathological and clinical findings of chronic ulcerative colitis (UC) and Crohn’s disease (CD).
4. Recognize the extraintestinal manifestations of IBD and be able to discuss their management.
5. Recognize the intestinal complications of UC and CD, including colonic dysplasia and carcinoma, fistula formation, and abscess.
6. Establish a plan for treatment of the different presentations of IBD, including both medical and surgical options.
Intestinal Immunology
-
globulin classes (IgM, IgG, IgA, IgD, IgE); (2) cell-mediated immunologic responses, including natural as well
as antibody-dependent cytotoxicity; (3) export of immunoreactive cells to many other mucosal areas and to
systemic lymphoid sites; (4) immediate-type hypersensitivity reactions; and (5) suppression of many sys-
host from the environment and from microorganisms that come in contact with the GI tract daily. The normal
1
.
tissue associated with mucosal surfaces in the GI, respiratory, and urogenital tracts. The GI tract is a major
source of lymphoid cells that populate many other mucosal organs (Figure 5.1)2. When absorbing the es-
sential nutrients, the human intestine needs to discriminate innocuous food antigens from infectious or toxic
agents. To protect the host from the latter, the intestine is dependent upon an effective barrier, and a natural
(innate) and acquired (adaptive) immune system3.
The effective barrier relies upon an intact intestinal epithelium along with its associated factors such as
the overlying mucus, normal peristalsis, and the secretion of many protective factors (such as the trefoil pep-
consisting of a number of toll-like receptors (TLRs) and nitric oxide dismutase (NOD)-like receptors (NLRs),
115
Figure 5.1
The Trafficking Pattern Within the Intestinal Mucosal Immune System
Intestinal and pulmonary lymphoid tissue cells initially migrate to mediastinal and mesenteric lymph nodes and then to the lymphatic vessels
prior to entering the blood vessels. These go through the circulation to gastrointestinal and pulmonary mucosal immune system and to areas
within the genitourinary tract, salivary lacrimal glands, hepatobiliary tract, and lactating mammary glands.
to bind stereotypic microbial products called patho-

gen-associated molecular patterns (PAMPs), allow- antigens. Antigens are presented by antigen-pre-
ing the host to recognize pathogens and activate im- senting cells (APCs) in conjunction with molecules
mune cell responses. These receptors are expressed of the major histocompatibility complex (MHC). The
by many types of innate immune cells, including neu- adaptive immune system involves both humoral and
trophils, macrophages, dendritic cells, and intestinal cell-mediated immunity5. Humoral immunity is pri-
epithelial cells. These receptors bind stereotypic mi- marily mediated by B cells that produce antibodies,
crobial products on the epithelial cells of phagocytes primarily of the IgA subtype. Cell-mediated immu-
(such as neutrophils and macrophages), and natural nity is accomplished largely by T cells, which have
killer cells and their products. When the host is ex- been divided into three major immune phenotypes:
posed to foreign antigens, the innate immune system T helper 1 (Th1), T helper 2 (Th2), and a newly rec-
provides the initial quick response (within 6 hours) ognized subset called T helper 17 (Th17). The Th1
to possible pathologic foreign antigen exposure1. response is associated with the production of inter-
In contrast to the innate immune system, the leukin (IL)-2 and interferon gamma (IFN-g). The dif-
ferentiation of T cells along a Th1 pathway is stimu-
lated by IL-12 generated in response to exposure to
memory, unlike innate immune cells, enabling the infectious agents. The Th2 response is characterized
host to develop long-lasting immunity4. The adap- by the production of cytokines IL-4, IL-5, IL-10, and
tive immune system consists largely of B and T cells, IL-13, which amplify the humoral immune response.
Chapter 5 — Inflammatory Bowel Disease 117
Th1 and Th2 subsets reciprocally downregulate each Intestinal Mucosal Immune Elements
other through cytokine production. Both Th1 and
The gut is a very complex immune organ, having 40
Th2 pathways can be regulated by unique regulatory
square meters exposed to many antigens, including di-
T cells (Treg) subsets that produce IL-10 and trans-
etary proteins and bacterial components (Figure 5.2).
-
In addition to having many components of the
3
.
immune system found elsewhere in the body, it has
-
unique characteristics, some of which are:
tive immunity in IBD was that Crohn’s disease (CD)
is mediated by Th1 cells, whereas ulcerative colitis
Class II MHC molecule expression on intestinal epithelial
(UC) is mediated by Th2 cells. However, there is con-
cells, capable of presenting antigens to T cells. Class II
siderable evidence that the story is much more com-
MHC is usually not expressed by normal intestinal epithe-
lial cells but is expressed when these cells are exposed to
with active UC synthesize IL-1, tumor necrosis factor
proinflammatory cytokines (e.g., IFN-g).
alpha (TNF-a), and IL-6, whereas lamina propria T
The Peyer’s patch, a lymphoid structure found in the small
cells probably produce IL-2 and IFN-g. This immune
intestinal surface, covered by specialized epithelium, al-
response can be up-regulated further by presenta-
lows for processing of antigen.
tion of antigen to CD4 lymphocytes by colonic epi-
The M cell, a cell that makes up the surface epithelium of
thelial cells that express HLA class II antigens. Stud-
Peyer’s patches and allows translocation of antigen into
ies have implicated a specialized type of T cell, the
the Peyer’s patch to interact with macrophages and den-
natural killer (NK) T cell, which seems to mediate
dritic cells.
the Th2 response in UC. These NK T cells, which are
Secretory IgA, which is dimerized and secreted onto mu-
not “classic” NK T cells in that they do not express
cosal surfaces to bind antigen (Figure 5.2). It does not bind
the typical NK T-cell receptors seen with classic NK T
complement.
cells, secrete large amounts of IL-5 and IL-13 and are
actually cytotoxic for intestinal epithelial cells.
The afferent limb of the immune system is concerned
with the appropriate uptake and processing of anti-
which appears to be involved in the pathogenesis of
gen such that immunologic memory takes place. The
both CD and UC, has been discovered and centers on
afferent limb of the mucosal immune system of the
the Th17 cell lineage6. Th17 cells have been shown
gut has at least three sites where antigen can enter.
to produce a variety of cytokines, most notably IL-6
One of these sites is called the M cell overlying the
-
lymphoid follicle. The second is thought to be the in-
kine that not only facilitates T cell activation but also
testinal epithelial cell (IEC). The third is through the
paracellular space around the IEC (Figure 5.3).
macrophages, epithelial cells, and endothelial cells,
The M cell is a specialized epithelial cell located
in Peyer’s patches overlying lymphoid follicles. Anti-
e.g., IL-1, IL-6, TNF-a, and chemokines. Th17 cell de-
gen can traverse the cell essentially intact and is then
velopment is inhibited by Th1 and Th2 cells but is
deposited into an APC, such as the macrophage or
promoted by IL-6, TGF-b, IL-21, and the IL-23 recep-
dendritic cell. The macrophages and dendritic cells
tor (IL-23R). IL-23R, which is highly expressed by
function as they do elsewhere, processing antigen
activated Th17 cells, also is expressed by NK cells,
and presenting it to T cells in the vicinity. T cells then
NK T cells, other CD4+ T cells, and CD8+ T cells. The
migrate to the lymphoid follicle, where clonal expan-
interaction of IL-23 with its receptor has been shown
sion occurs. T cells from this expansion then migrate
-
via the lymphatics to the general circulation7.
mation in various mouse models of colitis.
The antigen-processing and -presentation ca-
pacities of the IEC are less well understood. It has
been inferred that IECs may take up antigen from the
gut lumen, as it can express MHC class II proteins on the etiology and pathogenesis of IBD.
its surface. How this route for antigens differs func- Antineutrophil cytoplasmic antibodies (ANCAs)
tionally from the route proceeding through M cells have been reported in the serum of approximately
remains uncertain (Figure 5.3). 86% of patients with UC and 50% of patients with CD
The other components of the effector limb are, to versus 15% of individuals who are normal controls9
our knowledge, similar in function to the rest of the Distinct from the ANCA found in vasculitides, the im-
immune system. These components include macro- -
phages, T cells, and polymorphonuclear neutrophils. clear, not cytoplasmic, and is referred to as
The majority of our current therapy for medical Approximately 5% of patients with UC who undergo
treatment of IBD focuses on the inhibition of events surgery and have the ileal anal pouch anastomo-
in the afferent limb. sis will develop chronic pouchitis that is recurrent
In addition to clinical and phenotypic differenc-
es noted between UC and CD, immunologic and other
differences have been recognized between these metronidazole). Preoperative p-ANCA and anti-CBir1
two disorders, as well. First, UC is associated with -
increased production of IgG1 and IgG3, whereas CD opment of chronic pouchitis after ileal pouch-anal
is associated with increased production of IgG28. IgG1 anastomosis10 It is generally said that those with CD
and IgG3 antibodies account for the predominant IgG who are p-ANCA positive often have features similar
response to proteins and T cell–dependent antigens. to UC: left-sided colonic involvement by endoscopy,
IgG2 provides the predominant IgG response to car- symptoms of rectal bleeding, and histopathologic
bohydrates and many bacterial antigens. Delineation features of crypt abscesses without granulomas.
of the stimuli and antigens that induce the increased An association between anti-Cbir 1 and CD was
secretion of IgG subclasses may provide insight into assessed in 303 CD patients, of whom 51% were
Figure 5.2
Distinct Features of the Gut Mucosal Immune System
found to be anti-Cbir 1 positive. Interestingly, anti- the intestinal tract lumen mandates mechanisms
Cbir1 had 61% association with complicated CD ver- for handling foreign antigens that are constantly
present. The human body has several ways through
which environmental antigens such as bacteria, tox-
small bowel disease, irrespective of other markers11. ins, viruses, and complex antigens are processed and
The presence of this antibody was most correlated subsequently presented to cells of the mucosal im-
mune system. They can enter by means of the M cells,
be taken up by pinocytosis in enterocytes, or enter by
antigen transport paracellularly between IECs.
-
tivation of TLR-5, one of several TLRs that are effec-
tors of the innate immune response. Oral Immunization and Tolerance
The gut mucosa also contains multiple cytokines,
As a result of the existence of many different path-
i.e., molecules that modulate cellular interactions
ways for the uptake and processing of antigens by
among the resident cell populations. These include
the GI tract, the human body possesses the ability
to induce a number of local and systemic immune
TNFs); immunoregulatory cytokines (e.g., interleukin
-
(IL-) 2, 4, 6, and 8); and growth and regulatory cy-
zation or oral tolerance. The term oral immunization
tokines (e.g., IL-10 and transforming growth factors).
refers to the body’s protective immunologic reac-
tions that provide defense against various infectious
agents. The induction of IgA antibody secretion is a
Antigen Presentation in the Intestine major outcome of this immunization. Alternatively,
The close proximity of the external environment of -
Figure 5.3
Afferent Limb of the Mucosal Immune System
responsiveness of the humoral or cellular immunity Epidemiology

UC is a disease known to occur worldwide, but the
responsiveness serves as a protective mechanism
highest incidences have been reported in North
against excessive or untoward immunologic re-
America and Europe. Its incidence among Caucasians
sponses within the mucosa, as well as systemically,
ranges from 1.2 to 24.3 cases per 100,000 people an-
to antigens encountered in the environment. An im-
nually, with a worldwide prevalence of 7.6–505 per
balance between immunization and immunologic
100,000 depending on the region. CD is also known
tolerance within the intestinal mucosa (immuno-
to occur worldwide, but primarily in the same ar-
logic dysregulation) may be the etiology of IBD, GI
eas as UC. Its incidence ranges from 0.03 to 20.2
allergies, and autoimmune disorders of the GI tract
per 100,000 people per year, with prevalence rates
and other organs.
of 3.6–322 cases per 100,000 people per year12,13. In
areas where time trends have been evaluated, the in-
cidence of UC has remained remarkably steady from
Overview the 1950s through the 1980s as compared to CD,
which had a six-fold increase over the same period.
In general, there is a higher prevalence of IBD in the
Definitions northern parts of North America and Europe than in
- the southern parts14.
matory disorder of the GI mucosa. This disorder is The incidence rate of UC is slightly higher in
- men, whereas there is a higher incidence rate of CD
tion that extends in a contiguous fashion beginning in women15-17. The diagnosis of CD peaks at ages 20-
at the anal verge to involve a portion of the colon 30 years, whereas the peak age of diagnosis for UC
or the entire colon. If the endoscopic and histologic is 30-40 years. Some studies also describe a second
involvement is in the rectum, it is termed idiopathic peak of onset at 60-70 years.
ulcerative proctitis; if involvement is distal to the Although the incidence of IBD was thought to
be lower in non-white populations (such as African-
Americans in the United States), more recent stud-
extensive colitis; and if the entire colon is involved, it
is termed pancolitis. Classic symptoms of UC include perhaps the lower incidence was previously related
bloody diarrhea, tenesmus, and fecal urgency. to access to care.18 Jewish people are generally per-
Crohn’s Disease (CD) is a chronic idiopathic dis- ceived to be more susceptible to IBD than white,
order of the GI tract characterized by transmural in- non-Jewish populations living in the same area. IBD
occurs most commonly among Caucasians and in de-
almost any portion of the GI tract, from the mouth to creasing order of prevalence among blacks, Hispan-
the anus. The most classic site of involvement is the ics, and Asians.
ileocecal region. Characteristically, the disease does
not involve the rectum and has a patchy distribution
with areas of intervening uninvolved mucosa, thus Genetics
yielding the classic “skip lesion.” Clinically, CD may Familial aggregation of IBD has long been well rec-
present in a varied fashion, anywhere from failure to ognized. First-degree relatives (offspring, siblings,
thrive (i.e., falling off the growth curve, especially in and parents) of patients have the greatest risk, par-
children and adolescents), to fever, weight loss, diar- -
tients with UC or CD have a 10- to 15-fold increase
mass. in the risk of having the same disease as the patient.
The two diseases may also occur in the same family.
The discordance of proband/relative pairs typically the minimally bioactive subunit of bacterial peptido-
ranges from 20% to 25%. In the majority of reports glycan. In these patients the immune system appears
thus far, the familial tendency is strongest for CD19,20.
Data derived from studies of twins add support and destruction of intestinal cells27.
to the notion that these disorders have a genetic The initial work that led to discovery of the
- NOD2 gene and its association with this disorder in-
cordance of IBD in monozygotic twins compared to
dizygotic twins. In addition, there have been no reas mammalian counterparts of plant disease-resis-
ports of a monozygotic twin pair, one with UC and tant gene products that function as receptors within
the other with CD, thus supporting the concept that the cell (cytosolic receptors) for muramyl dipeptide.
the phenotypes of IBD have a distinct genetic basis. Subsequently, NOD2 was characterized as being
highly restricted to monocytes, having the ability
syndromes. In only three of these has the association to induce nuclear factor kappa B (NFkB) activation.
been consistent and, therefore, of possible pathogen- NFkB activation results in monocyte activation and a
ic importance. These three disorders include Turn- protective immune response.
er’s syndrome, glycogen storage type Ib, and the Her-
mansky-Pudlak syndrome (triad of albinism, platelet
aggregation defect, and accumulation of ceroid-like
-
pigment in tissue)21-25. IBD is also associated with
ceptibility locus for CD on chromosome 16. Using
various diseases that have known genetic predis-
positional-cloning strategy, the researchers then
position. These disorders include ankylosing spon- 28
. It was ini-
dylitis, psoriasis, atopy, eczema, celiac sprue, cystic
tially perceived that these confer susceptibility to CD
by means of altering the recognition of bacterial LPS
sclerosis, and other autoimmune diseases (including
and/or by activating NFkB in monocytes.
autoimmune thyroid disease, autoimmune hemolytic
In an independent study, Ogura and associates
anemia, primary biliary cirrhosis, myasthenia gravis,
used transmission disequilibrium and case-control
and Cogan’s syndrome)26.
analysis to demonstrate a truncated NOD2 protein
The NOD2 gene associated with CD29. They also showed that the
The NOD2 gene has been reported to be associated disease-associated NOD2 variant was functionally
with CD. Scientists from the United States and Eu- less active in conferring responsiveness to bacterial
-
dent studies that demonstrated a mutation in a gene in the ability to “sense” bacteria in monocytes could
known as NOD2, located on chromosome 16, that ap-
pears to be associated with CD. The NOD2 gene en- the adaptive immune system.
codes a protein associated with the innate immune
system. The NOD2 gene is found in monocytes that
There is clear evidence for the activation of intestinal
normally recognize bacteria and are then activated to
lymphocytes, macrophages, and other cells of the im-
destroy that bacteria. The mutations in NOD2 found
mune system in leading to an upregulated immune
in patients with CD disease lead to a disruption in
response in IBD. In any immune response there are
monocyte activation, thereby making it much more
-
spond to a component of the bacterial cell wall that
serve as a trigger for the response and as a target for
is found in many species of organisms. This compo-
the effector arm of the response. Most of the antigens
nent was initially perceived to be bacterial lipopoly-
in the intestinal lumen are of microbial origin.
saccharide (LPS). However, it is well established that
In IBD, initiating signals are most likely derived
the correct ligand for NOD2 is muramyl dipeptide,
for restricting the growth of various bacteria, it is not

against which either tolerance has not developed (in surprising that mutations in the ATG16L1 and IRGM
the case of less pathogenic organisms) or immune genes may lead to increased susceptibility to CD. Of
response is not adequate (in the case of more viru- note, the NOD2 gene has also been found to play a
lent organisms). It is likely that a number of bacteria role in autophagy. Finally, the IL23R gene, located on
contribute to the development of CD, although this chromosome 1, has also been postulated as a sus-
has not been shown. On the contrary, in healthy in- ceptibility gene for CD and UC. As described above,
IL23R is a central component of the Th17 pathway
by intestinal bacteria. Failure to suppress this in- with CD and UC.
gene, could result in the uncontrolled immune re-

sponse within the intestine in patients with IBD. As a Intestinal Microbiome
result of failure of “normal” suppressor mechanisms,
Multiple clinical and experimental observations have
immune activation in IBD may be inappropriately
suggested involvement of intestinal bacterial micro-
vigorous and prolonged. Based on the NOD2 gene
biota in the pathogenesis of IBD. The most obvious
-
observation perhaps is that CD and UC preferentially
netically determined inability to mount an appropri-
occur in regions of the bowel that contain the highest
ate immune response.
concentration of bacteria, namely the terminal ileum
Therefore, patients with IBD are genetically pro-
and colon where bacterial concentrations approach
grammed to mount an intense immune response
1012 organisms per gram of luminal contents. Inter-
-
estingly, diverting the fecal stream in patients with
sponse to common luminal bacteria or bacterial
CD can treat and even prevent disease, whereas re-
products. These luminal bacteria, although they may
-
have no role as etiologic agents, are capable of trig-
matory changes within only 1 week32. Other human
-
data have shown that antibiotics are useful in the
tered by genetically programmed immune cells of
treatment and/or postoperative prevention of CD
the intestinal innate immune system.
and pouchitis. Additionally, there is limited data from
-
It should be noted that the NOD2 gene on chromo-
some 16 is only one of a number of gene loci that active CD33,34. Finally, probiotics have been shown to
have been implicated in CD. Of note, genome-wide -
- tion of pouchitis. The most glaring evidence of the
ous chromosomes, including chromosomes 1, 2, 3, necessary role of bacteria in the pathogenesis of IBD
5, 10, 17, and 18 in addition to chromosome 2230. from rodent data is that genetically susceptible mice
To date there are 99 IBD susceptibility loci: 71 as- or rats in a gnotobiotic (germ-free) environment do
sociated with CD, 47 with UC, and 28 with both CD
and UC26. Three other potential CD genes have been -
tion after bacterial colonization. Just as in humans,
IRGM, located on chromosome 5, are members of a
family of genes involved in autophagy, an autono- prevented with antibiotics and probiotics.
mous process in cells, which involves not only main- With respect to the human gastrointestinal mi-
tenance of cellular homeostasis and organelle turn- crobiome, much has been learned. Complex math-
over, but also processing of intracellular pathogens ematical models have estimated that the human
and subsequent antigen presentation and regulation gastrointestinal microbiome contains at least 1800
of cell signaling31. Given that autophagy is important genera and between 15,000 and 36,000 species of
the host itself. Genetic defects in host microbial kill-

almost all (>98%) can be grouped into four phyla: ing or impaired mucosal barrier function can lead to
(64% of the total and including the family immune hyper-responsiveness to intestinal bacteria,
groups XIVa and as the microbes have more exposure to epithelial
Bacillus cells and can trigger the production of high levels of
and Bacteroidetes (23% of the
total); Proteobacteria (8% of the total and including Recent studies have demonstrated that there
the family Enterobacteriaceae Acti- may be modulation of the gut microbiome following
nobacteria (3%)35,36. dietary alteration. A study by Leach, et al37, evaluated
Four general mechanisms have been postulated the effect of exclusive enteral nutrition in a patient
to explain how components of the normal intestinal population with CD and compared them with a co-
microbiome may initiate or contribute to the devel- hort of healthy volunteers consuming a regular diet,
36
First, mi- -
cal bacteria. Prior to dietary intervention the diver-
adhering to or invading intestinal epithelial cells and sity of bacteria was similar in both groups. After 8
- weeks, the patients with CD who were actively treat-
kine production, or by producing enterotoxins. ed were found to have a substantial decrease in bac-
Second, a breakdown in the balance between terial diversity whereas the healthy control cohort
protective and harmful intestinal bacteria, termed had stable intestinal bacterial composition. These
“dysbiosis,” may lead to disease. Most studies com- changes in the actively treated patients with CD
paring the intestinal microbiome in IBD with that were maintained for several months following con-
in healthy controls show a decreased biodiversity clusion of therapy. Another recent study focused on
in the IBD populations by 30–50%. A recent study the impact of diet on the microbiome in healthy hu-
found that this reduction in biodiversity was due man patients. This study highlighted that long-term
- agrarian dietary patterns are associated with an
cally ) by 300-fold and Bacteroides enterotype dominated by 38
. The entero-
by 50-fold. The loss of these organisms is important type genus has been seen in people from
because they are known to produce short-chain fatty rural Africa39. In a Westernized diet (i.e. a diet high
acids, such as butyrate, which nourish colonocytes. in animal protein and fats and low in carbohydrates)
As a result of the decrease in these organisms, the there were high quantitites of Bacteroides and low
relative concentrations of Proteobacteria and Ac- quantitites of 38
. These and other studies
tinobacteria increased in IBD patients relative to -
controls, although quantitative PCR analysis showed crobiome. We are in the infancy of understanding the
that the absolute numbers of Enterobacteriaceae microbiome and future studies are required to better
were not higher in IBD patients than in controls.
Loss of protective bacteria, however, could set the Finally, genetic defects in host immunoregula-
stage for overgrowth of pathogenic bacteria. Another tion can lead to a heightened immune response to
- even nonpathogenic bacteria, e.g., abnormal antigen
crobiota of patients with CD and UC were similar to processing or presentation, loss of tolerance, or over-
each other. In addition, the study did not identify any ly aggressive T cell responses.
individual species that was particularly prevalent
in grossly abnormal diseased tissue; thus, no active
bacterial etiologic agent was suspected of causing or Disease Modifiers
propagating disease.
Two environmental factors, smoking and the use of
The third and fourth ways in which bacteria
oral contraceptives, have been associated with the
could play a role in the pathogenesis of IBD deal with
clinical expression of IBD and are therefore termed
- both UC and CD remain unknown. It is, however, well

ed that UC is more common in nonsmokers than in recognized that the macrophage is an important cell
that releases IL-1 early in the response. IL-1 is a cy-
two years of cessation of smoking and is highest for tokine that has been recognized to turn on various
previously heavy smokers compared to previously
light smokers. Cigarette smoking appears protective such as promotion of cytokine release by lympho-
for UC, and former smokers are 1.7 times as likely as cytes and macrophages and promotion of neutrophil
those who have never smoked to develop UC. In con-
trast, smoking is a risk factor for CD and smokers are bowel persists and does not resolve, as would be the
more than twice as likely to develop the disease as case with infectious enterocolitis, when the infecting
nonsmokers40. The mechanism underlying these ef- -
fects is not clear. matory response remains in the bowel chronically
With respect to the effect of oral contraceptives, until the spontaneous endogenous factors attenuate
a meta-analysis of 14 studies including 75,815 pa-
tients demonstrated an association between oral
contraceptive use and the development of both UC
and CD41. Differential Diagnosis
-
tory disorders of the GI tract of unknown etiology. It
Mucosal Inflammatory Mechanisms
acute colitis and enteritis when establishing that a
perpetuation of the mucosal immune response in patient has either diagnosis. The differential diagno-
ses of UC and CD are extensive and include infectious
etiologies of colitis (Figure 5.4) bacterial pathogens,
Table 5.1
tumors, and many other etiologies (Table 5.1)
Differential Diagnosis of Intestinal and
The terms colitis and enteritis denote colonic and
Colonic Inflammatory Diseases
from any etiology. UC and CD are idiopathic chronic

Infectious Conditions -
Noninfectious Conditions
Bacteria
Collagenous colitis tine. Prior to suggesting that an individual has IBD,
Bacterial toxins
Lymphocytic colitis
Toxigenic E. coli
Diverticular-associated colitis
Clostridium difficile be excluded. The differential diagnosis of UC and CD
Diversion colitis
Bacterial invasion
Ischemic colitis includes both infectious and noninfectious causes
Salmonella
Medication-induced colitis -
Shigella
NSAID-induced enterocolitis
Campylobacter tious etiologies of acute colitis and enteritis include
Gold-induced enterocolitis
Yersinia direct bacterial invasion, bacterial toxins parasitic
Chemical colitis
Mycobacterium
Glutaraldehyde-induced colitis infections, and viral infections.
Gonorrhea
Radiation enterocolitis Noninfectious causes include microscopic colitis,
Aeromonas
Appendicitis
Lymphogranuloma venereum diversion colitis, NSAIDs, chemical colitis, radiation
Neutropenic enterocolitis
Parasites and ischemia. The term microscopic colitis refers to a
Solitary rectal ulcer syndrome
Amebiasis
Malignancy syndrome of chronic watery diarrhea that occurs pre-
Chlamydia
Carcinoma dominantly in women in the fourth to sixth decades
Schistosomiasis
Lymphoma
Viruses of life with characteristic histological abnormalities
Leukopenia
Cytomegalovirus
Mesenteric venous thrombosis -
Herpes simplex
Typhlitis tures . Radiographic studies are usually normal in
42
Adenovirus
include lymphocytic colitis, in which there are in- strating no association between NSAID use and fre-
47
.
cells in the lamina propria, and collagenous colitis, Ischemia more commonly causes segmental coli-
which includes the features of lymphocytic colitis tis that may be confused with CD, but occasionally
with the additional presence of a subepithelial col- can cause a diffuse colitis similar in appearance to
lagen band42. UC. Injury to the rectum from radiation for prostate
cancer or gynecologic malignancy can present a clini-
occurs in segments of the colon excluded from the fecal picture suggestive of either UC or CD complicated
cal stream, typically when an ileostomy or colostomy
is created. When excluded segments are examined and more proximal colon from radiation can cause
before reanastomosis, endoscopic evidence of colitis chronic diarrhea, strictures, malabsorption, and
is found in >90% of patients, and histologic evidence other features that may mimic extensive CD. The soli-
is found in nearly all segments. Symptoms as a result tary rectal ulcer syndrome may be confused with CD
of the diversion colitis occur in up to half of these pa- involving the rectum, but it can be differentiated on
tients. This form of colitis is believed to result from a the basis of histology; solitary rectal ulcer syndrome
-
tyrate. Reapplication of butyrate in a topical fashion of the lamina propria48.
has been demonstrated to ameliorate the symptoms It is important to realize that not every disorder
43
. -
Diverticular disease–associated chronic colitis ery lesion of the ileum or cecum is CD. Two classic
occurs in a segmental nature in patients who are typ- types of disorders can be easily mistaken for small
ically over age 45. Clinical features classically include
abdominal pain, diarrhea, and rectal bleeding. Ra- nodes that lead to clinical symptoms of acute right
diographic evaluation shows diverticulosis, and en-
multiple diverticula, with histological results of mu- Figure 5.4

cosal biopsies and/or surgical resection specimens Infectious Colitis - with Campylobacter
cases, granulomas. Therapy with topical mesalamine
the involved segment of colon is generally curative.
are limited to peridiverticular areas of the sigmoid

colon44 -
es, and segmental colitis has been described and is
known to mimic CD.
use can cause ulceration in the GI tract, including the

ileum, colon, and rectum. At times, lesions that result
from NSAID use can be confused with CD. The most
common site of NSAID-induced damage is the small
intestine, reported in 65% of patients45. In addition, There is erythema, edema, and granularity present, mimicking the
there is substantial evidence suggesting that NSAIDs appearance of mild ulcerative colitis. Photo courtesy of Kate Fors-
sell, MD, and Donald Tsynman MD, University of Rochester Medical
disease 46
- Center, Division of Gastroenterology and Hepatology.
lower quadrant pain suggestive of ileitis; and condi- acute appendicitis, cecal diverticulitis, tubo-ovarian
tions that involve the small intestine directly, such as -
pic pregnancy), ovarian cysts, ovarian tumors, and
disorders. These disorders directly involve the small endometriosis (Table 5.2).
intestine and create a clinical and radiologic picture
that can mimic regional enteritis.
Other disorders that may mimic CD include Features of Ulcerative Colitis
Figure 5.5
Cryptitis and Crypt Distortion in Early Ulcerative Colitis Pathologic Features
the colon that involves the mucosa and the submu-

cosa. The disease begins in the rectum and extends
proximally to involve all or part of the remaining co-
lon in a continuous fashion (i.e., with the absence of
skip lesions). The colonic mucosa appears reddened,
granular, and friable. In cases of severe UC, extensive
the mucosa. The lamina propria becomes edematous

and the capillaries become dilated and congested,
-
plasma cells, macrophages, and lymphocytes is pres-

ent. Additionally, eosinophils and mast cells are pres-
ent in higher numbers in patients with UC. In early
by neutrophils forming crypt abscesses. This cryp-

titis is associated with the discharge of mucus from
the goblet cell and an increase in epithelial cell turn-
over. Histologically, this is notable for the presence
of goblet cell depletion, with the cells turning more
basophilic, a marker of young, immature cells. (Fig-
may be confused with an acute self-limited colitis
The crypt epithelial lining appears infiltrated by neutrophils forming can help establish a diagnosis of UC include the pres-
crypt abscesses. Microscopic findings are crypt abscesses, mucosal ence of crypt architecture distortion, crypt atrophy,
inflammation, and crypt distortion. This cryptitis is associated with increased intercrypt spacing to <6 crypts/mm, ir-
the discharge of mucus from the goblet cell and an increase in epi- regular mucosal surface, basal lymphoid aggregates,
thelial cell turnover. Histologically, this is notable for the presence of
goblet cell depletion, with the cells turning more basophilic, a marker make the diagnosis of UC with approximately 80%
of immature cells. Photos courtesy of Christa Whitney-Miller, MD, probability.
Assistant Professor, University of Rochester School of Medicine & -
Dentistry, Department of Pathology & Laboratory Medicine. -
ations. These ulcerations can be deep and undermine Table 5.2

the surrounding epithelium. At this stage, there is Disorders that Can Directly Involve
- the Ileum and Can Mimic Crohn’s Disease
tion in the submucosa.
As the disease enters remission, the histologic Ileal carcinoid
appearance may be entirely normal. This occurs Lymphosarcoma of the ileum
most frequently after mild disease. More commonly, Metastatic carcinoma (including stomach, pancreas, colon, breast,
however, there is evidence of altered crypt architec- malignant melanoma)
ture or actual dropout of glands. Other architectural Vascular disease (ischemic ileitis, vasculitides including polyarteritis
nodosa, systemic lupus erythematosis, rheumatoid arthritis,
that do not extend into the muscularis mucosa. If progressive systemic sclerosis, necrotizing angiitis, essential
mixed cryoglobulinemia, and dermatomyositis)
Behcet’s disease
mucosa) despite the presence of clinical remission, it Radiation enteritis
has been demonstrated that individuals have a high Intestinal infections
risk of disease recurrence. Other commonly seen Infestations (ileocecal tuberculosis, amebiasis, anisakiasis, Yersinia
changes in pathology include neuronal hypertrophy enterocolitica, Mycobacterium avium intracellulare)
- Other infections (Salmonella, Shigella, Campylobacter jejuni, Chla-
cosa. mydia trachomatis)
- Chronic nongranulomatous ulcerative jejuno-ileitis
ures 5.6 and 5.7). These lesions represent prolifera- Eosinophilic gastroenteritis
Amyloidosis
tissue on a stalk of submucosa. Despite the severity
-
long-standing disease, the mucosa appears atrophic, clude loss of the normal vascular markings, mucosal
with loss and shortening of crypts. There is usually granularity, friability, mucus exudate, and focal ulcer-
a decrease in the number of goblet cells, and Pan- ation.
eth cell metaplasia may be present. The muscularis The earliest signs of UC are blunting or actual
mucosa becomes thickened and the lamina propria
Figure 5.6
cells, particularly plasma cells located near the base Endoscopic Photographs of Pseudopolyps in Ulcerative Colitis
of the mucosa. Patients with acute, fulminant hem-
orrhagic UC may develop toxic megacolon, a condi-
tion in which the large bowel becomes congested and
atonic. This results in massive dilation of the colon
that may lead to perforation. If the colon is resected,
have been observed, in addition to mucosal disease.

Several of the pathologic manifestations of UC are il-
lustrated in Figures 5.7, 5.8–5.10.
Endoscopic Features
-
Figure 5.7 detectable as small areas of bleeding when the intes-

Inflammatory Pseudopolyps tinal mucosa is rubbed. Finally, in patients who have
severe UC, the mucosa spontaneously bleeds with
the presence of ulceration. Patients who have long-
standing disease may have pseudopolyps. Once re-
mission is achieved, the colonic mucosa can return to
near normal, with a thin, pale, atrophic appearance.
In UC, colonoscopy helps to determine the extent
is either normal or shows changes only of backwash

ileitis. Multiple biopsies can be taken during colonos-
copy to assess for the presence of dysplasia (and to
assess for the presence of polyps and strictures), to
is doubt about the presence of CD.

Backwash ileitis is present in approximately 10–
In this case of ulcerative colitis, broad-based ulcers have isolated 20% of patients with pancolonic UC. This is charac-
islands of regenerating mucosa to create pseudopolyps.
the terminal ileum. Morphologically, backwash ileitis
resembles colonic disease (diffuse loss of vascular
loss of the vascular pattern, along with hyperemia pattern, friability and, in more severe cases, ulcer-
and edema of the mucosa (Figure 5.11). Thickening ation)49 -
and blunting of the valves of Houston (which are nor- oscopy should be avoided in patients with severely
mally sharp, crescentic folds) are often present when active colitis because of the risk of perforation or
edema occurs. Granular and friable mucosa then de- hemorrhage; if necessary, an endoscopic examina-
tion limited to the rectum may be performed to con-
Figure 5.8
Carcinoma Arising in Ulcerative Colitis
Radiologic Features
Patients with a severe attack of UC should have a
plain radiograph of the abdomen with supine and
upright views to examine for complications including
colonic or small bowel dilatation, perforation with
free air, and marked mucosal edema with a thumb-
printing appearance of the mucosa.
Plain abdominal radiographs can also help detect
feces in the colon. In areas of the colon where there is
feces are usually not present when the entire colon is
sided colitis, however, to have retained stool in the

This portion of the colon, in a patient with long-standing ulcerative
proximal colon.
colitis, shows very atrophic mucosa with complete loss of mucosal
In patients with bowel symptoms and endo-
folds. In the distal end of the specimen is an irregular ulcerated area
(shown at higher power in Figure 5.9).
ray should still be performed to exclude CD. The best
small bowel radiographic tests to assess for ileal aph- Figure 5.9
thous ulcers are air contrast enteroclysis or a small Colloid (Mucinous) Carcinoma Occurring in Ulcerative
bowel follow-through with a peroral pneumocolon. Colitis
These two radiographic techniques provide air con-
trast views of the distal small intestine. The use of
computed tomography (CT) and magnetic resonance
imaging (MRI) enterography has increased based
on good sensitivity for detection of small bowel CD-
related lesions50,51. If small bowel radiography or CT
enterography are not revealing and there is still a
suspicion of Crohn’s, the use of video capsule endos-
copy has been advocated.
strictures that cannot be traversed with an endo-

scope. The earliest radiographic change of UC seen
on a double (air)-contrast barium enema is granu- The tumor illustrated in Figure 5.8 is composed of sheets of mucin
larity. The mucosal line becomes irregular and is containing numerous malignant “signet ring” cells. The tumor had
not as sharp as is usually seen in a normal colon. As dissected easily through the muscularis propria into perirectal soft
tissues and had involved numerous lymph nodes as well.
the disease becomes more severe, the mucosal line
becomes more thickened and irregular, and the ap-
en face occurs.
Copenhagen found that only 1% of patients had a
Deep ulcerations can appear, suggesting that ulcer-
relapse-free course when followed for 18 years after
ation has penetrated the mucosa. The haustral fold
the initial diagnosis. About one-half of patients will
appearance varies with the severity of the disease.
present with proctitis or proctosigmoiditis, which
In mild disease they are normal; however, as disease
commonly causes rectal bleeding, urgency and diar-
becomes more active, they become edematous and
rhea. However, constipation is a presenting symptom
thicker. Loss of haustral folds can occur, especially in
in up to 30% of patients with proctitis or proctosig-
individuals with long-standing disease. However, the
lack of haustral folds can also be seen in normal indi-
viduals, especially in the left colon. Figure 5.10
Long-Standing Ulcerative Colitis
Clinical Features
The onset of symptoms in patients with UC can be
gradual or sudden, with an increase in bowel move-
ments and bloody diarrhea, fecal urgency, cramping
abdominal pain, and fever. The course of UC can be
variable, with exacerbations and periods of improve-
ment or remission that can occur with or without
UC have intermittent attacks of their disease, but the

length of remission may vary from a few weeks to
many years. About 10–15% of patients have a chronic
- This endoscopic biopsy shows evidence of mucosal atrophy, glan-
tack requiring colectomy. Few patients have a single dular distortion, marked acute and chronic inflammation within the
attack. A recent large population-based study from lamina propria, and thickening of the muscularis mucosa.
Figure 5.11
Endoscopic Photograph of Distal Colon Showing Mild Colitis with Subtle
Features of Crohn’s Disease
Loss of Vascular Pattern and Presence of Granularity
Pathologic Features
-
ers of the bowel wall are involved). Any segment of
the GI tract can be involved, from the mouth to the
anus, although the disease most commonly affects
the terminal ileum and cecum. CD is also character-
ized by in which diseased areas alternate
with grossly normal bowel segments. Two types of
ulcers appear in CD. One is a linear or serpiginous
ulcer that extends along or across the intestinal mu-
cosa. These ulcers may interconnect and surround
islands of “normal” mucosa, leading to a cobblestone
appearance seen grossly and radiographically. The
other pattern of ulceration is aphthous, consisting
of smaller (usually in the range of 1–2 mm in diam-
eter) punched-out ulcers that develop over lymphoid
Photos courtesy of Donald Tsynman MD, University of Rochester Medical Center, Divi-
follicles. Aphthous ulcers appear as pinpoint lesions
sion of Gastroenterology and Hepatology
within otherwise normal bowel.
like penetrations of the bowel wall, probably aris-

moiditis . The frequency of diarrhea may vary from
52
a few stools every day to every other day, to multiple -

loose or liquid stools a day; the diarrhea is usually lous connection with another part of the bowel or
worse in the morning and immediately postprandial. adjacent viscus such as bladder, vagina, ureters, and
Individuals who have moderate or severe symptoms other organs. (Figure 5.12).
often have nocturnal stools. Abdominal pain is usu- The earliest lesion of CD is focal neutrophilic in-
ally described by the patients as cramping in nature -
and may be worse after meals or bowel movements. phils. This occurs especially over areas of overlying
In patients who have severe and extensive disease, mucosal lymphoid aggregates, with associated cryp-
anorexia, weight loss, and nausea are common in the titis and subsequent crypt abscess formation. With
absence of bowel obstruction. -
In patients with mildly active UC, the physical ex- thous ulcer. In established disease, transmural in-
amination is often normal or there may be abdomi-
nal tenderness, particularly with palpation over the -
sigmoid colon. Patients with more severe disease plastic change within the epithelium, i.e., Paneth cell
may have pallor, dehydration, tachycardia, fever, di- metaplasia within the large bowel. The hallmark of
minished bowel sounds, and diffuse abdominal ten- CD is the presence of noncaseating granulomas with-
in the bowel wall or in regional lymph nodes. The end
and suggests toxic dilatation or perforation. Club-
-
chronic disease. rosa often appears granular and the mesenteric fat,
as a result, tends to wrap around the exterior of the Figure 5.12

bowel (creeping fat). The bowel wall appears rub- Fissuring Ulcer in Crohn’s Disease
-
bowel lumen, with stricture formation and eventual

obstruction.
Endoscopic Features
In CD, colonoscopy and esophagogastroduodenos-
-
-
ity. Typically, there are focal ulcers, skip areas with
normal-appearing mucosa, and deep longitudinal
ulcers (rake ulcers) in severe disease (Figure 5.13).
-
relate with clinical disease activity. The endoscopic
evaluation of strictures should include brushing for A deep fissuring ulcer is present in this section of the small intestine through the muco-
cytology and biopsies. sa, submucosa, and into the muscularis. It is associated with transmural inflammation.
Radiologic Features
In patients with CD, barium studies, including an air- Figure 5.13
contrast barium enema and a single-contrast small Crohn’s Disease with Large, Irregularly Shaped Ulceration in
bowel follow-through examination, can identify Rectosigmoid Area (Normal-Appearing Mucosa in Background)
the extent of disease and the presence of complica-
a small bowel air-contrast study (enteroclysis) can

provide additional information for evaluating jejunal
and ileal disease. CT enterography has been shown
enterography has a similarly high sensitivity for de-

tecting small bowel disease, but is most sensitive in
50,51
. An upper GI
barium study may be useful in CD with strictures in-
volving the gastric and duodenal region. Abdominal
or pelvic abscesses or masses can be visualized using
ultrasound, either abdominal or transrectal, as well
as CT or magnetic resonance imaging (MRI). In ad-
dition to evaluating for potential abdominal abscess,
CT and MRI are useful adjuncts to barium small
bowel studies for evaluating extraintestinal abnor-
Photos courtesy of Donald Tsynman MD, University of Rochester Medical Center, Divi-
sion of Gastroenterology and Hepatology
and MRI can also assess bowel-wall thickening and
Clinical Features
and allowing at least rudimentary assessment of CD
The signs and symptoms of CD result from chronic
activity. Some abdominal abscesses are amenable to
CT-guided percutaneous drainage. Finally, endoscop-
symptoms depend upon the anatomical location of
ic ultrasound–guided drainage has been performed
the disease. The classic location of disease is the ileo-
for perirectal abscesses.
cecal region; thus, the typical symptoms are cramp-
Video capsule endoscopy ing right lower-quadrant abdominal pain and diar-
The advent of video capsule endoscopy (VCE) has en- rhea. On occasion, the presentation can mimic acute
abled physicians to visualize the terminal ileum with appendicitis, with severe right lower-quadrant pain,
a higher sensitivity than when using small bowel fever, and a palpable mass. Often, surgery is required
radiology53. It has been advocated that radiographic to discover that the appendix is normal but the ter-
studies (small bowel follow-through, CT enterog- minal ileum is the site of abnormality. Patients who
raphy, or MR enterography) be performed prior to present with colonic disease have a disease course
VCE in patients with CD to assess for the presence of most closely approximating patients with UC, with
unsuspected small intestinal strictures. Small bowel bloody bowel movements, diarrhea, and weight loss.
strictures, which occur frequently in patients with Approximately 10–15% of patients present with
known CD, are considered to be a contraindication perianal CD, initially characterized by a perirectal ab-
to VCE because of the potential for capsule reten- scess, painful and edematous external hemorrhoids,
tion. A patency capsule, which can be administered -
prior to the use of a VCE to assess for the presence of tula (this complication can occur in up to 10% of
women with rectal CD54).
patency capsule is a self-dissolving capsule that is One-fourth to one-third of patients with CD
the same size as the video capsule. It contains a ra- present before age 20. The GI symptoms may be
overshadowed or preceded by the presence of ex-
detected by a scanning device placed on the abdomi- traintestinal manifestations. Presenting symptoms
nal wall. When its passage is blocked by a stenosis, in children are diarrhea in >50%, rectal bleeding in
the patency capsule dissolves in 40–80 hours after approximately 20%, weight loss in 10%, and growth
ingestion. failure in 2%. However, the sole manifestation of IBD
Capsule endoscopy should be considered in might be that the child begins to fall off the growth
those individuals suspected of having CD who have curve. The onset of CD in children may be insidious,
had a negative work-up. The standard work-up with weight loss in up to 93% and growth failure in
should include colonoscopy with an attempt to in- 40% before the onset of intestinal symptoms. In pa-
tubate the terminal ileum, EGD, and small bowel tients who have CD that is mildly active, the physical
radiography. Small bowel radiography should exam- examination may be normal. As the disease activity
ine for mucosal abnormalities as well as exclude the increases, patients may develop one or more of the
presence of any ileal strictures that might impede following symptoms: fever, weight loss, muscle wast-
passage of a video capsule. Care must be taken not to ing, abdominal tenderness (especially in the lower
overinterpret the presence of aphthous ulcerations abdomen), and a palpable mass, usually in the ileoce-
in the small bowel, as individuals with other disor- cal region of the right lower abdomen. Digital rectal
ders (such as celiac disease) and healthy individuals examination may reveal large, edematous violaceous
may have these lesions. Thus, the presence of these -
sures, and anal stenosis. Patients with CD may have
ulcers on the lips, gingiva, or buccal mucosa.
at sites of trauma, but they can also occur on the face,

Extraintestinal Manifestations of trunk, and upper extremities. PG parallels IBD disease
Inflammatory Bowel Disease course in approximately 50% of patients56. Erythema
Extraintestinal manifestations are common in pa- nodosum is another cutaneous disorder associated
tients with IBD, occurring in 21–36% of individuals. with IBD. The prevalence of EN is reported to be 2–7%
A wide variety of disorders involving virtually every in patients with IBD57,58. The lesions appear as tender,
organ system has been reported. One important ques- red-purple nodules, usually on the extensor surfaces
tion in discussing these extraintestinal manifestations of the lower extremities. EN correlates well with bow-
is whether they represent manifestations of the same el disease activity and often occurs in conjunction with
underlying pathogenesis or they represent distinctly peripheral arthritis. These lesions usually respond to
different disease processes from that of IBD. The latter treatment of the underlying IBD.
may occur coincidental to the presence of IBD or as a
consequence of the bowel disease or its treatment.
The extraintestinal manifestations of IBD can be Ocular Manifestations
Ocular manifestations of IBD may include uveitis,
disorders involving the skin, eyes, joints, and mouth. episcleritis, and scleritis. Uveitis is a potentially severe
Usually, these disorders occur in patients with colonic complication that can lead to blindness if not treated,
disease, and activity of these colitis-related manifesta- and often presents with photophobia, headaches, and
tions parallels the activity of the underlying intestinal blurred vision. Scleritis and episcleritis, on the other
disease. The second group of manifestations includes hand, are generally mild and present with burning and
those that are secondary to complications of or di- itching. Uveitis typically follows a course independent
rect extension of bowel disease. These usually occur of bowel activity, while scleritis/episcleritis often par-
in patients with CD rather than in patients with UC. allel bowel activity59.
This group of extraintestinal manifestations includes
kidney stones, obstructive uropathy, malabsorption,
and gallstones. The third group includes those disor- Musculoskeletal Manifestations
ders that cannot be clearly categorized into either of
- Musculoskeletal diseases comprise the most common
estinal manifestations include osteoporosis, hepatic extraintestinal manifestations seen in patients with
diseases, and amyloidosis. Complications involving IBD. These abnormalities can be grouped broadly into
vascular, hematologic, pulmonary, cardiac, and neu- rheumatologic disorders and metabolic bone diseases.
rological systems probably belong to this third group
Rheumatologic manifestations
as well. This review will focus on the clinical features
The rheumatologic manifestations associated with
of the more common extraintestinal manifestations of
IBD include peripheral and axial arthropathy. The
IBD.
pathogenesis of these rheumatologic manifestations
is unknown, although the presence of enteric bacteria
Dermatologic Manifestations
a role.
Pyoderma gangrenosum (PG) and erythema nodosum Peripheral arthropathy occurs in 5–20% of pa-
(EN) are the two most commonly encountered derma- tients with IBD. The risk of developing peripheral
tologic manifestations of IBD. Pyoderma gangreno- arthropathy increases with the extent of colonic dis-
sum, an idiopathic disorder of skin ulceration, occurs ease and with the presence of complications such as
in approximately 5% of all patients with UC and less abscesses, perianal disease, erythema nodosum, sto-
commonly in patients with CD.55 Approximately 50% matitis, uveitis, and pyoderma gangrenosum.
of all cases of PG occur in patients with IBD. Classically, The peripheral arthropathy associated with IBD
these skin lesions form on the lower extremities, often
is pauciarticular arthritis (affecting <5 joints) and typ- lateral sacroiliitis are more likely to progress to AS.
ically involves the large joints (knees, elbows, ankles). AS occurs in 5–10% of patients with IBD, and the
It usually manifests as acute, self-limited episodes last- majority of these patients are HLA-B27–positive. Pa-
ing a median of 5 weeks. Approximately 20–40% of all tients with AS often experience severe onset of back
patients will have more than one episode of arthritis. pain at young age, usually associated with morning
This type of peripheral arthropathy usually parallels stiffness or exacerbated by periods of rest. Symptoms
the underlying bowel disease activity and is associat- are usually unrelated to the underlying bowel disease
ed with an increased incidence of erythema nodosum activity. Physical examination reveals limited spinal
and uveitis. In contrast, type 2 peripheral arthropathy -
- sion. Radiographs in early stages may be normal or
volves the small joints. This typically presents with show only minimal sclerosis. The course is typically
persistent symptoms lasting a median of 3 years. progressive, resulting in permanent skeletal damage.
Type 2 polyarticular arthropathy is usually indepen- Advanced cases may demonstrate squaring of ver-
dent of bowel disease activity. There is an increased tebral bodies, marginal syndesmophytes, and bony
risk of uveitis but not erythema nodosum in patients proliferation and ankylosis classically known as the
with type 2 peripheral arthropathy. In general, neither
type leads to permanent joint deformity. Both types Peripheral arthropathy usually responds to either
of peripheral arthropathy are seronegative, i.e., rheu- medical or surgical treatment of colitis. Other treat-
matoid factor negative. Additionally, these two clinical ment modalities include rest, physical therapy, and
types of peripheral arthropathy appear to represent intra-articular steroid injections. The use of NSAIDs
immunogenetically distinct entities. Type 1 periph- in the management of IBD-associated peripheral ar-
eral arthropathy is associated with HLA-B27, B35, and thropathy requires caution because of the reported
DRB`*0103, whereas type 2 is associated with HLA- association of exacerbation of IBD with NSAID use.
B4459. There is one controlled clinical study on the risk of
Axial arthropathy is less frequent than peripheral -
arthropathy, occurring in 3–5% of patients, although a genase (COX)-2–selective NSAIDs using celecoxib. The
frequency of up to 25% has been reported. In contrast trial was of 2 weeks duration and found no increased
to the peripheral type, axial arthropathy does not par- -
allel bowel disease activity. The axial arthropathy as- cebo. The results of this study cannot be translated
sociated with IBD may be categorized into spondylitis into universal safety since there are individuals who
and isolated sacroiliitis59.
The IBD spondylitis is generally considered one of still suggested that caution be exercised when using
the spondyloarthropathies. The majority of patients NSAIDs in patients with IBD. It should also be pointed
with spondylitis are HLA-B27-positive. Ankylosing out that there are animal data showing worsening of
spondylitis (AS) in these HLA-B27–positive patients,
when present, is clinically identical to AS seen in the Treatment of axial arthropathy is similar to treat-
spondyloarthropathies. Microscopic colitis may be ment of peripheral arthropathy with one notable ex-
present in 60% of patients with AS who had no GI ception: in contrast to peripheral arthropathy, which
symptoms or prior diagnosis of IBD. Furthermore, the usually responds to treatment of colitis, medical or
presence of microscopic colitis in those patients is as- surgical therapy of the underlying IBD does not alter
sociated with the subsequent development of CD. the progressive nature of axial arthropathy. Other
Isolated sacroiliitis, in contrast, can be asymptom- agents used with reported success include sulfasala-
atic, although sacroiliac joint changes are often pres- zine, mesalamine, methotrexate, azathioprine, and
ent on MRI. The majority of patients with sacroiliitis
are negative for HLA-B27 and do not progress to AS,
-
Other Extraintestinal Manifestations nutritional status (including dietary calcium intake),

weight, smoking status, and risks for trauma.
Hypercoagulability with thromboembolic events can
occur in patients with CD or UC. A population-based
study in Manitoba demonstrated a 3-4 fold increased
Nephrolithiasis
risk of deep venous thrombosis and pulmonary embo-
The prevalence of nephrolithiasis is reported to be
compared with the age-adjusted general population . 60 7–10% in patients with IBD. The two most common
Primary sclerosing cholangitis (PSC) occurs in stone types are uric acid and calcium oxalate. Many
3-7% of patients with UC61 and less frequently in CD factors are involved in the pathogenesis of renal
patients. PSC typically follows a course independent stones in patients with IBD, including abnormal urate
of bowel activity. There is a four-fold increased risk excretion, decreased intestinal absorption of sodium
- and water with resultant intravascular volume deple-
matory bowel disease, and is usually associated with tion and oliguria, and hypercalcemia. Calcium oxalate
ulcerative colitis and PSC62. stones result from hyperoxaluria associated with ei-
ther distal ileal CD or ileal resection. Since the absorp-
tion of the sodium-bound oxalate occurs in the colon,
Complications of IBD the increased risk of calcium oxalate stones is present
only in patients with an intact colon. In contrast, pa-
tients with an ileostomy are predisposed to the forma-
tion of uric acid stones because of their frequent de-
Decreased Bone Mineral Density hydration. Management of nephrolithiasis in patients
Analysis of all controlled published studies using with IBD is the same as that in the general population,
dual energy X-ray absorptiometry (DEXA), the gold and consists of analgesia, hydration, alkalinization of
standard for evaluating bone mineral density (BMD), the urine for uric acid stones, lithotripsy, and surgery.
shows that 40–50% of patients with IBD have osteo- Calcium oxalate stones in these patients form when
penia, and up to 30% may have osteoporosis. General- -
ly, both disorders have been observed more frequently ing to luminal calcium. Unabsorbed fatty acids also
in patients with CD than in patients with UC63, which alter colonic permeability thus favoring oxalate ab-
may be related to small bowel malabsorption of cal- sorption. Thus, supplementation of oral calcium may
cium and vitamin D in CD. In addition, decreased calci- decrease the development of calcium oxalate stones
by enhancing the formation of the insoluble calcium
strictures may play a role in CD. Another possibility is oxalate complex to be excreted into the stools.
that patients with CD are more likely to receive chron-
ic therapy with glucocorticoids, which reduce BMD.
Other agents known to be associated with a decrease Other Genitourinary Complications
in bone mineral density include methotrexate and cy-
Other genitourinary complications can occur in pa-
closporine A.
tients with IBD, most commonly in CD. Obstruction
of the ureter (classically right-sided) occurs primar-
Risk factors
ily in patients with distal ileal CD; however, left-sided
Risk factors for osteoporosis and osteopenia can be di-
ureteral obstruction can be seen in jejunal CD. Fis-
vided into those that are measurable and those that are
tulas can also develop from the bowel to the urinary
tract at various levels, including the bladder (colove-
include BMD, serologic and urinary markers of bone
-
vagina, or the ureter in patients with CD.
able factors include glucocorticoid therapy, treatment
with other drugs, sex hormone status, exercise status,
Cholecystolithiasis Pregnancy and IBD

Cholecystolithiasis is a complication that can occur The rate of fertility in patients with UC is the same as
in more than 25% of individuals with CD, with a rela- that of the general population, although there is evi-
tive risk of 1.8 compared with the general popula- dence of decreased fertility among women who have
tion64. The classic scenario occurs in an individual had proctocolectomy with ileal pouch anal anasto-
- mosis (IPAA) for UC66,67. There is evidence to suggest
ous ileal resection(s). In such patients, it is presumed fertility in women with CD is somewhat impaired68,
that a decrease in the bile salt pool allows cholesterol particularly in those with active disease69. Possible
supersaturation, which can lead to cholesterol nucle- explanations for impaired fertility in women with CD
ation and subsequent gallstone formation. Individu- include the severity of disease, avoiding pregnancy
als with UC and CD disease in the colon only have on medical advice, dyspareunia (especially in the
the same risk for gallstone formation as the general presence of severe perineal disease), and impaired
population. ovulation or fallopian tube obstruction as a conse-
quence of a pelvic septic complication. Male fertility
may also be impaired in those taking sulfasalazine.
Amyloidosis This agent can cause dysmorphic sperm as well as
decreased total sperm count and sperm motility. This
Secondary systemic amyloidosis is a rare but seri-
side effect is reversible and resolves completely upon
ous complication of long-standing IBD, occurring in
cessation of sulfasalazine. It is thought that the sperm
0.9% of patients with CD and 0.07% of patients with
defects due to sulfasalazine are caused by the sulfa-
UC65. Amyloidosis in patients with IBD often affects
pyridine moiety, as this side effect is not seen with
the kidney and presents with proteinuria followed
other 5-aminosalicylic acid (5-ASA) compounds70. CD
-
has been associated with oligospermia in some men.
ciency. Diagnosis can be made by liver, rectal, or renal
IBD itself may have an impact on the pregnancy.
biopsy. Fat-pad aspiration is the most sensitive diag-
A meta-analysis in 2007 found increased risk of pre-
nostic test for the detection of systemic amyloidosis
term birth or low birth weight among patients with
in patients with IBD.
IBD compared with controls. In this meta-analysis,
an increased risk of congenital abnormalities was
noted among newborns born to mothers with UC
Anemia
but not CD71. However, this outcome was heavily in-
Anemia in patients with IBD can have multifactorial
etiologies. Anemia in either UC or CD can occur as a reproduced.
consequence of blood loss in the GI tract. This com- If needed, endoscopy can be performed safely
- -
mation or resection can lead to vitamin B12 malab- copy, EGD, and endoscopic retrograde cholangiopan-
sorption in patients with CD. Iron absorption may be creatography (ERCP) with an attempt to use a lead
shield and limit radiation exposure. Colonoscopy is
with CD, and folate malabsorption can result from not advised unless needed in a life-threatening situ-
ation. In general, no endoscopic procedure should be
have strictures or ileocolic resections are candidates performed unless absolutely required. Ultrasound
for the development of bacterial overgrowth. In bac- and MRI can be performed during pregnancy. How-
terial overgrowth, serum B12 levels are classically ever, attempts should be made to avoid CT scans,
low, and folate levels may be normal or elevated due barium enemas, small bowel follow-through exami-
to bacterial production of folate. In patients with CD nations (which likely have the most radiation expo-
who have refractory anemia, the use of parenteral sure of all radiographic studies), and upper GI radio-
iron or erythropoietin has been advocated. graphic studies.
Most medications used to treat IBD can be used this agent to cross the placenta compared with whole
during pregnancy with some exceptions and modi- 74
.
Given the potential to cross the placenta, some have
its derivatives) and sulfasalazine are thought to be advocated withholding anti-TNF therapy during the
low-risk during pregnancy, though sulfasalazine last trimester, due although agreement on these
should be given with folic acid 2 mg daily. Steroids recommendations is not widespread. The potential
risks of treatment must be weighed against the risks
association with cleft lip, cleft palate or premature of disease exacerbation if therapy is withheld.
rupture of membranes. Antibiotics that can be safely
used in pregnancy include amoxicillin and cephalo-
sporins. Metronidazole may be associated with cleft Colorectal Cancer in IBD
It is estimated that colorectal cancers (CRCs) occur-
trimester and used only for short courses if needed.
ring in patients with UC account for 1% of all CRCs.
This represents an increased cancer risk of 10- to 25-
avoided because of the association with skeletal ab-
fold compared to the general population. The cancers
normalities. Methotrexate is teratogenic and is con-
that occur in association with UC are classically diag-
traindicated in pregnancy. Azathioprine and 6-MP
nosed in patients between 40 and 45 years of age75.
are known to be teratogenic in animals; however,
When the cancers in patients with UC are compared
this effect has not been consistently reproduced in
stage-for-stage with age-matched controls, the prog-
humans. These medications are associated with pre-
nosis for the two groups is similar.
term birth, but not congenital abnormalities or low
Most studies have suggested that risk factors for
birth weight72. Overall, these drugs are considered to
development of CRC in patients with UC include the
be low-risk and could be continued during pregnan-
endoscopic extent of the disease (pancolitis), the du-
ration of disease (>8 years), and the age at diagnosis
thought to exceed the medication risks. The percep-
-
tion is that cyclosporine is safe if needed, but this has
tum (proctitis) are not considered to be at increased
been poorly studied73. In all cases, a formal discus-
risk for CRC relative to the general population. Other
established risk factors for the development of CRC
and risks of the various medications in pregnancy
in UC include a family history of CRC, coexisting PSC,
should occur and be documented.
76
. A
-
-
nant women when needed. Adalimumab, although
gree relative places a patient with UC at two-fold risk
-
for the development of CRC.
imab; both are category B medications. Category B
As a consequence of the elevated risk for devel-
opment of CRC, most patients enter a colonoscopic
to demonstrate a risk to the fetus and there are no
surveillance program to help lessen risk and detect
adequate and well-controlled studies in pregnant
CRCs at an early stage. The presence of dysplasia
women, or animal studies have shown an adverse ef-
(unequivocal neoplastic proliferation of epithe-
fect but adequate and well-controlled studies in preg-
lium), which has been shown to serve as a precan-
nant women have failed to demonstrate a risk to the
fetus in any trimester73. A third FDA-approved agent,
GI pathologist, is an indication for colectomy. In an
certolizumab pegol, is also considered category B in
effort to search for carcinoma or dysplasia, surveil-
pregnancy. This agent is a PEGylated Fab fragment
lance colonoscopy is indicated in patients with UC
of anti-tumor necrosis factor alpha monoclonal an-
after 8–10 years of disease. In general, surveillance
tibody. The PEGylated portion reduces the ability of
colonoscopy should be performed during a period of
disease remission, and biopsies should be obtained tinely in low-risk patients awaits additional informa-
at 10 cm intervals throughout the colon, with addition regarding longer-term follow-up. Chromoendos-
tional biopsy specimens from suspicious areas (i.e., copy may be most valuable in high-risk patients such
macroscopically visible lesions). Dysplasia may be
patchy, and thus there may be considerable sam- not proceed to colectomy, and to ensure adequate re-
pling error during colonoscopy. At least one study section of polypoid or minimally raised lesions. Thus,
has shown that a minimum of 33 jumbo biopsies is chromoendoscopy has not yet become the standard
required in order to achieve 90% sensitivity for the of practice and awaits further study.
detection of colonic dysplasia or cancer. The optimal -
time interval between repeat examinations is not
- and plaque-like. CRCs arising in patients with panco-
litis are relatively evenly distributed throughout the
colon, in contrast to sporadic CRC that occurs most
or high grade. In those patients with diagnoses of in- commonly in the rectosigmoid and cecum. The pres-
ence of a stricture in a patient with UC should raise
suspicion of cancer; overall, approximately 25–33%
low-grade or high-grade dysplasia, immediate con- of UC-related strictures are malignant. Histologically,
half of these tumors are mucinous (colloid) carcino-
should be obtained, and colectomy should be con- mas that secrete copious amounts of extracellular
mucin, which aids in dissection of the tumor through
grade dysplasia, in which the incidence of synchro- the muscularis propria. Colonic carcinogenesis in UC
nous cancer may be high77. is thought to be driven by sequential episodes of so-
Chromoendoscopy has been used by some matic gene mutation and clonal expansion. Several
groups and has been demonstrated to increase the of the genetic alterations (including aneuploidy and
- mutations of oncogenes, tumor suppressor genes,
nize which polypoid lesions are of concern and man- and DNA repair genes) that occur during this process
date biopsy. The most commonly used mucosal dye
sprays are carmine indigo and methylene blue78. The The data suggest that there is a 2- to 3-fold in-
natural history of dysplastic lesions discovered by creased risk of CRC among all patients with CD, with
chromoendoscopy, but not visible with routine white those patients who have Crohn’s colitis having a risk
light colonoscopy, is unknown. A recommendation to in excess of 5- to 6-fold79. The evidence suggests that
use chromoendoscopy-enhanced surveillance rou- the CRC risk in extensive Crohn’s colitis is similar
Figure 5.14
Schematic of Molecular Pathogenesis of Multistage Colonic Carcinogenesis in Chronic Ulcerative Colitis
to that in patients with extensive UC (15- to 17-fold mon disease severity indices for UC and CD are shown
increased risk). The most recent guidelines recom- in Tables 5.3-5.5. In patients with UC, symptomatic
mend that patients with long-standing CD involving improvement may precede endoscopic improve-
at least one-third of the colon undergo surveillance ment, whereas in CD there is often a poor correlation
colonoscopy in a fashion similar to that of UC77.
used in the treatment of IBD are shown in Table 5.6.
Medical Therapy
Medical therapy for patients with IBD is palliative
Aminosalicylates
and not curative of their disease. The primary goals Aminosalicylates are the most common drugs pre-
of medical therapy are to: scribed for the treatment of patients with IBD. Sul-
induce remission composed of an agent that has antibacterial activity,

maintain remission sulfapyridine, bound to 5-ASA (mesalamine). In the
alleviate or minimize the intestinal symptoms 1970s, it was discovered that the 5-ASA component
alleviate or minimize the extraintestinal symptoms
provide therapy that has minimal toxicity activity while the sulfa moiety functions solely as
improve the quality of life of patients a carrier ensuring delivery to the colon, where sul-
maintain adequate nutrition fasalazine is broken down by colonic bacteria into
its constituents80. This observation, along with the
is judged by subjective and objective criteria. Com- to the creation of sulfa-free aminosalicylates. These
Table 5.3
Mayo Scoring System for Assessment of Ulcerative Colitis Activity
Variable Scoring
Stool pattern Normal # daily stools = 0

1-2 more stools than normal = 1
3-4 more stools than normal = 2
> 5 stools than normal = 3
Most severe rectal None = 0

bleeding of the day Blood streaks < 50% of the time = 1
Blood in most stools = 2
Pure blood passed = 3
Endoscopic findings Normal or inactive colitis = 0

Mild colitis (mild friability, erythema, decreased vascularity) = 1
Moderate colitis (friability, marked erythema, vascular pattern absent, erosions = 2
Severe colitis (ulcerations and spontaneous bleeding)= 3
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005 Dec
8;353(23):2462-76
Table 5.4
Common indices of Crohn’s disease clinical severity
Index Variables Scoring Multiplier

# Liquid Stools
X2
(Sum of 7 days)
0 = none
Abdominal pain 1 = mild
X5
(Sum of 7 days) 2 = moderate
3 = severe
0 = generally well
1 = slightly under par
Crohn’s Dis- General well-being
2 = poor X7
ease Activity (Sum of 7 days)
3 = very poor
Index1 4 = terrible
Arthritis or arthralgia; iritis or uveitis; erythema nodosum;
Extraintestinal
pyoderma gangrenosum; aphthous stomatitis; anal fissure, X20
Complications (#)
fistula or abscess; fever > 37.8° C
Antidiarrheal drugs 0 = no
X30
(Previous 7 days) 1 = yes
0 = no
Abdominal mass 2 = questionable X10
5 = definite
Males: 47-observed
Hematocrit X6
Females: 42-observed
Body weight [1-(ideal/observed)]x 100 X1
0 = very well
1 = slightly below par
General well-being 2 = poor
3 = very poor
4 = terrible
0 = none
1 = mild
Abdominal pain
2 = moderate
Harvey-Brad-
3 = severe
shaw Index2
# daily liquid stools
0 = no
1 = dubious
Abdominal mass
2 = definite
3 = definite and tender
Arthritis or arthralgia; iritis or uveitis; erythema nodosum;
Extraintestinal complica-
pyoderma gangrenosum; aphthous stomatitis; anal fissure,
tions
fistula or abscess
1. Best WR, Becktel, JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study.
Gastroenterology 1976;70:439-444. 2. Harvey RF, Bradshaw JM. A simple index of Crohn’s disease activity. Lancet 1980;1:514.
Table 5.5
Crohn’s Disease Endoscopic Index of Severity (CDEIS)
Sigmoid Transverse Right

Scoring Rectum Illeum Total
and Left Colon Colon Colon
Deep ulcerations (12 pts) Total 1
Superficial ulcerations (12 pts) Total 2
Surface involved by disease (cm) Total 3
Surface involved by ulcerations (cm) Total 4
Total 1 + 2 + 3 + 4 = Total A
# segments totally or partially explored n
Total A/n = Total B
Ulcerated stenosis (3 pts) Total C
Nonulcerated stenosis (3 pts) Total D
Total B + C + D = CDEIS
From Mary JY, Modigliani R. Development and validation of an endoscopic index of severity for Crohn’s disease: a prospective multicentre study. Gut 1989;30:983-989.
Table 5.6
Medical Treatment Options
Disease activity Ulcerative colitis Crohn’s disease

Oral aminosalicylate Oral aminosalicylate (?; see text for discussion)
Topical aminosalicylate Hydrocortisone enemas
Mild
Hydrocortisone enemas Metronidazole
Hydrocortisone suppositories Ciprofloxacin
Oral aminosalicylate
Aminosalicylate (?; see text for discussion)
Topical aminosalicylate
Oral corticosteroids
Azathioprine/6-mercaptopurine
Azathioprine/6-mercaptopurine
Moderate Nicotine patch
Metronidazole/ciprofloxacin
Oral corticosteroids
Methotrexate
Parenteral corticosteroids
Infliximab, adalimumab, or certolizumab pegol
Infliximab
Oral/IV corticosteroids Oral / IV Corticosteroids
Severe Cyclosporine Cyclosporine (?)
Infliximab Infliximab, adalimumab, or certolizumab pegol
Aminosalicylate Azathioprine/6-mercaptopurine
Maintenance Azathioprine/6-mercaptopurine Methotrexate
Infliximab Infliximab, adalimumab, or certolizumab pegol
Ciprofloxacin
Metronidazole
Fistulizing
6-Mercaptopurine/azathioprine
Crohn’s disease
Infliximab, adalimumab, or certolizumab pegol
Methotrexate (?)
include several oral and topical mesalamine prepa- Oral preparations

rations, alternative azo-bonded carriers, and 5-ASA In UC patients with mild-to-moderate disease activity,
dimers (Table 5.7). oral aminosalicylates have been shown to be superior
The precise mechanism of action of 5-ASA is not to placebo for induction of remission81. Effective doses
of these drugs are 4–6 g/day in 4 divided doses for
properties have been discovered. Mesalamine has sulfasalazine, 2–4 g/day for mesalamine, and 1.5–3
been shown to have effects on the arachidonic acid g/day for olsalazine. Sulfasalazine and mesalamine
pathway including the 5 -lipoxygenase pathway, preparations have been shown to have comparable ef-
prostaglandin and thromboxane synthesis, and inhi-
bition of platelet activating factor synthase. Further- UC, in which there is a dose-response relationship for
more, mesalamine inhibits the production of free both sulfasalazine and mesalamine82,83. Maximal doses
oxygen radicals, impairs the function of lymphocytes should be considered in patients who fail to respond
and monocytes, and decreases the production of IL-1 to standard doses of mesalamine or sulfasalazine. In
and immunoglobulins. Lastly, sulfasalazine has been addition, these medications have been shown to be
demonstrated to block the activation and production effective for maintenance of remission in 50–75%
of NFkB, mitogen-activated protein kinase, and TNF. of UC patients84. A meta-analysis suggests that once
daily dosing of mesalamine is as effective as conven-
tional dosing for maintenance of remission85. No con-
Table 5.7
Aminosalicylate Therapy for IBD
Delivery Proprietary name Unit dose Generic name Site Dose (g/day)
Oral Tablet
Azulfidine 500 mg Sulfasalazine Colon 3–6 g/day
Asacol 400 mg Mesalamine Distal ileum 1.6–4.8 g/day through colon

Asacol HD 800 mg Mesalamine
Dipentum 250 mg Olsalazine Colon 1.5–3 g/day
Colazal 750 mg Balsalazide Colon 6.75 g/day
Apriso 375 mg Mesalamine Distal Ileum 1.5–3.0 g/day

through colon
Lialda 1200 mg Mesalamine MMX Colon 2.4–4.8 g/day
Oral Capsule
Pentasa 250 or 500 mg Mesalamine Duodenum through colon 2–4 g/day
Suppository
Canasa 1000 mg Mesalamine Rectosigmoid to 20 cm 0.5–1.0 g/day
Enema
Rowasa 1 or 4 grams Mesalamine Left colon to splenic 1–4 g/day

flexure
trolled dose-response data above 1.5 g/day exist for effects have led to discontinuation of medication in
aminosalicylates as maintenance therapy in UC, but up to 30% of patients93. Up to 80% of men develop
some uncontrolled data suggest that the dose needed reversible oligospermia and sperm dysmotility70.
to induce remission should be used as maintenance Sulfasalazine competitively inhibits intestinal absorp-
therapy. There are no controlled data regarding the ef- tion of folic acid by inhibiting the enzyme folate con-
fectiveness of aminosalicylates for severe UC. jugase (primarily in the jejunum); therefore, supple-
- mentation with at least 1 mg per day of folic acid is
ment of CD is an area of debate, as studies of 5-ASA recommended94. Adverse effects linked to plasma sul-
medications for treatment of CD have yielded mixed fapyridine levels include GI symptoms such as nausea,
results. As a result, there are no FDA-approved 5-ASA vomiting, anorexia, and dyspepsia, as well as malaise
medications for treatment of CD. Sulfasalazine has and headaches. There are also idiosyncratic reactions
been shown to be more effective than placebo in in- that include fever, rash, agranulocytosis, hepatitis,
ducing remission in mild-to-moderate active colitis86 pancreatitis, interstitial nephritis, and pneumonitis.
but not for isolated ileal Crohn’s disease. In addition, The newer oral 5-ASA preparations generally have
sulfasalazine has not been shown to be effective for fewer side effects and have been tolerated by ap-
maintenance of remission in patients with CD87. Two proximately 80% of sulfasalazine-intolerant patients.
However, patients taking either sulfasalazine or me-
for the induction and maintenance of remission in CD salamine can experience a worsening of colitis95. Ol-
86,87
. salazine is associated with a dose-related diarrhea
that occurs in 10–30% of patients and is likely due to
Topical mesalamine preparations ileal secretion by means of induction of small bowel
Mesalamine is available topically in the form of en- chloride secretion96. There are also multiple case re-
emas, suppositories, and foams, though foams are not ports of interstitial nephritis associated with 5-ami-
currently available in the United States. These agents nosalicylate use, which appears to be an idiosyncratic
are indicated primarily for patients with mild-to-mod- reaction97.
erate UC restricted to the colon distal to the splenic
have been shown to induce and maintain remission Corticosteroids

in patients with distal UC of mild-to-moderate activ-
Corticosteroids have long been the mainstay of ther-
ity, often with fewer side effects than oral sulfasala-
apy primarily for moderate and severe IBD (both in
zine88,89. In addition, combination oral and topical me-
CD and UC), including when patients require hos-
salamine may be more effective than oral mesalamine
pitalization. Despite their frequent use, the exact
alone for the induction and maintenance of remission
mechanism of action in IBD is not fully understood.
of mild-to-moderate distal UC90. Topical mesalamine
Corticosteroids block the arachidonic acid pathway
-
through their inhibition of phospholipase A298. Cor-
mine therapy in patients with extensive colonic dis-
ticosteroids also interfere with the normal functions
ease91. Mesalamine suppositories (taken once, twice,
of neutrophils, monocytes, and eosinophils99. Other
studies have shown that corticosteroids decrease
production of cytokines and NFkB100. Corticosteroids
can be given orally, parenterally, or topically, with
topical steroids being reserved for the treatment of
Mesalamine and Sulfasalazine Side
distal colitis. Hydrocortisone enemas are effective for
Effects
treatment of distal UC, and will induce either clinical
Up to 45% of patients treated with sulfasalazine for response or remission in over 50% of patients. Due
IBD experience adverse effects, the majority of which
are related to the sulfapyridine moiety92. These side even when given topically, newer oral and topical for-
mulations (e.g., budesonide) that have less systemic the use of corticosteroids in CD patients to maintain
remission. Recent data, however, suggest some long-
have been developed. -
Corticosteroids, whether given orally or parenter-
has been examined for maintenance of remission in
with moderate-to-severe disease activity. Oral predni- patients with ileocecal CD following induction therapy
sone at doses of 40–60 mg daily has been shown to with budesonide or conventional corticosteroids. Al-
be superior to 20 mg daily for moderate UC, although though budesonide may result in lower CDAI scores
the higher doses were associated with more side ef- and longer time to relapse, budesonide is not more ef-
fects. Parenteral corticosteroids are usually given in fective than placebo for maintenance of remission110.
the form of methylprednisolone at 40–60 mg daily (or The side effects of corticosteroids are classically de-
hydrocortisone in doses up to 300 mg daily), although pendent on dose and duration of therapy. Short-term
some physicians prefer adrenocorticotropic hormone
(ACTH) for steroid-naïve patients at a dose of 120
units daily. ACTH therapy, however, has the potential face, acne, weight gain, and hypertension. Long-term
to lead to bilateral adrenal hemorrhage. There are no side effects include metabolic bone disease, osteone-
well done, adequately powered studies assessing the crosis111, posterior subcapsular cataracts, and growth
superiority of divided dose versus continuous infusion retardation in children112. Corticosteroids may be
used during pregnancy but an increased risk of cleft
found in the addition of sulfasalazine to corticoste-
roids in patients with UC or CD of moderate-to-severe trimester113.
activity for the maintenance of remission101. Topical
corticosteroids have been shown to be less effective
than topical mesalamine for distal UC102, although Immune-Modifier Drugs
the combination may be superior to either alone103.
Studies of newer corticosteroid agents, particularly Azathioprine and 6-MP
Azathioprine is a prodrug that is nonenzymatically
patients with distal UC104-106 converted to 6-MP after absorption. 6-MP is metabo-
of corticosteroids to induce remission in UC, they are lized eventually to 6-thioguanine nucleotide metabo-
no more effective than placebo for maintenance of re- lites (6-TGN), the perceived active metabolites. Recent
mission in patients with UC. data suggest there may be individuals who produce
Corticosteroids, given orally or parenterally, are excessive 6-methylmercaptopurine (6-MMP), anoth-
also indicated for the treatment of moderate-to-severe er metabolite of 6-MP that has been associated with
abnormal ALT and AST and asymptomatic elevation
involvement. Effective doses of corticosteroids are of amylase and lipase. The enzyme involved with the
equipotent to 0.5–0.75 mg/kg/day of prednisone. A formation of 6-MMP is thiopurine methyltransferase
controlled ileal-release oral formulation of budesonide (TPMT). There is a population polymorphism in the
(Entocort® TPMT gene, with 89% of the population homozygous
CD107-109 for wild-type TPMT, 11% heterozygous for the TPMT
with active CD is 9 mg orally daily (once-daily dosing). mutation, and 0.3% homozygous for the TPMT mu-
tation.114. Those with heterozygous and homozygous
liver and has potent topical vasoconstrictive effects, TPMT mutations have decreased-to-absent enzyme
- activity and are at higher risk of leukopenia when
treated with azathioprine and 6-MP115. TPMT geno-
has less adrenal suppression than prednisone. type or enzyme activity testing should be considered
As with UC, there have been little data to support in patients prior to beginning treatment with 6-MP/
AZA. The target dose used to treat IBD patients who patients with moderate-to-severe CD when adminis-
have normal TPMT activity is 2–3 mg/kg for azathio- tered in a dose of 25 mg by intramuscular injection
prine and 1.0–1.5 mg/kg for 6-MP; patients with in-
termediate TPMT activity should be given half of those sparing effect130. Based upon data from pharmacoki-
doses, and patients with low-absent TPMT activity netic studies, subcutaneously administered metho-
should avoid these drugs, given the risk of severe leu- trexate is likely to be as effective as intramuscularly
kopenia, sepsis, and death.
Azathioprine and 6-MP are effective for the treat- studies have not been performed. In contrast, oral
ment of active luminal CD116,117 118
, and methotrexate is no more effective than placebo in pa-
for both steroid-sparing and maintenance of remis- tients with CD. Toxicity, often manifested as nausea
sion in CD119,120 - or diarrhea, has been reduced by co-administration
cacy for induction of remission in small trials in pa- of folic acid at a dose of 1 mg daily. A controlled trial
tients with active UC121-123. It has also demonstrated in patients with CD demonstrated that methotrexate
at a dose of 15 mg intramuscularly every week can
UC124,125. The odds ratio for induction of remission in a maintain remission in patients who achieved remis-
recent meta-analysis was 1.59 compared to placebo, sion at a dose of 25 mg weekly131. The potential for
and the odds ratio for maintenance of remission was
2.56126. Azathioprine and 6-MP have a slow onset of laboratory chemistries at baseline and periodically
thereafter. Although it is not formally recommended,
3–6 months in patients with CD. obtaining a liver biopsy after a cumulative dose of 1.5
In general, approximately 15% of individuals g in patients with risk factors for liver disease or in
will be intolerant to therapy. Side effects limiting a those with persistently elevated liver enzymes has
patient’s ability to take azathioprine or 6-MP may be been suggested by some investigators. Methotrexate
either idiosyncratic or dose-related. Idiosyncratic side has also been effectively used in children with CD.
effects include rash, fever, pancreatitis, arthralgias,
myalgias, nausea, and hepatitis. Dose-related side ef- UC has not been established, as the only randomized
fects include leukopenia, anemia, thrombocytopenia, controlled trial of methotrexate for the induction of
and liver enzyme abnormalities. Some patients who remission in UC used a low-dose (12.5 mg weekly)
develop nausea with azathioprine can tolerate 6-MP
without side effects and vice versa. placebo132. Further evaluation is merited in patients
A meta-analysis of six studies evaluating the risk -
for lymphoma in patients on azathioprine and 6-MP nance of remission.
compared to that risk in the general population and
Cyclosporine
interval 2.07-7.51) with these drugs , and a prospec-
127 Cyclosporine is a potent immunosuppressive agent
tive population cohort study found a 5-fold risk. This that has a rapid onset of action. It has proven to be
increased risk is likely due to the drugs, as the base-
line risk of lymphoma in patients with IBD does not severe UC refractory to corticosteroids such as fail-
appear to be increased compared to the general popu- ure to respond to 7 days of IV corticosteroids. Cyclo-
lation128. There is also evidence that previous and sporine is given IV in a dose of 2 mg/kg to 4mg/kg
current thiopurine use may increase the risk of non- daily and titrated to appropriate trough levels for pa-
tients with severe UC133,134. Based upon a single trial,
bowel disease129. cyclosporine at a mean dose of 7.6 mg/kg/day has
135
,
Methotrexate
Methotrexate is effective in inducing remission in over placebo when used at 5.0 mg/kg/day136,137.
Cyclosporine has not been shown to be effective ticosteroids146. In UC, the current recommended dose
for maintenance of remission in either CD or UC. In is the same as that for CD.
two large series that reported their collective mor- Human anti-chimeric antibodies (HACAs) and
bidity, there were 9–12% severe adverse events, and -
three patients died. Therefore, cyclosporine has been ated with decreased duration of response147-149. In an
used primarily as a “bridge” until other agents such effort to lessen antibody production, concurrent use
of immunomodulators has been suggested by some
patient to achieve a sustained remission. Potential experts, but extensive data suggest that the most ef-
fective means of preventing antibody formation is
and opportunistic infections. With the advent of anti- 139
. In
TNF therapies, cyclosporine is no longer used in the patients with loss of response or partial response to
treatment of CD.
-
-
Biologic Agents
ineffective in patients with high levels of HACAs or
The cytokine TNF-a is elevated in the bowel muco- 150
.
sa, serum, and stool of patients with active IBD. In-
Two other anti-TNF agents, adalimumab and cer-
tolizumab pegol, both administered subcutaneously,
are also FDA-approved for induction and mainte-
nance treatment of active CD. Adalimumab is a fully
is administered as a 2-hour infusion, and the clinical
human monoclonal antibody approved for the treat-
effect lasts approximately 8 weeks. Two multicenter
ment of CD and is dosed every 2 weeks, starting with
-
160 mg at week 0, 80 mg at week 2, and 40 mg every
fusions administered every 8 weeks after induction
other week thereafter151-154. Dose escalation of up to
therapy of 5 mg/kg at weeks 0, 2, and 6 can main-
40 mg weekly is needed in approximately 40% of pa-
tain remission in patients with treatment-resistant
tients over time due to loss of response155,156. In mul-
CD138,139 -
tiple randomized controlled trials, adalimumab has
-
been demonstrated to induce and maintain clinical
140,141
. Dose
remission in patients with moderate-to-severe ulcer-
escalation of up to 10 mg/kg every 8 weeks or 5 mg/
ative colitis157,158.
kg every 4 weeks is needed in up to half of patients
Certolizumab pegol is a humanized (95% hu-
over time, due to loss of response142. The combina-
man) polyethylene glyocolated Fab fragment of an
anti-TNF monoclonal antibody, and is dosed every
relatively newly diagnosed moderate-to-severe CD
four weeks at 400 mg after loading doses of 400
has very recently been shown to be more effective
mg at weeks 0 and 2. Certolizumab pegol has been
than either therapy alone143.
demonstrated in randomized controlled trials to be
-
effective in maintenance and remission of Crohn’s
ative colitis who are steroid-refractory or steroid
disease159,160. For loss of response, an extra dose of
dependent despite the use of 5-ASA medications or
400 mg may be given 2 weeks after the last dose with
thiopurines144. Randomized controlled trials have
the hope of recapturing response161.
Side effects reported with anti-TNF agents in-
maintenance of remission in moderate-to-severe ul-
clude infectious complications such as acute sinus-
cerative colitis refractory to conventional therapy145,
itis, reactivation of tuberculosis in patients previ-
and as rescue therapy in moderately severe ulcer-
ously exposed, reactivation of hepatitis B infection,
ative colitis that is unresponsive to intravenous cor-
and fungal infections162. In addition, there have been
acute infusion reactions, delayed hypersensitiv-

ity reactions, myalgias, arthralgias, fever (frequently than placebo171.
2–12 days after infusion), and the formation of au-
toantibodies (ANA and anti–double-stranded DNA), have been shown to be effective agents for the treat-
leading in rare cases to drug-induced lupus-like re- ment of pouchitis in UC patients172. Long-term use
actions. Severe hepatic necrosis has been reported of metronidazole has been associated with superin-
very rarely. fection (e.g., vaginal yeast infections) and peripheral
A potential association with non-Hodgkin’s lym-
phoma has been suggested163; of note, there seems to associated with Achilles tendonitis, Achilles tendon
be an increased risk of a highly lethal but extremely rupture, and bacterial superinfection.
- Rifaximin, an oral, non-systemic, broad-spec-
imab or adalimumab has been used in combination trum antibiotic, was not more effective then placebo
with azathioprine or 6-MP especially in males ages in a small controlled trial of patients with pouchi-
35 or younger. The exposure to azathioprine/6-MP tis173,174 -
in these cases was typically for at least 2 years dura- tenance therapy in patients with recently treated
tion. There have been no reported cases in patients pouchitis. In addition, in a phase II trial, an extended
with IBD who have only used anti-TNF therapy164. In- intestinal release formulation of rifaximin at a dose
creased risk of skin cancer has been reported.
Natalizumab, a humanized monoclonal anti- in inducing remission compared with placebo in pa-
body to alpha4 integrin, is the newest FDA-approved tients with moderately active Crohn’s disease33. Ri-
therapy for moderate to severely active Crohn’s dis- faximin is unique compared to other antibiotics be-
ease165,166. Natalizumab is administered as a 300 cause only a small percent of the agent is absorbed
mg infusion at weeks 0, 4, 8 and then every 4 weeks (<0.4% overall).
thereafter. The most serious risk of natalizumab is
progressive multifocal leukoencephalopathy (PML),
caused by reactivation of the JC virus. As of February Probiotics
2012, the incidence of PML among patients treated
Probiotics are agents that change the bacterial milieu
with natalizumab was 2.1 cases per 1000 patients.
Risk factors for PML include anti-JC virus antibody
bacteria to the GI tract. Several agents, including lac-
positivity, prior use of immunosuppressants, and in-
tobacillus GG, Nissl, and others, have been ex-
creased duration of natalizumab therapy167.
amined in their ability to treat acute UC or CD with
-
-
Antibiotics
To date, there have been no large placebo-controlled as prophylaxis against pouchitis for patients who
have recently undergone total proctocolectomy with
broad-spectrum antibiotics in CD. Additionally, there ileoanal J pouch surgery. It has also demonstrated
have been no large controlled trials evaluating the ef-
2-week course of antibiotics.175,176. Recently VSL-3
with perianal CD. Several small studies have dem- has been demonstrated to be effective compared to
placebo in two prospective, randomized, placebo-
at 10-20 mg/kg/day34,168 controlled trials for the induction of remission and
gram daily169, and combination of metronidazole and mucosal healing in patients with active ulcerative
170
for the treatment of luminal CD, and colitis177,178
particularly colonic CD. A meta-analysis of three tri- in CD and other conditions.
Nicotine sia, colonic perforation (estimated to occur in 2–3% of

hospitalized patients), and uncontrolled hemorrhage.
Ulcerative colitis tends to occur in patients who
Less commonly, surgery is mandated in UC to control
are nonsmokers or former smokers. It is well docu-
extraintestinal manifestations of the disease.
mented that individuals who have active disease and
Total proctocolectomy with ileal pouch–anal
resume smoking may go back into remission. On
anastomosis (IPAA or ileoanal J pouch) is the most
the other hand, individuals with CD who smoke can
commonly performed procedure for UC in the United
lessen their disease severity by smoking cessation.
States. In general, functional results and quality of life
Two randomized, double-blind, placebo-controlled
after colectomy are good. The most common compli-
-
cation is pouchitis, which occurs in at least 45% of
tive UC 179,180
, although a trial using low-dose nicotine
patients; in roughly 5 to 7% of patients, symptoms
patches for maintenance of remission in UC showed
become chronic. The pouch failure rate varies from
that nicotine therapy was not effective181.
0.5% to 13%, with a mean rate of 7%186. Pouchitis is
typically managed successfully by metronidazole, cip-
-
Nutritional Therapy cal mesalamine and the probiotic, VSL #3, are effective
A meta-analysis of six randomized controlled trials for the prevention of recurrent pouchitis after an ini-
comparing enteral nutrition with corticosteroids for tial attack is treated187. Female patients who have had
induction of remission in Crohn’s disease favored IPAA with total proctocolectomy for UC have a higher
corticosteroid therapy (odds ratio of 0.33, 95% con- rate of infertility67. In women who desire to conceive
182
. However, there are who need colectomy, it is recommended to proceed
small studies suggesting that supplemental enteral with a subtotal colectomy and a Hartman’s pouch.
Eventual creation of a J-pouch with proximal diverting
activity in Crohn’s disease183,184 A technical review loop ileostomy followed by takedown of the diverting
by the American Gastroenterological Association in loop ileostomy can take place following childbirth.
2001 concluded based on six studies that total par- Individuals with CD typically require surgery for
- continued symptoms despite medical therapy. Other
indications for surgery in patients with CD include
obstruction, perforation, hemorrhage, and abscess.
to enteral nutrition in treating luminal Crohn’s dis-
ease185. Nutritional therapy is of paramount impor- frequently require incision and drainage of local ab-
tance in children and adolescent patients in order to scesses. Examination under anesthesia to identify
ensure adequate growth and sexual maturation. En- the extent of perianal disease and to place setons is
teral and parenteral nutrition have not been shown
to be more effective than placebo in the treatment of
patients with active UC. Enteral and parenteral nu- Surgical construction of internal intestinal
trition are important adjunctive therapies for treat- pouches such as the ileal J pouch or continent ileosto-
ment of malnutrition in adults with IBD. my (Koch pouch) should be avoided in patients with
CD. The risk of recurrent disease within the pouch ne-
cessitating eventual resection of the segment of bow-
Surgery el required to make the pouch is present in up to 50%
of patients over 5 years188. Overall, 5–13% of patients
Approximately 30% of patients with UC will ultimate-
who are thought to have UC and undergo IPAA with
ly undergo surgical intervention. The most common
creation of a J-pouch are ultimately found to have CD.
indication for surgery is failure to respond to aggres-
One area of intense interest has been medical
sive medical therapy. Other common indications for
therapy to prevent the postoperative recurrence of
surgery include development of carcinoma or dyspla-
CD. Clinical recurrence rates range from 10% to 20%

at 1 year, 18% to 55% at 5 years, and 52% to 76% Pearls and Pitfalls
at 10 years after surgery, with a median time of 3–5
years. Repeat surgery is needed in 5% of patients at 1
for the Board Exam
year and 30% at 10 years. Risk factors for recurrence At 8 years after onset of symptoms, patients with
include prior surgery for CD, presence of an anasto- left-sided or extensive colitis (ulcerative colitis or
mosis, shorter preoperative disease duration189, pen- Crohn’s disease) should begin colorectal cancer
etrating disease190, and smoking191. Medications that surveillance with colonoscopy. Patients with
have shown promise in reducing the risk of postop- ulcerative proctitis are not at increased risk for
erative recurrence in CD include mesalamine, antibi- colorectal cancer and do not require surveillance
colonoscopy.
of seven randomized controlled trials of mesalamine If a patient with inflammatory bowel disease is
compared with placebo showed that mesalamine diagnosed with primary sclerosing cholangitis,
may be superior to placebo (odds ratio 0.68, 95% CI annual surveillance colonoscopy should begin
0.52-0.90). However, the studies in this meta-anal- immediately.
ysis that were adequately powered failed to show Oral aminosalicylates, topical mesalamine and
topical steroids are all appropriate therapies for
antibiotics, a small randomized controlled trial using mild to moderate distal ulcerative colitis, but topical
metronidazole for 3 months compared with placebo mesalamine agents are superior. Combination oral
and topical aminosalicylates are superior to either
alone.
severe endoscopic recurrence192. A European study Infliximab is effective in patients with ulcerative
using a different nitroimoidazole antibiotic, ornida- colitis who are steroid refractory or steroid
dependent despite adequate doses of oral
disease recurrence at one year compared with pla- aminosalicylates or thiopurine, or who are intolerant
cebo193 - of these medications.
creasing the risk of postoperative recurrence in CD Although oral mesalamine is used in clinical practice
in two studies194,195 in the treatment of Crohn’s disease, controlled trials
have not consistently demonstrated efficacy.
reducing the rate of postoperative recurrence in CD 6-mercaptopurine/azathioprine, methotrexate
when compared to placebo196. and anti-TNF monoclonal antibody therapy are all
When deciding on medical therapy for preven- effective in the treatment of moderate to severe
tion of postoperative recurrence in CD, it is helpful to Crohn’s disease. The SONIC study published in 2010
risk-stratify patients. Patients at high risk for recur- demonstrated that patients with moderate to severe
rence (i.e., those with some or all of the risk factors Crohn’s disease who were treated with infliximab
mentioned above) or those with particularly severe plus azathioprine combination therapy or infliximab
disease are often started on therapy, often with met- monotherapy were more likely to achieve steroid-
ronidazole for 3 months and either a thiopurine or free clinical remission compared with patients
a TNF inhibitor within 2–4 weeks of surgery. Those receiving azathioprine monotherapy.
with a low risk of recurrence, particularly those who Anti-alpha 4 integrin antibody, natalizumab, is
have not had prior surgery for CD, may be given a effective in the treatment of patients with moderate
3-month course of metronidazole followed by a colo- to severe active Crohn’s disease who have had
noscopy 6 months after post-operatively to look for an inadequate response or are unable to tolerate
endoscopic and histologic evidence of recurrence. If immunomodulator and anti-TNF monoclonal
recurrence is found, appropriate therapy should be
initiated.
antibody therapy.
Pregnancy considerations: Infertility is increased
Most Efficient Source Reviews
among patients who have undergone ileal pouch- for Examination Preparation
anal anastomosis. Anti-tumor necrosis factor Kornbluth A, Sachar DB; Practice Parameters Commit-
therapy is considered to be low risk during tee of American College of Gastroenterology. Ulcer-
conception and during pregnancy in at least the first ative colitis practice guidelines in adults. Am J Gastro-
two trimesters. Azathioprine is also considered to enterol 2010;105:501-23.
be safe to continue during pregnancy. Methotrexate Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice
is contraindicated in patients planning conception or Parameters Committee of American College of
during pregnancy, as it is teratogenic. Gastroenterology. Management of Crohn’s Disease in
TPMT phenotype (preferred) or genotype testing Adults. Am J Gastroenterol 2009; 104(2):465-83.
should be performed before initiating thiopurine
therapy to identify patients at risk for myelotoxicity.
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Smith PR. European trial of cyclosporine in chronic active concentrations in patients with inflammatory bowel
Crohn’s disease: a 12-month study. The European Study disease. The American Journal of Gastroenterology
Group. Gastroenterology 1995;109:774-82. 2010;105:1133-9.
137. Feagan BG, McDonald JW, Rochon J, et al. Low-dose 151. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimum-
cyclosporine for the treatment of Crohn’s disease. The ab for maintenance of clinical response and remission in
Canadian Crohn’s Relapse Prevention Trial Investigators. patients with Crohn’s disease: the CHARM trial. Gastro-
N Engl J Med 1994;330:1846-51. enterology 2007;132:52-65.
138. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Mainte- 152. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human
nance infliximab for Crohn’s disease: the ACCENT I ran- anti-tumor necrosis factor monoclonal antibody (adalim-
domised trial. Lancet 2002;359:1541-9. umab) in Crohn’s disease: the CLASSIC-I trial. Gastroen-
139. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Com- terology 2006;130:323-33; quiz 591.
parison of scheduled and episodic treatment strate- 153. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimum-
gies of infliximab in Crohn’s disease. Gastroenterology ab for maintenance treatment of Crohn’s disease: results
2004;126:402-13. of the CLASSIC II trial. Gut 2007;56:1232-9.
140. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the 154. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab
treatment of fistulas in patients with Crohn’s disease. N induction therapy for Crohn’s disease previously treat-
Engl J Med 1999;340:1398-405. ed with infliximab: a randomized trial. Ann Intern Med
141. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab 2007;146:829-38.
maintenance therapy for fistulizing Crohn’s disease. N 155. Bultman E, de Haar C, van Liere-Baron A, et al. Predic-
Engl J Med 2004;350:876-85. tors of dose escalation of adalimumab in a prospective
142. Regueiro M, Siemanowski B, Kip KE, Plevy S. Infliximab cohort of Crohn’s disease patients. Aliment Pharm Ther
dose intensification in Crohn’s disease. Inflammatory 2012;35:335-41.
Bowel Diseases 2007;13:1093-9. 156. Cohen RD, Lewis JR, Turner H, Harrell LE, Hanauer SB,
143. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, Rubin DT. Predictors of adalimumab dose escalation in
azathioprine, or combination therapy for Crohn’s disease. patients with Crohn’s disease at a tertiary referral center.
N Engl J Med 2010;362:1383-95. Inflammatory Bowel Diseases 2012;18:10-6.
144. Kornbluth A, Sachar DB. Ulcerative colitis practice 157. Sandborn WJ, van Assche G, Reinisch W, et al. Adali-
guidelines in adults: American College Of Gastroenter- mumab induces and maintains clinical remission in pa-
ology, Practice Parameters Committee. The American tients with moderate-to-severe ulcerative colitis. Gastro-
Journal of Gastroenterology 2010;105:501-23; quiz 24. enterology 2012;142:257-65 e1-3.
145. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab 158. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalim-
for induction and maintenance therapy for ulcerative umab for induction of clinical remission in moderately to
colitis. N Engl J Med 2005;353:2462-76. severely active ulcerative colitis: results of a randomised
146. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as controlled trial. Gut 2011;60:780-7.
159. Lichtenstein GR, Thomsen OO, Schreiber S, et al. Contin- 175. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriother-
uous therapy with certolizumab pegol maintains remis- apy as maintenance treatment in patients with chronic
sion of patients with Crohn’s disease for up to 18 months. pouchitis: a double-blind, placebo-controlled trial. Gas-
Clin Gastroenterol Hepatol 2010;8:600-9. troenterology 2000;119:305-9.
160. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab 176. Mimura T, Rizzello F, Helwig U, et al. Once daily high dose
pegol for the treatment of Crohn’s disease. N Engl J Med probiotic therapy (VSL#3) for maintaining remission in re-
2007;357:228-38. current or refractory pouchitis. Gut 2004;53:108-14.
161. Sandborn WJ, Schreiber S, Hanauer SB, Colombel JF, 177. Sood A, Midha V, Makharia GK, et al. The probiotic prepa-
Bloomfield R, Lichtenstein GR. Reinduction with certoli- ration, VSL#3 induces remission in patients with mild-to-
zumab pegol in patients with relapsed Crohn’s disease: moderately active ulcerative colitis. Clinical Gastroen-
results from the PRECiSE 4 Study. Clin Gastroenterol terology and Hepatology : The Official Clinical Practice
Hepatol 2010;8:696-702 e1. Journal of the American Gastroenterological Association
162. Afif W, Loftus EV, Jr. Safety profile of IBD therapeutics: 2009;7:1202-9, 9 e1.
infectious risks. Med Clin North Am 2010;94:115-33. 178. Tursi A, Brandimarte G, Papa A, et al. Treatment of re-
163. Herrinton LJ, Liu L, Weng X, Lewis JD, Hutfless S, Allison lapsing mild-to-moderate ulcerative colitis with the pro-
JE. Role of Thiopurine and Anti-TNF Therapy in Lympho- biotic VSL#3 as adjunctive to a standard pharmaceutical
ma in Inflammatory Bowel Disease. The American Jour- treatment: a double-blind, randomized, placebo-con-
nal of Gastroenterology 2011;106:2146-53. trolled study. The American Journal of Gastroenterology
164. Kotlyar DS, Osterman MT, Diamond RH, et al. A system- 2010;105:2218-27.
atic review of factors that contribute to hepatosplenic 179. Sandborn WJ, Tremaine WJ, Offord KP, et al. Transder-
T-cell lymphoma in patients with inflammatory bowel dismal nicotine for mildly to moderately active ulcerative
ease. Clin Gastroenterol Hepatol 2011;9:36-41 e1. colitis. A randomized, double-blind, placebo-controlled
165. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for ac- trial. Annals of Internal Medicine 1997;126:364-71.
tive Crohn’s disease. N Engl J Med 2003;348:24-32. 180. McGrath J, McDonald JW, Macdonald JK. Transdermal
166. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab in- nicotine for induction of remission in ulcerative colitis.
duction and maintenance therapy for Crohn’s disease. N Cochrane Database Syst Rev 2004:CD004722.
Engl J Med 2005;353:1912-25. 181. Thomas GA, Rhodes J, Mani V, et al. Transdermal nico-
167. Bloomgren G, Richman S, Hotermans C, et al. Risk of tine as maintenance therapy for ulcerative colitis. N Engl
natalizumab-associated progressive multifocal leukoen- J Med 1995;332:988-92.
cephalopathy. N Engl J Med 2012;366:1870-80. 182. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional
168. Ursing B, Alm T, Barany F, et al. A comparative study of therapy for induction of remission in Crohn’s disease. Co-
metronidazole and sulfasalazine for active Crohn’s dis- chrane Database Syst Rev 2007:CD000542.
ease: the cooperative Crohn’s disease study in Sweden. 183. Takagi S, Utsunomiya K, Kuriyama S, et al. Effectiveness
II. Result. Gastroenterology 1982;83:550-62. of an ‘half elemental diet’ as maintenance therapy for
169. Arnold GL, Beaves MR, Pryjdun VO, Mook WJ. Prelimi- Crohn’s disease: A randomized-controlled trial. Aliment
nary study of ciprofloxacin in active Crohn’s disease. In- Pharm Ther 2006;24:1333-40.
flammatory Bowel Diseases 2002;8:10-5. 184. Harries AD, Jones LA, Danis V, et al. Controlled trial of
170. Greenbloom SL, Steinhart AH, Greenberg GR. Combina- supplemented oral nutrition in Crohn’s disease. Lancet
tion ciprofloxacin and metronidazole for active Crohn’s 1983;1:887-90.
disease. Can J Gastroenterol 1998;12:53-6. 185. Koretz RL, Lipman TO, Klein S. AGA technical review on
171. Khan KJ, Ullman TA, Ford AC, et al. Antibiotic therapy in parenteral nutrition. Gastroenterology 2001;121:970-1001.
inflammatory bowel disease: a systematic review and 186. Stein RB, Lichtenstein GR. Complications after il-
meta-analysis. The American Journal of Gastroenterol- eal pouch-anal anastomosis. Semin Gastrointest Dis
ogy 2011;106:661-73. 2000;11:2-9.
172. Shen B, Achkar JP, Lashner BA, et al. A randomized clini- 187. Navaneethan U, Shen B. Diagnosis and management of
cal trial of ciprofloxacin and metronidazole to treat acute pouchitis and ileoanal pouch dysfunction. Curr Gastroen-
pouchitis. Inflammatory Bowel Diseases 2001;7:301-5. terol Rep 2010;12:485-94.
173. Isaacs KL, Sandler RS, Abreu M, et al. Rifaximin for the 188. Tekkis PP, Heriot AG, Smith O, Smith JJ, Windsor AC,
treatment of active pouchitis: a randomized, double- Nicholls RJ. Long-term outcomes of restorative procto-
blind, placebo-controlled pilot study. Inflammatory Bowel colectomy for Crohn’s disease and indeterminate colitis.
Diseases 2007;13:1250-5. Colorectal Dis 2005;7:218-23.
174. Shen B, Remzi FH, Lopez AR, Queener E. Rifaximin for 189. Sachar DB, Wolfson DM, Greenstein AJ, Goldberg J,
maintenance therapy in antibiotic-dependent pouchitis. Styczynski R, Janowitz HD. Risk factors for postopera-
BMC Gastroenterol 2008;8:26. tive recurrence of Crohn’s disease. Gastroenterology
1983;85:917-21.
190. Sachar DB, Lemmer E, Ibrahim C, et al. Recurrence
patterns after first resection for stricturing or pen-
etrating Crohn’s disease. Inflammatory Bowel Diseases
2009;15:1071-5.
191. Moskovitz D, McLeod RS, Greenberg GR, Cohen Z. Op-
erative and environmental risk factors for recurrence of
Crohn’s disease. Int J Colorectal Dis 1999;14:224-6.
192. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial
of metronidazole treatment for prevention of Crohn’s
recurrence after ileal resection. Gastroenterology
1995;108:1617-21.
193. Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole
for prophylaxis of postoperative Crohn’s disease recur-
rence: a randomized, double-blind, placebo-controlled
trial. Gastroenterology 2005;128:856-61.
194. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postoperative
maintenance of Crohn’s disease remission with 6-mer-
captopurine, mesalamine, or placebo: a 2-year trial. Gas-
troenterology 2004;127:723-9.
195. D’Haens GR, Vermeire S, Van Assche G, et al. Therapy of
metronidazole with azathioprine to prevent postoperative
recurrence of Crohn’s disease: a controlled randomized
trial. Gastroenterology 2008;135:1123-9.
196. Regueiro M, Schraut W, Baidoo L, et al. Infliximab pre-
vents Crohn’s disease recurrence after ileal resection.
Gastroenterology 2009;136:441-50 e1; quiz 716.
CHAPTER 6
Small Bowel Disease
Rupa Mukherjee, MD, and Daniel A. Leffler, MD, MS
Learning Objectives
1. Recognize the typical and atypical presentations of small intestinal diseases.
2. Identify different etiologies for villous atrophy of the small intestine other than celiac disease.
3. Know the risk factors for and presentation of acute and chronic mesenteric ischemia.
4. Review the advantages and limitations of the different diagnostic tests available to diagnose diseases of the small intestine.
Introduction
The small intestine is a complex organ that plays a critical role in the digestion of proteins, lipids and carbo-
hydrates and the absorption of nutrients and minerals. Derangements in the structure and function of the
small intestine can lead to various disease states. In this chapter, we will explore some of the major diseases
ischemic disorders of the small intestine, and other rare conditions.
Celiac Disease
Introduction
-
tion of proline-rich and glutamine-rich gluten protein in wheat, rye and barley in genetically susceptible
individuals.1,2
malabsorptive disorder date back to the second century AD. The hallmark small intestinal lesion of celiac dis-
in 1953.3
Epidemiology
While celiac disease in the past has been diagnosed primarily in Caucasians of Northern European ancestry,
the disease is found in most continents and the prevalence of celiac disease is increasing.3 Recent studies
159
have documented rising prevalence in non-Caucasian of potentially immunogenic epitopes in the small in-
groups, particularly Middle Eastern and North African testine. Tissue transglutaminase or transglutamin-
populations. 4 The prevalence of celiac disease ranges ase 2 (TG2), a ubiquitous intracellular and faculta-
from 1:70 and 1:200 based on antibody screening tive extracellular enzyme that can associate with the
extracellular matrix, plays a central role in disease
the United States and most Western and Middle East- pathogenesis.10 -
ern countries.5 In a recent study that reviewed the dues found in dietary gluten and deamidates them to
prevalence of celiac disease in the United States, the negatively charged glutamic acid residues. The nega-
prevalence was reported to be 0.71% (1:141), rare tively charged gluten peptides are then able to bind
in minority groups and found in 1% of non-Hispanic -
whites. 6 Most individuals with the disease are cur- ing highly immunogenic regions such as a 33mer pep-
rently not diagnosed. Women are diagnosed more
frequently than men.
Th1 T-cell activation. 11 Activation of the T-helper
cells leads to both a cytotoxic T-cell response that is
Genetics manifested histologically as the hallmark enteropa-
thy of celiac disease, and to a humoral B cell response
Interplay of genetic and environmental factors con-
leading to anti-gliadin and auto-antibody production.
tributes to the enteropathy that characterizes celiac
Clinically, there is a variable spectrum of disease pre-
disease. The central role of human leukocyte antigen
sentation ranging from asymptomatic disease to se-
(HLA) class II genes and, to a lesser extent, non-HLA
vere malabsorption.
genes as predisposing hereditary factors has been
validated. The vast majority of patients with celiac
disease carry a variant of HLA-DQ2 (DQ2.5;DQA1*05/
DQB1*02) while the remaining patients carry HLA-
Clinical Categories
DQ8 (DQA1*03/DQB1*0302).7 Less than 1% of pa- Recently, a multidisciplinary task force of sixteen phy-
tients with celiac disease carry other HLA genotypes. sicians from seven countries arrived at a consensus
Recent genome-wide association studies and linkage for celiac disease and related terms, and these are
12
The revised
implicated in celiac disease susceptibility through categories for celiac disease include asymptomatic,
8
classical and potential celiac disease, among other
However, the overall increased genetic risk conveyed -
by these polymorphisms is likely modest, estimated ease includes villous atrophy, symptoms of malab-
at 3% to 4%, compared to 30% to 35% contribution sorption, and the resolution of mucosal lesions and
by HLA-DQ2 and/or HLA-DQ8. 9 symptoms upon complete withdrawal of gluten from
the diet. Earlier data suggested that the severity of
Pathogenesis the severity of clinical symptoms although a more re-

cent study suggests that the degree of histologic dam-
In addition to genetics, environmental factors play an
age and serum antibody titers do, in fact, directly cor-
important role in the pathogenesis of celiac disease.
relate with clinical presentation.13, 14
-
Patients with atypical celiac disease often pres-
tor. Dietary gluten contains a number of distinct T-
ent with anemia, dental enamel defects, osteoporosis,
cell epitopes rich in proline and glutamine residues.
increased transaminases, neurologic symptoms, in-
The high proline content of dietary gluten results in
fertility, arthritis and/or short stature. They usually
peptides that are not easily degraded by gastrointes-
exhibit minimal or no gastrointestinal symptoms.
tinal proteases, leading to an elevated concentration
Patients with asymptomatic celiac disease are
Chapter 6 — Small Bowel Disease 161
often diagnosed incidentally during screening or sec- cally evaluating for the presence of human leukocyte
ondary to evaluation for an associated disorder (type antigens (HLA) DQ2 and/or DQ8 haplotypes. Testing
I diabetes mellitus, autoimmune thyroid disease, os- for celiac disease should ideally occur while patients
teoporosis) with a high risk for celiac disease or due are on a gluten-rich diet, including at least the equiv-
to family history. These patients often have classic alent of two slices of bread per day. Testing begins
with serologic evaluation. Due to high sensitivity and
no clinical symptoms commonly associated with ce-
liac disease. In some cases, a minor symptom such today is IgA anti-tissue transglutaminase (tTG) (98%
as fatigue is recognized only after starting the GFD; in 18
In contrast, the anti-
gliadin (AGA) antibody tests are no longer used due to
subclinical celiac disease as opposed to true asymp-
tomatic disease. AGA test called deamidated gliadin peptide (DGP IgA/
Patients with potential celiac disease have nor- IgG) is now available and has far greater diagnostic
mal small intestinal mucosa but elevated celiac anti- accuracy than the original AGA test (97% sensitivity,
bodies, and this places them at an increased risk for
developing celiac disease in the future. is lower than that of tTG, IgG DGP is the preferred
DGP should be considered for all patients with vil-

Clinical Manifestations lous atrophy and a normal tTG titer at diagnosis. The
anti-endomysial antibody (EMA) is both highly sen-
Celiac disease was classically considered to be a mal-
absorptive disorder of childhood. However, the clas-
sic presentation of diarrhea and weight loss has now
antibody (AGA). Patient who tests positive for either
been replaced largely by non-intestinal or atypical
antibody should be referred for an endoscopy (Table
symptoms, and the disease often presents later in life.
6.1). 18 Serologic testing of all forms is less sensitive
15
The clinical manifestations of celiac disease can
in children who are less than 2 years of age.18 It is
important to note that between 2-5% of patients with
symptoms, extra-intestinal symptoms and subclini-
celiac disease have abnormally low levels of IgA.19 As
cal disease.16,17 Gastrointestinal symptoms include
a result, a total serum IgA level should generally be
diarrhea, steatorrhea, abdominal pain and weight
measured initially in addition to the tTG-IgA. If total
loss. A number of non-intestinal manifestations have
IgA levels are low, an IgG-based assay should be used
also been described. Studies describe an association
to test for celiac disease.
between celiac disease and neuro-psychiatric con-
Another test that can be helpful in evaluation of
ditions such as peripheral neuropathy, headaches,
potential celiac disease is HLA typing. Testing for
-
HLA-DQ2 or HLA-DQ8 is particularly useful in pa-
order and epilepsy. Other non-intestinal manifesta-
disease including osteopenia and osteoporosis, “id-

individuals with a family history of celiac disease but
iopathic” short statue and/or developmental delay,
who are seronegative. HLA-DQ2 or HLA-DQ8 are usu-
dental enamel defects and infertility.16
ally requisite for the development of celiac disease
and it is extremely rare for individuals not carrying
either HLA-DQ2 or HLA-DQ8 to develop celiac dis-
Diagnosis
ease.20 Conversely, these haplotypes are highly preva-
The diagnosis of celiac disease is based on serologic lent, found in approximately 30% of the general pop-
ulation.20 Thus, while the negative predictive value of
- HLA testing approaches 100% the positive predictive
value in most clinical scenarios is less than 30%.

Table 6.1
Patients with positive celiac antibodies while on
Celiac Antibody Assay and HLA Typing: Sensitivity and Specificity
a gluten-containing diet should, with few exceptions,
undergo a biopsy of the small intestine. Exceptions
Sensitivity
Serum Antibody Assay and HLA Specificity (%) include patients with elevated celiac antibodies and
(%) (reported
Typing (reported range) biopsy-proven dermatitis herpetiformis.
range)
Dermatitis herpetiformis (DH) is a chronic, in-
IgA Tissue Transglutaminase (tTG) 98 (78-100) 98 (90-100)
tensely pruritic rash characterized by papulovesicu-
IgA/IgG Deamidated Gliadin Peptide lar eruptions usually distributed symmetrically on ex-
97 (75-99) 95 (87-100)
(DGP) tensor surfaces of the body such as the buttocks, back
Endomysial (EMA) 95 (86-100) 99 (97-100) of the neck, elbows and back of the knees 21 (Figure
IgA Anti-Gliadin Antibody (AGA) 85 (57-100) 90 (47-94) 1). Men and women are equally affected. A connec-
IgG Anti-Gliadin Antibody (AGA) 85 (42-100) 80 (50-94)

celiac disease, was recognized in 1967 although the
HLA-DQ2 and DQ8 Haplotypes >99% 10% exact causal mechanism is unknown. Most patients
with DH have evidence of villous atrophy although
Figure 6.1 not all patients manifest gastrointestinal symptoms.
Dermatitis Herpetiformis (DH) Therefore, any patient diagnosed with DH should be
evaluated for celiac disease by serologic testing. DH
show linear IgA deposition in the dermal papillae. 21

In terms of treatment, dapsone is particularly effec-
tive in treating the cutaneous lesions although it has
no effect on reversing intestinal damage. 22 A strict,
lifelong gluten-free diet must be followed and should
allow for discontinuation of dapsone therapy; the diet
also is possibly protective against the development
of small intestinal lymphoma, for which individuals
with DH are at risk. 22
-
cally described using the Marsh-Oberhuber classi-
23
Adapted from: glutenfreediet.ca atrophy, either complete or partial (Figure 2) with

crypt hyperplasia and increased intraepithelial lym-
phocytes (IELs). These histologic features, although
typical, are not pathognomonic for celiac disease and
are present in a variety of other including tropical
sprue, viral or bacterial infections, common variable
enteropathy (AIE) and medication effect (Table 6.2).24

Other histologic features of celiac disease include
Direct immunofluorescence of skin specimen taken from a patient with DH showing abnormal- appearing enterocytes at the villous tips,
granular-linear deposition of IgA along the dermoepidermal junction. an increase in intraepithelial lymphocytes, a lamina
Adapted from: Van L, Browning John C, Krishnan R et al. Dermatitis herpetiformis: po- -
tential for confusion with linear IgA bullous dermatosis on direct immunofluoresence. phocytes and macrophages, an increase in the size of
Dermatology Online Journal. 14(1):21. the crypts both vertically and horizontally, and an in-
-
of four biopsies should be taken from the second and/ tence or recurrence of signs, symptoms and/or labo-
or third portion of the duodenum and two biopsies ratory abnormalities consistent with active celiac
from the duodenal bulb to maximize the likelihood of disease despite treatment with a gluten-free diet for
detecting villous atrophy.25 at least six months. 28 There are multiple causes of
NRCD. The most common include small intestinal
bacterial overgrowth (SIBO), microscopic colitis, re-
Treatment fractory celiac disease (RCD) and food intolerances.
More rare causes for NRCD include tropical sprue,
The cornerstone of treatment is the complete elimi-
nation of gluten from the diet and from non-dietary
One of the most serious complications of celiac
sources. 26 Patients need to maintain strict, lifelong
disease is refractory celiac disease (RCD). 28 RCD is
adherence to a gluten-free diet (GFD). In conjunction
with the diet, treatment includes counseling with a
villous atrophy on small intestinal biopsies despite
skilled celiac nutritionist particularly for patients
at least six months on a strict gluten-free diet and
with newly-diagnosed disease. The GFD is typically
with no evidence of an alternate etiology of NRCD,
more expensive than a non-gluten-free diet, not read-
as described above. 29 RCD occurs in approximately
ily available in many countries, and often of limited
1% of celiac patients and is subdivided into two sub-
groups, type I RCD and type II RCD. Cellier and col-
adherence and patient quality of life. Even with strict
leagues showed that patients with type I RCD have
adherence to the diet, some patients can have pro-
normal surface T cell receptor, CD3 and CD4 or CD8
gressive or unresponsive disease that requires com-
expression by intraepithelial lymphocytes (IELs)
bination therapy for management. Other important
with a polyclonal pattern on T cell receptor gene re-
aspects in the management of celiac disease include
arrangement studies. Patients with type II RCD dem-
bone loss with surveillance bone mineral density

scans and pneumococcal vaccination given the asso- Table 6.2
ciation of celiac disease with hyposplenism. It is im- Etiologies for Villous Atrophy
portant to monitor response to the diet with periodic
antibody testing and, in some cases, with follow-up Etiologies for Villous Flattening
small intestinal biopsy particularly in cases concern-
Celiac Disease
ing for progressive or nonresponsive celiac disease
(discussed further below). In these cases, patients Refractory Celiac Disease
may require treatment with corticosteroids or other Autoimmune Enteropathy
immunosuppressive agents including azathioprine Collagenous Sprue
27
It is important to remember that if a
Eosinophilic Enteritis
patient does not respond to the GFD clinically or con-
tinues to have elevated celiac antibodies, the most Lymphocytic Enterocolitis
likely cause is lack of adherence to the diet and/or Common Variable Immunodeficiency Syndrome (CVID)
Tropical Sprue
of diagnosis and treatment of patients with subclini-
cal celiac disease are largely unknown. Duodenal Crohn's Disease
Up to 30% of patients with celiac disease either Gastrinoma
fail to fully improve on a gluten-free diet or have re- Drugs: Olmesartan, Non-steroidal Anti-inflammatory Drugs
current signs and symptoms of celiac disease after (NSAIDs)
initial improvement. These patients are categorized
Infection: Giardiasis, Bacterial Overgrowth
as having nonresponsive celiac disease (NRCD).
onstrate a loss of surface T cell receptor, CD3 and CD8

expression and may have a monoclonal T cell recep- affect results in subgroup analysis. 28 Patients with
tor gene rearrangement.29 Distinguishing between type II RCD who do not respond to steroid therapy
the two RCD subgroups is critical since type II RCD typically require more aggressive treatment with im-
munosuppressants such as 6-MP and azathioprine. 29
mortality as well as the development of lymphoma, In those patients who fail conventional immunosup-
pressants, various immune targeted therapies have
(EATL) whereas type I RCD has no association with
malignancy and carries a favorable prognosis.
The treatment strategy for each subgroup also Cladribine, a synthetic purine nucleoside homologue,
- has been studied in an open-label, prospective cohort
lines for either RCD I or RCD II. Patients with type I study of thirty-two patients with RCD II. 29 Eighteen
RCD have been treated with oral corticosteroids, spe- patients responded favorably to Cladribine with in-
28
Another -
agent that has been studied in a small pilot study of pared to unresponsive patients. However, sixteen
ten patients with type I RCD is mesalamine. 28 In this RCD II patients progressed to EATL despite therapy
study, 5 out of 10 patients had a complete response and all sixteen patients died. Autologous hemato-
while 1 patient had a partial response on mesalamine; poietic stem cell transplantation (auto-SCT) has also
been evaluated in patients unresponsive to cladribine
Figure 6.2 treatment and holds some promise.
Celiac Disease While the GFD remains the only available treat-
ment for celiac disease, based on our current under-
standing of celiac disease pathogenesis, there are
several potential non-dietary targets for therapeutic
intervention. These targets can be categorized in the
-
and oral proteases, intraluminal therapies such as

gluten-sequestering polymers and/or neutralizing
gluten antibodies, agents involved with gluten toler-
ization and immune modulation such as a gluten vac-
that
can induce mucosal tolerance and agents that modu-
late intestinal permeability such as the zonulin recep-
tor antagonist, larazotide acetate.26,30 Other thera-
peutic targets that are currently being explored can
down regulate theeadaptive immune response such
as inhibitors of tissue transglutaminase 2 and HLA-
DQ2 inhibitors. These agents are in various stages of
clinical testing.
Top Panel: Small intestinal biopsy with Marsh IIIb sub-total villous
atrophy; Bottom Panel: Small intestinal biopsy with Marsh IIIc total
Medication-Induced Enteropathy
villous atrophy
Courtesy of Dr. Robert Najarian, Department of Pathology and Labora- As described above, there are various etiologies for
tory Medicine, Beth Israel Deaconess Medical Center, Boston, MA enteropathy other than celiac disease. Medication-
USA
induced enteropathy is becoming increasingly rec-
ognized. Two particular agents have been associated in the early 1980s described a familial syndrome of
with a severe, sprue-like enteropathy - non-steroidal intractable diarrhea in infants who also had autoim-
- mune diseases such as type I diabetes mellitus, thy-
tensin II receptor antagonist, olmesartan. The ad- roiditis, and hemolytic anemia. 34
verse effects of NSAIDs on the upper gastrointestinal
tract have been well documented. Data suggest that
NSAIDs can also be harmful to the small intestine. In Epidemiology
addition to causing diaphragm-like strictures (Figure
Much of the epidemiological data comes from the
6.3), ulcerations, perforations and diarrhea, NSAID
pediatric population. In two European multi-center
use can lead to villous atrophy. 31 The prevalence of
studies, 25-29% infants with intractable diarrhea
NSAID-induced enteropathy is unknown, limited
were diagnosed with AIE. 35, 36 The largest case se-
mostly to case series and case reports. The pathogen-
ries on adult AIE comes from the Mayo Clinic. In this
esis of this condition is likely multifactorial. Olmes-
study, the median age of patients with AIE was 55
artan was recently discovered as the cause of a previ-
years (range, 42-67 years), 87% were Caucasian and
ously unexplained severe enteropathy in a case series
47% were female. 80% of the patients had a predis-
of 22 patients seen at the Mayo Clinic with explained
position to autoimmune diseases as indicated by the
chronic diarrhea and enteropathy while taking olmes-
presence of circulating autoantibodies.33
artan for hypertension. 32 Celiac disease was excluded
in all patients. Intestinal biopsies showed villous at-
Pathogenesis
in 15 patients, and marked subepithelial collagen de-
position was noted in 7 patients. Tissue transgluta- The pathophysiology of AIE is characterized by im-
minase antibodies were not detected in any patient, mune dysregulation. The majority of patients have
and no patient improved clinically on a gluten-free circulating anti-enterocyte antibodies, fewer patients
diet. Clinical response was seen in all 22 patients and have anti-goblet cell antibodies, suggesting an impor-
histologic recovery in all 18 patients who underwent tant role for the humoral immune system in disease
follow-up biopsies upon discontinuation of olmesar- pathogenesis.37 In the Mayo clinic experience, 93%
tan. 32 Medications should therefore be considered as of the patients had evidence of gut epithelial cell anti-
a potential etiology of enteropathy in all patients lack-
Figure 6.3
ing elevated celiac serologic markers.
NSAID-induced Small Intestinal Diaphragm-like Stricture
Autoimmune Enteropathy (AIE)
Introduction
Autoimmune enteropathy is a rare disorder charac-
terized by severe diarrhea, weight loss secondary to
malabsorption, villous atrophy of the small intestinal
mucosa and the presence of autoantibodies, primar-
ily, anti-enterocyte and anti-goblet cell antibodies. 33
AIE is generally a pediatric condition and often occurs
described in the late 1970s, and further case reports Adapted from: uptodate.com
bodies. However, the presence of these autoantibod- possible triggers such as viral diseases, type of diar-
rhea since secretory diarrhea as opposed to osmotic
other diseases such as HIV, allergic enteropathy and is characteristic of AIE. The cornerstone of diagnosis
- -
ence cannot be used to establish a diagnosis of AIE.37, ings include variable degrees of villous atrophy, lym-
38
Patients with AIE may also have other autoanti-
bodies including anti-nuclear, anti-smooth, gastric a relative paucity of surface lymphocytosis (<40 lym-
parietal antibodies and thyroglobulin. In general, it -
- bers of crypt apoptotic bodies (Figure 6.4).33 T-cell
rial or viral in nature, elicit an immune response that receptor gene rearrangements studies are usually
alters intestinal permeability leading to the clinical
sequelae of AIE.34 of both plasma cells and lymphocytes. Crypt abscess-
es are found in severe cases. Moreover, there is an
absence of goblet and Paneth cells.33 Unlike celiac
Clinical disease, there are fewer numbers of intraepithelial
lymphocytes. In addition, patients with AIE generally
The predominant feature in AIE is severe, intractable
do not respond to the GFD. 33
secretory diarrhea often requiring total parental nu-
The original diagnostic criteria for AIE were
trition. Severe malabsorption leads to weight loss
proposed by Unsworth and Walker-Smith, two pedi-
and growth failure, particularly in children.34 Dis-
atric gastroenterologists, in the early 1980s.40 Their
ease severity is largely determined by the extent of
criteria included ongoing diarrhea with severe en-
small bowel involvement. It has been reported that
teropathy and small intestinal villous atrophy; no
AIE could be a manifestation of a more diffuse auto-
response to exclusion diets including a gluten-free
immune disorder of the gastrointestinal tract char-
diet; predisposition to autoimmune diseases—pres-
acterized by gastritis, colitis, pancreatitis and hepa-
ence of circulating anti-enterocyte and/or anti-goblet
titis.39 AIE can also have extra-intestinal involvement
cell antibodies or associated autoimmune disease; no
which includes thyroid disease, interstitial nephritis, 40
rheumatoid arthritis and interstitial pneumopathy.
More recently, the Mayo group has published a set of
There are two severe variants of AIE, the IPEX (im-
diagnostic criteria based on their case series of adult
mune dysregulation, polyendocrinopathy, enteropa-
-
thy, x-linked) syndrome and APECED (autoimmune
-
polyendocrinopathy-candidiasis-ectodermal dystro-
though the presence of autoantibodies is supportive
phy) syndrome.34 IPEX syndrome is a severe form of
of a diagnosis of AIE, their absence does not exclude
AIE with polyendocrinopathies (type I diabetes mel-
the diagnosis.33
litus and skin manifestations). In the APECED syn-
-
ciencies, mucocutaneous candidiasis and ectodermal
dystrophy. The syndrome is more commonly seen in
Treatment
Finnish, Sardinian and Iranian Jewish populations.39 The guiding principle of therapy is supportive care
with adequate hydration and nutritional support—
an elemental diet for moderate cases and total par-
Diagnosis enteral nutrition for more severe cases. Immunosup-
pressive therapy with corticosteroids (budesonide
AIE should be considered in patients, particularly 37
In
infants, presenting with severe diarrhea requiring
steroid-refractory patients, other immunosuppres-
parenteral nutrition. As part of the diagnostic work-
sive agents such as cyclosporine, tacrolimus, myco-
up, it is important to ascertain the timing of diarrhea,
phenolate mofetil and azathioprine/6-MP have been
used successfully.33,34,41,42 There are also case reports ry of this disease is more prolonged that previously
thought. There are no clear gender differences. In
pediatric and adult cases unresponsive to classic im- one case series of ten patients with refractory/un-
munosuppressive therapy.41,43 The Mayo study found
that 93% of patients required immunosuppressive collagenous sprue. 47
therapy. 60% of patients had a complete clinical re-
sponse after 1-8 weeks of steroid therapy although
66% of these patients ultimately become steroid- Pathogenesis
dependent or refractory and required additional
It has been reported that increased collagen I syn-
immunomodulation for maintenance of remission.
Only 1 of 15 patients remained in long-term clinical
the main pathophysiologic mechanism leading to the
remission (>1 year) on low dose prednisone (5mg/
deposition of a subepithelial band of collagen that is
day) without requiring additional immunosuppres-
pathognomonic for collagenous sprue. Daum and col-
leagues showed that tissue from small intestinal biop-
remission in two patients.
sies of patients with collagenous sprue have increased
mRNA expression of collagen I, slightly increased
mRNA expression of tissue inhibitor of metallopro-
Collagenous Sprue teinases (TIMP-1) without similarly increased mRNA
expression of matrix metalloproteinases (MMP).48
The normal width of the collagen band in the small
Introduction intestine is 5-7 m whereas in collagenous sprue, the
collagen band can be of variable thickness (7-80 m)
Collagenous sprue is a rare disease of the small intes-
histologically in 1970. 44 In 1970, Weinstein and col- Table 6.3

leagues described a disease of the small intestine that Diagnostic Criteria for Autoimmune Enteropathy
is refractory to the GFD and characterized by villous
atrophy with the presence of distinct subepithelial, Proposed Diagnostic Criteria for Adult AIE*
eosinophilic hyaline deposits of collagen primarily in 1. Adult-onset chronic diarrhea (>6 weeks' duration)
the small intestine as well as the stomach and colon.
2. Malabsorption
44
Clinical features include severe diarrhea, progres-
sive weight loss, severe malabsorption and occasion- 3. Specific Small Bowel Histology:
ally abdominal pain when associated with a vasculi-
Partial/complete villous blunting
tis.45 Fourteen cases of collagenous colitis have been
described in association with collagenous sprue. It is Deep crypt lymphocytosis
known that both celiac disease and collagenous sprue
are associated with collagenous colitis.46 The pre- Increased crypt apoptotic bodies
vailing opinion is that collagenous sprue is a distinct Minimal intraepithelial lymphocytosis
clinical and pathologic disease, entirely separate from
celiac disease. 4. Exclusion of other causes of villous flattening
5. Anti-enterocyte and/or anti-goblet cell antibodies
Epidemiology Note: Criteria 1-4 are required for a definite diagnosis of AIE. The presence of anti-
enterocyte and/or anti-goblet cell antibodies is supportive of a diagnosis of AIE but
Given the rarity of this disorder, little is known about their absence does not exclude the diagnosis.
its epidemiology. There are case reports of diagno- *Adapted from: Akram et al. Adult autoimmune enteropathy: Mayo Clinic Rochester
sis during infancy suggesting that the natural histo- Experience. Clin Gastroenterol Hepatol. 2007;5:1282-1290.
in the proximal small intestine.46 The commonly ac- “dirty” owing to the incorporation of capillaries and
cepted cutoff width for the collagen band is greater numerous stromal cells.46
than 10 m. The abnormal morphology of the subepi-
thelial collagen band is an important identifying his-
Clinical
an irregular and jagged interface with the lamina pro-
pria. In addition, the collagen has been described as
persistent diarrhea with severe malabsorption re-
-
Figure 6.4 sive weight loss to the gluten-free diet.
Autoimmune Enteropathy (AIE) -
liac antibodies and evidence of vitamin and nutrient
49
Diagnosis
-
-
-
rophy and a clear-cut layer of subepithelial collagen
(>10 m) that extends into the lamina propria (Figure
6
sprue are refractory to the gluten-free diet. 50
Treatment
sprue. A thorough investigation of the diet should be

undertaken to exclude any unusual allergens as the
source of refractory sprue. As a trial, gluten may be re-
stricted from the diet, although patients with collage-
nous sprue are partially or totally unresponsive to the
GFD. For pharmacologic therapy, data generally show
favorable response using long-term, high dose corti-
costeroids although the dosing, duration and taper-
Top and middle panels*: Biopsy of the small intestine with marked villous blunting ing of steroids remain empirical. Budesonide is par-
and crypt hyperplasia without intraepithelial lymphocytosis. Goblet and Paneth cells ticularly useful in mild to moderate cases. In severe
are markedly decreased. cases, as with refractory celiac disease, a combination
Bottom panel**: At higher power, there is surface epithelial injury with disruption of nutrition support, steroids and immunosuppressive
of the brush border (arrow) and intense neutrophilic inflammation including crypt therapy such as azathioprine, 6-mercaptopurine (6-
abscesses (asterisk). There is no abnormal lymphocytosis in the surface epithelium. MP), cyclosporine or anti-tumor necrosis factor (TNF)
agents may be useful but lack clinical trials. Small in-
*Courtesy of Dr. Robert Najarian, Department of Pathology and Laboratory Medicine,
Beth Israel Deaconess Medical Center, Boston, MA USA testinal transplant may be indicated in patients with
**Adapted from: Akram et al. Adult autoimmune enteropathy: Mayo Clinic Rochester collagenous sprue refractory to immunosuppressives
experience. Clin Gastroenterol Hepatol. 2007;5:1282-1290. with ongoing severe malnutrition. 51,52
an acute diarrheal illness similar to infectious enteri-

Tropical Sprue tis frequently precedes the development of tropical
sprue; India, which has a high prevalence of this dis-
ease, frequently has epidemics affecting households
Introduction and communities; small bowel bacterial overgrowth
Tropical sprue is a chronic diarrheal illness of the has been diagnosed in patients with tropical sprue;
small intestine of unknown etiology characterized and antibiotics are generally effective treatment. Ad-
ditional factors that are believed to play a role include
intestinal mucosal abnormalities.53 A number of ob- genetic susceptibility, local environment, and dietary
servations support a possible infectious etiology for practices.
were described in Barbados by Hilary in 1759.

Clinical
Tropical sprue should be considered in patients with
Epidemiology chronic diarrhea and nutrient malabsorption who
Tropical sprue, as the name suggests, occurs predom- have spent at least one month in the tropics or an area
inantly in the tropics and subtropics although not in where tropical sprue is endemic. Steatorrhea with up
all countries in this geographic region are affected. to 10 grams to 40 grams of stool fat per day is a com-
It is predominantly present in the Caribbean and
southern and southeast Asia, less commonly in Africa and abdominal discomfort are also seen. Megaloblas-
or the Middle East and rarely in the U.S. 54 Within a tic anemia, glossitis, dermatitis, peripheral neuropa-
country, disease presentation can vary, for example, thy, osteopenia and hypoalbuminemia characterize
tropical sprue is milder in northern India compared severe cases of tropical sprue related to malabsorp-
with southern India. 53 The disease affects indigenous
populations and visitors who stay for more than a
Figure 6.5
month, but is seldom seen in visitors who visit an en-
Collagenous Sprue
demic area for less than two weeks. In two carefully
studied populations, 5% to 13% of North Americans
living in Puerto Rico for 6 months or longer experi-
enced symptoms of tropical sprue. Expatriates from
the United States who return from the tropics or oth-
er areas endemic for tropical sprue can experience
symptoms of tropical sprue more than 10 years after
their return.55 This form of tropical sprue is called
latent sprue.
Pathogenesis
The exact pathogenesis of tropical sprue is unknown
although the leading theory is that infection with re-
sultant bacterial overgrowth of the small intestine
leads to disturbed motility, malabsorption and muco- Duodenal biopsy with near total villous atrophy and prominent subepithelial collagen
sal damage secondary to bacterial toxin production layer
and fermentation products.56 The microbial nature Courtesy of Dr. Robert Najarian, Department of Pathology and Laboratory Medicine,
of the disease is based on the following observations: Beth Israel Deaconess Medical Center, Boston, MA USA
- mg qid) for three to six months.60 An alternative to

53,57
tetracycline is doxycycline (100 mg bid) also taken
The symptoms of tropical sprue can be severe with for 3-6 months. The symptomatic response to folate
mortality in excess of 20% reported in acute cases replacement therapy can be dramatic with rapid
in southern India.58 - improvement in weight gain and megaloblastic ane-
12
with mia. Unfortunately, folate has variable effects on
resultant megaloblastic anemia. Neurologic mani- diarrhea, and up to 50% of patients treated with
festations and subacute combined degeneration of folate alone have persistent small intestinal dam-
the spinal cord secondary to vitamin B12 age. Patients with coexisting vitamin B12
are rare.53 Interestingly, vitamin B12 may require intramuscular B12 injections to reverse
- the megaloblastic anemia. In children and pregnant
bean while the reverse is true in India and southeast women in whom tetracyclines are contraindicated,
treatment with poorly-absorbed sulfonamide drugs
in the course of the disease while vitamin B12 - such as sulphaguanidine, succinylsulfathiazole,
ciency manifests later with more progressive dis- phthalylsulfacetamide or phthalylsulfathiazole are
ease and involvement of the terminal ileum. an option.61 The duration of therapy should be guid-
ed by improvement in symptoms and clinical indices
such as diarrhea, steatorrhea and anemia. Despite
Diagnosis antibiotic therapy, relapses or re-infection can occur
in up to 20% of patients living in the tropics.
-
agnostic for tropical sprue in patients with a compat-
ible clinical presentation and travel history who have
negative stool studies for infection and negative celi- Whipple’s Disease
-
tory cells (lymphocytes, plasma cells, eosinophils Introduction
Whipple’s disease is a multi-system chronic infec-
not unique to tropical sprue.59 In contrast, the vil-
tion with that -
lous blunting seen in celiac disease tends to be more
scribed by George Hoyt Whipple in 1907. Classically,
severe with complete or near complete absence of
Whipple’s disease affects the gastrointestinal tract,
villi. On laboratory evaluation, folate and vitamin
the joints and/or the central nervous system.62 Al-
B12
though the bacterium is ubiquitous in the environ-
usually seen 3-4 months after disease onset. Pancy-
ment and in healthy carriers, the disease is very rare
topenia may occur in the setting of long-standing vi-
with an estimated incidence of 1/1,000,000. This
tamin B12
suggests that an underlying genetic predisposition
include hypoalbuminemia that accompanies severe,
to the infection exists and, in fact, subtle defects in
chronic disease due to malabsorption and protein-
cell-mediated immunity have been reported. 63
hypocalcemia. The d-xylose test, a measure of small

intestinal absorptive capacity, is usually abnormal.
Epidemiology
The disease has a predilection for Caucasian males
Treatment with a mean age of 49-55 years at diagnosis who
have occupational exposure to soil or animals; the
The mainstay of treatment is folic acid (5 mg qd)
agent has been found in wastewaters in rural com-
supplementation with or without tetracycline (250
munities suggesting an agricultural origin. An HLA-
- positive macrophages in the lamina propria of small

netic risk factor.
64
Late onset Whipple’s disease is intestinal biopsies (Figure 6.6).66 Other histologic
extremely rare.
PAS-positive macrophages as well as lymphatic dila-
Pathogenesis
in the appropriate clinical setting, from histologic
The pathogenesis of the disease is unclear. Patients
complex disease in which PAS-
can be asymptomatic carriers and also have self-lim-
positive macrophages are also found. Staining for
iting primary infections.62 In the absence of clas-
acid-fast bacilli should differentiate between the
sical symptoms which include diarrhea and arthral-
two diseases. There has been an increased recog-
gias, the most frequent manifestation of
nition of Whipple’s disease in patients without in-
is endocarditis.65 Interestingly, the bacteria can be
testinal symptoms since the advent of polymerase
present widespread throughout the body with little
chain reaction (PCR) techniques that identify the
-
unique 16S ribosomal RNA of .68,69 The
totoxic effect upon host cells. Accurate diagnosis is
use of PCR on CSF samples has been especially im-
imperative because mortality approaches 100% in
portant given that some patients with CNS involve-
cases of disseminated or CNS disease without timely
ment may be asymptomatic. Of note, the CSF should
antibiotic treatment.
be sampled and tested in all patients with presumed
Clinical Table 6.4

Most Common Symptoms of Classical Whipple’s Disease
In predisposed patients, the major manifestations
of classical Whipple’s disease are diarrhea and ar-
thralgias. The arthralgias frequently occur before Symptom Occurrence
the onset of intestinal symptoms. Other cardinal
manifestations include weight loss and abdomi- Weight Loss 90%
nal pain (Table 4). Diarrhea and weight loss
can progress to a severe wasting syndrome result- Hypoalbuminemia 90%
ing in abdominal distension secondary to ascites.66
Diarrhea 80%
hyperpigmentation, steatorrhea and lymphadeon- Arthralgia 80%

pathy.56 Central nervous system involvement can
occur in 10-40% of patients. Headaches and cogni- Anemia 80%
tive dysfunction are the most common abnormali-
ties in patients with central nervous system (CNS) Lymphadenopathy 55%
involvement. Occasionally, intestinal symptoms can
be absent despite the presence of CNS involvement. Abdominal Pain 45%
Skin Hyperpigmentation 40%

(CSF) affects roughly 50% of patients. Cardiac and
pulmonary involvement have also been reported.61 Fever 35%
Neurological Signs 30%

Diagnosis
Adapted from: Moos et al. Changing paradigms in Whipple’s disease
The diagnosis of Whipple’s disease is based on and infection with T. whipplei. Eur J Clin Microbiol Infect Dis.
identifying the classic periodic acid–Schiff (PAS)– 2011;30:1151-1158.
Whipple’s disease before the start of antibiotic treat-

ment. A negative CSF-PCR test may predict a low 1952. Since then, the mainstay of therapy had been
likelihood of clinical relapse.69 A brain biopsy is tetracycline until it was discovered that single agent
rarely required to make the diagnosis of Whipple’s tetracycline led to a relapse rate of 35% along with
disease with CNS involvement. PCR can also be per- CNS relapse.62 Better results were achieved with a
formed on saliva and stool specimens for screening combination of high dose penicillin with strepto-
since the detection of the organism in either sample mycin or trimethoprim-sulfamethoxazole (TMP-
is highly predictive of classical Whipple’s disease.70 SMX). The current regimen includes TMP-SMX (one
It is important to emphasize that PCR results should double-strength tablet b.i.d.) for at least 1 year.62,71
be interpreted in the appropriate clinical setting The treatment regimen for severely ill patients, re-
since a number of individuals are asymptomatic car- ported in the only randomized, prospective trial to
riers. Other diagnostic techniques include the use of date, includes an initial phase of IV induction with
immunohistochemistry, particularly in PAS-negative antibiotics that penetrate the blood-brain barrier
tissue. Fluorescence in-situ hybridization (FISH) such as Ceftriaxone or Meropenem for two weeks
has also been used, mostly limited to research labo- followed by TMP-SMX for twelve months.72 Data
ratories, and is helpful in distinguishing contamina- suggest that the IV induction phase is critical since
tion from true infection.62 patients treated with TMP-SMX monotherapy had a
poorer prognosis.
Another key point is that only the SMX compo-
Treatment nent of TMP-SMX is effective since lacks
the target of TMP. As a result, alternative regimens
Whipple’s disease was considered to be a fatal illness
have been proposed for patients with SMX resis-
prior to the discovery of antibiotics. Chlorampheni-
tance. These include doxycycline (200 mg/day)
with hydroxychloroquine (600 mg/day).73 It is
Figure 6.6
critical to check the CSF for in cases of
Whipple’s Disease
CNS involvement since oral TMP-SMX has to be add-
ed to the regimen until the CSF-PCR turns negative
owing to doxycycline’s poor CSF penetration. One
of the major concerns of treatment is CNS relapse
on antibiotic treatment. One case report describes
Whipple’s disease.74 The rationale for this approach
been detected in patients with Whipple’s disease

and, therefore, supplementation with this inter-
feron could be helpful. Up to 50% of patients may
contain the characteristic macrophages of Whipple’s
disease or PCR-positive material in their CSF in the
absence of CNS symptoms; the positive PCR may in-
dicate remnants of bacterial DNA or colonization.62
In terms of follow-up, the most important criterion
is clinical improvement which should occur rapid-
Duodenal biopsy from a patient with Whipple’s disease. Numerous PAS-positive,
intensely red staining macrophages distend the villi and indicate the presence of T. treatment of intestinal symptoms can be monitored
whipplei.
Adapted from: Moos et al. Changing paradigms in Whipple’s disease and infection histologically; PAS staining may remain positive for
with Tropheryma whipplei. Eur J Clin Microbiol Infect Dis. 2011;30:1151-58. years despite histologic improvement.
Small Intestinal Bacterial disease and poorly reproducible. An alternative, non-

Overgrowth (SIBO) invasive technique is breath testing to detect radio-
labeled carbon, hydrogen or methane which is ex-
pelled in response to a fermentable substrate such as
Introduction glucose or lactulose. Classically, the lactulose hydro-
gen breath test is considered positive for SIBO when
Small intestinal bacterial overgrowth (SIBO) occurs
two distinct hydrogen peaks are measured, an early
when an abnormality in the gastrointestinal anatomy
peak representing abnormal small-intestinal bacteria
or altered motility leads to the overgrowth of bacte- 75
An elevated
ria (mostly coliform organisms) in the upper small
hydrogen peak can range from 10 parts per million
intestine.75 There are numerous etiologies for this
(PPM) to 20PPM. Breath testing is not standardized
condition. The most common causes are diabetes, ce-
-
liac disease, irritable bowel syndrome, scleroderma,
ing on the test that is used. Given these diagnostic
intestinal diverticulosis, afferent loop following a Bill-
pitfalls, some have advocated that a diagnosis of SIBO
roth II gastrojejunostomy, and intestinal obstruction
should include clinical response after treatment – a
caused by strictures, adhesions, or cancer. These con-
“test, treat and outcome” approach in addition to a
ditions may be present for years before the develop-
positive breath test.80
ment of symptoms.
Treatment
Clinical
-
disease or surgical defect such as a stricture, afferent
lar to other malabsorptive conditions and include
diarrhea, occasionally constipation, steatorrhea, gas,
surgical option is not feasible, then antibiotics are in-
bloating, and abdominal pain with resultant weight
dicated. The goal of therapy is to reduce but not com-
-
pletely eradicate the burden of bacteria to achieve
cies, particularly vitamin B12
symptomatic improvement. Rifaximin (1650mg dai-
causes for B12
to bacteria,76,77 bacterial metabolism of the vitamin to
line therapy as there is less clinical resistance with
metabolically ineffective metabolites and internaliza-
this agent than with other antibiotics such as doxycy-
tion of the B12 by the bacteria for their own metabolic 81,82
uses. Folic acid levels are usually high secondary to
Metronidazole combined with a cephalosporin and
bacterial production of folate.78 Serum albumin levels
single agent neomycin have also been tried. In a ran-
may be low secondary to protein-losing enteropathy
domized, controlled trial comparing rifaximin to met-
and remain low for months after adequate treatment.
ronidazole, 142 patients with SIBO were randomized
to seven days of rifaximin (1200mg/day) or metroni-
dazole (750 mg/day). The patients treated with rifax-
Diagnosis imin achieved higher glucose breath normalization
One of the main challenges in diagnosing SIBO is that rates at one month compared to the metronidazole
group (63.4% versus 43.7%).83 In terms of treatment
standard is to obtain a jejunal aspirate. A jejunal cul- duration, a 7-10 day course of antibiotics is usually
ture >105 colony-forming units per milliliter (CFU/
ml) of bacteria is generally considered diagnostic.79 of probiotics, and these are currently not routinely
However, jejunal culture is rarely performed in clini- recommended.84 In terms of dietary changes, diets
should aim to reduce the non-absorbable carbohy-
drate content so that they are not a source of nutrition many patients have a history of seasonal allergies,
for the bacteria. In general, a higher fat, low carbohy- food sensitivities, eczema, asthma, atopy and elevat-
ed serum IgE levels suggesting that a hypersensitiv-
can develop along with SIBO, a trial of a low lactose ity response may play a key pathogenic role.88 Once
diet may be considered. Recurrence is common after eosinophils are activated, they can produce cytokines
treatment and may require longer course of therapy that self-perpetuate the accumulation of additional
or rotating antibiotic regimens. Severe cases of SIBO eosinophils. These cytokines are interleukin (IL)-3,
can mimic ileitis or enteritis so in patients with ane- IL-5, and granulocyte-macrophage colony-stimulat-
needs to be excluded.85 in eosinophils of patients with eosinophilic enteritis

but not in control subjects.89
Infiltrative Diseases
Clinical
Eosinophilic enteritis can present with a wide spec-
Eosinophilic Enteritis trum of GI involvement. Symptoms can be chronic
and debilitating in nature depending on the site and
layer that is involved. Mucosal disease, which is the
most common subtype (25-100% cases), common-
Introduction
ly presents with guaiac positive stool, anemia and
Eosinophilic enteritis is a rare disorder characterized weight loss secondary to malabsorption and/or pro-
tein-losing enteropathy. Involvement of the muscu-
the absence of eosinophilic involvement of extra-GI laris mucosae (13-70%) frequently presents as small
organs and the exclusion of other known causes for bowel obstruction. Sub-serosal disease (12-40%) of-
eosinophilia such as drug reaction, parasitic infection ten manifests as eosinophilic ascites.87 Eosinophilic
or malignancy.86 Eosinophilic enteritis can present enteritis can also present as obstructive jaundice
with a wide array of GI manifestations depending on and mimic appendicitis and pancreatic cancer. Ex-
the extent of involvement and the layer of gastrointes- traintestinal manifestations have also been reported
tinal wall that is involved. and these include eosinophilic cystitis, splenitis and
hepatitis. In general, the prognosis for this condition
is good. Some patients can progress to severe malab-
Epidemiology sorption and malnutrition while others recover spon-
Although a rare disorder, more than 280 cases have taneously.
been reported worldwide since the initial description
by Kaijser in 1937.87 The disease affects both adults
and children. It occurs predominantly in Caucasians Diagnosis
with some cases reported in Asians. A slight male The diagnosis of eosinophilic enteritis is made by en-
predominance has been reported. The disease can af- doscopic mucosal biopsies which typically show >20
fect all age groups although the majority of patients -
present in the 3rd to 5th decades.88 croscopic examination. (Figure 6.7) Biopsies should
90
be taken from both normal and abnormal-appearing

mucosa since even normal-appearing mucosa can
Pathogenesis
The etiology and pathogenesis of this disease are not multiple biopsies (minimum 4-5) should be taken
well understood although it has been observed that from different sites throughout the small intestine
including areas with visible abnormalities such as

nodularity and/or erythema to minimize sampling
Mastocytosis
error.91 -
able, ulcerated mucosa. In cases of severe disease,
87
there is complete loss of villi, submucosal edema and Introduction

According to the 2008 World Health Organization
-
ing. Patients with suspicion for sub-serosal disease -
should have an abdominal paracentesis performed to eloproliferative neoplasm. Systemic mastocytosis
97
demonstrate the presence of eosinophilic ascites. 87 results from the clonal proliferation of abnormal mast
The exclusion of parasitic infections, malignancy and cells that accumulate in one or more extracutaneous
other extraintestinal disease should be performed organs.98 Systemic mastocytosis involves the bone
but is not necessary to the diagnosis. marrow, liver, spleen, lymph nodes, and/or gastroin-
testinal tract with or without cutaneous lesions. The
cutaneous variant occurs primarily in the pediatric
Treatment population.99
The treatment of eosinophilic enteritis is largely em-
pirical as there have been no prospective, randomized
clinical trials studying different treatment options. Epidemiology
Most patients with mild disease respond to conserva- Systemic mastocytosis is rare and is usually diag-
tive management. Patients with more severe disease nosed after the second decade of life. Much of the epi-
often require aggressive therapy such as corticoste- demiologic data is based on a retrospective review of
roids and/or other immunosuppressive agents. In 342 adult patients with systemic mastocytosis seen at
general, corticosteroids including budesonide are the Mayo Clinic between 1976-2007.100 In this study,
the mainstay of treatment in both adults and chil-
dren.92 The dose and duration are guided by clini- Figure 6.7
cal judgment but most patients require daily dosing, Eosinophilic Gastritis
and improvement can be seen within two weeks re-
gardless of site or layer of bowel wall that is involved.
Other agents that are effective in some cases include
antihistamine and mast cell stabilizing agents, and
anti-allergy medications that suppress cytokine pro-
duction.93 A few case reports have documented the
use of montelukast (selective leukotriene receptor
antagonist) in both adults and children with good re-
sults.94 In terms of steroid-sparing immunosuppres-
sive medications, azathioprine has been studied with
promising results. One small study evaluated the use
of a humanized, anti-interleukin 5 (IL-5) antibody in
patients who are refractory to other treatments with
encouraging results.95 Diet elimination therapy may
-
Biopsy from stomach with numerous eosinophils.
the use of this diet.96 In general, surgery should be
avoided unless it is needed to treat symptoms second- Courtesy of Dr. Jeffrey Goldsmith and Dr. Robert Najarian, Department of Pathology
and Laboratory Medicine, Beth Israel Deaconess Medical Center, Boston, MA USA
ary to perforation and/or small bowel obstruction.
55% of patients were male with a median age of 57 markers CD2 and/or CD25, which may be detected by
(range, 19-87). The median time to diagnosis from 97
symptom onset was 33 months (range, 0-516).100
Clinical
Pathogenesis The prevalence of gastrointestinal symptoms in sys-
Mastocytosis is frequently associated with a gain- temic mastocytosis ranges from 14-85%. The most
of-function somatic mutation within the type III re- common symptom is abdominal pain (mean 51%)
followed by diarrhea (mean 43%) that is often severe
D816V mutation found in 80% of patients.101 Mast and progressive. Nausea and vomiting (mean 28%)
cells, hematopoietic progenitor cells, germ cells, me- are frequently seen. Patients can also have severe
lanocytes and interstitial cells of Cajal in the gastroin- peptic ulceration secondary to hyperacidity.103,104 It
testinal tract all express KIT. Therefore, it is believed is estimated that GI bleeding occurs in 11% of pa-
that KIT plays an important role in normal mast cell tients. The diarrhea that characterizes systemic mas-
development, hematopoiesis, gametogenesis and tocytosis likely occurs due to a combination of factors
melanogenesis. Upon differentiation of hematopo- including gastric acid hypersecretion, malabsorp-
etic progenitor cells into mature cell types, KIT ex- tion from mucosal injury and edema and intestinal
pression is usually down-regulated. However, the
exception is in mast cells that continue to retain high also contribute to diarrhea. Other common, non-GI
levels of cell surface KIT expression. It is postulated
that the interaction between KIT and its ligand, stem malaise. Many of these disease manifestations are
cell factor (SCF), plays a pathogenic role in mast cell secondary to the release of large amounts of vasoac-
proliferation, maturation, chemotaxis and survival.102 tive mediators such as histamine from mast cells. Po-
Neoplastic mast cells abnormally express cell surface tential triggers for histamine release include alcohol,
aspirin, opiate narcotics and opioides in general, and
105
Figure 6.8
Mastocytosis
Diagnosis
The diagnosis of mastocytosis is based on the iden-
-
cal, immunohistochemical and molecular/genetic
markers. In current practice, the diagnostic approach
begins with examination of the bone marrow with
immunostaining for tryptase and/or KIT (CD 117)
(Figure 6.8).106, 107 Of note, neither tryptase nor KIT/
CD117 immunostaining is able to distinguish be-
tween normal and neoplastic mast cells.108 Instead,
the detection of aberrant CD25 expression by bone
marrow mast cells is a more reliable diagnostic tool
since it can distinguish abnormal from normal mast
Colonic biopsy with mast cells highlighted by positive c-KIT staining. cell aggregates. Neoplastic mast cells generally ex-
Adapted from: Lee JK, Enns R, Zetler P. Gastrointestinal manifestations of systemic press CD25 and/or CD2, and the abnormal expres-
mastocytosis. World J Gastroenterol. 2008;14(45):7005-8. sion of at least one of the two cell surface markers
counts as a minor criterion toward the diagnosis of
systemic mastocytosis according to the WHO systemic amyloidosis are primary (AL) or light chain
tem.109 Serum tryptase is frequently elevated in the amyloidosis and secondary (AA) or reactive amyloi-
majority of patients, and is used as a minor criterion dosis.116 AL amyloidosis is associated with plasma
for diagnosis.106 However, serum tryptase can also cell dyscrasias such as multiple myeloma. This form
be elevated in cases of acute myeloid leukemia (AML), of amyloidosis has the greatest involvement of the
chronic myeloid leukemia (CML) and myelodysplastic gastrointestinal (GI) tract. Secondary amyloidosis is
syndrome (MDS) so its diagnostic utility is limited in
cases where patients have a second neoplasm in addi- as Crohn’s disease, ankylosing spondylitis, and Re-
tion to mastocytosis. Mast cells release large amounts iter’s syndrome, infections such as leprosy, tubercu-
of histamine and this can be measured in the urine. losis and osteomyelitis and has been associated with
Elevated urinary histamine levels have been reported malignant neoplasms.116 Other types of amyloidosis
in approximately 75% of patients with mastocytosis. are hemodialysis-related amyloidosis which is char-
It has also been reported that the urinary excretion acterized by the deposition of beta-microglobulins,
of a metabolite of prostaglandin D2 from mast cells is autosomal dominant systemic amyloidosis such as
arguably a more sensitive marker than urinary hista- familial amyloidotic polyneuropathy and senile amy-
mine for diagnostic purposes.110 loidosis which is found in 10-36% of patients over 80
years old and mainly involves the heart and to a lesser
extent the GI tract. In one study, 41-44% of elderly
Treatment patients had amyloid deposits in the sub-serosal
veins localized to the small and large intestine.117-119
Overall, the prognosis of systemic mastocytosis is
poor. Treatment is generally palliative and involves
symptom control. Interferon- with or without cor-
ticosteroids has been used to control cutaneous, he-
Epidemiology
matologic and gastrointestinal symptoms but is lim- The reported incidence rate in hospitalized patients
ited by poor tolerability and toxic side effects.111, 112 varies from 0.09-0.8% and in autopsy studies is re-
Other options include splenectomy, allogeneic bone ported at 0.4-0.7%.116 Primary amyloidosis is two
marrow transplantation, and tyrosine kinase inhibi- times more common in males than in females. This
tors.113,114 In terms of gastrointestinal involvement, was shown in a recent single center study in which
histamine-mediated overproduction of gastric acid amyloidosis of the GI tract was found in 62% of the
can frequently lead to peptic ulceration. This can be male patients.120 Most patients are diagnosed in their
managed with proton pump inhibitors. In addition, 6th or 7th decade of life, with a median age of 63-64
the persistent diarrhea characteristic of mastocysto- years. 120
sis can be treated with cromolyn sodium.
Pathogenesis
Amyloidosis The major mechanisms leading to amyloidosis include
-
tion.121
Excess concentration of precursor proteins
Introduction in tissue can lead to cell toxicity. The fundamental
question of why there is excess production of the pre-
Amyloidosis is a rare disorder characterized by the
cursor proteins remains unclear. Other unanswered
-
questions include the source of the precursor protein,
tein that disrupts tissue structure and function.115
why certain organs are selected and the mechanisms
Amyloidosis can be acquired or hereditary, localized
of cellular and tissue damage.
to a single organ such as the gastrointestinal tract or
Based on autopsy studies, amyloid deposition in
systemic in nature. The most common forms of sys-
the GI tract is greatest in the small intestine.115 Amy- In terms of gastrointestinal involvement, bleed-
loid deposits are frequently found in the vasculature, ing is the presenting symptom in 25-45% of patients
the intima or adventitia in the submucosa. As the ves- with amyloidosis of the GI tract.124 Bleeding is usually
sel wall thickens with accumulated amyloid deposits, due to ischemia or infarction, ulceration or secondary
the vessel lumen can narrow and ultimately occlude
leading to ischemia and infarction.115 Amyloid can
with small intestinal involvement with AL amyloidosis
and 2.3% with AA amyloidosis.125 Likely etiologies for
the entire muscle layer. malabsorption are dysmotility secondary to dysauto-
-
-
Clinical growth and/or ischemia. Patients with malabsorption
typically present with diarrhea, steatorrhea, hypoal-
The most common presentation is weakness, fatigue,
buminemia secondary to a protein-losing enteropathy,
purpura and unintentional weight loss.116, 122 Purpura
anorexia and weight loss. The degree of weight loss
is particularly pronounced around the eyes (“raccoon
(mean loss 30 pounds) has been found to be a predic-
eyes”).123 Involvement of the joints produces pain simi-
tor of survival. Other gastrointestinal manifestations
lar to a seronegative arthritis. Deposits in the shoulder
include mesenteric ischemia, perforation, intussus-
can produce pain and swelling that has been termed
ception, obstruction, pseudo-obstruction and consti-
the “shoulder pad” sign.116 Carpal tunnel syndrome
pation.115 Interestingly, AL amyloidosis preferentially
-
presents with constipation, mechanical obstruction or
ings. Amyloidosis can also lead to autonomic dysfunc-
chronic intestinal pseudo-obstruction secondary to
tion with orthostatic hypotension, diarrhea and im-
amyloid deposition in the muscularis mucosae, sub-
potence. Patients can also present with shortness of
mucosa and muscularis propria while AA amyloidosis
breath secondary to a restrictive cardiomyopathy.
typically presents with diarrhea and malabsorption
owing to involvement of the muscularis propria.126
Figure 6.9
On endoscopy, patients with AL amyloidosis typically
Amyloidosis
have polypoid protrusions and thickening of the val-
vulae conniventes while patients with AA amyloidosis
granular appearance to the mucosa.116
Diagnosis
Patients with AL amyloidosis should have serum and
urine tested for monoclonal light chains using immu-
chains are detected in up to 89% of patients. Nearly

-
uria at the time of diagnosis. The gold standard for
diagnosing amyloidosis is Congo red staining of bi-
opsies typically obtained from the rectum or subcu-
Submucosal vessels showing apple-green birefringence by Congo Red stain. taneous fat that characteristically show apple-green
Adapted from: Ebert et al. Gastrointestinal manifestations of amyloidosis. Am J
Gastroenterol. 2008;103:776-787. birefringence under polarized light (Figure 6.9).127
Patients with AL amyloidosis typically have hypogam-
maglobulinemia which is in contrast to patients with
AA amyloidosis who have hypergammaglobulinemia -

ondary intestinal lymphangiectasia include malig-
(IL-6) production. nancies such as lymphoma involving the mesenteric
lymph nodes or lymphatics, right-sided heart failure,
thoracic duct obstruction, retroperitoneal lymph
Treatment node enlargement, cirrhosis/portal hypertensive
gastropathy, mesenteric venous thrombosis, chronic
There is no targeted therapy for GI amyloidosis other
pancreatitis with pseudocysts and occult infections
than nutritional support and anti-diarrheal medica-
such as Whipple’s disease. 133
tions and/or octreotide for management of diarrhea.
The goal of treatment is to suppress or eliminate
Figure 6.10
-
Intestinal Lymphangiectasia
eral, treatment of AL amyloidosis requires high dose
chemotherapy such as melphalan and hematopoietic
stem cell transplantation (HSCT).128 Mortality can be
toxic megacolon and GI bleeding occurring in 20-22%

of cases.129, 130 Median survival is less than 2 years
with chemotherapy alone and increases to 60% at
128
Treatment of AA amyloidosis
involves controlling the underlying disease process.
Lymphangiectasia
Introduction
Lymphangiectasia is commonly divided into primary
intestinal lymphangiectasia and secondary lymphan-
giectasia. Primary intestinal lymphangiectasia (PIL)
also called Waldmann’s disease is a rare disorder
characterized by dilated intestinal lacteals resulting in
blocked lymphatic drainage.131 The resultant effect is
intestine with resultant edema. This can manifest as

anasarca with pleural effusions, pericarditis or chy-
colleagues in 1961 who described eighteen cases of

“idiopathic hypercatabolic hypoproteinemia.” These
patients were noted to have edema along with hypo-
proteinemia, hypoalbuminemia and hypogammaglob- Top Panel: Intestinal biopsy from a patient with primary intestinal lymphangiectasia.
ulinemia.132 Histologic examination of small intestinal Notable features include markedly dilated lymphatic ducts. Bottom panel: Video
- capsule image showing characteristic creamy yellow-white swollen villi throughout
the small intestinal mucosa.
able degrees of lymphatic vessel dilatation, leading to
the alternate term, “intestinal lymphangiectasia.” Courtesy of Dr. Robert Najarian, Department of Pathology and Laboratory Medicine,
Secondary intestinal lymphangiectasia is caused Beth Israel Deaconess Medical Center, Boston, MA USA
Epidemiology linghausen, Turner (XO) or Noonan, Klippel-Trenau-

nay and Hennekam syndrome.
The incidence and prevalence of PIL is unknown. PIL
is commonly a disease of infancy, diagnosed in chil-
dren before age three years, although it may be di-
Diagnosis
agnosed in young adults and older patients.131 Rare
familial forms of the disease have also been reported.
lymphangiectasia. These include hypoproteinemia,
hypoalbuminemia, hypogammaglobulinemia, and
Pathogenesis lymphopenia. The primary test that should be per-
formed if there is any suspicion of intestinal lymphan-
The exact etiology of PIL is unknown. Intestinal lym-
giectasia is the stool alpha-1-antitrypsin test. Patients
phangiectasia causes lymph leakage into the lumen
with intestinal lymphangiectasia have elevated levels
of the small bowel and this can lead to hypoalbumin-
of stool alpha-1-antitrypsin clearance due to enteric
emia and lymphopenia. Edema is the consequence
protein losses. An abnormal test result should trig-
of hypoproteinemia secondary to diminished oncotic
ger further evaluation with an endoscopy. The gold
pressure. Mutations in several genes that regulate
standard for a diagnosis of PIL is made by endoscopic
lymphangiogenesis in the duodenal mucosa – VEG-
FR3, PROX1, FOXC2 – may play a role.135
on endoscopy include a creamy yellow-white appear-
ance of the jejunal villi that corresponds to marked
dilation of the lymphatics within the intestinal muco-
Clinical sa (Figure 6.10). 131 The density of lymphangiectasia
The main clinical manifestation of primary intestinal can be variable with size ranging from mm to cm. His-
lymphangiectasia, found in 95% of patients, is periph- tologic examination shows dilated mucosal and sub-
eral edema.131 Edema is usually pitting secondary to mucosal lymphatic vessels. There is no evidence of
hypoalbuminemia and can be symmetric or asym- villous atrophy or infection. Video capsule endoscopy
metric and commonly involves the lower extremi- can be a useful tool to detect the extent of intestinal
ties. In severe cases, edema can involve the face and/ lymphangiectasia, particularly in children.136
effusions, as well as chylous ascites, chyluria, or chy- Treatment

Treatment consists of two components, maintenance
hypogammaglobulinemia, hypoalbuminemia and
of nutritional status and treatment of the underlying
lymphopenia. In the congenital form of the disease,
cause. In general, the cornerstone of treatment is a
lymphedema of the legs or of a single extremity is
low-fat diet supplemented with medium-chain tri-
seen. Lymphedema is differentiated from peripheral
glycerides (MCT).134,137 The rationalize for limiting fat
edema in that it is less pitting, localized to the lower
in the diet is to prevent the engorgement of the intes-
limbs predominantly, and usually bilateral. Lymph-
tinal lymphatics with chyle, thereby preventing lym-
edema of the upper limbs and breasts, however, has
phatic rupture and subsequent protein loss. MCTs
been reported. Gastrointestinal manifestations of
are directly absorbed into the portal venous system
intestinal lymphangiectasia include a protein-losing
and provide nutrient fat without the lacteal engorge-
enteropathy, moderate diarrhea with steatorrhea and
ment. Studies have shown that after a few weeks on
a low fat diet supplemented with MCT, patients can
Patients also complain of fatigue, abdominal pain and
-
involuntary weight loss.
dices including their hypoalbuminemia, lymphopenia
A few syndromes have been associated with PIL.
and immunoglobulin levels.138 In some severe cases,
These include the yellow nails syndrome, von Reck-
patients may require parenteral nutrition. Surgery if they have received more than 30Gy, 40% if they
can be useful in rare cases where disease is segmental have received 10-30Gy and 20% develop symptoms
and/or localized. A peritoneovenous (LeVeen) shunt if they have been exposed to less than 10Gy.145 Com-
is another alternative to decompress the blockage of mon symptoms include anorexia, nausea, vomiting,
131
cramping and diarrhea.139 The incidence of chronic
radiation enteritis is 6% (range, 0.5% to 17%).140
Chronic symptoms usually develop within 1 to 2 years
Radiation Enteritis but can occur as late as 20 years after radiotherapy.146
The most common clinical complaint is colicky ab-
dominal pain due to partial small bowel obstruction
(SBO). SBO is usually caused by a radiation-induced
Introduction
stricture but it may also result from impaired motil-
Radiation-induced injury to the gastrointestinal tract 139
Fistulas can also develop long-
(GI) has been reported since the use of x-rays in term between intestinal segments or between pelvic
1898.139
Figure 6.11
Radiation Colitis
Pathogenesis
Radiation-induced injury to the GI tract can be de-
scribed as both acute and chronic in nature. The
degree and extent of injury is directly related to the
intensity and duration of radiation exposure. Radia-
tion targets cellular DNA and can lead to immediate
cell apoptosis. It also induces cellular and genetic
alterations that can result in altered cell function.140
Radiation damage to nearby vasculature and connec-
tive tissue can lead to an obliterative endarteritis and
intestinal ischemia.141 When severe, these changes
strictures and altered intestinal motility with bacte-

rial overgrowth.142,143 Certain clinical factors can pre-
dispose to radiation enteritis. These include the re-
gion and volume of small intestine that is irradiated,
previous abdominal or pelvic surgery causing adhe-
thin body habitus, hypertension, collagen vascular

disease and some forms of chemotherapy.144
Clinical
Gastrointestinal symptoms secondary to radiation
enteritis can occur early or late in the process of ra-
diotherapy. Acute injury to the small intestine usually
Endoscopic view of the colon with evidence of radiation colitis.
second week of radiotherapy. It is often dose-depen- Adapted from: http://www.gastrointestinalatlas.com
dent. For example, 90% of patients develop symptoms
- imperative since involvement of the major vessels

tulization include feculent vaginal discharge, pneu- supplying the GI tract can have life-threatening con-
maturia or rapid passage of undigested food in stool. sequences. One of the most common symptoms is
Abscesses can form, frequently in the pelvic region. acute abdominal pain secondary to mesenteric isch-
Rectal bleeding from radiation proctitis is common emia. This is in contrast to patients with chronic
147
Diarrhea mesenteric ischemia who usually report chronic ab-
is also frequently seen. The most likely causes for
diarrhea include bile salt malabsorption, severe fat vasculitis frequently have pain that is out of propor-
malabsorption, bacterial overgrowth and rapid in-
testinal transit.139 of patients with systemic vasculitis, nearly 1/3 had
had abdominal pain, 34% nausea or vomiting, 27%

Diagnosis diarrhea, 16% hematochezia or melena and 6% re-
ported hematemesis.151 Other clinical associations
Clinical evaluation for radiation enteritis includes
include pancreatitis, cholecystitis or ischemic hepa-
blood work, imaging studies and various procedures.
titis. Patients with gastrointestinal vasculitis fre-
Barium contrast studies can help identify strictures
quently complain of pain after eating (intestinal an-
gina), weight loss, vomiting and diarrhea. They can
best studies to evaluate for obstruction and perfora-
also present with an acute small bowel obstruction
tion. Endoscopy with biopsies from the affected area
secondary to stricture formation, intussusception
or massive GI bleeding secondary to aneurysm for-
mation. This makes early diagnosis and immediate
vascular pattern and friability on histologic examina-
management crucial to prevent long-term morbidity
tion consistent with radiation injury (Figure 6.11).
and mortality.
Treatment
Specific Disorders
Acute enteritis is usually reversible with support-
ive care. Reducing the radiation dose can minimize
Polyarteritis Nodosa (PAN)
symptoms while still maintaining tumor control.148
Polyarteritis nodosa (PAN) affects both small and
Anti-spasmodic, anti-motility and anti-diarrheal
medium-sized arteries and can be associated with
agents are useful in the early phase. Diarrhea due
hepatitis B infection. Gastrointestinal involvement
to bile salt malabsorption can be managed with cho-
occurs in 14-65% of patients, commonly affecting
lestyramine.149 Chronic small bowel strictures and
the gallbladder and small intestine.152,153 Severe GI
manifestations include pneumatosis intestinalis, in-
often requiring surgery.150 Severely malnourished
farction or perforation, pseudomembranous colitis
and cholecystitis. Treatment includes corticoste-
roids and cyclophosphamide.
Gastrointestinal Vasculitis Systemic Lupus Erythematosus (SLE)

Similar to PAN, systemic lupus erythematosus (SLE)
also involves small and medium-sized vessels. GI
Introduction involvement occurs in nearly 50% of patients. One
of the more feared GI complications is mesenteric
Gastrointestinal manifestations of systemic vasculi- vasculitis which can persist for months with non-
tis are rare and clinical presentation is usually non-
acute abdomen.154 Risk factors for mesenteric vas- Behcet’s Disease

culitis include peripheral vasculitis and central ner- Behcet’s disease is a necrotizing vasculitis of un-
vous system SLE. SLE can also be associated with the known etiology that predominantly affects young
presence of antiphospholipid antibodies which can males. It is characterized by oral and genital ulcer-
lead to mesenteric thrombosis and infarction. ations, uveitis and skin lesions.157 GI ulceration with
resultant bleeding is common and can affect the small
Henoch-Schonlein Purpura (HSP)
intestine. Other sites of involvement include the ter-
A classic small vessel vasculitis, HSP typically occurs
minal ileum, cecum, ascending colon and esophagus.
in children although adults are also affected. Patients
frequently present with the clinical triad of arthritis, Takayasu Arteritis
hematuria and lower extremity purpura. Up to 50% Takayasu arteritis is a chronic vasculitis that typically
of patients have involvement of the GI tract.155 Symp- affects the aorta and its branches. The majority of pa-
toms include colicky abdominal pain, nausea, vom- tients are female, notably Asian, with an age of onset
iting, diarrhea and occult or overt GI bleeding. The between 10-40 years. GI involvement is mostly sec-
ondary to mesenteric ischemia that causes abdominal
pain, diarrhea and occasionally GI hemorrhage.158
in these organs. Symptoms generally resolve sponta-
neously in most patients although some require cor- Jejunal Vasculitis
ticosteroids, immunosuppressive agents and plasma Jejunal vasculitis is a poorly understood disease. It
exchange for the management of severe disease. is characterized by segmental vasculitis of the small
intestine with resultant protein-losing enteropathy
Rheumatoid Vasculitis and abdominal pain.159 A possible variant of this
Rheumatoid vasculitis tends to occur 10-15 years af- condition is an ulcerative, non-granulomatous jejuni-
ter the onset of rheumatoid arthritis (RA). It is a rela- tis characterized by chronic diarrhea, multiple small
tively rare disease; less than 1% of patients with RA bowel ulcerations and villous atrophy. Patients with
develop clinical signs of vasculitis. Of these patients, this disease often suffer from bouts of intermittent
however, up to 38% develop GI manifestations, nota-
small bowel obstruction.160
bly, mesenteric ischemia.156
Figure 6.12
Mesenteric Ischemia
Patient with non-occlusive mesenteric ischemia after an episode of gastrointestinal hemorrhage and shock. (A) Initial superior mesenteric
angiogram showing diffuse vasoconstriction. (B) Repeat angiogram after papaverine infusion for 24 hours, showing partial relief of the
vasoconstriction. (C) Angiogram performed after 48 hours of papaverine infusion, showing dilation of all vessels.
Adapted from: Brandt et al. Intestinal ischemia. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th edition. Philadelphia,
PA, 2010:2027-2048.
Drug-Induced Vasculitis less than 12 hours before diagnosis, 56% viability if

Certain medications have been associated with small symptoms occurred between 12-24 hours and 18%
intestinal vasculitis, notably, propylthiouracil (PTU) viability if symptoms were ongoing for more than 24
and hydroxyuria.161 hours before diagnosis.167 Patients at risk for AMI are
those older than 50 years with long-standing conges-
tive heart failure (especially if poorly-controlled),
cardiac arrhythmias, recent myocardial infarction,
Ischemic Disorders of the Small hypovolemia, hypotension, sepsis, and any patient
Intestine who complains of sudden severe abdominal pain.163
Factors that place patients in a high-risk group for
AMI include a previous history of arterial emboli, vas-
Introduction culitis, deep vein thrombosis, hypercoagulable states
Ischemic disorders of the small intestine are primarily

protein C resistance), or chronic post-prandial pain.
comprised of acute and chronic mesenteric ischemia
It is important to note that younger patients are not
and also encompass arterial and venous disorders. A
without risk for AMI especially with use of vasoactive
complete review and medical position statement on
drugs such as cocaine or amphetamines or with an
intestinal ischemia has been published by the Ameri-
underlying thrombophilia.
can Gastroenterological Association.163, 164
Clinical
Pathogenesis of Ischemic Injury 165
Nearly all patients with AMI have sudden onset, se-
Ischemic injury occurs when the small intestine is
-
deprived of oxygen and nutrients. The small intes-
ings on physical exam. Sudden, acute pain followed by
tine can tolerate up to a 75% reduction in mesenteric
rapid and forceful bowel evacuation is highly sugges-
tive of SMA-embolus. Pain can be absent in up to 25%
this point, its compensatory mechanisms are no
of patients with non-occlusive mesenteric ischemia.165
longer protective. The sympathetic nervous system
In these cases, abdominal distension and/or GI bleed-
plays a key role in maintaining resting splanchnic ar-
ing are often signs of impending infarction. 75% of
teriolar tone. Other vasoactive substances that have
patients have evidence of occult blood.
been implicated in the pathogenesis of ischemic in-
jury include vasopressin, prostaglandins, and angio-
tensin II.
Diagnosis
Numerous serum markers and non-invasive imaging
Acute Mesenteric Ischemia (AMI) studies have been recommended for the diagnosis
of AMI. According to the AGA position statement on
AMI can result from emboli, arterial and venous
intestinal ischemia, no serum marker is sensitive or
thrombi or secondary to vasoconstriction in the set-
-
sis.163 Elevations in the levels of serum markers sug-
high with an average of 71% (range, 59-93%).163
gestive of ischemia such as lactate usually only occur
The single most important factor in improving sur-
after transmural bowel infarction has developed and,
vival is the prompt diagnosis of AMI before the onset
therefore, cannot be used for diagnostic purposes in
of intestinal infarction. In a single center study from
the early stages of AMI when improved survival is
Madrid that evaluated 21 patients with superior
heightened. In terms of non-invasive imaging studies,
mesenteric artery (SMA) embolus, 100% of patients
CT is the imaging modality of choice to detect arterial
had intestinal viability if duration of symptoms was
and venous thromboses and ischemic bowel.169 It is tients often develop a fear of eating with resultant
important to note that a normal CT scan does not ex-
clude AMI. CT-angiography (CTA) and MR-angiogra- bloating, episodic diarrhea or constipation.163
phy (MRA) also show promise in the diagnosis of AMI.
Before the widespread use of CTA and MRA, selective
mesenteric angiography was frequently used to diag- Diagnosis
nose AMI. Mesenteric angiography has a sensitivity of
163
Treatment one test, called provocative balloon tonometry, can

In general, the cornerstone of treatment is early use of directly test the physiologic adequacy of the intes-
vascular imaging and intra-arterial papaverine to treat tinal circulation and differentiate symptomatic from
both occlusive and non-occlusive AMI (Figure 6.12).163 asymptomatic stenoses.171 However, in practice, bal-
Exploratory laparotomy is mandatory where signs of loon tonometry is rarely used and limited to special-
peritonitis are present. If a diagnosis of acute throm- ized centers. Angiography usually shows vessel oc-
bosis is made, almost universally, emergency surgical
revascularization is recommended. Although throm- CMI because occlusions can be present without cor-
bolytic therapy and percutaneous angioplasty have responding clinical symptoms. In general, a combi-
been recommended by some investigators for the nation of clinical signs and symptoms, arteriographic
management of chronic mesenteric ischemia (CMI) demonstration of an occlusive process, exclusion of
and SMV thrombosis, these modalities are rarely used other gastrointestinal disorders and clinical suspi-
in the management of acute SMA thrombosis. cion are required to make a diagnosis of CMI.
In addition to hemodynamic resuscitation, broad-
spectrum antibiotics are frequently started. Anticoag-
ulation is not used routinely in the immediate postop- Treatment
erative period but may be appropriate 48 hours after
Therapy traditionally involves surgical revascular-
embolectomy or arterial reconstruction.167,168 Antico-
ization.172, 173 A newer technique that was developed
agulation carries a high risk of intestinal or intraperi-
in the 1980s is percutaneous transluminal mes-
toneal hemorrhage so should be used with extreme
enteric angioplasty (PTMA) with or without stent
caution.
placement.174 Surgical revascularization has success
rates of 59-100% based on reported studies, and re-
currence rates of 0-26.5%. Mortality rates are usu-
Chronic Mesenteric ally below 10%. The clinical success rate of PTMA
Ischemia (CMI) varies from 63-100% with little mortality. However,
compared to surgical revascularization, symptom re-
Chronic mesenteric ischemia, also called intestinal
currence is greater with PTMA. In general, relatively
angina, accounts for less than 5% of cases of small in-
healthy patients with CMI should be treated with
testinal ischemia. The main etiology for CMI is mes-
surgical revascularization while poorer risk patients
enteric atherosclerosis, with rare cases of vasculitis.
should receive PTMA. There is a limited role for
for arterial emboli in patients with ongoing perito-

Clinical
CMI is characterized by postprandial abdominal pain,
usually within 30 minutes after eating, which gradu-
ally increases in severity over weeks to months. Pa-
Small Bowel Transplant time TPN can be discontinued.

Outcomes data on post-transplant recipients is
Intestinal transplant is a potentially life-saving proce-
mainly derived from three sources – the international
dure for patients with intestinal failure and resultant
intestinal transplant registry (ITR), UNOS database
nutritional and metabolic complications. Patients
and reports from individual centers. The long-term
include those with severe malabsorptive disorders
outcomes of small intestinal transplantation were re-
such as collagenous sprue with uncontrolled diar-
ported in a study in 2010. Based on this data, current
rhea, congenital conditions and/or surgery that lead
patient survival in the short term (1 year) and long
to the small bowel syndrome with less than 200cm
term (5-10 years) are reported to be 78-85% and
functional small intestine.175 In the United States,
56-61%, respectively, in single-center series. 178 This
nearly 760 intestinal transplants of some form have
same study reported that several new studies evalu-
been performed in adults since the inception of the
ating quality of life after intestinal transplantation
United Network for Organ Sharing (UNOS) in 1987.
correlated decreases in quality of life to post-trans-
176
In adults, isolated small intestinal transplants are
plantation complications, ongoing need for invasive
more common than multivisceral transplants. To
devices and/or nutritional support. 178
date, there are no randomized, controlled trials com-
The most common complications post-intestinal
paring intestinal transplantation to other therapies.
transplantation are acute and chronic rejection, cy-
Intestinal transplants have primarily been per-
tomegalovirus ( ) infection and post-transplant
formed in patients who develop life-threatening
lymphoproliferative disease (PTLD).179 It has been
complications secondary to intestinal failure and/
reported that acute rejection occurs in 79% and 71%
or long-term total parental nutrition (TPN) therapy.
of patients who are intestine-only and intestine-liver
Medicare has approved payment for intestinal trans-
recipients, respectively. Chronic rejection occurs in
plant in patients who fail TPN therapy for one of the
13% and 3% respectively in these cohorts. in-
following reasons: impending or overt liver failure,
fection occurs in 24% and 18% of intestine-only and
thrombosis of the major central venous channels (2
intestine-liver recipients while PTLD occurs in 7%
thromboses in subclavian, jugular or femoral veins),
and 11% of these patient cohorts.175 Patients with re-
frequent central-line related sepsis (2 episodes of
jection often present with fever and gastrointestinal
systemic sepsis secondary to line infection per year,
symptoms such as cramping, diarrhea and increased
1 episode of line-related fungemia, septic shock or
stomal output. An upper endoscopy with small intes-
acute respiratory distress syndrome) and frequent,
tinal biopsies performed biweekly, at least initially, is
severe dehydration.177
indicated for any suspicion of graft rejection. Biopsy
The management of and standards of care for
specimens should be obtained even from normal-
the recipient of an intestinal transplant continues to
appearing mucosa since early rejection may not be
evolve. All patients require a thorough cardiopul-
apparent endoscopically. Cytomegalovirus ( ) en-
monary evaluation pre-transplant. The etiology for
teritis can resemble graft rejection clinically. There-
mesenteric thrombosis resulting in intestinal failure
fore, biopsy specimens from a patient with suspicion
needs to be determined. In addition, any patient with
of enteritis should be reviewed by a pathologist
metastatic malignancies or active or uncontrolled
with experience in intestinal transplantation. In the
systemic infections including HIV are excluded from
setting of acute rejection, high dose cortiocosteroids
transplantation.175 Intestinal transplant recipients
are initiated and immunosuppression is reduced.
require life-long immunosuppression; regimens usu-
Steroid-refractory patients are often treated with the
ally include tacrolimus and prednisone. Within the
antibody OKT3, also known as thymoglobulin, for
up to 14 days.177 Graft versus host disease (GVHD)
study should be obtained to determine that no anas-
is another rare but serious complication which is a
tomotic leak is present. Enteric feeding should be ini-
major cause of morbidity and mortality post intesti-
tiated at this time. Once initiated, enteric nutrition is
nal transplantation. Onset can be acute, and patients
gradually increased to meet nutritional goals at which
typically complain of abdominal pain, nausea, vomit-

tropical sprue, small intestinal bacterial overgrowth
ing and profuse diarrhea. The diagnosis is made by
(SIBO), common variable immunodeficiency (CVID),
180
A
and secondary to medication effect, among other
new sphingosine-1 phosphate receptor agonist called
etiologies.
W-061 has been shown in a rat model to successfully
The non-classical or atypical presentation of celiac
inhibit GVHD post-small bowel transplantation and
disease is currently the most common presentation
prolong graft survival by 100 days in rats with estab-
of this illness.
lished GVHD.181 However, this agent has not yet been
The diagnostic evaluation of celiac disease - checking
tested in human subjects with intestinal GVHD.
for the presence of celiac antibodies and obtaining
Mortality from complications post-transplant
small intestinal biopsies - should be performed with
-
a patient on a gluten-containing diet.
clude sepsis or multi-organ failure (69% cases), lym-
Given that IgA deficiency is common in patients
phoma (14%), ischemia/bleeding (13%), and rejec-
with celiac disease, the serum IgA level needs to be
tion (12%).177
obtained when evaluating IgA-based celiac antibody
A novel therapeutic agent called teduglutide,
titers such as the tissue transglutaminase (tTG) and
a glucagon-like 2 peptide (GLP-2) analog, was re-
anti-endomysial antibody (EMA).
cently approved for use in patients with the short
Key histologic findings on small intestinal biopsies
bowel syndrome (SBS) with intestinal failure which
from a patient with autoimmune enteropathy (AIE)
reduces their need for parenteral support. 182 The
that distinguishes AIE from celiac disease include a
conventional management of patients with SBS in-
relative paucity of surface lymphocytosis, absence
cludes dietary manipulation, oral rehydration solu-
of goblet and/or Paneth cells, increased numbers
tions, antidiarrheal and antisecretory treatments.
of crypt apoptotic bodies and fewer numbers of
However, the evidence in support of these interven-
intraepithelial lymphocytes.
tions is lacking. Teduglutide might improve intestinal
Although the presence of autoantibodies such as
structure and functional integrity by promoting mu-
the anti-enterocyte and anti-goblet cell antibodies is
cosal growth and possibly reducing gastric emptying
supportive of a diagnosis of AIE, their absence does
and secretion thereby reducing intestinal losses and
not exclude the diagnosis.
promoting intestinal absorption. In a 3-week, phase
Asymptomatic infection of the cerebrospinal fluid
II study, teduglutide reduced diarrhea by around 700
(CSF) affects roughly 50% of patients with Whipple’s
g/day and fecal energy losses by around 0.8 MJ/day.
disease.
183
In two randomized, placebo-controlled, 24-week,
184,185 In patients diagnosed with CNS Whipple’s disease,
it is important to check the CSF for the presence of T.
Moreover, in studies of up to 24 weeks’ duration, te-
whipplei using PCR both prior to and during antibiotic
duglutide appears to be safe and well-tolerated. 184
therapy to ensure adequate CNS penetration.
Treatment with this agent could promote intestinal
In a positive breath test for small intestinal
rehabilitation through its intestinotrophic and pro-
bacterial overgrowth (SIBO), two distinct hydrogen
absorptive effects, leading to a reduction in diarrhea
peaks are measured, an early peak representing
and reduction in the need for parenteral support.
abnormal small-intestinal bacteria and a late peak
representing normal colonic flora.
The gold standard for diagnosing amyloidosis is
Pearls and Pitfalls Congo red staining of biopsies typically obtained
from the rectum or subcutaneous fat that
for the Board Exam characteristically show apple-green birefringence
Although celiac disease is a common etiology for
villous flattening, villous flattening can exist in a under polarized light.
variety of other conditions such as collagenous sprue, The cornerstone of treatment of intestinal
lymphangiectasia is a low-fat diet supplemented References

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CHAPTER 7
Gastrointestinal Infections of
the Small Intestine and Colon
Christina M. Surawicz, MD
Learning Objectives
1. Identify organisms that affect the small intestine and cause generally noninvasive diarrhea.
2. Identify organisms that affect the ileocolonic area and cause invasive diarrheas.
3. Review the role of diagnostic tests for evaluation of acute diarrhea.
4. Review the rationale for empiric antibiotic treatment in some cases of infectious diarrhea.
5. Identify infectious agents that can cause chronic diarrhea.
Introduction
Worldwide, infectious agents are the most common cause of diarrhea, and are a major contribution to mor-
bidity and mortality in developing countries, especially in epidemics, which often affect children. Current
developed countries. Examples of this include Shiga toxin (STEC Escherichia coli 0157:H7) colitis due
to contaminated ground beef and unpasteurized apple juice, infection associated with imported
raspberries, and with lunch meats and cantaloupes. Travelers to developing countries
can acquire a variety of infectious agents that cause acute (and occasionally chronic) diarrhea. Pathogens that
cause diarrhea can generally be assigned to one of two groups: small intestinal pathogens, which are typically
noninvasive, and ileocolonic pathogens, which are often invasive.
Generally infectious gastroenteritis is self-limited but mortality can occur. Currently, and noro-
virus are the two major causes of mortality among GI infections in developed nations . 1
Pathophysiology
The mechanisms of diarrhea include decreased absorption, increased secretion, increased luminal osmolal-
ity, and changes in gut motility.
Enteropathogenic bacterial pathogens cause diarrhea by one or more of several mechanisms:
Enterotoxin production. Adhesive enterotoxigenic bacteria adhere to intact microvilli and secrete enterotoxins that stim-
ulate secretion and/or impair absorption. Examples of these are Vibrio cholerae and enterotoxigenic E. coli (ETEC).
Cytotoxin production. These toxins cause cell injury and inflammation. An example is Clostridium difficile.
Preformed toxin. Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms,
usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus.
195
Digestive Diseases Self-Education Program®
Enteroadherence. Organisms adhere to the intes- are viruses, but can also include enterotoxigenic
tinal mucosa, where they attach and efface absorp- and Some parasites
tive cells. Examples of these are enteropathogenic can affect either the small intestine or the colon. Most
E. coli (EPEC), enterohemorrhagic E. coli (EHEC), small intestinal parasites are typically non or minimally
enteroaggregative E. coli (EAEC), and diffusely ad- invasive: and
herent E. coli (DAEC). The most common colonic pathogens
Mucosal invasion with inflammation and/or ul- are bacteria, such as , -
ceration. These organisms penetrate the mucosa, nella and Shigatoxin Some organisms affect both
spread, and cause mucosal damage with erosions small bowel and colon ( ).
and ulcers. Examples are Shigella, enteroinvasive E. Infections can be associated with symptoms out-
coli, and Campylobacter jejuni. side the gastrointestinal (GI) tract. Examples are hemo-
Penetration of the mucosa and proliferation in lytic uremic syndrome due to Shiga toxin–
the submucosa. Examples are Salmonella and Yer- coli (STEC), reactive arthritis associated with Yersinia
sinia enterocolitica. or other bacterial pathogens, and Guillain-Barré syn-
drome following infection.
Many organisms cause disease by more than one
-
leases intestinal secretagogues, including arachidonic Specific Infections – Small
acid metabolites, kinins, and vasoactive substances.
The net result of these processes is secretion of water Intestinal Pathogens
and electrolytes. Toxin production mediates intestinal
Viruses
system with increased transit. Mucosal mast cells may Viral gastroenteritis is the most common cause of
play a role in the recruitment of white blood cells. acute diarrhea worldwide, in both children and
adults, accounting for 75% of all infectious diarrhea.2
These viruses include rotavirus, norovirus, enteric
adenovirus, astrovirus, and torovirus. These are self-
Clinical Presentation limited illnesses that typically cause acute diarrhea
Though there are general differences in the presenta- with associated vomiting.
tion of small bowel vs. colonic infection (Table 7.1), Rotavirus and, to a lesser extent, enteric adenovi-
overlap is common. Diarrhea due to small intestinal rus cause most acute diarrhea in children. Rotavirus
disease is typically high volume, watery, and often as-
sociated with diffuse mid abdominal pain and cramps. Table 7.1
Malabsorption can occur and dehydration is frequent. Characteristics of Infectious Diarrhea
Diarrhea due to colonic pathogens is generally smaller
in volume but dehydration can still occur. Stools may
be bloody when invasive pathogens are involved. Small intestinal Colonic
Lower abdominal pain is frequent, and tenesmus may
occur, especially when there is rectal involvement. Large volume stools Small volume stools
-
Watery Can be bloody
diagnosis.
Diffuse abdominal pain/cramps Lower abdominal pain
Infectious agents that cause diarrhea can be clas-
Malabsorption Tenesmus
are usually noninvasive, or (2) ileocolonic pathogens,
which are more likely to be invasive (Table 7.2). The Dehydration Dehydration
pathogens most frequently found in the small intestine
Chapter 7 — Gastrointestinal Infections of the Small Intestine and Colon 197
is the main cause of diarrhea in children age <2 and Table 7.2
is highly contagious, commonly spreading in day care Source of Infectious Diarrhea
centers and among family members. Adenovirus types
40 and 41 have been found in stools from 8.6% of
young children with acute gastroenteritis3. Norovi- Noninvasive pathogens (small intestine) Invasive diarrhea (ileocolonic)
rus can cause diarrhea in all age groups and sickens Viruses
5.5 million people in the US yearly. The most com- Rotavirus Viruses
mon infective vehicles are leafy vegetables, fruits, Calicivirus (norovirus, Norwalk agent) Cytomegalovirus
nuts and mollusks. Food handlers are responsible Adenovirus (enteric) Herpes simplex virus type II
for 50 - 80% of cases.4 Epidemics of norovirus on Astrovirus
cruise ships and in nursing homes have produced
Bacteria Bacteria
Vibrio cholera Campylobacter species
Viruses are spread by fecal-oral contamination,
Salmonella Salmonella species
aerosolized vomitus, contaminated food and fomi-
Toxigenic E. coli (ETEC, EPEC, EAEC) Shigella species
tes. Examples include norovirus acquired from raw
Aeromonas hydrophila E. coli 0157:H7 (EHEC)
oysters from contaminated freshwater estuaries and
Listeria monocytogenes Yersinia
a recent outbreak of norovirus in soccer teammates
Tuberculosis Clostridium difficile
traced to a contaminated reusable grocery bag.
Noncholera Vibrio
Individuals can remain contagious for up to 3
Aeromonas hydrophila
weeks, and there is no lifelong immunity. Alcohol
Plesiomonas shigelloides
hand gels may not adequately kill viruses nor pre-
EIEC
vent transmission in hospitals, although studies sug-
Listeria monocytogenes
gest that their use does reduce transmission5. Care-
Tuberculosis
ful hand washing is therefore important to prevent
transmission. Parasites
Diagnostic tests for viral gastroenteritis are not Giardia lamblia Parasites
readily available and are usually unnecessary, as Cryptosporidia Ameba
these illnesses are typically self-limited. Treatment Isospora belli Trichuris trichiura
primarily involves maintaining oral rehydration. Two Cyclospora cayetanensis
vaccines for rotavirus are now available for use in chil- ETEC, enterotoxigenic E. coli; EPEC, enteropathogenic E. coli; EAEC, enteroaggregative E.
dren but not adults. A recent study showed reduced coli; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli.
rates of hospitalization for rotavirus in children, sug-
6 ETEC, EAEC, and DAEC can all cause traveler’s di-
arrhea (TD). EAEC is associated with diarrhea in chil-
Bacteria dren (both in developing countries and in the United
There are several strains of States). It can be chronic in children who are mal-
that may cause diarrhea. Those that affect the small nourished or immunocompromised and is recognized
intestine include Enterotoxigenic (ETEC), Entero- as an emerging food-borne pathogen. EPEC, which is
pathogenic (EPEC), Enteroaggregative (EAEC), and uncommon, causes acute and chronic diarrhea in chil-
Diffusely Adherent (DAEC). These all cause disease dren and sporadic epidemic infantile diarrhea (wean-
by enterotoxin production or adhesion to the brush ling diarrhea), a severe problem in malnourished chil-
border. The symptoms are self-limited watery diar- dren in developing countries.
rhea with vomiting or fever. The typical incubation There are no good diagnostic tests for these infec-
period ranges from several hours to 2 days and in-
fection usually lasts 3 days or less. Nausea, cramps, ETEC can be treated with antibiotics (quinolones or
and fever are less common. -
motility agents.
There are two biotypes of - small-intestinal parasites, and Giardia lamblia and
01, the classic strain and El Tor, both of which can are the most common in the
cause epidemics. These are usually noninvasive organ- United States.
isms. 01 causes epidemic cholera but is rare Giardia is a common waterborne cause
in travelers. The pathogen colonizes the upper small of diarrhea worldwide. The cysts are resistant to de-
intestine but is noninvasive so it does not cause bacte- struction by chlorine, and outbreaks have occurred
remia. Diarrhea is due to stimulation of cAMP-mediat-
ed chloride secretion, inhibition of sodium absorption, can remain viable for months, even in cold water.
and production of platelet-activating factor, with pos- Cysts also resist destruction by gastric acid. Trans-
sible resulting alteration in prostaglandin synthesis. mission can occur by fecal-oral transmission, as may
Treatment is oral rehydration solutions and antibiotics occur with epidemics in day care centers, drinking
contaminated water (typically associated with camp-
cholera vaccines are available. Although they do not ing), and with anal sex. The incubation period is 1–2
provide 100% protection they can be used for travelers weeks. Symptoms include abdominal cramps, bloat-
to high risk areas. ing and gas, and explosive fatty diarrhea. Cysts form
In 2004-2005, there were 2.5 – 3 cases in the lumen and are excreted in stools. As few as
per million population yearly in the US, with 30% oc- 10–25 cysts can cause disease when they transform
curring in pregnant women7. The organism resists into the pathogenic trophozoites which attach to the
salts, nitrates, acid, and freezing and can multiply in duodenal and jejunal mucosa, though the mechanism
refrigerated products.8 Multiple epidemics of of diarrhea has not been established.
monocytogenes gastroenteritis have been linked to con- Chronic infection can occur in immunocompe-
taminated chocolate milk, lunch meats, and unpasteur- tent individuals, as well as those with immunocom-
ized cheeses and a recent large US outbreak was due to promise including hypogammaglobulinemia, IgA
contaminated cantaloupes.
Pregnant women, diabetics, and immunocompro- HIV. Some people are asymptomatic cyst excreters.
mised individuals are most susceptible, and the illness The diagnosis rests on detection of cysts in the
can be fatal. Infection in pregnant women has been stool (3 stools over 6 days, since excretion is inter-
associated with increased maternal mortality and a mittent); one stool exam has a yield of 50–70%. Use
20-fold increase in miscarriages and stillbirths. There of an ELISA to detect Giardia antigen in the stool
are two forms of noninvasive, which typically detects 30% more cases than stool microscopy. An
causes a febrile illness, and invasive, which can cause
septicemia and meningoencephalitis. The latter can Duodenal aspiration for trophozoites may occasion-
infect a fetus via the placenta and may lead to spon- ally be necessary when stools are negative but is not
taneous abortion, stillbirth, or sepsis in the neonate. routinely performed. Duodenal biopsies can also be
Infections are most common in the third trimester of helpful. Villous blunting and increased intraepithe-
pregnancy. Diagnosis is made by blood culture. Typi- lial lymphocytes, which can mimic celiac sprue, are
cal symptoms are nausea, vomiting, diarrhea, fever, common and the Giardia trophozoites can be seen
muscle aches, and headache if there is meningial in- with conventional microscopy and routine H&E
volvement. Vaginal cultures are not helpful as women staining.
may be asymptomatic carriers. Routine stool cultures Treatment is effective; quinacrine 100 mg three
are often negative and false positives can occur as peo- times daily for 7 days (not to be used if the patient is
ple can be asymptomatic carriers.
daily for 7 days, or combination therapy can be given.
Parasites—Protozoa Nitazoxanide (500 mg twice daily for 3 days) and a
Parasites can cause a wide variety of symptoms (Ta- single dose of tinidazole (2 g) can also be used. Ten
ble 7.3). Protozoal infections are the most common to twenty percent of patients relapse and require re-
Table 7.3 been reported in day care centers, among livestock/

Association of Parasites with Specific Clinical Syndromes veterinary workers, and recently in a water park.
Clinically, diarrhea is profuse and watery and
lasts up to a month. Diagnosis is made by stool ex-
Malabsorption amination of 3 stools, using acid-fast stains or immu-
Coccidiosis -
Giardia gen-detection assays and polymerase chain reaction
Strongyloides (PCR). Until recently there was no effective therapy,
Capillariasis but nitazoxanide is now approved by the Food and
Cryptosporidia Drug Administration for use in treatment of -
Isospora belli (and ) infection.
Diarrhea with Blood -
Amebiasis nensis is a protozoan that causes prolonged watery
Schistosomiasis diarrhea. Organisms resemble but
Trichuriasis are larger (8–10 mm vs 4-6 mm) and therefore eas-
Occult Blood in Stools ily detected on microscopic stool examination. They
Hookworm
Strongyloides
Chronic Tropical Diarrhea older names Cyanobacteria and blue-green algae.
Parasites Initial reported cases from travelers to Nepal and an
Ameba outbreak among hospital workers in Chicago were
Post amebic dysentery likely due to contaminated water. Highly publicized
Giardia lamblia outbreaks associated with raspberries from Gua-
Coccidiosis temala were reported in 1996 and 1997. Infection
Cryptosporidia rates in these epidemics were very high (82%) 10.
Isospora belli causes prolonged diarrhea (4–6 weeks)
Tropical sprue with nausea, vomiting, myalgia, and cramps, usually
without fever. Treatment with TMP-SX shortens the
duration of the illness.
peat treatment and post infectious irritable bowel Isospora belli is recognized as
syndrome (IBS) is commonly seen after Giardia in- a pathogen in immunocompetent and immunosup-
fection.9 pressed individuals. It is a parasite in tropical areas
The most common - and can cause chronic diarrhea. Transmission is by
tosporidium organisms that cause infection are the fecal-oral route. Diagnosis is made by stool exam
hominis and Fecal contamination of water or small bowel biopsy. It may be associated with eo-
leads to ingestion of oocysts, but person-to-person sinophilia. Treatment is TMP-SX.
and animal-to-person transmission also occurs. The Microsporum are spore-
sporozoites most commonly infect the small intes- forming organisms that have, as a group, been rec-
tine where they attach to enterocytes between their ognized as pathogenic in immunosuppressed indi-
microvilli. In immunosuppressed individuals, organ- viduals, especially those with human HIV. However,
isms can be also seen in colonic, pancreatic, and bili- cases also occur in immunocompetent individuals.
ary mucosa. Multiple species infect humans; two that involve the
caused recent U.S. epidemics gut are and
via contaminated water. The organism resists chlo- Symptoms are watery diarrhea, abdomi-
rine and can even persist despite the use of state-of- nal pain, malnutrition, nausea and vomiting.
the-art water-treatment facilities. Outbreaks have
Parasites—Helminths can be seen on small bowel biopsies. Eosinophilia is

There are three categories of helminths: nematodes common (present in 75%). Colitis can occur and is
(roundworms), cestodes (tapeworms), and trema- often right-sided.
and ). Diagnosis of strongyloides
The nematode Ascaris is the most com- detection of larvae may only be 30%. Serology (IgG
mon parasite worldwide that infects humans. Worms antibody) is the best diagnostic test (84–100% sen-
can live in the small bowel for up to 2 years and grow sitive) but may not differentiate carriers from those
to 35 cm in length. They do not multiply in the host. with acute disease and can take weeks to perform.
Infection is often asymptomatic. Heavy infestation The combination of stool and serology will give a di-
can cause pneumonia, small bowel, appendiceal, or agnostic yield of 89%. Treatment is ivermectin.
biliary obstruction and pancreatitis. Treatment is Because strongyloides can complete its lifecycle
with mebendazole or albendazole, although pyrantel entirely within the human host, immunosuppressed
pamoate is used during pregnancy. patients can develop a hyperinfection syndrome
(Ancylostoma duodenale and Necator when a high worm burden triggers a systemic in-
americanus
reach the intestine after penetrating the skin, when occur as the result of superinfection as well as pneu-
they can cause “ground itch” and migrating through monitis and brain involvement. Hyperinfection syn-
the lungs. Symptoms are diarrhea, vague abdominal drome has a high fatality rate.11 Patients with HTLV-1
pain, and nausea. Eosinophilia is common and be- infection are especially susceptible to strongyloidia-
cause the worms can consume up to 0.5 cc of blood sis. Because delayed diagnosis and treatment of dis-
seminated in immune suppressed
Empiric treatment with albendazole should be con- patients can have dire consequences, pre-transplant
sidered if clinical suspicion is high. screening of high risk individuals is recommended
is found in most transplant centers.12 Serology (IgG ELISA
in tropical and semitropical areas, including South- antibody testing) is recommended for anyone from
east Asia, rural southern United States, and northern endemic areas, or who has GI symptoms or eosino-
Italy. The organism is free living in the soil, but its philia before transplant. Serology is better than stool
presence is unrelated to sanitation. It is estimated screening, which has sensitivity of 15 – 30% for a
that 100 million people worldwide are infected. single stool but up to 100% if 7 stools are examined
High-risk populations are military veterans from
13
. Treatment should include ivermectin and empiric
Asia and prisoners of war, and epidemiologic assess- antibiotics. Immune suppressive therapy should be
ment is helpful when this infection is suspected. stopped, if possible.
The four major cestodes, or tape-
burrow into the skin. This is associated with a ser- worms, are (from beef), -
piginous urticarial rash (larva currens) on the but- lium (from pork), Diphyllobothrium latum (from
tocks, perianal area, and feet. The larvae then access Hymenolepis nana (the dwarf
the circulation, and spread to the lungs where they tapeworm). can be as long as 10–12 meters,
can cause cough. Once coughed up, they are then and Diphyllobothrium can be up to 12 meters long.
swallowed after which they migrate into the small the most common in the United States, can
intestine. Unlike most parasites, can be acquired from raw beef. The worms are typically
complete its life cycle entirely within the human host 30–40 mm long and 1 mm wide.
and the rhabditiform larvae can develop into infec- Humans with tapeworms are often asymptomat-
tive larvae within the small bowel lumen. -
Typical GI symptoms are nausea, vomiting, an- ia, and epigastric pain. can cause chronic
orexia, and vague abdominal pain, with infection diarrhea and megaloblastic anemia from vitamin B12
of the small bowel and rarely, the colon. The larvae 12
. Eosin-
festation is an acute illness with small intestinal in-

or proglottids in stools. Treatment for all tapeworms volvement, but the colon can also be affected. Many
is praziquantel. contaminated foods have transmitted but
the most common vehicles are poultry, egg yolks,
fresh produce, ground beef, and milk. Exposure to
Specific Infections – Ileocolonic animals, including pet turtles or snakes, even when
not clinically ill, can also transmit infection.
Pathogens is a self-limited illness. Dysentery is
uncommon. Bacteremia, which accounts for remote
Bacteria
species are a major valves, occurs in 2–14% of cases17.
cause of diarrheal illness in the world.14 There may Antibiotics reduce the numbers of bacteria but
be up to 4 million annual cases in the United States. may not reduce the duration of symptoms and so are
is most common, followed by Poultry generally reserved for those with severe symptoms,
is the leading source of infection, although organisms in infants or the elderly, in immunocompromised
are also transmitted by the fecal-oral route, or by con- patients or others with severe underlying illness, in
taminated milk, eggs, or water. Initial symptoms de- those with prosthetic joints or heart valves, or if sys-
velop 1–7 days after ingestion and include nausea, temic disease is suspected. In addition to immunosup-
anorexia, cramping, and watery or bloody diarrhea pression, risk factors for infection include sickle cell
lasting a week or (rarely) longer. The illness can mimic anemia, schistosomiasis, and hypochlorhydria. The
appendicitis (as can Yersinia). Colitis is common as are number of strains that are resistant to common an-
extraintestinal manifestations, most notably post-in-
fectious arthritis and Guillain-Barré syndrome (GBS). know which antibiotic will be effective. Quinolones
is thought to be the cause of 40% of and ceftriaxone are commonly used, the latter for sys-
GBS cases and roughly 1 in 1000 patients with temic infection. Strains with dual quinolone and cef-
infection will develop GBS. 15 It is not known whether triaxone resistance have been reported. These strains
treatment of alters the likelihood of develop- may cause more invasive illness and bacteremia. A
ing GBS so mild-to-moderate illness does not gener- carrier state is diagnosed if stools remain positive for
ally require antibiotic treatment. Therapy is recom- over a year. 18 Quinolones may be effective to treat the
mended for severe disease or for symptoms that carrier state.
last longer than a week. Recommended antibiotics Typhoid fever is caused by and is rare
include erythromycin or macrolides (azithromycin). in the United States but common in developing coun-
- tries, especially India. Nontyphi strains can cause an
wide, especially in Southeast Asia, and can be associ- illness that mimics typhoid ( and -
ated with a more severe and prolonged course. eraesuis). Diarrhea is uncommon, with constipation
There are more than 2200 sero- occurring frequently early in the illness. Transmission
types of including occurs from consuming contaminated food (especially
and 16
They poultry, eggs, and dairy products) or water. The inci-
are among the most common bacterial pathogens dence is highest in infants (2–4 months of age) and the
that affect humans. species can cause two elderly. The diagnosis is made by blood culture early in
very different clinical syndromes—gastroenteritis the course of the illness, and potentially by stool cul-
and colitis, i.e., nontyphoidal and typhoid fever. ture later. There are four classically described stages
Nontyphoidal gastroenteritis to the disease:
(enterocolitis from infection with
) is a common cause of bacte- Week 1: nonspecific symptoms, including fever and chills
rial diarrhea in the United States, with an estimated Week 2: right lower quadrant pain, diarrhea and rose
1–2 million cases yearly. The most common mani-
spots studies, 5 days of therapy is adequate. Single 1-g dose

Week 3: complications such as colon ulcers with bleeding
or perforation patients with except for those infected with
Week 4: resolution dysenteriae type 1. Quinolone resistance is increasing.
Azithromycin has recently been shown to be effective.
The current treatment of choice is an oral quino- Systemic administration of second- and third-genera-
lone. However, multidrug-resistant strains can be re- tion cephalosporins has also been used for systemic
illness. It is not known whether therapy can prevent
Chloramphenicol use is no longer recommended. complications of shigellosis.
is very common worldwide. It Two types of affect the colon. One is
causes colitis and has two pathogenic mechanisms: di- enteroinvasive (EIEC), which causes an illness
rect invasion of the colonic epithelium and production that resembles sonnei infection but is gener-
of an enterotoxin. Most human infection is due to one ally mild and can be treated with a quinolone. The
of four species: S. and other is STEC (including the 0157:H7 strain), which
S. 19
Pandemics are usually associated with causes hemorrhagic colitis.20 One hundred serotypes
In the United States, infection with - cause human disease. The 0157 strains and non-0157
nei is most common, followed by strains (especially 0111, which accounts for approxi-
Humans are the only natural host for these bac- mately half of cases) often cause epidemics, with 250
teria, which are usually spread by fecal-oral contact deaths yearly; sporadic cases also occur. Non-0157
or, less commonly, by contaminated food or water. STEC infections may account for 20–50% of STEC in-
Infections are most common in children (age 1–4), fections. Unlike the 0157 strain, these organisms do
men who have sex with men, travelers, and people in not ferment sorbitol. The peak season is summer.
institutions. Risk factors include exposure to sewage,
and those who live with poor sanitary conditions. The of hemorrhagic colitis in 1982. The organism is usu-
organism is virulent, and ingestion of <100 organisms ally acquired from unpasteurized milk or under-
can cause disease. The usual incubation period is 1–4 cooked ground beef, although there are other vehi-
days. cles, including unpasteurized apple juice, basil pesto,
Clinically, the illness begins with a 2-day pro- sprouts, venison, and petting zoos. The most common
drome of fever, cramps, and secretory diarrhea. Over route of acquisition of STEC is food and water that
the next few days, the bacteria localize to the colon, is contaminated by cattle manure (even though the
- cattle are usually asymptomatic). Person to person
entery, left colon and rectal involvement are promi- contact can cause secondary infection, and even water
nent. The initial symptoms of nausea, cramps, and ingested while swimming can cause infection. Some
watery diarrhea subside, followed by bloody mucoid waterborne epidemics have occurred, as well as an ep-
diarrhea and tenesmus, fever, and systemic toxicity. idemic at a county fair where bacteria were dispersed
The major cause of death is dehydration, but other po- by an airborne route.
tentially lethal complications of shigellosis include in- The organism itself is not invasive, but it produces
testinal perforation, toxic megacolon, dehydration and a Shiga-like toxin. The typical presentation is nausea,
sepsis. Extraintestinal complications such as seizures vomiting, low-grade or absent fever, followed within
(usually with fever), encephalopathy, hemolytic ure- 2–3 days by severe abdominal pain and diarrhea that
- may become bloody. Symptoms usually resolve with-
tory arthritis can occur. These complications may be in a week unless there are complications. Colonic in-
more likely in young malnourished children. Treat- volvement with the 0157:H7 strain is often localized
ment of infection is always recommended. to the right side; thus in elderly patients, the clinical
Chronic symptoms are rare. presentation might mimic ischemic colitis, and in a
Treatment is a quinolone or azithromycin. In most pediatric population, the initial diagnosis might be in-
- the year 2000.26 This strain possesses a partial gene

nally, diagnosis rested on use of MacConkey-Sorbitol deletion that causes increased production of toxins
agar, but this will detect only the 0157 strains. Thus A and B and may explain its increased viru-
Shiga-based toxin assays to detect other strains may lence. These strains produce a binary toxin in addition
be preferred for diagnosis. Severe complications to toxins A and B, but it is not known if this toxin is
are hemolytic uremic syndrome (HUS), a microan- pathogenic. Clindamycin and quinolone resistance
giopathic hemolytic anemia with thrombocytopenia, are a characteristic of this strain. Widespread quino-
renal failure, and thrombocytopenic purpura.21 HUS lone use may explain some epidemics that are nota-
occurs in 2–8% of adults and 10% of children age ble for increased morbidity and mortality, as well as
younger than 11, most commonly in those younger increases in metronidazole treatment failure rates.
than 5. The risk of HUS in children is 5 – 15%, with There is increasing evidence that proton pump inhibi-
an overall mortality up to 25% and rates of long term tor therapy predisposes to infection.27-32
renal disease occurs are high22. Predictors of HUS infection (CDI), formerly called -
include short incubation period, high white blood cile–associated diarrhea, should be suspected in any-
cell count, high C-reactive protein, and low serum one who develops diarrhea during or soon after anti-
albumin.23 Sequelae may include permanent kidney biotic therapy. Diarrhea can even occur up to 8 weeks
damage, seizures due to CNS involvement with vas- after the end of a course of antibiotics. The diagnosis is
culitis, and death. STEC is the most common cause made by detection of toxin in the stool. Tis-
of HUS in the United States. The Shiga like toxins I sue culture assay for toxin B was the gold standard, but
and II are absorbed, causing endothelial damage to most laboratories now use enzyme immunoassay (EIA)
blood vessels, platelet aggregation, thrombi, and mi- tests for toxin A and B or PCR for toxin B. Some strains
crovascular ischemia. (1–3%) produce a mutant toxin A that is not detected
Several publications indicate that both antibiotic by EIA tests, so testing only for toxin A is not advisable.
treatment and antimotility agents are associated with One common algorithm is to use a common Clostridial
an increased risk of HUS in children, probably because antigen glutamate dehydrogenase (GDH) as a screen, as
antibiotics increase release of toxins by the organ- 33
ism; thus these agents should not be used24. The im- If negative, no further testing is done. If positive, a fol-
portance of non 0157:H7 strain is highlighted by the low-up test for toxin A and/or B is indicated. However,
epidemic of STEC 0104:H4 that occurred in Germany overall sensitivity is much less than tissue culture as-
in 2011 due to contaminated sprouts 25. The outbreak say. In one study, even when GDH was negative, 1.9%
caused 3,816 documented infections, 54 deaths, with of cases had toxigenic by culture.34 Since
this strategy will still miss cases, more laboratories
Moreover, unlike STEC 0157:H7, most (88%) of the are moving to more expensive but more accurate PCR
HUS cases were in adults. This organism was identi-
and was traced to clinical suspicion, empiric therapy should be strongly
fenugreek seeds imported from Egypt. considered.
is the most com- Colitis should be suspected when there is fever,
mon nosocomial infection of the GI tract. This gram abdominal pain, and diarrhea. White blood cells may
positive anaerobe causes disease by production of two be present in the stools but are not a reliable indi-
toxins, A, an enterotoxin and B, a cytotoxin. Epidemics cator of colitis; they were absent in 70% of toxin-
have been documented in hospital settings, nursing positive stools in one study.35 A leukemoid reaction
homes, and rehabilitation centers. The association of is seen in patients with severe disease and may be
disease with antibiotic therapy is well rec- a useful clinical clue. A rising white cell count in
ognized, but sporadic community cases in otherwise someone on antibiotics should raise suspicion for
healthy individuals are on the rise, possibly as a result It is reasonable to treat for presumptive
of an epidemic strain, Nap1 BI/027, that emerged in in anyone who develops severe diarrhea in
the hospital, in some cases of chronic diarrhea, when should be considered for early colectomy.38 Surgery,
symptoms worsen or progress, when colitis is pres- when indicated, should be a total colectomy with
ent, or in anyone who has a history of prior ileostomy. Mortality from fulminant toxic colitis or
infection. perforation ranges from 2% to 8%.
Currently there are three antibiotics that are Several centers have documented an increased
commonly used to for treat disease: met- incidence of CDI in patients with IBD, up to two or
- three times higher than in the previous decade.39-41
ommended doses are metronidazole, 500 mg orally Risk factors are immunomodulator therapy and co-
three times daily, vancomycin, 125 mg orally four lonic disease (rates are higher for patients with ul-
cerative colitis than with Crohn’s disease). Multiple
day all for 10 days. This dose of vancomycin was as stool specimens may be needed to detect
effective as the higher dose of 250 mg four times and pseudomembranes may be absent on colonos-
- copy. Morbidity and mortality are increased with
cantly less costly. Early clinical trials indicated that increased rates of colectomy. There may be no prior
metronidazole and vancomycin were equivalent for antibiotic use. These patients should be given van-
the treatment of mild disease. However, in a recent
study comparing metronidazole and vancomycin, in with early surgical consultation.
patients with severe disease, vancomycin remained Most patients with CDI respond to treatment
effective, but response rates to metronidazole fell to with resolution of diarrhea, but 20% of patients will
76%.36 have recurrence; these patients are even more likely
Treatment guidelines are changing to account to have further recurrences (40–65%).42 The patho-
for the broad range of clinical presentations of CDI. physiology is likely related to persistently abnormal
The Infectious Disease Society of North America pub-
lished recommendations in 201037 that recommend Risk factors include older age, intercurrent antibi-
that metronidazole should be given, 500 mg three otics, renal disease, and prior recurrences. This is
times daily for 10–14 days for mild-to-moderate becoming an increasingly challenging clinical prob-
disease. For severe disease vancomycin should be lem. The initial therapeutic approach to relapsing
given, 125 mg every 6 hours for 10–14 days. Severe colitis is to repeat the same or an alternate
antibiotic or giving vancomycin in tapered or pulsed
fever, severe abdominal pain, severe diarrhea, elevat- doses for longer courses (several weeks) which has
ed white blood cell count (>15,000), creatinine rise 42
A course of
by 50%, and decreased albumin. If disease is severe 2 weeks of vancomycin followed by 2 weeks of rifaxi-
- min was effective in two small series. 44,45 Metroni-
tension—oral vancomycin should be started, dosed dazole should not be given long-term due to risk of
at 500 mg every 6 hours and supplemented by van- irreversible peripheral neuropathy.
- is a probiotic that de-
mycin in 100 ml normal saline every 6 hours), and creased recurrences of CDI as an adjunct to antibiotic
intravenous metronidazole, 500 mg every 8 hours. treatment.46 However, cases of funge-
The use of antidiarrheals is contraindicated. mia, especially in immunocompromised or intensive
In these critically ill patients, serial clinical eval- care patients, suggest the need for prudent use. Fecal
uation is important to look for signs that urgent sur- microbiota transplant puts stool from healthy donors
gery may be needed. A surgical series from Quebec into the colon of patients with RCDI, either by enema,
colonoscopy or NG tube. Of 296 patients published in
clinical predictors of 30-day mortality: elevated lac- small series and case report, there was 92% overall
tate (>5), elevated white blood cell counts (>20), be- -
ing on pressors, and being age 75. These patients als have been completed. 47-52
A recent phase II trial using monoclonal antibod- Noncholera such as

ies to toxin A and B showed decreased recurrences of and cause diarrhea
when used with antibiotics but this prod- by invading the colonic mucosa. The illness is usually
uct is not available.53
and Yersinia cause a self-limited illness with
pseudotuberculosis are pathogens that can cause nausea, vomiting, and diarrhea. may
acute or chronic colitis. It commonly results from manifest with ecchymotic, bullous skin lesions. Pa-
ingestion of contaminated milk products or pork tients with chronic liver disease are at increased risk
illness presents with right lower quadrant pain due as they can develop a fatal infection. Other risk fac-
to acute terminal ileitis with mesenteric adenitis, it tors are diabetes, immunosuppression, and achlor-
can be misdiagnosed as acute appendicitis or Crohn’s hydria. Severe infections can be treated with azithro-
disease. The colonoscopic features include aphthoid mycin or a quinolone.
ulcers, which occur more commonly in the right side -
of the colon; terminal ileoscopy can show edema, ul- mon in the United States but can be seen in immi-
cers, and round or oval elevations of the mucosa. The grants from endemic areas.57 It frequently involves
organism can be cultured from stool, but a special the ileocecal area and can closely mimic Crohn’s dis-
cold- enrichment technique is necessary, and results ease. Only half of patients will have concomitant pul-
may not be available for a week or longer. Reactive monary involvement. Diarrhea is uncommon but ab-
arthritis may begin 2–3 weeks later, and is associat- dominal pain is present in 80–90% of patients. Skin
ed with HLA-B27 positivity. Cultures of lymph nodes, tests (PPD) will be positive in 50–97% of patients
with GI tract tuberculosis. Colonoscopy with biopsy
may take weeks for the organism to grow. In a typi- -
cal clinical setting, serology with elevated antibody mation. PCR is a good diagnostic test when used on
titers may be useful to make the diagnosis.
In most cases treatment is not necessary but it cytology that demonstrates acid-fast bacilli may be
may be prudent to treat severe enteritis, mesenteric a useful technique when submucosal involvement is
adenitis, and those with erythema nodosum and ar- present. Empiric treatment may be needed in some
cases.
azithromycin.
Aeromonas spe- Parasites
cies ( ) Parasites can cause a variety of symptoms (Table
and Plesiomonas shigelloides can cause a self-limited 7.3).
watery diarrhea, often in children.54 Infection is of- exists in 2
ten associated with ingestion of contaminated water forms: an infectious cyst and an invasive trophozoite
(Aeromonas Plesiomonas). Aeromo- and can cause a wide range of disease, ranging from
nas often causes small bowel infection. An acute asymptomatic carriage (90%, after which spontane-
colitis that mimics ischemic colitis, ulcerative colitis ous clearing is frequent) to severe dysentery (10%).
or Crohn’s disease occurs rarely,55 but it is not clear In the United States, dysentery is less common than
if these infections actually cause chronic colitis or mild symptoms of colicky abdominal pain and diar-
if they trigger the onset of IBD. A study from Spain rhea that may alternate with constipation, thus mim-
found that when Aeromonas caused traveler’s diar- icking IBS. The trophozoites penetrate the colonic
rhea, half the patients went on to have chronic diar- mucosa, most commonly in the cecum and ascending
rhea.56 The role of therapy is unclear, but effective an- colon and can cause deep ulceration. Hematogenous
tibiotics include quinolones, and azithromycin. One spread to the liver can cause liver abscesses. Non-
should treat if symptoms are severe. pathogenic strains such as are very common
in men who have sex with men. Other nonpathogen- ent in any immunosuppressed individuals; treatment
ic amebae include - is also reasonable in immune competent individuals if
and Iodamoeba buetschlii other causes of diarrhea are not obvious. However, re-
and their presence in stool may indicate ingestion of sponse to therapy may be due to eradication of other
contaminated food or water. undetected pathogens and there is no evidence that it
Stool exam is the initial diagnostic test, but is changes the natural history. Treatment is metronida-
not very sensitive. Other stool tests include an ELISA
- (600 mg orally twice a day for 3 days) in resolution
nation, and PCR. Some consider biopsy to be the gold of persistent diarrhea associated with sup-
standard. Serology (which is positive in 75–85% of porting its pathogenicity.60
patients with acute amebic colitis) is helpful to di- also known as

agnose invasive amebiasis, as it will be negative in whipworm, is a common nematode infection. It is esti-
and positive in but of course mated that 25% of the world population harbors this
results will be delayed. parasite. Transmission is fecal-oral in areas with poor
Treatment is recommended for all patients, even sanitation and hygenic practices. The main symptom
those who are asymptomatic as they can still spread is diarrhea. With a large worm burden (i.e., more than
infection. The preferred regimen is metronidazole 200 worms), colitis and dysentery with bloody diar-
750 mg tid for 10 days for the invasive trophozoites rhea can occur. Rectal prolapse is frequently seen.61, 62
followed by iodoquinol 650 mg TID for 20 days or Diagnosis is made by stool exam. Eosinophilia is pres-
paromomycin 500 mg TID for 7 days for the infec- ent in 15%. Treatment is metronidazole or albenda-
tious cysts.58 Tinidazole 2 g/day for 3 days can also zole.
-
low-up stool tests. Viral colitis
This is the only ciliate that HSVII can cause
infects humans (it usually infects pigs). It is usually distal proctitis, usually acquired from receptive
asymptomatic but may cause acute colitis. Symptoms anal intercourse with an infected individual. Typical
include bloody diarrhea, abdominal pain, nausea, and symptoms include severe anal pain and discharge,
vomiting and weight loss. Rare cases of chronic colitis sometimes associated with urinary retention and/
have been described, with resolution after tetracycline or constipation. Diarrhea is uncommon. Diagnosis is
- best made by culture of anal swabs or skin lesions but
zoites in the stools. sigmoidoscopy and biopsy can be helpful. Treatment
This organism, originally with acyclovir is usually effective.
infection is com-
and its pathogenicity has long been the subject of demon with immunosuppression, but cases of self-lim-
bate. Its presence in the stools of asymptomatic indi- ited colitis have been reported. These cases were di-
viduals (such as cafeteria workers being screened) agnosed when intranuclear inclusion cells were
argues against pathogenicity. However, multiple case found in biopsies; therapy is not necessary in self-lim-
reports of individuals with diarrhea and large num- ited disease. In immunosuppressed patients, biopsy
bers of organisms in their stools, who respond to for viral culture is also recommended and treatment
treatment with therapy, argue for its role as a patho- with an antiviral agent such as ganciclovir. The associ-
gen. Some suggest that symptoms may only occur ation of and IBD is discussed later in this chapter.
when a high number of organisms, i.e., more than 5
59
Typical symp-
Fungi
Most fungal infections occur in immunosuppressed
toms are diarrhea, abdominal pain, nausea, vomiting,
patients, with the exception of histoplasmosis, which
can involve the colon and small intestine, as well
One reasonable approach is to treat when pres-
as other areas of the GI tract when it disseminates.
In South America, Paracoccidioidomycosis (South broid poisoning is an allergic histamine reaction

American Blastomycosis) can cause a granulomatous
-
these infections, organisms can be recognized in bi- composes. Scombroid poisoning is not fatal and usu-
opsy specimens. occurs ubiquitously
but can be invasive in immunosuppressed patients,
in whom colonic ulcers have been described. Fungal -
infections are uncommon in immunocompetent indi- ray eels may accumulate a toxin that causes gastroen-
vidual. Candida may be found in the stools of asymp- teritis and neurological symptoms, including altered
tomatic individuals. There are a few case reports of sense of taste, hot and cold paresthesias, and nerve
otherwise healthy individual with chronic diarrhea, palsies. In the Caribbean, GI symptoms typically pre-
and Candida in their stools whose symptoms resolved cede neurologic symptoms. There are no diagnostic
with a short course of nystatin. tests and no therapy. In 20%, the symptoms may last
for months.
Special Syndromes
Traveler’s Diarrhea
Food Poisoning million cases per year. Risk to travelers is associated

with the countries visited: generally Africa and the
The worldwide distribution of food has led to out-
Middle East have a high risk while the Caribbean and
breaks that can occur many thousands of miles from
parts of South America have an intermediate risk.
the source of the contaminated food. In the United
Organisms are generally acquired by the fecal-oral
States, food-borne illnesses cause 5000 deaths annu-
route from contaminated food and water, thus care
ally and 324,000 hospitalizations.63 Those at great-
in diet can decrease one’s risk. Risk is higher with de-
est risk are the very young, very old, and immuno-
creased stomach acid from gastric surgery or medi-
compromised. The most common cause is norovirus;
cations. Recent studies suggest a genetic predisposi-
other causes are (raw poultry),
tion.64
(poultry and eggs), 0157:H7 (un-
and second week of travel, particularly in rainy sea-
dercooked hamburger and other vehicles),
sons and summer months.
(water), and (lunch meats).
The most common clinical syndrome consists of
Food poisoning due to preformed toxins usually pres-
abdominal cramping, bloating, malaise, and watery
ents initially with vomiting. Ingestion of preformed
diarrhea. The typical illness lasts 24 hours, but the
toxins such as or Bacillus ce-
course can last 4–5 days or up to a week. A minor-
reus regularly results in symptoms within 6 hours of
ity (5–10%) will have dysentery with blood and te-
ingestion. usually proliferates in unrefriger-
nesmus. Rarely (2%) diarrhea will last longer than
ated dairy products. has been linked to fried
a month.
rice when room-temperature rice contains spores that
Bacterial pathogens cause the majority of TD in
later germinate if the rice is kept at room temperature.
those who go to areas with poor hygiene. The most
An incubation period of 8–12 hours suggests -
common bacterial causes in American travelers are
tridium perfringens whose typical vehicles are meat,
ETEC and EAEC (40–60% of cases), and -
poultry and gravy. Longer incubation periods (>14
accounts for 10–25% of cases.65
hours) suggest an invasive pathogens (especially if
Less common are noncholera -
fever and dysentery are present).
and Parasites are usually protozoa:
Two marine toxins can cause illnesses: scom-
a, and No
broid poisoning and ciguatera reef poisoning. Scom-
Prophylaxis with bismuth subsalicylate (2 tab- recent increase in epidemic 69
lets with meals and at bedtime, for a total of 8 tablets Bacterial infections with
daily) provides protection rates of 40–65%.66 Protec- and STEC have been documented, as well as
tive rates with rifaximin are 70%.67 The most effective case reports of and
prevention is being careful about the food and bever- Parasitic coinfections in IBD are relatively un-
ages that one consumes. A general rule is “Boil it, cook common but can have disastrous consequences if
it, peel it, or forget it.” Even ice cubes made with con- they are not recognized and the patient receives im-
taminated water transmit pathogens that can cause munosuppressive therapy. There are case reports of
diarrhea. Moist room-temperature foods pose the fatal amebiasis in patients with ulcerative colitis giv-
highest risk. Travelers who visit family are at higher en steroids, and hyperinfection syndrome with -
risk than those who stay in hotels. gyloides can also be serious or fatal.70, 71
Antibiotic prophylaxis for TD is reasonable for The role of and IBD, especially in ulcerative
travelers with IBD, immunosuppression, post gas- colitis, is of great interest. It is well known that
trectomy, or susceptibility to dehydration. Rifaximin reactivation occurs with immune suppression after
has been approved for prevention of TD. Manage- organ transplant and with HIV infection, among other
- scenarios. Moreover, can occasionally cause coli-
tility agents. Patients with severe diarrhea or dys- tis, even in immunocompetent individuals. In patients
entery should also have stool cultures sent. Empiric with ulcerative colitis, superinfection with has
antibiotics, such as a quinolone or azithromycin, are been reported in series and case reports and has been
reasonable. Azithromycin is the drug of choice for felt to cause poor outcomes and increased need for
children age 2–8 and pregnant women. The Cochrane colectomy. While some feel that found in colonic
biopsies is incidental, there is increasing evidence
duration of symptoms compared to placebo (84% vs. that it can worsen the course of the disease.
50% at 3 days).68 Loperamide has been shown to de- Diagnosis of in biopsy specimens should
crease symptoms and duration of illness, and is safe inclusion cells, but
in the absence of severe dysentery, but should not be should include additional testing on tissue such as
given if STEC is suspected. shell vial culture or PCR for DNA. Positive
culture from blood does not correlate well with gut
infections. Treatment with ganciclovir or other ap-
Infections and IBD propriate agents should be given, as this can result in
clinical improvement. colitis should especially
GI infections can play a role in IBD in several different
be suspected in steroid-refractory IBD as it has been
ways. Several infections can mimic IBD, including Yer-
detected in 20–36% of these cases. 72 Its occurrence
sinia and which causes ileocolitis with
in ulcerative colitis appears higher than in Crohn’s
granulomas on biopsy that can be easily confused
disease.
with Crohn’s disease. The colitis seen with
or can resemble ulcerative colitis. In
these cases, stool culture, histology, and clinical his-
tory can help make this important distinction. Evaluation of Acute Diarrhea
Sometimes, infection can trigger the onset of IBD. The evaluation of acute diarrhea starts with obtain-
Early case reports of post infectious IBD date back to ing a detailed history including inquiry about recent
the 1960s and this has become an increasingly rec- travel, antibiotics, occupational exposures and recent
ognized phenomenon. Finally, coinfection can worsen hospitalizations. A more thorough evaluation is indi-
the course of chronic IBD. This occurs most notably cated when symptoms are severe or prolonged, when
with and . The yield of stool cultures in there is evidence of colitis (occult or gross blood in
the stools, severe abdominal pain and tenderness and
but these should still be done, especially with the fever), or when empiric therapy has failed. In addi-
tion, diarrhea in the elderly or severe abdominal pain -

in someone age >50 is an indication for prompt evalu- fectious colitis as well as IBD. In contrast, crypt archi-
ation. Though often recommended, fecal leukocytes tecture is often abnormal in IBD, with crypt distortion
- branched glands and a villous surface. Lamina pro-
85% respectively.73 Stool lactoferrin, a byproduct of -

white blood cells, has also been recommended as a macytosis, basal lymphoid aggregates, and basal lym-
screening test as it has a much higher sensitivity and phoid hyperplasia are also more common (Table 7.4).
widely available.
Like fecal leukocytes, stool culture is widely per- Therapy of Acute Diarrhea
formed but is seldom helpful. Indications for stool
culture include severe diarrhea, bloody diarrhea,
-
concern for an epidemic, immunosuppression, re-
hydration solution is ½ tsp salt, ½ tsp baking soda,
cent hospitalization or antibiotic exposure, or per-
and 4 Tbsp sugar in 1 L water. Diluted fruit juice and
sistent diarrhea (with or without prior antibiotic
saltines are a good substitute. Some antidiarrheal
therapy).74 In the US, routine stool culture will detect
agents can be safely used (bismuth subsalicylate, lop-
and though most
eramide) in most infectious diarrheas. These agents
labs will also screen for STEC. If there is suspicion for
should not be used in children (they may increase the
risk of hemolytic uremic syndrome in STEC), in adults
as sometimes certain culturing techniques need to be
with severe colitis when toxic megacolon could oc-
employed. The overall yield of stool cultures is 1–5%.
cur, or with diarrhea. Zinc supplementation
In the hospital setting, patients who develop diarrhea
improves the course of acute diarrhea in children.73
within 3 days of admission usually do not need test-
Antibiotic therapy can shorten the duration of illness
ing for enteric pathogens other than .75
in infectious diarrheas due to bacteria but are not
Diagnosis of parasites has traditionally depended
always indicated. Indications for treatment include
on microscopic detection. Improved methods for de-
suspected shigellosis or toxic appearance as would
tection of some parasites are now available but are
be expected with dysentery. This includes moderate
more expensive. Monoclonal anti–Giardia lamblia an-
to severe diarrhea, bloody stools, high fever (>39° C)
tibody stains detect cysts in stool and may double the
or severe abdominal pain, severe enteritis, older indi-
yield of standard microscopy. Giardia antigen in stool
viduals, immunocompromised patients, and empiric
can be detected with commercial EIA kits with a sen-
therapy for persistent diarrhea. 74, 76
-
are available for Testing one or two
cholera,
specimens by EIA tests for Giardia or
parasites, and sexually transmitted patho-
has a sensitivity greater than 95% and is better than
gens. Pathogens that may be treated include -
direct microscopy. The advantage of direct micros-
pylobacter (with prolonged symptoms), some cases
copy is the ability to detect different organisms. The
and Plesiomonas.
Empiric therapy often consists of oral quinolones
organism.
(which are the drugs of choice for EPEC, ETEC, -
Colorectal mucosal biopsy is helpful in differenti-
and cholera), and the second choice is TMP-SX.
ating infectious colitis from IBD. In the former, crypt
However, 20% of and many are
-
resistant to quinolones, which limits its use for these
mation is acute, and often more marked in the upper
infections. Some recommend that quinolones not be
third of the mucosa. Crypt abscesses, giant cells, and
used in children, thus erythromycin is usually the
Table 7.4 consideration. Parasites are more commonly culpable

Histology of Infectious Colitis
evaluation is stool culture and exam for ova and para-
Characteristic Histology sites. Bacterial that can cause chronic infections are
Preservation of normal histology rare but include Chron-
Acute inflammation, often superficial (upper one-third of lamina ic symptoms are more often due to parasitic infec-
propria) tion such as , and -
Crypt abscesses is uncommon in the
Microgranulomas United States but commonly acquired in travel to
Diagnostic Findings developing countries. Blastocystis hominis is seen in
stools from patients with diarrhea, but it is not clear
Specific Diagnostic Finding
whether it is a true pathogen. Other causes of chronic
Pseudomembranes C. difficile
diarrhea include EPEC, -
(E. coli 0157:H7–less common)
and recurrent Tuberculo-
Viral inclusions
sis has a predilection for ileocecal involvement and
Intranuclear and/or intracytoplasmic Cytomegalovirus
its symptoms are more typically chronic than acute.
Intranuclear Herpes simplex virus type II
Epidemic chronic diarrheal syndromes as described
in Brainerd, Minnesota, and Henderson County, Illi-
Parasites
Diagnostic organism on surface of Entamoeba histolytica
Diarrhea that persists after infection may also be
77, 78
biopsy Cryptosporidium
from post infectious IBS or IBD and not true chronic
Schistosomiasis
infection. Infectious diarrhea is becoming increas-
Granulomas, organisms visible within C. trachomatis
ingly recognized as a trigger for IBS.79-81
Granulomas Syphilis
described as “postdysenteric” IBS in 1962 by Chaud-
Tuberculosis
hary and Truelove.82 Several recent prospective stud-
drug of choice for pediatric when treatment is patients after 1 year depending upon the study. Risk
indicated. Azithromycin is another alternative to qui- factors for post-infectious IBS include: severity of the
nolones. Either azithromycin or erythromycin should initial illness, female gender, and psychological factors
be considered in immunocompromised or severely ill (in some but not all studies). Forty percent will have
- resolution of symptoms at 5 years. Postinfectious IBS
pecially if travel was in southern Asia. Azithromycin is can occur after either bacterial or viral infection. 83, 84
also the best choice for pregnant women and children Persistent TD suggests parasitic infection. A
age 2–8. Two new antibiotics have been added to our reasonable therapeutic approach is empiric antibiot-
therapeutic armamentarium. Rifaximin, a nonabsorb- Giardia therapy,
able antibiotic, has been approved for treatment of TD depending on suspected most likely pathogen, with
due to noninvasive strains of Metronidazole or further evaluation only if symptoms persist.
nitazoxanide are indicated for treatment of persistent
diarrheas due to Giardia and
Diarrhea Due to Non-GI Infections
Non-GI infections that can cause diarrhea include
Infectious Causes of Persistent or sepsis, bacterial or viral pneumonia, HIV, severe
Chronic Diarrhea acute respiratory syndrome, brucellosis, leptospiro-
sis, Dengue fever, and Lyme disease.85
When diarrhea lasts longer than 2 to 4 weeks, infec-
tion is less likely but some chronic pathogens still bear
PCR for Toxin B can occasionally be negative. There

Pearls and Pitfalls is no harm in empiric therapy for patients with sus-
for the Board Exam pected CDI who have moderate or severe symptoms.
Small intestinal pathogens, viruses (like Norovirus Severe C. difficile infection (CDI) requires therapy
and Rotavirus) bacteria (like ETEC, Enterotoxigenic with oral vancomycin and IV metronidazole.
E. coli) and parasites (like Giardia, cryptosporidia) are A patient with severe CDI, as evidenced by increased
generally noninvasive so they do not cause bloody WBC, elevated serum creatinine, a lower albumin,
diarrhea. abdominal distension, requires maximal medical
Ileocolonic pathogens, predominantly bacteria like therapy and early surgical consultation.
Campylobacter, Shigella, Salmonella and STEC can There is no uniform effective for recurrent CDI – pulse
be invasive and thus cause bloody diarrhea. regimens of vancomycin may decrease recurrences.
Antidiarrheals and antibiotics are contraindicated Yersinia infection causes ileocolitis and mesenteric
in Shiga toxin E. coli (STEC) and suspected STEC as adenitis that can mimic Crohn’s disease or appendi-
they increase the risk of Hemolytic Uremic Syndrome citis.
(HUS). Recurrent giardiasis is common with immune defi-
The most common causes of HUS are Shigella and ciency, such as IgA deficiency, which should be ruled
STEC infections. out.
Food poisoning with initial nausea and vomiting is Salmonella infection has a hematogenous phase so
typically due to a preformed toxin from S. aureus or one can get distant infections of grafts, and joints.
B. cereus. There is no long-lasting immunity to Norovirus.
Shigatoxin E. coli, like 0157:H7, is an enterohemor-
rhagic E. coli, and produces a toxin and also invades
the colonic mucosa. In contrast, Enterotoxigenic E. Most Efficient Source Reviews
coli (ETEC) also produces a toxin but does not invade
the mucosa it affects the small intestine and is a ma- for Examination Preparation
jor cause of traveler’s diarrhea. The terminology is
confusing because both organisms produce a toxin Pfeiffer ML, DuPont HL, Ochoa TJ. The patient
but affect different parts of the GI tract. presenting with acute dysentery - A systematic
Headache and meningismus in a patient with diarrhea review. Journal of Infection, 2012; 64:374-286.
should raise suspicion for Listeria monocytogenes in- This is a good review of the literature published
fection. Pregnant women and immune suppressed between 2000 and 2011 on pathogen-specific
individuals are at increased risk. dysentery. The most frequent causes are
Eosinophilia is more common with helminth infec- and although Shiga
tions than protozoal infections. toxin-producing is also important. There
Strongyloides hyperinfection (disseminated disease) are nice tables that also outline the annual mean
occurs with immune suppression. Eosinophilia may numbers of cases and laboratory detection rates.
be absent. This has a high mortality if not recognized DuPont HL. Approach to the patient with infectious
and treated. colitis. Curr Opin Gastroenterol, 2012; 28:39-46.
Quinolones are not a wise choice to treat traveler’s This is an excellent review article that provides
diarrhea in Southeast Asia due to increased rates of current recommendations for evaluation and
quinolone resistant Campylobacter. treatment of patients with infectious colitis.
Azithromycin, single dose, is effective for treatment Cohen SH, Gerding DN, Johnson S, et al. Clinical
of acute traveler’s diarrhea, and is a safe alternative practice guidelines for
to quinolones for children and pregnant women. infection in adults: 2010 update by the Society for
There is no perfect diagnostic test for C. difficile. Even Healthcare Epidemiology of America (SHEA) and
12. Roxby AC, Gottlieb GS, Limaye AP. Strongyloidiasis in

the Infectious Diseases Society of America (IDSA). transplant patients. Clin Infect Dis 2009; 49:1411-23.
Infect Control and Hosp Epidemiol 2010; 30:431-455. 13. WGO Guidelines: Management of strongyloides. http://
This is clinical practice guidelines from the www.worldgastroenterology.org/assets/downloads/en/
Infectious Disease Society of America and Society pdf/guidelines/15management_strongyloidiasis_en.pdf.
for Healthcare Epidemiology of America from Accessed December 8, 2012.
14. Dasti JI, Tareen AM Lugert R, et al. Campylobacter jejuni:
2010. It is an excellent overview of
a brief overview on pathogenicity-associated factors
infection, diagnosis, treatment and and disease-mediating mechanisms. Int J Med Microbiol
recommendations. Note, however, that the American 2010;300:205–11.
College of Gastroenterology Guidelines 15. Nachamkin I, Allos BM, Ho. Campylobacter spe-
have been submitted and hopefully will be published cies and Guillain-Barré syndrome. Clin Microbiol Rev.
in 2013 (Surawicz the lead author). 1998;11(3):555.
16. Weber CJ. Update on Salmonella infection. Urol Nurs
2009;29(2):129–31. Review.
17. Eyckmans P, Vrooninks V, Vandenbroucke J. Salmonella
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phism in the gene encoding osteoprotegerin, an anti- Curr Gastroenterol Rep 2007;9:378–84.
inflammatory protein produced in response to infection 81. Ghoshal UC, Park H, Gwee KA. Bugs and irritable bowel
with diarrheagenic Escherichia coli, is associated with an syndrome: the good, the bad and the ugly. J Gastroenterol
increased risk of nonsecretory bacterial diarrhea in North Hepatol 2010;25:244–51.
American travelers to Mexico. J Infect Dis 2009; 199:477- 82. Chaudhary NA, Truelove SC. The irritable colon syndrome.
85. A study of the clinical features, predisposing causes, and
65. Pawlowski SW, Warren CA, Guerrant R. Diagnosis and prognosis in 130 cases. Q J Med, 1962; 31:307-22.
treatment of acute or persistent diarrhea. Gastroenterolo- 83. Marshall JK. Post-infectious irritable syndrome following
gy 2009;136:1874–86. Excellent review, clinically relevant. water cntaminaton. Kidey Int Suppl 2009; Feb(112):S42-3)
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and treatment of Traveler’s diarrhea. Clin Infect Dis, 2005; AM, et al. Incidence of post-infectious irritable bowel
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traveler’s diarrhea (TD): a systematic review and meta- 85. Reisinger EC, Fritzsche C, Krause R, et al. Diarrhea caused
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for traveler’s diarrhea. Cochrane Database Syst Rev organisms we might not know have GI manifestations.
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69. Meyer AM, Nizar N, Ramzan EV, et al. The diagnostic yield
CHAPTER 8
Gastrointestinal Bleeding
Thomas O.G. Kovacs, MD, and Dennis M. Jensen, MD
Learning Objectives
1. Identify the most common causes of UGI hemorrhage.
2. Describe the role of medical and surgical management for acute non-variceal upper gastrointestinal (UGI) bleeding.
3. Describe which patients with ulcer hemorrhage should be treated endoscopically.
4. Describe long-term medical therapies to prevent recurrence of ulcer hemorrhage.
5. Discuss the most common causes and the current diagnosis and treatment of patients with severe hematochezia and presumed lower (L) GI
hemorrhage.
Acute gastrointestinal (GI) bleeding is a common worldwide clinical problem and continues to be associated
been estimated at 30-100 patients per 100,000 with about 400,000 hospitalizations per year for acute non-
variceal upper GI bleeding in the United States. A recent report using a national inpatient database showed
that hospitalizations for UGI bleeding decreased by > 20% over the decade of 2001- 2009, due to a decrease
in UGI hemorrhage. Lower (L) GI bleeding occurs less frequently, with an incidence of 6 – 20 per 100,000 and
was also noted to decrease over the past decade. The incidence of LGI bleeding increases substantially with
age (200 per 100,000 by age 80 years) and LGI hemorrhage may occur more frequently than UGI bleeding in
the elderly. Overall, for patients hospitalized for GI bleeding, 40% occurred in the UGI tract, 25% in the LGI
1
Mortality rates from UGI hemorrhage are high, varying from 3.5 to
7% in the United States. A large United Kingdom study reported a mortality rate of 14%. Mortality rates for
lower GI bleeding range from 2 to 5%.
Despite decades of overall improvement in emergency and intensive unit care, blood banking, phar-
macologic therapy and endoscopic hemostasis, mortality from UGI bleeding has not changed signif-
icantly over the past 20-30 years. The most likely reason for this is the increasing proportion of elderly
patients comprising the population of UGI bleeding patients. Currently 44% of UGI hemorrhage hospital-
izations occur in patients older than 60 years of age. In one study, the mortality rate in patients over 80
years old with UGI hemorrhage was 11.2% compared to 0.4% for patients less than age 60. Most deaths
from bleeding are not directly from hemorrhage, but are related to worsening of underlying major co-
existent medical illness or to complications of hospitalization and surgery. For example, in a large Hong
Kong study of patients with peptic ulcer bleeding who had an overall mortality rate of 6.2%, 80% of the
deaths were attributable to causes not directly related to the GI bleeding. The most frequent causes of death
were multi-organ failure (24%), pulmonary conditions (24%) and terminal malignancy (34%).
215
After the initial hemodynamic stabilization of the subsequent mortality is negligible. In a subgroup of
patient, the management of GI hemorrhage includes patients, however, bleeding persists or recurs and
determining the source of bleeding, treating active may be associated with mortality rates of 25 – 30%
bleeding or major stigmata of recent hemorrhage en- in patients with severe co-morbid conditions. Other
doscopically, evaluating the underlying pathophysiol- conditions such as Mallory-Weiss tear, angiodysplasia,
ogy, and preventing recurrent bleeding. watermelon stomach, and Dieulafoy’s lesion, occur
less frequently than peptic ulcers (Table 8.1), but are
important causes of UGI hemorrhage and contribute
UGI Bleed Etiology substantially to the morbidity and cost of care associ-
ated with UGI bleeding.3 A recent report has also sug-
Peptic ulcer disease is the most common cause of
gested that mortality from nonulcer bleeding is com-
acute UGI hemorrhage, accounting for about 50% of
parable to that from ulcer hemorrhage in high-risk
cases2 (Table 8.1). Conversely, UGI hemorrhage is the
patients (American Society of Anesthesiologists score
most common complication of peptic ulcer disease.
of 3 or 4).
About 25% of ulcer patients bleed at some time dur-
ing the course of their disease with a greater propor-
tion of duodenal ulcer than gastric ulcer patients ex-
periencing hemorrhage. In about 75-80% of cases, Risk Factors
hemorrhage from ulcers stops spontaneously and Independent risk factors for ulcer hemorrhage are
older age (> 65 years), use of nonsteroidal anti-in-
Table 8.1
UCLA-CURE HEMOSTASIS RESEARCH GROUP RESULTS OF
of prior peptic ulcer. After a single episode of ulcer
DIAGNOSIS FOR SEVERE UGI HEMORRHAGE
hemorrhage and ulcer healing, the relative risk for re-
current ulcer hemorrhage during long-term follow-up
Number of is 10 to 20 times that of a control population, depend-
Final Diagnosis* Percentage ing on the number of risk factors present. These risk
Patients
factors appear to be additive. For example, NSAID use
Peptic Ulcers 56.7 530
and a history of prior peptic ulcer disease result in a
Esophageal or Gastric Varices 12.2 114 17-times-higher relative risk for ulcer hemorrhage
UGI Angiomas 5.1 48 than in a control population.
Ingestion of NSAIDs may cause either gastric ul-
Mallory Weiss tear 5.0 47
cers (GUs) or duodenal ulcers (DUs). Complications
UGI tumor 4.5 42 may develop shortly after starting NSAIDs and are
Gastric or Duodenal Erosions 4.4 41
Esophagitis 4.3 40 meta-analysis showed considerable variability of the
risk of UGI bleeding among individual NSAIDs. Ce-
Osler-Weber-Rendu
0.9 8 lecoxib and ibuprofen had the lowest relative risks,
Syndrome
whereas piroxicam and ketorolac had the highest
Watermelon stomach 0.9 8 relative risks. The risk of NSAID-related ulcer bleed-
Dieulafoy’s lesion 0.6 6 ing is dose-dependent. In a placebo-controlled trial
comparing 300 mg or 1200 mg daily of aspirin for
Other 5.4 51
prophylaxis of transient ischemic attacks, the 1200-
100.0 935 mg dose was found to have twice the relative risk of
*Final diagnosis as a rate in 935 consecutive patients with severe hemorrhage as the 300-mg dose. Nevertheless, the
UGI bleeding (admitted to UCLA or the West Los Angeles VA -
Medical Center ICU’s). Most diagnoses were made by emergency
er relative risk of bleeding (7.7 times) than the group
endoscopy, although rarely surgery, or autopsy was required.
randomized to placebo.Studies have also shown that
Chapter 8 — Gastrointestinal Bleeding 217
in low dose (between 75 and 325 mg/day) ASA users, Several scoring systems have been created to
concomitant use of NSAIDs, steroids, anticoagulants stratify patients into high or low risk, with a view to
or dual anti-platelet therapy and advanced age may assisting appropriate triage to either a monitored care
increase the risk of ulcer bleeding.4 Corticosteroiduse setting and early endoscopy or to early discharge.
alone is not associated with an increased risk for com-
plications such as ulceration or bleeding. However, using only the objective criteria (pulse, systolic blood
concomitant steroid and NSAID use doubles the risk of pressure, blood urea nitrogen and hemoglobin), but
ulcer complications compared with NSAID use alone, none of the subjective components of the GBS, outper-
and increases the chance of UGI bleeding by 10-fold. formed both the Rockall Score and GBS in predicting
In large trials (e.g. over 8000 patients) of COX2- clinical outcomes in UGI bleed patients.
inhibitors compared to non-selective NSAIDs, other
independent risk factors for development of ulcers or
ulcer complications included cardiovascular disease Initial Resuscitation and Medical
and coumadin ingestion.
Although Helicobacter pylori is a risk factor for Management
the development and recurrence of peptic ulcer dis- The initial approach to the patient with UGI hemor-
ease, it has not been shown to be an independent risk rhage should combine an evaluation of the severity of
factor for ulcer hemorrhage. However, has the bleed, and a brief history and physical examina-
been shown to increase the risk of ulcer bleeding in tion with early and vigorous resuscitation. If the pa-
low-dose ASA users, and eradication reduces tient is not hypotensive, orthostatic changes in pulse
the risk of ulcer bleeding in low-dose ASA users with a and blood pressure should be determined. An early
prior history of ulcer hemorrhage.4 decision must be made whether hospitalization is re-
quired and whether ICU or monitored bed admission
is indicated. All patients with severe, acute UGI bleed-
Presentation ing should be considered for admission to a closely
monitored, high acuity bed, because the major com-
Patients with UGI bleeding present with hemateme-
plications of bleeding leading to mortality are better
sis (30%), melena (20%), or both (50%). Hemato-
managed in this setting.
chezia may be the only manifestation in about 5-10%
of patients with bleeding ulcers. In one study, about Table 8.2
15.3% of all patients presenting with hematochezia A prospective effectiveness study of an urgent endoscopic
were found to have an UGI source5 (Table 8.2). Often, approach to patients hospitalized with severe hematochezia
elderly patients, inpatients or those on NSAIDs or as- (300 patients)
pirin present with bleeding ulcers and have no pain.
For this reason, these ulcers are sometimes referred UGI Sources of Severe Hematochezia – 15.3% prevalence
to as “silent.” Specific lesion diagnosed Prevalence (%)*
Various symptoms and signs have been used to Peptic ulcers 54.3%*
predict severity of the bleeding episode (Table 8.3). Varices 13.0%*
These are shock, red hematemesis (as opposed to
Angiomas 8.7%*
coffee ground emesis), hematochezia, or inability to
Ulcerative esophagitis 6.5%*
clear the nasogastric (NG) lavage. Severe coagulopa-
Gastroduodenal erosions 4.3%*
thy is another indicator of poor prognosis. Mortality
Cancer 2.2%*
after a bleeding episode has also been correlated with
age greater than 60 years, inpatient hemorrhage, and Upper – other (e.g. Dieulafoy’s 11%*
lesion, polyps)
especially if cardiovascular, respiratory, hepatic, or CURE Hemostasis Research Group
malignant in nature. *Expressed as the percent of UGI sources
Resuscitation should be started immediately and Airway protection is critical during severe UGI
concurrently with the initial evaluation. Important hemorrhage, in selected patients. For example, in
determinants of resuscitation include adequate intra- one study of severe UGI hemorrhage, respiratory
venous (IV) access, accurate assessment of blood loss, complications occurred in 22% of patients. Patients
with respiratory complications had a much higher
Patients with UGI hemorrhage may present with mortality than patients without these complications
hematochezia in the absence of hematemesis. A na- (70% vs 4%). Protection of the airway with endo-
sogastric (NG) aspirate in such patients that is gross- tracheal intubation should be strongly considered
- to prevent aspiration in patients with ongoing he-
ever, a clear NG aspirate does not rule out an upper matemesis, altered mental status, altered respira-
source. Even the presence of bile without blood may tory status, or with severe neuromuscular disorders
be misleading, because bleeding from a duodenal le- (where mechanically assisted ventilation is indicated
sion may be intermittent. for sedated procedures).
In patients with a bloody NG aspirate, gastric la-
vage is usually done to remove blood from the stom-
ach prior to endoscopy to improve visualization. Medical Therapy
There is no therapeutic value to iced-saline lavage. If
The main goals of medical management are reduc-
lavage is done, lukewarm tap water should be used
tion of morbidity, mortality, risk of rebleeding, trans-
because it is as safe as, and cheaper than saline. Large
fusion needs, duration of hospitalization, and need
volume gastric lavage may be uncomfortable for the
for interventions (endoscopy, angiography, or sur-
patient and may increase the risk of aspiration. In-
gery). Histamine H2-receptor antagonists (H2RAs),
travenous erythromycin (250 mg IV bolus or 3mg/
somatostatin and its analogues, and proton pump in-
kg over 30 min) prior to endoscopy6 has also been
hibitors (PPIs) have been the most extensively stud-
reported to clear the stomach of clots and improve
ied in the medical management of non-variceal UGI
emergency endoscopic examination in patients with
bleeding.
severe UGI hemorrhage. A recent cost-effectiveness
The use of acid-reducing medications is based
-
on studies showing that acid and pepsin interfere
cin (a motilin receptor agonist that stimulates gas-
with the hemostatic process of ulcers and non-vari-
trontestinal motility) before endoscopy for acute UGI
ceal UGI lesions. In vitro studies have demonstrated
bleeding, resulted in cost savings and an increase in
quality-adjusted life years.7
the intrinsic and extrinsic pathways of the clotting
Table 8.3 cascade, acid inhibits platelet aggregation, and acid
RISK FACTORS FOR RECURRENT BLEEDING FROM PEPTIC affects pepsin activity, with maximal clot lysis at pH
ULCERS 2, but limited effect at pH above 5. These results
suggested that increasing intragastric pH to greater
than 6 could improve the coagulation process. Fur-
Age older than 65 years.
thermore, since clinical trials have shown that ulcer
Severe co-morbid medical or surgical illness.
Inpatient start of hemorrhage.
acid suppression should be maintained for at least 72
Persistent hypotension or shock.
hours after successful endoscopic hemostasis.
Persistent hematochezia; red blood emesis or red NG
Although H2 -
aspirate.
able to inhibit acid secretion, the results of both phar-
Transfusion of 6 or more units RBCs for a single bleed.
macokinetic studies and clinical trials do not support
Rebleeding from the same lesion while hospitalized.
their use for the medical management of non-varice-
Severe coagulopathy.
al UGI bleeding. Intravenous H2RAs are ineffective
Ulcers > 2 cm diameter.
in maintaining a sustained high gastric pH, because
tolerance develops within 12 hours of the infusion. fered11

Somatostatin or octreotide may have theoreti- reduced 30-day mortality in the Asian trials but not
in the non-Asian studies. The effects of PPI therapy
decreased secretion of gastric acid and pepsin, with on rebleeding and need for surgery were also mark-
stimulation of mucus production), but there is no edly greater in the Asian than non-Asian trials11. Pos-
sible reasons for these differences include younger
therapy for non-variceal UGI hemorrhage. patients in Asian studies (age 57 years vs 66 years in
PPIs reduce both basal and stimulated acid se- non-Asian trials) with fewer comorbidities; a lower
cretion by inhibiting the H+K+ATPase, the proton parietal cell mass in Asian patients, leading to a more
pump of the parietal cell. Several studies have shown profound decrease in acid secretion; a higher rate of
that the IV infusion of high-dose proton pump inhibi- Helicobacter pylori infection in Asian patients which
tors provides sustained, high intragastric pH and is associated with a greater PPI effect on acid sup-
that an omeprazole infusion (80 mg bolus followed pression; and greater likelihood that Asians are slow
by 8 mg/hour) can maintain intragastric pH steadily metabolizers of PPIs. Each of these factors would
above 6 during a 72 hour period without the devel- produce a greater PPI antisecretory effect in Asians
opment of tolerance. In the United States, the only than in non-Asians.
PPIs available as IV formulation are pantoprazole
and esomeprazole. of high-dose IV PPIs after successful endoscopic he-
Several randomized controlled trials have dem- mostasis for prevention of recurrent peptic ulcer
hemorrhage in non-Asian patients with high-risk
3 days after successful endoscopic treatment of pa- stigmata12. This multi-national trial (over 85% were
tients with bleeding ulcers and high-risk stigmata of Caucasian) randomized patients endoscopically treat-
hemorrhage8,9. In Asian patients, Lau and coworkers ed for major stigmata of ulcer hemorrhage to either
esomeprazole continuous infusion or placebo for 72
after primary hemostasis with endoscopic coagula- hours. The esomeprazole group had lower rebleeding
tion, high dose omeprazole infusion reduced the rate rates, rates of endoscopic therapy, lower blood trans-
of rebleeding, transfusion requirements, and dura- fusion requirements and shorter hospital stay12.
tion of hospitalization compared to placebo8. In an- Based on published randomized clinical trials,
other Asian trial, Sung and colleagues reported that a the recommended dose of PPIs for patients with
combination of endoscopic therapy and omeprazole
infusion was superior to omeprazole infusion alone intravenous bolus, followed by an 8mg/hr infusion
in preventing recurrent bleeding in ulcer patients for 72 hours. This has become the standard of care
with non-bleeding visible vessel and adherent clots9. in most countries for high-risk patients with severe
These studies illustrate that intravenous PPI infusion ulcer hemorrhage and major stigmata after suc-
cessful endoscopic hemostasis. However, PPIs are
stand-alone therapy. not approved by the Food and Drug Administration
More recently, several reviews and meta-anal- (FDA) for such medical therapy of either non-varice-
yses of high-dose IV PPI use after successful endo- al UGI or peptic ulcer bleeding. After the patient’s
condition stabilizes, intravenous PPI therapy may be
that PPIs reduce rebleeding, surgery, transfusion re- switched to oral PPI therapy. Patients with low-risk
quirements, and duration of hospitalization without
decreasing mortality10. should be treated with high dose oral PPI’s twice per
Further review of the available studies sug- day (double the standard dose).
gested important differences in outcomes of Asian Recent studies suggest that North American sub-
and non-Asian patients in randomized controlled jects may require an even higher equivalent dose of
trials; when analyzed separately, results clearly dif- intravenous PPI. Howden et al. showed that a 90-mg
bolus of intravenous lansoprazole, followed by an in- doscopic therapy. More recent trials have suggested
travenous infusion of 9 mg/hr in - negative that: 1) high-dose oral PPI (pantoprazole 40 mg twice
subjects, maintained intragastric pH greater than daily or omeprazole 40 mg/d) is just as effective as
an intravenous infusion after endoscopy therapy; 2)
of the second 24-hour period. Another intravenous oral PPI (omeprazole 40 mg twice daily) was similar
PPI, pantoprazole (80 mg bolus, followed by an infu- to intravenous omeprazole in effectiveness in ulcer
sion of 8 mg/hr for 24 hours) produced intragastric patients with low-risk stigmata of hemorrhage; and
pH greater than 6 for only 28% of the 24 hour obser- 3) oral PPI (rabeprazole 20 mg twice daily) was as
vation period. effective as endoscopic treatment with hemoclips.
Two other aspects of PPI use for nonvariceal UGI In a recent report in patients with ulcer hem-
bleeding have recently been considered: pre-endo- orrhage (but no major stigmata of hemorrhage),
scopic use and the use of oral PPIs. A retrospective frequent oral PPI treatment with lansoprazole (120
report suggested that use of PPIs (both intravenous mg initially, then 30 mg every 3 hours) achieved in-
and oral) before endoscopy in ulcer hemorrhage pa- tragastric 24-hour pH control similar to the control
achieved with intravenous lansoprazole (90-mg bo-
as rebleeding, surgery, duration of hospitalization lus followed by 9mg/h infusion). The intragastric
and mortality. pH increased to a pH of 6 more rapidly (1 hour ear-
A prospective, randomized, placebo-controlled lier) with the intravenous PPI than with the oral PPI,
study in Hong Kong showed that high dose PPI (as but the pH effects were comparable afterwards.
an intravenous bolus and infusion) of omeprazole High-dose intravenous PPI treatment is expen-
before endoscopy in patients with suspected ulcer sive; oral PPIs are much less costly. Cost-effective-
hemorrhage decreased the need for endoscopic ther- ness analyses in patients with high-risk endoscopic
apy, decreased the number of actively bleeding peptic stigmata who had successful endoscopic therapy
ulcers, and decreased duration of hospitalization13. A have shown that both intravenous and oral PPI treat-
meta-analysis including a total of 1512 patients con- ment are more cost-effective than intravenous H2RAs
or placebo. When intravenous PPI was compared
- with oral PPI, divergent results were obtained; one
portion of patients with stigmata of hemorrhage, but analysis favored intravenous use and the other sup-
- ported oral dosing.
tant clinical outcomes such as mortality, rebleeding
or surgery. Two recent cost-effectiveness analyses
suggest that intravenous PPIs prior to endoscopy in Endoscopic Stigmata
patients with UGI bleeding was cost-effective in Chi-
na, but only slightly more effective and more costly of Ulcer Hemorrhage
in North America. In patients with UGI hemorrhage After patient stabilization, endoscopy is the preferred
suspected to be from an ulcer, high dose intravenous procedure for diagnosis and treatment of UGI hem-
PPI therapy before endoscopy appears reasonable if orrhage because of its high accuracy and low compli-
there will be a delay in endoscopy. However, it is not cation rate. Endoscopy is diagnostic in almost 95%
a substitute for urgent endoscopy and hemostasis for of patients with severe UGI hemorrhage. Endoscopy
high risk patients. also may show stigmata of recent hemorrhage (SRH)
Oral dosing may be an alternative option for on ulcers that have important prognostic value 14.
the management of non-variceal UGI bleeding. In By consensus, stigmata have been divided into
an Asian population, a high dose of oral omeprazole manifest-
ed as (a) arterial or spurting bleeding, (b) oozing,
more than placebo in ulcer patients with non-bleeding or (c) oozing beneath an overlying clot; or recent
visible vessel or adherent clots who did not receive en- such as (a) non-bleeding visible ves-
sel (NBVV), (b) overlying clot without oozing, or (c) studies, patients with active arterial hemorrhage had
a >90% rate of continued bleeding or rebleeding when
(VV) or “pigmented protuberance” usually refer to an treated medically over the last 3 decades, no matter
elevated red, blue, purple, or white plug or mound, what the medical therapy. In the Hong Kong series, for
protruding from an ulcer base, that resists washing. less severe active bleeding described as oozing bleed-
The visible vessel is usually visualized as a small (<4 ing without a clot or visible vessel, patients had 27%
mm diameter), smooth, organized structure distin- rate of continued bleeding whereas in CURE studies,
guishable from a clot. An adherent clot is larger (> continued bleeding occurred in only 10% of patients
6 mm), amorphous, some shade of red and obscures with oozing bleeding and no other ulcer stigmata. For
the underlying SRH (often a VV). The visible vessel is non-bleeding adherent clots, CURE patients on medi-
usually single and often is found in the center of the cal management had a 33% rebleeding rate in com-
ulcer crater. (Figure 8.1) The color, shape, and size parison to a 10 to 15% rate for other clinical trials of
of a non-bleeding visible vessel can be quite variable. healthier, younger patients. The prevalence of stig-
In a deep duodenal ulcer or in a posterior gastric ul- mata of ulcer hemorrhage and their related outcomes
cer a visible vessel can be pulsatile, indicating a large in ICU patients with severe ulcer bleeding are summa-
underlying artery. rized in Table 8.4.
Pathologically, the visible vessels in resected gas- Recent experience has shown that approximately
tric ulcers correlate with a small organized clot in a 20-25% of patients with severe ulcer bleeding who re-
side hole of an underlying vessel, projecting above an quire ICU admission have a non-bleeding visible ves-
ulcer base, rather than a protruding vessel. This is sel. Approximately 50% of these patients rebleed dur-
sometimes referred to as a sentinel or pigmented clot. ing hospitalization when treated medically, and 40%
The implications of these stigmata of recent hem- with severe hemorrhage, who were not treated with
endoscopic hemostasis, required ulcer surgery for
clinical trials of endoscopic hemostasis. In one study, hemostasis. Only about 15% of ulcer patients treated
active spurting ulcer bleeding (Figure 8.2) seen at medically without endoscopic hemostasis have active
endoscopy (but not treated endoscopically) was as- arterial type bleeding (ranging from arterial spurt to
sociated with a need for emergency surgery in 69% moderate pulsatile bleeding) at endoscopy. Of these
of patients and a 23% mortality rate. In contrast, treated medically with arterial bleeding, 80% had
rebleeding rates of 15-29% were reported for ulcers continued bleeding and 70% needed surgery. The
with oozing bleeding at endoscopy, treated medically, data on patients who have oozing bleeding without
when no other SRH (such as clot or VV) was seen. In other stigmata are variable with less than 10% in Los
another study, an ulcer with a non-bleeding visible
Figure 8.1
vessel had a 50% chance of rebleeding on medical
Non-bleeding visible vessel
therapy during hospitalization (Table 8.4). Other en-
doscopic stigmata of recent hemorrhage such as an
adherent clot (Figure 8.3) was reported to have re-
bleeding rates between 10-35% on medical therapy.
10% chance of rebleeding on medical therapy (Figure

8.4).
Recent analyses of medically-treated patients in
Center for Ulcer Research and Education (CURE) ran-
domized, controlled trials, have yielded somewhat dif-
ferent rebleeding rates, according to stigmata of ulcer
hemorrhage, in comparison to other studies14 These
are summarized in Figure 8.5. In prospective CURE
Figure 8.2 and the patient should be hemodynamically stable

Spurting ulcer before initiating emergency upper endoscopy.
Hypotension or shock, hematemesis of red blood, and
loss. Endoscopy in such patients should be performed

within four to eight hours after admission to an ICU
and/or when there is an adequate resuscitation with
in patients who continue to bleed despite resuscitative

measures, who rebleed in hospital, or who have
cirrhosis. This approach allows the majority of patients
with UGI hemorrhage to stop bleeding and results in the
evaluation of a subgroup of patients with more severe
UGI bleeding. Table 8.4 and 8.6 summarizes recent
experience with endoscopic appearance of bleeding
peptic ulcers and subsequent clinical outcomes based
on this approach. Carefully performed endoscopy
will provide an accurate diagnosis of the source of the
UGI bleed and also reliably identify those high-risk
hemostasis14.
Angeles having further bleeding, compared to 27% of Newer techniques such as endoscopic Doppler
oozers with further bleeding in Hong Kong studies in
prospective or randomized studies. Most investiga-
tors distinguish arterial bleeders from oozers. Reports have suggested substantial interobserver
In the patient with severe UGI bleeding, all disagreement in the interpretation of endoscopic
resuscitative measures should be started immediately stigmata of recent hemorrhage. The use of Doppler
ultrasound has shown that some visible vessels do
Figure 8.3 not demonstrate an arterial signal, whereas some
Ulcer with overlying clot with oozing ulcers with a clean base or pigmented spot show
an arterial signal. Persistence of a positive Doppler
signal after endoscopic treatment correlates with
rebleeding, suggesting that endoscopic ultrasound
may also be a useful guide to the completion of
endoscopic hemostasis if treatment is continued until
as with hemoclipping. A recent decision-analysis

comparing Doppler-based management of acute ulcer
hemorrhage with standard treatment showed an
average cost savings ranging from $560 to $1160 per
patient in the Doppler-directed group.
Both endoscopic and clinical criteria have been
used to determine which patients with acute ulcer
hemorrhage could be managed as outpatients or
considered for early discharge after endoscopy.
Several scoring systems have been reported that are
Figure 8.4 reproducible effectiveness

Ulcer with flat spot easy and rapid application
low complications rate
low cost
portability to the bedside
widespread availability
Endoscopic techniques have been grouped into

three general types according to whether tissue con-
tact is necessary to achieve hemostasis (Table 8.5).
A combined-therapy group (dilute epinephrine in-
jection plus thermal or mechanical treatment) is
considered separately.
The major thermal endoscopic therapies are
multipolar probes (MPEC), heater probe, and ar-
gon plasma coagulation (APC). The contact probes
(heater and MPEC probes) can be applied en face or
tangentially for peptic ulcers with major stigmata
based on factors associated with recurrent bleeding of hemorrhage. Target irrigation, suctioning us-
or death. Shock; advanced age; severe comorbid ing therapeutic endoscopes, and tamponade of the
bleeding point allow the localization of the ulcer
bleeding, non-bleeding visible vessel, and large ulcer stigma and permit endoscopic treatment. Large-
(>2 cm) suggest a higher probability of rebleeding diameter probes (3.2 mm), with moderate tampon-
and death. The absence of these high-risk factors has ade on the SRH, and slow coagulation provide the
been incorporated into guidelines to identify patients most effective hemostasis and prevention of rebleed-
who can be safely managed as outpatients or be ing. This relies on coaptive coagulation of the under-
discharged early from the hospital. Prompt endoscopy lying artery in the ulcer base. APC coagulates poorly
(within 24 hours) is essential if such guidelines are to -
be applied successfully. Additional valuable criteria -
include the availability of adequate home support for comes a monopolar coagulator) which is ineffective
patients judged to be at low risk for ulcer rebleeding. for the treatment of larger underlying vessels. Coap-
Using these scoring systems, several authors have tive coagulation is not possible with APC.
Injection techniques use epinephrine (usually
acute ulcer hemorrhage can be safely managed as 1:10,000 or 1:20,000), sclerosants, or clotting fac-
outpatients. Similar guidelines have been used to tors (non-USA) and are the most frequently used
predict who could be safely discharged early from the technique for emergency hemostasis either alone
hospital, thus reducing the overall length of stay for (in non-USA) or in combination with thermal or me-
patients with ulcer bleeding.15 chanical techniques (in USA). Mechanical techniques
such as hemoclips can provide hemostasis by grasp-
ing underlying vessels and sealing them or by closing
Endoscopic Therapy acute lesions.
Several different techniques have been developed

for endoscopic treatment of ulcer bleeding. An ideal
Injection Treatment
endoscopic hemostasis technique should posses the
following features: Injection therapy for ulcer bleeding has been ad-
vocated because it is easy to use, inexpensive, and
Table 8.4 widely available, and many endoscopists have had

Prevalence of Stigmata of Ulcer Hemorrhage and Outcomes of ICU Patients prior experience sclerosing esophageal varices14,16.
with Severe Ulcer Bleeding Epinephrine injection (1:10,000 to 1:20,000)
provides local tamponade, vasoconstriction, and ini-
More Bleeding* tiates platelet aggregation thereby promoting initial
Endoscopic Appearance % of Total hemostasis. Saline injection alone causes local ves-
on Medical Therapy
Active bleeding** 12% 88% sel compression or tamponade. Sclerosants such as
alcohol, ethanolamine, and polidocanol cause tissue
Non-bleeding visible vessel 24% 50%
Non-bleeding adherent clot 10% 33% or larger ulceration, and possible perforation.
Oozing bleeding without clot or The technique involves injection through a
7% 10%
vessel*** sclerotherapy catheter with a 25-26 gauge retract-
Gray slough, flat red or black spot 14% 7% able needle in four quadrants around an actively
bleeding point or non-bleeding vessel. Dilute epi-
Clean ulcer base 33% 3%
nephrine/saline solution (1:10,000 – 1:20,000) is
This included 200 patients admitted to an ICU with severe bleeding whose injected in increments of 0.5 to 1.5 mL up to a total
ulcer could be identified on emergency endoscopy in UCLA-CURE studies. All of 25 to 30 mL. If alcohol is used, 0.1 mL to 0.2 mL
patients received medical therapy with an H2 receptor antagonist but did not increments are injected, up to a maximum of 1 mL.
have therapeutic endoscopy. Caution is recommended with alcohol to avoid tissue
damage, necrosis, and perforation and not to exceed
*Refers to more bleeding requiring transfusion of RBC. 1 mL injection volume. Alcohol injection should not
be repeated if rebleeding occurs and alcohol injection
**Includes patients with arterial type bleeding from a visible vessel, the base of should not be combined with thermal modalities.
the ulcer crater, or from under an adherent clot. This technique of epinephrine injection is effec-
tive for active arterial ulcer bleeding, or prevention
*** Includes oozing from the ulcer crater in the absence of other stigmata such as a
of non-bleeding visible vessel rebleeding. Adding
visible vessel or adherent clot.
a second endoscopic treatment with epinephrine
Figure 8.5 the rate of recurrent bleeding, surgery, and mortal-

Natural history of ulcer hemorrhage: UCLA-CURE and others
patients with bleeding ulcers and major stigmata
of hemorrhage, the risk of further bleeding was sig-
-
dure (electrocoagulation, heater probe, or endoclip)
was added to injection of epinephrine17.
Electrocoagulation
Electrical current generates heat which can coagu-
late tissue, including arteries. In bipolar electroco-
more electrodes separated by 1 to 2 mm at the probe
than with a monopolar probe, providing less depth

of tissue injury and less potential for perforation.
Electrocoagulation involves applying a large-di-
ameter probe (3.2 mm diameter) or a smaller probe Precise deployment is critical. An en face ap-
(2.4 mm diameter) directly on the ulcer stigmata or proach allows optimal capture of the target site and
bleeding site to compress the underlying vessel with
moderate appositional (tamponade) pressure before grasp a non-bleeding visible vessel ; but placing two
coaptive coagulation. The pressure on the stigmata additional clips to ligate proximally and distally from
- the bleeding point is suggested (Table 8.6) to stop
derlying vessel, reduces the heat sink effect, and, with
application of heat, can coaptively seal arteries (i.e. by Doppler ultrasound probe. Endoclips are effec-
weld the walls together). Use of low energy (12-16 tive for active arterial bleeding, non-bleeding visible
W on a BICAP II generator) and long duration (8-10 vessel and adherent clot16. A recent meta-analysis
seconds) can weld the walls of arteries up to 2 mm in compared the effects of hemoclips to injection or
diameter. Coaptive coagulation with low power set- thermocoagulation (heater probe or electrocoagu-
tings and long duration provides deeper coagulation, lation) for bleeding ulcer treatment. Hemoclips sig-
especially useful for therapy of large, chronic ulcers -
with larger arteries14,16. Electrocoagulation is effec- pared with injection alone, and were comparable to
tive for actively bleeding ulcer, non-bleeding visible thermocoagulation.
vesselor adherent clot. Endoclipping is limited by the vessel size (> 2
as proximal lesser curve and posterior duodenal

Heater Probe
(although multiple clips are often needed)16. Stud-
The probe effectively transfers heat from its end or
ies have shown that not all clips are equally effective.
sides to tissues, allowing heat transfer whether ap-
They differ in size, shape, deployment characteris-
tics, ability to grasp and release a bleeding point and
of heater probes lessens sticking. The technique in-
to rotate, and in long-term clip retention. For exam-
tamponade directly on the bleeding point or visible

vessel. Coagulation occurs with energy setting of
Table 8.5
150 J) per tamponade station (before changing the
Endoscopic methods for hemostasis of non-variceal hemorrhage
probe position)14,16. (Table 8.6). The heater probe is
effective for actively bleeding ulcer, non-bleeding vis-
ible vessel, or adherent clot.
Type of method No tissue contact Tissue contact
Laser photocoagulation Electrocoagulation

Endoclips Argon Monopolar
Thermally active
Several devices, including metallic clips, endoloops, Nd:YAG laser Multipolar
and rubber band ligation, have been described for the Argon plasma coagulator Heater probe
mechanical endoscopic treatment of bleeding ulcers. Tissue glues
Topical or inject-
Endoclips have been the most extensively studied. Clotting factors Injection Treatments
able
Clipping devices are designed to grasp the submucosa, Nanopowder
seal bleeding vessels, or approximate the sides of le- Inject + thermal
Combination
sions during endoscopy. The clips produce hemostasis Inject + hemoclip
in the manner similar to surgical ligation. They do not Endoscopic clips
- Mechanical Band ligation
cant histologic damage, in contrast with coagulation. Detachable loop
the TriClip (Cook Ireland Ltd. Limerick, Ireland), the ditive effect. Both epinephrine injection and thermal
overall hemostasis failure rate was 33%, and the clips devices activate platelet coagulation and can produce
were dislodged in 41% at the follow-up endoscopy 24 tamponade of the vessel if coaptive hemostasis tech-
hours after placement. In another comparative trial, niques are used. Epinephrine also produces vessel
hemoclips were superior to TriClips in achieving pri- constriction, and thermal probes cause coaptive co-
mary hemostasis in patients with major stigmata of agulation. Endoclips cause vessel ligation, and can be
ulcer hemorrhage. All hemoclips appear to be safe used to close lesions16.
The combination therapy technique involves di-
injury, compared to thermal coagulation which does. lute epinephrine injection into four quadrants around
stigmata in the ulcer base, followed by thermal coag-
ulation with a heater probe or multipolar probe, or
Combination Therapy deployment of endoclips. Combination therapy has
become the standard treatment for actively bleed-
Combination treatment with epinephrine injection
ing ulcers and non-bleeding adherent clot. A recent
and thermal therapy (MPEC or heater probe) or en-
meta-analysis compared combination therapy (epi-
doclips has theoretical advantages because each tech-
nephrine injection plus other injection or thermal or
nique has different mechanisms of action for hemo-
mechanical method) with monotherapy (injection,
stasis. Combining the mechanisms of action of each
thermal or mechanical alone) in high risk bleeding ul-
-
Table 8.6
Summary of 30 Day Outcomes in Patients with Ulcer Hemorrhage (UCLA-CURE Hemostasis Research Group Studies).
Oozing
Adherent Non-Bleeding Active Shock or
Clean Ulcer Without
Stigmata Flat Spot Non-Bleeding Visible Arterial Inaccessible
Base Other
Clot Vessel Bleeding Ulcer
Stigmata
Prevalence 26% 14% 10% 14% 20% 15% 1%
Feed 100% 100% 100%

Feed Feed
Med. Rx Hemostasis Hemostasis Hemostasis 100%
Treatment Medical Rx Medical Rx
Endo Rx, with with with Bleeding
No Endo Rx No Endo Rx
if persists Combination Rx Endoscopic Rx Combination Rx
Rebleed 100%
< 3% 7% < 10% < 5% 15% 20%
Rate Surgery
Endo Rx of Endo Rx of
Endo Rx of Retreat Retreat Retreat
major stig- major
Retreat major stigmata major stigmata major stigmata major stigmata
mata stigmata
Rebleed after
No No Rare Rare < 5% < 5%
retreatment
Surgery No No Rare Rare Rare Rare

cer patients. The authors reported that dual therapy tion and observation, any endoscopic monotherapy
- (thermal probes, injection, or mechanical method)
is effective. Rebleeding rates are less than 5%, com-
to thermal or mechanical monotherapy. pared with rebleeding rates varying from 10% to
27% with medical therapy alone4,16.
Recommendations for endoscopic therapy Non-bleeding visible vessel

based on stigmata of hemorrhage Monotherapy with thermal coagulation (heater or
MPEC) is effective. With large- diameter probes (3.2
Active arterial bleeding

Combination therapy with epinephrine injection
(Figure 8.8), rebleeding rates are less than 5-10%,
(1:10,000 or 1:20,000) and either thermal coagula-
versus 50% rebleeding rate with medical therapy
tion (multipolar or heater probe) (Figure 8.6) or he-
alone4,16,18 -
moclipping (Figure 8.7) is recommended4,16,18. Suc-
cal outcomes as thermal coagulation for non-bleed-
cessful endoscopic hemostasis occurs in nearly 100%
ing visible vessels4,16,18. Combination therapy (with
of lesions. Rebleeding occurs less than 10-20% com-
epinephrine plus thermal probe) is not superior to
pared to continued bleeding or rebleeding of 85-95%
monotherapy for non-bleeding visible vessels in aver-
on medical therapy.
age risk patients, but may be helpful in high risk pa-
Ulcer oozing without stigmata of hemorrhage tients such as inpatients, those with slow healing, or
If oozing from an ulcer base persists despite irriga- multiple comorbidities.
Figure 8.6
Actively bleeding duodenal ulcer (first panel), after epinephrine injection and prior to electrocoagulation with Gold probe
(second panel). Ulcer base after combination therapy (third panel)
Non-bleeding adherent clot

Combination therapy is recommended four-quad- endoscopic combination therapy for adherent clot
rant epinephrine injection around the base of the overlying an ulcer20.
clot (Figure 8.9), use of a rotatable polypectomy
Flat spots or clean-based ulcers
snare to shave down the clot using a cold-guillotine
-
technique, and thermal coaptive coagulation or he-
moclipping to treat the residual pedicle, small clot or
non-bleeding visible vessel (Figure 8.10).
rebleeding rate on medical therapy alone- 7% for
The rebleeding rate after combination therapy
in a CURE trial was less than 5%, compared with
(Figure 8.11)4,16,18. In two newly recognized endo-
35% rebleeding rate with medical therapy alone19.
-
Figure 8.7
Actively bleeding DU treated with epinephrine injection and hemoclipping
bleeding visible vessel or oozing) are seen and these
SRH are separated. The Doppler ultrasound probe
often demonstrates a patent underlying non-visible
vessel underneath and endoscopic hemostasis of the
three stigmata are required to prevent rebleeding:
each SRH and between. The second is with isolated
-
15% of times, and when Doppler ultrasound probe
recommended.
Second Look Endoscopy

Some studies suggest that repeat (second-look) en-
Figure 8.8 doscopy for repeat endoscopic hemostasis 24 hours
Treatment of a non-bleeding visible vessel with electrocoagulation (multi- after the initial endoscopic therapy helps reduce
polar probe – MPEC)
glue are used alone in injection therapy. Others

have questioned this practice because outcomes for
rebleeding rate, transfusion requirement, hospital
stay, surgical intervention and mortality in patients
receiving frequent repeat endoscopy and endo-
scopic re-treatment compared with conservative
management with repeat endoscopy only for recur-
rent hemorrhage were similar. The Baylor group
has recommended selective second look endoscopy
only in high risk patients, based upon a scoring sys-
tem but the use of high-dose intravenous PPIs may
eliminate the need for this second procedure.
Routine second-look endoscopy for surveil-
particularly those at low risk for recurrent hemor-

rhage. Currently, routine second-look endoscopy is
Surgical Therapy
not recommended4. Clinical judgment or a scoring If endoscopic hemostasis fails or is unavailable for
system such as the Baylor score should guide the patients with continued severe ulcer bleeding or
decision about repeat endoscopy and hemostasis recurrent hemorrhage, surgery becomes a thera-
in selected high risk patients. To obviate the prob- peutic option. The main purpose is to prevent ex-
lem in high risk patients with major SRH, the CURE sanguination and death, with a secondary aim being
Hemostasis group recommends initial combination to prevent recurrent hemorrhage and ulceration.
therapy with both epinephrine injection and ther- Emergency surgery has a higher mortality rate
mal coaptive coagulation and/or hemoclipping. An- than elective procedures, and procedures involving
other recommendation is to check with Doppler ul- Figure 8.9
Clot overlying a visible vessel
been obliterated with the endoscopic treatment.
Re-treatment
Rebleeding after endoscopic therapy of UGI ulcers
which occurs in 10-25% of patients, is a challenging
problem21. One large randomized trial showed a sig-
re-treated endoscopically with epinephrine injec-

tion and heater probe, compared with emergency
surgery. These results, together with our own ex-
perience, suggest that repeat endoscopic therapy is
initial hemostasis for ulcer hemorrhage. Endoscopic

combination therapy is recommended for retreat-
ment in those with higher stigmata of hemorrhage.
Now, hemoclipping is more common than thermal
Figure 8.10
-
Combination therapy of adherent clot overlying an ulcer
cant tissue injury but thermal coagulation makes ul-
cers and other lesions larger and deeper and delays
their healing.
Complications of endoscopic hemostasis

Potential complications include perforation, precipi-
tation of bleeding from a non-bleeding visible vessel,
and delayed ulcer healing (which is seen with ther-
mal coagulation, but not hemoclipping). In a meta-
analysis of injection or thermal probe coagulation,
hemorrhage was induced in 0.4% of patients and
perforation in 0.7%. Perforations are more frequent
after endoscopic retreatments.
Figure 8.11 ly surgery in the management of acute GI bleeding

Clean ulcer base associated with peptic disease. Both the death rate
and transfusion requirements were lowered. How-
ever, this approach is probably not generalizable for
patients older than 65 who may have high risk ulcer
surgery.
The choice of operation is related to the sur-
geon’s experience, location of the ulcer, and overall
condition of the patient. Historically, truncal va-
gotomy and antrectomy provided high cure and low
recurrence rates (<3% in some series). Recurrence
rates after vagotomy and pyloroplasty or highly se-
lective vagotomy are higher (2.0-2.5% per year).
With the application of laparoscopic techniques
to ulcer surgery, the laparoscopic approach could
become even more appealing for a small subset of
type ulcer surgery. One study reported that lapa-

roscopic, highly selective vagotomy was a safe and
gastric resection have a higher mortality rate than effective alternative to conventional surgery. There
oversewing the ulcer and highly selective vagotomy was decreased morbidity, shorter hospitalization,
or vagotomy and pyloroplasty. and less recovery time. Peptic ulcer bleeding can be
In recent CURE multicenter studies, fewer than treated effectively with surgery and by experienced
5% needed emergency surgery if endoscopic hemo- surgeons, and it may be safer than some other alter-
stasis was utilized to treat high-risk patients with native treatments such as angiography.
active bleeding, visible vessels, or adherent clots. A
prospective, randomized study from Asia reported
that in patients with peptic ulcers and recurrent Angiographic Therapy
hemorrhage after initial endoscopic coagulation,
Angiography is potentially useful as a diagnostic
endoscopic retreatment reduced the need for sur-
and therapeutic modality. Its main role is in pa-
gery and was associated with fewer complications
tients with severe bleeding in whom endoscopy has
than surgery. Endoscopic therapy is also consider-
failed to reveal the bleeding site, when endoscopic
ably less expensive than emergency surgery for pa-
hemostasis is unsuccessful, or severe rebleeding oc-
tients with bleeding ulcers.
curs. It should also be considered in patients who
are at high risk for surgical intervention. For undi-
in the decision making regarding when to consider
agnosed patients, angiography can identify the site
surgical treatment. Criteria that are based solely
of bleeding if blood loss is occurring at a rate of 0.5
on number of units transfused, and that do not take
ml or more per minute. Extravasation will appear
complete clinical conditions into account, are in-
as a blush, which with duodenal ulcers or gastric
appropriate. Studies comparing early versus later
ulcers may remain localized or spread to a more de-
pendent position.
early surgery, especially for patients older than 60
Angiographic therapy of GI bleeding includes
years. A study in an indigent patient population (for
two different techniques: vasoactive drug infusion
patients often younger than 65 years) described the
and embolization. Intra-arterial infusion of vaso-
-
active drugs such as vasopressin causes vasocon-
cluding early endoscopy (within 24 hours) and ear-
striction, producing cessation of ulcer hemorrhage
in about 50% of cases. Embolic materials, such as and high-dose IV PPIs for therapy of high risk en-
absorbable gelatin sponge (Gelfoam®), tissue adhe- doscopic bleeding lesions, investigators compared
sives, or other occlusion devices, can be selectively the reintroduction of low-dose aspirin or placebo
injected through a catheter into the bleeding artery. for 8 weeks, while also giving patients a daily oral
Potential complications of embolization therapy PPI dose. The incidence of recurrent ulcer bleed-
include ischemia and perforation. In one study of ing at 30 days was twice as high (10.3% vs 5.4%)
angiographic treatment of patients with severe UGI in the low-dose aspirin group compared to placebo
bleeding (average transfusion requirement nine -
units per patient), extravasation occurred in 40% of tients who received low-dose aspirin had decreased
cases. Selective vasopressin infusion and emboliza- all-cause 30 day mortality rates (1.3% vs 10.3%)
tion were similarly successful. compared to the placebo group, and lower mortal-
A recent report from Hong Kong compared ar- ity rates secondary to cardiovascular and cerebro-
terial embolization to surgery as salvage therapy for vascular complications. Current recommendations
patients with ulcer bleeding who had failed endo- suggest that patients with UGI hemorrhage who
scopic hemostasis. The patient population included need secondary cardiovascular prophylaxis should
those who had failed primary endoscopic therapy resume low-dose aspirin treatment as soon as the
and those who had rebled after successful hemosta- cardiovascular risks outweigh the gastrointestinal
sis. Of note, the mean artery diameter in the ulcers risks (usually within 7 days) while remaining on
with continued hemorrhage or rebleeding was 2.6 PPIs4,18. Additionally, the combination of low-dose
mm. In this study, arterial embolization decreased aspirin and PPIs produces less recurrent bleeding
the need for subsequent surgery and reduced com- than a switch to clopidogrel alone.
plications, without increasing mortality rates. Patients with idiopathic (non- , non-
NSAID) ulcers should receive long-term antisecre-
tory therapy with PPIs4.
Follow-Up Medical Management
After the initial bleed is treated endoscopically and
hemostasis is achieved, medical management with
Summary For UGI Bleeding
PPIs is recommended for 6-8 weeks, unless the pa- UGI bleeding secondary to ulcer hemorrhage is a fre-
tient is also Helicobacter pylori positive, requires quent cause of hospitalization and inpatient bleeding,
low dose aspirin maintenance, or uses a non-selec- resulting in substantial patient morbidity and mortal-
tive NSAID. Patients positive for should re- ity. Randomized controlled trials and meta-analyses
ceive eradication therapy and should be retested to show that PPIs improve clinical outcomes in patients
document eradication 6-10 weeks after com- with ulcer hemorrhage. Patients with high-risk endo-
pletion of antibiotics22 scopic stigmata (e.g. arterial bleeding, non-bleeding
maintenance antisecretory treatment is not required visible vessel clot, but not oozing without other SRH)
unless patients also need long-term aspirin, NSAIDs should receive high-dose IV PPI after successful endo-
- scopic treatment for 72 hours. Patients with low-risk
tients should receive PPI maintenance treatment endoscopic stigmata should receive oral PPI at twice
4,16,18
. the usual clinical dose. High dose intravenous PPI
The optimum management approach for pa- therapy before endoscopy appears reasonable but is
tients who develop peptic ulcer bleeding while expensive. For patients with major stigmata of ulcer
receiving antiplatelet therapy, such as low-dose hemorrhage – active arterial bleeding, non-bleeding
aspirin or clopidogrel, or anticoagulants is contro- visible vessel, and adherent clot – combination thera-
versial. In a recent randomized trial in patients py with epinephrine injection and either thermal co-
with peptic ulcer bleeding while on low-dose as- agulation (MPEC or heater probe) or endoclips is rec-
pirin, who had successful endoscopic hemostasis ommended. Oozing bleeding is an intermediate SRH.
Patients with minor stigmata or clean-based ulcer do patient with hematochezia who has had a history of
melena or hematemesis in the last 30 days, a history
be triaged to less intensive care and be considered for of cirrhosis, prior bleeding ulcers or a recent naso-
early discharge. Oral PPI, probably BID, until ulcer gastric aspirate that is positive for blood.
healing is recommended, but these low risk patients Based upon these data, we prefer the term “se-
do not require high dose IV PPI for 72 hours. vere hematochezia” instead of “acute lower GI bleed-
ing,” because the latter can confuse clinicians. In
most ambulatory patients with hematochezia, the
Severe Hematochezia (AKA Lower bleeding stops spontaneously (in about 80%), allow-
ing elective diagnostic evaluation. However, 10-40%
Gastrointestinal Bleeding) of patients with colonic sources of bleeding have re-
current hemorrhage, usually within 48h of the initial
bleed, and these patients with continued and recur-
Introduction And Epidemiology rent severe hematochezia require urgent attention
to minimize further bleeding and complications.
as bleeding from a site distal to the duodenum (most Mortality rates still range between 3-5% because the
commonly the colon), has an annual hospitaliza- incidence of LGI bleeding increases markedly in the
tion rate of about 20 per 100,000 adults. If the pa- elderly, typically >65 yrs of age, and these patients
tient presents with severe hematochezia, clinicians A recent US
cannot determine the site of the lesion clinically as study reported that the all-cause in-hospital mortal-
foregut, midgut or colon. Even without a history of ity rate in LGI hemorrhage was 3.9%. The strongest
or signs of upper gastrointestinal (UGI) lesions, ap- predictors of mortality included advanced age, intes-
proximately 15 – 20% of patients hospitalized with tinal ischemia and comorbid illness23.
severe hematochezia have a foregut (UGI or proximal For patients who present with severe hemato-
jejunum) source of the severe hematochezia. chezia, the diagnostic and therapeutic approach is
From our experience and local algorithms (Fig- not standardized in most medical centers. However,
ure 8.12) we recommend a push enteroscopy in any we have found a standardized approach to be effec-
tive, safe, and cost effective24 (Figure 8.12). During
Figure 8.12 the resuscitation of patients with severe hematoche-
Algorithm severe hematochezia zia, we recommend nasogastric (NG) aspiration to
exclude a potential UGI source. If this is negative (no
bile or blood), then a rapid oral lavage to cleanse the
colon is recommended, followed by urgent colonos-
copy. Urgent colonoscopy provides an accurate diag-
nosis and if required, an opportunity for hemostasis
during the same examination. If urgent colonoscopy
is not diagnostic for a bleeding site, a slot anoscopy
examination is indicated to exclude anal canal bleed-
ing sources (such as internal hemorrhoids or anal
is recommended to exclude foregut lesions, because

some patients have post-bulbar bleeding sites which
cannot be seen with a standard endoscope. This ap-
proach improves the diagnostic and therapeutic ef-
24
(Figure 8.12).
Our primary criterion for proving (i.e. classifying comorbidity) were allocated to less intensive and
less expensive care, which often facilitated early dis-
bleeding is to identify stigmata of recent hemorrhage charge. As with non-variceal UGI hemorrhage, risk
– SRH - (such as active bleeding, non-bleeding visible -
- Doppler ultrasound probe. Elimination of underlying

tive cause” of the bleeding when fresh blood is in that -
location (such as the colon) or a lesion is found there cantly reduces rebleeding.
without stigmata and no other likely bleeding sites are
enteroscopy and capsule endoscopy. A lesion (such as Causes

diverticulosis found during the colonoscopy) is clas-
Diverticulosis
Diverticular bleeding is the most common colonic
of lesions are found; another lesion is the bleeding
etiology found in patients hospitalized with severe
site based upon stigmata of recent hemorrhage; or
hematochezia. Although anatomically diverticulo-
there is other endoscopic evidence to suggest this le-
sis involves most often the sigmoid and descending
sion as the primary bleeding site, such as its extent,
colon (about 70%), diverticular bleeding originates
ulceration, or number of lesions.
frequently (about 50%) from the right half of the co-
These diagnostic criteria were prospectively
applied to study 647 consecutive patients hospital-
bleeding colonic diverticula have been treated with
ized because of severe hematochezia. Although all
epinephrine injection, multipolar probe coagulation
patients were presumed to have colonic sources of
(MPEC) or hemoclips. We have carefully evaluated
bleeding at presentation, about 25% did not. Up to
17.5% had an UGI source (such as an ulcer, varices,
hemorrhage25,26 -
or angiomas), 4.6% had a small bowel source (identi-
tive bleeding (Figure 8.13), a visible vessel (Figure
8.14), or adherent clot (Figure 8.15) associated with
-
a single diverticulum. Of 340 patients with severe
lonic sources of hemorrhage in this study.
colon bleeding and diverticulosis, 20% had stigmata
The most common colonic causes of hemorrhage
presumptive diverticular bleeds, and 46% had an-

internal hemorrhoids, ischemic colitis, rectal ulcers,
delayed bleeding from post-polypectomy ulcers, co-
rectum, colon, small intestine or foregut (inciden-
lon polyps or cancer, and colon angiomas or radiation
tal diverticulosis) when complete evaluations were
performed25,26. Forty-nine (49) patients with SRH
also permitted triage of patients to level of care. High
received epinephrine injections and either MPEC or
risk patients (with SRH) were treated with colono-
hemoclipping of the SRH during urgent colonoscopy.
There were no initial treatment failures. The 30 day
lesions was made. This usually included combination
rebleeding rate was 12% (all after resuming antico-
therapy with dilute epinephrine injection (1:20,000
agulation for severe comorbidities); 6% required
dilution in saline) and hemoclipping (for acute le-
interventional radiology (IR) embolization or sur-
gery, and there was 1 complication (post-coagulation
Coagulation (usually with multipolar probe-MPEC)
syndrome). Their median discharge was 2 days after
was used for some focal lesions,angioma syndromes,
colonoscopy. In contrast, 34 other patients with de-
SRH on necks of diverticula, or chronic rectal or post-
polypectomy ulcers causing bleeding. Low risk pa-
or recurred, surgery or angiographic embolization

Figure 8.13 Figure 8.15

Bleeding diverticulum Clot on diverticulum
was performed. For these 34 patients, the rate of

continued bleeding or rebleeding was 50%, and 35% drugs (NSAIDs), anticoagulants and gingko. Based on
required surgery or embolization. The median hos- recent evidence, they were not asked to avoid small
pital time of this cohort was 5 days. All outcomes hard seeds, popcorn or nut shells. Only 11% of the
patients rebled from diverticula during a 4-year fol-
hemostasis group25,26. low-up period25,26. However, similar to initial diagno-
For long-term follow-up to assess further bleed- sis of “incidental diverticulosis,” 10% of the patients
ing or diverticular complications, all patients were had recurrent hematochezia from non-diverticular,
colonic sources. This rebleeding rate is substantially
and stool softeners to control constipation; absti- lower than the 50% rebleed rate for diverticulosis
within 5 years quoted in the surgical literature.
Figure 8.14
Others have reported primary hemostasis of
Diverticulum with non-bleeding visible vessel
acute diverticular bleeding with epinephrine injec-
tion and/or multipolar coagulation, but up to 38%
early rebleeding rates (within 30 days). In another
study epinephrine injection followed by endoclip
placement achieved hemostasis in all 11 patients
with acute diverticular bleeding. Late recurrent
hemorrhage (within 15 months) occurred in 2 pa-
tients (18%).
The location of the SRH in a diverticulum is im-
-
lar hemorrhage, the SRH was found about 50% of the
time in the neck and 50% in the base. Active bleed-
ing occurred more frequently in the base, and non-
bleeding visible vessel more frequently in the neck26.
We treat active bleeding (Figure 8.13) or adherent
clots (Figure 8.15) with a 1:20,000 epinephrine/sa- tation, stool softeners, rectal suppositories and sitz
line solution in 1-2 ml aliquots injections in divertic- baths. Despite medical treatment, bleeding may be
ula with SRH in the base, to decrease active hemor-
rhage and improve visualization. After epinephrine and microcytic anemia. Occasionally, internal hem-
injection, adherent clots can be safely guillotined off orrhoids may bleed profusely and require hospital-
with a rotatable snare to shave them down, similar ization and emergency hemostasis27 (Figure 8.17).
to peptic ulcers with adherent clots. After the bleed- Prior to assuming that severe hematochezia is
ing stops and for non-bleeding visible vessels (Fig- from more proximal lesions, the anal canal should
ure 8.14), either thermal coagulation (with MPEC) if always be examined by rigid slotted anoscope. If
on the neck of the diverticulum or endoclips if in the that technique is not diagnostic, then the anal canal
base of the diverticulum are applied across the non-
bleeding visible vessel on either side to occlude the
underlying feeding artery26 (Figure 8.16). This usu- active bleeding from internal hemorrhoids or SRH
-
may also be useful as radiologic targets for angiog- sis and facilitate bedside treatment. For inpatients
raphy if hemostasis fails or severe rebleeding occurs. with severe hematohezia, we recommend rubber
We also advocate India ink labeling of the diverticu- band ligation for emergency hemostasis of bleeding
lum with SRH after successful endoscopic hemosta- internal hemorrhoids27 (Figure 8.17). Emergency
sis. This facilitates localization and follow-up of the colonoscopy can be obviated in such cases, although
bleeding site, endoscopic retreatment (if necessary), an elective colonoscopy should still be considered in
surgery in case of early rebleeding, and histopatho- patients at risk for concomitant polyps or colorectal
logic correlation. cancer. Hemorrhoidal surgery is only recommended
for patients with continued severe bleeding who fail
were studied with a Doppler probe before endoscop- anoscopic treatment with banding and concomitant
- medical therapy.
Focal Ulcers or Colitis

by successful MPEC or hemoclip placement, but not
by epinephrine injection alone26. Table 8.7
Eight most common colonic sources of severe hematochezia
(486 cases)
Internal Hemorrhoids
Internal hemorrhoids are the most common cause
of colonic bleeding in ambulatory outpatient adults. Diagnosed lesion Frequency (%)*
Internal hemorrhoids are also the second most com- 1. Diverticulosis 31.9%
mon cause of severe hematochezia in patients hos- 2. Internal hemorrhoids 12.8%
pitalized with presumed colonic hemorrhage, ac- 3. Ischemic colitis 1.9%
cording to a recent Center for Ulcer Research and 4. Rectal ulcers 7.6%
Education (CURE) study. The medical history is re- 5. Colon angiomas or radiation
vealing because all such patients with severe hema- 7.0%
telangiectasia
tochezia or bleeding from internal hemorrhoids have
6. Ulcerative colitis, Crohn’s, other
recurrent BRB. Internal hemorrhoids are a plexus 6.2%
colitis
of veins above the squamocolumnar junction in the
7. Other LGI diagnoses 5.6%
rectum. Most internal hemorrhoid bleeding is self-
8. Post-polypectomy ulcer 4.7%
limited, manifested by bright red blood on the toilet
* Expressed as percent of colorectal sources
-
Figure 8.16 from a post-polypectomy induced ulcer bleeding

Hemoclips on non-bleeding visible vessel has increased in the last 2 decades, most likely due
to the increase in colonoscopy use for colorectal
cancer screening and the subsequent greater num-
ber of polypectomies. Most of our patients have
resumed taking over-the-counter (OTC) aspirin,
NSAIDs, anticoagulants (warfarin or clopidogrel),
health food store products that can induce bleeding
-
ter polypectomy and many had large sessile polyps
removed by piecemeal polypectomy28. For patients
who re-present to the hospital with severe hemato-
chezia after recent polypectomy, we recommend an
oral purge prior to colonoscopy. Colonoscopy usu-
Focal ulcers proximal to the sigmoid colon are an un-
ally reveals an ulceration at the site of a recent pol-
common cause of severe colonic hemorrhage. In one
ypectomy with a SRH on an ulcer. We treat such SRH
large series, these accounted for the bleeding site in
with endoscopic hemostasis, usually with combina-
8% of patients (Table 8.7). Bleeding colonic ulcers
tion therapy. Doppler ultrasound probe can improve
were caused by: recent polypectomy with ulceration
hemostasis. The focal nature of the delayed bleeding

ischemic ulcers, or infectious colitis (such as pseu-
from a post-polypectomy induced ulcer and frequent
domembranous colitis or cytomegalovirus - -
SRH facilitate endoscopic diagnosis and hemostasis.
ulcers). In our recent experience, the most common
Results are better in clinical outcomes than other co-
cause was delayed bleeding from a post-polypecto-
lonic etiologies of severe hematochezia, as detailed
my induced ulcer. The median time to severe colonic
in a recent CURE study of delayed bleeding from a
bleeding was 8 days (range 5 h to 17 days) after ini-
post-polypectomy induced ulcer.
tial polypectomy of colonic polyps (Figure 8.18). In
our experience, the prevalence of delayed bleeding Ischemic Colitis
Figure 8.17 Ischemic colitis is the most common form of ischemic
Internal Hemorrhoids – post-banding injury to the gastrointestinal tract. It is the third
most frequent colonic etiology of severe hematoche-
zia, and the second most common cause of inpatient
hematochezia, in a recently reported CURE study of
severe hematochezia.
Ischemic colitis occurs more frequently in the
elderly, especially with associated co-morbid con-
ditions. Other risk factors include cardiac disease,
recent major surgery, sepsis, hypertension, diabe-
tes, chronic renal failure, vasculitis, hypercoagulable
state, and medications such as digitalis, diuretics, es-
trogen, cocaine, pseudoephedrine, NSAIDs and alos-
etron.
and safe method to diagnose colonic ischemia and

exclude other forms of colitis. Early colonoscopy af-
ter cleansing the colon with purge in suspected cases
- cases, Doppler ultrasound probe scanning and hemo-

tion. Although the descending colon and splenic or
- Ischemic colitis should be considered in the dif-
age, complete colonoscopy is necessary to rule out ferentiated diagnosis of severe hematochezia, with
proximal colonic ischemia. Total colonic ischemia an emphasis on early recognition both for diagnosis
has a worse prognosis than segmental colonic isch-
emia. Right –sided colonic ischemia is associated -
with poorer outcomes than other colonic involve- nosis.
ment. Most (75-85%) patients have self-limited
ischemic colitis and improve with supportive medi- Rectal Ulcers
cal treatment. However, in elderly patients with as- Rectal ulcers may be a cause of severe lower GI hem-
sociated comorbid illnesses or those patients with orrhage especially in elderly or debilitated patients
vessel infarction, urgent surgical therapy is required
and morbidity is substantial. The ulcers may be either solitary or multiple, and as-
Our recent experience suggests that compared sociated with fecal impaction, rectal prolapse, isch-
to patients with non-ischemic colonic etiologies emia or trauma. In one series of patients with severe
causing severe hematochezia, ischemic colitis pa- hematochezia, 23 of 285 (8%) patients had rectal
tients had most of the time (> 85% of cases) diffuse ulcers found during colonoscopy30. Twelve of 23 pa-
mucosal involvement (Figure 8.19) without stigmata tients had major SRH, such as active bleeding (Figure
- 8.20), visible vessel, or adherent clot. This subgroup
scopic hemostasis); had clinical outcomes that were was treated endoscopically with combination hemo-
stasis techniques30. Initial hemostasis was successful
diagnoses; and in-patient ischemic colitis patients in patients with rectal ulcers and SRH, but recurrent
bleeding was frequent, especially in patients with in-
rebleeding and surgery, and longer hospital and inpatient hematochezia, suggesting that this group of
tensive care unit stays) than if the ischemic colitis oc- patients was at especially high risk for rebleeding.
curred as an outpatient29. In a minority of ischemic
colitis cases, focal lesions with SRH occur and are
Colonic Tumors
Colonic tumors, either cancer or stromal tumors, oc-
amenable to endoscopic hemostasis. In those focal
casionally present with hematochezia and may oc-
Figure 8.18 cur anywhere in the rectum or colon. Overt bleeding
Clot on post-polypectomy ulcer suggests that the lesion has ulcerated into underly-
ing vessels, usually an artery. Although endoscopic
therapy with thermal devices, injection, or hemoclips
combination therapies usually produces temporary
hemostasis, surgical resection is the best long-term
treatment14.
Colonic Angiodysplasia
Bleeding colonic angiodysplasias most often occur
in the right colon and are usually multiple or dif-
fuse (Figure 8.21). They may be associated with ad-
vanced age and medical conditions such as chronic
and collagen vascular disorders. Bleeding from an-

giodysplasia is usually mild to moderate and is self-
limited. Such bleeding is usually intermittent and
Figure 8.19 3% and 1.7% of patients, respectively) treated with

Ischemic colitis MPEC probe. In contrast, heater probe has been as-
sociated with an approximately 8% and APC with a
10% complication rate in patients with severe hem-
orrhage from right colon angiomas. No perforations
occurred with these devices. However, perforations
have been reported more often than with MPEC for
hot biopsy forceps, monopolar electrocoagulation,
Nd-YAG laser, or argon plasma coagulator (APC) he-
mostasis of right colon angiodysplasia. This relates
to deeper coagulation and the potential for transmu-
ral coagulation with these non-MPEC thermal devic-
es. Related to dissection of coaxial gas, pneumoperi-
toneum or pneumatosis coli have also been reported
with APC, and argon or YAG laser treatments of co-
lonic angiodysplasia.
Radiation Telangiectasia
Radiation telangiectasia can occasionally cause se-
vere hematochezia, although these are most often as-
usually presents with slow GI bleeding and chronic sociated with mild to moderate chronic rectal bleed-
ing. Chronic radiation injury and GI bleeding develop
performed randomized, prospective studies compar- months to years after radiation therapy for prostatic,
ing patient outcomes for angiodysplasia treated with gynecologic, rectal or bladder tumors. The radiation
heater or multipolar electrocautery (MPEC) probe3. damage is caused by altered vascularity and ensuing
Patients often required more than one session of en- mucosal ischemia. Rectal telangiectasia and friabil-
doscopic hemostasis to obliterate multiple colonic ity are the endoscopic features of radiation proctitis.
angiomas. The main risk of endoscopic coagula- Endoscopic hemostasis with thermal treatment has
tion of angiodysplasia is severe, delayed bleeding been effective and safe for patients with chronic or
and post-coagulation syndrome (which occurred in recurrent acute bleeding despite medical therapies14.
Figure 8.20
Bleeding diverticulum General Measures And Diagnosis
As in upper GI hemorrhage, several tools for risk
bleeding to identify potential patients who may ben-

-
mostasis.
Risk factors including abnormal vital signs 1
hour after initial medical assessment (suggesting he-
modynamic instability), gross blood on initial rectal
examination, (suggesting continued bleeding), initial
reported to be independent predictors of severe

lower GI bleeding and adverse outcomes31 ). Patients
with these high-risk factors should have urgent di-
agnosis and receive focused therapy with the aim of which also provides potential therapeutic interven-
improving outcomes. tion32. The diagnostic yield of colonoscopy in severe
- hematochezia ranges from 48% to 90%. Several fac-
vere hematochezia should be to start aggressive re- tors determine the “yield” including timing of colo-
suscitative measures in a monitored care setting14,32. noscopy, thoroughness of colonic preparation, and
An orogastric or nasogastric tube is recommended to 32
.
determine whether evidence of UGI bleeding (coffee A randomized controlled trial of urgent colo-
grounds, blood clots) is present. In the patient with noscopy versus standard care (tagged red blood cell
- scan, followed by angiography, if positive, with elec-
potension are usually present, along with nasogastric
tube evidence of bleeding if the hemorrhage origi- -
nates from the UGI tract. If there is bile without blood gent colonoscopy but failed to reveal any other sta-
or coffee grounds in the nasogastric aspirate, a lesion -
proximal to the ligament of Treitz is unlikely when on- comes. This study has been criticized for the overall
going hematochezia is documented. In patients with poor quality of the colon preparation in the urgent
colonoscopy group (by limiting the purge to only 4
bile should not be considered a negative nasogastric liters), for the small sample size, early termination
tube aspirate. Since continuity has not been estab- of the study, and failure to use current combination
lished between the nasogastric tube in the stomach
and the duodenum, the patient may have a duodenal with SRH.
ulcer or other duodenal lesions. In addition, 1% to Subsequently, several studies have reported that
5% of patients who present with severe hematoche-
zia have a small bowel source of hemorrhage14. hospital stay and direct costs.
In a retrospective study comparing early colo-
noscopy to angiography for severe lower intestinal
Colonoscopy
Figure 8.21
Prior to preparation for emergency colonoscopy, tap Ascending colon large angioma
water enemas are recommended to clear the distal
colon and permit examination of the rectosigmoid
-
in selected patients (Figure 8.12). This is particularly

indicated in patients with a history of bleeding inter-
nal hemorrhoids, anorectal disease, colitis (IBD, id-
iopathic or antibiotic associated), or recurrent diar-
rhea. A rigid sigmoidoscopy is not adequate because
there may be lesions in the blind area of the rectum,
which cannot be seen with a rigid instrument.
If no evidence of UGI bleeding is found (e.g. there
is bilious return on nasogastric tube lavage) and the
a rectosigmoid source of hemorrhage, cleansing the

colon with an oral purge is recommended, followed
by urgent colonoscopy in the monitored bed area or
ICU when the colon is clear of stool and clots by the
purge. Urgent colonoscopy is a safe diagnostic test,
hemorrhage, the likelihood of post-polypectomy 60 min., and 4 hrs.) is recommended to identify

bleeding and logistical factors such as admission on
a weekday or late in the day predicted early colonos- localization and etiologic diagnosis are not possible
copy, while signs and symptoms of severe bleeding
predicted angiography use. as angiography and/or endoscopy or enteroscopy
Should the colonoscopy, anoscopy and push en- are recommended prior to surgical exploration.
teroscopy not be diagnostic, then scintigraphy and Delayed scans (12 to 24 hrs) are not reliable for
angiography are warranted in patients with recur- localization in the gut, particularly as a guide for
rent hematochezia. We also recommend capsule en- surgical exploration, because blood in the gut (with
doscopy for patients with severe hematochezia who the radionucleotide) moves between scans and
have negative colonoscopy and push enteroscopy. In localization on delayed scans can be misleading.
our experience, urgent capsule endoscopy provides a
greater diagnostic yield than combined scintigraphy
and angiography, and an overall rate of bleeding site Angiography, Magnetic Resonance
localization of about 50%. For those patients who Imaging (Mri), Computed Tomography (Ct)
stop bleeding or present with less severe bleeding, and Barium X-Rays
colonoscopy within 24 hours of presentation should
If the rate of ongoing arterial bleeding is at least 0.5
still be considered the initial diagnostic and thera-
ml/min, selective visceral angiography may show ex-
peutic procedure of choice (Figure 8.12).
travasation of contrast into the lumen to identify a
bleeding site. Emergency visceral angiography can
be useful for diagnosis and treatment of colonic,
Scintigraphy
small bowel, or UGI lesions.
The threshold rate of GI bleeding for localization Two recent studies suggested that mesenteric
with radioisotope scanning is about 0.1 ml/min or angiography may have an important role in the di-
more. Scintigraphy may be particularly useful for agnosis and management of patients with acute LGI
hemorrhage. If extravasation of contrast into the gut
that are actively bleeding and at least moderately -
severe. Two different types of scintigrams are ten effective, with relatively low rebleeding (20%)
available: (a) sulfur colloid with technetium and and ischemic complication (10%) rate. However,
(b) autologous red blood cells (RBCs) tagged with in one study, 65% of patients with LGI hemorrhage
technetium. Sulfur colloid is rapidly cleared from who had failed endoscopic therapy had a negative
the circulation after intravenous (IV) injection but angiographic study; only 47% of patients with LGI
may extravasate into the gut lumen during active bleeding had angiography showing a source of hem-
bleeding and is not commonly used now. Repeat orrhage; and 57% of patients continued to bleed af-
IV injection may be performed. In contrast, tagged ter angiography. The majority of patients with LGI
RBCs stay in the vascular space for about 24 hours.
Technetium-tagged RBC scans are more commonly Major advancements in radiology, such as helical
used than sulfur colloid scan for patients with severe computed tomography (CT) or magnetic resonance
hematohezia suspected from a small bowel source or imaging (MRI) angiography, are being used in some
whose site was not found by emergency endoscopy centers instead of standard visceral angiography in
and colonoscopy. In many institutions, scintigraphy the diagnosis of patients with severe hematochezia.
has replaced emergency visceral angiography as an A multidetector row CT (MDCT), which can show
adjunct to colonoscopy, because scintigraphy is more contrast extravasation into the GI tract, is being eval-
uated as a potential diagnostic tool. In animal mod-
lower morbidity than angiography. Injection of els, bleeding rates from 0.3 to 0.5 ml per minute have
labeled RBCs and early scanning (at least 30 min., been reported using the MDCT.
Abdominal CT or MRI may be helpful for diag- surgical intervention in our patients with persistent
or recurrent severe hematochezia. Emergency sur-
with severe vascular disease and continued severe gery should be considered for patients with: (1) hy-
hematochezia. For patients with a previous diagno- potension or shock, despite resuscitative efforts, (2)
sis of severe peripheral vascular disease or abdomi- continued bleeding with transfusion of six or more
nal aneurysm with or without surgery, the physician units of blood and no diagnosis by emergency en-
should consider performing one of these tests for di- doscopy (push enteroscopy, colonoscopy, and anos-
agnosis of severe hematochezia, if colonoscopy and copy), and (3) when severe active bleeding cannot be
enteroscopy do not identify a bleeding site. Most pa- controlled by colonoscopy or angiography. Segmen-
tients with severe hematochezia do not require such tal resection after the bleeding site has been identi-
diagnostic testing because they do not have large
abdominal aneurysms or a past surgery for this di- of about 7%. “Blind” segmental resection or subtotal
agnosis. colonoscopy are associated with much higher mor-
Barium studies (barium enema or small bowel tality rates, ranging from 25-57%.
follow-through) have no role in the emergency as-
sessment of severe hematochezia since they cannot
demonstrate active bleeding or SRH. Barium also Summary For LGI Bleeding
takes several days to clear the colon or small bowel
Severe hematochezia remains a challenging medi-
and this interferes with subsequent evaluation or
cal, surgical, and interventional radiology problem.
treatment by colonoscopy, angiography, or surgery.
of the cause and localization of the bleeding are es-

sential for patient management. Urgent colonoscopy
Small Bowel Evaluation after adequate purge is recommended and should be
As an emergency examination, a small bowel evalu- performed by experienced endoscopists with the ex-
ation with push enteroscopy is indicated for those pertise to recognize, localize and treat stigmata of
patients with negative colonoscopy and upper en- hemorrhage in the colon with appropriate hemosta-
doscopy. Standard push enteroscopy provides ex- sis techniques. With this approach, patients can be
amination of the proximal 60-80 cm of the jejunum14. effectively managed with decreased rebleeding rates
We recommend capsule endoscopy in patients with as well as reduced transfusion requirements, median
severe recurrent hematochezia who do not have a hospital stays and direct costs of medical care.26,32
diagnosis or localization made by urgent colonos-
copy, anoscopy, push enteroscopy, and RBC scanning.
Deep enteroscopy is now also possible with tech- Pearls and Pitfalls
niques such as single or double balloon enteroscopy
and overtubes. This may be indicated in selected
for the Board Exam:
patients with small bowel lesions, documented or
Peptic ulcer disease is the most common cause of
suspected positive capsule endoscopy, RBC scans or
UGI bleeding.
angiography.
Resuscitation and stabilization should be the initial
management steps in caring for a patient with acute
UGI bleeding.
Emergency Surgery After initial stabilization and resuscitation, the
Although both colonoscopy and angiography are po- management of a patient with UGI bleeding should
tentially diagnostic and therapeutic, urgent surgery include determining the source of bleeding, stopping
is indicated if colonic bleeding is massive, persists, or the acute hemorrhage, treating the underlying
abnormality and preventing rebleeding.
Endotracheal intubation for airway protection should bowel movements, complains of light headedness,
be considered in patients with UGI bleeding and and is found to be hypotensive and anemic,
altered mental status and ongoing hematemesis. nasogastric tube placement should be the next step
NSAIDs are important risk factors for peptic ulcer after appropriate resuscitation.
bleeding. In this same patient, if urgent upper endoscopy
Active ulcer bleeding and an ulcer with a non- and colonoscopy are negative, scintigraphy and
bleeding visible vessel are indications for endoscopic angiography should be the next diagnostic tests.
therapy. Endoscopic therapy of a bleeding diverticulum
Ulcers with a flat spot or black slough, or an ulcer includes epinephrine injection and either multipolar
with a clean base do not require endoscopic therapy. electrocoagulation or hemoclipping.
For a patient who stabilizes following a severe UGI A definitive diverticular hemorrhage is defined as
bleed associated with NSAID ingestion, and who the finding of stigmata of recent hemorrhage-active
tests positive for H. pylori, management includes bleeding, visible vessel or adherent clot, associated
stopping NSAIDs, eradicating H. pylori and proton with a single diverticulum.
pump inhibitor maintenance therapy.
Patients with UGI hemorrhage who require secondary
cardiovascular prophylaxis should resume low-dose
aspirin treatment within 7 days while remaining on
twice daily PPIs. for Examination Preparation
PPI maintenance therapy is recommended for a Laine L, Jensen DM. Management of patients with
patient with UGI hemorrhage caused by an NSAID- ulcer bleeding. Am J Gastroenterol. 2012; 107:345-
related gastric ulcer who needs to continue NSAID 360.
treatment, Barkun AN, Bardou M, Kuipers EJ et al. International
Surreptitious NSAID ingestion is the most likely Consensus: Recommendations on the management
cause of recurrent benign ulcer bleeding. of patients with nonvariceal gastrointestinal
Patients at low risk for recurrent bleeding are bleeding. Ann Intern Med. 2010;152:101-13.
candidates for outpatient management. These Jensen DM. The ins and outs of diverticular
include young age, absence of associated medical bleeding. Gastrointest Endosc. 2012; 75:388-91.
problems, hemodynamic stability and absence of Strate LL, Naumann CR. The role of colonoscopy
SRH. and radiological procedures in the management of
Mallory-Weiss tear, angiodysplasia, watermelon acute lower intestinal bleeding. Clin Gastroenterol
stomach and Dieulafoy’s lesions are other less Hepatol. 2010;8:333-43.
frequent causes of UGI bleeding.
In a patient with UGI bleeding and a suspected
aortoenteric fistula, an abdominal CT scan with
intravenous contrast should be the next step after a References
negative upper endoscopy. 1. Laine L, Yang H, Chang S-C, Datto C. Trends for incidence
The two most common causes of severe of hospitalization and death due to GI complications in
the United States from 2001 to 2009. Am J Gastroenterol.
hematochezia requiring hospitalization are
2012; 107: 1190-95.
diverticulosis and internal hemorrhoids.
2. Kovacs TOG, Jensen DM. “Complications of peptic ulcer
Appropriate resuscitation and urgent colonoscopy disease” in Gastrointestinal Disease: An Endoscopic Ap-
after vigorous bowel preparation will produce the proach. Dimarino Jr. AJ,Benjamin SB, Eds. Slack Thoro-
highest yield for diagnosis and therapy in an elderly fare NJ. Pp 411-438. 2002.
patient hospitalized with painless hematochezia. 3. Kovacs TOG. Mallory-Weiss Tears, Angiodysplasia, Wa-
termelon Stomach, and Dieulafoy’s: A Potpourri. Tech-
In a patient who presents with painless bloody
niques in Gastrointestinal Endoscopy. 2005;7:139-147.
4. Laine L, Jensen,DM. Management of patients with ulcer 19. Jensen DM, Kovacs TOG, Jutabha R, et al. Randomized
bleeding. Am J Gastroenterol. 2012;107: 345-60. trial of medical or endoscopic therapy to prevent recur-
5. Kovacs TOG, Jensen DM. Upper or small bowel hemor- rent ulcer hemorrhage in patients with adherent clots.
rhage that presents as hematochezia. Techniques in Gas- Gastroenterology 2002 123:407-413.
trointestinal Endoscopy 2001;3:206-215. 20. Kahi CJ, Jensen DM, Sung JJ, et al. Endoscopic ther-
6. Carbonell N, Poulwels L, Boelley PY et al. Erythromycin apy versus medical therapy for bleeding peptic ulcer
infusion prior to endoscopy for acute upper gastrointas- with adherent clot: a meta-analysis. Gastroenterology.
tinal bleeding: a randomized, controlled trial. Am J Gas- 2005;129:855-62.
troenterol 2006;101:1211-1215. 21. Jensen DM. Treatment of Patients at High Risk for Re-
7. Winstead NS, Wilcox CM. Erythromycin prior to en- current Bleeding from a Peptic Ulcer. Ann Intern Med
doscopy for acute upper gastrointestinal hemorrhage: 2003;139:294-295.
a cost-effectiveness analysis. Aliment Pharmacol Ther 22. McColl KEL. Helicobacter pylori infection. N Engl J Med.
2007;15:1371-1377. 2010;362:1597-604.
8. Lau JY, Sung JJ, Lee KK, et al. Effects of intravenous 23. Strate LL, Ayanian JZ , Kotler G, Syngal S. Risk factors for
omeprazole on recurrent bleeding after endoscopic mortality in lower gastrointestinal bleeding. Clin Gastro-
treatment of bleeding peptic ulcers. N Engl J Med enterol Hepatol. 2008;6:1004-10.
2000;343:310-316. 24. Jensen DM. Management of Patients with Severe He-
9. Sung JJY, Chan FKL, Lau JYW. The effect of endoscopic matochezia – with all current evidence available. Am J
therapy in patients receiving omeprazole for bleeding ul- Gastroenterol. 2005;100:2403-2406.
cers with non-bleeding visible vessels or adherent clots. 25. Jensen DM, Machicado GA, Jutabha R, Kovacs TOG.
Ann Intern Med 2003;139:237-243. Urgent colonoscopy for diagnosis and treatment of se-
10. Leontiadis GI, Sharma VK, Howden CW. Proton pump vere diverticular hemorrhage. N Engl J Med 2000;342:78-
inhibitor treatment for acute peptic ulcer bleeding. Co- 82.
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11. Leontiadis GI, Sharma VK, Howden CW. Systematic re- Gastrointest Endosc. 2012;75:388-91.
view and meta-analysis: enhanced efficacy of proton 27. Ohning GV, Machicado GA, Jensen DM. Definitive thera-
pump inhibitor therapy for peptic ulcer bleeding in Asia py for internal hemorrhoids – new opportunities and op-
– a post hoc analysis from the Cochrane Collaboration. tions. Rev Gastroenterol Dis. 2009;9:16-26.
Aliment Pharmacol Ther 2005;21:1055-1061. 28. Sawhney MS, Salfiti Y, Okamoto A, et al. Risk factors for
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13. Lau JY, Leung WK, Wu JCY, et al. Omeprazole before emic colitis as a cause of severe hematochezia: risk fac-
endoscopy in patients with gastrointestinal bleeding. N tors and outcomes compared with other colon diagno-
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doscopic diagnosis and therapy of upper gastrointesti- cent hemorrhage on rectal ulcers in patients with severe
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2007;10:143-148. 2010;8:333-43.
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Intern Med . 2010;152:101-113.
CHAPTER 9
Gastrointestinal Cancers
Barbara H. Jung, MD
Learning Objectives
1. Review the epidemiology of various gastrointestinal cancers.
2. Identify risk factors for various gastrointestinal cancers.
3. Identify typical clinical presentations of the various gastrointestinal cancers.
4. Review the defined hereditary gastrointestinal syndromes.
5. Review current screening, surveillance, and prevention strategies for the various gastrointestinal cancers.
Cancer of the Esophagus

While esophageal cancer incidence worldwide is high, the incidence of esophageal cancer remains relatively
low in the United States, with 17,460 cases occurring in 2012 (Table 9.1)1. In most developed countries, the
incidence of esophageal adenocarcinoma has now surpassed esophageal squamous cell cancer.
Epidemiology
The incidence of esophageal squamous cell carcinoma varies by world region: in areas where it is endemic (Mid-
dle East, Southeast Asia), the incidence is greater than 100 in 100,000, equally affecting men and women. In
developed countries, the incidence is lower, with a predilection for males. The risk factors vary by region. In
endemic areas, carcinogenic food components such as nitrosamines, fungal contaminants, and human papil-
loma virus have been implicated, while the majority of cases in the United States are attributed to alcohol and/
or tobacco consumption. The risk is threefold higher in those of African American descent over white counter-
parts. A number of esophageal diseases can increase the risk of developing esophageal squamous cell cancer
(Table 9.2), including esophageal strictures; lye ingestion (poses a 1000-fold risk); Plummer-Vinson syndrome
-
nant disease caused by a gene defect at chromosome 17q25 and characterized by hyperkeratosis, esophageal
papillomas, and oropharyngeal leukoplakia); Fanconi’s anemia, especially following bone marrow transplant;
celiac disease; scleroderma with esophageal involvement; and achalasia. Esophageal cancer in association with
esophageal diverticula has also been described in elderly men.
Esophageal adenocarcinoma has increased dramatically in white men (8:1 vs. women) in developed coun-
has also been implicated as a risk factor. There appears to be an inverse relationship between esophageal ad-
245
Table 9.1 During the development of esophageal adeno-

Incidence and Mortality of Gastrointestinal Cancers in the United States, carcinoma, there appears to be a stepwise accumula-
2012 tion of mutations within the gene (occurs early
in the pathogenesis), encoding an inhibitor of cell
Male Female cycle progression, and mutations in the p53 gene (oc-
Cancer Incidence Deaths curs later in the pathogenesis, just prior to malignant
incidence incidence
transformation), encoding a tumor suppressor pro-
Esophageal* 17,460 13,950 3,510 15,070 tein involved in cell cycle and DNA repair. Aneuploidy
is often a feature of esophageal adenocarcinoma and
Gastric 21,320 13,020 8,300 10,540 may include activation of oncogenic as well
as increased expression of endothelial growth factor
Small Intestine 8,070 4,380 3,690 1,150 (EGF).
Pancreas 43,920 22,090 21,830 37,390
Liver and intra- Symptoms/Clinical Signs

28,720 21,370 7,350 20,550
hepatic duct Both esophageal squamous cell carcinoma and ad-
Gallbladder and enocarcinoma present clinically in a similar fashion.
9,810 4,480 5,330 3,200
other biliary Patients develop progressive dysphagia to solids,
weight loss, odynophagia when the mediastinum is
Colorectal 143,460 73,420 70,040 51,690
involved, hoarseness from recurrent laryngeal nerve
*Includes squamous and adenocarcinoma. Adapted from Siegel R, Naishadham D, and Jemal A.
Cancer Statistics, 2012. CA Cancer J Clin 2012;62:10–29. damaged epithelium. Often, these symptoms are as-
sociated with advanced disease.
enocarcinoma and Helicobacter pylori infection, simi-
lar to that observed between infection and
Barrett’s esophagus. The protective effect has been Diagnosis
postulated to stem from decrease in gastric acid
Esophagogastroduodenoscopy (EGD) with biopsies is
secretion with infection reducing the oc-
the procedure of choice to identify early lesions, and
currence of GERD, thereby minimizing subsequent
to provide histological samples for evaluation. Bar-
formation of Barrett’s metaplasia and esophageal
ium contrast studies, which is the preferred test to
adenocarcinoma alike.
evaluate dysphagia, and/or computed tomography
(CT) of the thorax can detect high-grade strictures or
Etiology/Pathogenesis
Squamous cell carcinoma arises from the midesoph-
agus with early invasion of the submucosa as well as Staging
regional lymph nodes. Direct invasion may lead to
Esophageal cancer stages are listed in (Table 9.3). Lo-
catastrophic gastrointestinal bleeding when the aor-
cal and distant metastases are often assessed by CT
ta is involved or aspiration as a result of developing a
of the thorax and abdomen. However, local and re-
gional disease with discernment of depth of invasion
Adenocarcinoma arises from the distal esopha-
and lymph node involvement, particularly the ce-
gus and has intestinal-type features with mucin
liac lymph nodes (more common in esophageal ad-
production. As in squamous cell cancer, local lymph
enocarcinoma), is best determined with endoscopic
node metastases occur early, and direct invasion of
-
adjacent structures can occur.
ration (FNA), the sensitivity for EUS in detecting
Chapter 9 — Gastrointestinal Cancers 247
regional metastases exceeds 85%. For patients with uracil is currently the standard of care for patients
suspected advanced disease on CT, but no evidence with unresectable disease.
of stage III–IV by EUS, positron emission tomography
(PET) scanning might be useful to help establish sur-
gical resectability. Prognosis
Esophageal cancer usually presents at an advanced
stage, and therefore the overall prognosis is poor. Tumor
Treatment histology has little impact on outcome, while survival
For stage I and II esophageal squamous cell carcino- is closely related to tumor spread. Patients with stage
ma or adenocarcinoma, radical surgery is the treat- I disease (T1N0M0) have a 5-year survival of approxi-
ment of choice. The choice of operation depends mately 65%, compared to those with stage IV disease
on a number of factors, including preference of the (TXNXM1) at <5% (Table 9.3).
surgeon, location of the tumor, body habitus, site
of prior surgery, condition of the patient, choice of
esophageal substitute (interposition), and history of Screening, Surveillance, Prevention
Surveillance every 1–2 years for esophageal squa-
important ones. Even if the patient has no evidence
mous cell cancer is currently recommended for pa-
of distant spread, a careful performance evaluation
tients at high risk, such as those with a history of
needs to be done, as postoperative mortality and
lye-induced or caustic strictures, tylosis, Fanconi’s
morbidity are high (10% and 75%, respectively).
anemia, or achalasia, and should be considered in
If available, endomucosal resection (EMR) may be
long-term alcohol or tobacco users and at the time of
attempted in poor surgical candidates with early
presentation with a head and neck cancer.
esophageal cancer2. Neoadjuvant chemoradiation
Screening for adenocarcinoma is primarily fo-
may at best improve short-term survival over sur-
cused through surveillance of patients with Barrett’s
gery alone and may be indicated in patients with
metaplasia based on the presence of dysplasia. The
stage II–III disease. Most patients are not surgical
recommended surveillance interval is 3–5 years with
candidates and require palliative measures. Esoph-
no dysplasia, 6–12 months for low-grade dysplasia
ageal strictures may be treated with a membrane-
and every 3 months for high-grade dysplasia in the
covered expandable metal stent or repeated esoph-
absence of eradication therapy3. The AGA Medical Po-
ageal dilations. Additional debulking modalities
sition Statement from 2011 further recommends the
include photodynamic therapy, radiation therapy,
endoscopy laser therapy, and bipolar coagulation.
a second pathologist, and use of white light endos-
-
Table 9.2
Comparison of Esophageal Cancers by Histologic Subtype in the United States
Incidence Incidence (black Male-female

Histological type Risk factors Location
(white men) women) ratio
Alcohol, tobacco, strictures, Fanconi’s

Squamous cell Males >
2.2/100,000 15/100,000 anemia, achalasia, Plummer-Vinson Midesophagus
cancer females
syndrome, tylosis, scleroderma
Barrett’s metaplasia, gastroesophageal

Adenocarcinoma 3/100,000 0.5/100,000 8:1 Distal esophagus
reflux disease, obesity, tobacco
Table 9.3
American Joint Commission on Cancer TNM Staging for Esophageal Cancer
Stage compo- Survival (5

Tumor (T) Nodal (N) Metastasis (M) Stage
nents year)
M0: no evidence for
T0: no primary tumor N0: no nodes 0 Tis, N0, M0 >90%
metastasis
N1: evidence for lymph M1: evidence of

Tis: carcinoma in situ 1 T1, N0, M0 >65%
node involvement metastasis
T1: invades lamina propria or NX: lymph nodes not MX: metastasis not
2a T2–3, N0, M0 ~30%
submucosa assessed assessed
T2: invades muscularis propria 2b T1–2, N1, M0 ~15%
T3, N1, M0
T3: invades adventitia 3 <10%
T4, any N, M0
T4: invades adjacent structures 4 Any T, any N, M1 <5%
copy to perform 4 quadrant biopsies every 2 cm, un- 1,000,000 new cases and 800,000 deaths in 20114.
less there is known dysplasia, in which case biopsies The decline in incidence from the second most com-
should be taken every 1 cm. Additionally, any irregular mon cancer overall just a few years ago is due to a
mucosa should be submitted in a separate jar. There is decrease in cancers of the distal stomach. However,
cancer of the gastric cardia is rapidly increasing,
use of chromoendoscopy or are advanced imaging perhaps for some of the same reasons as esopha-
techniques. Eliminating esophageal acid with great- geal adenocarcinoma. In the United States, gastric
er than once daily proton pump inhibitor dosing or adenocarcinoma ranks only 15th among cancer in-
other advanced measures is currently not endorsed. cidence, with an estimated 21,320 cases for 2012
Aspirin for prevention is recommended in patients (Table 9.1)1. The incidence rates are higher among
Asian Americans, blacks, and Hispanics compared
risk, but not solely for esophageal cancer prevention. to whites, and are higher in men and the elderly.
For therapy of dysplastic Barretts, radiofrequency ab-
lation, photodynamic therapy or endoscopic mucosal
resection (EMR) are recommended. If the dysplasia is Etiology/Pathogenesis
associated with a visible mucosal irregularity, EMR is
The pathogenesis of gastric cancer remains con-
recommended to allow staging3.
troversial. It was initially proposed that gastric ad-
enocarcinoma developed through a stepwise process
from atrophic gastritis to intestinal metaplasia, and
Cancer of the Stomach ultimately to carcinoma, but it is not clear that cancers
develop through precursor lesions nor is the natural
history of these proposed precursors. Known risk
Epidemiology factors include Lynch syndrome (formerly known as
Gastric adenocarcinoma remains the fourth most com-

familial adenomatous polyposis (FAP), Peutz-Jegh-
mon malignancy in the world, with approximately
ers syndrome, and a family history that includes an healing by repeat EGD may be needed. At least six bi-
opsies of a gastric lesion should be taken to increase
diffuse gastric cancer has been described with an al- the diagnostic histological yield, including the edge
tered E-cadherin gene, which encodes a cell adhesion and rim of the ulcer if present. CT of the thorax and
molecule. The most significant environmental risk abdomen helps delineate metastatic disease, but is
factor appears to be infection (2- to 5-fold not accurate in assessing the size of the primary tu-
increased risk)5, although the exact pathogenesis mor. EUS offers the advantage of assessing the perigas-
tric lymph nodes when combined with FNA. Surgical
containing nitrites may also be a risk factor. Other resectability may also be determined with a preop-
risk factors include pernicious anemia and prior erative staging laparoscopy to rule out peritoneal
gastric surgery. involvement. Patients with gastric adenocarcinomas
The genetics of gastric carcinoma are not fully are staged by the tumor-nodal-metastasis system.
understood. The tumor suppressor gene p53 is the
most common defect in gastric carcinoma, and ap-
pears to be affected early in gastric tumorigenesis. Histological Classification/Molecular
There is emerging data that the proteins encoded Genetics
by p53 and the cdk2 inhibitor p21 act in a protective
Gastric adenocarcinoma can be classified as dif-
fashion to prevent the formation of gastric cancer,
fuse or intestinal types, with the latter having histol-
especially if transforming growth factor (TGF)-beta
ogy similar to the small bowel mucosa. The intestinal
signaling is functional to induce p21 expression.
type is more common (50–75%), occurs more often
in men, older patients, and is associated with
pylori infection. The diffuse type is less common,
Symptoms/Clinical Signs
affects men and women equally, tends to occur in
Presentation of gastric cancer varies by world re- younger patients, is associated with blood group
gion. In Japan, where the gastric adenocarcinoma A, has a poorer prognosis, and rarely is associated
incidence is high, a national screening program de- with
tects about 50% of gastric cancers at an asymptom-
atic and early stage, with the tumor confined to the
mucosa and submucosa. In the United States, gastric Treatment
cancer is found early in <20% of patients. Advanced
Surgical resection of the primary carcinoma with
gastric adenocarcinoma often presents with weight
removal of involved lymph nodes is the treatment
loss and abdominal pain. Anorexia, occult blood loss,
of choice. In patients with advanced stages, palliative
and early satiety are other common symptoms. Para-
surgery is often performed to relieve abdominal
neoplastic conditions associated with gastric adeno-
pain and/or obstruction. EMR for early polypoid
carcinoma include Trousseau’s syndrome (multiple
gastric cancers, while championed in Japan, is not a
deep venous thromboses), acanthosis nigricans, and
standardized approach in the United States. There is
dermatomyositis.
no evidence for survival benefit with neoadjuvant
chemotherapy or radiation therapy for patients
with gastric adenocarcinoma. Small improvements
Diagnosis
in survival (up to 3 months) are seen with adjuvant
EGD with biopsy is the best method to diagnose chemotherapy post resection, as well as in advanced
gastric adenocarcinoma. There are two morphologic nonresectable cases, with the current standard
types - ulcerated versus polypoid – but they have little regimen consisting of epirubicin, cisplatin, and
-
tric ulcers may be malignant, and ascertainment of
Prognosis Cancer of the Small Intestine

The prognosis of a patient with gastric adenocarci-
noma is stage dependent, but somewhat better than
esophageal carcinoma. Patients with T1 tumors (lim- Epidemiology
ited to the mucosa and submucosa) and often classi-
Small intestinal cancer is rare and accounts only for
around 2% of all gastrointestinal cancers, with an
with T2 tumors (extending into the muscularis) and
estimated incidence of 8,070 cases for 2012 (Table
9.1)1. Adenocarcinoma is the most common type of
while patients with T3 tumors (involving the serosa)
small intestinal cancers, and its distribution in the
small intestine is more often proximal, with about
20%. Patients with T4 tumors (demonstrating local
half of tumors occurring in the duodenum. Other
invasion into adjacent organs) almost always have dis-
tumors of the small intestine include, in decreasing
tant metastases and extensive lymph node involve-
frequency, endocrine tumors (such as carcinoids),
lymphomas, and malignant gastrointestinal stromal
survival at 5 years.
tumors. The small intestinal distribution of these
tumors is generally distal, occurring more common-
ly in the jejunum and ileum6.
Screening, Surveillance, Prevention
In Japan, where gastric adenocarcinoma is preva-
lent, a decline in gastric cancer–associated mor- Etiology/Pathogenesis
tality has been observed in screened individuals.
Malignant transformation is relatively rare in the
Screening of the general U.S. population for gastric
small bowel as compared to the large bowel, despite
cancer is not recommended except in high-risk in-
the much larger surface area of the small intestine.
dividuals with FAP, Lynch syndrome, and personal
Theories for a small intestinal environment that
or family history of gastric adenoma or adenocar-
protects against neoplastic formation include fast
cinoma.
transit times, lower bacterial load with less conver-
sion of carcinogens, and liquid contents with lower
concentration of noxious substances. Key risk factors
Lymphoma of the Stomach
for development of small intestinal cancer include
Patients with gastric lymphomas have a better Crohn’s disease (adenocarcinoma), celiac disease (ad-
prognosis than patients with gastric carcinomas. enocarcinoma and T cell lymphoma), Peutz-Jeghers
Diagnosis is usually made at endoscopy with biopsy. syndrome (with small bowel hamartomas that may
Gastric lymphomas are derived from B cell clones, transform into adenocarcinoma), and Familial Ad-
most arise from extranodal mucosa-associated lym- enomatous Polyposis (FAP), where duodenal and other
phoid tissue, and are strongly associated with - small intestinal adenomas that may transform into
lori infection. In 80% of patients, gastric lymphoma adenocarcinoma.
may regress with eradication of when the
-
cosa and does not exhibit a t(11;18) chromosome Symptoms/Clinical Signs
translocation. Staging can be done by CT, bone mar-
Small bowel cancer typically presents late in its
row biopsy, and/or laparotomy, if necessary. Sur-
course, with abdominal pain (80%), weight loss
gery and or chemoradiotherapy may be required
(50%), and obstructive symptoms (25%). Anemia
for gastric lymphomas that do not regress after
pylori eradication or with more advanced disease.
Diagnosis the prevention of FAP adenomas although the ideal

chemopreventive agent for duodenal adenomas in
Diagnosis of small intestinal tumors is often de-
patients with proctocolectomy still needs to be estab-
lished.
CT of the abdomen or small bowel follow through (or
CT-enteroclysis, if available) may reveal a mass. En-
-
Carcinoid Tumors of the Small Intestine
tion of the jejunum. Wireless capsule video endoscopy
may be superior to barium studies in detecting small Carcinoids are rare neuroendocrine tumors that
bowel masses, particularly if the intestinal lesions do comprise up to 40% of small bowel malignancies, and
not inhibit passage of the capsule. are second in incidence to adenocarcinomas. Carci-
crypts of Lieberkühn of the intestine, and are more of-

Treatment ten found in the ileum or appendix. On endoscopy, they
have a yellow appearance and are often diagnosed in-
Surgery is the only curative approach for small bowel
cidentally after biopsy. Carcinoids are typically slow
adenocarcinoma, as radiotherapy is poorly toler-
growing, but desmoplastic reactions can cause small
ated and data on chemotherapy are unclear. Like-
bowel obstruction. Secretion of vasoactive hormones
wise, surgery may be required with carcinoids,
-
depending on their location. There is little evidence
-
of successful treatment for enteropathy-associated T
tension. Ileal carcinoids may be metastatic at presen-
cell lymphoma, although systemic chemotherapy or
tation, whereas carcinoids of the appendix typically
immunomodulatory therapy is usually given.
are not, particularly if they are <2 cm. Surgery with
local lymph node excision is the treatment of choice if
there is no evidence of metastasis. Octreotide, a long-
Prognosis acting analog of somatostatin, may be used to manage
As with most gastrointestinal cancers, the stage at symptoms from carcinoid syndrome.
diagnosis of the small bowel adenocarcinoma de-
-
cosa/submucosa having a much better prognosis. Pancreatic Cancer
Overall, 5-year survival ranges from 20% to 35%.
Prognosis of enteropathy-associated T cell lymphoma
is poor, and in most cases the malignancy is dissemi-
Epidemiology
nated upon presentation.
Pancreatic cancer incidence has been increasing
by 1.5% per year since 2004 and remains the fourth
Screening, Surveillance, Prevention leading cause of cancer death in men and women,
with an estimated 43,920 cases for 2012 in the United
For patients with polyposis syndromes such as FAP,
States. Pancreatic cancer has the highest incidence-
attenuated (A)FAP, or Peutz-Jeghers syndrome, an en-
to-death ratio of all gastrointestinal cancers, with
doscopic survey of the small bowel is recommended
37,390 deaths in 2012 (Table 9.1)1. The 5-year survival
every 1–4 years to assess for small bowel lesions,
is dismal at <5%, with a median survival of 6 months.
including the use of a side viewing scope to visu-
The peak incidence is in the seventh decade of life,
alize the ampullary region. Wireless capsule video
with a slight preponderance for men (1.3:1) and
endoscopy is currently being evaluated and may be
blacks (1.8:1).
the optimal tool to evaluate distal lesions. Some NSAIDs
to include COX2 and sulindac have been evaluated for
Etiology/Pathogenesis pressor p16, a cell cycle antagonist, is inactivated later

in the pathogenesis and seen in approximately 95%
More than 90% of pancreatic neoplasms are ductal
of pancreatic adenocarcinomas. The combination of
adenocarcinomas, the majority of which arise in the
both K-RAS and p16 effects is a molecular “signature”
head, neck, or uncinate process of the pancreas. To-
for pancreatic adenocarcinoma. Other genes that are
bacco increases pancreatic cancer risk by twofold,
affected include the tumor suppressor p53 (75%), and
and this risk remains elevated for >10 years following
biallelic loss of SMAD4 (55%), a signal-transduction
smoking cessation. Data on dietary fat, meat, fruit, and
molecule for TGF-beta. These latter two gene effects
seem to occur later in the pathogenesis of pancreatic
to play only a modest role, possibly via small increase
adenocarcinoma. There is evidence of deregulation of
in risk from chronic pancreatitis in a subset of heavy
several other signaling pathways, including EGF re-
drinkers. Chronic pancreatitis, however, is a risk fac-
ceptor (EGFR), Akt, and NF-kB signaling.
tor, with a total risk of 4% at 20 years for developing
pancreatic cancer. A recent diagnosis of diabetes mel-
litus appears to be associated with an increased risk
of pancreatic adenocarcinoma (Table 9.4). Previous
partial gastrectomy may be another risk factor. -
As outlined in (Table 9.4), up to 10% of pancreatic ing from abdominal discomfort to anorexia, weight
cancers may be inherited, either as part of a cancer loss, depression, and fatigue. Painless jaundice may
syndrome with an increased risk of pancreatic can- be present up to 50% of the patients, and repre-
cer (Peutz-Jeghers syndrome, FAP, BRCA2 mutation,
familial atypical multiple mole melanoma syndrome, compression by the tumor. Back pain usually repre-
and Lynch syndrome), other hereditary conditions sents nerve involvement and will preclude resectabil-
ity. Presentation with clinical pancreatitis due to an
pancreatitis), or familial pancreatic carcinoma (FPC)7. obstructing mass at the head of the pancreas with im-
Hereditary pancreatitis, which is separate from FPC, is pingement of the main pancreatic duct occurs in <5%.
an autosomal-dominant condition caused by inherited
mutations in the cationic trypsinogen gene protease
serine 1 (PRSS1), with a penetrance of 80%, and con- Diagnosis
ferring a lifetime risk of 40% for pancreatic adenocar- Diagnosis of pancreatic adenocarcinoma usually in-
cinoma, and which is doubled in cigarette smokers. In volves helical dual phase (arterial and portal) con-
some families with pancreatic cancer, the underlying trast abdominal CT, with subsequent EUS with FNA
genetic defect remains to be determined. FPC is most of the pancreas. FNA is important is differentiating
- adenocarcinoma from lymphoma andeautoimmune
tives with pancreatic cancer and/or early pancreatic pancreatitis. EUS is highly sensitive (~90%) and par-
cancer (<50 years), or with multiple affected second- ticularly useful in detecting small lesions and vas-
degree relatives. The relative risk correlates with the cular involvement, key elements in staging. Also,
number of affected family members (18-fold with 2; magnetic resonance cholangiopancreatography
(MRCP) is highly sensitive for pancreatic carcinoma.
smokers (Table 9.4). With endoscopic retrograde cholangiopancreatog-
The genetic pathogenesis of pancreatic adenocar- raphy (ERCP), a classic “double duct” sign indicative
cinoma is thought to be stepwise, as shown in progres- of compression of both common bile duct and pancre-
sive precursor lesions called pancreatic intraepithelial atic duct is suggestive of a pancreatic head carcinoma.
neoplasia (panIN). Activating K-RAS mutations occur Laparoscopy with biopsies may reveal metastasis in as
in >90% of tumors and occurs early in pancreatic ade- many as 30% of patients with a normal CT scan. Ele-
nocarcinoma pathogenesis, but also can be seen in be- vated serum CA19-9 levels, a sialylated Lewis A antigen
nign conditions such as pancreatitis. The tumor sup-
(Table 9.5), may aid in differentiating pancreatic cancer Table 9.4

from nonmalignant etiologies. Genetic markers such Risk Factors for Pancreatic Cancer
as detection of K-RAS in the serum or feces have
not proven an integral component for diagnosis of
Environmental Tobacco
pancreatic cancer.
(2- to 20-fold risk) Alcohol consumption
Aromatic amine exposure
Cadmium exposure
Treatment
Diabetes mellitus
Resectable disease Cancer syndromes Peutz-Jeghers syndrome

- (2- to 10-fold risk) Familial adenomatous polyposis
rior mesenteric artery (SMA) or celiac axis involve- Lynch syndrome
ment, a patent superior mesenteric vein–portal vein Familial atypical multiple mole
melanoma
disease. A pancreaticoduodenectomy (Whipple proce- Familial breast cancer
dure) is the treatment of choice and the only curative
Family history ≥2 first-degree relatives affected
approach. Only 15–20% of patients will meet these cri-
(>50-fold risk) ≥3 second-degree relatives af-
teria following staging. The role of adjuvant radiation
fected, one age <50
is currently being investigated. About one-third of pa-
tients are not candidates for postoperative chemoradia-
tion, but neoadjuvant chemoradiation including gem- Hereditary metabolic Hereditary pancreatitis (75-fold
citabine used as a radiosensitizer is being advocated to diseases risk)
increase the number of patients that may be surgical Cystic fibrosis
candidates.
Locally advanced disease tion vs. 23 weeks with radiation alone) and pallia-
For tumors that encase vascular structures, such as tive benefit (pain relief in 50–85% with radiation) for
- locally advanced disease. Survival with metastatic dis-
mors associated with bulky peripancreatic lymph- ease is around a median of 5 months.
adenopathy without evidence of metastatic disease, the

Metastatic disease
Chemotherapy is never curative and its potential pal- In FPC, surveillance by EUS and MRCP in high-risk in-
dividuals may start at age 40 or 10 years before the
Gemcitabine is the current standard of care for meta- age of the youngest affected family member. In patients
static pancreatic cancer. with Peutz-Jeghers syndrome, surveillance may start at
age 25–30, while age 35 is recommended in hereditary
pancreatitis patients8. Prevention is focused on surgi-
Prognosis cally resecting precursor lesions that are detected9.
The prognosis of patients with pancreatic adeno- Precursor and cystic lesions for pancreatic
carcinoma remains poor. With a curative approach carcinoma
towards a patient’s disease, the 5-year survival after Pancreatic cancer may arise from cystic tumors of the
resection is 25–30% for node negative and 10% pancreas (Table 9.6), although overall, those account
for node positive disease. Chemoradiation provides for only 1% of all pancreatic neoplasms. It is impor-
a survival advantage (42–44 weeks with chemoradia- tant to note that the natural history of these lesions is
Table 9.5
Examples of Oncofetal Antigen Markers in Gastrointestinal Tract
Primary tumor with

Marker Epitope Other tumors with serum elevation
serum elevation
CEA Multiple glycosylation sites on an immu- Colorectum Stomach, pancreas, biliary tract, liver
noglobinlike protein
CA 19-9 Sialylated Lewis A Pancreas Stomach, biliary tract, liver, colorectum
CAM 17.1 Sialyl I blood group antigen Pancreas Biliary tract
CA 50 Sialylated Lewis A Pancreas Stomach, biliary tract, liver, colorectum
CA 242 Mucinlike antigen Colorectum Pancreas
CA 72-4 Mucinlike glycoprotein (sialosyl-2-6-6-al- Pancreas, ovary Colorectum
pha-N-acetylgalactosaminyl)
CA 125 Mucinlike molecule Ovary Colorectum
Alpha-feto- Multiple isoforms of an albuminoid Liver Biliary tract, stomach
protein molecule
CEA, carcinoembryonic antigen.
not understood. Recently the rate of progression has both (“mixed type”). IPMNs may be associated with
been called into question, as many cystic lesions are invasive ductal adenocarcinoma (Table 9.6). The
found incidentally during imaging and do not appear Peutz-Jeghers gene, STK11/LKB1, is inactivated in up
to progress during monitoring. to one-third of IPMNs, and some patients with Peutz-
Microscopic epithelial neoplasms aris- Jeghers syndrome develop IPMNs. Surgical resection
ing in small pancreatic ducts with varying amounts is the preferred treatment, and if resected before the
of mucin and degrees of cytologic and architectural development of invasive carcinoma, they are highly
atypia are called PanIN lesions curable.
and mucinous, PanIN 3 (high-grade dysplasia) re- IPMNs are most commonly seen in men in their
sembles carcinoma and commonly harbors genetic seventh decade of life, few of whom have a history of
abnormalities similar to pancreatic adenocarcinoma recurrent acute pancreatitis, or symptoms suggestive
but without invasive features. Histological grading by of chronic pancreatitis due to intermittent obstruction
the pathologist is done taking the most advanced le- of the pancreatic duct with mucus plugs; most lesions
sion into account. These are thought to progress to are found incidentally on imaging studies. In most cas-
pancreatic ductal adenocarcinoma. es, routine laboratory tests are normal. Typical ERCP
IPMNs are grossly visible (usually >1 cm), pancreatic duct without stricturing, with or without
noninvasive, mucin-producing neoplasms arising from
the main pancreatic duct or branch ducts, with vary- secondary to mucus or mural nodules. The papilla can
ing degrees of ductal dilatation, and the dilation can
- orifice. EUS with FNA and cyst CEA levels analy-
dominantly involve the main pancreatic ducts (“main sis may confirm the diagnosis. EUS features sug-
duct type,” 75%, arising in head and more aggres- gestive of malignancy include an enlarged pancreatic
sive) but can be seen involving the secondary ducts duct, irregular cystic lesions, and large mural nodules.
(“branch duct type,” pancreatic head and tail) or CT and magnetic resonance imaging (MRI) aid in iden-
tifying adenopathy, vascular invasion, and metastatic with chemotherapy and/or antagonizing agents such
disease. as octreotide (somatostatin analog).
MCNs usu-
ally present at a mean age of 50, with strong female
predominance (4:1), but are often asymptomatic. Cancer of the Gallbladder and
Over 90% occur in the body or tail, and 80% are mac-
rocystic and usually 4–5 cm in diameter with a thick Bile Ducts
capsule (Table 9.6). MCNs should be considered po-
tentially malignant and, whenever safe, surgically
resected. Typically, this will involve a distal pancre- Epidemiology
atectomy, while a pancreaticoduodenectomy may Cancers of the biliary tract are relatively rare, with
need to be performed for lesions in the pancreatic 9,810 cases in the United States occurring in 2012
(Table 9.1)1. Gallbladder cancer, accounting for two-
(premalignant or overtly malignant) neoplasms from thirds of these cancers, has a female preponderance
serous neoplasms or pseudocysts. Intracystic carci- (similar to gallstone disease) and is more common
noembryonic antigen (CEA) levels >250 ng/ml reliably among individuals of Native American, Mexican,
Japanese, Chilean, and Bolivian descent.
out this neoplasm. Bile duct cancer (cholangiocarcinoma) is often
found near the hepatic hilum (two-thirds of total)
rare and represent 1–2% of all pancreatic neo- and can involve the bifurcation of the right and left
hepatic ducts (Klatskin tumor). The remaining one-
biologically active substances that can result in spe- third of bile duct carcinomas affects the distal extrahe-
patic duct, and a minority are located in intrahepatic
a similar histologic appearance, they can be distin- ducts.
guished by the use of immunostaining for the hormone
being secreted. The remaining 15% are nonfunction-
ing and usually found incidentally or because of a local Etiology/Pathogenesis
mass effect.
EPTs that are functioning are associated with a Gallbladder cancer is strongly associated with choles-
clinical syndrome caused by inappropriate secretion
of hormones such as insulin (hypoglycemia, hypoka- of the gallbladder wall). In patients with anomalous
lemia), glucagon (diabetes, migratory necrolytic ery- pancreaticobiliary ductal junction, gallbladder can-
themic rash), somatostatin (gallstones, steatorrhea,
diabetes, hypochlorydria), gastrin (Zollinger-Ellison of duodenal contents through the abnormal open-
syndrome), and vasoactive intestinal peptide (watery ing. Gallbladder polyps, especially if they are >1 cm
diarrhea, hypokalemia, achlorhydria). in size, may progress to gallbladder cancer. While
The peak incidence for all EPTs is age 30–60 bile contains multiple components that might be
and may be part of multiple endocrine neoplasia mutagenic, the precise mechanism of gallbladder car-
syndrome, consisting of pancreatic, pituitary, and cinogenesis has not been established.
parathyroid neoplasia. Additionally, EPTs can be a Risk factors for cholangiocarcinoma include pri-
component of von Hippel-Lindau disease (14% devel- mary sclerosing cholangitis and its association
op nonfunctioning EPTs, and >50% have >1 tumor). with ulcerative colitis; infections with liver parasites
Most EPTs present as malignant tumors except for such as and -
insulinomas, for which the majority may often be be- rini and carriers of species; anatomical
nign. Surgery offers best chance of cure. Metastatic changes of the bile duct such as choledochal cysts and
disease can be treated by surgical debulking, and Caroli’s disease (multiple cystic dilations of the biliary
tree); and exposure to thorium dioxide (a discontin-
Table 9.6
Classification of Cystic Lesions of Pancreas
Clinical features Male-female ratio
Pseudocyst History of pancreatitis or abdominal trauma Equal
Intraductal papillary mucinous

History of pancreatitis, abdominal pain, or found incidentally Male > female
neoplasms
Commonly symptomatic, with abdominal pain and early satiety but

Mucinous cystadenoma 1:4
increasingly asymptomatic
Commonly symptomatic, with abdominal pain and early satiety but
Serous cystadenoma increasingly asymptomatic, can be associated with von Hippel- 1:4
Lindau syndrome
EUS, endoscopic ultrasound; CEA, intracystic carcinoembryonic antigen.
ued radiologic contrast agent), asbestos, and tobacco. Histological Classification

Gallbladder carcinoma is often classified as either
papillary (15%, not associated with gallstones and
better prognosis), colloid (10%), or infiltrative
Gallbladder cancer progresses slowly and presents (65%, associated with gallstones with worse prog-
- nosis). Cholangiocarcinomas are typically divided
ness and early satiety. The majority of patients by its anatomic location: intrahepatic, hilar, and
with cholangiocarcinoma will present with pain- extrahepatic, and also histologically into nodular,
less jaundice due to extrahepatic involvement. In- infiltrating, and papillary patterns. Cholangiocar-
trahepatic involvement may cause elevated liver cinomas are often associated with an intense des-
function tests and abdominal pain. moplastic fibrous reaction.
Diagnosis Treatment
Most gallbladder cancers are diagnosed incidentally Surgical resection is the only potentially curative
at the time of cholecystectomy. Painless jaundice, the treatment modality for gallbladder cancer. Adjuvant
presentation of cholangiocarcinoma, may be evaluated or neoadjuvant chemotherapy may be offered for
with abdominal ultrasound or contrast CT. ERCP en- advanced disease. Radiation therapy has not been
ables cytologic brushings for assessment of malig- proven to be a useful adjunct.
nant cells of the biliary tree; however, this is plagued Surgical resection is the only curative treatment
by low sensitivity. MRCP allows for local and regional modality for cholangiocarcinoma. Intrahepatic chol-
staging as well as assessment of the biliary tree, and angiocarcinoma is treated with hepatic resection. Liv-
EUS with FNA can be used for tissue diagnosis. Serum er transplantation is generally not an option due to ex-
CA 19-9 may be elevated in biliary tract cancers (Ta- ceedingly high recurrence rates. Perihilar tumors are
ble 9.5). commonly unresectable. Distal extrahepatic chol-
angiocarcinoma may be approached by a Whipple
Malignant
Morphology/EUS features Aspirate
potential
Anechoic; thick walled; lack of septations, solid components, or Amylase >5000 U/L, negative staining for
None
calcifications mucin
Papillary growth of tumor in main pancreatic duct (PD), dilated Mucinous columnar cells with variable
Yes
main PD with “mucin lakes” or side branches atypia, fluid stains positive for mucin
Large cysts, “macrocystic”, peripheral calcifications indicative Mucinous cells with variable atypia, fluid
Yes
of malignancy stains positive for mucin, CEA >200 ng/ml
Small cysts with a “honeycomb” appearance, rarely has a
Cuboidal epithelium that stains positive Almost none
macrocystic component, central calcification (“stellate scar” with
for PAS (glycogen), CEA <5 ng/ml (rare reports)
“sunburst pattern”)
procedure. The role of adjuvant chemotherapy or counts for <1% of carcinomas of the gastrointestinal
radiation is generally not curative, but may relieve tract. Peak age of presentation for ampullary cancer is
tumor-associated pain. Palliative measures include during the sixth decade of life, and it has a better prog-
surgical hilar bypass or ERCP-guided metal stenting nosis than pancreatic adenocarcinoma, with an overall
to relieve obstructive jaundice. 5-year survival approaching 40%. Jaundice is the most
common presenting symptom, with pain, weight
loss, and gastrointestinal bleeding as other manifes-
Prognosis tations. Complete evaluation of the ampulla can be
done with a side-viewing endoscope, the most sen-
Patients with early gallbladder cancer may be cured
sitive method for diagnosis. In FAP patients, ampul-
with cholecystectomy; however, more extensive
lary cancer is the second most common cancer after
stages of disease have an overall poorer survival, even
colorectal cancer, and these patients require EGD with
with extended resections yielding 5-year survivals of
a side viewing scope and ampullary surveillance every
20%.
1–4 years.
The overall prognosis of cholangiocarcinoma is
poor, with a 5–10% 5-year survival. Distal extra-
hepatic cholangiocarcinomas offer the best chance of
surgical resectability (up to 50% may be resectable), Hepatocellular Cancer
but even with resection, median patient survival is
about 24 months. Patients without resection and
with distal extrahepatic cholangiocarcinomas had a Epidemiology
median survival of 8 months.
The prevalence of hepatocellular cancer (HCC) dif-
fers among geographic regions, ethnic groups, and gen-
der. The prevalence of chronic hepatitis B virus (HBV)
Ampullary Cancer correlates with HCC in most areas of the world and
Typically categorized separately from bile duct can- in certain ethnic groups in the United States, such
cer, cancer of the ampulla of Vater is rare and ac- as Asian Americans, due to vertical transmission of
as worsening ascites, jaundice, or variceal bleeding.

of HCC occur in Asia and sub-Saharan Africa, result- -
ing in between 250,000 and one million deaths glob- rhotic), hepatic arterial bruit, ascites, splenomegaly,
ally per year. HCC is a cancer with a relatively low, but fever, clubbing, and muscle wasting.
growing, incidence in the United States, with 28,720 An increasing number of patients are asymp-
incident cases in 2009 (Table 9.1), and a very high tomatic at the time of diagnosis, especially if par-
mortality with 20,550 deaths1. Most patients in the ticipating in a screening program for high-risk
United States who develop HCC have the hepatitis C patients. Cirrhotics may present with decompensa-
virus (HCV) with cirrhosis. tion of their underlying liver disease, which should
always prompt a work-up for HCC. Paraneoplastic
syndromes may include hypercalcemia, polycythe-
Etiology/Pathogenesis mia, hypoglycemia, and symptomatic porphyria
cutanea tarda (light-sensitive dermatosis).
In most patients with HCC, a risk factor can be identi-
-
-
sis alone, independent of its etiology, is a risk factor,
Diagnosis
with the estimated incidence of HCC being around 5% Transabdominal ultrasound is a highly sensitive and
per year. Alcohol consumption is a common cause of -
cirrhosis in Western countries, and therefore is com- dominal CT (liver protocol), with a phase prior to
monly associated with HCC. Persistent HBV infection -
from vertical transmission increases the risk of HCC -
approximately 100-fold. Unlike HBV, which is integrat- tal veins, is better at identifying lesions >1 cm. Other
ed into the genome of the host, HCV-associated HCC sensitive options are MRI with either gadolinium
likely requires a cirrhotic liver. Inherited metabolic or ferridex for enhancement of the HCC, or contrast
disorders such as hemochromatosis, tyrosinemia, 1- “bubble” transabdominal ultrasound, which has an
improved diagnostic yield compared to traditional
glycogen storage diseases, are associated with an in- ultrasound. Alpha-fetoprotein (AFP) is elevated
creased risk for HCC mostly in the setting of cirrhosis. >20 ng/dl in up to 70% of patients with HCC (Table
Autoimmune diseases, such as primary biliary cirrho-
sis and autoimmune chronic active hepatitis, can also
progress to cirrhosis and HCC. Other general risk fac- including viral hepatitis and with tobacco usage.
tors include male gender, older age, and nonalcoholic A level >200 ng/ml has a high predictive value for
fatty liver disease. Predisposing toxins other than af- HCC in cirrhotics at a cost of loss of sensitivity. Des-g-
latoxin include thorium dioxide, androgenic steroids carboxy prothrombin, induced by diminished g-car-
via hepatic adenomas, and vinyl chloride. At the mo- boxylation of prothrombin precursors in HCC cells is
growth factor gene have been associated with an in- follow therapeutic responses. Biopsy is not essential
creased risk of HCC in patients with cirrhosis. in lesions >2 cm that are radiologically characteristic,
but has been advocated in lesions 1–2 cm in size that
do not have clear features on imaging. Bleeding and
Symptoms/Clinical Signs needle track tumor seeding remain concerns with
biopsy. Lesions <1 cm have a low likelihood of being
Abdominal pain is the most common presenting symp-
HCC and may be followed by serial imaging studies
tom, and HCC patients may also present with fatigue,
for up to 2 years.
malaise, weight loss, and anorexia, as well as symp-
toms of decompensated portal hypertension, such
Histological Classification injection into the HCC is minimally invasive, simple,

safe, and associated with low cost. Radiofrequency ab-
Fibrolamellar HCC is a histological variant character-
lation (RFA) uses a heat-generating probe transcutane-
ized by plump and deeply eosinophilic hepatocytes
ously or in situ to destroy tumor cells and has a more
predictable necrotic effect in tumors >2 cm. Although
in younger whites in the absence of cirrhosis and does
RFA requires fewer treatment sessions compared to
not produce AFP. It is characterized by a lower me-
ethanol injection, tumor seeding of the needle tract
tastasis rate and is, therefore, more amenable to sur-
has been noted in up to 12% of cases. Hepatic artery
gical resection and/or liver transplantation.
shrink the tumor as a palliative approach and does not

appear to affect patient survival. Complications such
Treatment as infection, abscess, liver failure, and death may oc-
Surgical resection should be offered in patients with cur. Monotherapy with sorafenib, an orally available
a single lesion with otherwise healthy livers or patients multitargeted tyrosine kinase inhibitor that inhibits
with hepatic vein pressure gradient <10 mm Hg and Raf kinase and also blocks the intracellular portion
no evidence of hepatic decompensation. Tumor recur-
rence in the resected liver is high at 50–70%. Trans- -
plantation is the preferred treatment in patients with tients with advanced HCC . Combinations of local
11
more advanced cirrhosis, unless the tumor is >5 cm therapies with sorafenib are being investigated.
or there are more than three tumors and one is >3
cm, known as the Milan criteria after the study by
Mazzaferro et al. in Italy10. Prognosis
In order to decrease waiting time to transplant, pa-
No current tumor-staging system has been shown to
tients with HCC are given extra points to their model for
correlate with prognosis, as underlying hepatic func-
end-stage liver disease (MELD) score. The MELD score,
tion is an additional important determinant of out-
which was engineered to predict mortality in chronic
alcoholic or viral liver disease, is less reliable in predict-
small HCCs can be cured at an appreciable frequency,
ing outcomes for other etiologies of liver disease, but is
patients with symptomatic HCCs have a dismal prog-
still used to rank for determining organ allocation. Cur-
nosis.
rently, extra points are given for a solitary nodule of 2–5
cm or three nodules <3 cm each. Note that currently no
points are given for small lesions. Neoadjuvant thera-
py has been tried to slow HCC growth while awaiting
transplant, although systemic chemotherapy appears High-risk individuals who are potential candidates
to be ineffective. for treatment of HCC and patients on a liver trans-
There are several techniques that can be directed plant list should enter a surveillance program (Table
at the tumor. Transarterial chemoembolization (TACE), 9.7). Screening is carried out with an imaging mo-
which employs injection of a chemotherapeutic agent dality, such as transabdominal ultrasound, abdomi-
into the hepatic artery followed by hepatic artery ob- nal CT, or MRI, in combination with a serological AFP
struction, may reduce tumor burden and delay pro- level every 6–12 months. Surveillance intervals have
gression, particularly if the waiting time to transplanta- been determined by approximate tumor doubling
tion is expected to be >6 months. With nonresectable times and not risk, and therefore, individual risk does
tumors, a variety of ablative therapies are available. not warrant shortened intervals. Treatment of viral and
with large or multifocal HCC who do not have vascular

invasion or extrahepatic spread. Percutaneous ethanol and cirrhosis. However, this reported reversal does not
lessen the malignant potential for HCC in these condi- due to the asymptomatic nature of CRC development
tions, and surveillance should be continued even if in average-risk individuals. Distal CRCs (i.e., cancers
etiology and/or elevated AFP may undergo surveil- -

lance every 3 months. The most effective preventive ure) until about age 70, when proximal cancers begin
measure to date worldwide will be universal HBV vac- to outnumber distal cancers. Another key risk factor
is family history.
and possibly improved treatments for HCV and HBV. CRC refers to average risk individuals
-
ily history, with an average age of discovery at age 68.
Colorectal Cancer Sporadic CRCs account for two-thirds of all CRCs. -
milial CRC refers to higher risk individuals with a fam-
ily history of CRC, or other cancers associated with a
Epidemiology
CRCs. Patients with familial CRC typically present at
Colorectal cancer (CRC) is one of the most prevalent a younger age than those with sporadic disease, and
cancers in the United States, affecting 1 in 18 Ameri- usually require surveillance to prevent or detect CRC
cans during an average lifetime. It has the highest in-
cidence among gastrointestinal cancers in the United relatives with an adenoma or CRC increase an indi-
States, affecting 143,460 patients in 2012, and is the
third most common cause of cancer deaths in men relative (age <45) is affected with CRC, that individu-
and women (behind lung cancer and prostate for men al’s lifetime risk is nearly sixfold higher than an aver-
and lung and breast cancer for women), with 51,690 age-risk person (Table 9.8). Individuals with certain
deaths in 2012 (Table 9.1)1. Men and women are af- recognized syndromes, such as Lynch syndrome (for-
fected nearly equally. A key risk factor is age, with merly known as HNPCC) and FAP, have an 80% and
dramatic increases in CRC incidence after age 50, 100% lifetime risk, respectively, of developing CRC
and thus this age has been used to initiate screening (Table 9.8).
Table 9.7 Ethnicity and race are risk factors for CRC devel-
At-Risk Groups that Warrant Screening and Surveillance for opment. Blacks have a higher incidence and death rate
Hepatocellular Carcinoma for CRC compared to whites in the United States and
have a higher proportion of CRCs under age 50 com-
pared with whites (10.6% vs. 5.5%). There is a slight
Cirrhotics Hepatitis B carriers preponderance of right-sided high-risk adenomas and
colon cancers in blacks. It is not clear to what extent
Asians (males age >40, genetic, dietary, lifestyle, socioeconomic, or preventive
Hepatitis B
females age >50) issues account for the differences detected in blacks,
Family history of hepato- but screening has been suggested to begin at age 45 by
Hepatitis C
cellular carcinoma some professional organizations. In Ashkenazi Jews, a
Alcoholics Africans age >20 -
yposis coli (APC) gene (I1307K) doubles the risk for
Genetic hemochromatosis adenoma development and confers an increased prev-
alence of CRC. Additionally, both obesity (especially
Consider in abdominal obesity) and diabetes have been indepen-
A. 1-Antitrypsin deficiency dently associated with an increased risk of CRC. Physi-
B. NASH cal activity has consistently been shown to protect
C. Autoimmune hepatitis against CRC although the mechanism is not known.
Environmental factors also confer risk for CRC Table 9.8

development. As listed in (Table 9.9), consumption Lifetime Risk for Colorectal Cancer (CRC) adapted from Johns et al. 20
of red meat is epidemiologically associated with a
higher risk for CRC. Likewise, high fat intake, alco-
hol, tobacco usage, high BMI, lack of physical activity, Lifetime risk
Family history or syndrome
diabetes mellitus and menopause confer some risk. for CRC
Lifetime risk in US (not strictly average risk population)
5.1%
vegetable, and selenium are associated with a lower (American Cancer Society 2012)
One first-degree relative, any age, with CRC ~11%

antioxidants is still inconsistent. Drugs that inhibit
prostaglandin synthesis such as aspirin are associat-
Two second-degree relatives, any age, with CRC ~15%
ed with reduced CRC risk. The role of statins remains
One first-degree relative age <45 with CRC ~20%
-
servational and animal model studies, folic acid may
One first-degree relative < 45 with CRC ~22%
act as a chemopreventive, but two controlled clini-
cal trials failed to show a reduction in recurrence of Lynch syndrome 80%
colonic adenomas with folic acid supplementation.
-
Familial adenomatous polyposis 100%
matory bowel disease increases CRC risk. The risk of
CRC in ulcerative colitis (and Crohn’s colitis) begins
to rise after 8–10 years duration and increases each
colorectal tumor and further transformation is accel-
year thereafter, particularly with pancolitis. The risk
erated by differing forms of genomic instability. The
of CRC in long-standing ulcerative colitis has been de-
affected colonocyte stem cell evades intrinsic normal
creasing, perhaps because of therapy or perhaps be-
cellular controls, such as cell cycle checkpoints and
cause CRC incidence, in general, has been decreasing.
programmed cell death (apoptosis), and deregulates
It is important to note that CRC arising from chronic
normal cell signaling pathways. These changes shift
the homeostatic balance toward one of cellular pro-
liferation and transformation.
that have a different genetic pathogenesis.
Histologically, CRCs develop clonally from single
Prior personal development of adenomas and a
cells, which progress to dysplastic aberrant crypt foci,
prior history of CRC are strong risk factors to develop
then small adenomatous polyps (typically tubular),
a subsequent adenoma or cancer. High growth hor-
to large adenomatous polyps (typically tubulovillous
mone production in acromegalics theoretically may
or villous), to adenomas with carcinoma to
be trophic for growth of adenomas but this has not
frank invasive CRC. Polyp size (>1 cm) and histology
been proven.
(villous) are predictors for adenomas to contain can-
cer. Only a minority of adenomas progress to cancer,
and the process may take 1–2 decades. In Lynch syn-
Etiology/Pathogenesis
drome, the adenoma to cancer progression is more
Changes at the genetic level of normal colonocytes rapid and may occur in as short as 1–2 years. In in-
alter growth characteristics, allowing unparalleled
proliferation and transformation such that lesions not proceed through polyp stages but rather through
can be detected macroscopically as adenomas. The
trigger for these events is generally believed to come Paralleling the histology, an adenoma-to-car-
from the interaction of the colon with its environment. cinoma genetic sequence is well described for the
Later, the uncontrolled growth rate of an expanding majority of sporadic CRCs. There are two well-char-
Table 9.9 mutation and LOH of the tumor suppressor p53

Some Environmental Links with Colorectal Cancer gene. CIN is the pattern of tumor development in
FAP CRCs, except that FAP patients inherit a germ-
line mutation in one allele of the APC gene, making
For development of
Protective against colorectal cancer it easier (and thus earlier presentation) for muta-
colorectal cancer
tion or loss of the remaining normal APC allele to
Red meat diet Diet high in fish, or vegetables, or dairy, or fruit initiate adenoma formation. Microsatellite instabil-
ity (MSI), observed in 15–20% of sporadic CRCs, is
High fat diet Selenium named for frameshifts (or instability) that occur at
Tobacco Calcium, vitamin D DNA microsatellite sequences and are detected at
electrophoresis of DNA. The cancer cells are com-
Alcohol Aspirin, nonsteroidal anti-inflammatory drugs monly diploid.
The etiology for MSI is inactivation of the DNA
High BMI Fiber ?
mismatch repair system, an enzyme system func-
Lack of physical activity Statins ? tioning in the nucleus to repair interstrand nucleo-
tide mispairs and loops of DNA that are formed on
Diabetes mellitus one strand containing a mismatched number of
Menopause complementary microsatellite sequences. The MSI
pattern in sporadic cancers is caused by an epigen-
etic event, hypermethylation, at one of the DNA mis-
match repair genes’ promoter sequence, hMLH1,
acterized genetic pathways for CRC development,
preventing its transcription and translation. With
based on the form of genomic instability detected
loss of hMLH1 protein, the DNA mismatch repair
within the tumor. (CIN), ob-
system fails, and mutations accumulate in the colo-
served in 80–85% of sporadic CRCs, is named due to
nocyte’s genome due to nonrepair of DNA poly-
the breakage and rearrangement of chromosomes
merase mistakes that may naturally occur (hyper-
that occur and thus contain aneuploid nuclei. The
mutable phenotype).
etiology for CIN is not known.
Certain key tumor suppressors drive the patho-
genesis of MSI tumors, which are different from
is the allelic mutation of a tumor suppressor gene,
those observed in the CIN pathway. Tumor suppres-
followed by loss of the remaining normal allele
sor genes, such as TGF-beta receptor 2 and activin
(termed -
type 2 receptor (growth suppressor molecules) and
pressors are so named because their gene product
BAX (a proapoptotic gene), are mutated at both al-
functions to inhibit cell proliferation and tumori-
leles in MSI tumors due to the presence of coding
genesis, and both copies of the tumor suppressor
microsatellite sequences that are frameshifted (Fig-
must be inactivated to gain the growth advantage.
ure 9.1). The B-RAF gene, downstream from K-RAS,
As shown in (Figure 9.1), the APC gene product, part
is often mutated in MSI tumors. MSI is the pattern in
of the Wnt signaling pathway that regulates intra-
Lynch syndrome (HNPCC) tumors, except that one
cellular concentrations of the proto-oncogene beta-
of the DNA mismatch repair genes (hMLH1, hMSH2,
catenin and considered the gatekeeper for colonic
hMSH6, hPMS2) is mutated in the germline, making
neoplasia, is the earliest target for inactivation.
it easier (and thus a more rapid progression) for
Mutation and LOH of APC initiates neoplasia,
colorectal tumor formation once the remaining nor-
followed by clonal expansion of proliferating ade-
mal allele is mutated12.
noma cells that acquire activating mutations in the
There are important clinical, pathological, and
proto-oncogene K-RAS, furthered by LOH at chro-
prognostic differences for CRC patients depending
mosome 18q (site of the DCC, SMAD2 and SMAD4
on the form of genomic instability. Sporadic CRCs
genes), and followed by development of cancer with
can be categorized into two groups: those that dem- Figure 9.1
onstrate MSI (i.e., lost a component of DNA mis- Genetic Pathogenesis of Colorectal Cancer
match repair) and those that do not demonstrate
MSI (termed microsatellite stable -
press all components of the DNA mismatch repair
system). MSS tumors, for the most part, encompass
CIN tumors. As listed in (Table 9.10), MSI tumors
are frequently mucinous and show a poor histologi-
cal differentiation and more often are in the right
colon compared to MSS tumors. MSI tumors demon-
strate a surrounding lymphoid reaction, which may
contribute to an improved patient prognosis when
matched stage-wise with patients with MSS tumors.
Immune cells may be triggered to the tumor based
There are at least two genomic instability pathways for colorectal cancer to develop.
on neoantigens from truncated proteins as a con- Both may require disruption of the Wnt signaling pathway, which includes APC and
sequence of frameshifts of targeted genes. Patients ultimately leads to nuclear accumulation of beta-catenin. The chromosomal instability
with MSI tumors do not have improved survival pathway is defined by loss and gain of chromosomes, leading to aneuploidy, and targets
mutation of RAS and p53, followed by loss of heterozygosity of the other p53 allele, to
- form cancer. The microsatellite instability pathway is defined by loss of DNA mismatch
pared to patients with MSS tumors. repair, causing frameshift mutations throughout the cell’s genome and including tumor
- suppressor genes important in cell signaling (TGFBR2, ACVR2, IGF2R), apoptosis (BAX),
and transcription (TCF4, E2F4).
cers, compared to sporadic CRCs, demonstrate a
different biology and distinct timing and pattern of
molecular alterations. It is presumed that the pres-
-
of CRC include colonic perforation, Trousseau’s syn-
plasms more often multifocal, mucinous, or poorly
drome (adenocarcinoma with associated deep vein
differentiated. MSI and aneuploidy have been as-
thrombosis), and malignant ascites. Bacteremia with
sociated with dysplasia and cancers in ulcerative
should trigger evaluation of the
colitis patients. Mutations in p53 occur early (com-
colon for adenomas or adenocarcinoma13.
pared to sporadic CRCs), and APC mutations and K-
RAS activation are rare in the colitis-associated neo-
plastic process.
Diagnosis
Colonoscopy is the preferred diagnostic tool to detect
Symptoms/Clinical Signs and sample CRC. Barium enema is not as sensitive as
colonoscopy, and will miss two-thirds of all lesions
Patients with adenomas or early cancers are most
seen at colonoscopy. Serum CEA is used as a surveil-
often asymptomatic. Detection of these lesions
lance tool once a baseline is established after iden-
requires a screening intervention, and ultimately
tifying CRC or after chemotherapy treatment and
colonoscopy to remove the visualized lesions.
has no role for asymptomatic screening for colorec-
Symptoms of CRC are usually due to luminal nar-
tal neoplasia (Table 9.5). Abdominal CT is useful to
rowing or blood vessel disruption from the primary tu-
evaluate for liver metastasis to help stage the patient.
mor, and include stool pattern changes, hematochezia,
abdominal pain, tenesmus, and weight loss. Chronic
Histological Classification
be the sole presenting symptom in 10–20% of patients
with CRC that is more often right-sided in location Adenomas are considered the classic precursor lesion
and a more advanced stage. Unusual presentations for CRC. Grossly, adenomas can be described as pe-
Table 9.10 poor histological grade, surgical margins of <5 cm after

Differences Between Microsatellite-Unstable and Microsatellite-Stable resection, lymphatic and venous invasion, perineural
Colorectal Tumor -
tration (which is present in many MSI tumors).
In ulcerative colitis or Crohn’s disease, high-grade
Microsatellite unstable Microsatellite stable
dysplasia identified from surveillance colonic biop-
Mutator phenotype Loss of heterozygosity (mostly)
Diploid nuclei Aneuploid nuclei also develop a polypoid-like mass lesion, termed a
dysplasia-associated lesion or mass (DALM), which
Frequently mucinous (40%) Few mucinous tumors (<10%) -
vanced adenoma. However, DALMs have the character-
Poor histological differentiation Well histological differentiation
discrete lesions, with the borders not circumferentially
Proximal colon location (70%) Fewer proximal tumors (~50%) -
tially distinguished from sporadic adenomas in older
Young patients (germline mutations) or
old patients (hypermethylated hMLH1 Few young patients
DALM lesions generally require surgical total procto-
gene)
colectomy.
Few p53 mutations p53 commonly affected
Peritumoral and infiltrating lymphoid

Treatment
reaction common
Adenomas are generally treated by polypectomy at
Improved survival matched by stage colonoscopy. Polyps containing carcinoma in situ
without evidence for invasion may also be treated
No survival benefit with 5-fluorouracil
with polypectomy. Occasionally, large villous adeno-
mas that cannot be managed by therapeutic colonos-
copy may require surgical resection.
dunculated (stalked), sessile (no stalk), and flat or
Therapy for CRC can be divided into colon and
depressed. The histological architecture of an ade-
rectal cancer components. The main treatment for
-
colon cancer is surgery. Surgery with wide resec-
taining their original crypt architecture), tubulovil-
tion margins is the only therapy needed for stage
I and II disease, although some stage II patients do
nonbranching fronds). In general, the larger the
receive chemotherapy. For stage III disease, adju-
polyps, the more likely they will contain villous archi-
-
tecture. All adenomas are by definition dysplastic,
rouracil, leukovorin, and oxaliplatin) for 6 months is
as opposed to hyperplastic polyps and hamartomas,
standard and has been shown to improve survival.
which have long been thought to be nondysplastic.
For stage IV, surgery may be curative in highly se-
However, newest research points to sessile serrated
lected patients with resectable bowel disease and
tumors, especially if large and on the right side of the
resectable isolated hepatic or pulmonary metastases.
colon, as precursors to CRC with likely more rapid
Unresectable liver lesions may also be managed locally
progression than adenomas.
with TACE or RFA if symptomatic (see section on Hepa-
CRCs are typically adenocarcinomas, and there
tocellular Carcinoma). In many patients with stage IV
disease, surgery is often palliative to prevent bowel
signet ring cell carcinomas. In addition to stage, im-
obstruction. Chemotherapy is offered but may not
improve overall survival. Palliative chemotherapy
regimens for stage IV colon cancer include chemo- chronous adenomas and cancer and are surveyed by
colonoscopy. For adenomas, the interval for surveil-
lance colonoscopy may depend on the size, number,
and architecture of the adenomas, but is generally
as bevacizimab (antibody to vascular endothelial within 3–5 years of the original clearing colonosco-
growth factor) and cetuximab (antibody to EGFR) py. For CRC, all patients should have a pre- or peri-
operative documentation by colonoscopy of a can-
tumor shrinkage and add about 5 months to the cer- and polyp-free colon. Surveillance colonoscopy
survival of stage IV patients. Use of cetuximab is limited should be performed one year after surgery, then every
clinically to those with nononcogenic (wild-type) 3–5 years. A consensus update by the US multi-soci-
K-RAS, since K-RAS is a key downstream signal for ety task force now includes recommendations on the
surveillance of serrated polyps attributing a higher
these biologic agents, with thromboembolic events risk to lesion > 10 mm, a sessile serrated histology
in bevacizimab and papulopustular acneiform rash (versus a more benign hyperplastic histology), pres-
with EGFR receptor blockers, treatment should be ence of dysplasia and location in the proximal colon.
carefully individualized. Recommended surveillance intervals range from 5
Rectal cancers are treated surgically by low an- years for nondysplastic sessile serrated polyps to
terior resection or abdominal perineal resection, often 3 years for sessile serrated polyps either > 10 mm,
- dysplasia or a classical (but rare) serrated adenoma.
tion. Stage I disease is approached with wide surgi- Yearly surveillance is suggested for serrated polypo-
cal resection with or without chemoradiation. The sis syndrome (see below)14.
incidence of loco-regional recurrence from rectal can-
cer is decreased through the use of total mesorectal
excision. Stage II and III disease is treated by wide Screening, Surveillance, Prevention
surgical resection in combination with adjuvant or
CRC is a common malignancy with a very high case
neoadjuvant (with an attempt at anal sphincter pres-
-
ervation) chemoradiation. The approach to stage IV
ter outcome when detected in the asymptomatic
disease is generally palliative with surgical bypass of
state. As adenomas and early cancers are often as-
local bowel obstruction and chemoradiation for local
ymptomatic but potentially curable if found and re-
management.
Table 9.11
Prognosis Colorectal Cancer Stages and Survival
The prognosis of CRC is principally based on the stage
of the disease at presentation (Table 9.11). Staging may
Astler-Coller-Dukes Five-year
be performed using imaging techniques such as CT Stage AJCC TNM stage
stage survival (%)
or MRI or determined at surgery. Rectal cancer is
best staged with rectal EUS. Patients whose tumors I T1–2, N0, M0 A, B1 85–95
demonstrate MSI may have improved survival when
compared to patients with MSS tumors (Table 9.10). II T3–4, N0, M0 B2, B3 60–80
III Any T, N1–3, M0 C 30–50

Follow-Up
Patients with documented adenomas or CRC are at IV Any T, any N, M1 D <5
higher risk for developing synchronous and meta-
AJCC TNM, American Joint Commission on Cancer tumor-nodal-metastasis staging.
moved, while symptomatic CRC is more likely to be ing. If polyps are detected by any screening modal-
advanced in stage, screening asymptomatic men and ity, a colonoscopy should be performed to evalu-
women age >50 for colorectal neoplasia has been ate the observed polyp, remove it, and to clear the
shown to detect cancers at an earlier stage compared remainder of the colon of lesions. Because of this,
to those not screened and, with some modalities, to colonoscopy has become the preferred modality for
improve survival. Tests that have been evaluated for CRC screening in many centers. However, the effec-
CRC screening that reduce mortality include fecal oc- tiveness of colonoscopy in reducing mortality for
right-sided colon cancers is less robust. Right-sided
while data on the mortality validity of colonoscopy, lesions may be more easily missed due to a predilec-
double-contrast barium enema (DCBE), fecal genetic
markers, and CT colonography are forthcoming. Se- to visually detect, as well as more easily obscured
with suboptimal bowel preparation. As well, there
as a screening tool for CRC. may be other biological characteristics of right-sid-
As listed in (Table 9.12), multiple society guide- ed lesions that impact the effectiveness of current
lines group the options for CRC screening in aver- screening intervals to prevent mortality. Attention
age-risk adults age >50 into tests for the primary has also been given to available quality performance
detection of cancer and tests that detect adenomas indicators and the role of operator performance in
as well as cancer15. Each test has a different sensi- lowering mortality from colon cancer, with some
evidence that gastroenterology specialty training is
include guaiac-based FOBT (gFOBT), fecal immu- effective in lowering mortality from proximal colon
nochemical tests (FIT), and stool DNA tests (sDNA). cancers16.
While gFOBT and FIT are recommended annually, Patients at increased risk for CRC should not fol-
no interval has been established for sDNA. Screen- low the guidelines for average-risk individuals. As de-
ing for CRC with FOBTs will increase the diagno- picted in (Figure 9.2), the health care provider must
sis of asymptomatic neoplasia, will detect early determine risk for a patient and that risk determines
stage lesions, and reduce CRC mortality by about the approach to reduce CRC incidence. An individual
15–18%. FOBT remains an imperfect test and will with a personal history of polyps or cancer is at in-
miss 30–50% of cancers that are present at the creased risk for colonic adenomas and colon can-
time of the test. The preferred guaiac based test cer, and should be surveyed with colonoscopy(see
is one with high sensitivity. Tests that detect ad Follow-Up, above). A key component of determining
enomatous polyps and colon cancer include colo- risk is family history for CRC (Table 9.8). Individuals
noscopy (every 10 years), CT colonography (every
DCBE (every 5 years) (Table 9.12). Flexible sigmoid- diagnosed with CRC at any age should be advised
oscopy reduces colon cancer mortality by about to have screening colonoscopy starting at age 40
(or 10 years younger than the earliest diagnosis in
and FOBT only detects about 75% of adenomas and their family, whichever is earliest), and repeated ev-
cancers. Data on the effectiveness of colonoscopy
with adenoma or CRC diagnosed at age >60 or two
sigmoidoscopy studies as well as studies indicating second-degree relatives with CRC should be advised
missed right-sided colonic lesions. Colonoscopy is to be screened beginning at age 40. Individuals with
diagnostic and therapeutic, as it is the main tech- one second-degree or third-degree relative with
nique used to remove observed lesions. DCBE is CRC should be advised to be screened as average-
<50% as sensitive to colonoscopy, and thus its in- risk individuals. Guidelines for individuals with or
terval has been recommended at 5 years (instead of at risk for FAP and Lynch syndrome are listed below.
10 years as for colonoscopy) if used for CRC screen- In patients with long-standing and extensive colitis as-
Figure 9.2
Approach to Screening and Surveillance for Colorectal Cancer (CRC)
Using the approach outlined, a health care professional can distinguish average-risk patients (recommended screening for CRC starting at age 50)
from higher risk patients (who should be surveyed for colorectal neoplasia at more frequent intervals and at younger ages). With specific high-risk
syndromes, involvement of a gastroenterologist familiar with the syndromes is important in proper surveillance and conveying risk to patients
or families.
Hereditary Colorectal Cancer Syndromes

The human colorectal cancer syndromes represent
dysplasias) should be performed. These should begin
the extreme end of a spectrum of phenotypic expres-
after 8–10 years of disease duration and be repeated
sion when a gene is mutated in the germline. In the
every 1–2 years.
case of FAP and Lynch syndrome, these syndromes
As listed in (Table 9.9), aspirin and NSAIDs have
exaggerate the risk of sporadic CRC and patients
been associated with a reduced lifetime risk for CRC,
present at least 2–3 decades earlier with CRC.
Keys to the recognition of some of the heredi-
ventive agents. The main hurdle to fully recommend
tary colorectal cancer conditions are a high index of
these drugs in average risk patients to reduce CRC in-
suspicion and taking a careful family history. If pa-
cidence has been their toxicity, particularly for gastro-
tients are approached as depicted in (Figure 9.2),
intestinal bleeding. In FAP patients, COX-2 inhibitors
more patients might be recognized and appropri-
and the NSAID sulindac are effective in reducing the
ately followed. In particular, Lynch syndrome, with its
number and size of polyps and can be used as an ad-
subtle phenotype, is frequently missed as a diagnosis.
junct to endoscopic screening after colectomy in those
More widespread testing of all colorectal cancers
with retained colonic mucosa. These drugs do not de-
may reduce the risk of missing a Lynch syndrome
lay the onset of polyposis in FAP.
cancer. Most of the syndromes have a high propen-
sity for CRC development, as well as the development
of other cancers in recognized patterns (Table 9.13).
Table 9.12
Guidelines for Colorectal Cancer Screening for Average-Risk Women and Men Age ≥50
Interval (beginning Percent significant

Comments
at age 50) lesions detected
Tests that Detect Adenomatous Polyps and Cancer
Flexible sigmoidoscopy Every 5 years 70–85% through Diagnostic and therapeutic through sigmoid colon; if
sigmoid colon; 0% positive, requires colonoscopy to clear remainder of
elsewhere colon*; perforation risk
Colonoscopy Every 10 years 85–97% Diagnostic and therapeutic; sedation generally given;
perforation risk
Double-contrast barium enema (DCBE) Every 5 years 40–73% If positive, requires colonoscopy, No longer recom-
mended by the US Preventative Task Force
Computed tomography colonography Every 5 years 85–97% Ignores polyps <6 mm; radiation exposure; prep
required; if positive, requires colonoscopy
Tests that Primarily Detect Cancer
Guaiac fecal occult blood test (gFOBT) Annually 12–40% Inexpensive; if positive, requires colonoscopy*†
Immunochemical-based stool test Annually 25–65% Inexpensive; if positive, requires colonoscopy*†
Stool DNA test Uncertain 15–52% Expensive; if positive, requires colonoscopy
The options are acceptable choices for colorectal cancer screening in average-risk adults. Since each of the following tests has inherent characteristics related to
accuracy, prevention potential, costs, and risks, individuals should have an opportunity to make an informed decision when choosing a screening test.
†
There is no justification for repeating FOBT in response to an initial positive finding. Adapted from Levin B, et al. Screening and surveillance for the early detection
of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and
the American College of Radiology. Gastroenterology 2008;134:1570–95.
Familial adenomatous polyposis (FAP) brain tumors, particularly medulloblastomas. Other

FAP is an autosomal-dominant condition charac- phenotypic associations are listed in (Table 9.13).
terized by the development of >100 adenomatous The majority of FAP patients are asymptomatic until
polyps in the colon. All patients will develop CRC if cancer development, although symptoms of anemia
left untreated (Table 9.8). The mean age for polyp and hematochezia could be present. Because of the
development is age 16, and the mean age for CRC diffuse nature of the polyposis, surgical colectomy
development is age 40. Untreated FAP has a life ex- with mucosal proctectomy and ileoanal pouch pull
pectancy of 42 years. The genetic cause of FAP is the through is the procedure of choice. Abdominal des-
inheritance of a mutated APC gene, considered part moids may develop in 12–20% of FAP patients post
of the gatekeeper pathway for colorectal neoplasia. colectomy. After CRC, cancer of the duodenum, par-
There are two variants of FAP that were previously ticularly the Ampulla of Vater, is the most common
thought to be separate syndromes, but are known site for cancer development. EGD, particularly with
to be caused by a germline mutant APC gene: Gard- a side-viewing endoscope, should be performed ev-
ner’s variant, with extracolonic manifestations, and ery 1–4 years depending on the number and size of
a portion of Turcot’s syndrome, linking CRC and duodenal adenomas, with careful sampling of the
ampulla to determine the presence of ampullary ad- strate MSI and are often right-sided in location and
enoma. lose expression of MMR proteins17 (Table 9.10).
An attenuated form of FAP (based on a differ- At least two variants are recognized: Muir-Torre
ent location of mutations within the gene) car- syndrome, which in addition to the Lynch cancer as-
ries much the same cancer risks as classic FAP, but sociations demonstrates certain skin tumors (Table
presents about one decade later, with fewer polyps 9.13), and a portion of Turcot’s syndrome, linking
(20–100) that tend to be more right-sided in location. CRC and brain tumors, particularly glioblastomas. Pa-
People who have a genetic diagnosis of FAP, or tients with Lynch syndrome are often asymptomatic
are at risk of having FAP but genetic testing has not until cancer formation occurs, usually at uncharac-
been performed or is not feasible, should have an- teristically young ages. There is no premorbid clinical
nual sigmoidoscopy, beginning at age 10–12 years,
to determine if they have developed the phenotype. before cancer. Thus, obtaining a careful family his-
Attenuated FAP (AFAP) family members should have tory is paramount in potentially recognizing this syn-
colonoscopy due to the right-sided tendency for pol- drome. The presence of neoplasia in a Lynch patient’s
yps. Genetic testing should be considered in patients colon should trigger a subtotal colectomy with an ile-
with FAP who have relatives at risk. Genetic counsel- osigmoid or ileorectal anastomosis. The markedly in-
ing should guide genetic testing and considerations of creased risk for metachronous polyps mandate such
colectomy (Figure 9.3). aggressive surgical treatment, as Lynch syndrome pa-
tients have a 50% risk for the development of a sec-
MYH-associated polyposis (MAP)
MAP is an autosomal-recessive condition character- People with a genetic or clinical diagnosis of
ized by oligopolyposis (3–100 adenomas) with no Lynch syndrome or who are at increased risk for
evidence of a germline APC gene mutation. MYH nor- Lynch syndrome should have colonoscopy every
mally repairs DNA oxidative damage, and the lack of 1–2 years beginning at age 20–25, or 10 years ear-
repair allows the APC gene to develop somatic mu- lier than the youngest age of colon cancer diagnosis
tations as a result of oxidative stress. The clinical
spectrum and care of patients is similar to that of FAP
Figure 9.3
(Table 9.13). The lack of family history, as this is a re-
Approach to Genetic Testing for Familial Colorectal Cancer Patients
cessive transmission, may suggest this syndrome in
the presence of a small number of multiple adenomas.
Lynch syndrome (formerly known as HNPCC)

Lynch syndrome is an autosomal-dominant cancer
predisposition syndrome without apparent anteced-
ent polyposis, and carriers have an early onset of CRC
development, typically about age 40. There may be
rapid progression through an adenoma-carcinoma
sequence in Lynch syndrome patients, and there is an
80% lifetime risk for CRC development (Table 9.8).
Lynch syndrome is the most common genetic
cancer syndrome, and is estimated to cause 3–5% of
all CRCs. A spectrum of associated cancer risks exists,
particularly that of the female reproductive tract, the
Genetic counseling by an expert or certified genetic counselor precedes genetic
stomach and small intestine, and the urinary tract
testing. Genetic testing must be appropriately interpreted to convey actual
(Table 9.13). The germline cause for Lynch syndrome
risk to patients, including whether the test was positive for a mutation, nega-
is inherited mutations in one of the DNA mismatch
tive for a mutation, or no mutation was detected.
repair genes, and tumors from these patients demon-
Table 9.13
Familial Cancer Syndromes and Their Phenotypic and Cancer Associations
Polyposis syndrome Genes affected Noncancer associations
Congenital hypertrophy of the retinal pigment epithelium,

FAP and variants, including MYH APC, MYH
desmoid, dental abnormalities, epidermoid cysts
hMSH2, hMLH1, hPMS2, Sebaceous adenomas and carcinomas,
Lynch syndrome and variants
hMSH6 keratoacanthomas (Muir-Torre)
Familial type X Unknown None
SMAD4 + BMPR1A + ENG +

Juvenile polyposis syndrome Rare congenital abnormalities, hemorrhagic telangiectasias
PTEN(?)
Macrocephaly, visceral, and cutaneous hamartomas; pigmentation

Bannayan-Riley-Ruvalcaba syndrome PTEN + (?)
of penis in males; Hashimoto’s thyroiditis
Facial trichilemmomas, mucocutaneous papules, goiter, fibrocystic

Cowden disease PTEN
breast disease, cerebellar gangliocytomas (Lhermitte-Duclos)
Peutz-Jeghers syndrome LKB1 / STK11 Mucocutaneous melanosis
Serrated (hyperplastic) polyposis

Unknown Hyperplastic polyps, serrated adenomas
syndrome
Hereditary mixed polyposis syndrome CRAC1 None
Familial CRC type X

cancer screening should begin at age 30, and EGD This is an autosomal-dominant disorder(s) charac-
should be considered for gastric cancer screening. terized by a 2.3-fold increase in CRC development,
Genetic testing for Lynch syndrome should be offered the lack of MSI and the presence of intact DNA mis-
match repair, and the lack of increased risk for typical
inherited DNA mismatch repair gene mutation (Fig- extracolonic Lynch syndrome tumors (Table 9.13).
ure 9.3). It should also be offered when the family mu- The cause for this disorder(s) is not known. Patients
tation is not already known, but if two or more Lynch with this syndrome, if distinguished from Lynch syn-
syndrome–related tumors are present, if an individ- drome, do not have to undergo screening for extraco-
ual is age <45 with CRC or Lynch syndrome–related lonic tumors.
Hamartomatous polyposis syndromes

criteria for Lynch syndrome (2 successive genera- This group of heterogeneous syndromes is character-
<50, and FAP is excluded). As Lynch syndrome still is (nondysplastic but disorganized tissue indigenous
commonly missed, the universal testing of all CRCs for to the site of origin). These include juvenile polypo-
loss of mismatch repair protein expression has been sis syndrome, Bannayan-Riley-Ruvulcaba syndrome,
advocated recently18. Cowden disease, Peutz-Jeghers syndrome, hyper-
their expression, a germline mutation for this condi-

tion remains to be found. Yearly surveillance colonos-
copies are recommended, while further evidence is
Cancer associations being sought14.
Colorectal, duodenal ampullary, medulloblastoma
Colorectal, endometrial, ovarian, kidney, ureter, bladder,

stomach, small intestine, glioblastoma (pancreatic?) Pearls and Pitfalls
Colorectal for the Board Exam
Esophageal adenocarcinoma is most common in old-
Colorectal, pancreas, gastric, duodenal er white men and associated with a history of GERD,
Barrett’s metaplasia and obesity.
(?) similar to Cowden disease H.pylori infection appears to be protective of both
(?) similar to Peutz-Jeghers syndrome Barrett’s and esophageal adenocarcinoma.
Barrett’s surveillance is based on the presence of
Medullary thyroid, breast, endometrial, probable colorectal dysplasia with intervals ranging from 3–5 years in
cancer risk cases with no dysplasia, 6–12 months for low-grade
dysplasia and every 3 months for high-grade dyspla-
Small intestine, stomach, pancreas, colorectal, esophagus,
sia.
ovary, lung, uterus, breast
Germline e-cadherin mutations lead to a hereditary
Colorectal form of diffuse gastric cancer.
Paraneoplastic conditions associated with gastric
adenocarcinoma include Trousseau’s syndrome
Colorectal
(multiple deep venous thromboses), acanthosis ni-
gricans, and dermatomyositis.
plastic polyposis, and hereditary mixed polyposis Patients with FAP most often die from small bowel
syndrome19. The affected genes that cause these syn- cancers long after they underwent prophylactic
dromes are listed in (Table 9.13). Surveillance of the proctocolectomy.
gastrointestinal tract and other organs for cancer are Ileal carcinoids may be metastatic at presentation,
- whereas carcinoids of the appendix typically are not,
drome’s phenotypic pattern for cancer development particularly if they are <2 cm.
(Table 9.13). The most important environmental risk factor for
pancreatic cancer is smoking.
Serrated polyposis syndrome (also known as The Peutz-Jeghers gene, STK11/LKB1, is inactivated
hyperplastic polyposis syndrome) in up to one-third of IPMNs.
Mucinous Cystic Neoplasm (MCNs) usually are seen
the presence of one of the following: (1) at least 5 ser-
in the body or tail of the pancreas in asymptomatic
rated polyps proximal to the sigmoid colon with two
in women around 50.
or more greater or equal to 10 mm; (2) any serrated
Environmental risk factors for cholangiocarcinoma
polyps proximal to the sigmoid colon in the presence
include infections with liver parasites such as Clo-
of a family history of serrated polyposis syndrome;
norchis sinensis and Opisthorchis viverrini and carri-
or (3) greater than 20 serrated polyps of any size
ers of Salmonella species.
throughout the colon. While many of the polyps dis-
Fibrolamellar HCC is a histological variant character-
play the CpG Island Methylator Phenotype with ab-
ized by abundant fibrous stroma in younger whites in 2012;93:844-57.

the absence of cirrhosis and lack of AFP. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Sha-
The etiology for MSI is inactivation of the DNA mis- heen NJ. American Gastroenterological Association
match repair system. technical review on the management of Barrett’s
Both flat high-grade dysplasia and DALM lesions esophagus. Gastroenterology 2011;140:e18-52; quiz
generally require surgical total proctocolectomy. e13.
In stage IV colon cancer, use of the EGFR inhibitor
cetuximab is limited to patients with wild-type K-
Acknowledgements
RAS.
The author acknowledges the previous contributions to
Individuals with a first-degree relative with an ad-
this revised chapter of John M. Carethers, MD, AGAF.
enoma or CRC diagnosed at age <60 or two first-de-
gree relatives diagnosed with CRC at any age should
have screening colonoscopy starting at age 40 (or 10
years younger than the earliest diagnosis in their fam- References
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CHAPTER 10
Pancreatic Physiology and Disease
Fred S. Gorelick, MD and Anil B. Nagar, MD
Learning Objectives
1. Understand the mechanisms regulating the formation and secretion of bicarbonate and digestive enzymes by the pancreas.
2. Appreciate the mechanisms of acute pancreatitis and the impact of genetic factors.
3. Employ diagnostic studies in an efficient and cost-effective manner both to confirm the diagnosis of acute pancreatitis and to determine its
likely etiology.
4. Select the safest and most cost-effective approach for evaluating patients with suspected chronic pancreatitis.
5. Understand the appropriate application of medical, endoscopic, and surgical treatments for acute and chronic pancreatitis and their
complications.
6. Appreciate the diagnostic approach and management of pancreatic adenocarcinoma and pancreatic endocrine tumors.
Introduction
The exocrine pancreas has an essential role in digesting food. Its secretion of 500–1,000 ml of bicarbonate-
by acinar cells) necessary for the intraluminal breakdown of dietary macronutrients. This includes the hydro-
lysis of protein, starch, fat, nucleic acids, and fat-soluble vitamin esters into smaller molecules that can either
be absorbed directly by enterocytes or be acted upon further by bile or intestinal brush-border enzymes to
permit absorption by the small intestine. The bicarbonate in pancreatic juice plays a critical role in neutraliz-
ing gastric acid entering the small intestine, which would otherwise inactivate pancreatic digestive enzymes
and bile acids and prevent digestion of dietary substrates.
Scattered among the exocrine pancreatic acini (which comprise over 80% of the pancreas) are the endo-
crine cells of the islets of Langerhans, comprising only about 2% of the gland. The islet cell hormones, such as
insulin and glucagon, have a profound effect on the regulation of metabolism.
well as to neoplasms arising from both the endocrine and exocrine tissues of the gland.
275
Figure 10.1
Pancreatic Acinus
Normal Pancreatic Function
Pancreatic Organization
The basic secretory unit of the exocrine pancreas is
Acinar the acinus (Figure 10.1), which primarily consists of
acinar cells that are highly specialized for the syn-
Centroacinar thesis, storage, and secretion of large amounts of
protein mainly in the form of digestive enzymes. The
Duct apices of the acinar cells converge on a central lu-
-
acinar cells. Acini empty into intralobular ducts that
join to form the interlobular ducts that empty into
This figure shows the relationships and major features of the units the main pancreatic duct. The pancreas is formed by
of the exocrine pancreas. The pancreatic acinar cells of the acinus
have prominently stained zymogen granules in the apical area of the the fusion of the dorsal and ventral pancreatic buds
cell. The connecting ductule does not contain zymogen granules. The (Figure 10.2). Developmental differences in pancre-
cell protruding into the duct at the junction between acinar and duct atic and biliary duct anatomy are observed (Figure
cells depicts the centroacinar cell. The centroacinar cell functions
10.3); some, including pancreas divisum (Figure
similarly to the duct cell. From Pancreatic Physiology and Pancreatitis
GastroSlide 20, AGA Institute. 10.3c) and annular pancreas (Figure 10.3e), can
have clinical consequences.
Figure 10.2
Pancreatic Development
Pancreatic Development
Formation Rotation Fusion

Common
Stomach bile duct
Ventral
Ventral Dorsal pancreatic
pancreas pancreas duct
Dorsal
duct
5 weeks 6-7 weeks 8 weeks
This figure demonstrates that the stomach, duodenum, liver, and biliary system including the gallbladder and pancreas are derived from closely
related structures in early embryological development. The pancreas, liver, gallbladder, and biliary system bud from the duodenum during early
embryological development. The pancreas starts as two components, the ventral and dorsal pancreas. In the process of development, the
organs enlarge, and the ventral pancreas together with the common bile duct rotates. Then, in most cases, the pancreatic duct from the dorsal
pancreas fuses with the pancreatic duct from the ventral pancreas to form the main pancreatic duct. After fusion the pancreatic secretions
from the entire pancreas and biliary secretions gain access to the duodenum by way of the ventral pancreatic duct. Improper fusion or rotation
may cause disease. From Pancreatic Physiology and Pancreatitis GastroSlide 10, AGA Institute.
Chapter 10 — Pancreatic Physiology and Disease 277
Figure 10.3
Variations in Ductal Anatomy
Pancreas - Variations in Ductal Anatomy
Common
a b
Uncommon
c d e
The upper two images (A, B) represent the most common duct anatomic relationships. Image C represents the most common form of pancreas
divisum. Image D is a variant of normal, with the duct of Wirsung joining the common bile duct at a site significantly proximal to the duodenum.
This anomaly is often associated with congenital dilation of the common bile duct as shown. Image E represents the ductal anatomy in
annular pancreas, a congenital disorder probably due to fixation and malrotation of the ventral pancreas. This may result in obstruction of the
duodenum as shown. From Pancreatic Physiology and Pancreatitis GastroSlide 12, AGA Institute.
-
Secretion of Water and tion, whereas centroacinar cells and the epithelial
Electrolytes cells that line the intralobular and small interlobu-
with water entering passively along osmotic gradi-

ents. The major cations, Na+ and K+, are secreted at cells is much greater than that of the acinar cells, the
concentrations similar to plasma concentrations. Al-
though the total anion concentration does not vary of stimulated secretion. Second, HCO3- in pancreatic
with the secretory rate, the amounts of the major juice is exchanged for Cl- in the pancreatic duct in a
anions, HCO3- and Cl-, do. At low secretory rates the time-dependent diffusional process. At high secre-
concentration of HCO3- is only 30–60 mmol/L, but -
it rises to as high as 135 mmol/L at high secretory change process.
rates, with a corresponding decrease in Cl- concen- The peptide hormone secretin is the most po-
tration (Figure 10.4). tent stimulus for water and bicarbonate secretion by
centroacinar and duct cells. Bicarbonate secretion
and Cl- concentrations in pancreatic juice appears is inversely related to duodenal pH and requires a
to involve 2 components. First, acinar cells secrete pH of >4.5: it also parallels secretin release (Figure
Figure 10.4
Pancreatic Bicarbonate Secretion
The graph illustrates that with stimulation (i.e., a meal) there is an increase in the flow rate of pancreatic secretions. Furthermore, with
increasing flow rates there is a dramatic change in the concentrations of chloride and bicarbonate. The increase in bicarbonate concentration
results in a secretion that is alkaline. The bicarbonate ion comes from ductal epithelial cells in the pancreas. In contrast to acinar cells, the
ducts secrete a large volume of fluid with a high concentration of bicarbonate. Because the volume of secretion from the acinar cells is thought
to be small compared to ductal secretion, with increasing stimulation of the pancreas, the concentration of ions approaches that of the ductal
secretions. Of note, the alkaline secretion of the pancreas combined with alkaline secretions from the biliary system and the duodenal mucosa
neutralize the acid secretion delivered to the duodenum from the stomach. This pH-neutral environment is important for optimal digestive
enzyme and intestinal mucosal function.
Figure 10.5
Pancreatic Bicarbonate Secretion Is Related to Duodenal pH
Optimal digestion and absorption occur near neutral pH. Sensors in the duodenal lumen activate pathways leading to bicarbonate secretion.
The result is neutralization of acidic contents from the stomach delivered to the duodenum. The major sensor in the duodenum that mediates
pancreatic bicarbonate secretion is the secretin or S cell. The apical microvilli of the S cell face the luminal contents. The S cells respond to a
low pH in the duodenal lumen by releasing secretin from the basolateral region of the cell. Secretin, in turn, enters the circulation and acts as a
hormone to stimulate sodium bicarbonate and water secretion from the pancreatic ducts as well as the biliary system. The threshold for secretin
release and water and bicarbonate secretion is pH 4.5. Below this pH, pancreatic water and bicarbonate secretion are related to the total amount
of titratable acid delivered to the duodenum. In addition to acid, other luminal factors including lipids may contribute to secretin release.
10.5). Secretin stimulates duct cells to produce intra- Figure 10.6

cellular cyclic AMP (cAMP) which in turn stimulates Pancreatic Duct Ion Transports
secretion. Additionally, the peptide hormone chole-
cystokinin (CCK) and, particularly, cholinergic neural
stimulation mediated by acetylcholine, potentiate
the effects of secretin on postprandial increase in wa-
ter and bicarbonate secretion. Bicarbonate is secret-
ed by pancreatic centroacinar and duct cells against
large concentration and electrochemical gradients.
Most of the HCO3- is derived from CO2 in blood
by the action of the enzyme carbonic anhydrase. The
HCO3- can be exchanged for Cl- at the apical (lumi-
nal) cell surface by an active process that appears at
least in part to be driven by the active secretion of H+
across the basolateral cell surface into the interstitial
space mediated by a Na+/H+-exchanger and other
active H+, Na+, and K+ transport mechanisms that
are not shown. Secretion of Cl- across the apical cell
surface is an important step in water and electrolyte This image shows the delivery mechanisms to provide a source for HCO3- for the duct
secretion, and it takes place through a Cl- channel cell. There are two delivery systems. In one, membrane diffusible CO2 is catalytically
- converted to HCO3- and H+ by the action of carbonic anhydrase (CA) that hydrates
CO2, thereby forming H2CO3 that then dissociates to HCO3- and H+. The duct cell
tance regulator (CFTR) and is stimulated by cyclic
is rich in CA. The HCO3- is then available for apical secretion. H+ is removed from
AMP (Figure 10.6). the cell by a basolateral Na+/H+ antiport to maintain a constant intracellular pH. In
Bicarbonate enters the duct either by the ex- the other delivery, HCO3- is transported into the cell by a Na+-facilitated transport.
change of chloride for bicarbonate or by direct bi- There is evidence that bicarbonate may move directly through the cystic fibrosis
transmembrane conductance regulator channel. From Steward MC, Ishiguro H, Case
- RM. Annu Rev Physiol 2005;67:377–409. From Pancreatic Physiology and Pancreatitis
brosis transmembrane regulator, CFTR, and through GastroSlide 108, AGA Institute.
the chloride-bicarbonate exchanger, SLC26A6. The
cations, Na+ and K+, reach the pancreatic duct by Figure 10.7
paracellular routes. Since pancreatic bicarbonate Luminal pH and Lipase Activity
secretion is required to neutralize gastric acid as it
enters the small bowel, patients with pancreatic exo- Pancreatic activity is pH-dependent
Luminal pH and Lipase Activity

The lower small bowel pH impairs digestion through
a number of mechanisms. For example, these pa-
Denatured
- enzyme
lysis because pancreatic lipase is inhibited and can Lipase

activity
be inactivated when the duodenal pH falls below 4.5
(Figure 10.7).
3 4 5 6 7 8
Secretion of Protein pH
In humans, pancreatic juice has a protein concentra- This image illustrates that maximal activity of pancreatic lipase occurs at about pH 7.
tion range of about 1–10%. The four major catego- At pH <4, lipase is irreversibly inactivated. The results demonstrate the importance
ries of digestive enzymes are proteases (digesting of neutralization of gastric acid delivered to the duodenum for normal fat digestion
to occur. From Pancreatic Physiology and Pancreatitis GastroSlide 61, AGA Institute.
proteins and peptides), amylase (digesting starch),

Classes of Pancreatic Enzymes Pancreatic Acinar Cell Enzymatic Secretory Products
Relative levels of pancreatic digestive

Pancreatic Acinar Cell Enzymatic Secretory Products
enzymes
Proenzymes Enzymes
Chymotrypsinogen (A,B) -Amylase
Kallikreinogen Sterol esterase
Procarboxypeptidase A (1,2) Lipase
Proteases
90% Amylase - 7% Procarboxypeptidase B (1,2) DNase
Prophospholipase (I,II) RNase
Lipases - 2% Proelastase
Nucleases <1% Mesotrypsin Lysosomal enzymes

Trypsinogens (1,2,3)
Trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase,

The pie chart depicts the relative amounts (by weight) of the different and prophospholipase A2 are stored in the pancreas and secreted
classes of pancreatic digestive enzymes. Proteases make up the most into the duodenal lumen as inactive proenzymes forms. If these en-
abundant class of enzymes. From Scheele G, et al. Gastroenterology zymes were active in the pancreas, they would digest the pancreatic
1981;80:461–73. From Pancreatic Physiology and Pancreatitis GastroSlide gland. Other enzymes such as amylase and lipase are stored and se-
51, AGA Institute. creted in their active forms. The active forms of these enzymes have
no effect on the pancreatic gland because it does not contain starch
or triglyceride.
lipases (digesting triglycerides and phospholip-

gest triglycerides. The sites hydrolyzed by each class
ids), and nucleases (digesting nucleic acids)(Figure
of pancreatic enzymes are provided in Table 10.1.
10.8). Most of these proteins are digestive enzymes
The relative level of each digestive enzyme group
or cofactors, which include 20 isozymes of 12 differ-
varies, with proteases making the greatest contribu-
ent enzymes (Figure 10.9). The remainder includes
tion by mass (Figure 10.8). To prevent acinar cell in-
pancreatic secretory trypsin inhibitor, several tryp-
jury, all the proteases, as well as phospholipase and
sin-like enzymes that are not primarily digestive en-
colipase, are secreted by the pancreas as inactive
zymes, and glycoproteins (Figure 10.10). In addition,
proenzymes (zymogens). After entering the intes-
pancreatic juice contains colipase, a protein cofactor
tinal lumen, trypsinogen is converted to trypsin by
that contributes to lipolysis by binding to bile salt–
an intestinal brush-border protease, enterokinase
lipid surfaces, enhancing the ability of lipase to di-
Table 10.1
Sites of Pancreatic Enzyme Substrate Cleavage
Enzyme Substrate Site of action Products
Carbohydrates (amylose, -1,4 linkage between hexoses (but not at Maltose, maltotriose,
Amylase
amylopectin, glycogen) branch points or end points) -limit dextrins
Endopeptidases (trypsin, chymo-
Proteins, peptides Internal peptide bonds Small peptides
trypsin, elastase)
Exopeptidases (carboxypeptidase
Proteins, peptides Peptides bonds at carboxyl terminal Small peptides, amino acids
A and B)
Fatty acids and monoglyc-
Lipase Triglycerides Ester linkage of fatty acid in position 1
eride
Phospholipases Phospholipids (e.g., lecithin) Ester linkage in position 2 Fatty acids, 1,1-diglyceride

Nonenzymatic Acinar Cell Products Intestinal Zymogen Activation Cascade
Non-enzymatic Acinar Cell Products Intestinal zymogen activation

Zymogen Activation Cascade
Enterokinase
Trypsinogens
Bradykinin
Ions: Na+, Cl-, Ca2+ Trypsin
Glycoprotein-2 (GP 2) Chymotrypsinogens Chymotrypsins
Lithostathine (PSP/reg) Kallikreinogen Kallikrein

Pancreatitis-associated protein Procarboxypeptidases Carboxypeptidases
Pancreatic secretory trypsin inhibitor Procolipases Colipases
Procolipases Prophospholipases Phospholipases
Proelastase Elastase
Proprotease E Protease E
The table lists the nonenzymatic secretory products of the acinar Trypsinogens Trypsins
cell. Procolipase, when Activated, facilitates the action of lipase.
GP-2 is a glycoprotein linked to the inner zymogen granule mem-
brane and may have a role in protein sorting or membrane recycling. This image demonstrates that enterokinase at the duodenal brush border activates
Some GP-2 isreleased from the zymogen granule membrane and trypsin. Trypsin, in turn, activates the other proenzymes (also called zymogens)
secreted. GP-2 is enriched in stones and mayhave a role in their for- secreted by the pancreas. From Pancreatic Physiology and Pancreatitis GastroSlide
mation. Lithostathine may prevent stone formation in the pancreas. 57, AGA Institute.
Pancreatitis-associated protein increases with pancreatitis,
although the function is not known.
Pancreatic secretory trypsin inhibitor has an important role in
preventing intrapancreatitic zymogen activation. The ions, especially Figure 10.12
Na+ and Cl-, are important for transport of the secretory products Functional Lipase Reserve
from the acinar lumen into the pancreatic ductal system by pulling
water into the luminal space by osmotic forces. Water and ion flow
then “wash out” the luminal space.
(enteropeptidase). Trypsin then can activate the

other proenzymes as well as trypsinogen molecules
(Figure 10.11). Unlike the other digestive enzymes,
amylase, lipase, and ribonuclease are secreted as ac-
tive molecules. Notably, the exocrine and endocrine
pancreas has an enormous functional reserve, so up
to 90% of a healthy pancreas can be removed before
exocrine dysfunction (measured by increased fat ex-
cretion) is observed (Figure 10.12).
The acinar cell synthesizes and secretes low con-
centrations of a trypsin inhibitor capable of inhibit-
ing trypsin and, to some extent, chymotrypsin. The The experimental results in this image demonstrate that the capacity of the pancreas
presence of pancreatic secretory trypsin inhibitor to secrete lipase must decrease to a level <10% of normal before a person on a
probably protects against damage to the pancreas normal diet will develop excess fecal fat excretion (steatorrhea). Note that some
fat (~6 g/day) is always excreted into the stool. Similar reserves are found for the
due to premature activation of trypsin in the acinar endocrine pancreas. The fact that the pancreas has large reserves means that much of
cell or before it reaches the intestine. However, once the pancreas can be removed or damaged before endocrine or exocrine insufficiency
pancreatic juice enters the duodenum, trypsinogen occurs. Furthermore, it suggests that when a patient with chronic pancreatitis
presents with steatorrhea, >90% of the gland has been destroyed. From DiMagno E,
is converted to active trypsin to such an extent that et al. N Engl J Med 1973;288:813.
the relatively small amount of trypsin inhibitor pres-
ent does not interfere with the normal digestive pro-

cess. An additional protective mechanism against from the Golgi complex in a vesicle to form immature
the potential harmful effects of premature trypsin secretory granules that ultimately become zymogen
activation within the pancreas is the ability of sev- granules, the storage compartments for digestive en-
eral acinar cell proteases (e.g., chymotrypsin C) and zymes and other secretory proteins.
of trypsin itself to destroy trypsin. Mutations that There are two forms of secretion. Constitutive
interfere with these degradation mechanisms are as- or basal secretion is comprised of newly synthesized
sociated with an increased risk of developing acute proteins and is a small fraction (~5%) of regulated
pancreatitis. secretion. Constitutive secretion may provide con-
The secreted proteins of the exocrine pancreas, stant low levels of digestive enzymes to the upper
primarily digestive enzymes, are synthesized in the GI tract. Regulated or stimulated secretion comes
acinar cell on ribosomes of the rough endoplasmic from zymogen granules and represents the major re-
reticulum. Newly synthesized proteins then enter sponse to a meal. When the acinar cell is stimulated
the cisternal space and remain membrane-bound to secrete, the zymogen granule undergoes regulated
until secreted into the acinar lumen. The secretory secretion and fuses with the apical plasma mem-
proteins are transported as a mixture to the Golgi brane (exocytosis), releasing digestive enzymes and
complex, where additional post-translational pro-
cessing occurs, and digestive enzymes destined to the acinar lumen (Figure 10.13).
enter zymogen granules are largely sorted from ly- Stimulation of protein secretion by pancreatic
sosomal enzymes destined for packaging into lyso-
the basolateral cell surface by various ligands. Prob-
Figure 10.13 ably the most important in humans is the cholinergic
Pancreatic Acinar Cell Exocytosis neurotransmitter acetylcholine (Figure 10.14). Acti-
vation of this G-protein receptor leads to phospho-
lipase C activation and its subsequent conversion of
Acinar Cell phosphatidylinositol to inositol 1,4,5-triphosphate
Exocytosis
(1,4,5-IP3) and 1,2-diacylglycerol (DAG). The 1,4,5-
IP3 causes an increase in cytosolic calcium concen-
tration due to the release of calcium from endoplas-
mic reticulum stores and is essential for secretion.
The downstream targets of calcium remain unclear.
Some ligands can cause increased cAMP levels in
the acinar cell and secretion. The effects of increas-
* ing calcium and cAMP in the acinar cell are synergis-
tic with respect to secretion. Changes in membrane
phospholipids are also likely to have a role in exocy-
tosis.
Exocytosis involves the movement of zymogen granule to the apical surface of the
acinar cell, followed by fusion of the membranes of the granules and the apical plasma Regulation of Pancreatic Secretion
membrane and fission. This results in release of the granule content in the lumen of the
acinus. The resulting excess plasma membrane is recycled to the internal membranes During the basal or fasting state, the volume of pan-
of the cell. In this electron micrograph, the upper granule is approaching the apical creatic juice secreted into the duodenum is low, 10%
plasma membrane but has not fused yet. The lower granule has already undergone
fusion and fission and the contents are in the extracellular space. The granule contents
or less of maximal levels of enzyme or bicarbonate
are washed out with activation of chloride channels in the granule membrane resulting secretion. However, brief periods of increased pan-
in water movement across the membrane. From Pancreatic Physiology and Pancreatitis creatic enzyme and bicarbonate secretion occur
GastroSlide 69, AGA Institute. (Courtesy of G. Palade, San Diego, CA.)
about every 60–90 minutes, in temporal association
with the increased motor activity of phase III of inter- detected CCK receptors (CCK1) on pancreatic acinar
digestive migrating motor complexes (Figure 10.15). cells, it is likely that CCK regulates pancreatic secre-
Cholinergic neural input is the primary regulator of tion in humans primarily by binding to afferent or
the increase in both motor and secretory activity, and efferent vagal neurons or other intrapancreatic cho-
secretion of the peptide motilin from duodenal endo- linergic nerves rather than to acinar cells. Since both
crine cells into the blood appears to play a role in the secretin and CCK are released from mucosal cells in
the proximal duodenum, diseases that affect this part
inhibitor of pancreatic secretion in the fasting state. of the small intestine can result in decreased pancre-
Meal-stimulated pancreatic secretion is divided atic stimulation, pancreatic atrophy, and pancreatic
into cephalic, gastric, and intestinal phases, although
considerable overlap occurs (Figure 10.16). After in- children with celiac disease, can have pancreatic in-
gestion of a meal, the exocrine pancreas secretes bi-
carbonate and enzymes at about 60–75% of the lev- The pancreas requires negative feedback inhibi-
els attained after intravenous infusions of maximally -
effective doses of secretagogues such as secretin and zymes are present in the small intestine and when
cholecystokinin (CCK).
The cephalic phase is stimulated by the thought, FIGURE 10.14
sight, taste, or smell of food. It can produce a secre- Acinar Cell Receptor–Mediated Secretion
tory response 25–50% of maximal and is regulated
by vagal cholinergic innervation. The gastric phase Acinar Cell
Receptor Mediated Secretion
by gastric distension, resulting in a small increase in Exocytosis
pancreatic secretion. The stimulation of pancreatic

secretion prior to the entry of food into the small
intestine probably prepares the duodenum for the
Ca2+ cAMP
digestion.
Pancreatic secretion is maximal during the in-
testinal phase. During this phase, secretin is released GRP
from “S” cells in the duodenal mucosa into the blood VIP
CCK1
from the duodenum in response to duodenal acidi- Ach Secretin
release (Figure 10.5). Long-chain fatty acids and bile

acids may also help stimulate the secretion of secre- Pancreatic acinar cell agonists that stimulate digestive enzyme secretion act
tin. The rise in plasma secretin concentration after through two separate pathways. In one pathway, agonists such as gastrin-re-
a meal (potentiated by vagal cholinergic stimulation leasing peptide, cholecytokinin, and acetylcholine mediate secretion through
and circulating CCK) is responsible for the increase increases in cellular calcium. In the other pathway, agonists such as vasoac-
in pancreatic water and bicarbonate output. tive intestinal polypeptide and secretin mediate secretion through increases
Increased digestive enzyme secretion is stimu- in cyclic AMP. Note that a simultaneous increase in both calcium and cyclic
lated by fatty acids, oligopeptides, amino acids, and AMP, following stimulation with a combination of agonists, results in a syn-
calcium entering the proximal small intestine. This ergistic effect on secretion. That is, the observed response is greater than
leads to release of CCK from cells (sometimes des- would be expected from the additive responses of the individual agonists
ignated “I cells”) in the duodenal mucosa into the acting alone. The double arrows indicate that the cellular mechanisms that
circulation and activation of cholinergic enteropan- cause secretion are largely unknown. Whether there is a CCK1 receptor on
creatic pathways, both of which stimulate pancre- the human pancreatic acinar cell remains unclear. From Pancreatic Physiology
atic enzyme secretion. Although some studies have and Pancreatitis GastroSlide 64, AGA Institute.
Figure 10.15 food is no longer present. This suppression of pan-

Secretory Pattern of Pancreatic Digestive Enzymes creatic secretion may be imparted by intraduodenal
pancreatic serine proteases such as trypsin, chymo-
trypsin, and elastase and by bile acids. The proteases
Pancreatic Secretory Pattern
may act by degrading peptides within the duodenal
15 lumen that stimulate the release of cholecystokinin
Meal
and secretin from duodenal mucosal cells. Negative
10
feedback regulation of the pancreas occurs by two
Trypsin
additional mechanisms. Release of pancreatic poly-
5
output peptide from pancreatic islet cells acts on central
vagal pathways to reduce exocrine secretion. The
0
presence of free fatty acids in the ileal lumen stimu-
Fasting (interdigestive) Fed
lates the release of peptide YY, which also reduces
Midnight 6 am Noon exocrine secretion in animal models, although its im-
portance in humans remains unclear.
This graphic shows the output of the digestive enzyme, trypsin, into the duodenum both
during the fasting state and after a meal. During fasting there are small periodic in-
creases in trypsin output. These increases correlate with activation of the motility of
Endocrine Hormones Secreted by the
the intestine during the migrating motor complex. With a meal there is a much larger Pancreas
increase in trypsin output due to the inputs of several meal stimuli that mediate secre-
tion through both neural and humoral mechanisms. From DiMagno E, Layer P. Human The islets of Langerhans contain a number of dif-
exocrine pancreatic secretion in the pancreas. In The Pancreas: Biology, Pathobiology, -
and Diseases. Go VLW, DiMagno E, Gardner JD, et al., Eds. New York: Raven, 1993, p. sulin is produced by B cells in the center of the is-
275–300. From Pancreatic Physiology and Pancreatitis GastroSlide 34, AGA Institute.
let, whereas glucagon is produced by A cells in the
periphery. The other major cell types are the D cell,
Figure 10.16 which secretes somatostatin, and the F cell, which
Phases of Pancreatic Secretion During a Meal secretes pancreatic polypeptide. Notably, pancreatic
islets are directly upstream of many exocrine acinar
Pancreatic Secretion During a Meal cells in a portal system, and therefore very high con-
centrations of islet hormones reach the pancreas.
Phase Stimulant Regulatory Enzyme Islet hormones may affect both acinar cell digestive
pathway secretion
% max. enzyme content and secretion. One effect of this re-
Cephalic Anticipation, Vagal 25 lationship might be the relative pancreatic exocrine
sight, smell,
mastication,
taste
mechanisms governing pancreatic endocrine hor-
Gastric Distension Vagal 10-20
mone secretion is beyond the scope of this chapter.
Intestinal Oligopeptides Vagal 50-80
Essential amino Enteropancreatic However, each of these cell types can develop into an
acids reflexes
Fatty acids (>C8) CCK
Gastric acid Enzyme secretion
to the excess of the hormone produced.
This table presents the stimuli and regulatory pathways that are involved in mediating
the secretory response of the pancreas during the different phases of a meal. Note that Acute Pancreatitis
up to one half of the secretory response occurs before the meal enters the intestine
(intestinal phase). This part of the response is mediated by various stimuli during the ce- -
phalic and gastric phases of the meal and is regulated by vagal efferents. The probable ing in the exocrine pancreas with variable involve-
purpose of this pancreatic secretion before the meal enters the duodenum is to “prime” ment of peripancreatic tissues and other organ sys-
the intestine so that when the meal first enters the duodenum, digestion will create
products such as peptides, amino acids, and free fatty acids that can, in turn, stimulate tems. It ranges in severity from a mild, self-limited
the intestinal phase of secretion.
disease to a catastrophic one with multiple organ vascular damage. These include interleukins (IL) IL1,
failure and high risk of death. However, if the patient
survives and the primary cause of pancreatitis can inhibitor factor, platelet activating factor, and ICAM-1.
Stimulation of innate immunity, through LPS
returns to normal clinically, biochemically, and mor- and ligands generated from cell injury such as ATP
phologically. Disease incidence ranges from 10 to 50 and mitochondria DNA, leads to toll-like receptors
per 100,000 per year. Although some studies suggest (TLRs) activation and has an important role in acute
a substantial increase in the incidence of acute pan- pancreatitis. Substance P is produced by nerves in
creatitis over the last 30 years, it is unclear to what
Damage to fat cells within the pancreas leads to re-
make the diagnosis versus an increase in risk factors lease of triglyceride and it subsequence processing
such as gallstone disease and obesity. to free-fatty acids by lipase. Some free fatty acids
damage acinar cells and promote pancreatitis. A con-
-
Pathophysiology matory mediators during acute pancreatitis is likely;
this response might be suppressed by enteric feed-
Acute pancreatitis is to be primarily initiated by
ing. Some mediators of injury appear to primarily
three pathologic responses within the pancreatic aci-
mediate pancreatic damage, while others are more
nar cell: (1) activation of inactive digestive enzymes
important in causing damage to other organs such
(zymogens), particularly proteases; (2) inhibition of
as the lungs. For example, the release of angiopoi-
etin during acute pancreatitis may have a central role
mediators. At later stages of disease, zymogen activa-
in mediating enhanced vascular permeability. That
tion may occur at other sites. As activation of tryp-
such a diversity of damaging mediators is elaborated
sinogen to trypsin can lead to activation of all other
during acute pancreatitis makes it unlikely that inhi-
zymogens, this appears to be an essential early step.
bition of a single pathway would have a substantial
therapeutic impact.
a mutation in the human cationic trypsinogen gene
Cytokines cause damage directly and by stimu-
(known as ) results in a
form of inherited pancreatitis, and that mutations in
the gene for pancreatic secretory trypsin inhibitor
that range from necrosis to programmed cell death
(known as
(apoptosis). The pattern of cell death corresponds to
) increase the risk of pancreatitis. The mech-
disease severity; the greater the levels of cell death
anisms of enzyme activation remain unclear, but dis-
from necrosis, the more severe the disease. In addi-
ordered calcium signaling appears to be key. When
-
trypsinogen is converted to trypsin, the trypsinogen
mation, multiple cytokines from the pancreas are in-
activation peptide (TAP) is released. Elevations in
and end organ damage (Figure 10.17).

and are a good early marker of severity but are not
commonly used. Therapies that block zymogen (pro-
the pancreas can lead to such local complications as
teases) activation in the acinar cell have not been
pancreatic and peripancreatic necrosis, fat necrosis,
successful because of issues relating to timing (given
-
too late), potency, and possibly the lack of agents
tinal ileus as well as circulatory volume losses due
-
-
peritoneum and peritoneum and “third-space” losses
matory mediators, injurious cytokines, edema, and
into the dilated stomach and intestine in the setting
ischemia. A long list of pathologic cytokines cause
of an ileus (Table 10.2). The production and release
Table 10.2
Complications of Acute Pancreatitis
- Pathogenesis and Etiological Factors

mation, particularly from injured fat cells, can result
in severe systemic complications. These may include
for acute pancreatitis (Table 10.3), gallstone disease
multi-organ failure (especially respiratory failure
and alcohol abuse account for about 70–80% of cases
due to the acute respiratory distress syndrome and
in industrialized countries. Other less common causes
acute renal failure), hypotension, and “leaky” capil-
include hyperlipidemia, 2–3%; adverse reaction to
endoscopic retrograde cholangiopancreatography
(sepsis-like) syndrome (Table 10.2).
(ERCP), known as , 2–3%; ma-
lignancy, 1%; medications, 1%; miscellaneous causes,
localized, involving only the pancreas and peripan-
2%; and idiopathic disease, about 10%.
creatic tissues, and resolves spontaneously in a few
Gallstone disease commences when a stone,
days to a week. The other 15–25% of cases have a
usually only a few millimeters in diameter, migrates
severe course, with multiple local and systemic com-
down the common bile duct and obstructs the pan-
plications, prolonged hospitalization, and risk of
creatic duct at the duodenal papilla (Figure 10.18).
death. The mortality rate for hospitalized patients
While the precise mechanisms responsible for gall-
with acute pancreatitis ranges from 3–5%, but may
stone pancreatitis and post-ERCP pancreatitis re-
be higher in some subgroups, such as the aged.
Table 10.3
Causes of Acute Pancreatitis
Gallstone disease
Chronic excessive alcohol use

Drugs (confirmed by rechallenge)
All-trans-retinoic acid Hydrocortisone Pentamidine
Alpha-methyldopa Ifosfamide Pravastatin
Azathioprine Isoniazid Premarin
Azodisalicylate Lamivudine losartan Procainamide
Bezafibrate Meglumine Pyritinol
Cannabis Mesalamine (Asacol) Simvastatin
Carbimazole Mesalamine (Dipentum) Sulfamethoxazole
Clomiphene 6-Mercaptopurine Stibogluconate
Codeine Methimazole Sulindac
Cytosine arabinoside Metronidazole Tetracycline
Enalapril Nelfinavir Trimethoprim-sulfamethoxazole
Ethinylestradiol/lynestrenol Noreth/mestranol Valproic acid
Furosemide Omeprazole
Infections
Ascariasis Cytomegalovirus
Clonorchiasis Tuberculosis
Mumps Mycobacterium avium complex
Coxsackievirus
Blunt or penetrating abdominal trauma

Postendoscopic retrograde cholangiopancreatography and sphincter of Oddi manometry
Postoperative (especially after pancreatic and biliary surgery and operations involving cardiopulmonary bypass and boluses of intravenous calcium)
Genetic hyperlipidemia (hypertriglyceridemia)
Hypercalcemia
Pancreatic or ampullary tumors, lymphoma
Sphincter of Oddi dysfunction
Duodenal disease
Peptic ulcer
Crohn’s disease
Periampullary diverticulum
Choledochal cyst
Toxins
Organophosphate insecticides
Scorpion venom
Pancreas divisu
Solid organ transplantation (kidney, liver, heart)
Vasculitis
Polyarteritis nodosa
Systemic lupus erythematosus
Thrombotic thrombocytopenic purpura
Henoch-Schönlein purpura
Cystic fibrosis
Hereditary pancreatitis
Idiopathic disease
Figure 10.17 main unclear, sudden duct obstruction and increase

Pancreatic Cytokine Production and Inflammatory Reaction duct pressure are likely to be essential for both.
This could account for the rarity of acute pancreati-
tis in conditions with gradual duct occlusions such
Mediators of Injury Lungs as ampullary tumors. Experimental studies suggest
that the combination of obstruction and pancreatic
Microcirculation stimulation may be needed to produce pancreatitis.
Liver The effects of sudden obstruction are likely related to
ICAM-1 effects on the acinar cells and pancreatic nerves. The
IL-1
TNF PAF success of pancreatic duct stenting in reducing the
TNF PAF Endothelin incidence of post-ERCP pancreatitis underscores the
MIF
IL-1 INOS ICAM-1 importance of acute obstruction in causing disease.
IL-61 Proinflammatory
Angiopoietin-2
obstruction is unlikely, cholestatic conditions might
on the acinar cell that enhance injury.

When a common duct stone obstructs the pan-
creatic duct at the ampulla of Vater, it can precipitate
Insults to the pancreatic acinar cell lead to upregulation of intracellular signaling
systems such as nuclear factor-kB (NF-kB), activating protein-1 (AP-1), and p38 MAP
kinase. The signaling systems upregulate the production of cytokines, chemokines, and duct may not occur and is probably not necessary to
growth factors from the pancreatic acinar cell. The proinflammatory cytokines that are cause disease.
initially produced cause local inflammatory response and cell death and also mediate
Typically, alcoholic acute pancreatitis occurs in
the influx and activation of inflammatory cells that produce more cytokines. The result
is a propagation and augmentation of the inflammatory response and pancreatitis. individuals with at least 10 years of heavy alcohol
The image lists proinflammatory cytokines and other inflammatory molecules (i.e., use. Although chronic alcoholics have been reported
iNOS and ICAM-1). These pancreas-derived cytokines act both directly on target to have a 15-fold increased risk of developing acute
tissue, causing cellular injury and organ dysfunction, and indirectly by activating a
local inflammatory response in the organ that in turn leads to cellular injury and organ pancreatitis compared to nonalcoholic controls, only
dysfunction. IL, interleukin; TNF, tumor necrosis factor; PAF, platelet activating factor; about 5–10% develop pancreatitis, indicating a major
NO, nitric oxide. From Pancreatic Physiology and Pancreatitis GastroSlide 137, AGA role for other hereditary or environmental risk fac-
Institute.
tors. A key risk factor in disease development may
be cigarette smoking. Indeed, recent studies have
Figure 10.18 suggested that smoking acts as an independent risk
Mechanism of Gallstone-Induced Pancreatitis to substantially increase the risk of both acute and
chronic pancreatitis and may predispose to disease
even in the absence of alcohol. Although some pro-
pose that acute alcoholic pancreatitis can only devel-
op in a gland that has underlying chronic pancreatitis,
others have reported that alcohol can produce acute
and potentially reversible pancreatitis in the absence
of underlying disease.
A variety of possible adverse effects of alcohol on
the sphincter of Oddi and the pancreas have been de-
scribed both in humans and in experimental animals.
These have included an increase in pressure or spasm
of the sphincter of Oddi, protein plug formation in
the pancreatic ducts, increased fragility of acinar cell
From Pancreatic Physiology and Pancreatitis GastroSlide 184, AGA Institute. lysosomes and zymogen granules, and changes in
pancreatic secretory proteins. Alcohol-related abnor- tential causes of acute pancreatitis, but only a fraction
malities in acinar cell signaling or increased oxidant (~50) of these have been shown to cause disease with
stress may also have a role. The contribution of each rechallenge (Table 10.3). The disease mechanisms are
of these factors remains unclear. virtually unknown, but a few probably cause pancre-
atitis by elevating serum triglycerides. Some of these
about 10% of acute pancreatitis cases (Table 10.3), drugs typically produce acute pancreatitis within a
including genetic hyperlipidemia (with serum tri- month of starting treatment, presumably by a hyper-
glycerides typically >1000 mg/dl on presentation sensitivity reaction. These include azathioprine, mer-
with acute pancreatitis), hypercalcemia, surgery captopurine, sulfonamides, metronidazole, lisinopril,
(particularly upper abdominal surgery and thoracic enalapril, and aminosalicylates. Other drugs (e.g., di-
procedures involving cardiopulmonary bypass), solid danosine, pentamidine, and valproic acid) may pro-
organ transplantation (liver, heart, kidney), abdomi- duce pancreatitis after months of administration,
nal trauma (blunt or penetrating), ERCP (incidence suggesting cumulative effects of the drug or toxic me-
of 1–10%), sphincter of Oddi dysfunction, and infec- tabolites.
tions (e.g., ascariasis, clonorchiasis, mumps, cytomeg- Whether pancreas divisum (PD; a variant of
alovirus infection). pancreatic ductal anatomy that involves 5–7% of the
Pancreatic cancers and ampullary tumors infre- general population) causes pancreatitis is controver-
quently present as acute pancreatitis. Benign ana- sial. Normally, the duct of Santorini (arising from the
tomic abnormalities that interfere with emptying of embryologic dorsal pancreas and forming the acces-
the pancreatic duct, such as choledochal cysts or duo- sory pancreatic papilla) fuses with the duct of Wir-
denal diverticula, are also uncommon causes of acute sung (derived from the embryologic ventral pancreas
pancreatitis. and forming the major papilla) to drain the entire
Autoimmune pancreatitis (AIP) patients may pancreas (Figure 10.2). In PD, the ventral and dorsal
present with very mild pancreatitis, but more com- ducts fail to fuse, and most of the pancreas is drained
monly they present with pancreatic masses and ob- through the accessory papilla (Figure 10.3c). In some
structive jaundice (see chapter section on Chronic individuals with PD, the accessory papilla may be in-
adequate to accommodate the volume of pancreatic
AIP (the more common Type I) diagnosis is usually secretions under some circumstances, leading to rela-
made with imaging studies demonstrating an en-
larged “sausage-shaped” pancreas, irregular narrow- Given the prevalence of PD, it is important to evaluate
ing without dilation of the pancreatic duct, elevated for other potential etiologic factors before ascribing
serum IgG4 levels, involvement of other organs (bile pancreatitis to this common anatomical variant.
ducts, lacrimal and salivary glands, kidneys and retro- Another potential cause of acute pancreatitis is
peritoneum), and a response to corticosteroids. His- sphincter of Oddi dysfunction. Sphincter of Oddi ma-
tological examination of the pancreas demonstrates nometry is used to make this diagnosis and is based
positive stains for IgG4 that involves the small ducts sphincter pressure of >40 mm Hg.
and venules and sparing arterioles. AIP is often dif- Patients with AIDS have an incidence of acute
pancreatitis of as high as 4–10% in some series. This
differentiation is critical because of the different ther- is due in part to infections involving pancreatic tis-
apeutic and prognostic implications. Various diagnos- sue (e.g., cytomegalovirus infection, cryptosporidi-
tic criteria for AIP have been proposed, including the osis, cryptococcosis, toxoplasmosis, or infection with
Japanese Pancreas Society criteria and the HISORt Mycobacterium tuberculosis or
(Histology, Imaging, Serology, other Organ involve- complex) and in part to drug toxicity (e.g., didano-
ment, and Response to steroid Therapy) criteria. sine, pentamidine, trimethoprim-sulfamethoxasole).
At least 300 drugs have been implicated as po- Patients with AIDS also frequently have an elevated
serum amylase concentration in the absence of panin incidence; the leading causes are trauma, biliary
creatitis either by clinical evaluation or by pancreatic tract disease, drugs and infections. Other causes in
imaging studies. It is unclear whether this hyperamy- children include genetic hyperlipidemia (chylomi-
lasemia is due to abnormalities in renal tubular func- cron disease), congenital malformations (pancreas
tion, increases in the salivary isoamylase fraction of divisum; choledochal, pancreatic ductal, or duodenal
-
mation below the threshold for detection by imaging and glycogen storage disease type I. In Trinidad
studies. and countries in the Caribbean region, the venom
About 10% of adult patients are categorized as
having idiopathic acute pancreatitis. Several studies pancreatitis is rarely severe and may be caused by a
have suggested that occult gallstone disease (biliary neurotoxin that selectively hyperstimulates the pan-
microlithiasis or gallbladder sludge) can be demon- creas, a mechanism similar to acute pancreatitis that
strated in 50–75% of these patients by microscopic is caused by exposure to cholinesterase inhibitors
examination of bile or duodenal juice for cholesterol used in some insecticides.
or bilirubinate crystals (>5 crystals per high power
hereditary pancreatitis that is inherited as an auto-
CCK) or by repeated abdominal ultrasonographic ex- somal dominant trait and may present in childhood
aminations. Treatments directed at gallstone disease or adolescence as recurrent acute pancreatitis. Most
(e.g., cholecystectomy, endoscopic sphincterotomy, of these patients have a point mutation in the gene
or ursodeoxycholic acid therapy) can reduce the like- (PRSS 1) coding for cationic trypsinogen on chromo-
lihood of recurrent acute pancreatitis in these pa-
tients. Others have suggested that sphincter of Oddi all of which appear to result in gain of function either
dysfunction may account for at least 15% of cases of by resulting in enhanced activation of trypsinogen in
acute pancreatitis otherwise considered idiopathic. the acinar cell or by impairing one of the mechanisms
Fifty percent of patients with idiopathic acute pan- this cell has developed to inhibit or degrade trypsin.
creatitis may develop overt chronic pancreatitis on Approximately 20% of cases of acute pancreati-
follow-up. Some mutations of CFTR that cause mild
to moderate reductions in ion transport and do not Some of these may turn out to be related to less com-
- mon mutations in CFTR that do not result in classical
erwise unexplained episodes of acute pancreatitis in
adults. Endoscopic ultrasound evaluation of the pan-
creas is a useful test in idiopathic pancreatitis and
can help diagnose microlithiasis, occult pancreatic Pathology
malignancies, early chronic pancreatitis, and pan-
The pancreas in mild (sometimes called interstitial)
creas divisum. In patients with a normal endoscopic
acute pancreatitis demonstrates edema and intra-
ultrasound evaluation the clinician may consider
pancreatic and peripancreatic fat necrosis with little
conservative follow up, empiric cholecystectomy, ge-
necrosis of pancreatic secretory tissue. In severe
netic testing and ERCP. When ERCP is performed in
(or necrotizing) acute pancreatitis, the pancreas is
the setting of idiopathic pancreatitis, consideration
grossly edematous and demonstrates gray-white
should be given to performance by a practitioner
proteolytic destruction of the parenchyma, hemor-
experienced in sphincter of Oddi manometry. Acute
rhage, and chalky white fat necrosis resulting in a
pancreatitis complicates anywhere from 1 in 100 to
variegated appearance (Figure 10.19). Histologically
1 in 4,000 pregnancies, and is most often due to gall-
severe acute pancreatitis demonstrates (1) necrosis
stone disease (occurring in the 3rd trimester) and
of pancreatic parenchyma, (2) hemorrhage and ne-
occasionally hypertriglyceridemia. Acute pancreati-
crosis of blood vessels, (3) fat necrosis within the
tis in childhood, although uncommon, is increasing
pancreas, and (4) damage to peripancreatic tissue Figure 10.19

- Acute Pancreatitis: Gross Specimen
ure 10.20).
Gross specimen in severe pancreatitis

Diagnosis
Clinical features
The hallmark of acute pancreatitis is abdominal pain,
present in 95% of patients, typically epigastric and
radiating to the back in about half and two-thirds of
patients. This pain is frequently worsened by inges-
tion of food or alcohol and by vomiting, and may be
somewhat relieved by leaning forward or assuming
a knee-chest position. Nausea, vomiting, and ab-
dominal pain are frequently reported, whereas he- This autopsy specimen demonstrates an enlarged gland with areas of hemorrhage and
matemesis, melena, and diarrhea occur infrequently chalky white necrosis. From Pancreatic Physiology and Pancreatitis GastroSlide 163,
AGA Institute. (Courtesy of Dr. Robert Homer, VAMC, West Haven, CT.)
(Figure 10.21).
Abdominal tenderness may be mild and limited
to the epigastrium or marked and accompanied by
aged acinar cells or their escape from ducts causes
abdominal rigidity and rebound tenderness. Fever,
an elevation in the circulating level of these enzymes.
tachycardia, tachypnea, and hypotension may be
When measured within 24 hours from the onset of
present, depending on the severity of the presenta-
symptoms, serum amylase concentration will be
tion. Icterus may be apparent because of either bili-
elevated in 80–85% of all patients with acute pan-
ary obstruction or concomitant liver disease. Dull-
ness to percussion, diminished breath sounds, or Figure 10.20
rales at the lung bases may be found because of atel- Acute Pancreatitis: Microscopy
ectasis or pleural effusion.
A variety of other symptoms and signs may de-
velop because of complications of the disease (Table Histology severe disease
10.2). The frequently mentioned Cullen’s sign and
Grey Turner’s sign (bluish discoloration of the skin in
only rarely observed in acute pancreatitis and can

also be seen in patients with a ruptured abdominal
aortic aneurysm or with other causes of retroperito-
neal hemorrhage. Rarely, patients with severe acute
pancreatitis will not present with abdominal pain
but with altered mental status or acute respiratory
failure and the diagnosis may be missed.
Laboratory testing
-
Microscopic examination of severe pancreatitis demonstrates loss of pancreatic
architecture, severe inflammation, edema, necrosis of fat and parenchymal tissues,
vascular injury, and hemorrhage. From Pancreatic Physiology and Pancreatitis
diagnosis. Release of digestive enzymes from dam- GastroSlide 162, AGA Institute. (Courtesy of K. Barwick, Jacksonville, FL.)
Figure 10.21 creatitis, but may be normal in patients with acute

Presenting Feature of Acute Pancreatitis alcoholic pancreatitis or pancreatitis due to hypertri-
glyceridemia. Serum triglyceride levels over 400 mg/
ml may interfere with the measurement of amylase
Acute Pancreatitis: presenting symptoms
(and to some extent, lipase). Dilution of the serum
minimizes this problem and allows more accurate
Abdominal pain enzyme measurements. Serum amylase may also be
Nausea / vomiting elevated in some conditions that can closely mimic
Tachycardia acute pancreatitis (e.g., cholangitis, gastrointestinal
Low grade fever perforation or ischemia, ruptured ectopic pregnan-
Abdominal guarding cy) as well as in acute or chronic renal failure, sali-
vary gland disease, and macroamylasemia. In mac-
Loss of bowel sounds
roamylasemia, complexed amylase molecules are too
Jaundice
large to be cleared by the kidney resulting in elevated
0 20 40 60 80 100
serum amylase levels in the absence of pancreatitis.
% patients
Macroamylasemia can be diagnosed by fractionation
of the serum amylase or by demonstration of a very
The cardinal feature of acute pancreatitis is abdominal pain, which is present in low (<1%) amylase/creatinine urinary clearance
95% of patients. Absence of pain may be associated with a delayed diagnosis or ratio. Macroamylasemia can be associated with non-
severe disease, and may be a reason why some patients with severe disease are
not diagnosed until postmortem examination. Tachycardia, low-grade fever, and
peritoneal signs such as guarding and rebound tenderness are common physical disease, ulcerative colitis, and rheumatoid arthritis.
signs. The presence of guarding on physical examination is a useful prognostic feature For patients with abdominal pain, elevations in se-
in acute pancreatitis. From Lankisch PG, Schirren CA, Kunze E. Am J Gastroenterol rum amylase greater than three times the upper limit
1991;86: 322–26. Feinstein AR, Horwitz RI, Wells CK. Am J Med 1993;95:61–70. From
Pancreatic Physiology and Pancreatitis GastroSlide 219, AGA Institute.
acute pancreatitis in the absence of renal failure or
macroamylasemia.
Figure 10.22
Measurement of serum lipase concentration may
CT Findings in Acute Pancreatitis
be more sensitive than measurement of amylase be-
cause lipase levels remain elevated in serum some-
what longer than amylase levels and lipase tends to
Peripancreatic Fluid
Acute Pancreatitis: in Acute
dynamic CT be more markedly elevated in patients with acute
Pancreatitis alcoholic pancreatitis. Serum lipase measurement
-
though lipase may also be elevated due to other acute
intra-abdominal processes such as cholangitis and
gastrointestinal perforation or ischemia. Notably, the
assays measuring pancreatic as well as non-pancreat-

ic lipase activities in the serum. In acute or chronic re-
nal failure, amylase levels, and to some extent lipase,
normal, although more typically renal failure causes

values less than three times normal.
CT scan with intravenous contrast demonstrating diffuse edema of the pancreas, Measurements of urinary amylase excretion, se-
acute peripancreatic fluid collection, and peripancreatic fat stranding. Note that there
rum amylase isozymes, or serum concentrations of
is uptake of contrast material throughout the pancreas, indicating absence of necrosis.
From Pancreatic Physiology and Pancreatitis GastroSlide 251, AGA Institute. other pancreatic enzymes (e.g., trypsin, elastase, and
phospholipase) have not proven to be more useful Table 10.4

than standard amylase and lipase determinations. An Ranson’s Criteria of Severity
increase of more than three times the upper limits of
normal in serum transaminase levels in a patient with Gallstone pancreatitis Pancreatitis due to other causes
acute pancreatitis, especially if the values quickly re- On admission: On admission:
turn to normal, strongly suggests a gallstone etiology.
Age >70 years Age >55 years
The levels of serum amylase and lipase provide
no prognostic information. Furthermore, such mea- WBC >18,000/µl WBC >16,000/µl
surements are of little value during the course of Glucose >220 mg/dl Glucose >200 mg/dl
disease and should not be routinely assayed once the Lactate dehydrogenase >
diagnosis has been made. Lactate dehydrogenase >350 U/L
400 U/L
AST >250 U/L AST >250 U/L
Abdominal imaging
Abdominal ultrasound has a low sensitivity for con- Within 48 hours of admission: Within 48 hours of admission:
- Decrease in hematocrit >10 Decrease in hematocrit >10
aminations are often technically inadequate because
Increase in BUN >2 mg/dl Increase in BUN >5 mg/dl
patients may have an ileus. However, ultrasound is
very useful in determining whether cholelithiasis or Serum calcium <8 mg/dl Serum calcium <8 mg/dl
common bile duct dilation is present. Computed to- Base deficit >5 mmol/L PaO2 < 0 mm Hg
mography (CT) scans may be normal in 15–30% of Fluid deficit >4 L Base deficit >4 mmol/L
patients with mild acute pancreatitis (although the
Fluid deficit >6 L
diagnosis in these patients is often uncertain) but are
almost always abnormal in patients with moderate- AST, aspartate aminotransferase; BUN, blood urea nitrogen.
to-severe disease (Figure 10.22). However, a CT scan
study for differentiating severe acute pancreatitis Table 10.5
from other catastrophic intra-abdominal processes. Modified Glasgow Criteria of Severity
Highest value observed during initial 48 hours after

Estimating Severity admission:
Age >55 years
A variety of approaches have been proposed to try to
WBC >15,000/µl
differentiate the 75–85% of patients who will have
Glucose >180 mg/dl
a mild course from those destined for more serious
Blood urea nitrogen >45 mg/dl
illness and possible death. The Ranson’s criteria list
PaO2 <60 mm Hg
(Table 10.4) was the most commonly used prognos-
Serum calcium <8 mg/dl
tic indicator in the United States, whereas the modi-
Serum albumin <3.3 g/dl
Lactate dehydrogenase >600 U/L
Ranson’s criteria, have been used in the United King-
dom. For both sets of criteria, the more risk factors
accrued, the greater the probability of a prolonged,
(APACHE) II score, which can be calculated at the
complicated course and death. However, both re-
time of admission and then recalculated throughout
quire 48 hours of hospitalization to compute mean-
the course of hospitalization to measure improve-
ingful data, and neither can be calculated at later
-
time points to follow the patient’s course.
cates severe pancreatitis, but the APACHE II score
A more useful but complex scoring system is
has been criticized for assigning too heavy a weight
the Acute Physiologic and Chronic Health Evaluation
a mortality of about 50% in some series.

risk factor for morbidity and mortality in acute pan- Dynamic (bolus contrast-enhanced) CT has been
creatitis, the addition to the APACHE II score of a fac- used as a predictor of severity. The failure of more
tor accounting for body mass index has been used. than one-third or one-half of the gland to enhance
When values obtained at 48 hours after admission following intravenous contrast administration has
are compared, the Ranson, Glasgow, and APACHE II been interpreted as necrosis and associated with a
scores perform similarly in predicting the severity of severe course and development of infected necrosis
disease: they accurately identify a group of patients (Figure 10.23). However, a dynamic CT performed
likely to do well while predicting a severe course for too early in the course of the disease may underes-
those patients who will develop complications (and timate the incidence of reduced perfusion because it
in some cases die) as well as for many patients who often takes days to develop (Figure 10.24). Further-
will recover without complications. more, like the multiple criteria scores, dynamic CT
Recently, a mortality-based scoring system
- have an uncomplicated course. In addition, this pro-
mission appears to identify patients at risk for in- cedure is expensive and carries a possible risk of
creased mortality (Table 10.6). One of the measures nephrotoxicity from intravenous contrast agents.
in the BISAP, serum levels of the BUN on admission For these reasons, unless the patient is participating
and its trends during hospitalization, may have the in a formal study or other compelling reasons exist,
greatest prognostic value. Patients with BUNs of >25 contrast CT scans should be generally be performed
mmol/dl on admission had a 5-fold increase in risk of
developing organ failure and death from acute pan- the initial 2–3 days of illness.
creatic compared to those with values of <25 mmol/ MRI and various individual laboratory tests are
dl. The trend in the BUN may also be very important, being evaluated as predictors of severity. Serum lev-
with a rising value indicating a worse prognosis. Mild els of the C-reactive protein (CRP) appear to provide
organ failure is not uncommon on presentation, but a valid measure of severity and are widely available.
often resolves without sequela. However, persistent However, the CRP usually only reaches its peak value
and especially, worsening, organ dysfunction carries after several days of disease and is usually not a good
early marker of severity.
Table 10.6
BISAP Score and Mortality in Acute Pancreatitis
Differential Diagnosis
BISAP Other intra-abdominal processes may present simi-
Measure in first 24 hours Points Mortality
score larly to acute pancreatitis and can elevate serum lev-
els of amylase and lipase. These include a perforated
Blood urea nitrogen >25 mg/dl 1 0–1 <1% or penetrating duodenal or gastric ulcer, a ruptured
abdominal aortic aneurysm, cholangitis, intestinal
ischemia or infarction, and ruptured ectopic preg-
Impaired mental status 1 2 2%
nancy. Rare entities such as acute intermittent por-
phyria, familial Mediterranean fever, and lead poi-
Systemic inflammatory response
1 3 5–8% soning may also present with symptoms and signs
syndrome
similar to those of pancreatitis.
Age >60 years 1 4 12–19%

Management
Pleural effusion 1 5 22–27% Although there are many therapeutic considerations
in the management of acute pancreatitis, supportive Figure 10.23

Pancreatic Necrosis: CT Scan
the mainstay of therapy. Preliminary studies suggest
that aggressive early (beginning in the emergency
department as soon as the diagnosis is suspected)
- Acute Pancreatitis: Pancreatic necrosis shown by dynamic CT scan
ity. However, the recommendations regarding the op-
need to be established. In deciding the rate of infu-
correct microcirculatory dysfunction against the risk

of volume overload.
Mild acute pancreatitis

Most patients require only bed rest, no oral intake,
intravenous hydration and electrolyte replacement,
and analgesia. Fentanyl is the analgesic of choice be-
cause it may be less likely than other opiates to raise CT scan with intravenous contrast bolus demonstrating an absence of pancreas
opacification in the usual anatomical location of the pancreas (marked). This is
pressures in the sphincter of Oddi. Nasogastric suc- indicative of pancreatic necrosis. CT scanning can be used to estimate severity of
tion can decrease symptoms of nausea, vomiting, and pancreatitis. From Pancreatic Physiology and Pancreatitis GastroSlide 278, AGA
abdominal distension, but it does not shorten the Institute.
course of the disease and is now rarely used. In the
absence of complications, once abdominal pain and
tenderness abate and hunger returns, these patients
can be fed. Recent data shows that a solid low-fat diet Figure 10.24
may be used for initial feeding. This is safe and may Progression of Pancreatic Necrosis
reduce the duration of hospitalization.
Severe acute pancreatitis Progression of Pancreatic Necrosis

The most critical need in the earliest stages of severe
acute pancreatitis is vigorous resuscitation with in-
travenous hydration and electrolytes to prevent, or
treat, hypovolemia and shock. The presence of he-
moconcentration with an admission hematocrit of
have been associated with the development of organ

failure and a less favorable outcome. Volume require-
ments can be very large, and patients may require an
intensive care unit in which hemodynamics (mean
CT scan with intravenous bolus contrast on day 1 demonstrates normal opacification
arterial pressure, pulmonary capillary wedge pres- of the pancreas; a follow-up CT scan on day 3 demonstrates progression of necrosis,
sure, and cardiac index), intra-peritoneal pressure, as demonstrated by absence of pancreatic opacification. This is an important finding
urine output, and respiratory and renal function can and suggests that a CT very early in the presentation may underestimate the severity
of pancreatitis. From Pancreatic Physiology and Pancreatitis GastroSlide 463, AGA
be closely monitored. Large amounts of narcotic an-
Institute. (Courtesy of H. Schwatz, Derby, CT.)
algesics are often needed to relieve pain, and naso-
gastric suction is typically required to treat severe most commonly used regimens are imipenem (or
ileus and gastroparesis. Patients should be carefully other carbapenems) or cefuroxime administered in-
monitored for fever, SIRS, and persistent organ fail- travenously for 10–14 days. Enthusiasm for this ther-
ure. Extrapancreatic sites of infection should be ac- apy has substantially decreased because of its cost,
tively evaluated and treated. -
The use of pharmacologic agents to (1) inhibit gence of superinfection with fungi or multiresistant
trypsin and other proteases (e.g., aprotinin, gabex- bacteria, with a shift in the bacterial spectrum from
ate), (2) diminish pancreatic secretion (e.g., atro- predominantly gram-negative bacteria to gram-pos-
pine, somatostatin and its analogues), or (3) reduce itive organisms. Currently, antibiotic prophylaxis for
patients with pancreatic necrosis is usually not rec-
lessen disease severity has not been successful. Ad- ommended. If a decision is made to use prophylactic
ditionally, therapeutic peritoneal lavage has not been antibiotics, they should be started within 48 hours
found to be effective. in patients with severe acute pancreatitis, >30% ne-
Hypertriglyceridemia may lead to pancreatitis crosis of the pancreas on CT scan, and organ failure.
when levels of >1000 mg/dl are observed. If this Antibiotics are indicated in patients with suspected
group of patients develops necrotizing pancreatitis, cholangitis, extrapancreatic infections, and suspect-
measures to acutely reduce triglyceride levels have ed infected necrosis.
been used. These include use of combined hepa- Nutritional support is not necessary in patients
rin and insulin, apheresis and oral hyperlipidemic with mild pancreatitis. Nutritional support should be
agents. There is little data to suggest that these mea- considered for those patients who appear unlikely
sures have an impact on morbidity or mortality. to resume oral intake within 7–10 days of onset of
The prophylactic use of antibiotics in the treat- acute pancreatitis. One preliminary study suggests
ment of patients predicted by multiple criteria scores that instituting enteral feeding into the jejunum 48–
or dynamic CT to have severe acute pancreatitis had 72 hours after admission may reduce the release of
become widespread, but is losing popularity. The
Figure 10.25 disease and needs to be further studied. In patients
Nutrition Support and Infection in Acute Pancreatitis with severe acute pancreatitis, enteral feeding is
usually well tolerated and less expensive than total
parenteral nutrition (TPN). In addition, enteral feed-
Nutritional Support and Infection ing may decrease septic complications by helping to
maintain the integrity of the intestinal mucosa, re-
ducing intravenous bacterial seeding and maintain-
ing better glycemic control (Figure 10.25). Even if
nutritional requirements can only be partially met by
jejunal feeding, enterally fed patients generally do as
-
ly fewer metabolic and septic complications. Small
clinical trials suggest that gastric feeding by nasogas-
tric tube might be as well tolerated as jejunal feed-
ing with similar outcomes, but this requires further
study. For those patients who cannot be fed enterally,
lipid emulsions can be used as a component of TPN if
This meta-analysis suggests that patients supported by enteral feeding have fewer the serum triglyceride level is maintained below 500
infectious complications than patients on TPN. Ref.: Marila PE, Zaloga GP. Meta- mg/dl. If an operation is necessary to treat a compli-
analysis of parenteral nutrition versus enteral nutrition in patients with acute
pancreatitis. From Marik PE, Zaloka GP. Br Med J 2004 Jun 12;328(7453):1407. From cation of acute pancreatitis, surgical placement of a
Pancreatic Physiology and Pancreatitis GastroSlide 264, AGA Institute. jejunal feeding tube greatly facilitates subsequent
nutritional support by obviating the need for TPN. present. Replacement is best accompanied by proper
Gallstone disease should be suspected as the monitoring in the ICU setting.
likely cause of acute pancreatitis in areas of high in- Jaundice occurs in about 15–20% of patients
cidence, for patients who abstain from alcohol or use with acute pancreatitis, but total serum bilirubin
it moderately, for women, for people older than age usually remains below 4 mg/dl. A higher level or
60, for patients with an alanine aminotransferase or protracted elevation indicates either coexisting pa-
aspartate aminotransferase more than three times renchymal liver disease (e.g., alcoholic hepatitis or
cirrhosis, chronic viral hepatitis) or obstruction of
hours, for those with a history of gallstones, and for the common bile duct by a gallstone, tumor, pancre-
those with gallstones or a dilated common bile duct
seen on abdominal ultrasound or CT. Early ERCP for on the second hospital day of a rising total serum
possible sphincterotomy and stone extraction should bilirubin concentration has been associated with
be performed for patients with likely gallstone acute persistent common bile duct stones for patients with
gallstone acute pancreatitis.
(right upper quadrant abdominal pain and tender- Pulmonary complications of acute pancreatitis
ness, fever >39°C, leukocyte >20,000/ml). However, include hypoxemia and abnormal chest radiograph
in western countries, cholangitis complicates gall- -
stone pancreatitis in less than 10% of cases. Studies -
trates indicative of acute respiratory distress syn-
performed within 24–72 hours of hospital admission drome (ARDS). Obese patients and those with
reduces the severity of the disease for patients with hypertriglyceridemia are at increased risk for ARDS.
presumed gallstone pancreatitis of moderate-to-se- At 3–7 days after admission, 5–10% of patients de-
vere degree who do not have cholangitis. In patients velop respiratory failure requiring mechanical ven-
without clinical features of cholangitis, but suspicion tilation. At about the same time, acute renal failure
for retained CBD stone, an MRCP should be consid- may also develop, necessitating dialysis. Although
ered prior to ERCP. Figure 10.26
Hypocalcemia in Acute Pancreatitis
Complications
Cardiovascular collapse (“shock”) is the most lethal
after hospital admission. It results from hypovolemia Hypocalcemia in Acute Pancreatitis
retroperitoneum and peritoneum, and third-spacing
well as a “capillary leak” syndrome and myocardial
Treatment is vigorous rehydration guided by hemo-

dynamic monitoring in an intensive care unit and
supplemented by the use of vasopressors, if needed.
Although hypocalcemia is common, clinically
is rare (Figure 10.26). Calcium administration is re- This figure demonstrates the difference between the common dilutional hypocalcemia
and the less common event of decreased ionized calcium with associated “fat
to a reduction in ionized calcium and should be done necrosis.” Magnesium levels should also be determined and replaced prior to calcium
replacement. From Pancreatic Physiology and Pancreatitis GastroSlide 272, AGA
slowly. Hypomagnesemia should be corrected if also Institute.
Figure 10.27 the presence of persisting respiratory or renal fail-

CT Scan in Infected Necrosis ure is associated with a mortality of as high as 50% in
some series, both complications are often reversible.
Patients with moderate-to-severe acute pancre-
Infected pancreatic necrosis atitis may develop septic complications resulting
from infected pancreatic necrosis or abscess forma-
tion, even if treated with prophylactic antibiotics.
These usually present a week or more after hospital
necrosis with gas
admission as clinical deterioration (worsening pain
or nausea or vomiting), fever (especially if >39.5°C),
or leukocytosis (particularly if >20,000/ml) that is
associated with increased mortality. If septic compli-
cations are suspected, CT scanning of the abdomen
-
creatic bed (Figure 10.27) is highly suggestive, but
not diagnostic, of pancreatic infection.
Needle aspiration should be performed of any
This CT image demonstrates air in the pancreas bed in a patient with infected -
necrosis. Gas is seen within an area of necrosis. From Pancreatic Physiology tions adjacent to it for detection of infection (Fig-
and Pancreatitis GastroSlide 283, AGA Institute. ure 10.28). Aspirates should be sent for culture and
immediately Gram-stained. The presence of both
bacterial organisms and polymorphonuclear leuko-
Figure 10.28 cytes strongly indicates infected necrosis or abscess,
Infected Necrosis Diagnosed by Needle Aspiration whereas the absence of bacteria suggests the pres-
and Gram Stain -
ity of this approach are both about 90%, and most
false-negative and false-positive results appear to oc-
Pancreatic necrosis: infected and non-infected
Non-infected Patients with aspirates indicative of infected ne-
crosis should be treated with intravenous antibiotics
and debridement and/or drainage. Delaying drain-
age intervention for more than 4 weeks after onset
of symptoms is associated with a reduced mortal-
Infected ity. A percutaneous or endoscopic approach should
be initially considered. Studies suggest that a mini-
mally invasive approach is associated with reduced
morbidity and complications when compared to
open necrosectomy for management of patients with
infected necrosis. Emerging clinical evidence sug-
gests that an endoscopic transgastric necrosectomy
CT images cannot distinguish between sterile necrosis and infected necrosis unless may be preferred over surgical video assisted retro-
there is gas in the necrotic tissue. If sterile necrosis is suspected, CT-guided needle peritoneal debridement in management of infected
aspiration of necrotic tissue should be performed. Aspirated material should be sent
for gram stain and fungal stains. Due to antibiotic use, cultures may be negative. pancreatic necrosis.
From Gerzof SG, Banks PA, Robbins AH, et al. Gastroenterology 1987;93:1315–20. Operative debridement and drainage has been
Isenmann R. Rau B, Beger HG. Br J Surg 1999;86:1020–24. From Pancreatic Physiology -
and Pancreatitis GastroSlide 281, AGA Institute.
crosis (CT-guided aspirates negative for bacterial or
fungal organisms) if their severe acute pancreatitis is -

complicated by respiratory or renal failure. However, ing pain and those increasing in size—should be
such therapy has not been shown to be superior to considered for therapy. Pseudocysts can be drained
aggressive non-operative care. endoscopically, surgically, or by placement of a per-
Failure of a patient with severe acute pancreati- cutaneous drainage catheter. The treatment decision
tis to improve after several weeks of vigorous sup-
portive care, particularly in the presence of a large given patient and the local expertise. Patients should
- be evaluated for endoscopic cyst drainage prior to
tes on CT, suggests the presence of disruption of the surgical drainage, given its high success rate and
pancreatic duct with a duct leak. If a pancreatic duct <5% complication rate of bleeding and perforation.
leak is suspected, then imaging (such as magnetic Endoscopic drainage may be transmural (gastric
or duodenal) or transpapillary. The transpapillary
approach is suitable for pancreas cysts that commu-
of a leak and identify its location. Endoscopic place- nicate with the pancreatic duct or large cysts in the
ment of a stent is sometimes able to bridge the site pancreatic head. ERCP should be attempted prior to
of duct disruption and close a leak. However, if endo- pseudocyst drainage, since pseudocysts that commu-
scopic treatment is unsuccessful, operative resection nicate with the pancreatic duct can result in pancre-
or internal drainage may be required.
After an initial improvement in their clinical Endoscopic ultrasound can facilitate pseudocyst
course, some patients may be left with a persisting drainage by helping to avoid large vascular struc-
- tures and identify the distance between pseudocyst
wall and gastric lumen. Surgical drainage may be
which has been called . These pa-
tients may have persisting anorexia and weight loss,
abdominal pain, and nausea and vomiting. With time collections that are not in close proximity to the gas-
this complication usually resolves spontaneously,
but if it is persistent and symptomatic, drainage of Figure 10.29
the organized necrosis is necessary. Depending on Pancreatic Pseudocyst
the size, location, and consistency of the collection,
non-operative endoscopic internal drainage guided
Pancreatic Pseudocyst
by endoscopic ultrasound or percutaneous catheter
drainage guided by CT or transabdominal ultrasound
can sometimes be accomplished. However, some pa-
tients will require operative internal (if possible) or
cyst
external drainage.
Two-thirds to three-fourths of patients with
-
tions early in the course of the illness. Only about
collection or pseudocyst (Figure 10.29). Asymptom-

atic or only mildly symptomatic pseudocysts (e.g.,
intermittent mild pain) should be followed by ultra- CT scan demonstrates a large cystic lesion with a thick wall. Drain-
sound or CT for at least 6 weeks, because about half age by percutaneous aspiration frequently results in recurrence.
will resolve. Endoscopic transmural or transpapillary drainage is preferable.
Asymptomatic pseudocysts or those diminish- From Pancreatic Physiology and Pancreatitis GastroSlide 296, AGA
ing in size can be followed up without treatment Institute.
tric or duodenal walls, and if there is a clinical suspi- the gallbladder has already been resected or if the
cion that a cystic neoplasm has developed. Surgical patient is not a good operative candidate, endoscopic
drainage in these cases should be accompanied by sphincterotomy is also highly effective in preventing
resection of part of the cyst wall, which can be sub- recurrence of biliary pancreatitis. If alcohol is the
mitted for histology. likely cause, patients should be strongly advised to
For clinically infected pseudocysts (patients abstain. Genetic hyperlipidemia requires treatment
typically presenting with fever and leukocytosis with diet, avoidance of exacerbating factors (e.g., al-
who have pseudocyst aspirates demonstrating both cohol, estrogens, thiazides), control of hyperglycemia,
polymorphonuclear leukocytes and bacterial organ-
isms on Gram-stained smear), percutaneous catheter drug believed to be the cause of pancreatitis should
drainage is as effective as surgery. Endoscopic drain- be avoided.
age of infected pseudocysts has been described. A small number of patients, in whom no cause can
be established after history and physical examination,
of acute pancreatitis. Potential causes include stress determination of serum triglyceride and calcium lev-
gastritis, Mallory-Weiss tear, development of a pseu- els, and abdominal ultrasound, are initially consid-
doaneurysm in the peripancreatic arterial circula- ered to have “idiopathic” acute pancreatitis. Several
tion, bleeding from small vessels in the wall of a reports have suggested that a substantial number of
pseudocyst into the cyst contents, and gastric vari- these patients will have occult gallstone disease, iden-
ces due to splenic vein thrombosis. Bleeding from
a pseudoaneurysm or into a pseudocyst from the or by performing repeated imaging studies. Genetic
cyst wall may not communicate with the GI tract (in hyperlipidemia can be missed because serum triglyc-
which case it is best diagnosed by CT angiography). erides were not measured until after the patient had
It can also result in bleeding via the pancreatic duct been fasting for several days, resulting in a substan-
(hemosuccus pancreaticus), with melena and blood tial fall in levels. Intraductal mucinous tumors can
or clot found upon endoscopy in the region of the du- cause pancreatitis due to acute duct obstruction. A
odenal papilla, without any mucosal lesion that could pancreatic or ampullary cancer or other tumor such
account for it. as lymphoma should be considered in patients over
Angiography is of great value in identifying the the age of 40 years who have a smoldering course af-
site of bleeding from a pseudoaneurysm. Often this ter initially mild pancreatitis, especially if it is accom-
- panied by symptoms of weight loss or fever or in the
giographic embolization, although some patients re- setting of recently diagnosed diabetes mellitus.
quire direct operative control. -
Chronic, and occasional acute, pancreatitis can pathic” acute pancreatitis and the means of diagnos-
be complicated by splenic vein thrombosis. This may ing them are given in Table 10.7. Many patients with a
present with bleeding gastric varices and is treated single episode of unexplained acute pancreatitis will
by splenectomy. not have another episode. Therefore, unless the initial
attack was particularly severe, invasive procedures
-
Management after Recovery etry of the sphincter of Oddi, should generally not be
performed until the patient has a second attack of ap-
After a patient has recovered from an attack of acute
parent idiopathic pancreatitis.
pancreatitis, the most likely cause should be identi-
Patients with gallstone disease should generally un-

dergo cholecystectomy as soon as possible. Cholecys- Chronic Pancreatitis
tectomy within 2 weeks of illness is safe, and delay -
is associated with increased biliary complications. If
of the gland and atrophy of both exocrine and endo- pancreatitis and increases the risk of developing al-
crine tissue. An individual episode of acute pancre- coholic pancreatitis.
atitis does not appear to lead to chronic pancreatitis For chronic pancreatitis related to alcohol use,
current theories of pathogenesis can be divided into
-
data on the incidence or prevalence of chronic pan- terations in the physiochemical properties of pancre-
creatitis. However, estimates for incidence are 2–10 atic juice and/or in the function of the sphincter of
per 100,000 and for prevalence, 25–130 per 100,000. Oddi lead to duct obstruction as the principal cause of
pancreatic damage (duct obstruction theories). The
second is that repeated or continuous injury to pan-
Pathogenesis and Etiologic Factors
In industrialized countries, excessive alcohol con-
a secondary event (toxic-metabolic theories). There is
sumption accounts for about 70% of cases (Table
-
10.8). Typically, patients give a history of at least 10
ing the pathogenesis of alcoholic chronic pancreatitis
years of consumption of 80–175 g of ethanol per
(or of any other cause of chronic pancreatitis) as es-
day. The risk of developing alcoholic pancreatitis is
tablished. Probably more than one mechanism is in-
directly related to the amount consumed. However,
volved, and it is likely that different mechanisms may
whether there is a lower threshold at which alcohol
predominate in different patients or even at different
intake poses no risk remains unclear. Diets high in
stages of the disease in the same patient.
protein and either very high or very low in fat pre-
The tropical or nutritional form of chronic pan-
dispose to chronic pancreatic injury from alcohol. Ge-
creatitis is observed primarily in areas of India, Indo-
netic, dietary, and other environmental factors prob-
nesia, and Africa. Patients typically present in child-
hood with abdominal pain and diffuse pancreatic
chronic pancreatitis, because only 5–10% of individu-
-
als with the highest levels of alcohol use develop this
though survival statistics have been much improved,
disease. For example, patients with mutations in the
many succumb to the complications of diabetes. Mal-
CFTR protein and chymotrypsinogen C are at greater
nutrition appears to be a major etiologic factor in
risk for developing alcoholic pancreatitis. Smoking
tropical pancreatitis; however, the disease is probably
is a substantial independent risk factor for chronic
Table 10.7
Possible Causes of Occult (“Idiopathic”) Acute Pancreatitis
Cause Useful diagnostic test(s)

Occult gallstone disease (ultrasound negative) Biliary drainage for crystal analysis
Repeated abdominal ultrasound
Endoscopic retrograde cholangiopancreatography (ERCP)
Endoscopic ultrasound
Undiagnosed hypertriglyceridemia Previous serum triglyceride values
Serum triglyceride determination after patient is on regular diet
and medications
Abnormalities of the ampulla, bile duct, and/or pancreatic duct ERCP
Pancreatic cancer, ampullary or other tumors Computed tomography
Endoscopic ultrasound
Fine-needle aspiration biopsy
Sphincter of Oddi dysfunction ERCP with sphincter of Oddi manometry
Cystic fibrosis Molecular genetic testing
Table 10.8 heterogeneous, and other environmental and genetic

Causes of Chronic Pancreatitis factors, such as variants of pancreatic secretory tryp-
sin inhibitor, SPINK 1, and chymotrypsinogen C, likely
Chronic excessive alcohol use (70% of cases in industrialized countries)
play a role.
Cigarette smoking
Long-standing obstruction of the main pancreat-
Tropical chronic pancreatitis (primarily in India, Indonesia, Africa)
Chronic obstruction of the pancreatic duct pancreatitis. This type of obstruction can result from
Ampullary stenosis or neoplasm papillary stenosis or ampullary neoplasms, pancre-
Pancreatic tumors atic tumors, endoscopically placed pancreatic duct
Pseudocysts stents, pseudocysts, and strictures of the pancreatic
Pancreatic duct stents duct as a consequence of trauma or, rarely, a previous
Traumatic or inflammatory strictures of the pancreatic duct severe episode of acute pancreatitis. Whether pancre-
Pancreas divisum (uncertain) as divisum can result in chronic pancreatitis (in addi-
Pancreatic trauma tion to producing episodes of recurrent acute pancre-
Genetic hyperlipidemia (hypertriglyceridemia) atitis) remains unclear; if it does so, it is uncommon.
Obstructive chronic pancreatitis, which appears
Hyperparathyroidism
to be a distinct type of chronic pancreatitis, is charac-
Cystic fibrosis (including cystic fibrosis transmembrane conductance regula-
terized by dilatation of the main pancreatic duct and
tor mutations that do not produce pulmonary disease)
-
Hereditary disease (e.g., mutation in the cationic trypsinogen gene)
curs in alcoholic chronic pancreatitis, protein plugs
Idiopathic disease (10–30% in industrialized countries) or stones in the pancreatic duct are very uncommon,
and morphologic and functional abnormalities may
regress substantially once the obstruction is relieved.
Chronic pancreatitis is often seen in patients with
mutations in the cationic trypsinogen gene that cause
hereditary pancreatitis, and the condition may also
develop in association with pancreatic trauma, hy-
Table 10.9
-
Clinical Features of Type I and Type II Autoimmune Pancreatitis
sis (Table 10.8). Other familial occurrences of chronic
pancreatitis have been described, with the onset of
AIP Type Type I Type II disease in the third or fourth decade of life.
An estimated 10–40% of patients with chronic
Age 60’s 50’s pancreatitis in industrialized countries have no ap-
Gender Male>female Male = female having an idiopathic form. These patients appear to
cluster in two age groups: a younger one age ~15–30
Clinical features Jaundice, fatigue, wt loss Abdominal pain years in which abdominal pain predominates, and an
older group age ~50–70 years with pancreatic exo-
Serum IgG 4 Elevated Normal
absence of pain.
Associated organ Biliary, salivary, lymph node, Recent studies have suggested that some patients
involvement retroperitoneal with idiopathic chronic pancreatitis have an increased
incidence of a variety of mutations in the CFTR gene
Pathology Lymphocytoplasmic periductal Granulocytic and epithelial
that do not produce the pulmonary abnormalities
-
Relapse rate High Low
pose patients to developing of chronic pancreatitis.
In some male patients, this “atypical” manifestation Figure 10.30

Pathology of Type I Autoimmune Pancreatitis
bilateral absence of the vas deferens.
A possible autoimmune cause for some cases Autoimmune Pancreatitis
of idiopathic chronic pancreatitis has also been Lymphoplasmacytic Infiltrates
proposed. Two types of autoimmune pancreatitis
have been described and are summarized in Table
10.9. These patients typically have mild abdominal
pain, as well a mass in the head and/or body of the
the pancreatic duct, an intense lymphoplasmacytic Periductular

lymphoplasmacytic inflitrate
an elevated serum IgG4 level; they frequently have a

Fibrosis
favorable response to treatment with corticosteroids
(see Table 10.9 and Figures 10.30 and 10.31 for
AGA: Courtesy of T. Smyrk
pathology and imaging).
Autoimmune pancreatitis has also been de-
Pathology of autoimmune pancreatitis is characterized by prominent mononuclear
scribed in association with other autoimmune dis- infiltrate (rich in plasma cells) that surrounds pancreatic ducts but spares the
eases including sclerosing cholangitis, primary bili- parenchyma. There are also broad bands of fibrosis that are selectively associated
with ducts. From Deshpande V, Mino-Kenudson M, Brugge W, et al. Arch Pathol Lab
Med 2005;129:1148–54. From Pancreatic Physiology and Pancreatitis GastroSlide 418,
arthritis, sarcoidosis, and Sjögren’s syndrome. Sug-
AGA Institute. (Courtesy of T.C. Smyrk, Dept of Laboratory Medicine and Pathology,
gestions that autoimmune pancreatitis can evolve Mayo Clinic, Rochester, MN.)
into a more typical form of chronic pancreatitis need
further study.
Figure 10.31
Imaging of Autoimmune Pancreatitis
Pathology
In chronic pancreatitis, the normal exocrine secre-
Autoimmune Pancreatitis
tory tissue of the pancreas atrophies and is replaced
ERCP CT
tissue, and a marked increase in interlobular collagen

(Figure 10.32). The pancreatic duct demonstrates
alternating strictures and dilated regions that often
is often proliferation of small ducts.
Narrowing, strictures and dilation Fusiform enlargement of pancreas
Diagnosis AGA: Courtesy of M. Topazian
Changes of autoimmune pancreatitis shown by endoscopic retrograde

Clinical features cholangiopancreatography (ERCP) and computed tomography (CT). Note smooth long
Pain is the most common presenting symptom—usu- strictures in head and body of pancreas (ERCP) and bulky areas of diffuse pancreatic
ally epigastric; dull and constant in character; and enlargement by ERCP. From Pancreatic Physiology and Pancreatitis GastroSlide 427,
AGA Institute. (Courtesy of M. Topazian.)
radiating to the back, to both upper quadrants, and

Chronic Pancreatitis: Histology Multiple Pancreatic Calcifications Seen on a Plain Abdominal
Film
Chronic Pancreatitis: calcifications

imaged x-ray
Calcifications
Fibrosis
Inflammation
Observing pancreatic calculi on plain films of the abdomen confirms the

diagnosis of chronic pancreatitis. As the spinal column obscures their
Pancreatic histology showing the classic findings of chronic pancreatitis: fibrosis, detection in the body, calcifications are best seen in the pancreatic head
chronic inflammation, and calcification. Note that the latter is within the duct lumen. or tail. In alcoholic pancreatitis, calcification is observed in 20–50% of
From Pancreatic Physiology and Pancreatitis GastroSlide 340, AGA Institute. (Courtesy patients. The radiograph demonstrates irregular calcifications in the region
of K. Barwick, Jacksonville, FL.) of pancreatic tail (arrow). From Pancreatic Physiology and Pancreatitis
GastroSlide 364, AGA Institute.
occasionally to the lower quadrants, particularly fat-soluble vitamins (A, D, E, and K) are generally un-
the left. The pain may be partially relieved by sitting common, osteoporosis is often being described in pa-
bent forward or lying prone, and may be worsened tients with chronic pancreatitis. Osteoporosis is likely
by ingestion of food or alcohol and accompanied by multifactoral and involves decreased vitamin D levels,
nausea and vomiting. For some patients, the pain di- enhanced bone reabsorption, and the concomitant
minishes or resolves completely over long periods of effects of cigarette smoking. Reduced breakdown of
time (5–15 years), coincident with the appearance the R-protein by pancreatic proteases may lead to re-
duced binding of intrinsic factor to vitamin B12 and
mellitus (“burnout” of the gland). Only 10–20% of pa-
tients have little or no pain, particularly the older age Diabetes mellitus occurs in about 50% of pa-
group with idiopathic disease. tients, usually after the diagnosis has been well estab-
Patients typically lose weight due to pain and lished. However, patients with little or no pain may
nausea, malabsorption due to pancreatic exocrine present initially with diabetes, as may patients with
- tropical chronic pancreatitis (sometimes called tropi-
tus. Steatorrhea occurs in about 30–50% of patients ). Ketoacidosis
when secretion of lipase and other digestive enzymes and nephropathy are uncommon, but retinopathy
has been reduced to <10% of normal (Figure 10.12). and neuropathy occur as often as in primary forms of
diabetes for similar durations of the disease.
generally exceeds that found in other malabsorptive During episodes of pain, patients usually have
states and can be up to 50% of dietary fat. In the ab- mild-to-moderate epigastric tenderness without
sence of ingestion of lipid oils (e.g., mineral oil), a his- guarding or rebound tenderness. Generally the ab-
tory of oil leakage from the anus or an “oil slick” in the dominal tenderness is less impressive than the de-
gree of pain reported. A rounded, palpable abdominal
mass suggests the presence of a pseudocyst (although Figure 10.34

Pancreatic Calcifications Detected by Transabdominal Ultrasound
dullness suggest the possible presence of pancreatic
ascites, and dullness to percussion and diminished
Chronic Pancreatitis: calcifications imaged
breath sounds at the lung bases may be signs of a pan-
by ultrasonography
creatic pleural effusion.
Imaging and laboratory studies

-
tions in the region of the pancreas (Figure 10.33)
is present in about one-third of patients and estab-
lishes the diagnosis with a high degree of reliability;
no further diagnostic testing is necessary. On ultra-
(Figure 10.35). ERCP provides exquisitely detailed

views of the pancreatic duct system, demonstrating
strictures and ectatic changes in the pancreatic duct
The normal pancreas has an echo pattern that is slightly more dense and irregular
than that of the liver. Increased parenchymal echos and heterogeneity is seen with
chronic pancreatitis (Figure 10.36). The Cambridge fibrosis. This ultrasound demonstrates prominent pancreatic echos from calcifications
and fibrosis within the gland (arrows). From Pancreatic Physiology and Pancreatitis
chronic pancreatitis (Table 10.10).
MRCP provides a noninvasive means of imaging
the pancreatic duct. Because it is noninvasive and the person performing the procedure, and EUS is not
as widely available as abdominal ultrasonography, CT,
replaced ERCP for routine imaging of the pancreatic MRCP, or ERCP.
duct. Of all the tests of pancreatic structure, endo- Alternatively, the diagnosis of chronic pancreati-
scopic ultrasound (EUS) is the only one that can pro-
vide a detailed evaluation of both the duct system and function. The classic Dreiling tube, which aspirates
the parenchyma. EUS can identify subtle changes in duodenal content after various forms of pancreatic
early chronic pancreatitis that are not seen with other stimulation (meal, secretin, secretin with cholecysto-
modalities (Figure 10.37). However, the accuracy of kinin), is used in only a few centers because of patient
EUS is highly dependent on the skill and judgment of discomfort, cost, and lack of technical expertise. The
Table 10.10
Cambridge ERCP Criteria for Diagnosing Chronic Pancreatitis
Class Side branches Main duct

Equivocal <3 abnormal Normal
Mild >3 abnormal Normal
Moderate >3 abnormal Abnormal
Severe ≥3 abnormal Severely abnormal with strictures, dilation, etc.
Characteristics of the radiographic appearance of the main pancreatic duct and its side branches during ERCP are used to classify chronic
pancreatitis and are known as the Cambridge criteria. In patients with severe but not mild changes on ERCP, there is a good correlation with
measured exocrine insufficiency. From Axon ATR, Classen M, Cotton PB, et al. Gut 1984;25:1107–12. Bozkurt T, Braun U, Leferink S, et al. Gut
1994;35:1132–36. From Pancreatic Physiology and Pancreatitis GastroSlide 368, AGA Institute.
Figure 10.35 typical direct assays of exocrine function are the vol-
Pancreatic Duct Dilation and Calcifications Found on Abdominal CT ume of secretion, bicarbonate, protein, and enzyme
content. Whether less uncomfortable and less inva-
sive studies using endoscopic aspiration of pancreatic
secretions will prove as clinically useful as the “tube”
Chronic Pancreatitis: calcifications by CT tests will require further study. Direct tests of pancre-
atic function are of greatest potential use when the
clinical diagnosis of chronic pancreatitis is in ques-
tion, and in patients with mild-to-moderate pancre-
Indirect tests of pancreatic function include mea-

surement of fecal concentrations of chymotrypsin or
elastase 1. Although less expensive and more conve-
nient than direct tests, these and other indirect tests
are reliable only in patients with advanced disease
(e.g., those with steatorrhea), for whom the diagnosis
Abdominal CT demonstrating dilation of pancreatic duct and calcifications in the The most sensitive imaging studies, EUS and
pancreatic head and tail. CT detects pancreatic calcification with greater sensitivity ERCP, and the direct tests of pancreatic function (e.g.,
than an abdominal X-ray and is often used if the abdominal film is negative. From
Pancreatic Physiology and Pancreatitis GastroSlide 366, AGA Institute. secretin stimulation test for measurement of bicar-
bonate concentration), are abnormal in most patients
with chronic pancreatitis, and correlate well in those
with moderate-to-severe disease. However, in pa-
tients suspected of having mild or early chronic pan-
Figure 10.36
results in 15–30% of cases, creating diagnostic uncer-
ERCP Changes in Advanced Chronic Pancreatitis
-
creatic histology (which is rarely available).
Steatorrhea (fecal fat excretion of >7 g/ 24 hours
Advanced Chronic Pancreatitis: ERCP on a diet of 100 g of fat/day) is the hallmark of pan-
Markedly
determination (Sudan stain) indicates a stool fat ex-
dilated
branches
Markedly dilated Differential Diagnosis

main pancreatic
duct In addition to chronic pancreatitis, chronic upper ab-
dominal pain may be due to peptic ulcer disease, gas-
tric or pancreatic cancer, chronic partial obstruction
of the small intestine, chronic mesenteric ischemia
(“intestinal angina”), or functional abdominal pain
Contrast injected by ERCP demonstrates pancreatic duct anatomy in chronic
pancreatitis with marked dilation of the main pancreatic duct and the tail and clubbing must be distinguished from that due to diseases of the
of most secondary ducts. Short strictures of the main pancreatic duct, particularly
toward the tail, are seen. From Pancreatic Physiology and Pancreatitis GastroSlide also result from diseases other than chronic pancre-
371, AGA Institute. (Courtesy of A. Shah, Rochester, MN.)
atitis. For example, it often occurs in children with ce-
liac disease because of effacement of the proximal du- Figure 10.37

odenal mucosa leads to loss of cells that secrete CCK Demonstration of EUS Findings in Chronic Pancreatitis
and secretin and stimulate pancreatic secretion and
enzyme synthesis. Patients with gastrojejunostomies
Chronic Pancreatitis:
in this case the defect is caused by dilution of pancre- EUS findings
atic enzymes and their ineffective mixing with food.
Management Dilated main

duct
Pain Hyperechogenic
duct wall
Abstinence from alcohol may result in improvement
in pain in alcoholic chronic pancreatitis, particularly
Echogenic strands
for patients with early or mild disease (before devel-
Potent oral narcotic analgesics are often needed for Some endoscopic ultrasonographic (EUS) findings in chronic pancreatitis are shown.
The left panel demonstrates dilation of the main pancreatic duct with a stricture.
pain relief. For patients disabled either by pain or
The center panel shows a highly echogenic pancreatic duct. The right panel shows
by the narcotic analgesia required to control pain, a echogenic stranding suggesting fibrosis and dilation of secondary ducts. From
trial of high doses of a non–enteric-coated pancreatic Pancreatic Physiology and Pancreatitis GastroSlide 373, AGA Institute.
enzyme supplement (that should soon be available)
with meals and at bedtime, along with a proton-
pump inhibitor, can be tried in the hope of ameliorat- Figure 10.38
ing pain by reducing pancreatic stimulation. Patients EUS-Guided Celiac Plexus Blockade
with idiopathic chronic pancreatitis without steator-
rhea are the group most likely to have pain relief with
this approach.
Attempts to block nerve transmission of pain
by celiac or splanchnic nerve blocks (Figure 10.38)
or by thoracoscopic splanchnicectomy have gener-
ally been disappointing. Even if some pain relief is Celiac
artery
achieved, it is usually short-lived. When tolerable
levels of oral analgesics are ineffective and a trial of
pancreatic enzymes is unsuccessful, patients should Aorta
be considered for operative treatment. Preoperative

evaluation by CT and frequently ERCP (or in some
cases MRCP) is essential in determining the type of
operation to be performed and in identifying com-
plications such as pancreatic cancer or pseudocysts. The figure represents an EUS image of the celiac axis in the region of the celiac
For patients with a dilated pancreatic duct, a lateral ganglion. The arrow indicates the injection track that will be used to introduce
anesthetic into the celiac ganglion. Alcohol injection can destroy nerves and may
pancreaticojejunostomy (Figure 10.39) with some provide more long-term relief. EUS-guided celiac plexus block appears to be safe and
removal of the anterior pancreatic head is used. This effective for controlling pain in patients with chronic pancreatitis in the short term,
approach is used in alcoholic pancreatitis where the with only 10% having persistent benefit after 24 weeks, but young patients (age <45)
and those with prior surgery for chronic pancreatitis do not benefit from this procedure.
pancreatic duct shows areas of stricture and dilata-
Typically relief is limited to only a few months. From Gress F, Schmitt C, Sherman S, et
tion (“chain of lakes” appearance); it produces reso- al. Am J Gastroenterol 2001;96:409–16. From Pancreatic Physiology and Pancreatitis
of patients when pain is assessed at 6 months after age diabetes that results. Autotransplantation of the
surgery. However, successful outcomes decrease to pancreas or of pancreatic islets has been attempted,
about 50–60% when pain is assessed 3–5 years after to try to prevent or mitigate diabetes, but so far this
surgery. approach has met with limited success.
Other nonoperative attempts to control the pain
of the pancreas or nondilated ducts generally ben- of chronic pancreatitis have included administration
of a combination of antioxidants, to prevent or reduce
- oxidative injury to the pancreas, and of the inhibi-
coduodenectomy; Figure 10.40) or by one of several tory somatostatin analogue octreotide, to reduce the
duodenum-sparing techniques. Carefully selected metabolic workload of the gland. Neither approach
patients have been reported to have good results in
chronic pancreatitis and a dilated pancreatic duct,
over time. However, pancreatic resection carries the decompression of the duct either endoscopically or
risk of producing or worsening diabetes and insulin surgically may alleviate pain. Endoscopic therapy
dependence. usually consists of sphincterotomy, stricture dila-
Very rarely, patients who continue to have inca- tion, and extracorporeal shock wave lithotripsy with
pacitating pain after previous unsuccessful attempts pancreatic stone fragmentation and extraction. Typi-
at surgical relief may undergo total pancreatectomy. cally the duct is also stented for variable durations,
However, this is a last-resort intervention because of and multiple procedures over a period of months are
- necessary.
Surgical drainage is the other method of duct de-
compression and involves creation of a longitudinal
Figure 10.39
pancreaticojejunostomy. In a prospective study, 39
Lateral Pancreticojejunostomy (Puestow Procedure)
patients with chronic pancreatitis and symptomatic
pancreatic ductal obstruction were randomized to
endoscopic or surgical therapy and outcomes mea-
Lateral Pancreaticojejunostomy
sured. Patients randomized to the surgical group had
the endoscopic group. Patients who were random-
more procedures than those in the surgical group.

This study has been criticized because of the
small number of patients and the possibility that
more refractory patients were randomized to the en-
doscopic group. The current approach in our institu-
therapy, reserving surgery for the non-responders.

Additional prospective randomized, controlled stud-
This surgical procedure is performed to reduce pain in chronic pancreatitis. The main
pancreatic duct has been opened along its middle and proximal thirds and anastamosed endoscopic treatments in comparison with those of
side-to-side into the jejunum. This treatment often provides moderate and long-lasting
surgery and of medical care directed at symptom
pain relief and has been known as the Puestow procedure. The use of this procedure
requires dilation of the pancreatic duct for the anastomosis to the small intestine. control. Spinal cord stimulation has been used for
From Schlosser W, Beger HG. Ann Ital Chir 2000;71(1):65–70. Sakorafas GH, Farnell chronic visceral pain. A recent report suggests that
MB, Nagorney DM, et al. Surg Clin North Am 2001;81(2):457–65. Koniger J, Freiss H, placement of a SCS at a T5 or T6 level resulted in im-
Muller M, et al. Rocz Akad Med Bialymst 2004;49:53–60. Hines OJ, Reber HA. Curr
Opin Gastroenterol 2005;21(5):568–72. Bell RH Jr. J Gastrointest Surg 2005;9(1):144– proved pain and reduced narcotic use. Prospective
54. From Pancreatic Physiology and Pancreatitis GastroSlide 392, AGA Institute. studies are awaited.
Figure 10.40
Malabsorption
Pylorus-Preserving Whipple Procedure
should receive pancreatic enzyme supplements with

meals and snacks. Enzyme replacement taken with
Pylorus Preserving Whipple
each meal substantially reduces (but rarely com-
pletely corrects) steatorrhea, permits stabilization of
body weight, and reduces diarrhea and bloating. Be-
cause of new FDA requirements for demonstration
(Abbott Laboratories). Zenpep, Viokace, and Ultresa

(Aptalis), Pancreaze (Janssen Pharmaceutical), only
Viokace is an uncoated preparation. Since pancreatic
enzymes are degraded by gastric acid, the effective-
ness of uncoated enzyme supplements (currently
unavailable) can be enhanced by acid suppression,
or alternatively, by the use of enteric-coated prepara-
Pylorus-sparing Whipple resections are performed to relieve pain in chronic
tions. Since there is some evidence that acid reduc-
pancreatitis. The surgery is also used to treat pancreatic neoplasms and chronic
tion may even improve responses to enteric-coated pancreatitis. This operation is usually performed in chronic pancreatitis patients who
preparations, PPIs should be tried in poor respond- have failed to experience relief after a lateral pancreatojejunostomy, or in patients
who do not have a dilated pancreatic duct. Removal of endocrine tissues and the
ers. Dosage should be individualized based on clini- resulting diabetes are a consequence of pancreatic resection that is not observed
cal symptoms, the degree of steatorrhea present, and with lateral pancreatojejunostomies. From Schlosser W, Beger HG. Ann Ital Chir
2000;71(1):65–70. Sakorafas GH, Farnell MB, Nagorney DM, et al. Surg Clin North
the fat content of the diet. Evidence that timing of
Am 2001;81(2):457–65. Koniger J, Freiss H, Muller M, et al. Rocz Akad Med Bialymst
enzyme supplement ingestion during meals affects 2004;49:53–60. Hines OJ, Reber HA. Curr Opin Gastroenterol 2005;21(5):568–72.
pharmacology is lacking. Bell RH Jr. J Gastrointest Surg 2005;9(1):144–54. From Pancreatic Physiology and
Pancreatitis GastroSlide 395, AGA Institute.
Patients who still fail to improve should be
evaluated for noncompliance, poor dietary intake
(a particular issue with chronic alcoholics), and un-
recognized primary small bowel disease (e.g., bacte- even ones as large as 10 cm, will resolve spontane-
rial overgrowth, celiac sprue). For the rare patient ously, treatment is expectant. However, symptomatic
pseudocysts should be treated after the pseudocyst
an adequate body weight despite pancreatic enzyme
supplementation, medium-chain triglycerides, which operative internal drainage has been the standard
do not require intraluminal lipolytic activity for ab- treatment, percutaneous catheter drainage and
sorption, can be added to the diet. endoscopic internal drainage (currently using en-
doscopic ultrasound guidance) are used. Infected
Complications
pseudocysts should generally be drained using per-
About 10% of patients with chronic pancreatitis
cutaneous catheters.
develop pseudocysts, usually in the body or tail of
Leakage of pancreatic juice from a pseudocyst or
the gland. Pseudocysts <6 cm in diameter are usually
asymptomatic, but larger ones can produce pain and
high protein and amylase concentration in the peri-
may infrequently become infected, bleed, rupture, or
toneum (pancreatic ascites) or in the pleural space
obstruct the common bile duct or gastrointestinal
(pancreatic pleural effusion), usually on the left side.
tract. Pseudocysts are easily diagnosed by abdominal
Patients should undergo imaging with MRCP or ERCP
ultrasound or CT, and must persist for >1 month af-
to identify the site of leakage and to plan therapy. Se-
ter an attack of acute pancreatitis to be distinguished
lected patients can be treated by endoscopic stenting
of the pancreatic duct. Others, depending on the loca- gastrointestinal bleeding and is found at endoscopy
tion of the leak, will require distal pancreatectomy or
internal drainage of a damaged duct or pseudocyst esophageal varices. The diagnosis can be usually be
to a Roux limb of jejunum. In some patients, conser- -
vative treatment with no oral intake, TPN or jejunal trast-enhanced CT, and the treatment is splenectomy.
feeding of an elemental diet, octreotide administra- Patients with chronic pancreatitis of any etiol-
tion to decrease pancreatic secretion, and repeated ogy have an increased risk of pancreatic cancer. To
aspiration of ascites or pleural effusions will lead to what extent the increased risk is due to smoking
resolution in 2–3 weeks. rather than the chronic pancreatitis remains unclear.
Bile duct or duodenal obstruction occurs in While the risk appears to be modest to moderate (2-
5–10% of patients with chronic pancreatitis. Fibro- to 16-fold) for most etiologies, it is much higher for
sis in the head of the pancreas can produce a long, patients with hereditary or tropical chronic pancre-
tapered stricture involving the intrapancreatic com- atitis (>50-fold).
mon bile duct, and is usually diagnosed by a combi- The diagnosis of pancreatic cancer in patients
nation of liver tests (elevated serum levels of alkaline
phosphatase and bilirubin), abdominal ultrasound,
and ERCP. or EUS) for both conditions can be very similar. A
Biliary drainage should be performed only for progressive rise in the serum level of the tumor
patients who develop cholangitis or whose liver tests marker CA 19-9 may suggest the presence of cancer.
indicate persistent obstruction. Endoscopic treat- Cytology of aspirates of pancreatic juice or pancre-
ment with balloon dilation and plastic stents has atic duct brushings has a sensitivity of only 25–50%.
been disappointing, with surgical diversion the gold
standard. Endoscopic stenting of the common bile a sensitivity of 75–85%. EUS-guided FNAB appears
duct (CBD) is an option for patients who are poor op- to be even more sensitive. K-ras mutations are found
erative candidates. in pancreatic juice or FNAB specimens from most pa-
Placement of uncovered metal stents is compli- tients with pancreatic cancer, but are also found in
cated by mucosal hyperplasia limiting their useful- specimens from patients with only chronic pancre-
ness. Partially covered metal stents are more likely atitis. Therefore, evaluation for this mutation does
metal stents appear reasonably effective in some useful in this setting.

patients with chronic pancreatitis-related CBD stric- No general recommendations are currently
tures; however, complications regarding stent place- available for screening patients with chronic pancre-
atitis for pancreatic cancer. At the time of diagnosis,
fully covered metal stents are under way and may of- pancreatic cancer in patients with chronic pancreati-
fer a reasonable alternative to surgery, especially in tis is only rarely resectable.
patients who are at high operative risk.
Duodenal obstruction can result from a large
Pancreatic Neoplasms
Pancreatic cancer is the fourth leading cause of adult
pseudocyst or gastrojejunostomy is required.
cancer deaths in the United States, accounting for
about 5% of cancer deaths. The most common pan-
due to chronic pancreatitis can produce splenic vein
creatic neoplasm is adenocarcinoma derived from
thrombosis with splenomegaly, gastric varices, and
ductal epithelium. Importantly, ampullary carcinoma
upper GI bleeding. This should be suspected when a
has a much more favorable course compared to the
patient with known pancreatic disease or a history
more common adenocarcinoma of the pancreas, with
of chronic heavy alcohol use presents with upper
cure rates of greater than 50%. Acinar cell carcino-
mas, lymphomas, and other tumors originating from mon presenting symptom, due to compression of the
islet cells are rare. Cystic neoplasms have been iden- common bile duct. Other symptoms include weight
loss, anorexia, fatigue, depression, and back pain
use of abdominal CT. (which indicates retroperitoneal invasion by the can-
cer into the celiac nerve plexus). The development of
acute pancreatitis may rarely be the initial presen-
Risk Factors tation. Patients with chronic pancreatitis may have
up to a 16-fold risk of developing pancreatic cancer;
The risk of developing pancreatic cancer increases
this unfortunate transition is often accompanied
after age 50 and reaches a peak between ages 65
by a change in a patient’s symptoms (Table 10.11).
and 80. Cigarette smoking is the best-established
Thromboembolic phenomena such as pulmonary
environmental risk factor for pancreatic adenocar-
embolus, lower-extremity deep venous thrombosis,
cinoma. Other possible risk factors include chronic
and portal and splenic vein thrombosis may occur.
pancreatitis, exposure to certain chemicals (particu-
Many patients develop glucose intolerance within
the 2 years prior to their diagnosis, perhaps making
fat and meat, and type 2 diabetes arising in nonobese
this the earliest sign of pancreatic cancer. However,
patients over the age of 50.
screening for pancreatic cancer in an individual >65
Hereditary pancreatitis, caused by mutations in
who develops diabetes in the absence of other symp-
cationic trypsinogen, carries a 40- to 60-fold increase
toms is not warranted.
in the risk for developing pancreatic cancer. Familial
pancreatic cancer is rare but well established, and
Imaging
in some kindreds has been associated with a p16
Although abdominal ultrasound will frequently iden-
germline mutation. Additional predisposing genetic
tify a pancreatic mass, spiral (helical) CT has greater
conditions include hereditary chronic pancreatitis,
sensitivity and provides valuable staging informa-
BRCA2 germline mutations, and Peutz-Jeghers
syndrome.
Figure 10.41
Morphologic and Genetic Features Pancreatic Carcinoma: Histology
With pancreatic adenocarcinomas, 60–75% occurs

in the head of the gland. On gross examination, the
that is poorly demarcated due to the desmoplastic Pancreatic

3-15 fold increase
reaction produced by the neoplasm. Histologically, Cancer
adenocarcinoma usually is well differentiated, con-
sisting of ductlike structures lined by cuboidal or
columnar cells, frequently producing mucin, which
(Figure 10.41).
Normal
Diagnosis
Histologic appearance of pancreatic adenocarcinoma arising in the setting of chronic

Clinical
pancreatitis with adjacent normal tissue. From Lowenfels AB, Maisonneuve P,
Because most pancreatic cancers arise from the head Cavaillini G, et al. N Engl J Med 1993;328:1433–37. From Pancreatic Physiology and
of the gland, jaundice (with or without pain) is a com- Pancreatitis GastroSlide 405, AGA Institute.
Table 10.11 identify the tumor. When the differential diagnosis is

Symptoms Suggesting Cancer Development in Chronic
Pancreatitis due to focal chronic pancreatitis or autoimmune pan-
creatitis, FNAB and serial measurements of serum CA
Changing pain pattern
19-9 levels can provide useful information, particular-
Weight loss unresponsive to enzyme replacements
ly in the evaluation of patients who are relatively poor
Development of biliary and/or gastric output obstruction
operative candidates. However, testing for CA 19-9
New onset of depression
Migratory thrombosis
it to be a useful screening test for pancreatic cancer.
From Pancreatic Physiology and Pancreatitis GastroSlide 407,
Many surgeons advocate laparoscopy prior to re-
AGA Institute.
section for those patients who appear resectable by
other imaging studies, to identify undetected liver me-
tion concerning potential resectability of the tumor. tastases or small peritoneal implants.
The presence of distant metastases (including liver
metastases) and local vascular involvement (particu-
larly the superior mesenteric artery) are the primary Treatment
At the time of diagnosis, approximately 85% of pa-
pancreatic cancer is suspected but not seen on ab- tients are unresectable because of distant metastasis
dominal ultrasound and CT, EUS is the most useful test (e.g., to the liver or distant lymph nodes) or invasion
to identify very small or subtle lesions, provides stag- or encasement of the celiac or superior mesenteric
ing information complementary to that of helical CT -
(Figure 10.43), and provides an opportunity to biopsy ic and portal veins. Venous involvement is a relative
lesions. If EUS is not available or is not diagnostic, an contraindication for surgery as venous resection and
ERCP should be performed because a dominant stric- grafting is performed in select centers. A pancreatico-
ture will usually be seen in the pancreatic duct, often
with an associated stricture of the common bile duct in experienced hands carries a mortality of <5% and
(sometimes referred to as the double duct sign) in the morbidity of 20–30%, is performed to resect tumors
setting of pancreatic cancer. Cytologic brushings of in the head. Distal pancreatectomy and splenectomy
pancreatic or bile duct strictures have a sensitivity of is performed to resect tumors in the body and tail, but
50–70%, with the higher end of this range achieved since these tumors often present at a later stage due
with a combination of brushing and intraductal biop- to the absence of jaundice, they are rarely resectable.
sy. The symptoms and pancreatic imaging in patients Survival is poor even for patients who undergo
with autoimmune pancreatitis may be similar to those resection, with a median survival of 15–17 months
of pancreatic cancer (discussed in both the “Acute and a 5-year survival of 5–20%. A substantial num-
Pancreatitis” and “Chronic Pancreatitis” sections of ber of the 5-year survivors will eventually succumb to
this chapter). recurrent pancreatic cancer. Postoperative adjuvant
CT-guided FNAB has a sensitivity of 75–85%, and therapy with chemotherapy, alone or combined with
the sensitivity of EUS-guided FNAB has been reported
- patients, and preoperative neoadjuvant may provide
mation is not required for patients who are acceptable
operative candidates and have a pancreatic mass that The vast majority of pancreatic cancer patients
appears resectable under CT and, if performed, EUS. are unresectable, with a median survival of 6–10
FNA may very rarely identify a pancreatic lymphoma, months for those with locally advanced disease and
which would not be treated surgically. Because pan- 3–6 months for those with distant metastases (usually
creatic cancers typically are highly desmoplastic, pre- to the liver). Patients with locally advanced disease are
operative or even intraoperative biopsies may fail to generally treated with chemotherapy, radiation ther-
apy, or chemoradiation. For patients with metastatic Figure 10.42

pancreatic cancer, gemcitabine is now the most widely Metastatic Cancer of the Pancreatic Head
used chemotherapeutic agent because it provides bet-
ter pain control, improved performance status, and a
modest increase in survival compared to treatment
- Nodules in liver Mass in pancreas
gemcitabine for treatment of metastatic disease.

For most patients with pancreatic adenocarci-
noma, palliative management is of greatest concern.
Pain control is of primary importance and can usually
be achieved by use of long-acting opioid analgesics
and celiac plexus neurolysis, which can be performed
guided either by radiologic guidance or by endoscopic
present because of duct obstruction in the head of the

Pancreatic cancer metastatic to the liver is seen on an abdominal CT scan. An irregular
gland, and treatment with pancreatic digestive en- hypodense mass in the head of the pancreas and multiple hypodense liver lesions are
zyme supplements may help mitigate weight loss and present. From Pancreatic Physiology and Pancreatitis GastroSlide 457, AGA Institute.
reduce diarrhea.
Patients with jaundice who are good operative
candidates and appear in imaging studies to have re-
endoscopic or percutaneous biliary decompression Figure 10.43

unless they have cholangitis (a relatively rare event EUS-Guided FNA of Pancreatic Cancer
in the absence of previous instrumentation of the bili-
ary tract). Jaundice can be relieved in patients with
unresectable disease with endoscopic placement of
an expandable metal biliary stent; percutaneous or
surgical drainage are also options. Gastric outlet or
duodenal obstruction can be palliated with the endo-
Biopsy
scopic placement of enteral stents or surgical gastro- needle
jejunostomy.
Pancreatic
Uncommon Pancreatic Tumors mass
occur in the elderly and can be associated with pan-

niculitis, subcutaneous nodules, and polyarthritis.
tumors are most common in young women. They of-

ten occur in the body and tail of the pancreas and are
often large at the time of detection. Resection is often A linear endosonographic image of a needle within a hypoechoic pancreatic mass. The
curative. biopsy shown on the right demonstrates cells with enlarged hyperchromatic nuclei and
visible nucleoli that are consistent with pancreatic cancer. From Pancreatic Physiology
and Pancreatitis GastroSlide 406, AGA Institute.
similar to carcinoma of the head. Pancreatic lymphoma
is more common in males and often presents with a

often confused with pseudocysts (Figure 10.44). The
provide accurate diagnosis. Treatment is usually a
combination of chemotherapy and radiation therapy, adult woman without a history of acute pancreatitis,
with a limited role for surgery. -
- atitis, should make one suspect a cystic neoplasm.
ma; breast, lung, and prostate cancers; and gastroin- There are two main types of neoplastic cysts,
testinal malignancies may metastasize to the pancre- mucinous and nonmucinous. Distinguishing be-
as. Metastatic tumors to the pancreas usually present
as part of advanced disease; however, isolated metas- helpful. Nonmucinous cystic lesions of the pancreas
tases may be seen with renal cell carcinoma. include serous cystadenomas and cystic endocrine
tumors. Serous cystadenomas are benign with a typi-
cal microcystic appearance. A characteristic central
Cystic Neoplasms of the Pancreas
Cystic lesions of the pancreas include neoplasms
and will often have a very low carcinoembryonic an-
and encompass a wide range of biological behaviors
tigen (CEA) level (<5 ng/ml). Mucinous cystic lesions
from indolent and benign to aggressively malignant
include mucinous cystadenomas, cystadenocarcino-
(Table 10.12). These neoplasms often are asymptom-
mas, and intraductal papillary mucinous neoplasms
atic and found incidentally on abdominal ultrasound
-
or CT. When symptoms are present, they are often
Mucinous cystadenomas almost always occur in

postprandial bloating, or nausea.
females and are usually unilocular, located in the tail
On imaging, cystic neoplasms appear as well-
of the pancreas, and do not communicate with the
Table 10.12
Pancreas Cysts
Frequency
Cyst Type Features
/Cancer risk
Macrocystic
Pseudocyst Common/None
Thick wall
Serous cystadenoma Micro- or macrocystic Rare/Low
Mucinous
Macrocystic Very rare/High
cystadenoma
Macrocystic
Mucinous
Thick wall Cancer present
cystadenocarcinoma
Intra-cystic mass
Intraductal papillary mucinous neoplasm Macrocytic Common/low

pancreatic duct. These lesions carry a moderate risk Figure 10.44

of malignant transformation. If malignant transfor- Mucinous Cystadencarcinoma of Pancreas
mation occurs, the prognosis for surgical cure may
be better than it is for the more common pancreatic
Cysadenocarcinoma
within the cyst wall. Cystic lesion
IPMNs are the most common pancreatic neo-
plasm with a cystic appearance and they arise from
ductal epithelium and may involve the main pancre-
atic duct or side branches. In contrast to other cystic
neoplasms, men and women have about the same
disease incidence, and the head of the pancreas is
the most commonly involved segment. With involve-
ment of the main pancreatic duct, abdominal CT may
demonstrate a dilated pancreatic duct with pancre-
atic atrophy. ERCP may identify a dilated pancreatic
- A CT scan of the abdomen reveals a cystic lesion in the body of the pancreas
with mild wall irregularity in a patient with no prior history of pancreatitis.
of mucus (Figure 10.45). Main-duct IPMN often un- Surgical pathology identified a mucinous cystadencarcinoma. From Pancreatic
dergoes malignant transformation and should be Physiology and Pancreatitis GastroSlide 443, AGA Institute.
resected if possible. Branch-duct IPMN is associated
with a more indolent clinical course. Both lesions
may present with pancreatitis due to mucin ob-
structing the pancreas duct.
Figure 10.45
Intraductal Papillary Mucinous Neoplasm of Pancreas
Pancreatic Endocrine Tumors
Pancreatic endocrine tumors arise from the islet
cells. They are rare and may be hormonally function- Papillary-mucinous tumor of the pancreas
al or nonfunctional. When functional, they are clas-
Functional tumors are diagnosed based on the hor- Mucus in

dilated
monal manifestations and by measurement of hor-
ampulla Filling
mone levels in the blood. defects in
Anatomic localization is usually accomplished by pancreatic
abdominal CT, somatostatin receptor scintigraphy, duct
secondary to
and EUS. These tumors are best treated by surgical mucus or
resection, if possible. If not, symptoms related to hor- tumor
mone overproduction can sometimes be mitigated by
surgical tumor debulking, pharmacologic reduction
in hormone secretion by the somatostatin analogue
octreotide, or in the case of gastrinoma, use of proton The characteristic endoscopic view of the ampulla of Vater in a patient with main-
duct intraductal papillary mucinous neoplasm is shown, with thick viscous material
pump inhibitors to block gastric acid secretion. seen within a markedly enlarged pancreatic ductal orifice. A pancreatogram reveals a
diffusely dilated pancreatic duct with multiple filling defects due to retained mucous
endocrine tumor (1–2 per million people/ year), pro- within the duct. From Pancreatic Physiology and Pancreatitis GastroSlide 375, AGA
Institute. (Courtesy of D. Carr-Locke, Boston, MA, and J. Lee, Houston, TX.)
ducing symptoms resulting from blood glucose levels
under 50 mg/dl, which are relieved by glucose ad- der normal conditions. Secretin provocation testing
ministration. About 90% of insulinomas are benign, is useful in individuals with borderline elevations in
and >70% are solitary lesions. EUS is often very use- serum gastrin levels and in patients with conditions
ful in localizing insulinomas, which can be too small that can show elevations in serum gastrin levels un-
to be seen by CT and are less likely to appear on so- related to gastrinoma (such as atrophic gastritis).
matostatin receptor scintigraphy than other endo-
crine tumors. About 10% of patients presenting with intolerance, weight loss, anemia, and a characteristic
severe hypoglycemia may have diffuse islet hyperpla- rash called necrolytic migratory erythema. Most glu-
sia (nesidioblastosis) instead of a discrete mass. cagonomas are large, solitary, and malignant.
- -
trinomas produce massive hypersecretion of gastric sult in a secretory diarrhea and hypokalemia. They
acid resulting in severe peptic ulcer disease and, for tend to be large, solitary tumors, and more than half
some patients, chronic diarrhea due to acid-related are malignant.
damage to enterocytes and inactivation of pancreatic -
digestive enzymes and bile acids; 40–75% of these docrine neoplasia (MEN) syndromes are a group of
tumors may arise from the duodenum. The major- autosomal dominantly inherited diseases associated
ity of gastrinomas are malignant, and multiple le- with neoplasm and/or hyperplasia of various endo-
sions are common. These tumors exhibit a distinct crine systems. The pertinent features are summa-
response to intravenous secretin, characterized by a rized in Table 10.13.
rapid rise in serum gastrin levels that is not seen un-
TABLE 10.13
Multiple Endocrine Neoplasia (MEN) Syndromes
Organ system MEN I MEN II or IIa MEN II or IIb
Pituitary Adenomas
Parathyroid Adenomas Hyperplasia

Hyperplasia
Pancreatic islets Islet cell tumors
Adrenal Cortical hyperplasia Pheochromocytoma Pheochromocytoma
Thyroid C-cell hyperplasia Medullary carcinoma Medullary carcinoma
Other Mucocutaneous Ganglioneuromas
Mutant gene locus 11q13 10q11.2 (RET gene mutation in small 10q11.2 (methionine-codon gene) to
cysteine-rich extracellular domain) threonine mutation at 918 of RET
it should be delayed for as long as possible and

Pearls and Pitfalls minimally invasive approaches are the preferred
for the Board Exam surgical option.
Many pancreatic enzymes are stored as inactive Only symptomatic pseudocysts should be consid-
pro-enzyme and normally activated in the small in- ered for drainage procedures with endoscopic drain-
testine. Their activation within the pancreas may age the preferred method.
initiate pancreatitis. Surgery is the preferred for management of chronic
Gallstones and alcohol abuse account for approxi- pancreatitis associated bile duct strictures.
mately 70% of the etiology of pancreatitis. Pancreatic cancer patients with jaundice do not ben-
Cigarette smoking increases the risk of acute and efit from routine pre-operative ERCP and bile duct
chronic pancreatitis; its mechanism is independent stenting.
of alcohol. Surgical resection should be considered for all pa-
Trauma, biliary tract disease, drugs and infections tients with main duct IPMN’s.
are the leading etiology of pancreatitis in children.
The majority of mutations that increase the risk of
pancreatitis affect pancreatic trypsin activity.
Most Efficient Source Review
Mutations in the human cationic trypsinogen gene
(PRSS 1) and pancreatic secretory inhibitor (SPINK For Exam Preparation
1) result in hereditary pancreatitis. AGA Institute Technical Review on Acute Pancreati-
The levels of amylase and lipase do not provide tis. Chris Forsmark and John Baillie. Gastroenterol-
prognostic value regarding severity or outcome of ogy;2007;132:2022-2044.
pancreatitis. Diagnosis and Treatment of Cystic Pancreas Tumors.
Serum levels of BUN and its trend has prognostic Clinical Gastroenterology and Hepatology. Moham-
significant in predicting organ failure and death in mad Al-Haddad, Max C. Schmidt, Kumar Sandraseg-
acute pancreatitis. A BUN of >25 mmol/dl is predic- aran, John Dewitt. 2011;9:635-648.
tive of an increased severity of disease. Pancreatic cancer. Vincent A, Herman J, Schul-
ERCP is not required in all patients presenting with ick R, Hruban RH, Goggins M. Lancet. 2011 Aug
acute biliary pancreatitis. 13;378(9791):607-20
In patients at high risk for post-ERCP pancreatitis, Modern treatment of patients with chronic pan-
placement of a prophylactic pancreatic duct stent creatitis.Gastroenterol Clin North Am. 2012
for a short period results in reduced incidence and Mar;41(1):63-76.Trikudanathan G, Navaneethan U,
severity of post-ERCP pancreatitis. Vege SS.
Routine use of antibiotics to prevent infection in Differences in clinical profile and relapse rate of
all patients with acute pancreatitis is not recom- type 1 versus type 2 autoimmune pancreatitis Ra-
mended. ghuwansh p. Sah, Suresh t. Chari, Rahul Pannala,
Vigorous resuscitation with intravenous fluids is crit- Aravind Sugumar, Jonathan e. Clain, Michael j. Levy,
ical in the initial management of acute pancreatitis. Randall k. Pearson, Thomas c. Smyrk, Bret t. Pe-
When alimentation is required for patients with se- tersen, Mark d. Topazian, Noki Takahashi, Michael
vere pancreatitis, enteral feeding is preferred over b. Farnell, j and Santhi s. Vege. Gastroenterology
TPN and results in fewer infectious complications. 2010;139:140–148.
Autoimmune pancreatitis has 2 distinct subtypes
with different clinical outcomes. Biliary strictures
are a common extra-pancreatic presentation.
Sterile necrosis and organized necrosis is best man-
aged medically. If surgical management is planned,
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362(17):1605–17.
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6. Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pan- 25. Maisonneuve P, Lowenfels AB, Mullhaupt B, et al. Ciga-
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CHAPTER 11
Diseases of the Biliary Tract
Rahul Kuver, MD
Learning Objectives
1. Review biliary tract anatomy including developmental abnormalities.
2. Review the physiology of bile formation and gallbladder motility.
3. Describe the clinical manifestations, diagnosis, complications, and treatment of gallstone-related disorders.
4. Describe the clinical manifestations, diagnosis, and treatment of acalculous disorders.
5. Describe the clinical manifestations, diagnosis, and treatment of neoplastic disorders.
Biliary System Anatomy and Physiology
Biliary Tract Embryology

The liver develops embryologically from the hepatic diverticulum into a hepatic portion, which forms the
liver parenchyma and the intrahepatic bile ducts; and a cystic portion, which forms the gallbladder, cystic
duct, and the common bile duct. The primitive gallbladder is fully developed by 12 weeks gestation, and bile
secretion begins at 16 weeks gestation. Continued biliary system development is primarily related to growth
until birth.
Biliary Tract Anatomy

Hepatocytes secrete bile through active transport mechanisms into bile canaliculi, the smallest branches of
the biliary tree in the liver. Bile passes through the small terminal, interlobular, and large hilar bile ducts
into the duodenum. The hilar intrahepatic ducts, measuring 1.0-1.5 mm in diameter, merge to form the main
left hepatic ducts. The junction of the cystic duct with the common hepatic duct to form the common bile
duct can vary, with a direct connection found in ~70% of the population. A parallel or spiraling course of the
cystic duct in relation to the common bile duct can also occur. The common bile duct, approximately 7 cm in
and enters the second part of the duodenum, joining the main pancreatic duct to form the ampulla of Vater.
321
In general, stimuli that contract the gallbladder will Figure 11.1

Neurohumoral Control of Extrahepatic Biliary System
the gallbladder into the duodenum (Figure 11.1).
Sympathetic and parasympathetic innervation of the
gallbladder is responsible for visceral pain sensation
and motility, respectively. The extrahepatic biliary
tract arterial supply is primarily from the right he-
patic artery and collateral vessels of the gastroduo-
denal artery. Unlike the hepatic parenchyma, which
the biliary ducts are entirely dependent upon arte-

rial perfusion. Interference with the bile ductal blood
supply, which may occur following bile duct surgery
or hepatic artery thrombosis, commonly leads to bile
duct strictures.
Gallbladder Motility
Gallbladder contractility is regulated by the fat con-
Ingested nutrients, especially fat, stimulate CCK release that contracts
tent of ingested food, the vagal nerves, and the hor- the gallbladder and relaxes the sphincter of Oddi, mediated through non-
mone cholecystokinin (CCK). Vagal nerve stimulation adrenergic, noncholinergic (NANC) nerves. Vagal (cholinergic) stimuli
and cholinergic agonists also prompt gallbladder contract the gallbladder and somatostatin relaxes it.
contraction. The hormones motilin and somatostatin

stimulate and inhibit gallbladder contractility, re-
spectively. Since meal stimuli that release CCK also
Hepatic Cholesterol Metabolism
release somatostatin, the latter peptide acts as a The liver predominantly regulates total body cholester-
physiological “brake,” regulating the magnitude of ol balance, plasma lipid, and plasma lipoprotein levels.
Sources of hepatic cholesterol include synthe-
CCK actions. sis, hydrolysis of stored cholesterol esters, and uptake
of serum cholesterol from different lipoproteins (Figure
11.2). Sources of lipoprotein cholesterol taken up by
Sphincter of Oddi Function the liver include chylomicron remnants and low-
density lipoproteins (LDL) (taken up by mechanisms
The sphincter of Oddi consists of smooth muscles
involving the LDL receptor and LDL receptor-related
that surround the terminal common bile duct, main
protein) and high-density lipoproteins (HDL) (bound
pancreatic duct, and ampulla of Vater. Major func-
by the scavenger receptor B1 with cholesterol trans-
tions include regulation of bile and pancreatic exo-
ferred without internalization of the particle). He-
-
olism to bile acids and other sterols, active transport
possesses both a variable basal pressure as well as
into bile, or transport into the serum in lipoproteins
tonic contractile activity. Sphincter relaxation is pro-
moted by neural (nonadrenergic, noncholinergic me-
Cholesterol excretion into bile and bile acid synthesis
diated by VIP and nitric oxide) and hormonal (CCK
are the two principal pathways for cholesterol elimi-
and secretin) mechanisms.
nation from the body.
The rate-limiting hepatic enzyme in cho-
lesterol biosynthesis is HMG-CoA reductase. The ac-
Chapter 11 — Diseases of the Biliary Tract 323
tivity of this enzyme is inhibited by accumulation of Figure 11.2

free cholesterol within the hepatocyte. In addition, Principal Pathways of Cholesterol Metabolism in Liver
HMG-CoA reductase is phosphorylated, and its activ-
ity is therefore sensitive to hormones that alter the
intracellular concentration of cyclic AMP.
Uptake of cholesterol in lipoproteins is medi-
ated by the hepatic LDL receptor and the LDL recep-
tor–related protein. In general, lipoprotein uptake is
stimulated by a reduction in hepatic free cholesterol
(low cholesterol diet, inhibition of cholesterol syn-
thesis) or by certain hormones (estrogen). Uptake is
inhibited by conditions or treatments that lead to ac-
cumulation of hepatic free cholesterol. Two enzymes
control the process of hepatic cholesterol storage: (1)
acyl cholesterol acyltransferase (ACAT), which forms
cholesterol esters; and (2) neutral cholesterol ester
hydrolase, which cleaves cholesterol esters into free
cholesterol and free fatty acids. Synthesis of choles-
terol esters by ACAT is regulated by the availability of
cholesterol substrate and by the amount of enzyme. In
contrast, cholesterol ester hydrolase is not regulated,
and the breakdown of cholesterol ester is constant.
Cholesterol from the diet and peripheral tissues enter the liver in association with
The main driving force behind biliary cholesterol
serum lipoproteins. Intrahepatic sources of cholesterol include de novo synthesis
secretion is the magnitude of the metabolically ac- and hydrolysis of cholesterol esters. The liver stores cholesterol by esterification,
tive hepatic pool of free cholesterol. Changes in the or exports it into the serum via lipoproteins. Excretion of cholesterol into bile and
amount of cholesterol in this pool determine the rate biotransformation of cholesterol to bile acids provide the only significant routes for
cholesterol elimination from the body.
of biliary cholesterol secretion and the lipid compo-
sition of bile. Cholesterol secretion into bile is tightly
coupled to bile acid secretion. enzyme (which decreases with age), and other meta-
bolic and hormonal factors. In the alternate pathway,
cholesterol is initially oxidized by the enzyme ste-
Bile Acid Synthesis rol 27-hydroxylase. Bile acid synthesis is transcrip-
tionally regulated by the nuclear hormone receptor
Bile acids are synthesized from cholesterol by satu-
farnesoid X receptor in partnership with the retinoid
ration of the sterol nucleus and the addition of two
X receptor.1 Chenodeoxycholate and cholate are the
or three hydroxyl groups. Bile acid synthesis requires
only two bile acids synthesized by the human liver.
oxidative cleavage of the side chain, leaving behind a
Lithocholate, deoxycholate, and ursodeoxycholate
carboxylic acid (hence the term bile acid). At physi-
are formed by the action of intestinal bacteria on un-
ologic pH in solution, this carboxylic acid group is al-
absorbed bile acids that enter the colon.
most fully ionized, so bile acids also may be referred
After initial synthesis, bile acids are conjugated
to as bile salts.
to the amino acids taurine or glycine and secreted.
There are two pathways of bile acid biosynthesis:
Bile acid secretion is the main driving force in bile
the classic and the alternate pathways (Figure 11.3).
formation and secretion of biliary cholesterol. Bile
Cholesterol-7 alpha-hydroxylase is the rate-limiting
acids also solubilize other sterols, including lipo-
enzyme in the classic pathway. Its activity is regu-
philic drugs and steroid hormones, thereby enabling
lated by the availability of cholesterol substrate, the
their excretion from the body.
hepatocellular bile acid concentration, the amount of
Figure 11.3 Fibroblast growth factor 19 (FGF 19), secreted

Classic and Alternate Pathways of Bile Acid Synthesis by ileal enterocytes in response to luminal bile ac-
ids, acts as a feedback regulator to inhibit hepatocyte
cholesterol 7 alpha-hydroxylase gene expression.2
Dysfunction of this signaling pathway is postulated
to explain chronic diarrhea in patients with idio-
pathic bile acid malabsorption, a clinical entity that
responds to treatment with bile acid sequestrants.3
The human gallbladder also secretes FGF 19 into bile,
although the function of biliary FGF 19 has not been
elucidated.4
Bile Secretion
The adult liver secretes about 1500 ml of bile daily.
Bile is a complex mixture of inorganic and organic
Cholesterol 7alpha-hydroxylase is the rate-limiting enzyme in the classic pathway, materials, including water, electrolytes, bilirubin,
which leads to the synthesis of both cholate and chenode-oxycholate. Sterol
bile acids, phospholipids, cholesterol, and proteins.
27-hydroxylase is the initial enzyme in the alternate pathway, which leads primarily to
the synthesis of chenodeoxycholate. The classic pathway is predominant in humans. Bile formation is driven by active transport of bile
salts into the canaliculus via ABCB11 (also called the
bile salt export pump). The osmotic and electrical ef-
fects of the negatively charged bile salts then draw
electrolytes and water into the canaliculus via inter-
Figure 11.4
Mechanisms of Bile Formation
(A) Pathways contributing to bile flow. (B) Relationship between bile flow and bile acid secretion. Hepatocytes secrete bile acids into the bile canaliculus
through active transport mechanisms. Bile canalicular flow is composed of bile salt-dependent and independent hepatocyte secretion. Bile is diluted by sodium
bicarbonate-rich ductular secretion. Total bile flow is the summation of canalicular flow and ductular secretion. (C) Hepatocyte canalicular membrane transport
proteins involved in bile formation. Shown are the names of each transport protein, with the transport substrate shown in parentheses. MDR3 (also known
as ABCB4) transports phospholipids; the bile salt export pump (BSEP; also known as ABCB11) transports bile salts; the multidrug resistance protein 1 (MDR1,
also known as P glycoprotein) transports cationic drugs; ABCG5/G8 is involved in the efflux of sterols, including cholesterol and plant sterols; the breast
cancer related protein (BCRP, also known as ABCG2) transports sulfated molecules; and MRP2 (also known as ABCC2) extrudes conjugated bilirubin, reduced
glutathione and other organic anions.
cellular tight junctions. There is a linear relationship tion can be induced therapeutically via use of resins,
between bile volume and bile salt secretion that is such as cholestyramine, which bind bile acids in the
gut lumen. This has the effect of reducing bile acid
and B). A small proportion of canalicular bile forma- return to the liver, which responds by up-regulating
tion is mediated through secretion of other anions, bile acid synthesis, thereby depleting the cholesterol
electrolytes, and glutathione (bile salt independent substrate pool in the liver. In turn, this leads to up-
regulation of LDL receptors, increased LDL uptake,
Phospholipids (almost entirely phosphatidylcho- and reduction of circulating LDL cholesterol.
line) and cholesterol enter bile in the form of unila-
mellar vesicles generated at the luminal surface of
the canalicular membrane. Vesicle secretion in bile Gallstones
requires active transport of lipids across the canalicu-
lar membrane, mediated by the transporters ABCB4
or mixed stones on the basis of their chemical com-
and ABCG5/G8, and is linked to bile salt secretion,
position. Approximately 90% of gallstones are cho-
although the mechanisms are not understood.5 Bile
lesterol or mixed gallstones, which consist of over
is diluted and alkalinized by intrahepatic ductular
50% cholesterol, or 30–50% cholesterol, respective-
secretion, which is controlled by secretin. Thus, bile
ly. The other 10% of gallstones are pigmented stones
composition and volume are determined by numer-
that contain <30% cholesterol.
ous active transport mechanisms in the hepatocyte
and biliary tree that respond to physiological stimuli.
The molecular mechanisms of bile formation at the
canalicular membranes of hepatocytes have been
Figure 11.5
Gallstone Pathogenesis
(Figure 11.4C).6
Enterohepatic Circulation
The enterohepatic circulation transports bile acids
from the liver to the small intestine and back to the
liver after reabsorption in the terminal ileum. The
circulating bile acid pool is primarily maintained by
However, the pool of bile acids recycles 5–15 times

each day, to produce a 20–30% loss per day. Under
stable conditions, the rate of loss of bile acids is
matched by an equivalent rate of hepatic synthesis.
With extensive ileal disease or resection, bile acid
-
tion, and the bile acid pool diminishes. The result
is reduced hepatic bile acid secretion, a diminished
cholesterol carrying capacity in bile, and increased
risk for gallstone formation. A diminished bile acid
pool is also a cause of diarrhea (mild malabsorption) The pathogenic scheme of cholesterol gallstones includes (a) hepatic secretion of
bile supersaturated with cholesterol, (b) nucleation of cholesterol molecules to form
and steatorrhea (severe malabsorption). crystals, and (c) stasis of bile within the gallbladder.
To treat hyperlipidemia, bile salt malabsorp-
Cholesterol Gallstone Pathogenesis gle phase as micellar cholesterol. As the cholesterol

concentration increases, bile cholesterol may exist in
The following factors are required for the forma-
either 2 or 3 phases: micelles plus cholesterol crys-
tion of cholesterol gallstones: (1) hepatic secretion
tals, micelles plus vesicles (composed of phosphati-
of bile supersaturated with cholesterol (lithogenic
dylcholine and cholesterol), or micelles plus vesicles
bile); (2) stasis of bile within the gallbladder; and (3)
plus cholesterol crystals (Figure 11.6). Bile calcium
nucleation of cholesterol molecules to form crystals
also plays a role in gallstone pathogenesis. Calcium
(Figure 11.5). Contributory kinetic factors include al-
salts are present in most gallstones, and these salts
teration in the rate of nucleation and crystal growth,
can serve as an initial nidus for stone growth.
increasing trapping of nascent crystals in a mucin gel
where they agglomerate and accrete, and reduced Cholesterol supersaturation of bile
gallbladder contractility. Lithogenic bile contains high concentrations of cho-
More than half of cholesterol gallstone weight lesterol, which is prone to precipitate. The rate of
is cholesterol. The remainder consists primarily of biliary cholesterol secretion is nonlinearly related
mucin glycoprotein and calcium salts of bilirubin, to the rate of secretion of bile acid and phospholip-
phosphate, and carbonate. Cholesterol is insoluble in id. When the bile acid secretory rate decreases, bile
water but can dissolve in bile when complexed with becomes relatively enriched with cholesterol and
phospholipid and bile acids as micelles. At low con- more likely to form gallstones. A relative increase
centrations, biliary cholesterol exists in a soluble sin- in biliary cholesterol secretion, as well as decreases
in the secretion of bile acid or phospholipids, have
Figure 11.6
both been implicated in the production of lithogenic
Cholesterol Gallstones
bile. In dilute bile, cholesterol is carried in phospho-
lipid bilayer vesicles. Vesicles, like membranes, have
a liquid crystal structure and can accommodate a
large amount of cholesterol relative to phospholipid.
As bile is concentrated in the gallbladder, bile salts
act as detergents to dissolve these vesicles, forming
mixed micelles composed of bile salts, phospholipid,
and cholesterol. The cholesterol-carrying capacity
of mixed micelles (relative to their phospholipid ca-
pacity) is much less than that of vesicles, and as the
phase transition progresses, a point may be reached
at which both the mixed micelles and the remain-
ing bilayers are saturated with cholesterol. Further
concentration results in cholesterol supersaturation,
which can be followed by precipitation of excess cho-
lesterol as solid cholesterol monohydrate crystals.7
Gallbladder motility
Cholesterol from supersaturated bile can diffuse into
the gallbladder wall and accumulate in gallbladder
smooth muscle, where it produces a marked de-
Cholesterol gallstones develop in the gallbladder initially from bile supersaturated
with cholesterol, which then precipitates out of bile, forming micelles and vesicles.
crease in contractility. The resulting gallbladder sta-
Multilamellar vesicles then form in the mucin gel layer lining the gallbladder mucosa. sis in turn contributes to stone formation by allowing
Cholesterol monohydrate crystals subsequently aggregate in the mucin gel (biliary greater concentration of bile (and hence greater su-
sludge) to form gallstones.
persaturation) by providing time for crystals to form
and fuse into macroscopic stones, and by delaying
or preventing expulsion of mucus and sludge. Litho-

genic bile retained within the gallbladder may alter the bile of patients with pigment gallstones, and their
motility and stimulate epithelial secretion of mucin, presence may also affect mucin secretion.9
a potent nucleating agent.
The process of gallbladder sludge accumulation Biliary sludge (microlithiasis)
and stone formation is promoted by slowed and in- The formation of sludge within the gallbladder rep-
complete emptying of bile from the gallbladder. Con- resents one of the earliest stages of gallstone forma-
ditions characterized by prolonged fasting or dimin- tion. The appearance of sludge, a viscous gel con-
ished intestinal CCK release are conducive to sludge taining mucin and precipitates of cholesterol and
formation within the gallbladder. calcium bilirubinate, commonly antedates the ap-
pearance of gallstones.10 The precipitation of choles-
Bacterial infection terol as sludge in the gallbladder and its passage into
Using molecular techniques, bacteria have been found
in both mixed and pure (>90%) cholesterol stones, mechanism to rid the body of excess cholesterol, be-
raising the hypothesis that bacteria participate in -
cholesterol stone formation. With gallbladder stasis, absorbed by the small intestine, whereas crystallized
biliary tract infection may occur, with subsequent cholesterol is not.11
bilirubin deconjugation via the bacterial b-glucuron-
idase enzyme. However, after initiation of the litho-
genic process, bile composition may change, and Risk Factors for Gallstones
mixed or even pure cholesterol stones may eventually
Gallstones are more common among women, who
form. Like foreign bodies, stones may become colo-
are twice as likely to be affected when compared to
nized with bacteria, resulting in precipitation of bili-
men.12
rubinate salts or remodeling of the existing stones.8
gender and appears to vary from 0.5% to 3% (men)
and 1.5% to 4% (women). Advanced age is also a risk
Nucleation factors
factor for gallstones, likely due to enhanced biliary
Biliary cholesterol supersaturation is a necessary but
cholesterol secretion. Genetic predisposition is rec-
-
ognized, and several genes predisposing to gallstone
tion. The process of cholesterol crystal precipitation
requires nucleation via fusion of supersaturated ves-
Genetic effects account for 25% of the phenotypic
icles to form large multilamellar liquid crystals. Vari-
variance among twins.13 Two single gene defects as-
ous antinucleating factors present in bile normally
sociated with cholesterol gallstones have been iden-
appear to inhibit vesicle fusion and retard nucleation,
-
stones; other proteins promote cholesterol crystal
and a mutation in CYP7A1, the rate-limiting enzyme
nucleation and growth, and are found in increased
in bile acid synthesis in the liver.14 High-risk popu-
concentrations in the bile of gallstone patients. Most
lations include individuals of Native American and
crystal formation appears to take place in the micro-
Scandinavian descent. First-degree relatives among
environment of the mucin gel lining the gallbladder.
index cases have a 4.5-fold increased risk of devel-
Cholesterol supersaturation of bile stimulates mucin
oping gallstones. However, single gene defects as-
secretion via mechanisms that are not well under-
sociated with gallstones are rare and do not account
stood. Gallbladder mucin synthesis and secretion
for racial and familial predisposition to cholesterol
are stimulated by prostaglandins and inhibited by
gallstone disease. High serum triglyceride levels and
prostaglandin synthesis antagonists such as aspi-
low serum HDL cholesterol levels are also associated
rin. Excess mucin provides an environment in which
with gallstone disease (Table 11.1).
cholesterol can nucleate. Crystals formed in gallblad-
Obesity is a risk factor for gallstones due to as-
der mucin are entrapped and can aggregate to form
Table 11.1 trimester, and in 10.2% by 4–6 weeks postpartum.

Risk Factors for Cholesterol Gallstone Formation Regression of sludge and stones was so common that
the postpartum ultrasound only showed 4.2% with
Obesity
new sludge or stones. Pre-pregnancy body mass in-
Female gender
dex and serum leptin levels were independent pre-
Parity
dictors of incident gallbladder disease.15
Maternal family history
Systemic conditions associated with gallstone
Ethnic predilection (Hispanic and Native American)
formation include cirrhosis, diabetes mellitus and
Increasing age
ileal dysfunction like that which occurs in Crohn’s
Rapid weight loss
disease. Conditions favoring cholelithiasis in diabe-
Ileal disease
tes mellitus include hypertriglyceridemia and gall-
Lipid abnormalities
bladder dysmotility. Drugs including estrogens, clo-
High triglycerides
Low high-density-lipoprotein cholesterol
associated with gallstone formation.
Medications
Contraceptive steroids Black pigment stones—pathogenesis and
Postmenopausal estrogens risk factors
Total parenteral nutrition Calcium salts in a protein matrix can crystallize in the
Lipid-lowering agents gallbladder to form black pigment stones. This type
Fibric acid derivatives of stone comprises the majority of non–cholesterol-
containing stones found in the gallbladder in West-
sociated cholesterol supersaturation of bile. During ernized societies. Although heterogeneous in compo-
rapid weight loss, bile lithogenicity increases further sition, they appear black due to the presence of metal
because of reduced synthesis of bile acids, and gall- salts of bilirubin that have been exposed to reactive
bladder motility is impaired because of inadequate oxygen species. Calcium bilirubinate can make up
fat stimulation, increasing the risk of gallstone for- 10–90% of stone weight. Risk factors for black pig-
mation. Biliary sludge and/or gallstones develop af- ment stones include old age, chronic hemolytic states
ter dietary restriction and bariatric surgery in 25% such as sickle cell disease, TPN, Crohn’s disease, and
and 50% of obese patients, respectively. Similarly, cirrhosis. Black pigment stones can also form up-
the absence of enteral food stimulation during total stream of biliary strictures, as in primary sclerosing
parenteral nutrition (TPN) impairs intestinal CCK re- cholangitis.
lease and leads to gallstones in up to 45% of patients
Brown pigment stones—pathogenesis and
after 3 months of TPN therapy.
risk factors
In women, the risk of harboring gallstones is
Brown pigment stones, which can form anywhere
directly related to the number of pregnancies. As
in the biliary tract, result from stasis and infection.
pregnancy progresses, bile becomes super-saturated
Bacterial enzymes deconjugate bilirubin from gluc-
with cholesterol because of high levels of estrogens,
uronic acid and hydrolyze phospholipids, resulting
and gallbladder motility is impaired because of el-
in supersaturated solutions of calcium salts of bili-
evated levels of progestins. Thus, stasis of lithogenic
rubin and fatty acids. In Western countries, this type
bile within an enlarged, sluggish gallbladder occurs
of stone is most commonly found in the common bile
during late pregnancy, predisposing to sludge and
duct several years following cholecystectomy, where-
gallstone formation. Conjugated estrogens and con-
as in certain parts of Asia, brown pigments stones are
traceptive steroids are also risk factors for gallstones
associated with recurrent pyogenic cholangitis. In
because both increase biliary secretion of choles-
rural areas of Asia, where the incidence of this type
terol. In a study of 3254 pregnant women, sludge or
of stone is the highest, an association with a diet typi-
stones were found in 7.9% of subjects by the third
cally low in total calories and animal protein content
but high in vegetable content has been proposed. and resolves slowly. The pain may radiate to the in-
Conversely, in Japan the trend toward a Westernized terscapular region or (rarely) to the right shoulder.
diet of high protein, high calorie, and high carbohy- Vomiting and diaphoresis are not uncommon. The
drate content has been linked to a falling incidence of -
brown pigment stones. fortable position. Residual tenderness in the upper
abdomen may persist after an attack. Pain lasting >6
hours suggests development of cholecystitis. The in-
Clinical Course and Complications terval between attacks is unpredictable and may be
weeks, months, or years.
Natural history of asymptomatic gallstones True biliary colic should be differentiated from
A cohort of 123 asymptomatic individuals with gall-
stones found by oral cholecystography was followed discomfort, and fatty food intolerance are common
for 11–24 years. New-onset biliary pain developed at complaints of many patients, with or without chole-
- lithiasis. Accurately differentiating true biliary colic
lative incidence of biliary pain was 15% at 10 years -
and 18% at 20 years. Two percent developed compli- nant of the success of cholecystectomy in relieving
cations, all of which were preceded by repeated at- symptoms.
tacks of biliary colic. No deaths related to gallbladder Cholecystectomy done for gallstone-induced bil-
disease occurred in this cohort.16 iary colic is usually curative, but is far less successful
-
Natural history of symptomatic gallstones tomatic, incidentally detected cholelithiasis. Many
Once an episode of biliary colic has occurred, there is
a high risk of repeated attacks of pain. Cohort stud- or subsequently recur. The diagnosis of biliary colic
ies that followed symptomatic gallstone patients is ultimately based on clinical judgment.
indicate that 58–72% of patients continued to have
symptoms and complications. More than 90% of Acute cholecystitis
complications such as cholecystitis, cholangitis, or Acute cholecystitis is caused by obstruction of the
pancreatitis are preceded by symptoms of uncompli- cystic duct by gallstones in 90% of cases. In addi-
cated biliary colic. tion to pain, patients with acute cholecystitis usually
-
tion (e.g., right upper quadrant mass, tenderness)
Biliary Colic and systemic toxicity (e.g., fever, leukocytosis). Bac-
terial infection of the gallbladder is secondary, but
Approximately one-third of patients with gallstones can lead to empyema with or without perforation.
present with clinical symptoms or complications of The differential diagnosis includes other causes of
gallstone disease. Biliary colic is the main complaint in -
70–80% of symptomatic patients. Patients with motil- nography and biliary scintigraphy are useful tools in
ity disorders of the biliary tree, such as sphincter of diagnosing cholecystitis.
Oddi dysfunction, may also present with biliary colic. Most patients with acute calculous cholecystitis
Classically, the pain of biliary colic is episodic, have had previous attacks of biliary colic. The pain of
severe, and located in the epigastrium or (less fre- acute cholecystitis typically lasts longer than 3 hours,
quently) in the right upper quadrant or other parts and near the end of this time period, it shifts from
of the abdomen (Table 11.2). The pain may be pre- the epigastrium to the right upper quadrant, with the
cipitated by eating, but often develops without any emergence of localized tenderness due to peritoneal
precipitating events. Typically, the pain begins sud- irritation. With time the intensity of pain may dimin-
denly, increases rapidly in intensity over a 15-min- ish, but the tenderness may increase. Vomiting is a
ute interval to a steady plateau lasting up to 3 hours,
Table 11.2
Common Clinical Manifestations of Gallstone Disease
Biliary Colic Acute Cholecystitis Choledocholithiasis
Intermittent obstruction of Impacted stone in the cystic duct

Pathophysiology
the cystic duct Acute inflammation of the gallbladder Intermittent obstruction of the
No inflammation of the mucosa common bile duct
gallbladder Secondary bacterial infection in 50%
Severe, localized epigastric

visceral pain growing in 75% are preceded by attacks of biliary colic
intensity over 15 min and Visceral epigastric pain gives way to Often asymptomatic
remaining constant for 1–3 moderately severe, localized pain in the Symptoms (when present) are
Symptoms
hours right upper quadrant, back, shoulder, or indistinguishable from biliary
Frequency of attacks varies rarely chest colic
from days to months Nausea with some emesis is frequent Predisposed to cholangitis and
Gas, bloating, flatulence, and Pain lasting >6 hours favors cholecystitis acute pancreatitis
dyspepsia are not related to over colic
stones
Febrile but usually <102°F unless Often a completely normal

complicated by gangrene or perforation. examination if the obstruction is
Right subcostal tenderness with inspiratory intermittent
Often a completely normal
Physical findings arrest (Murphy’s sign) Jaundice with pain suggests
examination
Palpable gallbladder in 33%, especially stones, whereas painless
in patients having their first attack. Mild jaundice and a palpable
jaundice in 20%, higher frequency in elderly gallbladder favor malignancy
Leukocytosis of 12,000–15,000 with Elevated bilirubin and alkaline

Usually normal bandemia is common phosphatase seen with CBD
In patients with findings of Bilirubin may be 2–4 mg/dl and obstruction
only uncomplicated biliary transaminase and alkaline phosphatase Bilirubin >10 mg/dl suggests
Laboratory colic, an elevated bilirubin,
findings
may be elevated even in the absence of malignant obstruction or co-
alkaline phosphatase, or CBD stone or hepatic infection existing hemolysis
amylase suggests coexisting Mild amylase elevation is seen even in Transient “spike” in
common bile duct (CBD) absence of pancreatitis. If bilirubin >4 or transaminases or amylase
stones amylase >1000, suspect CBD stone suggests passage of a stone
Diagnostic tests Sonography Sonography ERCP

(see text for details) Biliary microscopy Hepatobiliary scintigraphy Transhepatic cholangiogram
After initial attack, 30% have

no further symptoms Natural history is not well
50% resolve spontaneously in 7–10 days
The remainder develop defined, but complications are
without surgery
Natural history symptoms at a rate of more frequent and severe than
Left untreated, 10% are complicated by a
30–50% in 2 years and for asymptomatic stones in the
localized perforation and peritonitis
severe complications at rate gallbladder
of 1% per year
Cholangitis Gallbladder Cancer Bile Duct Cancer

Chronic bacterial/
parasitic carriage
Impacted stone in the common bile duct causing >80% with gallstones Chronic inflammation
bile stasis Sequential multistep (e.g., primary sclerosing
Bacterial superinfection of the stagnant bile. Early transformation from metaplasia cholangitis), leads to
bacteremia to dysplasia to neoplasia metaplasia-dysplasia
sequence
Progressive obstructive
Charcot’s triad of pain, jaundice, and fever is
jaundice
present in 70%Pain may be mild and transient and Often those of gallstones
Usually painless, acholic
is often accompanied by chills Uncommonly diagnosed
stool
Mental confusion, lethargy, and delirium are preoperatively
20% can be complicated
suggestive of bacteremia
with bacterial cholangitis
Fever in 95%Right upper quadrant tenderness in 90%

Similar to gallstones Obstructive jaundice,
Jaundice in 80%
Jaundice suggests local palpable gallbladder if
Peritoneal signs in only 15%
extension with ductal tumor distal to cystic
Hypotension and mental confusion coexist in 15%
obstruction duct junction
and suggest gram-negative sepsis
Leukocytosis in 80%; remainder may have normal

WBC count with bandemia as the only hematologic
finding Bilirubin >12 mg/dl
Bilirubin >2 mg/dl in 80%, but when <2 mg/dl the Similar to gallstones Elevation of alkaline
diagnosis may be missed Often with features of phosphatase with
Alkaline phosphatase is usually elevated cholecystitis mild or no change in
Blood cultures usually positive, especially during transaminases
chills or fever, and grow two organisms in half of
patients
ERCP
ERCP Sonography
EUS
Transhepatic cholangiogram Abdominal CT
Abdominal CT
Cholecystectomy should not

be offered for all patients with
High mortality if unrecognized, with death from
stones for fear of cancer Often slowly progressive,
septicemia
Cholecystectomy should and may not be detected
Emergent decompression of the CBD (usually by ERCP)
be considered for calcified until unresectable
dramatically improves survival
gallbladder and for growths
(adenomyoma, polyps) >15mm
common symptom. A low-grade fever is common, but may also be confused and hypotensive (Reynold’s
hyperpyrexia is uncommon. In elderly patients, pain pentad). Pain, usually characteristic of biliary colic,
and fever may be absent, and localized tenderness occurs in 90% of patients. Chills and fever due to
may be the only presenting sign. bacteremia occur in 65–90% of patients, and clinical
On physical examination, Murphy’s sign—an jaundice is present in 80%. Clinical signs are non-
abrupt arrest in inspiration during direct palpation
of the right upper quadrant—may be present. In (occasionally) rebound tenderness. Depending on
30–40% of patients, the gallbladder can be perceived the progress of the illness, endotoxemia with shock
as a palpable mass. Jaundice occurs in approximately or multiple liver abscesses may result. On the other
15% of cholecystitis patients, even without choledo- hand, cholangitis may be a short, self-limited and re-
cholithiasis and obstruction. current illness in untreated patients. Blood cultures
are often positive, with the most commonly found
Gallstone pancreatitis organisms being , Klebsiella, Pseudomonas, en-
Small gallstones can pass into the common bile duct terococci, and anaerobic species.
from the gallbladder, and subsequently pass into the
duodenum within 1–2 days. A potential complica-
tion of stone or sludge passage through the ampulla Diagnostic Studies
of Vater is acute pancreatitis. The pathogenesis is
thought to be due to stone impaction in the common
Laboratory tests
channel of the pancreatic and bile ducts, resulting
In uncomplicated biliary colic, there are usually no ac-
companying changes in hematologic and biochemical
duct. Gallstone pancreatitis should be suspected in
tests. In acute cholecystitis, leukocytosis with a “left
the setting of acute pancreatitis, gallbladder stones
on ultrasonography, and an elevated alanine ami-
of the gallbladder can partially obstruct the common
notransferase level. Biliary sludge or microscopic
bile duct, causing mild elevation of the serum trans-
aminases, alkaline phosphatase, and bilirubin.
cases of idiopathic acute pancreatitis.
Jaundice is often one of the presenting features
of choledocholithiasis, and the serum bilirubin level
Choledocholithiasis
is usually between 2 and 10 mg/dl, while the alkaline
If gallstones remain in the common bile duct, they
are likely to give rise to complications. Whether clini-
in the setting of choledocholithiasis is often intermit-
cally overt or not, common duct stones are frequent-
tent, in contrast to malignant jaundice, which is usu-
ly associated with infected bile. Biliary obstruc-
ally relentlessly progressive, and is usually a sign of
tion from choledocholithiasis results in jaundice,
ascending cholangitis. If the level of bilirubin is above
pruritus, and ascending cholangitis. Acholic stools
15 mg/dl, malignant obstruction should be strongly
are uncommon in bile duct obstruction resulting
suspected. Acute obstruction of the bile duct by a
from gallstones because the obstruction is rarely
stone initially (within hours) is accompanied by el-
complete. Clay-colored stools are more commonly
evations of transaminases that may be quite striking
observed with malignant obstruction. Also, the pal-
and may resemble the pattern seen with acute hepa-
pable gallbladder found in malignant obstruction
titis. With persistent obstruction, transaminases de-
(Courvoisier’s sign) is uncommon with obstruction
cline, while alkaline phosphatase progressively rises,
due to gallstones.
eventually producing a typical cholestatic pattern.
A common complication of choledocholithiasis
is cholangitis, which is rare in malignant obstruction.
Radiologic studies
The typical clinical picture of acute cholangitis, oc-
-
curring in 70% of cases, consists of biliary pain, jaun-
cated biliary colic, because only 13% to 17% of gall-
dice, and chills and rigors (Charcot’s triad). Patients
Figure 11.7
Ultrasound Examination Showing Gallstones
exclude other entities such as perforated ulcer or in-
testinal obstruction. Occasionally, when emphysema-
tous cholecystitis is present, intramural gas outlining
the gallbladder can be seen.
-
tivity for the diagnosis of gallstones and should be
obtained routinely if gallstones are suspected (Fig-
include thickening of the gallbladder wall (>2 mm),

-
in the gallbladder is less clear. Sludge is common in

extrahepatic biliary obstruction. Without distal ob-
struction, sludge can be associated with abdominal
pain (i.e., biliary colic), acute cholecystitis, or pancre-
atitis, and should be regarded as part of the spectrum
of gallstone disease. Ultrasonography may also show
dilatation of intrahepatic or extrahepatic bile ducts,
suggesting distal obstruction. Ultrasonography will The stones appear in the gallbladder as high-level echoes with a postacoustic shadow
(thin arrow). There is a stone impacted in the neck of the gallbladder (curved arrow),
detect only 40–50% of common bile-duct stones
and the gallbladder wall is thickened (thick arrow), suggestive of acute cholecystitis.
(Figure 11.9). (Courtesy of Dr. Scott Schulte, University of Washington, Seattle, WA.)
CT can also be used in the detection of cholelithi-
asis, but its sensitivity for common bile duct stones is Figure 11.8
only 30–40%. CT is useful in demonstrating dilated Ultrasound Examination Showing Gangrenous Cholecystitis
bile ducts and mass lesions, and may be the test of
choice if clinical suspicion of a malignancy obstruct-
ing the common bile duct is high.
The biliary and pancreatic ducts can also be suc-
cessfully imaged using magnetic resonance cholan-
giopancreatography (MRCP) (Figure 11.10).17 This
provides a noninvasive, high-quality image and
can add useful information about the hepatic and
pancreatic parenchyma. The sensitivity of MRCP
for common bile duct stones is 95–100%, with a
a 2- to 4-hour fast, the patient is given an intrave-

nous injection of a 99mTc-labeled iminodiacetic
acid derivative (IDA), which is excreted into the
bile ducts, with sequential imaging under a gamma
camera. In a normal study, the gallbladder, common
bile duct, and small bowel become visible in 30–45 The gallbladder wall is thickened with intramural air (thick arrow). The debris in the
minutes. A normal 99mTc-IDA scan virtually rules gallbladder represents sloughed gallbladder mucosa (thin arrow). (Courtesy of Dr.
Scott Schulte, University of Washington, Seattle, WA.)
Figure 11.9 with complications, including bleeding, pancreati-

Ultrasound Examination Showing Common Bile Duct Stones tis, perforation and infection. These procedures
should not be used for diagnosis and prior non-
invasive testing (e.g., US, CT, MRCP or endoscopic
ultrasound (EUS)) should usually be performed
documenting an abnormality requiring endoscopic
intervention. EUS has emerged as a useful tool in
diagnosing bile-duct lesions, including stones (Fig-
ure 11.11).19 It has the added advantage of being
able to “stage” a malignant obstruction in the pan-
creas or the adjacent bile ducts. For stone disease,
it has a positive and negative predictive value of
98% and 88%, respectively. However, like magnetic
resonance imaging (MRI), it is a purely diagnostic
procedure. Therefore, if there is a high clinical sus-
picion of choledocholithiasis, ERCP may allow for
more expedient therapeutic management. How-
ever, under more equivocal clinical circumstances,
as time and resources allow, the therapeutic endos-
Figure 11.10
The stone appears as an opacity within the duct with postacoustic shadowing (thin
arrow). The extrahepatic biliary ducts are markedly dilated (thick arrow). (Courtesy of Representative Image from Magnetic Resonance
Dr. Scott Schulte, University of Washington, Seattle, WA.) Cholangiopancreatogram (MRCP)
out the diagnosis of acute cholecystitis in a patient

with abdominal pain. Failure to image the gallblad-
der by 90 minutes despite adequate views of the
liver, common bile duct, and small bowel strongly
suggests acute cholecystitis. False negative studies
occasionally occur in patients with acalculous cho-
lecystitis. False positives can result with nonfasting,
prolonged fasting, chronic alcoholism, and chronic
cholecystitis. Delayed repeat scanning reduces the
false positive rate and increases the sensitivity
-
spectively. Administration of low-dose morphine at
1 hour may contract the sphincter of Oddi and aug-
-
layed repeat scans in some circumstances.18
Endoscopic studies
Endoscopic retrograde cholangiopancreatography
The intrahepatic and common bile ducts are clearly visible (thick
(ERCP) is the method of choice for endoscopic interven- arrow), as is the pancreatic duct (thin arrow). Also clearly seen is an
tion on the biliary tree. Percutaneous transhepatic chol- anomalous right intrahepatic bile duct (curved arrow). (Courtesy of Dr.
angiography (PTC) is an alternative method used when Scott Schulte, University of Washington, Seattle, WA.)
ERCP is unsuccessful. Both studies are associated

copist may elect to initiate the case with an EUS, and Figure 11.11
- Endoscopic Ultrasound Image Showing Common Bile Duct Stone with
scopes in order to perform an ERCP while the patient Postacoustic Shadowing
is under the same session of sedation.
Biliary drainage and microscopy

Direct examination of gallbladder bile is more sen-
sitive than ultrasonography in diagnosing biliary
sludge, but is not widely available. Bile examination
under polarizing or light micro-scopy may be useful
in the evaluation of patients with suspected sludge
or stones and a nondiagnostic ultrasound. Many dif-
ferent protocols for bile microscopy have been de-
scribed. It is essential that gallbladder bile, rather
than hepatic or ductal bile, be obtained to maximize
sensitivity for detecting sludge.
Treatment for Gallstone-Related Disorders
Laparoscopic cholecystectomy Gb, gallbladder; cbd, common bile duct. (Courtesy of Dr. Michael Saunders, University
Laparoscopic cholecystectomy has become the stan- of Washington, Seattle, WA.)
dard of care in management of most gallstone-relat-
ed disorders. It has become clear over time that there
is a substantial learning curve associated with lapa- or cholangiography. The risk of bile duct injury may
roscopic surgery. With experience, however, overall be reduced by routine use of intraoperative cholangi-
complication rates are comparable to those of stan- ography. Endoscopic treatment using combinations
dard open cholecystectomy. of sphincterotomy, nasobiliary tube drainage, and
Conversion from a routine laparoscopic cho- biliary stent placement are successful in facilitating
lecystectomy to an open procedure is necessary in leak closure without operative intervention in >90%
<5% of cases. This occurs primarily when the anato- of cases.
or adhesions, or if excessive bleeding occurs. Patients Nonoperative treatment

who are in the last trimester of pregnancy or with In the 1980s, many nonsurgical treatments for gall-
suspected gallbladder perforation are not candidates stone disease, including dissolution therapy and ex-
for laparoscopic cholecystectomy. End-stage liver tracorporeal shock wave lithotripsy, were evaluated.
disease with portal hypertension, severe coagulopa- However, stone recurrence is high following any non-
thy, and suspected gallbladder malignancy are rela- operative treatment, since the original predisposing
tive contraindications. factors are left intact. This problem, in conjunction
Complications from laparoscopic cholecystec- with the advent of laparoscopic cholecystectomy, has
tomy occur in approximately 1% of cases overall, led to a decline in the use of nonsurgical alternatives.
with bile duct injury in <0.5% of patients. Mortality Nonoperative therapy now is limited to a highly se-
rates <0.07% have been observed. Bile leaks after lected group of patients.
laparoscopic cholecystectomy most commonly oc-
cur from accessory ducts or the cystic duct remnant. Oral bile acid dissolution
Diagnosis can be made by hepatobiliary scintigraphy Ursodeoxycholic acid is the most commonly used bile
acid for this indication. It is thought to act by reduc-

ing the secretion of cholesterol in bile and by shift- certain Native Americans, and, perhaps, patients
ing the phase equilibrium from micellar to lamel- with gallstones >3 cm. Prophylactic cholecystectomy
lar phases, which have higher cholesterol-carrying is currently not recommended for asymptomatic pa-
capacity, thereby preventing bile supersaturation. tients with diabetes mellitus. Patients with diabetes
Only 15% of patients with symptomatic, uncompli- mellitus develop symptomatic disease in 15% of cas-
cated stone disease are potential candidates for this es over a 5-year period, like nondiabetic patients. In
therapy. Prospective patients should undergo oral addition, no difference in complication and mortality
cholecystography or hepatobiliary scintigraphy to rates between patients with or without diabetes has
document cystic duct patency and adequate gallblad- been reported.
within the gallbladder and measure <1 cm. Pigment- Symptomatic stones
The decision to proceed with cholecystectomy should
therapy. Dissolution rates ranging from 60% to 90% be individualized, but given the high risk of recur-
can be obtained in appropriate candidates. Unfortu- rent biliary colic and gallstone complications, most
nately, stones will recur in nearly half the patients patients should be referred for cholecystectomy. For
within 5 years of therapy. Moreover, bile acid treat- patients who wish to undergo surgery, a laparoscopic
ment is costly and lengthy, often requiring at least cholecystectomy is usually recommended.
6–12 months to complete. Currently, the main role
for ursodeoxycholic acid in gallstone management is
Acute cholecystitis
Most physicians agree that early surgery is indicat-
the prevention of gallstones during periods of rapid
ed once the diagnosis of acute cholecystitis is secure
weight loss.
and the patient’s condition has been adequately
stabilized. However, the choice of a laparoscopic or
open cholecystectomy depends to a large extent on
Optimal Management
the surgeon’s experience. Many physicians advocate
Cholelithiasis is diagnosed in a variety of clinical cir- the laparoscopic approach for acute cholecystitis.
cumstances. A patient may be asymptomatic, have a Selected patients are admitted to the hospital, start-
history of one or more uncomplicated biliary pain
episodes, or have complications of acute cholecys- to surgery within 24–48 hours. Under one-third of
titis, gangrene, jaundice, or even gallbladder cancer. the cases managed in this fashion have to be con-
- verted to an open cholecystectomy for technical rea-
cal circumstances that are present. sons. For patients who have a major complication
such as a perforation, an urgent open laparotomy
Asymptomatic stones should be performed. A percutaneous cholecystos-
Adult patients with silent or incidental stones should
tomy should be considered for hospitalized patients
be observed and managed conservatively regardless
with acute cholecystitis who are at excessive risk for
of age or gender. The natural history of gallstones
surgery.
in these patients is generally benign, and the risk
of a major complication is low. Moreover, warning Choledocholithiasis
symptoms of biliary colic usually arise before a seri- Increasing age, serum bilirubin, AST, alkaline phos-
ous complication occurs, and there is no evidence to phatase, and a dilated common bile duct are clinical
suggest that prophylactic cholecystectomy reduces predictors of common bile-duct stones in patients
morbidity or mortality. The potential exceptions to with gallstones. Options for management of choledo-
cholithiasis include laparoscopic common bile duct
groups thought to be at higher risk for the develop- exploration and stone extraction at the time of cho-
ment of gallbladder carcinoma, such as individuals lecystectomy or by the use of preoperative or post-
operative ERCP with sphincterotomy (Figure 11.12). ledocholithiasis and its complications, the chances
The choice of technique depends on local expertise. for a successful clinical outcome are enhanced by
Common duct stones can be removed endoscopically multidisciplinary participation and input. Any rec-
in 90–95% of patients in expert hands. Endoscopic ommendations regarding the management of sus-
sphincterotomy alone can be considered in patients
who are either unable or unwilling to undergo cho- largely on the availability of appropriate radiologic,
lecystectomy. However, endoscopic sphincterotomy surgical, and endoscopic expertise. In cases of mild
without subsequent cholecystectomy may be asso- gallstone pancreatitis, early cholecystectomy (i.e.
ciated with an unacceptably high risk of recurrent during the initial hospitalization) is safe and pre-
symptoms or complications.20 Thus in most patients, vents future admissions for recurrent pancreatitis.21
endoscopic sphincterotomy should be accompanied
gallstones. Rare Complications of Gallstones

If the liver enzyme values are only mildly ele-
Figure 11.12
vated and there is only mild-to-moderate suspicion
Endoscopic Retrograde Cholangiogram Showing Filling
of common duct stones, many physicians proceed
Defect within the Common Bile Duct (thick arrow),
directly to laparoscopic surgery with intraoperative
Representing Common Bile Duct Stone
cholangiography, or perform pre-operative MRCP. If
a common duct stone is discovered at the time of the
operation, the management options to be considered
include laparoscopic stone extraction, conversion to
an open common duct exploration, or postoperative
ERCP.
Occasionally, large common bile duct stones
that cannot be cleared endoscopically are encoun-
tered. In these cases, options include surgical man-
agement, a repeated attempt at endoscopic removal,
and endoscopic biliary stenting. A second attempt at
endoscopic removal is often successful. Such stones
often can be extracted after fragmentation with lith-
otripsy baskets or intraductal electrohydraulic lith-
otripsy. Endoscopic stenting has been used in some
patients for long-term management. Complications
are not infrequent with this option, and include re-
current biliary colic, pancreatitis, stent migration,
and stent occlusion with subsequent cholangitis.
However, stent therapy in conjunction with oral bile
acid therapy can reduce the size of large stones and
facilitate subsequent extraction.
If choledocholithiasis is complicated by cholan-
gitis, prompt intervention is necessary. Antibiotics
should be started immediately, and plans made for
biliary decompression, usually by ERCP. Appropriate
antibiotics include mezlocillin, piperacillin, ampicil- There is also a filling defect in the cystic duct, which likely represents
a stone (thin arrow). (Courtesy of Dr. Scott Schulte, University of
Washington, Seattle, WA.)
Whichever treatment option is pursued for cho-
Emphysematous cholecystitis results from infection combination of bile infection, malnutrition or dietary
with gas-forming organisms in diabetic or elderly pa- factors, biliary stasis, and possibly parasitic infesta-
tients in the absence of gallstones. Emergency antibi- tion. b-Glucuronidase can be inhibited by glucarolac-
otic coverage and prompt cholecystectomy are recom- tone, whose levels are increased in patients with a
mended. low-protein and low-fat diet. The role of infection by
, which results from gall- parasites such as Ascaris lumbricoides or Clonorchis
stone erosion through the gallbladder wall, most com- sinensis is controversial. Although these parasites are
widespread in the developing world, primary intra-
the colon. Clinical presentation is similar to acute cho- hepatic stones are found primarily in Southeast Asia.
lecystitis. This diagnosis should be suspected when This suggests that factors in addition to parasitic in-
radiographic evidence for pneumobilia is present. fection are needed for these stones to form. Primary
Duodenal obstruction caused by a gallstone is known intrahepatic stones can also occur in patients with be-
as Bouveret’s syndrome. nign biliary strictures.
Gallstone ileus can present as acute small bowel Patients present with frequent, recurrent epi-
obstruction when gallstone diameter is >25 mm. The sodes of cholangitis. Radiologic studies such as ultra-
ileocecal valve is the most common site of obstruc- sonography or CT showing biliary ductal dilation and
- ductal stones are essential in establishing the diagno-
sociation with dilated small bowel are suggestive of sis. Often, the central ducts and the left intrahepatic
gallstone ileus. Delays in diagnosis are associated with ducts are disproportionately dilated, with acute taper-
mortality rates of 20%. ing of the more peripheral ducts. CT is also useful to
- exclude concomitant hepatic abscesses. Cholangiogra-
pression of the common bile duct from gallstone im-
paction in the gallbladder neck or cystic duct. Jaundice During the acute episode, most patients will re-
and biliary obstruction can result. Cholangiography spond to intravenous antibiotics and supportive care.
will demonstrate extrinsic compression of the com- If conservative management fails, patients may re-
mon bile duct. Cholecystectomy is the treatment of quire emergent decompression by ERCP, percutane-
choice. ous drainage, or surgery. To prevent future attacks,
Porcelain gallbladder - surgery may be indicated, especially for patients with
gallbladder stones, stones in the intrahepatic ducts,
gallbladder carcinoma is a known complication in as or disease localized to the left lobe of the liver. The
many as 20% of cases. Prophylactic cholecystectomy type of procedure performed depends on the extent
is indicated. and location of any stones or strictures. Endoscopic
sphincterotomy and stone extraction may be useful
in selected patients. Patients with severe primary in-
Primary Intrahepatic Stones (Recurrent trahepatic cholelithiasis may progress to cirrhosis and
Pyogenic Cholangitis) may require liver transplantation.
Primary intrahepatic stones, seen primarily in south-

east Asian countries, can lead to the syndrome of re-
Salmonella typhi, Gallstones, and the
current pyogenic cholangitis.22 Primary intrahepatic
stones are generally calcium bilirubinate or mixed
Gallbladder
stones. They are typically brown pigment “earthy” , the causative agent of typhoid fever,
stones containing calcium salts of fatty acids (from can cause acute cholecystitis and, in a subset of pa-
hydrolysis of lecithin by bacterial phospholipases) as tients, can persist in the gallbladder for years in an as-
well as calcium salts of bilirubin (from hydrolysis of ymptomatic carrier state. Chronic persistent carriage
bilirubin by bacterial b-glucuronidase). of in the gallbladder often occurs in the pres-
The pathogenesis of these stones likely involves a
a likely mechanism allowing persistent carriage of prises (1) type I SOD (biliary-type pain, AST or alka-
this organism.23 Antibiotic therapy is ineffective in line phosphatase >2–3 times the upper limit of normal
this situation; cholecystectomy is the most effective -
treatment for chronic carriage in patients with trahepatic biliary ducts); (2) type II SOD (biliary type
gallstones. Chronic carriage of in the gallblad- pain and 1 or 2 associated criteria); and (3) type III
der is associated with an elevated risk for gallbladder SOD (biliary-type pain alone).
carcinoma.24 Treatment is based on categorization from the
Medical therapy with nifedipine should initially be at-

Acalculous Disorders tempted for type III and mild-to-moderate type II SOD.
Type I and type II SOD patients with severe symptoms
of the Biliary Tract should be referred for ERCP. Type I patients nearly
universally respond to endoscopic sphincterotomy,
and manometry is not required. The majority of pa-
Sphincter of Oddi Dysfunction tients with type II SOD and abnormal manometry will
Sphincter of Oddi dysfunction (SOD) is an acalculous have symptom relief after sphincterotomy. Lower suc-
disorder associated with biliary-type pain with or cess rates (55–60%) are observed with type III SOD,
without abnormal liver tests or recurrent pancreatitis. even with abnormal manometry; this subset of pa-
Histologic changes including muscular hypertrophy, tients likely has visceral hyperalgesia and foregut dys-
motility syndromes that are not addressed by sphinc-
terotomy.25 The risk of complications from endoscopic
Adult and pediatric age groups appear suscep- sphincterotomy is 2–33 times greater in patients with
tible. Characteristic features include female gender, known or suspected SOD. Pancreatitis occurs in 25%
age in the 4th and 5th decades of life, and recurrent and is severe in 1–3%; the incidence and severity is
abdominal pain after cholecystectomy. Less than 50% reduced with pancreatic duct stent placement and this
of patients develop serum hepatic or pancreatic bio- should be placed in all patients undergoing SOD ma-
chemical parameter elevations. nometry. Surgical biliary sphincterotomy and sphinc-
Upper gastrointestinal tract diseases should be teroplasty yields excellent pain relief in 75% of select
excluded. Measurement of hepatic and pancreatic cases for up to 5 years, with low morbidity and mor-
biochemistries during episodes of biliary or pancre- tality. Persistent pain after successful sphincterotomy
may be from residual SOD, chronic pancreatitis, or
elevations in hepatic biochemistries suggest cho- functional GI disease.
ledocholithiasis or hepatic disease rather than SOD.
Imaging with abdominal ultrasonography and/or CT
to exclude structural biliary and pancreatic disease Gallbladder Dysmotility
is required. SOD is diagnosed manometrically dur- Gallbladder dysmotility, also known as chronic acalcu-
ing ERCP when basal sphincter pressures exceed 40
mm Hg. Hepatobiliary scintigraphy can be used as a fraction less than 35%, and is a poorly understood
screening test to determine whether there is delayed clinical entity.26 It may be diagnosed by biliary scintig-
biliary duct transit of the radiotracer.18 If such a delay raphy with CCK infusion. The clinical manifestations
is demonstrated, then ERCP with sphincterotomy can of gallbladder dysmotility are not well understood,
- but it is often suspected in patients with biliary-type
versely, a normal scintigraphy would support a non- pain who do not have gallstones on ultrasonography.
biliary source for the patient’s pain. These patients frequently undergo cholecystectomy,
The Milwaukee system has been developed to and chronic cholecystitis is present histologically in
classify patients with possible SOD. This system com- many, but not all, cases.
The natural history of patients with gallblad- age of anaerobic and gram-negative bacteria is re-
der dysmotility is not well described. Symptoms of
biliary-type pain will resolve in 25–40% of patients preferred but may be contraindicated in severely ill
without treatment. In patients who undergo chole- patients. Decompression by percutaneous cholecys-
cystectomy, symptoms resolve in 60–100% post- tostomy tube placement is often effective.
operatively. However, symptoms may also improve
following treatment for other upper gastrointestinal
Gallbladder Polyps
recommendations about treatment for this entity.
The prevalence of gallbladder polyps is estimated at
1–4%, and the vast majority of these polyps (95%)
are benign.28 Cholesterol polyps are the most com-
Acute Acalculous Cholecystitis -
- bladder adenomas (<1%). The frequency of associa-
tion between gallbladder adenomas and carcinoma
and occurs in 5–10% of patients with cholecystitis.27 is unknown. Histological features of carcinoma are
Acalculous cholecystitis usually occurs in the setting principally found in gallbladder adenomas of at least
of major surgery, critical illness, extensive trauma, or 12 mm. Ultrasonography can help distinguish polyps
burn-related injury. Patients are predominantly male from cholelithiasis.
and older than 50 years of age. Many are receiving Less than 10% of patients with polyps will devel-
total parenteral nutrition (TPN), where bile inspissa- op symptoms from the polyps alone or with gallblad-
- der carcinoma over 15 years. For patients with pol-
tions with salmonella or cytomegalovirus infections yps <10 mm in diameter, no associated cholelithiasis,
in immunocompromised hosts, and systemic vas- and age <50 years, cholecystectomy is generally not
culitides (polyarteritis nodosa, systemic lupus ery- indicated in the absence of biliary symptoms. Polyps
thematosus), are also known to be causes of acute between 10–18 mm in diameter have a small but ap-
acalculous cholecystitis. The pathogenesis probably preciable risk of carcinoma. Thus, cholecystectomy is
involves a combination of biliary stasis, chemical in- recommended in good operative candidates. Patients
Symptoms normally associated with gallstone- risk of carcinoma and require cholecystectomy. Pa-
related cholecystitis may be absent, especially in el- tients with PSC have an increased risk of cancer and
derly patients. Unexplained fever and/or hyperamy- polyps of any size should be considered for cholecys-
lasemia should prompt the exclusion of acalculous tectomy. Laparoscopic cholecystectomy is the treat-
cholecystitis. Complications in acalculous cholecysti- ment of choice unless the suspicion of malignancy
tis develop more rapidly than in calculous cholecys- is high, in which case an open exploration should be
titis. Approximately 50–70% of patients with acalcu- considered.
lous cholecystitis may have gangrene, empyema, or
perforation of the gallbladder at the time of surgical
exploration. Mortality rates of 10–50% are observed. Biliary Cysts
For this reason it is important to suspect and pursue
Cysts can occur throughout the extrahepatic and in-
an early diagnosis. Ultrasonography demonstrating
trahepatic biliary tree. They are congenital anoma-
lies, found predominantly in females, with an inci-
highly suspicious for acalculous cholecystitis. Use of
dence that varies widely throughout the world. Cysts
CT is not practical for ill patients requiring intensive
are primarily a disease of children and young adults,
care. False positive results from prolonged fasting
with up to 90% of patients diagnosed before the age
limit the accuracy of hepatobiliary scintigraphy.
of 30. Although cysts are anatomically variable, they
Supportive treatment including antibiotic cover-
have many clinical features in common. Treatment of the other types of biliary cysts should be
- primarily surgical, as medical therapy has been asso-
portant in planning operative management (Figure ciated with high mortality rates. Death with medical
11.13). Type I cysts are the most common and rep- therapy has been caused by cyst rupture, cholangitis,
resent 75–85% of reported cases. Type V cysts are carcinoma, or cirrhosis. The preferred surgical man-
considered to be synonymous with Caroli’s disease. agement for type I or type IV cysts is cyst excision
Biliary cysts may present with either of two typi- and reconstruction of the extrahepatic biliary tree
cal syndromes, depending primarily on the patient’s via choledochojejunostomy or hepaticojejunostomy.
age. In infancy, jaundice is the most common sign, Type II cysts should be excised, while treatment for
and may be accompanied by abdominal pain, vom- type III cysts varies depending upon the anatomy.
iting, failure to thrive, hepatomegaly, or a palpable Treatment of intrahepatic cysts (type IVA or V) de-
abdominal mass. Complications may include biliary pends upon the extent of liver involvement. Long-
cirrhosis and portal hypertension. This presentation term postoperative follow-up is recommended, since
may be identical to that of biliary atresia. In the non- recurrent cholangitis, stone formation, strictures,
infantile form, the most common presenting symp- and pancreatitis have been reported. Cyst excision
tom is epigastric pain. Intermittent jaundice and lowers but does not completely eliminate the risk of
recurrent cholangitis may occur. Abdominal masses,
cirrhosis, and portal hypertension are less common Figure 11.13
than in the infantile form. Other, less common pre- The Five Types of Choledochal Cysts
sentations include carcinoma associated with the
structures by the cyst.

Reported complications of biliary cysts include
recurrent cholangitis, stone formation, stricture for-
mation, pancreatitis, biliary cirrhosis, liver abscess,
and cyst rupture. However, the most ominous com-
plication is malignancy, which occurs primarily in
patients age >10. Carcinomas, most commonly ad-
enocarcinoma, can occur in the cyst wall or in the re-
mainder of the biliary or pancreatic ducts. The prog-
nosis after development of a malignancy is generally
poor.
Diagnosis of biliary cysts requires a high level of
suspicion. Ultrasonography is the best initial diag-
nostic technique. Hepatobiliary scintigraphy char-
acteristically shows a dilated biliary tract and tracer
obstruction. CT and MRI may be useful, especially in

older patients. Percutaneous cholangiogram or ERCP
may provide more detailed anatomic information for
planning operative approaches. Type Ia cysts are considered choledochal cysts in the narrow sense. Type Ib and Ic
Type III cysts are also known as choledochoceles. represent segmental or diffuse fusiform dilation of the common bile duct, respectively.
Type II cysts are diverticula in the extrahepatic ducts, and type III cysts are
These are differentiated from the other types of cysts
choledochoceles. Type IVa cysts consist of multiple intra- and extrahepatic cysts, while
by their lack of premalignant potential and their abil- type IVb are multiple cysts of the extrahepatic ducts only. Type V cysts consist of single
ity to be cured by endoscopic biliary sphincterotomy. or multiple cystic dilations of the intrahepatic ducts.
malignancy, since cancer may develop in other por- survival rates after liver transplantation in excess of
tions of the hepatobiliary tree. 90% and 80%, respectively, have been reported.
Choledochal cysts can occur in the presence of PSC should be suspected in a man with chronic
pancreatobiliary maljunction (PBM) in which the -
tory bowel disease. Unlike primary biliary cirrhosis
found outside the duodenal wall and forms an abnor- (PBC), PSC has no available serum marker for non-
mally long common channel. In this condition, chron- invasive diagnosis. 70–80% of PSC patients will test
positive for antineutrophil cytoplasmic antibodies,
because the hydrostatic pressure within the pancre- -
atic ductal system is higher than that in the biliary mains unknown. ERCP has traditionally been consid-
ductal system. A consequence of such exposure is the ered the gold standard for diagnosing PSC, although
development of cholangiocarcinoma and gallbladder MRCP has a similar diagnostic accuracy and should
cancer. PBM can also occur in the absence of chole- be used instead of ERCP whenever possible. Segmen-
dochal cysts, in which case the gallbladder mucosa is
still considered premalignant. In these patients, pro- bile ducts with associated saccular dilatation (“beads
phylactic cholecystectomy is recommended.29
Twenty percent of patients will have only intrahepat-
Primary sclerosing cholangitis ic and hilar bile duct involvement.
Primary sclerosing cholangitis (PSC) is character-
ized by diffuse intra- and/or extrahepatic bile-duct obliteration, and ductopenia are the dominant histo-
30
Chronic bile duct ob-
struction eventually leads to biliary cirrhosis, hepatic occur in varying stages of other conditions including
failure, and complications from portal hypertension. PBC, autoimmune hepatitis, and chronic extrahepatic
Seventy percent of PSC patients are men with an bile duct obstruction. Liver biopsy is helpful for judg-
average age of 40 at diagnosis. Of PSC cases, 70–80% ing the stage of disease activity in PSC.
for PSC. Ursodeoxycholic acid at doses of 13–15 mg/

bowel disease develop PSC. Immunologic and genetic kg/day appears to lead to hepatic biochemical im-
alterations have been cited as pathogenic factors for
PSC. or survival. Ursodeoxycholic acid may be effective in
Asymptomatic elevations in serum liver bio- patients with PSC-associated stone disease.
chemistries or symptoms including fatigue (75%), Clinical cholangitis in PSC is more common in
pruritus (70%), and hepatomegaly (50%) are com- patients with a previous history of biliary tree ma-
monly seen. Elevations in serum alkaline phospha- nipulation. Once it is suspected, empiric intravenous
tase (3–5 times the upper limits of normal) and a antibiotic coverage for gram-negative and anaerobic
less pronounced increase in serum aminotransfer- bacteria should be initiated, and diagnostic imaging
ases are common. Jaundice (60%) and weight loss and/or therapeutic cholangiography should be con-
(40%) are suspicious for advanced hepatic disease, sidered in order to exclude biliary obstruction. The
dominant stricture, or bile duct cancer. Fever and presence of a dominant biliary tract stricture is as-
abdominal pain suggest bacterial cholangitis. Per- sociated with sudden asymptomatic elevations in
sistent elevation in total bilirubin is worrisome for serum alkaline phosphatase and/or bilirubin. Bal-
advanced disease.
Median survival from the time of diagnosis in or radiological methods often provides satisfactory
PSC ranges from 9 to 12 years. Liver transplanta- results. Long-term endoscopic stenting to prevent
tion is the only life-extending therapy available for recurrent stricture formation is not supported by
patients with end-stage PSC. One-year and 3-year controlled data. Brush cytology and/or forceps biop-
sies of all dominant strictures are required in order bowel disorder (IBD) in the former. This condition is a
to evaluate for the presence of cholangiocarcinoma, variant of IgG4-related systemic disease, with autoim-
though they have only modest sensitivity. Rapid clin- mune pancreatitis being the best-studied manifesta-
ical decompensation with jaundice and marked se- tion. Serum levels of IgG4 are elevated, and intra- and
rum hepatic biochemical elevations is highly suspi- extrahepatic biliary strictures are found on cholangi-
cious for super-imposed cholangiocarcinoma, which ography, with characteristic multifocal IgG4-contain-
occurs in 5–30% of patients (Figure 11.14). The
overall median survival is approximately 5 months ducts. IgG4-related cholangitis/pancreatitis with distal
once cholangiocarcinoma is diagnosed. biliary duct or pancreatic duct strictures can, if misdi-
agnosed as malignant, lead to surgical resection.31
Biliary strictures
The possible causes of biliary strictures include
postsurgical damage, chronic pancreatitis, infection Biliary Ductopenic Disorders
-
Paucity of interlobular bile ducts can occur as a re-
virus (HIV) cholangitis, and malignancy. Post–liver
with the diagnosis being made in infancy. (1) Syn-
transplant strictures commonly occur at the ductal
dromic paucity (also called Alagille syndrome) is an
anastomosis; multiple intra- and extrahepatic stric-
autosomal dominant disorder due to mutations in
tures commonly develop following hepatic artery
the JAG1 gene, which encodes the Jagged 1 ligand for
thrombosis. Treatment of post-transplant strictures
the Notch family of receptors. Intrahepatic cholesta-
is with endoscopic dilation and stenting or retrans-
sis and biliary hypoplasia are characteristic, with
plantation if underlying severe ischemia is present.
patients developing pruritus and hepatomegaly. Ex-
Pancreatic cancer is the most common cause of ma-
trahepatic manifestations include congenital heart
lignant biliary obstruction, and biliary drainage may
be needed for palliation.
a characteristic triangular face with a broad forehead
If biliary obstruction is prolonged, secondary
and a pointed chin. Cirrhosis occurs rarely, and the
hepatic parenchymal damage may occur. This, in
cholestasis is mild. (2) Nonsyndromic paucity of the
bile ducts is not due to a known genetic defect. Se-
bile duct obstruction, may result in secondary bili-
vere cholestasis progressing to biliary cirrhosis is
ary cirrhosis. The risk of developing cirrhosis varies
characteristic.
with the completeness and duration of obstruction.
Interlobular ductopenia can also develop in
Chronic pancreatitis with associated CBD stricture
and chronic obstruction may be associated with sec-
of conditions, including PSC, PBC, graft-versus-host
ondary biliary cirrhosis. Common bile duct stones
disease, liver allograft rejection, and drug-induced
rarely cause obstruction of this duration and sever-
liver disease. An idiopathic variant is also described.
ity unless they are intra-hepatic and intractable (for
Biliary atresia can occur, and is diagnosed in
example, in recurrent pyogenic cholangitis). Liver bi-
neonates with persistent jaundice, pale stools, and
opsy should be considered and even if the patient has
dark urine that are found to be due to a conjugated
cirrhosis, every effort should be made to relieve the
obstruction, usually with surgery, since reversal of
cholangiopathy affects varying segments of the intra-
portal hypertension and secondary biliary cirrhosis
and extrahepatic biliary systems. Timely diagnosis
can occur in some.
and referral for Kasai portoenterostomy is critical,
IgG4-related cholangitis shares certain radiologic
with up to 60% of infants achieving biliary drainage,
and clinical features with PSC, although two notable
and 80% of these surviving to adolescence. Failure
differences are responsiveness to corticosteroid ther-
-
plantation, and biliary atresia remains the major
Figure 11.14 cases with milder increases in serum transaminases.

Endoscopic Retrograde Cholangiogram with Representative Normal biochemical parameters are found in 20% of
Images of High-Grade Stricture in Right Hepatic Duct due to patients. Ultrasonography or CT imaging can detect
Cholangiocarcinoma in Primary Sclerosing Cholangitis biliary duct dilatation in ~80% of cases.
Cholangiography most commonly shows papil-
lary stenosis with intrahepatic sclerosing cholangi-
tis. Other variations include sclerosing cholangitis
without papillary stenosis, papillary stenosis alone,
or long extrahepatic strictures. Treatment is direct-
ed at biliary tree abnormalities as well as identi-
alone, endoscopic sphincterotomy has been associ-

ated with symptomatic improvement. Up to half of
-
tunistic pathogen.
Neoplastic Disorders of the

Biliary Tract
Gallbladder Carcinoma
Although rare (1–2% in resected gallbladder speci-
The characteristic “beads-on-a-string” appearance of primary mens), gallbladder cancer has a high mortality rate
sclerosing cholangitis is observed as well. (Courtesy of Dr. and accounts for one-third to one-half of gallstone-
Todd Baron, Mayo Foundation, Rochester, MN.) related deaths in the United States. Gallstones are
present in 80% of individuals with gallbladder can-
cer, although it is not clear that gallstones themselves
indication for liver transplantation in the pediatric are the causal factor. For some groups with high rates
population. Even with a successful establishment of of gallbladder cancer, such as Pima Indians and pa-
- tients with gallstones in the setting of a
sive cholestasis and cirrhosis that necessitates liver typhi carrier state,23 the risk of malignancy may in-
transplantation.32
symptomatic gallstones.
Histologically, the majority of gallbladder can-
HIV Cholangiopathy cers are adenocarcinomas of scirrhous or papillary
HIV-associated biliary tract disease resembles scle- form. Clinical manifestations range from abdominal
rosing cholangitis with papillary stenosis. A CD4 T pain to unexplained weight loss and jaundice. A pal-
cell count <50/mm3 is a risk factor for HIV cholan- pable right upper quadrant mass is often reported.
giopathy. Diarrhea is usually present and is related Surgical resection offers the only substantial chance
to small-intestinal involvement with characteristic for cure, especially if cancer is found incidentally at
pathogens such as . The cholecystectomy for gallstone-related disease. Ra-
most common presentation is epigastric and/or diation and chemotherapy are associated with poor
right upper quadrant abdominal pain and fever. Se- outcomes in nonresectable cases. Five-year survival
rum alkaline phosphatase is elevated in >75% of rates are reported at <5%.
Cholangiocarcinoma hepaticojejunostomy. Lesions in the mid-to-distal

bile duct may require pancreaticoduodenectomy
Intrahepatic cholangiocarcinomas are being diag-
(Whipple’s procedure). A 5-year survival rate of 80–
nosed with increasing frequency, whereas the in-
85% can be achieved with liver transplantation in
cidence of extrahepatic cholangiocarcinomas is
selected patients with perihilar cholangiocarcinoma
decreasing.33 The majority of neoplasms (90%) are
who complete radiation and chemotherapy in a spe-
-
cialized treatment protocol.34
rhous nature. Approximately 60–70% arise at the
If the tumor is unresectable, therapy is palliative,
bifurcation of the hepatic ducts and are known as
with endoscopic or percutaneous stent placement or
Klatskin tumors; 20–30% arise in the distal common
surgical bypass to relieve jaundice and pruritus. Ex-
bile duct; and 5–10% arise within the liver. Risk fac-
pandable metal stents may provide longer periods of
-
stent patency and palliation of symptoms than stan-
and s), certain chemical ex-
dard plastic stents.
posures, congenital biliary cysts, pancreaticobiliary
Other treatment modalities have shown limited
maljunction, intrahepatic biliary stones, and primary
sclerosing cholangitis.
using combination cisplatin and gemcitabine was
The average age at diagnosis of cholangiocarci-
shown to prolong survival by ~3 months compared to
noma is 60, with a slightly higher incidence in men
gemcitabine alone in unresectable locally advanced
than women. The most common symptoms and signs
or metastatic cholangiocarcinoma.35 Radiation ther-
include right upper quadrant abdominal pain, weight
apy may provide limited palliation. Historically, the
loss, pruritus, jaundice, and occasionally hepatomeg-
overall prognosis has been poor, with less than 5%
aly. Patients may occasionally present with cholangi-
of patients surviving 5 years. However, these tumors
tis. The gallbladder may be palpable and nontender
are generally slow-growing, and longer-term sur-
in patients with a distal common bile duct tumor
vival is possible with palliative treatment. Recently,
(Courvoisier’s sign).
photodynamic therapy has been shown to improve
-
palliation and survival in patients with advanced
tion, with increases in the serum alkaline phospha-
cholangiocarcinoma.36
tase and bilirubin levels. Serum transaminases may
also be moderately increased. Elevated serum levels
of CA 19-9 are seen in about half of patients. Ultra-
Ampullary Carcinoma
sonography is often the initial diagnostic test, and
shows dilatation of the intra- and extrahepatic bile Adenocarcinoma is the most common malignancy
ducts to the level of the obstruction. CT imaging may involving the ampulla of Vater. Risk factors include
familial adenomatous polyposis, though sporadic
uncommon. MRCP has been advocated as a more cases are common. Clinical manifestations include
reliable imaging choice than CT, as it provides a de- jaundice, pruritus, bleeding, and acholic stools. Chol-
tailed 3-D image of the intrahepatic and extrahepatic angitis or pancreatitis from malignant obstruction
biliary tree.33 are other uncommon presentations. Imaging stud-
with ERCP or PTC (Figure 11.15). Brush cytology or ies typically reveal intra- and extrahepatic bile duct
direct needle aspiration of intraluminal masses may dilatation, with or without a duodenal mass. ERCP is
-
The only curative treatment for cholangiocarci- sualization of the ampulla. Ampullary adenomas and
noma is surgical resection, but only 25% of tumors early carcinomas may be amenable to endoscopic or
are resectable at the time of diagnosis. The surgical local surgical resection (ampullectomy). For patients
procedure performed varies depending on the lo- with ampullary carcinoma, the treatment of choice
cation of the tumor. Proximal tumors may require is Whipple’s resection. Five-year survival rates vary
resection of part of the liver and reconstruction via from 15% to 60%. Palliation of malignant jaundice
Figure 11.15
Endoscopic Retrograde Cholangiogram with Representative
cretion by terminal ileum enterocytes can lead to
Images of Cholangiocarcinoma
dysfunctional feedback inhibition of CYP7A1, the
rate limiting enzyme in bile acid synthesis, in the
liver. The result is an expanded bile acid pool that
allows increased amounts of bile acids to reach the
colon. This is postulated to account for idiopathic
bile acid malabsorption as a cause for chronic diar-
rhea.
Factors essential for the formation of cholesterol
gallstones are: (1) Hepatic secretion of bile super-
saturated with cholesterol (lithogenic bile); (2) stasis
of bile within the gallbladder; and (3) nucleation of
cholesterol molecules to form crystals.
Risk factors for cholesterol gallstone formation in-
clude: obesity, female gender, parity, maternal fam-
ily history, ethnicity, increasing age, rapid weight
loss, ileal disease, lipid abnormalities, and medica-
tions (e.g. contraceptives, estrogens, TPN, lipid low-
ering agents, and fibric acid derivatives).
Biliary sludge and/or gallstones develop after di-
The malignancy appears as a high-grade stricture in the dis- etary restriction and bariatric surgery in 25% and
tal common bile duct (thin arrow). The proximal biliary tree is 50% of obese patients, respectively. Also, TPN
markedly dilated (thick arrow). (Courtesy of Dr. Scott Schulte, leads to gallstones in up to 45% of patients after
University of Washington, Seattle, WA.) 3 months.
Natural history of asymptomatic gallstones: New
onset biliary pain developed at a rate of 2% per year
can be achieved by ERCP with sphincterotomy and/
for the first 5 years.
or stent placement. Response to radiation and che-
Natural history of symptomatic gallstones: Once an
motherapy is poor.
episode of biliary colic has occurred, there is a high
risk of repeated attacks. More than 90% of compli-
cations (e.g. cholecystitis, cholangitis, or pancre-
Pearls and Pitfalls atitis) are preceded by symptoms of uncomplicated
biliary colic.
for the Board Exam If gallstones remain in the common bile duct, they
Interference with the bile ductal blood supply (e.g. are likely to give rise to complications. Whether
after bile duct surgery or hepatic artery thrombosis), clinically overt or not, common bile duct stones are
commonly leads to bile duct strictures. frequently associated with infected bile.
With extensive ileal disease or resection (e.g. A common complication of choledocholithiasis is
Crohn’s disease), bile acid loss increases and the cholangitis, which is rare in malignant obstruction.
bile acid pool diminishes. The result is a diminished The typical clinical picture of acute cholangitis in-
cholesterol carrying capacity in bile and increased cludes biliary pain, jaundice, and chills and rigors
risk of gallstone formation. A diminished bile acid (Charcot’s triad). Patients may also be confused and
pool is also a cause of diarrhea (mild malabsorption) hypotensive (Reynolds’s pentad).
and steatorrhea (severe malabsorption). Mirizzi’s syndrome is extrinsic compression of the
Diminished fibroblast growth factor 19 (FGF19) se- CBD from gallstone impaction in the gallbladder
neck or cystic duct, resulting in jaundice and biliary hepatomegaly. Extrahepatic manifestations include
obstruction. Cholecystectomy is the treatment of congenital heart defects, notched butterfly verte-
choice. brae, eye defects, and a characteristic triangular
Antibiotic therapy is ineffective in patients with face with a broad forehead and a pointed chin.
asymptomatic carriage of Salmonella typhi in the Risk factors for cholangiocarcinoma include infec-
gallbladder, which is a risk factor for gallbladder tion by liver flukes (e.g. Opisthorchis viverrini), cer-
carcinoma. tain chemical exposures, biliary cysts, pancreatico-
Acalculous cholecystitis usually occurs in the setting biliary maljunction, intrahepatic biliary stones, and
of major surgery, critical illness, extensive trauma or PSC.
burns, TPN, salmonella infection, CMV infection,
and systemic vasculitides.
Unexplained fever and/or hyperamylasemia should Most Efficient Source Reviews
prompt exclusion of acalculous cholecystitis. 50-
70% of patients may have gangrene, empyema or for Examination Preparation
perforation at the time of surgery; hence, high index Gore RM, Thakrar KH, Newmark GM, Mehta UK, and
of suspicion and early diagnostic testing are essen- Berlin JW. Gallbladder imaging. In: Gallbladder
tial. If a patient too ill for surgery, percutaneous cho- Disease (Ko CW, editor). Gastroenterol Clin North
lecystostomy is often effective. Am, 2010; 39 (2): 265-287.
Type III biliary cysts, also known as choledocho- Yoo K-S and Lehman GA. Endoscopic management
celes, are differentiated from the other types of of biliary ductal stones. In: Gallbladder Disease (Ko
biliary cysts by their lack of premalignant potential CW, editor). Gastroenterol Clin North Am, 2010; 39
and their ability to be cured by endoscopic biliary (2): 209-227.
sphincterotomy. Treatment of the other types of bili- Mendes F, Lindor KD. Primary sclerosing cholangi-
ary cysts is primarily surgical. tis: overview and update. Nature Rev Gastroenerol
Pancreaticobiliary maljunction (PBM) is often seen Hepatol 2010: 7:611-619.
in patients with choledochal cysts. Chronic reflux of Khan SA, Davidson BR, Goldin RD, Heaton N, et al.
pancreatic juice into the bile ducts occurs because Guidelines for the diagnosis and treatment of chol-
the hydrostatic pressure is higher in the pancreatic angiocarcinoma: an update. Gut epub: 10.1136/
ductal system than in the biliary ductal system. A gutjnl-2011-301748; 2012.
consequence of such exposure is the development
of cholangiocarcinoma and gallbladder carcinoma. Acknowledgements
PBM can also occur in the absence of choledochal The author acknowledges the previous contributions to
cysts, in which case the gallbladder mucosa is still this revised chapter of Sum P. Lee, MD, PhD; Cynthia W.
considered premalignant; prophylactic cholecystec- Ko, MD; Thomas Trouillot, MD; and Jayant Talwalker, MD.
tomy is recommended.
IgG4-related cholangitis shares certain radiologic
and clinical features with PSC, although two notable
differences are responsiveness to steroids and the
References
1. Chiang JY. Regulation of bile acid synthesis: Pathways,
lack of association with IBD.
nuclear receptors, and mechanisms. J Hepatol 2004;
Syndromic paucity of interlobular bile ducts (Ala- 40:539–51. (A concise review of the molecular mecha-
gille’s syndrome) is an autosomal dominant disorder nisms of bile acid synthesis with an emphasis on the role
due to mutations in the JAG1 gene, which encodes of nuclear hormone receptors.)
the Jagged1 ligand of the Notch family of receptors. 2. Song KH, Li T, Owsley E, Strom S, Chiang JY. Bile acids
Intrahepatic cholestasis and biliary hypoplasia are activate fibroblast growth factor 19 signaling in human
hepatocytes to inhibit cholesterol 7alpha-hydroxylase
characteristic, with patients developing pruritus and
gene expression. Hepatology 2009; 1:297-305.
(This study describes a new signaling mechanism that 2001;121:118–23. (The first report of the identification of
provides feedback inhibition to the classical bile acid various species of oxidized forms of cholesterol (oxys-
pathway in hepatocytes, and thereby links luminal bile terols) in samples of human bile and gallstones. Higher
acid levels in the terminal ileum to hepatic bile acid pro- levels of oxysterols were found in pigment gallstones,
duction). in which bacterial DNA was also present. The authors
3. Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le postulated that biliary oxysterols result by the action of
Roux CW. A new mechanism for bile acid diarrhea: de- reactive oxygen species produced by inflammatory cells
fective feedback inhibition of bile acid biosynthesis. Clin in the setting of bacterial infection of bile.)
Gastroenterol Hepatol 2009; 7:1189-1194. 10. Ko CW, Sekijima JH, Lee SP. Biliary sludge. Ann Int Med
(Primary bile acid malabsorption causes chronic watery 1999;130:301–11. (A review of the biochemical, radiologic,
diarrhea that often is misdiagnosed as being functional. and clinical aspects of biliary sludge, with an emphasis
This paper provides a physiologic basis for this type of di- on its role in biliary colic, acute pancreatitis and acute
arrhea by demonstrating that patients with this condition cholecystitis. Clinical conditions and events associated
have defective signaling between the terminal ileum and with the formation of biliary sludge include rapid weight
the liver involving FGF 19, thereby leading to an expanded loss, pregnancy, ceftriaxone therapy, octreotide therapy,
bile acid pool and enhanced bile acid delivery to the co- and bone marrow or solid organ transplantation. A proto-
lon). col for the microscopic diagnosis of sludge is proposed.)
4. Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, 11. Wang DQ, Lee SP. Physical chemistry of intestinal absorp-
Jansen PL, Schaap FG. The human gallbladder secretes tion of biliary cholesterol in mice. Hepatology 2008;48:177–
fibroblast growth factor 19 into bile: towards defining 85. (This study in a mouse model provides evidence for
the role of fibroblast growth factor 19 in the enterobiliary the hypothesis that precipitation of cholesterol into crys-
tract. Hepatology 2012; 55:575-583. tals allows a more efficient means of cholesterol elimina-
(This paper shows that human gallbladder epithelial cells tion from the GI tract.)
synthesize and secrete FGF 19 into bile in quantities that 12. Diehl AK. Epidemiology and natural history of gallstone
are several orders of magnitude greater than that pro- disease. Gastroenterol Clin North Am 1991;20:1–19.
duced by ileal enterocytes. The functional significance (A review of the literature concerning the epidemiol-
of FGF 19 in bile remains to be defined). ogy and natural history of gallstone disease. The various
5. Zanlungo S, Rigotti A, Nervi F. Hepatic cholesterol trans- risk factors for gallstone formation are discussed, as
port from plasma into bile: implications for gallstone dis- are the data regarding markedly differing rates of gall-
ease. Curr Opin Lipidol 2004;15:279–86. (A review of the stone prevalence in various ethnic groups such as Na-
mechanisms of hepatic cholesterol transport including tive Americans of the Southwest. The point is made that
those involved in biliary cholesterol secretion.) asymptomatic gallstones become symptomatic at a low
6. Arrese M, Trauner M. Molecular aspects of bile forma- rate. Conversely, symptomatic gallstones predict future
tion and cholestasis. Trends Mol Med 2003;9:558–64. (A clinical events, thus providing a framework for determin-
review of the molecular mechanisms of bile formation at ing which patients benefit from cholecystectomy.)
the canalicular membrane of hepatocytes and in intra- 13. Katsika D, Grjibovski A, Einarsson C, et al. Genetic and
hepatic cholangiocytes, with descriptions of the various environmental influences on symptomatic gallstone dis-
membrane transporters involved.) ease: a Swedish study of 43,141 twin pairs. Hepatology
7. Portincasa P, Moschetta A, van Erpecum KJ, et al. Path- 2005;41:1138–1143. (A large population-based study of
ways of cholesterol crystallization in model bile and na- twin pairs that helps to further define the relative con-
tive bile. Dig Liver Dis 2003; 35:118–126. (A review of the tributions of genetic and environmental factors to symp-
concepts involved in cholesterol crystallization in model tomatic gallstone disease and gallstone surgery-related
and native bile, including a description of the physical diagnoses. Concordances and correlations were higher
chemical as well as modulatory factors involved.) in monozygotic compared with dizygotic twins for males
8. Swidsinski A, Lee SP. The role of bacteria in gallstone and females. Genetic effects accounted for 25% (95% CI,
pathogenesis. Front Biosci 2001;6:E93–103. (This article 9–40%), shared environmental effects for 13% (95% CI,
reviews the data regarding the role of bacteria in cho- 1–25%), and unique environmental effects for 62% (95%
lesterol gallstone pathogenesis. The point is made that CI, 56–68%) of the phenotypic variance among twins.
both bacterial and non-bacterial mechanisms may play a These results show heritability to be a major susceptibil-
role in cholesterol gallstone pathogenesis, and that most ity factor for symptomatic gallstone disease.)
gallstones are colonized by a bacterial biofilm even in 14. vanBerge-Henegouwen GP, Venneman NG, Por-tincasa
situations where bile is culture-negative.) P, et al. Relevance of hereditary defects in lipid transport
9. Haigh WG, Lee SP. Identification of oxysterols in hu- proteins for the pathogenesis of cholesterol gallstone
man bile and pigment gallstones. Gastroenterology disease. Scand J Gastro Suppl 2004;241:60–69. (This re-
view article discusses the mechanisms of bile formation, tory. Endoscopic sphincterotomy was then done as the
and provides a description of single gene defects that gold standard for the presence or the absence of stones.
have been associated with gallstone formation. Specifi- 78 (66%) patients had choledocholithiasis; 17 (14%) had
cally discussed are mutations in ABCB4, the phospha- other bile duct diseases; 24 (20%) had a clear bile duct
tidylcholine flippase; and in CYP7A1, the rate limiting or did not require an invasive endoscopic procedure. The
enzyme in bile acid synthesis; both have been linked to sensitivity of endoscopic ultrasonography was 93%, and
cholesterol gallstones.) specificity 97%. This study shows that EUS is at least as
15. Ko CW, Beresford SA, Schulte SJ, et al. Incidence, natu- sensitive as ERC for choledocholithiasis.)
ral history, and risk factors for biliary sludge and stones 20. Boerma D, Rauws EA, Keulemans YC, et al. Wait-and-see
during pregnancy. Hepatology 2005;41:359–65. (This is a policy or laparoscopic cholecystectomy after endoscop-
prospective study of the incidence, natural history and ic sphincterotomy for bile-duct stones: a randomised
risk factors for biliary sludge and stones in 3254 women trial. Lancet 2002;360:761–65. (This is a prospective, ran-
during pregnancy and the postpartum period. Sludge or domized trial of 120 patients comparing a wait-and-see
stones were found by ultrasound in 5.1% by the second policy with laparoscopic cholecystectomy in patients
trimester, 7.9% by the third trimester, and 10.2% by 4–6 who have undergone an endoscopic sphincterotomy for
weeks postpartum. Regression of sludge and stones removal of CBD stones who also have residual gallblad-
was common. Twenty-eight women (0.8%) underwent der stones. Primary outcome was recurrence of at least
cholecystectomy within the first year postpartum. Pre- one biliary event during 2-year follow-up, and secondary
pregnancy body mass index and serum leptin levels were outcomes were complications of cholecystectomy and
independent predictors of sludge or stone formation.) quality of life. 12 patients were lost to follow-up. Of 59 pa-
16. Gracie WA, Ransohoff DF. The natural history of silent tients allocated to wait-and-see, 27 (47%) had recurrent
gallstones–the innocent gallstone is not a myth. N Engl J biliary symptoms, compared with one (2%) of 49 patients
Med 1982;307:798–800. after laparoscopic cholecystectomy. 22 (81%) of 27 pa-
17. Soto JA, Barish MA, Yucel EK, et al. Magnetic resonance tients underwent cholecystectomy, mainly for biliary pain
cholangiography: comparison with endoscopic retro- (n = 13) or acute cholecystitis (7). These results do not
grade cholangiopancreatography. Gastroenterology support a wait-and-see policy after endoscopic sphinc-
1996;110:589–97. (This is a prospective study to determine terotomy for CBD stones in patients who have residual
the sensitivity and specificity of MRC for the evaluation gallbladder stones.)
of biliary tract abnormalities in 46 patients, with ERCP 21. Aboulian A, Chat T, Yaghoubian A, Kaji AH, Putnam B,
as the gold standard. Sensitivity for the detection of bile Neville A, Stabile BE, de Virgilio C. Early cholecystec-
duct dilatation (n = 27), biliary strictures (n = 10), and in- tomy safely decreases hospital stay in patients with mild
traductal abnormalities (n = 7) was 96.3%, 90%, and 100%, gallstone pancreatitis: a randomized prospective study.
respectively. Specificity of MRC to demonstrate normal Ann Surg 2010; 251:615-619.
bile ducts was 94.1%.) (This study demonstrates in a prospective randomized
18. Ziessman HA. Nuclear medicine hepatobiliary imaging. fashion that patients with mild gallstone pancreatitis who
Clin Gastroenterol Hepatol 2010;8:111–16. (A comprehen- undergo prompt cholecystectomy (i.e. within 48 hours of
sive review of the uses of hepatobiliary imaging. Biliary admission) had excellent outcomes).
tract diseases for which this modality is used include 22. Kim MH, Sekijima J, Lee SP. Primary intrahepatic stones.
acute cholecystitis, biliary obstruction, SOD dysfunction, Am J Gastroenterol 1995;90:540–48. (Primary intrahepatic
chronic cholecystitis, post–liver transplant complica- stones, which lead to the clinical syndrome of recurrent
tions such as bile leak, biliary stent patency, and biliary pyogenic cholangitis, are prevalent in certain regions
atresia.) of the Far East. The composition, pathogenesis, natural
19. Prat F, Amouyal G, Amouyal P, et al. Prospective controlled history, and clinical management of primary intrahepatic
study of endoscopic ultrasonography and endoscopic stones are reviewed.)
retrograde cholangiography in patients with suspected 23. Crawford RW, Reyes-Rosales R, de la Luz Ramirez-Agu-
common-bile duct lithiasis. Lancet 1996;347:75–79. (This ilar M, et al. Gallstones play a significant role in Salmo-
study was designed to examine whether EUS could be nella spp. gallbladder colonization and carriage. Proc Natl
used as a diagnostic test to determine the need for sub- Acad Sci USA 2010;107:4353–58. (In Mexico City, 5% of pa-
sequent endoscopic sphincterotomy in patients with tients with gallstones were found to carry S. typhi, with
suspected choledocholithiasis. 119 patients with strongly bacterial biofilms visualized on these stones. Conversely,
suspected choledocholithiasis were studied prospective- patients with gallbladders infected with E. coli did not
ly. During the same period of sedation or within 2 hours of harbor biofilms on gallstones, a finding that was corrobo-
each other, endoscopic ultrasonography and ERC were rated by studies in mouse models of persistent Salmonella
carried out by investigators unaware of the patient’s his- infection during cholesterol gallstone formation.)
24. Dutta U, Garg PK, Kumar R, et al. Typhoid carriers among malignant polyps were over 60 years of age. Polypoid le-
patients with gallstones are at increased risk for carcino- sions of the gallbladder were diagnosed by preoperative
ma of the gallbladder. Am J Gastroenterol 2000;95:784–87. ultrasonography in only 36 patients. All types of polypoid
(In this case-control study from India, patients with con- lesions of the gallbladder, whether benign or malignant,
comitant gallstones and a chronic S. typhi carrier state were frequently solitary, and gallstones coexisted in the
had a significantly elevated risk of developing gallblad- majority of patients with all polypoid lesions of the gall-
der carcinoma (OR = 14; CI 2–92). Older age and smoking bladder except cholesterol polyps. The lesions were >10
were also found to confer an elevated risk.) mm in 88% of the malignant polyps and in only 15% of the
25. Baillie J. Sphincter of Oddi dysfunction: overdue for an benign polyps. Risk factors for malignancy were the age
overhaul. Am J Gastroenterol 2005;100:1217–20. (A re- of the patient (>60 years), the coexistence of gallstones,
view of sphincter of Oddi dysfunction, with an emphasis and the size of the polypoid lesions (>10 mm in diameter).
on the pitfalls of diagnosis and treatment. This review This study supports cholecystectomy in asymptomatic
contains helpful clinical insights gleaned from years of patients if these risk factors are present.)
experience by an investigator involved in the manage- 29. Kamisawa T, Takuma K, Anjiki H, et al. Pancreaticobiliary
ment of this group of patients.) maljunction. Clin Gastroenterol Hepatol 2009;7:S84–S88.
26. Goncalves RM, Harris JA, Rivera DE. Biliary dyski- (A review of congenital pancreatico-biliary maljunction,
nesia: natural history and surgical results. Am Surg a condition that is often associated with congenital cho-
1998;64:493–97. (This is a retrospective analysis of the ledochal cysts. Patients with PBM are at risk for devel-
symptomatic outcomes in patients thought to have fea- oping cholangiocarcinoma or gallbladder carcinoma. For
tures consistent with biliary dyskinesia. 78 patients with those patients with choledochal cysts, surgical interven-
symptoms consistent with biliary colic and an abnormal tion is recommended, whereas for those patients without
gallbladder ejection fraction on a CCK hepatobiliary scan choledochal cysts, prophylactic cholecystectomy should
in the absence of cholelithiasis were studied. Patients be offered.)
were divided into three groups: Group I patients under- 30. MacFaul GR, Chapman RW. Sclerosing cholangitis. Curr
went cholecystectomy, and of these 80% had complete Opin Gastroenterol 2005;21:348–53. (A review of primary
symptomatic resolution whereas the remaining 20% had sclerosing cholangitis. with an emphasis on recent dis-
symptomatic improvement. Chronic cholecystitis was coveries relevant to etiology, epidemiology, diagnosis
found in 95% of resected specimens. Group II patients and treatment. Salient points include the use of MRCP
did not undergo cholecystectomy, and of these, 75% not- as a cost-effective and accurate means of diagnosing
ed persistence of symptoms whereas 25% had symptom- primary sclerosing cholangitis compared to ERCP; the
atic resolution without any treatment. Group III consisted potential role of ursodeoxycholic acid as a hepatobiliary
of patients with an abnormal ejection fraction who had and colorectal carcinoma chemopreventative agent; and
improvement of symptoms after treatment for an alterna- the role of liver transplantation and its outcome.)
tive diagnosis. These findings suggest that an abnormal 31. Alderlieste YA, van den Elzen BDJ, Rauws EAJ, et al. Im-
ejection fraction does not always indicate gallbladder munoglobulin G4-associated cholangitis: One variant of
disease. Conversely, patients with persistent biliary type immunoglobulin G4-related systemic disease. Digestion
symptoms in combination with an abnormal gallbladder 2009;79:220–28. (A review of the newly recognized entity
ejection fraction in the absence of other attributable called immunoglobulin G4-associated system disorder, in
causes can expect a favorable response to cholecystec- which cholangitis and pancreatitis are known occur.)
tomy.) 32. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lan-
27. Barie PS, Eachempati SR. Acute acalculous cholecysti- cet 2009;374:1704–13. (A comprehensive review of bili-
tis. Gastroenterol Clin North Am. 2010; 39:343-357. (A re- ary atresia including epidemiology, pathophysiology, di-
view of acute acalculous cholecystitis, with descriptions agnosis and treatment. The emphasis on timely referral
of risk factors, diagnostic studies, and clinical manage- of neonates with persistent jaundice found to be due to
ment.) conjugated hyperbilirubinemia to centers with expertise
28. Terzi C, Sokmen S, Seckin S, et al. Polypoid lesions of in performing Kasai portoenterostomy leads to good out-
the gallbladder: report of 100 cases with special refer- comes in the majority of cases.)
ence to operative indications. Surgery 2000;127:622–27. 33. Khan SA, Thomas HC, Davidson BR, et al. Cholangiocar-
(This is a retrospective analysis of the clinico-pathologic cinoma. Lancet 2005;366:1303–14. (A review of cholan-
correlates of gallbladder polyps in 100 patients, designed giocarcinoma. Salient points include observations that
to identify characteristics of polyps that would predict the incidence of intrahepatic cholangiocarcinoma is
the need for cholecystectomy. 74 benign polyps and 26 increasing worldwide; a discussion of the role of diag-
malignant polyps were found. Twenty-seven percent of nostic tests, including MRI, CT, EUS, and PET; and discus-
patients with benign polyps and 73% of patients with sions regarding the roles of surgery, liver transplantation,
and the use of biliary stents for palliation.)

34. Heimbach JK, Haddock MG, Alberts SR, et. al. Trans-
plantation for hilar cholangiocarcinoma. Liver Transpl
2004;10:S65–68. (A description of the results of a chemo-
radiation protocol followed by liver transplantation for
perihilar cholangiocarcinoma. In a highly selected group
of patients, 5-year survival rates of approximately 80%
were achieved using this protocol.)
35. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gem-
citabine versus gemcitabine for biliary tract cancer. N
Engl J Med 2010; 362:1273–81. (This trial showed that in
unresectable locally advanced or metastatic biliary tract
cancer, the combination of cisplatin and gemcitabine
prolonged median survival by ~3 months. This study high-
lighted the challenges faced in finding effective treat-
ments for cholangiocarcinoma that is advanced or meta-
static, as survival in these patients is dismal.)
36. Prasad GA, Wang KK, Baron TH, et al. Factors associ-
ated with increased survival after photodynamic therapy
for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007;
5:743–48. (This study on 25 patients with cholangiocarci-
noma treated with photodynamic therapy [PDT] showed
on multivariate analysis that the presence of a visible
mass on imaging studies and increasing time between
diagnosis and PDT predicted a poorer survival rate after
PDT. The results suggest that patients with unresectable
cholangiocarcinoma without a visible mass might benefit
from timely treatment with PDT.)
CHAPTER 12
Viral Hepatitis
Steve S. Choi, MD, and Carl L. Berg, MD
Learning Objectives
1. Review the virology of hepatitis viruses and host immune responses when patients are infected with one of the five major hepatitis viruses.
2. Recognize the clinical features and spectrum associated with acute and chronic viral hepatitis.
3. Recognize the extrahepatic manifestations associated with various forms of acute and chronic viral hepatitis.
4. Review which patient populations should receive vaccination to prevent viral hepatitis A and B.
5. Review the indications for treatment and specific options available for treatment of chronic viral hepatitis.
Introduction
Infection with a hepatitis virus is the most common cause of acute and chronic liver disease worldwide. These
-
tion, mode of infection, and the type of response they elicit in the human host following acute infection.1 Table
12.1 compares the viral characteristics and epidemiology for the 5 recognized hepatitis viruses. Nearly half of
all cases of acute viral hepatitis in the United States are the result of hepatitis A virus (HAV), one third result
from infection with hepatitis B virus (HBV), and about 20% are from hepatitis C virus (HCV). In contrast,
because of the high rate of chronicity following infection with HCV, this virus represents the most common
cause of chronic viral hepatitis in the United States, accounting for the majority of cases. Fifteen percent of
chronic hepatitis in the United State is secondary to HBV, and <5% is from HBV plus hepatitis D virus (HDV)
co-infection.
Natural History of Viral Hepatitis

Following exposure to a hepatitis virus, many patients experience a well-described series of events that cul-
minate in the development of jaundice and the clinical recognition of acute hepatitis.
Acute Viral Hepatitis

Four distinct phases of viral hepatitis have been described. The prodrome begins following exposure to the vi-
353
Table 12.1
Characteristics and Epidemiology of Hepatitis Viruses
Age group most

Virus Family Type Worldwide endemicity Modes of infection
commonly infected
Varies by geography
Infants and children Person-person via fecal-oral spread and con-
High-prevalence areas: nearly all adults
taminated food
A Picornaviridae ssRNA exposed
Low-prevalence areas: ~33% of population
Adults Same as for children, homosexual activity
exposed
~300 million worldwide; varies by geography
High prevalence (China and southeast Asia):
Perinatal exposure
>8% of population
Infants Sexual activity, intravenous drug use, con-
B Hepadnaviridae dsDNA Medium prevalence (Africa and eastern
Children and adults taminated instruments, and other parenteral
Europe): 2–8% of population
exposures
Low prevalence (North America and western
Europe): <2% of population
Vertical and sexual transmission rare but
~170 million worldwide
C Flaviviridae ssRNA All increased in setting of HIV coinfection
1–2% of population
Drug use and other parenteral exposures
~15 million people worldwide (~5% with
Sexual activity, drug use and other parenteral
D Deltaviridae ssRNA chronic HBV, most commonly in eastern All
exposures
Europe)
Varies by geography
High prevalence (India): 40–70% of population Person-person via fecal-oral spread and con-
E Caliciviridae ssRNA All
Low prevalence (North America and Europe): taminated food
1–5% of population
this period, patients are typically asymptomatic and point jaundice becomes clinically apparent. The ic-
exhibit no signs or symptoms of hepatitis. The incu- teric phase of acute viral hepatitis may last from a
bation period varies for each of the hepatitis viruses minimum of 1–2 days to as long as several weeks at
but is generally on the order of days to weeks for HAV which point the entire process begins to resolve. The
and hepatitis E virus (HEV) and can range from sev- resolution phase is characterized by a return of the
eral weeks to months for other types. The next phase, serumaminotransferasesand bilirubin to normal and
the prodrome, is characterized by the development
some cases protect against reinfection.
myalgias, arthralgias, fatigue, and loss of appetite. Although it is generally considered that jaun-
Some patients have nausea and vomiting, and some dice is the hallmark of acute hepatitis, jaundice is a
may notice a change in the taste and smell of food.
- patients infected with HCV. At least 75% of patients
ly unremarkable except for mild hepatic tenderness. with acute viral hepatitis never develop jaundice.
Serum aminotransferasesare typically elevated, and As a result, the vast majority of patients with acute
serologic and/or virologic evidence of hepatitis may
- remain anicteric, and are totally unaware they have
rus infection. The prodrome lasts 3–5 days at which acute hepatitis. Years later, many such patients are
Chapter 12 Viral Hepatitis 355
found to have serologic evidence of previous viral Table 12.2

infection and/or chronic hepatitis. Anicteric asymp- Fulminant Hepatic Failure and Chronicity Rates for Hepatitis Viruses
tomatic infection is more common following perina-
tal exposure and in young children, whereas adults
tend to develop jaundice following acute infection.
Virus Fulminant hepatic failure Chronicity rate
The development of jaundice in the setting of either
acute HBV or acute HCV infection often predicts im- 0.1%, mostly in adults
munologic clearance of the virus; such patients are A 30% or less in patients with None, regardless of age
much less likely to develop chronic viral hepatitis.2 chronic liver disease
Fulminant hepatic failure develops in a small 90% when exposed perina-
1%, mostly in adults
percentage of patients following acute viral hepatitis tally
B 25% or less in patients with
(Table 12.2). This is characterized by marked eleva- 50% when exposed as child
chronic liver disease
tions in serum aminotransferases, profound jaundice, 5% when exposed as adult
loss of hepatic function, coagulopathy, and the devel- C Reported but rare 60–85% regardless of age
opment of hepatic encephalopathy. Fulminant hepat- Coinfection: 20–25% Coinfection: ~2%
ic failure occurs in about 0.1% of patients following D
Superinfection: uncommon Superinfection: >90%
acute infection with HAV, in about 1% of patients fol-
0.5–4% overall
lowing acute HBV, and in up to 20–25% of individu- None in immunocompetent
E 15–30% if exposed during
als following coinfection with HBV and HDV.3 Acute individuals
pregnancy
infection with HEV has also been reported to cause
fulminant hepatic failure, particularly if the exposure
occurs during the third trimester of pregnancy.4 Ful- HBV plus HDV.10 In contrast, nearly all patients who
minant hepatic failure is reported to rarely occur fol- develop acute coinfection with HBV and HDV do not;
lowing acute infection with HCV. However, patients they either resolve these infections or develop acute
with chronic HCV appear to have an increased risk liver failure. Nearly all individuals exposed to HAV
for developing acute liver failure if they develop ei- and HEV and about 95% of adults exposed to HBV re-
ther acute HAV or HBV.5 Similarly, acute infection solve the acute infection and develop protective an-
with HAV, HCV, or HEV in patients with chronic HBV tibodies; however, development of chronic HEV has
is associated with an increased risk of severe hepati- been reported among immunosuppressed persons,
tis and acute liver failure.6, 7 in particular recipients of solid organ transplant.11
Patients with chronic viral hepatitis B, C, and B
plus D superinfection may develop progressive liv-
Chronic Viral Hepatitis er disease and cirrhosis. In general, approximately
Resolution of acute viral hepatitis does not occur 20–30% of patients with chronic HBV and HCV will
in all cases. Rather, many patients go on to develop develop cirrhosis over 2–3 decades.12 In contrast,
chronic viral hepatitis. The risk for development of approximately 25–33% of patients with chronic vi-
virus and, in the case of HBV, the age at exposure never progress to cirrhosis over their lifetime. Those
(Table 12.2). Nearly 90% of individuals exposed to patients with nonprogressive chronic hepatitis C
HBV during the perinatal period develop chronic in- tend to have a normal serum alanine aminotrans-
fection. This declines to 50% if the exposure occurs
during childhood and to only 5% in adults.8 The de- Patients who are of older age, obese, diagnosed with
velopment of chronic viral hepatitis is reported to oc- fatty liver disease, immunosuppressed (i.e., HIV coin-
cur in 60–85% of patients exposed to HCV.9 Nearly all fection), or have a history of alcohol use demonstrate
patients with chronic HBV who subsequently acquire an increased rate of progression to cirrhosis.13 Pa-
superinfection with HDV go on to develop chronic tients with inactive chronic HBV, characterized by
the presence of anti-HBe antibody, a persistently ral antigens. Extrahepatic manifestations may occur
normal serum ALT, and levels of HBV DNA in serum during both the acute phase of the hepatitis infection
as well as in patients with chronic viral hepatitis B or
on liver biopsy and nonprogressive disease.14 In cir- C. Patients with acute hepatitis A or B may develop a
rhotic patients with chronic viral hepatitis, decom- reaction similar to serum sickness with fevers, a skin
pensation develops in about 3–5% of patients on an rash, arthralgias, and frank arthritis. These manifes-
annual basis. Patients with cirrhosis secondary to tations typically resolve with the onset of the icteric
chronic viral hepatitis B, C, and B plus D superinfec- phase of the acute hepatitis.
tion are at increased risk to develop hepatocellular Essential mixed cryoglobulinemia (EMC) is high-
carcinoma (HCC).15 HCC may also develop in patients ly associated with chronic HCV infection, although
with chronic HBV in the absence of cirrhosis and is it may also be seen in patients with chronic HBV.17
related to the chronicity of infection and viral load. In EMC, production of antibodies directed at the in-
fecting virus form large complexes with the protein
products of these viruses, which are then deposited
Extrahepatic Manifestations of in small vessels throughout the body. The precipita-
tion of these complexes within the vascular system
Viral Hepatitis triggers a vasculitis, which can lead to arthralgias,
Extrahepatic manifestations occur in about 25% of palpable purpura, a patchy erythematous rash most
patients with viral hepatitis A, B, or C.16 In most cases commonly seen in the lower extremities, and in some
these are believed to be mediated by circulating im- cases glomerulonephritis (Figure 12.1). The latter
may cause proteinuria, hypertension, and renal in-
90% of patients with EMC.

FIGURE 12.1
Several types of glomerulonephritis have been
HCV Cryoglobulinemia
observed in patients with chronic viral hepatitis.
Patients with chronic HBV can develop either mem-
HCV - Cryoglobulinemia
HCV - Cryoglobulinemia
HCV RNA
branous glomerulonephritis, which is much more
positive
HCV RNA common in children, membranoproliferative glo-
All Patients with EMC
negative merulonephritis (MPGN), or IgA nephropathy. The
underlying liver disease tends to be mild in patients
who present with HBV-related glomerulonephritis.
Anti-HCV antibodies can be About half of all children with acute HBV-related
demonstrated in the vessel membranous glomerulonephritis develop sponta-
walls of skin biopsies of
patients with cryoglobulinemia neous viral clearance. In contrast, >98% of patients
and cutaneous vasculitis with MPGN have chronic HCV infection and cryo-
globulinemia. Patients with chronic HCV and MPGN
also have milder liver disease than patients without
Agnello V, et al., N Engl J Med 1992; 327(21):1490
Agnello V. et al., Springer Semin Immunopathol 1997; 19:111 EMC.18 Both types of glomerulonephritis, in HBV and
HCV infection, have been reported to either improve
More than 90% of patients with essential mixed cryoglobulinemia are positive for HCV or resolve following successful antiviral therapy.
RNA. Of note, the HCV RNA levels may be up to 1000-fold higher in the cryoprecipitate
Spontaneous remission of glomerulonephritis has
compared to those in the plasma. Antibodies to hepatitis C virus have been noted in the
vessel walls of skin biopsies of patients with cryoglobulinemia and cutaneous vasculitis. been observed following seroconversion of HBV with
From Agnello V, Chung RT, Kaplan LM. A role for chronic hepatitis C infection in type loss of HBV e-antigen (HBeAg) and development of
II cryoglobulinemia. N Engl J Med 1992;327(21):1490. Angello V. The etiology and HBV e-antibody (anti-HBe). Eradication of HCV RNA
pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection.
Springer Semin Immunopathol 1997;19:111. From Viral Hepatitis Gastro Slide 296, in patients with EMC and MPGN during and following
AGA Institute. interferon therapy has been associated with a decline
in proteinuria and improvement in renal function. extrahepatic manifestations of chronic HCV, success-
Therapy with rituximab may also be effective in the ful interferon therapy has been reported to be an ef-
short run by controlling the production of antibodies fective treatment for these lymphomas.
that play a role in the immune complex formation.19 It Several nonimmunologicextrahepatic manifesta-
appears that viral eradication, however, is important tions have been associated with chronic HCV infec-
for long-term control of EMC. tion. These include insulin resistance, Moran’s corne-
Polyarteritisnodosa (PAN) is a rare complica- al ulcer, lichen planus, and porphyria cutaneatarda.
tion occurring in only 1–5% of patients with chronic The manner in which HCV contributes to these dis-
HBV infection; conversely, 40–50% of patients with
PAN are found to be positive for HBV surface anti- porphyria cutaneatarda have been noted to be more
gen (HBsAg).17 This systemic vasculitis is thought to common in patients with chronic HCV. However, this
occur when antibodies complexed with HBsAg are does not appear to be unique to HCV, as other chronic
deposited along vascular endothelium of medium- liver disorders and excess alcohol use have also been
- noted to enhance the phenotypic expression of these
cally causes aneurysmal dilatation, which may on oc- disorders.
casion lead to rupture, internal bleeding, and death.
The process affects blood vessels from numerous
organs, including the heart, liver, brain, mesentery, Hepatocellular Carcinoma and
and kidney. Symptoms of polyarteritis are dependent
Viral Hepatitis
chest pain, altered mental status, abdominal pain, HCC represents the third most common cause of can-
and hematuria. The natural history of polyarteritis cer death worldwide. Approximately 500,000 deaths
is highly variable. However, in severe cases, mortal- result from HCC yearly, and the geographic distri-
ity is high despite treatment with immunosuppres- bution of this cancer closely tracks the prevalence
sive agents and/or plasma exchange. Antiviral agents of HBV and HCV.20 Although HCC can develop in the
for HBV have the potential to improve morbidity and setting of cirrhosis from any etiology, this risk is par-
mortality in patients with PAN. ticularly increased in patients with chronic HBV and
HBV infection has also been associated with HCV. However, the manner in which these two viruses
papularacrodermatitis. This is most commonly found contribute to the development of carcinogenesis ap-
in young children and is thought to result from the pears to be very different. Although HBV is not spe-
development of immune complexes with HBsAg that
deposit in the dermis. The disorder is associated integration of the HBV genome into host genes may
with symmetrical, erythematous, maculopapular, alter cell growth, cellular differentiation, cell cycle
nonpruritic eruptions over the face, buttocks, limbs, progression, and oncogenesis. The longer a patient
and occasionally the trunk; and axillary and inguinal is infected with HBV, the higher is the risk for HCC as
lymphadenopathy. These lesions typically appear
during the prodrome phase of acute HBV and resolve or cirrhosis. The risk for developing HCC in patients
during the icteric phase. with active HBV and cirrhosis is approximately 90-
Aplastic anemia may also accompany acute HAV fold higher than observed in the general population.
and HBV infection. As with other extra-hepatic mani- Patients with prolonged HBsAg and HBeAg positivity
festations of viral hepatitis, this association has re-
cently been linked to an immunopathologic mecha- while those HBsAg positive patients who have sero-
nism and not a direct toxic effect of these viruses converted (i.e., developed anti-HBe), retain a higher
on the marrow. Both B cell and mucosa-associated risk of HCC though this appears to be approximately
lymphoid tissue cell lymphomas have also been as- 10-fold lower than for patients with active HBV and
sociated with chronic HCV infection. As with other cirrhosis.21
Patients with chronic HCV are also at increased family history of HCC, and Africans over the age of 20
risk for developing HCC. However, this increased risk (Table 12.3).15
appears to be present in only those patients who
is no evidence that HCV integrates into the host ge- Hepatitis A

nome and increases the risk of oncogenesis in a man-
ner similar to HBV. The risk of developing HCC in pa-
contaminated stool with electron microscopy. It is a
tients with cirrhosis and chronic HCV is estimated to
nonenveloped virus with an icosahedral shape mea-
be in the range of 1–3% yearly. Chronic alcohol use
suring 27–32 nm in diameter. The genome consists of
and metabolic factors such as obesity and diabetes
a linear single-stranded RNA, and the virus is a mem-
appear to increase this risk further.22
ber of the Picornaviridae family. The virus is detected
Surveillance is recommended for all cirrhotic pa-
clinically by serologic testing for HAV antibody. Both
tients regardless of the etiology of their liver disease.
IgM, for diagnosis of acute infection, and IgGantibody
assays are available.
HBV patients, screening criteria are expanded for
this group of patients. Surveillance is recommended
for HBV carriers who are Asian males over the age of
Epidemiology
40, all Asian females over the age of 50, those with a
HAV most commonly gains access to the human host
Table 12.3 via the ingestion of contaminated food or water. The
Hepatocellular Carcinoma (HCC) Surveillance Recommendations virus can also be transmitted via male homosexual
activity. In underdeveloped countries with poor sani-
tation, nearly all children are exposed to HAV before
HBV carriers the age of 5 years, and nearly the entire adult pop-
Asian males age 40 ulation tests positive for antibodies to HAV. In con-
Asian females age 50 trast, only about 10% of children and 33% of adults
Those with cirrhosis who reside within developed countries such as the
Family history of hepatocellular carcinoma (HCC) United States and many European countries have
Africans age >20 been exposed to this virus and test positive for HAV
For noncirrhotic HBV carriers not listed above, the risk of HCC varies depend- antibody.23 Most of those who test positive are over
ing on the severity of the underlying liver disease and current and past the age of 50 and were exposed to HAV in childhood
hepatic inflammatory activity. Patients with high HBV DNA concentrations (Figure 12.2). Adults from low endemic areas of the
and those with ongoing hepatic inflammatory activity remain at risk for HCC. world, not previously exposed to HAV, are at high risk
Non-HBV cirrhosis for developing acute infection when traveling into
Hepatitis C endemic areas. The national rate of HAV infection has
Alcoholic cirrhosis steadily decreased since its peak in 1995; however,
Genetic hemochromatosis in 2007 there were approximately 25,000 new infec-
Primary biliary cirrhosis tions of hepatitis A in the United States.24 Many of
Although the following groups have an increased risk of HCC, no recom- these infections occur in children and are subclinical.
mendations for or against surveillance can be made because a lack of data Epidemics associated with contamination of water
precludes an assessment of whether surveillance would be beneficial:
1
-antitrypsin deficiency food products from endemic areas are responsible
Nonalcoholic steatohepatitis for pockets of acute HAV in developed countries. HAV
Autoimmune hepatitis has no human reservoir and does not cause chronic
liver injury.
Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology
2011; 53(3): 1020–1022.
Clinical Course ing, forms of acute HAV infection are associated with
an increased incidence of hepatic failure.
An incubation period following exposure to HAV
Studies have demonstrated that patients with
lasts 2–4 weeks, during which time patients shed vi-
chronic HCV are at increased risk to develop fulmi-
rus in their stool and transmit acute infection to oth-
nant hepatic failure if they develop acute HAV.5 As a
er susceptible individuals. A prodromelasting one to
result, it is recommended that patients with chronic
several days and during which time patients exhibit
HCV be vaccinated against HAV.25 It is also prudent to
vaccinate all patients with chronic liver disease, and
discomfort follows. Jaundice develops in about 25%
especially those with cirrhosis, against HAV unless
of infected patients. Patients without jaundice may
these individuals have detectable HAV IgG antibodies
never recognize they were exposed to HAV. Protec-
from previous HAV exposure or vaccination.
tive antibodies appear and acute hepatitis resolves
in all patients exposed to HAV (Figure 12.3). The risk
of developing icteric disease and fulminant hepatic
failure increases with increasing age. The overall in- Hepatitis B
cidence of fulminant hepatic failure following acute HBV is the most complex of the hepatitis viruses. It is
HAV is 0.1–0.3%. This increases to as high as 1.8% in a member of the hepadnavirus family. The genome is
patients age >49. Some patients occasionally develop a circular partially double-stranded DNA that codes
a prolonged episode of cholestatic HAV during which for four major protein products: the surface protein,
the elevation in alkaline phosphatase and jaundice core protein, polymerase, and X protein. The gene
persist for several weeks to months. Given time, this sequences for these proteins partially overlap. Two
also resolves spontaneously. Relapsing HAV may also of these proteins are further processed into smaller
occur. Such patients develop a second episode of fragments. HBsAg is composed of pre-S1, pre-S2, and
acute icteric hepatitis within 6–10 weeks of the in- S fragments. The gene for the precore protein pre-
dex infection. Neither the cholestatic, nor the relaps- cedes the genetic coding for the core protein in HBV.
Processing of the precore protein produces HBeAg. A
FIGURE 12.2
Age-Specific Incidence of Hepatitis A
Age-specific Incidence of Hepatitis A
HAV
Age-specific Incidence of Hepatitis A in the United States
25
20 5-14 yrs
15
Reported 15-24 yrs
25-39 yrs
Cases
(per 100,000) 10
0-4 yrs
5
40+ yrs
0
1983 1985 1987 1989 1991 1993
CDC, Viral Hepatitis Surveillance Program,1983-93
In the United States, the highest incidence of hepatitis A is among children age 5–14. Approximately one-third of reported cases of acute
hepatitis A occur among children age <15. The incidence of hepatitis A also varies by ethnic origin, with the highest rates among Native
Americans and Alaskan Natives and Hispanics. From Prevention of hepatitis A through active or passive immunization: recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(RR12):1–37. From Viral Hepatitis Gastro Slide 50, AGA Institute.
mutation in the precore region prevents the transla- Asian populations genotype D is rare, except in In-
tion of HBeAg. Serologically, such patients fail to ex- dians and possibly Pakistanis. HBV genotype A pa-
press e-antigen and are referred to as having a pre- tients with either high serum ALT levels or low HBV
core mutant form of HBV. Little is known about the DNA levels are most responsive to peginterferon al-
function of the X protein, although in animal models it pha therapy. Genotypes B and C patients with high
appears to be necessary to sustain infection and may serum ALT levels and low HBV DNA levels may also
promote oncogenesis. In addition to the human host, respond to peginterferon alpha therapy. Genotype D
viruses similar to HBV infect and replicate within HBeAg positive patients are the least responsive to
three different animal species: woodchuck, ground treatment with peginterferon. In HBeAg positive pa-
squirrel, and duck. These animal models have greatly tients, there is a clear correlation between genotype
facilitated our understanding of the molecular biol- and response to peginterferon therapy; however, this
ogy, replication cycle, and life cycle of HBV. relationship is less clear in HBeAg negative patients.
Several genotypes of HBV, A through H, exist
worldwide. Genotype A of the HBV is most common in HBeAg-positive patients, appears to be indepen-
in non-Asian Americans, whereas genotypes B, C, dent of HBV genotype.
and D are most commonly found in Asians. Even in
FIGURE 12.3
Serological Course of Acute Hepatitis A (HAV)
Serological Course of Acute Hepatitis A
HAV
Typical Serologic Course of Acute Hepatitis A Virus Infection
Symptoms
ALT Total anti-HAV
Fecal
HAV IgM anti-HAV
0 1 2 3 4 5 6 12 24
Months after exposure
HAV replicates in the liver, is excreted in bile, and is shed in the stool. Most patients with hepatitis A become symptomatic after an average
incubation period of 28 days (range 15–50 days). Peak infectivity occurs during the 2-week period before the onset of elevated aminotransferases
and jaundice. Fecal shedding of the virus usually disappears by the time patients become symptomatic. Specific antibodies develop rapidly in
patients with HAV infection. IgM antibodies against HAV are usually detectable 5–10 days before the onset of symptoms and can persist for
up to 6 months after infection. IgG antibodies, which appear early in the infection, persist indefinitely and confer lifetime protection against
reinfection. The diagnosis of acute HAV is made by detecting IgM anti-HAV in the serum. From Skinhøj P, Mathiesen LR, Kryger P, Møller AM.
Faecal excretion of hepatitis A virus in patients with symptomatic hepatitis A infection. Scand J Gastroenterol 1981;16:1057–59. Liaw YF, Yang
CY, Chu CM, Huang MJ. Appearance and persistence of hepatitis AIgM antibody in acute clinical hepatitis A observed in an outbreak. Infection
1986;14:156–58. Stapelton JT. Host immune response to hepatitis A virus. J Infect Dis 1995;171(Suppl 1):S9–S14. From Viral Hepatitis Gastro
Slide 46, AGA Institute.
Hepatitis B Serology some patients may have elevated serum ALT and low
levels of HBV DNA, whereas other patients may have
Multiple serologic tests are available to assess dif-
a normal serum ALT and markedly elevated levels of
ferent phases of HBV infection (Table 12.4). Follow-
HBV DNA. In these patients, it is important to serially
ing acute infection, patients express HBV core pro-
follow the HBV DNA levels and the ALT levels, and if
tein antibody (anti-HBc), HBsAg, HBeAg, and HBV
these remain unchanged, liver biopsy to assess liver
DNA. Both IgM and IgG assays are available for the
histology is useful to characterize them within the
detection of anti-HBc. The presence of anti-HBcIgM
active or inactive state.
is consistent with acute HBV infection. Hepatitis B
core antigen is produced intracellularly and can be
detected by immunohistochemical staining of liver
Epidemiology
histologic specimens (Figure 12.4). Core antigen
does not gain access to the serum and is therefore HBV infection is the most common cause of chron-
not clinically measurable. Spontaneous resolution of ic liver disease, with >300 million carriers world-
HBV infection is associated with loss of HBeAg, HBV wide (Figure 12.7). Approximately 250,000–500,000
DNA, and HBsAg and the appearance of anti-HBe deaths are attributed to various manifestations of
and HBV surface anti-body (anti-HBs). A period of acute or chronic HBV yearly. The carrier rate of HBV
time, lasting just a few weeks to several months, may varies widely throughout the world. The virus is com-
elapse between the disappearance of HBsAg and the mon in China, Southeast Asia, and sub-Saharan Af-
development of anti-HBs. During this “window,” the rica. In these high-prevalence areas, as much as 10–
presence ofanti-HBcIgM may be the only serologic 20% of the population are chronically infected with
marker of acute HBV infection (Figure 12.5). Chronic HBV. In contrast, <2% of the population have chronic
HBV infection is associated with persistence of anti- HBV infection in the United States, Canada, Western
HBcIgG andHBsAg as depicted in Figure 12.6). These Europe, Australia and New Zealand with the most
patients typically have elevated serum liver amino- common source of chronic HBV infection resulting
from immigration from areas with high prevalence.
biochemical and virologic characteristics that bridge In these high prevalence areas of the world as many
as 50% of all new infections are the result of vertical
Table 12.4
Serology Associated with Different Phases of Hepatitis Virus B (HBV)
Serologic testing
HBV
HBV e-
HBV surface antigen HBV core protein antibody HBV e-antigen surface HBV DNA (U/ml)
antibody
antibody
IgM IgG
Acute infection X X X >20,000
Resolved infection X X X
Vaccination X
Chronic infection
Replicative phase X X X >20,000
Nonreplicative phase X X X +/-
Flare of chronic HBV X X X +/- >2000
Mutant forms of HBV
Precore X X +/- >2000
and/or perinatal transmission. In contrast, HBV is

most commonly spread through sexual activity and and the patient will be unaware they were exposed
intravenous drug use in those areas of the world with to HBV. The age at which patients become infected
low prevalence for HBV. In these low-prevalence ar- plays a major role in determining whether they will
eas, the groups most likely to develop acute HBV are develop a severe, symptomatic acute icteric hepati-
adolescents and young adults. Although blood prod- tis or a subtle, subclinical anicteric infection. This is
ucts have been routinely screened for the presence also related to the likelihood that the acute form of
of HBsAg and anti-HBc since the mid-1970s, the risk HBV will resolve spontaneously or progress to chro-
of developing HBV following a blood transfusion re- nicity. For example, nearly all infants and about half
mained in the range of 1 in 200,000.26The introduc- of young children have a mild, subclinical anicteric
tion of nucleic acid testing for HBV DNA in 2009 has
lowered the risk of blood of HBV infection through have a 90% chance of developing chronic hepatitis.
blood transfusion to between 1 in 200,000 and 1 in In contrast, most adults develop acute icteric HBV,
500,000.27, 28 which almost always resolves spontaneously with
the development of anti-HBs. Approximately 1% of
patients with acute icteric HBV develop fulminant
Clinical Course
patients with HBV-HDV coinfection.
Following exposure to HBV, there is an incubation
The natural history of chronic HBV may progress
period of 1–4 months. This is followed by several
along two divergent pathways. Patients with active
HBV, HBsAg, HBeAg, HBV DNA, and elevated serum
comfort, and on occasion nausea and vomiting. Ap-
liver aminotransferases progress to worsening forms
proximately 25–30% of individuals will then develop
jaundice. The majority will have an anicteric form
FIGURE 12.4
Hepatitis B
Hepatitis B histology
HBV - Stage 3
HBV - Ground Glass Hepatocytes
Hepatocytes with a ground glass appearance (high power H and E stain). From Viral Hepatitis Gastro Slide 351, AGA Institute.
FIGURE 12.5
Serological Markers of Acute Hepatitis B Virus (HBV) Infection
Serological Markers of Acute HBV Infection
HBV - Diagnosis
Acute Infection
HBV DNA
HBeAg Anti-HBe
Anti-HBs
Anti-HBc
HBsAg Anti-HBc IgM
0 2 4 6
Months Years
Incubation period of HBV infection ranges from 60 to 180 days. HBsAg is the first serological marker of acute HBV infection. Early in the course
of acute HBV infection, markers of active viral replication (HBeAg and HBV DNA) are also detectable. As the patients recover, serum HBV DNA
level markedly decrease but may remain detectable by PCR assay for up to several decades, HBeAg to anti-HBe seroconversion occurs, and
finally HBsAg becomes undetectable. Persistence of HBsAg for >6 months indicates progression to chronic HBV infection. Anti-HBcIgM is the
first antibody to be detected and usually persists for several months. It may be the only marker of acute HBV infection during the “window”
period after HBsAg is cleared and before anti-HBs is detected. Recovery from acute HBV infection is indicated by the presence of anti-HBcIgG
and anti-HBs. From Viral Hepatitis Gastro Slide 80, AGA Institute.
FIGURE 12.6
Serological Markers of Chronic Hepatitis B Virus (HBV) Infection
Serological Markers of Chronic HBV Infection

HBV - Diagnosis
Chronic Infection
HBV DNA
HBeAg Anti-HBe
HBsAg
Anti-HBc IgG
Anti-HBc IgM
Months Years
Chronic HBV infection is indicated by the presence of HBsAg persisting for >6 months and detection of anti-HBcIgG. During the early phase of
chronic HBV infection, markers of HBV replication, HBeAg and high serum HBV DNA levels, are also present. Over time, patients seroconvert
from HBeAg to anti-HBe, accompanied by decrease in serum HBV DNA levels. From Viral Hepatitis Gastro Slide 81, AGA Institute.
FIGURE 12.7 greatest in patients who have already developed cir-

Epidemiology of Hepatitis B Virus (HBV) rhosis from years of active HBV. Following serocon-
version, serum aminotransferases typically return
Epidemiology of Hepatitis B
to normal; the serum level of HBV DNA falls to low
HBV - Epidemiology
levels, typically under 2000 U/ml, and in some cases
Prevalence of HBsAg Carrier State
HBV DNA is undetectable; and there is a marked de-
and the histology takes on the appearance of a mild

hepatitis. As a result, ongoing histologic progression
>8%
2-8% to cirrhosis is distinctly unusual following serocon-
<2% version, and the prognosis for these patients over
the next 5–10 years is excellent. The literature has at
times referred to these patients as “healthy carriers.”
However, this label is a misnomer and should no lon-
WHO ger be utilized. These patients remain at increased
risk to develop HCC, although this risk appears to
HBV infection is a global health problem. Approximately 350 million people worldwide
are chronic carriers of HBV. Chronic HBV is endemic in most parts of Africa, Asia,
be about one-tenth of that observed in patients with
and Alaska, with carrier rate >20%. In United States, the latest population survey active HBV infection. In some patients, this inactive
showed prevalence of chronic HBV to be 0.42%. However, in that study, people at high carrier state gives way to HBeAg negative chronic
risks, such as those imprisoned or incarcerated, were not surveyed. Hence, the actual
hepatitis, with HBV DNA and ALT again rising, and
prevalence may be even higher. From Kao JH, Chen DS. Global control of hepatitis B
virus infection. Lancet Infec Dis 2002;2:395–403. McWuillan GM, et al. Prevalence this is most often associated with the development of
of hepatitis B virus infection in the United States: the National Health and Nutrition a precore mutant or core promoter mutant. Regard-
Examination Surveys, 1976 through 1994. Am J Public Health 1999 Jan;89(1):14–18. less, in patients with either active or inactive disease,
From Viral Hepatitis Gastro Slide 61, AGA Institute.
the risk for developing HCC increases with age, the
duration of viral infection, and the magnitude of the
viral load. Over many years, patients who have sero-
rate at which patient’s progress to cirrhosis and liver converted may subsequently and spontaneously lose
failure is highly variable but on average requires ap- HBsAg and develop anti-HBs. If these patients clear
proximately 20 years or more of active infection. Pa- HBsAg after the age of 50 or after the development of
tients with chronic HBV are at increased risk for de- cirrhosis, they are still at increased risk of developing
velopment of liver cancer. In contrast, patients with HCC.29 Furthermore, serologic evidence of recovery
chronic active HBV may spontaneously seroconvert from HBV infection does not preclude its reactivation
to an inactive infection (Figure 12.8). Spontaneous and reverse seroconversion in the setting of immu-
HBeAgseroconversion occurs in approximately 5% nosuppression.30
of patients with chronic active HBV on a yearly basis.
The ability to seroconvert from active to inactive dis-
ease is determined by the manner in which the host Variant Forms of HBV
immune response interacts with this virus. Little is
known about the factors that modulate this process. Several mutations of HBV have been described.
These mutated viruses result from alterations in
in serum liver aminotransferases, followed by loss the nucleotide sequence compared to the wild-type
of HBeAg and detectable HBV DNA from serum, and strain. The most common of these HBV variants is
the appearance of anti-HBe. During this process, pa- the precore mutant, which fails to express HBeAg be-
tients may develop a clinical picture similar to acute cause of a sequence alteration resulting in a stop co-
fulminant hepatic failure. The risk for developing don in the precore area of the core gene. Other less-
acute liver failure during HBeAgseroconversion is common mutations that occur in the HBV genome
affect the surface and core genes. Mutations of these FIGURE 12.8
genes produce abnormal surface proteins, which Natural Course of Chronic Hepatitis Virus B (HBV) Infection
may not be recognized by the current HBsAg assays,
respectively, but this is very rare. In the case of the Natural Course of Chronic HBV Infection
HBV - Natural History

surface mutant, infection may still occur despite
Natural Course of Chronic HBV Infection
the presence of effective vaccination and presence
of anti-HBs. Patients with HBV gene mutations are HBeAg
recognized because they have persistent elevation Anti-HBe
HBV
in serumaminotransferases and active hepatitis on DNA
liver histology, test positive for various HBV serolog-
ic tests, and have measureable circulating HBV DNA.
Mutations in the basal core promoter region of HBV
decrease HBeAg production and have been shown in ALT
several studies to be associated with increased risk
of hepatocellular carcinoma. Immune
Tolerance
Immune
Clearance
Inactive
Carrier
Reactivation
Hepatitis C The natural history of chronic HBV infection consists of four successive phases: (1)
the immune tolerance phase, in which there is little hepatic inflammation despite a
high serum level of HBV DNA and positive HBeAg; (2) the immune clearance phase,
techniques after nearly a decade of research to iden- in which there is hepatic inflammation and decrease in serum HBV DNA level and
ultimately loss of HBeAg; (3) the inactive carrier phase, during which patients have
tify the viral pathogen responsible for non-A, non-B
low level of HBV DNA, negative HBeAg, and normal aminotransferases; and (4) the
hepatitis. It is now well recognized that chronic HCV reactivation phase, during which high levels of HBV DNA can be detected in serum
is one of the most common causes of chronic liver along with hepatic inflammation and many patients remain HBeAg negative but
disease and cirrhosis worldwide. In those parts of some patients may revert to HBeAg positive. Not all patients go through all the four
phases. The immune tolerance phase is most common in young Asian patients with
the world where HCV is more prevalent than HBV, perinatally acquired HBV infection. Some patients remain in the inactive carrier phase
HCV is the primary etiologic factor leading to hepato- with no evidence of reactivation; these patients have a better prognosis than those
cellular carcinoma. Nearly half of all liver transplants who develop reactivation. The immune clearance phase and reactivation phase may
be prolonged with recurrent exacerbations of hepatitis and fluctuations in serum HBV
performed worldwide are for cirrhosis and end-stage DNA levels. From Fattovich G, Rugge M, Brollo L, et al. Clinical, virologic and histologic
liver disease secondary to chronic HCV. outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type
HCV contains an enveloped RNA genome. This B. Hepatology 1986;6:167–72. Lok AS, Lai CL, Wu PC, et al. Spontaneous hepatitis B
e antigen to antibody seroconversion and reversion in Chinese patients with chronic
virus is 30–80 nm in diameter and a member of
hepatitis B virus infection. Gastroenterology 1987;92:1839–43. From Viral Hepatitis
the Flaviviridae family. Six major genotypes and Gastro Slide 70, AGA Institute.
several minor genotypes have been described. The
prevalence of various genotypes varies worldwide.
In North America, 70% of patients with HCV are in- is found in southern Africa, and genotype 6 is most
fected with genotype 1, and genotypes 2 and 3 ac- common in southeastern Asia. Mutations within the
count for nearly all of the remaining 30%.In contrast, HCV genome occur frequently. The development of
Europeans, Austrians, and Japanese with HCV have heterogenous, yet closely related, sequences of HCV
a slightly higher prevalence of genotypes 2 and 3. In RNA that occurs during viral replication in a single
the United States, >50% of genotype 1 HCV infection infected person is referred to as quasispecies. It is
is genotype 1a, while in other parts of the world, gen- believed that the development of quasispecies is one
otype 1b accounts for the majority (>80%) of geno- mechanism by which HCV evades the host immune
response and leads to chronic infection in such a high
implications as treatment of HCV enters an era of di- percentage of patients.
rectly-acting antiviral therapies. Genotype 4 is most The assay utilized to screen patients for HCV is
common in Egypt and the Middle East, genotype 5
ing antibodies produced by the HCV-infected patient. use of reusable and nonsterilized medical equipment
This antibody is a marker of previous exposure to in underdeveloped countries. In contrast, sexual and
HCV and not always indicative of chronic infection. vertical transmission, while possible, is uncommon
False-positive HCV-antibody reactions are uncom- except in individuals with high-risk sexual behaviors,
mon and are typically observed in patients with au- multiple sexual partners, or in the setting of HCV-HIV
toimmune disorders and high levels of circulating coinfection. Recent outbreaks of HCV infection unfor-
antibodies. The HCV recombinant immunoblot as- tunately highlight the fact that nosocomial infection
continues to occur in developed countries.
the presence of HCV antibodies as it has been used
to distinguish between prior exposure to HCV (posi-
tive RIBA) or a false signal (negative RIBA). The RIBA Clinical Course
assay itself is now less readily available having been
Following exposure to HCV, there is an incubation
supplanted by nucleic acid testing. The current gold
period of 2–20 weeks followed by a prodrome of
measurement of HCV RNA. This can be performed

only one to a few days. Serumaminotransferases are
with polymerase chain reaction (PCR)or transcrip-
typically elevated by only 5- to 10-fold, and <10% of
patients develop jaundice. Most patients are asymp-
tomatic and unaware they are acutely infected with
HCV and thus are rarely seen in clinical practice. Oth-
Epidemiology -
HCV is the second most common cause of chronic sea, and vomiting occur in <30% of these patients.
hepatitis worldwide and the most common cause of The diagnosis is dependent on detailed history of
chronic liver disease in areas of the world where HBV exposure and the measurement of HCV RNA levels
is not endemic. Nearly 170 million people worldwide within 2–3 weeks of exposure (Figure 12.10). Fulmi-
and about 4 million people in the United States have nant hepatic failure rarely, if ever, occurs. In contrast,
been exposed to HCV, many of whom are unaware approximately 60–80% of patients with acute HCV
that they are infected. Baby boomers (i.e., persons fail to resolve the acute infection and develop chron-
born during 1945–1965) comprise an estimated ic disease. Most of these patients have persistent or
27% of the population but account for nearly three- intermittent elevations in serum aminotransferases.
fourths of all HCV infections in the U.S. This popula- However, about 25–30% of patients will have per-
sistently normal aminotransferases despite ongoing
the burden of infection and its associated morbidi- viremia. Liver biopsy and histologic evaluation have
ties.31 HCV is transmitted from person to person via demonstrated that those patients with persistently
blood transfusions, intravenous drug use, and other normal aminotransferases tend to have milder hepa-
parenteral exposures (Figure 12.9). Prior to the de- titis and may either not develop progressive liver in-
velopment of a screening test for HCV in the early
1990s, the risk of developing non-A, non-B hepatitis much slower rate than do patients with persistently
from a blood transfusion was 5–10%. Since the de- elevated aminotransferases.
velopment of the anti-HCV assay and the universal The natural history of chronic HCV has been well
screening of all donated blood, the risk of develop-
ing HCV following a blood transfusion has declined to
about 1 in 3,000,000.26 In the United States, the most the portal space, bridges between portal spaces, and
common mode by which HCV is currently transmitted eventually forms cirrhotic nodules. The time required
is via contaminated needles utilized by intravenous for a patient with chronic HCV to develop cirrhosis is
drug users, following a break in universal precau- highly variable, but the minimal duration is probably
tions in patients receiving medical care, and from the not less than 1–2 decades. In many patients, cirrho-
sis may not develop for 3–4 decades. Certain factors FIGURE 12.9
have been shown to accelerate the progression to Sources of New Infections in the United States
cirrhosis. These include age at infection, chronic al-
cohol use, hepatic steatosis unrelated to alcohol con-
sumption, and coinfection with HIV. Liver biopsy can
be very useful in staging and estimating prognosis in Sexual exposure
patients with chronic HCV. In general, the greater the 15%
the higher is the risk of developing cirrhosis within

the next decade. For example, patients with active Transfusion
(before screening)
Intravenous drug use
er biopsy appear to progress and develop cirrhosis 10%
60%
within 5–20 years. However, <25% of patients with
biopsy appear to develop cirrhosis over the ensuing Other*

5%
two decades. Despite serving as the standard for the
and carries a risk of complications. Additionally, bi- Unknown

opsy is limited by sampling error and interobserver 10%
variability.
Several non-invasive methods to quantify hepatic
*Nosocomial; health-care work; perinatal
including a simple aspartate aminotransferase:platelet Compared to the period before 1990, the fractions of new cases due to injection drug
ratio index (APRI) as well as commercially available use and sexual activity have increased, while new cases due to transfusion have
disappeared. It seems contradictory to say that transmission between monogamous
sexual partners almost never happens but that sexual transmission is responsible for
almost 1 in 5 new infections annually in the United States. The apparent contradiction
is solved by considering the large reservoir of infected individuals (probably close
to 4 million) and the large number of sexual encounters that take place on a daily
basis. At the population level, even a tiny percentage of a very large number becomes
acid. Although these assays are less invasive, their sen- noticeable. Adapted from Alter MJ. J Hepatology 1999;31(suppl 1):88.
Combining
32
assays appears to increase the diagnostic accuracy

Transient elastography is an emerging non-inva- and may eliminate the need for liver biopsy in more
than half of patients.
measurement of liver stiffness. Stiffness is measured The prognosis of HCV patients who have devel-
through the generation of an elastic wave by means oped cirrhosis is dependent upon the underlying
of a vibrator applied to the thoracic wall at the level liver function. The survival of HCV patients with pre-
of the right liver lobe. Unfortunately, the presence served liver function, Child class A cirrhosis, and no
of fatty liver affects stiffness measurements and re- prior complications of cirrhosis (i.e., variceal hem-
duces the accuracy of the test. While no single non- orrhage, ascites, and/or hepatic encephalopathy)
invasive test delivers the information obtained from is approximately 90% after 5 years and 80% after
10 years. In contrast, patients who have developed
sis), combinations of two modalities of non-invasive complications of cirrhosis with or without a loss in
methods may differentiate between minimal and sig- hepatic function have a 5-year survival of 50% and
10-year survival of only 25%. The risk for patient
FIGURE 12.10 Serologic testing for HDV can identify patients

Acute Hepatitis C Virus (HCV) Infection with both acute and chronic infection. Serum test-
ing is usually limited to HDV antibody (anti-HDV)
Acute hepatitis C infection
measurements. Anti-HD IgM is detectable in patients
HCV - Diagnosis
with both acute and chronic infection and is a marker
Acute
1000
HCV Infection of ongoing liver injury. Anti-HDVIgG develops several
HCV RNA positive weeks following the primary infection and persists
800
in patients with chronic infection. In those few pa-
Anti-HCV
600
tients who resolve HBV and HDV, the serum titer of
ALT
(IU/L) anti-HDV will decline to very low levels. Anti-HDV
400
Symptoms
does not confer immunity to future reinfection. HDV
200 antigen (HDAg) can also be detected in patients with
Normal acute infection. However, HDAg is typically undetect-
0 ALT
0 2 4 6 8 10 12 24 1 2 3 4 5 6 7 able in patients with chronic infection secondary to
Weeks Months
Time After Exposure neutralization of the protein by high levels of circu-
Hoofnagle JH, Hepatology 1997; 26:15S lating anti-HDV. Measuring HDAg in patients with
suspected chronic infection is therefore not useful. In
The diagnosis of acute HCV can be quite difficult. Jaundice is infrequent, and many contrast, a PCR test, when available, for HDV RNA is
patients have few, if any, symptoms. These diagnostic difficulties are compounded
by considerable delay between HCV infection and the detection of antibodies in highly sensitive and diagnostic of active viral repli-
the patient’s serum. This was particularly true for early antibody tests for HCV in cation. Although HDAg, HDV RNA, or immunohisto-
which the average time between infection and seroconversion was 16 weeks. This chemical staining for HDAg in the liver may be useful,
window has been progressively shortened with newer generations of antibody
tests. However, even with the most sensitive newer tests the “window period” these are not readily available.
between HCV infection and seroconversion is at least 6–8 weeks. In contrast, HCV
RNA can usually be detected within 10–14 days after infection. From Hoofnagle JH.
Hepatology 1997;26:15S. Carithers RL Jr, Marquart A, Gretch DR. Diagnostic testing
for hepatitis C. Semin Liver Dis 2000;20:159–71. Pawlosky JM. Use and interpretation
Epidemiology
of virological tests for hepatitis C. Hepatology 2002;36(Suppl 1):S65–S73. From Viral Approximately 5% of people with chronic HBV, 15
Hepatitis Gastro Slide 229, AGA Institute.
million individuals, are coinfected with HDV. Both
HDV and HBV have a higher prevalence in southern
decompensation with stable cirrhosis is estimated and eastern Europe, certain parts of Africa, and the
at 3–5% yearly. HCC appears to develop only in HCV Amazon basin. HDV is uncommon in areas with low
prevalence for HBV, such as North America, northern
for this appears to be 1–3% yearly. Europe, and Japan. It is also less common in Asia,
Alaska, and South Africa despite the high prevalence
of HBV. HDV, like HBV, is transmitted via both paren-
Hepatitis D teral and sexual transmission routes. Two types of
infection have been described: coinfection, where
posed of a single-stranded RNA surrounded by an HDV and HBV infection occur simultaneously, and
envelope of HBV. The virus is 36–43 nm in diameter superinfection, where individuals with chronic HBV
and is the only member of the Deltaviridae family. develop acute HDV from a contact harboring both of
Three genotypes of HDV have been described, each these viruses.
though the virus can replicate within infected cells

independently, HBV must be present for HDV to pro- Clinical Course
duce intact virus capable of being transmitted to oth- The clinical course of HDV depends in large part on
er cells. As a result, HDV is only found in individuals the timing of HDV infection relative to that of HBV and
with acute or chronic HBV.
how these two viruses interact within the host. Pa- FIGURE 12.11
tients with coinfection typically present with severe Hepatitis D Virus (HDV) CoInfection
acute icteric hepatitis. The elevation in serum ami- HDV Co-infection
HDV
notransferases in these patients is frequently bipha-
sic: aminotransferases rise to high levels, fall toward HDV - Coinfection
the normal range, then elevate again 2–3 weeks later
ALT
of HBV, which is then suppressed by emerging HDV HDV RNA

replication, leading to the second aminotransferase IgM anti-HDV IgG anti-HDV
peak. Such patients are at high risk for development
HDAg
of fulminant hepatic failure, which develops rapidly
IgM anti-HBc IgG anti-HBc
following the second peak in aminotransferases. In
some cases, vigorous HDV replication may suppress HBsAg anti-HBs
HBV to such an extent that HBV DNA and HBsAg may

Months
become undetectable. The risk of developing chronic
HBV and HDV following an acute episode of coinfec-
tion is very low, only 2%. The diagnosis of acute co-
Coinfection with HDV and hepatitis B virus (HBV) is characterized by the presence of
infection is made by demonstrating that serologic markers of HDV and HBV during the acute phase. Coinfection is more likely to lead to
testing for markers to both acute HBV, especially anti- a fulminant course than acute HBV infection alone. From Viral Hepatitis Gastro Slide
HBcIgM, and HDV are present. In those cases where 168, AGA Institute.
acute HBV and HDV coinfection has resolved sponta-
neously, patients develop anti-HBs. Patients who de-
velop chronic HBV and HDV coinfection remain HB- tion of several epidemics within India and Pakistan
sAg positive and anti-HDV positive. Thus, anti-HDV of acute icteric non-A, non-B hepatitis that appeared
is a marker of exposure to HDV and is not protective to be spread from person to person via contaminated
against reinfection. water supplies. Viral particles approximately 27–30
Superinfection of HDV in an individual with nm in diameter have been visualized by electron
chronic HBV usually results in acute hepatitis and in microscopy in the stool of infected patients, demon-
some cases may lead to rapidly progressive liver fail- strating that this virus is spread via a fecal-oral route.
ure in a patient with previously stable chronic HBV. HEV is a nonenveloped, single-stranded RNA virus.
In contrast, fulminant hepatic failure is relatively un- Its genetic sequence and structure appear most
common. The diagnosis of superinfection is made by closely related to viruses with the family Calicivirus.
demonstrating that a patient has chronic HBV (HBsAg Serologic assays that detect circulating HEV an-
positive and anti-HBcIgM negative) and acute HDV tibodies (anti-HEV) to proteins of the viral envelope
infection (anti-HDVIgM positive) as depicted in Fig- have been developed and are available for clinical
ure 12.12. HDV superinfection may in rare cases ter- use. Both IgM and IgG assays help differentiate acute
minate HBV infection and cause clearance of HBsAg. infection from prior exposure.33 These assays have a
More likely, superinfection leads to chronic HBV and sensitivity of 95% for detecting patients with acute
HDV. This occurs in about 90% of patients with super- HEV infection. Anti-HEVIgMantibodies appear to
infection. Many patients with chronic HBV and HDV develop within 1 week of infection and persist for
coinfection develop rapidly progressive hepatitis that 4–5 months. High titers of IgG antibodies persist for
may progress to cirrhosis within just 3–5 years. at least 4–5 years. It remains unclear if antibodies
that develop following exposure to HEV are fully or
only partially protective against future reinfection.
Testing for the measurement of serum HEV RNA is
Hepatitis E also now commercially available; however, nucleic
FIGURE 12.12 occur as part of large epidemics, although sporadic

Hepatitis D Virus (HDV) Superinfection cases may occur as well. HEV has not been reported
to be spread either vertically from mother to infant
HDV Superinfection
or to be transmitted via heterosexual or homosexual
HDV
activity. Although humans are thought to be the only
HDV - Superinfection source of infection, HEV has been isolated from vari-
ALT ous farm animals and wild game utilized for food,
and these animals have been shown to develop hepa-
HDV RNA
titis following infection. Exposure to infected animals
IgM anti-HDV IgG anti-HDV or raw animal products, notably swine, are the most
common source of infection in western countries.34
HDAg
HBV DNA
HBsAg, IgG anti-HBc Clinical Course

Years The incubation period for HEV lasts 2–10 weeks. This
HDV superinfection occurs in an individual already chronically infected with hepatitis

B virus (HBV). Diagnosis is suggested by a negative test for anti-HBcIgM, positive toms are similar to those experienced by individuals
HBsAg, and presence of HDV markers. Clinically, it presents like an acute exacerbation with other forms of acute viral hepatitis. During this
of chronic hepatitis in a HBV carrier; occasionally the course is fulminant. Since the
HBsAg carrier permits continuous replication of HDV, the vast majority (>90%) of HDV time, variable increases in serum aminotransferases
superinfection progresses to chronic infection. From Hadziyannis S, et al. The role can be found. It is unclear exactly what percentage
of the hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece. of patients with acute HEV develop icteric hepatitis.
ProgClinBiol Res 1991;364:51–62. From Viral Hepatitis Gastro Slide 169, AGA Institute.
However, this appears to be much more common
in adults than children. For those patients who be-
come jaundiced, the icteric phase lasts 1–4 weeks.
ized with available commercial assays suffering from
Histologically, patients with acute HEV have diffuse
nuclear cells scattered throughout the hepatic lobule,

along with variable degrees of necrosis and cholesta-
Epidemiology sis. An occasional patient may develop prolonged
HEV is endemic in southeast and central Asia, the jaundice lasting 4–6 months accompanied by intra-
Middle East, northern and western parts of Africa, hepatic cholestasis and a profound elevation in se-
and Mexico. In these areas of the world, approxi- rum alkaline phosphatase. All patients who survive
mately 5% of children and up to 70% of adults test acute HEV resolve the infection spontaneously and
positive for anti-HEV IgG. In these areas, HEV typi- develop antibodies that protect against future rein-
cally occurs in large outbreaks that involve hundreds fection. Chronic HEV does not occur in immunocom-
petent individuals; however, in immunosuppressed
disease develops in 3–30% of adults and 0.2–10% individuals, particularly organ transplant recipients,
of children following infection. In contrast, HEV in- chronic HEV infection has been reported. HEV does
fection is uncommon in other parts of the world and not contribute to the development of cirrhosis or he-
patocellular carcinoma.
traveled to endemic areas. Only about 1–5% of the Fulminant hepatic failure is uncommon and de-
population from these areas tests positive for anti- velops in about 0.1–1% of patients except during
HEV IgG. pregnancy, where this occurs in up to 15–25% of
HEV is predominantly spread from person to susceptible women.3 This appears to be more com-
person through fecal-oral contamination. Most cases mon as the pregnancy continues. In one series, the
quency of people who already have HAV antibodies

and third trimesters was 8.8%, 19.4%, and 18.6%, from previous exposure. SIG can also be adminis-
respectively. The frequency of abortions, stillbirths, tered to individuals without previous HAV infection
and neonatal deaths is increased among pregnant who travel to endemic areas. However, a better alter-
women who survive acute HEV. Although severe HEV native for this latter group is active vaccination.
is uncommon following most cases of acute infection, HBV immune globulin (HBIG) is prepared from
the incidence of HEV is so high that this represents the serum of patients previously exposed to HBV or
the most common cause of fulminant hepatic failure those vaccinated who have a high circulating titer of
in areas of the world where this virus is endemic. anti-HBs. HBIG has been utilized to provide passive
immunity to health care workers who were not vac-
cinated, following occupational exposure to blood or
Prophylaxis against
However, within the past decade, most health care
Viral Hepatitis workers have received active HBV vaccine and there-
The best prevention for viral hepatitis is vaccination, fore rarely require HBIG following such an exposure.
which prevents acute infection, the sequelae associ- HBIG is regularly administered to neonates born to
ated with acute infection, and the development of mothers with chronic HBV. Vaccinating newborns
chronic hepatitis. Highly effective vaccines are avail- with HBIG along with active HBV vaccine can prevent
able for two of the hepatitis viruses, HAV and HBV.35 vertical transmission of HBV from infected mothers
The latter also prevents infection from HDV. A vac- in approximately 90% of cases and is more effective
cine for HEV has been developed recently.36, 37Two than administering either HBIG or vaccine alone.
types of prophylaxis exist for both HAV and HBV, pas- Finally, passive prophylaxis with HBIG can help pre-
sive and active. vent allograft reinfection with HBV in the setting of
liver transplantation although the role of HBIG in this
setting has greatly diminished with the availability of
Passive Prophylaxis potent oral antiviral agents that have high barrier to
A passive prophylaxis is composed of preformed resistance.
These antibodies are gradually degraded follow-

ing administration and provide only short-term Active Prophylaxis
(<4-month) protection against the infectious agent. Vaccines have been developed against HAV, HBV, and
As a result, passive prophylaxis is most useful in pro- HEV. The hepatitis B vaccine also prevents infection
viding immediate protection to those who have re- from HDV. The HEV vaccine has been shown to be ef-
cently been exposed to the infectious agent. Passive
prophylaxis is available for both HAV and HBV. These The HAV vaccines are a whole-virus prepara-
immunoglobulins, if given early, can prevent infection produced by growing attenuated HAV in tissue
tion, but if they are given late, they may only amelio- culture and followed by inactivation of the live virus
rate the infection. with formaldehyde. Given its relative lack of muta-
Serum immunoglobulin (SIG) is administered genesis, a single strain of HAV has been successfully
for passive immunity against HAV. It is prepared from utilized for vaccine production. Protective antibody
the serum of patients previously exposed to HAV and
therefore contains high levels of total HAV antibody. and levels of antibody following two doses of vaccine
It is most commonly administered to people who re- administered one month apart are similar to that ob-
side in nonendemic areas during local outbreaks of served following natural infection. HAV antibody is
acute HAV. Passive prophylaxis against HAV is not
cost effective in endemic areas given the high fre- of vaccine in over 70% of patients, and virtually all
patients will have seroconverted within one month. workers has been advocated for nearly two decades.
Therefore, HAV vaccination should be initiated at The HBV vaccine has been shown to prevent HCC.
least 2 weeks prior to any planned travel to endemic
areas. HAV vaccine is indicated for individuals who
reside in areas of low prevalence for infection, espe- Treatment
cially if they plan to travel to areas of the world with
The treatment of acute and chronic viral hepatitis
higher prevalence such as Mexico, Central and South
American, the Caribbean, Southeast Asia, and Africa.
that the patient will develop chronic infection, and
Recent studies have demonstrated that patients with
-
chronic HCV and chronic liver disease of other etiolo-
sis, cirrhosis, and HCC.
gies are at increased risk for development of acute
fulminant hepatic failure when they acquire acute
HAV. As a result, all such patients should be vaccinat-
Treatment of Acute Infection
ed against HAV unless they are known to be immune
on the basis of HAV IgG antibody positivity. Individu- Immunocompetent patients with acute HAV and HEV
als who reside in areas of low prevalence for infec- never develop chronic disease, and only about 5% of
tion need not be tested for prior exposure to HAV adults with acute HBV develop chronic infection. As
before vaccination. a result, the treatment for individuals who develop
Two types of hepatitis vaccines against HBV acute symptomatic icteric HAV, HBV, or HEV is sup-
are currently available. A plasma-derived vaccine portive and to monitor for signs of acute fulminant
-
treatment of a nonreplicative, noninfectious form of ing the treatment of acute HBV cannot be made, but
HBsAg from patients with active HBV. The concern patients with severe infection progressing to liver
for communicable diseases, including HIV, led to a
decline in use of this vaccine in developed parts of should be evaluated for transplantation and oral an-
the world and the subsequent production of a re- tiviral therapy initiated prior to transplant. Patients
combinant vaccine. The much less costly plasma- with acute HBV and HDV coinfection and pregnant
derived vaccine continues to be used in some parts women with acute HEV are at high risk to develop
of the world. The recombinant vaccine is produced fulminant hepatic failure and should be monitored
by inserting the cloned S gene into the yeast genome, closely. In contrast, 80% of patients with acute HCV
resulting in the synthesis of HBsAg, which is subse- are at high risk to develop chronic infection, and a
- study has demonstrated that over 90% of such pa-
cine are highly immunogenic and result in high titers tients will become HCV RNA undetectable if treated
of anti-HBs in over 90–95% of patients within 4–6 with interferon-alpha.38 As mentioned before, the
months of the administration of three doses of vac-
cine. Although the serum titer of anti-HBs declines to have important implications when properly recog-
undetectable levels in approximately 40% of patients nized. As a result, treatment for acute hepatitis can
over decades, immune memory and clinical immunity be recommended in the case of acute HCV, but an
against HBV appear to persist. The need for a booster optimal regimen has not yet been established. Treat-
dose of vaccine is therefore controversial. HBIG plus ment should be delayed 8–12 weeks from the onset
HBV vaccine is indicated for all infants born to moth- of infection to allow for spontaneous resolution,
ers with chronic HBV. In developed countries such as which would preclude the need for pharmacologic
the United States and many European countries, uni- intervention. In patients with symptomatic acute
versal vaccination of all newborns is advocated. This infection and with a favorable IL28B genotype (CC),
strategy is most effective in preventing chronic HBV there is a greater likelihood of spontaneous resolu-
infection. The universal vaccination of all health care tion.39 There are no formal recommendations regard-
ing the use of ribavirin in the setting of acute disease, the inert molecule polyethyleneglycol (PEG) to inter-
and thus its use should be determined on an individ- feron. Peginterferons have a half-life of 46–92 hours
ual basis. Therapy with pegylated interferon therapy and therefore provide continuous antiviral and im-
for acute HCV can be recommended, and the effective munomodulatory activity over several days. The
treatment duration may be shorter than that needed prolonged half-life of these agents allows interferon
for chronic disease, with durations of 12–24 weeks to be dosed once weekly. Peginterferons have been
suggested;40 however, a role for newer, directly-act- shown to be more effective for treatment of chronic
ing antiviral therapies has yet to be determined. HBV and HCV than standard interferons.41
The major limitations of interferon and peginter-
feron are the side effects of these agents.42 Nearly all
Treatment of Chronic Infection -
algias, arthralgias, fever, and headache, which can be
Patients who develop chronic infection with HBV or
severe in up to 10–15%. Other common side effects
HCV are candidates for treatment. Since the rate of
of interferon include thrombocytopenia, neutro-
chronicity is so high following infection with HCV, pa-
penia, diarrhea, thinning of the hair, irritability, de-
tients with acute HCV should also be considered for
pression, and both hyper- and hypothyroidism. Ap-
therapy. An increasing number of therapies are avail-
proximately 20% of patients must reduce the dose of
able for treatment of these chronic viral infections.
peginterferon because of these side effects. However,
Peginterferon is utilized for treatment of chronic
only about 5% of carefully selected patients cannot
HCV, HBV, and HDV superinfection of HBV carriers.
tolerate these adverse events and prematurely dis-
Ribavirin is utilized along with interferon in the
continue peginterferon therapy.
treatment of chronic HCV. Additionally, the direct-
acting antiviral agents (DAAs), boceprevir and tela-
Hepatitis B
previr, have recently been approved in the U.S. for the
The primary goal of HBV treatment is to convert ac-
treatment of patients with genotype 1 chronic HCV
tive infection to an inactive state.43 This is accom-
-
plished by suppressing HBV DNA, which is associat-
veloped for treatment of chronic HBV (Table 12.5).
ed with a decline in serum ALT into the normal range
and improvement in liver histology, including regres-
to be effective in patients with chronic HBV. This
cytokine was subsequently utilized and shown to
liver failure and HCC. HBV DNA suppression can be
be effective for treatment of chronic non-A, non-B
achieved with either peginterferon or one of several
hepatitis several years prior to the development of
antiviral agents.43, 44
serologic testing for HCV and the ability to detect and
Classically, patients with active chronic HBV who
measure HCV RNA. Interferon-alfa has antiviral, an-
require treatment are divided into two groups: those
tiproliferative, and immunomodulatory effects. The
with and those without e-antigen. Patients with e-
antiviral effect of interferon is dependent upon bind-
antigen–positive active HBV typically have persis-
ing to a membrane-associated receptor that triggers
tent elevations in serum ALT, a serum HBV DNA level
a series of intracellular events culminating in the
-
Patients with e-antigen–negative active HBV typi-
thetase and a protein kinase. The immunomodula-
cally have lower levels of serum HBV DNA, >2000 U/
tory effect of interferon is less well understood but
ml, but also have persistent elevations in serum ALT
appears to be equally important in eradicating these
and active hepatitis on liver biopsy. In contrast, pa-
viruses (Figure 12.13).
tients with a persistently normal serum ALT and lev-
One of the limitations of interferon-alfa in treat-
els of HBV DNA below these cutoffs values typically
ing viral hepatitis is the very short half-life of this
agent, only about 6 hours. As a result, long-acting in-
terferons have been produced by covalently linking
Table 12.5
Antiviral Therapy for Chronic Viral Hepatitis
Treatment Duration of therapy Tests to assess response

Hepatitis B (HBV)
Peginterferon-alfa 2a 180 mcg QW Treat for 48 weeks and stop. e-antigen (eAg) positive:
Monitor serum ALT, HBV DNA, eAg, and anti-
HBefor seroconversion (loss of HBeAg and
appearance of anti-HBe).
Lamivudine 100 mg QD Treat indefinitely. eAg negative:
Monitor serum ALT and HBV DNA.
Adefovirdipivoxil 10 mg QD Treat for 6–12 months after HBV eAg eAg positive:
seroconversion (loss of HBV eAg and Monitor serum ALT and HBV DNA for evidence of
appearance of HBV antibody) occurs. resistance.
Entecavir 0.5 mg QD Treat indefinitely. eAg negative:

Monitor serum ALT and HBV DNA for efficacy
and evidence of resistance.
Telbivudine 600 mg QD
Tenofovir 300 mg QD
Hepatitis C (HCV) Duration of therapy Tests to assess response
Treatment
Peginterferon-alfa 2a 180 mcg/week 48 weeks for HCV genotypes 1,4,5,6 Rapid virologic response:
and ribavirin 1000–1200 mg/day Undetectable HCV RNA levels at week 4 of
therapy
Peginterferon-alfa 2b 1.5 mcg/kg/week
and ribavirin 800–1400 mg/day Extended rapid virologic response:
Undetectable HCV RNA levels at week 4 through
Peginterferon-alfa 2a 180 mcg/week 24 weeks for HCV genotypes 2 and 3 week 12 of therapy
and ribavirin 800 mg/day
Early virologic response:
Peginterferon-alfa 1.5 mcg/kg/week 2-log decline in HCV RNA from pre-treatment
2b and 800 mg/day baseline or HCV RNA undetectable at 12 weeks
ribavirin
Virologic response:
180 mcg/week 48 weeks for HCV genotypes 1 HCV RNA undetectable by end of treatment
Peginterferon-alfa 2a 1000–1200 mg/day 24 weeks for HCV genotype 1 with
and ribavirin and 750 mg q8h (12 weeks) eRVR Sustained virologic response:
telaprevir HCV RNA undetectable 24 weeks after treatment
1.5 mcg/kg/week 48 weeks for HCV genotypes 1; was discontinued
Peginterferon-alfa 2b 800–1400 mg/day treatment duration may be decreased
and ribavirin and 800 mg q8h (after 4 to 24 weeks if RVR achieved
boceprevir week lead-in with
peginterferon and
ribavirin)
these latter patients, regardless of e-antigen status, FIGURE 12.13

has not been demonstrated. A small group of patients Mechanisms of Action of Interferon (IFN)
with chronic HBV fall into the “gray zone” between
these two patterns. Some have elevated serum ALT Mechanisms of action of IFN
IFN Mechanism
and low HBV DNA whereas others have a normal ALT IFN
and high levels of HBV DNA. It is important to obtain

serial measurements of the ALT and trend the HBV HCV IFN IFN receptor
DNA in such patients when assessing whether a liver dsRNA

biopsy is indicated to advance a treatment decision.
JAK-STAT signaling
Peginterferon alfa-2a is effective for treatment Transcription of ISGs

of patients with HBeAg-positive chronic active HBV.
The currently licensed dose is 180 mcg/week for 48
P
weeks. Shorter durations of therapy and lower dos- PKR
es of peginterferon have been proposed in patients P

eIF-2
with HBeAg positive chronic HBV; however, these
regimens have been shown to be less effective than
the currently licensed dose.45 Approximately 33% IFNs are proteins produced by nucleated host cells in response to viral infection.
Alpha-IFN is produced by B-cells and monocytes. IFN has both antiviral and
of such patients will achieve seroconversion within immunomodulatory effects. The antiviral effect is caused in part by viral mRNA
3 years, with loss of HBeAg, appearance of anti-HBe, degradation mediated through 2,5-oligoadenylate synthetase, which can activate
normalization in serum ALT, and improvement in liv- ribonucleases. IFN also leads to activation of protein kinase and in turn eukaryotic
initiation factor-2, which inhibits peptide chain initiation. IFN also inhibits viral entry,
er histology. HBeAg seroconversion following treat-
uncoating, mRNA translation, and assembly. The immunomodulatory effects of IFNs
ment with peginterferon is more common than seen are mediated in part by an increase in the expression of human leukocyte antigen
with oral-based therapies but does not occur in ev- (HLA) class I on the surface of hepatocytes, which enhance presentation of virally
ery patient. The resulting HBeAg seroconversion is encoded peptides to sensitized cytotoxic T-cells. Moreover, IFNs increase fragment
crystallizable region receptor expression, and natural killer cell pathways. From Khalili
long lasting, and patients do not require additional M and Perrillo RP. Interferon therapy for hepatitis B. Clin Liver Dis 1999;3:363–87.
therapy except in patients who progress to HBeAg- From Viral Hepatitis Gastro Slide 114, AGA Institute.
negative chronic hepatitis. Those patients most likely
to achieve seroconversion with peginterferon thera- HBeAg seroconversion is typically associated
py have high levels of serum ALT and lower levels of
HBV DNAs. The highest rates of seroconversion are in the aminotransferases during therapy is actually
seen in patients with genotype A where the serocon- desirable. Patients with cirrhosis and marginal he-
version rate is approximately 50%, seen 3–5 years patic function appear to be at increased risk for de-
after completing treatment. compensation during and following treatment with
Peginterferon alfa-2a at a dose of 180 mcg/week interferon. As a result, interferon-based therapy
is also effective in patients with e-antigen–negative should only be considered in rare cases of compen-
chronic active HBV. Approximately 60% of these sated cirrhosis with no evidence of portal hyperten-
patients develop normalization in serum ALT, and sion, but in general, cirrhotic HBV patients should
about 15% become HBV DNA undetectable in serum not receive interferon therapy.
during post-treatment follow up suggesting durable Five oral antivi-
HBV DNA suppression. Combining peginterferon ral agents are currently approved for treatment of
with oral antiviral agents, such as lamivudine, has chronic HBV and have been shown to be highly ef-
not been shown to enhance biochemical or virologic fective in suppressing HBV DNA. These agents are
response regardless of e-antigen status or HBeAg- lamivudine, adefovir, entecavir, telbivudine, and te-
seroconversion in patients with e-antigen-positive nofovir. Decisions for treatment are based on HBeAg
chronic HBV. positivity, HBV viral load, and serum ALT levels; how-
ever, in patients with high normal ALT levels and high over several months to such an extent that they no
HBV DNA levels, liver biopsy may be helpful to docu- longer require liver transplantation.
Due to the long duration of therapy, the main
to make recommendations on therapy. limitation of these oral agents is the development of
In e-antigen–positive chronic HBV, these thera- resistance. Lamivudine has the highest rate of viro-
pies are associated with normalization of ALT values logic resistance: approximately 70% within 5 years
in 50–75% of patients and loss of serum HBV DNA in of starting therapy. Other oral therapies also exhibit
20–75% of patients at the end of 1 year of therapy. varying amounts of resistance at a 5 year follow-up:
adefovir, 29%; entecavir, 1.2%. In contrast, tenofo-
seroconversion, approximately 12–21%, after 48 vir, which has very limited data beyond week 72 of
weeks of therapy, while extension of the duration of therapy, did not generate any resistance to therapy
oral antiviral therapies to 4–5 years was associated although patients in one study with detectable levels
with a progressive increase in the rate of HBeAg of HBV DNA after 72 weeks of tenofovir treatment
seroconversion, to 31%–48%; however, the rate of received additional emtricitabine (FTC). Patients on
HBsAg loss remained low (0%–10%). In HBeAg- antiviral therapies should be monitored for recur-
negative chronic HBV, these therapies normalize rence of HBV DNA every 3–6 months during treat-
ALT levels in 60–80% of patients and loss of serum ment by monitoring for elevations in serum ALT
HBV DNA occurs in 60–93% of patients after 48 levels and serial measurements of HBV DNA levels.
weeks of treatment while extending treatment with Conversion to an alternate antiviral regimen should
these oral agents did not affect HBsAg loss (0%- be considered when patients develop virologic resis-
5%).46 tance (Table 12.6).44
Tenofovir appears to possess the lowest resis- -
tance rate of the oral therapies in treatment-naïve
patients. Unlike interferon-based therapy, no partic- in serum HBV DNA from its nadir during treatment
ular HBV genotype has a higher HBeAgseroconver- in a patient demonstrating virologic response). Vi-
sion rate during treatment with any of the available rologic breakthrough is often related to medication
oral therapies. Once an antiviral agent is initiated, -
this should be continued for at least 12 months after sessed before testing for genotypic resistance. Sever-
HBeAgseroconversion has been documented. If ther- al commercial genotypic resistance assays are avail-
apy is discontinued prior to, or within 3–6 months able; however, reliable performance of these assays
of, seroconversion, active HBV infection will recur. If requires a HBV DNA level greater than 1000 copies/
viral suppression is achieved but HBeAg seroconver- mL. Initially, serum HBV DNA levels tend to be low
sion not achieved, therapy may be continued with a because most antiviral-resistant mutants have im-
-
version may occur later). The oral agents are effec- -
tive at viral suppression in eAg negative patients, but tion in ALT during treatment in a patient who has
in this setting, e seroconversion will not occur, and achieved an initial response) typically follows viro-
thus therapy should be continued unless sAg loss is logic breakthrough, and therapy should ideally be al-
documented. tered before biochemical breakthrough occurs since
The use of antiviral agents has been shown to be
effective in patients with decompensated cirrhosis ALT elevation (greater than 5-times upper limit of
due to chronic HBV. Survival is markedly improved normal) along with hepatic decompensation.
in these patients, and loss of HBV DNA is associat-
ed with a marked improvement in hepatic function. Hepatitis C
More than 50% of patients with acute decompensa- The treatment for chronic HCV is pegin-
tion, when treated with oral therapies, can improve terferon combined with ribavirin.41, 47 Ribavirin is a
Table 12.6
Management of Antiviral-Resistant Hepatitis B Virus (HBV)
Prevention
Avoid unnecessary treatment
Initiate treatment with potent antiviral with low rate of drug resistance or combination therapy
Switch to alternative therapy in patients with primary nonresponse
Monitoring
Test for serum HBV DNA (polymerase chain reaction assay) every 3–6 months during treatment
Check for medication compliance in patients with virologic breakthrough
Confirm antiviral resistance with genotype testing
Treatment
Lamivudine resistance: add adefovir or tenofovir; stop lamivudine and switch to combination of emtricitabine (200 mg) and
tenofovir (300 mg)*
Adefovir resistance: stop adefovir and switch to combination of emtricitabine
(200 mg) and tenofovir (300 mg)*; switch to or add entecavir*†
Entecavir resistance: switch to tenofovir or combination of emtricitabine (200 mg) and tenofovir (300 mg)*
Telbivudine resistance‡: add tenofovir; stop telbivudine and switch to combination of emtricitabine (200 mg) and tenofovir
(300 mg)*
Adapted from Lok AS, McMahon BJ. Chronic Hepatitis B: Update 2009.Hepatology 2009;50:661-2, with permission.
*In HIV coinfected individuals; insufficient in vivo data in those without HIV infection.
Durability of viral suppression unknown, especially in those with prior lamivudine resistance.
†
Clinical data not available.

‡
guanosine nucleoside analogue with broad spectrum agents. In the absence of ribavirin, the relapse rate in
in vitro antiviral activity against many viruses. The patients treated with peginterferonmonotherapy is
exact mechanism of action is unknown, but ribavirin nearly 50%. This is reduced to under 20% when pa-
is phosphorylated intracellularly to form triphos- tients are treated with peginterferon and ribavirin.
phate RTP. The incorporation of RTP by RNA poly- The major side effect of ribavirin is a dose-de-
merase may lead to early termination and inhibition pendent hemolytic anemia, which is exacerbated by
of replication.48 Ribavirin alone affects the replica- the marrow-suppressive properties of interferon.
tion of HCV to only a minimal degree, and treatment More than half of all patients treated with interferon
of HCV patients with ribavirin monotherapy had and ribavirin have a decline in serum hemoglobin of
2–4 g/dl. About 20% of patients have a >4g/dL de-
serum ALT did normalize in up to 80% of patients cline in hemoglobin. This typically responds to low-
treated with ribavirin monotherapy, suggesting that ering the dose of ribavirin. Some patients develop
this agent might be acting as a modulator of the im- very severe anemia and a decline in hemoglobin to
mune response. This is supported by studies in which <8.5 g/dl and must discontinue ribavirin. The kidney
ribavirin has been shown to alter cytokine release. excretes ribavirin. Serum levels of ribavirin increase
Virologic response (VR), the percentage of patients
who become HCV RNA undetectable on treatment, is this enhances the toxicity of this agent. As a result,
increased only marginally when ribavirin is utilized ribavirin must be used with caution and accompa-
nied by appropriate dose reduction in patients with
is to reduce relapse in patients who have become abnormal renal function. Patients with chronic re-
HCV RNA undetectable during treatment with these nal failure on hemodialysis can be treated with this
agent at a dose of 200 mg daily49, 50 combined with >75 kg). In contrast, peginterferon alfa-2b is dosed
reduced dose peginterferon while monitoring for according to body weight, 1.5 mcg/kg/week also
anemia and other side effects. Another adverse effect with weight-based dosing of ribavirin (800 mg for
associated with ribavirin is its teratogenicity. Thus, patients <65kg, 1000 mg for patients 65–85 kg, 1200
women with chronic HCV and the female partners of mg for patients 85–105 kg, and 1400 mg for patients
males receiving HCV treatment must ensure they do
not become pregnant when receiving peginterferon and/or ribavirin may be necessary in the setting of
and ribavirin. As the half-life of ribavirin is very ex- moderate-to-severe anemia, thrombocytopenia, neu-
tended, pregnancy should not be planned until >6 tropenia, or depression. The goal of treating chron-
months after completion of ribavirin therapy. Other ic HCV is to achieve a sustained virologic response
side effects associated with ribavirin include nausea (SVR), and large controlled trials suggest that both
and a pruritic, erythematous rash. These side effects of the interferon agents are similar at achieving this
also improve with dose reduction or discontinuation -
of this agent. tectable 24 weeks after completing a course of inter-
feron and ribavirin. Long-term follow-up of patients
Virologic response to peginterferon and
ribavirin response. The duration of therapy and the SVR that
Two types of peginterferon have been shown to be could be achieved is highly dependent upon the par-
effective for treatment of chronic HCV: peginterferon ticular HCV genotype. Patients with genotypes 2 or
alfa-2a and peginterferon alfa-2b. For genotype 1 3 can achieve a SVR of approximately 80% after 24
HCV disease, peginterferon alfa-2a is administered weeks of therapy. In contrast, the SVR in patients with
genotype 1 is only 40–45% and requires 48 weeks of
of ribavirin (1200 mg/day in individuals who weigh treatment. African Americans, most of whom have
TABLE 12.7
Predictors of Favorable Response to Treatment with Peginterferon and Ribavirin
General Characteristics Pre-Treatment

HCV genotype other than 1 Absence of both insulin resistance and steatosis
Low baseline viral level Statin use
White race
Interleukin-28B genotype* On-Treatment
Absence of fibrosis Response during treatment (RVR or EVR)‡
Body weight <85 Kg Adherence to treatment
Age <40 years Standard dose of ribavirin
Female gender
ALT quotient ≥3†
HCV-specific immune response
* C (vs. T) allele is advantageous for single-nucleotide polymorphism (SNP) rs129789860; T (vs. G) allele is advantageous for SNP rs8099917.
† The alanine aminotransferase (ALT) quotient is the average of the serum ALT level divided by the upper limit of the normal range.
‡ A rapid virologic response (RVR) is defined as an undetectable HCV RNA level (<50 IU/mL) at week 4 of treatment. An early virologic
response (EVR) is defined as a decrease in the HCV RNA level of at least 2 log10 IU/mL or the complete absence of serum HCV RNA at week
12 of treatment.
Adapted from Rosen HR. Chronic hepatitis C infection. New Eng J Med 2011;364:2429-38.
- FIGURE 12.14
viduals of other races, only 25–30%. Patterns of Response to Treatment in Hepatitis Virus C (HCV)
A genetic polymorphism on chromosome 19
in the region of the interleukin-28B gene (IL28B)
encoding IFN- lambda-3 carries a more favorable
7
response rate for HCV genotype 1 disease to stan-
Null response Virologic
dard therapies. The CC genotype is more prevalent 6
Log HCV RNA (IU/mL)

breakthrough Relapse
in European and Asian populations, likely conferring 5

Partial
the higher response rate in this group compared to 4 response
black populations, in which the TT genotype is more 3

prevalent.51 Although testing for IL28B status is
2
clinically available, the predictive value of the IL28B
genotype for SVR has been attenuated by the recent 1 eRVR
SVR
RVR
introduction of directly-acting antiviral agents. The
0 4 12 18 24 30 36 42 48 54 60 66 72
best application of the IL28B test might be to iden- EVR
tify patients who could avoid the use of direct-acting Weeks on Treatment
antiviral agents altogether or to propose a shorter Rapid virologic response (RVR): undetectable hepatitis C virus (HCV) RNA at week 4.
duration of therapy in patients with a favorable Extended RVR (eRVR): HCV RNA <10-15 IU/mL at weeks 4 and 12, as defined by clinical
genotype. Other factors associated with a lower SVR trials with telaprevir-based therapy. Early virologic response (EVR): ≥2 log10 reduction
from baseline HCV RNA, but virus remains detectable (partial EVR) or is undetectable
include male gender, obesity, insulin resistance, and (complete EVR) at week 12. Partial response: ≥2 log10 reduction from baseline
HCV RNA at week 12, but virus remains detectable through week 24 or treatment
liver transplant. (Table 12.7) Patients with genotypes end. Virologic breakthrough: undetectable HCV RNA during treatment followed by
appearance of HCV RNA, despite continued treatment. Sustained virologic response
4, 5, and 6 appear to have SVR closer to that observed (SVR): undetectable HCV RNA at 24 weeks after treatment completion. Relapse:
for genotype 1 than genotypes 2 or 3. undetectable viremia during treatment and/or at the end of treatment, but subsequent
The various patterns in HCV RNA response that viremia following treatment cessation. Null response: detectable circulating HCV
RNA throughout treatment. Null-response: <2 log10 reduction from baseline HCV RNA
can occur during and following treatment with inter-
during treatment. Adapted from Ghany MG, Strader DB, Thomas DL, et al. Diagnosis,
feron are illustrated in Figure12.14. Following the management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-74;
initiation of peginterferon and ribavirin, a rapid and Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated
marked decline in HCV RNA is typically observed.30 chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16.
Patients with rapid virologic response (RVR) are

already HCV RNA undetectable within 4 weeks af-
ter the onset of treatment. RVR occurs in approxi- patients who achieve VR can achieve SVR. As a result,
mately 10–15% of patients with genotype 1, and patients with EVR who fail to become HCV RNA un-
such patients have an SVR approaching 90% if they detectable by week 24 are unable to achieve SVR and
are able to complete their course of therapy. Ap- should discontinue treatment (Table 12.8).40Previ-
proximately 80% of patients with genotype 1 and ous studies have suggested that extending therapy to
>95% of patients with genotypes 2 and 3 achieve 72 weeks in this patient population may enhance the
likelihood of SVR, though this may no longer be rel-
2-log (100-fold) decline in serum HCV RNA from the evant since the emergence of more potent directly-
pretreatment baseline or having undetectable HCV acting antiviral therapies.
RNA in serum within 12 weeks of starting treatment. Overall, patients who have accomplished HCV
Only patients with EVR may eventually achieve SVR RNA negative status while on therapy have a 65–80%
with ongoing therapy. Thus, treatment should be chance of achieving SVR. Patients with genotypes 2
discontinued in the 20–25% of patients who do not and 3 should only be treated for 24 weeks, although
achieve EVR. Patients with a VR are HCV RNA unde- there have been recent studies examining the possibil-
tectable by week 24 of treatment. Again, only those ity of shortening therapy in genotype 2 or 3 patients
with RVR from the standard 24 weeks of therapy to protein 3/4A (NS3/4A) serine protease, boceprevir
14 weeks.52 A longer duration of treatment has not and telaprevir. Both protease inhibitors are indicat-
been shown to enhance SVR in patients with these ed for use inpatients with genotype 1 HCV infection
genotypes. Monitoring changes in HCV RNA during that have not previously received treatment as well
treatment is essential in the management of patients as those who have previously failed interferon-based
with chronic HCV. HCV RNA should be documented at treatment.53-56 Both protease inhibitors are currently
baseline, prior to the onset of therapy, and at weeks 4, indicated for genotype 1 HCV infection though pre-
12, and 24 to quantify the reduction of HCV RNA lev- liminary testing has shown that these agents have
els and document when it became undetectable. HCV antiviral activity against HCV genotype 2 (bocepre-
RNA should then be documented at the end of thera- vir and telaprevir) and genotype 3 (boceprevir).57
py and 24 weeks after the discontinuation of therapy Although both boceprevir and telaprevir must be
to document SVR or relapse. Approximately 20% of administered with peginterferon and ribavirin, their
patients with genotype 2 and 3 relapse following dis- emergence does mark a transition to a new standard
continuation of treatment. Relapse approaches 20% of care in the treatment of genotype 1 chronic HCV
in patients with HCV genotype 1 treated with pegin- infection. (Figure 12.16)
terferon and ribavirin alone. Boceprevir is a linear peptidomi-
The characteriza- meticketoamide serine proteaseinhibitor that binds
tion of the genomic structure of the hepatitis C virus reversibly to the HCV NS3active site. In a response-
(Figure12.15) and its life cycle has led to the devel- guided approach (after a 4-week lead in with pe-
opment of directly acting antiviral agents (DAAs). gylated interferonalfa-2b and weight-based ribavir
to lower viral levels in order to reduce the risk of
peginterferon and ribavirin, DAAs are designed to emergence of drug-resistant mutations), patients
inhibit viral proteins involved in the HCV lifecycle. whose tests for HCVRNA were negative by week 8
The Food and Drug Administration has presently and remained so up to week 24 were given 24 weeks
approved two inhibitors of the HCV nonstructural of boceprevir with peginterferon and ribavirin after
5.15
FIGURE 12.15
Hepatitis C Virology
The genomic structure of the hepatitis C virus (HCV): the cleavage of the polyprotein by viral and host-cell proteases produces both structural
viral proteins (core protein and envelope proteins E1 and E2) and nonstructural viral proteins (NS2 through NS5B), with a number of putative
activities and functions. Potential targets of anti-HCV drugs currently in development are denoted with an X.
Adapted from Rosen HR. Chronic hepatitis C infection. New Eng J Med 2011;364:2429-38., with permission.
Rosen HR. Chronic hepatitis C. NEJM 2011;364:2429-38.

the lead-in phase. Rates of sustained virologic re- anemia (49% compared to 29% of individuals tak-
sponse were 63% among patients receiving a total ing peginterferon and ribavirin alone). In individuals
of 28 weeks of therapy compared to patients receiv- treated with peginterferon, ribavirin, and boceprevir,
ing standard of care peginterferon and ribavirin for anemia necessitating treatment with erythropoietin
48 weeks (38%). Patients who received 48 weeks analogues was reported in 43% of recipients. Addi-
of treatment (i.e., 44 weeks of boceprevir with pe- -
ginterferon and ribavirin after the lead-in period) ceprevir recipients (37% v. 18% of controls). Rash
achieved an SVR rate of 68%.53 In both the 28-week was reported though with less frequency than with
and 48-week boceprevir treatment groups, higher telaprevir.
SVR rates were achieved among whites than among
blacks. Patients with a less than 1.0 log10 IU/mL de- Telaprevir
cline in HCV RNA level during the lead-in phase had Like boceprevir, telaprevir is a selective peptido-
mimetic NS3/4A protease inhibitor that forms a
recommended that patients with compensated cir-
although this recommendation is based on limited FIGURE 12.16

data. Based on modeling, if the virological response Results of Trials Evaluating Combination Protease Inhibitor and Pegin-
did not meet criteria for response-guided therapy terferon/Ribavirin Therapy in Treatment-naïve Patients with Genotype 1
(slow virological response), triple therapy for 32 Chronic HCV Infection
5.16
weeks (preceded by the 4-week lead-in treatment)
followed by 12 weeks of peginterferon and ribavirin
alone is recommended which differs from the phase
3 trial design. All therapy should be discontinued if
to 15 IU/mL at week 24. In patients who were pre-

viously treated with a course of peginterferon and
boceprevir was added to peginterferon and ribavi-

rin therapy, especially in patients who experienced
relapse after completing therapy (patients who
achieved an undetectable HCV RNA level at the end
of a course of peginterferon and ribavirin therapy
but with a recurrence of detectable HCV thereafter)
with an increase in SVR to 75% compared to 29% in
those treated with standard peginterferon and riba-
virin alone. In patients who experienced a decrease
in HCV RNA level of 1 log10 IU/mL or more after the
lead-in period (partial responders), SVR rates of 79%
were reported, while patients with a poor response
Rosen HR. Chronic
The trials hepatitis C.follows:
shown are as NEJMADVANCE
2011;364:2429-38.
and SPRINT-2. B/RGT denotes boceprevir
in the HCV RNA level of less than 1 log10 IU/mL after plus response-guided therapy, PR peginterferon–ribavirin, PRB peginterferon–ribavirin
the lead-in period (null responders) achieved an SVR plus boceprevir, and T telaprevir. Numbers denote numbers of weeks of treatment; for
rate of 34%. Bocepreviris dosed at 800 mg given by example, patients randomly assigned to T12PR24 received telaprevir for 12 weeks,
mouth every eight hours with food. In addition to ad- followed by peginterferon–ribavirin for 12 more weeks.
verse effects of peginterferon and ribavirin therapy, Adapted from Rosen HR. Chronic hepatitis C infection. New Eng J Med 2011;364:2429-
38., with permission.
the principal adverse effect of boceprevir included
Table 12.8
Virological Responses and Definitions
Virological response Definition Clinical utility

Rapid virological response (RVR) HCV RNA negative at treatment week 4 by a sensi- May allow shortening of course for genotypes
tive PCR-based quantitative assay 2 and 3 and possibly genotype 1 with low viral
load
Extended rapid virological response HCV RNA negative at treatment week 4 through May allow shortening of course for genotype 1
(eRVR) week 12 by a sensitive PCR-based quantitative on telaprevir, peginterferon and ribavirin treat-
assay ment
Early virological response (EVR) 2-log reduction in HCV RNA level compared to Predicts likelihood of achieving a sustained
baseline (partial EVR) or HCV RNA negative at virologic response (SVR)
treatment week 12 (complete EVR)
End-of-treatment response HCV RNA negative by a sensitive test at the end of
24 or 48 weeks of treatment
Sustained virological response (SVR) HCV RNA negative 24 weeks after cessation of Best predictor of long-term response to treat-
treatment ment
Breakthrough Development of viral resistance while on therapy
with directly acting antiviral agent
Relapse Reappearance of HCV RNA in serum after treat-
ment is discontinued
Partial responder 2-log decrease in HCV RNA but still HCV RNA posi-
tive after 24 weeks of treatment
Null responder Failure to decrease HCV RNA by <2 logs after 24
weeks of treatment
HCV, hepatitis C virus; PCR, polymerase chain reaction.
Adapted from Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, Management, and Treatment of Hepatitis C: An Update. Hepatology 2009;49:1335-74, with
permission.
covalent, reversible enzyme-inhibitor complex. terferon and ribavirin, for a total of 48 weeks. In pa-
tients who achieved eRVR (of which more than half
dosepeginterferon-alfa-2a and ribavirin was shown of the telaprevir-treated patients achieved), duration
of treatment was shortened to 24 weeks of total ther-
(75%) when evaluated in aresponse-guided antivi- apy and was associated with an SVR rate higher than
ral strategy when compared to standard of care pe- 80%. Virologic failure was more common in patients
ginterferon and ribavirin (44%) in treatment-naïve with genotype 1a than in those with genotype 1b.In
patients infected with genotype 1 HCV infection. In treatment-experienced patients, the addition of tela-
contrast to boceprevir, telaprevir was administered -
creases the SVR, particularly in prior relapsers with
weeks or for 8 weeks, followed by 4 weeks of place- SVR rates approaching 90% in this group compared
bo. Patients who did not have an extended rapid vi- to those treated with standard peginterferon and
ribavirin alone (24%). SVR rates of 59% were re-
HCV RNA level (<25 IU/mL) at week 4 and at week ported in previous partial responders (compared to
12 of therapy, received 36 additional weeks of pegin- 15% in peginterferon and ribavirin-treated controls)
and ~30% in prior null responders (compared to 5% available for prevention of recurrent HBV and HBV
in controls).Telaprevir is dosed at 750 mg given by plus HDV coinfection. However, no effective treat-
mouth every eight hours with food. Major side effects ment is available for preventing recurrence of HCV.
of telaprevir included rash, pruritus, anemia, and Patients with recurrent HCV following liver trans-
gastrointestinal symptoms. Rare but serious skin re-
actions resulting in death from progressive rash and much more rapid rate than following the initial infec-
systemic symptoms have been reported recently. It tion. In general, approximately 25–33% of patients
is now recommended that discussion of these risks
occur prior to starting therapy with immediate dis- cirrhosis within 5 years of undergoing transplanta-
continuation of all three components of combination -
treatment, including peginterferon and ribavirin, sis progression in this setting remain controversial.
should serious skin reactions arise on therapy. Response to peginterferon and ribavirin therapy in
SVR rates achieved with the arrival of boceprevir reduced compared to other patients with chronic
and telaprevir, treatment of genotype 1 HCV con- HCV. Only about 25–40% of patients achieve SVR.
tinues to be limited by the continued requirement
of peginterferon and ribavirin. A further potential therapy with DAAs additional to peginterferon and
limitation in the administration of DAAs to standard ribavirin suggest that the drug-drug interactions be-
peginterferon and ribavirin is the potential for drug- tween protease inhibitors and immune suppression
drug interactions as both boceprevir and telaprevir can be monitored, but the data are limited.59 Despite
can inhibit hepatic drug-metabolizing enzymes such this poorer response, therapy should be considered
as cytochrome P450 2C (CYP2C), CYP3A4, or CYP1A. in post-transplant patients with aggressive histology,
Boceprevir and telaprevir were noted to cause in- as the outcomes associated with repeat transplanta-
teractions with statins, immune suppressants, and tion for patients with aggressive HCV are mixed, and
drugs used to treat HIV coinfection, opportunistic retransplantation for recurrent HCV is controversial
infections, mood disorders, and drug addiction sup- in many centers.60
port medications.57 Newer direct-acting antiviral -
therapies, including NS3 protease, NS5A replication
complex and NS5B polymerase (nucleos/tide and of immune suppression, and these patients develop
non-nucleoside) inhibitors, are currently in clinical cirrhosis, graft failure, and typically die within only
trials and offer the hope of treatment without the 2–4 years following transplantation unless recur-
burden of interferon-induced adverse effects. These rence can be prevented. HBIG has been successfully
future therapies, some of which are free of interferon utilized to prevent reinfection of the liver allograft
and/or ribavirin and, more promisingly, as short as following liver transplantation in patients with HBV.
12 weeks in duration, may enable patients with mild- HBIG should be administered intravenously at high
er disease to forego the current standard of care.58 doses during the anhepatic phase of the transplant
and at regular doses thereafter to maintain adequate
Liver transplantation levels of circulating HBsAb. The frequency of HBIG
Liver transplantation is indicated for patients who administration and level of circulating antibodies
have developed fulminant hepatic failure from se- necessary to prevent reinfection of the allograft re-
vere acute viral hepatitis and complications from mains controversial. However, it has been repeat-
cirrhosis, including variceal hemorrhage, ascites, he- edly demonstrated that passive prophylaxis with
patic encephalopathy, liver failure, and HCC. Recur- HBIG alone can prevent reinfection of the allograft
rence of viral hepatitis B, C, and B and D coinfection in nearly all patients who enter the transplant with
are nearly universal following transplantation unless inactive HBV, i.e., anti-HBe positive and undetect-
effective prophylaxis is utilized. Such treatment is able HBV DNA. In order to reduce HBV viral load and
replication in the pre-transplant population, these

with increasing age with an overall incidence of
patients are routinely placed on oral antiviral thera-
fulminant hepatic of 0.1–0.3% but increases to as
pies. In contrast, approximately 33–67% of patients
high as 1.8% in patients age >49.
who enter the transplant with active HBV, i.e., HBeAg
Fulminant hepatic failure occurs in about 0.1%
positive and HBV DNA positive, develop recurrence
of patients following acute infection with HAV, in
of HBV within the allograft despite HBIG administra-
about 1% of patients following acute HBV, and in up
tion, with higher rates occurring in cirrhotics with
to 20–25% of individuals following coinfection with
active replication. A number of studies have recently
HBV and HDV.
Nearly 90% of individuals exposed to HBV during
antivirals with or without HBIG therapy post-trans-
the perinatal period develop chronic infection
plant. Combination therapy has typically involved
though chronicity of infection declines to 50% if
-
the exposure occurs during childhood and to ~5% in
py;61 however, more recent studies have demonstrat-
adults; whereas chronic viral hepatitis is reported to
-
occur in 60–85% of patients exposed to HCV.
ing patients from low dose HBIG and lamivudine to
Hepatocellular carcinoma (HCC) can develop in the
combination oral therapy as well as the possibility of
setting of cirrhosis from any etiology, this risk is
using a single agent (entecavir) without HBIG after
particularly increased in patients with chronic HBV
transplant.62, 63 Ultimately, once transplant recipients
and HCV however, HCC may develop in patients
have developed recurrence of HBsAg, continued ad-
with chronic HBV without cirrhosis resulting from
ministration of HBIG is no longer useful.
chronicity of infection and viral load.
Surveillance is recommended for all cirrhotic patients
Recurrence of HCV in the al-
regardless of the etiology of their liver disease with
lograft is nearly universal as outlined above. Several
further recommendations for HBV carriers who are
groups have examined the potential for interferon
Asian males over the age of 40, all Asian females
and ribavirin-based therapy prior to transplant as a
over the age of 50, those with a family history of
means of preventing allograft infection. These strat-
HCC, and Africans over the age of 20.
egies have typically employed low, escalating doses
Chronic HCV infection is found in over 90% of patients
of interferon and ribavirin, often employed just prior
with essential mixed cryoglobulinemia (EMC), and
to anticipated transplant. The rate of viral eradica-
>98% of patients with membranoproliferative
tion in the pre-transplant setting appears to be mod-
glomerulonephritis (MPGN) have chronic HCV
est, particularly in patients with genotype 1 disease.
infection and cryoglobulinemia.
Moreover, the complication rates associated with
Eradication of HCV RNA in patients with EMC and
therapy in the cirrhotic, pre-transplant population
MPGN may result in a decline in proteinuria and
are high. The emergence of DAAs may enhance the
improvement in renal function.
response to interferon in this population; however,
40–50% of patients with polyarteritisnodosa (PAN)
in this patient population, considerable risk has been
are found to be positive for HBV surface antigen
(HBsAg), and antiviral agents for HBV have the
anemia necessitating transfusion, high risk of sepsis,
potential to improve morbidity and mortality in
-
patients with PAN.
perienced clinicians.64-66
Genotype A of the HBV is most common in non-Asian

Americans, whereas genotypes B, C, and D are most
Pearls and Pitfalls commonly found in Asians. HBV genotype A patients
with either high serum ALT levels or low HBV DNA
for the Board Exam levels are most responsive to peginterferon alpha
The risk of developing icteric disease and fulminant
therapy while Genotype D patients are the least
hepatic failure following acute HAV increases
responsive to treatment with peginterferon. ribavirin.

The natural history of chronic HBV may progress Overall, on treatment viral kinetics are the best
along two divergent pathways: chronic active predictors of response to therapy in chronic HCV as
HBV infection marked by HBsAg, HBeAg, HBV patients who have accomplished HCV RNA negative
DNA, and elevated serum liver aminotransferases status while on therapy have a 65–80% chance of
progressing to cirrhosis/liver failure or spontaneous achieving sustained virologic response (SVR).
seroconversion which occurs in approximately 5% of It is recommended that patients with compensated
patients with chronic active HBV on a yearly basis cirrhosis receive fixed duration (48 weeks) of triple
which may present as a clinical picture similar to therapy with boceprevir, peginterferon and ribavirin
acute fulminant hepatic failure. while triple therapy for 32 weeks (preceded by the
Despite seroconversion (which is marked by the 4-week lead-in treatment) followed by 12 weeks of
spontaneously loss of HBsAg and development of peginterferon and ribavirin alone can be pursued
HBsAb), patients who clear HBsAg after the age of if the virological response did not meet criteria for
50 or after the development of cirrhosis are still at response-guided therapy (slow virological response).
increased risk of developing HCC. In contrast to boceprevir, telaprevir is administered
The clinical course of HDV depends in large part with peginterferon and ribavirin for the first 12
on the timing of HDV infection relative to that of weeks, and patients who achieved eRVR (defined
HBV and how these two viruses interact within the as an undetectable HCV RNA level at week 4 and
host: coinfection can result in severe acute icteric at week 12 of therapy), duration of treatment was
hepatitis while superinfection of HDV in an individual shortened to 24 weeks of total therapy with an SVR
with chronic HBV results in acute hepatitis and may rate higher >80%.
lead to rapidly progressive liver failure in previously Boceprevir and telaprevir cause interactions with
stable chronic HBV. statins, immune suppressants, drugs used to treat HIV
Fulminant hepatic failure resulting from acute HEV coinfection, opportunistic infections, mood disorders, and
is uncommon and develops in about 0.1–1% of drug addiction support medications.
patients except during pregnancy, where this occurs Approximately 25–33% of patients with recurrent HCV
in up to 15–25% of susceptible women. develop advanced fibrosis or cirrhosis within 5 years
In e-antigen–positive chronic HBV, oral antiviral of undergoing transplantation. Only about 25–40% of
therapies are associated with normalization of ALT patients achieve SVR with peginterferon and ribavirin
values in 50–75% of patients and loss of serum HBV alone; unfortunately, studies examining the safety
DNA in 20–75% of patients at the end of 1 year and efficacy of triple therapy with protease inhibitors
of therapy with each agent having similar efficacy additional to peginterferon and ribavirin are lacking.
for HBeAgseroconversion (~12–21%, after 48
weeks of therapy). In HBeAg-negative chronic HBV, Acknowledgements
these therapies normalize ALT levels in 60–80% The authors acknowledge the previous contributions from
of patients and loss of serum HBV DNA occurs in Neeral Shah, MD to this revised chapter.
60–93% of patients.
Patients with advanced decompensated cirrhosis
due to chronic HBV can improve over several months
to such an extent that they no longer require liver
transplantation when treated with oral antiviral for Examination Preparation
therapies. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis,
Patients with significant renal dysfunction requiring management, and treatment of hepatitis C: an
hemodialysis can be treated with reduced dose update. Hepatology 2009;49:1335-74.
peginterferon alfa-2a along with 200 mg/day of Ghany MG, Nelson DR, Strader DB, et al. An update
15. Bruix J, Sherman M, Practice Guidelines Committee AAf-

on treatment of genotype 1 chronic hepatitis C virus tSoLD. Management of hepatocellular carcinoma. Hepa-
infection: 2011 practice guideline by the American tology 2005;42:1208-36.
Association for the Study of Liver Diseases. 16. Amarapurkar DN, Amarapurkar AD. Extrahepatic mani-
Hepatology 2011;54:1433-44. festations of viral hepatitis. Ann Hepatol 2002;1:192-5.
Lok AS, McMahon BJ. Chronic hepatitis B: update 17. Han SH. Extrahepatic manifestations of chronic hepatitis
B. Clin Liver Dis 2004;8:403-18.
2009. Hepatology 2009;50:661-2.
18. Coccoli P, Esposito P, Cianciaruso B, et al. Hepatitis C and
Rosen HR. Chronic hepatitis C infection. N Eng J kidney disease. Dig Liver Dis 2007;39 Suppl 1:S83-5.
Med 2011;364:2429-38 19. Saadoun D, Resche Rigon M, Sene D, et al. Rituximab
plus Peg-interferon-alpha/ribavirin compared with Peg-
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with renal failure. Arch Med Res 2007;38:628-33.
CHAPTER 13
Cirrhosis and Liver Transplantation
Guadalupe Garcia-Tsao, MD
Learning Objectives
1. Describe the natural history of cirrhosis.
2. Recognize the most appropriate management for patients with compensated cirrhosis.
3. Recognize the most appropriate management for patients with decompensated cirrhosis.
4. Identify candidates for liver transplantation and recognize its indications and contraindications
Introduction
conversion of normal architecture into structurally abnormal nodules (Figures 13.1 and 13.2). The process is
two main stages, referred to as compensated and decompensated.1,2
or jaundice (Figure 13.3).1 These are complications that result from the main consequences of cirrhosis: portal
-
diac output, decreased blood pressure) secondary to systemic vasodilatation. This hyperdynamic circulation
contributes to the development of the complications of cirrhosis, such as variceal hemorrhage and ascites,
and to further decompensation in the form of refractory ascites, dilutional hyponatremia, and the hepatorenal
syndrome (Figure 13.5).
Clinical signs of portal hypertension and the hyperdynamic circulation are splenomegaly, caput medusae,
-
tests including serum albumin, total bilirubin, and prothrombin time.

The transition from compensated to decompensated cirrhosis usually takes many years, occurring at a
rate of 5–7% per year. The development of hepatocellular carcinoma (HCC) will accelerate the progression of
cirrhosis at any stage (Figure 13.6). The prognosis of cirrhosis is dependent on whether a patient has com-
pensated or decompensated cirrhosis at diagnosis. The median expected survival in patients with compen-
sated cirrhosis is around 12 years (or more), while median survival with decompensated cirrhosis is about 1.5
years.1 To improve survival rates, clinicians must have an understanding of the management, screening, and
prevention of complications in patients with cirrhosis, as well as an understanding of the issues that identify
candidates for liver transplant.
389
FIGURE 13.1 GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER
Gross Images of Normal and Cirrhotic Livers
Normal Cirrhosis
Irregular surface
Nodules
Left is a normal liver with a smooth surface and homogeneous appearance. Right is a cirrhotic liver with an irregular surface and nodules that
give it a heterogeneous appearance. (Courtesy of Dhanpat Jain, MD.)
FIGURE 13.2 HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER
Histological Images of Normal and Cirrhotic Livers
Normal Cirrhosis
Nodules surrounded by
fibrous tissue
Left is a normal liver with conserved architecture. Right is a cirrhotic liver with regenerative nodules surrounded by fibrous tissue (stained blue).
(Courtesy of Dhanpat Jain, MD.)
Chapter 13 — Cirrhosis and Liver Transplantation 391
FIGURE 13.3
Natural History of Chronic Liver Disease
NATURAL HISTORY OF CHRONIC LIVER DISEASE
Natural History of Chronic Liver Disease
Chronic
liver Compensated Decompensated
cirrhosis cirrhosis Death
disease
Development of
complications:
Variceal hemorrhage
Ascites
Encephalopathy
Jaundice
Cirrhosis represents the end histological stage resulting from chronic liver injuries of various etiologies. Initially, cirrhosis is compensated. The
transition to a decompensated stage is marked by the development of variceal hemorrhage, ascites, hepatic encephalopathy, and/or jaundice.
Once decompensation occurs, the patient is at risk of death from liver disease.
Cirrhosis
and Liver
FIGURE 13.4
Portal Hypertensive Hemorrhage Complications of Cirrhosis
Transplan-
COMPLICATIONS OF CIRRHOSIS
varices, or portal hypertensive gastropathy. Varices

and variceal hemorrhage are the complications of cir- Complications of Cirrhosis Result from Portal
rhosis that result most directly from portal hyperten- Hypertension or Liver Insufficiency
tation
sion.3 Portal pressure is commonly determined by
measuring the hepatic venous pressure gradient
Portal
hypertension
Variceal hemorrhage
(or occluded) pressure minus the free hepatic vein Ascites

pressure. Portal hypertension exists when there is Cirrhosis
cirrhosis and HVPG is elevated above normal (5 mm Encephalopathy
Hg). The formation of gastroesophageal varices occurs Liver
insufficiency
Jaundice
>10 mm Hg.4 Gastroesophageal varices are present
in approximately 50% of patients with newly diag-
nosed cirrhosis and the majority of patients have Cirrhosis leads to two clinical syndromes: portal hypertension and liver insufficiency.
an HVPG of at least 12 mm Hg.5 The prevalence of Development of variceal hemorrhage and ascites are the direct consequence of portal
varices correlates with the severity of liver disease, hypertension, while jaundice occurs as a result of a compromised liver function.
Encephalopathy is the result of both portal hypertension (portosystemic shunting)
ranging from 40% in patients with Child’s class A cir- and liver dysfunction (decreased ammonia metabolism). Ascites in turn can become
rhosis to 85% in patients with Child’s class C cirrho- complicated by infection (spontaneous bacterial peritonitis) and by the development
sis (Figure 13.7). of a functional renal failure (hepatorenal syndrome).
This section reviews the current approach to the
prevention of initial and recurrent variceal hemor-
FIGURE 13.5
More Complications of Cirrhosis
Hyperdynamic
Circulation
Variceal
hemorrhage
Varices
Portal
Hypertension RA/DH
Ascites
Cirrhosis HRS
Liver
Insufficiency Encephalopathy
Jaundice
Further decompensation of cirrhosis is due to development of a hyperdynamic circulatory state that is due to splanchnic and
systemic vasodilatation. This hyperdynamic circulatory state is responsible for variceal growth and hemorrhage, development of
ascites and its complication: refractory ascites (RA), dilutional hyponatremia (DH), and the hepatorenal syndrome (HRS).
FIGURE 13.6
Hepatocellular Carcinoma can Complicate both Compensated and Decompensated Cirrhosis
NATURAL HISTORY OF CHRONIC LIVER DISEASE
Hepatocellular carcinoma
Chronic
liver Compensated Decompensated
cirrhosis cirrhosis Death
disease
Development of
complications:
Variceal hemorrhage
Ascites
Encephalopathy
Jaundice
The development of hepatocellular carcinoma can occur in both the compensated and the decompensated patient with cirrhosis,
and therefore it is not a distinct stage of cirrhosis. In the compensated patient, hepatocellular carcinoma can precipitate decompen-
sation. In the decompensated patient, it can lead to further decompensation and death.
FIGURE 13.7
Prevalence of Esophageal Varices in Cirrhosis
PREVALENCE OF ESOPHAGEAL VARICES IN CIRRHOSIS
Prevalence of Esophageal Varices in Cirrhosis
100
80
60
%
40
20
0
Overall Child A Child B Child C
Cirrhosis
Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72
Gastroesophageal varices are present in ~50% of cirrhotic patients at large. However, the prevalence of varices varies accord-
and Liver
ing to the severity of liver disease, ranging from 40% in Child class A cirrhotic patients to 85% in Child class C cirrhosis. From
Pagliaro et al. In Portal Hypertension: Pathophysiology and Management. 1994:72.
Transplan-
rhage, management of acute variceal hemorrhage,
and treatment of portal hypertensive gastropathy.
tation hemorrhage by 50%.7 In high-quality randomized
controlled trials, endoscopic variceal ligation (EVL)
Prevention of First Variceal Bleeding Therefore, either of

8,9
these therapies should be used for the prevention of

Variceal hemorrhage occurs at a yearly rate of
5–15%, and the most important predictor of hemor-
The choice of treatment is based on local re-
sources and expertise, patient preference and char-
orrhage (15% per year) occurs in patients with large
acteristics, side effects, and contraindications. A
varices. Other predictors of hemorrhage are decom-
decrease in HVPG >10% in patients treated with
pensated cirrhosis (patients with Child’s class B or C
cirrhosis) and the presence of red wale signs on up-
per endoscopy.6
death.10
vasodilatory properties, is a promising alternative
lol, nadolol) reduce portal pressure by reducing por-
therapy that deserves further evaluation.11 It could
be used (at a dose of 12.5 mg/day) in patients who
are intolerant to propranolol or nadolol and who are
tion) blocking effect. In patients with cirrhosis and
not candidates for ligation. Nitrates alone are not ef-
medium/large varices that have never bled, nonse-
FIGURE 13.8
Management Algorithm for Primary Prophylaxis of Variceal Hemorrhage
Primary Prophylaxis of Variceal Hemorrhage
Diagnosis of Cirrhosis
Endoscopy (EGD)
No Varices Small Varices Medium/Large Varices
Follow-up EGD in 2-3 years* Red signs or Child C

No Yes
Beta-blockers Beta- Beta-blockers

optional blockers or EVL**
If not given, follow-
up EGD in 1-2 years*
*If cirrhosis is decompensated, follow-up EGD should be done every year.

†Dose of nonselective -blockers (propranolol, nadolol) should be increased stepwise until the maximum tolerated dose or until a resting
heart rate of 50–55/min; there is no need to repeat endoscopy once the patient is on nonselective -blockers.
‡Choice between -blockers or EVL depends on local resources and expertise, patient preference and characteristics, side effects, and
contraindications.
FIGURE 13.9
Prophylactic Antibiotics Improve Outcomes are associated with an increased long-term mortal-
in Cirrhotic Patients with GI Hemorrhage ity in patients over the age of 50. The combination of
variceal hemorrhage beyond that achieved with either

Prophylactic Antibiotics Improve Outcomes
therapy alone. Prophylactic portosystemic shunt sur-
in Cirrhotic Patients with GI Hemorrhage
gery should not be used because although it is bene-
60
No antibiotics
Antibiotics has been associated with an increased rate of hepatic
40 encephalopathy and an increased mortality. This rec-
% ommendation also extends to the prophylactic use of
*
20
* * other types of shunt therapies such as the transjugu-
lar intrahepatic portosystemic shunt (TIPS).
0
Infection Death Rebleeding Thus, the treatment of choice for the prevention
Bernard et al., Hepatology 1999; 29:1655 Hou M-C et al.,
of initial variceal bleeding in patients with medium- to
(Meta-analysis of 5 trials) Hepatology 2004; 39:746
* Significantly lower
or EVL (Figure 13.8). While repeat endoscopies are
necessary in patients after EVL, they need not be re- FIGURE 13.10
Management Algorithm in Acute Esophageal Variceal Hemorrhage
have small varices with red wale signs, or severe liver
as high as for patients with large varices. Because these

Management of Acute Variceal Hemorrhage
Variceal Hemorrhage Suspected
Transfuse to hemoglobin ~ 7-8 g/dL
Initial Management Early pharmacotherapy
Antibiotic prophylaxis
ered optional because they may prevent their growth
and thereby may prevent hemorrhage.12 Nonselective Endoscopy (within 12 hours): variceal hemorrhage confirmed
Perform EVL (sclerotherapy if EVL not possible)

in preventing the development of varices in patients
with cirrhosis and portal hypertension who have not High risk patients:
Child C (<14 points) or
Not high risk
yet developed varices.13,14 Child B with active

hemorrhage Continue vasoactive
drug
Early TIPS (<72 hours)
should be considered TIPS,, if bleeding persists or
with severe rebleeding
Management of Acute Variceal Bleeding
The initial therapy for acute variceal hemorrhage is
resuscitation in an intensive care unit. Blood volume
Cirrhosis
restitution should be undertaken promptly but with
caution, with the goals of maintaining hemodynamic FIGURE 13.11
stability and hemoglobin around 7–8 g/dlL.13,14 Over- Management Algorithm for Patients Bleeding from Gastric Varices
and Liver
transfusion or volume overexpansion can precipitate
variceal rebleeding and as recently shown in a ran-
domized clinical trial that included patients with cir-
Transplan-
rhosis, a restrictive transfusion strategy (transfusion
when the hemoglobin fell below 7 g/dl with a target
vival.15
tation
The incidence of bacterial infections in patients
with cirrhosis who are admitted to the hospital with
an upper gastrointestinal (GI) bleed is 45%. Prophy-
lactic antibiotics have been shown not only to lower
the rate of bacterial infections (including spontane-
ous bacterial peritonitis), but also to reduce the risk
of rebleeding and death.16 This applies to patients,
with or without ascites, admitted to the hospital with
upper GI bleeding (variceal or nonvariceal) (Figure
cin; however, intravenous ceftriaxone should be con- In patients with acute gastric variceal bleeding, initial management consists of
sidered in patients with advanced cirrhosis who are transfusion to a hemoglobin of 7–8 g/dl, pharmacotherapy with vasoactive agents,
and antibiotic prophylaxis. If cyanoacrylate is available, obturation of the gastric
hospitalized in settings with a high prevalence of
varices is attempted with cyanoacrylate. If cyanoacrylate is not available or if bleeding
cannot be controlled, then transjugular intrahepatic portosystemic shunt (TIPS) is
17
recommended. A surgical shunt may be considered in patients with Child-Pugh class
The most effective approach for the control of ac- A cirrhosis.
tive variceal hemorrhage is combined therapy with
a systemic vasoconstrictor and endoscopic therapy. effective than EVL and is the recommended treatment
Safe vasoconstrictors include terlipressin, soma- (Figure 13.11). Even though the off-label use of octyl-
tostatin, and somatostatin analogues (octreotide, va- cyanoacrylate has been reported in the U.S., the FDA
preotide). These agents should be initiated at admis- has not yet approved these adhesives. Where glue or
sion to the hospital and continued for up to 5 days. expertise are unavailable, TIPS should be considered
The vasoconstrictor currently available in the United
States is octreotide, which is used as a 50-µg bolus varices.14 Balloon-occluded retrograde transvenous
followed by an infusion of 50 µg/hour.13,14 obliteration (BRTO) is a technique that obliterates
Octreotide has replaced vasopressin and nitrates gastric varices via an endovascular approach. It can be
in controlling acute variceal bleeding because it has no performed when TIPS is contraindicated and/or when
major side effects and has been shown to be effective.18 endoscopic management fails.21 BRTO is widely used
Endoscopic variceal ligation (EVL) is the endoscopic in Asia and is gaining popularity in the United States.
treatment of choice for hemostasis of active esopha- The primary indication for TIPS in variceal bleed-
geal variceal hemorrhage, and is successful in 70–90%
ing is failure of endoscopic/drug therapy. However,
of cases. EVL is a local therapy aimed at variceal oblit- data from a randomized controlled trial show that
eration through the placement of rubber rings on vari- early (within 72 hours) TIPS placement in Child’s
ceal columns. It is more effective than sclerotherapy class C patients (with a score <14 points) or in Child’s
and is associated with fewer side effects.19 However, class B patients with active hemorrhage following
in patients for whom EVL is not feasible, sclerotherapy initial vasoactive/endoscopic therapy is associated
is a reasonable alternative. (Figure 13.10). with improved outcomes including survival.22 There-
Gastric varices are less prevalent than esoph- fore, early TIPS placement should be considered in the
ageal varices, yet are present in 5–33% of patients subgroup of patients with acute variceal hemorrhage,
with portal hypertension. Type 1 gastric varices even in the absence of failure of endoscopic/drug ther-
(GOV1) are the most common and are located along apy (Figure 13.10). In all other patients, TIPS should be
the lesser curvature of the stomach. Type 2 (GOV2) ex- performed after endoscopic/drug therapy has failed.
tend from the esophagus below the gastroesophageal Balloon tamponade is very effective in control-
junction toward the fundus; type 3 (IGV1), are isolat- ling bleeding temporarily. However, its use is associ-
ed varices located in the fundus; and type 4 (IGV2) ated with potentially lethal complications and should
are isolated ectopic varices located in the antrum, be restricted to patients with uncontrollable bleed-
corpus, and around the pylorus.
The presence of IGV1 (fundal) varices necessi- is planned within 24 hours. When bleeding is from
tates the performance of Doppler ultrasound of the fundal varices, only the gastric balloon needs to be
splenic vein to exclude the presence of splenic vein
thrombosis. Bleeding from GOV1 varices is generally esophageal varices, an initial trial with gastric balloon
treated successfully with EVL. Gastric varices located -
in the fundus (GOV2 or IGV1) are much less common, geal balloon only if bleeding persists. (http://www.
but are important to detect since they pose a higher youtube.com/watch?v=imFCMWeWDpU&NR=1)
risk of massive bleeding than esophageal varices. Fur- Uncontrolled data suggest that placement of a self-
thermore, bleeding from GOV2 and IGV1 varices is not expanding covered esophageal stent may be an option
as well controlled by standard endoscopic therapy. If for refractory esophageal variceal bleeding, but fur-
isolated fundal varices are secondary to splenic vein ther evaluation is needed. Emergency surgical shunt
thrombosis, then the treatment of choice for bleeding surgery is an option if all else fails, but the high mor-
is splenectomy.20 tality rate of shunt surgery limits its application in the
For bleeding fundal varices (GOV2 or IGV1), oblit- setting of acute variceal hemorrhage.
eration with tissue adhesives such as butyl-cyanoac-
rylate (also referred to as ) is more
FIGURE 13.12
Lowest Rebleeding Rates Obtained in Patients Treated with Variceal Band Ligation Plus -Blockers and in HVPG Responders
LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERS
Lowest Rebleeding Rates are Obtained With

Ligation + -Blockers and in HVPG Responders
80
60
%
40
Rebleeding
20
0
Untreated -blockers Sclero- -blockers Ligation Ligation HVPG-
therapy + ISMN + pharma* responders
(19 trials) (26 trials) (54 trials) (6 trials) (7 trials) (5 trials) (6 trials)
From Bosch and Garc a-Pag n, Lancet 2003; 361:952 * non-selective -

and Garcia-Tsao and Bosch, NEJM 2010. blockers ± nitrates
Cirrhosis
Next to hepatic venous pressure gradient (HVPG) responders (i.e., patients who achieve a reduction in HVPG <12 mm Hg or >20% from baseline)
in whom the rebleeding rate is ~10%, patients treated with combination pharmacological (nonselective blockers ± nitrates) plus endoscopic
band ligation have the lowest rebleeding rates of around 14%. Rebleeding rates with these two therapies are placed in the context of no
and Liver
therapy (red bar) and other less-effective therapies (orange and yellow bars). From Bosch J, Garcia-Pagan JC. Prevention of variceal
rebleeding. Lancet 2003;361:952–54. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J
Med 2010;362:823–32. Lo GH, et al., Hepatology 2000;32:461. De la Pena J, et al., Hepatology 2005;41:572.
FIGURE 13.13 Transplan-

tation
Management Algorithm for Prevention of Recurrent Variceal Hemorrhage
MANAGEMENT ALGORITHM FOR THE PREVENTION OF RECURRENT VARICEAL HEMORRHAGE
Prophylaxis of Recurrent Variceal Hemorrhage
Control of Acute Variceal Hemorrhage
Pharmacological therapy
plus
Endoscopic Variceal Band Ligation
Recurrent Hemorrhage
NO YES
Surveillance Endoscopy Is patient on EVL + Pharmacotherapy?

and/or
NO YES
Life-long Pharmacotherapy
Initiate combination Rx TIPS/Shunt Surgery
Further bleeding
Prevention of Recurrent Variceal Treatment of Portal Hypertensive

Hemorrhage
Gastropathy and Gastric Antral
Patients who survive an episode of acute variceal
hemorrhage have a very high risk of rebleeding and Vascular Ectasia
death. The median rebleeding rate in untreated indi- Portal hypertensive gastropathy (PHG) is a com-
viduals is around 60% within 1–2 years of the index mon feature of cirrhosis, and its prevalence paral-
hemorrhage.23 It is therefore essential that patients lels the severity of portal hypertension and liver
without evidence of hemorrhage for at least 24 hours dysfunction. It is recognized endoscopically as a mo-
be started on therapy to prevent recurrent bleeding saic mucosal pattern (with or without submucosal
prior to hospital discharge. hemorrhage), predominantly located in the fundus
The most effective pharmacological therapy and body of the stomach. When bleeding from PHG
in this setting is the combination of nonselective occurs, it is usually in the form of occult chronic GI
bleeding. The initial management is with iron sup-
plus isosorbide mononitrate (ISMN), while the most -
effective endoscopic therapy is band ligation. Never- ues to bleed and becomes transfusion-dependent,
theless, the combination of pharmacological therapy TIPS may be considered.25
± ISMN) and band ligation is the pre- Gastric antral vascular ectasia (GAVE) is less
ferred therapeutic strategy, as it results in rebleeding commonly seen than portal hypertensive gastropa-
rates between 12% and 28% (median 14%), which thy, and may occur in the absence of portal hyper-
is lower than rebleeding rates observed with either tension. It is characterized by red spots without a
therapeutic strategy alone (~33%)(Figures 13.12 and background mosaic pattern and/or line arrays of
13.13).13,14 These are the lowest rebleeding rates re- erythema converging on the pylorus (“watermelon
ported, except those observed in patients on pharma- -
tiate from diffuse GAVE. Therapy for bleeding from
reduction (below 12 mm Hg and/or >20% from base- GAVE consists of endoscopic electrocoagulation or
line), where rebleeding rates as low as 6% have been laser therapy, although multiple treatment sessions
reported (Figure 13.12). may be required. Bleeding from GAVE does not re-
TIPS is the treatment of choice for patients who spond to portal pressure-reducing methods such as
develop recurrent variceal hemorrhage despite treat- TIPS, but responds to liver transplantation.25
shunt can be considered in patients with preserved

hepatic function in centers where the expertise for Ascites
performing this procedure is available. A large mul-
Ascites is the most common cause of decompensa-
ticenter trial comparing TIPS (bare stent) vs. distal
tion in patients with cirrhosis, occurring at a rate of
splenorenal shunts in patients with Child’s class
7–10% per year. The clinical presentation of ascites
A or B cirrhosis showed similar rates of rebleed-
is increased abdominal girth, often in association
ing, encephalopathy, and mortality in both groups
with lower-extremity edema. Approximately 5% of
with a higher rate of shunt dysfunction in the TIPS
patients with ascites can develop right-sided pleural
group.24 The advent of covered TIPS stents, which
effusions (hepatic hydrothorax) that result from di-
appear to have lower rates of occlusion and hepatic
rect passage of ascites into the pleural space through
encephalopathy, may tip the balance in favor of TIPS
diaphragmatic defects. Inguinal or umbilical hernias
in this setting, although it is likely that it will remain
can develop when ascites is massive. The most life-
second-line therapy after EVL plus pharmacological
threatening complication of ascites is spontaneous
therapy (Figure 13.13).
occurs in the absence of a recognizable secondary
FIGURE 13.14
Ascites Can Be Characterized by Serum-Ascites Albumin Gradient and Ascites Protein
ASCITES CAN BE CHARACTERIZED BY SERUM-ASCITES ALBUMIN GRADIENT (SAAG) AND ASCITES PROTEIN
Ascites Can Be Characterized by Serum-Ascites

Albumin Gradient (SAAG) and Ascites Protein
Source of
ascites
Hepatic sinusoids Peritoneum

SAAG > 1.1 SAAG < 1.1
Capillarized sinusoid Normal leaky sinusoid Peritoneal lymph

Ascites protein < 2.5 Ascites protein > 2.5 Ascites protein > 2.5
Sinusoidal Post-sinusoidal Peritoneal pathology

hypertension hypertension - Malignancy
-Cirrhosis - Cardiac ascites - Tuberculosis
-Late Budd-Chiari - Early Budd-Chiari
- Veno-occlusive disease
Cirrhosis
The three main causes of ascites—cirrhosis, peritoneal pathology (malignancy or tuberculosis), and heart failure—can be easily distinguished
and Liver
by combining the results of both the serum-ascites albumin gradient (SAAG) and ascites total protein content. SAAG >1.1 g/dl indicates
ascites that is the result of sinusoidal hypertension. SAAG <1.1 g/dl indicates that ascites is not the result of sinusoidal hypertension and
that the source is likely peritoneal. SAAG however does not allow us to distinguish intrahepatic causes (e.g., cirrhosis) from posthepatic
Transplan-
causes of ascites (e.g., heart failure, Budd-Chiari) since, in both instances, SAAG will be high. This differential is extremely important, as
constrictive pericarditis is one of the few curable causes of ascites, and the distinction between cardiac or hepatic origin of ascites is especially
important in alcoholic patients with significant management implications. The ascites total protein content can make this distinction since,
unlike the “capillarized” sinusoids of intrahepatic portal hypertension, the sinusoids of posthepatic obstruction are normal (“leaky” to protein).
tation
In peritoneal causes of ascites, the fluid is typically an “exudate”, i.e., has a protein level >2.5 g/dl.
cause of bacterial peritonitis (see below). protein levels are an indirect marker of the integrity
of hepatic sinusoids. While normal sinusoids are per-
meable structures that “leak” protein, the sinusoids in
nal ultrasonography. A diagnostic paracentesis is a cirrhosis are “capillarized” and do not leak as much
safe procedure that should be performed in every pa- protein. Therefore, ascites protein will be lower (<2.5
g/dl) in cirrhotic ascites.
id should be tested for albumin (with simultaneous The three main causes of ascites are cirrhosis,
estimation of serum albumin), total protein, polymor- peritoneal pathology (malignancy or tuberculosis),
phonuclear blood-cell count, and bacterial cultures. and heart failure. These three causes of ascites can
The serum-ascites albumin gradient (SAAG, se- be easily distinguished by combining the results of
rum albumin minus ascites albumin) and ascites both the SAAG and ascites total protein content. Cir-
protein levels are useful in the differential diagno- rhotic ascites typically has a high SAAG and low as-
sis of ascites.19 The SAAG correlates with sinusoidal cites total protein level. Cardiac ascites is associated
pressure and therefore will be elevated (>1.1 g/dl) with a high SAAG and high ascites total protein level.
in patients in whom the source of ascites is the he- Ascites secondary to peritoneal malignancy typically
has a low SAAG and high ascites total protein level
(Figure 13.14). LVP (more than twice a month,26 and may be reason-
The initial approach to treating ascites involves able to perform earlier in patients with a MELD score
dietary sodium restriction (usually 2 g or 88 mEq/ <15.
day) and oral diuretics. Fluid restriction is not required The peritoneovenous shunt, a subcutaneously
unless there is hyponatremia (serum sodium <130 placed silicone tube that transfers ascites from the
mEq/L). Spironolactone is more effective than loop di- peritoneal cavity to the systemic circulation, can be
uretics and should be started at a dose of 50–100 mg considered in patients who are not candidates for
daily. The dose should be adjusted every 3–4 days to a TIPS or transplant. This shunt, however, can be affect-
maximal effective dose of 400 mg/day. If weight loss ed by occlusion, infection, bleeding, and disseminated
is inadequate or if hyperkalemia develops, furosemide intravascular coagulation.
can be added at an escalating dose of 40–160 mg/day. The treatment of hepatic hydrothorax is the same
as that described for ascites. However, the use of oral
and 2 kg (4 lb)/week subsequently. Excessive loss of diuretics and repeated thoracentesis is only transient-
weight (>1 lb/day) in the patient with ascites and no ly effective for patients with refractory hydrothorax,
peripheral edema should be avoided because it will and in these cases, TIPS should be considered. Chest
lead to intravascular volume depletion and pre-renal tube placement for drainage should be avoided, as
acute kidney injury. Other side effects of diuretic thera- it is often complicated by hemodynamic, renal, and
py (with spironolactone) include encephalopathy, elec- electrolyte abnormalities. Attempts to achieve chemi-
trolyte abnormalities, and painful gynecomastia.26,27 cal pleurodesis are generally not successful. However,
video-assisted thoracoscopy in combination with
drugs (including cyclooxygenase-2 inhibitors) should chemical pleurodesis may be more effective. The de-
be avoided, since they reduce diuretic-induced natri-
uresis and may precipitate renal failure. hydrothorax is liver transplantation.
Large-volume paracentesis (LVP) is a reasonable
approach in patients with tense ascites. Albumin at
an intravenous (IV) dose of 6–8 g per liter of ascites Spontaneous Bacterial Peritonitis
removed should accompany LVP, particularly with re-
About a third of hospitalized patients with cirrhosis
movals >5 liters.
are diagnosed as having a bacterial infection, and
Approximately 10% of patients with cirrhosis
the most common are the “spontaneous” infections,
and ascites become diuretic resistant or develop com-
mainly spontaneous bacterial peritonitis (SBP). The
plications that require alternative strategies. In this
most frequent clinical manifestations of SBP are
population, the standard of care is LVP plus albumin.
abdominal pain and tenderness, fever, and elevated
The frequency of LVP is dictated by how quickly the
white blood cell count. However, up to one third of
ascites reaccumulates. TIPS (with uncovered stents)
patients with SBP may be entirely asymptomatic or
is more effective than LVP plus albumin in preventing
present with hepatic encephalopathy and/or renal
ascites recurrence, but is associated with a higher rate
dysfunction. All patients with cirrhosis and ascites
of encephalopathy and stent dysfunction. However, a
who are hospitalized emergently should undergo a
recent meta-analysis of individual data suggests that
diagnostic paracentesis to exclude SBP.29,30
The diagnosis of SBP is established with an ascit-
particularly in patients with the model for end-stage 3
Bac-
liver disease (MELD) score <1528 (The Liver Trans-
plantation section of this chapter below discusses
of cases even with sensitive detection methods (i.e.,
the MELD scoring system.) As mentioned previously,
inoculation into blood culture bottles). SBP is mostly
covered TIPS stents may further improve outcomes,
a monobacterial infection, and the bacteria impli-
but this requires future investigation. Until then, TIPS
cated in SBP are mainly gram-negative enteric organ-
should be considered in patients requiring frequent
isms. Anaerobes and fungi very rarely cause SBP, and
FIGURE 13.15
Norfloxacin Reduces Recurrence of Spontaneous Bacterial Peritonitis (SBP)
NORFLOXACIN REDUCES RECURRENCE OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)
Norfloxacin Reduces Recurrence of

Spontaneous Bacterial Peritonitis
All SBPs SBP caused by gram-

negative bacteria
1.0
.8
Probability Placebo
Placebo
of SBP .6
recurrence p=0.0063
.4
p=0.0013
Norfloxacin
.2
Norfloxacin
0
0 4 8 12 16 20 0 4 8 12 16 20
Months Months
Cirrhosis
Gines et al., Hepatology 1990; 12:716
In a randomized, placebo-controlled trial involving 80 cirrhotic patients who had recovered from an episode of SBP, the 1-year probability
and Liver
of developing recurrent SBP was significantly lower in patients randomized to oral norfloxacin (400 mg/day) than in patients randomized to
placebo (20% vs. 70%) (left panel). As shown in the right panel, recurrent SBP caused by gram-negative bacteria did not occur in any of the
patients randomized to norfloxacin. Therefore, the use of long-term antibiotic prophylaxis is recommended in this setting. From Gines P, Rimola
Transplan-
A, Planas R, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo controlled
trial. Hepatology 1990;12:716–724.
their presence should raise the suspicion of second-

ary bacterial peritonitis.
Empiric antibiotic therapy with IV-administered
tation Progressive renal dysfunction associated with
SBP can be prevented by the administration of IV al-
bumin, particularly in patients who have any evidence
third-generation cephalosporins (cefotaxime, ceftri- of renal dysfunction (BUN >30 mg/dl and/or creati-
axone) should be initiated as soon as the diagnosis is nine >1 mg/dl) and/or a serum bilirubin >4 mg/dl
at the time of diagnosis.32 The recommended dose of
become available. Recently, success rates for third albumin used is arbitrary (1.5 g/kg at day 1, and 1 g/
generation cephalosporins have been reported to be kg at day 3) and different from that used after LVP.
as low as 40% in nosocomial SBP because of the pres- Patients who survive an episode of SBP have a very
ence of multi-drug-resistant organisms.31 Therefore,
extended-spectrum antibiotics (e.g., carbapenems, the index episode of SBP.33 It is therefore essential
piperacillin/tazobactam) should be used as initial that patients recovering from SBP be started on pro-
empirical therapy in patients with hospital-acquired phylactic therapy prior to hospital discharge. Nonab-
SBP, and particularly in those who have received an- sorbable (or poorly absorbable) antibiotics are most
tibiotics in the previous 90 days. effective for such prophylaxis by selectively eliminat-
Aminoglycosides should be avoided, as they are ing gram-negative organisms in the gut. These agents
associated with a high incidence of renal toxicity in reduce the rate of SBP recurrence to around 15–20%
patients with cirrhosis. (Figure 13.15).33 The recommended antibiotic is oral
Hepatorenal Syndrome
disposes to the development of SBP (possibly relat- Acute kidney injury (AKI) occurs in ~20% of hospi-
ed to decreased ascitic bacterial complement levels talized patients with cirrhosis. The most common
and opsonic activity), long-term prophylaxis in this causes of AKI are prerenal azotemia (that is volume-
patient population is not generally recommended responsive), acute tubular necrosis, and hepatorenal
as the risk for developing antibiotic resistance out- syndrome (HRS), a functional type of prerenal AKI
weighs the small effect in preventing infection. How- that does not respond to volume expansion and ac-
counts for only ~17% of cases of AKI in patients with
patients with advanced liver failure (Child–Pugh cirrhosis.35,36
score >9 points, with serum bilirubin level >3 mg/ HRS occurs in patients with advanced cirrhosis
dl) impaired renal function (serum creatinine level and ascites. It represents the extreme of the spectrum
>1.2 mg/dl, blood urea nitrogen level >25 mg/dl), of abnormalities that lead to cirrhotic ascites, with
or serum sodium level <130 mEq/L, in whom the maximal peripheral vasodilatation and maximal acti-
1-year probability for an index episode of SBP is ap- vation of sodium and water-retaining and renal vaso-
proximately 60%.34 This risk has been shown to be constrictive hormones, leading to renal vasoconstric-
tion and renal failure. In patients with cirrhosis and
previously, short-term antibiotic prophylaxis is intense ascites, the incidence of HRS is 18% at 1 year
dicated in patients with cirrhosis (with or without and 39% at 5 years. Predictors of HRS include a de-
ascites) admitted with GI hemorrhage (Figure 13.9). creased cardiac output and high plasma renin activ-
FIGURE 13.16
Mechanism of Action of Vasoconstrictors Plus Albumin in Hepatorenal Syndrome
MECHANISM OF ACTION OF VASOCONSTRICTORS + ALBUMIN IN HEPATORENAL SYNDROME
Cirrhosis Vasoconstrictors
Intrahepatic Arteriolar
resistance resistance
(vasodilation)
Albumin
Sinusoidal
pressure Effective arterial
blood volume
Sodium and
Ascites water retention
Activation of
neurohumoral
systems
Hepatorenal Renal
syndrome vasoconstriction
The most commonly used therapy for hepatorenal syndrome (HRS) type 1 is the combination of potent vasoconstrictors (ornipressin, terlipressin,
and octreotide plus midodrine), which act by ameliorating the vasodilatory state of advanced cirrhosis, plus albumin, which acts by expanding
the arterial blood volume.
ity. Clinically, HRS has been divided into types 1 and ascites, hyponatremia, and low mean arterial pressure.
2. Type 1 HRS is characterized by rapid progression The urinary sediment is normal and the kidneys have
of renal failure (acute kidney injury) and has a high no major structural abnormalities. There is usually oli-
mortality rate (median survival 2 weeks in untreated guria, and the urine sodium may be <10 mEq/L.
patients). In contrast, type 2 HRS is associated with di- The mainstay of therapy for HRS is liver transplan-
uretic-refractory ascites, progresses more slowly, and tation. Various therapies have been used to “bridge”
has a better prognosis than type 1 HRS.37, 38 a patient to transplantation, including the combina-
Type 1 HRS is a diagnosis of exclusion and should tion of systemic vasoconstrictor therapy plus albu-
be made only after discontinuing diuretics, expanding min, TIPS, and extracorporeal albumin dialysis. The
intravascular volume with albumin, and having ex- bulk of the evidence favors potent vasoconstrictors
cluded or treated other causes of AKI, i.e., (1) those as- (particularly terlipressin), which act by ameliorat-
sociated with worsening of the hemodynamic status of ing the vasodilatory state of advanced cirrhosis, in
the cirrhotic patient (sepsis, vasodilators, large volume conjunction with albumin, which acts by expanding
paracentesis not accompanied by albumin infusion); the arterial blood volume (Figure 13.16). Terlipres-
(2) conditions that decrease the effective arterial blood sin, at a dose 0.5–2.0 mg IV every 4–6 hours, leads
volume (GI hemorrhage, overdiuresis, diarrhea); (3) to the reversal of type 1 HRS in 46% of cases (com-
conditions that induce renal vasoconstriction (non- pared to 11% in untreated patients).39,40 Although
the probability of survival in treatment-responsive
of nephrotoxic agents (e.g., aminoglycosides). Clinical patients is greater than in those who do not respond
features associated with HRS include diuretic-resistant to vasoconstrictors, the overall mortality rate re-
FIGURE 13.17 Cirrhosis

and Liver
Poor Correlation of Ammonia Levels with Presence or Severity of Hepatic Encephalopathy
Transplan-
POOR CORRELATION OF AMMONIA LEVELS WITH PRESENCE OR SEVERITY OF HEPATIC ENCEPHALOPATHY
Poor Correlation of Ammonia Levels With

Presence or Severity of Encephalopathy
400 tation
350
300
250
Venous
total 200
ammonia
µmol/L 150
100
50
0
Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Severity of Hepatic Encephalopathy
Ong et al., Am J Med 2003; 114:188
There is poor correlation between the severity of hepatic encephalopathy and venous ammonia levels. Patients with grade 0 encephalopathy
(i.e., no encephalopathy) have ammonia levels that overlap with those with overt encephalopathy stages 1–3. It would be reasonable to obtain
ammonia levels in patients admitted with coma (stage 4) of unknown etiology. From Ong JP, Aggarwal A, Krieger D, et al. Correlation between
ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003;114:188–93.
mains high at ~58% in treated patients. Note that its pathogenesis. In cirrhosis, ammonia accumulates
improvements in renal function are slow, with clini- because of shunting of blood through portosystemic
cally noticeable changes occurring at or after day 3. collaterals and decreased liver metabolism. In ad-
Where terlipressin is not available, evidence points dition, other toxins such as manganese accumulate in
towards the use of noradrenaline as it has been shown the brain, particularly the globus pallidus, which leads
in randomized trials to be as effective as terlipressin.41, to impaired motor function.
42
In clinical practice, at least in the United States, the HE associated with cirrhosis is of gradual onset
combination subcutaneous octreotide/oral midodrine and is rarely fatal. This type of encephalopathy has
recently been designated as type C, to distinguish it
bility of administration outside an intensive care unit.43 from the encephalopathy associated with acute liver
However, if a mean arterial pressure increase is not failure (type A) and HE associated with portosystemic
observed with maximal doses, the patient should be bypass in the absence of cirrhosis (type B).44 Type
transferred to an intensive care unit where a noradren- C encephalopathy is characterized by alterations in
aline infusion should be initiated. consciousness and behavior, ranging from inversion
of sleep/wake pattern and forgetfulness (stage 1), to
confusion, bizarre behavior, and disorientation (stage
Hepatic Encephalopathy 2), to lethargy and profound disorientation (stage 3),
Hepatic encephalopathy (HE) is a reversible syndrome

On physical exam, the hallmark of HE is the pres-
characterized neuropathologically by astrocyte swell-
ence of asterixis. In early stages, there may just be
ing (Alzheimer’s type II astrocytosis). Ammonia, a
a slight distal tremor. Additionally, patients with HE
toxin normally removed by the liver, plays a key role in
may have a sweet-smelling odor to their breath (fe-
tor hepaticus). HE is a clinical diagnosis. Serum am-
FIGURE 13.18 monia levels are unreliable, correlate poorly with the
Pathophysiology of Hypoxemia in Hepatopulmonary Syndrome (HPS) stage of HE (Figure 13.17), and should not be used ei-
ther to make the diagnosis or to follow patients with
PATHOPHYSIOLOGY OF HYPOXEMIA IN HEPATOPULMONARY SYNDROME HE.45 Psychometric tests such as the number con-
nection test and electroencephalograph (showing a
Hepatopulmonary Syndrome
Pathophysiology of Hypoxemia slowing of brain waves) are used in research but are
not used routinely for clinical diagnosis. Minimal HE
Intrapulmonary vascular dilation (formerly called subclinical hepatic encephalopathy)
Normal Diffusion-perfusion Anatomic shunt
defect (Type 1) (Type 2) occurs in about 30–70% of patients with cirrhosis
without overt HE and is associated with a poor qual-
Alveolus
ity of life. Minimal HE is detected by psychometric
8µ O2 O2 O2 and neuropsychological testing alone, testing that is
8-500µ not widely recommended.
The mainstay of therapy for overt HE is the
Capillary
tors. Precipitants are present in over 80% of cases

and include dehydration, infections, overdiuresis,
The normal pulmonary capillary is 8 microns in diameter. The red blood cell is slightly
gastrointestinal bleeding, a high oral protein load,
<8 microns in diameter, and red cells pass through pulmonary capillaries one cell constipation, and the use of narcotics and sedatives.
thickness at a time. This facilitates oxygenation of the red cells. In type 1 HPS, the A common cause of HE is TIPS placement.
pulmonary capillaries are dilated up to 500 microns, and passage of red cells through
The pharmacological treatment of HE is based on
the pulmonary capillaries may be many cells thick. Therefore, a large number of red
cells are not oxygenated. In type 2 HPS, anatomical shunting prevents adequate agents that reduce ammonia production in the gut,
oxygenation of the red cells. such as lactulose and nonabsorbable antibiotics (e.g.,
neomycin, metronidazole, or rifaximin). Lactulose is and medical therapy is not effective. Variable results
administered in divided daily doses ranging from 15 with TIPS insertion have been reported, and it is not
ml/day to 120 ml/day, adjusted to obtain two or three generally recommended. The only viable treatment
soft bowel movements per day. In patients hospitalized for HPS is liver transplantation.48,49
with stage 3 or stage 4 HE, water-based or lactulose
enemas can be used until consciousness improves to
where lactulose can be taken by mouth. Other alterna- Portopulmonary Hypertension
tives are L-ornithine, L-aspartate, and sodium benzo-
Portopulmonary hypertension (PPH) is another pul-
monary complication of cirrhosis. It is characterized
by pulmonary vasoconstriction resulting from vaso-
therapies may only be required transiently, especially
constrictive substances, produced in the splanchnic
in the acute setting.46
circulation, that bypass metabolism by the liver. Symp-
In patients with recurrent or persistent HE, a
toms of PPH are exertional dyspnea, syncope, and
change in dietary protein from an animal source to
chest pain. Physical examination reveals an accentu-
ated second sound and a prominent right ventricular
ammonia-reducing strategies. Rifaximin has also been
shown to be effective in maintaining remission in pa-
arterial pressure >25 mm Hg on right heart catheter-
tients with recurrent HE and in decreasing HE-moti-
ization, provided that the pulmonary capillary wedge
vated hospitalizations.47 Strict protein restriction is
pressure is <15 mm Hg. Recently there has been for-
not necessary, and is proscribed in the long term. In
Cirrhosis
mal recognition of PPH as an indication for liver trans-
patients with post-TIPS HE, occlusion or reduction
plantation based on results of hemodynamic measure-
of the shunt may be helpful to control symptoms re-
ments. However, a mean pulmonary arterial pressure
and Liver
fractory to medical therapies.
>50 mm Hg constitutes an absolute contraindication
for liver transplantation.50
Transplan-
Hepatopulmonary Syndrome
Hepatocellular Carcinoma
Hepatopulmonary syndrome (HPS) is a pulmonary
tation
complication of portal hypertension that presents in
HCC is a complication of cirrhosis that can lead to
5–10% of patients awaiting liver transplantation and
clinical decompensation and decrease the chance of
is a predictor of poor survival. It results from pulmo-
nary vasodilatation that leads to gas exchange abnor-
cancer and the third most common cause of cancer-
malities and hypoxemia (Figure 13.18). The clinical
related mortality worldwide. In the United States,
presentation is variable, and ranges from subtle short-
there has been a twofold increase in the number of
ness of breath that appears only upon exertion, with
cases of HCC over the past two decades. This rapid in-
mild gas exchange abnormalities, to severe hypoxemia
crease in the rate of HCC correlates with an increase
requiring supplemental oxygen and resulting in a sig-
48,49
in the prevalence of chronic hepatitis C. HCC develops
at a rate of 1–4% per year in cirrhosis secondary to
chronic hepatitis C.51
vascular spiders may be seen. The diagnosis is made by
The diagnosis of HCC should be entertained in
excluding major intrinsic cardiopulmonary disease, and
patients with compensated cirrhosis who suddenly
<80 mm Hg, or an alveolar arterial oxy-
2 decompensate, and in patients with cirrhosis who de-
gen gradient >15 mm Hg on arterial blood gases, along
velop portal vein thrombosis. The diagnosis is generally
with intrapulmonary vasodilatation shown by contrast
made by dynamic radiologic imaging (mostly comput-
echocardiography and/or perfusion lung scanning.
-
Treatment options for hepatopulmonary syndrome
ing with contrast). In selected cases, the use of serum
are limited. Spontaneous resolution occurs rarely
FIGURE 13.19
Proposed Algorithm for Staging and Treatment of Hepatocellular Carcinoma
Adapted from BCLC algorithm.
alpha-fetoprotein (AFP) levels and/or liver biopsy vided there is no vascular invasion or extrahepatic
disease.53 In these patients, radiofrequency ablation
biopsy is generally not necessary when two dynamic (RFA) with or without transarterial chemoemboliza-
radiologic techniques show that a liver mass in a cir- tion (TACE) has been used as a bridge to liver trans-
rhotic liver has typical features of HCC (arterial hy- plantation for controlling tumor burden. Five-year
pervascularity with early washout in the portal/ve- disease-free survival rates >50% have been reported
nous phase), and/or the AFP levels are >200 ng/ml.52 for both resection and liver transplantation. How-
The prognosis and treatment of HCC is related to ever, only 30% of patients are currently candidates
tumor stage, liver function, and performance status for these curative therapies at the time of diagnosis.
(Figure 13.19). Surgical resection should be consid- TACE is recommended for nonsurgical can-
ered in patients with a single mass (usually <5 cm) didates who have a reasonable liver function and
in the setting of good liver function (Child’s class A), multinodular tumors that are beyond Milan criteria.
Sorafenib, a multikinase inhibitor with antiprolifera-
portal hypertension (i.e., HVPG <10mmHg).52 tive and antiangiogenic activity, is recommended for
Liver transplantation is an effective option for patients with advanced HCC who are not candidates
patients with up to 3 tumors, each measuring <3 for locoregional treatment and who have a good liver
cm, or a single mass <5 cm (Milan criteria), pro- function (Child’s class A).54 The median survival for
patients with intermediate and advanced HCC ranges TABLE 13.1

from 11 to 20 months (Figure 13.19). Median Survival in Cirrhosis
For symptomatic, inoperable tumors in patients
with a poor liver function, survival is <3 months, and
Compensated cirrhosis >12 years
in these patients treatment should be supportive.
Decompensated cirrhosis 1.6 years
Systemic chemotherapy and radiation therapy are of
Jaundice
little value in this setting (Figure 13.19).
Encephalopathy
Screening and surveillance for HCC have been
Ascites
employed in patients with cirrhosis in order to de-
Variceal hemorrhage
tect tumors at an early and treatable stage. Serial ul-
trasound examination every 6–12 months is recom- Hepatopulmonary syndrome 10 months
mended.52 Decision analysis studies show that this Spontaneous bacterial peritonitits 9 months
is the most cost-effective strategy, and furthermore, Hepatorenal syndrome
a randomized controlled trial of surveillance vs. no Type 2 6 months
surveillance showed that mortality was reduced by Type 1 2 weeks
37% in the surveillance arm.55 Surveillance should be
performed in all patients with cirrhosis at high risk er transplantations have been performed per year in
the U.S., while >16,000 patients were on the waiting
secondary to hepatitis B, hepatitis C, or alcohol; non- list. The number of transplants performed per year
alcoholic fatty liver disease; hemochromatosis; or has been stable since 2005. The major limitation
Cirrhosis
primary biliary cirrhosis. Patients on the transplant
waiting list should also be screened because HCC in-
of liver transplantation is the shortage of donor or-
gans, which leads to an increased number of deaths
and Liver
creases the priority for transplant (see below). on the waiting list. In 2009, approximately 2500 U.S.
patients died or were removed from the list because
they were too sick for transplant.
Liver Transplantation
Transplan-
Liver transplantation is now a standard treat-
Indications
tation
ment that improves quality of life and survival in pa-
tients with end-stage liver disease. The current mean The most common indication for liver transplanta-
1-year and 3-year patient survival rates after liver tion in adults is decompensated cirrhosis. Other in-
transplantation in the U.S. are ~90% and ~80%, re- dications for liver transplantation are HCC, fulminant
spectively. For the last 5 years an estimated 6000 liv- or subfulminant liver failure, HPS, PPH, and rare dis-
TABLE 13.2
Child-Turcotte-Pugh Score
Points 1 2 3
Encephalopathy None Grade 1–2 or precipitant induced Grade 3–4 or chronic
Ascites None Mild to moderate (diuretic responsive) Tense (refractory)
Bilirubin (mg/dl) <2 2–3 >3
Albumin (mg/dl) >3.5 2.8–3.5 <2.8
<4 4–6 >6
PT (sec prolonged) or INR
<1.7 1.7–2.3 >2.3
Child A, 5–6 points; Child B, 7–9 points; Child C: 10-15 points. Refer for transplant evaluation at 7 points.
TABLE 13.3 with hepatitis B undergoing liver transplantation.

Model for End-Stage Liver Disease (MELD) Appropriately selected patients with cirrhosis
secondary to alcohol use do well after transplanta-
Predicts 3-month mortality among patients with chronic liver tion, with survival rates that are equivalent to pa-
disease on the liver transplant waiting list tients with other chronic liver diseases. In most cen-
MELD = [0.957 × LN (creatinine) + 0.378 × LN (bilirubin) + 1.12 ters, an abstinence period of 6 months is required
× LN (INR) + 0.643] × 10 prior to consideration for liver transplantation. This
Minimum score = 6: risk of death on waiting list 20% period not only allows evaluation of the patient’s
Maximum score = 40: risk of death on waiting list 100% ability to stop alcohol ingestion and receive adequate
rehabilitation, but also allows the liver disease to im-
prove. With abstinence, it is common to see a rever-
eases such as primary hyperoxaluria and familial am- sal from decompensated to compensated cirrhosis.
yloid polyneuropathy (FAP) syndrome. In children, Recurrence of alcoholic cirrhosis can occur in pa-
the most common indication is biliary.56, 57 tients who consume large amounts of alcohol after
The indication for liver transplantation in these transplantation
disorders is based on the presence of predictors of Liver transplantation is indicated for patients
a poor survival; in cirrhosis, the presence of decom- with cholestatic diseases such as primary biliary
pensation (ascites, encephalopathy, jaundice) and cirrhosis and primary sclerosing cholangitis. Intrac-
associated complications, such as refractory ascites, table pruritus and recurrent bacterial cholangitis
spontaneous bacterial peritonitis, and hepatorenal are additional indications for liver transplantation
syndrome, which are associated with a progressive- in these patients. Recurrent disease has been recog-
ly poorer survival (Table 13.1). In general, patients nized in patients with both primary biliary cirrhosis
with a Child-Pugh score of >7 (Table 13.2) or a MELD and primary sclerosing cholangitis.58
score >15 (Table 13.3) should be considered for liver Autoimmune hepatitis recurs in about 20%
transplantation. of patients after liver transplantation. It is therefore
Cirrhosis secondary to hepatitis C is currently recommended that steroids not be tapered off com-
the most common indication for liver transplanta- pletely in these patients. Patients with Budd-Chiari
tion. In these patients, it is important to recognize syndrome and cirrhosis, and those with acute or
that recurrent disease after transplant is universal subacute Budd-Chiari syndrome who fail TIPS or
and that ~20% of these patients may progress to cir- shunt surgery, should be considered for liver trans-
rhosis in <5 years. Recurrence is higher in patients plantation. Although liver transplantation reverses
with a high pretransplant viral load, and therefore the underlying prothrombotic disorder in patients
antiviral therapy should be recommended in patients -
with cirrhosis prior to decompensation, when treat- cy, long-term anticoagulation is recommended given
ment is generally better tolerated. In patients with the common coexistence of multiple thrombophilic
decompensated cirrhosis, antiviral therapy is poorly disorders.
tolerated and is associated with an increased rate of As mentioned previously, selected patients with
complications, including death.58 cirrhosis and HCC are candidates for liver transplan-
Similarly, patients with cirrhosis secondary to
hepatitis B will have a high risk of post-transplant a single mass <5 cm (Milan criteria) are candidates
recurrent disease if hepatitis B e-antigens and/ for liver transplantation, provided there is no vascu-
or high HBV-DNA levels are present. In contrast to lar invasion or extrahepatic disease. Therefore, the
therapy for hepatitis C, the use of parenteral hepa- evaluation of patients with HCC involves a CT scan of
titis B immune globulin and/or oral nucleos(t)-ide the chest to rule out metastatic disease.
analogues are well tolerated, effective in preventing
recurrent disease, and recommended for all patients
Contraindications Patients with a Child-Pugh score <7 have a bet-

ter survival without liver transplantation than with
There are a number of absolute contraindications
transplantation; therefore, it is patients with a Child-
for liver transplantation. Transplantation is contra-
Pugh score 7 who should, in general, be considered
indicated in patients with severe coronary artery
for liver transplantation (Table 13.2). Initially, the
disease, cardiomyopathy, and arrhythmias. Porto-
prioritization for liver transplantation in patients
pulmonary and hepatopulmonary syndromes are
with cirrhosis was based on time spent on the wait-
not contraindications to liver transplantation un-
ing list. Ultimately it became clear that prioritization
less the mean pulmonary pressure is >50 mm Hg.
needed to be based on severity of illness.
Extrahepatic malignancy, a history of malignancy
In February 2002, the United Network of Organ
with a disease-free period <2 years (at least), un-
Sharing (UNOS) changed its prioritization scheme to
controlled infection (either intrahepatic or extrahe-
the MELD.59 The MELD system is a good predictor of
patic), or active alcoholism or substance abuse are
short-term mortality, relies on objective biochemi-
additional contraindications to liver transplantation.
With the advent of highly active antiretroviral treat-
INR), and consists of a continuous score ranging
ment, successful liver transplantation is possible for
from 6 (mild disease) to 40 (severe disease)(Table
HIV-infected subjects with a CD4 count >400/mm3.
-
Therefore, HIV infection is no longer considered an
tion has consistently been seen in patients with
absolute contraindication to transplantation; how-
ever, these patients should be referred to specialized
below 14, there may be a survival disadvantage with
Cirrhosis
centers. The presence of non-tumoral thrombosis
of the portal and splanchnic venous systems was
previously considered a major contraindication to
liver transplantation unless severity of liver disease
is underestimated by the MELD score.60
and Liver
Patients with fulminant hepatic failure, primary
transplantation, but it may be currently considered
graft nonfunction, and acute hepatic artery throm-
in selected cases.56
Selection Transplan- FIGURE 13.20

Evolving Concepts in Allocation: Transplant Benefit
EVOLVING CONCEPTS IN ALLOCATION – MORTALITY RATES BY MELD – “TRANSPLANT BENEFIT”
Evolving Concepts in Allocation:
tation
Mortality Rates by MELD – “Transplant Benefit”
In patients with indications for liver transplanta-
tion and the absence of contraindications, additional
10000
requirements include the willingness to undergo Waitlist
Transplant
a transplant, evidence of medical compliance, ad- 1000
equate social support system, and the ability to pro- Mortality
rate per
vide the costs of transplantation and medications 1000
100
after liver transplantation. patients
Once a patient with end-stage liver disease is 10

HR=3.64 HR=2.35 HR=1.21 HR=0.62 HR=0.38 HR=0.22 HR=0.18 HR=0.07 HR=0.04
activated for liver transplantation, the question of P<0.001 P<0.001 P=0.41 P<0.01 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001
1
organ availability arises. The effective allocation of 6-11 12-14 15-17 17-20 21-23 24-26 27-29 30-39 40+
organs has been a challenging issue. The challenge MELD

HR=hazard ratio
for the medical system is to identify and transplant
patients at a time when the survival in the natural
This demonstrates the relative risks and benefits of liver transplantation based on the
history of their disease is shorter than the survival model for end-stage liver disease (MELD) score. In patients with MELD <14, there is a
after transplant. In addition, liver transplantation higher risk of 3-month mortality with transplantation compared to 3-month mortality
needs to be performed before the development of without transplantation. In patients with MELD between 15 and 17, there is no survival
advantage or disadvantage with liver transplantation. Survival advantage is seen only
complications that either substantially increase the once MELD scores are >17, with the greatest advantage seen at higher MELD scores.
risks for or disqualify a patient from transplantation.
bosis are given highest priority for organ allocation on, biliary necrosis and infection ensue, and the pa-
independent of MELD score. For patients with cir- tient may require hepatic retransplantation. Hepatic
rhosis, the highest MELD score within a particular due to stenosis of the
UNOS region and blood group determines the order anastomosis at the inferior vena cava presents with
on the waiting list for liver transplantation. If two or ascites and occurs in 1–2% of the cases. It is often
more patients have the same MELD score, then pri- successfully treated by transvenous dilatation with
ority for liver transplantation is based on the amount or without stenting. Biliary complications occur in
of time spent at the current MELD score. There are a about 8–15% of the patients and include biliary leaks
few special conditions whereby patients can receive
a higher MELD score (known as MELD exception while strictures occur later. Biliary complications are
points), including HCC, hepatopulmonary syndrome, treated with endoscopic retrograde cholangiopan-
FAP, and primary hyperoxaluria. Once a patient is creatography therapy or percutaneous transhepatic
listed for a liver transplant, the MELD score must cholangiography with stenting, surgical intervention,
or symptomatic therapy with antibiotics. In the pres-
listing a patient early in the current UNOS listing cri- ence of diffuse or focal biliary strictures, hepatic ar-
teria, since calculation of waiting time starts with each
increase in the MELD score.
Given the critical shortage of donor organs, live may be required.61
donor liver transplantation is being performed in- Infectious complications include a wide range of
creasingly in both children and adults. The results of viral, bacterial, and fungal infections and are tied to
adult-to-adult living donor liver transplantation are the level of immunosuppression required, presence of
excellent worldwide, but these procedures are not yet surgical complications, and length of stay in the inten-
performed in all centers. sive care unit. The most common infections within the
tree, abdominal cavity, surgical wound, urinary tract,

Complications or lungs. Patients with fulminant hepatic failure or im-
munosuppression prior to transplant are at additional
Early post-transplantation complications are related
risk for other, more invasive fungal infections imme-
to the graft, surgical problems, and infection. The
diately after transplant. Infections due to cytomegalo-
long-term complications that impact 10- and 20-year
virus ( ) and Epstein-Barr virus are common after
survival are recurrent disease (especially hepatitis C)
and other complications secondary to immunosup-
Prophylaxis has made an impact on decreasing
pressive medications. Acute cellular rejection rarely
the rate of infections. Ganciclovir has reduced the inci-
dence of , trimethoprim-sulfamethoxazole has re-
patient is noncompliant or treatment is not pursued.
duced the incidence of Pneumocystis pneumonia, and
Complications related to the graft include prima-
-
ry nonfunction, a rare complication occurring in only
tions in high-risk patients. Long-term post-transplant
1–2% of transplants and characterized by the absence
patients with good graft function and low levels of
of bile production, liver failure (encephalopathy and
immunosuppression have a normal risk for standard
coagulopathy), and renal failure. Most of these pa-
tients require retransplantation urgently.
pneumonia.
Most postoperative complications present within
Long-term graft and patient survival rates for pa-
hemorrhage occurs
tients transplanted with hepatitis C infection are low-
in ~20% of the patients, and about half will require
er than those of patients who undergo transplantation
reoperation. Hepatic artery thrombosis is a severe
for other causes. The inferior long-term survival rates
complication that occurs in 2–12% of the cases and
for hepatitis C carriers after transplantation is often
requires surgical repair when detected early. Later
due to hepatitis C infection of the graft. For those who hepatitis C (Figure 13.22). Although hepatitis C vire-
undergo retransplant for recurrent hepatitis C cir- mia can be detected as soon as 2 weeks after trans-
rhosis, 1-year patient retransplant survival rates are plant, clinically obvious recurrent hepatitis C usually
even more dismal, approaching 55%. Unfortunately, occurs 1–6 months after transplantation. Liver biopsy
the success rate of therapy to clear hepatitis C viremia and blood levels of immunosuppressant agents (spe-
with pegylated interferon and ribavirin is <30% after
transplant. With the addition of a protease inhibitor, -
the success rate appears to be greater but with great- thelialitis is more consistent with acute cellular re-
er toxicities and need to reduce the dose of immuno- jection, whereas lobular hepatitis suggests recurrent
suppressants. The advent of more effective, less toxic HCV (Figures 13.21 and 13.22). A biopsy with portal
therapies are awaited. hepatitis, endothelitis, and lymphocytic cholangitis in
Acute cellular rejection occurs in 20–30% of a patient with subtherapeutic levels of immunosup-
transplant recipients. This form of rejection typically pressive drugs indicates the presence of acute cellular
occurs within 1–4 weeks after liver transplantation. rejection. First-line treatment is with high-dose cor-
There are three major histologic features associated ticosteroids (i.e., 1 g methylprednisolone every other
day × 3 doses IV), to which >90% of patients respond.
- Chronic (ductopenic) rejection occurs in 5–10%
cytic), destructive or nondestructive nonsuppurative of patients undergoing initial liver transplantation,
cholangitis involving interlobular bile duct epithe- and usually occurs between 6 weeks and 6 months
lium, and endothelialitis or phlebitis (Figure 13.21). after the procedure. Histologically, it is characterized
FIGURE 13.21
Cirrhosis by the loss of interlobular and septal bile ducts, and is
and Liver
Acute Cellular Rejection
Histological Features of Acute Cellular Rejection
Transplan-
tation
The left panel is a medium-power views of a transplant biopsy showing a portal triad with dense mixed inflammatory infiltrate that includes
lymphocytes, plasma cells, and numerous eosinophils, endothelialitis (yellow arrow) and cholangiolitis (green arrow). In the right panel, the
bile duct (green arrow) is difficult to visualize due to severe cholangiolitis. (Courtesy of Marie Robert, MD.)
FIGURE 13.22
Histological Features of Post-Transplant Recurrent Hepatitis C
Recurrent Hepatitis C
The left panel shows apoptosis (arrows) and lymphocytosis of sinusoids (not always present). The right panel shows a portal tract with dense
lymphocytic infiltrate. The duct is obscured and the vein shows changes suggestive of endothelialitis (arrow). These images highlight the
difficulties of using portal changes to distinguish rejection from recurrent hepatitis C. The lobule shows lymphoid infiltration and focal interface
hepatitis. (Courtesy of Marie Robert, MD.)
often associated with hepatic foam cell arteriopathy,

but this is not a necessary component. Induction and to cyclosporine or tacrolimus nephrotoxicity affects a
maintenance of immunosuppression with triple-drug majority of these patients. Hypertension and diabetes
therapy (cyclosporine, prednisone, and azathioprine) are additional cofactors that contribute to renal insuf-
and other combinations that include antilymphocyte
preparations have led to an overall decrease in the in- reducing CNI doses by adding mycophenolate mofetil
cidence of both cellular and ductopenic rejection. In or sirolimus, or by using sirolimus alone, to reduce re-
addition, the availability of FK506 as a rescue therapy nal dysfunction.
has saved grafts in some patients experiencing chron- Drug interactions between immunosuppressive
ic ductopenic rejection. agents and other commonly prescribed drugs are well
Standard baseline immunosuppression after liver described. Possible interactions should be considered
transplantation consists of the combination calcineu- when transplant recipients are using additional medi-
rin inhibitors (CNIs) such as cyclosporine or tacroli- cations, including antibiotics, antifungal and antiviral
mus, an immunomodulator such as mycophenolic agents, and seizure medications. Patients on chronic
mofetil or azathioprine, and corticosteroids. Over immunosuppression are at increased risk for the de-
time, many patients can remain on CNIs alone unless velopment of certain malignancies, including skin can-
low-dose corticosteroids are needed to prevent recur- cer, non-Hodgkin’s lymphoma, and certain genital ma-
rent disease (as with autoimmune hepatitis) or issues lignancies. In addition, patients with ulcerative colitis
with recurrent acute cellular rejection necessitate who have undergone transplantation are at increased
more immunosuppression.62 risk for the development of colon cancer. Therefore,
Complications related to chronic immunosup- increased vigilance and appropriate screening are
pressive therapy include renal dysfunction, arterial warranted.
hypertension, osteopenia, hyperlipidemia, diabetes Advances in liver transplantation are now focused
on improving 10- and 20-year survival rates and over-

at endoscopy. Early means within first 24-48 hours
all quality of life. Liver transplantation is no longer
of admission.
considered an experimental procedure but is a proven
Ascites is the most common decompensating event
and effective therapy for patients with irreversible liv-
in cirrhosis. Initially, most respond to diuretics (spi-
er disease. Unfortunately, the success of this lifesaving
ronolactone must be used alone or in combination
procedure is restricted by the shortage of organ do-
with furosemide). It is not an emergency unless it
nors. Expansion of the donor pool currently includes
becomes infected (spontaneous bacterial peritoni-
the use of marginal livers, split livers, and live donor
tis).
liver transplantation.
Hepatic hydrothorax should not be treated with a
chest tube.
SBP is diagnosed with an ascites neutrophil count
Pearls and Pitfalls (not total WBC count) >250/mm3. Diagnostic para-
for the Board Exam centesis should be performed in any patient with
A liver biopsy is not always needed to make the di- cirrhosis that deteriorates.
agnosis of cirrhosis. It can be established through Only clear indications for antibiotic prophylaxis are
clinical, laboratory and/or imaging findings. 1) patients admitted with GI hemorrhage (short-
Cirrhosis can be compensated or decompensated. term prophylaxis); 2) patients who have recovered
These two entities are entirely different prognos- from an episode of SBP.
tically. Decompensated cirrhosis is defined by the Episodic hepatic encephalopathy is usually precip-
lopathy and jaundice. Cirrhosis

presence of ascites, variceal hemorrhage, encepha-
Upper endoscopy should be performed in any pa-

itant-induced. The key is to identify and treat the
precipitant. In this setting, lactulose can be discon-
tinued once precipitant resolves.
and Liver
tient with cirrhosis to screen for the presence/size
of varices.
Recurrent or persistent hepatic encephalopathy
requires combination of rifaximin and lactulose ti-
Transplan-
Non-selective beta-blockers (propranolol, nadolol) trated at a dose that will produce 2-3 soft-formed
reduce portal pressure and are recommended in BM/day.
primary or secondary prophylaxis of variceal hemor- Patients with cirrhosis are predisposed to develop
tation
rhage. acute kidney injury. At diagnosis, discontinue di-
For primary prophylaxis (patient with varices who uretics, vasodilators and lactulose, panculture, and
has never bled), either non-selective beta-blockers expand intravascular volume with albumin.
or variceal ligation are recommended. Choice de- A patient with cirrhosis should be referred to a
pends on patient preferences, resources, side ef- transplant center at their first decompensation re-
fects and/or contraindications. gardless of MELD score.
For secondary prophylaxis (patient who has recov- HCC is an indication for liver transplant regardless
ered from an episode of variceal hemorrhage), non- of decompensation. Tumor within Milan criteria is
selective beta-blockers plus variceal ligation are the gold standard for HCC exception points.
recommended. Certain inherited and metabolic liver diseases
First-line therapy for patients with cirrhosis admit- qualify nationally for MELD exception points (e.g.
ted with GI hemorrhage consists of resuscitation hereditary hypercholesterolemia, hyperoxaluria).
(avoiding overtransfusion and keeping hemoglobin Severe portopulmonary hypertension and hepa-
~7-8), antibiotics and infusion of splanchnic vaso- topulmonary syndrome also qualify for exception
constrictor. points, when within accepted guidelines (pulmo-
Candidates for early (preemptive) TIPS are patients nary pressure <35 mm Hg, paO2<60 mm Hg).
with variceal hemorrhage who are Child C (score Most common 3-month post-transplant complica-
10-13) or Child B (score 7-9) with active hemorrhage tions are acute cellular rejection, hepatic artery
variceal hemorrhage in patients with cirrhosis of the liver

thrombosis and biliary stricture. and esophageal varices. A prospective multicenter study.
Recurrent hepatitis C is universal in anybody trans- New England Journal of Medicine 1988;319(15):983-989.
planted with a detectable viral load. 7. D’Amico G, Pagliaro L, Bosch J. Pharmacological treat-
ment of portal hypertension: an evidence-based ap-
proach. Sem Liv Dis 1999;19:475-505.
8. Gluud LL, Klingenberg S, Nikolova D, Gluud C. Banding
Most Efficient Source Reviews ligation versus beta-blockers as primary prophylaxis in
for Examination Preparation esophageal varices: systematic review of randomized tri-
als. Am J Gastroenterol 2007;102(12):2842-2848.
Garcia-Tsao G, Bosch J. Management of varices and 9. Gluud LL, Krag A. Banding ligation versus beta-blockers
variceal hemorrhage in cirrhosis. N Engl J Med 2010 for primary prevention in oesophageal varices in adults.
Mar 4;362(9):823-832. Cochrane Database Syst Rev 2012;8:CD004544. doi:
Garcia-Tsao G, Lim JK. Management and treatment 10.1002/14651858.CD004544.pub2.:CD004544.
10. Villanueva C, Aracil C, Colomo A et al. Acute hemody-
of patients with cirrhosis and portal hypertension:
namic response to beta-blockers and prediction of long-
recommendations from the Department of Veterans
term outcome in primary prophylaxis of variceal bleed-
Affairs Hepatitis C Resource Center Program and the ing. Gastroenterology 2009;137(1):119-128.
National Hepatitis C Program. Am J Gastroenterol 11. Tripathi D, Ferguson JW, Kochar N et al. Randomized
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Bruix J, Sherman M. Management of hepatocel- for the prevention of the first variceal bleed. Hepatology
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lular carcinoma: an update. Hepatology 2011
12. Merkel C, Marin R, Angeli P et al. A placebo-controlled
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Lucey MR, Terrault N, Ojo L, Hay JE, Neuberger J, small esophageal varices in cirrhosis. Gastroenterology
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guideline by the American Association for the Study vention and management of gastroesophageal vari-
ces and variceal hemorrhage in cirrhosis. Hepatology
of Liver Diseases and the American Society of Trans-
2007;46(3):922-938.
plantation. Liver Transpl 2013 Jan;19(1):3-26.
14. Garcia-Tsao G, Bosch J. Management of varices
and variceal hemorrhage in cirrhosis. N Engl J Med
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24. Henderson JM, Boyer TD, Kutner MH et al. Distal spleno- cites club. Gut 2007;56:1310-1318.
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153. 45. Ong JP, Aggarwal A, Krieger D et al. Correlation between
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31. Fernandez J, Acevedo J, Castro M et al. Prevalence and Liver Dis 2008;28(1):70-80.
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Med 1999;341:403-409. drome--a liver-induced lung vascular disorder. N Engl J
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M. Norfloxacin prevents spontaneous bacterial perito- 50. Krowka MJ, Mandell MS, Ramsay MA et al. Hepatopul-
nitis recurrence in cirrhosis: results of a double-blind, monary syndrome and portopulmonary hypertension: a
placebo-controlled trial. Hepatology 1990;12:716-724. report of the multicenter liver transplant database. Liver
34. Fernandez J, Navasa M, Planas R et al. Primary prophy- Transpl 2004;10(2):174-182.
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Gastroenterology 2007;133(3):818-824. ogy 2007;132(7):2557-2576.
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cinoma. Hepatology 2005;42(5):1208-1236.

53. Mazzaferro V, Regalia E, Doci R et al. Liver transplanta-
tion for the treatment of small hepatocellular carcinomas
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699.
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Evaluation of the patient for liver transplantation. Hepa-
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plantation. Gastroenterology 2008;134(6):1764-1776.
58. Kotlyar DS, Campbell MS, Reddy KR. Recurrence of dis-
eases following orthotopic liver transplantation. Am J
Gastroenterol 2006;101(6):1370-1378.
59. Kamath PS, Wiesner RH, Malinchoc M et al. A model to
predict survival in patients with end-stage liver disease.
Hepatology 2001;33(2):464-470.
60. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port
FK, Wolfe RA. The survival benefit of liver transplantation.
Am J Transplant 2005;5(2):307-313.
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transplantation. Transpl Int 2005;18(6):627-642.
62. Post DJ, Douglas DD, Mulligan DC. Immunosuppression
in liver transplantation. Liver Transpl 2005;11(11):1307-
1314.
CHAPTER 14
Metabolic, Hereditary, Inflammatory

and Vascular Diseases of the Liver
Douglas M. Heuman, MD, FACP, AGAF, FACG
Learning Objectives
1. Understand the pathways of alcohol metabolism leading to steatosis and the features, natural history and treatment of alcoholic hepatitis and
alcoholic cirrhosis
2. Understand the role of obesity and insulin resistance in pathogenesis of non-alcoholic fatty liver disease, appreciate the increasing importance
of non-alcoholic steatohepatitis as a cause of cirrhosis, and know how to approach to its diagnosis and treatment.
3. Understand the distinction between macro- and micro-vesicular steatosis and the role of mitochondrial fatty acid oxidation defects in the latter.
4. Be familiar with the spectrum of genetic defects of bilirubin metabolism and bile formation that can lead to jaundice and cholestasis.
5. Be familiar with inborn errors of metabolism that can involve the liver, including cystic fibrosis, tyrosinemia, type 1 glycogen storage disease,
and Gaucher’s disease.
6. Understand hereditary hemochromatosis disorders in terms of the hepcidin – ferroportin axis that regulates iron absorption, and know how to
diagnose and manage hereditary hemochromatosis
7. Understand how defective copper handling in Wilson’s disease leads to low ceruloplasmin and progressive hepatic and extrahepatic disease,
and be familiar with strategies for diagnosis and treatment of Wilson’s disease
8. Understand the pathogenesis and varying presentations of liver disease caused by alpha-1-antitrypsin gene abnormalities.
9. Appreciate the role of genetic predisposition, environmental triggers and molecular mimicry in pathogenesis of autoimmune liver diseases.
10. Recognize the similarities and differences between autoimmune hepatitis and primary biliary cirrhosis, and the ability of sarcoidosis to mimic
the latter.
11. Know the features of liver allograft rejection, including acute cellular rejection and chronic ductopenic rejection
12. Be familiar with the spectrum of hepatic vascular diseases and the physiological consequences of obstruction of flow in the hepatic artery,
portal vein or hepatic veins.
Hepatic Disorders Associated with Steatosis

Steatosis, or fatty liver, characterizes a number of metabolic liver diseases. Microvesicular steatosis is the hall-
mark of certain rare disorders caused by impaired mitochondrial oxidation of fatty acids (Figure 14.1). Macrove-
sicular steatosis is a prominent feature of two of the most common liver disorders: alcoholic liver disease and
nonalcoholic fatty liver disease. Both conditions are characterized by accumulation of fat in hepatocytes. In most
leading to cirrhosis and hepatocellular carcinoma. Recent studies have found that genetic polymorphisms in lipid
metabolism, particularly the i148m variant of the PNPLA3/adiponutrin gene, may determine susceptibility to fat
accumulation and progressive liver injury in both alcoholic and non-alcoholic fatty liver diseases.1
417
Figure 14.1
Patterns of Fatty Liver Disease
A. Microvesicular steatosis, seen with rare disorders of mitochondrial fatty acid oxidation.
B. Macrovesicular steatosis,the common finding in both alcoholic and non-alcoholic fatty liver.
C. Nonalcoholic steatohepatitis is a progressive inflammatory process often leading to cirrhosis.
Alcohol induced liver disease 2, 3 suggested that the liver injury in women may occur at
alcohol intake as low as 7 drinks per week.5
Chronic ingestion of ethyl alcohol is one of the most
An ingested dose of alcohol is absorbed almost
common causes of advanced liver disease in the west-
completely in the stomach and upper small intestine.
ern world. The term alcoholic liver disease encom-
It is metabolized in the liver via two main pathways:
passes three related conditions: alcoholic fatty liver,
cytosolic alcohol dehydrogenase and the microsomal
alcoholic hepatitis, and alcoholic cirrhosis.
cytochrome P450 2E1 ethanol oxidizing system.6 Both
reactions generate acetaldehyde, which subsequently
Epidemiology and Pathogenesis:
is oxidized to acetate (Figure 14.2). In naïve individu-
Approximately 14 million adult Americans meet diag-
als cytosolic alcohol dehydrogenase is the major met-
nostic criteria for alcohol use disorder. Hepatic ste-
abolic pathway, whereas after prolonged alcohol use,
atosis is nearly universal among heavy drinkers. The
cytochrome P450 2E1 is induced and accounts for a
risk of alcoholic hepatitis and cirrhosis increases with
large fraction of alcohol metabolism. Acetate result-
the amount and duration of regular alcohol use, and
ing from alcohol oxidation can be oxidized further via
the Krebs cycle or converted to fatty acids. In addi-
Alcohol ingestion exceeding six drinks (about 48-60 g
tion, in the course of alcohol oxidation, reduced NADH
alcohol) per day in men or 2 drinks per day in women
is formed and the resulting increase in the cellular
is associated with increased risk of liver cirrhosis,4
NADH:NAD ratio alters the redox status of the cell, fa-
Lower amounts of alcohol intake may also contribute
voring fatty acid synthesis. Alcohol also increases pe-
to liver damage, especially if combined with other in-
ripheral lipolysis and delivery of free fatty acids (FFA)
jurious factors such as metabolic syndrome or viral
to the liver. As a consequence free fatty acids accumu-
hepatitis. “Safe” limits for alcohol use are not clear-
which accumulate in cytosolic fat droplets.

safe limit of 21 drinks per week for men and 14 for
As compared to simple steatosis, the mechanisms
women has been proposed, though some studies have
Chapter 14 — Metabolic, Hereditary, Inflammatory And Vascular Diseases Of The Liver 419
leading to alcoholic hepatitis and cirrhosis, with cell Figure 14.2

Pathways of Hepatic Alcohol Metabolism
are less well understood. Increased intestinal perme-
ability and changes in the gut microbiome accompany
alcoholic hepatitis. Endotoxin originating from gut
bacteria may sensitize Kupffer cells, which then re-
-
and interleukin-8.7 CYP2E1 mediated reactions may

generate reactive oxygen species and trigger a cas-
cade of injury via lipid peroxidation and other types of
oxidative damage, leading to apoptosis and activation
of stellate cells.8 Acetaldehyde spontaneously com-
bines with proteins to form adducts that may be im-
munogenic. The fact that a genetic polymorphism of
the phospholipase adiponutrin (PNPLA3) is strongly
associated with alcoholic cirrhosis.9 suggests that an Oxidative injury is produced by acetaldehyde (the product of alcohol
oxidation) and by free radical products of cytochrome P450 2E1
inherited abnormality of lipid metabolism may be cru- (induced by chronic alcohol use). Acetate derived from alcohol
cial in alcoholic liver injury. The mechanism by which metabolism can itself be utilized for fat synthesis, and also displaces
this gene variant predisposes to liver injury currently other energy substrates from catabolism via the Krebs cycle, thereby
promoting fat accumulation. Accumulation of reduced NADH as a
is under investigation.10 consequence of alcohol oxidation also favors fatty acid synthesis.
Clinical features and diagnosis:

Fatty liver is the most common and mildest manifes- fever and nausea. Hepatomegaly is the most com-
tation of alcoholic liver disease. Cytosolic fat droplets
may coalesce into large vacuoles that displace the nu- coagulopathy are present and patients may develop
cleus. Fatty liver can develop after a single episode of hepatic encephalopathy. Portal hypertension often oc-
heavy alcohol consumption. On physical examination curs and presents with ascites and/or gastrointestinal
hepatomegaly may be noted. Most cases are asymp- bleeding, often with thrombocytopenia and spleno-
tomatic and the steatosis regresses over time if alco- megaly. Polymorphonuclear leukocytosis is common.
hol consumption is stopped. Transaminase elevations are usually modest and the
Alcoholic hepatitis, or steatohepatitis, is a pro- AST:ALT ratio is elevated, usually to values over 2.
Alcoholic cirrhosis may occur as the sequel to
unpredictably in about 20% of patients who engage one or more episodes of overt alcoholic hepatitis, or
in prolonged heavy alcohol ingestion.7 Hepatocytes may evolve insidiously without overt alcoholic hepa-
undergo ballooning degeneration and apoptosis that
is most prominent in the perivenular region (zone 3). seen, most prominently in the perivenular zone. This
- -
generative micronodules. After cessation of alcohol
presence of Mallory bodies, hyaline cytoplasmic in- use, remodeling of the cirrhotic liver occurs, and
clusions composed of precipitates of keratin-like in- gradually over many years a more macronodular pat-
tern develops.
though characteristic, are not invariably present and
Alcoholic liver disease may frequently coexist
may be clinically silent. The most common symptoms with other causes of liver injury such as hepatitis B
include right upper quadrant discomfort, low-grade or C, or hemochromatosis. Initial evaluation of the
Figure 14.3 Glucocorticosteroids appear to improve survival in

Alcoholic Hepatitis patients with severe acute alcoholic hepatitis, al-
11
patients with milder alcoholic hepatitis. Key prog-

nostic indicators are age, elevated bilirubin, coagu-
lopathy, azotemia, and presence of hepatic encepha-
lopathy. A score of >32 on the discriminant function
of Maddrey and colleagues or a MELD score > 18 may
be used to identify patients with alcoholic hepatitis
to justify steroid therapy. Steroids are given as meth-

ylprednisolone 32mg/day or equivalent for 4 weeks,
followed by a 2 week taper. They should not be used
in those who are septic or experiencing active gas-
trointestinal bleeding.12 Lack of improvement in bili-
rubin after seven days of steroids is associated with
poorer prognosis.13 Anti-oxidants as single therapy
day course of N-acetylcysteine to patients with se-

Characteristic features include steatosis, ballooning degeneration of hepatocytes, and vere alcoholic hepatitis receiving steroid therapy
an inflammatory infiltrate containing neutrophils, with greatest injury in perivenular may further improve early mortality.14 Pentoxifyl-
hepatocytes (zone 3). A Mallory’s hyaline cytoplasmic inclusion can be seen in the
line is a nonselective phosphodiesterase inhibitor
inset (arrow). Photo courtesy of Dr. H. Robert Lippman.
that decreases TNF gene transcription. In one study
of severe alcoholic hepatitis it appeared to reduce
both mortality and renal failure, but pentoxifylline
patient with presumed alcoholic liver disease should was not effective as a salvage therapy in patients un-
include screening tests to exclude other causes of responsive to steroids.15 Anti-TNF therapies such as
liver disease. Alcohol use in the setting of other
types of liver injury, such as hepatitis C, increases the
severity of disease, rate of progression, and risk of associated with increased risk of severe infections.
mortality in a dose dependent manner. Cessation of
propylthiouracil, and lecithin remain unproven. Cir-
liver disease of any cause. rhosis is often present by the time alcoholic steato-
hepatitis is diagnosed, and patients with alcoholic
Treatment and prognosis: hepatitis who continue to drink invariably progress
Long-term control of alcoholism is the most impor-
to cirrhosis.
tant element of therapy. Appropriate precautions
If alcohol use ceases, steatohepatitis starts to
should be taken to manage alcohol withdrawal, in-
improve within a few weeks, and gradually resolves
cluding seizures and delirium tremens. Protein calorie
over months to years. Liver function improves and
stabilizes. However once alcoholic cirrhosis is pres-
common and need to be addressed. After withdrawal,
-
the patient should be encouraged to participate in a
cations, including variceal hemorrhage and hepa-
treatment program for relapse prevention.
tocellular carcinoma, and should undergo regular
Patients with severe alcoholic hepatitis have a
surveillance endoscopy and liver imaging. They also
substantial risk of death within weeks to months,
are at risk to experience decompensation of cirrhosis
following stressful events such as infection or major

Table 14.1
surgery. If liver function worsens in an ostensibly so-
The Metabolic Syndrome
ber alcoholic, the clinician should consider the pos-
sibility of surreptitious drinking. Liver transplan-
Adult Treatment Panel criteria for the
tation is effective therapy for patients with alcoholic
metabolic syndrome: 3 or more of the
cirrhosis who are experiencing life threatening com-
following
plications of cirrhosis Demonstrated commitment
Waist circumference > 102 cm for men and 88
to sustained sobriety is a requirement for listing in
cm for women
most liver transplant programs, though selected pa-
tients have been transplanted successfully despite Fasting serum triglycerides > 150 mg/dl
recent alcohol abuse.16
HDL cholesterol < 40 mg/dl for men and < 50
mg/dl for women
Nonalcoholic fatty liver disease Blood pressure ≥ 130/85

(NAFLD)17
Fasting blood glucose ≥ 110 mg/dl
Nonalcoholic fatty liver disease is a common dis-
order characterized by macrovesicular hepatic ste-
body mass index > 35. The histological hallmarks
consumption. NAFLD is the hepatic manifestation of of NASH, steatosis with ballooning hepatocytes and
the metabolic syndrome and is strongly associated -
with obesity, type 2 diabetes mellitus, hyperten- tered in about 4% of the general population and 10-
sion and hyperlipidemia. Prevalence of NAFLD has 20% of patients with NAFLD.
increased progressively in the U.S. with the rising Insulin resistance, the central feature of the met-
prevalence of obesity. NAFLD spans a spectrum from abolic syndrome, is thought to play a critical role in
inconsequential steatosis to active progressive non- development of NAFLD. Fatty tissue is metabolically
alcoholic steatohepatitis (NASH) leading to cirrhosis active and secretes a variety of signaling molecules
and hepatocellular carcinoma.18 The pathogenesis termed adipokines. One of these, adiponectin, is an
of the metabolic syndrome, NAFLD and NASH are in- insulin-sensitizing hormone, whose release declines
completely understood.19 as fat accumulates; low circulating levels of adiponec-
tin are a hallmark of the metabolic syndrome. Other
chemotactic adipokines are released in increasing
Epidemiology and pathogenesis: amounts in response to fat accumulation, and cause
NAFLD is present when liver contains more than 5%

fat by weight.20 Magnetic resonance imaging studies
indicate that nearly 30% of Americans have fat in the
promote insulin resistance. They act on adipose
liver, in most cases due to NAFLD. NAFLD is strongly
tissue to further suppress secretion of adiponectin,
associated with the metabolic syndrome of central
reduce expression of insulin receptors, and promote
obesity, hypertension, type II diabetes mellitus and
lipolysis. Free fatty acids released by lipolysis enter
dyslipidemia (Table 14.1), prevalence of which has
the circulation and are taken up by muscle and other
increased dramatically in the U.S. over the past four
tissues, where fatty acids are employed preferential-
decades. Over 80% of subjects with the metabolic
ly as substrate for energy metabolism. This inhibits
syndrome have NAFLD and over 90% of subjects
uptake and utilization of glucose. The pancreas re-
with NAFLD have insulin resistance. The prevalence
sponds to the resulting hyperglycemia by secreting
of NAFLD is directly related to the degree of obe-
additional insulin, resulting in hyperinsulinemia. In
sity; NAFLD is present in over 80% of subjects with
liver, hyperinsulinemia activates SREBP-1c and other abolic syndrome if liver ultrasound shows a hyper-
lipid satiety signals. This stimulates de novo syn-
thesis of fatty acids and incorporation of free fatty is reduced liver attenuation compared to the spleen
acids into triglycerides, while impairing secretion of
triglyceride-rich very low density lipoproteins. As a spectroscopy is the most accurate way to quantify
consequence fat accumulates in hepatocytes. hepatic steatosis but is also the most expensive. Liver
We do not know why, in some patients, the indo- biopsy, though not always required, currently is the
lent accumulation of fat in the liver becomes trans- only test that can reliably distinguish NAFLD from
NASH and is the gold standard for assessing sever-
- 22
tosis appears to play an important role in the genesis NASH on biopsy increases with age, degree of obe-
of NASH. The potential sources of oxidative stress in- sity, magnitude of ALT elevation, AST:ALT ratio > 1,
clude mitochondria, microsomal cytochromes P450, thrombocytopenia, presence of diabetes and hyper-
peroxisomes and iron overload. Free fatty acids tension, and severity of insulin resistance. A variety
also can directly trigger apoptosis by activating a ly- of blood tests may indicate the presence of NASH and
sosomal pathway that leads to increased local TNF
production. Dying hepatocytes in turn release medi- age, body mass index, hypertriglyceridemia, plate-
- lets, albumin, AST and ALT23 (formula and calculator
tivation of stellate cells. A genetic polymorphism in
the phospholipase adiponutrin (PNPLA3) is strongly
associated with severity of steatosis and with risk of of cytokeratin-18 fragments have also been shown to
progressive liver injury and cirrhosis in patients with be a biomarker for steatohepatitis. These tests, along
nonalcoholic fatty liver disease.21 The mechanism for with emerging noninvasive technologies for quanti-
this association is currently under investigation.
the need for liver biopsy in the future.
Liver histology in NAFLD is characterized by
Clinical features and diagnosis the presence of one or more large cytosolic fat vacu-
oles that push the nucleus to the edge of the cell. In
Most subjects with NAFLD, including those with
mild cases only a few cells may be involved, whereas
NASH, are asymptomatic. Some may complain of fa-
in severe cases the liver may resemble adipose tis-
tigue or mild right upper quadrant discomfort. Hepa-
sue. Steatohepatitis is diagnosed by the presence of
tomegaly may be noted on physical exam but often is
steatosis along with varying combinations of glyco-
hard to appreciate in the obese abdomen. Cirrhosis
in patients with NASH usually evolves insidiously
over many years and becomes manifest only when
may be associated with cytologic ballooning but are
patients develop features of advanced liver disease
such as jaundice and anasarca.
usually scattered and includes a mixture of neutro-
NAFLD typically is detected incidentally by the
phils and lymphocytes. A validated NASH activity
-
score has been published (Table 14.2) and a score
ratory studies. Approximately 75% of subjects with
of 4 or greater correlates well with the presence of
persistently elevated ALT values and no other obvi-
active steatohepatitis.24 Fibrosis in NASH is initially
ous cause have NAFLD. However transaminases may
pericentral and pericellular, progressing to central-
be persistently normal, even in the presence of NASH
central or central-portal bridging and ultimately cir-
and cirrhosis. Most subjects with NAFLD have other
rhosis. In children and in morbidly obese subjects, a
features of the metabolic syndrome, but NAFLD may
occur in the absence of these features. A diagnosis of
patients with metabolic syndrome and NAFLD who
NAFLD can be made tentatively in patients with met-
also consume alcohol, the cause of liver injury may vances, the degree of steatosis often decreases and
- the features of steatohepatitis may be lost. Thus
bination with other liver diseases such as hepatitis C, -
and the combination appears to increase severity of ably represent end-stage NASH. As with cirrhosis
25
of other causes, NASH may lead to liver failure and
increases the risk hepatocellular carcinoma.29 The
long term mortality of NASH cirrhosis is compara-
Treatment and prognosis: ble to that of hepatitis C cirrhosis, although a larger
proportion of mortality in NASH is due to cardio-
A rational approach to treatment of NAFLD focuses
vascular rather than hepatic causes.30 NASH and/
on improving insulin sensitivity via diet and exercise.
or cryptogenic cirrhosis currently account for about
In general, for those who have a BMI> 25, a diet with
1 in 7 referrals for liver transplantation in the U.S.,
and this proportion is expected to increase. Follow-
recommended. Sustained exercise should be under-
ing transplantation, hepatic steatosis almost always
taken for 30-60 minutes, 3-5 times each week if the
recurs, and many develop steatohepatitis. While the
patient’s health permits. For those with a BMI > 30,
majority of subjects have preserved graft function af-
particularly with other end-organ diseases such as
sleep-apnea, pharmacologic weight loss treatment
after transplant progress rapidly to recurrent NASH
may be considered. For those with a BMI > 35, par-
cirrhosis.
ticularly with diabetes, bariatric surgery offers the
best possibility of correcting obesity and insulin re-
sistance and may lead to resolution of NAFLD and
Microvesicular steatosis syndromes
in NASH remains unproven,26 and caution is urged in Fatty acid oxidation disorders: At least 20 different
performing such operations in subjects with cirrho- enzymes and transporters are required for mito-
sis because of the risk of precipitating liver failure.
All patients should be advised to avoid alcohol. Treat- Table 14.2
ment of adults with NASH using an insulin sensitiz- NASH Activity Score (NAS)
ing drug (pioglitazone) or an anti-oxidant (vitamin
E) results in modest improvement in steatosis and
27 Parameter Score
have not been established in diabetics, cirrhotics
Steatosis: < 5%
or in NAFLD patients without histologically proven
5-33% 0
NASH. Metformin and ursodeoxycholic acid fail to
34-66% 1
improve liver histology in NASH and are not indi-
> 66% 2
cated. Omega-3-fatty acid supplementation is effec-
Lobular inflammation: 3
No foci 0
NASH; effects on liver histology are currently under
< 2 foci per 200x field 1
study. Iron depletion via phlebotomy has been sug-
2-4 foci per 200x field 2
gested for patients with NASH who have evidence of
> 4 foci per 200x field 3
elevated iron stores. Coffee ingestion (two or more
Cytologic ballooning: 0
cups per day) appears to have a protective effect in
none 1
fatty liver disease, and is associated with lower risk
few 2
of cirrhosis;28 the mechanism is obscure.
many
NAFLD has an excellent prognosis in the inter-
mediate term (up to 10 years), but NASH progresses Active steatohepatitis usually associated with a NASH > 4
to cirrhosis in about 20% of cases. As cirrhosis ad-
chondria to take up fatty acids and degrade them via Certain drugs also may produce liver injury char-
successive removal of 2-carbon units, yielding acetyl acterized by microvesicular steatosis. These include
coA for oxidation via the Krebs cycle. Rare hereditary intravenous tetracyclines, valproate, and a number of
anti-retrovirals.
genes may be associated with liver failure, cardiomy-
opathy and/or sudden death in infancy or childhood,
often precipitated by the stress of an infection such Hereditary hyperbilirubinemias
-
A number of inherited disorders of bilirubin metabo-
tantly. Prior to recognition of the underlying meta-
lism are associated with hyperbilirubinemia in the
bolic disorders this clinical entity was termed Reyes
absence of other features of cholestasis or liver dis-
syndrome. Disorders of fatty acid oxidation can be
ease.33 These must be distinguished from acquired
causes of jaundice (Table 14.3).
blood of newborns. Universal screening of newborns
Gilbert syndrome is a very common autosomal
for six of these fatty acid oxidation disorders, along
recessive condition associated with mild unconjugat-
with 23 other important inherited disorders, has
ed hyperbilirubinemia, especially after fasting. The
been recommended, since dietary and other inter-
cause is an abnormality in the promoter region of the
ventions can prevent many of the complications.31
gene UGT1A1 that encodes bilirubin UDP-glucurono-
In fatty liver of pregnancy, women in the third
syl-transferase, the enzyme responsible for bilirubin
trimester of pregnancy acutely develop hepato-
glucuronidation. In affected patients the thymidine-
megaly and liver failure with diffuse microvesicular
adenine repeat sequence that serves as the DNA-
steatosis. This syndrome occurs when a mother
dependent RNA polymerase attachment site for gene
heterozygous for a fatty acid oxidation gene defect,
transcription contains one extra TA repeat (seven
such as long chain hydroxyacyl coA dehydrogenase
instead of six). As a consequence, UGT1A1 gene ex-
pression is reduced. As many as 12-16% of the U.S.
defect. The syndrome is thought to be caused by toxic
population are homozygous for the Gilbert syndrome
intermediates of fatty acid oxidation that are gener-
allele, but most are so mild that they go undetected.
ated by the fetus and transferred via the placenta to
Gilbert syndrome has no adverse health consequenc-
the maternal circulation. Immediate delivery of the
es and does not require treatment.
infant can arrest the process, but in some cases with
Criggler-Najjar syndrome is a rare autosomal re-
fulminant hepatic failure, liver transplantation may
cessive condition resulting from structural mutations
be required to save the mother’s life.32
or deletions in the UGT1A1 gene leading to failure of
bilirubin glucuronidation. Affected individuals have
Table 14.3 marked unconjugated hyperbilirubinemia from the
Liver Biopsy Findings in Subjects with Persistently Abnormal time of birth and are at risk to develop kernicterus
Liver Enzymes without Obvious Cause with bilirubin encephalopathy and die of neurologi-
cal complications. The type 1 variant, associated with
Biopsy finding Prevalence (total n= 354)
complete absence of functional protein, is usually
N (%)
lethal if untreated. In type 2, the milder variant, the
NASH 120 (34) genetic abnormality leads to production of an altered
Fatty liver 115 (32) protein with reduced activity. Phenobarbital, which
Cryptogenic hepatitis 32 (9) induces UGT1A1 expression, improves hyperbiliru-
Iatrogenic 27 (7.6) binemia in type II patients but is ineffective in type
Normal 21 (5.9) 1. Phototherapy increases excretion of unconjugated
autoimmune 7 (1.9) bilirubin in bile and urine and is useful in lowering
circulating bilirubin concentration. Liver transplan-
(Adapted from Skelly et al, J Hepatol, 2001: 35:195-9)
tation corrects the defect and is curative.
Dubin Johnson syndrome is caused by autosomal

recessive inherited defects in the canalicular trans- -
porter ABCC2, which excretes conjugated bilirubin membrane conductance regulator), a cyclic AMP-reg-
across the canalicular membrane into bile. Marked ulated ion channel that mediates chloride transport
conjugated hyperbilirubinemia is present from birth across epithelial cell membranes. Affected infants
but liver enzymes and serum bile acid levels are nor- and children have salty sweat with high chloride
mal. The liver becomes black from accumulation of content. Chloride transport is necessary for muco-
amino acid and epinephrine metabolites, whose ex- sal salt and water secretion, and its absence leads to
cretion also is impaired. Conjugated bilirubin is non- drying of mucus with inspissation of secretions. Con-
toxic and patients do not develop liver failure or neu- sequences include chronic bronchitis with recurrent
rological damage. The prognosis is excellent and no pneumonia, bronchiectasis and progressive pulmo-
-
ciency. Hepatobiliary involvement with chronic cho-
lestasis is encountered in some patients.38 Treatment
Hereditary cholestatic disorders with ursodeoxycholic acid may alleviate cholestasis
and ameliorate liver injury, but some patient’s prog-
Progressive familial intrahepatic cholestasis (PFIC)
ress to biliary cirrhosis, usually in the second or third
and benign recurrent intrahepatic cholestasis (BRIC)
decade. Liver transplantation, with or without con-
refer to a group of inherited disorders in which bile
current lung transplantation, may improve survival
formation is impaired, leading to generalized cho-
in selected patients.
lestasis.34-36 In PFIC cholestasis is continuous and
Hereditary Tyrosinemia type 1 is caused by ge-
progressive, leading to cirrhosis in infancy and early
death or liver transplantation; in BRIC cholestasis is
-
milder, intermittent and nonprogressive PFIC Type
lism of the amino acids phenylalanine and tyrosine.
1 (Byler’s disease) and BRIC type 1 were originally
Accumulation of a toxic intermediate in this path-
way leads to liver injury beginning in infancy, with
mutations affecting ATP8B1, an aminophospholipid
progression to cirrhosis, portal hypertension, and
transporter present in liver and bile ducts, entero-
hepatocellular carcinoma in childhood.39 Affected
cytes, and pancreatic acini.35 ATP8B1 normally trans-
individuals manifest hepatomegaly and splenomeg-
fers phosphatidylserine from the outer to the inner
aly on physical examination. Early diagnosis through
neonatal metabolic screening has been advocated.
on membrane composition appears to be necessary
-
for normal bile salt secretion. Patients with PFIC
clohexanedione) inhibits an early step in the path-
1 are homozygotes while patients with BRIC type
way, blocking accumulation of the toxic metabolite
1 are heterozygotes for ATP8B1 mutations. PFIC
and preventing liver injury. In selected cases with ad-
type 2 and BRIC type 2 are due to defects of the bile
vanced cirrhosis or early hepatocellular carcinoma,
salt export protein ABCB11 in the canalicular mem-
liver transplantation is curative.
brane.37 In both type 1 and type 2 PFIC and BRIC, bile
salt retention occurs at the level of the hepatocyte,
bile ductules are intact and GGT levels are normal. In
contrast, PFIC type 3 is due to a defect in the phos-
Storage diseases affecting the liver
phatidylcholine transporter ABCB4 in the canalicular Glycogen storage diseases are a family of conditions
membrane. Absence of biliary phospholipid allows -
biliary bile salts to disrupt canalicular and biliary cogenolysis, leading to fasting hypoglycemia, some-
epithelial cell membranes, resulting in elevated GGT times accompanied by lactic acidosis.40 Children may
- exhibit failure to thrive and delayed development.
Treatment consists of continuous glucose supple-
mentation. Type 1 (von Gierke disease) is caused deplete excess iron, usually via phlebotomy, effec-
tively arrests disease progression.
(debranching enzyme). A peculiar feature of these

two conditions is development of hepatic adeno- Epidemiology and pathogenesis:
mas, which occur in a large proportion of patients
Inheritance of hemochromatosis is linked to the HLA
who survive to adulthood. These hepatic adenomas
histocompatibility locus on chromosome 6. In 1996
are sometimes complicated by hemorrhage or ma-
the most common genetic cause of hemochromatosis
lignant transformation (hepatocellular carcinoma).
was traced to an HLA-like protein called HFE. Most
Occasional children or young adults with glycogen
patients with hemochromatosis are homozygous for
storage diseases may progress to cirrhosis or pres-
a single C282Y amino acid substitution in this gene;
ent with acute liver failure. Results of liver trans-
a second substitution, H63D, causes less severe func-
plantation are excellent.41
tional impairment. The C282Y allele probably origi-
-
nated in northern Europe among Celtic populations,
ciencies of at least 40 different lysosomal enzymes
and it is very common in their descendants. One in
involved in catabolism of membrane lipids. Most
eight people of European ancestry is heterozygous
are rare. An exception is Gaucher disease (glucocer-
for this trait, and one in 200 is homozygous. The
-
frequency of the gene mutation, and of hemochro-
reditary disorder in Ashkenazi Jews. Accumulation
matosis, is much lower in populations of Asian or
of glucosylceramide in macrophages of the Gau-
African origin. Heterozygotes have normal or near-
cher patient leads to marked hepatosplenomegaly,
normal iron metabolism; only C282Y homozygotes
bone pain with pathological fractures, anemia and
(or occasional C282Y/H63D compound heterozy-
thrombocytopenia. Liver function usually is normal,
gotes) are at risk to develop serious iron overload.
The penetrance of the trait is quite variable. In a large
portal hypertension.
population undergoing genetic screening, few of the
Median age at presentation is 10 years, and some
-
cases are not detected until adulthood. Infusion ther-
cal disease or severe iron overload. The reason for
45
apy with recombinant glucocerebrosidase helps mo-
this variable expression is unclear but may relate to
bilize lipid and improves all manifestations.42
additional genetic polymorphisms.46 Currently HFE
genetic screening is not recommended for normal
risk individuals, but guidelines do recommend that
Hereditary hemochromatosis43, 44
Hereditary hemochromatosis refers to a group of hemochromatosis should be offered counseling and
inborn errors of metabolism in which chronic exces- genetic testing, and those found to be homozygous
sive absorption of iron from the intestine results in for C282Y should undergo diagnostic evaluation.
deposition of iron in tissues. Hereditary, or primary, The discovery of HFE hemochromatosis led to
hemochromatosis is distinguished from secondary the novel realization that the liver is an endocrine or-
causes of iron overload, such as hypertransfusion in gan. The liver plays a key role in negative feedback
patients with refractory anemias or excessive dietary regulation of iron homeostasis by sensing when iron
iron ingestion. Iron interacts with oxygen to produce is present in excess and secreting a hormone called
superoxide and hydroxy radicals that can damage hepcidin that down-regulates iron absorption from
critical cell components, especially lysosomes and the intestine (as well as reducing iron release from
macrophages). Hepcidin secretion from the liver
Consequences of iron overload include hepatic cir- ordinarily increases under conditions of iron excess,
rhosis, hepatocellular carcinoma, diabetes mellitus, when transferrin saturation is high, and it decreases
arthropathy, and cardiomyopathy. Intervention to
at least two receptor/transport protein complexes mobilization of stored iron.

present on the liver cell plasma membrane. Along Mutations in non-HFE genes affecting the hep-
with beta-2 microglobulin and the transferrin 1 re- cidin-ferroportin axis are responsible for a number
ceptor, HFE is an element of the plasma membrane of rare forms of hereditary hemochromatosis (Table
transporter complex through which the liver takes 14.4). Mutations of the hepcidin gene itself cause a
up circulating iron. HFE also is thought to be part form of autosomal recessive juvenile hemochromato-
of separate iron-sensing complex that includes the sis, characterized by failure of maturation and cardio-
transferrin 2 receptor and hemojuvelin.47 Hemojuv- myopathy. A similar syndrome of juvenile hemochro-
elin is a plasma membrane co-receptor for a circulat- matosis is caused by mutations of the hemojuvelin
ing growth regulatory peptide, bone morphogenetic gene. A syndrome resembling adult hemochromato-
protein 6 (BMP-6). BMP-6 binding to hemojuvelin
leads to up-regulation of liver hepcidin secretion. receptor (TfR2). Forms of hemochromatosis associ-
While the details of the mechanism are currently ated with HFE, hepcidin, hemojuvelin and Tfr2 all
are accompanied by reduced hepcidin production,
BMP-6 through a mechanism involving HFE and the with failure to down-regulate iron absorption. In
transferrin 2 receptor. If any element of the iron- contrast, genetic defects in ferroportin that reduce
its ability to bind hepcidin cause the enterocyte to
the ability of the liver to secrete hepcidin in response become less responsive to hepcidin. This results in
to iron overload is lost or diminished.48 Hepcidin se- a mild, autosomal dominant form of hereditary he-
creted from the liver travels in the blood to the site mochromatosis in which iron absorption is excessive
of iron absorption, the duodenal enterocyte. There it despite the fact that circulating hepcidin levels are
interacts with ferroportin, an iron transport protein increased (Table 14.4). In aggregate, these non-HFE
located on the basolateral plasma membrane that defects account for fewer than 5% of all cases of he-
participates in transfer of iron from the cell cyto- mochromatosis.49
plasm into the extracellular space. Hepcidin binding
to ferroportin causes the latter to be internalized and
degraded, thereby causing iron to be trapped in en- Clinical features and diagnosis
terocytes. When the enterocyte later becomes senes-
In classical HFE hemochromatosis, iron accumulates
cent and sloughs, its iron is eliminated from the body
-
via fecal excretion (Figure 14.4). Hepcidin also binds
mality is elevated fasting transferrin saturation (ratio
to ferroportin on macrophages, thereby preventing
of iron to total iron binding capacity), in excess of 45%,
Table 14.4
Adipocytokines and their Effects
Effect on inflammation
Adipocytokine Effect on insulin signaling
And fibrosis
TNF Inhibits insulin signaling Promotes
Leptin Corrects IR in lipodystrophy Promotes
Interleukin-6 preadipocyte differentiation Promotes
Angiotensinogen II - Promotes
Resistin Inhibits insulin signaling Promotes
Visfatin Increases insulin sensitivity Increased sensitivity to
endotoxin
Adiponectin Increases insulin sensitivity Inhibits
Plasminogen activator inhibitor-1 (PAI-1) - Promotes
with reduction of the unbound iron binding capacity. ever if ferritin is greater than 1000 mcg/l or if liver
As iron accumulates in tissues, serum ferritin rises. In enzymes are elevated at the time of diagnosis, liver
women, iron losses from menstruation and pregnancy biopsy is recommended in order to rule out cirrhosis.
provide partial protection and iron accumulates more Liver biopsy with hepatic iron quantitation may be
helpful if non-HFE hemochromatosis is suspected.
body iron stores and increase progressively with iron
accumulation. Ferritin elevation is sensitive but not
- Treatment and prognosis
Iron overload is most readily reversed by phleboto-
All patients with liver disease and all patients with
my. In normal individuals, total body iron averages
-
3 to 4 grams; in hemochromatosis, iron stores may
tive of hemochromatosis should have both ferritin and
exceed 20 grams. One milliliter of packed red blood
transferrin saturation measured; if either is elevated,
cells contains approximately 1 milligram of iron.
HFE genotype should be determined. Genetic testing
Thus removal of one unit of blood per week will de-
for non-HFE forms of hemochromatosis requires gene
plete iron stores by roughly one gram per month.
sequencing with mutational analysis and is not rou-
Complete depletion of excess iron may require a year
tinely available.
or more.
The cirrhosis of hereditary hemochromatosis de-
Progress can be monitored by periodic measurement
velops insidiously with minimal or no transaminase
of declining ferritin levels and transferrin saturation.
elevations. Liver biopsy shows intense iron deposi-
The goal of therapy is a serum ferritin between 50
tion as hemosiderin in hepatocytes (Figure 14.5), with
and 100 mcg/L. Once excess iron has been removed,
lesser accumulation in macrophages; in contrast, in
occasional repeat phlebotomy may be offered as
secondary causes of iron overload such as transfusion
needed to prevent reaccumulation. Rate of iron re-
related siderosis, macrophage iron usually predomi-
accumulation may be slowed if patients avoid iron
nates. Diabetes mellitus is a common feature of hemo-
supplements, vitamin C supplements, and iron rich
chromatosis, partly because of iron deposition in the
foods. Iron chelators generally are not required un-
pancreas with loss of beta cell function, but also be-
less phlebotomy is contraindicated (for example in
cause of insulin resistance in peripheral tissues. Depo-
patients with severe anemias). Iron toxicity may be
sition of iron in the skin gives it a slate grey cast. These
aggravated by hepatic steatosis; patients should be
features have led to the description of hemochromato-
advised to avoid alcohol and maintain ideal weight.
sis as “bronze diabetes.” Deposition in joints results in
Removal of excess iron halts disease progres-
a form of osteoarthritis that most prominently affects
the second and third metacarpophalangeal joints of
and portal hypertension, as well as better diabetic
the hands. The pituitary also may be affected, leading
control, cardiac function, skin pigmentation, and
to reduced secretion of gonadotropins with impaired
sense of energy and well-being. However testicular
sexual maturation, amenorrhea or sexual dysfunction;
atrophy and arthropathy usually do not improve, and
other pituitary hormones are less commonly affected.
patients with established cirrhosis or diabetes at the
Iron deposition in the myocardium may result in ar-
time of diagnosis have a reduced life expectancy de-
rhythmias and dilated cardiomyopathy. Cardiac mani-
spite optimal treatment.50 A major cause of death is
festations are especially prominent in the rare juvenile
hepatocellular carcinoma, which develops in up to
forms of hemochromatosis.
3% per year of hemochromatotic cirrhotics. Risk of
By the time hepatic cirrhosis develops in classi-
hepatocellular carcinoma is not eliminated by phle-
cal hemochromatosis, ferritin levels are almost always
botomy, though it may be reduced. In a hemochro-
greater than 1000 mcg/L. In newly diagnosed patients
matotic patient with cirrhosis, current guidelines
with ferritin below this level and without evidence of
for liver cancer surveillance recommend liver ultra-
liver disease, liver biopsy may not be required. How-
sound every six months. Liver transplantation can
be life-saving for hemochromatosis patients with de- Wilson’s Disease52, 53

compensated cirrhosis or early stage hepatocellular
Wilson’s disease is an uncommon autosomal reces-
carcinoma. In the past, survival after transplantation
sive genetic disorder in which copper transport
in hemochromatosis was relatively poor.51 due to in-
within the hepatocyte is impaired. Copper, like iron,
creased risk of opportunistic infections and cardiac
is an essential component of certain key enzymes
failure. Pretransplant depletion of excess iron ap-
involved in oxidation and reduction, and like iron it
pears to improve these risks, and more recent data
can interact with oxygen to produce toxic free radi-
indicate that survival after transplantation for se-
cals and other reactive oxygen species. Excess cop-
lected patients with hemochromatosis is now com-
per normally is eliminated via biliary excretion. In
parable to other indications.
Wilson’s disease the failure of copper transport leads
to buildup of copper in hepatocytes and eventu-
Figure 14.4
The Hepcidin – Ferroportin Axis
ENTEROCYTE
Fe+3
Hepcidin Ferroportin
Fe+3
BLOOD
Transferrin
BMP6
Fe+3 Fe+3
Transferrin BMP6 Transferrin
HJV
TfR 2 HFE HFE
2
microglobulin TfR1
Iron sensing complex Iron transport complex
Hepcidin Fe+3
HEPATOCYTE
Hepcidin is secreted by the liver in response to excess iron. It binds to and down-regulates ferroportin, thereby suppressing 52 intestinal iron
absorption. HFE and transferrin receptor 2 on the sinusoidal membrane of hepatocytes, as well as the intracellular protein hemojuvelin, all
appear to be necessary for up-regulation of hepcidin in response to iron. Abnormalities of hepcidin, HFE, hemojuvelin, and transferrin receptor
type 2 lead to forms of hemochromatosis in which hepcidin production is reduced. Abnormalities of ferroportin that prevent binding of hepcidin
lead to hemochromatosis with high hepcidin.
ally causes hepatocellular necrosis. Copper released cases in eastern European populations. However un-
from injured hepatocytes may then accumulate in like hemochromatosis, the Wilson’s gene defects are
extrahepatic tissues, including brain and kidneys, to diverse, and over 380 different gene abnormalities
produce additional damage in these organs. Deple-
tion of excess copper via treatment with chelators disease. Wilson’s disease occurs worldwide; as many
can arrest disease progression. as 1 in 30,000 individuals are homozygous and 1 in
100 may be asymptomatic heterozygous carriers.
Epidemiology and pathogenesis:

The Wilson’s disease gene, named ATP7B, codes for
Clinical features and diagnosis
a copper transporting p-type membrane ATPase Wilson’s disease typically becomes symptomatic
found in the trans-Golgi network of hepatocytes. between the ages of 5 and 45, though a few percent
may present at older ages. The rate of copper accu-
for biliary secretion. In the absence of functional mulation is related to the severity of the gene defect.
ATP7B, copper cannot be eliminated and accumu- H1069Q homozygotes typically develop disease in
lates in hepatic lysosomes. ATP7B also is required their teens and twenties;54 in contrast, with frame-
for transporting copper within hepatocytes to the shift and nonsense mutations that result in complete
site of post-translational assembly of ceruloplasmin, absence of functional ATP7B, disease usually pres-
a copper-containing oxidoreductase produced and ents in childhood. Liver injury may be either acute
secreted by the liver. Low circulating levels of ce- or chronic. The acute pattern, seen mainly in young
ruloplasmin are a characteristic feature of Wilson’s females, may resemble acute viral hepatitis and in
- severe cases may cause acute liver failure, which of-
tion, H1069Q, may account for as many as half of all ten is accompanied by hemolytic anemia and acute
Figure 14.5
Cirrhotic Liver in Hereditary Hemochromatosis.
A. Cirrhotic nodule with hemosiderin-laden hepatocytes on H&E stain. B. Iron-containing cytosolic granules in hepatocytes stained with
Prussian blue. Photo courtesy of Dr. H. Robert Lippman.
kidney injury. Clinical clues in these patients include Table 14.5

a low alkaline phosphatase, relatively modest trans- Differentiation between alcohol-induced versus nonalcoholic fatty liver
aminase elevations, and low cholinesterase. Chronic disease
or subacute liver injury, seen more commonly in ado-
lescents and adults, is associated with more indolent Alcohol-induced liver
Parameter NAFLD
progression to cirrhosis, accompanied by gradual disease
extrahepatic deposition of copper in the basal gan- History of ETOH ++++ -
glia, kidneys, joints and elsewhere. The resulting ex- AST/ALT > 2 +++ -
trahepatic manifestations often dominate the clinical AST/ALT < 1 + +++
picture. Deposition in the cornea of the eye produces Mallory bodies Many Few
Kayser-Fleisher rings, visible on slit lamp examina- Glycogen nuclei Few Frequent
tion, which are characteristic for this disease. Depo- Cholestasis Present Rare
sition in the basal ganglia produces a variety of neu- Central vein lesions Present Rare
ropsychiatric symptoms including dysarthria, dys-
phagia, incoordination, tremor, dystonia, depression, has 55
loss of emotional control, inability to focus on tasks, been proposed to standardize diagnosis (Table 14.5).
loss of inhibitions and bizarre behavior.
The diagnosis of Wilson’s disease is based on a
combination of clinical and laboratory features. Ce- Treatment and prognosis
ruloplasmin should be checked in any patient with
evidence of liver disease, especially if associated with Untreated, Wilson’s disease is uniformly fatal, but
with timely intervention the prognosis is excel-
ceruloplasmin in a young patient with abnormal liver lent. Treatment of Wilson’s disease involves a two-
enzymes is strongly suggestive of Wilson’s disease, pronged approach, to mobilize and eliminate exces-
and should lead to ophthalmological and neurologi- sive copper stores and to prevent further copper
cal evaluation. However ceruloplasmin may be in absorption. Chelators such as D-penicillamine or
the low normal range in some patients with Wilson’s trientine bind tissue copper and facilitate its elimi-
disease, and corneal rings and neurological mani- nation via urine. Of the two, D-penicillamine is more
festations occur only when copper accumulation is -
advanced. Because 95% of circulating copper ordi- fects, including hypersensitivity, bone marrow sup-
narily is contained in ceruloplasmin, total plasma pression, and proteinuria. For this reason trientine is
copper is usually low in Wilson’s disease. However,
free plasma copper is increased, leading to increased In the early stages of chelation therapy, neurological
urinary copper excretion. Urinary copper increases symptoms can worsen. Dietary restriction of high-
further following administration of a copper chela- copper foods is indicated. Copper absorption can be
tor such as D-penicillamine or trientine. Liver biopsy prevented by treatment with oral zinc. Zinc induces
demonstrates copper containing cytosolic granules synthesis of the metal binding protein metallothio-
that take up rhodamine stain. Quantitative liver nein in intestinal epithelial cells; the metallothionein
copper is usually markedly elevated ( > 250 mcg/g sequesters copper, preventing its systemic uptake.
Because zinc can complex with chelators and reduce
or whole gene sequencing is available and can some- their effectiveness, many practitioners reserve zinc
times identify known disease associated mutations for maintenance therapy. Tetrathiomolybdate, an ex-
to establish a genetic diagnosis. This is mainly of perimental treatment, acts both to trap copper in the
GI tract and to chelate copper in the circulation.
degree relatives, since failure to identify a known With copper depletion, liver injury subsides and
Wilson’s genotype does not exclude the diagnosis. liver enzymes normalize within six months, though
manifestations of established cirrhosis often persist. Epidemiology and pathogenesis

Neurological and psychiatric manifestations respond
Alpha-1-antitrypsin is produced in the liver by the
more slowly, with progressive improvement for up to
gene SERPINA1 (for SERine Protease Inhibitor A1).
Certain common point mutations in this gene at key
be permanent. If severe jaundice and coagulopathy
“hinge points” cause the newly synthesized glyco-
are present at the time of diagnosis or if patients
protein to become abnormally folded, tangled and
present with fulminant hepatic failure, liver trans-
polymerized, accumulating in the endoplasmic re-
plantation is usually indicated. Because the donor
ticulum of the hepatocyte to produce large globular
liver has a normal ATP7B gene, liver transplantation
inclusions. As a consequence, the amount of alpha-
reverses the underlying metabolic defect of Wilson’s
1-antitrypsin secreted into the plasma is reduced
disease and should eliminate the need for long term
(though not completely absent). It is the accumula-
chelation therapy.56
tion of the abnormal protein in the liver that leads to
liver injury. Thus from the viewpoint of the hepatolo-
Alpha-1-Antitrypsin Deficiency57
as a hepatic storage disease. Rare mutations, asso-
Alpha-1-antitrypsin is a circulating protease inhibi- ciated with complete failure to synthesize the pro-
tor, synthesized and secreted by the liver. It protects tein (null alleles) or production of a dysfunctional
the lung from injury by neutrophil elastase and other protein, result in lung disease but do not cause liver
serine proteases. Common hereditary abnormalities disease. The abnormal alpha-1-antitrypsin proteins
of alpha-1-antitrypsin are associated with liver and can be detected in plasma by isoelectric gel electro-
lung disease that can present in infancy, childhood or phoresis. Compared to the normal M allele, the Z
adult life. -
culating levels of alpha-1-antitrypsin, whereas the
S allele is associated with more modest reductions.
Genotypes associated with liver disease include ZZ
Figure 14.6 homozygotes, some SZ compound heterozygotes,
Cirrhotic Liver in Alpha-1-Antitrypsin Deficiency and occasionally SS homozygotes. Heterozygotes for
S and Z alleles are 2.7% and 0.6% of the U.S. popula-
tion, respectively, and one in 5000 Americans is a ZZ
homozygote, the genotype most strongly associated
with liver disease. Carriage of even a single Z allele
may increase the risk of cirrhosis.

Neonatal hepatitis is one of the most common pre-
cause of neonatal hepatitis. About 10-20% of ZZ ho-

mozygous infants develop conjugated hyperbiliru-
binemia with jaundice and bilirubinuria beginning
four to eight weeks after birth. Transaminases are
modestly elevated, and there may be mild hepato-
Immunostain reveals alpha-1-antitrypsin positive (red) cytosolic inclusions. Photo megaly. In some, intense cholestasis may develop
courtesy of Dr. H. Robert Lippman.
of life. Others with overt liver disease in infancy prog- cirrhosis are good candidates for liver transplanta-
ress to cirrhosis in childhood or adolescence.58 Most tion, provided their lung function is adequate. Liver
homozygotes, however, do not develop neonatal transplantation cures the gene defect.
hepatitis; they escape detection in infancy and only
come to medical attention as adults when complica-
tions of liver or lung disease may become apparent. Inflammatory Liver Diseases
Cirrhosis in adults develops insidiously with mild
transaminase abnormalities. Cirrhotics are at risk
for development of hepatocellular carcinoma. Many
Primary biliary cirrhosis59
patients with advanced liver disease have little or no
lung disease, and the converse is also true. Lung dis- Primary biliary cirrhosis (PBC) is an autoimmune
ease is most typically emphysema; atypical features disorder in which small interlobular bile ducts un-
include relatively young age of onset (often between
ages 30 and 50) and disproportionate involvement to cholestasis and cirrhosis.
of the lung bases. Lung disease is accelerated by
smoking or environmental irritants, but may occur
in their absence. An element of bronchiectasis often
is present. Additional rare manifestations of alpha- Epidemiology and pathogenesis
- PBC is encountered most commonly in patients of
culitis (c-ANCA positive). The possibility of alpha- European ancestry. It is rare before adolescence, and
peak incidence is in middle age. Women are affected
infants and children with jaundice, in any older child at least 10 times as often as men; prevalence is about
or adult with transaminase abnormalities or other 1 in 1000 in U.S. women over age 45.
evidence of chronic liver disease, and in any patient PBC is thought to have both a genetic predisposi-
with chronic obstructive pulmonary disease. Plasma tion and an environmental trigger.60 Genetic predis-
alpha-1-antitrypsin level is usually subnormal in position is suggested by a 100-fold increased preva-
SZ and ZZ homozygotes, but it is often normal in SS
homozygotes and in MZ and MS heterozygotes. Liver 1-6%) and high rate of concordance in monozygotic
biopsy reveals PAS-positive diastase resistant cyto- twins. A variety of genes involved in immunoregula-
plasmic globular inclusions in hepatocytes; these can tion have been implicated in susceptibility to PBC.
- Other autoimmune diseases such as Sjogren’s syn-
taining (Figure 14.6). Allelic phenotyping is commer- drome and CREST syndrome frequently accompany
cially available and can detect the common M, S and Z PBC. Environmental bacteria that contain lipoylated
alleles. Rarer genotypes may require mutation analy- proteins may, by molecular mimicry in genetically
sis. Family members should be tested and counseled. susceptible patients, induce an immune reaction that
targets the patient’s own lipoylated proteins. Other
environmental triggers may include xenobiotics and
Treatment and prognosis toxins.
Patients should be advised to avoid alcohol and to- The characteristic autoantibody of PBC, anti-mi-
bacco. Augmentation therapy, consisting of infusions tochondrial antibody, is present in 95% of cases. Its
of human plasma alpha-1-antitypsin, slows progres- binding is directed against the lipoic acid-containing
- E2 component of the pyruvate dehydrogenase com-
ease. Treatments aimed at preventing accumulation plex, an important enzyme located on the mitochon-
of abnormal alpha-1-antitrypsin, by accelerating its drial inner membrane. In most somatic cells when
degradation via proteasome or autophagosome path- apoptosis occurs, this epitope is blocked by attach-
ways, are being explored. Patients with complicated ment of a glutathione residue, but in bile duct cells this
reaction does not occur and the antigen is exposed. -
the liver and attack bile ductular cells.61 - especially magnetic resonance imaging with cholan-
matory process obliterates small bile ducts. Because giopancreatography, are helpful in excluding other
bile drainage from canaliculi feeding those ducts is causes of cholestasis. On magnetic resonance imag-
blocked, cholestasis occurs and injures hepatocytes. ing64 about half of patients with PBC exhibit a low
density halo surrounding central portal veins on T2
the diagnosis.

The hallmark of PBC is cholestasis. The earliest
Treatment and prognosis
symptoms are pruritus and fatigue. Pruritus in the PBC usually progresses slowly over decades, though
past has been attributed to cutaneous neurotoxicity uncommon variants of PBC with features of auto-
of retained bile salts. Recently, it has been shown immune hepatitis or premature ductopenia may
that cholestasis is associated with elevated levels of progress more rapidly. Ursodeoxycholic acid, a hy-
a circulating phospholipase, autotaxin, whose prod- drophilic bile salt, given at a dose of 13-15 mg/kg
uct, lysophosphatidic acid, may cause pruritus; treat- daily appears to alleviate cholestasis and slows pro-
ments that reduce autotaxin activity also reduce pru- 65
Ursodeoxycholic acid
ritus,62 Impaired biliary excretion of cholesterol and probably works by attenuating toxicity of retained
phospholipids leads to hyperlipidemia, often with -
cutaneous xanthelasmas and tendinous xanthomas. lic acid are greatest in the early stages of disease,
before onset of jaundice. Numerous immunosup-
malabsorption of fat soluble vitamins (A, D, E and K). pressive therapies have been studied in PBC, but
Osteoporosis is common. As disease progresses, pa- none to date has been shown to prolong survival.66
tients develop jaundice and eventually experience the Systemic steroids are ineffective and aggravate os-
full spectrum of complications of cirrhosis. Presinu- teoporosis. Symptomatic treatment and supportive
soidal portal hypertension is caused by involvement treatment are essential. Pruritus often responds to
of portal venules in the obliterative process, and may bile acid binding resins such as cholestyramine or
develop prior to cirrhosis. colesevelam. When this fails, rifampin, naltrexone
The earliest laboratory clue is elevation of al- or sertraline may be effective. Patients should re-
kaline phosphatase. Immunogloblin M is usually ceive calcium and vitamin supplements. Bone den-
elevated, and anti-mitochondrial antibodies can be sity should be monitored and osteoporosis treated.
detected in more than 90%. The diagnosis of PBC Hyperlipidemia of cholestasis does not appear to
- increase risk of cardiovascular events, and does
ings of persistently elevated alkaline phosphatase, not require treatment unless there is evidence of
IgM, and anti-mitochondrial antibody. Liver biopsy atherosclerotic disease. When cirrhosis and portal
hypertension are present, management should in-
63
In the clude surveillance for varices and hepatocellular car-
earliest stage of PBC, liver biopsy reveals scattered cinoma. Patients with end stage PBC are excellent
- candidates for liver transplantation. PBC may recur
over a period of years in the transplanted liver, and
lesion” of nonsuppurative destructive cholangitis is -
the histological signature of PBC (Figure 14.7). With nic rejection.
-
Autoimmune hepatitis67 activity in the absence of treatment often is relent-

lessly progressive, but in some cases it may wax and
Autoimmune hepatitis (AIH) is a common progres-
wane spontaneously and may even go into prolonged
spontaneous remission.70
that immunosuppressive treatment can prevent cir-
rhosis and prolong life in AIH was one of the land-
the diagnosis. Transaminase elevations are usual
mark events in evolution of modern hepatology.
and often striking, whereas alkaline phosphatase
abnormalities are less prominent. A characteristic
feature is elevation of immunoglobulins, especially
Epidemiology and pathogenesis. IgG. One or more of three major auto-antibodies
AIH can affect patients of any age. It is somewhat (anti-nuclear, anti-smooth muscle and/or anti-liver
more common among women than men. Like PBC, kidney microsomal antibodies) is present in about
AIH is thought to be caused by an environmental
trigger in a genetically susceptible individual.68 AIH liver/liver-pancreas antigen, or perinuclear anti-
is more common in patients with certain HLA DR neutrophil cytoplasmic antibody may support the
haplotypes, and may occur in association with other diagnosis.69 Liver biopsy features typical of AIH in-
autoimmune diseases such as Hashimoto’s thyroid- -
itis, rheumatoid arthritis, or celiac disease. In containing plasma cells, located principally in the portal
trast to PBC, where the target of injury is interlobu- tracts, produce piecemeal necrosis of hepatocytes
lar bile duct epithelium, the target of injury in AIH with destruction of the limiting plate (interface hep-
is the periportal hepatocyte. The antigenic trigger
is not known, and may vary in different subtypes of -
the disease. Type 1 AIH is the most common form. It
to standardize diagnosis of AIH. The original diag-
or anti-smooth muscle antibodies in about 80%; nostic scoring system, proposed in 199971 has more
the asialoglycoprotein receptor, expressed strongly 72
The elements of both are
on the surface of periportal hepatocytes, has been listed in Table 14.6. In a few cases patients may ex-
implicated as the principal antigenic target. Type II hibit features of both primary biliary cirrhosis and
autoimmune hepatitis is uncommon and dispropor-
tionately affects children and young adults. In type Table 14.6
II AIH, anti-liver kidney microsomal antibodies have Syndromes Associated with Hyperbilirubinemia
been shown to be directed against cytochrome P450
2D6. Viruses containing homologous sequences may Unconjugated hyperbilirubinemia:
trigger type II AIH by molecular mimicry. Additional 1. Hemolytic anemia
AIH types have been proposed, but are not yet uni- 2. Neonatal jaundice of newborn
versally accepted.69 3. Ineffective erythropoiesis
4. Gilbert syndrome
5. Criggler Najjar syndrome
Conjugated hyperbilirubinemia
Classically AIH presents as an acute or subacute 1. Hepatic parenchymal diseases
hepatitis with fatigue, malaise, nausea and jaun- 2. Mechanical biliary obstruction
dice for weeks to months, sometimes accompanied 3. Dubin Johnson syndrome
by arthralgias. Many cases of low grade AIH are so 4. Rotor syndrome
indolent as to escape detection and present with 5. Iatrogenic
complications of cirrhosis. At the other extreme, a 6. In association with syndromes of intrahepatic cholestasis46
few may present with acute liver failure. Disease
Figure 14.7 nases and immunoglobulins, usually within months,

Primary Biliary Cirrhosis while histological improvement may require a year
or more. Where response is inadequate, cyclosporine
or mycophenolate may be employed.75 Some type I
patients with mild disease will remain in remission if
treatment is withdrawn after 2 years. However type
at time of diagnosis usually relapse if treatment is

stopped. Patients who develop complications of cir-
rhosis may undergo liver transplantation but often
require chronic post-transplant steroid treatment to
prevent recurrence of AIH in the allograft.
Primary sclerosing cholangitis76

Primary sclerosing cholangitis is an autoimmune dis-
-
bile ducts produces intra- and extrahepatic stric-
A chronic inflammatory infiltrate surrounds and invades a biliary ductule, with

and cholangiocarcinoma. This condition is discussed
destruction of epithelium. This is the characteristic “florid duct lesion” of early stage
PBC. in detail in the Biliary Disorders section.
autoimmune hepatitis and the distinction may be dif-

73
This overlap syndrome is less responsive to
IgG4 Related Disease77
immunosuppressive treatment than typical AIH and A recently recognized autoimmune disorder, IgG4 re-
often follows a clinical course resembling that of pri- lated disease is associated commonly with abdomi-
mary biliary cirrhosis. nal pain, pancreatitis and pancreatic masses. Often
the common bile duct is also involved, resembling
primary sclerosing cholangitis or cholangiocarci-
Treatment and prognosis noma, and patients may become jaundiced.78 Treat-
ment with steroids usually leads to resolution. This
Without treatment, a substantial proportion of pa-
disorder is discussed further in the Biliary and Pan-
tients with AIH will progress to cirrhosis and die of liv-
creatic Disorders sections.
er failure within 2 years. Since the pioneering studies
of Sherlock and others in the 1960s, it has been clear
that administration of glucocorticosteroids in phar-
macological doses will arrest disease activity in most
Hepatic sarcoidosis79
cases and prolong survival.74 Typically treatment in Sarcoidosis is a chronic systemic disease of unknown
adults begins with 40-60 mg of prednisone daily, re- etiology characterized by noncaseating granulo-
duced to a maintenance dose of 20 mg after a month.
Addition of azathioprine or 6-mercaptopurine allows Prominent features include generalized lymphade-
the steroid dose to be reduced by half without loss
liver is often involved with granulomas in the portal
may further reduce steroid side effects. Response is tracts and, to a lesser extent, the lobules.80 The typi-
accompanied by normalization of serum transami- cal abnormality on liver function testing is elevation
of the alkaline phosphatase, with transaminases ei- rejection usually requires treatment with a period
ther mildly elevated or normal. Elevated serum an-
giotensin converting enzyme supports the diagnosis glucocorticoids or anti-lymphocyte globulin. Chronic
but can be seen in other conditions. While hepatic ductopenic rejection is characterized by progressive
granulomas in many cases are incidental and of no
- Chronic ductopenic rejection most often follows epi-
sodes of acute cellular rejection. Once established, it
cirrhosis, often with cholestatic features.81 Acute often cannot be reversed. If patients are compliant
-
as fever, lymphadenopathy and hypercalcemia of- lant and aggressive in treating acute rejection, graft
ten respond to treatment with glucocorticosteroids, loss due to chronic ductopenic rejection is unusual.
but there is little evidence that steroids can prevent
Sarcoidosis patients who develop cirrhosis may Graft versus host disease
undergo liver transplantation if lung function is ad-
Graft versus host disease (GVHD)85 may occur fol-
equate.
lowing transfusion or transplantation of blood, bone
marrow, stem cells or tissues from one individual to
another. T-lymphocytes from the allogeneic donor, if
Liver allograft rejection not contained by an intact host immune response,
In the past half century, the evolution of orthotopic may respond to host antigens and attack host tis-
liver transplantation has revolutionized the manage- sues. The syndrome is particularly common during
ment of end stage liver disease.82,83 Following liver the second month following allogeneic hemopoietic
transplantation, calcineurin inhibitors (tacrolimus, cell transplantation, occurring in between 1/3 and
cyclosporine) and other immunosuppressive medi- 2/3 of recipients. Risk and severity increase with de-
cations are employed continuously to prevent graft gree of HLA dissimilarity between donor and recipi-
rejection. Despite these treatments, about 20% of liv- ent. Features of acute GVHD include maculopapular
er transplants are complicated by episodes of acute rash, nausea, abdominal pain, secretory diarrhea,
cellular rejection. Acute cellular rejection typically mucosal ulcerations with gastrointestinal bleeding,
- and/or cholestatic hyperbilirubinemia. Features on
plantation but may occur at any time if immunosup- liver biopsy resemble those of acute cellular rejec-
pressive therapy is interrupted. The usual present- -
bocytopenia usually precludes biopsy. Severe GVHD
alkaline phosphatase. If not treated promptly it may has a poor prognosis. Treatments include steroids,
progress to jaundice. Acute cellular rejection may photopheresis and anti-TNF but these are not consis-
tently effective.
patients with autoimmune hepatitis) or inadequate
maintenance immunosuppression, or may be trig-
gered by cytomegalovirus infection. The diagnosis is Hepatic vascular diseases86, 87
established by liver biopsy. Features include chronic
-
-
Diseases of liver perfusion
age to interlobular bile ducts, and venular endothe-
litis. Histological severity of acute cellular rejection Hepatic artery thrombosis is seen most often as a
complication of liver transplantation, though rarely
ranging from 0 to 9.84 Mild acute cellular rejection can it may occur in other settings, as a consequence of
be managed conservatively, but severe acute cellular atherosclerosis or nontransplant hepatic surgery.
Cigarette smokers are at increased risk. Because bocytopenia, and esophageal varices with hemor-
of the liver’s large portal venous blood supply, loss
of arterial perfusion alone usually does not lead to liver parenchyma remains intact, and liver function
extensive parenchymal necrosis. However the bile is generally preserved. Treatment in noncirrhotic
ducts depend upon the hepatic artery for perfusion, patients is directed at preventing propagation of
and thrombosis leads to ischemic biliary strictures thrombus via anticoagulation and, when necessary,
with cholestasis, recurrent cholangitis and liver ab- alleviating portal hypertension with pharmacologi-
- cal therapy or surgical portosystemic shunting. An-
mediately, retransplantation usually is required. ticoagulant treatment for portal vein thrombosis in
Shock liver is commonly encountered following the cirrhotic patient is controversial.
episodes of severe hypotension. The simultaneous Splenic vein thrombosis, an occasional compli-
drop in perfusion pressure to both the hepatic arte- cation of pancreatitis or pancreatic cancer, results in
rial and portal venous systems produce liver hypoxia isolated gastric varices with hemorrhage; splenec-
that is most pronounced in the perivenular zone, tomy is curative.
resulting in necrosis of zone 3 hepatocytes. Trans- Intrahepatic portal venopathies include several
aminases and lactate dehydrogenase increase imme- conditions that cause diffuse injury to small portal
diately and dramatically, often to levels greater than venules, leading to portal hypertension with well-
10,000 IU/ml. Except in the most severe cases, liver preserved liver function.31 Provided variceal hem-
synthetic function is preserved. When hypotension is orrhage can be controlled with TIPS or other inter-
corrected, necrosis ceases and enzymes decline ex- vention, the prognosis is good. Idiopathic portal
ponentially to normal over a period of days to weeks. hypertension is seen most commonly in India and
Complete structural and functional recovery is usual. Asia. In this disorder, progressive endothelial dam-
In some cases, severe illness with hypoxemia -
or shock may result in ischemic injury of the bile nules, leading to portal hypertension and variceal
duct, and recovery may be accompanied by devel- hemorrhage. Synonyms include hepatoportal scle-
phenomenon of ischemic cholangiopathy also has is unknown, though some cases have been linked to
been termed “sclerosing cholangitis in the critically
ill patient”88 and is distinct from primary sclerosing
cholangitis. Prolonged stenting or surgical drainage occur. Nodular regenerative hyperplasia may ac-
may be required to relieve cholestasis. company autoimmune vasculitides such as systemic
Portal vein thrombosis occurs in a number of lupus erythematosus or rheumatoid arthritis or
clinical settings. In cirrhosis, increased hepatic resis- may occur sporadically. The cause is thought to be
immune-complex injury of hepatic venules leading
to thrombus formation. The portal vein may be oc- to perivenular ischemia with compensatory hyper-
cluded following invasion by hepatocellular carcino- trophy of periportal hepatocytes. The liver becomes
ma. Patients with thrombotic diatheses may develop diffusely nodular, grossly resembling cirrhosis, but
spontaneous portal vein thrombosis. Infections with-
in the mesenteric vascular system, such as appendi- missed on needle biopsy and wedge biopsy may be
citis or diverticulitis, may lead to septic thrombosis required.
of the portal vein, a process termed pylephlebitis. Schistosomiasis (bilharziasis) is one of the most
Occasional cases of acute mesenteric venous throm- common causes of portal hypertension worldwide.
bosis may present with ischemic compromise of the Adult worms lodged in the bowel wall produce eggs,
intestine, but most portal system thromboses are as- some of which may enter the portal circulation and
ymptomatic or present insidiously with pre-hepatic embolize to the liver, occluding small portal venules
portal hypertension leading to splenomegaly, throm- and eliciting a granulomatous reaction with oblitera-
intrahepatic portosystemic shunt or side-to-side por-

hypertension with well-compensated liver function, tocaval shunt. Patients who fail to respond to these
though severe prolonged cases may develop true cir- measures may require liver transplantation.
rhosis.
Hepatic sinusoidal obstruction syndrome,90 also
termed hepatic veno-occlusive disease, is a distinct
Disorders of hepatic venous outflow disorder caused by acute generalized toxic injury of
sinusoidal and hepatic venular endothelial cells.91 It
Chronic hepatic congestion is encountered in con-
is encountered mainly in the setting of bone marrow
ditions associated with increased central venous
transplantation, as a consequence of the effects of
pressure, including right heart failure, constrictive
radiation and chemotherapeutic drugs employed for
pericarditis, and tricuspid valvular disease. The
myeloablation, though some cases have been caused
congested liver becomes enlarged with distended
by plant alkaloids in bush teas or mold-contaminated
sinusoids, most prominently in zone 3. Extravasa-
grains. Patients develop acute onset of tender hepato-
tion of erythrocytes from sinusoids may lead to he-
megaly, ascites, edema and jaundice, generally within
-
a few weeks of undergoing myeloablative treatment.
brosis evolves over time, giving the liver a “nutmeg”
About three fourths of patients recover spontane-
appearance, and true cirrhosis eventually develops.
ously, but peak ALT > 750 is associated with a poor
Physical exam reveals an enlarged, pulsatile liver,
outcome. Because of improvements in the regimens
and pressure on the liver may produce hepatojugular
employed for induction in bone marrow transplanta-
tion, this syndrome has become rare.
is characterized by a relatively high concentration
of protein, usually greater than 2.5 g/dl, though the
serum-ascites albumin gradient is typically greater
than 1.1 g/dl. Treatment is directed at the underlying
disease. Palliative large volume paracentesis may be Pearls and Pitfalls
required for symptomatic relief. for the Board Exam
Budd-Chiari syndrome refers to hepatic venous
A large proportion of board examination ques-
-
tions take the form of clinical vignettes. In ap-
ferior vena cava or the hepatic veins or their major
proaching the patient with liver disease, consid-
branches.89 It is termed primary if caused by a throm-
er the following.
bus or venous web, secondary if occlusion is due to
other causes such as tumor, abscess or cyst. Most
primary cases are due to hypercoagulable states, es- Patients may have multiple liver diseases. An adult
pecially myeloproliferative disorders and prothrom- patient presenting with unexplained persistently ab-
- normal transaminases or other evidence of chronic
festations include abdominal pain, liver disease should be screened at least once for
hepatomegaly, ascites, splenomegaly, and portal hy- chronic viral hepatitides (hepatitis B and C serolo-
pertensive bleeding. Severity varies and some cases gies), major hereditary liver diseases (ceruloplasmin,
may be asymptomatic. Doppler ultrasound shows ferritin, transferrin saturation, alpha-1-antitrypsin),
and autoimmune liver disease (quantitative immuno-
globulins, anti-nuclear antibody, anti-smooth muscle
is often patchy and can be missed on liver biopsy. antibody, anti-liver kidney microsomal antibody).
Treatment begins with chronic anticoagulation. A Many common liver diseases (alcoholic liver dis-
localized thrombus or web may be amenable to an- ease, nonalcoholic steatohepatitis, drug induced
gioplasty or stenting. Patients with severe portal hy- liver injury) lack a specific screening test. Suspicion
of these conditions is based on history, risk factors,
and a compatible clinical picture. accompanied by evidence of hemolytic anemia or

Liver biopsy is useful for obtaining two types of neuropsychiatric symptoms. A clue to the diagno-
information in the evaluation of liver diseases: i) sis is low alkaline phosphatase in the setting of el-
distinguishing features that help to establish the evated transaminases. If the patient with Wilson’s
etiology of liver injury, and ii) the severity of disease, disease has neurological symptoms, Kaiser-Fleisher
particularly the extent of fibrosis and presence or corneal rings are invariably present.
absence of cirrhosis. If disease etiology can be In an adult patient whose clinical presentation is
established by other means, and if disease severity suggestive of viral hepatitis, but whose serologies
is clinically apparent, biopsy often is not required. fail to identify a viral etiology, first consider the pos-
In adults, isolated unconjugated hyperbilirubinemia sibility of drug toxicity. If the patient has no clear
(more than 80% indirect reacting), without liver history of potentially hepatotoxic exposure or fails to
enzyme abnormalities and with normal synthetic improve quickly following withdrawal of a presumed
function, commonly occurs because of Gilbert syn- toxin, then consider autoimmune hepatitis. A liver
drome and is of no clinical significance. Other con- biopsy showing plasmacytic infiltration is strongly
siderations include i) bilirubin overproduction due to supportive, and rapid response to steroids +/- aza-
hemolysis or ineffective erythropoiesis, or ii) drug thioprine is confirmatory.
inhibition of bilirubin conjugation, especially in HIV Chronic cholestatic liver diseases typically present
patients receiving protease inhibitors (atazanavir, in- with pruritus and elevated alkaline phosphatase,
dinavir). A brief history with complete blood count, with or without low grade elevation of transami-
LDH and haptoglobin determinations is usually suf- nases. In adult patients who present in this man-
ficient evaluation. In infants, other considerations ner, ultrasound is indicated to screen for evidence of
include physiologic jaundice of the newborn and bile duct obstruction and rule out space occupying
hereditary defects of bilirubin conjugation (Crigler- infiltrative lesions of the liver such as cancer metas-
Najjar syndrome). tases. If the ductal system appears normal and no
Hereditary hemochromatosis is very common in indi- masses are found, in a female patient suspect pri-
viduals of European ancestry, but the penetrance is mary biliary cirrhosis; this can usually be suspected
low. Many individuals who are homozygous never by the finding of elevated IgM and anti-mitochon-
develop iron overload, and it is only those with iron drial antibody and confirmed by liver biopsy. In a
overload who develop end organ injury and disease. cholestatic male or a patient who lacks serological
Advanced liver fibrosis rarely is found in patients evidence of PBC, think of sarcoidosis or primary
whose ferritin at diagnosis is less than 1000. If fer- sclerosing cholangitis. Ultrasound is imperfect to
ritin can be kept low (ideally below 200) with oc- exclude biliary obstruction, so if ductal stricture or
casional phlebotomy, tissue injury should not occur. obstruction is still suspected, MR cholangiography
Low ferritin excludes iron overload, but high ferritin should be done.
is nonspecific. Ferritin elevation can occur because In a post-liver transplant patient who develops a
of increased total body iron stores, but it also may new elevation of liver enzymes, major diagnostic
be elevated as an acute phase reactant in response considerations include i) acute cellular rejection;
to systemic or hepatic inflammation. A patient ii) recurrence of the liver disease for which trans-
with liver disease and high ferritin should not be plantation was originally performed; iii) hepatic
assumed to have hemochromatosis; testing for HFE artery thrombosis; iv) anastomotic biliary stricture;
genotype is indicated to confirm the diagnosis, and v) hepatic congestion; vi) opportunistic infection, es-
liver biopsy may be needed. pecially cytomegalovirus; or vii) drug hepatotoxicity.
Wilson’s disease is rare in life but common on board The distinction generally requires liver ultrasound to
examinations! It should be suspected in a child or evaluate parenchyma and ducts with Doppler evalu-
young adult who has acute or chronic liver disease ation of hepatic arterial and venous flow, followed
Hinds DA. Variant in PNPLA3 is associated with alcoholic

by liver biopsy. liver disease. Nat Genet 2010 Jan;42(1):21-23.
Jaundice and transaminase elevation in the setting 10. Stickel F, Hampe J. Genetic determinants of alcoholic liver
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Cholestasis with hilar biliary strictures in a patient Wetterslev J, Gluud C. Systematic review: glucocortico-
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ary Group systematic review with meta-analyses and trial
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CHAPTER 15
Digestive Health and Disease In Women
Learning Objectives
AFTER REVIEWING THE CHAPTER, THE LEARNER WILL BE ABLE TO:
1. Discuss differences in sex-based biology
2. Review effects of hormones on the GI tract
3. Recognize the presentation and management of gastrointestinal and hepatobiliary diseases in women
4. Assess the effect of pregnancy on the presentation and/or course of GI and hepatobiliary diseases
5. Evaluate the overall effect of sex differences in GI and Liver patients
Sex Differences in Gastrointestinal Physiology

Women are higher utilizers of health care compared to men in the United States and there are many GI disor-
ders that affect women more than men including: functional bowel disorders, gallstones, and autoimmune
liver disease. Variations in disease development or expression may be based on physiologic differences and
sex and gender are often misused. There is a distinction that should be applied as follows: The term sex
used to discuss biological differences, distinctions, or functions. The term gender should be used for socio-
cultural contexts.1
Many factors may be associated with sex-based differences. Genetic factors certainly can play a role
with enhanced expression of X-linked genes in women, related to protective effects of Y-linked genes (men),
or sex-limited gene expression. Developmental and hormonal factors may additionally impact expression
of these genetic factors. 2
In addition to genetic factors, the environment and social factors certainly play a role. As an example,
women seek healthcare more often than men. The interplay of genetics and environment affect these sex-
based differences. Hormones also play a role across the continuum of the life cycle. Various triggers and
regulatory processes promote changes in the hormonal environment. In turn these changes affect not only
the reproductive life cycle but may affect other physiologic parameters.
The body composition of women vs men is different (Table 15.1). Women have less bone and muscle
mass and a higher proportion of body fat. The length of the esophagus is longer in men compared to women,
regardless of height; however the functional diameter is similar for both sexes. Changes in the reproductive
445
Table 15.1 major estrogen post-menopause. E2 is produced in

Sex-Based Differences: Body Composition and Structure the ovaries of women and testes and adrenal glands
of men. In women, estradiol supports ovulation,
conception, and pregnancy and plays a role in bone
Sex-Based Differences: health and cholesterol and E3 plays a major role in
Body Composition and Structure pregnancy.
Body composition: women vs men Estrogen receptors are activated by estrogen.
% body fat There are two types of estrogen receptors: ER (with
bone mass
muscle mass
tein coupled receptor). With regard to ER receptors,
Structural differences
Gastrointestinal system
there can be nongenomic effects via activation of the
Shorter esophagus in women regardless of height cytoplasmic protein kinase cascade and genomic ef-
Brain fects via nuclear transcription factors. Receptor dis-
Differences in pain threshold and cognitive style
tribution varies in men and women.
Heart
Less ventricular mass, smaller chamber in women Progesterone is involved in the menstrual cycle
Reproductive system and plays a key role in supporting gestation and
Pelvic floor pregnancy. This hormone has many effects on oth-
Karlstadt RG. Am J Gastroenterology 1998; 93:671 I-7 er systems of the body. Progesterone may reduce
spasm and relax smooth muscle, reduces gall blad-
Karlstadt RG. Gender differences-do they really count? Am J Gastroenterology
1998;93:671. Blair ML. Sex-based difference in physiology: what should we teach in
der activity and may lower esophageal sphincter
the medical curriculum? Advan. Physiol. Edu. 31: 23-25, 2007 pressure. Progesterone likely plays a role in the in-
creased prevalence of heartburn and GERD during
pregnancy. 6
Testosterone is secreted in the testes and ova-
implications go beyond simple structure and include
ries. In women, this hormone helps to maintain
functional issues, including problems related to con-
muscle mass and plays a role in libido. Testosterone
tinence and defecation.3
production is reduced after menopause. Estrogen
There are body structure differences, particu-
replacement therapy can also lead to testosterone
larly with regard to the percentage of body fat that in
decline.
turn can affect drug metabolism. It is not complete-
Sex-based biology promotes the study of bio-
ly understood why there are differences in the way
logical differences between men and women. It
that drugs are absorbed, distributed, metabolized
and eliminated in women vs. men. One hypothesis
ished with studies revealing physiologic differences
is that women express more of one of the metabol-
between men and women. Sex differences can be
ic enzymes found in the liver, cytochrome CYP3A.
found in many biological functions such as respons-
However, other factors are also likely to be relevant
es to stimuli and medications, and there is a com-
to these issues. For example, it is also known that
plex interaction between biology and environmental
women take more medications and supplements
than men, which can affect the rate of drug-drug in-
ogy has created a paradigm shift not only in the way
teractions and side effects. 4
researchers view health and disease but also in the
Estrogen is produced both in women and in
way studies are designed and in the manner in which
men. In women, it is produced in the ovaries, ad-
drugs are developed and studied. This chapter will
renal glands, and adipose tissue. This hormone is
focus on the sex differences in gastrointestinal and
responsible for the development of female sex char-
hepatobiliary disorders.
acteristics. There are 3 main types of estrogen: es-
trone (E1), estradiol (E2) and estriol (E3). 5 E1 is the
Chapter 15 — Digestive Health and Disease in Women 447
toms for the same endoscopic grades of esophagitis, a

Functional Disorders shorter length of the esophagus regardless of height,
and a higher sensitivity to esophageal balloon disten-
sion. 12,13 (Table 15.2) To date, the standards for pH
GERD
in order to avoid underdiagnosing GERD in women.

esophagitis seen on pathology or by documented ex- There are several studies that review hormonal
cessive acid exposure in the esophagus. GERD has effects as related to GERD. One such study concluded
ing the menstrual cycle do not predispose to GERD.

In this study, lower esophageal sphincter pressure
GERD varies worldwide but in the US, it is estimated (LESP), 24 hour pH monitoring and serum progester-
that 40% of the population has symptoms monthly, one levels were measured in 19 healthy women dur-
19.8% have at least weekly symptoms and 7-10% ing the follicular phase and luteal phase. Although a
have daily heartburn.7 A case control study showed
a higher prevalence of GERD in women compared all (except one volunteer) when going from follicular
to men (66% v 48%, p = 0.001).8 Obesity has also
ferences in LESP or esophageal acid exposure time
in women. An increased BMI has been shown to be
9 across phases of the menstrual cycle. 14
In an older study, LESP was measured in 7
the risk for GERD, erosive esophagitis, and esopha- healthy women at three distinct times: with use of
geal adenocarcinoma. 10 0.1 mg ethinylestradiol (estrogen agent) daily, with
A study examining the incidence of GERD and use of 0.1 mg ethinylestradiol plus 25 mg dimethis-
its complications found on endoscopy revealed that
Table 15.2
Gender Differences in GERD
are more common in younger men than younger
increase more rapidly in women compared to men Gender Differences in GERD
GERD
such that the prevalence in elderly patients is similar
Gender Differences in GERD
in both sexes.11
Manometry
There are several factors that contribute to the LESP same in women and men
development of GERD. The most important patho- Shorter esophagus in women
physiologic factor is thought to be Transient Lower 24-hour pH studies
Asymptomatic women had less reflux than men
Esophageal Sphincter Relaxation (TLESR). When an Symptomatic women had less reflux than men
individual swallows, it is appropriate for the lower Esophageal Sensory Response
esophageal sphincter (LES) to relax, but in the case of Asymptomatic women have lower pain threshold
than men
TLESR’s, the LES relaxes in the absence of swallow- Not affected by phases of menstrual cycle
ing. Hormonal, neural agents, smoking, medications Findings on EGD
and foods may be associated with the lowering of LES Fewer women with erosive esophagitis and Barrett s
Less common in women
pressure. In some patients, the presence of a hiatal II-15
hernia, poor esophageal clearance (e.g. esophageal

dysmotility), delayed gastric emptying, and impaired Liu JJ et al, Scand J Gastroenterol 2006; 41: 144-148, Li Q et al, Am J Gastroenterol
mucosal defensive factors may all contribute. 1994; 89:722-725, Fass R et al, Dig Dis Sci 1993; 38: 1926-1928, Richter JE et al, Dig
Dis Sci 1992; 37:849-856, Ter RB et al, Dis Esophagus 1998; 11: 106-108, Nguyen P et
The sex differences related to GERD for women al, Am J Gastroenterol 1995; 90: 901
include: higher frequency and severity of GERD symp-
terone (progestation agent) daily and while men- should be performed during endoscopy and the pa-
struating (taking no oral hormones). LESP decreased tient should be positioned in a left pelvic tilt or left
- lateral position to preclude compression on the vena
gen and progesterone but not while taking estrogen cava or aorta. In a case-controlled study of 83 con-
alone. The authors hypothesized that a rise in plasma secutive patients undergoing EGD at approximately
progesterone alone or in combination with estrogens week 20 gestational age, there was no difference in
in pregnancy causes increased rates of symptomatic the percentage of patients delivering healthy babies
heartburn. 15 (95%) when compared to age-matched controls; both
Despite this study, the cause of GERD during birth weight and APGAR scores were similar.
pregnancy is not completely understood although a Treatment of GERD in pregnancy should begin
decrease in LES pressure, most likely related to el- with lifestyle and dietary changes. For moderate to
evate hormone levels, is thought to play a role. One
study showed that in 55% of pregnant women with should be considered. Most recommendations re-
symptoms of heartburn and in 20% of asymptom- lated to safety of GERD medications in pregnancy
atic pregnant women, LES pressure decreased over are from case reports and cohort studies as opposed
the course of pregnancy as measured by manometry.
LES pressure returned to normal after delivery.16 It for pregnancy for any drug should be checked. It can
is generally recognized that symptoms suggestive of be noted that antacids containing sodium bicarbon-
GERD begin during pregnancy and stop after deliv- ate should not be used during pregnancy because of
ery. A study of 607 pregnant women demonstrated the risk of maternal or fetal metabolic alkalosis and
that both the prevalence and severity of heartburn -
progressively increased during pregnancy with an
increased risk related to parity and maternal age. congenital malformations.6 Proton pump inhibitors
Twenty-two percent of pregnant participants com- (PPI’s) should be reserved for the intractable patient
-
second trimester, and 72% in the third trimester. 17 ease (note that omeprazole is Category C, the other
Mechanical and other factors may play a role PPI’s are Category B).
during pregnancy. Pregnant women have elevated With regard to sex-related differences in over-
intra-gastric pressures during anesthesia compared all surgical treatment of GERD, a recent systematic
to men, nonpregnant women and children. These el- analysis of clinical trials and case series (published
evated pressures subsequently rapidly decrease after between 1997 and 2011) found that endoscopic stud-
delivery.18 ies of GERD and Barrett’s enrolled as many women
During pregnancy, the initial diagnosis and treat- as men and women were more likely to undergo am-
ment of GERD can be based on presentation of symp- bulatory pH studies. Surgical treatment was found to
toms. There is usually no need for extensive diagnos- be more common in men except in the United States
tic workup. Barium studies should be avoided due to (US) with an equal sex distribution. In the US, women
the risk of teratogenicity from radiation. In pregnant are more likely to have invasive diagnostic testing
patients with GERD symptoms who have been sub- and are more likely to undergo surgery than in other
jected to endoscopy (EGD), 2/3 have evidence of his- geographic locations. This might suggest healthcare
tological esophagitis, but it should be noted that visu-
ally, only mild esophagitis is usually present. 19 Despite treatment approaches to GERD.20
the fact that EGD is rarely necessary for the pregnant
patient with GERD, it has been shown that the proce-
dure is relatively safe for both mother and fetus with Functional Disorders
close monitoring of blood pressure and oxygenation
The April 2006 edition of Gastroenterology con-
and minimal sedation. Maternal-fetal monitoring
tains a series of articles presenting the Rome III cri-
teria. An excellent review of sex, age, and cultural Figure 15.1

factors in functional bowel disorders can be found in Diagnostic Criteria for Functional Dyspepsia and Subgroups (Rome III)
this volume of the journal.21
Diagnostic Criteria for Functional Dyspepsia and Subgroups (Rome III)
Dyspepsia
Dyspepsia Diagnostic Criteria for Functional Dyspepsia and Subgroups
(Rome III)
The Rome III Criteria subdivides functional
1. One or more:
dyspepsia into two entities: postprandial distress
a) Bothersome postprandial fullness
syndrome and epigastric pain.22 (Figure 15.1 and b) Early satiety
Table 15.3). Interestingly, prevalence studies have c) Epigastric pain
d) Epigastric burning
not always shown gender differences as are seen in
AND
most other functional bowel disorders (Table 15.4) 2. No structural disease to explain symptoms
However, in one of the few studies to examine the
relationship of gender and dyspepsia symptom Postprandial distress Epigastric pain
syndrome syndrome
*All criteria must be fulfilled for the last 3 months with symptom onset at
gender with dyspepsia subgroups (P=0.002): 52% least 6 months before diagnosis II-32
vs 32% (males vs. females) presented with frequent

Diagnostic criteria for Functional Dyspepsia using Rome III definitions. Functional
upper abdominal pain, 28% vs 36% (males vs.
dyspepsia is subdivided into those with postprandial distress syndromes and those
females) with early satiety, 11% (both men and with epigastric pain syndromes. Tack J, Talley NJ, Camilleri M, Holtman G, Hu P,
women) with nausea/vomiting and 10% vs 20% Malagelada J-R, Stanghellini V. Functional Gastroduodenal Disorders. The Functional
(males vs. females) with combination symptoms.23 Gastrointestinal Disorders.3rd Edition.pub Degnon Associates, Inc., Virginia. Pp419-
486, 2006 Tack J, Talley NJ, Camilleri M, Holtmann G, Ju P, Malagelada J-R,
Stanghellini V. Gastroenterology 2006;130: 1466-1479.
Irritable Bowel Syndrome Table 15.3

Diagnostic Criteria for Functional Dyspepsia and Subgroups (Rome III)
IBS is the most common functional bowel disorder,
the most common GI diagnosis seen in US gastroen-
terology practices, and one of the most common rea- Diagnostic Criteria for Functional Dyspepsia and Subgroups (Rome III)
sons for primary care physician visits. Patients with Dyspepsia
IBS typically suffer from diarrhea, constipation, or an Diagnostic Criteria for Functional Dyspepsia and Subgroups
(Rome III)
alternation of both but a key feature for the diagnosis
Postprandial Distress Syndrome Epigastric Pain Syndrome
of IBS is the presence of abdominal pain. Up to 20% One or both: All of the following:
of the US population report symptoms consistent Bothersome postprandial Pain/burning in epigastrium of
moderate severity at least once a
fullness, occurring after
with IBS.24 In the health-care seeking population, ordinary size meals, at least
week
Pain is intermittent
women outnumber men 3:1; the ratio in the com- several times a week
Not generalized or localized to
Early satiety, preventing
munity is thought to be closer to 1-2:1. (Table 15.5) finishing a regular meal that
other abdominal or chest regions
Not relieved by defecation or
These differences are less apparent in non-Western occurs at least several times
a week
passage of flatus
Not fulfilling criteria for
countries. Several issues including cultural factors, gallbladder or Sphincter of Oddi
disorders
health care seeking behaviors, application of diag- *All criteria must be fulfilled for the last 3 months with symptom onset at
nostic criteria, and methodology of survey assess- least 6 months before diagnosis II-33
ments all contribute to these differences. Observed

Definition of subtypes of Functional dyspepsia. References: Tack J, Talley NJ, Camilleri
gender differences appear to diminish with age. In M, Holtman G, Hu P, Malagelada J-R, Stanghellini V. Functional Gastroduodenal
one study, in persons aged less than 30 years the in- Disorders. The Functional Gastrointestinal Disorders.3rd Edition.pub Degnon
cidence of IBS was four times greater in women, but Associates, Inc., Virginia. Pp419-486, 2006, Tack J, Talley NJ, Camilleri M, Holtmann
G, Ju P, Malagelada J-R, Stanghellini V. Gastroenterology 2006;130: 1466-1479.
the sex difference disappeared with advancing age. 25
(Figure 15.2)
Table 15.4 Table 15.5

Gender-based Prevalence of Dyspepsia Population-based Studies Gender Distribution in Population Studies
Gender-based Prevalence of Dyspepsia Population-based Studies Gender Distribution in Population Studies
Gender-based Prevalence of Dyspepsia IBS Gender Distribution in Population Studies

Population-based Studies Country Female-to-male ratio
Spain 2001 2.42
Country Total Prevalence
Men %
Women Sample Authors Australia 2000 2.01
Canada 2003 1.75
Multinational 28.1 23.7 32.3 5581 Stanghellini
Japan 2004 1.73
Denmark 10.0 8.0 12.0 1119 Kay
Bangladesh 2001 1.35
Denmark 13.5 12.5 14.5 4581 Kay
Hong Kong 2002 1.30
Denmark 28.0 25.0 31.0 1198 Hollnagel China 2004 1.25
Norway 20.4 22.6 18.1 14390 Johnsen Singapore 2004 1.21
Sweden 16.7 12.9 20.4 1290 Agreus Iran 2003 1.17
UK 41.0 41.0 41.0 7428 Jones Taiwan 2003 1.05
Norway 2004 1.04
USA 2.9 2.6 2.7 5430 Drossman
India 2001 0.85
USA 25.8 26.9 24.7 1021 Talley
Korea 2001 0.85
USA 31.9 18.3 37.7 465 Shaib
Gwee et al. Neurogastroenterol Motil 2005; 17:317 III-6
USA 15.0 9.9 5.3 2298 Choung
Australia 24.4 21.4 27.4 561 Westbrook
II-34 IBS is also seen throughout the world, with prevalence estimates ranging
from 9-23% depending on the sample studied and the criteria selected
(1). This is a study evaluating gender differences in IBS prevalence in
Prevalence of dyspepsia overall and distribution by gender in reported population community (and not clinic) populations in non-US countries. While there
studies. All studies used either Rome I or Rome II criteria. Stanghellini V. Relationship seems to be a large female predominance of irritable bowel syndrome (IBS)
between upper gastrointestinal symptoms and lifestyle, psychosocial factors and in the West, the presentation appears to differ in Asian economies with a
comorbidity in the general population: results from the Domestic/International lack of female predominance (2). Drossman DA, Camilleri M, Whitehead
Gastroenterology Surveillance Study (DIGEST). Scand J Gastroenterol Suppl. WE, American Gastroenterological Association technical review on
1991;231:29-37. Kay L, Jergensen T, Schultz-Larsen K, Davidsen M. Irritable bowel irritable bowel syndrome. Gastroenterology 1997; 112:2137. Gwee KA
syndrome and upper dyspepsia among the elderly: a study of symptom clusters in a Irritable bowel syndrome in developing countries--a disorder of civilization
random 70 year old population. Europ J Epidemiol.1996;12:199-204. Kay L, Jergenssen or colonization? Neurogastroenterol Motil. 2005 Jun;17(3):317-24.
T. Redefining abdominal syndromes. Results of a population-based study. Scand
J Gastroenterol. 1996;31:469-475. Hollnagel H, Norrelund N, Larsen S, Occurrence
of abdominal symptoms in a 40 year old population in Glostrup. Ugeskr Laeger
1982;144:267-73. Johnsen R, Straume B, Forde OH. Peptic ulcer disease and non-
ulcer dyspepsia- a disease and a disorder. Scand J Prim Health Care 1988;6:239-43. The Rome III criteria for IBS requires the pres-
Agreus L, Svardsudd k, Nyren O, Tibblin G. The epidemiology of abdominal symptoms: ence of recurrent abdominal pain and/or discomfort
prevalence and demographic characteristics in a Swedish adult population. The for at least 3 days per month during the last 3 months
abdominal symptom study. Scan J Gastroenterol. 1994;29:102-9. Jones RH, Lydeard
SE, Hobbs FD, Kenkre JE, Williams ET, Jones SJ, Repper JA, Cladow JL, Dunwoodie
WM, Bottomley JM. Dyspepsia in England and Scotland. Gut 1990;31:401-5. Drossman sociated with at least 2 of the following 3 symptoms:
DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thomspon WG, Whitehead WE, Janssens 1) improvement with defecation, 2) change in stool
J, Funch-Jensen P, Corazziari E Householder survey of functional GI disorders: frequency, and/or 3) change in stool appearance or
prevalence, sociodemography and health impact. Dig Dis Sci 1993:38:1569-80. Talley
NJ, Zinsmeister AR, Schleck CD, Melton LJ 3rd. Dyspepsia and dyspepsia subgroupsL form. Alarm symptoms may suggest the possibility
a population-based study. Gastroenterology 1992;102:1259-68. Lower prevalence of structural disease, but do not necessarily negate a
noted. Approximately 24% had functional gastroduodenal disorders, but most were diagnosis of IBS.26 (Figure 15.3)
functional aerophagia. Ahlawat Sk, Locke GR, Weaver AL, Farmer SA, Yawn BP, Talley
NJ. Dyspepsia consulters and patterns of management : a population based study
Although as noted, IBS has a female predomi-
Aliment Pharmacol Therapeutics 2005;22:251-259. Shaib and El-Serag. Prevlance and nance, it appears to have an even greater sex differ-
Risk Factors of functional dyspepsia in a multiethnic population in the United States. ence in the IBS with constipation subgroup (IBS-C)
A J Gastroenterol 2004: 99: 2210-2216. Higher female prevalence is lost if exclude
compared to the others. One study supporting a
patients with concomitant GERD symptoms. Choung RS, Locke GR, Schleck CD,
Zinsmeiser AR, Talley NJ. Do Distinct Dyspepsia Subgroups Exist in the Community? A strong relationship between constipation predomi-
population based study. Am J Gastro. 2007: 102: 1983-1989. Westbrook JI, Talley NJ. nant IBS and female sex involved 2495 university
Empiric clustering of dyspepsia into symptom subgroups: a population based study. students in Wakayama, Japan. In this study, 268
Scandinav J. Gastroenterol. 2002;37:917-923.
(10.75%) had IBS as per the Rome II criteria. IBS
with constipation was associated with female sex
Figure 15.2 clinic setting, both constipation and abdominal dis-

Gender Differences Diminish with Age tension associated with bloating were more com-
monly reported by female patients despite simi-
lar levels of GI symptom severity, abdominal pain
Gender Differences Diminish with Age
IBS
Gender Differences Diminish with Age and psychological symptoms between the men and
9 women with IBS.31 Women also more often reported
8 non-pain related symptoms including nausea, altera-
7
6
tions of taste and smell, unpleasant sensations on the
Incidence rate 5
per 1000
IBS - Women
tongue, muscle stiffness in the morning, greater food
4
persons/yr
3
sensitivity, and side effects from medications. (Figure
2
IBS - Men
15.4)
1
There may be factors related to gender, i.e. those
0
20-29 30-39 40-49 50-59 60-69 70-79 traits related to social factors, which affect bowel
Age groups
function. For women, bowel functioning may be per-
Garc a Rodr guez et al. Scand J Gastro 2000; 306 III-7
ceived as a source of embarrassment or shame; this
In an observational study by Garcia Rodriguez et al. in 2000, patients may result from socially acceptable precepts that for
aged 20-79 years newly diagnosed with IBS (N = 2956), together with a girls and women, bodily functions should be kept
comparison cohort randomly sampled from the general source population, private. Because of our society’s focus on thinness,
were followed-up during a mean time of 3 years. They found an overall
incidence of 2.6 per 1000 person-years for IBS. In persons aged less than bloating and constipation may not represent a physi-
30 years the incidence of IBS was four times greater in women, but the sex cal discomfort but may serve as a source of psycho-
difference tended to disappear with advancing age. References: Garcia logical stress.
Rodriguez LA, Wallander MA, Johansson S, Olbe L. Detection of colorectal
tumor and inflammatory bowel disease during follow-up of patients with
initial diagnosis of irritable bowel syndrome. Scand J Gastroenterol. 2000 seeking of health care. In one study, IBS patients had
Mar;35(3):306-11. greater psychological disturbance than either IBS
non-patients (non seekers of health care) or controls.
In fact, the IBS non-patients were not psychologically
P < 0.001); there was no sex difference found for different from normal.32 Another study reported the
IBS with diarrhea.27 Similarly another survey study psychological disturbances in men and women with
of 3022 residents in Olmsted County, Minnesota IBS and found that female IBS patients had higher
showed that constipation predominant IBS patients scores for depression (Beck Depression Inventory)
were more likely to be women. A study of 429 sub- and trait anxiety but not state anxiety (State-Trait
jects with IBS observed that the female to male ratio Anxiety Inventory). This latter inventory differenti-
ates between different types of anxiety: one that is
tion relative to severity of diarrhea.28 Another study temporary and related to a cause and another that is
found that there appears to be a higher prevalence of a more general and long-standing characteristic. Al-
bowel movements and looser stools in men with IBS though IBS males and females both showed elevated
scores of depression on the Minnesota Multiphasic
common in women.29 Finally, related to symptom Personality Inventory, women with IBS had higher
subgroups, a recent systematic review and meta- scores for depression and lower scores for energy
analysis of all population-based studies up to Octo- than the men. Suggesting greater somatization or
ber 2011 found the prevalence of IBS to be modestly fear of pain, women also demonstrated higher scores
higher in women and did conclude that subtypes var- on the hysteria scale. It is interesting to note that no
ied according to gender with women more likely to gender differences in the prevalence of axis I psychi-
have IBS with constipation and women less likely to atric disorders were found.33
meet the criteria for IBS with diarrhea than men.30 Quality of life issues in IBS have been evaluated.
In a study of 714 IBS patients from a university
symptoms, psychological ratings and quality of life impact of the menstrual cycle on rectal perceptual
responses found that rectal distension during men-
cantly higher in women compared to men. Men and ses was associated with increased abdominal pain,
women differed in rating of pain and discomfort and bloating, and rectal sensitivity compared with most
women more frequently reported headache, dizzi- other phases of the menstrual cycle.36 Another study
ness, backache, muscular soreness, lack of appetite,
insomnia, and fatigue.34 sensitivity to rectosigmoid distension. Women with
Several studies have attempted to look at the in- IBS demonstrated the greatest rectosigmoid sensitiv-
ity to distension when compared to healthy women
it was found that women with irritable bowel syn- and male IBS patients and controls.37
drome using oral contraceptives had lower cogni- PET scans showed sex-related differences in
tive, anxiety, and depression symptoms, however no brain activation after visceral stimulus as reported
in a study by Naliboff et al.38 In response to visceral
of irritable bowel syndrome.35 The menstrual cycle stimulus, women showed greater activation in the
variation was similar regardless of oral contraceptive following areas: the ventromedial prefrontal cortex,
use or predominant bowel pattern. It was noted that right anterior cingulate cortex, and left amygdala
in the pre-menses period, i.e. the time estrogen and (i.e. limbic and paralimbic regions). In contrast, men
progesterone levels decrease, symptoms were gener- showed greater activation in the right dorsolateral
ally more pronounced. Another study assessing the prefrontal cortex, insula, and dorsal pons/periaque-
Figure 15.3 ductal gray.
Rome III Criteria
and small bowel may be seen in association with IBS,
Rome III Criteria it is important to note that there have been several
IBS
studies assessing transit in the GI tract and sex-re-
Rome III Criteria lated differences. A study of gastric emptying dem-
Improvement onstrated that woman have a slower rate of gastric
Recurrent with defecation emptying39 but another study showed no gender re-
abdominal pain or lated differences in GI transit. 40 In a study measuring
discomfort at least Change in
stool gastric emptying and antral motility in healthy men,
3 days/month are frequency premenopausal women, postmenopausal women,
associated with
and postmenopausal women taking estrogen and
2 or more of Change in stool
appearance/form
progesterone hormone replacement (HRT), it was
found that pre- and postmenopausal women, and
Criteria fulfilled for the last 3 months with symptom onset at least 6
months prior to diagnosis postmenopausal women taking oral estrogen and
Longstreth G Gastroenterology 2006; 130:1480
progesterone had slower gastric emptying of liq-
III-8
uids compared to men. Both premenopausal women
and postmenopausal women taking HRT had slower
Employing a consensus approach, in 2006, Longstreth and colleagues revised the
emptying of solids than did men, but postmenopausal
Rome II diagnostic criteria to establish the Rome III criteria for functional bowel
women, not on HRT, emptied solids similarly to men.
disorders, including IBS. The diagnosis of IBS requires the presence of recurrent
No differences were found in postprandial antral mo-
abdominal pain and/or discomfort for at least 3 days per month during the last 3
tility parameters between men and premenopausal
months with onset > or =6 months prior. Symptoms are associated with at least 2
women.41 Pregnancy may affect GI transit time as
of the following 3 symptoms: 1) improvement with defecation, 2) change in stool
shown by the results of a study of women with mild
frequency, and/or 3) change in stool appearance or form. Alarm symptoms suggest
the possibility of structural disease, but do not necessarily negate a diagnosis of IBS.
References: Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller in the third trimester vs post partum.42
RC Functional bowel disorders Gastroenterology. 2006 Apr;130(5):1480-91. In terms of treatment for IBS, there have been
some gender differences noted. The review of all the Constipation and Pelvic Floor Dysfunction
treatment options for IBS is beyond the scope of this
Constipation is a symptom-based disorder; although
infrequent stool is the most frequent symptom in-
related issues will be reviewed related to treatment.
terpreted by physicians, it is not the most frequent
Tegaserod is a 5-HT4 agonist that initially received
FDA approval for women with IBS with constipa-
stool passage, sensation of incomplete evacuation,
tion (IBS-C) and men and women under the age of
and frequent straining are more commonly reported
65 years with chronic idiopathic constipation (CC).
symptoms for patients. A diagnosis of constipation is
It was suspended in March 2007 because of higher
based on symptoms related to parameters of defeca-
cardiovascular events in patients who received tega-
tion (bowel frequency and bowel consistency) and
serod vs. those on placebo. In April 2008, tegaserod
can be differentiated based on the outcome of physi-
was further restricted. Currently tegaserod is avail-
ologic testing (i.e. transit tests; balloon expulsion).
able only in situations that are immediately life-
Constipation is a common condition with es-
threatening or serious enough to qualify for hospital-
timates of its prevalence in North America ranging
ization.43 Alosetron is a 5-HT3 antagonist which was
from 1.9% to 27.2%, with an average of 15%. Preva-
FDA approved for the treatment of women with IBS
lence estimates by gender reveal a female-to-male
with diarrhea (IBS-D).44 The 5-HT3 antagonists have
predominantly antidiarrheal and anti-nociceptive ef- Figure 15.4
fects. Also due to concerns of serious adverse events, Gender Differences in Symptoms
i.e. ischemic colitis and serious complications of con-
stipation, alosetron was initially withdrawn but sub-
Gender Differences in Symptoms
IBS
sequently re-released in 2002 under a restricted ac-
Gender Differences in Symptoms
cess program. Alosetron is indicated in women with
severe IBS-D. 70
* Men (n=237)
Women (n=477)
Lubiprostone is a novel therapy that activates 60
* P<0.05
type 2 chloride channel initially approved for the 50 *
*
treatment of chronic idiopathic constipation in % 40
Prevalence *
adults with a dose of 24 micrograms twice a day. It 30
now also has approval (in a different dose of 8 micro- 20
grams twice a day) for adult women with IBS with 10
constipation. 45 In August 2012, the FDA approved 0

Abdominal Bloating Urinary Muscle Altered
pain with urgency stiffness taste / smell
the use of linaclotide, a guanylate cyclase-C agonist distension
(that reduces pain and improves motility) for the Lee et al. Am J Gastroenterol 2001; 96:2184 III-17
treatment of IBS-C (dose 290 micrograms daily) and

for the treatment of chronic constipation (dose 145 Lee et al. looked at 714 IBS patients from a university clinic setting for GI and
micrograms daily). There is no restriction to either extracolonic symptoms, psychological symptoms (validated questionnaire SCL-90R),
men or women.46 47 and health-related quality of life (HRQOL, validated generic questionnaire SF-36).
Despite similar levels of GI symptom severity, abdominal pain and psychological
Recently probiotics have come of interest for gas- symptoms between the men and women with IBS, abdominal distension associated
trointestinal problems. In one study of 362 women with a sensation of bloating was more commonly reported by female patients, as were
with IBS, B. infantis 35624 at a dose of 1 x 10(8) cfu, symptoms of constipation. Female patients also more often reported non-pain related
symptoms of nausea, alterations of taste and smell, and unpleasant sensations on
the tongue, muscle stiffness in the morning, greater food sensitivity, and side effects
from medications. Forty percent of female patients reported menstrual cycle-related
of abdominal pain as well as the composite score and worsening of symptoms, but few symptom differences were found between pre-
scores for bloating, bowel dysfunction, incomplete and postmenopausal women, making it unlikely that most of the gender differences
observed are directly tied to the menstrual cycle. Lee OY, Mayer EA, Schmulson M,
evacuation, straining, and the passage of gas. 48 Chang L, Naliboff B. Gender-related differences in IBS symptoms. Am J Gastroenterol.
2001 Jul;96(7):2184-93
ratio of 2.2:1. Non-Caucasians and those of lower symptom (IBS-C); defecation disorders (e.g. pelvic
socioeconomic status report constipation more fre- -
quently than other groups. The symptom of constipa- chanical obstruction); and slow transit constipation
tion appears to increase with advancing age, particu- (least prevalent).
larly after age 65. The Rome III diagnostic criteria provide consis-
Normal defecation is a complex series of events tent diagnostic parameters for use in clinical practice
related to neuromuscular activity and transit in the -
tional chronic constipation characterized by two or
more of the following: straining during at least 25%
of defecations, sensation of incomplete emptying for
striated composite of muscles that encloses the at least 25% of defecations, sensation of anorectal
bladder, uterus, and rectum. Together with the anal obstruction for at least 25% of defecations, need to
use manual maneuvers to facilitate evacuation for at
regulating storage and evacuation of both urine and least 25% of defecations, and fewer than three def-
stool. Damage to these structures or to the nerves in- ecations per week. In addition, loose stools should
nervating these muscles may lead to loss of function. rarely occur without the use of laxatives, and there
In order for defecation to occur, stool transfers
from the sigmoid colon to the rectum assisted by
colonic high amplitude contractions. These types of within the previous 6 months and symptom duration
contractions typically occur after awakening or meals. of at least 3 months. 26 (Table 15.6)
Rectal distension due to the presence of stool occurs Constipation is more prevalent in women but in
addition, women seek healthcare more often than
sphincter (IAS). This is facilitated by the rectoanal in-
- in hormone levels or differences in the physiology of
thetic nerves). When the IAS relaxes, the fecal material pain perception in women. As noted above, rectal
is sampled in the anal canal and when voluntary def- sensitivity has also been shown to change with men-
ecation is desired, intraabdominal pressure increases. ses in IBS patients versus healthy women.
Relaxation of the puborectalis muscle (the sling-like Symptoms of constipation can vary greatly be-
muscle around the rectum) occurs and descent of the tween patients. Taking a history to note the exact na-
ture of the symptom, stool form and other symptoms
anal canal to 135 degrees from the normal 92 degrees such as the need for digitation, is important to elicit.
at rest. Rectal sensation allows stool to enter into the A thorough history may reveal secondary causes of
anal canal and inhibition of the external anal sphincter constipation, such as connective tissue disorders, hy-
(EAS) results in passage of the stool. pothyroidism, or neurologic disorders such as mul-
- tiple sclerosis or Parkinson’s disease.
synergia (paradoxical contraction or failure of relax- The physical exam should include an abdominal
examination, rectal examination and detailed neuro-
can result in a functional obstruction and subsequent logic exam to evaluate the patient for signs of a neu-
symptoms of constipation. Older women may expe- ropathy and other neurologic problems. The rectal
examination should pay attention to the anal area
evacuation, most commonly with failure of the ano-
rectal angle to open or via excessive perineal descent. scars from previous episiotomies or obstetric scars.
There are three primary causes of constipation: Digital exam should determine presence of an anal
functional constipation (most prevalent), which in- stricture, stool in the vault and stool may be tested
cludes idiopathic constipation and irritable bowel for presence of blood. The examiner will be able to
syndrome with constipation as the predominant assess anal sphincter tone at rest (largely a function
of the IAS) and during a squeeze attempt (represent- Table 15.6

ing the EAS). Asking the patient to bear down dur- Functional Constipation: Rome III Criteria
is within normal limits (between 1-4 cm), can assess

Constipation
Functional Constipation: Rome III Criteria

tain if puborectalis muscle contraction occurs with
Criteria fulfilled for at least 3 months with symptom onset at
least 6 months prior to diagnosis
highly reliable if abnormal as the patient may feel in- Chronic constipation must include 2 of the following:
Straining during at least 25% of defecations
hibited during the exam resulting in contraction of Lumpy or hard stools in at least 25% of defecations
the muscles. Sensation of incomplete evacuation for at least 25% of defecations
Sensation of anorectal obstruction/blockage for at least 25% of
A systematic review of studies by Rao and col- defecations
leagues, assessing the utility of diagnostic tests in Manual maneuvers to facilitate at least 25% of defecations (eg, digital
evacuation, support of the pelvic floor)
patients with constipation, found that no single test < 3 defecations per week
can provide a pathophysiological basis for constipa- Loose stools are rarely present without the use of laxatives
tion.49 Patients must often undergo more than one There are insufficient criteria for irritable bowel syndrome (IBS)
test to identify the underlying mechanism(s) of their Longstreth GF, et al. Gastroenterology 2006; 130:1480 IV-11
symptoms.
In the absence of alarm signs and symptoms, The Rome III diagnostic criteria were developed to provide a consistent diagnostic
there is no evidence to support the use of laboratory approach for use in clinical practice and clinical trials. The Rome III criteria define
testing, x-rays, or endoscopy in the routine manage- functional chronic constipation as a chronic bowel disorder characterized by two or more
of the following: straining during at least 25% of defecations, sensation of incomplete
ment of constipated patients. However, there is good emptying for at least 25% of defecations, sensation of anorectal obstruction for at
evidence to support the use of physiological tests, least 25% of defecations, need to use manual maneuvers to facilitate evacuation for
at least 25% of defecations, and fewer than three defecations per week. In addition,
loose stools should rarely occur without the use of laxatives, and there should be
pathophysiologic features and to direct treatment.
insufficient criteria for irritable bowel syndrome. Chronicity is established by symptom
An evidence-based approach should be empha- onset within the previous 6 months and symptom duration of at least 3 months. In
sized for establishing treatment for patients with contrast, patients with irritable bowel syndrome, also a functional bowel disorder,
experience recurrent abdominal pain and discomfort associated with two or more of
the following: symptom improvement with defecation, symptom onset associated
drugs for the treatment of chronic constipation, such with a change in the frequency of bowel movements, and a change in the form or
as tegaserod (no longer available) and lubiprostone, appearance of the stool. Longstreth GF, et al. Gastroenterology. 2006; 130:1480
has been discussed above in the section related to
IBS. It can be noted that randomized controlled trials
the treatment of dyssynergic defecation. peptide and nitric oxide, and a reduction in the num-
Slow-transit constipation is overall less common ber of interstitial cells of Cajal, which play a role in
than other types of constipation but, when docu- regulating gastrointestinal motility.
mented, it occurs most commonly in young women. Hirschsprung’s disease represents one form of
These patients often present with the complaint of slow-transit constipation with absence of ganglion
very infrequent bowel movements (once a week or cells in the distal bowel. This appears to be conse-
fewer). The onset of this disorder commonly occurs quence of embryologic development where there
with puberty. Associated symptoms include: infre- is an arrest in the caudal migration of neural-crest
quent urge to defecate, bloating, abdominal pain, cells through the gut. This results in narrowing of
and abdominal discomfort. On microscopic evalu- the bowel lacking ganglion cells with proximal dila-
ation, there appear to be changes in the number of tation. Most patients with this disorder present in
myenteric plexus neurons expressing the excitatory infancy or early childhood; there are some patients
neurotransmitter substance P, abnormalities in the who exhibit involvement of a short segment of the
inhibitory neurotransmitters vasoactive intestinal colon who may present later. Genetic mutations have
been seen in Hirschsprung’s disease with mutations It is generally believed that functional defecation
in the RET proto-oncogene or the gene for the endo- disorders are likely to be acquired behavioral disor-
thelin-B receptor. ders; at least two thirds of patients learn to relax the
The prevalence of functional defecation disor- external anal sphincter and puborectalis muscles ap-
propriately when provided with biofeedback train-
ing. One hypothesis is that pain associated with re-
of Functional Defecation Disorders). At tertiary repeated attempts to defecate large amounts of stool
ferral centers, the prevalence of dyssynergic defeca- along with hard stools may resultant in a response
tion among patients has been reported with a very to contract the anal sphincters in an attempt to mini-
mize discomfort. Against this proposition is the fact
ing expertise in various institutions. It is important that rectal discomfort is not more common in pelvic
to note that in general, the prevalence of dyssynergia
may be overestimated owing to the high false-pos- sit constipation. Increased muscle tension may also
itive rates seen in some studies related to patients result from symptoms of anxiety and/or psychologi-
feeling inhibited and therefore unable to relax. In cal stress. Sexual abuse has been reported in 22%
one tertiary care center, the prevalence of dyssyner- of women with functional defecation disorders, and
gia was 3 times higher in women than men, but was 40% of women with functional lower gut disorders,
similar in younger and older individuals.
dysfunction accounts for about 1/3 of cases of con-
Table 15.7
stipation in the community setting but up to 70% in
Functional Defecation Disorders: Rome III Criteria
a tertiary care center setting.50 Four patterns of anal
and rectal pressure changes have been described: A
Functional Defecation Disorders: Rome III Criteria normal pattern is characterized by increased intrar-
ectal pressure associated with relaxation of the anal
Criteria fulfilled for at least 3 months with symptom onset at
least 6 months prior to diagnosis sphincter. The type I pattern is characterized by both
Must satisfy criteria for functional constipation
During repeated attempts to defecate the patient must mm Hg) and increased anal pressure. The type II pat-
have at least two of the following: tern is characterized by inadequate propulsion (in-
Evidence of impaired evacuation, based on balloon expulsion
test or imaging
Inappropriate contraction of the pelvic floor muscles (i.e., anal ation or contraction of the anal sphincter. The type III
or less than 20% relaxation of the basal
sphincter or puborectalis) pattern is characterized by increased intrarectal pres-
resting sphincter pressure by manometry, imaging, or EMG
Inadequate propulsive forces assessed by manometry or
imaging relaxation of basal anal sphincter pressure. Both types
I and III are consistent with dyssynergic defecation
Longstreth GF, et al. Gastroenterology 2006; 130:1480 IV-38
(Figure 15.5).
Biofeedback is effective treatment for patients
The prevalence of functional defecation disorders in the general population is with functional defecation disorders. With this pro-
unknown. At tertiary referral centers, the prevalence of dyssynergic defecation among
patients with chronic constipation has ranged widely, from 20%–81%. The prevalence cess, patients receive visual or in some cases, auditory
of dyssynergia may have been overestimated owing to the high false-positive rates feedback on striated muscle activity recorded by anal
seen in some studies. This may be a result, in part, of anxiety in which patients are or perianal EMG or pressure sensors. Simulated def-
unable to relax in the artificial and public laboratory setting. In one tertiary care center,
ecation in which the patient practices evacuating an
the prevalence of dyssynergia was 3 times higher in women than men, but was similar
in younger and older individuals. The criteria for functional defecation disorders require
symptoms of constipation and abnormal diagnostic tests because symptoms alone do phragmatic muscle training, may also be effective. 51
not consistently distinguish patients with from patients without functional defecation Controlled and uncontrolled studies suggest an over-
disorders. Although retaining diagnostic criteria for dyssynergia, the revised criteria
acknowledge recent studies that suggest that inadequate propulsive forces may also
cause functional defecation disorders. Longstreth GF, et al. Gastroenterology 2006; training.
130:1480
Botulinum type A toxin injected into the pu- According to the NIH Consensus conference, in wom-
borectalis muscle may be effective in the treatment en less than 40, fecal incontinence rates were 6% and
increased to 15% at age greater than 40. Men had a
muscles. Controlled trials are lacking and this ap- rate of 6-10% with only a slight increase as they age.
proach cannot be recommended over biofeedback, Overall, the severity of fecal incontinence increased
with age. 54 There is a study that also indicates that
clinical experience. high level sport activity is an independent risk factor
for anal incontinence in healthy young women.55
dysfunction, rectal surgery can be considered only Anatomical and functional factors play a role in
the normal maintenance of fecal continence. Ana-
ter careful evaluation. Surgery (subtotal colectomy) tomic factors include the Pelvic Barrier and the Rec-
may be effective for patients with slow transit con- tal Curvatures and Transverse Rectal Folds. Rectal
stipation and is indicated in those who have docu-
mented Hirschsprung’s disease (resection of abnor- causes a decrease in the anal resting pressure, the
mal bowel segment with re-anastomosis -sometimes RAIR. In association with this is an anal contractile
done in stages).
Figure 15.5
Pelvic Floor Dyssynergia
Fecal Incontinence
Constipation
incontinence (FI) as an involuntary loss of liquid or Pelvic Floor Dyssynergia
stool that is a social or hygiene problem. The preva- Inadequate reflex relaxation or paradoxical contraction of pelvic floor
muscles with defecation
lence of this disorder is hard to assess because of a Inadequate propulsive forces with or without inappropriate contraction or
less than 20% relaxation of the anal sphincter during attempted defecation
lack of reporting and diagnosis.
Present in 40% of tertiary referral center patients with severe, refractory
An epidemiological study determined that the constipation
50% of patients with dyssynergia also have slow transit constipation
prevalence of fecal incontinence in community
Dyssynergia Dyssynergia Inadequate
dwelling persons is around 2-3% and this may in- Normal Type I Type II expulsion
Rectal
crease with age to greater than 10%. Among nursing 50
home residents the prevalence of fecal incontinence mmHg
0
Anal
approaches 50%. 52 The NIH Consensus statement 50
mmHg
reported similar results; with an overall prevalence 0
Remes-Troche JM and Rao SS, Curr Gastroenterol Rep 2006; 8:291

of fecal incontinence in nursing homes of about 45% Surrenti E, et al. Am J Gastroenterol 1995; 90:1471 IV-41
Nelson and colleagues examined the preva-

lence of fecal incontinence in Wisconsin through PFD may be a behavioral disorder; a learned condition through repetitive actions. It
the Wisconsin Family Health Survey. In this popula- involves the inappropriate or paradoxical contraction of the pelvic floor muscles when
one attempts to evacuate. It accounts for about 1/3 of cases of constipation in the
tion-based analysis, 2750 households (comprising
community setting but up to 70% in a tertiary care center setting. Four patterns of
6959 individuals) were surveyed. FI was found in anal and rectal pressure changes have been recognized during attempted defecation.
2.2% of the population. A multivariate analysis was A normal pattern is characterized by increased intrarectal pressure associated with
conducted demonstrating that the following risk relaxation of the anal sphincter. The type I pattern is characterized by both adequate
propulsive forces (intrarectal pressure ≥45 mm Hg) and increased anal pressure. The
type III pattern is characterized by increased intrarectal pressure (≥45 mm Hg) with
independent associations: female sex, age (continu- absent or insufficient (<20%) relaxation of basal anal sphincter pressure. Both types
ously adjusted), physical limitations, and poor gen- I and III are defined as dyssynergic defecation. The type II pattern is characterized by
inadequate propulsion (intrarectal pressure <45 mm Hg) and insufficient relaxation or
eral health. 53 contraction of the anal sphincter. Bharucha AE et al Gastroenterol 2006;130:1510-
There appears to be an association between fecal 1518, Crowell MD. Rev Gastroenterol Disord 2004; 4Suppl 2:S17, Remes-Troche JM,
incontinence and increasing age, and in some stud- Rao SS Curr Gastroenterol Rep 2006; 8:291, Surrenti E, et al. Am J Gastroenterol 1995;
90:1471
ies, there are sex-related differences in prevalence.
of rectal contents) involving the EAS and a sensory rhea (i.e. laxatives) or constipation (i.e. anticholiner-
mechanism that is poorly understood. A rich net- gics), which if severe, can lead to FI. Finally, physi-
work of nerves supplies the anorectum with sensory, cal immobility and cognitive impairment can cause
motor and autonomic nerves as well as the enteric multifactorial changes leading to FI.
nervous system. The principal nerve is the pudendal Numerous studies have reported obstetrical
nerve that arises from the second, third and fourth risk factors for developing FI. A review by Wang and
sacral nerves (S2,3,4) to innervate the EAS. The sen-
sation of rectal distension is most likely transmitted risk factors reported with FI and the four main fac-
along the S2, S3, and S4 parasympathetic nerves. tors that consistently were associated with a higher
Disruption to either the structural or functional risk of FI were: forceps delivery, third or fourth de-
components of the anorectal system can result in fe- gree tears, length of second stage of labor, and fetal
cal incontinence. Defects in the anal sphincter muscle, weight >4000g. The predominant event appears to
such as those caused by obstetrical injury or hemor- be rupture of the anal sphincter, although pudendal
rhoidectomy or other surgical procedures may re- nerve damage and defects in anorectal sensation
sult in FI. Both the IAS and EAS can be involved with also play a role. Stretching of the pudendal nerves
during childbirth is hypothesized to lead to progres-
incontinence. Disorders of the rectum including IBD, sive dennervation, thus affecting the anal sphincter
radiation, prolapse, and aging can cause changes in muscles with resulting incontinence years later. In-
compliance of the rectum or diminution of sensa- jury to the anal sphincter in the obstetric popula-
tion. Problems with the puborectalis muscle, such as tion is reported in a wide range from approximately
excessive perineal descent, aging, or trauma can lead 0.6% to as high as 20%. 57 (Figure 15.6)
to an obtuse anorectal angle or sphincter weakness. In a nested case-control study from Mayo Clinic,
Injury to the pudendal nerve from obstetric or sur- antecedent risk factors for fecal incontinence were
gical injury can also result in FI. Finally neurologic investigated. It was found that internal sphincter
conditions such as spinal cord or head injuries, back injury and reduced perineal descent are indepen-
surgery, MS, diabetes or stroke can result in neuro- dent risk factors for fecal incontinence. A history of
muscular abnormalities leading to FI. These include
-
opathy or loss of accommodation.56 could provide opportunities for prevention.58
Disturbances of anorectal sensation caused by Eason and colleagues published one of the larg-
obstetric, CNS or ANS injury can result in a loss of est prospective studies in which 949 women who
stool awareness and rectoanal agnosia (inability to had given birth in 5 hospitals in Quebec, Canada
differentiate between formed or unformed stool). from 1995-1996 completed a questionnaire three
- months after birth: 29 women (3.1%) reported in-
function with fecal retention and impaired sensation continence of stool, and 242 (25.5%) had involun-
those found in other studies that investigated FI less

infections, or radiation injury can result in diarrhea, than 1 year after delivery. 59
urgency, rapid stool transport and impaired sensa- Long-term studies have also been performed to
tion in addition to decreased rectal compliance. determine the future prevalence of FI in those with a
Liquid stool consistency and high volume can history of vaginal delivery. In 1997, a 30 year retro-
result in diarrhea with either overwhelming the nor- spective cohort study was conducted by Nygaard and
mal anorectal mechanism or loss of accommodation colleagues to compare rates of fecal incontinence
and thus result in FI. Similarly, malabsorption from in three groups of women: women who had anal
any cause including food intolerances can result in sphincter disruption from an episiotomy, those who
FI related to diarrhea. Drugs either can lead to diar- had an episiotomy without anal extension, and those
who had a Cesarean section delivery. The prevalence Figure 15.6

of bothersome fecal incontinence (to stool) ranged Pathophysiology of Obstetrical Trauma
from 15-27 % in the three groups. Regardless of the
mode of delivery, the study concluded that anal in- Pathophysiology of Obstetrical Trauma
Fecal Incontinence / Gyn Issues

continence is not uncommon in this population of
Pathophysiology of Obstetrical Trauma
middle-aged women.60
Forceps
Nonobstetrical anal sphincter defects may re- delivery
sult from surgery, manipulation (e.g. anal dilatation), Anal sphincter
trauma and systemic conditions such as scleroder- Third or disruption
fourth
degree tear Pudendal nerve Fecal
can cause anatomic disruption of the anal sphinc- damage Incontinence
ter, via damage to the IAS or loss of endovascular Length of Anorectal
second stage sensation
cushions. Anal dilatation or lateral sphincterotomy of labor
abnormalities
can result in permanent incontinence secondary to Large
fragmentation of the anal sphincter muscles. (Figure (>4000 g)
birth weight
15.7) Wang, et al. Int Uro J Pelv Floor Dysf 2006 May;17(3):253 V-11
Constipation with chronic straining over time

can lead to progressive dennervation of the pel- Numerous studies have reported obstetrical risk factors for developing FI. In a
review by Wang and colleagues, the literature was examined to determine the most
sphincter weakness. One study used defecography to significant obstetric risk factors reported with FI. Fetal characteristics, maternal
characteristics, intrapartum interventions and mode of delivery were the key topics
determine the association among chronic straining, investigated. The four main factors that consistently were associated with a higher
perineal descent and fecal incontinence and found risk of FI were forceps delivery, third or fourth degree tears, length of second stage
that perineal descent at rest and during straining of labor, and fecal weight >4000g. The main mechanistic event is rupture to the anal
sphincter, although pudendal nerve damage and defects in anorectal sensation also
was similar in women with chronic straining at stool
play a role. Stretching of the pudendal nerves during childbirth leads to progressive
and women with incontinence. Since women with dennervation of the anal sphincter muscles and incontinence years later. Injury to the
chronic straining may be at risk for the development anal sphincter in the obstetric population is reported at ~ 0.6% to as high as 20%.
Wang A, Guess M, Connell K, Powers K, Lazarou G, Mikhail M.Fecal incontinence: a
review of prevalence and obstetric risk factors. Int Urogynecol J Pelvic Floor Dysfunct.
of descent on defecography may predict future anal 2006 May;17(3):253-60
incontinence. 61 Additionally, studies have found that
excessive perineal descent and sphincter weakness
can lead to rectal prolapse that is associated with fe- the autonomic nervous system can result in FI. The
cal incontinence. (Figure 15.8) most common disorder of these disorders is diabetes
Approximately 10% of patients with fecal in- mellitus, where duration of disease correlates with
continence may have proximal lesions with cauda anorectal function. There are multifactorial reasons
equina nerve injury. In a minority of patients, there whereby diabetic neuropathy can lead to fecal in-
is a combination of peripheral and central lesions. continence including: anal sphincter weakness, im-
56
Diseases of the CNS can result in loss of anorectal paired rectoanal sensation, reduced compliance and
diabetic diarrhea. 62
and loss of accommodation. Spinal cord injuries are In physically or cognitively limited individuals,
one example and generally lead to constipation. For especially those who are immobile, FI is often associ-
lesions below T12, resting anal sphincter tone is re-
duced, rectoanal sensation is blunted and the use of present with paradoxical liquid stool seeping around
laxatives to treat the underlying constipation predis- the fecal mass resulting in a pseudo-diarrhea. Rectal
poses these individuals to FI. Examples of other CNS sensation can be blunted, especially if the rectum be-
lesions resulting in FI include stroke, dementia, brain comes dilated, and the IAS may be inhibited, further
tumors and multiple sclerosis. Disorders that affect predisposing individuals to FI. 63
Figure 15.7 severity, none are routinely used in practice nor have
Nonobstetrical Anal Sphincter Defects Causing FI they been universally adopted into clinical trials.
If a comprehensive history is obtained, underly-
Nonobstetrical Anal Sphincter Defects Causing FI
ing problems can be localized. Passive incontinence
Fecal Incontinence / Gyn Issues
suggests dysfunction of the IAS or a sensory abnor-
Nonobstetrical Anal Sphincter Defects Causing FI mality. In contrast, urge incontinence where individ-
uals have the urge to defecate but cannot make it to
Anorectal surgery for:
Hemorrhoids
the toilet in a timely fashion suggests EAS dysfunc-
Fissures tion or luminal disease. The volume and type of stool
Fistulas lost can assess severity. Stools that are liquid are
Anal dilatation or
sphincterotomy continence mechanisms.
Perineal inspection and digital rectal exam are a
Accidental perineal trauma
necessary part of the physical examination in a pa-
Scleroderma tient with fecal incontinence. With a thorough digital
V-12 rectal exam, IAS tone, EAS contraction, puborectalis
contraction, fecal mass/impaction and “anal wink”
Nonobstetrical anal sphincter defects include surgery or manipulation, trauma and can all be evaluated. An intact anal wink suggests
systemic conditions such as scleroderma. Surgery for hemorrhoids, fistulas and fissures
can cause anatomic disruption of the anal sphincter, through inadvertent damage to
the IAS or loss of endovascular cushions. Anal dilatation or lateral sphincterotomy can nervation, by assessing the presence of a brief con-
result in permanent incontinence secondary to fragmentation of the anal sphincter traction of the EAS when the perianal skin is lightly
muscles. Postoperative rates of FI in patients after lateral sphincterotomy have touched.
approached 45%, with 5 year rates of 1-8%. Direct sphincter damage can also be a
result of perineal trauma or pelvic fracture. Systemic conditions that affect smooth Diagnosis of fecal incontinence should be tai-
muscle can also result in a thinning of the IAS and dysfunction of the anal sphincter. A lored to the patient’s presentation. Endoscopic evalu-
recent study compared the MR images of the anal sphincter in those with scleroderma
and fecal incontinence to those with scleroderma alone, FI alone or neither. In patients
with FI and scleroderma, there was descent of rectal air and feces into the anterior anal
of the colon or malignancy may be indicated. This is
canal, with forward deviation of the significantly (P < .05) atrophied internal sphincter. especially important in patients with a recent change
Endoanal MR imaging helped to outline the deformity of the anal sphincter, though in bowel habits or diarrhea.50 Determining anorectal
the slower gadolinium-enhancement pattern on dynamic studies of the IAS. Bharucha
physiology with various other diagnostic modalities
AE. Fecal incontinence. Gastroenterology. 2003 May;124(6):1672-85. Review. Rao S.
Pathophysiology of adult fecal incontinence. Gastroenterology. 2004 Jan;126 (1 Suppl
1):S14-22. Review. deSouza NM, Williams AD, Wilson HJ, Gilderdale DJ, Coutts GA, sphincter function has been anorectal manometry.
Black CM. Fecal incontinence in scleroderma: assessment of the anal sphincter with This allows assessment of resting anal pressure (IAS
thin-section endoanal MR imaging. Radiology. 1998 Aug;208(2):529-35
function) and voluntary and involuntary squeeze
(EAS function). In addition to motor function, rectal
compliance and sensation can also be evaluated.
It is imperative to perform a detailed history
Endoanal ultrasound can identify anal sphinc-
in order to develop a diagnosis and treatment plan
ter defects of either the IAS or EAS. Defecography
with the patient. Careful characterization of bowel
habits is important, and the social impact to the in-
during cough, squeeze, and straining and can offer
dividual should also be addressed with quality of
functional information related to continence and def-
life questions. Because of the embarrassing nature
ecation. Functional pelvic MRI can also assess sphinc-
of the symptom, the health care provider should ask
directly about this symptom as it is likely underre-
without radiation exposure. Pudendal nerve termi-
ported due to this embarrassment. Severity tools
nal motor latencies might be useful in determining
have incorporated three different areas: stool loss,
if there is a pudendal neuropathy, although some
use of coping mechanisms, and impact or changes in
recent studies have suggested limitations. EMG can
lifestyle. While there are multiple scales for rating FI
localize injury affecting the EAS and is recommended Figure 15.8

when a proximal neurogenic lesion (involving sacral Anatomical Disturbances of the Pelvic Floor Resulting in FI
roots or cauda) is suspected. It can identify myogenic
versus neurogenic injury of the EAS. Fecal Incontinence / Gyn Issues
Anatomical Disturbances of the Pelvic Floor Resulting in FI
The main goal of pharmacotherapy is to identify Anatomical Disturbances of the Pelvic Floor
and treat the underlying disorder leading to diar- Resulting in FI
rhea or constipation. When these disorders cannot
mount. Diet, medications, biofeedback, surgery, and

additional novel options under investigation are the Descending Perineum
Rectal Prolapse
management options. These therapies can be exam- Syndrome
ined in well-written reviews. 64-67 Ulcer
Fistula
Chronic Pelvic Pain and Endometriosis

Lembo A, et al. N Engl J Med 2003; 349:1360 V-13
ety of Obstetricians and Gynecologists as noncyclic

pain lasting 6 months or more, localized to the pelvic Women with long standing chronic constipation and excessive straining for many years
can develop descending perineum syndrome. The chronic straining over time can lead to
region, causing functional disability. Although preva- progressive dennervation of the pelvic floor muscles thus resulting in perineal descent
and sphincter weakness. One study used defecography to determine the association
15-20% of women aged 18-50 experience pain last- among chronic straining, perineal descent and fecal incontinence. The authors found
that “women with chronic straining at stool have perineal descent at rest and during
ing greater than 1 year. Chronic pelvic pain has many
straining similar to that of incontinent women. Women with chronic straining are also
different etiologies, including gynecological, GI, uri- prone to develop anal incontinence, suggesting that perineal descent at defecography
nary, and musculoskeletal. Psychological problems in women with straining at stool may predict future anal incontinence.” Additionally,
may complicate the presentation. In the UK a large studies have found that excessive perineal descent and sphincter weakness can lead
to rectal prolapse and, in turn, fecal incontinence. Berkelmans I, Heresbach D, Leroi
primary care database revealed that gastrointestinal AM, et al. Perineal descent at defecography in women with straining at stool: a lack
etiologies were the most commonly found (37.7%), of specificity or predictive value for future anal incontinence? Eur J Gastroenterol
followed by urinary causes (30.8%) and gynecologic Hepatol. 1995 Jan;7(1):75-9.
problems (20.2%). The four most common diagno-
ses determined for the cause of chronic pelvic pain
include: endometriosis, adhesions, irritable bowel Endometriosis is divided into 4 stages: minimal,
syndrome, and interstitial cystitis. 68 mild, moderate, and severe as determined by the size
Endometriosis is a common condition in women and depth of lesions in the peritoneum and ovaries,
of childbearing age. Prevalence data suggest endo- the presence and extent of adhesions and whether
metriosis affects 10% of fertile women, 25-40% in the posterior cul-de-sac is obliterated. 70
women who are infertile and 50% of teenage girls The presentation of endometriosis is variable
with severe dysmenorrhea. Endometriosis may also with over 25% of women having no symptoms. Symp-
be seen in 2-4% of postmenopausal women related toms have been described as progressive, cyclical or
to estrogen therapy. Taller and thinner women, those constant. Frequent symptoms include dysmenor-
with shorter menstrual cycle length and the use of rhea, chronic pelvic or back pain, infertility, premen-
caffeine or alcohol increase the risk of endometrio- strual staining, painful defecation and proctalgia.
sis. Smoking and exercise decrease the risk. Rare Bowel involvement with endometriosis occurs
cases of endometriosis have been reported in men, in up to 37% of cases. Patients may be asymptom-
due to metaplasia of the mesothelium lining the pel- atic; intestinal symptoms, when they occur, usually
vic peritoneum or due to maturation of embryonic include abdominal pain, constipation or diarrhea.
rest tissue.69 Hematochezia, nausea, vomiting or defecatory pain
have also been reported. Cyclical symptoms are presence of estrogen, the medical treatment goal is
more commonly reported when endometriosis in- to create states of pseudopregnancy, pseudomeno-
volves the appendix than the rectosigmoid. 71 pause or chronic anovulation. The goals of therapy
Chapron et al. describe 143 cases with intestinal are to both reduce the mass of the implants and to
- manage pelvic pain or other symptoms. Pain relief
trating endometriosis. The most commonly affected appears to occur similarly with regard to treatment
areas were the sigmoid colon, rectosigmoid junction with medications or surgery.
Endometriosis is common in women and must
endometriosis of the intestine. The appendix, cecum be differentiated from irritable bowel syndrome or
and ileocecal junction and small bowel were involved other gastrointestinal problems in order to plan ef-
less often: 6.4%, 4.1%, and 4.7% of cases respective- fective therapy. The diagnosis of endometriosis
ly. 72 (Figure 15.9) should be considered in any woman of reproductive
In another review of endometriosis of the GI age who presents with abdominal pain, especially if
tract, involvement of the rectum and sigmoid was in the pelvis or lower abdomen.
found in approximately 90% of cases whereas in-
volvement of the ileum, appendix and cecum oc-
curred in 5-15% of patients.73 Inflammatory Bowel Disease (IBD)
Pain is more common in lesions that are deeply
-
lated to ulcerative colitis and Crohn’s disease. The
-
focus will be on fertility, pregnancy, and treatment.
relating with pain symptoms. Intestinal bleeding and
A comprehensive review of special considerations
accumulation of ascites can occur cyclically. Scarring
for women who have IBD covers other issues includ-
may result in strictures and obstructions. Peritonitis
ing; body image, menstruation, cervical screening,
may occur relating to bleeding from lesions on the
hormone replacement therapy, osteoporosis, and ir-
intestinal surfaces. Intussusception or volvulus are
ritable bowel syndrome in IBD.76
possible complications related to large lesions or
Ulcerative colitis (UC) patients managed non-
scar tissue. The development of endometrial carci-
operatively have a high (97%) rate of achieving
noma in an endometrioma is very rare. 74
pregnancy which then falls to 56% after ileal pouch
There are several studies assessing the most
anal anastomosis (IPAA). Overall infertility rates are
appropriate modalities for imaging or evaluation of
higher after IPAA. 77 (Figure 15.10) Most studies from
patients suspected of having endometriosis involv-
primarily referral populations, show decreased fertil-
ing the GI tract. A retrospective study of 234 women
ity in women with Crohn’s disease (CD). Reasons for
who were believed to have endometriosis and un-
decreased fertility are likely both physical and social.
derwent air contrast barium enema prior to surgery
There is a small report of abnormal sperm morphol-
showed that 174 (74.3%) of the patients had intes-
ogy, motility and number in men with CD.78 There
tinal lesions with 31% of women having more than
are several factors that may affect fertility. Women
one intestinal lesion. Twelve of twenty-seven lesions
-
75
Endo-
metriosis is rarely seen at the time of colonoscopy.
their disease, surgical history and disease activity. 79
Fixation or distortion of the colon may result in a
There are several studies that assess the impact
of disease on pregnancy. In a study of 227 women
colonoscopy may include: polypoid lesions, extrin-
with UC, the overall relapse rate during pregnancy
sic compression, a localized extramucosal mass or a
was similar to that in non-pregnant women.80 There
stricture. MRI may aid in the diagnosis and endorec-
are fewer data on the outcome of pregnancy in wom-
en who conceive with active Crohn’s disease. In a
Because endometriosis is dependent on the
study of 186 women with inactive disease at concep-
tion, the relapse rate was the same as in non-preg- Figure 15.9
nant women. 81 Deeply Infiltrating Endometriosis of the Digestive Tract: Anatomical Distri-
It is important to address medical management bution
of IBD as well as any other health issues before con-
Deeply Infiltrating Endometriosis of the Digestive Tract: Anatomical Distribution
ception. 82 It is very important to induce or maintain

Deeply Infiltrating Endometriosis of the
remission in patients who are planning or may be- Digestive Tract: Anatomical Distribution
come pregnant. Care from a high-risk obstetrician is
advised and attention to nutrition is important. Omentum
1.7%
In the pregnant patient it is very important to
consider various issues during the different trimes-
Small bowel
taken to avoid drugs that could be teratogenic. IBD 4.7%
Cecum and
patients tend to do well in the second trimester. It ileocecal junction
4.1%
should be remembered that radiation exposure in Sigmoid colon
Appendix 17.4%
weeks 12-16 can affect fetal CNS, and this must be 6.4%
taken into consideration if any studies are being Rectosigmoid

junction and rectum
considered. (Figure 15.11) The second trimester is Chapron C, et al. Human Reproduction 2006: 21:1839
65.7%
V-54
the best time to consider surgery if it is necessary.

(Figure 15.12) In the third trimester, it is important In a retrospective review of deeply infiltrating endometriosis, Chapron et al had
to monitor the patient for anemia as IBD-associated 143 cases with intestinal involvement. The most commonly affected areas were the
sigmoid colon, rectosigmoid junction and rectum accounting for 82% of deep infiltrating
anemia may become severe. Risk for pre-term birth
endometriosis of the intestine. The appendix, cecum and ileocecal junction and small
should be assessed and frequent monitoring should bowel were involved less often: 6.4%, 4.1%, and 4.7% of cases respectively. Chapron
be done. (Figure 15.13) C. et al. Deeply infiltrating endometriosis: pathogenetic implications of the anatomical
Parity, disease activity and surgical history are distribution Human Reproduction 2006: 21:1839-45
all important factors in the decisions surrounding

delivery. High risk OB experience should be pur- include: older maternal age, ileal Crohn’s disease,
sued. Normal labor and delivery can be expected previous bowel resection, and active disease at con-
in UC patients, and although women who are status ception.
post restorative proctocolectomy appear to do well, Drug therapy during pregnancy requires careful
it is still uncertain whether long-term pouch func- consideration and should be driven by the history
tion is intact after vaginal delivery. For the majority of the disease. There are case reports of congenital
of patients, however, C-section is indicated for ob- malformation in babies exposed to sulfasalazine but
stetric reasons only. Delivery for women with CD
is controversial. C-section is recommended in the
setting of active perineal disease. Episiotomy should Kernicterus may be thought to potentially complicate
be avoided but if necessary, a mediolateral incision is therapy with sulfasalazine because sulphonamides
preferred.83 may displace bilirubin from albumin, however, clini-
Pregnancy outcome related to IBD appears to be cally this has not been an issue, with low concentra-
related to whether high-risk groups or population- tions of the drug found in cord blood.81 This drug is
based studies are reviewed. Women with IBD are known to have reversible adverse effects on sperm
more likely to deliver pre-term (< 37 weeks), are morphology, motility, and number. 5-aminosalicylic
more likely to have low birth weight babies (<2500 acid (5-ASA) has minimal systemic absorption and
gm) and small for gestational age babies (<10th per- limited transplacental access. There may be higher
centile for age) and to undergo a C-section. The rate pre-term delivery in babies whose mothers took
of congenital anomalies is the same as the general
population (0-3%).84 Predictors of adverse outcomes mine the relationship as this may be due to disease
Figure 15.10 inactivation. Prednisolone may be considered the

Fertility in Ulcerative Colitis (UC) preferred steroid as it is metabolized most readily by
the placenta. There have been isolated cases of neo-
IBD
Fertility in Ulcerative Colitis (UC) premature rupture of membrane (PROM). In addi-
100
No surgery
100
No surgery tion, a case-control study of corticosteroid use in 1st
After IPAA After IPAA
75 75
trimester and animal studies suggest increased risk
% 50 % 50
of cleft palate. Breastfeeding during corticosteroid
25 25
usage is considered safe. 81,82,85
0
Pregnancy rate
0
Infertility rate
The utility of antibiotics for active disease in
Rates similar in healthy women and those with UC pregnancy is generally felt to be low and other treat-
Infertility rates of 7-9% (2 UK studies)
ments are usually preferable. It should be noted that
Reduced fertility rates in women with ileo-pouch anal
anastamosis (IPAA) metronidazole is Category B but both rifaximin and
Usually associated with tubal disease
Early evaluation with hysterosalpingogram
Often IVF overcomes problems with tubal disease Reluctance to continue 6-mercaptopurine (6-
Olsen et al. Gastro 2002; 122:15
VI-3
MP) and azathioprine throughout pregnancy is no
Johnson et al. Dis Colon Rectum 2004; 47:1119
longer widespread. In general, women who require
Fertility in Ulcerative Colitis (UC) Fecundity decreased (30-50%) after IPAA. UC
patients managed non-operatively have a 97% rate of achieving pregnancy. Falls to from continuing them throughout pregnancy. Nei-
56% after IPAA Infertility rate is 13% in UC without surgery, 38% after IPAA. Olsen
et al. Gastro 2002; 122:15. Willoughby et al. Gut 1980; 21:469. Hudson et al. Int J
Gynecol Obstet 1997; 58:229. Johnson et al. Dis Colon Rectum 2004; 47:1119 due to the slow onset of action. It should be noted
that both azathioprine and 6-mercaptopurine are
Category D drugs.
activity and not to the drug. 82 There are accumulating data in small studies
In terms of corticosteroids, prednisone and and treatment registries regarding the safety of inf-
budesonide are both Category C. It is known that dif- liximab, an anti-TNF biologic therapy, in pregnancy.
ferent steroids undergo varying degrees of placental
Figure 15.11 risk of infection in the puerperium. Most practitio-

Considerations During First Trimester ners aim to give the last dose approximately 8 weeks
prior to term in order to minimize fetal levels at the
time of delivery. 86 There are limited data on adali-
IBD
Considerations During First mumab and certolizumab pegol during pregnancy.
Trimester Early experience in Crohn’s disease does not appear
Harmful exposures to be associated with an increased risk of adverse
embryolethal
birth outcomes. Similar considerations apply as with
87
Organ development is critical
Methotrexate should be stopped 3-6 months be-
fore attempted conception. It is known to be tera-
Embryogenesis occurs in 1st trimester
togenic and is a known abortifacient. Thalidomide
is similarly known to be teratogenic. Both are Cat-
Fetus most sensitive to teratogens in 1st trimester
egory X.
There are other gender-related issues that are
Week 1 Week 4 Week 8 Week 12
VI-10
chologic factors related to body image and the abil-

Kroser J, Srinivasan R. Drug therapy of inflammatory bowel disease in fertile women
Am J Gastroenterol 2006;101(12 Suppl):S633-9.
be noted that the menstrual cycle may be disrupted Figure 15.12

related to disease activity, medications or nutritional Considerations During Second Trimester
factors. Although oral contraceptives can be consid-
ered, monitoring should be implemented for throm-
IBD
boembolic problems. The onset of menopause may Considerations During Second
also be earlier in IBD patients. Finally, a higher inci- Trimester
dence of abnormal cervical cytology in women with IBD patients generally do well in
2nd trimester
IBD has been found compared to the normal popula-
tion and women with IBD should be screened as are Add nutritional supplements as
needed
other immunocompromised women. 88
Safest time for surgery if required
Radiation exposure weeks 12-16

Liver Diseases and Gallstones affects fetal CNS
Genetic screening usually offered
Liver diseases and disorders of the biliary tree may
have sex-based differences related to pathophysiolo- Conception Week Week Birth
12 24
gy, clinical presentation and treatment. This section VI-11
will review these differences in alcoholic liver dis-

Considerations During Second Trimester. No different from general population for
ease, autoimmune hepatitis, primary biliary cirrho- genetic diseases (other than IBD)
sis (PBC), benign solid liver lesions, polycystic liver
disease, hepatocellular carcinoma, and gallstones.
There is emerging literature on sex differences in
viral hepatitis and in liver transplantation which are
oping more serious liver disease than men even after
beyond the scope of this chapter.89-92 It is important
adjustment for body weight.93 Women are also more
to note, however, the sex disparity in liver transplan-
likely to develop liver disease even with less con-
tation wait-list mortality, with women having a 19%
sumption of alcohol than men. In one study where
increased risk of mortality compared to men with
417 cases of patients admitted with cirrhosis and
similar MELD scores.
ascites were interviewed, women were noted to be
Alcoholic liver disease can affect the liver in
younger than men (54% of women were between the
many ways. Fatty liver due to alcohol is predomi-
nantly macrovesicular in character. Alcoholic hepa-
Figure 15.13
Considerations During Third Trimester
a predominance of neutrophils accompanied by fat
and varying degrees of hepatocyte necrosis. Fibrosis
may result and in both fatty liver and alcoholic hepa- IBD
Considerations During Third
Trimester
in cirrhosis and end-stage liver disease.
Development of liver disease seems to correlate Anemia screening
with both the amount and duration of alcohol intake.
IBD-associated anemia may become severe
velop liver disease, it is hypothesized that there are
co-factors that predispose to the development of liv- Women with CD have lower hemoglobin than controls
er disease including consumption practices, genetics,
co-morbid conditions such as HCV, and nutritional Anticipate risk for preterm birth frequent OB monitoring
factors.
Sex clearly plays a role as it has been observed Week 23 Week 26 Week 29 Week 32 Week 36
VI-12
ages of 45 and 65 while 58% of male patients were Because PBC is recognized early, often related
between the ages of 55 and 75). The relative risk of to abnormal lab values, up to 60% of patients may
be asymptomatic at diagnosis. Fatigue and pruritus
higher in women. 94 (Figure 15.14) are common symptoms. Other manifestations of PBC
In the United States, the estimated prevalence of include hepatomegaly, jaundice and xanthelasma.
autoimmune hepatitis (AIH) is 50 per million. There 97
Extrahepatic manifestations or disorders associ-
ated with PBC include osteopenia and osteoporosis
male ratio of greater than 3 to 1. In fact, autoimmune in 0-20% of patients, celiac disease, sicca syndrome,
hepatitis was initially described as a disease of young thyroid disease, arthritis, scleroderma, Raynaud’s
girls with chronic hepatitis and associated hyper- and limited cutaneous systemic sclerosis (CREST)
gammaglobulinemia, which responded to corticoste- syndrome.
roid treatment. The international autoimmune hepa- Ursodeoxycholic acid (UDCA) is the only ap-
titis group scoring system assigns positive points for proved therapy for PBC and has been shown to
historical features typical of AIH; one of the factors delay the progression to end-stage liver disease
is female sex. (The complete review of these factors and enhance survival, while being well-tolerated.98
can be found in the GTP slide set, Slides VII 10-14 in Other therapies have been employed but have not
Liver Disease and Gallstones.)
Young women with AIH in remission on therapy agents (colchicine) and immunosuppressants (corti-
may have successful pregnancies. There is a modest costeroids, azathioprine, chlorambucil, cyclosporine,
increased risk of prematurity and fetal loss; however, methotrexate and thalidomide).
excess maternal morbidity has been reported in only Approximately one third of patients with PBC
those patients with underlying portal hypertension. will have evidence of osteopenia or osteoporosis.
Patients should be advised to maintain immuno- American Association for the Study of Liver Diseases
suppressive therapy and undergo close monitoring (AASLD) guidelines recommend that bone mineral
density should be assessed with dual X-ray absorp-
during pregnancy but may more commonly occur in tiometry at diagnosis and every 2 years thereafter.
the post-partum period, when maternal immune re- Lifestyle changes , regular exercise, smoking ces-
sponses are enhanced. sation and vitamin D and calcium supplementation
Primary biliary cirrhosis (PBC) is a disease pri- should be encouraged. Although vitamin D and calci-
marily of women with only 5% of patients with PBC um supplementation are frequently given to patients
being men.95 Although the pathogenesis of PBC is with PBC and osteoporosis, there is little evidence
not clear, PBC is characterized by a T-lymphocyte- that this regimen is effective.99 Nevertheless, calcium
mediated attack on the small intralobular bile ducts. supplementation is generally recommended because
Antimitochondrial antibodies (AMA) are found in 95
The rationale for other therapies (such as bisphos-
of 98 percent for the disease. AMA titers do not cor- phonates, calcitonin and PTH) is similar to that for
relate with disease severity or rate of progression patients with osteoporosis who do not have PBC. At
and may vary greatly among patients but tend to be least two studies have suggested that alendronate in-
stable over time in any given patient. There is no ap- creases bone mineral density in osteopenic patients
parent difference in the clinical spectrum or course with PBC.100 Hormonal replacement therapy, sug-
of patients with PBC who are AMA-positive or AMA- gested via the transdermal route, is recommended
negative.96 The other associations with PBC besides when determined to be appropriate.
female sex include cigarette smoking, a history of Up to 85% of patients with PBC will have hyper-
other autoimmune disorders (e.g. autoimmune thy- cholesterolemia. The mechanism for the develop-
ment of hyperlipidemia in cholestatic disorders is
recurrent urinary tract infections. different from that in other conditions that suggest
that the atherogenic potential may also be differ- perplasia, and hepatic adenoma. Some of these le-
ent. As a result, recommendations for lipid-lowering sions are closely linked to female sex steroids.
therapy in asymptomatic patients is not clear, where Hemangiomas are the most common mesen-
some experts recommend treatment, while others chymal hepatic tumor, usually noted to be solitary;
do not. however, multiple lesions may be present in both the
Antihistamines have been used to safely treat right and left lobe of the liver in up to 40 percent of
mild pruritus. However, AASLD guidelines recom- patients. Most patients with hepatic hemangiomas
are asymptomatic and have an excellent prognosis
patients who fail or are intolerant to the side effects with symptoms more likely to be seen in patients
of cholestyramine, rifampicin should be used as a with large lesions. The diagnosis is often considered
second line therapy with opioid antagonists con- in patients found to have a focal liver lesion where
sidered for resistant cases. Liver transplantation hemangiomas need to be distinguished from other
has been indicated for uncontrollable itching symp- tumors.101 They are considered to be vascular mal-
toms. However, it is generally for liver failure that formations or hamartomas that have formed con-
liver transplantation is recommended for patients genitally and that enlarge by ectasia rather than by
with PBC. One year and 5 year survival after liver hyperplasia or hypertrophy. Estrogen receptors
transplantation for this condition is 92% and 85%, have not been demonstrated in all tumors and tumor
respectively. Recurrence after liver transplantation is growth may occur both in the absence of estrogen
seen in 8-18% at 5 years and 22-30% 10 years. therapy and in postmenopausal women. But clearly,
Incidental liver lesions found in patients without
liver disease include: hemangioma, focal nodular hy- by the phenomenon of enlargement during preg-
Figure 15.14
Gender and Development of Alcoholic Liver Disease
Alcoholic Liver Disease
Women Are More Susceptible to

Alcoholic Liver Disease
35 120
Male
Female
25
80
Distribution Relative
(%) risk for
15 cirrhosis
40
0 0
<34 35 45 55 65 75+ 0 20 40 60 80+
-44 -54 -64 -74 -19 -39 -59 -79
Age Range Daily ETOH
consumption (g)
Tuyns AJ and Pequignot G, Int J Epidem 1984: 13:53 VII-5
In many studies gender is a factor for development of liver disease from alcohol. Women are more likely to develop liver disease with less
consumption of alcohol than men. In this French study by Tuyns and Pequignot, 417 cases of patients admitted with cirrhosis and ascites were
interviewed. They found that that the female patients were younger than the male patients with 54% of patients between the ages of 45
and 65 while 58% male patients were between the ages of 55 and 75. The relative risk of developing liver disease was significantly higher
in females than males. Tuyns, AJ and Pequignot G, Greater risk of ascitic cirrhosis in females in relation to alcohol consumption, Int J Epidem
13:53-57, 1984.
nancy and enlargement during estrogen and proges- young women (20 to 44 years-old), are frequently lo-
terone therapy with regression after withdrawal of cated in the right hepatic lobe, and are typically soli-
therapy. In one report, enlargement occurred over tary (70 to 80 percent). However, multiple adeno-
time in 23 percent of patients receiving estrogen mas have been described in patients with prolonged
hormone therapy, compared to only 10 percent of contraceptive use, glycogen storage diseases (GSD),
controls.102 and hepatic adenomatosis. The size of hepatic adeno-
The risks to patients with hemangiomas associ- mas is variable and can range from 1 to 30 cm. 105
ated with use of oral contraceptives (OC’s) and with The majority of hepatic adenomas are seen in
- young women with a history of prolonged OC use.
dence to conclusively link estrogens to either the de- Presentation at diagnosis may include abdominal
velopment or growth of hemangiomas. Controversy pain localized to the epigastrium or right upper
exists as to whether to advise patients with heman- quadrant, the presence of a mass on physical exam,
giomas to avoid pregnancy as full-term pregnancies or hepatic adenomas may be found as an incidental
without complications have been reported. In one
study, authors concluded that hepatic hemangiomas sudden life threatening collapse associated with
- rupture and intra-abdominal bleeding. The manage-
ment of asymptomatic patients who are taking OC’s
enlargement occurs only in a minority of patients. is controversial. Some experts suggest a conservative
Routine liver ultrasound follow up in women with approach in patients with small lesions (<5 cm) with
hepatic hemangiomas receiving hormone therapy discontinuation of contraceptive medication, close
appears appropriate. 103 observation of the lesion with repeated imaging, and
Focal nodular hyperplasia (FNH) is the next most alpha fetoprotein (AFP) determinations. Complete
common benign solid tumor of the liver. The etiology regression of tumor has been documented after dis-
of FNH is linked to the effects of female hormones, continuing contraceptive medications. Of high con-
including OC’s. A hospital-based case-control study cern is that growth, rupture, and malignant trans-
was conducted in Italy involving 23 women with formation (even despite a decrease in size of the
adenoma) have all been documented after discon-
of the liver and 94 controls in the hospital for acute tinuation of OC’s. As a result, other experts recom-
diseases. Focal nodular hyperplasia was not associ- mend surgical resection of all adenomas regardless
ated with either menstrual or reproductive factors. of size if possible. Patients should generally be ad-
Ever OC use was reported by 83% of cases versus vised against pregnancy since the behavior of a liver
59% of controls. The multivariate OR was 2.8 (95% adenoma during pregnancy is unpredictable. Resec-
tion of the lesion prior to pregnancy may be the best
(95% CI, 1.2-16.9) for use for 3 or more years. The option for patients hoping to become pregnant.
-
cant. However, when the authors looked more close- -
ly due to defects of embryonic foregut (e.g., cystade-
study suggests a quantitative estimate of the associa- noma). Parasitic cysts are one type of infectious cyst.
tion between use of OC’s and focal nodular hyperpla- Fibrocystic diseases of liver include polycystic liver
sia of the liver.104 disease (PCLD), single hepatic cyst, congenital he-
The management of FNH is usually conservative.
Discontinuation of OC’s is not necessary; however, complexes.
follow up imaging is recommended in patients tak- In Autosomal Dominant Polycystic Kidney Dis-
ing OC’s to establish the stability of FNH. ease (ADPKD), hepatic cysts develop later than re-
Hepatic adenomas are uncommon benign epi- nal cysts. The prevalence of both hepatic and renal
thelial liver tumors and are seen predominantly in cysts increases with age. Hepatic cysts occurring in
ADPKD are different from autosomal dominant poly- hemangiomas and focal nodular hyperplasia behave
cystic liver disease. The latter disorder is not associ- indolently and can be observed. Hepatic adenomas
ated with kidney involvement or cerebral aneurysms often require surgery, but small, asymptomatic le-
and results from mutations in different genes. Al- sions may be carefully observed with meticulous
though the overall prevalence of a polycystic liver in observation postpartum. As pregnancy impacts sur-
patients with ADPKD is similar in men and women, vival in hepatocellular carcinoma, resection may be
women develop cysts at an earlier age. Of great im- indicated. 108
portance is that fact that massive cysts occur almost Gallstone disease is highly prevalent affecting
exclusively in women, particularly those who are more than 20 million Americans. Despite the high
multiparous. This accelerated hepatic growth sug- prevalence, more than two thirds of patients are
gests an underlying sensitivity of cysts to female ste- asymptomatic. There are two major types of gall-
roid hormones.106 Consistent with this hypothesis is stones: Cholesterol and Pigment stones (either black
the observation that postmenopausal estrogen may or brown). There appear to be varying prevalence
be associated with selective enlargement of hepatic rates among different ethnic groups: 16.6 percent
cysts as well as the hepatic parenchyma. Number and among non-Hispanic white women, 26.7 percent
size of cysts correlate with number of pregnancy and among Mexican American women, and 13.9 percent
use of female hormonal replacement therapy. among non-Hispanic black women. Native Ameri-
For patients with polycystic liver disease, men cans appear to have the highest prevalence of chole-
and women have equal lifetime risk to develop he- lithiasis in North America. As an example, 73 percent
patic cysts. Women have more and larger hepatic of female Pima Indians over the age of 25 years have
cysts and the cysts develop following puberty. Severe gallstones. Similar high rates have been found in mul-
hepatic cyst disease correlates with both pregnancy tiple other Native American populations.109
and exogenous female steroid hormones. Bile becomes increasingly lithogenic with age,
with increased cholesterol secretion and with de-
cancer worldwide and the third most common cause creases in bile acid secretion. Female gender in-
of cancer mortality. Hepatocellular carcinoma (HCC) creases the incidence 3-4 times up to age 50. In
accounts for between 85% and 90% of primary liver addition to a possible role of estrogen, a linear asso-
cancers. The incidence of HCC continues to increase ciation between BMI and incidence of gallstones has
in the United States. In almost all populations, males
have higher liver cancer rates than females, with Rapid weight loss increases gall bladder (GB) sludge
male:female ratios usually averaging between 2:1 with stone formation seen within 6 months in up to
and 4:1. The largest discrepancies in rates (>4:1) are 50% of patients who undergo gastric bypass surgery.
found in medium-risk European populations. The Other factors related to increased stone formation
global age distribution of HCC varies by region, inci- include total parenteral nutrition, (patients on TPN
dence rate, sex, and, possibly, by etiology. In almost have a higher frequency of GB sludge detection as
all areas, female rates peak in the age group 5 years early as 3 weeks after initiation of TPN), drugs, and
older than for males.
Role of OC’s in the development of HCC is con- derivatives, octreotide and ceftriaxone are associ-
troversial. Eight case control studies examined the ated with gallstone formation. Diabetes, diseases of
relationship of OC use and HCC with no association the ileum, and spinal cord injuries also predispose to
found. Another recent meta-analysis of 12 case con- gallstone formation.
trolled studies examined the association between OC Estrogens decrease the concentration of bile
and HCC exposure. There is inconclusive evidence to acids by decreasing their uptake via Sodium (Na+)-
establish an association between OC and HCC.107 Taurocholate cotransporting polypeptide (NTCP)
With regard to liver lesions developing during and by reducing the biliary secretion of bile acids
pregnancy, it can be noted that gestational hepatic by ABCB11. Other transport factors may also play a
role. Cholesterol secretion in bile is also increased sis and mild decreases in bile formation. Measured
by estrogen resulting in a supersaturated bile prone serum values generally are found within the normal
to nucleate and form sludge and stones. Pregnancy range. 112
decreases the secretion rate of both bile acids and Development of palmar erythema and vascular
phosphatidylcholine in bile and increases the secre- spiders occur commonly during pregnancy, espe-
tion of cholesterol, also leading to cholesterol super- cially in women with lighter skin, and are due to the
saturation in bile. higher levels of circulating estrogens. An excellent
Mutations in canalicular transporters for bile review of liver disease and pregnancy may provide
acids and phospholipids can also affect biliary lipid more detailed information than what is summarized
composition. (Figures 15.15 and 15.16). The main below from the literature.113
transporters include: ABCB11 (bile acid trans-
porter), ABCB4 (phospholipid transporter), ATP8B1
Coincident Liver Disease
mild defects in these transporters may increase the During Pregnancy
rate of cholesterol gallstone formation seen in men
Pregnant women are affected by acute viral hepatitis
or non-pregnant women. These “minor” mutations
at the same rate as seen in the general population. In
may interact with effects of estrogens/progester-
the setting of good nutrition and medical care, both
ones in pregnancy or with use of oral contracep-
maternal and fetal outcomes are excellent except
tives to greatly increase the formation of sludge and
when the mother develops fulminant liver failure.
gallstones. Therefore, if a woman with one or more
Hepatitis E (endemic in India and other countries
mutations is also pregnant, the risk of developing
with poor sanitation, nutrition and medical care)
cholesterol sludge or stones is markedly increased
has a unique course in pregnancy. In comparison
during, and possibly after, pregnancy.110
to men and non-pregnant women, pregnant women
who are infected with hepatitis E have an extremely
high risk of developing fulminant liver failure with
Pregnancy and high fatality rates for both mother and baby. 114
Hepatobiliary Diseases -
sociation with hepatitis B and continues to be com-
During pregnancy liver function including synthesis
mon in the world where hepatitis B is endemic.
of proteins remains similar to function in the non-
Vertical transmission is the transmission of an infec-
pregnant woman. Serum albumin will be lower, un-
tious disease from mother to fetus/baby, often at the
related to liver function, but rather due to dilution to
time of birth. Hepatitis B immune globulin admin-
a lower concentration. In pregnancy the intravascu-
istered with hepatitis B vaccine to the newborn in-
lar volume increases by 40-50%. The other changes
fants of infected mothers has reduced the rate of the
of note is that synthesis of anti-thrombin III by the
vertical transmission of this infection. There are no
liver does fall with normal pregnancy and some
known additional risks to the fetus besides vertical
acute-phase reactant proteins will be synthesized in
transmission.115 Hepatitis C transmitted via vertical
higher amounts resulting in a rise in plasma levels. 111
transmission is less common but when it occurs, it
(Table 15.8) Serum alkaline phosphatase will also be
usually results in chronic infection of the baby. Al-
increased in the pregnant woman by 40-70% due to
though hepatitis C viral loads may change during
an isoform that the placenta makes. A greater rise in
pregnancy this is very unlikely to result in clinical
alkaline phosphatase is seen in women who develop
consequences for mother or baby. Increased AST/
cholestasis. 110
In pregnancy, the higher level of circulating es-
occur post delivery and are usually asymptomatic.
trogens inhibit several hepatobiliary transporters in-
In patients with autoimmune hepatitis, fertil-
volved in bile formation that may result in cholesta-
ity may be reduced without good control of the
a unanimous consensus for this strategy as there is

medications are stopped. Consensus expert opinion
agrees that it is safer to continue medications than increases the risk of bleeding. It is worthwhile to
to stop them during pregnancy. Patients must be note that cesarean sections in women with portal
hypertension may also present risks due to the large
occur post-partum.116 Similarly, fertility in Wilson’s number of intra-abdominal collateral vessels.119
disease may be reduced until copper levels have Patients who have undergone successful liver
decreased. Flares or relapses (which may be fatal) transplantation return to normal fertility within
have been reported in women who stopped medica- weeks to months. Follow up of the pregnancies in
tions during pregnancy. The outcome of pregnancy post transplant patients show that most women
otherwise depends on the severity of the underly- do well and that immunosuppressive drugs do not
ing liver or neurologic disease.117 D-penicillamine is appear to cause congenital abnormalities. 120 Still,
potentially teratogenic but it appears safe in these pregnancies in post-transplant patients should be
patients; other agents (trientine and/or zinc) may considered high risk as there is a much higher rate of
be considered as well. fetal loss, hypertension, and pre-eclampsia. Some of
Pregnancy in advanced liver disease is unusual this risk may be due to the underlying chronic renal
disease and hypertension in many post-transplant
with portal vein thrombosis or non-cirrhotic portal patients. As mycophenolate mofetil is increasingly
hypertension may have normal fertility; the manage- employed for post transplant immunosuppression,
ment of portal hypertension is complicated in these it should be remembered that this drug is character-
patients with concerns about ascites formation and ized as pregnancy Category D, and thus careful plan-
variceal bleeding. ning for pregnancy involving transplant physicians
In general, the increased volume seen in normal and obstetricians is recommended in the setting of
pregnancy may further enhance problems of ascites mycophenolate usage.
or edema and increase pressure in varices causing
Figure 15.15
pregnancy causes a direct worsening of cirrhosis. Relevant Transporters for Bile Acids, Lipids and Bilirubin
Although fetal loss is increased in these pregnancies,
the babies born alive are normal without an increase
in congenital malformations. It is important to re-
member that spironolactone should not be used as Gallstones
a diuretic during pregnancy due to its teratogenic Relevant Transporters for Bile Acids, Lipids and Bilirubin
effects. 118 NTCP OATPs
Sinusoid
Variceal bleeding is a most serious complica-
Na+
tion of portal hypertension and the risk is further Bile Acids Bilirubin
increased in pregnant women due to volume expan-
ABC B11
sion. Women with portal hypertension should be ABC C2
Liver
treated before or early during pregnancy to control ABC B4 ABC G5/G8
Cholesterol
variceal pressure. If bleeding does occur, the usual Gall
Phosphatidylcholine
(PC)
bladder
techniques to treat bleeding should be implement- Common
bile duct Hepatocyte
ed. Non-cirrhotic portal hypertension tends to have
a better prognosis than cirrhosis but acute variceal
to Bile duct VII-77
bleeding due to any cause can lead to death. Be-
cause of the increase in intra-abdominal pressure
during the second stage of labor, some experts rec- Cholesterol solubilization in bile depends on the relative concentrations (and
ommend avoiding vaginal delivery but there is not secretion rates) of cholesterol, phosphatidylcholine and bile acids in bile.
Figure 15.16
Effects of Estrogens/Pregnancy on Transporters Involved in Cholesterol Excretion
Gallstones
Effects of Estrogens/Pregnancy on Transporters
Involved in Cholesterol Excretion
NTCP OATPs
Sinusoid
Na+
Bile Acids Bilirubin
ABC B11
ABC C2
Liver
ABC B4 ABC G5/G8
Gall
Phosphatidylcholine Cholesterol
bladder (PC)
Common
bile duct Hepatocyte
to Bile duct VII-79
Pregnancy decreases the secretion rate of both bile acids and phosphatidylcholine in bile and increases the secretion of cholesterol, leading to
cholesterol supersaturation in bile. Geier A, et al. BBA 1773:283, 2007. Trauner M et al. Semin Liver Dis 2007; 27:77.
Table 15.8
Changes in the Liver During Normal Pregnancy
Liver Diseases Likely
Related to Pregnancy
Changes in the Liver During Normal Pregnancy
Gallstone development has already been described
Pregnancy and Liver Disease
above but the effect of pregnancy on gallstone for-
Changes in the Liver During Normal Pregnancy mation is noteworthy. Pregnancy promotes the en-
Hyperdynamic circulation mimics cirrhosis
hanced formation of gallstones via a decrease in the
Systemic maternal vasodilatation due, in part, to increased
nitric oxide secretion rates of both bile acids and phosphatidyl-
Systemic vascular resistance
Mean arterial pressure
choline in bile, as well as an increase in the secretion
Response to vasoconstrictors of cholesterol. In addition, decreases in gallbladder
Maternal cardiac output increases by 30-50% motility and emptying during pregnancy also pro-
Intravascular volume increases by up to 50% motes the formation of sludge and stones by pro-
Activation of the renin-angiotension system
Increased renal sodium reabsorption viding longer periods of stasis of bile. 121 Gallstones
Increased non-osmotic release of vasopressin and sludge frequently appear during pregnancy and
Glomerular filtration rate (GFR) and renal blood flow are most but not all disappear after delivery, but these
increased in pregnancy (decreased in cirrhosis)
events likely contribute to the increased risk of gall-
Bekheirnia MR and RW Schrier. Current Opinion in Pharmacology 2006; 6:202 VIII-8
stones and gallstone-related disease in women who
The hemodynamic changes that occur during normal pregnancy in part mimic those have been pregnant compared to nulliparous women
that occur during cirrhosis. In both cases there is systemic vasodilation and increases and men. Women with insulin resistance are likely
in cardiac output. In both conditions there is increased retention of sodium by the at even higher risk of these events. 122 (See GTP Slide
kidneys resulting in volume expansion. However in normal pregnancy, the GRF and
VIII-32 for the Effects of Pregnancy on the Risk for
renal blood flow are preserved. Glomerular Filtration Rate = GFR. Bekheirnia MR and
RW Schrier. Pathophysiology of water and sodium retention: edematous states with Gallstones.) Pregnant women should undergo the
normal kidney function. Current Opinion in Pharmacology 2006; 6:202 same evaluation for gallstone disease as non-preg-
nant women; ultrasound and MRI are considered ciency and supplemented as appropriate. Outcomes
safe during pregnancy. For patients experiencing re- may differ for mother and baby. Mothers generally
current biliary pain and all patients with acute choledo well after delivery but they may be susceptible to
cystitis, cholecystectomy is considered the standard gallstones in the future. Fetal distress and sudden in-
of care and can be done with reasonable risk, espe- trauterine fetal death do occur at higher rates, typi-
cially early in pregnancy. ERCP and sphincterotomy cally late in pregnancy.126 Ursodeoxycholic acid for
can be considered as temporary measures, with sub-
sequent cholecystectomy performed after delivery. 123 a number of case series and small controlled studies.
Herpes simplex hepatitis is rare, but pregnant Early delivery seems to reduce the fetal death rate but
women and immunocompromised patients appear there are no controlled studies.127
to be particularly susceptible to this disease. Herpes Acute Fatty Liver of Pregnancy (AFLP), on pa-
simplex hepatitis presents acutely and often rapidly thology, is represented by microvesicular steatosis.
progresses; it should be considered in any pregnant This fat formation may be due to abnormalities in
woman who presents with a syndrome consistent beta oxidation of fatty acids resulting in depletion of
with acute severe “hepatitis.” This disease presents hepatocyte ATP and cell death. 128 The placenta may
a high risk for the fetus and treatment of the baby be a source of fatty acids circulating to the maternal
should be implemented upon delivery. 124 Budd- liver, but pregnancy itself is associated with increased
Chiari syndrome can occur during pregnancy but all release of fatty acids and triglyceride from adipose
patients presenting with this disorder should also
undergo investigation for other processes that can These fatty acids in the hepatocytes have toxic ef-
promote thrombosis. fects on mitochondria and oxidative phosphorylation.
During normal pregnancy there may an increased
rate of oxidative phosphorylation of the products of
Liver Diseases Unique to Pregnancy beta oxidation of fatty acids that may compound the
injury as these reactive oxygen species can also cause
Hyperemesis gravidarum is not considered a primary
damage. 129
liver disease, but it is noteworthy to mention as in se-
AFLP is due to minor genetic mutations along
vere cases, liver enzymes may become elevated.125 In-
-
trahepatic cholestasis of pregnancy (ICP), known as a
haps in association with environmental factors. It
bland cholestatic disease, is also unique to pregnancy
was noted that mothers of children homozygous for
and is likely multifactorial in etiology: due to minor
mutations in Long-chain 3 hyroxyacyl CoA Dehydro-
mutations in genes for solute transporters, related
genase (LCHAD), an enzyme in the beta oxidation of
to the cholestatic effects of pregnancy, and it is addi-
fatty acids, were at risk for AFLP. This disease is au-
tionally likely related to other environmental factors.
tosomal recessive, indicating the mothers were car-
Liver biopsy is not necessary but would demonstrate
riers.127
cholestasis with bile in the canaliculi and inside the
AFLP usually presents late in pregnancy. The
-
range of presentations can be from mild to fulminant
sis. This is not unlike what would be seen in cholesta-
sis stemming from OC’s. Patients present with pru-
laboratory abnormalities vary. Radiologic evaluation
-
may require early termination of the pregnancy.110
itive with special stains for fat (Oil Red O). Typically,
Jaundice may occur in approximately 50% of patients.
enlargement of hepatocytes would be seen with mi-
Since laboratory evaluations to assess serum bile ac-
crovesicular steatosis evident with special staining.
ids may not be readily available everywhere, other
Maternal and fetal mortality is a concern and
causes of pruritus should be considered including
correlates with disease severity; AFLP can rapidly
biliary obstruction or reaction to medicines. In addi-
worsen to fulminant hepatic failure where mortality
-
rates for both mother and baby are high. There is

rapid improvement upon delivery although in some women may exhibit mild manifestations of HELLP
patients there may be worsening initially and there syndrome; however, severe disease with diffuse liver
are reports of new onset AFLP post-partum.110 Be- necrosis and infarcts in multiple organs can occur
cause of the unpredictable course and the possibility predicting a poor outcome. The placenta is often af-
of rapid worsening, treatment should include imme- fected with consequences to the fetus of growth re-
diate delivery of the baby. Babies should be tested tardation and hypoxia, even in early or mild disease.
The most severe complication of HELLP and pre-
Pre-eclampsia is the most common disease of eclampsia is the development of hepatic hematoma
pregnancy with liver involvement in 10-20% of pa- and/or rupture due to extensive necrosis. This rep-
tients. The pathophysiology is not clear but may resents an acute event presenting with sudden pain,
relate to abnormal placenta development and endo- hypotension and shock. Hematomas and ruptures
thelial function. When the liver is affected, there is will be evident on CT. If the hematoma is contained it
hepatocyte necrosis from ischemia due to the depo- can resolve spontaneously. Transfusions may be in-
dicated. Free rupture usually results in death unless
the bleeding is stopped.
The treatment of HELLP syndrome requires ur-
seen in association with pre-eclampsia but to meet gent delivery of the baby. Only in mild cases in which
the criteria for HELLP, patients must have elevated the fetus is immature should continuation of the
transaminases (AST/ALT), evidence of intravascular pregnancy even be considered, and even then with
hemolysis and thrombocytopenia.130 HELLP syn- close monitoring. The disease resolves rapidly after
drome primarily occurs in the third trimester of preg- delivery. Mortality is high and HELLP can develop in
nancy but has been reported to develop within the subsequent pregnancies if pre-eclampsia recurs.
Figure 15.17
Colon Cancer Screening Rates Higher in Men
Meissner et al examined patterns of screening among men and women in the United States, analyzing data from National Health Interview
Surveys obtained between the years 1987 and 2003. The NHIS includes questions on the use of fecal occult blood tests and endoscopy, but the
questions have evolved over time to accommodate new technologies. Broken lines on the graphs represent these changes. As can be seen
in the figure, colorectal cancer testing uptake has increased since 2000 for both women and men, but the rate of increase has been higher in
men. For the entire population, screening by colonoscopy has become more prevalent, whereas use of sigmoidoscopy for screening purposes
has declined. Meissner HI, Breen N, Klabunde CN, Vernon SW, et al. Patterns of colorectal cancer screening uptake among men and women
in the United States. Cancer Epidemiology, Biomarkers & Prevention 2006;15(2):389-94.
distinguish between the sexes, and men and women

Colon Cancer are included in the same screening guidelines that ap-
Screening in Women ply to men. The validity of employing gender neutral
Although, overall, men have a higher incidence of screening guidelines is questioned by many given the
colorectal cancer (CRC) than women, colorectal can-
cer is the third leading cause of cancer-related deaths ence the expression of CRC, leading to different phe-
in women. Among women in the Unites states, Afri- notypic expression in men and women. It would not
can-American women have the highest rate of colon be surprising to see customized guidelines for men
cancer. 131 Compliance with colon cancer screening and women in the future.
guidelines is not optimal, as compared with other Evidence supports a protective role for estro-
screening guidelines for cancers that affect women, gen in the development of CRC in women. The exact
such as breast and cervical cancer. One study exam- mechanisms remain unknown but estrogen has been
ined patterns of screening among men and women shown to decrease bile acids that are known to be
in the United States, analyzing data from National carcinogenic. Estrogen plays a role in target tissue
Health Interview Surveys obtained between the years growth, differentiation, and function, and estrogen
1987 and 2003. It was found that colorectal cancer
testing has increased since 2000 for both women and
men, but the rate of increase has been higher in men. general and most especially noted to be decreased in
132
(Figure 15.17) advanced Duke stages of CRC. The Women’s Health
The guidelines for colon cancer screening do not Initiative found CRC rates were reduced by 37%
Figure 15.18
Advanced Neoplasia is More Prevalent Among Men than Among Women 50-69 Years of Age
Special Issues - Colon Cancer
Advanced Neoplasia is More Prevalent Among

Men than Among Women 50-69 Years of Age
RR 1.91 1.62 2.10 0.88
14
12 P=0.70
Women Men
P=0.004
10
P=0.002
% 8
Advanced
neoplasia 6
P=0.15
4
0
Overall 50-59 60-69 70-79
Age (years)
Schoenfeld P et al. New England Journal of Medicine 2005; 352(20):2061 IX-8
Schoenfeld and colleagues highlight differences in colorectal cancer phenotype between men and women in their 2005 study of a VA population
published in the New England Journal of Medicine (the CONCeRN study). The group offered colonoscopy to consecutive asymptomatic women
referred for colorectal cancer screening and compared results with those for a population of age-matched men and women derived from the
VA Cooperative Study 380. Of 1463 women 40–79 years of age undergoing screening colonoscopy in the current study, advanced neoplasia
was found in 72 women (4.9%), whereas in the VA Cooperative 380 study, among 3196 subjects, almost all of whom were men, advanced
neoplasia was found in 7.9%. After adjusting for family history and fecal occult blood test results, men were found to be nearly twice as likely
to have advanced neoplasia than were women (8.6% versus 4.5%; relative risk, 1.91; 95% confidence interval, 1.42–2.56). Schoenfeld P, Cash
B, Flood A, et al. CONCeRN Study Investigators. Colonoscopic screening of average-risk women for colorectal neoplasia. New England Journal
of Medicine 2005; 352(20):2061-8. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for colorectal
cancer. New England Journal of Medicine 2000; 343:162–168.
among women taking combination hormone replace- A recent article determined the prevalence of ad-
ment therapy that translates to six fewer cancers per enomas, advanced adenomas and colorectal cancers
year per 10,000 women taking combination therapy.133 detected on screening colonoscopies and evaluated
In the 2005 study of a VA population published in the numbers needed to screen by 5 year age groups
the New England Journal of Medicine (the CONCeRN and by gender. The authors found that the num-
study), differences in CRC presentation between men
and women were described.134 In this study, colo- higher in women that in men of similar age, thereby
noscopy was offered to consecutive asymptomatic
women referred for CRC screening and the authors adenomas.135
compared these results with those for a population of In another study of a cross-sectional analysis of
age-matched men and women (from VA Cooperative data from a colonoscopy-based screening program in
Study 380). After adjusting for family history and fecal Poland, it was also found that male sex was indepen-
occult blood test results, men were found to be nearly dently associated with advanced neoplasia.136 Evaluat-
twice as likely to have advanced neoplasia at colonos- ing groups aged 40 to 49 years, 50 to 54 years, and 55
copy as were women (8.6% versus 4.5%; relative risk, to 59 years, the number of persons needed to undergo
colorectal cancer screening in order to detect one case
15.18)
compared to women who had a similar family history
Figure 15.19 of colorectal cancer. (Figure 15.19)
Numbers Needed to Screen to Detect Advanced Neoplasia Significantly Location of neoplasm also appears to differ
Greater in Women among the sexes. In women there seems to be a right-
ward shift of advanced neoplasia. The CONCeRN data
Special Issues - Colon Cancer
Numbers Needed to Screen to Detect Advanced cantly lower in women. It is interesting to note that
Neoplasia in Women although overall this study showed that advanced
x x colonic neoplasia was lower in women compared
60-66
Men to men, more cases of advanced neoplasia would be
Women
x x
55-59
Age
(years)
x x copy alone were used as a screening tool.133
50-54
Completion of colonoscopic examination has
40-49 x x been assessed and it has been found that completion
rates to the cecum are lower in women; this is espe-
0 5 10 15 20 25 30 35 40 45
Number needed to screen (95% CI) cially true in women who have had previous pelvic
Regula J et al. N Engl J Med 2006; 355(18):1863 IX-9
angulated sigmoid colon or may promote adhesions.
Colonoscopy completion is also less successful in thin
In keeping with the CONCeRN findings, Regula and colleagues, performing a cross-
sectional analysis of data from a colonoscopy-based screening program in Poland, women suggesting that less visceral fat may affect the
determined that male sex was independently associated with advanced neoplasia success of the procedure. Diverticulosis is associated
(adjusted odds ratio, 1.73; 95% confidence interval, 1.52 to 1.98; P<0.001). This with greater time to reach the cecum in women, but
screening program included over 50,000 participants aged 40-66 years and focused
on advanced neoplasia, that is, cancers or adenoma at least 10 mm in diameter, with interestingly this association is not seen in men.137
high-grade dysplasia or villous or tubulovillous histologic characteristics, as the target Obesity is associated with a higher incidence
of screening intervention. In groups aged 40 to 49 years, 50 to 54 years, and 55 to 59 of CRC and higher mortality. In one study, morbidly
years, the number of persons who would have to undergo colorectal cancer screening
obese women were found to be less likely to have
in order to detect one case of advanced neoplasia was significantly lower in men
than in women with a similar family history of colorectal cancer. Regula J, Rupinski been screened than women whose weight fell within
M, Kraszewska E, et al. Colonoscopy in colorectal-cancer screening for detection of the normal range. This phenomenon has not been ob-
advanced neoplasia. New England Journal of Medicine 2006;355(18):1863-1872.
served in men where screening rates among men in Figure 15.20

138 Biopsychosocial Conceptual Model
Women patients have expressed the desire to
have women as their physicians across various spe-
cialties. The issue of preference for endoscopist has Special Issues - Abuse
been studied via questionnaires given to female pa- Conceptual Model

tients age 40 to 79 (n=202) attending primary care Psychologic distress
139
The pre- Psychiatric diagnosis
Poor social networks
dictors of preference for a woman as the endoscopist
Ineffective coping
include: younger patient age, gender of the primary
care physician, current employment, and no previ-
Abuse Symptom amplification
ous colonoscopic procedure. Of these variables, us-
ing multivariable analysis, only female gender of the
Health care
primary care physician and employment were found Early life GI symptoms seeking
to be positive predictors for preferring a woman en- GI susceptibility Illness behavior Refractoriness
doscopist. Drossman DA, Talley NJ, Leserman J et al. Annals of Internal Medicine 1995;123(10):782 IX-27
tor for women to seek gender-concordant health pro- The biopsychosocial conceptual model of the effect of abuse on the development of
GI symptoms proposes a multidirectional interaction of early life experiences such as
fessionals. One study revealed that 50% of women abuse, coping mechanisms, social networks, psychological distress, illness behavior,
surveyed view women endoscopists as more empa- symptom amplification, and health care seeking behavior. Drossman DA, Talley NJ,
thetic; 77% of women with gender preference ex- Leserman J et al. Sexual and physical abuse and gastrointestinal illness: review and
recommendations. Annals of Internal Medicine 1995;123(10):782-94.
plained they talked more easily with women health
professionals.140 These psychosocial perceptions may
play a larger role in open access endoscopy where in Figure 15.21
the absence of meeting the endoscopist beforehand, Possible Mechanisms Mediating Abuse/GI Health Relationship
the patient may rely on gender stereotypes or percep-
tion. Another article found that the reasons for sex
Special Issues - Abuse
preferences in choosing a gastroenterologist are in-
Possible Mechanisms Mediating Abuse / GI
Health Relationship
education being an independent predictor of patients Abuse
feeling embarrassed.141 Finally one study concluded
CNS
that gender preference for the endoscopy nurse or as- Stress
sistant was more common than for the endoscopist.142 Fear

Hypothalamic Visceral
A comprehensive review of issues related to pituitary axis Cortisol hypersensitivity
screening in women details additional factors related
Inflammatory Cytokines
to risk factors, colonoscopy in women, and barriers to IL-1
screening.143 IL-12
Gastrointestinal
symptoms
Leserman J, Drossman DA. Trauma Violence Abuse 2007; 8:331 IX-28
Abuse and GI Disorders Individuals who suffer from any form of abuse may develop increased autonomic
There appears to be an increased incidence of GI reactivity in the gut in response to physical and psychological stressors. This may lead
to increased visceral hypersensitivity and various functional symptoms. Furthermore,
symptoms in girls with a history of abuse. In one
altered cortico-limbic pain modulatory pathways may promote visceral pain in
study involving a chart review and telephone in- response to emotions like fear and anxiety. Hyperfunction of hypothalamic-pituitary-
terviews of mothers of 72 female children who had adrenal axis in response to stress may increase cortisol and inflammatory cytokines
been forced to have sexual activity with an adult, it that in turn increase visceral hypersensitivity. Leserman J, Drossman DA. Relationship
of abuse history to function gastrointestinal disorders and symptoms: some possible
mediating mechanisms. Trauma Violence Abuse 2007;8:331-43.
ly more physical symptoms. The duration of abuse Obtaining an abuse history from patients with
GI complaints is key in developing a comprehensive
71% of the girls who were abused for greater than management plan. However, studies show that wom-
24 months reporting gastrointestinal symptoms. 144 en are reluctant to initiate a discussion on the sub-
Intimate partner violence (IPV) may also affect ject of abuse with their physicians, and physicians, in
gastrointestinal health. A cross sectional survey of turn, often feel uncomfortable eliciting this informa-
1152 women aged 18 to 65 recruited from family tion.153 There must be an integrated team approach
practices in South Carolina found that women who in place in order to address the issue of abuse once
had experienced physical or psychological IPV were this history is elicited.
more likely to have gastrointestinal complaints, in-
cluding pelvic pain, stomach ulcer, spastic colon,
indigestion, diarrhea, and constipation.145 Another Summary
146
In a year-long ret-
There are many gastrointestinal and hepatobiliary
rospective cohort study of women in Washington
diseases which affect men and women differently.
It is important to consider the many factors related
their partners were twice as likely to have been hos-
to sex with regard to disease pathophysiology, pre-
pitalized for gastrointestinal illness within the past
sentation and management. Further research will
year when compared to non-abused, age-matched
controls. 147 Sixty-seven percent of 70 women report-
will enhance our understanding of these differences
ing IPV to the police reported symptoms consistent
promoting improved outcomes for both men and
with functional dyspepsia and 47% met Rome III
women.
criteria for IBS, far exceeding rates for the general
population.148
In a multi-center study, sexual abuse (31.6%) Pearls and Pitfalls
was found at higher rates in patients with IBS ver-
sus patients with organic gastrointestinal diseases for the Board Exam
(14%) and healthy controls (7.6%). 149 Others have Up to 20% of the US population report symptoms
found that the kind of abuse reported by women pa- consistent with IBS. In the health-care seeking
tients seen in a referral-based gastroenterology cen- population and in the community, women outnumber
ter for functional disorders was more severe when men. More women have IBS with constipation than
compared to patients with organic disorders who men.
had experienced abuse. 150 There is an association between fecal incontinence
The biopsychosocial conceptual model of the ef- and increasing age, and in some studies, there are
fect of abuse on GI symptoms proposes a multicom- sex-related differences in prevalence.
ponent process that integrates interaction of early Numerous studies have reported obstetrical risk
life experiences such as abuse, with coping mecha- factors for developing FI. The four main factors that
nisms, social networks, psychological distress, ill- consistently were associated with a higher risk of FI
were: forceps delivery, third or fourth degree tears,
care seeking behaviors.151 It is hypothesized that length of second stage of labor, and fetal weight
those who suffer from abuse experience increased >4000g.
autonomic reactivity in the gut in response to physi- Bowel involvement with endometriosis occurs in up
cal and psychological stressors. This may result in to 37% of cases. The most commonly affected areas
increased visceral hypersensitivity and subsequent are the sigmoid colon, rectosigmoid junction and
functional symptoms along with many factors that rectum (82-90%).
may modulate or affect visceral hypersensitivity152 Ulcerative colitis patients managed non-operatively
(Figures 15.20 and 15.21). have a high (97%) rate of achieving pregnancy which
then falls to 56% after ileal pouch anal anastomosis. an infectious disease from mother to fetus/baby,
Most studies from primarily referral populations, often at the time of birth and was first identified in
show decreased fertility in women with Crohn’s association with hepatitis B. Hepatitis B immune
disease. globulin administered with hepatitis B vaccine to
Primary biliary cirrhosis (PBC) is a disease primarily the newborns of infected mothers has reduced the
of women and approximately one third of patients rate of the vertical transmission of this infection.
with PBC will have evidence of osteopenia or Hepatitis C transmitted via vertical transmission is
osteoporosis. American Association for the Study less common but when it occurs, usually results in
of Liver Diseases (AASLD) guidelines recommend chronic infection of the baby.
that bone mineral density should be assessed with Pregnancy in advanced liver disease is unusual as
dual X-ray absorptiometry at diagnosis and every 2 fertility is definitely impaired. However, women
years thereafter. with portal vein thrombosis or non-cirrhotic
Gallstones: Bile becomes increasingly lithogenic portal hypertension may have normal fertility; the
with age, with increased cholesterol secretion management of portal hypertension is complicated
and with decreases in bile acid secretion. Female in these patients with concerns about ascites
gender increases the incidence 3-4 times up to formation and variceal bleeding.
age 50. In addition to a possible role of estrogen, Patients who have undergone successful liver
a linear association between BMI and incidence transplantation return to normal fertility within
of gallstones has been identified with a 7-fold risk weeks to months. Follow up of the pregnancies in
in obese females. Rapid weight loss increases gall post transplant patients show that most women do
bladder (GB) sludge. well and that most immunosuppressive drugs do not
During pregnancy, liver function remains similar to appear to cause congenital abnormalities. There is
function in the nonpregnant woman. Serum albumin a much higher rate of fetal loss, hypertension, and
will be lower due to dilution to a lower concentration pre-eclampsia; some of this risk may be due to the
as in pregnancy the intravascular volume increases underlying chronic renal disease and hypertension in
by 40-50%. Synthesis of anti-thrombin III by the many post-transplant patients.
liver falls with normal pregnancy and some acute- Acute Fatty Liver of Pregnancy (AFLP) is due to
phase reactant proteins will be synthesized in higher minor genetic mutations along with the influx of
amounts resulting in a rise in plasma levels. Serum fatty acids during pregnancy perhaps in association
alkaline phosphatase will also be increased in the with environmental factors. Mothers of children
pregnant woman by 40-70% due to an isoform that homozygous for mutations in Long-chain 3 hyroxyacyl
the placenta makes. CoA Dehydrogenase (LCHAD), an enzyme in the beta
In comparison to men and non-pregnant women, oxidation of fatty acids, are at risk for AFLP. This
pregnant women who are infected with hepatitis E disease is autosomal recessive, indicating the
have an extremely high risk of developing fulminant mothers were carriers. Because of the unpredictable
liver failure with high fatality rates for both mother course and the possibility of rapid worsening,
and baby. treatment should include immediate delivery of the
Herpes simplex hepatitis is rare, but pregnant baby. Babies should be tested for LCHAD deficiency.
women and immunocompromised patients appear HELLP syndrome may be seen in association with
to be particularly susceptible to this disease. pre-eclampsia. Criteria for HELLP syndrome include
Herpes simplex hepatitis presents acutely and often elevated transaminases (AST/ALT), evidence of
rapidly progresses. This disease presents a high risk intravascular hemolysis and thrombocytopenia.
for the fetus and treatment of the baby should be HELLP syndrome primarily occurs in the third
implemented upon delivery. trimester of pregnancy but has been reported to
Vertical transmission indicates transmission of develop within the first few days post-partum in
some patients. The most severe complications of References

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CHAPTER 16
Nutrition, Obesity and Eating Disorders
Jeanette Keith, MD
Learning Objectives
2. Describe various techniques of nutritional assessment and appreciate the limitations of each method.
3. Know the techniques of enteral and parenteral nutrition support and potential complications.
5. Review the pathophysiology and treatment of obesity and the role of the gastrointestinal tract in energy metabolism.
6. Discuss the common eating disorders with emphasis on the gastrointestinal and nutritional complications.
Basic Nutritional Requirements
Macronutrients
Dietary protein is the source of essential and nonessential amino acids. Nine amino acids (histidine, iso-
leucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) are essential because
they cannot be synthesized in the human body and must be supplied from the diet. Other amino acids may be
conditionally essential in disease states. Protein is digested by a variety of gastric, pancreatic, and intestinal
proteases to amino acids and oligopeptides that are absorbed across the small intestinal mucosa by several
transport proteins. The liver is the main site for the metabolism of amino acids except for the branched chain
amino acids (isoleucine, leucine, and valine) that are metabolized in skeletal muscle, adipose tissue, and the
kidney.
Dietary fat provides a substantial portion of energy in the diet, serves as a carrier for fat-soluble vitamins,
and furnishes essential fatty acids. Dietary fat consists mostly of long-chain triglycerides that require digestion
to fatty acids and monoglycerides by pancreatic and other lipases to be absorbed. Bile salts are needed to solu-
enterocyte, absorbed fatty acids and monoglycerides are used to synthesize triglycerides that are incorporated
into chylomicrons and secreted into lymph. The limited amounts of short- and medium-chain triglycerides in the
diet are rapidly hydrolyzed, and absorption of the short- and medium-chain fatty acids and monoglycerides is
less dependent on bile salts. In addition, some short- and medium-chain triglycerides can be absorbed into the
portal blood without digestion.
487
Dietary carbohydrates are not essential be- malabsorption. Figure 16.2 is a bone biopsy of a pa-
cause carbohydrates can be synthesized by the body. tient with Crohn’s disease and osteomalacia.
Carbohydrates, however, are an important energy Minerals serve a diverse array of physiological
source, providing about 50–60% of the energy in a roles. These include important structural functions
typical American diet. Starches are digested by sali- (e.g., bone minerals such as calcium, phosphorus, etc.),
vary and pancreatic amylase to monosaccharides essential components of metalloproteins including
and oligosaccharides. Brush border disaccharidases many enzymes and transporters, and as ions involved
(sucrase, maltase, lactase, etc.) digest the oligosac- in neurotransmission, muscle contraction, regulation
charides and dietary sugars such as lactose, fructose, of acid-base balance, energy gradients, and second
and sucrose to monosaccharides that are absorbed messengers. Table 16.2 summarizes mineral and trace
across the mucosa by several sugar transporters.
evaluation.2,3 Dietary minerals are divided into mac-
- rominerals (calcium, chloride, phosphorus, potassium,
es, however, will be metabolized by gut bacteria to magnesium, sodium, and sulfur) that are present in
short-chain fatty acids that are absorbed by the co- the body at >50 ppm, and trace elements. Ten trace
lon.1 elements are considered essential for normal physi-
iodide, iron, manganese, molybdenum, selenium, and

Micronutrients zinc. Additional trace elements appear to be required in
other species, but an essential role in human metabo-
Vitamins are organic molecules that are generally re-
quired in small amounts in the diet for normal growth Figure 16.1
and physiological function. Some vitamins, such as vi- Patient with Celiac Disease and Osteomalacia Due to Vita-
tamin K, biotin, and niacin, can be synthesized by in- min D and Calcium Malabsorption
testinal bacteria and absorbed by the small bowel or
colon, providing an endogenous source of the vitamin.
Vitamin D is synthesized in the skin, and exposure to
the vitamin to meet nutritional needs. Water-soluble

vitamins serve mainly as coenzymes for various bio-
chemical reactions. The exception is vitamin C, which
functions mainly as an important antioxidant. Vitamin
A is crucial for the visual cycle, and also functions as
a regulator of gene transcription. Vitamin D interacts
with its nuclear receptor to affect gene transcription.
Vitamin K is needed for the post-transcriptional modi-
proteins. Vitamin E is the principal lipid-soluble an-

tioxidant. Most vitamins are preferentially absorbed
in the proximal small intestine. It is notable that folic
acid (vitamin B9) is exclusively absorbed in the jeju-
num. In contrast, vitamin B12 binds to intrinsic factor
produced in the stomach, and the complex is absorbed
by ileal enterocytes. Table 16.1 summarizes vitamin
-
ment. Figure 16.1 shows a patient with celiac dis-
2,3
ease and osteomalacia due to vitamin D and calcium

Chapter 16 — Nutrition, Obesity and Eating Disorders 489
lism has not been established. Figure 16.3 shows hy- Figure 16.2
Bone Biopsy of Patient with Crohn’s Disease and Osteoma-
lacia
Nutritional Assessment
A 60-year-old man with a history of alcohol
abuse and a 40 pack/year history of smoking presents
with refractory nausea and vomiting. He initially had
3 months of progressive early satiety, but for the 2
weeks prior to presentation had postprandial nausea
with vomiting and epigastric pain. He is now unable to
tolerate even liquids. Physical examination showed a
thin man in no acute distress with height 5 ft, 7 in and
weight 57 kg. His usual weight was 72 kg; he had lost Wide seams of unmineralized bone, osteoid, staining red, covers the
mineralized bone, staining black.
6 kg in the prior 2 weeks. He had wasting of temporal
muscles and loss of subcutaneous fat, and (2+) edema
to the knees was noted. Laboratory testing showed poorly differentiated adenocarcinoma. The patient
a low serum albumin of 2.4 g/dl; serum prealbumin was felt to have severe protein-calorie malnutrition
level was 0.05 g/L (normal 0.2–0.4). Upper gastroin- -
testinal (GI) endoscopy showed an obstructing mass ceived 10 days of preoperative total parenteral nutri-
in the distal antrum of the stomach that on biopsy was tion (PN) prior to subtotal gastric resection.
Table 16.1
Signs, Symptoms, and Evaluation of Vitamin Deficiencies
Vitamin Deficiency Lab evaluation

A (retinol) Night blindness, follicular hyperkeratosis Serum retinol
D (cholecalciferol, ergocal- Rickets, tetany, osteomalacia, osteoporosis
Serum 25-hydroxyvitamin D
ciferol) (Figures 15.1 and 15.2)
E (alpha-tocopherol) Hemolysis, retinopathy, neuropathy Serum tocopherol
K (phylloquinone) Abnormal clotting Prothrombin time
B1 (thiamine) Beriberi, Wernicke’s encephalopathy Red blood cell transketolase activity
Cheilosis, sebhorrheic dermatitis, angular
B2 (riboflavin) Red blood cell glutathione reductase activity
stomatitis
B3 (niacin) Pellagra (dermatitis, diarrhea, dementia) Urinary N-methyl-nicotinamide
B5 (pantothenic acid) Fatigue, weakness, paresthesias Urinary pantothenic acid
B6 (pyridoxine) Sebhorrheic dermatitis, cheilosis Plasma pyroxidal phosphate
Sebhorrheic dermatitis, allopecia, change in
B7 (biotin) Plasma biotin
mental status
B9 (folic acid) Megaloblastic anemia, glossitis Serum or red cell folate
Megaloblastic anemia, decreased vibratory or
B12 (cobalamin) Serum cobalamin
position sense
Assessment of a patient’s nutritional status begins Anthropometric measurements can provide semi-
by obtaining a detailed history and by performing a quantitative information on body muscle mass and
careful physical examination. The SGA technique uses fat reserves but are less commonly utilized in clinical
information from the history and physical examina- practice. Measurement of the triceps skin fold thickness
tion to stratify a patient’s nutritional risk (Table 16.3). (TSF) estimates body fat stores because about one-third
Five areas are focused on in the medical history: weight of body fat is located in the subcutaneous tissues. The
change, alterations in dietary intake, presence of gas- measurement is taken at the midpoint of the back of the
trointestinal symptoms, functional capacity, and nondominant arm using skin-fold calipers. A measure-
the patient’s disease state and its impact on nutritional ment of <3 mm indicates severe depletion of energy
requirements. The physical examination also empha- reserves. Measurement of the midarm muscle circum-
- ference (MAMC) is used to estimate the inner circle of
ing, lower extremity edema, sacral edema, and ascites. skeletal muscle mass surrounding a small central core
of bone. This serves as an index of protein reserves,
three categories: well nourished (category A), mild or since muscle is the largest protein compartment of the
moderate malnutrition (category B), and severe mal- body. The upper arm circumference is measured with
nutrition (category C). This technique has been shown a tape measure. The MAMC is equal to upper arm cir-
to be reproducible and a valid predictor of morbidity in cumference - (0.314 × TSF).3, 4 These anthropometric
surgical and other patients.2, 4 The history should also measurements are not sensitive enough to detect small
inquire about alcohol intake and use of medications, changes in body fat or muscle mass and, therefore, can-
herbals, and food supplements. Symptoms and physi- not be used to assess short-term nutritional depriva-
tion. Bioelectrical impedance analysis is a technique
should be noted. that measures body composition based on the differ-
Table 16.2
Signs, Symptoms, and Evaluation of Mineral and Trace Element Deficiencies
Mineral/trace
Deficiency Lab evaluation
element
Calcium Osteoporosis Serum calcium, 24-hour urinary calcium, bone density
Magnesium Weakness, tetany, arrhythmias, hypocalcemia, hypoka- Serum magnesium
lemia
Phosphorus Bone pain, weakness, fatigue, hemolytic anemia Plasma phosphorus
Sodium Hypovolemia, weakness Urinary sodium
Potassium Weakness, paresthesias, arrhythmias Serum potassium
Iron Microcytic hypochromic anemia Serum iron, total iron-binding capacity, ferritin
Copper Anemia, neutropenia, diarrhea Serum copper
Zinc Skin rash (Figure 15.3), growth retardation, poor wound Plasma zinc
healing, mental status changes
Iodine Hypothyroidism, goiter Urinary iodine
Chromium Glucose intolerance, peripheral neuropathy, encepha- Serum chromium
lopathy
Selenium Cardiomyopathy, muscle weakness Serum selenium, blood glutathione peroxidase activity
Manganese Hypercholesterolemia, dermatitis, dementia Serum manganese
ence in electrical conductivity of fat-free mass and fat.4 Table 16.3

The fat-free mass is mostly electrolyte-containing wa- Subjective Global Assessment (SGA)
ter that conducts an applied electrical current, whereas
fat is a poor conductor of electrical current. Medical History
A variety of laboratory tests are also used in nutri- 1. Weight change
tional assessment. Caution must be taken when inter- a. Overall change in past 6 months
preting results, however, as many of these tests are b. Percent change
affected by factors other than nutritional status. For c. Change in past 2 weeks
example, a low serum albumin may indicate compro- 2. Dietary intake
mised protein status, but it can also be due to infec- a. Overall change
b. Duration
the nephrotic syndrome. The serum albumin concen- c. Type of change (suboptimal solid diet, hypocaloric
tration is a powerful predictor of hospital morbidity liquids, full liquid diet, starvation)
and mortality. Serum albumin has a relatively long 3. Gastrointestinal symptoms (persisting >2 weeks): nau-
sea, vomiting, diarrhea, anorexia
4. Functional capacity
nutritional history over the previous 3 months but is
a. Change in function
not sensitive to recent changes in nutritional status.
b. Change in past 2 weeks
5. Disease states/comorbidities affecting nutritional needs
nutritional status over the preceding several weeks.
Decreased transferrin can be due to inadequate pro-
Physical Examination
tein and energy intake, but is also affected by iron
1. Loss of subcutaneous fat
status. Prealbumin has a rapid turnover rate, with a 2. Muscle wasting
3. Edema (sacral, pedal)
over the preceding week. Prealbumin levels are rap- 4. Ascites
idly reduced with protein-energy malnutrition and re-
stored with refeeding. Prealbumin is also decreased in Overall SGA Rating
patients with infections and liver failure and increased A—well-nourished (A rating in most categories or significant
in renal failure. Measurements of serum electrolytes, improvement)
minerals, BUN, creatinine, liver function panel, and B—mildly to moderately malnourished (neither A nor C is
cholesterol panel are usually included when assessing clearly indicated or majority of categories are rated B)
C—severely malnourished (C ratings in most categories or sig-
levels are used to evaluate patients with symptoms nificant physical signs)
Total daily energy expenditure is comprised of resting energy expenditure. In addition, the RQ or
the basal metabolic rate, thermic effect of feed- respiratory quotient (CO2 production divided by O2
ing, and energy due to physical activity. The resting consumption) provides information on substrate uti-
metabolic rate of healthy individuals is estimated us- lization. Metabolism of fat, protein, and carbohydrate
ing the Harris-Benedict equation. Resting metabolic have different respiratory quotients: 0.7, 0.8, and 1.0,
rate increases modestly in most illness, typically 20– respectively.3
25%, but can be more elevated in certain situations, A healthy adult requires 0.8 g/kg body weight/day
such as severe trauma or burns. Indirect calorimetry of protein. Protein requirements increase during ill-
is increasingly being utilized to evaluate a hospital- ness (see below) and can be >2 gm/kg ideal body
ized patient’s energy requirement. Bedside indi- weight (IBW)/day in critically ill patients, such those
rect calorimeters measure O2 consumption and CO2 with severe burns.
production, and this information is used to estimate
Figure 16.3 A large number of small intestinal diseases will

Hyperpigmented Skin Rash on the Fingers of Patient with result in impaired brush border membrane digestion
Short Bowel Syndrome and Zinc Deficiency of small peptides and oligosaccharides and defective
transport of nutrients across the luminal membrane.
Impairment in nutrient delivery from the enterocyte
into the body can be due to diseases affecting the lym-
phatic or portal venous circulations, such as lymphan-
giectasia or constrictive pericarditis. Defective release
of nutrients from the enterocyte can also be caused by
impaired packaging of nutrients within the intestinal
cell. For example, abetalipoproteinemia is caused by
a genetic defect in a microsomal triglyceride transfer
protein needed for chylomicron assembly and secre-
tion from the intestine. Some gastrointestinal diseas-
es result in abnormalities in several steps of nutrient
digestion and absorption. For example, patients with
Mechanisms of Malnutrition in bacterial overgrowth in addition to malabsorption.

Gastrointestinal Disease Excessive acid secretion severely lowers duodenal pH,
There are multiple factors that contribute to malnu- inactivating pancreatic lipase, causing precipitation of
trition in patients with gastrointestinal diseases and intraluminal bile salts, and damaging enterocytes lead-
more than one mechanism can co-exist in the same ing to malabsorption. Alterations in intestinal motility
patient. Inadequate food intake is the most common due to pain and narcotic use predispose to bacterial
mechanism resulting in malnutrition. Many gastroin- overgrowth that contributes to nutrient loss due to
testinal diseases cause anorexia or taste disturbances. -
Symptoms provoked by eating, such as nausea, vom- thesize folate which is secreted into the lumen and ab-
iting, abdominal pain, and diarrhea, often limit food sorbed, serum folate levels are elevated despite other
intake. Dysphagia or odynophagia from esophageal nutrient losses.
disorders can severely impair eating. Malabsorption Many drugs cause malabsorption or altered me-
-
vitamins, minerals, and trace elements. Malabsorption -
can be due to abnormalities in nutrient digestion within nides, carbamazepine, phenytoin, oral contraceptives,
the intestinal lumen (maldigestion), defective entero- methotrexate, sulfasalazine, and triamterene. Proton
- pump inhibitors can cause vitamin B12 malabsorp-
ery into the portal venous or lymphatic circulations. -
stat, and octreotide can all lead to fat malabsorption.
Glucocorticoids, phenytoin, thiazides, and tetracycline
causes fat, protein, and carbohydrate maldigestion due affect calcium absorption and/or excretion.
to lack of pancreatic lipase, proteases, and amylase.
Nutritional Support
triglyceride, fat-soluble vitamins, and other dietary lip- Short periods of nutritional deprivation are usually
ids because of poor solubilization of lipids into mixed
micelles. Bile salt malabsorption due to ileal disease impaired for over 1–2 weeks, detrimental effects on
or resection can also lead to intraluminal bile salt de- nutritional status and physiologic function often oc-
cur. Multiple factors determine how rapidly a patient
will become malnourished, including the pre-illness who have a functional gastrointestinal tract. An ad-
nutritional status, the severity of the ongoing dis- vantage of enteral feeding over parenteral nutrition
ease process, and the duration of metabolic stress. is that the integrity of the intestinal mucosal defense
Nutritional support should be considered for patients barrier is kept intact. In critically ill patients, enteral
who are unable to maintain adequate oral nutrition
for 10–14 days.5 In critically ill or severely injured 24–48 hours after admission and advanced to the goal
patients or in those with severe malnutrition, nutri- rate within 2–3 days.6 Patients with hemodynamic
tional support should be initiated earlier. It has been instability should not receive enteral nutrition until
suggested that nutritional support improves the out- they are resuscitated and stable. An absolute contra-
come of severely malnourished patients undergoing indication to enteral feeding is high-grade bowel ob-
major surgery, patients with severe trauma, and bone struction. Enteral feeding has not been demonstrated
marrow transplant patients. Nutritional support can -
be via the enteral route or intravenous route (paren- ies placement of a percutaneous gastrostomy tube has
teral). The enteral route is preferred over parenteral been associated with diminished survival.
nutrition if tolerated. Appropriate candidates for par- Nasogastric or nasoenteric tubes are used for
enteral nutrition, when enteral nutrition fails or is not short term feeding (generally <30 days) in hospital-
indicated, are those individuals who will require sup- ized patients. Larger-bore tubes can also be used for
port for at least 7 days. Provision of parenteral sup- gastric decompression and administration of medica-
port for <5-7 days is associated with increased risk -
of infectious complications and should be avoided. roscopic guidance, or by endoscopic techniques. If the
Long-term nutritional support is necessary to prevent tube is placed at the bedside, tube feeding should not
death from starvation in certain conditions, such as be initiated until the position of the tube is checked.
the short bowel syndrome, chronic intestinal pseudo- Neither the presence of bowel sounds nor evidence of
obstruction, permanent neurologic impairment, and
severe swallowing disorders. tube feedings. A gastrostomy tube should be consid-
ered when a patient requires enteral feeding for >30
days. These tubes can be placed endoscopically, radio-
Enteral Nutrition logically, or surgically.6, 7
Enteral feedings can be delivered by bolus, by
A 60-year-old woman with amyotrophic lat-
gravity, or by pump. Patients at home can easily use
bolus feeding. Intermittent gravity feeding is used for
swallowing solids and liquids, 20-lb weight loss in the
most patients. Pump feedings can be either continu-
past month, and aspiration pneumonia. The pneumo-
ous or intermittent. Continuous pump feeding is the
nia is treated with clindamycin. Swallowing evalua-
method of choice for jejunal feeding.
tion shows severe oropharyngeal dysphagia, with
There are many different tube-feeding formula-
aspiration of contrast. Because of the progressive
tions available today. Standard isotonic polymeric for-
dysphagia and high aspiration risk, a percutaneous
mulas will meet the needs of the majority of patients.
endoscopic jejunostomy is placed. The patient is be-
Polymeric formulas are made up of nonlactose car-
gun on a polymeric tube feeding providing 1800 kcal/
bohydrate, intact protein, and long-chain fatty acids.
day and 75 g/day protein. After initiation of the tube
Most formulations provide 1 kcal/ml; 12–20% of the
feeding, the patient develops watery diarrhea with up
calories are from protein, 45–60% are from carbo-
to 8 loose bowel movements per day. Stool studies are
hydrates, and 30–40% of the calories are from fats.
positive for toxins, and treatment
Elemental diets are formulations that contain oligo-
with metronidazole is initiated. The patient’s diarrhea
peptides or individual amino acids rather than whole
resolves, and she is discharged home on tube feedings.
protein. They also may contain medium-chain triglyc-
Tube feeding should be considered for patients
who are unable to achieve adequate intake orally and
be absorbed unchanged into the enterocyte. Some piration and those with demonstrated intolerance to
long-chain triglycerides, however, are needed to pro- gastric feedings or recurrent aspiration should be fed
vide essential fatty acids. Elemental formulas are usu- via a tube placed in the small intestine. Patients with
ally used for patients who have small bowel absorptive severe head injury have a high risk of impaired gastric
dysfunction, such as patients with Crohn’s disease and motility, and a jejunal tube should be considered for
short bowel syndrome, but their superiority compared the initial treatment in these patients.
to standard tube feedings is controversial. Patients with The most common complication in patients re-
ceiving enteral nutrition is diarrhea. There are multi-
the production of blood urea nitrogen. Renal formula- ple causes of diarrhea in these patients, many of which
tions are low in protein, phosphorus, magnesium, po- are not related to the enteral feeding, including antibi-
tassium, and sodium. Formulas enriched in branched- otic use; infection; and medica-
chain amino acids and low in aromatic amino acids tions, e.g., magnesium or phosphate salts, sorbitol-con-
have been employed to improve hepatic encephalopa- taining preparations, and others. These other factors
thy, but different studies of these diets have produced contributing to diarrhea should be corrected before
implicating and altering the tube feedings. Diarrhea is
formulas containing arginine, glutamine, omega-3 more common in the critically ill patient. Alterations in
fatty acids, and antioxidants are recommended for
- as contributors to diarrhea in enteral nutrition support.

Metabolic complications also occur with tube
to patients receiving enteral feeds. The average adult feeding, but less commonly than parenteral nutrition.
requires about 30 ml of free water per kilogram of These include hyperglycemia, electrolyte disturbanc-
IBW. One must subtract the total free water contained es, and rarely abnormal liver function. Other potential
in the tube feeding from the patient’s free water re- nasogastric or nasointestinal tube complications in-
quirement.6, 7 clude pulmonary intubation, nasal irritation, epistaxis,
There are multiple complications of tube feed- -
ing whether administered through nasoenteric or ageal stricture. Common complications of percutane-
percutaneous tubes. Aspiration of feedings is of par- ous endoscopic gastrostomy (PEG) tube placement
ticular concern. To decrease the risk of aspiration, it is include minor bleeding and wound infections that can
recommended to raise the head of the bed to at least be reduced by a prophylactic dose of antibiotics pre-
30 degrees while feeding and for one hour after, use procedure. Other complications are perforation, nec-
intermittent or continuous feeding rather than bolus buried
feeding, and monitor gastric residuals. Preliminary bumper can occur when there is too much pressure
between the external and internal bumpers. This re-
in aspiration pneumonia in bedridden gastrostomy sults in the internal bumper migrating from the stom-
patients receiving elemental feedings but additional ach lumen into the gastric wall. Symptoms include
studies are required.8 Tube feeding should not be abdominal pain with feeding and/or resistance when
withheld for a gastric residual volume of <250–500
ml.6, 9 Tube feeding should also not be stopped for one by radiological contrast study. Pneumopertioneum
high gastric residual if subsequent residual volumes
are normal. A trend toward increasing gastric residu- should not be a cause for concern if there are no peri-
als is more important than one isolated high reading. toneal signs.
Instead of stopping tube feedings, other interventions
such as adding a prokinetic agent, reducing sedation,
and raising the head of the bed should be tried to im- Parenteral Nutrition
prove feeding tolerance. Patients at a high risk for as-
The main indication for parenteral nutrition is the in-
ability to achieve adequate nutrition via the gastro- ill patient. Overfeeding can result in infection, fever,
intestinal tract for a prolonged period of time, and and delayed weaning from a ventilator. In critically
parenteral nutrition should only be used for pa-
tients who cannot tolerate enteral nutrition support. given to optimize nitrogen balance and preserve lean
In critically ill patients who cannot receive adequate body tissue. It is generally not possible to achieve posi-
enteral nutrition support within 7 days, parenteral tive nitrogen balance and repletion of lean body mass
nutrition should be provided. Parenteral nutrition during a period of severe metabolic stress. The protein
support should be initiated 5–7 days preoperatively requirement can increase up to 2.5 g/kg/day in severe-
in patients undergoing major upper gastrointestinal
surgery that cannot tolerate enteral feedings, and con- not dialyzed should receive only modest amounts of
tinued into the postoperative period. Parenteral nutri- amino acids. Some studies have suggested that solu-
tion begun in the immediate postoperative period has tions with higher concentrations of branched-chain
been found to result in increased mortality and infec- amino acids and lower amounts of aromatic amino
tious and other complications. It is, therefore, recom- acids reduce hepatic encephalopathy.10
mended to delay parenteral nutrition for 5–7 days Carbohydrate is given in the form of glucose. The
after surgery in patients who cannot tolerate enteral amount of glucose given per day ranges from 150 to
feedings.6 Parenteral nutrition is generally not given 400 g. For most patients, 20–30% of total calories are
to a terminally ill patient with a <3-month expected administered as intravenous fat emulsions. A mini-
survival. Provision of parenteral nutrition for < 5-7 mum of 5% of total calories in the form of lipids is nec-
days should be avoided.
Infusion of PN must be through a central vein patients may not need lipid infusion during short-term
such as the superior vena cava. Typically, a catheter is parenteral nutrition. Some studies indicate that lipid
placed into the subclavian vein and the tip advanced infusions are associated with an increased rate of in-
to the junction of the superior vena cava and the right fections in critically ill patients and should be avoided
atrium. This location probably has a lower risk of in-
fection than access through the femoral or internal should not be given to patients with serum triglycer-
jugular veins. Peripherally inserted central venous ides >400 mg/dl to avoid inducing pancreatitis.
catheter lines may also be used for infusion of paren- Patients must be carefully monitored while receiv-
teral nutrition. ing parenteral nutrition. Vital signs, input and output,
Parenteral formulations are comprised of water, and weight should be monitored daily. Electrolytes,
amino acids, glucose, fat, minerals, trace elements, phosphate, and glucose should be checked daily until
and vitamins. Several approaches are used in clinical values are stable. Insulin is added to the solution to
practice to calculate energy requirements. A factorial control the blood glucose level. If the formula contains
method uses the Harris-Benedict equation to calculate lipids, serum triglycerides should also be monitored.
the healthy basic metabolic rate, which is multiplied The catheter site also needs to be carefully maintained
by a stress factor based on disease severity. The aver- in order to reduce infectious complications. The dress-
age hospitalized patient referred for nutrition support ing should be changed every 48–72 hours, and infu-
requires about 1.25 times the energy estimated by the sion tubing should be changed daily.
Harris-Benedict equation, but greater stress factors Complications from parenteral nutrition in-
are needed for severe illnesses such as burns. Another clude those related to the central line and metabolic
method estimates the energy required based on the abnormalities.10 Central line insertion can lead to
body mass index (BMI): BMI <15, 35–40 kcal/kg/day; pneumothorax, hemothorax, chylothorax, brachial
BMI 15–19, 30–35 kcal/kg/day; BMI 20–29, 20–25 plexus injury, and puncture of the surrounding arter-
kcal/kg/day; BMI >30, <15 kcal/kg/day. ies. Subclavian vein thrombosis occurs in up to 50%
It is generally preferable to provide less energy of patients; however, most of the time it is clinically
than to administer excessive calories to a critically -
ing at the catheter insertion site or from contamina- parenteral nutrition support.11, 12
tion at tubing connections. The catheter should be Factors that determine the severity of the SBS
removed when there is persistent bacteremia, funge- include the length of remaining healthy small bowel
and colon, site of resection, presence of the ileocecal
overload, hypertriglyceridemia, hypercalcemia, hy- segment, and time since surgery.11, 12 In general, re-
section of 50% of the small intestine is well-tolerated,
Hyperglycemia occurs commonly and can increase the whereas loss of >75% necessitates parenteral nutri-
risk of infection. The optimal blood glucose is between tion. Patients with the SBS but with residual colon
100 and 150 mg/dl. have less severe symptoms than those with a compa-
With short-term parenteral nutrition, elevated rable length of small bowel and a small bowel ostomy.
serum aminotransferases and alkaline phosphatase The remnant colon plays an important role in absorb-
are frequently observed. These are generally of little ing nutrients that escape absorption in the small in-
clinical consequence and are not an indication for
stopping the parenteral nutrition. Infants receiving calcium, and other nutrients. In addition, electrolyte
parenteral nutrition often develop cholestasis, but this -
is rarely observed in adults. Long-term parenteral nu- tient decreases diarrheal volume and urgency. Severe
trition can be associated with serious liver abnormali- postprandial diarrhea can be a factor that discourages
adequate food intake.
and cirrhosis. Biliary complications, such as acalculous The ileocecal region provides a brake that slows in-
cholecystitis, gallbladder sludge, and cholelithiasis, testinal transit, allowing more time for nutrient absorp-
occur because of gallbladder stasis from lack of meal- tion. Peptide YY (PYY) is thought to be the predominant
stimulated gallbladder contraction. Osteomalacia and mediator of the ileocecal brake. PYY is located in en-
osteopenia have been observed in patients receiving teroendocrine cells of the ileum and colon as well
parenteral nutrition for >3 months.10 as in nerves of the enteric nervous system. PYY is
stimulated by incompletely digested fats, and inhib-
its vagally stimulated gastric acid secretion and gas-
Specific Disorders tric and intestinal motility. Glucagon-like peptide 2
(GLP-2) is secreted by endocrine cells in the ileum and
Short Bowel Syndrome colon, stimulates hyperplasia, and increases absorptive
The normal small intestinal length ranges from 3 to 8 capacity of the remnant bowel after jejunal resection.
meters. When there is <200 cm of small intestine, the Bile salts and vitamin B12
short bowel syndrome occurs. The short bowel syn- the ileum. For all these reasons, resection of jejunum is
drome (SBS) may be congenital, but more commonly tolerated better than a comparable ileal resection.
results from surgical resection of the small intestine. The remaining functional intestine, particularly
The most common cause of short bowel syndrome ileum, has the capability of adapting and becoming
in adults is intestinal ischemia. Other causes include
multiple resections for Crohn’s disease, tumors of the and height of the villi increase, leading to a greater
small intestine, and trauma. A “functional” short bow- absorptive surface area. This process takes about 1–2
el syndrome can also occur, resulting from severe mal- years after resection. The length of small bowel neces-
absorption due to various intestinal disease processes -
such as refractory sprue, chronic intestinal pseudo- continuation of PN is generally 100 cm if the colon is
obstruction, and radiation enteritis. Patients who not intact or 60 cm with an intact colon.
cannot increase their food intake to compensate for The goal of nutritional therapy in the SBS is to
provide enough macro- and micronutrients to prevent
nutrients despite increasing their nutrient intake are
considered to have intestinal failure, and will require avoid dehydration and electrolyte and acid-base dis-
turbances. Most patients who have lost a large amount ment can be problematic since a common side effect
of small intestine will require PN initially after sur- is diarrhea, and some patients require parenteral sup-
gery. Many can receive home PN and administer their plementation. Oral calcium supplementation is rec-
infusions at night. As soon as possible after surgery, ommended for all patients who are not receiving PN.
patients should begin receiving small amounts of food Fluid losses are a major concern after small bowel
to stimulate intestinal adaptation. The diet should be resection. Gastric hypersecretion occurs commonly
high in protein and low in simple sugars that can cause -
an osmotic diarrhea. Dietary fat should not be restrict- -
ed for most patients with the short bowel syndrome. id losses. A small number of patients have persistent
Low-fat diets generally do not reduce stool volume gastric hypersecretion. Control of diarrhea is essential
in these patients and can limit energy intake.11, 12 A in the management of patients with the short bowel
modest fat restriction may be useful in patients with syndrome, both to increase contact time for nutrient
moderate ileal resection and an intact colon, where absorption and to diminish postprandial symptoms
that discourage food intake. Most patients will re-
and electrolyte secretion. A low-fat, low-oxalate diet quire chronic antimotility agents such as loperamide
or diphenoxylate. If these fail, tincture of opium or
codeine is then used. Some patients are treated with
Medium-chain triglyceride supplements can be octreotide, but may develop tolerance and have other
useful as a readily absorbed energy source. Lactose- complications such as gallstones. Patients with <100
containing dairy foods should be limited in intolerant cm of jejunum are especially at risk for dehydration.
Oral rehydration solutions are useful in these patients.
as pectin, may help in the management of diarrhea. In The solution should be isotonic and contain at least 90
mEq/L of sodium.
acids by colonic bacteria and provide an important fuel Inclusion of the amino acid glutamine in the PN
for the colon and other tissues. solution is believed by some to enhance intestinal ad-
Short bowel patients who are not on PN often de- aptation and the transition from PN to oral intake. In
- December 2012, Teduglutide, a GLP-2 analogue was
granted orphan drug status by the FDA and approved
water-soluble vitamins that are absorbed in the duo- for targeted drug therapy for the treatment of SBS.13
denum and proximal jejunum are relatively unusual, It is a once daily injection that improves nutrient ab-
sorption while reducing the volume and frequency
Patients who have had >60 cm of their terminal ileum of PN therapy. Human growth hormone is also being
resected require vitamin B12 supplementation. Fat- evaluated as a therapy to reduce PN requirements for
SBS patients.
The goal of surgical treatment of the short bowel
syndrome is the same as medical therapy, i.e., to re-
have an intact colon because of vitamin K production duce or discontinue PN. Reversal of an ostomy with
by colonic bacteria. Trace metals such as zinc and se- reanastomosis is done whenever possible. Surgeries
lenium are lost in the feces and should be replaced if that have been done to slow intestinal transit include
segmental reversal of the small bowel, colonic inter-
are rare. Since iron is absorbed in the duodenum, position, construction of valves, and electrical pacing
supplementation is usually not necessary. Magnesium of the small intestine. Results from these surgeries are
highly variable and should only be considered in se-
- lected patients. Intestinal transplantation is indicated
mia because hypomagnesemia impairs parathyroid for patients who have developed life-threatening com-
hormone release and action. Oral magnesium replace- plications from intestinal failure or long-term PN ther-
apy. Some patients require liver transplantation sec- capacity to synthesize the protein. Thus, serum con-
ondary to end-stage liver disease from long-term PN centrations of proteins with a slow catabolic rate,
use. Intestinal transplants have been done with both such as albumin, gamma globulins, ceruloplasmin,
cadaveric donors and living donors. Patients require 1
life-long immunosuppression after transplantation. lipoproteins, are decreased. Malabsorption also oc-
The major post-transplant complications are acute curs in some small bowel diseases associated with
rejection, chronic rejection, cytomegalovirus enteri- protein-losing enteropathy. Loss of intestinal lym-
tis, and post-transplant lymphoproliferative disease phocytes results in lymphopenia and abnormalities
(caused by Epstein-Barr virus).11, 12 in cell-mediated immunity.
Clinical manifestations of protein-losing gastro-
enteropathy result mainly from hypoproteinemia
Protein-Losing Gastroenteropathy causing dependent edema, pleural and pericardial
effusions, malnutrition, and increased susceptibil-
Protein-losing gastroenteropathy encompass-
es multiple disorders in which excessive serum
because of malabsorption and excessive fecal loss of
protein is lost into the gastrointestinal tract.14, 15
serum-protein–bound nutrients. The diagnosis of pro-
Protein-losing gastroenteropathy is caused by one of
tein-losing gastroenteropathy should be considered in
two mechanisms: (1) mucosal damage with or without
patients with hypoalbuminemia who do not have other
ulcerations, or (2) increased lymphatic pressure within
causes such as malnutrition, proteinuria, or liver dis-
the stomach or small bowel due to lymphatic obstruc-
ease. The diagnosis is commonly made by measur-
tion or cardiovascular diseases causing high venous
ing fecal excretion of 1-antitrypsin by immunochemi-
pressure. Intestinal mucosal diseases causing erosions
cal methods, and calculating 1-antitrypsin clearance in
and ulcerations with protein-losing enteropathy in-
stool as follows:
-antitrypsin clearance = (fecal 1-antitrypsin
malignancies, and colitis. Mucosal 1
concentration)(stool volume/24 hours)/serum
diseases without ulcerations, but with loss of mucosal
-antitrypsin concentration
integrity and barrier function that can result in protein- 1
Clearance of 1-antitrypsin >24 ml/day in a pa-
losing gastroenteropathy, include celiac sprue, bacte-
tient without diarrhea and >56 ml/day in a patient
rial overgrowth, microscopic colitis, viral or parasitic
with diarrhea is abnormal. Patients with suspected
infections, amyloidosis, Menetrier’s disease, and
protein-losing gastropathy should have 1-antitrypsin
Helicobacter pylori gastritis. Primary lymphangiec-
clearance measured while taking proton pump inhib-
tasia is characterized by ectasia of enteric lymphat-
itors or other acid suppressants, since 1-antitrypsin
ics in children and young adults. It usually occurs spo-
is degraded by acidic gastric juice below pH 3.5.
radically, but in some cases appears to have a genetic
Treatment of protein-losing gastroenteropathy
etiology. Lymphatic obstruction and secondary lym-
should be focused if possible at correcting the under-
phangiectasia can be caused by lymphomas and other
lying disease.14, 15 Patients should be advised to ingest
malignancies, tuberculosis and other infections, retro-
a diet low in saturated fat and high in protein. Protein
-
intake should be increased to about 1.5–3.0 g/kg/day.
eases causing protein-losing gastroenteropathy include
Reduction of long-chain fatty acid intake reduces lym-
constrictive pericarditis, valvular heart diseases, and
cardiomyopathies. Repair of congenital heart defects
that are absorbed via the portal venous blood may
with the Fontan procedure has led to protein-losing
be helpful in those patients with lymphatic obstruc-
gastroenteropathy in about 10% of patients.
The loss of serum proteins in protein-losing gas-
with supplementation. If oral intake and supplemen-
troenteropathy is independent of molecular weight
tation do not meet nutritional needs, parenteral nutri-
or charge. Low serum levels of individual proteins
tion can be considered.14, 15
will occur if the extent of protein loss exceeds the
Food Allergies ly the cause of allergic rhinitis in the absence of other

symptoms. Exercise-induced anaphylaxis in adults is
-
triggered by foods in about one-third of cases. Risk
-
factors for the development of food allergies include
ducibly on exposure to a given food. 16-18
Food allergies
a family history of atopic disease and coexistent
must be distinguished from reactions to food that are
atopic dermatitis. The severity of an allergic reaction
not immunologically mediated, such as lactose intol-
erance, non-celiac gluten enteropathy or responses to
eaten, cooking or processing of food, co-ingestion of
toxins or pharmacologic agents in food.16-18 Food aller-
other foods, age, rapidity of food absorption, and as-
gies are most commonly due to an IgE-mediated reac-
sociated diseases, particularly asthma.
tion, although some diseases can be due to mixed IgE
Food allergy should be suspected in individuals
and non-IgE responses (e.g., eosinophilic gastroenteri-
who have anaphylaxis or other typical symptoms with-
tis; Figure 16.4) or cell-mediated immune mechanisms.
in minutes to hours after food ingestion, particularly
Individuals can develop immune sensitivity to food al-
if it occurs on more than one occasion. Children with
-
atopic dermatitis, enterocolitis, enteropathy, and aller-
gen, without demonstrating clinical symptoms when
gic proctocolitis, and children and adults with eosino-
ingesting that food. Such individuals should not be
philic esophagitis likely have food allergy. Mixed IgE and
considered as having a food allergy, since both the pres-
non-IgE mechanisms should be expected when gastro-
ence of clinical signs and symptoms and sensitization
intestinal symptoms are more chronic and not closely
are required.
associated with ingestion of the responsible food. For
The most common food allergy responses are cu-
example, children and adults with eosinophilic esopha-
taneous reactions such as IgE-mediated urticaria or
gitis typically improve with an elimination diet, but the
angioedema, atopic dermatitis or eczema, and allergic
causative role of IgE-mediated processes is unclear.
contact dermatitis. Food-induced anaphylaxis is an
Examples of non-IgE–mediated food reactions include
IgE-mediated, rapid-onset systemic reaction charac-
food- protein–induced enterocolitis or enteropathy
terized by cardiovascular collapse and/or respiratory
syndromes, allergic proctocolitis, and celiac disease.
distress due to airway obstruction or bronchocon-
Recommended methods for identifying the
striction. Immediate gastrointestinal hypersensitiv-
food(s) causing IgE-mediated food allergy in a patient
ity is an IgE-mediated food allergy in which upper GI
with suggestive symptoms include a skin prick test
symptoms such as vomiting occur within minutes and
-
lower GI symptoms such as diarrhea and cramping oc-
-
cur immediately or after several hours.16
-
Figure 16.4
termine, but studies suggest that it has increased in
Small Bowel Biopsy of Eosinophilic Gastroenteritis Showing
recent years. The prevalence of self-reported food
Mucosal Infiltration with Eosinophils
allergy in children and adults is much higher than
children, the most common foods causing allergy are

eggs, milk, peanuts, and tree nuts. In adults the foods
allergies to cow’s milk, egg, or wheat will eventually

tolerate these foods, but far fewer will tolerate tree
nuts or peanuts. Food allergies in adults can be due
to persistence of childhood allergies or new sensi-
tization after childhood. Food allergies that start in
adulthood are usually persistent. Food allergy is rare-
lergies, but must be administered by expert prac- intravenous steroids.

titioners who can provide symptomatic treatment She is 5 ft, 4 in tall and weighs 50 kg. Basal en-
including management of anaphylaxis. A response to ergy expenditure by the Harris-Benedict equation is
an elimination diet and oral food challenges may be 1240 kcal/day. Resting metabolic rate measured by
important in the diagnosis of non-IgE–mediated food indirect calorimetry is 1520 kcal/day. She is begun
allergies. Patch tests can be used to aid in the diagno- on PN, 1.5 L/day of a solution with 15% dextrose,
sis of food-induced contact dermatitis.16 4.25% amino acids, and 250 ml of a 10% lipid emul-
The mainstay of treatment of food allergies is sion. She develops hyperglycemia with a serum glu-
avoidance of ingesting the responsible foods. Patients cose 210 U/dl, which responds to the addition of 40
and/or caregivers must be taught how to read food U/day of human insulin to the PN.
labels carefully to identify offending foods. Several Crohn’s disease and ulcerative colitis are fre-
vaccines are produced in chick embryos or embry-
onic tissues and contain variable amounts of egg pro- several different mechanisms.19 Dietary intake is often
tein. Recommendations for giving vaccines to those reduced as many patients with IBD experience post-
with egg allergy vary depending on the amount of prandial pain and diarrhea that can lead to the avoid-
egg protein in the vaccine and the type of reaction ance of eating. Patients may be prescribed unneces-
experienced by the patient. Patients with potentially sarily restricted diets. Malabsorption is a frequent
life-threatening food allergy should wear medical complication of Crohn’s disease, particularly after in-
testinal resection. Patients with ileal resection of >100
card. Intramuscular epinephrine is the recommended
treatment for food-induced anaphylaxis and other to decreased enterohepatic circulation of bile salts.
life-threatening IgE-mediated food reactions. Delayed This leads to steatorrhea with the malabsorption of
administration of adequate intramuscular epineph- fat-soluble vitamins and divalent cations such as cal-
rine is an important factor in fatal anaphylaxis. Patients cium and magnesium. Low serum levels of vitamins A
with severe food allergy should be provided with an and D are found in about 25% of patients with Crohn’s
epinephrine autoinjector and instructed in its use. disease. With ileal resections of <100 cm, increased
Drugs such as antihistamines, steroids, and broncho- hepatic synthesis can compensate for bile acid mal-
dilators are only adjunctive treatment to appropriate absorption. A bile salt–induced secretory diarrhea
epinephrine therapy. results rather than steatorrhea. Ileal disease or re-
section also results in vitamin B12
IBD commonly leads to protein-losing enteropathy
Nutrition and Inflammatory Bowel Dis- that in addition to hypoalbuminemia causes exces-
ease (IBD) sive losses of nutrients that circulate in the plasma
as protein-bound complexes. Potassium, magnesium,
Case 3. A 40-year-old woman with a 15-year history
of ileal Crohn’s disease presents with a small bowel
obstruction. She has been on prednisolone 40 mg/day
-
for several months. Abdominal computed tomography
monly used to treat IBD can affect nutrient absorp-
tion. Sulfasalazine is a competitive inhibitor of folate
mass with partial obstruction of the right ureter. The
absorption; newer 5-aminosalicylic acid prepara-
terminal ileum is thickened. She undergoes surgery
tions do not affect folate absorption. Corticosteroids
with resection of 40 cm of terminal ileum. Her postop-
are an important factor in calcium malabsorption
erative course is complicated by spiking fevers to 103°F.
and osteoporosis. Osteoporosis is the most com-
Abdominal CT shows an anastomotic leak and an intra-
mon metabolic bone disease in IBD. The pathogen-
abdominal abscess that requires percutaneous drain-
protein and calorie malnutrition, adverse effects of

the right lower abdomen. The patient is continued on
cytokines on bone cells. Bile acid–binding resins are results.19 Meta-analyses have shown that the re-
used in some patients to control diarrhea, but can lead sponse of patients with active Crohn’s disease to
- enteral nutrition is inferior to that achieved with
ciencies of fat-soluble vitamins. Patients with ac- corticosteroids but probably better than placebo.
tive inflammatory bowel disease do not generally Enteral nutrition support has been particularly uti-
have greater energy expenditures and requirements lized in children with Crohn’s disease and growth
than would be predicted for healthy individuals by the failure. PN should be reserved for patients with
Harris-Benedict equation. Energy needs may, however, bowel obstruction, short bowel syndrome, high-
be increased in those individuals with abscesses or
- feeding. Studies suggest a limited role for primary
el disease. nutritional support in acute ulcerative colitis. Bowel
The goal of nutritional therapy for patients with rest will decrease the number of bowel movements,
IBD is to ensure adequate intake of all nutrients but does not lead to healing or remission. In patients
while modifying the diet to decrease gastrointestinal with IBD who are undergoing surgery, 7–14 days of
- preoperative nutritional support is recommended for
ciencies of vitamins and minerals that can be detected those who are severely malnourished.6
only by appropriate laboratory assays. Those at risk
should have periodic measurements of serum folate;
vitamin B12; vitamins A, D, and E; and mineral levels Obesity
-
Case 4. A 46-year-old woman presents with recur-
veloped. Appropriate supplementation and dietary
rent hematochezia. Her past medical history is re-
changes should then be initiated. For those patients
markable for polycystic ovarian syndrome, prediabe-
on long-term steroids, oral calcium supplementation
-
with vitamin D is recommended. Bisphosphonates are
emia. Her height is 5 ft, 6 in, and her weight is 249
added if the patient has osteoporosis.
pounds, giving her a BMI of 40.6 with a waist circum-
Calcium oxalate kidney stones are a common
ference of 45 inches and a waist-to-hip ratio of 1.2.
complication in patients with Crohn’s disease who
Colonoscopy reveals internal hemorrhoids and two 9
had ileal resection. Steatorrhea increases oxalate
mm sessile tubular adenomas. In addition to a high-
absorption by two mechanisms: (1) unabsorbed fat-
-
ty acids bind calcium, leading to a reduction in the
mend weight loss. She requests information regard-
formation of insoluble calcium oxalate, which leaves
ing diet, exercise, and pharmacologic intervention.
more oxalate free in solution for absorption, and (2)
When the patient returns for her follow-up appoint-
fatty acids and bile salts increase colonic permeability
ment 3 months later, her weight is up 8 pounds. She
to oxalate. A reduced-fat diet and calcium supplemen-
feels like she is failing because she has tried “every
tation are recommended to diminish oxalate absorp-
diet there is” and would like to have bariatric surgery.
tion and prevent hyperoxaluria and nephrolithiasis.
One year later, she presents to clinic and her weight
-
is 175 pounds, consistent with a 66% excess weight
tients with Crohn’s who have strictures and obstruc-
loss after a successful gastric bypass. Initially follow-
ing surgery, her pre-diabetes and hyperlipidemia re-
intake of vitamins and minerals due to the avoidance
solved. However, she was found to have an elevated
of fruits, vegetables, and whole grains. Fiber restric-
glucose despite dietary compliance. She reports mal-
tion is not necessary for the majority of patients with
aise, menstrual irregularity, nausea with vomiting
Crohn’s disease and should be recommended only to
new skin rash and a poorly healing scratch. Lab tests

Studies using enteral nutrition as primary
are remarkable for a negative urine pregnancy test
and a serum manganese level of 0.5 ng/ml (normal ty at both low and high BMIs. Normal BMI (18.5–24.9)
0.6-2.3 ng/ml). She admits to over-restricting to in- was associated with the lowest mortality, and an in-
crease her weight loss. Her intake of leafy green veg- crease in years of life lost due to obesity was noted at
etables is increased and her diet balanced with cor- a BMI >25. In contrast, the increase in years of life lost
rection of her manganese level. due to obesity was not seen in black men until they
Understanding the pathogenesis, health implica- reached a BMI of 32–33 and in black women until a
tions, and treatment of obesity is of great importance BMI of 37–38. Subsequent studies revealed that Asian
- populations develop metabolic complications of obe-
vances have emphasized that the GI tract, gut-derived sity at a BMI of 23–24.24 Of note, in middle-aged white
hormones, and the gut microbiome are key regulators men, a recent upward shift in healthier BMI has been
of food intake and energy homeostasis. Obesity plays observed, suggesting a changing relationship between
an important role in the pathogenesis of common di- BMI and health risks.25
Hispanic populations were not published until 2006
esophageal adenocarcinoma, colonic neoplasms, non- and, therefore, information on the relationships be-
alcoholic fatty liver disease, and others. This section tween BMI and mortality in that population is incom-
- plete.26
ogy, the role of the GI tract in the regulation of food Visceral fat or central adiposity is particularly im-
intake, and weight management strategies, including portant for the development of obesity-related comor-
the roles of surgical and endoscopic interventions. bid diseases.27 Measures of visceral obesity, such as a
waist circumference and more recently the waist-to-
hip ratio, waist-to-height ratio, and waist-to-thigh ra-
Definition and Risk Stratification tio, may be more effective in predicting obesity-relat-
ed mortality than BMI alone. At any BMI, abnormally
high visceral body fat represents an additive risk for
obesity-related complications. Visceral adiposity is of
particular importance as a risk factor for type 2 dia-
Metropolitan Life tables.20, 21 IBW is the weight at
betes, hypertension, and cardiovascular disease. In a
a given height that is associated with lowest risk of
recent study by Wise et al., waist-to-hip ratio, weight
morbidity and mortality, derived from the 1979 Build
gain, and increasing adult BMI were better predic-
Study that pooled data from 4.2 million whites from
tors of the risk of developing colon polyps in African
the United States and Canada. Another commonly
American women than BMI alone.28 The optimal sur-
used method is to stratify obesity based on an indi-
2 rogate measure of visceral fat for the general popula-
tion remains debated. Objective measures, including
The prevalence of obesity varies considerably
computed tomography and magnetic resonance im-
in different ethnic groups. For example, Mexican
aging, accurately assess visceral fat stores, but are too
American men have a higher prevalence of obesity
cumbersome and costly for routine clinical use.
compared to other males. Hispanic women are 21%
and African American women 51% more likely to be
obese than white females. The prevalence of obesity
for Hispanic women increased from 39.7% to 45.1%
Pathogenesis
from 1999 to 2008. Native Americans also have a Obesity is a disease process with genetic, environ-
high rate of obesity.22 mental, and behavioral components.29 Based on heri-
It is important to recognize that there are racial tability studies, genetics are thought to account for
differences in the association between BMI and mor- approximately 40–70% of a person’s weight, but the
tality.23 In 2003, investigators determined the years interplay between the genetic milieu and the environ-
of life lost secondary to obesity. In white populations, a ment is incompletely understood and ever evolving.30
classic U-shaped curve was seen, with excess mortali-
food intake is increased or decreased over time to 33

The incretin hormones responsible for
maintain a stable weight or reserve of stored energy in this effect are GLP-1 and GIP. These are short-acting
the form of body fat. The primary satiety signals from gut hormones that are rapidly degraded by the en-
the gut include cholecystokinin (CCK), PYY, pancreatic zyme dipeptidyl peptidase-4 (DPP-4). GLP-1 is one of
polypeptide (PP), glucagon-like peptide 1 (GLP-1), the most powerful incretins in humans, and manipu-
and oxyntomodulin (OXM). Other important satiety lation of the GLP-1 system forms the basis for many
signals include amylin, which is co-secreted with in- new therapies directed at the treatment of diabetes.
sulin from the pancreas, and glucose-dependent in- Novel agents for diabetes management include the
sulinotropic polypeptide (GIP), previously known as GLP-1 receptor agonist exenatide, DPP-4 inhibitors
gastric inhibitory peptide, which is released from the such as sitagliptin, and the amylin agonist pramlint-
K-cell in the proximal small bowel (primarily duode- ide.34
num and jejunum).31 Recently, the microbiome of gut bacteria has been
In the fasting state, the oxyntic cells in the fundus shown to have a role in energy uptake and energy
of the stomach produce high levels of the hormone storage.35 Gut bacteria reportedly facilitate the extrac-
ghrelin, which is a potent stimulator of hunger. Once tion of additional calories from indigestible dietary
food is ingested, the taste receptors determine palat- substances, and increase the activity of lipoprotein
ability, and secrete hormones as well as neurochemi- lipase, facilitating the storage of extra calories as fat,
cals that are transmitted to the central nervous sys- thereby contributing to weight gain.
tem, signaling continued food intake when the item is Gut bacteria strains have also been implicated as
deemed as safe or desirable. Following ingestion and -
mixing with salivary enzymes, the food is transferred mation that underlies the metabolic syndrome and
from the oral cavity to the stomach where digestion obesity. Higher levels of bacterial lipopolysaccharide
continues. In the stomach, food is mechanically bro- from gram-negative bacteria were found in the intes-
ken down into smaller particles. Gastric distension tinal contents of obese animals and humans.36 When
and the presence of intraluminal nutrients result in a obese adults with fatty liver were treated with anti-
decline in ghrelin levels. biotics targeting gram-negative bacteria, endotoxin
The smaller food particles enter the small bow- levels dropped and hepatic steatosis improved.37 The
el, and nutrients such as fat and protein stimulate the relationship between obesity and gut bacteria is a dy-
release of CCK, a strong satiety signal leading to meal namic one, as other studies have found that weight
termination. CCK release also slows gastric emptying -
to allow more time for the mechanical breakdown of tion of the microbiota of formerly obese participants
the ingested food, lengthens small bowel transit time to one resembling lean controls.38 One study found
to allow for nutrient absorption, and stimulates pan- that prebiotic supplementation altered gut bacteria
creatic enzyme secretion and gallbladder contraction. and increased GLP-1 and PYY, favoring satiety.39
CCK is distributed throughout the small bowel, but the Insulin from the pancreas and leptin from adipo-
majority is found in the duodenum and jejunum. cytes are the primary adiposity signals forming a
Other important hormones released by the pres- negative feedback loop that down-regulates food in-
ence of intraluminal nutrients are GLP-1, PP, PYY, and take at the level of the hypothalamus. Leptin is secret-
OXM, each in direct proportion to the calories con- ed in direct proportion to the amount of fat present.
sumed. They regulate short-term food intake by ini- Insulin release is based on the incretin response. In
tiating satiety, and possibly control body weight by obesity, there is dysregulation of the neurohormonal
modulating long-term food intake.32 regulation of energy balance leading to an enlarged
When glucose is administered orally, there is a adipocyte, which oversecretes hormones, proteins,
greater than expected insulin response as compared procoagulants, and cytokines such as leptin. Both
to that which occurs when the same amount of glu- insulin and leptin resistance occur in obesity, uncou-
cose is given intravenously. This is known as the in- pling energy expenditure from energy intake. Based
in modest weight loss when a singular intervention.

obesity is not the absence of regulation, but rather the When exercise was combined with dietary inter-
body’s defense of a higher body weight.40 vention, individuals that exercised lost more weight
than those who did not, regardless of diet. In the in-
terventions, weight loss increased as the exercise in-
Treatment tensity increased. Physical activity recommendations
based on the 2005 MyPyramid and the 2008 Physical
Options for dietary management of obesity include
Activity Guidelines for Americans are noted in Table
16.6. The activity can be done at one time or divided
low-calorie diets, and very low-calorie diets (Table 50, 51
16.4). 41 Regardless of the unique features of individ-
The role for prebiotics, probiotics, and antibiotic
ual diets, direct comparisons have had similar out-
-
comes at 1 year when weight loss was the primary
terventions remain uncertain. Small studies suggest
endpoint. It is important to note that there is a high
that gut microbes respond favorably to dietary ma-
recidivism rate with dietary management, with nearly
nipulation, weight loss, prebiotic and probiotic supple-
95% weight regain after 5 years in large population
mentation, as well as antibiotic therapy, and additional
studies.42 Weight loss of 10% body weight has been
larger trials are ongoing.52
shown to reduce obesity-related complications. 43
Surgical interventions for the treatment of obesity
Recent data suggest that consumption of excessive en-
include gastric banding, gastric bypass, and sleeve gas-
ergy may increase oxidant stress in the endoplasmic
trectomy with or without duodenal switch.53 Gastric
reticulum, 44 -
banding is a purely restrictive surgery where a band
cial effects independent of weight loss.
is placed around the upper stomach to restrict the to-
Pharmacologic therapy is indicated for over-
tal volume of food consumed. Sleeve gastrectomy is
-
also a restrictive procedure, but may have metabolic
ciated with obesity-related comorbidities. There are
-
seven classes of drugs approved for short-term use
section of the ghrelin-producing oxyntic cells. Gastric
(Table 16.5).45 Of note, sibutramine was withdrawn
bypass and the sleeve gastrectomy with duodenal
from the European market and in the U.S. due to in-
switch are combination restrictive-malabsorptive
creased adverse cardiovascular outcomes in a ma-
procedures. Weight loss success after surgery is de-
jor clinical trial examining the use of sibutramine in
high risk patients.46,47 Two new drugs were approved
calculated as weight lost/(preoperative weight - IBW)
for weight control in 2012. 48 Lorcaserin is a selective
and is required data to report weight-loss outcomes in
agonist of the serotonin (5-hydroytryptamine) 2C (5-
the surgical literature. In general, weight loss following
HT2c
surgical procedures approximates 40–70% EWL. There
phentermine plus extended-release topiramate. Both
medications reduce appetite thus promoting weight
following bariatric surgery that favor satiety despite
ongoing weight loss and may account for the ability to
as non-diabetic populations. Future drug therapy tar-
gets include newer sympathomimetic agents such as
PYY levels are higher in association with lower ghrelin
tesofensine, endocannabinoid receptor antagonists
levels. These changes modify the normal adaptive re-
(i.e., taranabant), experimental drugs targeting regu-
sponse, i.e., drive to eat, when weight loss occurs.54
latory pathways (e.g., the GLP-1 agonist liraglutide),
Even following a successful weight loss surgery,
combination drug therapy (i.e., a buproprion/naltrex-
20–30% of individuals will have 100% weight regain
one combination), and herbal preparations.
after 5–10 years. In cases of weight regain, it is es-
The role of exercise in weight loss has been ex-
sential to separate mechanical failure of the surgery
amined in a recent Cochrane review that included 43
as a cause versus dietary and behavioral noncompli-
studies with 3476 participants.49 Exercise resulted
Table 16.4
Dietary Interventions for Medical Weight Management
Expected
Intervention Features Example diet Limits
weight loss
Micronutrient and vitamin
deficiency, fluid and
800–1000 kcal/day total electrolyte abnormalities
Very low-calorie diet Optifast 3–8 lb/week
caloric intake unless supplemented; du-
ration 16 weeks; requires
physician monitoring
Dietary approach to
500 kcal/day deficit; all
Balanced deficit diet stop hypertension Poor long-term adherence 1–2 lb/week
food groups included
(DASH)
May need to monitor
500 kcal/day deficit;
for nutrient and vitamin
Low-calorie diet (LCD) specific food groups Low-fat diet 1–2 lb/week
deficiencies depending on
restricted
food restricted
No clinical trials; one
publication in abstract
500 kcal/day deficit,
Specialized LCD South Beach form; rare micronutrient 1–2 lb/week
e.g., low glycemic index
deficiency if certain foods
overrestricted
Poor long-term adherence;
Meal replacement 500–1000 kcal/day
Slimfast nutritional status should be 1–2 lb/week
options deficit
monitored
ance. Presently, surgical revision is the treatment of examples of devices under study. Delineation of roles
choice when mechanical failure is the primary cause for the bariatric surgeon and the gastroenterologist
of weight regain, whereas dietary, pharmacologic, be- as well as credentialing for these procedures is also
havioral, and endoscopic interventions are more ap- under evaluation.
propriate in other cases. Criteria for treatment algo-
rithms identifying the optimal intervention for a given
Eating Disorders
behavioral challenges, there is a growing recognition
that aberrant eating patterns and eating disorders
in the
may complicate the clinical management of patients
fourth edition, includes anorexia nervosa
who regain weight after bariatric surgery.
(AN), bulimia nervosa (BN), and eating disorders not
In the future, endoscopic bariatric interventions 56
will likely increase the role of gastroenterologists in
due for publication until mid-2013, and is anticipated
obesity management. 55 These procedures have been
-
-
tions. The lifetime prevalence of all eating disorders
dures, (2) bridge therapies, (3) preemptive therapies,
is approximately 5%. Eating disorders typically pres-
(4) metabolic procedures, and (5) primary endolu-
ent between ages 10–19 years, but can occur in adult-
minal bariatric surgical procedures through a natural
and mortality, and are best managed by a multi-disci-

plinary team including physicians, psychotherapists, outlined in Table 16.9. Nutritional complications of AN
and nutritionists with expertise in these illnesses. are common, but protein-calorie malnutrition should
The increased recognition of EDNOS in presurgical
bariatric patients as well as the emergence of AN as the refeeding syndrome, which can be associated
and BN in postoperative bariatric patients has sig- with sudden cardiac death, acute pulmonary edema,
- and other serious consequences. A soft diet providing
troenterologists are often involved in the nutritional 5–10 kcal/kg/day in multiple small portions over the
management and evaluation of the gastrointestinal day is the initial management and should be advanced
symptoms associated with EDs, an in-depth review as tolerated. Supplementation with thiamine, a mul-
is beyond the scope of this discussion. For detailed tivitamin with minerals and vitamin B complex, and
information regarding the management of patients high-phosphorus–containing foods (i.e., milk-based
with eating disorders.57 foods) should be initiated upon admission. Enteral or
parenteral nutrition support is reserved for patients
who have failed multiple previous attempts at dietary
Anorexia Nervosa treatment, weigh <60% of IBW, or are noncompliant
with standard therapy including oral feedings. The
AN is a serious condition that affects 0.5–1% of wom-
initial caloric intake should be no more than 20–25
en and 0.3% of men and has a high crude mortality
kcal/kg and 1–1.5 g of protein/kg/day. Energy intake
rate of 5.6% per decade of illness. AN is characterized
should never exceed 70–80 kcal/kg, carbohydrate
by a refusal to maintain body weight at or above a
intake should be <7 mg/kg/min, and protein should
minimally normal weight for age and height, intense
not be more than 1.5–1.7 g/kg/day. Full recovery with
fear of gaining weight, and a disturbance in the way
weight restoration has only been reported to occur
in which one’s body weight or shape is perceived.
in 30–57% of individuals. In adults, most treatment
Screening tools, such as the SCOFF test (Table 16.8)
guidelines are based on expert opinion rather than
and the Eating Attitudes Test, are widely available for
controlled clinical trials. Pharmacologic interven-
clinical use to detect eating disorders when suspect-
tions generally have had poor response; however, one
ed. Extremely low body weight separates individuals
with AN binge-purging type from those with bulimia
symptoms of obsessiveness with olanzapine ther-
nervosa. Gastroenterological manifestations of AN are
apy for participants in a day-treatment program. 58
Table 16.5
FDA-Approved Drug Classes for Medical Weight Management
Polytherapy Qsymia Increased risk of teratogenicity and increased heart rate
Monitor for fat-soluble vitamin deficiencies; co-administer with

Drugs that alter fat absorption Orlistat
a multivitamin
Antidepressants Buproprion Increased risk of side effects
Antiepileptic Zonisamide Increased risk of side effects
Diabetes medications associated with Liraglutide

FDA approved for use in diabetic patient populations
weight loss
Serotonin receptor Lorcaserin Possible increased risk of breast cancer
Sympathomimetics Phentermine Possible risk of addiction

Table 16.6 Bulimia Nervosa

Physical Activity Guidelines
BN is characterized by repeated binge eating fol-
lowed by inappropriate compensatory behaviors to
Physical activity recommenda-
counteract the food intake, associated with the feel-
Group tions for daily moderate physical
ings of loss of control. BN is seen in 1% of women and
activity*
0.1% men in the United States and western Europe.
All individuals, to Approximately 25–30% of bulimics have a history of
30 minutes/day
reduce risks AN. Individuals with BN, however, are generally nor-
To lose weight 60–90 minutes/day mal weight or overweight. Compensatory behaviors
aimed at preventing weight gain include self-induced
To prevent weight
30–60 minutes/day vomiting, laxative or diuretic abuse, fasting, and ex-
regain
cessive exercise. 59 In contrast to AN, pharmacologic
For children 60 minutes/day intervention in combination with cognitive behavior
therapy is the treatment of choice. A number of tri-
*Activity may be divided into smaller segments with equal health
benefits. Adapted from www.MyPyramid.gov. als have shown an improvement in patients with
bulimia nervosa who have been treated with fluox-
Clinical management and supportive psychotherapy etine. The tricyclic antidepressants, such as de-
sipramine, amitriptyline, and bupropion, are also
for adult patients with AN, whereas family-based more effective than placebo at decreasing binging
and vomiting. The better safety and side effect profile
with AN. For relapse prevention, cognitive behavioral of the selective serotonin reuptake inhibitors like
therapy may be more effective for maintaining a BMI fluoxetine make these drugs more attractive for
>17.5 kg/m2 without binge eating or purging. first-line therapy.60 Combination behavioral and
Table 16.7
Endoscopic Bariatric Procedures in Clinical Trials*
Endoluminal bariatric
Indication Features Examples
procedures
Restorative obesity surgery,
Reduce pouch size, repair
Revision procedures Weight regain, fistula repair endoscopic (ROSE), StomaphyX,
anastomosis
sclerotherapy
Bridge therapy Short-term weight loss Removable device Intragastric balloon
Early intervention, high risk Safe for early use, durability

Preemptive therapies Endoscopic-guided stapler
populations and repeatability important
Focuses on modifying gut hor-
Safety profile of medical
Metabolic procedures mones to treat comorbidities, Implanted duodenal sleeves
therapy
i.e., type 2 diabetes
Safety and outcomes must
Endoluminal bariatric Natural orifice bariatric proce- Primary obesity surgery, endo-
approximate laparoscopic
procedures dures scopic (POSE)
surgery
*Courtesy of C. Thompson; used with permission.
Table 16.8 drug therapy has been shown to be effective in de-

SCOFF Screening Test for Eating Disorders creasing binge eating episodes, reducing purging,
and lessening psychological symptoms, and results
SCOFF questionnaire in fewer relapses. In spite of these improvements
1. Do you make yourself Sick because you feel uncomfort- with treatment, BN remains a chronic disease with
ably full? a high relapse rate.
2. Do you worry you have lost Control over how much you
eat?
3. Have you recently lost more than One stone’s worth of Eating Disorders Not Otherwise Specified
weight (14 pounds) in a 3-month period?
EDNOS comprises almost 50% of the population di-
4. Do you believe yourself to be Fat when others say you
agnosed with aberrant eating patterns, and includes
are too thin?
disordered eating patterns that fail to meet the diag-
5. Would you say that Food dominates your life?
nostic criteria for AN and BN. 61, 62
patterns, binge eating disorder (BED) and night eat-
Answering yes to two of these questions is a strong indicator
ing syndrome, are becoming increasingly supported
of an eating disorder.
by clinical data as distinct clinical syndromes. BED
From Morgan, JF, Reid, F, Lacey, JH. The SCOFF questionnaire: has a prevalence of 0.7–3.0% in the USA. Unlike BN,
assessment of a new screening tool for eating disorders. Br Med J BED is associated with binge eating in the absence of
1999;319:1467. purging; affected individuals are often overweight or
obese. This syndrome may occur in patients undergo-
Table 16.9
Gastrointestinal Signs and Symptoms Associated with Eating Disorders
Common gastrointestinal symptoms Serious gastrointestinal and nutrition complications

associated with eating disorders associated with eating disorders
Anorexia
nervosa
hyponatremia
10. Unexplained diarrhea

11. Biliary colic
10. Olgivie’s syndrome
12. Mouth/tongue soreness
11. Cathartic colon
13. Dental decay
12. Refeeding syndrome
14. Pancreatitis, unexplained
13. Pancreatitis
15. Abnormal liver function tests
Bulimia
-
cially sepsis), antibiotics, micronutrient deficiency,
tential risk factor for weight regain. Similar to BN, BED
sorbitol-containing medication elixirs, magnesium or
and other forms of EDNOS respond to pharmacologic
phosphate salt supplements, and C. difficile diarrhea
intervention, and the greatest challenge is the pre-
are among the more common reasons why patients
vention of relapse. Studies are in progress to identify
on tube feeding have diarrhea. Try to avoid jumping
optimal treatment regimens and interventions for the
at the answer to “stop the tube feeding” without re-
bariatric patient with an associated eating disorder.
viewing these other potential elements carefully.
Resist the urge to hold the tube feeding when given
Editor’s pick one isolated, high residual in an otherwise well toler-
ated feeding regimen. Usually they are looking for
you to consider repositioning the patient, reduce se-
Pearls and Pitfalls dation, consider a prokinetic, and remeasure the re-
for the Board Exam sidual. Residual volumes < 250-500cc are considered
Recognizing the signs of a micronutrient deficiency is safe.
good for a question or two – it’s worth memorizing Obese patients, septic patients, and patients with
Table 16.1 and Table 16.2, or the corresponding tables triglycerides >400mg/dl can have intralipid parenteral
in a major GI text the week of the exam! infusions held the first week or two of parenteral nu-
Think zinc! Chronic diarrhea leads to zinc deficiency, trition support.
and zinc deficiency aggravates diarrhea. Buzzwords Recognize the paradigm shift in feeding pancreatitis
that may enhance the case presentation of zinc defi- patients. This is likely fodder for a board’s question.
ciency include alopecia, dysgeusia (altered or dimin- Feeding mild pancreatitis cases earlier - by initiating
ished taste), acrodermatitis or bullous pustular der- low fat solids when the acute pain subsides - is pre-
matitis, and low alkaline phosphatase. Of interest, ferred over advancing slowly thru clear liquids. Feed-
night blindness usually makes you think of vitamin A ing enterally in acute severe pancreatitis is preferred
deficiency, but it is associated with zinc deficiency as over parenteral feedings. Moreover, at least two clin-
well! ical trials support that gastric feedings may be as well
If the case has a mechanism for malnutrition or mal- tolerated as small bowel feedings in pancreatitis.
absorption, and a spectrum of symptoms includes Medium chain triglycerides can supplement calories,
nystagmus, peripheral neuropathy (especially sym- but do not provide essential fatty acids.
metric, distal, burning), and ataxia – think thiamine, Patients have to have a colon in order to get calcium-
even without the short term memory issues and con- oxalate kidney stones as a consequence of fat malab-
fabulation (Wernicke’s), or heart failure elements (wet sorption. The Boards love the physiology of calcium-
beriberi). Potential scenarios could include alcoholic oxalate stone formation in crohn’s disease, so this is
malnutrition, severe crohn’s, hyperemesis gravidarum, well worth 5 minutes in a major GI text to review!
or bariatric surgery as the underlying case disorder. Gastric bypass surgery (gastrojejunostomy or gastric
Isolated vitamin D 25-OH deficiency is not a sign of sleeve with duodenal switch) employs elements of
malabsorption; it is far more likely to reflect inade- restriction, and elements of malabsorption, but also
quate sunlight exposure. affects gut endocrine and paracrine function lead-
A normal INR or protime (you will not be given a vi- ing to reduced appetite signaling, increased satiety
tamin K “level”) does not rule out fat soluble vitamin signaling, and improved glucose control even before
deficiencies. As long as the patient has a colon, they significant weight loss.
have an endogenous source of vitamin K. The most common foods associated with IgE medi-
When patients on tube feeding have diarrhea, look ated food allergies include milk, peanuts, tree nuts,
very hard for secondary causes of diarrhea, rather shellfish, fish, soy, eggs, wheat.
than blame the tube feeding. Critical illness (espe- Know the difference between the clinical presenta-
tions of scombroid, ciguatera toxin poisoning, and IgE References:

mediated food allergies. The food poisoning/allergic 1. Morgan SL WR. Macronutrients. Fundamentals of Clini-
reaction scenarios are classics! cal Nutrition, 2nd edition. St. Louis, MO: Mosby-Year
Book, 1998:113-16.
Don’t miss the diagnosis of anorexia nervosa because
2. Klein S JK. The Malnourished patient: nutritional assess-
they throw you a delayed gastric emptying scan. That
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Treatment approach in anorexia cases will always Liver Disease, 7th edition. Philadelphia, PA: Saunders,
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Clinical Nutrition, 2nd edition. St. Louis, MO: Mosby-Year
management answer in these cases is not going to
Book, 1998:174-87.
be dependent upon drug therapy. This is in contrast
4. Gibson RS. Anthropometric assessment of body compo-
to bulimia, in which pharmacologic intervention has a sition and laboratory assessment of body composition.
higher success rate, although still often coupled with Principles of Nutritional Assessment. New York, NY: Ox-
psychological therapy. ford University Press, 1990:187-208, 263-284.
5. Souba WW. Nutrition support. N Engl J Med 1997;336:41-
48.
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cine and American Society for Parenteral and Enteral
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CHAPTER 17
Issues in Pediatric Gastroenterology
Learning Objectives
1. Recognize the common clinical problems encountered by pediatric gastroenterologists.
2. Review the unique pathophysiology and clinical issues present in children and adolescents with gastrointestinal disease.
3. Identify the clinical manifestations and therapies for the commonly encountered clinical problems (e.g., constipation, encopresis, chronic
abdominal pain, vomiting/gastroesophageal reflux, inflammatory bowel disease, and liver disease).
Introduction
-
ulated by >3000 physicians around the world who dedicate themselves exclusively to the care of newborns,
children, and adolescents who are affected by disorders of the gastrointestinal (GI) system, the liver, pancreas
and nutrition. While there are adult-onset and pediatric-onset GI disorders that share etiologies and com-
mon clinical features, the pediatric age group often poses additional diagnostic and therapeutic challenges.
Growth, development, and the psychosocial impact of disease on both the patient and their family are just
some of the unique management issues that will be highlighted in this chapter while also focusing on impor-
tant diagnostic considerations that should be considered when caring for children and adolescents with GI
disorders.
Recurrent Abdominal Pain of Childhood

interferes with normal activity and persists for >3 months.1 Recurrent or chronic abdominal pain has been
reported in up to 10–15% of school-age children and is one of the most common reasons for referral to a
pediatric gastroenterologist.2–5 Recurrent abdominal pain (RAP) of childhood has been coined as a diagnostic
term for children with chronic pain.2–4,6,7 The etiology of RAP includes organic as well as functional disorders
(Table 17.1). The long-term outcome of RAP can be variable; it has been shown that approximately 50% of
children with RAP of childhood go on to develop chronic abdominal pain as adults, and may also complain of
headaches and other chronic pain disorders.8
513
TABLE 17.1 TABLE 17.2

Etiologies of Pediatric Chronic Abdominal Pain Suggested Screening Investigations in Children with Recur-
rent Abdominal Pain
Complete blood counts

Celiac disease
Serum chemistries
Crohn’s disease
Acute phase reactants: erythrocyte sedimentation rate and/or
Constipation
C-reactive protein
Organic Infectious (parasitic)
Celiac serology: total IgA, tissue transglutaminase, and/or
Lactose or other food intolerance*
endomysial antibodies
Acid-peptic disorders including GERD
Consider fecal inflammatory markers: lactoferrin and/or
Dysmenorrhea/mittelschmerz
calprotectin
Ova and parasite testing
Functional dyspepsia Consider lactose breath testing
Functional abdominal pain
Functional nal pain. It is important for clinicians to recognize
Functional constipation
Aerophagia
Abdominal migraine quickly provide a tangible answer for long-stand-
ing symptoms, plus professional fears of litigation
GERD, gastroesophageal reflux disease. for “missing something.” Such concerns can lead to
*Often overdiagnosed; should prompt consideration of primary small
bowel pathology (see text).
multiple tests can add to the psychosocial stress of
The term functional is applied when structural, chronic symptoms and provide results that often
are unrelated to the presenting symptom or have no
clinical relevance.
- The planned use of simple screening laboratory
studies can reassure the patient and the family while
- augmenting the history and physical exam in helping
cially when it is present at a distance from the umbil- the clinician differentiate between organic and func-
ical region; vomiting; pain awakening the child from tional symptoms (Table 17.2). Inexpensive and easily
sleep; weight loss or growth failure; rectal bleeding; available diagnostic tests such as complete blood cell
constitutional symptoms (fevers, rash, arthralgias); count, erythrocyte sedimentation rate and/or C-re-
- active protein chemistry panel, liver function studies,
- and thyroid function can be obtained. Celiac serology
testing is also prudent when evaluating a patient with
growth disturbance, abdominal mass, aphthous chronic GI symptoms.11
stomatitis, joint swelling, or perianal abnormalities, Recent studies have suggested that measuring
warrant an evaluation to search for organic causes of the fecal levels of proteins that are associated with
pain, whereas the absence of such signs and symp-
toms is highly suggestive of a functional disorder.9,10 these patients. Tests for fecal lactoferrin and calpro-
tectin levels are now commercially available and can
12
Investigation In patients where the pain is associated with diar-

rhea, stool examination for blood, ova, and parasites
Careful history and physical exam with judicious lab-
can be considered.
Breath hydrogen testing for lactose malabsorp-
diagnose the etiology of pediatric recurrent abdomi-
Chapter 17 — Issues in Pediatric Gastroenterology 515
tion is also available, but the cause-effect relation- The main goal of the therapy is to reestablish a
ship between lactose intolerance and symptoms normal daily life for the patient and the family. Envi-
is far from proven. When lactose malabsorption is -
found during childhood, the clinician should at least cessful treatment of functional abdominal pain. It
consider whether this is truly primary or may pos- is important to try and identify and whenever and
sibly be secondary to another small bowel process wherever possible relieve stressors that provoke
such as Celiac disease. It should also be kept in mind and/or perpetuate the pain. The family should be
that the empiric diagnosis of lactose intolerance can discouraged from reinforcing the symptoms and
lead to over-diagnosis and the needless elimination poor coping strategies by allowing the child to miss
of dairy foods, with adverse impact on dietary intake school and sport activities. Cognitive behavioral and
of calcium and vitamin D.13 15
Additional evaluations such as endoscopy and When this conservative approach fails, drug
imaging studies (ultrasound, radiography) should therapy can be considered, especially when symp-
toms are interfering with a satisfactory quality of
outlined approach to evaluating the pediatric patient life. Since pain is transmitted via serotonergic path-
with recurrent abdominal pain. For example, in the ways, low-dose tricyclic antidepressants (TCAs) such
presence of mostly dyspeptic symptoms, a negative as amitriptyline (0.2–0.4 mg/kg/day, 5–20 mg/day)
esophagogastroduodenoscopy can be informative, or low dose selective serotonin receptors inhibitors
particularly if a short-term trial of antisecretory em- (SSRI’s) can be considered. It is worth noting that
piric therapy fails, or if symptoms reappear promptly a recent randomized prospective trial did not show
after cessation of treatment. In such cases, the ab- TCAs to perform better than education and reas-
sence of mucosal disease at endoscopy strongly sup- surance in pediatric recurrent pain patients newly
ports a diagnosis of functional dyspepsia. referred to the gastroenterologist.16 Accordingly,
reserving drug intervention for those who do not
respond to such conservative interventions seems
Treatment prudent.
-
-
most a week after starting treatment. These agents
dressed later in this chapter. Improved understand-
appear especially effective in diarrhea-predominant
ing of the nature of functional GI disorders (FGID)
patients. Smooth muscle relaxants, such as hyoscya-
has brought an increase in the pharmacologic and
mine and dicyclomine, can be effective when used
nonmedical therapies used in these conditions. Ap-
on an as-needed basis up to 3 times a day whenever
proaching FGID within the framework of a biologic-
the symptoms are present, but these medications be-
psychosocial model has greatly advanced therapy for
come less effective with chronic use.
these conditions. It is clear that the initial treatment
of FGID is based on acknowledging the child’s pain is
real and not imagined but that the pain is not being
caused by a serious underlying disease. An effective Functional Defecation Disorders
physician-patient-family relationship is the corner-
stone of effective treatment. It is essential to reassure
the family and the patient that the physician believes Functional Constipation and Encopresis
that the symptoms are “real” and not “in the child’s
Understanding the development of a normal stooling
pattern is important when assessing infants and chil-
examination, and laboratory tests. Such validation,
dren for disorders of defecation. Stool frequency in
education, and reassurance can be very effective and
newborns averages 4–6 stools per day, and declines
may explain the placebo response observed in stud-
gradually to a mean of 1.2 stools per day by age 4
ies of pediatric FGID therapy.14
years. Stool frequency and consistency varies with While encopresis may be associated with diarrheal
diet and feeding pattern. illness, neurologic abnormalities, or postoperative
Breast-fed babies are known to have widely conditions, in the overwhelming majority of cases
variable patterns of defecation; they may have any- encopresis results from chronic constipation with
thing between 8–10 bowel movements per day and
1 bowel movement per week. The normality of these
that have a yellow color, a seedy appearance, often Functional Nonretentive Fecal Soiling
-
Functional nonretentive fecal soiling is a more re-
cant effort or pain. Although parents commonly be-
come concerned about frequent or infrequent bow-
as an emotional disorder usually affecting school-
el movements, reassurance that the baby is thriving
age children, characterized by a chronic (>3 month)
and has a normal examination, including a soft,
history of defecating in socially inappropriate places
nondistended abdomen, is often all that is needed.
and situations, in the absence of fecal retention and
Formula-fed infants usually have less frequent and
without any structural or biochemical abnormalities.
sometimes more-formed stools than do breast-fed
These patients are not constipated, since they have
infants.
bowel movements daily and often evacuate com-
Up to 25% of children who are sent to a pediatric
pletely in their underwear, and have no other GI signs
gastroenterologist are referred because of concerns
or symptoms. Stools are characteristically described as
of constipation. While chronic childhood constipa-
“pasty” or “soft,” and there is no history of straining.
-
These children have normal sensorimotor function of
the anorectum and pelvic musculature. Management
than three times per week, children who defecate
often involves assistance with fecal consistency, reas-
more often than three times per week, but produce
surance, avoidance of anorectal invasion, and referral
to a clinical psychologist or psychiatrist experienced in
posturing and/or experience pain with defecation
treating children with this problem.
should also be considered constipated.
One of the most prevalent causes of constipation
in toddlers and school-age children is functional fecal
Evaluation of Disorders of Defecation
retention. Stool withholding during toilet training, or
during school hours or active play when the child Evaluation of pediatric patients with constipation
does not take time to defecate, can lead to painful or other disorders of defecation should begin with
defecation. To avoid further pain, the child will avoid a thorough history and physical exam. In fact, a de-
tailed history and a thorough clinical examination
muscles and assuming retentive postures (stiffening are often all that is needed to achieve a correct di-
with grimace or other facial expressions, stiffening agnosis of a functional defecation disorder. In the
or crossing legs while on tiptoes, or squatting with majority of cases, minimal laboratory and invasive
feet pressed against the perineum). This cycle of investigations are warranted.17
painful defecation and stool withholding can result The evaluation of children with constipation
- -
ary megarectum, and can lead to irritability, abdomi- frequent but potential organic causes listed in Table
nal pain, early satiety with reduced food intake, and 17.3. Items to be determined are age of onset, stool
frequency and size, diet (keeping in mind the role
Children who have encopresis pass bowel move- -
ments, voluntarily or involuntarily, in inappropriate sistency is frequently overestimated), observations
places (e.g., underwear, pants) but not in the toilet. pertaining to the child’s ability and urge to defecate,
TABLE 17.3 tion in almost 10% of cases) should be considered. A

Main Organic Causes of Constipation distended abdomen increases the risk of conditions
such as HD or malabsorption syndrome.
Neuropathies
A thorough clinical examination should include
Hirschsprung’s disease
(1) abdominal palpation to establish the presence,
Intestinal neuronal dysplasia
site, and extension of fecal masses; (2) careful neu-
Abnormalities of colon and rectum
rological exam including assessment of strength and
Ectopic anus
Anal stenosis
the lumbar and sacral area to detect signs of occult
Anal or colonic strictures (postoperative)
spinal dysraphism such as local pigmentation, hyper-
Spinal cord lesions
trichosis, lipoma, or skin pit at the level of a spinal le-
Spina bifida
sion; (4) sensory stimulation of the perianal area (in
Myelomeningocele
cooperative patients) and stimulation of the external
Spinal cord tumors
Systemic disorders
Hypo/hypercalcemia
Hypothyroidism
Diabetes mellitus
or other skin lesions and to exclude malformations
Diabetes insipidus
of the anorectum; and (6) careful rectal examination
Cerebral palsy
to assess the anal sphincter tone and the presence
Drugs
of feces in the ampulla (suggestive of functional fe-
Analgesics
cal retention) or their absence (with the latter again
Antacids
suggesting HD).
Anticholinergics
-
Many others
tive of an underlying organic disorder, appropriate
Other disorders
investigation should be pursued. Appropriate labo-
Cow’s milk protein allergy
ratory tests are listed in Table 17.4. Procedures such
Celiac disease
as barium enema, colonic transit study with radio-
Cystic fibrosis
opaque markers, anorectal manometry, radiographic
Lead toxicity
defecography, and suction rectal biopsy should be
toilet training, retentive postures, presence of soil- suspicion of an organic disorder. Sigmoidoscopy or
ing, and any therapies already attempted. colonoscopy, although occasionally performed, is
Past medical history must include the timing very rarely indicated and must be reserved for the
patient in whom there is a clinical suspicion of colitis
(i.e., stools positive for blood in the absence of anal
birth, or if rectal stimulation was required to produce
a bowel movement shortly after birth, Hirschsprung’s
disease (HD) should be considered. Perineal or peri-
anal infections or trauma may also contribute to Treatment of Constipation and Encopresis
painful defecation and the development of a defeca-
-
tion disorder. If growth and developmental retarda-
oped by the North American Society for Pediatric
tion or malnutrition is evident, organic disorders
Gastroenterology, Hepatology and Nutrition (NASP-
such as HD, endocrine or metabolic disease (e.g., hy-
GHAN), and provide useful algorithms for the treat-
-
ment of constipation in pediatric patients.17
liac disease (a condition that presents with constipa-
TABLE 17.4 is the consequence of the premature arrest of the

Tests to Consider When Investigating Child with Refractory Constipation craniocaudal migration of vagal neural crest cells in
weeks of gestation, leading to failure in the formation

Test To exclude of the enteric nervous system in the distal segment.
Celiac disease screening (total serum IgA, tTG HD occurs in 1 of 5000 live births, with a male
Celiac disease
antibodies, EMA) predominance of 4:1. It is generally sporadic, al-
Electrolyte imbal- though 3–7% of cases have familial clustering. The
Serum electrolytes
ance risk for short-segment disease is 5% in brothers and
Thyroid function screening (FT3, FT4, TSH) Hypothyroidism 1% in sisters of index cases; for long-segment dis-
ease, the risk is 10% regardless of gender. The risk
Fecal elastase or chymotrypsin, sweat chloride test Cystic fibrosis
for HD is increased in Down syndrome, multiple en-
Serum and urine lead Lead poisoning docrine neoplasia (MEN) type 2A (medullary thyroid
carcinoma and pheochromocytoma), and MEN type
any fecal impaction. In the past this was usually ac- 2B (ganglion neuromas and skeletal anomalies). The
complished with rectal agents, and such an approach affected intestine, where no ganglion cells are pres-
ran the risk of further adding to rectal discomfort. ent, cannot relax to allow normal peristalsis and pas-
The oral agent polyethylene glycol (PEG) 3350 at a sage of stool, resulting in severe dilatation of the more
dose of 1.0–1.5 g/kg has been shown to be an effec- proximal normally-innervated intestine. In HD, the in-
tive means of disimpaction without such potential ternal anal sphincter does not relax when the rectum
adverse effects.18 is distended with stool or a rectal balloon, and this
After disimpaction, a treatment program to keep serves as the basis for the use of anorectal manometry
the rectosigmoid free of accumulated stools must be to establish the diagnosis in the older child.
instituted. Such programs must account for the de-
velopmental age of the child and the social setting according to the length of the aganglionic segment.
involving the family and school. While the addition In the classic form (short-segment disease which ac-
counts for about 75% of cases), the aganglionic seg-
achieve in young children) may play an adjunctive ment is limited to the rectum and sigmoid colon. In
long-segment or subtotal colonic disease (10–15%
a regimen of stool softeners must be employed, such of cases) the aganglionic segment extends from the
as lactulose, magnesium hydroxide, sorbitol, or PEG -
3350. Additional measures, such as having the child onosis (3–6% of cases) involves the whole colon but
sit on the toilet for 10 minutes after breakfast and/or may also involve a variable amount of the distal small
after dinner and implementing a system of measured bowel. Total intestinal aganglionosis is sometimes
rewards or incentives for proper toilet use, can also associated with intestinal malrotation or volvulus.
be encouraged. Effective treatment and resolution of Ultrashort-segment aganglionosis may be consid-
pediatric constipation is an important clinical goal, ered the equivalent of a functional alteration, often
as there is now evidence that the condition not only involving just the internal anal sphincter, and is with-
out any detectable histological abnormalities.
67
Clinical Presentation
Hirschsprung’s Disease In the newborn, symptoms typically appear during
HD is a heterogeneous genetic disorder character- -
ized by the absence of parasympathetic ganglion um, or with a picture of intestinal obstruction during
cells in the submucosal and myenteric plexuses. It
passage of meconium is common (an estimated 95% screening diagnostic tests are an unprepped single
of affected neonates), it is not constant, and 5% of contrast enema and anorectal manometry. An ex-
affected children present late or with complications perienced pediatric radiologist should review the
contrast enema. Findings suggestive of HD include
in the neonatal period. The most common complica- an abnormal rectosigmoid ratio or a transition zone
tion occurring after the newborn age is enterocolitis, between a widened proximal colon and the nar-
which is invariably severe, and is an important cause rowed aganglionic segment. Anorectal manometry
of morbidity and even mortality. Enterocolitis can assesses the relaxation of the internal anal sphincter
present with signs and symptoms of an abdominal -
catastrophe including severe abdominal distension,
explosive diarrhea, vomiting, fever, lethargy, rectal
bleeding, and shock. is no relaxation or there may even be paradoxical
Beyond the newborn period and in the absence contraction of the internal anal sphincter. Anorectal
of episodes of enterocolitis, the presentation is typi- manometry is particularly useful when the agangli-
cally less dramatic, with intractable constipation and onic segment is short and the results of radiological
recurrent fecal impaction being the most common or pathologic studies are equivocal.
signs. Other elements in the patient’s history that The gold standard for diagnosis remains histo-
help differentiate HD from functional fecal retention
and other forms of constipation are: on rectal biopsy. Staining for acetyl cholinesterase
activity in mucosal tissue can augment such biopsies,
the presence of malnutrition or failure to thrive making the relatively noninvasive suction rectal bi-
the passage of stools that are never round and large, but opsy a reliable diagnostic method. The diagnosis is
rather ribbon-like based on the demonstration of total absence of gan-
early and repetitive use of rectal stimulation and rectal glion cells in the affected segment of the intestine,
agents to produce bowel movements with an overgrowth of large nerve trunks in the in-
the absence of soiling, which is a common finding in termuscular and submucosal zone. Two small sam-
chronic functional constipation ples of rectal mucosa and submucosa are required,
the absence of retentive posturing and of the urge to using the suction rectal biopsy technique. The two
defecate pieces must be taken not less than 2 cm above the
dentate line, to avoid sampling the physiological hy-
Invariably, physical examination reveals a distended poganglionic zone, and not more than 5 cm above the
abdomen and a contracted anal sphincter. Classically, dentate line, to avoid missing the diagnosis of short-
segment disease.
rectal vault, except in cases of ultrashort-segment
be an explosive discharge of foul-smelling liquid Treatment and Follow-Up

stool, with decompression of the proximal bowel.
Treatment of HD consists of resecting the agangli-
onic segment of the rectum and colon, pulling down
the normally innervated bowel and anastomosing it
Diagnosis at the anorectal region while preserving the sphinc-
The suspicion of HD is based on the history and phys- ter muscle. The past decade has seen an evolution in
ical examination as already described. Careful evalu- the surgical management of HD. The previous gold
ation will allow the clinician to avoid unnecessary standard, a two- or three-stage pull-through with
radiological or manometric tests in the majority of a preliminary stoma, is slowly being replaced by a
children who present with chronic constipation. one-stage approach. More recently, minimally inva-
When HD is suspected, the two most common sive approaches to the one-stage pull-through have
become popular. The one-stage approach, either by -

laparotomy or by combined laparoscopy and trans- ciently between 12 and 18 months of age. Older chil-
dren and adolescents may also develop GERD with
of life, and in small infants it appears to be at least as symptoms more typical of adults including heartburn
effective as staged procedures with an interval colos- and recurrent epigastric abdominal pain.
tomy.19 -
After the operation, some patients with HD con- sodes in infants is transient relaxations of the lower
tinue to have constipation and residual disease with esophageal sphincter (LES). Inadequate LES pres-
associated neuronal dysplasia must be kept in mind sure (chalasia) is quite uncommon. The length of the
as possible etiologies that would require reoperation. LES increases with age and this is associated with de-
Further biopsy to exclude residual aganglionic bowel creased GER as children get older. Other factors con-
may be necessary. Contrast studies to delineate anas- tributing to the pathogenesis of GERD in infants may
tomotic strictures or leaks should also be considered include increased intra-abdominal pressure, inad-
in such cases.
Finally, it is becoming increasingly clear that HD esophageal acid clearing), prolonged gastric empty-
should not be viewed simply as a disorder involving, and the gastroesophageal angle of His.
ing an aganglionic segment of distal colon; in reality, An increased prevalence of GERD is found in
this condition affects motor function in other parts certain subgroups of pediatric patients. Based on pH
of the gut, as well. The variability in clinical expres- probe studies, more than 65% of children with under-
responsible for HD. For example, abnormalities in likely on the basis of chronic supine positioning,
esophageal motility are common, and half of patients undernutrition, chronic constipation, scoliosis and
with HD have duodenal motor dysfunction.20 related deformities, convulsive disorders, spasticity,
and medications, all of which contribute to increased
intra-abdominal pressure, delayed gastric emptying,
Gastroesophageal Reflux Disease and GERD itself.21 The full clinical importance of GER
in this population is still an area of active research,
Interestingly, patients with severe underlying
neurological disorders may be more prone to GERD
and vomiting as a result of a higher prevalence of food
allergy. Thus in neurologically impaired children un-
symptoms or complications from GER. The most com-
mon manifestation of GER in infancy is frequent bouts
trial of a highly restricted diet with an amino acid–
of painless and effortless regurgitation in an infant
based formula may be warranted as it may improve
who is thriving. Common manifestations of GERD can
long-standing GI symptoms associated with esopha-
include vomiting (with or without hematemesis) and
gitis.22
dysphagia. While irritability has been postulated as a
Complications of GERD in infants can include
symptom of infant GERD, the role of GERD in isolated
esophageal as well as supra-esophageal symptoms
infant irritability/fussiness remains controversial. In
such as chronic cough and hoarseness, although the
the few available studies, acid inhibition does not ap-
role of GERD in causing chronic or recurrent respi-
pear to decrease crying or sleep disturbance in young
ratory symptoms is controversial. In a recent large
infants.63 Rarer manifestations can include slowed
randomized controlled trial, proton pump inhibitor
weight gain due to inadequate nutrient intake or ex-
therapy was not associated with any improvement in
cessive losses, respiratory complications (particular-
symptoms or lung function in children with asthma70.
ly reactive airway disease or aspiration pneumonia),
Rarely infants and young children with severe GERD
and obstructive apnea or cyanosis. Gastroesophageal
present with unusual posturing that can be mistaken
for convulsions or dystonia (Sandifer’s syndrome); hours in the absence of any antacid treatment for at
these symptoms resolve with treatment of the un- least 72 hours; it can provide a valid, reliable, and re-
the basis of the symptoms. In neurologically normal considered the silver rather than the gold standard,
infants, GERD very rarely leads to growth failure, -
intractable vomiting, or severe pulmonary disease rently being explored through the newer technology
and when present, these symptoms should lead to of impedance monitoring.24 Age-appropriate stan-
investigation for other potential causes of the child’s dards are available from reference populations, usu-
symptoms including metabolic, anatomic, or central ally infants and children with other GI complaints,
nervous system pathology.23 so the pH probe can provide information regarding
the frequency of GER episodes, the duration of epi-
sodes (related to clearance of acid from the esopha-
Diagnostic Evaluation gus), and the relationship of episodes of GER to other
symptoms (e.g., pain, posturing, coughing, hiccups,
For the approach to infants and children with sus-
wheezing). See Table 17.5 for normal values.
pected GERD, refer to the NASPGHAN guidelines.23
Assessing the infant or young child with symptoms or
Upper GI endoscopy with biopsy
signs of GERD is largely guided by history and physi-
This procedure can assess the presence and sever-
cal examination. In fact, in most infants with recur-
ity of esophagitis (thus also indirectly establishing
rent regurgitation and occasional vomiting, history
the diagnosis of GERD), strictures, and Barrett’s
-
esophagus. It must be stressed that as in adults, the
ably diagnose GERD and direct management and fol-
overwhelming majority of infants and children with
low-up. There is a wide array of diagnostic tests and pro-
GERD do not suffer from esophagitis and as such, a
cedures now available to diagnose GERD and assess for
normal study does not exclude the diagnosis. Endos-
complications, however it is important to recognize that
copy can be useful in evaluating patients with symp-
toms of GERD that are resistant to common treat-
on any of the commonly employed tests does not clearly
ment (see below), as it may disclose the presence
correlate with the severity of symptoms, the response to
of the increasingly recognized entity of eosinophilic
therapy, or the ultimate outcome.
esophagitis (EoE).25
but not diagnostic of EoE include white exudates on
the esophageal mucosa, severe spasm resulting in
Upper GI X-ray series
a “ringed” or “stacked coin” appearance down the
length of the esophagus, and linear furrowing of the
enough to diagnose GERD, it is used to evaluate for
esophagus. Biopsies are an important part of any en-
abnormal anatomy in the infant or child with severe
doscopy, and can help identify esophageal pathology
or intractable symptoms. This X-ray series assists in
-
excluding other potential causes of persistent or in-
tis. Additionally, any child presenting with idiopathic
tractable vomiting such as pyloric stenosis, antral or
duodenal web, malrotation, annular pancreas, or in
an older child, hiatal hernia or advanced complica- TABLE 17.5
tions of GERD such as esophageal strictures. If the in- Probe Monitoring (24 hour): Main Upper Limits of Normal Values
dication is only to rule out GERD, then the test should
not be performed.
Infants Children Adults
Esophageal pH monitoring Daily episodes of reflux (n) 73 25 45
This remains the most direct way to diagnose GERD. Episodes of reflux ≥5 minutes (n) 9.7 6.8 3.2
The pH monitoring is best when conducted for 24 Reflux index (% of time pH <4) 11.7% 5.4% 6%
food impaction should be considered as having EoE older child, avoiding caffeine, chocolate, and spicy
until proven otherwise. foods, reducing the intake of foods that contribute to
GER by prolonging gastric emptying (e.g., fried, fatty
foods), and aggressively treating constipation are
Treatment recommended although there is no clear evidence
any of these interventions are effective.
Pharmacological management is best initiated
time, is indicated for determining if GERD is indeed
with antisecretory therapy based on H2-receptor
-
antagonists. Use of over-the-counter antacids is not
ally, the initial therapy of infants with GER has been
recommended, as they may mask and delay the diag-
aimed at proper positioning and “correct” feeding
nosis and also are ineffective in healing esophagitis.
techniques. While esophageal pH studies have dem-
Metoclopramide (Reglan) is widely used, but proof
onstrated that infants in the prone position have
less GER, no studies have ever shown that prone
approximately one-third of patients (including dys-
positioning decreasing the frequency or severity
tonic movements and rarely other extrapyramidal
of symptoms. Moreover, since prone positioning is
reactions).23
associated with an increased risk of sudden infant
Proton pump inhibitors (PPI) are the most ef-
death syndrome (SIDS), prone positioning during
fective acid suppressants, and they are superior to
sleep should only considered in those extremely rare
H2-receptor antagonists in healing esophagitis. Their
case where the risk of death from GERD outweighs
use is indicated for documented esophagitis and in
the risk of SIDS. Positioning of toddlers and children
patients with GERD who fail to respond to H2-recep-
has not been studied adequately, though elevation of
tor antagonists. Data are now available on the safety
of prolonged use of PPI in children; however, as has
Other recommendations for infants include
been in shown in adults, it appears as though PPI us-
frequent burping and smaller, more frequent feed-
age in infants and young children is associated with
ings, although no studies have demonstrated that
an increased risk of a variety of respiratory and gas-
these measures decrease the frequency or severity
trointestinal infections.71 Table 17.6 lists pediatric
of symptoms. While thickening the feedings (adding
dosages of the drugs that have been found to be ef-
a tablespoon of cereal to 2 oz of formula) or using
fective in GERD and for which a pediatric dose is avail-
a formula with added rice starch does not improve
able.
Effective drug therapy and the relatively high
does reduce the number of vomiting episodes. In the
prevalence of regurgitation in infants and abdomi-
nal pain in children and adolescents can lead to the
TABLE 17.6
over-diagnosis of GERD, and this important clinical
Drugs Used for Gastroesophageal Reflux Disease
issue needs to be kept in mind by the clinician.26
in Pediatric Patients (age 1–12)
Surgical treatment of GERD has been available
for children for several decades. The most commonly
Histamine2-Receptor Antagonists performed operation for pediatric GERD is the Nis-
Cimetidine 40 mg/kg/day, divided TID or QID sen fundoplication. Fundoplication is extremely ef-
Ranitidine 5–10 mg/kg/day, divided TID or BID
Famotidine 1 mg/kg/day, divided BID be weighed against the risks of complications such
Nizatidine 10 mg/kg/day, divided BID as dumping syndrome, intractable gagging, and
Proton Pump Inhibitors retching, dysphagia, and gas-bloat. Ninety percent of
Omeprazole 1–3.3 mg/kg/day
Lansoprazole 1.4 mg/kg/day laparoscopic Nissen fundoplication, although side
Esomeprazole ≤20 kg = 10 mg/day
effects occur in up to 22% of surgically treated pa-
≥20 kg = 20 mg/day
tients and failure rates of 5–20% have been reported for approximately 3 million deaths per year accord-
with long-term follow-up.27 In addition, as the chil- ing to the World Health Organization (WHO).28
dren grow, fundoplications may “unwrap.” If symp- It has been estimated that in the United States
toms recur, the procedure may need to be repeated. there are 1 or 2 episodes of acute diarrhea per child
As a result, fundoplication is now most commonly per year in children age <5. This results in 220,000
performed in infants and children who have severe hospital admissions (or about 10% of all admissions
complications of GERD that have not responded to for children in this age range), and about 400 deaths
aggressive medical management, or in those children per year.29 Furthermore, it appears that acute diar-
with known anatomic predispositions to persistent rhea account for 20% of referrals to physicians in
GERD. children age <2, and 10% in children <3.29 Within
Children with underlying neurologic disorders the United States, the most underprivileged popula-
are particularly prone to persistent and severe GERD tions are the most severely affected; mortality rate
and its sequelae. However, since GERD is a motil- among African-Americans is 4 times higher than that
ity disorder, these children also seem more prone to of whites (32.2 versus 8.2 deaths per 100,000 live
postoperative complications including Nissen-bloat births).30
syndrome and severe post-operative gagging and
retching. In some cases, affected children improve can result from many different causes. Table 17.7 lists
with placement of a gastrostomy and nutritional causes in the approximate order of frequency. Intes-
restitution thus obviating the need for fundoplica- tinal infections are by far the most common causes
tion. If GERD remains a major problem, passage of of sporadic, acute-onset diarrhea. A large number
a transpyloric feeding tube can be considered, or the of pathogens are responsible for the occurrence of
surgeon can still perform a fundoplication. infectious diarrhea. Table 17.8 lists the agents most
commonly associated with intestinal infections and
acute diarrhea in children.
Acute Diarrhea
TABLE 17.7
normal value of approximately 10 ml/kg/day. Most Main Causes of Pediatric Acute Diarrhea
commonly, this situation implies an increased fre-
quency of bowel movements, which can range from
Enteric infections (including food
4 or 5 to >20 times per day.
Infections poisoning)
Acute-onset diarrheal episodes continue to be a
Extraintestinal infections
major problem for child health worldwide. The prev-
alence and severity of acute-onset diarrheal episodes Antibiotic associated
Drug induced
has declined over the past several decades through- Other drugs
out the developed world, however, acute diarrhea Cow’s milk protein allergy
remains a common problem and accounts for innu- Food allergies Soy protein allergy
merable physician visits and many hospitalizations. Multiple food allergies
Disorders of digestive/absorptive Sucrase-isomaltase deficiency
of age experience an average of 3 episodes of acute
processes Late-onset (“adult type”) hypolactasia
diarrheal illnesses per year. Chronic malnutrition
and undernutrition increase a child’s susceptability Acute appendicitis
to both acute and prolonged diarrhea as well as the “Surgical” conditions
Intussusception
risk of complications from these conditions. Acute
diarrheal illnesses remain one of the leading causes Vitamin deficiencies Niacin deficiency
of mortality in infants and young children accounting
Table 17.8 The importance of each single pathogen varies

Most Common Agents CausingPediatric Infectious Diarrhea widely between geographical areas and age groups.
In developed countries, bacterial infections are gen-
Approximate frequency in and then again in school age; infections with rotavi-
Pathogen cases of sporadic diarrhea rus, the single most common agent of infectious diar-
in developed countries (%) rhea worldwide, peak between 6 and 24 months of
age. In developed countries, intestinal infections are
Viruses
most commonly sporadically acquired; however, out-
Rotavirus 25–40 breaks of food-borne or water-borne infections are
well described and continue to occur.
Norovirus 10 Other infectious agents, including cytomegalo-
virus, herpesvirus, and atypical mycobacteria, which
Calicivirus 1–20
are not typically enteric pathogens, can cause acute
Astrovirus 4–9 diarrhea in immunocompromised children. It is well
accepted that extraintestinal infections (e.g., middle
Enteric-type adenovirus 2–4 ear, lung, and urinary tract infections) can result in
Bacteria acute diarrhea, usually self-limited, but the mecha-
nisms for such a relationship are not understood. A
Campylobacter jejuni 6–8 great number of drugs are known to be able to in-
duce acute diarrhea as a side effect; among them,
Salmonella 3–7
however, antibiotics have a special place, as the ad-
Escherichia coli ministration of many of them is often accompanied
enterotoxigenic (ETEC) by this symptom.
enteropathogenic (EPEC)
enteroaggregative (EAEC) 3–5
enteroinvasive (EIEC) Clinical Features
enterohemorrhagic (EHEC) In developed countries, acute diarrhea is almost
diffusely adherent (DAEC) invariably a benign, self-limited condition, subsid-
ing within a few days. The clinical presentation and
Shigella 0–3
course of the illness are dependent on the host and
Yersinia enterocolitica 1–2 on the infecting organism. As for the host, age and
nutritional status appear to be the most important
Clostridium difficile 0–2 elements. In fact, the younger the child, the higher
the risk for severe, life-threatening dehydration as a
Vibrio parahaemolyticus 0–1
result of high body water turnover and limited renal
Vibrio cholerae 01 — compensatory capacity. Malnutrition appears to fa-
vor a more prolonged and severe course. As for the
Vibrio cholerae non-01 ? infecting organism, different pathogenic mechanisms
Aeromonas hydrophila 0–2 deployed by different infectious agents result in vari-
able clinical features (summarized in Table 17.9). In
Parasites developed countries, children with acute diarrhea
usually present to medical care with minimal-to-mild
Cryptosporidium 1–3
dehydration. As compared to children with invasive
Giardia lamblia 1–3 pathogens, children suffering from rotavirus gas-
troenteritis tend to have more severe vomiting and
TABLE 17.9
Pathogenic Mechanisms and Localization of Main Intestinal Pathogens
Predominant patho-
Site of infection Agent Clinical features
genesis*
Direct cytopathic Proximal small Rotavirus Copious watery diarrhea to severe dehydration;
effect intestine Enteric-type adenovirus frequent lactose malabsorption; no hematochezia
Calicivirus Course may be severe
Norovirus
EPEC
Giardia
Enterotoxic Small intestine Vibrio cholerae Watery diarrhea (can be copious in cholera or ETEC),
Enterotoxigenic E. coli but usually mild course; no hematochezia
Enteroaggregative E.
coli
Klebsiella pneumoniae
Citrobacter freundii
Cryptosporidium
Enteroinvasive Distal ileum and Salmonella Dysentery: very frequent stools, cramps, pain, fever,
colon Shigella and often hematochezia with white blood cells in
Yersinia stools
Variable dehydration
Campylobacter Course may be protracted
Enteroinvasive E. coli
Amoeba
Cytotoxic Colon Clostridium difficile Dysentery, abdominal cramps, fever, hematochezia
Enterohemorrhagic E. EHEC or Shigella may be followed by hemolytic-
coli uremic syndrome
Shigella
*Elaboration of various types of enterotoxins affecting ion transport has been demonstrated as an additional virulence factor for almost all of
the bacterial pathogens.
more watery stools and present with more severe an episode of acute infectious enteritis may result
dehydration and metabolic acidosis. The acidosis in chronic symptoms. In some cases, the enteritis
associated with rotavirus gastroenteritis is often dis- is severe enough to produce total or subtotal villous
cordant with the severity of diarrhea and dehydra- atrophy. Certain forms of viral enteritis can disrupt
tion. High fever, crampy abdominal pain, and blood the enterohepatic circulation of bile salts, resulting
mixed with the stools are more common in children in bile salt malabsorption and resultant diarrhea. In
infected with invasive pathogens such as , some infants and young children, increased antigen
, Yersinia, and Entamoeba his- penetration secondary to damaged mucosa and in-
tolytica. creased permeability may induce a state of sensitiza-
In developed countries, acute diarrhea is usually tion producing cow’s milk protein allergy. Similarly,
- some children will develop celiac disease following a
suscitation and replacement of ongoing losses, the bout of enteritis. In developed countries, one of the
illness usually resolves within several days. However, most common causes of prolonged diarrhea after a
bout of acute gastroenteritis is the excessive intake of and differentiation, and immune function.69
While there is overwhelming evidence regarding
the effectiveness and safety of ORT for acute child-
hood diarrhea, this form of therapy is not widely
Management used in the United States.32
Refeeding
Rehydration
In breast-fed babies affected by gastroenteritis,
The major risk in acute diarrhea is the excessive loss
breast-feeding should be continued. Breast-feeding
of water and electrolytes causing dehydration and
not only decreases the risk of developing gastroen-
metabolic disarray. Fluid resuscitation followed by
teritis, but also promotes faster recovery. In formula
maintenance of hydration is the cornerstone of treat-
fed infants, the issue of feeding during enteritis has
ment. Sodium coupled glucose transport even in the
been much debated. For years the popular remedy
face of stimulated intestinal secretion and/or muco-
for acute diarrhea was some period of fasting fol-
-
lowed by the gradual reintroduction of the “usual”
feedings. The concept of providing “gut rest” to in-
with diarrhea.
fants suffering from acute infectious gastroenteritis
This is the basis of WHO-UNICEF-supported oral
has fallen out of favor, and most of the available evi-
rehydration therapy (ORT). Oral rehydration solu-
dence suggests that in the overwhelming majority of
tions (ORS) have proven extremely safe and effective
infants, it is appropriate to quickly resume feedings
and have revolutionized the management of child-
with a standard formula; there is no need to rou-
hood diarrheal illness throughout the world saving
tinely switch to a lactose free or soy based formula.
millions of lives. The ORS originally proposed by the
Lactose intolerance was once thought to be a major
WHO had an osmolarity of 311 and a sodium content
problem among infants suffering from acute gastro-
of 90 mmol/L; more recently, several clinical trials have
enteritis and was a reason to delay refeeding with
demonstrated the solutions with reduced-osmolarity
milk-based formulas. Despite the presence of re-
(225-260 mOsm/L) due to lower concentrations of glu-
ducing substances in the stools of many infants with
cose and sodium have been shown to be even more
acute diarrhea, lactose intolerance is not clinically
effective than the original ORS solutions. The use
-
of hypo-osmolar ORS is associated with diminished
oped countries. In a large multicenter study, only 3%
stool output while remaining extremely effective in
of the children had signs of lactose malabsorption at
producing rehydration and subsequently maintain-
admission, and none had symptoms of lactose intol-
ing hydration. A recent Cochrane review of all pub-
erance at day 5 post-enrollment after having been
lished controlled trials comparing low-osmolarity
fed lactose-containing formula.34
solutions with standard WHO solutions concluded
There is overwhelming evidence, supported by
that as compared to WHO standard ORS, reduced
many well-conducted studies as analyzed in a guide-
osmolarity ORS is associated with fewer unsched-
line published by the European Society for Pediatric
Gastroenterology, Hepatology, and Nutrition, that
post-randomization, and less vomiting, and no ad-
early refeeding is a safe and effective means of thera-
ditional risk of hyponatremia.31 In developing coun-
tries, the treatment of acute diarrhea should include
3 months of age.33 Thus, weaned children who are
the routine use of zinc supplementation, at a dosage
not severely dehydrated or acidotic should rapid re-
of 20 milligrams per day for children older than six
turn to full feedings after being orally rehydrated
months or 10 mg per day in those younger than six
months, for 10–14 days68. Supplementary zinc has
Antimicrobial treatment
Infections with Vibrio , and Giardia
its positive effect on protein synthesis, cell growth
lamblia should be treated; infections with Yersinia
enterocolitica should be treated in subjects with presents with blood streaking of stools in the ab-
sickle cell disease; and infections with sence of any other symptoms of illness. Some af-
enteriditis should be treated in very young infants fected infants will have diarrhea, mucus, and blood
if they are febrile or if they are bacteremic. Other in the stools and may have symptoms suggestive of
causes of acute diarrhea in immunocompetent chil- tenesmus. Affected infants otherwise appear quite
dren generally do not need to be treated with anti- healthy and are growing and developing normally.
microbials. Allergic enterocolitis should be considered in
the differential diagnosis of any infant with hema-
tochezia, regardless of whether the baby is breast-
Food Allergy fed or not. Interestingly, these symptoms seem to
occur quite commonly in exclusively breast-fed in-
Epidemiology in Industrialized Countries fants, and seem to be triggered by milk protein in the
mother’s diet. In the majority of affected infants, ra-
The prevalence of food allergy has increased world-
dioallergosorbent tests (RAST) and skin prick tests
wide, becoming a serious health problem in devel-
are negative as the allergic response is not mediated
oped countries. It is now estimated that approxi-
through IgE. There is no indication for colonoscopy,
mately 3% of all infants in industrialized countries
as this is a benign self-limited condition. If a colo-
are affected. Food allergy affects genetically predis-
posed subjects when they are exposed to certain
pattern, friable mucosa, and prominent lymphoid fol-
foods under certain conditions. Infant feeding pat-
licles with an erythematous halo. Histological chang-
terns and reduced incidence of infectious diseases
eosinophils, and many lymphoid follicles.

increasing trend.
Cow milk protein allergy (CMPA) can run in fami-
lies. A family history of atopy and/or food allergies is
often found in infants and children with milk allergy,
and remains one of the most important risk factors TABLE 17.10
for its development. Main Clinical Presentations of Cow’s Milk Protein Allergy
in Infants and Children
Clinical Presentation Gastrointestinal signs/symptoms Respiratory signs/symptoms

The clinical presentation of cow’s milk protein al- Nausea/vomiting Bronchitis/asthma
lergy (CMPA) is extremely variable in terms of onset, Diarrhea/malabsorption (enteropathy) Sneezing
severity, and symptomatology. In recent years, sev- Gastrointestinal bleeding Wheezing
eral previously undescribed clinical presentations Abdominal pain Rhinorrhea
of CMPA have been reported, leading to the concept Feeding difficulties Cough
that basically every system can be affected. Four Enterocolitis Stridor
main categories of symptoms can be attributed to Constipation
CMPA: gastrointestinal, respiratory, dermatological, Infantile colic
and systemic. Table 17.10 shows the main clinical
Dermatological signs/symptoms Systemic signs/symptoms
signs/symptoms of CMPA in infancy and childhood.
Erythematous rash Failure to thrive
This section will focus on the most important GI
Urticaria/angioedema Iron-deficiency anemia
manifestations of food allergy.
Eczema/atopic dermatitis Anaphylactic shock
Colitis/proctitis Lip swelling
months of life, cow’s milk colitis/proctitis typically

Enteropathy The diagnosis of eosinophilic gastroenteropathy

requires (1) the presence of the symptoms described
manifestations of food allergy is food-sensitive en- -
teropathy. Cow’s milk protein sensitive enteropathy tration of the GI tissue on biopsy (>20 eosinophils per
typically presents between 3 and 6 months of age as a
malabsorption syndrome, with vomiting, chronic diar- controversy exists on the exact number of eosinophils
rhea, and growth failure. Affected infants can appear needed for diagnosis); (3) lack of eosinophilic involve-
malnourished and may show abdominal distension ment of organs outside the GI tract; and (4) absence of
due to fermentation of malabsorbed carbohydrates. concomitant parasitic infections.
This syndrome can also develop in response to other Many affected children have elevated total and
dietary antigens, notably soy protein. Up to half of in-
fants with cow’s milk protein sensitive enteropathy
will also be sensitive to soy protein. gastric folds, and if there is muscular involvement of
The pathogenic mechanism involves a T cell–me- the antrum and pylorus, an obstructive picture may
diated reaction. Malabsorption is due to damage of be apparent. Endoscopic examination can be normal
the duodenal and jejunal mucosa; the lesion is less se- or can show erythema, edema, nodularity, ulcer-
vere than Celiac disease, but characterized by similar ations, and/or erosions. In the case of eosinophilic
esophagitis, the mucosa can appear furrowed or
a reduction of the crypt/villus ratio. Mononuclear cell ringed with linear exudates. Because of the patchy
distribution of the disease, multiple biopsies from
and eosinophils also may be present. multiple sites—especially the stomach and small
As with cow’s milk colitis/proctitis, in most cas- intestine—must be obtained.
es this syndrome is not associated with systemic IgE
responses, and skin prick tests as well as RAST tests
are characteristically negative. Although long thought Management of Food Allergy
to be limited to children 4–24 months of age, there is Clearly, the best way to treat CMPA is by complete
now evidence that in some cases CMP-induced enter- avoidance of CMPs. Thus, all cows’ milk and its deriv-
opathy may persist, with mucosal lesions being still atives must be rigorously eliminated, not only from
evident in later childhood.35 Interestingly, the preva- the diet of the affected child, but also, if he or she is
lence of this entity appears to be declining so that ce- being breast-fed, from the maternal diet.
liac-like villous atrophy is now quite rare in developed When instituting the diet, care must be exercised
countries. This decline may be due to improvements
in infant formulas.
formulas based on cow’s milk will need to be re-
Eosinophilic gastroenteropathy placed by nutritionally complete and balanced non-
- milk containing formulas. In clinical practice, the
terizes this entity. The clinical presentation depends on most widely used substitutes are soy protein–based
what parts of GI tract are involved and the extent of the and hydrolyzed cow’s protein based formulas. Both
- of these have been thoroughly evaluated for nutri-
cosa, malabsorption-like symptoms prevail (diarrhea, tional quality and found to produce completely nor-
failure to thrive, occult GI bleeding, and protein-losing mal somatic development in children. Milk derived
enteropathy with consequent hypoalbuminemia). If from other mammals, such as goat or donkey milk,
are not recommended.
obstructive symptoms can occur, such as nausea, ab- It should be emphasized that both soy-based
dominal bloating, vomiting, and abdominal pain. Most formulas and protein hydrolysates have their draw-
patients (70%) have peripheral eosinophilia. backs. Up to half of infants sensitive to cow’s milk
proteins will also be sensitive to soy protein. The and failure to thrive. The evaluation of infants and
American Academy of Pediatrics’ Committee on Nu- children with chronic diarrhea is best guided by the
trition has stated that although soy formulas are not age at onset (Table 17.11). The differential diagnosis
hypoallergenic, they can be fed to infants with IgE- will focus on the most common age of presentation,
associated symptoms of milk allergy, particularly af- from age 6 months to 2 years.
ter the age of 6 months.36 However, the Committee
did emphasize that the use of soy formulas is not rec-
ommended for the treatment of infants with non-IgE- Cow’s Milk Protein Allergy
associated syndromes and this constitutes the majority
This is the most common cause of chronic diarrhea in
of infants who suffer from CMPA.
this age group. See the previous section for a detailed
As for the protein hydrolysates, although they
discussion.
represent an excellent choice for most infants sus-
pected of being allergic to milk, they carry some re-
sidual allergenicity, as minute amounts of peptides
Chronic Nonspecific Diarrhea
of large molecular weight can be found in any of the
formulas containing extensively hydrolyzed proteins.
It is estimated that about 5% of allergic infants have very common, has been declining over the past de-
reactions to these formulas. These infants should be cade. This condition is not unlike irritable bowel
fed formulas with free amino acids as their sole pro-
tein source thus completely eliminating the potential children who are typically developing and growing
for allergic reactions. normally who are without any clinical or laboratory
evidence of malabsorption. Although several factors
were once thought to be responsible (including food
Chronic Diarrhea
is no proof that any of these factors clearly plays a
chronic diarrhea. This condition is more common in

intake of fruit juices that are rich in non-absorbable
infants and children who are already malnourished,
carbohydrates (particularly fructose and sorbitol) is
and has the potential to lead to chronic malnutrition
often found to be a contributing factor.
TABLE 17.11
Disorders Causing Chronic Diarrhea in Pediatric Age Group Based on Age of Onset
Neonatal (0–28 days) Infancy (1–24 months) Childhood (2–18 years)

Glucose-galactose malabsorption Cow’s milk protein allergy Celiac disease
Congenital microvillus atrophy Chronic nonspecific diarrhea (“toddler’s diar- Protracted post-infectious diarrhea
rhea”)
Short bowel syndrome Protracted post-infectious diarrhea Eosinophilic gastroenteropathy
Congenital chloridorrhea Celiac disease Inflammatory bowel disease
Congenital Na+-losing diarrhea Cystic fibrosis
Enterokinase deficiency Irritable bowel syndrome
Giardiasis
Small bowel bacterial overgrowth
Short bowel syndrome
Autoimmune enteropathy
The primary role of the physician in these cases is disease can present at any age. Current estimates
to reassure anxious parents that there is no evidence are that Celiac disease is present in nearly 1% of the
of major malabsorption or any serious underlying population.37 While it can present in children and ad-
process going on and to try and convince families olescents with a variety of different chronic gastroin-
to avoid unnecessary dietary trials that may result testinal complaints, Celiac disease can also present
in diminished caloric intake. A commonly employed without major gastrointestinal symptoms but rather
approach in this regard is to suggest that the empha- -
ciency anemia, early onset metabolic bone disease,
thriving), not on his or her stools. and dental enamel hypoplasia. The role of Celiac
disease in childhood psychiatric illnesses, seizures
and arthritis remains unclear. A variety of popula-
Protracted Post-infectious Diarrhea tions are at increased risk of developing Celiac dis-
Acute-onset diarrhea in developed countries is typi-

Celiac disease, children and adults with type 1 dia-
cally a self-limited condition, resolving well before
betes mellitus, Down syndrome, Turner syndrome,
14 days in the vast majority of cases. In the occasion-
al patient, however, it may run a prolonged course
evidence that children with autism are at higher risk
due to host factors (young age and malnutrition fa-
for Celiac disease than the general population. Chil-
voring a protracted course), as well as the microor-
dren suffering from Celiac disease frequently have GI
ganism responsible for the initial illness. In many of
symptoms such as chronic diarrhea, abdominal dis-
these now unusual cases, the pathogenic mechanism
tention, abdominal pain, poor weight gain or failure
that leads to a protracted course is either the onset
to thrive, vomiting, and occasionally, constipation.
of a milk protein allergy or—less commonly—that of
It is recommended that Celiac disease be an
a small bowel bacterial overgrowth (SBBO). Thus, a
early consideration in the differential diagnosis of
“clinical challenge” with cow’s milk protein to assess
children with delayed growth or failure to thrive and
tolerance is reasonable (see above), and if this fails,
persistent diarrhea, as well as with other persistent
it is reasonable to consider performing an H2 breath
GI symptoms, including recurrent abdominal pain,
test with glucose to rule out SBBO.37
constipation, and vomiting. The initial screening test
In some cases, prolonged post-infectious diarrhea
for such children should be assessment of the level
is iatrogenic. Initial dietary interventions, including
of anti-endomysial antibody (EMA), or anti-tissue
increased intake of juices and mineral drinks as well
transglutaminase (tTG) antibodies, tests that have
as low-fat diets, can lead to diarrhea when used for
-
prolonged periods of time. The high osmolarity, car-
ly.38 Anti-gliadin antibodies, both IgA and IgG, have
been also used to screen for Celiac disease; however,
perpetuate diarrhea, while the low-fat diet speeds
-
gastrointestinal transit and may result in bile salt de-
ity), their measurement is not recommended for de-
livery to the colon, inducing a bile salt diarrhea. Nor-
tecting Celiac disease in children. Even if serological
malization of the diet in such cases is often curative.
tests for Celiac disease are negative, symptomatic
children with chronic diarrhea, failure to thrive, or a
positive family history for Celiac disease or IgA de-
Celiac Disease
Celiac disease is an immune-mediated enteropathy disease and may confound interpretation of serol-
in genetically susceptible individuals caused by the ogy) should be evaluated with a duodenal biopsy.
ingestion of gluten. Although we are discussing it In fact, small bowel biopsy remains the diagnos-
in the differential diagnosis of the young child with tic gold standard, and establishing the diagnosis of
chronic diarrhea, it should be stressed that Celiac Celiac disease still requires an intestinal biopsy in
most cases although the latest European guidelines chronic cough, reactive airways disease, and recur-
recognize high titer serology in the appropriate set- rent pneumonia are hallmarks of CF, it is important
ting as a way to make the diagnosis.64 In addition, be- to recognize that infants with CF have normal lungs
cause the histological changes in Celiac disease may and normal lung function at birth whereas infants
be found in a non-uniform distribution in the small
bowel, multiple biopsy specimens must be obtained -
from the proximal as well as more distal parts of the nal manifestations need to be considered in patients
duodenum.39 with CF (Table 17.12).
A gluten-free diet (which can include oats from Older patients with recurrent pancreatitis with-
sources that are not cross-contaminated during pro- out pulmonary involvement are also being found to
cessing and shipping40) constitutes the only current have other chromosomal abnormalities involving
treatment for Celiac disease and must be followed the CFTR gene. Diagnosis of CF is made by demon-
for life. It is imperative that comprehensive dietary stration of an elevated sweat chloride level and/or
counseling be provided by expert dietitians and pe- by detecting the genetic markers. Treatment of the
riodically reviewed, as manufactured foods’ ingredi- pulmonary disease associated with CF is directed at
ents often change. Guidelines from the American Di- decreasing the frequency and severity of pulmonary
etetic Association for the treatment of Celiac disease infections with a combination of aggressive nutrition,
are a reliable source of information.41 combinations of bronchodilators, mucolytics and chest
physiotherapy and aggressive antimicrobial therapy.
Cystic Fibrosis exocrine pancreatic enzyme replacement therapy, and

supplementation of fat-soluble vitamins. Many cen-
Estimated to affect about 1 in 2000 live births, CF is
ters routinely administer sodium bicarbonate and/
the most common lethal autosomal recessive defect
or proton pump inhibitors to increase the effective-
in Caucasians. Striking improvements in care, and
ness of enzyme therapy as pancreatic bicarbonate
recent genetic studies identifying the chromosomal
and pathogenetic abnormalities predisposing to the
development of the disease and its complications,
TABLE 17.12
are leading to improved quality of life for these pa-
Gastrointestinal Manifestations of Cystic Fibrosis
tients, who now are living into their 40s.
The CF gene is on the long arm of chromosome
7 and encodes the CF transmembrane conductance Pancreatic
regulator (CFTR), which is a cAMP-dependent chlo- Pancreatic insufficiency (common)
ride channel. Approximately 75% of children with Recurrent pancreatitis (uncommon)
CF in North America suffer from exocrine pancreatic Hepatobiliary
- Neonatal cholestatic jaundice
mozygous for the deltaF508 mutation which results in Hepatomegaly
the deletion of a phenylalanine at position 508. Five Biliary cirrhosis
to ten percent of infants with CF present with signs Portal hypertension
and symptoms of intestinal obstruction immediately Cholelithiasis
after birth due to meconium ileus. Some of these Intestinal
infants will experience intestinal perforation and Neonatal meconium ileus
meconium peritonitis while in utero. More common Neonatal small bowel atresia
presentations during infancy include chronic diar- Intestinal mucosal dysfunction
rhea, failure to thrive, and/or recurrent rectal pro- Meconium ileus equivalent (also called distal intestinal
lapse all of which result from exocrine pancreatic in- obstruction syndrome)
Rectal prolapse
secretion is markedly impaired and results in much can cause asymptomatic intestinal malabsorption
lower than normal post-prandial duodenal pH which and/or chronic diarrhea, and can be associated with
inactivates pancreatic lipase and also increases the protein-energy malnutrition and stunting.
risk of acid peptic disease. New therapies including The gold standard to diagnose SBBO in chil-
gene therapy, lung transplantation, ion-transport dren, as in adults, remains quantitative cultures of
regulatory therapy, airway clearance therapy, and duodenal aspirates collected in sterile conditions.
42
However, this technique is cumbersome and inva-
sive and so other modalities have been investigated
and validated. Currently most centers employ the
Giardiasis H2 breath test with either lactulose or glucose. In
SBBO, several studies have shown an elevated fasting
Giardia lamblia can cause chronic diarrhea and mal-
breath H2, which is considered a useful indicator of
absorption by a number of different mechanisms.
Transmitted by food and water and by person-to-
person contact, giardiasis is common in rural areas,
literature is available with lactulose as a substrate,
glucose has also been shown to be an effective sub-
used, and also among children who spend time in
strate for the diagnosis of SBBO in both adults and
day-care in the United States and Europe. Children
children. The combination of an elevated fasting
may be asymptomatic carriers, but they may also
breath H2 concentration and increased breath H2 ex-
present with chronic diarrhea, bloating, signs and
cretion after a sugar load has been reported to have
symptoms of malabsorption, and more rarely, failure
-
Giardia
tocols of antibiotic therapy, usually using metronida-
trophozoites or cysts in the stool (up to 90% sensitiv-
zole or poorly absorbable oral antibiotics, have been
ity once 3 consecutive stool samples are searched).
utilized to treat SBBO in children. Recent literature
An ELISA test for Giardia antigen in the stool is wide-
has suggested that chronic acid suppression may
ly available and is more sensitive and less expensive
contribute to SBBO.43
than traditional ovacyst and parasite examination of
the stool. The treatment of choice is nitazoxanide
7.5mg/kg/dose twice daily for 3 days with metroni-
dazole 5 mg/kg/dose 3 times a day for 5–7 days as Inflammatory Bowel Disease
an alternative. Approximately 20–25% of patients with Crohn’s dis-
ease (CD) and ulcerative colitis (UC) are diagnosed
before the age of 20 years. Although functional dis-
Small Bowel Bacterial Overgrowth orders are much more common, the incidence and
prevalence of IBD, particularly CD, have increased
SBBO is the colonization of the small intestine by bac-
-
teria that are normally found only in the colonic mi-
erature has shown that IBD that presents in child-
hood usually involves more intestine than adult
stagnant loop syndrome, small intestinal stasis syn-
phenotypes and results in a more aggressive disease
drome, and contaminated small bowel syndrome. It
course.44
was long thought that SBBO was limited to patients
The most common clinical manifestations of
with surgical or anatomical abnormalities, but subse-
both UC and CD are presented in Table 17.13. In some
quently SBBO has been recognized in children with-
cases, growth delay may be the only clinical presen-
out any anatomical abnormalities of the intestine,
tation, without any digestive signs or symptoms.45 A
in situations such as protein-energy malnutrition,
report from the Hospital for Sick Children in Toronto
acute infectious diarrhea, persistent post-infectious
observed that approximately 20% of CD patients
diarrhea, and even recurrent abdominal pain.37 SBBO
presented with “nonclassic” signs and symptoms
46
This de- TABLE 17.13
lay is a usually a byproduct of the insidious and non- Common Clinical Presentations in Pediatric Inflammatory
Bowel Disease
frequency of misdiagnoses, particularly functional
bowel disorders. The median time delay from onset Ulcerative
Symptom Crohn’s disease
of symptoms to recognition and established diagno- colitis
sis was 7.1 months for CD and 6.7 months for UC.47 Abdominal pain 62–95% 54–76%
Interestingly, patients with indeterminate colitis had
Diarrhea 52–78% 67–93%
the longest diagnostic delay—14 months.
The diagnostic criteria used to diagnose child- Hematochezia 14–60% 52–97%
hood-onset IBD are similar to those applied to adult- Weight loss 43–92% 22–55%
onset IBD. Pediatric gastroenterologists typically per-
Fever 11–48% 4–34%
form upper and lower endoscopy at the time of initial
44% (tags, fis-
evaluation, since approximately one-third of children 7% (tags,
Perianal lesions sures, fistula,
- fissures)
abscess)
tion at the time of presentation. Findings of granu-
lomas in the upper tract or focally enhanced gastric Growth failure 20–40% 5–10%
may help dif- Joint symptoms 10–20% 10%
ferentiate CD from UC in indeterminate cases.48 This
Fevers 25–40% 15–30%
is especially true in children <5 year of age in whom
the colon is the predominant site of involvement at ditionally, chronic undernutrition/malnutrition can
presentation.49 It has been reported that a large per- contribute to growth failure and pubertal delay, and
centage of children who present with colitis before factors that contribute to malnutrition include fecal
loss of trace elements and protein, fat and carbohy-
patients as they reach puberty.50 For Pediatric UC, it drate malabsorption, and perhaps most importantly,
has been reported that close to 80% of children pres- inadequate intake.
ent with pancolitis.51 This is in contrast to adults in Diminished bone mineral density is a serious
whom roughly one-third present with pancolitis. potential complication of pediatric IBD, although
Isolated small bowel disease is more commonly children with UC are generally less affected than
seen in children than in adults. The search for small those with CD. The etiology is multifactorial and
bowel disease is particularly important in children can include direct effects of cytokines on bone me-
capsule endoscopy can be an important diagnostic

tool to search for proximal small bowel disease in the therapy, and decreased physical activity. Although a
face of growth failure and normal upper and lower direct correlation between the disease activity and
endoscopy, or growth delay out of proportion to vis- degree of osteopenia has not been shown, children
ible mucosal disease.52 Delayed growth is a not an with active disease are more likely to have persistent
uncommon extraintestinal manifestation of IBD in cytokine elevations, to be treated with corticoste-
children, with >35% of children with CD and 6–10% roids, and to suffer intestinal loss of nutrients than
of those with UC presenting with impaired growth.53 children in remission and thus are at greater risk of
Assessments of growth parameters such as, height, bone demineralization. Strategies to prevent bone
weight and body mass index are an important part demineralization in children include avoiding long-
of monitoring disease activity and treatment suc- term corticosteroid use, prescribing adequate daily
cess.54,55 Impaired linear growth and pubertal delay vitamin D (800–1000 U) and calcium (1000–1500
in children with IBD may be the result of persistent mg), and encouraging physical activity.65
- Dual-energy X–ray absorptiometry (DEXA) may
TABLE 17.14 zine and balsalazide have been long approved and
Dosages Recommended for Pediatric Crohn’s Disease and Ulcerative Colitis -
diatric UC. 66 With such a small clinical trial literature,
most therapeutic evidence for Pediatric IBD is ex-
Drug Dosage trapolated from the adult IBD literature. Table 17.14
1–2 mg/kg/day prednisone equivalent, IV or PO in lists the usual pediatric dosage of drugs commonly
Prednisone
divided doses (maximum 40–60 mg) employed in the pharmacologic therapy of CD. It has
<25 kg: 6 mg × 8 weeks been suggested that salicylates such as mesalamine
Budesonide
>25 kg: 9 mg × 8 weeks are often under-dosed in children, as there has nev-
Sulfasalazine 50–75 mg/kg/day (maximum 4 g) er been a well-powered study addressing dosing in
children. Optimal dosing is likely 50 mg/kg/day but
Mesalamine 50–100 mg/kg/day (maximum 4.8 g/day)
can be escalated to 80–100 mg/kg/day to the adult
Metronidazole 10–20 mg/kg/day maximum of 4.8 g/day.
Azathioprine 2.5–3.0 mg/kg/day Steroid alternatives and steroid weaning re-
6-Mercaptopurine 1.0–1.5 mg/kg/day mains a priority in the treatment plan of pediatric
IBD patients. The use of budesonide reduces corti-
Methotrexate 15 mg/m2/week (maximum 25 mg)
costeroid-related side effects by approximately 50%,
Infliximab 5 mg/kg every 8 weeks* and may be a better alternative to systemic corti-
*Dose escalation and/or decreased interval occur in about 50% of patients. costeroids in children with ileal-cecal disease who
are able to swallow the enteric coated capsules. Im-
be used to make the diagnosis; however, standard munomodulators, most commonly the thiopurines
interpretation of DEXA using a T-score may not be ac- (6-MP and azathioprine), remain the most effective
curate in pre-pubertal children, as it does not take steroid-sparing therapeutic strategy available to pe-
into account the bone age of the child, and thus over- diatric patients to date. A study by Markowitz et al.
estimates the degree of demineralization.54 There-
fore, software that utilizes gender and age-corrected the time when corticosteroids are introduced. After
Z-scores must be used to make DEXA meaningful in 600 days on 6-MP, most children remained in clini-
this setting.65 Since the pathophysiology of decreased
bone density in children is different than that seen use.56 The delayed onset of action of thiopurines ren-
in postmenopausal women, bisphosphonates are not ders these drugs less effective for the induction of
generally indicated for the treatment of bone demin- remission, and much more effective in maintaining
eralization in children with IBD. remission. In fact, >80% of children with IBD are
The management of pediatric IBD patients is a placed on immunomodulator therapy within 2 years
complex effort that requires a comprehensive team of diagnosis.57 For those who do not tolerate or re-
approach to achieve optimum results. The principal spond to thiopurines, methotrexate has become an
goals of treatment include maximizing therapeutic increasingly utilized alternative immunomodulator.58
- In both Canada and Europe, nutritional therapy
ditional treatment goals include maximizing physi- is not uncommonly used as a primary therapy, in lieu
cal growth and psychosocial development while as- of steroids, for the induction of remission.59 Most pa-
suring treatment adherence and ensuring optimal tients are then transitioned or “bridged” to immuno-
quality of life. The prevention of long-term disease modulators. Compliance is an important issue, as the
complications and changing the natural history of children are not able to eat a regular diet during this
these diseases has become an important therapeutic 6–8 week period. Elemental formula has not been
outcome for both children and adults. shown to be more effective than polymeric formula,
To date, the only medication approved to treat and thus for palatability reasons more patients are
- placed on polymeric formula, allowing oral rather
than enteric tube administration. When necessary, a Table 17.15

nasogastric tube can be placed every night by the Frequency of Various Clinical Forms of Neonatal Cholestasis
child and removed in the morning before school.
The more common role of enteral nutrition is for
Disorder Percentage
weight loss and growth failure. Additional calories Idiopathic neonatal hepatitis 30–35
may be needed to achieve “catch-up growth” so that
children are able to achieve the ideal body weight for Extrahepatic biliary atresia 25–30
their age and height. In the event that a child needs
1
-Antitrypsin deficiency 7–10
long-term enteral supplementation, a gastrostomy
tube may be placed. Intrahepatic cholestasis syndrome (e.g., Alagille’s, Byler’s) 5–6
The prospective REACH trial demonstrated the
Bacterial sepsis 2
approval for this indication in 2006.60 While regu- Hepatitis cytomegalovirus 3–5
has been shown to be more effective than episodic Rubella, herpes 1

use, there remain many other clinical questions re-
Endocrine (hypothyroidism, panhypopituitarism) 1
garding how to optimize the use of biologic therapy
in pediatric CD.61 Galactosemia 1
investigation including questions as to whether bio-
Inborn errors of bile acid biosynthesis 2–5
logics are best used as monotherapy or with a con-
comitant immunomodulator and if so, for how long
dual therapy should be continued.61
bilirubinemia caused by a still unknown substance in
breast milk that inhibits bilirubin conjugation. This
Hepatobiliary Disease in Infants entity is rarely severe and the risk of kernicterus is
minimal. Its treatment typically consists of tempo-
and Young Children rarily interrupting breast milk feedings for 2–5 days.
Newborns often present with transient and self-lim- A 5-day course of phenobarbital has also been prov-
ited jaundice (also referred to as physiologic jaun- en effective and can be used when discontinuation of
breast-feeding is opposed by the mother.
days to weeks of life. This is due to intense hemoly- The differential diagnosis of persistent indirect
hyperbilirubinemia in newborn infants includes he-
newborn hepatic metabolism, including the conju- molytic diseases of the newborn including glucose
gating enzyme systems. This leads to an unconjugat-
ed (elevated indirect-reacting) hyperbilirubinemia. congenital spherocytosis and erythrocyte pyruvate
The total bilirubin peaks within a few days of birth
and gradually resolves. Treatment of severe unconju- hypothyroidism, and type I and type II Crigler-Najjar
gated hyperbilirubinemia is initiated only when the -
risk of kernicterus is increased; treatment typically sence of bilirubin uridine diphosphate–glucuronyl
consists of phototherapy to convert the unconjugat- -
ed bilirubin to non-toxic water soluble isomers that ciency. Gilbert’s syndrome is another cause of persis-
are excreted in the urine, hydration, and, if necessary, tent indirect hyperbilirubinemia in infancy and can
exchange blood transfusion. be associated with mild or intermittent indirect hy-
Breast-fed infants also can present with persis- perbilirubinemia throughout life59. When coupled
tent jaundice; these patients have an indirect hyper- with G6PDH Gilbert’s syndrome can put infants at
TABLE 17.16 TABLE 17.17

Laboratory Evaluation of Neonates with Cholestasis Signs and Symptoms of Metabolic Liver Disorders
Tests of Hepatic Function Historical Features

Serum bilirubin level (total and direct) Dietary changes: onset following introduction of new foods,
Serum albumin history of food avoidance
Coagulation profile (PT, PTT) Persistent vomiting
Blood ammonia Diarrhea
Serum glucose
Seizures
Fasting serum total bile acid level (cholylglycine level)
Respiratory distress (secondary to metabolic acidosis)
Measures of Nutritional Status Unusual odors of breath or urine
Fat-soluble vitamin levels (vitamin A, 25-hydroxyvitamin D, vitamin E, PT) Developmental delay
Complete blood count Family history for stillbirths, miscarriages, or other infants
Trace elements (zinc) with severe illness
Physical Findings
Diagnostic Tests
Viral and bacterial cultures, viral serology (TORCH), RPR Poor growth
Thyroid function tests (TSH, free T4) Unusual facial features
Metabolic screen (urine and serum amino acid levels, urine organic acid Ophthalmologic abnormalities: cherry-red spot, cataracts,
screen, urine and serum bile acid analysis) corneal clouding, Kayser-Fleischer rings
Sweat chloride Hepatomegaly
Urine-reducing substances/blood test for galactosemia
Neuromuscular weakness
1
-Antitrypsin phenotype
Iron, ferritin
Ultrasonography
Hepatobiliary scintigraphy*
Percutaneous liver biopsy anisms. Stresses such as sepsis, hypoxia, ischemia,
Cholangiogram (endoscopic, intraoperative) surgical procedures, medications, and parenteral
PT, prothrombin time; PTT, partial thromboplastin time; TORCH and RPR, nutrition can quickly lead to the development of cho-
titers for congenital viral and other infections such as syphilis; TSH, lestasis, especially in premature infants, in whom im-
thyroid-stimulating hormone. maturity of metabolism is more pronounced.
*Many centers no longer include routine use of scintigraphy in this setting.
Overall, liver diseases are uncommon in pedi-
atric patients, with estimates of prevalence ranging
from 1 in 1000 to 1 in 6000. In newborn infants, the
The presence of direct hyperbilirubinemia in most common hepatic illnesses are biliary atresia,
young infants is indicative of hepatobiliary pathology intrahepatic cholestatic syndromes, viral infections,
and metabolic disorders (especially 1-antitrypsin
immediate attention and a diagnostic assessment
by experienced physicians. Any infant with persis- is of paramount importance that biliary atresia be
tent jaundice at 2 weeks of age should have total and diagnosed before 6-8 weeks of age, since the prog-
conjugated bilirubin determined in order to rule out nosis quickly deteriorates when surgical interven-
cholestatic liver disease. tion is delayed beyond this age.
Newborn infants are predisposed to cholestasis,
due to developmental aspects of bile metabolism.
Evaluation and Management
As with many pediatric conditions, a careful history
and well-conducted physical examination can sub-
conjugation, and immature bile acid transport mech- stantially narrow down the differential diagnosis of
TABLE 17.18 gram to assess the liver for possible lesions that
Potential Laboratory Tests for Infants Suspected of Having would contraindicate a percutaneous liver biopsy,
Metabolic Liver Disorder and then a liver biopsy. A hepatobiliary radionuclide
excretory scan (HIDA scan) is also often obtained to
Complete blood count with differential and platelet count
Peripheral blood smear However, this test is time-consuming, sometimes de-
Blood glucose laying diagnosis by >5 days, and it is known to have
Serum electrolytes, arterial blood gas 10% false negative and false positive diagnostic er-
Serum triglyceride level rors, eliminating its routine use in many pediatric
Serum cholesterol level liver centers. In the few patients (<5%) where the
Serum uric acid level diagnosis remains unclear even after a liver biopsy,
Serum lactate an intraoperative cholangiogram is indicated (Table
Serum pyruvate 17.18).
Complete urinalysis Initial therapy for biliary atresia consists of a
Urine Clinitest laparotomy and a hepatoportoenterostomy (Kasai
Urine ferric chloride test
Plasma and urine quantitative amino acid determination procedure is not curative, with the majority of pa-
Plain abdominal radiograph (for adrenal calcifications) tients eventually requiring a liver transplant.
Long-bone radiograph When biliary atresia is determined not to be the
Bone marrow aspirate cause of neonatal cholestasis, often the combination
Percutaneous liver biopsy (including electron microscopy) of liver biopsy with other tests will reveal the diagno-
Serum 1-antitrypsin levels, serum 1-antitrypsin phenotype
determination diagnose, as the presentation may be subtle.
Red blood cell galactose-1-phosphate uridyl transferase In the management of infants and children with
activity liver disease, nutrition and general supportive treat-
Serum ceruloplasmin; serum copper; 24-hour urinary copper ment are crucial. Nutritional support entails ad-
determination equate and appropriate intake of energy (carbohy-
Sweat chloride determination; genetic markers for cystic drate and fat), protein, fat soluble and water soluble
fibrosis vitamins, and minerals to promote normal growth
Acid phosphatase, angiotensin converting enzyme and development. The potential problems related
Urine, stool, or red cell porphyrin levels to poor absorption must be considered. By reduc-
ing the concentration of micelles in the lumen of the
proximal small bowel, cholestasis interferes with the
neonatal cholestasis.62 Age of onset, severity of ill-
normal digestion and absorption of long-chain fats.
Medium-chain fatty acids, vitamins (especially fat-
can provide valuable information for the subse-
soluble vitamins), and mineral supplementations are
quent evaluation. Initial screening laboratory studies
should include a complete blood count with smear,
to look for evidence of hemolysis; prothrombin
time; total and conjugated bilirubin; liver enzymes Pearls and Pitfalls
(SGOT, SGPT, GGTP, alkaline phosphatase); and 1-
antitrypsin (Table 17.16). Further evaluation entails for the Board Exam
appropriate screening laboratory tests, including Recurrent abdominal pain is common in children
- occurring in more than 25% of school age children
ders, and structural abnormalities (Table 17.17). with functional causes being most common.
In ruling out biliary atresia, the evaluation Lactose intolerance is over diagnosed in children
should include screening laboratory tests, a sono-
and pre-teens. Outside of high-risk groups (e.g. usually involves more bowel and has a more
African Americans, Asian Americans), the presence aggressive course as compared to the adult
of childhood lactose intolerance should trigger an phenotype.
investigation to rule out underlying causes of small Pediatric ulcerative colitis leads to colectomy in
bowel disease (e.g. giardiasis, Celiac disease). 25% of those affected.
Hirschsprung’s Disease is a relatively uncommon In Pediatric Crohn’s disease, the monitoring of
cause of childhood constipation but critically linear growth velocity and sexual development
important to recognize when present. Clinical is critical to the accurate assessment of disease
clues include delayed passage of meconium (> 24 activity.
hours) as a newborn, need for laxatives or rectal Neonatal jaundice is most often physiologic and
stimulation since infancy and absence of stool in this can be confirmed by fractionating the bilirubin
the rectal vault on digital rectal exam of a toddler or and demonstrating that it is almost all indirect
school age child. bilirubin.
Gastroesophageal Reflux and regurgitation are Biliary Atresia is a critically important entity to
common in infants and are often benign. When identify and treat early as long term outcomes are
accompanied by poor growth, feeding difficulties, vastly improved when a modified Kasai procedure is
pain or extra-esophageal symptoms, treatment and performed before 6-8 weeks of life.
further evaluation can be considered.
Upper GI Series in the infant or child is only an
anatomic study and not a test of reflux. It can be Most Efficient Source Reviews
used to diagnose congenital and acquired anatomic
abnormalities that can lead to reflux and vomiting. for Board Preparation
Helicobacter pylori has been shown not to be an Di Lorenzo C, Colletti RB, Lehmann HP, et al. Chronic
important etiology of recurrent abdominal pain in Abdominal Pain in Children: A Clinical Report of
children. the American Academy of Pediatrics and the North
Toddler’s Diarrhea is a common form of diarrhea American Society for Pediatric Gastroenterology,
in this age group. The etiology is “iatrogenic” and Hepatology and Nutrition. J Pediatr Gastroenter Nutr
caused by prolonged dietary changes that lead to 2005;40:245–48.
the intake of a low fat diet supplemented by high Rudolph CD, et al. Guidelines for evaluation and
osmolarity and often sugary fluids. treatment of gastroesophageal reflux in infants and
Celiac disease affects about 1% of the population children: recommendations of the North American
and screening at risk populations with a total serum Society for Pediatric Gastroenterology and Nutrition.
IgA level and IgA tissue transglutaminase antibody J Pediatr Gastroenterol Nutr 2001;32 Suppl 2:S1–S31.
is recommended. Baker SS, Liptak GS, Colletti RB, et al. Evaluation and
Pediatric Celiac disease is ultimately diagnosed Treatment of Constipation in Infants and Children:
by the gold standard of endoscopic small bowel Recommendations of the North American Society for
biopsy which should include multiple samples Pediatric Gastroenterology, Hepatology and Nutrition
including at least two from the duodenal bulb. J Pediatr Gastroenter Nutr 2006;43:1–13.
Cystic Fibrosis is the most common inherited lethal Kim SC, Ferry GD. Inflammatory bowel diseases
disease in Caucasians. Neonatal genetic screening in pediatric and adolescent patients: clinical,
is now common but the gold standard remains the therapeutic, and psychosocial considerations.
sweat test which should be performed when there Gastroenterology 2004;126(6):1550–56.
is clinical suspicion even if there has been neonatal Curbside Consultation in Pediatric GI: 49 Clinical
genetic screening. Questions. Eds: Joel R Rosh, Athos Bousvaros. Slack
Pediatric Inflammatory Bowel Disease (IBD) Inc, 2013. ISBN 1617110140, 9781617110146
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Syllabus

Digestive Disease Self-Education Program

A Core Curriculum and Self-Assessment in Gastroenterology and Hepatology

A Core Curriculum and Self-Assessment in Gastroenterology and Hepatology

Arthur J. DeCross, MD, AGAF

AGA Institute Education

Maura H. Davis Director, Education

Kelley M. Blanchard Senior Coordinator, Education

Brenda Helmandollar Design and Composition

advertise or endorse a product.

Printed in the United States of America

Arthur J. DeCross, MD, AGAF

he American Gastroenterological Association (AGA) Institute expresses appreciation to the Gov-

Carl L. Berg, MD Jeanette Keith, MD

Dennis Jensen, MD Hospital of the University of Pennsylvania

Rupa Mukherjee, MD Sidney Barritt, IV, MD

Karthik Ravi, MD C. Richard Boland, MD, AGAF

Reza Shaker, MD Jennifer Christie, MD

C. Prakash Gyawali, MD, MRCP, AGAF Ioannis Oikonomou, MD

Charles Halsted, MD, AGAF Amy S. Oxentenko, MD

Jonathan Huang, DO Henry P. Parkman, MD

Melissa Teitelman, MD, MSCE

Anne C. Travis, MD, MSC

Jamile Wakim-Fleming, MD, FACG

Arnold Wald, MD, AGAF

C. Mel Wilcox, MD, FASGE

Richard K. Wood Jr., MD

Accreditation and CME Credits

Test Taking Tips from the Experts

Suzanne Rose, MD, MSEd

Norma Saks, EdD

Planning for the Examination

examination can be found on the ABIM website: http://www.abim.org/specialty/gastroenterology.aspx

Studying for the Examination

Make a study schedule

or two before it is actually required. This does not -

Remember: Taking any examination poorly

Take practice tests

Analyze each question: What is the question asking?

Test Error Analysis

Question # Esophagus 1. Know the answer 1. Material was not 1. Deliberate

Stomach/Duodenum 2. Predict the answer, studied 2. Misinterpreted

Liver i.e. make an 2. Material studied but 3. Impulsive

Biliary Tract intelligent guess learned incorrectly

Pancreas 3. Not know the 3. Material studied

Small intestine answer at all but could not recall

Consider working in a group or with a partner

Taking the Actual Examination

Classifying Questions and Time Management

Always read through the case description or “stem” of a question first

We wish you great success!

Foreword ..................................................................................................................... iii

Seth Sweetser, MD and Karthik Ravi, MD

Circulating Secretagogues .............................................................................................................................. 91

Endoscopic Features ...................................................................................................................................... 127

Clinical Categories......................................................................................................................................... 160

Clinical ........................................................................................................................................................... 176

Introduction ............................................................................................................................................................ 195

Follow-Up Medical Management .......................................................................................................................... 231

Pancreatic Cancer .................................................................................................................................................. 251

Secretion of Water and Electrolytes ..................................................................................................................... 277

Biliary Colic .................................................................................................................................................... 329

Epidemiology ................................................................................................................................................. 368