Naspghan Manual

The NASPGHAN Fellows Concise Review of
Pediatric Gastroenterology,
Hepatology and Nutrition
First Edition ● 2011
Editors-In-Chief
Judith M. Sondheimer, MD
Professor of Pediatrics
Georgetown University School of Medicine
Chief of Pediatric Gastroenterology
Georgetown University Hospital
Christine Waasdorp Hurtado, MD, MSCS, FAAP

Assistant Professor of Pediatrics
University of Colorado School of Medicine
Denver, CO
Supported by
Castle Connolly Graduate Medical Publishing, Ltd
17 Battery Place, Suite 643 ● New York, NY 10004 ● Tel: 212.644.9696 ● Fax: 646.827.6443
www.ccgmp.com ● email: info@ccgmp.com
Castle Connolly Graduate Medical Publishing, Ltd. publishes reveiw manuals to assist
residents and fellows in preparing for board certification exams, and practicing physicians
in preparing for board recertification.
NASPGHAN and Castle Connolly Graduate Medical Publishing, Ltd.

would appreciate being informed of any errata you may come across.
Please email us at info@ccgmp.com
Disclaimer
This book was written by a large group of pediatric gastroenterology fellows, each of
whom selected a faculty mentor with whom to write their particular subsection. The
subsections were reviewed by the mentors and also by the Editors. The book was written
by fellows for fellows as a template for study and examination preparation. While every
effort has been made to provide correct and up to date information, the book should not be
considered a patient care manual. Indeed, part of the value of the book was in educating
the fellow-authors about the process of writing a study guide. The Editors and publisher
welcome comments from readers on both form and content.
Notice
This book is intended for use by licensed Physicians, Nurse Practicioners, and Physician Assistants only.
It is not intended for use in the delivery of health care services, and cannot replace sound clinical judgement
or individualized patient care for such purposes.
The authors, publishers, distributors, and sponsors of this book expressly disclaim all warranties, express or
implied, with respect to this book and its contents, including any warranties as to the quality, accuracy,
completeness or suitability o fthe information contained in this book for any particular purpose. Without limiting
the foregoing, the caution the reader that use of this book does not guarantee passage of any board certification
exams, written or otherwise.
The authors, publishers, distributors and sponsors of this book expressingly disclaim any liability to any person
or organization for any loss or damage caused by any errors or omissions in this book.
ISBN: 978-0-9846361-1-2
Our thanks to Copy Editor Sarah Herndon and Senior Design Director Tara Rolandelli
©2011. All Rights Reserved. Castle Connolly Graduate Medical Publishing, Ltd. and NASPGHAN
Dedication
The editors and authors of the Fellows Concise Handbook of Pediatric Gastroenterology
would like to dedicate this book to B Li, MD, Professor of Pediatrics at the Medical College
of Wisconsin and past president of NASPGHAN. It was Dr. Li’s vision to develop a guide for
board preparation and re-certification while he was president of NASPGHAN in 2009-10.
It is completely consistent with his character that he entrusted the development of this
handbook not to a group of senior colleagues, but to the NASPGHAN Fellows Committee.
When funds were obtained from Nestle USA for a NASPGHAN-endorsed board review, he
immediately identified this handbook as the project that should receive funding. Thank you,
Dr. Li. We are inspired by your dedication to education and want to thank you for your
personal interest in our success as physicians and persons.
Preface
The NASPGHAN Fellows Concise Handbook of Pediatric Gastroenterology is a product of discus-

sions that took place in 2009 between B Li,MD, then president of NASPGHAN, and the NASPGHAN
Fellows Committee. The lack of an up-to-date and comprehensive review that would assist fellows
in preparing for certifying examinations was identified as an issue of importance to Pediatric GI,
Hepatology and Nutrition fellows throughout North America. With the encouragement of Dr. Li and
our publisher, Michael Wolf, Ph.D., Nestlé Nutrition agreed to fund a printed version of what had
originally been planned as an on-line resource. Thanks to Jose Saavedra, MD, Medical Director of
Nestle USA for his support in the development of this new resource.
We used the weighted topic list prepared by the American Board of Pediatric Gastroenterology
Sub-board to guide the outline of the Handbook. Sections have been weighted as to length and
emphasis to reflect the relative importance assigned to the topics by the Sub-board. To improve
the Handbook’s utility as a study guide, we have focused on factual content and have not included
discussions of current controversies in diagnosis, therapy and causation - interesting as they may be.
The number of images and color pictures in the Handbook has been limited because of time. It is
vital to remember that ours is a visual sub-specialty. The complete pediatric gastroenterologist in-
terprets radiographs, endoscopy images, physical findings and histology slides. Physicians preparing
for exams should be sure to access other resources that fill this information void. We also elected
not to include a comprehensive list of medications and dosages, as this information is constantly
changing and available elsewhere. The listed dosages in the Handbook are guidelines, and addi-
tional resources should be used to confirm therapeutic dosing.
The last section of the Handbook contains questions and answers derived from the content. Most
of the questions were written by fellows with support from their mentors. The questions do not
claim to represent the questions one will encounter on the board examination. They are simple
questions which should prompt the reader to review the referenced section listed with the ques-
tion.
The Handbook contains an index which will expand its utility as a general reference, not just a
study guide. Many thanks to Angel Colon, MD for creating the index and reviewing the ques-
tions and answers. Thanks also to Shikha Sundaram, MD, Rob Kramer, MD, Cara Mack, MD, and
Ed DeZoeten, MD who assisted us with editing the over 150 manuscripts submitted by our many
authors. Most of all thank you to the fellows and their mentors who created the content of the
Handbook. Many fellow-authors wrote several sections. Your contributions have made this resource
a reality! Thank you in particular to Maria Perez, DO, current Chair of the NASPGHAN Fellows Com-
mittee, for her many beautifully written sections and for her indispensible help in recruiting fellows
to contribute to the Handbook.
We thank our families for their help and encouragement. Thanks to Henry Sondheimer and thanks
to Tim Hurtado and our children Emily, Evan, and Morgan. We never could have completed this
task without your generosity.
It is our hope that The Handbook will be updated every two years. If you find the book helpful
in your practice or exam preparation, or have suggestions for enhancing the review, please let us
know! Good reading!

Judith M. Sondheimer, MD
Dear Colleague:
We are delighted to present to you the first edition of The NASPGHAN Fellows
Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition, to be
distributed to assist you in preparing for the boards in pediatric gastroenterology
and nutrition. We hope that this manual will help you not only in this endeavor
but, even more importantly, in the practice of high quality, state-of-the-art pedi-
atric gastroenterology and nutrition.
We applaud the heroic efforts of the NASPGHAN Fellows Committee, ably and
enthusiastically led by Drs. Christine Waasdorp Hurtado and Maria Perez. These
two individuals energetically and tirelessly recruited pediatric gastroenterol-
ogy fellows throughout North America to contribute manuscripts, critiqued at
their local institution by attending pediatric gastroenterologists. Thus we extend
gratitude to all contributors – fellows and faculty alike. In addition, we are very
grateful to Dr. Judith Sondheimer, a highly respected, senior pediatric gastroen-
terologist, who graciously agreed to be Senior Editor-in-Chief.
We also thank Michael D. Wolf, PhD and his staff at Castle Connolly Graduate
Medical Publishing for their wonderfully effective efforts in bringing this ambi-
tious project to completion. We also express our gratitude to our sponsor, the
Nestlé Nutrition Institute, without whose support this important project would
not be possible.
While this is a board review text it is important to note that the American Board
of Pediatrics was not involved in any part of this process. We do hope you will
all find this book useful not only in your board preparations but in your clinical
practice.
Very best wishes,
Kathleen B. Schwarz, M.D.

Professor of Pediatrics
Johns Hopkins University School of Medicine
President, North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition
List of Contributors
We would like to thank Associate Editors:
Ed deZoeten, MD, PhD
Robert Kramer, MD
Cara Mack, MD
Shikha S. Sundaram, MD, MSCI
Mazen I. Abbas, DO, MPH Sonal S. Desai, MD

Imad Absah, MD Edwin deZoeten, MD, PhD
Maisam Abu-El-Haija, MD Molly Dienhart, MD
Arun Aggarwal, MD Frank DiPaola, MD
Sabina Ali, MD Jennifer L. Dotson, MD
Razan Alkhouri, MBBS Chelly, Dykes, MD
Naim Alkouri, MD Dawn Ebach, MD
Ammar Al-Rikabi, MD Mounif El-Youssef, MD
Dina Al-Zubeidi, MD Karan McBride Emerick, MD
Julia L. Anderson, MD Steve Erdman, MD
Shruti Arya, MD Rima Fawaz, MD
Katherine Atienza, DO Lina M. Felipez, MD
Ruba Azzam, MD Minela Fernandez, MD
Susan S. Baker, MD, PhD Laurie Fishman, MD
Jane Balint, MD Thomas Flass, MD, MS
Barbara Bambach, MD Deb Freese, MD
Julie Bass, MD Juliana Frem, MD
Vince F. Biank, MD Joel Friedlander, DO, MBE
Anas Bitar, MD Craig Friesen, MD
Samra S. Blanchard, MD Yonathan Fuchs, MD
Ellen Blank Katryn Furuya
Brendan Boyle, MD Megan E. Gabel, MD
Julia Bracken, MD Kriston Ganguli, MD
Gia Bradley, MD Jennifer Garcia, MD
Herbert Brill, MD Cheryl Gariepy, MD
David Brumbaugh, MD Lynette Gillis, MD
Luis Caicedo, MD Vi Lier Goh, MD
Carolina S. Cerezo, MD Roberto Gomez, MD
Jorge Chavez-Saenz, MD Mariana Gomez-Nájera, MD
Anupama Chawla, MD Alka Goyal, MD
Edaire Cheng, MD Alex Green, DO
Lay Har Cheng, MD, MSPH Leana Guerin, MD
Rebecca Cherry, MD Nitika Arora Gupta, MD
Ashish Chogle, MD, MPH Michael S. Halata, MD
Lillian Choi, MD Alfredo Larrosa Haro, MD, PhD
Jose Cocjin, MD Jeri E.F. Harwood, PhD
Conrad Cole, MD, MPH, MSc Solange Heller, MD
Steven Colson, MD Lina Maria Hernandez, MD
Emily Contreras, MD James Heubi, MD
Carmen Cuffari, MD Meredith Hitch, MD
James Daniel MD Edward Hoffenberg, MD
Adam Davis MD Anna Hunter, MD
Amy R. DeFelice, MD Christine Waasdorp Hurtado, MD, MSCS, FAAP
Karen DeMuth, MD Paul E. Hyman, MD
Jolanda Denham, MD David Israel
Nirav K. Desai, MD Daniel Kamin
Jess L. Kaplan, MD Isabel Rojas, MD
Aubrey J. Katz, MD Rachel Rosen, MD
Ajay Kaul, MD Philip Rosenthal, MD
Melissa Kennedy, MD Thomas Rossi, MD
Julie Khlevner, MD Robert Rothbaum, MD
Crystal Knight Gary Russell, MD
Debora Kogan-Liberman, MD Sabina Sabharwal, MD
Robert Kramer, MD Rina Sanghavi, MD
Ben Kuhn, MD William San Pablo, MD
Joel E. Lavine, MD, PhD Miguel Saps, MD
Daniel H. Leung, MD Ahmed Sarkhy, MD, FRCPC
Henry C. Lin, MD Meghana Sathe, MD
Simon Ling, MD Cary Sauer, MD
Cheryl A. Little, MD Ann Scheimann, MD, MBA
Mark E. Lowe, MD Kathleen B. Schwarz, MD
Brandy Lu, MD Steven M. Schwarz, MD
Ying Lu, MD Jeffrey B. Schwimmer, MD
Sarah Shrager Lusman, MD Timothy Sentongo, MD
Cara Mack, MD Thomas J. Sferra, MD
Nisha Mangalat, MD Ala K. Shaikhkhalil, MD
Maria Mascarenhas, MD Darla R. Shores, MD
Elizabeth M. McDonough, MD Michelle Sicard, MD
Maireade McSweeney, MD, MPH Lesley Smith, MD
Khyati Mehta, MD Aliza Solomon, MD
Jeremy Middleton, MD Inbar Spofford, MD
Elizabeth Mileti, DO Arvind Srinath, MD
Steve Min, MD Janis Stoll, MD
Aminu Mohammed, MD Carolyn Sullivan, MD
Javier J. Monagas, MD Jillian S. Sullivan, MD
Christopher J. Moran, MD Shikha S. Sundaram, MD, MSCI
Brigitte Moreau, MD Pornthep Tanpowpong, MD, MPH
Véronique Morinville, MD Sharon Taylor, MD
Michael Narkewicz, MD Kelly Fair Thomsen, MD
Catherine Newland, MD Justine M. Turner, MD
Samuel Nurko, MD, MPH Aliye Uc, MD
Stephanie Page, MD Paul Ufberg, MD
Pablo J. Palomo, MD Charles Vanderpool, MD
Raza A. Patel, MD, MPH Alexandra B. Vasilescu, DO, MS
Tiffany Patton, MD Preeti Viswanathan, MD
Adam Paul, DO Ghassan Wahbeh, MD
Maria E. Perez, DO Mei-Lun Wang, MD
David Piccoli, MD Sheree Watson, MD
John Pohl, MD Jessica Wen, MD
Carol Potter, MD Lisa Wheelock, MD
Jaya Punati, MD Asha Willis, MD
Phil Putnam, MD Harland S. Winter, MD
Ruben E. Quiros-Tejeira, MD Desale Yacob, MD
Riad Rahhal, MD Lillienne Yoon, MD
Ramya Ramraj, MD Elizabeth L. Yu, MD
Meenakshi Rao, MD, PhD Shamila B. Zawahir, MD
Sara Rippel, MD Garrett C. Zella, MD
Yolanda Rivas, MD Zili Zhang, MD, PhD
Leonel Rodriguez, MD, MS Monica M. Zherebtsov, MD
Norberto Rodriguez-Baez, MD
Contents
1. Mouth and Esophagus

A. Normal Anatomy, Development and Physiology........................................ 1
B. Normal Microanatomy.............................................................................. 5
C. Normal and Abnormal Esophageal Motility............................................... 7
D. Deglutition..............................................................................................11
E. Dysphagia...............................................................................................13
F. Congenital Anomalies.............................................................................15
G. Gastroesophageal Reflux and Gastroesophageal Reflux Disease................19
H. Esophagitis
1. Eosinophilic Esophagitis................................................................ 23
2. Infectious Esophagitis................................................................... 25
3. Histology of Esophagitis............................................................... 29
I. Upper GI Bleeding...................................................................................31
J. Esophageal Caustic Injury....................................................................... 33
K. Esophageal Foreign Bodies..................................................................... 35
2. Stomach
A. Normal Anatomy, Development, Physiology and Microanatomy............... 39
B. Congenital Anomalies of the Stomach.....................................................41
C. Pyloric Stenosis....................................................................................... 43
D. Colic...................................................................................................... 45
E. Gastritis................................................................................................. 47
F. Helicobacter Pylori................................................................................. 53
G. Ingestions and Trauma........................................................................... 57
3. Small Intestine
A. Normal Anatomy, Development and Physiology.......................................61
B. Normal Microanatomy............................................................................ 67
C. Normal and Abnormal Motility................................................................71
D. Congenital Anomalies
1. Meckel Diverticulum..................................................................... 75
2. Malrotation.................................................................................. 77
3. Cysts........................................................................................... 79
4. Gastroschisis And Omphalocele.................................................... 81
E. Necrotizing Enterocolitis......................................................................... 83
F. Intussusception...................................................................................... 87
G. Celiac Disease........................................................................................ 89
H. Tropical Sprue........................................................................................ 93
I. Protein-Losing Enteropathy..................................................................... 97
J. Appendicitis .......................................................................................... 99
K. Food- and Water-Borne Diseases...........................................................101
L. Enteric Infections ..................................................................................105
M. Autoimmune Enteropathy...................................................................... 115
N. Small Bowel Obstruction....................................................................... 117
O. Small Bowel Trauma..............................................................................121
P. Short Bowel Syndrome—Intestinal Failure..............................................127
Q. Small Bowel Bacterial Overgrowth.........................................................133
R. Small Bowel Transplantation..................................................................137
S. Small Bowel Tumors..............................................................................141
4. Colon
A. Normal Anatomy, Development And Physiology.....................................147
B. Microanatomy.......................................................................................153
C. Normal and Abnormal Motility..............................................................157
D. Hirschsprung Disease............................................................................161
E. Chronic Constipation.............................................................................165
F. Rectal Prolapse......................................................................................169
G. Hemorrhoids.........................................................................................171
H. Lower GI bleeding.................................................................................175
I. Colitis
1. Inflammatory Bowel Disease—Crohn’s Disease............................177
2. Inflammatory Bowel Disease—Ulcerative Colitis...........................183
3. Other Inflammatory Lesions of the Bowel....................................187
4. Colitis Not Due to Inflammatory Bowel Disease............................191
J. Perianal Disease....................................................................................195
K. Polyps ..................................................................................................199
L. Intestinal Pseudo-Obstruction............................................................... 205
5. Biliary Tree—Intra- and Extrahepatic Bile Ducts and Gall Bladder
A. Normal Anatomy, Development, Physiology and Microanatomy..............207
B. Gall Stones........................................................................................... 209
C. Cholecystitis..........................................................................................213
D. Biliary Atresia........................................................................................217
E. Other Disorders of the Bile Ducts...........................................................219
6. Liver
A. Normal Anatomy, Development and Physiology.................................... 223
B. Microanatomy.......................................................................................225
C. Jaundice...............................................................................................227
D. Elevated Aminotransferases...................................................................231
E. Hepatomegaly..................................................................................... 233
F. Ascites..................................................................................................237
G. Liver Masses......................................................................................... 239
H. Cirrhosis and Portal Hypertension..........................................................243
I. Fulminant Liver Failure...........................................................................249
J. Cholestatic Liver Diseases
1. Newborn....................................................................................253
2. Older Child.................................................................................257
K. Infectious and Inflammatory Diseases
1. Congenital Hepatic Infections......................................................261
2. Viral Hepatitis.............................................................................265
3. Bacterial, Parasitic and Other Infections of the Liver......................271
4. Chronic Hepatitis—Autoimmune Hepatitis and
Crossover Syndromes in Children.................................................275
5. Granulomatous Hepatitis.............................................................279
L. Congenital Hepatic Fibrosis................................................................... 283
M. Vascular Disease of the Liver................................................................. 285
N. Metabolic/Genetic Liver Disease
1. Bile Acid Synthetic Defects......................................................... 289
2. Disorders of Bilirubin Metabolism................................................293
3. Disorders of Carbohydrate Metabolism (Glycogen Storage)..........297
4. Disorders of Amino Acid Metabolism...........................................301
5. Disorders of Lipid Metabolism—Fatty Acid Oxidation.................. 305
6. Urea Cycle Defects..................................................................... 309
7. Alpha-1-Antitrypsin Deficiency.................................................... 311
8. Wilson Disease............................................................................313
9. Peroxisomal Disorders.................................................................317
10.Familial Hepatocellular Cholestatic Disorders................................319
O. Other Acquired Liver Diseases
1. Reye Syndrome...........................................................................325
2. Drug-Induced Liver Injury............................................................327
3. Iron-Storage Disorders.................................................................331
4. Non-Alcoholic Fatty Liver Disease and
Steatohepatitis (NAFLD/NASH)....................................................335
5. Acute Graft versus Host Disease and Veno-Occlusive Disease...... 339
P. Systemic Diseases Affecting the Liver.................................................... 343
Q. Liver Transplantation............................................................................ 349
7. Pancreas
A. Normal Anatomy, Development and Physiology.....................................353
B. Exocrine Function..................................................................................357
C. Congenital Anomalies of the Pancreas...................................................361
D. Acute Pancreatitis................................................................................. 363
E. Chronic Pancreatitis.............................................................................. 367
F. Shwachman-Diamond Syndrome...........................................................371
G. Cystic Fibrosis........................................................................................375
8. Nutrition
A. Nutritional Requirements of Pre-Term and Term Infants,
Children and Adolescents..................................................................... 379
B. Comparison of Human Milk and Cow-Milk-Based Formulas................... 383
C. Special Formulas.................................................................................. 387
D. Nutritional Assessment......................................................................... 389
E. Growth Failure......................................................................................393
F. Malnutrition......................................................................................... 397
G. Obesity ............................................................................................... 401
H. Normal Digestion and Absorption ........................................................ 405
I. Disaccharidase Deficiency......................................................................413
J. Congenital Enzyme and Transport Defects............................................. 417
K. Vitamin and Mineral Absorption, Function and Deficiency States........... 423
L. Essential Amino Acids...........................................................................431
M. Nutritional Therapy................................................................................435
N. Nutritional Supplementation: Enteral and Parenteral Nutrition................ 439
O. Nutritional Consequences of Cholestasis............................................... 445
P. Carbohydrate Malabsorption................................................................ 687
9. Diagnostic Testing
A. Endoscopy........................................................................................... 449
B. Intestinal Biopsy....................................................................................451
C. Liver Biopsy...........................................................................................455
D. Additional Studies
1. Esophageal pH and Impedance Monitoring.................................459
2. Gastric-Function Tests................................................................ 463
3. Motility Testing.......................................................................... 465
4. Pancreatic-Function tests............................................................ 469
5. Breath Tests................................................................................473
E. Laboratory Evaluations
1. Alkaline Phosphatase..................................................................475
2. Hematologic Manifestations of GI Disease...................................477
3. Testing for Microorganisms........................................................ 481
4. Stool Analysis............................................................................. 483
F. Radiologic Evaluations.......................................................................... 487
10. Therapy
A. Fluid Therapy........................................................................................493
B. Blood Replacement...............................................................................497
C. Drugs
1. Anti-Rejection and Anti-Inflammatory........................................ 499
2. Biologics.................................................................................... 505
3. Acid Control.............................................................................. 509
4. Prostaglandins............................................................................ 513
5. Sucralfate................................................................................... 515
6. Pancreatic Enzymes..................................................................... 517
7. Motility Agents...........................................................................519
8. Laxatives and Stool Softeners......................................................521
9. Anti-Pruritic Agents.................................................................... 523
10.Prebiotics/Probiotics....................................................................525
11. Anti-Diarrheal Drugs...................................................................529
D. Therapeutic Endoscopy..........................................................................531
11. Psychologic Considerations
A. GI Manifestations of Psychologic Disorders............................................537
B. Rumination...........................................................................................541
C. Feeding Refusal and Psychogenic Dysphagia......................................... 543
D. Eating Disorders................................................................................... 545
E. Munchausen By Proxy Syndrome.......................................................... 549
12. Miscellaneous
A. Abdominal Pain.....................................................................................553
B. Irritable Bowel Syndrome.......................................................................557
C. Abdominal Masses................................................................................561
D. GI Manifestations of Immunodeficiency................................................ 565
E. Cystic Fibrosis........................................................................................571
F. Chronic Diarrhea...................................................................................575
G. Food Allergy.........................................................................................579
H. GI Manifestations of Endocrine Disorders.............................................. 583
I. Secretory Tumors Affecting the GI Tract ............................................... 587
J. Graft versus Host Disease......................................................................591
K. Drug-Induced Bowel Injury....................................................................597
L. Radiation-Induced Injury....................................................................... 601
M. Ostomy Care........................................................................................ 605
13. Study Design and Statistics
A. Study Design and Statistics................................................................... 607
B. Research Methods: Evaluation of the Data............................................. 611
14. Principles of Teaching and Learning...........................................................617
15. Ethics.............................................................................................................621
16. Questions and Answers...............................................................................625
17. Index............................................................................................................ 691
1A. Normal Anatomy,
Development, and Physiology
Chelly Dykes, MD
Ajay Kaul, MBBS, MD
I. Developmental Stages of the Esophagus

A. Gestation week 4—primitive foregut forms as a ventral tubular structure
B. Lateral grooves invaginate on each side of the proximal foregut, and fuse to separate the respiratory
tube (ventral) from the esophageal tube (dorsal)
C. The dorsal tube fills with ciliated columnar epithelium
1. Incomplete fusion of lateral grooves causes partial or complete failure of separation of dorsal
and ventral compartments, producing several forms of tracheoesophageal fistula (TEF)
2. TEF or laryngopharyngeal cleft anomalies occur in 1:3,000–4,000 live births
D. Gestation week 10—esophageal lumen re-established
E. Gestation week 16—esophageal stratified squamous epithelium appears; swallowing can be ob-
served
F. Normal esophageal length
1. 8–10 cm at birth
2. Doubles in first year of life
3. Final adult length ~25 cm from cricopharyngeus to lower esophageal sphincter
II. Anatomy
A. Histology—see chapter on Normal Microanatomy
B. Structure
1. Anatomic limits
a. Upper limit—upper esophageal sphincter is at the level of the cricoid cartilage
b. Esophageal body traverses the chest in the posterior mediastinum
c. Esophagus is divided in thirds based on the type of muscle —striated muscle in the up-
per third, mixed striated and smooth muscle in the middle, and smooth muscle only in
the lower third
d. Lower esophageal sphincter (LES) is the anatomic distal end of the esophagus
e. There is a short abdominal segment of the esophagus below the diaphragm, composed
mainly of the lower 2–3 cm of the LES
2. Upper esophageal sphincter (UES)
a. Skeletal muscle
b. Anatomically poorly defined—comprised of three structures:
1) Musculature of the cricopharyngeus muscle
2) Lower border of the inferior pharyngeal constrictor
3) Upper fibers of the esophagus
3. LES composed of:
a. Expanded circular smooth muscle of the distal esophagus
b. Buttressed by the right crus of the diaphragm
C. Innervation
1. Afferents
a. Vagus nerve—transmits information about pain, temperature, chemical, osmotic stimuli
b. Spinal nerve—afferents from muscle layer and serosa transmit mechanosensitive infor-
mation and act as nociceptors
1) Afferents from intraepithelial nerve endings mediate acid-induced pain
2) Calcitonin gene-related peptide and substance P in these nerves mediate visceral
pain
2. Efferents are both parasympathetic and sympathetic
a. Vagus nerve provides predominate motor innervation
Section 1 - Mouth and Esophagus 1

b. Parasympathetic nerve supply
1) Nucleus ambiguus and dorsal motor nucleus of the vagus nerve
2) Innervation of the esophageal muscles and glands
c. Sympathetic nerve supply
1) Cervical and thoracic sympathetic chain (spinal segments T1–T10)
2) Regulates blood vessels, sphincter contraction, peristalsis, glandular activity
d. Preganglionic nerves terminate on cells of Auerbach (myenteric) plexus between circu-
lar and longitudinal layers of muscle, and stimulate smooth muscle. Auerbach plexus
also present in skeletal muscle, though function unclear
3. Motor Function:
a. Upper 1/3 of esophagus (including UES) is under central control (skeletal muscle)
b. Lower 2/3 of esophagus (including LES) has both central and peripheral control
(smooth muscle)
4. Pain sensation:
a. Noxious stimuli trigger chemoreceptors (direct irritants) or mechanoreceptors (pressure)
b. Both vagal and sympathetic afferents carry pain signals centrally
c. Pathways overlap with heart and respiratory system, making localization of pain dif-
ficult
d. Significant overlap between different pain receptors (chemical, mechanical, tempera-
ture), making types of sensation difficult to separate
5. Visceral hyperalgesia
a. Prolonged acid exposure in the esophagus causes altered sensory perception and sensi-
tization of neurons, with heightened pain signaling even to physiologic events
b. Visceral hyperalgesia may contribute to feeding problems
D. Vasculature
1. Arterial
a. Upper esophagus—branches of superior and inferior thyroid arteries
b. Midesophagus—branches of the bronchial and right intercostal arteries and descending
aorta
c. Distal esophagus—branches of the left gastric, left inferior phrenic, and splenic arteries
2. Venous
a. Upper esophagus—drained by superior vena cava
b. Midesophagus—azygos veins
c. Distal esophagus—portal vein (via left and short gastric veins). Varices occur in this area
III. Physiology
A. Swallowed food bolus is delivered to hypopharynx by tongue and mouth musculature
1. UES is constantly contracted (except while sleeping)
2. Coordinated swallow includes simultaneous elevation of soft palate, closure of the larynx,
and brief relaxation of cricopharyngeus to admit swallowed bolus through UES
3. Cricopharyngeal achalasia is characterized by failure of UES relaxation with swallowing
a. Associated with Chiari malformation (centrally mediated dysfunction of UES)
b. Can be associated with disorders of skeletal muscle or neurologic disorders that affect
skeletal muscle
B. Both the force applied to the bolus by voluntary swallowing and esophageal peristalsis propel the
bolus through the esophageal body
1. Average speed of esophageal peristalsis is about 1 cm/sec
2. Average speed of bolus through the hypopharynx during swallowing is 10 cm/sec
C. LES relaxation occurs simultaneous with swallowing
1. LES relaxation persists until resting pressure is restored by wave of esophageal peristalsis
2. Duration of relaxation is several seconds, sufficient to allow bolus to pass through the relaxed
LES
D. Spontaneous transient LES relaxation (TLESR) in the absence of swallowing is the most important
mechanism permitting gastroesophageal reflux
1. Spontaneous LES relaxations occur with increased frequency postprandially due to gastric
distension, which stimulates subdiaphragmatic nerves
2. Afferent sensory fibers from the stomach go to vagal nuclei, which lead to efferent vagal-
mediated relaxation of LES
2 The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition
E. Abnormal LES pressure
1. Resting pressure of LES is ~20–30 mm Hg. Resting pressure below 10 mm Hg is
abnormally low
a. Resting pressure is reduced by:
1) Drugs—theophylline, nitroglycerine, botulinum toxin
2) Inflammation
3) Displacement of LES into thorax (hiatus hernia), which reduces pressure due to
negative pressure environment
4) Disorders of smooth muscle
2. Increased resting LES pressure occurs with:
a. Displacement of LES into abdominal cavity, where resting pressure is augmented by
positive intraabdominal pressure
b. External abdominal compression
c. Cholinergic agents (bethanechol), gastrin
d. Esophageal achalasia and diffuse esophageal spasm may have abnormally high resting
LES pressure
F. Esophageal glands
1. Release mucous important for esophageal clearance of food and neutralizing any refluxed
acid
Recommended Reading
Braden K, Urma D. Esophagus anatomy and development. GI Motility Online. 2006. doi: 10.1038/gimo6.
Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th ed.
Philadelphia, PA: Elsevier Health Sciences; 2010.
Kleinman RE, Goulet OJ, Mieli-Vergani G, et al, eds. Walker’s Pediatric Gastrointestinal Disease: Pathophysiol-
ogy, Diagnosis, Management. 5th ed. Lewiston, NY: BC Decker; 2008.
Sengupta JN. Esosphageal sensory physiology. GI Motility Online. 2006. doi: 10.1038/gimo16.

1B. Normal Esophageal
Histology
Luis Caicedo MD
Carmen Cuffari MD
I. Introduction
A. Most of the esophagus is lined by squamous epithelium, a non-keratinized, stratified epithelium
B. Distal end lined by columnar epithelium
C. The normal squamo-columnar junction is at the level of the diaphragm
D. Esophageal squamous mucosa contains three layers – epithelium, lamina propria, and
muscularis mucosae
II. Squamous epithelium of the esophagus

A. Basal layer
1. Contains several layers of cuboidal basophilic cells, which divide and differentiate as they
move toward the surface and desquamate over a period of about 7 days
2. Basal layer accounts for 10-15% of the total epithelial thickness
3. Hyperplasia to >15% of epithelial thickness occurs in patients with GER and other inflamma-
tory conditions, especially in the distal esophagus
B. Above the basal cell layer, glycogenated cells progressively flatten and are identified with Periodic
acid-Schiff (PAS) stain
1. As cells approach the luminal surface, polarity changes from vertical to horizontal
2. Granular and keratinized layers are absent in esophageal mucosa
3. Scattered endocrine cells and melanocytes may be present
4. CD3+ lymphocytes are present in the lower and middle squamous cell layers
5. Antigen-presenting Langerharns cells are present just above the basal layer
C. Lamina propria
1. Projections of lamina propria (papillae) extend into the squamous epithelium at regular
intervals, creating an irregular lower border to the squamous epithelium
2. Mucosal integrity and growth are maintained in part by epidermal growth factor (EGF)
III. Histology of the gastroesophageal junction (GEJ)

A. Z line - a gross landmark representing the junction of squamous epithelium (pale red/pink) and
transitional cardiac mucosa of the proximal stomach (darker red)
B. The Z line is a histologic landmark. The LES is a muscular landmark defined manometrically.
The two are found within 1-2 cm of each other in the normal esophagus
1. True cardiac mucosa is a columnar epithelium, with tubular glands containing mucin
producing cells
2. Transitional cardiac mucosa, found just below the GEJ, is similar to cardiac mucosa, but
contains a few parietal cells
3. When cardiac mucosa overlies esophageal glands or squamous epithelial-lined ducts,
the sample is likely from the esophagus, representing metaplastic epithelial change due to
GERD, H pylori, chemical damage or other injury
IV. Lamina Propria of the esophagus

A. Consists of the non-epithelial portion of the esophageal mucosa above the muscularis mucosae
B. Consists of loose areolar connective tissue containing blood vessels, nerves, inflammatory cells, and
mucus-secreting glands
C. Lymphocytes, plasma cells, and occasional lymphoid follicles are present
D. Rests on the muscularis mucosa

V. Muscularis Mucosae of the esophagus
A. First identifiable in the esophagus at the level of the cricoid cartilage, and becomes thicker distally
B. Proximally consists of isolated or irregular muscle bundles
C. In middle and lower esophagus, the muscularis mucosae forms a continuum of longitudinal (exte-
rior) and transverse (internal) fibers
VI. Submucosa of the esophagus

A. Wide zone below the muscularis mucosae, consisting of loose connective tissue with blood vessels,
nerves, poorly formed submucosal ganglia, lymphatics, and submucosal glands
B. Contains an extensive lymphatic plexus
C. There are two types of submucosal glands: superficial (neutral mucin production) and deep (acidic
mucin production)
VII. Muscularis Propria of the esophagus

A. Well-developed circular and longitudinal layers
B. The upper third consists of striated muscle gradually changing to smooth muscle in the middle and
lower third of the esophagus
C. The lower esophageal sphincter is not a clearly defined anatomic structure, but consists of thick-
ened smooth muscle fibers that extend approximately 2 cm above and 3 cm below the diaphrag-
matic hiatus
VIII. Adventitia of the esophagus

A. The esophagus does not have a serosal layer
B. The external layer (adventitia) consists of loose connective tissue, with longitudinally directed blood
and lymph vessels and nerves
C. Gradually merges into the connective tissue of the mediastinum
D. Numerous elastic fibers at the GEJ anchor the esophagus to the diaphragm
Recommended Reading:
Gastrointestinal Pathology: An Atlas and Text (Lippincott Williams & Wilkins), Hardcover (2008) by Cecilia M
Fenoglio-Preiser, Amy E Noffsinger, Grant N Stemmermann, pages 11-20
Odze and Goldblum: Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2nd Edition (2009),
pages 16-17, 40
Biopsy Interpretation of the Gastrointestinal Tract Mucosa (Biopsy Interpretation Series) (Hardcover) Elizabeth
A. Montgomery, pages 1-2
1C. Normal and Abnormal
Esophageal Motility
Maria E. Perez, DO
Jaya Punati, MD
I. Physiology of Esophageal Motility

A. Primary peristalsis—Initiated by swallowing
B. Secondary peristalsis—Initiated by stretch on esophageal wall
C. Upper esophageal sphincter (UES) and lower esophageal sphincter (LES) are tonically contracted
between swallows
D. Sphincter relaxation induced by swallowing, vomiting, and release of gas
E. Transient relaxations of LES are not associated with swallow
1. Transient relaxations occur normally after meals in response to gastric distension
2. Transient relaxations are responsible for >90% of GE reflux episodes
II. Esophageal Manometric Evaluation

A. Indications
1. Diagnosis of achalasia, nutcracker esophagus, diffuse esophageal spasm
2. Evaluation of chest pain, dysphagia, and odynophagia
3. Accurate placement of esophageal pH probe, especially when anatomy is abnormal (hiatus
hernia, scoliosis)
4. Evaluation of medical therapy
5. Confirm diagnosis of systemic diseases associated with esophageal dysmotility
B. Equipment and procedure
1. Water-perfused or solid state manometry catheter with at least three recording sites
2. Catheter placed transnasally
3. Standard protocol involves three maneuvers
a. Pull through from stomach to esophagus to assess LES resting pressure and location
b. Wet swallows with water to determine LES relaxation
c. Assessment of peristalsis in esophageal body
d. High resolution manometry
1) One sensor per centimeter from pharynx to stomach
2) Enables detailed segmental assessment of esophageal motor function
3) Facilitates diagnosis of vigorous achalasia, LES pseudo-relaxation, and other
subtle abnormalities
Figure 1. Normal esophageal manometry. There is a decrease in pressure of the LOS when the child swallows
(-). There are normal amplitude peristalitic oesophageal contractions. Distance above LOS is indicated in cm.
Di Lorenzo C, Hillemeier C, Hyman P, et al. Manometry studies in chidlren: minimum standards for proce-
dures. Neurogastroenterol Mot. 2002 (14): 411-420.

Figure 2. Oesophageal manometry of a child with achalasia. There is a high LOS pressure, and there is absent
peristalsis and lack of LOS relaxation after wet swallows (-). Distance above LOS is indicated in CM.
Di Lorenzo C, Hillemeier C, Hyman P, et al. Manometry studies in chidlren: minimum standards for proce-
dures. Neurogastroenterol Mot. 2002 (14): 411-420.
III. Achalasia
A. Degeneration of myenteric plexus of the lower 2/3 of esophagus (smooth muscle)
B. Symptoms—Progressive esophageal obstruction, especially with solids; chest pain, aspiration,
weight loss, and chronic pulmonary disease
C. Manometric findings—Absent or abnormal peristalsis, incomplete LES relaxation, elevated baseline
LES pressure
D. Possible etiologies—Autoimmune, infectious, environmental
E. Allgrove syndrome—Achalasia, ACTH insensitivity, and alacrimia. Autosomal-recessive gene on
chromosome 12q13
F. Rozycki syndrome—Achalasia, autosomal-recessive deafness, short stature, vitiligo, muscle wasting
G. Other associations—Chagas disease, paraneoplastic syndrome, sarcoidosis, Down syndrome, pyloric
stenosis, Hirschsprung disease, intestinal pseudo-obstruction
H. Making the diagnosis
1. Upper GI barium x-ray showing dilated esophagus and bird beak deformity at LES
2. Fluoroscopy showing abnormal or absent esophageal peristalsis
3. Manometry showing absence of peristalsis in esophageal body, failure of LES relaxation dur-
ing swallow, and elevated resting LES pressure
I. Treatment
1. Balloon dilation of LES—Good results in 60%. Complications include perforation, fever, pleu-
ral effusion
2. Heller myotomy of the LES produces symptom relief in >75%
3. Gastroesophageal reflux occurs after both surgical and dilation therapy
4. Botulinum toxin injection of LES inhibits acetylcholine release at neuromotor junction, with
short-term symptom relief
5. Isosorbide dinitrate—Decreases LES pressure and improves esophageal emptying
6. Nifedipine—Calcium channel blocker reduces LES pressure and decreases amplitude of
esophageal contractions
IV. Diffuse Esophageal Spasm

A. Manometry shows simultaneous esophageal contractions after >20% of wet swallows
V. Nutcracker Esophagus
A. Manometry shows high amplitude peristaltic contractions in patients with chest pain
B. Associated anxiety, depression, and somatization
VI. Collagen vascular diseases produce secondary esophageal dysmotility, pain, dysphagia, and
aspiration
A. Scleroderma, polymyositis, dermatomyositis, and mixed connective tissue disorder
B. 73% prevalence of esophageal dysmotility in pediatric scleroderma and mixed connective tissue
disorder
C. Manometric findings
1. Low or absent LES pressure
2. Decreased or absent distal (smooth muscle) esophageal peristalsis
3. Normal UES and upper esophageal peristalsis (striated muscle)
VII. Neurologic disorders producing esophageal dysmotility

A. Disorders of striated muscle produce UES dysfunction—CP, muscular dystrophies, cranial nerve
abnormalities, and Arnold Chiari malformation
B. Muscular dystrophy reported to be associated with reduced esophageal peristaltic amplitude
Recommended Reading
Camilleri M, Bharucha AE, Di Lorenzo C, et al. American Neurogastroenterology and Motility Society con-
sensus statement on intraluminal measurement of gastrointestinal and colonic motility in clinical practice.
Neurogastroenterol Motil. 2008;20:1269-1282.
Connor FL, Di Lorenzo C. Motility. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sander-
son IR, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, and Management. 4th ed. Hamil-
ton, Ontario: BC Decker; 2004:55-69.
Di Lorenzo C, Hillemeier C, Hyman P, Loening-Baucke V, Nurko S, Rosenberg A, Taminiau J. Manometry stud-

ies in children: minimum standards for procedures. Neurogastroenterol Motil. 2002:14:411-420.
Hussain SZ, Di Lorenzo C. Motility disorders: diagnosis and treatment in the pediatric patient. Pediatr Clin
North Am. 2002;49:27-51.
Mohr F, Steffen R. Physiology of Gastrointestinal Motility. In: Walker WA, Goulet O, Kleinman RE, Sherman
PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA:
Elsevier Saunders; 2011.

1D. Deglutition
Pornthep Tanpowpong, MD, MPH
Aubrey J. Katz, MD
Deglutition is a complex process encompassing three phases (oral, pharyngeal and esophageal), requiring
coordination and normal anatomic structures.
I. Three phases of deglutition

A. Oral: voluntary activity
1. Mouth functions as both sensory and motor organ
2. Physical changes in food bolus produced by oral cavity include changes in size, shape, vol-
ume, pH, temperature, and consistency
B. Pharyngeal: reflexive and complex
1. Lasts for about 1 second in healthy individuals
2. Steps include:
a. Tongue loading and transport of bolus posterior in solid feedings
b. Elevation of the pharyngeal tube simultaneous with bolus delivery
c. Velopharyngeal closure
d. Relaxation of the upper esophageal sphincter (UES)
e. Closure of the laryngeal vestibule, followed by a peristaltic wave in the posterior pha-
ryngeal constrictors, propels the bolus past the UES
C. Esophageal:
1. UES is a manometrically defined high-pressure zone measuring ~3 cm in length, which is
composed of striated muscle located just caudad to the hypopharynx. The UES is tonically
closed at rest, and opens during swallowing. Resting pressure is variable, ranging from
30–80 mm Hg
2. Distention of the esophagus produces reflex ↑in UES resting pressure (protective response)
3. In some studies, acidification of the esophagus causes ↑UES resting pressure
4. The main UES muscle is the cricopharyngeal muscle, which is enervated by vagal branches of
the pharyngeal plexus
II. Changes in components of oral and pharyngeal cavities during development

A. In infants the tongue lies entirely within the oral cavity. The larynx is positioned high in the neck.
The oropharynx is small in volume
B. During childhood, the base of the tongue descends. The larynx descends to the level of the seventh
vertebra by adulthood
III. Neurology of deglutition

A. All phases of deglutition can be modified by sensory feedback (touch and pressure receptors), which
may have implications in management of swallowing-impaired individuals
B. Swallowing may be evoked by stimulating the oropharyngeal regions innervated by cranial nerve IX
and the superior laryngeal and recurrent laryngeal nerves of vagus
C. Cerebral cortex is not essential for the pharyngeal and esophageal phases of swallowing
1. The neurons important to these phases are located in the pons and medulla
2. Deglutition can occur in infants with no nervous tissue rostral to the midbrain (anencephaly)
IV. Non-nutritive sucking bursts are faster in frequency and shorter in duration than nutritive
sucking bursts
A. In preterm infants, non-nutritive sucking during gavage feeding is associated with improved weight
gain due to either:
1. More efficient nutrient absorption
2. Decrease in energy requirements secondary to a lessening of infant activity or restlessness

V. Causes of disordered deglutition in pediatric patients:
A. Prematurity
B. Nasopharyngeal disorders—choanal atresia, nasal and sinus infection, tumor, septal deflection
C. Oral and oropharyngeal disorders—cleft lip/cleft palate, craniofacial syndromes
D. Laryngeal disorders—stenosis, webs, clefts, paralysis and laryngomalacia
E. Congenital defects—laryngotracheopharyngeal cleft, tracheoesophageal fistula and/or esophageal
atresia, esophageal web and stricture, vascular anomalies such as double aortic arch or right aortic
arch
F. Trauma to upper airway, oropharynx
G. Neurologic defects—hypoxia, microcephaly, cortical atrophy, CNS infection, Arnold-Chiari malfor-
mation, dysautonomia, sensory integration or processing disorders, and CNS injury
H. Neuromuscular diseases—myotonic muscular dystrophy, myasthenia gravis, poliomyelitis
I. Muscular disorders—achalasia
VI. Historical features in evaluation of dysphagia

A. Drooling or open-mouth posture suggests oral phase abnormalities
B. Dysphagia while swallowing suggests pharyngeal phase abnormalities:
1. Anatomical abnormality
2. Oropharyngeal incoordination
3. Neurologic disorder
C. Dysphagia after swallowing suggests esophageal abnormalities
D. Dysphagia with solids suggests only anatomical/mucosal lesions
E. Dysphagia with solids and liquids suggests motility disorder
VII. Physical examination

A. Structure of the face, oral cavity, and oropharynx
B. Is there an intact hard and soft palate?
C. Is the tongue midline and of normal size and motility?
D. Is the size of the mandible normal (rule out Robin sequence)?
E. Is the control of head, neck, and body position normal?
F. Gag reflex - If present, and if weak or hyperactive
G. Observational feeding trial
1. Primitive reflexes or movements
2. Positions of the head, neck and body during swallowing
3. Abnormal feeding behaviors (such as tongue thrust and averting the mouth)
4. A change in voice quality after feeding
Recommended Reading
Kleinman RE, Goulet O, Mieli-Vergani G, et al, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diag-
nosis, and Management. 5th ed. Hamilton, Ontario: BC Decker; 2008.
1E. Dysphagia
Javier J. Monagas, MD
Paul E. Hyman, MD
Dysphagia is the sensation of difficulty swallowing or of food sticking as it passes from mouth to stomach.
There are three phases of deglutition, including oral, pharyngeal, and esophageal. The symptoms associated
with the oral phase include drooling, constantly open mouth, poor sucking, refusal to swallow, cough, gag-
ging, choking, respiratory distress, and aspiration. The symptoms of the pharyngeal phase include dysphagia
while swallowing. Finally, dysphagia of the esophageal phase presents as dysphagia after swallowing. Odyno-
phagia—painful swallowing—often accompanies dysphagia.
I. Differential Diagnosis
A. Oral phase
1. Nasopharyngeal disorders
a. Choanal atresia or stenosis
b. Sinus and nasal infections
2. Oral cavity abnormalities
a. Cleft lip/palate
b. Hypopharyngeal web/stenosis
c. Craniofacial syndromes with micrognathia—Robin sequence
d. Trauma, infection, and mucositis
e. Tonsillar or adenoid hypertrophy
f. Pharyngitis
3. Profound developmental delay may be associated with uncoordinated chewing and swallow-
ing behavior
4. Skeletal muscle hypotonia; cranial nerve abnormalities with spasticity, dystonia, or paresis
B. Pharyngeal phase
1. Anatomic defects of the pharynx
a. Pharyngeal webs cause obstruction and dysphagia
2. Anatomic defects of the larynx
a. Laryngeal stenosis
b. Laryngopharyngeal cleft
c. Laryngeal web
3. Cricopharyngeal dysfunction
a. Cricopharyngeal achalasia
b. Muscular hyperplasia
c. Cricopharyngeal incoordination
d. Dysphagia occurs due to failure to relax the upper esophageal sphincter, due to central
or cranial nerve damage
4. Neurologic defects: Physiologic feature is poor motor oral-pharyngeal coordination
a. CNS: head trauma, brain injury (infection, hypoxia), microcephaly, anencephaly, myelo-
meningocele, Chiari malformation, dysautonomia
b. Neuromuscular disorders: myotonic dystrophy, myasthenia gravis, Guillain-Barré syn-
drome, poliomyelitis, spinal muscular atrophy
C. Esophageal phase
1. Stricture—caustic ingestion, peptic esophagitis, eosinophilic esophagitis, epidermolysis bul-
losa, trauma, gastric rest, pill esophagitis
2. Anatomic abnormalities—diverticulae, TE fistula, aberrant cervical thymus, webs
3. Disorders of esophageal motility
a. Achalasia:
1) Abnormal or absent peristalsis

2) Failed lower esophageal sphincter relaxation
3) Hypertensive lower esophageal sphincter
4) Mechanism for dysphagia is that bolus transit is impaired. Stretching of the
esophageal wall stimulates nociceptors that cause dysphagia
b. Diffuse or distal esophageal spasm
1) Simultaneous esophageal contractions after 20% more swallows
2) Lower esophageal sphincter relaxation is normal
3) Dysphagia caused by esophageal dilation proximal to the transient muscular
obstruction
4) Treatment with calcium channel blockers or anticholinergics
c. Nutcracker esophagus
1) Very strong simultaneous esophageal body contractions
2) Esophageal contractions are so strong that odynophagia is the more prominent
symptom
d. Systemic neuromuscular disorders causing dysphagia
1) Systemic lupus, scleroderma
2) Diabetes
3) Thyroid disorders
4) Amyloidosis
5) Chagas disease
6) Graft vs host disease
7) Mitochondrial disorders
8) Paraneoplastic syndromes
e. Vascular anomalies
1) Double aortic arch and right aortic arch with left ligamentum arteriosum com-
presses the esophagus
2) Aberrant right subclavian artery is a common variant. Although the filling defect
on the esophagus may be dramatic, this lesion rarely causes esophageal obstruc-
tion
3) The best test for diagnosis of vascular abnormalities is MRA
f. Dermatologic
1) Dermatologic disorders affecting the squamous epithelium of the esophagus
2) Usually associated with oral and pharyngeal disease
3) Epidermolysis bullosa causes esophageal inflammation and stricture
g. Inflammation and injury
1) All forms of esophagitis may cause dysphagia
2) Caustic burns
3) Radiation injury affects both epidermal and muscle layers
II. Testing for Dysphagia

A. Videofluoroscopy (modified barium swallow) to detect abnormalities in swallowing, aspiration, and
esophageal obstruction (oral and pharyngeal phase)
B. Barium swallow to detect anatomic abnormalities, including obstruction (esophageal phase)
C. Upper endoscopy to assess for mucosal disease (esophageal phase)
D. Esophageal manometry to diagnose motility disorders
Recommended Reading
Davis AM, Bruce A, Cocjin J, Mousa H, Hyman P. Empirically supported treatments for feeding difficulties in
young children. Curr Gastroenterol Rep. 2010;12:189-194.
Hussain SZ, Di Lorenzo C. Motility disorders. Diagnosis and treatment for the pediatric patient. Pediatr Clin
North Am. 2002;49(1):27-51.
Kahrilas P, Smout A. Esophageal disorders. Am J Gastroenterol. 2010;105:747-756.
1F. Congenital Anomalies
Nirav K. Desai, MD
Rachel Rosen, MD
Congenital anomalies of the esophagus occur approximately once in every 3,000–5,000 live births. Esopha-
geal atresia and tracheoesophageal fistula (TEF) are the most common anomalies.
I. Esophageal Duplication
A. Foregut duplications account for one-third of all GI duplications
1. Amongst foregut duplications, esophageal are the most common
B. Duplications appear as cysts, diverticulae, and tubular malformations
C. Gastric mucosa is frequently observed in duplications, irrespective of site of origin
D. Diagnosis
1. Identified on upper GI and/or CT of chest
2. May be difficult to distinguish from bronchogenic cysts
3. Vertebral anomalies occur in up to 50% of patients with esophageal duplication
E. Most common presenting symptoms are respiratory distress in neonates and dysphagia in older
children
F. Small cysts may be asymptomatic
G. Older children may have gastrointestinal/bronchial hemorrhage and spinal meningitis if the wall of
duplication erodes from acid production
H. Management is surgical excision
II. Esophageal Stenosis

A. Stenosis due to tracheobronchial rest (TBR) is most common
1. Due to abnormal separation of foregut into trachea and esophagus
2. Found within 3 cm of gastric cardia
3. Often results in significant obstruction
B. Intrinsic congenital esophageal stenosis caused by congenital malformation of the esophageal wall
1. May not be present at birth
2. Incidence is 1/25,000–50,000 live births
C. Fibromuscular stenosis and membranous webs occur in middle third
1. Fibromuscular stenosis has smooth wall and is 1–4 cm in length, with partial obstruction of
esophageal lumen
2. Membranous diaphragm is least common
D. One-third of reported cases of TBR and fibromuscular stenosis are associated with esophageal atre-
sia and TEF
E. Symptoms and signs
1. High lesions present with respiratory symptoms
2. Lower lesions present with vomiting
3. Majority present as dysphagia after solid foods are introduced
F. Diagnosis by upper GI (UGI) and endoscopy
G. Treatment is via excision with end-to-end anastamosis
1. Fibromuscular stenosis can be treated by dilation
2. Esophageal webs are amenable to dilation
III. Esophageal Atresia/Tracheoesophageal Fistula (TEF)

A. Incidence is 1/3,000–4,000 live births, highest amongst Caucasians
B. 0.5%–2% risk of recurrence among siblings of affected child
C. Anatomy
1. In esophageal atresia, proximal and distal portions of esophagus do not communicate
a. Upper segment is a dilated blind-ended pouch with hypertrophied muscle
b. Distal end is atretic, with thin walls
c. Gastroesophageal sphincter is typically incompetent, with defective vagus nerve

2. In TEF, there is an abnormal communication between trachea and esophagus
a. 84% of patients demonstrate a blind-ending upper esophageal pouch, with fistula
from trachea to distal esophagus (see Figure 1)
b. 50%–70% have other anomalies, including genitourinary, cardiac (35%), gastrointesti-
nal (25%), and musculoskeletal (20%), as well as VACTERL association (10%)
c. Right-sided aortic arch occurs in <2% of cases
D. Signs and symptoms of esophageal atresia/TEF
1. Prenatal history of polyhydramnios
2. Smaller than normal gastric air bubble
3. NG tube that meets resistance prior to entering stomach may also lead to diagnosis
4. Cough, emesis, and cyanosis during feeding
5. Distal fistulae may produce progressive abdominal distension with air
6. H-type TEF often diagnosed late
a. Newborns may have choking or respiratory distress with eating
b. Recurrent pneumonia or wheezing
c. Diagnosis depends on visualizing the fistula, either during endoscopy, or during a
barium esophagram with contrast injected via slowly withdrawn NG tube
E. Treatment is surgical
1. Cardiac evaluation is mandatory prior to surgical repair
2. Postoperatively, there is a 10%–17% risk of anastamotic leak, leading to formation of salivary
fistula, mediastinitis, and/or pneumonitis
3. 25%–40% of patients have gastroesophageal reflux postoperatively due to impaired mid-
esophageal peristalsis
4. Tracheomalacia occurs in up to 75% of cases
5. Barrett’s esophagus is a long-term complication of TEF
6. Recurrent infections postoperatively raise the possibility of recurrent or missed fistula in older
children
IV. Esophageal Web

A. Mucosal membrane occludes esophageal lumen, usually found in proximal esophagus
B. Associated with TEF
C. More common in females
D. Plummer-Vinson syndrome: webs associated with glossitis, iron deficiency anemia, and
koilonychias (spoon nail)
E. Webs occur as an inflammatory complication of epidermolysis bullosa, cicatrical pemphigoid,
Stevens-Johnson syndrome, psoriasis, idiopathic eosinophilic gastroenteritis, and GVHD
V. Esophageal Ring
A. A-ring: asymptomatic, caused by hypertrophied circular muscle 1.5–2.0 cm above squamocolumnar
junction
B. B-ring: also called Schatzki ring, contains only mucosa
C. C-ring: indentation of esophagus caused by diaphragmatic crura
D. Symptoms are similar to esophageal atresia, with complete membrane/web
E. Diagnosis by endoscopy or UGI series
F. Therapy: dilation or surgical resection
Figure 1. T ypes of esophageal atresia and tracheoesophageal fistula.
From: Esophageal Atresia/Tracheoesophageal Fistula overview
www.ncbi.nlm.nih.gov/books/NBK5192/
Recommended Reading
Achilidi O, Grewal H. Congenital anomalies of the esophagus. Otolaryng Clin N America. 2007;40:219-244.
Teitelbaum JE. Mouth and esophagus. In: Kleinman RE, Goulet OJ, Mieli-Vergani G, et al, eds. Walker’s Pedi-
atric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 5th ed. Lewiston, NY: BC Decker;
2008: 7-17.

1G. Gastroesophageal Reflux
and Gastroesophageal
Reflux Disease
Nirav K. Desai, MD
Rachel Rosen, MD
Gastroesophageal reflux (GER) is the retrograde movement of gastric contents into the esophagus. This is a
normal physiologic process that occurs throughout the day in healthy infants, children, and adults. Most epi-
sodes last <3 minutes, occur postprandially, and have few or no symptoms. Gastroesophageal reflux disease
(GERD) is the pathologic sequelae that can occur with GER. GERD is the most common esophageal disorder.
I. Pathophysiology
A. 90% of GER episodes in infants and children occur during transient lower esophageal sphincter
relaxation (TLESR)
1. TLESR are not associated with swallowing or esophageal peristalsis
2. TLESR occur up to 6 times per hour in normal adults, especially after meals
3. TLESR are rare during sleep
4. Gastric distension increases the frequency of TLESR
B. Lower esophageal sphincter (LES) pressure, usually between 8–30 mm Hg
C. Relaxation of LES is vagally mediated via brainstem and precipitated by swallowing
D. Nocturnal reflux is uncommon in healthy children, and is characteristic of GERD
II. Natural History

A. During infancy, GER manifests as effortless regurgitation
1. 50% of infants have GER in the first 3–6 months
2. Less than 20% of infants still have GER at 12–15 months
B. GERD with onset after 2 years of age is less likely to resolve spontaneously
III. Differential Diagnosis

A. Other forms of esophagitis: infection, eosinophilic esophagitis, chemical esophagitis
B. Gastric disorders: peptic ulcer disease, gastritis
C. Motor abnormalities: esophageal spasm, achalasia
D. Other disorders associated with vomiting: urinary tract infection, increased intracranial pressure,
food allergy, child neglect or abuse, eating disorder
IV. Clinical Diagnosis

A. Diagnosis is often clinical, based upon typical symptoms and the lack of signs and symptoms of
other disorders
B. No unique symptom complex is diagnostic of GERD
C. Adolescents are more likely to have typical heartburn than young children and infants
D. Upper airway symptoms: limited data link reflux to hoarseness, chronic cough, sinusitis, otitis me-
dia, and erythema/cobblestoning of the larynx
E. Reflux is not a common cause of irritability, unexplained crying, or distress in otherwise healthy
infants
F. Most apparent life-threatening events (ALTE) are not related to GERD

V. Testing for GERD
A. Barium upper GI (UGI) is useful to rule out anatomic abnormality
B. Esophageal pH monitoring is useful to evaluate efficacy of antisecretory therapy
C. Impedance and/or pH monitoring is useful to correlate symptoms with reflux episodes, and also
useful to differentiate eosinophilic esophagitis from GERD in patients with peptic esophagitis
1. If GERD is suspected as a cause of apnea or ALTE, impedance testing/pH monitoring with
polysomnography may provide data confirming the association of symptoms with reflux
events
2. Impedance: detects acid, weakly acidic, and non-acid reflux. Superior to pH monitoring alone
for relation between symptoms, GER, and postprandial reflux
D. Motility studies are useful to confirm achalasia or other disorders of the esophagus that mimic
GERD
E. Endoscopy and biopsy
1. Visible breaks in mucosa of the distal esophagus is reliable evidence of reflux esophagitis
2. Visible esophageal erythema, pallor, and lack of vascular markings are very subjective
3. Esophageal mucosal biopsies are not sensitive or specific enough to confirm GERD
related esophagitis
4. Biopsy is important to rule out other causes of esophagitis and monitor/diagnose Barrett’s
esophagitis
F. Nuclear scintigraphy is not recommended to diagnose GERD
G. Gastric emptying studies do not diagnose GERD, and are only useful in patients with a history sug-
gesting gastric retention
H. Esophageal/gastric ultrasound is not recommended to diagnose GERD
VI. Treatment
A. Lifestyle change in infants
1. Formula-fed infants may benefit from a 2–4-week trial of extensively hydrolyzed formula
2. Thickened formula may reduce regurgitation, but does not reduce reflux episodes
3. Prone positioning decreases acid exposure, but may increase SIDS. Left-sided positioning also
decreases reflux compared to right-sided positioning
B. Lifestyle changes in children/adolescents
1. No evidence for elimination of any specific food
2. Obesity, late night eating, and large meals all contribute to GERD
3. Prone sleeping or elevation of the head of the bed may be helpful
C. Pharmacologic therapy
1. Histamine-2 receptor antagonists have rapid onset of action, but tachyphylaxis or tolerance
may develop
2. Proton pump inhibitors are superior to histamine-2 receptor antagonists for treating erosive
esophagitis or GERD symptoms
a. Twice-daily dosing is not routinely indicated
b. Pediatric patients with endoscopically diagnosed reflux esophagitis or nonerosive reflux
disease are treated with PPIs for three months
c. No controlled studies support the empiric use of acid suppression to treat infant irrita-
bility
3. Prokinetic agents
a. Insufficient evidence to support routine use of metoclopramide, erythromycin, dom-
peridone, bethanecol, or cisapride for GERD
4. Buffering agents, alginate, or sucralfate may be useful for on-demand symptom suppression,
but are not recommended for long-term use
D. Surgical therapy: Nissen fundoplication
1. May be beneficial in children with relapsing severe GERD
2. Indications: failure of medical therapy, dependence on long-term medical therapy, nonadher-
ence to medical therapy, intractable pain, neurological impairment, recurrent bleeding, and
aspiration
E. Three groups of patients with asthma and positive tests for GERD may benefit from anti-reflux
therapy
1. Asthmatics with heartburn
2. Asthmatics with nocturnal respiratory symptoms
3. Asthmatics who are steroid dependent or have difficult-to-control asthma
VII. Barrett Esophagus
A. Metaplastic mucosa in the esophagus occurring in linear patches usually distal, usually in setting of
chronic reflux associated esophagitis. Incidence in children lower than adults. May be as high as
5% of patients with documented chronic erosive esophagitis.
B. Three types of metaplastic change
1. Gastric fundic-type epithelium containing mucous, chief and parietal cells
2. Cardia-type epithelium containing mucous secreting cells may predispose to esophageal
adenocarcinoma
3. Intestinal-type epithelium (specialized columnar epithelium) containing prominent goblet cells
predisposes to esophageal adenocarcinoma
C. Risk of esophageal adenocarcinoma (EA) in Barrett esophagus
1. Intestinal-type epithelium associated with increased risk of EA
2. Cardia-type metaplasia now felt to increase risk of EA but extent not yet clear
3. Risk for EA in adults with Barrett esophagus ranges from .5 to 1.6% per year
4. Risk for EA increased in long segment (>3cm) Barrett and in dysplastic epithelium
5. Pediatric risk difficult to calculate because of small numbers
6. At risk pediatric patients – Down syndrome, Cornelia de Lang syndrome, severe neurologic
impairment , esophageal atresia, congenital diaphragmatic hernia, cystic fibrosis – all have
chronic esophagitis as common feature
7. Biomarkers (p53, beta-catenin, cyclin D1, aneuploidy, tetraploidy ) are under investigation as
markers for dysplasia and EA risk
8. No specific pediatric guidelines for surveillance endoscopy in Barrett esophagus. Adult rec-
ommendations suggest endoscopy q 3-5 years for Barrett esophagus without dysplasia and
every 6-12 months with dysplasia
Recommended Reading
Rudolph C, Hassall E. Gastroesophageal reflux. In: Kleinman RE, Goulet OJ, Mieli-Vergani G, et al, eds.
Walker’s Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 5th ed. Lewiston, NY:
BC Decker; 2008: 59-71.
Sherman PM, Hassall E, Fagundes-Neto U, et al. A global, evidence-based consensus on the definition of gas-
troesophageal reflux disease in the pediatric population. Am J Gastroenterol. 2009;104:1278-1295.
Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesophageal reflux and asthma in children: a system-
atic review. Pediatrics. 2010;124:e925-930.
Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guide-
lines: Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and
Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
(ESPGHAN). JPGN. 2009;49:489-547.
Spechler SJ et al. American Gastroenterological Association Technical Review on the Management of Barrett’s
Esophagus. Gastroenterology 2011; 140: e18-e52

1H-1. Eosinophilic Esophagitis
Ben Kuhn, MD
Eosinophilic esophagitis is characterized by significant eosinophilic infiltrate localized to the esophagus. The
etiology appears to be an increased immunologic response to allergen exposures. There is a strong link to
atopy.
I.Definition
Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis requiring the following criteria:
A. Symptoms of esophageal inflammation - pain, heartburn, and recurrent emesis. Older children and
adolescents may present with food impaction and dysphagia
B. Esophageal mucosal biopsy shows an eosinophilic infiltration with >15 eosinophils/high-power field
(40X)
C. Exclusion of other disorders associated with similar clinical, histological, or endoscopic features
II. Etiology
A. Inflammatory condition of the esophagus caused by a mixed IgE and non-IgE mediated allergic
response
B. The precipitating allergens cannot always be identified. Food antigens and aeroallergens are sus-
pected
C. Non-IgE response involves T helper 2 (Th2) signaling via cytokines IL-5, IL-13, eotaxin-1, -2, and -3
(pro-inflammatory and chemo-attractant)
D. Chronic EoE associated with tissue remodeling and collagen deposition in the lamina propria
III. Epidemiology
A. Incidence in children in the United States is 1.23 per 10,000
B. Prevalence in children in the United States is 4.3 per 10,000 (0.043%)
C. Prevalence is increasing due to chronic and non-fatal nature of EoE, but incidence was shown to be
stable between the years of 1982-1999
IV. Clinical Symptoms

A. EoE may present with GERD that is unresponsive to acid suppressing therapy
B. Two thirds of children with EoE have a history of asthma, eczema, food allergies, environmental
allergies, chronic rhinitis, or family history
C. In infants and toddlers, food refusal, vomiting, and pain with eating may be prominent
D. Preschool and school-aged children may have chronic abdominal pain and vomiting
E. Adolescents may have symptoms of gastroesophageal reflux, dysphagia, and recurrent food impac-
tion are common
F. 55% of adult food impactions are related to EoE
V. Endoscopic Findings
A. Longitudinal furrowing of the esophageal body
B. White exudates, often in 1-3 mm plaques
C. Edema
D. Friability
E. Small-caliber esophagus or stricture at any location of active disease
F. “Trachealization” of the esophagus (circumferential ridges)
VI. Histologic Findings Consistent with EoE

A. Hyperplasia of the basal zone of the esophageal mucosa beyond 1/3rd the total mucosal thickness
B. Increased height of papillae beyond 1/3rd the total mucosal thickness
C. Superficial eosinophilic microabscesses
D. Eosinophilic inflammatory infiltrate with eosinophils count >15/hpf

VII. Differential Diagnosis
A. GERD
B. IBD
C. Celiac Disease
D. Viral Esophagitis
E. Parasitic Infection
F. Drug Allergy
G. Hypereosinophilic Syndrome
H. Churg-Strauss Syndrome
VIII. Treatment
A. Topical steroids (fluticasone or budesonide)
1. 50% histological remission and 67% resolution of vomiting compared to placebo in one
study
2. Dose used in this study 880 mcg/day
3. Upon discontinuation of steroids, 90% of patients had recurrence of symptoms
B. Elimination Diet, dictated by food allergy testing with skin prick or allergy patch test
1. One study demonstrated symptomatic and histological improvement in 75% of patients
C. Six Food Elimination Diet: (Milk, Soy, Egg, Wheat, Peanut, and Fish/Shellfish)
D. Elemental Diet
E. Anti-IL-5 and anti-IL-13 monoclonal antibody therapy is still experimental
IX. Endoscopy
A. Follow-up EGD with biopsies should be performed after intervention, to evaluate endoscopic and
histological improvement if symptoms persist
B. The incidence of stricture and risk factors for development of strictures is unknown
C. Strictures can be treated with dilation, but have an increased risk of perforation
D. Controversy remains surrounding the benefit of complete histological remission, defined as < 1
eos/hpf on four or more random endoscopic biopsies of the esophagus, to prevent stricture
formation
Recommended Reading
Franciosi, J. P. and C. A. Liacouras (2009). “Eosinophilic esophagitis.” Immunol Allergy Clin North Am. 29(1):
19-27, viii.
Kagalwalla, A. F., T. A. Sentongo, et al. (2006). “Effect of six-food elimination diet on clinical and histologic
outcomes in eosinophilic esophagitis.” Clin Gastroenterol Hepatol. 4(9): 1097-1102.
Konikoff, M. R., R. J. Noel, et al. (2006). “A randomized, double-blind, placebo-controlled trial of fluticasone
propionate for pediatric eosinophilic esophagitis.” Gastroenterology. 131(5): 1381-1391.
Liacouras, C. A., P. Bonis, et al. (2007). “Summary of the First International Gastrointestinal Eosinophil Re-
search Symposium.” J Pediatr Gastroenterol Nutr. 45(3): 370-391.
Putnam, P. E. (2008). “Eosinophilic esophagitis in children: clinical manifestations.” Gastroenterol Clin North
Am. 37(2): 369-381, vi.
Putnam, P. E. (2009). “Evaluation of the child who has eosinophilic esophagitis.” Immunol Allergy Clin North
Am. 29(1): 1-10, vii.
1H-2. Infectious Esophagitis
Kelly Fair Thomsen, MD
Esophageal infections are rare in children. Herpes simplex virus is the most common in an immunocompe-
tent host. Candida infections are rare and most often associated with prolonged antibiotic or PPI exposure or
abnormal anatomy or motility.
Fungal Infections
I. C
andida albicans causes 95% of fungal infections of the esophagus. C tropicalis, C krusei and C stellatoidea
are also implicated
A. Background:
1. Symptoms not diagnostic: dysphagia, odynophagia, substernal chest pain, and emesis
2. Occurs with/without oral candidiasis in healthy persons
a. In oncology patients, oral thrush and esophageal candidiasis usually coexist
3. Definitive diagnosis requires esophageal biopsy and culture
B. Predisposing factors
1. Mucositis – secondary to chemotherapy or radiation
2. Leukopenia
3. Steroid use (including inhaled steroids)
4. Acquired or congenital immunocompromise
5. Stasis, abnormal motility: scleroderma, achalasia
6. Severe malnutrition (immunocompromise most likely mechanism)
7. Broad-spectrum antibiotic therapy (especially in malnourished or
immunocompromised patients)
8. Underlying esophageal disease (EoE, GERD)
C. Diagnostic findings
1. Endoscopic findings: Adherent white plaques on the esophageal wall
2. Histology: Tangled hyphae and unicellular forms invading surface epithelium
3. Culture is of limited use, as Candida is frequently present in the mouth and GI tract
without esophagitis
4. Radiologic findings: Air contrast barium esophagram may show ulcerations and exudates
D. Therapy
1. In healthy individuals, may be self-limited
2. Candida esophagitis treated first-line with oral or IV fluconazole or oral itraconazole solutions
for 14–21 days after clinical improvement. Duration of treatment depends on severity of ill-
ness, and patient factors such as age and degree of immunocompromise
3. If esophageal biopsy is not possible, empirical therapy for Candida may be indicated
4. Rare complications are stricture and fungal balls
II. Other, much less common causes of fungal esophagitis

A. Cryptococcosis: clinically similar to Candida; described in AIDS; can be seen on culture or biopsy
B. Histoplasmosis: associated with disseminated Histoplasma infection in immunocompromised
patients. Severe systemic disease with fever, bone marrow failure, and hepato-splenomegaly.
Treated with amphotericin B followed by itraconazole
C. Blastomycosis: very rare
D. Aspergillosis: very rare

Viral Infections
I. Herpes simplex affects stratified epithelium. HSV1 is most common, but HSV2 is also seen
A. Occurrence
1. Occurs in children with normal immunity
2. Occurs as superinfection after physical or chemical esophageal injury
3. Most often occurs in immunocompromised children
4. Occurs with or without oral herpetic lesions
B. Symptoms
1. Odynophagia and/or dysphagia
2. Often associated with fever and malaise
3. Retrosternal, squeezing chest pain with swallowing, very similar to pill esophagitis
4. Dehydration, ketosis, and weight loss secondary to voluntary limitation of oral intake.
Drooling may be prominent
C. Endoscopic and histological findings

1. Herpetic vesicles occur in the first 1–2 days of infection
2. Volcano ulcers: distinct round lesions with yellow borders characteristic of infection occur
after several days
3. Histological findings best seen at the edge of ulcers
a. Nuclear inclusions
b. Multinucleate giant cells
c. Prominent mononuclear cell infiltrate
D. Diagnostic testing
1. Viral culture
2. Immunohistochemical stains
3. Previously well patients should be screened for unsuspected immunodeficiency – HIV testing
E. Therapy
1. In immunocompetent individuals, this is usually self-limited, resolving in 1–2 weeks
2. Acyclovir in immunocompromised host or severe cases
3. Foscarnet in cases of acyclovir resistance
II. CMV
A. Occurrence
1. CMV esophagitis is rare in immunocompetent patients
2. Usual host: AIDS or organ transplant patients
3. Patients with previous mucosal damage
B. Endoscopic and histological findings

1. Ulcerations similar to HSV, but usually more linear and deeper
2. Basophilic nuclear inclusions in biopsies from edge of ulcer
C. Treatment: ganciclovir or foscarnet

1. Duration guided by clinical/endoscopic response
2. High recurrence risk
III. Less common viral infections

A. Varicella zoster in immunocompromised patients
B. HIV—Idiopathic esophageal ulceration (IEU)
1. Giant ulcers can be seen in primary HIV infection, as well as in chronic AIDS with CD4 <100
2. Clinically indistinguishable from CMV
3. Chronic IEU has been described in up to 40% of adults with AIDS
Bacterial Infections
I. Mycobacterium tuberculosum
A. Occurs as part of systemic infection, or advanced pulmonary or mediastinal infection
B. Upper GI series may reveal extensive lymphadenopathy displacing the esophagus
Differential Diagnosis
I. Peptic esophagitis, eosinophilic esohagitis, pill esophagitis, foreign body

A. These conditions occur without systemic signs of illness
B. Odynophagia and retrosternal pain may be severe in eosinophilic esophagitis and pill esophagitis,
but is less severe in peptic esophagitis

1H-3. Histology of
Esophagitis
Dina Al-Zubeidi, MD
Riad Rahhal, MD
Leana Guerin, MD
I. Causes of Esophagitis
A. There are two main disease entities associated with esophagitis in children: gastroesophageal reflux
disease (GERD) and eosinophilic esophagitis (EoE)
B. There is clinical and histologic overlap between these conditions, so definitive diagnosis usually
requires clinicopathologic correlation
C. Other conditions causing esophagitis include inflammatory bowel disease (IBD) [especially Crohn’s
Disease], pill-induced or radiation-induced esophagitis, graft vs host disease, and infectious esopha-
gitis
D. Viral infections with CMV and HSV in immune competent patients are rare. (See Infectious
Esophagitis)
E. Candidal esophagitis is also rare in immune competent hosts. (See Infectious Esophagitis)
F. Bacterial causes of esophagitis are rare in immune competent hosts
G. HIV-infected children may experience esophagitis from tuberculosis, HSV, or CMV
II. Tips for Best Biopsy Yield

A. The site of biopsy should be above the distal 15% of the esophagus to avoid confusion with nor-
mal variance associated with Z-line
B. Biopsies should include epithelium, lamina propria, and muscularis mucosae
C. Biopsies should be oriented in a perpendicular plane to maximize diagnostic yield
D. Three main features in the histological diagnosis of esophagitis: increased thickness of the basal
zone, elongation of stromal papillae with vascular ingrowth, and inflammation (eosinophils,
lymphocytes and neutrophils)
E. For definitive diagnosis of esophagitis, the presence of 2 of 3 of these features is preferable
III. Grading of Esophagitis

A. Different histologic grading systems for esophagitis exist, but are not often used
B. Correlation between macroscopic and histologic features is generally poor; partly because the
esophagitis may be patchy, but also because histologic esophagitis may exist when the esophagus
is macroscopically normal
IV. GERD
A. Minimal histologic criteria include simultaneous occurrence of elongated papillae, and basal zone
hyperplasia and inflammation, in particular, the presence of eosinophils. Moderate esophagitis is
diagnosed if there is ingrowth of vessels in the papillae, and at least one eosinophil present. There
are no eosinophils in a normal esophageal biopsy
B. Classically, four biopsies are recommended for GERD, with two biopsies taken near the Z line, and
two taken 2 cm above the Z line
V. EoE
A. Unlike the rest of the GI tract, normal esophageal mucosa harbors no eosinophils, and infiltration
of the epithelium by eosinophils represents a sign of esophagitis
B. In the AGA consensus recommendations, a peak eosinophil count of more than 15 per HPF (x40) is
required for the diagnosis of EoE
C. Preferential eosinophilic localization is in the superficial portions of the esophageal epithelium and
formation of eosinophilic microabscesses, defined as clusters of 4 or more eosinophils
D. Multiple level biopsies are needed for diagnosing EoE
E. Other causes of esophagitis (especially GERD) should be excluded either by a PPI trial or Ph probe
study

VI. Other Causes of Esophagitis
• Presence of esophageal intraepithelial lymphocytes may indicate Crohn’s disease
• Nonspecific esophagitis has also been found in a lesser degree in patients with ulcerative colitis
• When indicated, use of special stains and cytopathologic examination of biopsies reveals special
features, such as intracytoplasmic inclusion in viral esophagitis
Recommended Reading
Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review
and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-1363.
Geagea A, Cellier C. Scope of drug-induced, infectious and allergic esophageal injury. Curr Opin Gastroen-
terol. 2008;24(4):496-501.
Genevay M, Rubbia-Brandt L, Rougemont A-L. Do eosinophil numbers differentiate eosinophilic esophagitis

from gastroesophageal reflux disease? Arch Pathol Lab Med. 2010;134 :815-825.
Liacouras CA, Bonis P, Putnam PE, et al. Summary of the First International Gastrointestinal Eosinophil Re-
search Symposium. J Pediatr Gastroenterol Nutr. 2007;45(3):370-391.
Thompson M. Esophagitis. In: Kleinman E, Walker WA, eds. Walker’s Pediatric Gastrointestinal Disease: Physi-
ology, Diagnosis, Management. 5th ed. Hamilton, Ontario.: BC Decker; 2008.
1I. Upper GI Bleeding
Tiffany Patton, MD
Ruba Azzam, MD
Upper gastrointestinal (UGI) bleeding refers to bleeding from a site proximal to the ligament of Treitz. Pre-
sentation of UGI bleeding includes hematemesis, coffee ground emesis, and melena. The cause of bleeding
varies with age.
I. Epidemiology
A. Upper GI bleeding is the indication for 5% of all childhood upper endoscopies. The incidence in-
creases to 6%–25% in critically ill children, with only 0.4% caused by life-threatening bleeds
B. Presentation:
1. Hematemesis—vomiting of bright red blood (usually an indication of a large-volume or rap-
idly bleeding lesion)
2. Coffee-ground emesis—refers to the appearance of blood denatured by contact with gastric
acid
3. Melena—black, tarry stools caused by bacterial oxidation of blood from anywhere in the GI
tract proximal to the colon (may occur with as little as 50–100 mL of UGI bleeding)
II. Pathogenesis
C. The cause of UGI bleed varies with age:
1. Neonates—swallowed maternal blood, hemorrhagic disease of the newborn, stress gastritis,
peptic ulcer disease, vascular anomaly, coagulopathy, and milk protein sensitivity
2. Infants—stress gastritis, peptic ulcer disease, Mallory-Weiss tear, vascular anomaly, gastroin-
testinal duplications, esophageal/gastric varices, foreign body, and hereditary telangiectasia
3. Child/Adolescent—Mallory-Weiss tear, esophagitis/gastritis, peptic ulcer disease, varices,
caustic ingestion, vasculitis (HSP), Crohn disease, hemobilia, foreign body, tumor and telangi-
ectasia
III. Diagnosis
A. History and physical examination are critical to determining the etiology of UGI bleeding. Clinical
signs may be associated with specific diseases:
1. Hyperactive bowel sounds, borborygmi (UGI bleed)
2. Petechiae, purpura (coagulopathy, thrombocytopenia, intense vomiting, Henoch-Schönlein
purpura)
3. Hemangioma, telangiectasia (vascular anomalies)
4. Caput medusae, spider angioma, jaundice (chronic liver disease)
5. Epistaxis (nose bleed)
6. Blood in hypopharynx (adenoid and tonsillar disorders)
7. Hyperpigmented lesions on gums and lips (Peutz-Jeghers syndrome)
B. Evaluation
1. First assess vital signs, cardiovascular stability, and level of consciousness. Assess physical signs
and symptoms of pallor, diaphoresis, restlessness, lethargy, and abdominal pain. Orthostatic
changes (increase in pulse by 20 beats/min or decrease in systolic blood pressure >10 mmHg
when moving from supine to sitting) can be more ominous signs of rapid blood loss
2. Laboratory evaluations required in any undiagnosed, clinically significant upper GI bleed:
complete blood count with platelets and differential, reticulocyte count, coagulation panel
(PT, PTT, INR), chemistry panel, liver function tests, blood type and crossmatch
3. Nasogastric tube placement and irrigation. Aspiration of bright red blood or coffee grounds
confirms that the bleeding point is proximal to the pylorus
C. Imaging modalities should be chosen after consideration of the differential diagnostic list
1. Plain films of the neck and chest may show the presence of foreign bodies or free air, sug-
gesting a perforation
2. Upper GI contrast study can detect ulceration, radiolucent foreign bodies, and duplication
cysts

3. Abdominal ultrasound can assess portal blood flow when portal hypertension is suspected
4. Nuclear medicine (radiolabeled RBC scan) can detect actively bleeding sources with flow as
low as 0.1 mL/min
5. Angiography can detect active bleeding at a rate of 0.5 mL/min or higher (therapeutic coil-
ing/embolization of a bleeding vessel can be done simultaneously)
D. Endoscopy
1. Is the currently preferred diagnostic and therapeutic modality, but is not required in hemody-
namically stable patients without anemia
2. Identifies mucosal lesions and determines source of bleeding in ~90% of cases
3. Contraindicated if patient is unstable or has profound anemia
IV. Treatment/Management
A. Fluid and blood resuscitation as needed to correct shock, fluid loss, and anemia
B. Correct any coagulopathy or metabolic/electrolyte abnormality
C. Pharmacologic therapy:
1. Acid suppression with IV/PO proton pump inhibitors is helpful in acid peptic disease
(most common cause of UGI bleeding in children)
2. Sulcralfate (40–80 mg/kg/day divided in 2–4 doses) binds directly to ulcer bases, facili-
tating healing in peptic ulcer disease
3. Octreotide
a. A synthetic octapeptide analogue octapeptide that reduces splanchnic and portal
blood flow. May be used in variceal and nonvariceal bleeds
b. Vasopressin causes peripheral vasoconstriction and may aggravate or produce
renal failure
c. 1–2 mcg/kg IV bolus octreotide, followed by 1–4 mcg/kg/hour continuous
infusion
d. Dose of octreotide may be reduced by 50% over 12 hours when bleeding is con-
trolled, and discontinued completely when reduced to 25% of original starting
dose
D. Endoscopic intervention (see Therapeutic Endoscopy)
a. Injection therapy (usually with 1:10,000 epinephrine in normal saline) can be injected
into and near an oozing lesion
b. Contact thermal methods with heater probe; monopolar and bipolar probes provide
hemostasis by local tamponade, coagulation, and blood vessel wall fusion
c. Endoscopic clip placement provides compression of bleeding vessel
E. Esophageal/gastric variceal management (see Therapeutic Endoscopy)
a. Injection sclerotherapy
b. Band ligation
c. Sclerosing glue (N-butyl-2-cyanoacrylate) injected into varix solidifies on contact with
blood, plugs the variceal lumen, and sloughs in 6 weeks to 6 months
d. Intraesophageal balloon tamponade (Sengstaken-Blakemore tube or Linton tube)
Recommended Reading
Boyle JT. Gastrointestinal bleeding in infants and children. Pediatr Rev. 2008;29:39-52.
Gilger MA, Whitfield KL. Upper gastrointestinal bleeding. In: Kleinman RE, Sanderson IR, Goulet O, Sherman
PM, Mieli-Vergani F, Shneider BL, eds. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario:
BC Decker Inc; 2008: 1286-1290.
Kamath BA, Mamula P. Gastrointestinal bleeding. In Liacouras CA, Piccoli DA, eds. Pediatric Gastroenterology:
The Requisites in Pediatrics. 1st ed. Philadelphia, PA: Mosby Elsevier, Inc; 2008: 87-97.
Park WG, Yeh RW, Triadafilopoulos G. Injection therapies for variceal bleeding disorders of the GI tract.
Gastrointest Endosc. 2008;67(2):313-323.
1J. Esophageal Caustic Injury
Frank DiPaola, MD
Phil Putnam, MD
Caustic ingestions are most commonly seen between 1 and 3 years of age. Most of these ingestions are acci-
dental and small in amount. According to National Poison Data System (NPDS), most pediatric toxic ingestions
involve cosmetic or personal care agents, analgesics, and cleaning agents. Ingestion of alkaline agents is more
common than acidic agents in the U.S.
A. Esophageal burns account for most of the severe and chronic complications of caustic ingestion
1. Liquid caustics are most likely to cause esophageal injury
2. Crystalline or powder caustics adhere quickly to mucosal surfaces and cause most damage in the
oropharynx and upper esophagus. These agents may cause lung injury if inhaled
B. Esophageal burns occur in 18%–46% of pediatric caustic ingestion cases
C. Cleaning agents are the most common causes of esophageal burns
1. Strong alkaline agents: dishwasher detergent, oven and drain cleaners
2. Strong acidic agents: toilet bowl cleaner, swimming pool and coffeemaker cleaners, soldering flux,
antirust compounds, and battery liquids
3. Industrial strength versions of cleaners, often found on farms, can cause more severe injury than the
same compound purchased for household use
4. Ammonia may cause caustic injury to the esophagus, as well as chemical pneumonitis
5. Hair relaxer (ammonia compound) rarely causes severe injury. Burns are usually superficial
6. Household bleach rarely causes injury because its pH is near neutral. Industrial strength bleaches
with a higher concentration of sodium hypochlorite may cause more severe injury
D. Mechanism of esophageal injury
1. Acidic agents induce coagulative necrosis that limits acid penetration, and damage is generally
restricted to the surface mucosa
2. Alkaline agents induce liquefaction necrosis, with very rapid transmural inflammation, and edema
with risk for perforation
3. Rapidity of injury depends on the concentration of the agent
• As little as 1 mL of 30% NaOH can cause transmural necrosis of the esophagus within sec-
onds
4. Following initial necrosis, additional damage results from inflammation, infection, and vascular
thrombosis
5. Perforation is a risk for about three weeks after ingestion, until scar formation is established
E. Signs and symptoms of caustic or acid ingestion
1. May be asymptomatic at presentation
2. Dysphagia is the most common symptom
3. Other symptoms: vomiting, drooling, hematemesis, chest or abdominal pain, respiratory distress
4. The absence of burns to the perioral area or mouth does not exclude esophageal injury
F. Evaluation and treatment
1. Document the ingested agent
a. Physical characteristics – solid, liquid, powder
b. Chemical characteristics – concentration, pH
c. Volume ingested
2. If caustic ingestion is suspected, vomiting should NOT be induced
3. Use water to wash away residual agent in mouth or on face
4. Endoscopy is indicated if ingestion is strongly suspected, to document presence and extent of
esophageal injury
a. Endoscopy should be performed between 6 hours and four days following ingestion
b. Endoscopy prior to 6 hours may not reveal the full extent of injury. Endoscopy after four days
increases the risk of perforation

c. Patients with a questionable history of ingestion, who are asymptomatic and without perioral
or oral burns, may be observed over several hours to determine PO tolerance and to monitor
for development of symptoms
5. Injuries are graded visually during endoscopy (see Table 1)
Table 1.
Grade 0 Normal
Grade I Erythema and edema
Grade II-A Noncircumferential, superficial ulceration <1/3
length of esophagus
Grade II-B Circumferential, deep ulceration >1/3 length of
esophagus
Grade III-A Circumferential ulceration, areas of necrosis <1/3
length of esophagus
Grade III-B Extensive necrosis >1/3 length of esophagus
G. Stricture management
A. Circumferential burns are most likely to be complicated by stricture
B. In patients with circumferential burns (grade IIB or III)
1. Place NG tube under direct visualization during endoscopy (not blindly, as perforation may
result) for nutrition and maintenance of lumen
C. In patients with circumferential burns, gastrostomy may be needed
1. Allows for placement of string to facilitate later retrograde dilation
2. String enters via nares and exits via gastrostomy and the ends are tied
3. In the Tucker string method of dilation, the dilator is attached to the string at the gastros-
tomy and pulled retrograde up the esophagus
4. Retrograde traction dilation has lower risk of perforation than antegrade dilation with bal-
loon or bougie
D. There is no evidence that steroids reduce incidence of stricture
E. Acid suppression indicated acutely and later for patients who develop esophageal dysmotility
F. Patients with grade II-B or grade III lesions should undergo UGI or repeat endoscopy three weeks
post-ingestion to monitor for stricture development
G. Repeated dilatations of strictures are often needed
1. 33%–48% of patients with caustic strictures have long-term success with serial dilatations
2. Long segment strictures are often resistant to dilation therapy, and require esophagectomy
with colonic interposition or gastric tube formation
H. Long-term outcome
A. Caustic injury increases the risk of esophageal squamous cell carcinoma
B. Suspect esophageal carcinoma in patients with late development of dysphagia
C. Periodic endoscopy for cancer surveillance recommended for patients starting at 20 years after caus-
tic injury to the esophagus
Recommended Reading
Hasan M, Maple JT. Traversing difficult esophageal strictures from the retrograde approach. Tech Gastrointest
Endosc. 2008;10(4):149-154.
Mas E, Olives J. Toxic and traumatic injury of the esophagus. Kleinman RE, Goulet OJ, Mieli-Vergani G, et al,
eds. Walker’s Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 5th ed. Lewiston,
NY: BC Decker; 2008: 105-116.
Uptodate online. Ferry GD. Caustic esophageal injury in children. Available at http://www.uptodate.com/con-
tents/caustic-esophageal-injury-in-children.
1K. Esophageal Foreign
Bodies
Frank DiPaola, MD
Phil Putnam, MD
There are more than 100,000 cases of pediatric foreign body ingestion every year in the United States. Most
cases occur in young children 6 months to 5 years of age. Coins are the most commonly ingested foreign
body. Fortunately, most ingested foreign bodies pass without complication.
I. Impacted foreign bodies

A. Most frequent site of impaction is the esophagus
1. Cervical esophagus (cricopharyngeus) is most common
2. Other sites of physiologic narrowing
a. Aortic arch
b. Lower esophageal sphincter
B. Common sites of impaction distal to the esophagus
1. Pylorus
2. At the junction of descending and transverse duodenum
3. Ileocecal valve
C. Patients with past GI tract surgery or congenital GI malformation (e.g., TE fistula) are at increased
risk of foreign body impaction and complications (obstruction, perforation)
II. Signs and symptoms of impacted foreign body

A. Esophageal impaction: choking, hoarseness, refusal to eat, vomiting, drooling, bloodstained saliva,
wheezing/respiratory distress, chest pain
B. Older children may localize symptoms to neck or lower chest, reflecting an esophageal impaction in
the upper or lower esophagus, respectively
C. Longstanding esophageal impaction: neck mass, chronic cough/stridor, aspiration pneumonia, dys-
phagia
D. Oropharyngeal/proximal esophageal perforation: neck swelling and/or erythema, tenderness, crepi-
tus
E. Intestinal impaction/obstruction: vomiting, abdominal distention
III. Diagnosis and localization

A. Examine chest for signs of respiratory distress that may indicate tracheal compression or aspiration
B. Inspect the neck for signs of complicated esophageal impaction or perforation
C. Examine the abdomen for signs of obstruction or perforation
D. Radiographs of the neck, chest, and abdomen in PA and lateral planes assist in localizing radi-
opaque foreign bodies and identifing multiple ingestions
1. Metal objects and steak bones may be identified on plain films
2. Fish or chicken bones, wood, plastic, most glass, and thin metal objects are not easily seen on
plain radiographs
3. Radiologic examination with a small amount of contrast may clarify the location of a foreign
body. Contrast studies should not be done routinely, as they carry a risk of aspiration and may
obscure the foreign body at subsequent endoscopy
4. CT with 3-dimensional reconstruction can be used to clarify the location of radiolucent ob-
jects
5. If radiographic assessment shows no foreign body, persistent symptoms related to the
esophagus require endoscopic evaluation

IV. Management
A. Urgent endoscopic intervention is required for sharp objects or disk battery in the esophagus, or
when esophageal impaction creates high-grade obstruction, causing inability to handle oral secre-
tions
B. Endoscopy for objects in the esophagus may be delayed up to 24 hours from time of ingestion, to
allow time for spontaneous passage:
1. In patients without high-grade obstruction
2. In patients not in acute distress
C. All foreign bodies should be removed from the esophagus within 24 hours, or if duration of impac-
tion in the esophagus is unknown
D. Blunt objects such as coins located beyond the esophagus can be observed for spontaneous pas-
sage. Blunt objects that fail to pass from the stomach should be removed endoscopically, but there
are no definitive guidelines as to duration of observation. Recommendations vary from 4 days to 4
weeks
E. Objects longer than 5 cm may not pass the duodenal sweep or may lodge at the ileocecal valve.
Removal from stomach is recommended
F. Endoscopic evaluation and removal should be attempted for sharp objects that cannot be visual-
ized by x-ray, as they may be in the esophagus, where perforation is a significant risk
G. Sharp, pointed objects localized in the stomach or proximal duodenum will most likely pass safely,
but endoscopic removal is recommended, if possible, to prevent complications
H. Sharp, pointed objects distal to the duodenum should be carefully monitored for progress and for
symptoms. Consider removal if object does not progress for three consecutive days.
I. Remove multiple magnets immediately, as they may attract across layers of bowel, causing pressure
necrosis, obstruction, and perforation
V. Food impaction
A. More likely in children with underlying esophageal pathology (e.g., stricture, achalasia, esophageal
dysmotility, and eosinophilic esophagitis)
B. Food may be removed en bloc, piecemeal, or pushed into the stomach after direct visualization of
the esophagus distal to the impaction to exclude stricture
VI. Disk batteries

A. Immediate removal of esophageal disk batteries is recommended
1. Mucosal injury can occur in <2 hours, even from an intact battery
2. Mechanisms of injury include electrical discharge with tissue hydrolysis and corrosive injury, as
well as pressure necrosis and/or leakage of contents, and can lead to fatal complications
B. Disk batteries >20 mm in diameter are more likely than smaller batteries to impact and/or cause
complications
C. Lithium batteries generally contain higher voltage and capacitance than other button batteries, and
are associated with major complications
D. Ingestion of even dead batteries is a matter of concern, as these batteries retain enough charge to
cause tissue injury
E. The National Battery Ingestion Hotline (NBIH) recommends:
1. No immediate attempt to remove a disk battery that has passed distal to the esophagus un-
less there are significant gastrointestinal signs or symptoms—severe pain, bleeding, obstruc-
tion
2. Immediate attempt to remove if the patient has coingested a magnet
3. Follow-up radiographs to document passage if battery not seen in stool within 1–2 weeks
4. Endoscopic removal from stomach if retained for >48 hours and if battery is >15 mm in child
<6 year old (batteries >15 mm less likely to pass the pylorus)
F. Fatalities from ingested batteries reported by NIBH database
1. 13 fatalities in USA related to ingested batteries between 1977 and 2009
2. All fatalities were in children <3 years of age
3. All fatalities involved esophageal impaction from 10 hours to 2 weeks duration
4. 9 of 13 fatalities involved exsanguination from esophageal fistulas into major arteries
5. Delayed, unanticipated, and uncontrollable bleeding occurred up to 18 days after battery
removal
G. Cylindrical batteries pose little threat for caustic injury
Recommended Reading
American Society for Gastrointestinal Endoscopy. Guideline for the management of ingested foreign bodies.
Gastrointest Endosc. 2002;55:802-806.
Gilger M. Foreign bodies of the esophagus and gastrointestinal tract. Uptodate.com. Accessed February 7,
2010.
Litovitz T. Emerging battery-ingestion hazard: clinical implications. Pediatrics. 2010;125:1168-1177.
Mas E, Olives J. Toxic and traumatic injury of the esophagus. Kleinman RE, Goulet OJ, Mieli-Vergani G, et al,
eds. Walker’s Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 5th ed. Lewiston,
NY: BC Decker; 2008: 105-116.
Sinclair K, Hill I. Button battery ingestion. Uptodate.com. Accessed February 7, 2010.

2A. Normal Anatomy,
Development, Physiology,
and Microanatomy
Maisam Abu-El-Haija, MD
Dawn Ebach, MD
I. Anatomy
A. Intraperitoneal organ arising from embryonic foregut
B. Divided into regions as shown in Figure 1 below
C. Blood supply of the stomach is via branches of the celiac trunk

1. Lesser curvature supplied by the right and the left gastric arteries
2. Cardia supplied by the left gastric artery
3. Greater curvature supplied by right gastroepiploic artery inferiorly and the left
gastroepiploic artery superiorly
4. Fundus supplied by the short gastric artery
D. Innervation by vagal and sympathetic nerves
1. Myenteric plexus (Auerbach’s plexus) between outer longitudinal and middle
circular layers
2. Submucus plexus (Meissner’s plexus) between circular muscular layer and the mucosa
3. Myenteric plexus and submucus plexus constitute the enteric nervous system
II. Physiology
A. Stomach layers: mucosa, submucosa, muscularis, and serosa
B. Gastric cell type and cell functions (see Table 1)
Table 1. Gastric Cells and Their Specific Functions
Parietal (oxyntic) cells Secrete intrinsic factor and gastric acid
Chief (zymogen) cells Secrete pepsinogen I and II
Mucous cells Secrete mucus layer
C. Gastric endocrine cells secrete hormones
1. G cells—gastrin
2. Enterochromaffin-like (ECL) cells—histamine
3. Enterochromaffin cells—atrial natriuretic peptide and melatonin
4. Gastric D cells—somatostatin
D. All of the above-mentioned gastric cells are present in the fundus, cardia, and antrum,
except chief cells, which are, only in the fundus
E. The fundus acts a reservoir for food. The body is a mixing chamber. The muscular antrum
releases small volumes intermittently into the duodenum
F. Total gastric volume ranges from 30 mL in newborns to 2 L in adults
III. Development
A. Originates from the primitive foregut
B. By the end of the 4th week, the stomach is recognized as a fusiform dilation
C. Enlarges ventrodorsally, with faster dorsal growth creating greater curvature
D. Stomach rotates 90° clockwise on longitudinal axis
E. The primitive gut is lined by endoderm that is mainly columnar or cuboidal epithelium. Foveolar
cells produce protective mucus and line the primitive gastric crypts
F. Foveolar epithelium eventually covers the surface of the stomach and the upper two-thirds of the
gastric pits
G. Primitive epithelium is encircled by the splanchnic mesoderm
H. Mesoderm differentiates into smooth muscle layers
Section 2 - Stomach 39
IV. Normal Histology of gastric pits/glands
A. Organized by region
1. Apical region is at the mucosal surface of the stomach also called the isthmus, or neck
region of the pit. Extends a short distance down the length of the gastric pit.
2. Body refers to tubular area between neck and base of pit
3. Base
B. Cell types in gastric glands
1. Mucous cells - generated in base of pit and migrate up the pit as they mature
2. Parietal/oxyntic cells – stain red with H and E. Secrete acid. Migrate down the pit
as they mature.
3. Chief cells – stain blue with H and E. Secret pepsinogen, other zymogens and
intrinsic factor
4. G cells – secrete gastrin in response to antral distension to promote acid secretion
from parietal cells
C. Cellular make up of gastric pits by region
1. Cardia – shallow pits containing mainly mucous cells. Very few parietal or chief
cells present
2. Fundus – deep, branched pits contain mucous cells at the apex; parietal/oxyntic cells in
the expanded body of the gland; and chief cells and neuroendocrine cells at the base.
Chief cells are found only in the fundus.
3. Antrum – deep pits containing mucous, parietal, and neuroendocrine (antral G cells
and D cells).
Recommended Reading
Feldman M, Scharschmidt BF, Sleisenger MH. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 6th
ed. Philadelphia, PA: Elsevier Saunders; 1998: 557-571.
Kleinman RE, Goulet OJ, Mieli-Vergani G, et al, eds. Walker’s Pediatric Gastrointestinal Disease: Pathophysiol-
ogy, Diagnosis, Management. 5th ed. Lewiston, NY: BC Decker; 2008.
Moore K, Persaud T. The Developing Human. 5th ed. Philadelphia, PA: WB Saunders; 1993: 239-249.
2B. Congenital Anomalies
of the Stomach
Katherine McGoogan, MD
Christopher Jolley, MD
I. Congenital Gastric Outlet Obstruction

A. Pyloric atresia
1. Associated with:
a. Junctional epidermolysis bullosa
b. Down syndrome
c. Autosomal-recessive familial form
2. Presentation at birth
a. History of polyhydramnios
b. Nonbilious emesis
c. Feeding difficulties
d. Abdominal distention
e. Stomach rupture within the first 12 hours of life can occur
3. Incidence is 3:100,000
B. Antral webs
1. Presentation depends on degree of obstruction
2. Can appear as a thin septum near the pylorus
C. Diagnosis of gastric outlet obstruction
1. Large dilated stomach on abdominal films or in-utero ultrasound
2. Upper GI series can show a pyloric dimple sign in pyloric atresia: a shallow cavity at the
proximal point of the atresia
3. Upper endoscopy can identify antral webs
D. Treatment of gastric outlet obstruction
1. Correction of dehydration
2. Correction of hypochloremic alkalosis
3. Nasogastric decompression
4. Surgical or endoscopic repair
II. Gastric Duplication

A. Usually occurs within the wall of the stomach along the greater curvature
B. Often does not communicate with the stomach lumen
C. Male:female ratio is 1:2
D. Composition
1. Alimentary epithelium
2. Submucosa
3. Smooth muscle coat
E. Presentation
1. Palpable cyst
2. Symptoms of gastric outlet obstruction (65%)
3. Bleeding if ectopic gastric tissue present (30%)
4. Volvulus
5. Perforation
6. Weight loss with failure to thrive
7. Pancreatitis if coexisting pancreatic duplication
F. Diagnosis
1. Upper GI series may show extrinsic defect on the lesser curve of the stomach
2. CT or ultrasound may outline the cystic structure
G. Treatment
1. Excision at time of discovery
2. Partial gastrectomy
III. Gastric Volvulus
A. Has acute and chronic forms
B. More frequently found in adults
C. Presentation triad
1. Sudden, severe epigastric pain
2. Intractable emesis and retching
3. Inability to pass a tube into the stomach
D. Often associated with other defects
1. Intestinal malrotation
2. Diaphragmatic defect
3. Asplenia
E. Imaging modalities
1. Upper gastrointestinal series
2. Computed tomography
F. Treatment is emergent surgery
IV. Congenital Microgastria

A. Very rare anomaly
B. Small, incompletely rotated stomach
C. Associated with malrotation, situs inversus, and skeletal anomalies
D. Presentation
1. Postprandial vomiting
2. Malnutrition
3. Rapid gastric emptying → diarrhea
4. Dumping syndrome
5. Dilated esophagus
E. Diagnosis by upper gastrointestinal contrast study
F. Treatment
1. Conservative management with frequent small feedings in less severe cases
2. Surgical attachment of a jejunal pouch to enlarge the reservoir
3. Nasojejunal or jejunostomy continuous feedings
4. Treatment for gastroesophageal reflux
5. Prokinetic agents to assist with gastric emptying
V. Pyloric Stenosis (see Pyloric Stenosis chapter)
Recommended Reading
Anatomy, histology, embryology, and developmental anomalies of the stomach and duodenum. In: Feldman
M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th ed. Philadelphia,
PA: Saunders Elsevier; 2010.
Duffy LF. Malformations of the gut. Pediatr Rev. 1992;13(2):50-54.
Hur J, Yoon CS, Kim MJ, Kim OH. Imaging features of gastrointestinal tract duplications in infants and chil-
dren: from oesophagus to rectum. Pediatr Radiol. 2007;37(7):691-699.
2C. Pyloric Stenosis
Julie Bass, MD
Craig Friesen, MD
Hypertrophic pyloric stenosis is the most common surgical disorder of the stomach in infants. The incidence is
variable, but appears to be increasing.
I. Presenting Signs and Symptoms

A. Nonbilious vomiting is the initial sign; emesis may contain streaks of bright red blood or coffee
grounds. Vomiting may be projectile
B. Dehydration, weight loss, and FTT
C. Onset as early as 7 days or as late as 5 months
D. M:F ratio 5:1
E. Vomiting produces hypercarbia, hypochloremia, and alkalosis
II. Differential Diagnosis

A. Antral web
B. Annular pancreas
C. Duodenal stenosis
D. Pyloric channel ulcer
E. Gastritis
F. Allergic gastroenteropathy
G. Pylorospasm
H. Gastroesophageal reflux
III. Physical Examination and Imaging

A. Pyloric mass found in mid-right epigastric area deep in the abdomen in 80% of patients
B. Imaging is indicated if emesis is bilious or if no pyloric mass is found
C. Upper GI series and pyloric ultrasonography reveal elongated pyloric channel
D. Upper GI also reveals semilunar indentations on antrum from hypertrophied muscle and
“double track” pyloric channel
E. Ultrasonography reveals pyloric length ≥16 mm or pyloric muscle thickness ≥4 mm
IV. Treatment
A. Correction of dehydration and hypochloremic alkalosis is essential to prevent postoperative compli-
cations, especially apnea
B. Ramstedt pyloromyotomy is curative
C. Post-operative vomiting occurs in 50% of cases due to local edema, delayed gastric emptying,
and GER
D. Normal pyloric thickness on ultrasound is seen by 6 weeks postoperative, but some abnormalities of
the gastric outlet may persist on barium studies
Recommended Reading:
Wyllie R, Hyams JS, Kay M. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders;
2006: 359-362.
2D. Colic
Julie Bass, MD
James Daniel, MD
Infantile colic refers to prolonged episodes of crying in otherwise healthy infants , which is not relieved by
routine comfort measures. Colic affects 700,000 infants each year in the US. The underlying etiology has not
been identified.
I. Identification of Infantile Colic

A. Rule of 3’s
1. Periods of crying lasting for 3 hours or more per day
2. Periods of crying occuring 3 or more days per week for >3 weeks
3. Problem usually resolves by 3 months of age
B. Episodes common in late afternoon/evening
C. Prevalence 9%–26% of all infants
D. Often interpreted as a disturbance of the GI tract because of infant grimacing, drawing up of
legs, and excessive flatulence
II. Proposed Etiologies

A. Excessive GI gas production from colonic fermentation of malabsorbed dietary carbohydrate
1. Trial of simethicone in colic shows no efficacy
2. Breath hydrogen tests do not support this proposed etiology
3. Excessive rectal gas is likely secondary to excessive crying and aerophagia.
B. Mode of feeding
1. Prevalence, pattern, and amount of crying associated with colic are
similar in breast- and bottle-fed babies
C. Protein Allergy/Intolerance
1. Some data indicates that a switch to hydrolyzed formula improves crying behavior
2. Consider short trial of hydrolyzed formula in infants already being fed
infant formula, especially in those with blood in the stool
D. Abnormal Motility
1. No data to support this proposed mechanism
E. GERD
1. Study of 24 infants with colic ≤3 months showed only 1 infant with GER
2. Controlled study of acid blockers in colic showed no difference from
placebo
3. Consider limited empiric trial of antireflux medication in infants with colic accompanied
by emesis
F. Gut hormones
1. Motilin—basal levels elevated in colicky babies independent of their diet
2. Motilin levels higher in infants who later develop colic
G. Non-GI Pathology
1. Dutch study showed two-fold increased prevalence of colic in infants of smoking mothers
2. Canadian study showed increased colic in infants of mothers with high maternal anxiety,
maternal alcohol consumption at 6 weeks, and shift work during pregnancy
3. Lower risk of colic in infants of mothers with stable partnership, full-time employment
III. Warning Signs in a Colicky Infant that Require Investigation for Underlying Organic Disease
A. Forceful or bilious vomiting
B. GI bleeding: hematemesis, hematochezia
C. Failure to thrive
D. Diarrhea
E. Constipation
F. Fever
G. Lethargy
H. Hepatosplenomegaly
I. Bulging fontanelle
J. Micro/macrocephaly
K. Seizures
L. Abdominal tenderness, distention
IV. Complications of Colic

A. Early discontinuation of breast feeding, frequent formula changes, maternal distress and irritability,
suboptimal father-infant interactions, increased risk for abuse
B. Later in life, some studies have identified more impulsive cognitive style, hyperactivity,
academic difficulties
Recommended Reading
NASPGHAN GE Reflux Clinical Practice Guildelines. J Pediatr Gastroenterol Nutr. 2009;49:4.
Wyllie R, Hyams JS, Kay M. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders;
2006: 169-174.
2E. Gastritis
Sharmila Zawahir, MD
Samra Blanchard, MD
I. Infections
A. H pylori
1. Most common cause of gastritis worldwide
2. Acute infection produces neutrophilic response, followed by chronic infection with lym-
phocyte and plasma cell infiltrates (see chapter on H pylori)
B. Other bacteria
1. H heilmannii: from cats, causes chronic active gastritis, associated with gastric carcinoma
and MALT lymphoma
2. M tuberculosis: rare cause of granulomatous gastritis, with gastric ulcers and mucosal
hypertrophy on endoscopy
3. Bacillus cereus: acute necrotizing gastritis
C. Viral
1. Cytomegalovirus
a. More common in immunosuppressed patients; but possible in
immunocompetent
1) Usually associated with Ménétrier’s disease (see below)
2) Hyperplastic gastric folds, protein-losing enteropathy, and
hypoalbuminemia
b. Infection in gastric fundus and body → wall thickening, ulceration, hemorrhage,
and perforation
c. Histology: acute and chronic inflammation, intranuclear cytoplasmic inclusions
in endothelial and epithelial cells; cytomegalic cells
d. Deeper inflammation of mucosa compared to HSV
e. Diagnosis by viral culture of mucosal biopsies, immunohistochemical detection
of CMV early antigen
f. Management: spontaneous recovery in 1–2 months, or ganciclovir
2. Other uncommon causes: hepatitis C virus, EBV, HHV-7, measles, varicella, influenza,
HSV
D. Parasitic
1. Cryptosporidiosis: rare cause of PUD and erosive gastritis
2. Fish parasites Anisakia simplex (found in sushi and sashimi in Japan), and Eustrongylides
wenrichi (fresh water fish) both cause eosinophilic gastritis in humans
3. Giardia lamblia can infect stomach and cause reactive gastritis, chronic atrophic gastritis,
or chronic active gastritis
E. Fungal (most common in immune compromised patients in association with systemic fungal
infection)
1. Candida albicans is the most common fungal organism causing gastritis
2. Aspergillus can cause focal invasive gastritis. Risk factors are neutorpenia, mucositis
and glucocorticoid use
II. Reactive Gastropathy

A. Reactive changes in gastric mucosa caused by ischemia, chemical agents, or trauma
B. Endoscopic: antral erythema, erosions, and ulcerations
C. Histology: foveolar hyperplasia, mucosal edema, paucity of inflammatory cells
D. Stress gastropathy
1. Occurs in setting of physiologic stress with secondary hypoperfusion
2. Risk factors: gastric hypersecretion, mechanical ventilation, steroids, coagulopathy, sepsis
3. Physiologic stress: shock, hypoxemia, burns, major surgery, multiple organ system failure,
or head injury
4. Erosions are multiple, superficial, and typically asymptomatic
5. Risk of perforation is low, except in newborns with reactive gastropathy
6. Can present with upper GI bleeding
7. Initially involves fundus and proximal body, followed by antrum
8. Within 24 hours of stress event
E. Neonatal gastropathy
1. Typically seen in sick infants in NICU setting
2. Infants on prostaglandin E to maintain patency of PDA
3. Focal foveolar hyperplasia
4. Antral mucosal thickening may cause gastric outlet obstruction
5. Indomethacin, dexamethasone
6. Other possible causes include: traumatic suctioning of upper GI tract, fetal distress,
hypergastrinemia with maternal stress or antacid use, hyperpepsinogenemia,
cow milk allergy
F. Medications causing gastritis
1. NSAIDs
a. Topical effect: antral erosions and acute hemorrhage within 15–30 minutes of
ingestion
b. Systemic effect: inhibition of COX-2–mediated production of prostaglandins
1) Prostaglandins promote gastric mucosal blood flow and secretion of
mucous and bicarbonate
2) Lack of prostaglandins compromises mucosal integrity and protective
barrier
3) Increased platelet-activating factor induces platelet dysfunction
c. Young children: ulceration at antrum and incisura
d. Older children/adults: reactive gastropathy with epithelial hyperplasia, mucin
depletion, enlarged nuclei, smooth muscle hyperplasia, vascular ectasia,
and edema
e. Factors increasing complications from NSAIDs: concomitant use of aspirin or
second NSAID, high drug dose, age >65 years, anticoagulant use, H pylori infec-
tion
f. Prevention of NSAID gastropathy by concomitant use of PPI or misoprostol (cy-
toprotectant)
g. H2 receptor antagonists are not effective for prevention of gastropathy
2. Other medications causing gastropathy
a. Valproic acid, dexamethasone, chemotherapy, KCl, iron, long-term fluoride
ingestion
3. Alcohol gastropathy
a. Subepithelial hemorrhages with minimal inflammation
b. Gastropathy is more severe when combined with NSAID or aspirin
G. Traumatic gastropathy
1. Subepithelial hemorrhages in fundus and proximal body due to forceful retching/vomit-
ing
2. Ulcerations on gastric wall next to or opposite a PEG or standard gastrostomy tube
3. Mallory-Weiss tears immediately above and below the GE junction
4. Linear erosions in herniated gastric mucosa of large hiatal hernias
5. Long-term nasogastric tube use
6. Gastric prolapse through gastrostomy tract
H. Exercise-induced gastropathy or gastritis
1. Long distance runners may experience altered blood circulation and motility during and
just after running
2. Symptoms, usually post-exercise: abdominal cramps or epigastric pain, nausea, GER,
vomiting
3. Anemia from chronic blood loss
4. Endoscopy: erosive and nonerosive gastropathy in all parts of the stomach
I. Radiation gastropathy
1. Exact tolerance level of stomach to radiation dose is not known
2. Erosions and ulcerations may progress to bleeding, perforation, fibrosis, and gastric
outlet obstruction
3. Acid suppression does not prevent radiation injury
J. Corrosive gastropathy
1. Severity depends on concentration, duration of exposure, volume, and amount of food
in stomach at time
2. Acid ingestion primarily causes gastric injury
3. Gastric injury also possible with large volume alkali ingestion
4. Acid pools in antrum because of acid-induced pylorospasm
5. Endoscopy: friability, erythema, ulcers, hemorrhage, necrosis
6. Healing may lead to antral and pyloric strictures
7. Common agents: oral iron, zinc-containing foreign bodies and fluids, lithium or mercuric
oxide button batteries, pine oil cleaner, hydrogen peroxide, potassium permanganate
K. Duodenogastric reflux (bile gastropathy)
1. Reflux of duodenal contents into the stomach occurs normally for about 5% of a 24-
hour period in adults
2. May produce gastric mucosal inflammation, intestinal metaplasia, gastric carcinoma
3. Symptoms: bilious emesis, oral bile reflux, nonspecific reflux symptoms
4. Endoscopy shows erosions and erythema. Bile in the stomach is not proof of pathologic
bile gastropathy
5. Histology: reactive gastropathy
6. Management
a. PPI may be effective
b. Prokinetics not thoroughly evaluated
c. Limited evidence for bile acid–binding agents
d. If refractory to medical therapy: Roux-en-Y duodenojejunostomy
III. Granulomatous Gastritis

A. Noninfectious
1. Inflammatory bowel disease (IBD)
a. Focal gastritis associated with Crohn disease is the most common cause of
granulomatous gastritis
2. Chronic granulomatous disease (CGD)
a. Inherited immune disorder, more often in boys
b. Upper GI symptoms with severe gastroenteritis, oral aphthous ulceration
c. Chronic active focal gastritis in antrum with granulomas or multinuclear giant
cells
d. Diagnostic finding at endoscopy: lipochrome-pigmented histiocytes
3. Other causes of noninfectious granulomatous gastritis: sarcoidosis, lymphoma,
Wegener granulomatosis
B. Infectious: TB, syphilis, histoplasmosis, parasites, foreign body granulomas
IV. Eosinophilic Gastritis

A. Diagnosis based on typical symptoms of gastritis (vomiting, abdominal pain, blood loss, gastric
outlet obstruction), eosinophilic gastric infiltrate, and exclusion of other causes of eosinophilic
infiltrate
B. Most often occurs as part of eosinophilic gastroenteritis
C. Other causes of mucosal eosinophilia: Crohn disease, scleroderma, parasitic infection
D. Eosinophilic infiltrate may be in mucosal, muscular, or serosal layers
E. Specific allergen sometimes identified: cow milk/soy protein, egg, wheat
F. Endoscopic findings: friability, erythema, erosions, swollen folds, pseudopolyps (antral)
G. Peripheral eosinophilia present in 50% of adults
H. Treatment: hypoallergenic diets, steroids, antiallergic medications
V. Lymphocytic Gastritis
A. Etiology
1. Celiac disease
2. Ménétrier disease
3. CMV
4. Chronic varioliform gastritis
5. Crohn disease
6. Idiopathic
VI. Hyperplastic
A. Ménétrier disease
1. Typical age of presentation in childhood is 4 years; however, can be seen in neonates
2. Usually benign and self-limited in children
3. In adults, this may be a premalignant condition
4. Associated with CMV infection
5. Giant gastric folds, increased mucus secretion, decreased acid secretion, protein-losing gastropathy
6. Differential for giant gastric folds:
a. Lymphoma
b. H pylori, CMV, anisakiasis
c. Granulomatous gastridites
d. Plasmocytoma
e. SLE
7. Endoscopy: giant rugal folds, erythema
8. Histology: elongated, tortuous foveolae; decreased parietal and chief cell glands, cystic dilations,
edematous lamina propria with increased eosinophils and lymphocytes
9. Raised CMV IgM, positive CMV PCR, positive tissue culture
B. PPI Gastropathy
1. Long-term or high-dose PPI use causes parietal cell hyperplasia
2. Occurs within 10–48 months of starting PPI
3. No dysplasia
4. Histology:
a. Sessile—hyperplastic, glandular dilation, foveolar hyperplasia, mild inflammation
b. Pedunculated—fundic gland polyp with cystic glandular dilation
5. Typically resolves with cessation of therapy
VII. Portal Hypertensive Gastropathy

A. Occurs in both cirrhotic and noncirrhotic portal hypertension, but more common in cirrhotic
B. Unrelated to severity of liver disease, size of esophageal varices, or hypersplenism
C. Endoscopic diagnosis
1. Mild: 2–5 mm erythematous patches in a mosaic pattern
2. Severe: cherry-red spots, confluent hemorrhagic appearance
D. Histology:
1. Ectasia of mucosal capillaries and venules, submucosal venous dilation, no significant inflammatory infil-
trate
2. Diagnosis is visual; biopsies are not necessary and may promote bleeding
E. Therapy
1. Nonselective beta blockers (propranalol, nadolol) reduce portal venous pressure and may improve blood
loss
2. Somatostatin analogues are used to control acute bleeding
VIII. Celiac Gastritis

A. Intraepithelial lymphocytic infiltrate in antrum, without gross endoscopic findings
B. Histology normalizes on gluten-free diet
IX. Graft vs Host Disease

A. Acute GVHD: 21–100 days after transplant
1. Anorexia, nausea, vomiting, upper abdominal pain
2. Variable endoscopic findings in stomach
3. Histology
a. Early: crypt cell apoptosis and drop-out
b. Advanced: gastric ulceration, edema, fibrosis, perforation
B. Chronic GVHD rarely involves stomach
X. Uremic Gastropathy
A. Acute renal failure or associated physiologic stresses may cause gastritis
B. GI bleed associated with ulcers/erosions
C. Gastric pH may increase in chronic renal failure due to increased urea in all tissues
XI. Autoimmune Gastritis:
A. Henoch-Schönlein purpura
1. Immune complex–mediated vasculitis of small- and medium-sized vessels, which peaks in
4–6 year olds
2. Involves skin, GI tract, kidneys and joints
3. Colicky abdominal pain, nausea, vomiting, GI bleed
4. Less common findings: intramural hematoma, intussusception, bowel infarction, bowel
perforation, pancreatitis, appendicitis, cholecystitis
5. Upper endoscopy is usually not required for diagnosis; however, may show hemorrhagic,
edematous mucosa with erosions in stomach, duodenum, and jejunum
6. Histology: leukocytoclastic vasculitis is often missed in shallow endoscopic biopsies
B. Pernicious Anemia
1. Achlorhydria, intrinsic factor deficiency, and B12 deficiency
2. Upper endoscopy shows absent or thin rugae
3. Histology shows atrophic fundic gland gastritis, absence of parietal cells
4. Complication: gastric adenocarcinoma
C. Autoimmune thyroiditis and goitrous juvenile hypothyroidism associated with gastritis and muco-
sal atrophy
D. Vitiligo associated with autoimmune atrophic gastritis
E. SLE associated with hypertrophic gastropathy
F. Connective tissue disorders may have associated mast cell or eosinophilic gastritis
XII. Collagenous Gastritis

A. Rare: presents with chronic iron deficiency anemia and epigastric pain
B. Endoscopic findings are nonspecific and nondiagnostic
C. Biopsies show subepithelial collagen fibrosis, with inflammatory infiltrate in the lamina propria
D. Some improvement with acid suppression and steroids
XIII. Cystinosis
A. Intralysosomal deposition of cystine causes damage to many organs
B. Cysteamine lowers intracellular cystine, but causes hypergastrinemia and gastric hypersecretion,
even after a single dose
XIV. Hypersecretory States

A. Zollinger-Ellison syndrome (see chapter on Secretory Tumors)
B. Systemic mastocytosis
1. Mast cell accumulation in skin, bone, bone marrow, liver, spleen, and GI tract
2. Excess histamine and cytokines produce gastric hypersecretion
3. Isolated cutaneous is the most common form (urticaria pigmentosa)
4. Systemic form: normal serum gastrin levels
5. Endoscopy: gastric and duodenal ulcerations and urticaria-like papules
6. Anesthesia is risky
7. Management is with H1 and H2 blockers and acid-suppressive therapy
C. Short bowel syndrome
1. Gastric hypersecretion because of lack of negative feedback inhibiting gastrin secretion
2. Hypersecretion may be transient, or persistent with PUD
3. May worsen nutritional status by inactivating pancreatic lipase and deconjugating bile
salts
D. Hyperparathyroidism
1. Hypercalcemia causes increased gastric acid secretion
2. Usually causes duodenal ulcer
Recommended Reading
Blecker U, Gold BD. Gastritis and peptic ulcer disease in childhood. Eur J Pediatr. 1999;158:541-546.
Dimmick JE, Jevon GP, Hassall E. Pediatric gastritis. Perspect Pediatr Pathol. 1997;20:35-76.
Dohil R, Hassall E, Jevon G, Dimmick J. Gastritis and gastropathy of childhood. J Pediatr Gastroenterol Nutr.
1999;29:378-394.
Sherman P, Czinn S, Drumm B, et al. Helicobacter pylori infection in children and adolescents: Working Group Report
of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr.
2002;35:S128-S133.
2F. Helicobacter Pylori
Sharmila Zawahir, MD
Samra Blanchard, MD
Helicobacter pylori (H pylori) is a slow-growing, Gram-negative, curved or S-shaped rod. This pathogen is
responsible for a wide spectrum of disease.
I. Epidemiology
A. Increased risk of infection: developing countries, lower socioeconomic status, crowded living
conditions, and household contacts
B. Transmission
1. Most commonly direct person-person contact
2. Water is a possible source, particularly home cisterns and water barrels in which organ-
isms may form biofilms
C. Acquired in early childhood
1. Infection may clear spontaneously
2. Life-long infection is common after the first infection
3. Infants are rarely infected, even if the mother is infected
D. Prevalence is decreasing in the developed and developing world
E. Re-infection rates are low, but recrudescence (same strain within 12 months) is common
1. Re-infection is more likely in children <10 years old
2. Re-infection rates are higher in developing areas with poor water and sanitation, and
high population density
F. Organism colonizes gastric tissue, including areas of gastric metaplasia and/or ectopy in the
duodenum, esophagus, and other sites
G. Infection produces chronic gastritis, which may remain asymptomatic
II. Host Factors

A. Natural reservoir: humans
B. Most often transmitted by asymptomatic individuals
C. Infection produces local and systemic host response
D. Impact of host genotype:
1. P olymorphism of inflammatory cytokine IL-1β associated with corpus gastritis, hypo-
chlorhydria, gastric atrophy, and gastric adenocarcinoma; but decreased risk of duode-
nal ulcer
2. In the absence of proinflammatory IL-1β polymorphism, infection produces antral
gastritis or self-limited infection
E. Impact of host immune response
1. Antral gastritis: associated with increased acid production and duodenal ulceration
2. Corpus gastritis: associated with decreased acid production and gastric ulcerations,
as well as adenocarcinoma
3. Humoral immune response leads to tissue damage, but not eradication of infection
4. H pylori–specific IgA and IgG seen early in infection
F. Acid homeostasis
1. Acute infection associated with transient hypochlorhydria (several months), which may
facilitate transmission
2. Antral predominant infection
a. Increased gastrin production causes:
1) Increased acid production
2) Increased parietal cell mass → increased acid delivery to duodenum,
producing gastric metaplasia
3. Pan-gastritis/corpus predominant infection
a. Decreased acid production from infection leads to decreased gastrin
production, and therefore hypochlorhydria
b. Gastric epithelial cell proliferation and progressive gland loss, leading to gastric
atrophy
c. Atrophy increases risk of gastric ulceration and gastric adenocarcinoma
III. Bacterial Factors

A. H pylori genome mutates rapidly by DNA incorporation from different strains
B. Ingestion of organism leads to colonization of gastric mucous layer
1. Inhibitors: acidity, motility, initial host immune response
2. Hydrolyzes urea locally, increasing the local pH and promoting survival
3. Flagella promotes motility to remain in mucous layer; nonflagellated forms are not
pathogenic
C. Outer membrane proteins (OMPs)
1. Bind to antigens on gastric epithelial cells, preventing mechanical clearance
2. DupA (duodenal ulcer promoting cytotoxin): associated with duodenal ulcer disease
D. Cytotoxin-associated gene (CagA)
1. Fragment of DNA encoding for components of type 4 secretion system, which enable
the organism to transport proteins into other cells
2. CagA+ strain infection increases risk of peptic ulcer disease (PUD) and gastric cancer
E. Vacuolating cytotoxin (VacA)
1. Pore-forming protein in 50% of H pylori strains
2. Associated with severe disease, as it helps protect organism from gastric acid
IV. Clinical Implications of Infection

A. GI system
1. Chronic gastritis
a. Reversible with eradication
2. Ulcer disease: duodenal/gastric
a. Less common in children
b. Antral predominant infection: increased risk of duodenal ulcer
c. Corpus predominant infection: increased risk of gastric ulceration and gastric
malignancy
d. DU associated with increased acid output
e. 90% of DU children have antral H pylori colonization
3. GER/GERD: no evidence for correlation with H pylori infection
4. Gastric carcinoma
a. Linked to CagA+ strains
b. Early childhood infection increases risk
c. Associated with reduced acid output and corpus predominant gastritis
d. Gastritis → atrophy → intestinal metaplasia → dysplasia
5. MALT lymphoma
a. Increased risk of this primary gastric malignancy
b. Eradication of H pylori infection leads to regression and remission in 70%–80%
of established MALT
B. Extraintestinal
1. Iron deficiency anemia:
a. Multiple mechanisms: chronic blood loss from gastritis/erosions/ulcers;
hypochlorhydria decreases iron bioavailability; vitamin C deficiency;
sequestration of iron by antral H pylori organisms
2. Short stature reported in some population studies: more pronounced in males
3. ITP
4. Chronic urticaria
C. Proposed benefits of infection
1. Stimulation of local and systemic immune system, which may help promote host defense
to exogenous pathogens
2. Protection from diarrheal diseases
V. Diagnosis:
A. Indications for H pylori testing
1. PUD diagnosed by endoscopy, family history of gastric cancer, documented MALT lym-
phoma, refractory iron deficiency anemia without other cause
2. Not indicated for recurrent abdominal pain or non-ulcer dyspepsia, asymptomatic chil-
dren, or newly diagnosed GERD
B. Invasive
1. Endoscopy with biopsy
a. Most reliable for diagnosis and identification of infection
b. Nodularity in stomach more common in children than in adults
1) Cobblestone appearance: 1–4 mm in diameter, uniform color
and smooth
2) Most frequently seen in antrum
2. Histology
a. Superficial infiltrate of plasma cells and lymphocytes
b. Lymphoid follicles with germinal centers are very suggestive of infection
c. Atrophy
1) Very rare in Western children
2) Loss of glandular tissue
d. Stains for identifying H pylori in tissue
1) Silver: Warthin-Starry, Dieterle, Steiner, Genta
2) Modified Romanovsky
3) Sayeed stains
e. Site of biopsy:
1) Mid-antrum is best for children; in adults, cardia is also a good site
2) Chronic PPI use can shift antrum-predominant to corpus-predominant
gastritis
3. Culture
a. Fastidious organism: requires microaerophilic environment and complex media
b. High specificity, but sensitivity varies between labs
c. Multiple biopsies increase yield
d. Culture allows for antibiotic sensitivity testing
4. Rapid urease test on gastric biopsy tissue
a. Urea breakdown by bacteria causes color change of pH indicator
b. Sensitivity increases with the size of the sample
c. Sens/Spec: 89/98%
C Noninvasive
1. Urea Breath Test
a. Patient injests urea labeled with 13C isotope
b. Safe in young infants, readily repeated
c. Urea hydrolysis produces labeled 13CO2 and appears in the breath in minutes
d. Can be used for diagnosis as well as post-treatment assessment
e. Sens/Spec: 88–95/95%–100%
f. False negative produced by antisecretory therapy, antibiotics
2. Serological tests
a. Early specific IgM, and later, persistent specific IgA and IgG
b. Not consistently sensitive or specific enough for use as sole diagnostic marker
of infection
c. Specific IgG tests (most common) have better sensitivity than IgA tests, but can-
not differentiate past vs active infection
1) Sens/Spec: 90-100/76%–96%
d. Antibodies may not be detectable early in infection
3. Stool antigen test
a. Monoclonal antibody–based test has high sensitivity and specificity
1) Sens/Spec: 95/97%
2) Polyclonal-based test only 94/86%
b. Reported correlation between severity of gastritis and positivity in stool
c. False negative with PPI
VI. Treatment
A. Endpoint is eradication of infection
B. Conventional regimens
1. Anti-secretory agent plus two or three antimicrobial agents for 10–14 days
a. PPI + clarithromycin + amoxicillin or metronidazole x 10–14 days
b. Addition of PPI increases eradication rates: inhibition of gastric acid may increase the
effectiveness of acid-sensitive antibiotics (i.e., clarithromycin)
c. Most common prescribed antibiotics: amoxicillin, metronidazole, clarithromycin, and tetracycline
2. Bismuth: unknown mechanism; contraindicated due to association with encephalopathy and acute
renal failure
C. Sequential regimens
1. PPI + amoxicillin x 5 days, then 5 days of triple therapy (PPI + two antibiotics)
2. Amoxicillin can decrease bacterial load and prevent clarithromycin resistance
D. Treatment failure
1. Sources
a. Patient noncompliance
b. Antibiotic resistance
c. Inadequate drug delivery
2. Clarithromycin should not be used for treatment failure
3. Some suggest bismuth-based quadruple therapy, or PPI + amoxicillin + tetracycline
4. Tetracycline not recommended in children <12 years
5. Antibiotic resistance
a. Rates are increasing, and may have been present prior to therapy (primary)
b. High resistance to metronidazole and clarithromycin reported
c. Very low reported resistance for amoxicillin
E. Adjunctive therapy
1. Probiotics to improve eradication: conflicting reports
F. Vaccination
1. Would be cost-effective; trials are ongoing
Recommended Reading
Howden CW, Hunt RH. Guidelines for the management of Helicobacter pylori infection. Ad Hoc Committee on Practice Pa-
rameters of the American College of Gastroenterology. Am J Gastroenterol. 1998;93:2330.
Kleinman RE, Goulet O-J, Mieli-Vergani G, Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Dis-
ease. 5th ed. Hamilton, Ontario: BC Decker, Inc; 2008.
S herman P, Czinn S, Drumm B, et al. Helicobacter pylori infection in children and adolescents: Working Group Report of the
First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2002;35:S128-
S133.
Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Elsevier; 2011.
2G. Ingestions and Trauma
Maireade McSweeney, MD, MPH
Laurie Fishman, MD
Significant injury can occur from ingestions, both foreign body and caustic, which are frequent during child-
hood. More significant injury may occur from trauma resulting in brain and organ damage. Abdominal inju-
ries from trauma are the third leading cause of pediatric traumatic death.
I. Gastric Ingestions
A. Foreign objects: (see Esophageal Foreign Bodies)
1. Often asymptomatic at time of presentation
2. Evaluation: Always obtain an x-ray to assess position of suspected foreign object
a. Radiolucent objects: wood, glass, plastic
b. Assess for red flag symptoms: decreased appetite, food refusal, fever, nausea/
vomiting, hematemesis, abdominal pain
3. Lead intoxication
a. Lead intoxication can occur with ingested toys secondary to gastric acid dissolu-
tion of lead
b. Immediate removal recommended if lead is suspected
B. Sharp and elongated objects:
1. Account for 15%–35% of perforations following foreign body ingestion (i.e., bones,
toothpicks, razors, toy pieces, and long straight pins)
2. Most can be managed conservatively (with weekly abdominal films to monitor passage)
3. Increased risk of perforation if multiple objects were ingested
4. Rule of thumb: objects >5 cm length (>3 cm in younger children) and >2 cm diameter
are unlikely to pass the pylorus. Consider endoscopic removal of long or large objects
while in stomach
5. Majority of perforations (postesophagus) occur near duodenal loop or ileocecal valve
C. Coins: most frequently ingested foreign body in children in the United States and Europe
1. Symptoms of gastric outlet obstruction or pain/peritonitis require immediate endoscopic
removal
2. Coins <2.5 cm diameter usually pass spontaneously
3. If coin does not pass stomach after 4 weeks, endoscopic removal is likely needed
4. Counsel parents to return to the emergency room if their child has red flag signs/symp-
toms
D. Gastric button batteries: (see Esophageal Foreign Bodies)
E. Bezoars: tightly packed collection of partially digested or undigested material. Often form in
patients with delayed gastric emptying or motility
1. Assess location with abdominal film or barium study
2. Surgical removal may be necessary for large bezoars or antral bezoars
3. Trichobezoars: hair bezoar; may give symptoms of gastric outlet obstruction or intestinal
obstruction
4. Phytobezoar: plant fibers - citrus, persimmon, cactus fruit, cloth fibers are common
5. Lactobezoars: milk-based bezoar; often have symptoms of vomiting, feeding
intolerance, and increased gastric residual volume. Withholding feedings for 2–3 days
while giving IVF will often dissolve lactobezoars
6. Phyto and trichobezoars can cause gastritis and iron deficiency anemia
F. Magnets—risk of abdominal trauma depends on quantity of magnets ingested:
1. If single magnetic object was ingested and is already postpyloric, monitor with serial
abdominal films. If in stomach, may consider removal
2. Multiple magnetic objects can appear on x-ray as single object. Consider endoscopic
removal if single magnet is seen in stomach
3. If multiple magnets are ingested, immediate intervention is necessary due to the high
risk of magnetic attractive forces across adjacent bowel loops leading to intestinal perfo-
ration, bowel obstruction (possible volvulus), and fistula formation in small/large intes-
tine
4. If multiple magnets are in the stomach: urgent endoscopic removal
5. If magnets are post-pyloric: obtain surgical consult for possible surgical removal
G. Corrosive gastritis: (see Esophageal Caustic Injury)
1. Most common from 12 months to 2 years of age. Less common than esophageal injury
2. May be caused by corrosion due to ingestion of strong acid (low pH) or alkaline (high
pH) ingestion
3. Acid ingestions generally are more likely to cause stomach injury than alkali ingestions
because of resistance of pharynx/esophageal squamous epithelium to coagulative necro-
sis. Alkaline ingestions are overall more common in incidence due to: (1) harsh taste of
acids and (2) common presence of alkali in household products
H. Severity:
1. Dependent on concentration, amount, type of agent ingested, and length of time in the
stomach. Ingestion can lead to damaged mucosa (friability/erythema), ulceration, gastro-
intestinal hemorrhage, necrosis, and perforation
2. In the long-term, corrosive ingestions carry increased risk of antral and pyloric stricture
formation (~4–6 weeks), which can lead to gastric outlet obstruction
3. EGD is contraindicated if perforation is expected
I. Acid ingestion:
1. Leads to coagulative necrosis and eschar formation especially in the antrum
2. Strong acid in antrum due to prepyloric spasm
J. Alkali ingestion:
1. Lye-based (NaOH, KOH) drain cleaners, ammonia, and dishwashing soap
2. Causes mucosal liquefactive necrosis → deep penetration of mucosal layers
K. Other agents:
1. Oral iron, zinc-containing foreign bodies, pine oil cleaner, nonsteroidal anti-inflammatory
agents (i.e., ibuprofren), oxidizing agents (hydrogen peroxide), and bleach (pH ~7)
2. Bleach produces ulceration that does not result in stricturing
L. Treatment for caustic ingestion:
1. Antibiotics, anti-reflux therapy (avoid induced emesis and gastric lavage)
2. May need to make NPO if deep burns and/or perforation suspected
3. Steroid therapy is controversial
II. Abdominal Trauma

A. Epidemiology:
1. Serious abdominal injuries account for ~8% admissions to pediatric trauma centers. It is
the third leading cause of pediatric traumatic death after head and thoracic injuries
2. Most common unrecognized fatal injury in trauma cases
3. 85% cases resultant of blunt trauma, such as:
a. Lap belt injury: can lead to both small bowel injury from motor vehicle collision
& traumatic diaphragmatic hernia
b. Bicycle injuries
c. Sports-related injuries
d. Child abuse
4. With blunt trauma, children are at higher risk of solid organ injury (spleen is the #1 solid
organ injured; liver is #2, but liver injury is the most common cause of lethal hemor-
rhage)
a. Solid organ injury is more common in children (vs adults) due to proportionally
larger solid organs, less subcutaneous fat, and less protective abdominal
musculature in children
5. Abdominal distension and vomiting are often late-onset findings
B. Examination: physical exam of abdomen, with rectal examination for blood
C. Diagnostic testing: only performed for intraabdominal injury in a stable patient; a rapid
abdominal CT is first choice
1. Other imaging options: Focused Abdominal Sonography for Trauma (FAST)
2. Diagnostic peritoneal lavage
3. Duodenal injury: rare, but often associated with a delayed diagnosis due to delayed
symptoms
4. Associated with symptoms of gastric outlet obstruction
5. Hematomas often managed nonoperatively with decompression and bowel rest
6. Perforation requires surgical repair
Recommended Reading
Avarello JT, Cantor RM. Pediatric Major Trauma: An approach to Evaluation and Management. Emerg Med
Clin N Am. 2007;25:803-836.
Clendenon JN, Meyers RL, Nance JM, Scaife ER. Management of Duodenal Injuries in Children. J Pediatr Surg.
2004;39:964-968.
Cordero B, Savage RR. Corrosive Ingestions. Pediatr Rev. 2006;27:154-155.
Kader HH. Foreign body ingestion: children like to put objects in their mouth. World J Pediatr. 2010. 6(4):
301-310.
Kay M, Wyllie R. Pediatric foreign bodies and their management. Curr Gastroenterol Rep. 2005;7:212-218.
3A. Normal Anatomy,
Anna Hunter, MD
Mei-Lun Wang, MD
I. Development
A. Primitive gut tube is formed by the incorporation of a portion of the yolk sac into the embryo during
craniofacial and lateral folding
1. Epithelial lining and glands are derived from endoderm
2. Lamina propria, muscularis mucosa, submucosa, muscularis externa, andadventitia/serosa
are derived from mesoderm
3. Posterior luminal digestive structures and enteric nervous system are derived from the ecto-
derm
B. Epithelial lining proliferates rapidly, occluding the lumen. This process is later followed by
recanalization
C. Primitive gut tube, which forms at 4 weeks, is divided into: foregut, midgut, and hindgut
1. Caudal portion of the foregut—upper duodenum
a. Blood supply—celiac artery
2. Midgut—lower duodenum, jejunum, ileum, appendix, ascending colon, and proximal two-
thirds of the transverse colon
a. Blood supply: superior mesenteric artery (SMA)
b. Midgut loop herniates through the primitive umbilical ring at 6 weeks’
gestational age
c. Midgut loop rotates counterclockwise 270° around the SMA as it returns to the ab-
dominal cavity at 11 weeks’ gestational age
D. Differentiation
1. Week 7: Primitive gut has a simple tubular form
2. Week 9: Development of villi
3. Week 12–14: Appearance of primitive crypts
4. Week 13: Completed development of both circular and longitudinal muscle layers
5. Week 16: Development of muscularis mucosa
6. Week 20: Presence of well-developed villi and crypts, along with lamina propria and special-
ized connective tissue
E. Anomalies
1. Duodenal/intestinal atresia or stenosis: Failure of recanalization
2. Omphalocele: Failure of the midgut loop to return to the abdomen, covered with outer
amniotic and inner peritoneal sac (see Gastroschisis and Omphalocele)
3. Vitelline fistula: Persistence of the vitelline duct (meconium discharge from the umbilicus)
4. Meckel’s diverticulum: Remnant of vitelline duct persists, forming a blind pouch
on antimesenteric border of the ileum
a. May contain ectopic gastric, thyroid, or endometrial tissue
5. Malrotation: Midgut undergoes only partial rotation
6. Non-rotation: Occurs in about 1 in 500 live births and has been described in 0.5%
of autopsies
a. Laxity of the umbilical ring, which allows reduction of the midgut without rotation
during the 10th week of fetal development, is a likely cause of non-rotation
II. Molecular Mechanisms

A. Hox genes: Expressed in the mesoderm of the gut, play a role in gut patterning along the AP axis,
including gross morphology, as well as epithelial differentiation
B. Hoxd13 and Hoxa13 play a role in the hindgut mesoderm-to-endoderm signaling and control final
epithelial phenotype
Section 3 - Small Bowel 61

C. In addition to Hox genes, at least two ParaHox transcription factor genes, Cdx2 and Pdx1, are critical
for gut tube development
1. Cdx2 likely patterns the vertebrate gut by regulating Hox gene expression in the endoderm.
During development, the homeobox gene Cdx2 exerts a homeotic function, providing the
positional information necessary for correct specification of the midgut endoderm
2. The early patterning of the embryo determines the expression pattern of ParaHox, Hox, and
other transcription factor genes in the endoderm and adjacent mesoderm. A complex interac-
tion between these two tissues leads to the final pattern of the gut tube along the AP axis.
Hedgehog, Bmp, Fgf, and Wnt signaling have all been implicated in various aspects of gut
development
III. Anatomy
A. The length of the small intestine varies from 3–10 meters (10–33 feet). Average small intestine
length is 6.5 meters (22 feet)
B. Small intestine is divided into duodenum, jejunum, and ileum
1. Duodenum: Approximately 25 cm in length. Extends from the pylorus to the duodenal-jejunal
flexure (attachment of the ligament of Treitz)
a. About 2.5 cm of the proximal duodenum are covered by the peritoneum; after that, it
becomes a retroperitoneal organ
b. There is no division between jejunum and ileum
c. The diameter of the small bowel decreases from the proximal to distal end
C. Jejunum tends to have a thicker wall and bigger folds (valvulae conniventes)
1. Jejunum lies closer to the umbilical region, and ileum towards hypogastrium and pelvis
D. Blood supply
1. Arterial
a. Branches of Superior Mesenteric Artery (SMA)
1) Inferior pancreaticoduodenal artery: supplies pancreas and duodenum
2) Jejunal and ileal branches of SMA: supply most of the small intestine
3) Ileocolic artery: supplies terminal ileum, cecum, appendix, and proximal
ascending colon
2. Venous
a. Superior mesenteric vein joins the splenic vein to form the portal vein
E. Innervation
1. Autonomic nervous system is comprised of the extrinsic and intrinsic enteric nervous systems.
a. Extrinsic nervous system
1) Parasympathetic (vagal and pelvic nerves): excitatory on all GI functions
a) Synapse in myenteric and submucosal plexus
2) Sympathetic (fibers originate in the spinal cord T8-L2): inhibitory on all
GI functions
b. Intrinsic nervous system
1) Myenteric plexus (Auerbach’s plexus) located between the circular and longitu-
dinal muscular fibers, from which the nervous branches are distributed to the
muscular coats of the intestine. Primarily controls the motility of the GI tract
2) Submucosal (Meissner’s plexus) which lies in the submucous coat of the intestine;
it also contains ganglia from which nerve fibers pass to the muscularis mucosæ
and to the mucous membrane. Primarily controls secretion and blood flow
IV. Immune System

A. The immune system of the small intestine is part of gut-associated lymphoid tissue (GALT).
It is comprised of:
1. Peyer’s patches: lymphoid follicles located mostly in the ileum and extending from
mucosa to submucosa
2. Lamina propria lymphocytes: mostly IgA-secreting B cells scattered in the lamina propria
3. Intraepithelial lymphocytes: located beneath the tight junctions between the epithelial cells
4. M cells: located in Peyer’s patches and isolated lymphoid follicles, in dome-shaped areas over-
lying B cell follicles (follicle-associated epithelium)
a. Function to pick up particles from the lumen and funnel them to hematopoietic cells in
the lymphoid tissue on their basolateral side
b. This allows antigens in the lumen to be sampled in a controlled manner and an appro-
priate immune response mounted
c. T he defining characteristic of the M cell is its ability to pick up and transcytose particles
from the gut lumen and deliver them to the lamina propria, where they are then pro-
cessed by hematopoietic cells
5. T cells can travel from Peyer patches to lamina propria and the epithelium
6. Primary sites for the induction of intestinal T and B cell responses are Peyer’s patches, colonic
lymphoid follicles and MLNs
7. Lamina propria (LP) and the intraepithelial cell (IEC) compartments are primarily effector sites
8. IgA: principal class of antibody produced by gut lymphocytes
a. Comprises 60%–70% of about 3 g of antibodies produced daily in an adult
b. IgA is actively transported across epithelia (carried out by Fc receptor-poly Ig recep-
tor located on the basal surface of the epithelial cells), then binds to and neutralizes
microbes in the lumen and mucosal organs
V. Normal Ion Transport

A. The intestinal epithelium acts as a physical barrier, separating the luminal environment and subepi-
thelial tissues. This polarized barrier is primarily maintained by apical junctional complexes, including
tight junctions and adherens junctions, which connect epithelial cells
1. Tight junctions are made of complex interactions between up to 40 proteins, including the
transmembrane proteins occludin, junctional adhesion molecule, and claudins.
a. These proteins are anchored to the actin filaments and MLC of the perijunctional acti-
nomyosin ring through cytosolic plaque proteins of the zonula occludens (ZO) family
2. Adherens junctions lie basolateral to the tight junctions, and are formed by the interaction of
the transmembrane protein E-cadherin with cytoplasmic proteins of the catenin family
a. Transport of electrolytes and water across the barrier occurs through cellular and
paracellular pathways
B. Sodium
1. Transport in the small intestine by:
a. Na + channels (passive): restricted diffusion through water-filled channels
b. Concentration driven, increases the negative electric potential across the
epithelial cell membrane
2. Na + – glucose or Na + –amino acid cotransport: primarily proximal bowel
a. And electrically neutral (gradient dependent):
1) Na + Cl- cotransport: primarily ileum
2) Na + /H + exchange: primarily proximal bowel
b. Principle:
1) Na + pumped out of the cell against electrochemical gradient by Na + /K- pump in
the basolateral membrane
C. Chloride
1. Cl- absorption occurs with Na + absorption by:
a. Passive diffusion through paracellular route
b. Na + Cl- cotransport
c. Cl- /HCO3- exchange–distal ileum
D. Potassium
1. Passive diffusion via paracellular pathway
E. Water
1. Secondary to solute absorption
2. Iso-osmotic in the small intestine
F. Secretion of water and electrolytes:
1. Secretory mechanisms are primarily located in the crypts
2. Cl- – primary ion secreted. It is transported through chloride channels regulated by cAMP
3. Na + passively follows Cl-, water follows Na + Cl- to maintain iso-osmotic conditions.
G. Iron
1. Absorbed as heme iron or free Fe2+ in the duodenum and jejunum
2. Heme iron is degraded in epithelial cells and free iron is released, which is bound to apofer-
ritin, making a complex called ferritin
a. Some of the ferritin-bound iron can be utilized, but most gets lost with epithelial cell
turnover
3. Free iron in the blood is bound to transferrin (beta1 globulin) which transports it from the
intestines to the liver and then bone marrow

4. Iron is stored in the liver as ferritin
5. Organic acids (ascorbic or citric) reduce Fe3 + to Fe2+, which is absorbed more efficiently
H. Calcium
1. Calcium absorption through the brush border depends on 1,25 dihydroxyvitamin D3, which
stimulates
synthesis of calcium-binding protein
2. Calcium remains bound to the protein inside the cell
3. Exit at the basolateral membrane is dependent on Ca + ATPase and Na + Ca + exchanger, both
vitamin
D3 dependent
4. Calcium absorption is regulated by serum calcium levels
I. GI Hormones
Table I. Review of Gastric Hormones
Hormones Mode of Cell Cell type Location Stimulus Action

Signaling
Gastrin hormone G Stomach Peptide, amino Increase in H+ secretion
acids, stomach (inhibits gastrin secretion)
distention, va- Trophic effect on gastric
gal (via GRP) mucosa
CCK hormone I Duodenum Peptides, amino Contraction of gall bladder
Jejunum acids Relaxation of sphincter of
Fatty acids Oddi Pancreatic enzyme
and HCO3- secretion
Growth of exocrine pan-
creas/gallbladder
Inhibits gastric emptying
Secretin hormone S Duodenum H + in the Pancreatic HCO3- secretion
duo-denum Biliary HCO3- secretion
Fatty acids in Inhibits gastric H+ secretion
duodenum
GIP hormone GIP cells Duodenum Fatty acids Stimulates insulin secretion
Jejunum Amino acids Inhibits gastric H+ secretion
Oral glucose
Motilin hormone Mo Small intestine Motility
Histamine paracrine ECL Stomach Increases gastric
H + secretion
Potentiates effects of gas-
trin and vagal stimulation
Somatostatin paracrine D Pancreas H + in the lumen Inhibits the release of all
Stomach GI hormones
Small and large Inhibits gastric H+ secre-
intestines tion
VIP neurocrine Neurons Smooth muscle Relaxation of GI smooth
and mucosa muscles, possibly also
vasodilation
Stimulates pancreatic
HCO3 secretion
Inhibits gastric H+
Stimulates intestinal
secretion
GRP neurocrine Vagus Gastric mucosa Stimulates gastrin release
(bombesin) nerve from G cells
Table I. (continued)
Enkephalins neurocrine Neurons Nerves of the Stimulates contraction of
(met-enkephalin, mucosa and GI smooth muscle,
leu-enkephalin) smooth muscle especially: LES, pyloric,
of the GI tract Ileocecal
Inhibits intestinal secretion
of fluid and electrolytes
Substance P neurocrine
Substance K neurocrine
Dynorphin neurocrine
Recommended Reading
Bevins CL, Salzman NH. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat
Rev Microbiol. 2011;9:356-368.
Cezard JP. The intestine: absorption and digestion. Normal physiology of intestinal digestion and absorption.
Kleinman RE, Goulet O-J, Mieli-Vergani G, Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gas-
trointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker, Inc; 2008.
DeSanta BP. The intestine: anatomy and embryology. In: Kleinman RE, Goulet O-J, Mieli-Vergani G, Sander-
son IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC
Decker, Inc; 2008.
Heath JK. Transcriptional networks and signaling pathways that govern vertebrate intestinal development.
Curr Top Dev Biol. 2010;90:159-192.
Verzi MP, Shivdasani RA. Wnt signaling in gut organogenesis. Organogenesis. 2008;4: 87-91.

3B. Normal Microanatomy
Pornthep Tanpowpong, MD, MPH
Steve Min, MD
Aubrey J. Katz, MD
Carolyn Sullivan, MD
I. Small Bowel Histology

A. Overview
1. Mucosa composed of three components: epithelium, lamina propria, and muscularis mucosa
2. Surface epithelium and lamina propria form intraluminal projections, called villi, which cover
entire luminal surface of small bowel (SB) (see Figure 1)
3. Intervening regions between and below the villi represent the crypts of Lieberkuhn
4. Ratio of villous length to crypt length in SB varies between 3:1 to 5:1
B. Epithelium
1. Divided into villous and crypt compartments
2. Villous epithelium consists of tall, columnar cells and absorptive cells
a. Apical surface contains brush border composed of microvilli and glycocalyx
b. Microvilli-glycocalyx involved in complex function interluminal digestive processes
c. Goblet cells, endocrine cells, and intraepithelial lymphocytes are also scattered among
villous epithelium
d. Usually 1 lymphocyte for every 5 epithelial cells
3. Crypt epithelium function in epithelial cell renewal
a. Endocrine cells and Paneth cells are most abundant throughout the crypt epithelium
b. Inflammatory cells such as neutrophils, or plasma cells, are not normally present within
any of the epithelial compartments
C. Lamina propria
1. Intermediate layer of the mucosa; surrounds the crypts, extends up the villi, and rests upon
the muscularis mucosa
2. Composed of smooth muscle layers that separate lamina propria from submucosa
3. Plasma cells are the most abundant in the lamina propria
4. Mast cells are also abundant, but generally decrease with distal progression in the small
bowel
D. Muscularis mucosa
1. Outermost layer of mucosa
2. Composed of smooth muscle arranged in an outer longitudinal and inner circular layer
(these layers, however, are not usually delineated on routine light microscopy)
3. Structural foundation for the mucosa
E. Submucosa
1. Lies between muscularis mucosa and muscularis externa, composed of collagenous and
elastic fibers, as well as scattered migratory cells and adipose tissue
2. Vascular and lymphatic structures cross submucosa
3. Neural structures also prominent in submucosa, ie, submucosal plexus of Meissner
F. Muscularis externa
1. Thick, outer smooth muscle layer that surrounds submucosa
2. Composed of two distinct muscular layers oriented perpendicular to each other (inner layer is
circular band, while outer layer is longitudinal running fiber)
3. Blood vessels, lymphatics, and nerve complexes (Auerbach’s plexus) course through
4. Fibrous tissue is minimal
II. Regional Characteristics of SB

A. Duodenum
1. Region of gastroduodenal junction, antral type mucosa may extend 1–2 mm into anatomic
duodenum, which may lead to a short 2–3 mm segment of transitional type epithelium
(features of both antral and small intestinal type epithelium)

2. F irst portion of duodenum (bulb) may contain shorter and broader villi with branching exten-
sions; also may find increased mononuclear cells within lamina propria
3. Brunner’s glands
a. Specifically localized in the duodenum, most concentrated just distal to gastroduodenal
junction, and gradually decrease along the duodenum
b. Collection of tubuloalveolar glands, predominantly within the submucosa, but often
extends through the muscularis mucosa
c. Function is not fully understood, but felt to play a role in protecting the duodenal
mucosa from acidic gastric contents; contributes to increased luminal pH
d. Hyperplasia of Brunner’s glands may impart a course nodularity to most of the duode-
num, as well as discrete or solitary nodules in the proximal duodenum
B. Jejunum
1. Least distinctive segment of small bowel
2. Jejunal villi are tall, and typically more slender and fingerlike compared to villi in duodenum
and ileum
3. Characteristic feature is the prominent plicae circulars (permanent circular folds), also termed
valves of Kerckring; these folds are tallest and most numerous in jejunum
C. Ileum
1. Fewer and shorter plicae circulars
2. Increased proportion of goblet cells within epithelium
3. Villi are shorter, with predominant fingerlike shape
4. Terminal ileum
a. Distal portion protrudes 2–3 cm into large intestine
b. Mucosal transition demonstrates gradual loss of villi
c. Ileocecal region can contain abundant fat within submucosa; amount is proportional to
adipose content in rest of abdominal cavity
5. Lymphoid nodules gradually increase in quantity with distal progression
6. Peyer’s patches are specialized clusters of lymphoid aggregates, and are most prominent in
the ileum
a. Occupy mucosa and portion of submucosa
b. Increase in size and number until puberty
c. Hyperplastic Peyer’s patches (focal lymphoid hyperplasia) may be found in terminal
ileum during childhood, and have been linked to idiopathic intussusception
III. Microscopic Examination

A. Aspects identified by light microscopy include the following:
1. Organisms (luminal, surface attached, and intramucosal) such as Giardia lamblia or E coli
2. Epithelial cells (cell height and degree of vacuolization, which is increased in abetalipopro-
teinemia from fat deposition)
3. Mitotic figures (evaluation of metaplasia, dysplasia, or malignant transformation)
4. Numbers of goblet cells, Paneth, and enteroendocrine cells (enteroendocrine cells are
increased in celiac disease)
5. Intraepithelial lymphocytes (IELs are nonspecific and are commonly seen in celiac disease,
cow’s milk protein allergy, autoimmune enteropathy, giardiasis, bacterial overgrowth or
cryptosporidiosis).
a. Available studies suggest a wide normal range of IELs (between 10–40 IELs/100 epithe-
lial cells). Additional findings need to be taken into consideration for diagnoses of small
bowel diseases
6. Increased mast cells in the epithelium can be seen in systemic mastocytosis
7. Eosinophils are increased in eosinophilic gastroenteritis
8. Lamina propria cellularity (lacteals, lymphocyte subclass, cytokine secretion, mast cells)
9. PAS staining (allows the preservation of the brush border and demonstrates mucus-contain-
ing goblet cells)
a. Presence of PAS-positive material in the apical cytoplasm of the upper crypt and low
villous epithelium indicates MID, which can be confirmed with electron microscopy
b. PAS-positive macrophage inclusions in lamina propria are seen in Whipple’s disease,
which is caused by bacterium Tropheryma whipplei
c. Paneth cells are found in the intestinal tract. They contain zinc and lysozyme (an en-
zyme that lyses certain kinds of bacteria) as well as large eosinophilic refractile granules
within their apical cytoplasm (see Figure 3)
Figure 1. Normal villi Figure 2. Villous flattening, “atrophy”
Figure 3. Normal Paneth cell (arrows)
Figure 1 and Figure 2 show normal villous structure compared with villous flattening
IV. Electron Microscopy

A. Glutaraldehyde fixation is used, ultra-structural studies should be routinely performed in protracted
diarrhea cases
1. MID can be detected and confirmed
2. Cryptosporidiosis or effacing of E coli in EPEC, microspordiosis in AIDS
V. Immunohistochemistry (IHC)
A. Requires snap-frozen tissue, because formalin fixation crosslinks tissue proteins and may alter ter-
tiary structure enough to prevent antibody recognition
B. IHC has a role in the diagnosis of celiac disease or autoimmune enteropathy
VI. Disorders in Which Biopsy Is Valuable

A. Celiac disease (villous atrophy, crypt hyperplasia, and increased IELs)
B. Immunodeficiency (lack of plasma cells in lamina propria, but mucosa pathology can be varied, such
as in common variable immunodeficiency [CVID] and severe combined immune deficiency [SCID])
C. Autoimmune enteropathy (usually severely abnormal mucosa)
D. Crohn’s disease (especially for granulomas)
E. MID (diagnosed with microvillous inclusions and increased secretory granules on electron micros-
copy, abnormal PAS-positive epithelial cells, villi flattening without crypt hyperplasia)

VII. Disorders in Which Biopsy May be Valuable
A. Giardiasis, strongyloidiasis, cryptosporidiosis
B. Lymphangiectasia, lymphoma, hypogammaglobulinemia
C. Eosinophilic gastroenteritis
VIII. Villous Atrophy

A. There are degrees of villous flattening “atrophy”
1. Mild: villous height and crypt depth are approximately equal
2. Moderate: crypt depth greater than villous height
3. Severe: flat mucosa represents severe villous flattening
4. Villous flattening without crypt hyperplasia can be seen in conditions, including microvillous
inclusion disease (MID)
IX. Diagnostic approach to children thought to have small intestinal diseases:

A. History, anthropometrics, and physical examination
B. CBC, ESR (older kids for IBD), serum and red cell folate, anti-TTG and EMA IgA
C. Stool for bacteria culture, Ova and parasites, EM for viruses, Giardia lamblia and cryptosporidiosis,
reducing substance
D. Small bowel follow-through contrast study
E. Invasive procedure such as small bowel biopsy, duodenal aspirate for Giardia lamblia
F. Response to elimination diet is a good way to diagnose food intolerance
Recommended Reading
Kleinman RE, Goulet O-J, Mieli-Vergani G, Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric
Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker, Inc; 2008.
3C. Normal and
Abnormal Motility
Arun Aggarwal, MD
Shruti Arya, MD
Michael S. Halata, MD
Definition: Antroduodenal manometry measures the intraluminal pressure of the antrum and duodenum.
Clinically, manometry provides useful information regarding contraction patterns in the antroduodenal region.
I. Normal Antroduodenal Motility

A. Normal motility meets the following criteria:
1. At least 1 MMC/24 hours
2. Conversion to the fed pattern following meal without return of MMC for at least 2 hours
3. Distal postprandial contractility (motility index per 2 hours > 13.67)
4. Small intestinal contractions exceeding 20 mm Hg
B. During fasting, the stomach and small bowel show a cyclic pattern, known as the MMC, which
serves as a marker of overall enteral neural function.
1. Each MMC (lasting 90–120 minutes) is usually divided into three phases
2. Phase III is the most characteristic, and consists of regular rhythmic peristaltic contractions
that start proximally and migrate down to ileum (Figure 1)
C. After ingestion of nutrients, the fasting pattern is interrupted by the fed pattern, which is character-
ized by the irregular occurrence of contractions with various amplitudes.
D. After solid meals, strong, repetitive contractions are often induced in the antrum, and the duodenal
response looks similar to that of Phase II, although the amplitude and frequency of contractions are
greater in the fed state (Figure 2)
E. An antral motility index has been used to calculate both the amplitude and frequency of these con-
tractions. The following formula is commonly used:
1. Motility Index = ln (Amplitude x No. of Contractions ± 1)
2. Normal value being 13.67–15.65 (5–95th percentile)
F. The presence of Phase III activity is a marker of neuromuscular integrity (Figure 1)
1. If no spontaneous Phase III activity is observed, intravenous erythromycin should be adminis-
tered
2. Erythromycin at doses that are 10%–20% of those used for antibiotic properties acts as a
motilin receptor agonist
3. The American Motility Society (AMS) Task Force recommends the use of erythromycin
1 mg/kg over 30 minutes if no MMC is recorded during fasting
II. Clinical Significance

A. Neuropathic disorders are associated with:
1. Antral hypomotility
2. Absence of Phase III activity
3. Abnormal propagation of MMC, bursts and sustained uncoordinated pressure activity (hyper-
contractility)
4. Lack of fed response (Figure 3)
B. Myopathic disorders are characterized by low amplitude contractions of <10 mmHg (Figure 4)
C. Antral hypomotility: a reduced motility index of postprandial distal antral contractions correlates
with impaired gastric emptying of solids from the stomach (Figure 5)
D. Mechanical obstruction: two patterns suggestive of obstruction have been described:
1. Postprandial clustered contractions (>30 min duration) separated by quiescence
2. Simultaneous prolonged (>8 seconds) or summated contractions
III. Pitfalls
A. Artifacts are characterized by simultaneous activity, e.g., cough, movement or straining artifact
B. Several dysmotility syndromes may share common manometric features, eg, diabetes mellitus, gas-
tric surgery, chronic intestinal pseudo-obstruction, idiopathic dysmotility, IBS, etc.

C. Primary phenomenon vs epiphenomenon may be an issue
1. The abnormal motor patterns do not necessarily imply a causative role in the patient’s
symptoms. Thus, stress may delay gastric emptying, impair antral contractility, suppress MMC
cycling, and induce intestinal irregularity
2. Dysmotility may, similarly, be a consequence of the disorder, such as fasting, vomiting, weight
loss, diarrhea and constipation
IV. Future
A. Wireless technology to evaluate gastric emptying and small intestine motility has now become avail-
able in the form of an ingestible capsule
1. The capsule is able to record pressure, temperature, and pH measurement data in both
elapsed and real time
2. Studies to validate its use in adults are now underway
Figure 1. Normal fasting antroduodenal ma- Figure 2. Normal postprandial pattern in a small
nometry. A normal Phase III front originating bowel manometry. There are irregular persistent
in the antrum and migrating aborally along phasic contractions in the antrum and small bowel
the duodenum into the jejunum can be ob-
served. During Phase III, the antrum contracts
at a frequency of 3/min, whereas the small
bowel contracts at a frequency of 11–12/min.
Phase III is followed by a period of quiescence
(Phase I) and is preceded by intermittent ir-
regular contractions (Phase II).
Figure 3. Antroduodenal manometry in a patient Figure 4. Antroduodenal manometry in a patient

with neuropathy. The tracing shows abnormali- with visceral myopathy. The tracing shows a nor-
ties in Phase III of the MMC. Some uncoordinated mal Phase III of the interdigestive motor complex,
clusters, as well as isolated irregular phasic con- although the amplitude is much lower than normal
tractions, can be observed. Throughout the study, (<10 mmHg).
there was no organized activity, and irregular
phasic contractions were seen. No Phase III could
be observed, even after provocative medications.
Figure 5. Antroduodenal manometry in a patient with
antral hypomotility. The tracing shows normal postpran-
dial activity in the small bowel, and absent response in
the antrum. This pattern is frequently seen in patients
with gastroparesis.
Recommended Reading
Camilleri M, Hasler WL, Parkman HP, et al. Measurement of gastrointestinal motility in the GI laboratory.
Gastroenterology. 1998;115:747-762.
Di Lorenzo C, Hillemeier C, Hyman P, et al. Manometry studies in children: Minimum standards for proce-
dures. Neurogastroenterol Motil. 2002;14:411-420.

3D-1. Meckel Diverticulum
Dina Al-Zubeidi, MD
Aliye Uc, MD
I. Embryology
A. True intestinal diverticulum. Contains all three layers of the intestine: mucosa, muscularis,
and serosa
B. Most common remnant of the omphalomesenteric duct
C. Results from failure of obliteration of the omphalomesenteric duct during the 5th week of fetal
development
D. The spectrum of duct anomalies include umbilicoileal fistula, umbilical sinus, umbilical cyst, and
a fibrous cord connecting ileum to umbilicus.
E. Meckel diverticulum is lined by ileal mucosa. Up to 50% of diverticuli contain ectopic gastric
mucosa, which can be a source of complications; mainly bleeding, ulceration, and perforation
1. Gastrointestinal bleeding may develop due to ulceration within the gastric mucosa, or
ulceration in the adjacent ileal mucosa
2. Rarely, pancreatic, colonic, or hepatobiliary epithelium may be found
II. Clinical Features

A. It presents only when complications arise
B. The “rule of 2’s” is commonly used to recall the features of Meckel diverticulum, and they include:
1. It occurs in 2% of the population
2. It is located within 2 feet of the ileocecal valve, on the antimesenteric border
3. It usually is 2 inches long
4. It presents before age 2 in over 50% of cases
a. 60% of patients present before 10 years of age
C. Painless major lower gastrointestinal bleeding is the most common presentation (up to 50% of all
cases)
D. Intestinal obstruction due to volvulus, intussusception, hernia, or fecolith may occur
E. Meckelian diverticulitis occurs in 10%–20% of cases, more commonly in older patients
1. The presentation is similar to that of appendicitis, but the location of the pain may be
variable
F. Periumbilical and postprandial abdominal pain due to chronic peptic ulceration of the Meckel diver-
ticulum may also rarely occur
III. Diagnosis
A. Only 25% of patients with Meckel diverticulum become symptomatic
B. Ectopic gastric tissue causing mucosal ulceration and bleeding may be identified by scintigraphy us-
ing 99m technetium scanning
1. This test has 85%–90% sensitivity and 95% specificity in children
2. False-negative studies are usually due to insufficient heterotopic gastric tissue in the diverticu-
lum or brisk hemorrhage, leading to diluted intraluminal Tc99 activity
3. The uptake of Tc99 may be obscured by activity of the bladder in AP images. Lateral or
oblique images may help distinguish urinary activity from the Meckel’s
IV. Management
A. All symptomatic Meckel diverticulae must be resected with the adjacent segment of ileum
B. Routine resection of an asymptomatic diverticulum encountered incidentally during an operation is
controversial, but evidence exists that supports removal in children
1. The risk of complications from a routine operation is 1%; potential lifetime risk of complica-
tions from a Meckel diverticulum is 4%–6%

Recommended Reading
Cooney DR, Duszynski DO, Camboa E, Karp MP, Jewett TC, Jr.The abdominal technetium scan (a decade of
experience). J Pediatr Surg. 1982;17:611-619.
Hanna E. Gastrointestinal bleeding. In: Bishop WP. Pediatric Practice Gastroenterology. New York, NY: Mc-
Graw Hill Medical; 2010.
Khan NA, Chandramohan M, McDonald S. Meckel divertculum. Radiol Pediatr. 2008; 110: 205-210.
Levy AD, Hobbs CM. Meckel diverticulum: Radiologic features with pathologic correlation. Radiographics.
2004:24:565.
Malik AA, Shams-ul-Bari, Wani KA, Khaja AR. Meckel’s diverticulum-Revisited. Saudi J Gastroenterol.
2010;16:3-7.
Sfakianakis GN, Conway JJ. Detection of ectopic gastric mucosa in Meckel’s diverticulum and in other aberra-
tions by scintigraphy. 1. Indications and methods: a 10-year experience. J Nucl Med. 1981;22:732-738.
3D-2. Malrotation
Dina Al-Zubeidi, MD
Riad Rahhal, MD
Rotational anomalies represent a spectrum of defects, from complete nonrotation, in which the entirety of the
small intestine is on the right side of the abdomen and the colon is positioned on the left, to relatively minor
abnormalities associated with incomplete fixation of the cecum and ascending colon.
I. Background
A. Nonrotation is thought to occur during the second stage of midgut development (10–12 weeks’
gestation)
B. Nonrotation characterized by two components:
1. The third part of the duodenum lies to the right of the vertebral column instead of curving
across to the left
2. The cecum lies in the upper abdomen to the left of the duodenum
C. The midgut is liable to twist around the narrow pedicle of mesentery at the base of superior mesen-
teric artery
D. True incidence is not known, because it may remain asymptomatic throughout life
II. Presentation
A. Symptoms of obstruction either due to Ladd’s bands impinging on duodenum or when volvulus
occurs
B. Rotational anomalies may become symptomatic at any age
1. However, 80% of patients who do become symptomatic do so in the first month of life
2. Risk of acute volvulus is highest during the neonatal period
C. In the infant, acute midgut volvulus presents with bilious vomiting, abdominal pain, progressive
abdominal distention, and tenderness
D. Rapid deterioration, with hypovolemia and persistent metabolic acidosis
E. Chronic intermittent abdominal pain in older child, with or without vomiting
F. Incidental finding
III. Diagnosis
A. Should be in differential diagnosis for any child with vomiting and abdominal pain
B. Higher index of suspicion for neonates with bilious emesis
C. Upper GI series is modality of choice to demonstrate duodenal-jejunal flexure (ligament of Treitz)
D. Role for small bowel follow through in questionable cases look for location of cecum
E. Barium enema can be used in some cases
IV. Management
A. Correct electrolytes and volume; resuscitate if acute presentation
B. Surgical treatment with Ladd’s procedure
C. Although there is some controversy, surgery is often indicated for asymptomatic or incidental malro-
tation, because advocates of this approach feel that benefits of preventing a catastrophic episode of
bowel ischemia/loss outweighs the risk of surgery
Recommended Reading
Gosche JR, Vick L, Boulanger SC, Islam S. Midgut abnormalities. Surg Clin North Am. 2006;86(2):285-299,viii.
Daneman A. Malrotation: the balance of evidence. Pediatr Radiol. 2009;39:S164-S166.
Meehan J. Surgical emergencies. In: Bishop WP. Pediatric Practice Gastroenterology. New York, NY: McGraw
Hill Medical; 2010.
Lloyd DA, Kenny SE. Congenital anomalies including hernias. In: Kleinman RE, Goulet O-J, Mieli-Vergani G,
Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton,
Ontario: BC Decker, Inc; 2008.

3D-3. Cysts
Dina Al-Zubeidi, MD
Aliye Uc, MD
Duplication cysts are uncommon congenital anomalies of the gastrointestinal tract. Understanding patterns of
presentation and management is important, as they may be revealed unexpectedly during work-up for
common symptoms/signs.
I. Incidence and Definition

A. Congenital in origin
B. Duplication cysts of the intestine are rare, 1 in 4,500–10,000 births
C. Tubular or spherical cysts arise anywhere from mouth to anus
D. Most common location is the ileocecal region
E. Most common structural findings are:
1. Well-developed smooth muscle layer
2. Epithelial lining usually resembles adjacent intestine, but may also be gastric or pancreatic
3. Attachment to a part of the gastrointestinal tract
4. Usually not in continuity with the intestinal lumen
5. Share a common blood supply with the native tract
6. In general, small bowel cysts are on the mesenteric border; large bowel cysts are on the an-
timesenteric border.
II. Presentation: variable

A. Asymptomatic or incidental
B. Abdominal mass
C. Obstruction of the adjacent intestinal lumen
D. Volvulus
E. Ectopic gastric tissue that may lead to bleeding, ulceration, or perforation
III. Diagnosis
A. May be detected on prenatal US
B. Most cysts are diagnosed before age 2
C. Contrast radiography, CT scan, or MRI may be helpful
IV. Management
A. Complete surgical excision of the cyst, with preservation of adjacent and arising organ, is the
treatment of choice
B. Cysts found incidentally have to be excised as well, as they are likely to enlarge and cause symptoms
in time
V. Mesenteric Cysts
A. Incidence and Definition
1. Rare, benign abdominal masses in children
2. The incidence is 1 in 20,000
3. In contrast to duplication cysts, mesenteric cysts have an endothelial cell layer, they are mini-
mally vascular, and they lack a muscular lining
4. Most are located in the small bowel mesentery
B. Presentation
1. Mesenteric cysts tend to present acutely, requiring urgent admission and surgical
intervention
2. Abdominal pain is the most common presenting symptom, followed by abdominal distention
or mass, anemia, anorexia, weight loss, and fever

C. Classification
1. Developmental
2. Traumatic
3. Infective
4. Neoplastic
D. Diagnosis
1. US or CT scan
` E. Management
1. Complete surgical excision
Recommended Reading
Lloyd DA, Kenny SE. Congenital anomalies including hernias. In: Kleinman RE, Goulet O-J, Mieli-Vergani G,
Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, On-
tario: BC Decker, Inc; 2008.
Prakash A, Agrawal A, Gupta RK, Sanghvi B, Parelkar S. Early management of mesenteric cyst prevents catas-
trophes: A single centre analysis of 17 cases. Afr J Paediatr Surg. 2010;7:140-143.
Shilyansky J, Picther G. Atresias, webs and duplications. In: Bishop WP. Pediatric Practice Gastroenterology.
New York, NY: McGraw Hill Medical; 2010.
Wardell S, Vidican DE. Ileal duplication cyst causing massive bleeding in a child. J Clin Gastroenterol.
1990;12:681-684.
3D-4. Gastroschisis
and Omphalocele
Gastroschisis and omphalocele are both congenital abdominal wall defects. Omphalocele often has
associated congenital anomalies; gastroschisis is not typically associated with other anomalies.
Gastroschisis
I. Overview
A. Abdominal wall defect, typically to the right of the umbilicus
B. Full thickness defect, with no sac or membrane covering the herniated, variable amount of intes-
tines, and occasionally organs
C. Occurs in 1/20,000 to 1/30,000 pregnancies
1. Males and females are affected equally
D. Etiology is currently unknown, but preconceptual (~30–90 days) maternal asthma and use of
bronchodilators is associated with an increased risk of gastroschisis. Ten percent of bronchodilator is
passed on to the fetus, producing vasoactive alterations. This risk is greatest for mothers <20 years
of age, and folic acid supplements appear to be very protective
II. Clinical Presentation

A. Associated intestinal anomalies (especially atresias) are seen in 10%–20% of affected children
B. Malrotation in almost all affected children
C. Other anomalies and chromosomal defects are rare
D. Intestinal dysmotility is almost universal
E. Gastroesophageal reflux is common
III. Diagnosis
A. Prenatal ultrasound will visualize the abdominal contents external to the abdomen
B. The intestines are thickened from chronic exposure to amniotic fluid
C. Maternal serum alpha fetoprotein will be elevated
IV. Treatment
A. Surgical repair after birth to minimize fluid balance issues and infection risks. Silo may be used to
expand abdominal capacity. Silos are silastic funnels that protect the bowel from additional injury,
minimize evaporative losses, and allow for bowel perfusion assessment while awaiting abdominal
well, defect closure
B. Parenteral nutrition may be required to provide adequate nutrition due to dysmotility and difficulty
with enteral feeds
V. Outcome
A. Survival is 90%–95%
B. Prolonged parenteral nutrition due to intolerance of enteral feeds
C. Gastroesophageal reflux may be severe
D. 5%–10% risk of adhesions
Omphalocele
I. Overview
A. Midline defect of the abdominal wall, with eviscerated abdominal contents contained in a membra-
nous sac that develops at 5–10 weeks’ of gestation
B. Prevalence is 1/3,000 to 1/20,000 live births
C. Affects males more than females. Racial and ethnic associations have been documented

A. Defect may be central, epigastric, or hypogastric region
B. Strong association with other anomalies
1. Associated with midline defects (heart, sternum, diaphragm, bladder)
2. Cardiac defects are the most commonly associated anomaly, with 50% of fetuses demon-
strating a variety of conditions from septal defects to coarctation of the aorta
3. Associated with other congenital anomalies, including Beckwith-Wiedemann syndrome and
trisomies 13, 18 (10%–40%) and 21.
4. Intestines with associated malrotation that may lead to volvulus
5. If associated with defects of diaphragm, sternum, pericardium, and heart is known as
the “Pentology of Cantrell”
C. Presence of anomalies is lower in the liveborn, due to increased risk of being stillborn (5%–60%)
in infants with multiple anomalies. Recent association of the size of the defect and associated
anomalies
1. Large defects, including intestine and other organs, are more likely to have nongastrointesti-
nal defects; smaller, intestine-only defects are more likely to have only other gastrointestinal
anomalies
III. Diagnosis
A. Diagnosis by prenatal US, with the abdominal contents visualized in the umbilical stalk with a
covering sac
B. Elevated maternal serum alpha fetoprotein
C. MRI has been used to document associated anomalies and contents of the omphalocele
D. Serial ultrasound is recommended to document continued growth, since there are concerns for fetal
growth restriction (5%–35%)
E. Karyotype is also currently recommended due to strong association with chromosomal abnormalities
IV. Treatment
A. Delivery by cesarean section has only shown a benefit in children with large omphalocele that con-
tains multiple organs, due to risk of rupture or dystocia
B. In some cases, silo or tenting of pouch may be necessary to allow gradual return of contents into
the abdominal cavity, followed by surgical repair when the infant is stable
C. Intestinal necrosis may occur with increasing abdominal pressure, resulting in ischemia
1. Ischemic bowel is resected and may lead to short bowel syndrome
V. Outcome
A. Outcome is dependent on the associated anomalies
Recommended Reading
Islam S. Clinical care outcomes in abdominal wall defects. Curr Opin Pediatr. 2008;20(3):305-310.
Ledbetter DJ. Gastroschisis and omphalocele. Surg Clin North Am. 2006;86(2):249-60, vii.
Mac Bird T, Robbins JM, Druschel C, et al. Demographic and environmental risk factors for gastroschisis and
omphalocele in the National Birth Defects Prevention Study. J Pediatr Surg. 2009;44(8):1546-1551.
Mann S, Blinman TA, Wilson RD. Prenatal and postnatal management of omphalocele. Prenat Diagn.
2008;28(7):626-632.
Scherger JE, Blank C. Gastroschisis and Omphalocele. Available at http://das/pdxmd/

body/0/0?type=med&eid=9-u1.0-_1_mt_5083101.
3E. Necrotizing Enterocolitis
Tiffany Patton, MD
Timothy Sentongo, MD
Necrotizing enterocolitis (NEC) is the most common cause of nonobstructive acute abdomen occurring in
neonates, characterized by necrosis of the intestinal mucosa.
I. Overview/Epidemiology
Usually occurs between 7–14 days of life, but can occur during subsequent postnatal weeks
A. One of the most common surgical emergencies occurring in the NICU
1. Occurs ~1–3/1,000 live births
B. Mainly affects low-birth weight, premature infants (>90% occur in infants weighing <2,000 g and
delivered earlier than 36 weeks gestation)
1. Occurs in 3%–7% of these infants
C. Occasionally occurs in full-term infants at a rate of 0.05 per 1,000 live births; usually within the first
week of life
D. Mortality ranges from 10%–50%, with highest mortality in VLBW infants (<1,500 g), males, and
African American infants
II. Pathogenesis (multifactorial)

A. Structural and functional intestinal immaturity contributes to the excessive inflammatory response
associated with abnormal intestinal bacterial colonization
B. Early enteral feedings with large volume of hyperosmolar formula
C. Impaired premature immune response, with low IgA secretion
D. Decreased absorption of feeds and incomplete hydrolysis of toxins due to:
1. Deficient gastric acid and pepsin production, with low lipolytic, proteolytic, and amylolytic
secretion rates
2. Increased permeability of intestinal wall
3. Decreased intestinal motility
E. Immature intestinal mucosa has increased susceptibility to reduce mesenteric blood flow causing
ischemic changes
F. Elective PRBC transfusion for anemia
III. Clinical Manifestations

A. Initial: temperature instability, apnea, bradycardia, and lethargy
B. Feeding intolerance, increased gastric residual volumes, abdominal distension (± bilious emesis),
tenderness, gross or occult blood in stools, and peritonitis
C. Laboratory values may show leukocytosis (± bandemia), neutropenia, thrombocytopenia, or acidosis
IV. Diagnosis
A. Clinical Picture (see Table 1)
B. Evaluation
1. Obtain complete blood count, comprehensive metabolic panel, and cultures from blood,
sputum (if intubated), and urine
C. Imaging
1. Plain abdominal radiographs (Two views: AP and left lateral decubitus)
a. Initially may show mild distension +/- ileus, progressing to pneumatosis intestinalis,
portal venous gas, or a sentinel loop (abnormal fixed bowel loop on two successive
abdominal films, indicative of a lack of peristalsis).

Table 1. Modified Bell Staging Criteria for Necrotizing Enterocolitis
Stage Classification of NEC Systemic signs Abdominal signs Radiographic
signs
IA Suspected Temperature instability, ap- Gastric retention, Normal or
nea, bradycardia, lethargy abdominal distention, intestinal
emesis, hemepositive dilation, mild
stool ileus
IB Suspected Same as above Grossly bloody stool Same as above
IIA Definite, mildly ill Same as above Same as above, plus ab- Intestinal
sent bowel sounds with dilation, ileus,
or without abdominal pneumatosis
tenderness intestinalis
IIB Definite, moderately ill Same as above, plus mild Same as above, plus Same as IIA,
metabolic acidosis and absent bowel sounds, plus ascites
thrombocytopenia definite tenderness,
with or without abdom-
inal cellulitis or right
lower quadrant mass
IIIA Advanced, severely ill, Same as IIB, plus hypoten- Same as above, plus Same as IIA,
intact bowel sion, bradycardia, severe signs of peritonitis, plus ascites
apnea, combined respiratory marked tenderness, and
and metabolic acidosis, DIC* abdominal distention
and neutropenia
IIIB Advanced, severely ill, Same as IIIA Same as IIIA Same as
perforated bowel above, plus
pneumoperi-
toneum
*DIC: disseminated intravascular coagulation.
V. Treatment/Management
A. Medical Management
1. Bowel rest for 10–14 days (NPO)
2. Gastrointestinal decompression with nasogastric tube
3. TPN therapy
4. Transfusion of blood products as necessary
5. Broad spectrum antibiotics for 7–14 days for Gram-negative coverage
B. Surgical Management
1. ~1 in 3 infants with NEC will require surgical intervention
2. Relative indications for surgery include clinical deterioration or worsening radiographic fea-
tures with any of the following:
a. Oliguria, hypotension, metabolic acidosis, thrombocytopenia, ventilatory failure, portal
venous gas, fixed abdominal masses, persistently dilated bowel loops, and abdominal
wall erythema
3. Absolute indications for surgery: intestinal perforation or stool/ bile on paracentesis
4. Surgical procedures may include peritoneal drain placement, exploratory laparotomy with
resection of diseased bowel, and enterostomy with stoma creation
C. Prevention
1. Nonaggressive enteral feeds, slow advancement with breast milk
VI. Differential Diagnosis

A. Neonatal sepsis, spontaneous intestinal perforation (usually occurs within first week of life, and not
associated with enteral feeds), congenital cause of intestinal obstruction (atresia, malrotation, or
volvulus), Hirschsprung disease, neonatal appendicitis, and neonatal pseudomembranous colitis
VII. Outcomes/Complications
A. Short-term: stricture and abscess formation (10%–35%), death (15%–30%, highest in infants
requiring surgery)
B. Long-term: most frequent cause of short bowel syndrome (up to 42% of surgical NEC cases), dis-
ease recurrence (5%), adverse neurodevelopmental sequelae (25%)
Recommended Reading
Berman L, Moss RL. Necrotizing enterocolitis: An update. Semin Fetal Neonatal Med. 2011; doi:10.1016/j.
siny.2011.02.002.
Claud E, Caplan M. Necrotizing enterocolitis. In: Kleinman RE, Sanderson IR, Goulet O, Sherman PM, Mieli-
Vergani F, Shneider BL, eds. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker
Inc; 2008: 513-518.
Henry M, Moss RL. Necrotizing enterocolitis. Annu Rev Med. 2009;60:111-124.
Neu J, Walker A. Necrotizing enterocolitis. N Engl J Med. 2011;364:255-264.

3F. Intussusception
Brigitte Moreau, MD
Véronique Morinville, MD
A. Described by anatomic location as ileo-colic, ileo-ileo-colic, colo-colic, and small bowel
intussusception (jejuno-jejunal and ileo-ileal)
B. Peak incidence is between 4 and 14 months, when most cases are idiopathic. Ninety percent
are ileocolic, and 5% have a lead point. Enlarged Peyer patches may play a role as a lead point
at this age
C. Under the age of 6 months and over 3 years of age: can be located in any segments of the
bowel; a pathologic lead point is possible and must be investigated
D. Any structural abnormality of the bowel can be a cause, such as a Meckel diverticulum, intestinal
polyps, or duplication cyst or small bowel lymphoma. Submucosal hemorrhage in HSP or other
conditions may act as lead points
1. Also described in conditions characterized by disturbances in intestinal muscular
contraction, such as cystic fibrosis or postoperatively

A. Symptoms of intestinal obstruction: colicky abdominal pain, often with bilious vomiting
B. Between bouts of colic, infants are quiet but irritable
C. The characteristic sausage-shaped abdominal mass may be palpated
D. Diarrhea occurs in 10% of patients prior to mucosal slough
E. Hypovolemia is variable, and some children can present atypically with lethargy only
F. Passage of blood and mucus per rectum is a later sign of intussusception
G. The classic triad of paroxysmal pain, vomiting, and passage of currant jelly stools occurs in less
than 1/3 of patients
III. Investigation
A. A plain abdominal radiograph should be done if concern for other diagnosis, to
include perforation
1. In intussusception: normal, or will show nonspecific features of intestinal obstruction
2. The typical finding of a soft tissue mass indenting the colon is seen in only about 25% of
patients
B. US: the doughnut sign in cross-sectional, or pseudokidney sign in longitudinal axis
1. Usually done before proceeding to contrast enema
C. CT can be highly accurate in the diagnosis, but is not commonly used
IV. Treatment
A. Hydrostatic reduction (saline enema is liquid contrast medium of choice) has a success rate
between 75%–90%
B. Air enema is considered better at reduction, is safer and faster, and uses less radiation, when
compared to liquid enema. Success rate up to 75%–95%
C. During endoscopy, pneumatic reduction of intussusception has been described, with
simultaneous identification of the intussuscipiens
D. Possible complications of reduction: intestinal perforation and tension
pneumoperitoneum
E. Enema reduction is contraindicated in children in refractive shock or with signs of peritonitis
F. Open surgical reduction is required when reduction is unsuccessful. In advanced cases, the
necrotic intussusception will need to be resected
1. An intussusception present for >48 hours, or one in an infant <6 months with bowel
obstruction on plain films, has a high likelihood of perforation
2. Other negative prognostic factors of successful reduction: isolated small intestinal
intussusception, multiple recurrences

Recommended Reading
Applegate KE. Intussusception in children: evidence-based diagnosis

and treatment. Pediatr Radiol. 2009;39:S140-S143.
Walker AW, Shneider BL, Sanderson IR, et al. Pediatric Gastrointestinal Disease. 4th ed. Hamilton, Ontario: BC
Decker Inc; 2004: Chapter 36.
Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Saunders Elsevier, Philadelphia,
3G. Celiac Disease
Thomas Flass MS, MD
Edward Hoffenberg, MD
I. Classic Disease Description

A. “A permanent sensitivity to gluten in wheat and related proteins found in barley and rye,
occurring in genetically susceptible individuals, and manifesting as an immune-mediated
enteropathy defined by characteristic changes seen on intestinal histology.”
II. Incidence and Prevalence

A. US/European prevalence is approximately 1:300 to 1:80 children. Refer to Table 1 for worldwide
data
B. Female predominance 2:1
C. Approximately 3 million people in the US with CD. Approximately 3 million cases in Europe
D. It is estimated that 90% of cases are undiagnosed
Table 1. Worldwide Disease Prevalence of Celiac Disease Based on Serologic Screening Tests
Saharawi 1:18 Switzerland 1:132 Southeast Asia No data available

Sweden 1:77 Russia 1:133
Finland 1:99–1:67 Netherlands 1:198
UK 1:100 Australia 1:251
Italy 1:106 Israel 1:157
USA 1:105 Iran 1:166–1:104
Ireland 1:122 India 1:310
Spain 1:118 Brazil 1:66–1:119
Table 2. Populations at Increased Risk for Celiac Disease (Child + Adult)
At-risk Population Prevalence (per 100 people)

Type 1 diabetes Up to 8%–10% with biopsy proven evidence and 16% with serologic
Down syndrome 3.8%–13% with 4:1 asymptomatic
Turner syndrome 4%–8%
Williams syndrome 9.5%
IgA deficiency 2%–8%
Autoimmune endocrinopathies, 2%–8%
including thyroiditis
First-degree relatives of 5.5%–9.5%, potentially 18% in siblings
celiac patients
Second-degree relatives 2.5%
III. Genetics of Celiac Disease

A. Ninety-five percent of patients have HLA-II DR3-DQ2 haplotype (coded by α and β subunit alleles
DQA1*0501- DQB*0201)
B. Five percent of patients have DR4-DQ8 haplotype
(α and β subunit alleles DQA1*03-DQB1*0302)
C. Homozygotes for HLA-DQ2 comprise 25% of CD patients
D. HLA-II genes are located on chromosome 6p21, also called the celiac 1 locus
E. Lack of DQ2/DQ8 completely excludes the possibility of developing celiac (high negative
predictive value, low positive predictive value)

F. DQ2/DQ8 on antigen-presenting cells with specific binding for deamidated gluten peptides,
present bound peptides to CD4+ lymphocytes to initiate an immunologic reaction
G. DQ2 or DQ8 molecule only accounts for 36%–53% of disease risk (genetic modifiers likely exist)
H. DQ2 gene is carried by 30% of the US population, but only 3% of these develop CD
I. Strong prevalence of CD in 1° relatives of patients with CD. 5.5%–18% of siblings, with the
highest rates in daughters and sisters of CD patients (Table 2)
IV. Pathogenesis: Current Model

A. Inciting event (i.e., viral infection) in individuals carrying DQ2/DQ8 while ingesting gluten pro-
teins (wheat, barley, rye) catalyzes breakdown in tolerance
B. Postinfection, epithelium is inflamed, with increased permeability to gluten peptides
C. Gluten itself increases intestinal permeability, stimulates inflammation, and resists digestion
D. When gluten peptides are deamidated by local TTG molecules, there is ↑ binding to HLA-II on
antigen-presenting cells
E. Activated APCs secrete inflammatory cytokines IL-15 and IFN-y
F. Fibroblasts are recruited, which that express MMP (matrix metalloproteinases) and directly injure
epithelial cells
G. IFNs ↑ the expression of HLA-DQ2/DQ8 on local APCs. ↑ binding/presentation of gluten peptides
to specific CD4+ T-cells in the lamina propria, with further ↑IFN-y and IL-15 secretion
H. IL-15 causes clonal expansion, with increased number of local intraepithelial lymphocytes (IEL).
These are mainly CD8+ T-cells unique to CD. There is subsequent phenotypic conversion of IELs
to cytotoxic NK cells, which then destroy local intestinal epithelium
I. The combined effect of ↑ inflammatory cytokines, infiltration of cytotoxic converted IELs, and
direct gliadin cytotoxicity leads to loss of epithelial cells, proliferation of crypt cells and mucosal
flattening/villous atrophy seen on biopsy
V. Clinical Presentation
A. The current trend is delayed onset of symptoms and older age at diagnosis
B. GI symptoms predominate in children < 3 yr.
C. 50% of older children/adults have no GI symptoms at the time of diagnosis
D. 30% of adults with CD have a previous diagnosis of IBS
E. 30% or more of children with CD have ↑ liver function tests that normalize on a gluten-free
diet. The prevalence of CD in patients with unexplained ↑ in LFTs ranges from 1.5%–9%
Table 3. Presenting Features of Celiac Disease

Classic Celiac Disease Non-GI Manifestations Neuropsychiatric Symptoms
Failure to thrive Dermatitis herpetiformis Ataxia
Chronic/recurrent diarrhea Dental enamel defects Epilepsy ± cerebral calcifications*
Abdominal distension Anemia Migraines*
Muscle wasting Apthous stomatitis Depression
Anorexia Arthritis/arthralgias Fatigue/malaise
Nausea and vomiting Hepatitis/transaminitis Anxiety*
Pubertal delay Peripheral neuropathy
Nonclassical GI complaints Short stature
Recurrent abdominal pain Infertility
Constipation Recurrent fetal loss*
GERD* Osteoporosis/osteopenia *Association less strong
Cutaneous manifestations
Vitamin deficiencies
Alopecia
Autoimmune disease
VI. Diagnosis
A. NASPGHAN/FISPGHAN currently recommends CD screening of the following patients:
1. Patients with classic symptoms of CD (see Table 3)
2. Patients with failure to thrive or growth failure
3. Patients with conditions carrying high risk for CD, noted in Table 4
B. Begin screening at-risk, asymptomatic individuals at age 3 if gluten has been part of the diet for
at least 1 year. Symptomatic individuals can be tested during the first year of life, but sensitivity
of testing improves with age
Table 4. Conditions Requiring Screening for Celiac Disease

Type 1 diabetes mellitus
IgA deficiency
First-degree relatives of patients with CD
Dermatitis herpetiformis
Autoimmune thyroid disease
Short stature
Dental enamel defects
Unexplained iron deficiency anemia
Delayed puberty
Unexplained osteoporosis/osteopenia
Down/Turner/William syndromes
↑Transaminases* (adults)
*
Consensus statement and technical review by the American Gastroenterological Association recommends
screening for CD in asymptomatic adults with increased alanine aminotransferase (ALT).
VII. Serologic Testing Current Recommendations by NASPGHAN/FISPGHAN

A. IgA antibodies against tissue transglutaminase (TTG) or antibodies against endomesium (EMA)
are the single best CD screening test
B. More complex “panels” of IgA and IgG antibodies against gliaden and reticulin are not recom-
mended because of low specificity and high false-positive rate in healthy individuals, especially
IgG antibodies
C. Sensitivity and specificity of IgA antibodies against TTG for identifying CD are 93%–96% and
96%–99%, respectively
D. Sensitivity of IgA anti-TTG and anti-EMA is reduced in patients < 5 years of age, especially those
<18 months of age
E. IgA antibodies are not sensitive or specific in IgA-deficient individuals
F. In symptomatic individuals, the positive predictive value of IgA anti-TTG antibodies is approxi-
mately 1.0. The positive predictive value of IgA anti-TTG is lower when used in general popula-
tion
screening
G. IgA anti-endomesial antibodies are similar in sensitivity and specificity to IgA anti-TTG, but are
often more costly, time-consuming, and operator dependant
H. Antibodies against deamidated gliadin peptide, a synthetic peptide, occur in patients with CD.
As a test, antideamidated gliadin peptide antibodies are less sensitive than IgA anti-TTG, but use-
ful in cases where IgA anti-TTG is borderline positive
I. Always screen for IgA deficiency by measuring quantitative IgA in symptomatic patients
J. IgG to TTG may be used in IgA-deficient patients, but specificity and sensitivity are slightly
decreased
K. If a patient is IgA deficient and there is a strong clinical suspicion of CD, proceed directly to up-
per intestinal endoscopy and duodenal biopsy
L. DQ2/DQ8 testing: not a useful screening tool because of very low positive predictive value. El-
evated negative predictive value makes it potentially useful in ruling out CD in at-risk individuals
who are asymptomatic or have questionable biopsy results
VIII.Interpreting Genetic Tests

A. Testing should report full DQ2/DQ8 subtyping, not merely DQ2 ± or DQ8 ±, and should include
a AND b subunit typing, since both infer risk (beta>alpha)
IX. NASPGHAN Recommendations Concerning Endoscopy and Duodenal Biopsy

A. Perform duodenal biopsy in all patients with IgA anti-TTG above the cutoff value
B. Take 4–6 biopsies from the 2nd portion and distal duodenum. The addition of duodenal bulb
biopsies may increase diagnostic yield
C. Marsh histologic grade ≥ 3 is diagnostic of CD (see Table 5). Marsh grade 2 plus IgA antibodies
to TTG is also diagnostic

D. Repeat biopsy after challenge with a gluten-containing diet is not recommended to confirm the
diagnosis if a patient has obviously improved on a gluten-free diet
E. If the patient has been on a gluten-free diet prior to biopsy, or is receiving steroids or immuno-
suppressants, biopsy results may not reflect the true level of disease
F. Four weeks on a gluten-containing diet is adequate to insure that pathologic changes will be
present on duodenal biopsy in patients taking a gluten-free diet before diagnostic biopsies
Table 5. Marsh Criteria for Grading Duodenal Biopsies for Potential Celiac Disease
Marsh 0 Normal mucosa and villous architecture
Marsh 1 Normal mucosa and villous architecture, but increased IELs (infiltrative)
Marsh 2 Enlarged crypts, increased crypt cell division, increased IELs (hyperplastic)
Marsh 3a Partial villous atrophy, shortened blunt villi, mild lymphocytic infiltration, enlarged hyperplastic
crypts
Marsh 3b Subtotal villous atrophy, enlarged crypts with increased immature epithelial cells, presence of
inflammatory cells
Marsh 3c Total villous atrophy and loss of villi, severe crypt hyperplasia, infiltrative inflammatory lesions
Marsh 4 Total villous atrophy, hypoplastic crypts with normal depth, normal numbers of IELs
X. Treatment and Clinical Course

A. The only recognized therapy of CD is lifelong adherence to a gluten-free diet. Oat gluten is safe
for most CD patients if it has not been contaminated with wheat protein during milling
B. Resolution of symptoms occurs within several weeks on a gluten-free diet. Normalization of small
bowel biopsy may take 6–12 months
C. Recheck TTG 6 months after starting gluten-free diet to measure compliance and response.
Thereafter, recheck TTG at intervals of 1 year or longer for asymptomatic patients on gluten-free
diet
D. Mortality risk of untreated CD is 2–3-fold higher than that of the general population and directly
related to duration of time on gluten-containing diet. Early compliance with a gluten-free diet
reduces risk of mortality to near baseline
E. The increase in all-cause mortality in CD is mostly due to GI malignancies (enteropathy-associated
T-cell lymphoma, non-Hodgkin’s lymphoma, and small bowel adenocarcinoma)
Recommended Reading
Hill, ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children:
recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J
Pediatr Gastroenterol Nutr. 2005;40(1):1-19.
Koning F, Schuppan D, Cerf-Bensussan N, Sollid LM. Pathomechanisms in celiac disease. Best Pract Res Clin
Gastroenterol. 2005;19(3): 373-387.
Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterology. 2005;128: S10-S18.
Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology. 2005; 128:S68-
S73.
Telega G, Bennet TR, Werlin S. Emerging new clinical patterns in the presentation of celiac disease. Arch Pedi-
atr Adolesc Med. 2008;162(2):164-168.
Fasano A, Araya M, Bhatnagar S, et al; for the Celiac Disease Working Group FISPGHAN. Federation of Inter-
national Societies of Pediatric Gastroenterology, Hepatology, and Nutrition consensus report on celiac disease.
J Pediatr Gastroenterol Nutr. 2008;47(2):214-219.
Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review
on the diagnosis and management of celiac disease. Gastroenterology. 2006;131(6):1981-2002.
3H. Tropical Sprue
Ala K Shaikhkhalil, MD
Jaya Punati, MD
Tropical sprue (TS) is an acquired disease of unknown etiology, characterized by malabsorption, multiple
nutritional deficiencies, and mucosal abnormalities in the small bowel. The exact etiology remains controver-
sial, but infection is believed to play an important role. The diagnosis is typically made after excluding other
known causes of malabsorption.
A. TS is endemic to tropical areas of the world. It can affect travelers in addition to native residents of
the tropics
B. In the era of globalization and worldwide travel, it is important for clinicians practicing in North
America and Europe to be aware of the possibility of TS in patients who present with nonspecific
GI complaints
C. Clinical impressions from around the world suggest that the incidence of TS is declining, possibly
related to the wide use of antibiotics for traveler’s diarrhea, and improved hygiene and sanitation
D. Geographic distribution of TS is interesting, as it does not occur in all tropical areas in a similar
fashion
E. TS accounts for ~ 40% of malabsorption in both adults and children in south Asia, and can occur in
epidemic forms
II. Pathology/Pathophysiology
A. Exact etiology of TS remains unclear, but is likely related to nutritional insufficiency and intestinal
infection, possibly with the liberation of cytopathic or secretory toxins
B. TS primarily affects the small bowel (initially proximally, then distally), but also causes structural
changes in the colon and stomach
C. Enteropathic changes include reduction in villus height, increase in crypt depth, and an associated
inflammatory infiltrate in the epithelium and lamina propria
D. These changes are similar to celiac disease, including the presence of intraepithelial lymphocytes,
but tend to be more severe in TS
E. The ability of the colon to absorb sodium and water is impaired, which significantly contributes to
the diarrhea
F. Small bowel bacterial overgrowth is frequently a part of this disorder, likely in relation to delayed
small bowel transit
G. Chronic atrophic gastritis is common, resulting in vitamin B12 deficiency that is corrected by ad-
ministration of intrinsic factor (note that H Pylori infection is very common in the tropics, and the
interaction between H Pylori and TS has not been well studied)
H. Nutrient malabsorption in TS arises from involvement of the proximal and distal portions of the small
intestine. Acute TS affects the jejunum, but chronic TS changes will eventually spread to the ileum
I. Folate and iron malabsorption represent proximal small bowel involvement, whereas vitamin B12 and
bile acid malabsorption represent terminal ileal involvement
J. Pathologic changes include impaired small intestinal transport, disturbed intestinal motility, pancre-
atic insufficiency, and gastrointestinal peptide hormone abnormalities
III. Clinical Features

A. The typical patient of TS presents with chronic diarrhea, glossitis, bloating, prominent bowel sounds,
and weight loss. Attack rates are more common in adults than in children
B. The illness often begins with an acute attack of watery diarrhea, with fever and malaise. Following
resolution of the acute symptoms, patients develop milder chronic diarrhea with progressive weight
loss. Fever is uncommon in the chronic form

C. Some patients present with signs of nutritional deficiency, but without the diarrhea
D. The signs of nutritional deficiency include pallor due to anemia, angular stomatitis, cheilitis and
glossitis due to vitamin B deficiency, and peripheral edema and skin and hair changes secondary to
hypoproteinemia. Megaloblastic anemia (due to vitamin B12 deficiency) is common
E. Other signs include subacute combined degeneration of the spinal cord and night blindness (these
are rare, and caused by deficiency of vitamin B12 and vitamin A, respectively)
F. Other physical findings include loss of weight loss and hyperactive bowel sounds
Table 1. Summary of clinical manifestations of tropical sprue and their causative factors
Symptom Cause
Diarrhea Malabsorbed nutrients with osmotic diarrhea; colonic
water secretion due to unabsorbed fatty acids
Pale, bulky, foul-smelling stool Fat malabsorption
Borborygmi, abdominal fullness Carbohydrate malabsorption
Pedal edema, skin changes Hypoproteinoemia secondary to loss of mucosal surface,
protein loss, and pancreatic insufficiency
Pallor Vitamin B12 and folate deficiency
Angular stomatitis, glossitis Vitamin B deficiency
Night blindness, corneal xerosis, Bitot’s spots Vitamin A deficiency
Muscle weakness Hypophosphataemia, hypokalemia, hypomagnesemia
Weight loss Anorexia, malabsorption
IV. Diagnosis
A. For diagnosis of TS to be established, infectious, immunological and inflammatory causes of malab-
sorption must be ruled out
B. The three tests that are commonly used in investigating absorption are stool fat estimation and ab-
sorption of both D-xylose and vitamin B12 two of the three tests have to be positive to establish the
diagnosis of malabsorption
C. Endoscopically, TS resembles celiac disease with scalloping of the mucosa. It is important to take
biopsies beyond the second portion of the duodenum, as villi in the 2nd part of the duodenum may
be shorter than they are more distally in the duodenum and the jejunum
D. Microscopy of small bowel biopsy typically shows reduction in villus height, increase in crypt depth,
and an associated mononuclear (lymphocytic) inflammatory infiltrate in the epithelium and lamina
propria
E. Performed small bowel series usually shows an increase in the caliber of the small intestine, and
thickened folds: examination is usually notable for the slow transit of the barium column through
the gut
V. Differential Diagnosis
A. Helminthic or protozoal infections (e.g., Strongyloides, giardia, isospora, and cryptosporidium)
B. Intestinal tuberculosis
C. Chronic pancreatitis (including tropical pancreatitis)
D. Small bowel bacterial overgrowth
E. Celiac disease
F. Crohn’s disease
G. Primary immunodeficiency
H. Malignancy (immunoproloferative small intestinal disease and small intestinal lymphoma)
VI. Tropical Enteropathy

A. Structural differences of the small bowel mucosa seen in residents of the tropical areas
B.. Differences include shorter villi, more elongated crypts, and increased lymphocytes, in the lamina
propria
C. Cause subclinical malabsorption (mostly of fat and vitamin B12, and, to a lesser extent, xylose)
D. Affected people are asymptomatic; a major distinction from tropical sprue which leads to overt
diarrhea and malnutrition
E. Tropical enteropathy is believed to be the gut’s adaptation to recurrent infection, but could also be
related to genetic factors
F. Tropical enteropathy and TS may represent opposite ends of a spectrum
VII. Treatment
A. Restoration of water and electrolyte balance, and replacement of nutritional deficiencies
B. Vitamin B12 should be given parenterally, but folic acid and iron can be given orally. These dietary
interventions should result in prompt improvement of the hematological abnormalities (megaloblas-
tic anemia) and restoration of appetite even before improvements in intestinal absorption
C. Folate supplementation can also improve villous atrophy
D. Although their role remains controversial, antimicrobial agents are widely used in the treatment of TS
1. Tetracycline 250 mg QID (or doxycline 100 mg QD) for 3–6 months is the antibiotic of choice
E. Restriction of long-chain fatty acids can help reduce the diarrhea
F. The prognosis for complete and permanent recovery with treatment is excellent, especially for those
who leave the area
VIII. Prevention
A. Other than the usual advice that is given to travelers, there are no specific preventive measures.
Early treatment of traveler’s diarrhea and the improving sanitary conditions worldwide are likely
responsible for the declining incidence of TS.
Recommended Reading
Philadelphia, PA: Saunders Elsevier; 2008: Chapter 102.
Ramakrishna BS, Venkataraman S, Mukhopadhya A. Tropical malabsorption. Postgrad Med J.

2006;82(974):779-787.
PA: Saunders Elsevier; 2006: Chapter 4.

3I. Protein-losing Enteropathy
Julie Bass, MD
William San Pablo, MD
Protein-losing enteropathy is the abnormal loss of proteins from the digestive tract resulting in decreased
serum protein concentration.
I. Background
A. Manifestation of variety of GI and extraintestinal diseases
1. Leakage of protein across gut or decreased uptake by lymphatics secondary to altered
mucosal permeability at any level of GI tract due to active inflammation
2. In lymphangiectasia, the intestinal lymphatics are obstructed
II. Mechanism
A. Normally sulfated glycosaminoglycan in basolateral portion of epithelium confines albumin to
intravascular compartment
1. Occurs due to strong electrostatic interaction between anionic sites in glycosaminoglycan
carbohydrate chains and arginyl residues within protein molecules
B. Pathologic state—loss of normal intestinal heparin sulfate proteoglycan expression allows diffusion
of albumin and other proteins from bloodstream to lumen of gut via three mechanisms:
1. Focal degradation by matrix-degrading metalloproteinases
2. Failed synthesis in rare genetic defects
3. Mislocalization in congenital disorders of glycosylation
III. Causes of PLE

A. Metabolic
1. Enterocyte heparin sulfate deficiency, congenital disorders of glycosylation
B. Mucosal inflammation, erosion, or ulceration
C. Infectious
1. Diarrhea, Clostridium difficile, CMV, Giardia lamblia, H pylori, and measles
D. Non-Infectious
1. Allergic gastroenteropathy, celiac, GI tumors, GVHD, HSP, IBD, polyposis
2. Portal HTN, NEC, SLE
E. Lymphatic obstruction (intestinal lymphangiectasia)
F. Secondary causes
1. Arsenic, CHF, pericarditis, thoracic duct damage, familial, tumors
2. Following cardiac surgery, especially Fontan procedure
IV. Lymphangiectasia
A. Dilation of lacteals, absence of inflammation, poor lymphatic drainage
B. Primary: presents from premature infant to adolescent with diarrhea, vomiting, growth retardation,
and lymphedema
C. Secondary
1. Cardiovascular: 4%–11% of Fontan patients develop PLE
2. SLE
3. Tumors

V. Clinical Manifestations
A. Variable, depending on degree of protein loss and nature of underlying disease
1. Changes in clotting factors rarely show clinical findings
2. Hypogammaglobulinemia not associated with infection
3. Lymphopenia may result in altered cellular immunity
B. Peripheral edema due to decreased plasma oncotic pressure
C. Pleural effusions and pericardial effusions, especially if thoracic duct is obstructed
D. Fat and carbohydrate malabsorption may occur due to small bowel involvement in primary disease
process
VI. Diagnosis
A. L abs: decreased albumin, transferrin, gamma-globulins (IgA, IgG, IgM), ceruloplasmin, and
fibrinogen
B. Urinary protein loss and hypoalbuminemia secondary to liver disease and malnutrition should be
excluded
C. Rule out eosinophilic gastroenteritis, IBD, and celiac disease
D. Diagnostic studies:
1. Fecal alpha-1 antitrypsin (<54 mg/dL) or fecal calprotectin (<50 µg/g)
2. Small bowel contrast studies: thickened folds
3. Endoscopy: mucosa with snowflake pattern, lesions are patchy (need multiple biopsies)
a. Histology findings: dilated lacteals
VII. Treatment
A. Treat underlying disease
B. Carbohydrate-deficient Glycoprotein Synthase Deficiency (CDG-1b): treatable-mannose supplemen-
tation circumvents enzymatic defect and corrects defective glycosylation
C. Intestinal lymphangiectasia
1. High-protein, low-fat diet supplemented with MCT
2. Octreotide helpful if MCT fails
3. Heparin therapy
4. Corticosteroids
5. Antiplasmin therapy
6. Surgery
D. PLE secondary to Fontan: medical treatment vs surgical treatment
Recommended Reading
3J. Appendicitis
Darla R. Shores, MD
Mark E. Lowe, MD
Appendicitis is a clinical diagnosis that can only be confirmed by pathology and requires a low threshold for
surgical consult to ensure timely intervention.
I. Pathophysiology
A. Obstruction of the lumen (fecal matter)
B. Swelling of the lymphoid tissue (post-infectious)
II. Peak age of onset

A. Adolescence
B. <2% of cases are children <2 years of age
III. Presentation
A. Typical
1. Pain, followed by vomiting, followed by right lower quadrant pain
2. Caution: symptoms may temporarily improve after perforation
B. Atypical Presentation
1. Persistent periumbilical pain or hip pain (especially if appendix is retroperitoneal)
2. Bloody diarrhea if appendix perforates against the sigmoid
IV. Physical Exam

A. Progression from RLQ tenderness to voluntary guarding, to involuntary guarding, to rebound
tenderness (signs of peritonitis)
B. Other common (but not necessary) findings: ill-appearing, low-grade fever, unwillingness to
move, anorexia
V. Labs
A. Elevated WBC, sterile pyuria, elevated CRP
B. None are specific to appendicitis
C. All may be normal, especially in the first several hours
VI. Radiology
A. Plain films
1. Only helpful in infants with perforation (paucity of gas, soft tissue edema)
2. Can possibly see a fecalith. Not needed in older children
B. Ultrasound
1. Highly operator-dependent
2. Can detect swollen/noncompressible appendix, periappendiceal fluid, or an abscess
3. Has most value in adolescent females, to distinguish from adenexal pathology
C. CT scan
1. Most extensively used
2. Can detect appendiceal wall thickening, periappendiceal fat stranding, or abscess
3. Ideally, should give IV and oral contrast
4. Sensitivity and specificity are >90%, and even higher with newer 3-mm thin cuts

VII. Perforation
A. Typically occurs 36 hours after the onset of pain
B. More common in infants (up to 70%) and those with fecalith (50%)
C. Change in symptoms/signs that may suggest perforation
1. High fever, tachypnea, right leg in drawn up position, diffuse abdominal tenderness,
low-volume diarrhea or bowel obstruction
2. Retroperitoneal appendicitis is more varied: may have psoas/obturator signs
D. Walled-off abscess
1. Symptoms can persist for days
2. Can develop extreme toxicity/sepsis
VIII. Pitfalls
A. Children <2 years (unable to obtain history well)
B. Obesity (may not be able to appreciate tenderness)
C. Narcotics (may mask pain)
IX. Differential Diagnosis

A. Infectious gastroenteritis (including yersinia)
B. Constipation
C. Urinary tract infection
D. Crohn disease
E. Pelvic inflammatory disease
F. Ovarian cyst
G. Right lower lobe pneumonia
H. Mesenteric adenitis
I. Typhlitis (immunocompromised patients)
J. Other etiologies of a surgical abdomen (obstruction, omental torsion)
X. Treatment
A. IV fluids
B. Broad-spectrum IV antibiotics (such as piperacillin-tazobactam)
C. Open or laparoscopic appendectomy is usually performed the same day
D. In cases of perforation or abscess, antibiotics and/or percutaneous drain may be done first, with
interval appendectomy following at a later time
Recommended Reading
Kleinman RE, Goulet O-J, Mieli-Vergani G, Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gas-
trointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker, Inc; 2008.
Kutasy B, Hunziker M, Laxamanadass G, Puri P. Increased incidence of negative appendectomy in childhood

obesity. Pediatr Surg Int. 2010;26:959-962.
Williams RF, Blakely ML, Fischer PE, et al. Diagnosing ruptured appendicitis preoperatively in pediatric patients.
J Am Coll Surg. 2009;208(5):819-825.
3K. Food and
Waterborne Diseases
Misam Abu-El-Haija, MD
Dawn Ebach, MD
Food and waterborne illnesses result from ingestion of food and water containing preformed microbial toxins,
invasive microorganisms or microorganisms, that secrete toxin in situ. The most common causes are rotavirus,
adenovirus, shigella, salmonella, and campylobacter.
Definitions
A. The Centers for Disease Control and Prevention (CDC) estimates 76 million cases, 323,000
hospitalizations, and 5,000 deaths annually in the United States
B. Globally, there are 1.5 billion episodes of acute gastroenteritis in 500 million children
<5 years of age
C. Five million of these children die; 20% from rotavirus
Main Etiologic Agents
I. Bacterial
A. Salmonella spp
1. Major cause of foodborne illness and second leading cause of death from
foodborne illness
2. Outbreaks have resulted from bacterial contamination of commercial products—eggs,
chicken, peanut butter, cheese
3. See Enteric Infections
B. E coli
1. The main species causing foodborne illness are enterohemorrhagic E coli (EHEC) and
enterotoxigenic E coli (ETEC)
C. Shigella spp
1. Food and water contamination
2. Outbreaks of bloody diarrhea
3. Most common US strain is S sonnei, which does not produce shiga toxin
D. Staphylococcus aureus
1. Food (egg, meat, and milk products, especially) at room temperature supports the
growth of S aureus
2. Some strains produce an enterotoxin while incubating in food which is ingested, causing
nausea, vomiting, and diarrhea within hours
3. Disease is self-limited but can cause death from hypovolemic shock
4. Disease severity and incubation period depend on the amount of enterotoxin ingested
5. There are almost twenty different enterotoxins and related toxins produced by S aureus,
with some differences in structure and biological activity
6. Staph toxins are superantigens. At picomolar concentrations, they massively activate
mononuclear cells and T cells, regardless of the antigenic specificity of the T cells
E. Campylobacter: jejuni 95%, fetus 5%
1. Occurs in meats, poultry, dairy
2. Resembles shigella in presentation
Section 3- Small Bowel 101

F. Bacillus cereus
1. Endospore-forming bacterium transmitted to humans, often via fried rice and Chinese
food
2. 1-8 hour incubation period
3. Nausea, vomiting, diarrhea, abdominal pain
4. Symptoms of nausea and vomiting are due to intoxication by the B cereus emetic toxin,
cereulide, produced in foods before ingestion
5. Symptoms of diarrhea are due to ingestion of viable cells or spores, producing protein
enterotoxins in the small intestine
G. Clostridium perfringens
1. Organism found in soil, uncooked or reheated meat, unpasteurized milk or juice, and
some canned foods (especially bean and pea products)
2. Enterotoxin produced by the organism within the GI tract
3. Diarrhea is the main symptom, and can be fatal
4. Disease is caused by C perfringens enterotoxin, which interacts with intestinal tight junc-
tion proteins, creating pores. Other C perfringens enteric toxins include the epsilon-toxin
and the beta-toxin, which also form pores in intestinal or extraintestinal target tissues
H. Aeromonas
1. Various species common in waters, usually contracted during summer months
2. Generally under 3 years of age with bloody diarrhea in 25%, fever and vomiting in 35%
3. Duration is 5–7 days
I. Yersinia enterocolitica
1. Invasive bacteria
II. Protozoal
A. All of these protozoal organisms are food or water borne
1. Amoebic:
a. Entamoeba histolytica
b. Entamoeba coli
c. Endolimax nana
d. Iodamoeba butschlii
2. Flagellates:
a. Giardia lamblia
b. Chilomastrix mesneli
c. Dientamoeba fragilis
3. Coccidia:
a. Isospora belli
b. Sarcocystis hominis
4. Ciliata:
a. Balantidium coli
b. Blastocystis hominis
B. E histolytica
1. Incidence: 3%–10% worldwide, asymptomatic in 90% of cases
2. Globally, the second leading cause of death from parasites
3. Two distinct species co-exist: E histolytica, the pathogen; and E dispar, the commensal.
Size: 8–30μ
4. Transmission: fecal-oral cyst ingestion, excysts in the ileocecum and forms trophozoites
5. E histolytica secretes three cytolytic peptides—amoebapores—in trophozoites, which
immobilize mucosal cells quickly. Cells lose cytoplasmic granules and, eventually,
the nucleus
6. Release of cysteine proteinases produces the classic “collar-button” abscess
7. Symptoms are bloody diarrhea, dysentery with tenesmus, weight loss
8. Unusual manifestations include NEC, toxic megacolon, and perianal ulceration/fistula
9. Diagnosis by O&P, serum mucosal IgA antibodies, and PCR
10. Treatment: paromomycin, metronidazole
11. Complications: trophozoites breach mucosal barrier, travel through portal system, and
produce liver abscess, with 7%–20% contiguous pulmonary infection
12. Liver abscess is 10x more common in men, and rare in children
13. Jaundice is due to biliovesicular fistula resulting from hepatonecrosis
C. Balantidium coli
1. Transmission is fecal-oral (swine-human). Size: 75–200 μ
2. Symptoms: most infections are asymptomatic. B coli lives on intestinal bacteria, but can
produce hyaluronidase, resulting in ulcers, bloody dysentery
3. Diagnosis by fresh stool exam, biopsy
4. Treatment: tetracycline, metronidazole
D. Giardia lamblia
1. Incidence: 1%–20%, with geographical variations; and transmission is via fecal-oral or
water contamination
E. Blastocystis hominis
1. Incidence: found in 1%–20% of O&P, asymptomatic carrier common
2. Size: 8–10 μ, granulated or vacuolated
3. Symptoms: appear with infection >5 cysts/HPF, and include cramping, bloating, diarrhea,
eosinophilia
4. Diagnosis by stool hematoxylin or trichrome stain
5. Treatment: metronidazole or nitrazoxanide
F. Isospora belli
1. A coccidian protozoa only of humans
2. Transmission is by fecal-oral cyst ingestion, more common in tropics
3. Size: sporozoites 9–11 μ, oocysts 12–30 μ
4. Symptoms: asymptomatic, or invade mucosa and produce diarrhea, pain, weight loss,
anorexia, steatorrhea, and eosinophilia
5. Diagnosis by O&P, duodenal aspiration
6. Treatment: TMP/S for 4 weeks
G. Cryptosporidium parvum
1. A coccidian intracellular protozoa 2–4 μ, with 30%–60% crèche transmission
2. Food (predominantly berries) and water-borne outbreaks
3. General incidence among hospitalized gastroenteritis is 2.5%–6%
4. Incubation is 7–10 days, 90% of patients develop a watery diarrhea of
2 weeks’ duration
5. Symptoms: diarrhea, pain, weight loss, fever, anorexia
6. Patients with AIDS can develop a fulminant syndrome
7. Biliary cryptosporidiosis is the most common extraintestinal manifestation, evident by US
revealing thickening of biliary ducts
8. Diagnosis: acid-fast counterstain. In HIV, check sputum, lung biopsy, and biliary tract
9. Treatment: if necessary, nitazoxanide or paromomycin
III. Diagnosis
A. Based on clinical presentation
B. Physical exam may show signs of dehydration
C. Polymerase chain reaction (PCR) is available for rapid detection of some infections: Salmonella,
Campylobacter, and E coli
D. No reliable commercial PCR test for Bacillus cereus, Clostridium perfringens, or Staphylococcus
aureus
E. Serologic and stool analysis
IV. Management
A. Symptomatic treatment and hydration
B. Most cases of food poisoning resolve within 24 hours
C. Immunocompromised hosts may have chronic severe disease with high mortality
D. Specific antimicrobials and antiparasitic agents are available (see above)
Section 3- Small Bowel 103

Recommended Reading
Abubakar I, Irvine L, Aldus CF, et al. A systematic review of the clinical, public health and cost-effectiveness of
rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.
Health Technol Assess. 2007;11(36):1-216.
Feldman M, Scharschmidt BF, Sleisenger MH. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease.
6th ed. Philadelphia, PA: Saunders Elsevier; 1998: 557-571.
Mead PS, Slutsker L, Dietz V, et al. Food-related illness and death in the United States. Emerg Infect Dis.
1999;5(5):607-625.
3L. Enteric Infections
Alexandra B. Vasilescu, DO, MS
Kathleen B Schwarz, MD
I. Bacteria
Enteric bacterial infections, causing diarrhea, dysentery and enteric fevers, are important health problems
throughout the world. These bacterial infections represent a notable burden, in particular, for children
living in less-developed regions of the world, where the number of diarrheal episodes and childhood
deaths reported worldwide remains of apocalyptic dimensions. They are also a risk for travelers from
industrialized countries who visit less-developed areas.
A. Salmonella
1. Gram-negative, motile bacilli
a. Genus of family of Enterobacteriaceae
b. Human pathogens: S enterica subspecies
c. O-oligosaccharide cell wall antigens and flagellar H-protein antigens
(2,300 species)
2. Epidemiology:
a. S typhi and S paratyphi
1) Colonize only humans
2) Fecal-oral transmission
3) 12.3 million cases/year (excluding China)
4) Annual incidence 0.5% worldwide
a) US decrease from 1/100,000 (1955) to 0.2 case per
100,000 (1966)
b) Estimated 21.6 million illnesses and 216,500 deaths
worldwide in 2000
b. Nontyphoidal salmonella: wild animals, poultry, swine, cattle, rodents,
reptiles
1) Host factors influence: (congenital and acquired immunodeficien-
cy), age <3 months, achlorhydria, antacid treatment, or antibiotics
2) Leading reported foodborne disease outbreak in US (grade A eggs,
raw fruits and vegetables)
3) Person-to-person and vertical transmission
a) Incidence greatest <5 years old, peak < 1 year old
4) Increase between 1970 and 1987 from 12 to 20/100,000
a) Estimated 94 million cases (mostly foodborne) and
155,000 deaths worldwide
3. Clinical Manifestations
a. Gastroenteritis
1) Incubation 6 hours–10 days
2) Acute self-limited enterocolitis
3) Bacterimia (infancy, peak at 3 months)
4) Diarrhea: blood, mucus, fecal leukocytes
5) Fever 70%
6) Detected in stool for 5 weeks–1 year
b. Extraintestinal manifestations
1) Infants (meninges, bones, lungs)
2) Osteomyelitis in sickle cell disease, HIV (prolonged diarrhea, bacte-
rimia, weight loss)
3) Meningitis: high mortality and neurologic sequelae

c. Enteric fever
1) Incubation 5–21 days
2) Chills, headache, cough, weakness, muscle pain (prodrome)
3) 30% develop rose spots on the trunk; most resolve by 4th week
4) Others improve initially, but then develop abdominal pain, Peyer’s
patches inflammation, secondary bacterimia
4. Diagnosis: stool culture, blood culture
5. Treatment
a. Contraindicated in patients 2–50 years old who are immunocompetent and
are only mild-to-moderately ill, especially if improving clinically, since treat-
ment prolongs carrier state
b. Antibiotics do not speed resolution, nor eliminate fecal excretion
c. Antibiotics are administered to patients with suspected or proven salmonel-
losis who are at high risk of complications, such as: <3 months of age, toxic
appearing, hemolytic anemia, malignancy, chronic colitis, immunodeficiency,
elderly
d. Antibiotics for immunocompetent individuals who are severely ill: Bactrim
(160 mg/800 mg PO BID), amoxicillin (500 mg TID), cefotaxime (2 grams IV
TID), ceftriaxone (1–2 grams IV QD)
1) Length of treatment: bacteremia 2 weeks, osteomyelitis 4–6
weeks, meningitis 4 weeks
e. Hygenic practices for prevention
B. Shigella dysenteriae
1. Gram-negative, non-lactose–fermenting, nonmotile bacilli
2. Genus of family of Enterobacteriaceae
a. S dysenteriae – group A (less developed countries)
b. S flexneri – group B (less developed countries)
c. S boydii – group C
d. S sonnei – group D (industrialized countries)
a. Incubation 1–4 days
b. Systemic symptoms (fever, headache, malaise, anorexia, vomiting)
c. Watery diarrhea → dysentery (tenesmus; small, frequent blood and mucus
containing stools)
d. Shiga toxin – HUS (children) or TTP (adults); shiga neurotoxin may cause
seizures
e. Self-limited in healthy individuals, lasting 5–7 days
1) Life-threatening in malnourished or immunocompromised
4. Diagnosis, Treatment, Prevention
a. Stool culture, rapid incubation at 37°C
b. Antibiotics: decreased duration of fever, diarrhea, intestinal protein loss and
pathogen excretion
1) May reduce the risk of developing complications
c. Medication regimen is determined by severity of illness, local resistance
patterns, and history of travel to an area of frequent resistance
1) TMP-SMX: 10 mg/kg TMP and 50 mg/kg SMX per day in two
divided doses for 5 days (max 160 mg TMP and 600 mg SMX)
2) Ampicillin 100 mg/kg/day in four divided doses for 5 days
3) In areas of high resistance to TMP-SMX and ampicillin, azithromycin
is the suggested first-line oral treatment
a) 12 mg/kg for first day (max 500 mg), then 6 mg/kg/dose
(max 250 mg) for an additional 4 days
4) Hand-washing for prevention
5) Oral vaccine in clinical trials
C. Yersinia
1. Gram-negative, non-lactose–fermenting, aerobic and facultatively anaerobic bacilli
(grow at 25° C)
a. Family Enterobacteriaceae (enterocolitica and pseudotuberculosis) – human
pathogens
2. Epidemiology
a. Swine is major reservoir for human infection (food-borne)
b. Most episodes occur in infant and young
c. More common in N. latitudes – N. Europe, Scandinavia, Canada, US, Japan
(1-8% of diarrhea)
a. Incubation 3–7 days
b. In Northern Europe, Scandinavia, Canada, US, Japan – responsible for
1%–8% of sporadic diarrhea episodes
c. Younger than 5 years old, watery diarrhea (blood 25%–30%), fever, and
abdominal pain
d. Cervical adenitis (pharyngitis)
e. Abdominal complications: appendicitis, diffuse ulceration of intestine and co-
lon, intestinal perforation, peritonitis, ileocecal intussusception, toxic mega-
colon, cholangitis, mesenteric venous thrombosis
f. Pseudoappendicitis syndrome
g. Associated with immunopathologic sequelae, including reactive arthritis, uve-
itis, Reiter’s syndrome, and erythema nodosum
a. May be isolated from stool, but should use selective media; alternative is
detection of the microorganism by PCR methodology
b. Most cases resolve, uncomplicated
c. 3rd generation cephalosporins (combination with aminoglycosides),
aztreonam, imipenem
1) Start IV and PO for total 2–6 weeks
d. No vaccines
D. Campylobacter
1. Small, nonsporing, motile, spiral-shaped, Gram-negative bacteria, microaerophilic,
seagull appearance
a. Family Campylobacteriaceae; thirteen species pathogenic to humans; C jejuni
and C coli are the most common species isolated from patients with diarrhea
2. Epidemiology
a. Reservoir in the intestines of wild and domestic animals
1) Half of cases from poultry
2) Also unpasteurized milk or contaminated water
b. Does not multiply in food to high concentrations, as does Salmonella, but
inoculum required to cause infection is lower
c. Annual incidence about 1% (summer months)
d. Bimodal incidence: 0–5 and 15–29 year olds
3. Clinical Manifestations:
a. Incubation: 3–6 days
b. Abdominal cramps (mimic appendicitis) and watery diarrhea, then bloody
diarrhea (lasting 4–5 days)
c. Fecal excretion for one month (immunocompromised longer)
a. Stool culture
b. Controversial use of antibiotics (may shorten course of diarrhea), as may
develop drug resistance
1) Used for immunocompromised
2) Erythromycin
c. Vaccine development: concerns about post-exposure arthritis or Guillain-
Barré syndrome
E. Escherichia coli
1. Gram-negative, lactose-fermenting, motile bacilli
a. Most E coli are part of normal fecal flora
2. Enteropathogenic E. coli (EPEC): first group shown to be pathogens
a. Nosocomial, neonatal and infant diarrhea
b. Ability to induce attaching and effacing lesion in intestinal enterocytes
c. Epidemiology: infantile diarrhea, nursery outbreaks

d. Clinical Manifestations: 109 colony-forming unit, self-limited watery diarrhea
(incubation: 6–48 hours) that may last up to 14 days
e. Treatment and prevention: course of triple oral antibiotics, shortens course
(bactrim, gentamicin, colistin); encourage breastfeeding and improving so-
cial/economic conditions
3. Enterotoxigenic E coli (ETEC); enterotoxins (heat stable or heat labile)
a. Epidemiology
1) Leading cause of dehydrating diarrheal disease among weaning
infants in the developing world
2) Traveler’s diarrhea
3) Contaminated food and water (peak in warm, wet season)
b. Clinical Manifestations: high innoculum (incubation: 14–30 hours); watery
diarrhea, fever, abdominal cramps, vomiting, self-limited for up to 5 days
c. Treatment and Prevention: self-limited; antibiotics shorten duration of illness
by 1–2 days (doxycycline, bactrim [resistant], ciprofloxacin; quinolones, fura-
zolidone)
4. Enteroinvasive E coli (EIEC); almost identical genetically, biochemically, and chemically
to Shigella
a. Epidemiology: developing countries, 1%–5% diarrhea
b. Clinical manifestations: watery diarrhea
5. Enterohemorrhagic E coli: shiga-like toxins; cause diarrhea or HUS
a. Epidemiology: food outbreak (E coli O157:H7); vehicles include raw meat,
fruits, vegetables, drinking or swimming water; person-person in daycare
b. Clinical Manifestations: follows 3–9 days after ingesting 100 organisms
1) Crampy abdominal pain, non-bloody diarrhea initially, then bloody
2) 25% hospitalized, 5%–10% develop HUS, 1% die (risks: young or
old age, bloody diarrhea; fever, high WBC, antimotility agents)
a) 2/3 of HUS don’t excrete organism at presentation
3) Complications include rectal prolapse, appendicitis, intussusception,
pseudomembranous colitis
c. Diagnosis, Treatment, Prevention: stool culture, antibiotic-treated patients
have same or poorer outcome than untreated; cooked meat; vaccines in
development
6. Diffusely Adhering E coli (DAEC)
a. Epidemiology: diarrhea <6 years old; frequent in warm season
b. Clinical Manifestations: self-limiting watery diarrhea
c. Diagnosis: DNA probe technique (epidemiologic surveys)
7. Enteroaggregative E coli (EAggEC): not all species are human pathogens
a. Epidemiology and Clinical Manifestations: sporadic outbreaks; watery, mu-
coid, secretory diarrhea; 1/3 bloody diarrhea, low-grade fever
b. Diagnosis and Treatment: stool culture, PCR assays, self-limiting, some ben-
efit for antibiotic use if known susceptibility
F. Intestinal Tuberculosis
1. The pathogen is Mycobacterium tuberculosis
2. Routes of GI infection include:
a. Ingestion of infected sputum in patients with active pulmonary TB
b. Spread through a hematogenous route from tuberculous focus in the lung to
submucosal lymph node
c. Local spread from surrounding organs involved by primary tuberculous
infection
3. Clinical features of intestinal TB include abdominal pain, weight loss, anemia, night
sweats; symptoms of obstruction such as palpable mass or pain in the right iliac fossa
4. Jejunoileum and ileocecal involvement is seen in >75% of patients
5. Diagnosis: colonoscopy, with multiple biopsies at the ulcer margins and tissue sent
for routine histology, smear, and culture; exploratory laparotomy is necessary if the
diagnosis is in doubt
6. Treatment: full course of antituberculous chemotherapy
II. Viral Infections
A. Rotavirus
1. Pathophysiology: virions are ingested, activated by trypsin in the small intestine, and
invade the villus enterocytes, leading to their destruction and the release of thou-
sands of progeny, which are then locally activated by trypsin to infect more entero-
cytes
a. Small intestinal epithelium is rapidly repopulated with less differentiated
enterocytes from the crypts, which lack digestive enzymes and mechanisms
for active sodium and water absorption (Na/K, ATPase), therefore diarrhea
(osmotic and secretory diarrhea)
2. Each year rotavirus causes 111 million episodes of gastroenteritis worldwide, 25 mil-
lion clinic visits, 2 million hospitalizations, and 352,000–592,000 deaths in children
<5 years old
a. Children in poorest countries account for 82% of deaths
3. Clinical Features
a. Incubation period of 2–7 days, abrupt onset of vomiting and fever, then
profuse watery diarrhea, causing dehydration, acidosis, and electrolyte imbal-
ance
b. Irritability, lethargy
c. Respiratory symptoms possible in 20%–40%
d. Vomiting settles in 24–48 hours, and diarrhea in 2–7 days
e. Acute complications: hypo/hypernatremia, febrile convulsions, AST elevation
4. Treatment
a. Correct dehydration, acidosis, and electrolyte imbalance
b. Encourage breast feeding; very small percentage have lactose malabsorption,
requiring lactose-free diet
c. Drugs (antiperistaltic or antiemetics) should be avoided
d. If mild disease, probiotics lactobacillus GG may decrease duration of diarrhea
5. Prevention
a. Hand-washing
b. Breastfeeding reduces the overall incidence of diarrheal diseases in the first
year of life
c. Vaccine
1) Rotashield (link to intussusception)
2) Rotateq (live) – Three oral doses in first 6 months of life (90% pro-
tection against severe dehydrating disease)
B. Enterovirus
1. Belong to Picornaviridae family (small RNA viruses)
a. Includes coxsackie, echovirus, and poliovirus
2. Most common route of transmission is fecal-oral route
3. Resilient, remain viable at room temperature for several days, can survive acidic pH of
GI tract
4. Nonpolio enteroviral infections cause an estimated 10–15 million symptomatic infec-
tions per year in the US
5. Risk factors include poor sanitation, crowded living conditions, and lower socioeco-
nomic status
6. Children younger than 5 years old are more susceptible because of poor hygiene
habits and lack of prior immunity
7. No specific antiviral medication or treatment is available for an enteroviral infection;
use supportive measures, fluid hydration, and antipyretics
C. Enteric Adenovirus
1. Ubiquitous human pathogens causing a variety of syndromes ranging from
respiratory infections to hepatitis
2. Account for 3%–5% of acute pediatric enteritis
3. Diagnosis made by EIAs
4. Replicate in host nuclei in patients with diarrhea

5. No specific treatment, although use of ribavirin in immunocompromised hosts has
been reported
D. Calcivirus (noroviruses and sapoviruses)
1. Pathophysiology: villus shortening and crypt hypertrophy in the proximal duodenum
associated with villus tip vacuolization and infiltration of the lamina propria with
inflammatory cells
a. Gastric and colonic mucosa are completely normal
2. Rapid onset of symptoms, rapid spread of disease through groups
3. Mild and self-limited 12–24 hours, with 1–2 days’ incubation
4. Asymptomatic shedding of virus
5. No specific treatment is available
E. Norwalk-like virus
1. May cause 10% of sporadic cases of diarrhea in developed countries
2. Affects especially the immunocompromised
3. Rapid onset of symptoms, predominant vomiting and rapid spread of disease through
groups, with high attack rate across all age groups
4. Illness is generally mild and self-limited
5. Infantile enteritis is clinically similar to rotavirus gastroenteritis, although resulting in
less severe dehydration
III. Parasitic Infections

A. Giardia lamblia
1. Motile trophozoite and also as a cyst, with the latter being the infective form
2. Infection transmitted by food, water, and person-to-person contact
3. Incubation period from the time of ingestion of cysts until the onset of symptoms is
3–20 days
a. Acute infection begins with persistent, watery diarrhea, and is associated
with anorexia, abdominal distention, flatulence, abdominal cramps,
malodorous, greasy stools; weight loss, and urticaria
b. Chronic giardiasis can be associated with immunoglobulin deficiency, which
may be associated with diffuse nodular lymphoid hyperplasia involving the
small and large intestine
c. 50% of persistent diarrhea will have fat malabsorption
d. Lactase deficiency is common
5. Diagnosis
a. Gold standard—identification of Giardia forms by microscopy of feces, duo-
denal fluid, or mucosal biopsy specimens
b. Multipe stool samples may miss 50%
c. Motile trophozoites identified on a wet saline mount of fresh liquid stool
obtained during the illness
d. Antigen-based fecal detection assays are specific, but not sensitive (80%)
6. Treatment:
a. Metronidazole (30 mg/kg/dose for 3 days)
b. Albendazole (400 mg daily for 7 days)
B. Ascaris lumbricoides
1. Largest human intestinal nematode; adult worms can reach 10–30 cm in length
2. Lifecycle:
a. Transmitted by fecal-oral route from ingestion of agricultural products or
food contaminated with parasite eggs
b. Swallowed eggs hatch in the intestine, producing larvae, which then migrate
through the blood to the pulmonary circulation, penetrate the alveoli, and
migrate up... through the blood to the pulmonary circulation, penetrate
alveoli and migrate up the tracheobronchial tree
c. A host swallows the larvae which, develop into adult worms in the intestine
3. Clinical manifestations:
a. Anorexia and abdominal cramps
b. Partial or total intestinal obstruction
1) May migrate into pancreatic and biliary systems, causing duct
obstruction with jaundice
c.
Rare complication: Loffler’s syndrome—fever, cough, sputum, asthma,
eosinophilia, and radiological pulmonary infiltration
4. Diagnosis
a. CBC with peripheral eosinophilia
b. Ova and adult worms in feces, and larvae in sputum or gastric washings
c. Ultrasound, ERCP, MRCP, and CT scanning are useful in the diagnosis of bili-
ary ascariasis
5. Treatment
a. Albendazole (single dose of 200 mg in children 2–5 years old, and 400 mg
for older children and adults)
b. Mebendazole (single dose of 500 mg )
c. Levamisole (single dose of 2.5 mg/kg)
d. Pyrantel pamoate (single dose of 10 mg/kg)
C. Tapeworm
1. Adult worms reside in the intestinal tract. Larvae reside in muscle tissue
2. Taenia saginata (Beef tapeworm)
a. Human is the definitive host, and cattle are the significant intermediate hosts
b. Human infection is acquired by eating undercooked beef
c. Contaminated feed or grazing ground with human feces is the source of
infection for cattle
d. Most patients are symptom-free, some with vague abdominal discomfort,
occasional diarrhea, or awareness of motile proglottids spontaneously
emerging from the anus
e. Diagnosis when Taenia eggs seen in feces by microscopy
f. Praziquantel as single dose 10 mg/kg
3. Taenia solium (Pork tapeworm)
a. Similar to T saginata; however, serious complication when autoinfection with
T solium larvae results in their dissemination to many sites (called cysticerco-
sis), including skeletal muscle, brain, subcutaneous tissue, eye, myocardium
1) The cysts remain alive for many years, but eventually produce a
local inflammatory reaction and calcify
2) Cerebral involvement presents as epilepsy, as space-occupying
lesion, or as focal neurologic deficits
3) Ocular involvement produces retinitis, uveitis, conjunctivitis, or
choroidal atrophy
b. Praziquantel 10 mg/kg single dose
4. Diphyllobothrium latum (Fish worm)
a. Found in Scandinavia, Baltic countries, Japan, and Swiss lakes
b. Ingestion of raw or undercooked fish
c. Infection is asymptomatic, although may cause abdominal discomfort,
vomiting, weight loss
d. Cleaves vitamin B12
e. Diagnosis and treatment as for other tapeworms
5. Hymenolepis nana
a. Infects children more often than adults
b. Has other natural hosts in rats and mice
c. Generally produces no symptoms, although very heavy infection may result
in diarrhea and abdominal pain
6. Hookworm (Ankylostoma duodenale and Necator americanus)
a. Adult worms attach firmly to the small intestinal mucosa by a buccal capsule
consisting of tooth-like or plate-like cutting organs
b. Infection acquired percutaneously from larvae in the soil contaminated by
human feces, or orally after ingestion of contaminated food or consumption
of uncooked meat containing the larvae
c. Man is the only reservoir of infection; favorable larvae development in warm,
moist soil
1) Infection occurs by contaminated soil, or via the skin when larvae
secrete a protease that facilitates boring into the skin and entry into
subcutaneous tissue

2) Larvae migrate through the venous and lymphatic circulation into
pulmonary capillaries, get into lung alveoli, and ascend the airways
3) Coughed up and swallowed, larvae then develop into adult worms
in the proximal small intestine, then attach to the mucosa and
begin to feed
a) Every 4–8 hours, worms change the site of attachment,
producing minute, bleeding mucosal ulcerations which
lead to hypochromic anemia
d. Hookworm infection is the leading cause of iron deficiency anemia (pro-
portional to worm load) in developing countries, and may affect cognitive
development
e. May cause protein-losing enteropathy
f. Diagnosis and Treatment
1) Detected in stool and duodenal fluid
2) Mebendazole 200 mg/day for 3 days
3) Albendazole 400 mg once
4) Levamisole and pyrantel pamoate
5) Anemia is treated with oral ferrous sulfate or gluconate, and
continued for 3 months after a normal hemoglobin level has
been achieved
7. Whipworm (Trichuris trichiura)
a. Infection is transmitted by ingestion of ova that have matured outside the
host for several weeks
b. Colonization involves the distal ileum and cecum, although the entire colon
may be involved
c. Clinical Manifestations
1) Light infection is usually asymptomatic, but with >20,000 ova per
gram of feces, diarrhea with blood and mucus is characteristic
2) Abdominal pain, anorexia, weight loss, tenesmus, rectal prolapse
3) May impair growth and development in young children
d. Diagnosis and Treatment
1) Barrel-shaped eggs detected in feces
2) Adult worms can endoscopically be seen attached to the colonic
mucosa, often with the presence of ulceration and inflammatory
changes
3) Albendazole or mebendazole as a single dose; multiple courses may
be necessary to clear infection
D. STD-related gastroenteritis
1. HIV-infected patients with chronic diarrhea should be treated symptomatically
2. If an enteric pathogen is cultured, specific therapy should be administered
3. A flexible sigmoidoscopy is recommended if a diagnosis is not obtained with stool
analysis
4. Small intestinal infections include the following pathogens
a. Cryptosporidium, Microsporidium, Isospora, Cyclospora, Giardia, and
Entamoeba
b. CMV
E. Fungal Infections
1. A well child with intact host defense mechanisms is generally not considered to be
susceptible to fungal infections of the digestive tract
2. Chronically immunosuppressed patients secondary to myelotoxic agents, immunosup-
pressive therapies, and/or HIV/AIDS are susceptible to intestinal fungi infections
3. Candidiasis: Candida species, most common in intestinal illness Candida albicans;
major risk factor is neutropenia
a. Esophagitis seen in immunosuppressed children and hematologic malig-
nancy; oral thrush seen in only 20% of cases; nystatin oral; ketoconazole or
fluconazole
b. Peritonitis seen after bowel surgery or in patients with chronic peritoneal
dialysis
c. C albicans may invade the small bowel and large intestine in terminally
ill patients
4. Aspergillosis: genus Aspergillus
a. Most cases seen in severely immunocompromised
b. Amphotericin B is treatment of choice
5. Zygomycosis (aka mucormycosis or phycomytosis)
a. Ubiquitous agents found in organic debris, on fruit and in soil; grow rapidly
on any carbohydrate substrate
b. May invade subcutaneous or submucosal tissues in an immunocompetent
host
c. Intestinal zygomycosis in the immunosuppressed host or severely malnour-
ished, may cause acute fulminant invasive infection
d. Treatment includes amphotericin B (1–1.5 mg/kg) and surgical debridement
6. Coccidioidomycosis
a. Coccidioides is a dimorphic fungus endemic in the southwest United States
b. Usually a pulmonary infection, but spores may escape and, with dissemina-
tion, the terminal ileum and colon are involved
c. Treatment of primary pulmonary disease with fluconazole
(6–12 mg/kg daily), and disseminated disease requires amphotericin B
Recommended Reading
Ashkenazi S. Shigella species. In: Yu VL, Weer R, Raoult D, eds. Antimicrobial Therapy and Vaccines. 2nd ed.
New York, NY: Apple Tree Production; 2002:615.
Bhan MK Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. Lancet. 2005;366(9487):749-762.
Cover TL. Yersinia enterocolitica and Yersinia pseudotuberculosis, In: Blaser MJ, et al, eds. Infections of the
Gastrointestinal Tract. New York, NY: Raven Press; 1995:811-823.
Horvath KD. Intestinal tuberculosis: return of an old disease. American J Gastro. 1998; 93(5):692-696.
Koch J. Gastrointestinal Manifestations of HIV. HIV InSite. Knowledge Base Chapter. June 1998.
Majowicz SE Musto J, Scallan E, et al. The global burden of nontyphoidal Salmonella gastroenteritis. Clin
Infect Dis. 2010;50(6):882-889.
Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI.
Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003;9:565-572.

3M. Autoimmune Enteropathy
Imad Absah, MD
Mounif El-Youssef, MD
Autoimmune enteropathy (AIE) is an important cause of diarrhea in infancy and early childhood. The target of
the autoimmune attack is the epithelium. AIE is a T-cell–mediated disorder resulting in profuse diarrhea and
protein-losing enteropathy.
Types of Autoimmune Enteropathy

AIE is divided into 3 forms:
1- X-linked IPEX syndrome
2- IPEX-like form in boys and girls
3- Autoimmune manifestations limited to GI tract
4- Autoimmune Polyendocrinopathy–Candidiasis-Ectodermal Dysplasia
I. IE Type 1, Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX)

A
Syndrome
A. Pathogenesis
1. IPEX syndrome is a rare X-linked disorder
2. Result of specific mutation in the FOXP3 gene, which results in compromised sup-
pressor function of regulatory T-cells
B. Clinical Presentation — early onset of the following:
1. Diabetes mellitus due to Islet cell destruction, which is usually present before the
intestinal manifestations and requires insulin supplementation
2. Severe secretory diarrhea with stool volume of 75–150 mL/kg/day, potentially
bloody/mucoid stools, possible hypoalbuminemia and electrolyte disturbances re-
quiring bowel rest and TPN
3. Eczema-like dermatitis
C. Other Clinical Features
1. Thyroiditis (usually hypothyroidism)
2. Hematologic abnormalities (Coombs positive anemia, neutropenia, and thrombocy-
topenia)
3. Chronic hepatitis in some cases
D. Evaluation
1. Endoscopic Findings
a. EGD varies from normal-looking mucosa to some mild granularity and ery-
thema
b. Colonoscopy will show diffuse erythema and loss of vascularity throughout
the colon
2. Histology
a. Villous atrophy
b. Massive mononuclear (T cell) infiltration of the lamina propria (as opposed
to celiac disease, which has intraepithelial lymphocytic infiltrate)
3. Blood Work
a. No pathognomic laboratory abnormalities for AIE
b. Normal lymphocyte count
c. Normal immunoglobulin levels, except for IgE levels, which are usually
markedly elevated
d. Periodic peripheral eosinophilia can be noted
e. Antienterocytes/anticolonocyte antibodies are highly sensitive for AIE
f. Anti-75-AIE (antibody against gut and kidney antigen 75 kDa) is a highly
specific antibody that is usually detected in patients with IPEX and AIE
g. Abnormal T-cell activation studies
4. Genotyping of suspected mutations based on clinical presentation

II. AIE Type 2, IPEX-like Without FOXP3 Mutation
A. Pathogenesis
1. Regulatory T-cell dysfunction
B. Clinical Presentation
Affects girls and boys
1. Multiple autoimmune symptoms and IPEX-like disease (see above)
2. No FOXP3 mutation
III. AIE Type 3

A. Patients present with secretory diarrhea
B. Antienterocytes/anticolonocytes and anti-75-AIE antibodies positive
C. No extraintestinal manifestations
IV. A
IE Type 4, Autoimmune Polyendocrinopathy–Candidiasis-Ectodermal Dysplasia (APECED)
Syndrome {Newer terminology = Autoimmune Polyglandular Syndrome-1 [APS-1]}
1. Polyendocrinopathy
2. Mucocutaneous candidiasis
3. Ectodermal dysplasia
4. Associated with AIRE gene (autoimmune regulator) on 21q22.3
5. More frequent in Finns, Iranian Jews, and Sardinians
6. Usually present with milder clinical course, because the immune target is the enteroendocrine cells
rather than the absorptive cells
A. Differential Diagnosis
1. Immune deficiencies (low immune globulins or lymphocytes)
2. Wiskott-Aldrich syndrome (low CD8)
3. APECED syndrome (AIRE gene mutation)
4. Omenn syndrome (low B-cell count, mutation in RAG1 or RAG2 genes)
5. Celiac disease (intraepithelial lymphocyte infiltration)
B. Treatment and Outcome
1. AIE has high mortality rates
2. Bowel rest and TPN are needed to compensate fluid and protein loss, and manage
electrolytes disturbances
3. Chronic immune suppression using combination of steroid, tacrolimus, and
azathioprine
4. Bone marrow transplant (BMT)
Recommended Reading
Mieli-Vergani G, Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed.
Hamilton, Ontario: BC Decker, Inc; 2008: 339-344.
Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease. 4th ed. Saunders Elsevier, Philadelphia,
PA: Saunders Elsevier; 2011: 354-355.
3N. Small Bowel Obstruction
Anas Bitar, MD
Thomas J. Sferra, MD
Small bowel obstruction can be due to either mechanical or functional etiologies. The functional causes are
either myopathic, neuropathic, or secondary to other underlying disease. Identification and treatment prior to
bowel injury is critical.
I. Mechanical: Intrinsic or Extrinsic (See Table 1)
Table 1. Causes of Mechanical Small Bowel Obstruction in Infants and Children

Causes
Anatomic Location Intrinsic Extrinsic
(intraluminal or extraintestinal)
Duodenum Duodenal atresia/stenosis Ladd’s bands/midgut malrotation
Duodenal web Annular pancreas
Duodenal hematoma Preduodenal portal vein
Intestinal duplication cyst Adhesions
Pyloric stenosis Neoplasm
SMA syndrome (Cast or Wilkie’s syndrome)
Small Intestine Intestinal atresia/stenosis Malrotation/midgut volvulus
Crohn’s disease Meconium ileus/meconium plug syndrome
NEC Meckel diverticulum
Neoplasm Neoplasms
Intestinal duplication cyst Adhesions
Intussusception Hernias (ex: inguinal)
Ascariasis Distal intestinal obstruction syndrome
II. Functional
A. Visceral Myopathies
1. Primary (disorders of the intestinal smooth muscle)
a. Familial (primary) visceral myopathies (4 types)
b. Sporadic infantile or childhood visceral myopathy
c. African degenerative leiomyopathy
d. Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)
e. Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)
2. Secondary (systemic diagnosis involving the intestinal smooth muscle)
a. Connective tissue diseases: dermatomyositis/polymyositis, SLE, mixed connective
tissue diseases, Ehlers-Danlos type IV, scleroderma
b. Myopathies: myotonic muscular dystrophy, Duchenne’s dystrophy, desmin
myopathy, mitochondrial myopathy
c. Infiltrative and inflammatory disorders: amyloidosis, ceroidosis (Brown bowel
syndrome), leiomyositis
B. Visceral Neuropathies
1. Primary (disorders of the enteric nervous system)
a. Familial visceral neuropathies
b. Sporadic visceral neuropathies (hyper or hypoganglionosis)
c. Ganglioneuromatosis with MEN type IIB

d. Sporadic and familial aganglionosis
e. Disorders of the intestinal cells of Cajal (reduced density, delayed maturation)
f. Unclassified enteric neuropathies
2. Secondary (systemic diagnosis affecting the enteric nervous system)
a. Central or peripheral neural disease: Riley-Day syndrome, diabetic
polyneuropathy, mitochondrial neurogastrointestinal encephalopathy
b. Infectious/postinfectious: Chagas, postviral (CMV, VZV, HSV-1, EBV, Rota, HIV),
Lyme disease, Kawasaki disease, Guillain-Barré syndrome
c. Toxic agents: fetal alcohol syndrome, jellyfish envenomation, drugs (prokinetics,
opioids, macrolides, calcium channel blockers, vinblastine, anticonvulsive)
d. Radiation
e. Autoimmune: celiac, eosinophilic gastroenteritis
f. Endocrine/metabolic: electrolyte imbalance, uremia, thyroid disease, porphyria,
carnitine deficiency, vitamin E deficiency
g. Tumor-associated: chemotherapy, neural crest tumors, paraneoplastic syndrome,
thymoma
h. Miscellaneous: Ogilvie’s syndrome (acute chronic pseudoobstruction), Crohn’s,
angioedema, anorexia nervosa/bulimia
III. Pathophysiology:
Intestinal obstruction
Luminal hydrostatic pressure >
Mucosal lymphatic pressure
Intestinal stasis
Strangulation
Obstruction of lymphatic flow
Elevated venous pressure Compression of arterial supply
Bowel wall edema
Increased net filtration and

third spacing into lumen
Hypovolemia
Mucosal injury Bacterial
Dehydration
Ischemia overgrowth
Shock
Perforation
A. Manifestations and Diagnosis

1. The age of the patient, time of presentation, and signs/symptoms are the major keys for
diagnosis.
a. Examples:
1) The most common causes (33%) of obstruction in the newborn period are
atresia and stenosis
2) Gastroschisis is associated with intestinal atresia
3) Pyloric stenosis presents in the first two months of life
2. Adhesive obstructions are most common one to two years following surgery, and the
most commonly implicated procedures are for gastroschisis and malrotation in the
newborn period and appendicitis and IBD in children. Up to 45% of polyhydramnios
etiologies are due to fetal malformations and genetic disorders
a. The most common structural defects associated with polyhydramnios are
those that interfere with fetal swallowing and/or absorption of fluid, such as
gastrointestinal obstruction due to esophageal or intestinal atresia
b. Congenital small intestinal abnormalities associated with polyhydramnios are:
1) Duodenal atresia
2) Jejunal atresia
3) Ileal atresia (the most commonly affected site)
3. Imaging modalities used to diagnose intestinal obstruction are:
a. Abdominal radiography:
1) Diagnostic in 45%–60% of the time
2) Remains the cornerstone as the initial radiographic assessment
b. Abdominal CT scan:
1) Accuracy is excellent
2) Helps identifying the underlying cause of the obstruction in most cases
3) The use of IV and PO contrast is recommended
c. Ultrasound: Preferred if you are suspecting intussusception or pyloric stenosis
d. Upper GI and SB contrast series: preferred in suspected cases of malrotation or
SMA
4. Manometric studies help in identifying and differentiating between myopathic and
neuropathic forms of functional obstructions
Table 2. Summary of Manifestations and Modalities of Diagnosis of SB Obstruction

Partial or Complete Obstruction Strangulation Obstruction
Neonates Children & Adolescents
Signs & • Maternal polyhydramnios • Colicky abdominal pain • Constant abdominal pain
symptoms • Abdominal distensiona • Abdominal distensiona • Hematochezia (15% of
• Vomiting b
• Nausea/vomitingb patients with volvulus)
• Failure to pass meconium • Obstipationc • Peritoneal signs
within the first 24–48 hours • Fever
• Currant jelly stools • Tachycardia
(intussusception) • Leukocytosis
• Acidosis
Physical • Hyperactive bowel sounds • Absent bowel sounds
exam • Abdominal tenderness • Painful mass
• Abdominal mass
(intussusception and volvulus)
X-ray • Distended loops of bowel
findings • Air fluid levels
• Paucity of colonic air (presence
of colonic gas suggests partial
obstruction)
CT scan • Finding fluid luminal contents • Bowel wall thickening
findings and/or fluid-filled loops • Target sign
of bowel proximal to the • Serrated beak sign
obstruction • Pneumatosis intestinalis
• Presence of localized transition • Portal venous gas
zone • Mesenteric haziness
• Presence of collapsed loops of • No enhancement with IV
small bowel or colon distal to contrast
the obstruction
a
Bowel distension is more prominent with distal (ileal) obstruction.
b
Emesis is usually bilious and more prominent with proximal (jejunal) obstruction.
c
Patient with intestinal obstruction may pass stool early on due to the peristalsis below the level of obstruction, but
continued passage of gas or stool >6–12 hours after the onset of symptoms suggests partial obstruction.

IV. Management
A. Bowel decompression (inserting large-bore NG tube)
B. Fluid resuscitation (NS or Ringer’s lactate)
C. Use of antibiotics is not well supported by data
D. Close observation and monitoring of fluid status and electrolytes
E. Trial of conservative management in partial obstruction
F. Early surgical intervention in complete obstruction or malrotation (to prevent volvulus and ischemia)
G. Prokinetic agents (e.g., erythromcin and cisapride) may be useful for acute and chronic therapy of intestinal
pseudoobstruction
Recommended Reading
Baerg J, Kaban G, Tonita J, Pahwa P, Reid D. Gastroschisis: A sixteen-year review. J Pediatr Surg. 2003;38(5):771-774.
Dalla Vecchia LK, Grosfeld JL, West KW, et al. Intestinal atresia and stenosis: a 25-year experience with 277 cases. Arch Surg.
1998;133:490.
Dashe JS, McIntire DD, Ramus RM, et al. Hydramnios: anomaly prevalence and sonographic detection. Obstet Gynecol.
2002;100:134.
Koletzko S, Schwarzer A. Other Dysmotilities Including Chronic Intestinal Pseudo-Obstruction Syndrome. In: Mieli-Vergani G,
Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker,
Inc; 2008:693-713.
Moyer MS, Warner BW. Surgical disorders, intestinal obstruction. In: Mieli-Vergani G, Sanderson IR, Sherman PM, Schneider
BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker, Inc; 2008:345-351.
Murray SR. Hydramnios: A Study OF 846 Cases. Am J Obstet Gynecol. 1964;88:65.
3O. Small Bowel Trauma
Anas Bitar, MD
Small bowel injury can result from both blunt and penetrating trauma to the abdomen. The GI tract is
damaged in 5%–20% of blunt abdominal trauma injuries, and in 70% of penetrating abdominal injuries
I. Blunt Trauma
A. Occurs most frequently from motor vehicle collisions, assaults, recreational accidents, or falls
B. This is the most common mechanism of injury to the small bowel
C. 5%–20% of patients with blunt abdominal trauma will have intestinal and mesenteric injury
D. Blunt injuries often occur near points of fixation, such as the ligament of Treitz or ileocecal valve
E. Intestinal rupture often occurs along the antimesenteric border
F. The postulated mechanisms involved in blunt intestinal injury include the following:
1. Crush injury—acts by compressing fluid-filled bowel between vertebral bodies and
the blunt object (e.g., duodenal compression between the spine and steering wheel).
The spectrum of injuries ranges from stretching of the bowel wall to full-thickness
perforation
2. Deceleration injury—causes stretching, shearing, and tearing of bowel loops at points of
fixation, such as the ligament of Treitz, the ileocecal valve, and the phrenocolic ligament.
Spectrum of injury ranges from tearing the bowel wall, to shearing the mesentery, to
loss of vascular supply
3. Closed-loop rupture—caused by a sudden increase in intraabdominal pressure
II. Penetrating Trauma

A. Occurs more frequently in urban areas and typically is secondary to knife or gunshot wounds
B. These types of injuries include abrasion of the serosa, full-thickness penetration of the bowel
wall, and mesenteric or other vascular injury
III. Clinical Presentation

A. Abdominal pain
B. Edema and ecchymosis of the abdominal wall
C. Skin laceration and penetration
D. Decrease or absence of bowel sounds
E. Guarding
F. Direct and rebound tenderness
G. Gastrointestinal hemorrhage
H. Shock (hypotension, narrow pulse pressure, and tachycardia)
IV. Small Intestinal Injury

A. The small bowel is the most frequently injured organ after penetrating injuries
B. Hollow viscous injuries are often characterized by a delay in diagnosis after blunt abdominal
trauma
C. Delay in the diagnosis and management of blunt hollow viscous injury is associated with
increased morbidity and mortality, as shown by recent studies
D. Occasionally, a large tear in the mesentery occurs without bowel involvement. In these instances,
bowel necrosis and subsequent perforation occur hours or even days after the initial injury, and
the patients may have frank peritoneal signs, acidosis, and sepsis

V. Postoperative Complications After Resection of the Small Bowel
A. Intraabdominal abscess
B. Sepsis
C. Anastomotic leakage
D. Wound infection
E. Enteric fistulas
F. Intestinal obstruction
G. Short bowel syndrome
VI. Duodenal Injury

A. Duodenal injuries have different characteristics than the rest of small bowel injuries
B. The majority of duodenal injuries are caused by penetrating trauma
C. A motor vehicle accident causing impact of the steering wheel on the epigastrium is the most
common mechanism of blunt duodenal injuries
D. Isolated injury to the duodenum is rare and does not usually cause significant clinical signs of
peritonitis or hemodynamic instability
E. Most duodenal injuries are accompanied by other intraabdominal injuries because of the close
anatomic relationship of the duodenum with other solid organs and major vessels
F. Hyperamylasemia occurs in about 50% of patients with blunt injury to the duodenum
G. Definitive diagnosis requires an upper gastrointestinal series (gastrografin) or a CT scan of the
abdomen with oral and IV contrast in hemodynamically stable patients
1. The radiographic finding of a duodenal hematoma (coiled spring or stacked coin sign) is
not an indication for surgical exploration
2. The presence of retroperitoneal hematomas around the duodenum should raise
suspicion of an associated pancreatic injury
3. Duodenal hematomas are expected to resolve in 10–15 days, and management consists
of nasogastric suction until peristalsis resumes and after the slow introduction of solid
food
H. Exploration is indicated in the event of persistent duodenal obstruction
I. Complications
1. Duodenal Fistula: (5%–15% of patients)
a. Duodenal fistulas are generally managed nonoperatively with nasogastric
suction, IV nutritional support, and aggressive stoma care. Usually, closure will
occur within 6–8 weeks
2. Abscesses: (10%–20% of patients)
a. Abscesses are initially managed by percutaneous drainage
b. Surgical drainage is indicated if multiple abscesses are present or when located
between small bowel loops
VII. Diagnostic Tests

A. All currently available diagnostic modalities have advantages, disadvantages, and limitations
B. In modern trauma centers in the 21st century, better noninvasive technology favors the use of
ultrasound and CT in the evaluation of trauma victims
C. The test of choice depends on the hemodynamic stability of the patient and the severity of
associated injuries
D. A chest radiograph is a useful test to reveal:
1. Pneumoperitoneum
2. Abdominal contents in the chest (ruptured hemidiaphragm)
3. Lower rib fractures
E. An abdominal radiograph is a useful test (in blunt trauma) to identify:
1. Presence of free air (intraperitoneal air or trapped retroperitoneal air)
2. Fractures of thoracolumbar vertebral bodies, lower ribs, and pelvis
a. Transverse fracture of a vertebral body (ie, Chance fracture) suggests a higher
likelihood of significant blunt injury to the bowel
3. Radiopaque foreign bodies (e.g., bullets, shrapnel)
F. Abdominal Ultrasonography (see Table 1)
1. The objective of ultrasound evaluation is to search for free intraperitoneal fluid and
hemoperitoneum
2. Also helpful in identifying dilated bowel loops secondary to ileus or obstruction
3. Sensitivity in adults for identifying bowel injury ranges from 85%–99%, with specificity
97%–100%
a. No further workup needed after negative ultrasound in stable patient
b. Variably low sensitivity in children suggests that it should not be used to exclude
intraabdominal injury
G. Computed Tomography of Abdomen (see Tables 2, 3 and 4)
1. CT is the preferred and most frequently used method for evaluation of blunt abdominal
trauma in the hemodynamically stable patient, as well as in selected instances of
penetrating trauma to the posterior abdomen
2. Use of oral contrast in children with potential bowel perforation is controversial, because
false-negative scans are common
3. Retroperitoneum is best evaluated by CT
4. Accuracy of CT in evaluation of bowel injury is 82%, with sensitivity of 64% and
specificity of 97%
5. Usually, the presence of free abdominal fluid on CT without solid organ injury should
raise suspicion for mesenteric, intestinal, or bladder injury, and exploratory laparotomy is
often warranted
a. Extravasation of contrast material is an absolute indication for laparotomy or,
more recently, angiography and embolization
H. Diagnostic Peritoneal Lavage (DPL) (see Table 5)
1. DPL is a rapid and accurate test used to identify intraabdominal injuries after blunt
trauma in a hypotensive or unresponsive patient without obvious indication for
abdominal exploration
2. DPL is highly sensitive to the presence of intraperitoneal blood; however, its specificity is
low
3. Overall, DPL is not a reliable test to identify small bowel injuries, particularly small injuries
with minimal leakage
4. Disadvantages of DPL:
a. Invasiveness
b. Significant injuries, including diaphragmatic tears and retroperitoneal
hematomas; duodenal, minor intestinal, renal, and pancreatic injuries may be
under diagnosed by DPL alone
c. Low accuracy in the diagnosis of hollow viscous injuries
d. DPL results can be misleading in the presence of a pelvic fracture
e. Low to moderate specificity, and because positive DPL findings prompt surgical
exploration (therapeutic laparotomy), a significant number of explorations will
be nontherapeutic
I. Focused Assessment Sonography for Trauma (FAST)
1. Noninvasive, and takes less time than DPL
2. High sensitivity (up to 100%) for detecting intraperitoneal fluid, which accumulates in
dependent areas around the liver, spleen, and pouch of Douglas
J. Angiography
1. The only role of angiography in acute bowel trauma is to identify the site of visceral
bleeding
2. It is also used to evaluate renal artery thrombosis, manage pelvic hemorrhage in patients
with pelvic fractures, and bleeding from minor hepatic and splenic injuries
K. Laparoscopy (see Table 6)
1. The use of diagnostic laparoscopy in blunt trauma patients is very limited. It is an
invasive and expensive method, and does not seem to be superior to other methods,
with reported missed small bowel, splenic, and retroperitoneal injuries
a. Laparoscopy is the best method for evaluating diaphragmatic injuries after
thoracoabdominal penetrating injuries

Table 1. Advantages and Disadvantages of Ultrasound
Advantages Disadvantages
Noninvasive Examiner dependent
Low cost Obesity
Can be repeated Gas interposition
Does not require radiation Lower sensitivity for free fluid <500 mL
Useful in the emergency department False negatives: Retroperitoneal and hollow viscous injuries
Patients unstable hemodynamically to undergo CT scan
Table 2. Indications and Contraindications for Abdominal Computed Tomography

Indications Contraindications
Blunt trauma Clear indication for exploratory laparotomy
Hemodynamic stability Hemodynamic instability
Normal or unreliable physical examination Agitation
Mechanisms causative of duodenal and pancreatic trauma Allergy to contrast media
Table 3. Advantages and Disadvantages of Abdominal Computed Tomography

Advantages Disadvantages
Noninvasive Expensive
Adequate assessment of the retroperitoneum Time (need to transport the patient to the radiology
The most sensitive and specific study to identify and assess department)
solid organ injuries (liver and spleen) Specialized personnel and equipment required
Assessment of renal perfusion Hardware
High specificity Limited in evaluation of hollow viscous injuries
Table 4. Abdominal CT Findings in Abdominal Trauma

Type of Injury Findings
Bowel injury Oral contrast extravasation indicating bowel wall
disruption (the most specific finding). Free intraperitoneal/
retroperitoneal air
Free intraperitoneal/retroperitoneal fluid
Intramural air
Focal areas of bowel wall thickening
Abnormal bowel wall enhancement
Bowel wall hematoma (i.e., duodenal hematoma
Mesenteric vascular injury Diffuse bowel wall thickening
Diffuse bowel wall enhancement
Mesenteric infiltration
Mesenteric hematoma
Table 5. Indications and Contraindications for DPL
Indications Contraindications
• Equivocal physical examination Clear indication for exploratory laparotomy
• Unexplained shock or hypotension Previous exploratory laparotomya
• Altered sensorium and obtunded or intoxicated patients Pregnancya
(closed head injury, drugs, etc.) Obesitya
• Patients with potential intraabdominal injury who
will undergo general anesthesia for extraabdominal
procedures
• Spinal cord injury
Relative contraindications
a
Table 6. Indications for Laparotomy: Abdominal Injury

Blunt Injuries Penetrating Injuries
• ontinued hemodynamic instability despite resuscitation
C • Most gunshot wounds
• Signs of continuing hemorrhage • Selective operation for stab wounds with:
• Need for blood replacement o Hypotension
• Pneumoperitoneum or hemoperitoneum o Unexplained blood loss
• Physical signs of peritoneal irritation o Evisceration
• Signs of significant injury to the intestine, pancreas, o Physical signs of peritoneal irritation
bladder, ureter, renal vasculature, or rectum o Signs of significant amounts of blood or intestinal
contents on peritoneal lavage or CT
Recommended Reading
Cheng AB, Testa PA, Legome EL, Kaplan LJ. Penetrating Abdominal Trauma in Emergency Medicine: Differential Diagnoses &
Workup. Available at http://emedicine.medscape.com/article/822099-diagnosis. Updated April 21, 2010.
Dayan PS, Klein BL. Acute care of the victim of multiple trauma. In: Behrman RE, ed. Nelson Textbook of Pediatrics. 18th ed.
Pennsylvania, PA: Elsevier; 2008.
Radwan MM, Abu-Zidan FM. Focused Assessment Sonograph Trauma (FAST) and CT scan in blunt abdominal trauma:
surgeon’s perspective. Afr Health Sci. 2006;6(3):187-190.
Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL. Sabiston Textbook of Surgery. 18th ed. Pennsylvania, PA: Elsevier;
2008: Chapter 20.
Uppot RN, Wills JS, Gheyi VK, . Bowel Trauma. Available at http://emedicine.medscape.com/article/364264-overview. Updated
May 27, 2009.

3P. Short Bowel Syndrome:
Intestinal Failure
Molly Dienhart, MD
I. Definition: Anatomical as well as functional

A. Short bowel syndrome is the most common cause of intestinal failure
1. Loss of intestinal length or competence below the minimal amount necessary
to maintain normal digestion and absorption of nutrients and fluids required for
maintenance in adults or for growth in children
B. More simply, it has also been defined as the need for parenteral nutrition
II. Etiologies
A. Congenital malformations—gastroschisis, malrotation with volvulus, atresias, omphalocele, or
aganglionosis
B. Necrotizing enterocolitis
C. In older children: malrotation, trauma, and intraabdominal neoplasia
III. Goal of Therapy

The goal of therapy is to achieve intestinal adaptation, weight gain, and linear growth, with maximal
enteral nutrition and minimal parenteral support
IV. Bowel Adaptation

A. Process by which the function of the remaining bowel gradually improves
B. Begins within 1–2 days after surgery
1. Continues for up to 2–5 years
C. Involves the development of increased surface area through a combination of hyperplasia,
dilatation, and elongation
1. Hyperplasia involves increased crypt cell production, crypt depth, and lengthening of
villi, as well as increased number of transporters per cell, with a subsequent increase in
enzyme activity
2. This leads to increased absorption of nutrients and electrolytes per unit of bowel length
V. Enteral Feeds
A. The most potent stimulus for intestinal adaptation, as they provide fuel for enterocytes
1. In the absence of enteral feeds, mucosal hypoplasia will occur
B. More complex nutrients (i.e., intact proteins and long-chain triglycerides vs free amino acids and
MCTs) are more effective at stimulating cellular hyperplasia
C. Enteral tolerance continues to improve for up to 2–5 years following resection
D. Stimulate the normal physiologic flow of intestinal secretions as well as peristalsis, which may
help decrease the risk of small bowel bacterial overgrowth
VI. Anatomic Considerations

A. The impact of short bowel syndrome is related not only to the length, but also the location of
the lost bowel
1. Secretion and absorption of fluids are in complicated balance in the normal human GI
tract, and the loss of a section of bowel will disrupt this balance and likewise the absorp-
tion of nutrients
B. Proximal Loss
1. Loss of the most proximal portion of the small intestine is actually generally well
tolerated
2. Depending on the exact location of loss, there is potential for increased acidity of
secretions due to decreased bicarbonate secretion
3. Biliary and pancreatic secretions may be impaired, and the absorption of iron may need
to be considered

C. Distal Loss
1. The distal small bowel has a larger effect on nutrient absorption, with the distal ileum
having more of an impact than the proximal jejunum
a. Distal ileum is more specialized and can have greater consequences
b. Sole segment for active reabsorption of bile salts
1) Compensatory increase in bile acid production is commonly inadequate
2) Decrease in bile salt concentration leads to fat malabsorption and fat-
soluble vitamin deficiency
c. Subsequent increase in colonic fluid loss:
1) LCFA and BA in the colon act as a stimulus for colonic water secretion
2) Digestion of LCFA by colonic bacteria stimulates further colonic electrolyte
loss
d. Loss of the ileal brake—decreases exposure time of the luminal contents to the
mucosal surface and further impairs absorption
e. Absorption of vitamin B12 will also be impaired
2. Colon
a. The colon serves to reabsorb water (10%–15% of total water absorption) and
electrolytes, as well as short-chain fatty acids, which are salvaged from starches
and soluble fibers that pass into the colon
b. In the absence of the colon, one has increased loss of intestinal fluid, which can
in some cases result in ongoing need for additional fluid supplementation
c. The salvage function of the colon is amplified in importance in the setting of a
significant loss of small bowel
VII. Function
A. A major factor which contributes to one’s ability to adapt and tolerate enteral nutrition
B. Initial insult can affect function
1. e.g., gastroschisis
2. Early prenatal insults resulting in obstruction, leading to longstanding dilatation of the
more proximal bowel
3. Prolonged decreased perfusion
VIII. Time of Injury

A. The intestine doubles in length during the 3rd trimester of gestation, and continues to grow in
early childhood
1. Subsequently, an infant, and potentially a premature infant, has a greater capacity for
growth following injury than would an older child or adult
B. The greatest capacity for normal intestinal growth is in the first 3–4 years of life, making this the
most opportunistic window for adaptation to occur
C. Furthermore, the ability of portions of the GI tract to adapt and take on additional functions of
the lost portions of bowel is increased in younger patients
IX. Length of Residual Bowel

A. Residual bowel length has been shown to be a predictor of mortality and also of independence
from parenteral nutrition
B. Greater than 10% of predicted small bowel length
1. Decreased mortality
2. Increased probability of weaning from parenteral nutrition support
C. The expected small bowel length is again determined by age:
1. 19–27 weeks of gestation ~115 cm
2. 27–35 weeks ~172 cm
3. >35 weeks ~240 cm
4. Final length averaging between 400 and 700 cm
D. This is also strongly influenced by the presence or absence of the colon, as well as by the pres-
ence of the ileocecal valve
1. It has been shown in studies with adults and older children that the tolerable length of
small bowel decreases as the colon length increases
X. Management
A. Early in the postoperative period, focus is on fluid and electrolyte management to account for
intestinal losses
1. High enterostomy: losses may be significant even in the absence of enteral feedings,
given the high secretory function of the proximal GI tract. Can be exacerbated by gastric
hypersecretion (up to 30–50 mL/kg/day)
B. Loss of the normal hormonal feedback loop occurs with loss of bowel
1. This results in hypergastrinemia, which in turn leads to gastric acid hypersecretion
a. The low duodenal pH results in decreased pancreatic enzyme activity and precipi-
tation of bile acids, which impairs micelle formation and fat absorption and can
damage the proximal small bowel
1) Excess fluid secretion contributes to a secretory diarrhea
2) Generally resolves after 6–12 months, but can last longer
3) The use of acid-blocking medications can help to moderate this effect
b. Proximal intestinal losses have a high concentration of sodium and chloride,
which need to be adequately replaced to prevent electrolyte imbalances
c. The longer the small bowel, the more potential for continued reabsorption of
fluid and electrolytes
1) Patients with shortened small bowel that is in continuity with part or all
of the colon are at much lower risk of such high fluid losses, as there is
potential for reabsorption of fluid and electrolytes in the colon
2) Relatively more potassium and bicarbonate and less sodium and chloride
are needed in patients with some colon
XI. Enteral Feeding

A. Initiation of enteral feedings can begin once bowel function has started, following the initial
surgical intervention
B. Consideration must be given to carbohydrate, protein, and fat choice
C. More complex substances have the potential to be a better stimulus for the developing
enterocytes; however, in patients who have sustained mucosal damage, these complex
substances may be harder to digest and absorb
1. Elemental formulas are less likely to cause increased hypersensitivity
2. Long-chain triglycerides are a potent stimulus if cholestasis exists; may be harder to
absorb
D. Generally, enteral feeds are initially delivered to the stomach via continuous drip
1. Decrease the risk of increased gastric emptying and subsequent rapid transit of nutrients
through the already shortened GI tract
a. In patients with poor gastric emptying, or those at high risk of reflux/aspiration
or proximal duodenal motility problems, jejunal feedings can be beneficial
2. Allows for the constant saturation of nutrient receptors to aid in adaptation
E. Enteral nutrition choice is also influenced by the amount and location of the GI tract that remains
intact
1. If there is a substantial portion of small intestine intact, either as an end ileostomy or
with a short rectosigmoid segment, there are little lipid restrictions and LCT can be used
a. Soluble fibers will help increase the viscosity and slow gastric emptying
b. These patients can also be maintained on high-dose antimotility or antisecretory
agents, but will typically need significant fluid and sodium provision/replacement
2. Patients who have short segment small bowel and all or most of the colon intact will
often benefit from a combination of MCT and LCT
a. Soluble fibers not only increase viscosity and slow gastric emptying, but also are a
source of short-chain fatty acid calorie salvage in the colon
b. These patients are more likely to require increased potassium and bicarbonate
provision
3. MCT are less likely to stimulate colonic salt and water secretion than malabsorbed LCTs
4. Because production of SCFAs occurs in the colon, patients with a colon are more likely
to benefit from the addition of complex carbohydrates and soluble fibers (cereals, un-
sweetened fruits, and lean meats)

F. Advancement of feeds should result in weight gain and growth of the patient. As growth is
achieved, parenteral support is weaned
1. Degree of parenteral weaning will be a lesser caloric quantity than the concomitant
enteral increase to account for malabsorption
a. Absorption can range from 30%–70% of what is ingested, and this needs to be
accounted for in calculation of needs
b. Will depend on how much and what bowel exists
2. Reducing parenteral nutrition is based on estimates of enteral absorption as evidenced
by weight gain, hydration status, stool output, physical exam (skin), and laboratory
studies, including albumin
3. In addition to caloric supplementation, one must consider electrolytes, vitamins, and
trace elements
a. With colon: potassium and bicarbonate supplementation
b. Without colon: zinc, magnesium, and sodium
c. Lack of terminal ileum: fat-soluble vitamins and B12
XII. Pharmacologic Therapy

A. Acid blockade: decrease the water and sodium losses related to secretory diarrhea associated
with gastric hypersecretion
1. Acid duodenal pH can also interfere with pancreatic enzyme activity and micelle
formation
B. Imodium: peripheral opioid analogue that inhibits small bowel and colonic motility, and thereby
improves fluid absorption and decreases fluid loss through stool
C. Bile acid–binding resins: can be used in patients who have had a limited ileal resection
1. Modulates increased BA colonic load in those who have a colon, to reduce secretory
diarrhea
D. Motility agents: to enhance gastric or small bowel motility
1. Erythromycin (primarily acts in antrum of the stomach)
2. Amoxicillin-clavulanate (action in small bowel)
3. Antibiotics for bacterial overgrowth:
a. Metronidazole, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate,
ciprofloxacin
E. GLP-2: A new potential therapy for patients with short bowel syndrome, as it has been shown to
improve energy absorption and lean body mass
1. Studies with this therapy are ongoing
F. Zinc: Losses can be significant, 12 mg/dL in ostomy, 17 mg/dL in diarrhea
1. Vicious cycle in that zinc depletion leads to diarrhea and also to impaired wound healing
XIII. Surgical Therapy

A. Indications for pursuing surgical options include:
1. Recurrent bacteremia, dilated bowel, or SBBO that is not responding to therapy
2. Options: longitudinal tapering procedures, longitudinal lengthening procedures, and
ostomy takedowns to re-establish intestinal continuity
3. Bowel transplant is an option in some centers
B. The goals of surgery include continuity, improvement in motility, prolongation of transit time, and
enhancement of the mucosal surface area
1. Tapering procedures can help, but have the increased risk of losing more potential
surface area, and often need to be repeated
2. Lengthening procedures not only decrease the caliber of the bowel, hopefully allowing
for better motility and decreased risk of bacterial overgrowth, but also have the benefit
of increasing the surface area available for absorption of nutrients
C. Preexisting liver disease increases mortality, and is now a contraindication
XIV. Other Considerations

A. Tube feeds: oral feeding skills, timing of feeds (day feeds—development; night feeds—increased
night stooling)
B. PN: cycling as tolerated
1. Some protected effect toward the liver
2. Allows for some time that child is not connected to an infusion
XV. Complications of SBS and Parenteral Nutrition
A. Cholestatic liver disease
1. Multifactorial, and its development has been associated with: shorter remaining bowel,
longer need for PN, lack of enteral feedings, recurrent catheter associated infections, or
sepsis and prematurity
B. Calcium bilirubinate stones, leading to chronic cholecystitis
1. Risk factors: duration of PN, lack of enteral feeds and the potential decrease in
enterohepatic circulation of bile acids secondary to intestinal loss
C. Catheter-related complications are an important concern, including:
1. Infection, thrombus formation, and occlusion
2. Sepsis is the leading cause of death in patients with intestinal failure
3. Loss of central venous access secondary to thrombotic occlusion of all vessels can only
be treated with intestinal transplant to end the need for PN
D. Small bowel bacterial overgrowth
E. Enterocolitis
F. Pancreatitis and renal disease
G. Bowel obstruction: anatomical (secondary to stricture or adhesions) or functional (related to
motility or dysmotility through dilated sections of bowel)
1. Challenges to advancement of enteral feeds, and therefore prolongation of PN
2. Medical therapy is used to treat bacterial overgrowth and improve motility
3. If progression of feeding continues to be impeded, surgical options must be considered
XVI. Outcomes
A. Overall survival for patients with SBS is ~85%
B. 70%–80% survive without the need for long-term PN
C. For those on long-term PN, survival rate is ~50%
D. Extreme short bowel, progressive liver disease, and recurrent bacteremia increase the mortality of
these patients, and also exacerbate each other:
1. Those with recurrent infections are at increased risk of severe liver disease
2. Those with severe liver disease are more likely to succumb to sepsis
3. Intestinal transplantation is sometimes the only option for some of these patients
a. With low likelihood of achieving end of PN support and high subsequent risk
of developing liver disease, combined intestinal and liver transplantation is
sometimes indicated
4. Progression to Stage 3 or 4 fibrosis is not generally considered to be reversible
a. Isolated liver transplantation for patients who have been able to tolerate at least
half of their estimated needs enterally but have not seen an improvement in liver
disease
5. Presumption that transplantation results in improvement of liver disease and subsequent
increased tolerance of enteral feeds
Recommended Reading
Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with
short bowel syndrome correlates with clinical outcomes. J Pediatr. 2001;139:27-33.
Quirós-Tejeira RE, Ament ME, Reyen L, et al. Long-term parenteral nutritional support and intestinal adapta-
tion in children with short bowel syndrome: a 25-year experience. J Pediatr. 2004;;145(2):157-163.
Touloukian GJ, Smith GJW. Normal intestinal length in preterm infants. J Ped Surg. 1983;18(6):720-723.
Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders Elsevier;
2006: Chapter 34.

3Q. Small Bowel
Bacterial Overgrowth
Melissa Kennedy, MD
Maria Mascarenhas, MD
A. Small Bowel Bacterial Overgrowth (SBBO)
B. Definition: abnormally high bacterial counts in proximal small bowel (>105 colony-forming units
of bacteria per mL of luminal aspirate)
C. Increased number of bacteria in the small intestine leads to nutrient malabsorption
D. Most common disorders associated with SBBO: short bowel syndrome, intestinal dysmotility
syndromes, and chronic pancreatitis
E. SBBO also associated with inflammatory bowel disease, intestinal fistula, bowel surgery of any
kind, immunodeficiencies, liver disease, cystic fibrosis, and hypochloridia associated with proton
pump inhibitor use
1. Possible association with irritable bowel syndrome and children with chronic abdominal
pain.
II. Pathogenesis
A. Distribution and concentration of bacterial flora in the GI tract of a healthy child:
1. Stomach and proximal small bowel: few bacteria, <104 CFU/mL of jejunal contents,
primarily lactobacilli and Gram-positive aerobes (staphylococci and streptococci)
2. Terminal ileum: transitional zone between aerobic flora in stomach and small bowel, and
anaerobes in colon, 108 –1010 CFU/mL, primarily Bacteroides, Bifidobacterium,
Clostridium, and Coliforms
3. Colon: Mainly anaerobes, 1011–1012 CFU/mL, primarily Bacteroides, Bifidobacterium,
Clostridium and Enterococci
B. Physiologic mechanisms preventing SBBO: antegrade peristalsis, presence of gastric acid and bile,
digestion by proteolytic enzymes in the small intestine, intestinal mucous layer, ileocecal valve,
intact immunity
1. SBBO develops when host defenses are compromised by related conditions
2. In general, SBBO involves multiple organisms in varying numbers. Common species are
streptococci, Bacteroides, E coli, and Lactobacillus
C. SBBO can lead to mucosal inflammation and villous atrophy
1. Light microscopy of small intestinal biopsies can show villous atrophy, increased cellular-
ity in lamina propria
D. Ulceration and erosions can occur
E. Gram-negative bacteria produce endotoxins, which activate inflammatory cytokines, which in
turn can alter the function of hepatocyte transporters and cause jaundice and liver injury
F. Malabsorption
1. Fat malabsorption as bacteria deconjugate bile acids
2. Steatorrhea and deficiency of fat-soluble vitamins A, D, E, and K
3. Carbohydrate malabsorption occurs as bacteria ferment carbohydrates
a. Bacteria decrease enterocyte disaccharidase and brush border hydrolase activity
b. Malabsorbed carbohydrate can be fermented by bacteria to excessive amounts
of D-lactate
c. D-lactate encephalopathy and D-lactic acidosis can occur
4. Protein malabsorption can occur with decreased uptake of amino acids and bacterial
degradation of protein precursors
a. Bacteria degrade protein and urea into ammonia
b. Elevated ammonia levels can lead to encephalopathy
5. Anaerobic bacteria utilize vitamin B12, SBBO can lead to B12 deficiency

A. Can be asymptomatic
B. Symptoms can include diarrhea, steatorrhea, hematochezia, abdominal pain, bloating, cramping,
anemia, weight loss, feeding intolerance, dyspepsia, and flatulence
C. Severe cases can present with unexplained acidosis, tetany (secondary to vitamin D deficient
hypocalcemia), night blindness (vitamin A deficiency), dermatitis, arthritis, and hepatic injury
D. Other clinical signs and symptoms can include neuropathy from cobalamin (B12) deficiency,
macrocytic anemia (B12 deficiency), microcytic anemia (bleeding ulcers), metabolic bone disease,
or episodic ataxia and delirium with carbohydrate ingestion secondary to D-lactic acidosis
E. Additional physical exam findings may include scarring from previous surgery, abdominal
distention, and borborygmi
IV. Diagnosis
A. Diagnosis often made based on presenting symptoms, as currently available diagnostic tests can
be invasive and may be inaccurate
B. Laboratory evaluation:
1. Macrocytic anemia (B12 deficiency)
2. Fat soluble vitamin deficiency (A, D, and E). Vitamin K less often deficient, as bacteria
produce Vitamin K
3. Hypocalcemia (secondary to Vitamin D deficiency)
4. Microcytic anemia (secondary to bleeding intestinal ulcers)
5. D-lactic acidosis (secondary to D-lactate production by bacteria)
a. D-lactate is normally undetectable, and acidosis should be considered at D-lac-
tate concentrations in excess of 3 mmol/L
6. Elevated liver enzymes or cholestasis
C. Diagnostic tests
1. Aspiration and culture of duodeno-jejunal fluid:
a. Current gold standard
b. Bacterial counts >105 CFU/mL in the proximal small intestine are diagnostic
c. Test is invasive, subject to contamination by oropharyngeal bacteria, and SBBO
can be patchy and therefore missed by single aspiration. Also, it is difficult to
grow anaerobic bacteria unless sample is collected under research conditions
2. Breath hydrogen tests
a. Breath hydrogen produced by bacterial fermentation and measured after
ingestion of a carbohydrate substrate
b. Sensitive and less invasive
c. D-glucose is preferred substrate, as lactose and lactulose are poorly absorbed in
children and less likely to give false positive from disaccharidase deficiency
d. Test considered positive if: baseline exhaled fasting breath hydrogen is 20 parts
per million or greater, or exhaled levels increase by more than 10 ppm over
fasting level
e. Early peak within one hour of test carbohydrate is diagnostic
f. Decreased motility may lead to false negatives, and rapid gastric and intestinal
emptying may lead to false positives
g. Coadministration of intestinal transit markers in combination with scintigraphy
increases specificity
A. Empiric treatment with antibiotics often given to patients with clinical picture of small bowel
bacterial overgrowth
1. Lack of clinical trials in children, and no specific approved therapy
B. Involves suppression of strict and facultative anaerobes, with goal to reduce, not eradicate, the
flora
C. Rifaximin, a nonabsorbable antibiotic is the current antibiotic of choice is generally given for a
7–10 day course
1. Other antibiotic choices include metronidazole, neomycin, or amoxicillin/clavulanic acid
D. Probiotics may be useful in prevention of SBBO, or immediately following antibiotics in recalci-
trant SBBO
1. Probiotics should be used with caution in patients with central lines, as there have been
reports of bacteremia
2. More research is needed to investigate the risks, benefits, and efficacy of probiotic
therapy
E. Treatment of underlying disorder, such as prokinetics in motility disorders and surgical bowel
lengthening in short bowel syndrome
VI. Differential Diagnosis

A. Celiac disease
B. Lactose intolerance
C. Functional abdominal pain
D. Irritable bowel syndrome
E. Constipation
F. Malabsorption
G. Intestinal pseudo-obstruction
H. Giardiasis
I. Intestinal motility disorders
Recommended Reading
Cole C, Ziegler T. Small bowel bacterial overgrowth: a negative factor in gut adaptation in pediatric SBS. Curr
Gastroenterol Rep. 2007;9:456-462.
de Boisseu D. Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain, or both. J
Pediatrics. 1995;128(2):203-207.
Collins BS, Lin H. Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial
overgrowth in children with chronic abdominal pain. J Pediatr Gastroenterol Nutr. 2011;52(4):382-386.
Stoidis CN, Misiakos EP, Patapis P, Fotiadis CI, Spyropoulos BG. Potential benefits of pro and prebiotics on
intestinal mucosal immunity and intestinal barrier in short bowel syndrome. Nutr Res Rev. 2010;21:1-9.

3R. Small Bowel
Transplantation
Cheryl A. Little, MD
I. Intestinal Failure Definition

A. Inability to maintain protein, energy, fluid, electrolyte, and/or micronutrient balance due to GI
disease when on a normal diet
B. Intestinal failure produces malnutrition, and even death, if the patient does not receive parenteral
nutrition or an intestinal transplant
C. Leading cause of intestinal failure is short bowel syndrome caused by surgical resection
II. Diseases in Which Small Bowel Transplantation is Performed

A. Short bowel syndrome
1. Volvulus
2. Gastroschisis/ruptured omphalocele
3. Trauma
4. Necrotizing enterocolitis
5. Ischemia (mesenteric thrombosis)
6. Crohn disease
7. Intestinal atresia
B. Malabsorption (mucosal defect)
1. Microvillus inclusion disease
2. Secretory diarrhea
3. Autoimmune enteritis
C. Motility disorder
1. Pseudo-obstruction
2. Total intestinal aganglionosis
3. Hirschsprung’s disease (long-segment)
D. Desmoid tumors of the intestine
E. Multiple polyposis syndromes with malignant potential
F. Extensive radiation enteritis
III. Indications for Small Bowel Transplantation

A. Anatomic or functional diseases that preclude enteral feeding plus failure of parenteral nutrition
due to:
1. Lack of vascular access
2. Life-threatening complications of parenteral nutrition
a. Liver injury
b. Recurrent infections
c. Frequent severe dehydration despite supplementing IVN with extra fluid
B. High risk of death
C. Severe short bowel syndrome: residual small bowel <10 cm in infants or <20 cm in adults
D. Intestinal failure with frequent hospitalizations, narcotic dependency, or pseudo-obstruction
E. Patient unwillingness to accept long-term parenteral nutrition
IV. Contraindications to Intestinal Transplantation

A. Contraindications to intestinal transplantation are similar to those for other types of transplants
1. Active infection such as pneumonia, sepsis, or fungal infection in recipient
2. Significant coexistent conditions in the recipient with no potential for improvement after
transplantation
3. Uncontrolled infection or malignancy in the recipient that is not eliminated by transplant
4. Psychosocial factors
a. Lack of capacity to assume management after transplant
b. Absence of family support

V. Types of Small Bowel Transplantation
A. Three basic transplant procedures
1. Isolated intestinal transplant: transplantation of jejunoileum alone
2. Composite liver: bowel transplant
a. Pancreas and duodenum included to facilitate en bloc engraftment and obviate
biliary reconstruction
b. Some centers report that combined liver-intestine transplantation has lower
incidence and severity of acute rejection than isolated intestinal transplantation
3. Multivisceral transplant: Composite visceral or multi-organ transplant
When the small intestine (jejunoileum) is transplanted alone, it is referred to as an
isolated intestinal transplant (Panel A), with systemic drainage to the vena cava. A
composite liver and intestinal transplant usually includes the duodenum and an intact
biliary system and portal circulation, with the native foregut preserved (Panel B). In a
multivisceral transplant, which involves the liver, stomach, duodenum, pancreas, and
small intestine, the foregut is removed and a new stomach is transplanted (Panel C).
This type of transplant sometimes includes the colon, kidney, or both. The transplanted
organs are shown in light gray, and the native organs or structures are shown in darker
gray
A B C
Figure 1. Three types of transplants in intestinal failure
VI. Post-transplant Management

A. Induction therapy with monoclonal (alemtuzumab, basiliximab, daclizumab) or polyclonal (anti-
thymocyte globulin) antibody preparations often administered pre- or intraoperatively
B. Tacrolimus via enteric route and intravenous steroids begun immediately after surgery and
maintained at discharge
1. High levels of immunosuppression early in the postoperative period (tacrolimus levels,
20–25 ng/mL)
2. Mycophenolate mofetil avoided because of GI side effects
3. Sirolimus used in combination with tacrolimus by some programs
C. Broad-spectrum intravenous antibiotics administered for about 1 week after the transplant
D. Regular monitoring for evidence of bleeding
E. Monitor serum pH and lactate levels to detect intestinal ischemia
F. With return of GI function indicated by decreasing G-tube returns and increasing gas and enteric
contents in the ileostomy, feedings are advanced as tolerated
G. No-fat or low-fat diet used to avoid chylous ascites, a consequence of loss of graft lymphatic
drainage during procurement
H. Antiviral prophylaxis with ganciclovir and/or cytomegalovirus (CMV) immunoglobulin (CytoGam)
I. Monitor regularly for:
1. CMV antigenemia
2. Epstein-Barr virus by polymerase chain reaction
3. Routine bacterial culture
4. Ileostomal endoscopy and biopsy of graft for diagnosis of infection or rejection
J. Monitor fluid status, stool losses, and serum electrolytes
VII. Complications
A. Surgical complications
1. Graft thrombosis
2. Graft ischemia
3. Technical failure
B. Graft rejection can occur any time, but is most common in the first 6–12 months
1. No reliable serum marker for intestinal rejection
2. Diagnosis based on multiple parameters, the three most important of which are:
a. Clinical course
1) Increased stomal output (>40–60 cc/kg/day)
2) Bloody stoma output
3) Cyanotic or congested ileal stoma
4) Clinical signs and symptoms
i. Abdominal pain/distention
ii. Cramping
iii. Decreased stoma output
iv. Signs of intestinal obstruction
v. Mild fever, leukocytosis, and pronounced bandemia
vi. Acidosis
b. Endoscopic appearance of the allograft
1) Diagnosis can be difficult because of patchy findings and presence of
bleeding
2) Endoscopy should be as extensive as possible, with numerous biopsies
3) Inflammation and ulceration are typical, but graft may appear normal in
early rejection
c. Histology of biopsy specimens
1) Mucosal necrosis and loss of villous architecture, with transmural
cellular infiltrate
2) Crypt cell apoptosis, cryptitis or crypt loss, necrosis, and endotheliitis
3. Treatment
a. Intravenous bolus of methylprednisolone (10 mg/kg), followed by steroid cycle
and optimization of tacrolimus serum level
b. Antithymocyte globulin or muromonab for steroid-resistant rejection
4. If the graft includes other organs, monitor serum markers for rejection of those organs
a. Liver: transaminases, GGT
b. Kidney: serum creatinine
c. Pancreas: amylase and lipase
5. 50% of intestinal rejection episodes occur without rejection of other transplanted
organs
C. Infection
1. Bacteria from the intestinal graft infect via two routes
a. The lymphatics divided in procurement may leak infected lymph into peritoneal
cavity, causing peritonitis
b. Direct bacterial translocation into portal circulation, with dissemination to other
sites
c. Most common organisms include Escherichia coli, Klebsiella, Enterobacter,
staphylococci and Enterococcus
d. Pneumocystis carinii prophylaxis required
2. Viral
a. CMV infection reported in 15%–30% of patients with intestinal grafts
1) CMV can cause loss of transplanted organ and death
2) Incidence of CMV disease highest in CMV-negative recipient with CMV-
positive graft
3) CMV enteritis usually presents with fever, increased stoma output, GI
symptoms, decreased WBC count, and flu-like symptoms
4) CMV DNA by quantitative PCR
5) Endoscopic findings: superficial ulcers and CMV inclusion bodies

6) Treat CMV infection
i. Ganciclovir and CMV immunoglobulin (CytoGam)
ii. Immunosuppression should be reduced until the CMV infection is
controlled, but should not be discontinued, to avoid breakthrough
rejection
b. Epstein-Barr virus (EBV)
1) Highest risk in EBV-negative recipient with EBV-positive graft
2) Acute EBV virus infection typically associated with severe malaise and
fever, flu-like symptoms, increase of liver function tests, splenomegaly, and
lymphadenopathy
c. Adenovirus
d. Rotovirus, norovirus, and enterovirus may produce severe malabsorption and inflammation
in the transplanted intestine
3. Fungal
D. Post-transplantation Lymphoproliferative Disorder (PTLD)
1. More common in intestinal transplant than other solid organ transplant
a. Incidence higher after multivisceral transplantation than isolated intestinal transplantation
b. Pediatric patients and EBV antibody-negative adult patients are at the highest risk
2. Usually presents 2–6 months after transplant, but can appear at any time
3. Begin surveillance for PTLD immediately after transplant using EBV polymerase chain reaction (PCR)
4. Two approaches to prevent PTLD
a. Prophylaxis with ganciclovir or intravenous immunoglobulin for 3–12 months
b. Prophylaxis for 2–6 weeks, followed by surveillance and preemptive therapy, should
surveillance identify increased EBV replication
5. Initial treatment
a. Reducing immunosuppression by about 50% relieves PTLD in about 1/3 of cases
b. If improvement not evident after two weeks, discontinue all immunosuppression and
consider possible additional therapeutics
1) Chemotherapy
2) Monoclonal antibody administration
3) Adoptive immunotherapy
4) Intestine-only graft can be removed
E. Graft vs host disease
1. The small intestine is an immunocompetent organ; its population of lymphoid cells can mount an
immunologic response to the host (see graft vs host disease)
F. Graft dysfunction/malabsorption
1. Common symptom is diarrhea
a. Carbohydrate and amino acid absorptive capacity of the transplanted intestine normalize
within the first several months
b. Fat absorption is impaired for several months following intestinal transplantation
2. Eosinophilic gastroenteritis likely secondary to food allergies
3. Vitamin B12 deficiency occurs when reduced intestinal allografts are taken from adult donors for
children, or when the abdomen will not close without distal intestinal resection
VIII. Outcomes
A. The 1-year graft survival for recipients of intestinal and multi-organ transplants in North America increased
from 52% in 1997 to 75% in 2005
B. The 1-year rate of patient survival improved from 57% in 1997 to 80% in 2005
C. Rates of patient survival at 3 and 5 years for transplantations performed between 1997 and 2000 have
remained modest at 61% and 47%, respectively
Recommended Reading
Fishbein T. Intestinal transplantation. N Engl J Med. 2009;361:998-1008.
Greenstein S. Intestinal Transplantation. Available at emedicine.medscape.com. Accessed January 1, 2009.
3S. Small Bowel Tumors
Anas Bitar, MD
I. Small Intestinal Polyps and Polyposis (See Polyp Chapter)

A. Polyp types: Common conditions in which polyps occur within the small intestine are
summarized in Table 1.
1. Epithelial polyps: These are divided histologically into:
a. Neoplastic polyps: malignant carcinoma and benign adenoma (abnormal epithe-
lial growth with potential malignancy)
b. Non-neoplastic polyps: hamartomatous polyposis syndromes, hyperplastic polyps,
and inflammatory polyps
2. Non-epithelial polyps:
a. Submucosal leiomyoma
b. Lymphoid
c. Paraganglioma
d. Carcinoid tumor
e. Submucosal lipoma
f. Submucosal neurofibroma
g. Submucosal schwannoma
h. Ganglioneuroma
II. Small Intestinal Neoplasms

A. Small Intestinal Adenocarcinoma:
1. Very rare in children
2. Risk factors: familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, and small
bowel Crohn disease
3. Symptoms: GI bleeding and small bowel obstruction
4. Diagnosis:
a. Contrast studies remain the primary investigative tool
b. Capsule endoscopy may aid in the diagnosis
c. Biopsy (via upper endoscopy with small-bowel enteroscopy, retrograde ileoscopy,
or surgical enterotomy) and histopathological examination is the gold standard
B. Small Intestinal Lymphomas:
1. The predominant malignant tumor of the small intestine in childhood
2. The most common sites for primary extranodal non-Hodgkin’s lymphoma (NHL) in
children are: distal ileum, cecum, and appendix
3. Involvement of the GI tract with Hodgkin’s lymphoma is extremely rare
4. Male-to-female ratio 2:1 in children
5. Clinical features: abdominal pain, change in bowel habits, nausea and vomiting
6. Diagnosis: biopsy for histopathology, immunophenotype, and cytogenetics
7. Treatment: resection with associated mesentery and lymph nodes, and chemotherapy
C. Burkitt Lymphoma (BL)
1. Represents the majority of pediatric intestinal lymphomas (up to 75% of all intestinal
NHL)
2. Very aggressive B-cell lymphoma with high proliferation rate
a. Fatal within months if not treated
3. Terminal ileum and ileocecal regions are the most common sites of origin
4. Symptoms: abdominal pain due to intussusception and obstruction
5. Diagnosis: imaging and endoscopic studies (submucosal or mural lesion)
6. Endoscopic biopsies may only show nonspecific mucosal abnormalities

7. In endemic BL (equatorial Africa and Papua New Guinea), EBV genome is present in the
majority of neoplastic cells
8. Mandibular and CNS involvement are common in endemic BL
9. Prognosis: timely diagnosis followed by aggressive chemotherapy (methotrexate and
cytarabine) regimens cure ~90% of patients
D. Immunoproliferative Small Intestinal Disease (IPSID)
1. Endemic in the underdeveloped regions of the Mediterranean basin, Middle East, and
Far East
2. IPSID is considered a variant of MALT lymphoma, characterized by infiltration of the
small intestinal mucosa with a neoplastic population of marginal zone B cells
a. Characteristic plasma cells produce IgA heavy chain (alpha chain disease), which
can be detected in the serum
b. Campylobacter jejuni is a possible environmental cofactor (while H pylori is
associated with gastric MALT lymphoma)
c. Genetic predisposition has also been suggested
3. Symptoms: malabsorption, obstruction, protein-losing enteropathy, weight loss,
intermittent diarrhea, colicky abdominal pain, anemia, and clubbing of the fingers
4. Radiological findings: luminal and mural small intestinal disease (masses, irregular filling
defects, and wall thickening)
5. Endoscopy with biopsy is the diagnostic procedure of choice
a. Upper endoscopy shows thickening, erythema, and nodularity of the small
intestinal mucosa
6. Treatment: early antibiotics (tetracycline or metronidazole + tetracycline/ampicillin)
may induce remission. Advanced stages are treated with surgery and chemotherapy
(anthracycline-based combinations)
E. Intestinal T-Cell Lymphoma
1. Associated with Celiac disease (enteropathy-associated T-cell lymphoma [EATL])
2. Represent <5% of all GI lymphomas, but has very poor prognosis
3. Peak in late adult life
F. Large Cell Lymphoma
1. Diffuse large B-cell lymphoma (DLBCL) is the most common (30%) subtype of all NHL
(intestinal and nonintestinal)
2. Characterized by diffuse proliferation of large neoplastic B cells, that often destroys the
underlying architecture of the site of involvement
3. DLBCL is an aggressive (fast-growing) lymphoma
III. Mesenchymal Tumors

A. Smooth Muscle Tumors
1. Intestinal Leiomyomatosis
a. Much more common in the proximal gut (especially esophagus) than the small
and large intestine
2. Intestinal Leiomyosarcomas
a. Rare (0.3% of all neoplasms in children <15 years of age and 20% of all small
intestinal malignancies in some pediatric centers)
b. Often arises from the smooth muscle of the muscularis propria
c. Slight female predominance and slight preference for the distal small intestine
d. Nearly 50% of intestinal leiomyosarcoma occur during infancy
e. In general, metastatic disease is unusual in the pediatric population
f. Symptoms: bleeding, obstruction, intussusception, and perforation
g. Prognosis: relatively favorable with complete resection (5-year survival 40–50%)
B. Neural Tumors
a. These include benign ganglioneuromas, schwannomas/neuromas, neurofibromas
and granular cell tumors, as well as malignant peripheral nerve sheath neoplasms
1. Intestinal ganglioneuromas are the only type that may be encountered as polypoid
lesions
a. This benign tumor consists of a mixed proliferation of ganglion cells and various
glial elements
b. Sessile or pedunculated polyps may occur anywhere in the intestinal tract as:
1) Solitary ganglioneuromas are most likely incidental findings
2) Multiple or diffuse ganglioneuromas alert to the presence of underlying
syndrome (MEN2B, NF I, JPS and Cowden’s syndrome) or familial disease
2. Intestinal neurofibromas are less common
a. These neurofibromas consist of a proliferation of bland spindle cells with a
prominent collagenous stroma
b. Presence of plexiform neurofibroma or multiple neurofibromas raise the
possibility of underlying neurofibromatosis
3. Intestinal Schwannomas are very rare in children
a. Schwannomas constitute <3% of all small and large intestinal tumors
C. Vascular Tumors
1. Benign Hemangiomas
a. Intestinal hemangiomas are rare
b. Consist of proliferation of capillaries and/or other small intestinal vessels
c. Constitute the most common tumor of infancy in the Western population
d. Symptoms: GI bleeding and intussusceptions
2. Benign Lymphangiomas
a. Found in the mesenteric soft tissue of the small and large intestine
b. Symptoms: intestinal obstruction or intussusception
3. Malignant vascular tumors (angiosarcoma and Kaposi sarcoma) of GI tract
a. Very rare during childhood
b. Pediatric intestinal Kaposi Sarcoma (KS) is often associated with
immunosuppression and EBV infection
4. Lipomas
a. Benign intestinal lipomas are found primarily in the colon. but can also appear in
the small intestine

144
Table 1. Polyposis Syndromes Affecting Small Intestine in Children
Gene Clinical Features Diagnosis Pathology Cancer Risk Management & Surveillance
Adenomatous Syndromes
Familial APC ➘100s-1,000s colonic polyps - Colonoscopy: Adenomatous • Colon cancer 100% -Colonoscopy annually at age 10 years
Adenomatous ➘ Fundic gland polyps ≥100 polyps • Lifetime risk of duodenal -EGD q 3–4 years and annually if
Polyposis (FAP) ➘Duodenal, jejunal and ileal polyposis adenomatous (tubular, & periampullary polyps detected
➘CHRPE: congenital hypertrophy of retinal polyps tubulovillous malignancy 1%–5% -Chemoprevention (Celecoxib) has
pigment epithelium - Mutational and villous • Hepatoblastoma (0.7% been proposed as a treatment for
➘Osteomas analysis adenomas) of children <5 years old) duodenal polyposis
➘Nasopharyngeal angiofibroma • Thyroid, brain, -Annual a-fetoprotein and hepatic U/S
➘Dental abnormalities pancreatic cancers from infancy to 7 years
➘Lipomas, fibromas, epidermoid cysts • Desmoid tumors (lifetime Surgical Treatment:
risk 15%–21%) -Subtotal colectomy with IRA
-Total colectomy with IPAA
Attenuated APC ➘Oligopolyposis in the colon - Colonoscopy: • Late onset of colorectal Endoscopic examinations at later age
FAP (AFAP) ➘Fundic gland polyps and duodenal polyps <100 colorectal cancer (18–20 years) in patients with family
more prominent than colonic polyps adenomas history of atypical form of polyposis
Gardner syndrome: variant of FAP with osteomas and soft tissue tumors (desmoids and epidermoid cysts)
Turcot syndrome: variant of FAP with central nervous system (CNS) tumors
Hamartomatous Polyposis Syndromesa
Juvenile SMAD4 ➘Age of presentation is 2–12 Giardiello Criteria: Same as • Colorectal cancer (rare) Colonoscopy and polypectomy at least
Polyposis BMPR1A ➘Rectal bleeding ≥3 (some state solitary • Upper GI malignancies every 2 years
Syndrome ➘Rectal prolapse >5)5 polyps in juvenile polyp (stomach and Surgical Treatment:
(JPS) ➘Abdominal pain the colorectum (cystic dilation duodenum) Colectomy with ileorectal anastomosis
➘Intussusception or polyposis of crypts • Pancreas
➘Juvenile polyps in the colon, stomach, throughout the and excess
jejunum, ileum and duodenum GI tract or any of lamina
number of polyps propria)
with a family No muscle
history of JPS fibers in the
stroma
The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition
Table 1. Polyposis Syndromes Affecting Small Intestine in Children
Gene Clinical Features Diagnosis Pathology Cancer Risk Management & Surveillance
Peutz-Jeghers LKB1/ ➘50%–60% present before age 20 Giardiello Criteria: Hyperplasia of • GI tract and -EGD, colonoscopy & SBFT/capsule
Syndrome STK11 ➘Mucocutaneous pigmentation (perinasal and Hamartomatous the smooth extraintestinal endoscopy every 2 years
(PJS) perioral areas and buccal mucosa) polyps + at least 2 muscle layer (pancreatic, breast and -Regular screening with removal of
➘GI polyps preferentially in the small intestine of the following: extending gonadal) malignancies polyps through upper and lower
(jejunum > ileum > duodenum) or equally 1-Family history in a tree- • There have been reports endoscopy and double balloon
distributed in the stomach, colorectum and 2-Mucocutaneous like manner of adolescents with enteroscopy (or intraoperative
small bowel pigmentation toward the PJS who developed enteroscopy) may reduce laparotomies
➘Abdominal pain due to obstruction/polyp 3- Small bowel epithelial layer gastric and jejunal for malignancy and infarction due to
intussusception polyposis adenocarcinomas intussusception
➘Anemia due to GI bleeding -Extensive small bowel resection is not
recommended
Cowden PTEN ➘Hamartomatous neoplasms of the skin, International Juvenile or • Breast Routine occult blood tests.
Disease (CD)/ mucosa, GI tract, bones, CNS, eyes and GU Cowden hyperplastic • Thyroid Barium swallow and enema to exclude
Multiple tract Consortium • Skin hamartomas of the GI tract.
Hamartoma ➘Cutaneous manifestations (90%) Operational • Malignant potential Alternatively, upper and lower
Syndrome ➘Thyroid involvement (66%) Diagnostic Criteria of polyps (colonic endoscopy may be used.
➘Polyps in the esophagus, stomach, small (see Table 2) adenocarcinoma) is low
bowel or colon (35%–40%)
Bannyan-Riley- PTEN ➘GI hamartomas (45% of patients) • Breast
Ruvalcaba ➘Macrocephaly • Thyroid
Syndrome ➘Speckled penis
(BRRS) ➘Delayed development
➘Lipomatosis
➘Hemangiomatosis
a
Mechanism of inheritance for all is AD with variable penetrance.
Section 3 - Small Bowel

145
Table 2. International Cowden Consortium Operational Diagnostic Criteria
Major Criteria
Breast cancer
Thyroid carcinoma, especially follicular thyroid carcinoma
Macrocephaly (>97 percentile)
Lhermitte-Duclos disease
Endometrial cancer
Minor Criteria
Other thyroid lesions (e.g., adenoma, multinodular goiter)
Mental retardation (intelligence quotient <75)
GI hamartomas
Fibrocystic disease of the breast
Lipomas
Fibromas
GU tumors (e.g., uterine fibroids, renal cell carcinoma) or malformations
Pathognomonic Criteria
Facial trichilemmomas
Acral keratoses
Papillomatous papules
Mucosal lesions
Recommended Reading
Bosserhoff AK, Grussendorf-Conen EI, Rubben A, et al. Multiple colon carcinomas in a patient with Cowden
syndrome. Int J Mol Med. 2006;18(4):643-647.
Chen YM, Ott DJ, Wu WC, Gelfand DW. Cowden’s disease: a case report and literature review. Gastrointest
Radiol. 1987;12(4):325-329.
Moyer MS, Warner BW. Surgical Disorders, Intestinal Obstruction. In: Kleinman RE, Goulet O-J, Mieli-Vergani
G, Sanderson IR, Sherman PM, Schneider BL. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton,
Ontario: BC Decker, Inc; 2008: 345-351.
del Junco G. Pathology for Colon and Rectal Surgeons. 2002;21.
Pervez S, Mumtaz K, Ullah SS, Akhtar N, Ali N, Aaqil H. Immunoproliferative small intestinal disease (IPSID). J
Coll Physicians Surg Pak. 2011;21(1):57-58.
4A. Normal Anatomy,
Michelle Sicard, MD
Carmen Cuffari, MD
I. Colonic Development
A. Embryonic midgut and hindgut contribute to development of colon, rectum, and anus
1. Midgut components of colon
a. Cecum to right 1/2 to 2/3 of transverse colon
1) Blood supplied by superior mesenteric artery
2. Hindgut components of colon
a. Distal 1/3 to 1/2 of transverse colon, descending colon, sigmoid colon, rectum,
and superior part of anal canal
1) Blood supplied by inferior mesenteric artery
3. Distal end of anorectal canal
a. Blood supplied by iliac artery branches
II. Development of Colonic Midgut Components

A. Physiologic umbilical herniation of midgut out of abdominal cavity
1. Starts at 6th week and ends 10th week
2. Midgut rotates 90° counterclockwise around superior mesenteric artery axis, leaving
caudal midgut to left
B. Physiologic umbilical herniation reduction occurs
1. Large intestine returns after small intestine and does an additional 180°counterclockwise
rotation
2. Fixation of large intestine occurs
C. Ascending colon mesentery fuses with parietal peritoneum on posterior abdominal wall and
disappears
1. This leaves the ascending colon retroperitoneal
2. The small intestine mesentery goes from median plane of posterior abdominal wall, and
from duodenojejunal junction inferiorly to ileocecal junction
D. Cecum and appendix
1. Cecal diverticulum develops into primordium of cecum and appendix, and appears
around the 6th week
2. Appendix initially at caudal midgut loop, then distal end of cecum at birth
a. Unequal cecal growth leaves appendix medial of cecum
b. High variability in appendix location: retrocecal (posterior to cecum—seen in
64% of people), retrocolic (posterior to colon), pelvic (over pelvic brim)
III. Development of Colonic Hindgut Components

A. Descending colon mesentery fuses with left posterior abdominal wall peritoneum and becomes
retroperitoneal
B. Cloaca
1. Terminal part of hindgut
2. Lined with endoderm
3. Divided by the urorectal septum into the urogenital sinus and rectum during the
6th week
4. Cloacal membrane
a. Composed of endoderm of cloaca and ectoderm of proctodeum (anal pit)
5. By the 7th week, the urorectal septum fuses with the cloacal membrane, giving rise to
anal membrane and urogenital membrane
6. The perineal body in an adult is where the urorectal septum fuses with the
cloacal membrane
Section 4 - Colon 147

7. The cloacal sphincter is divided by the urorectal septum to give anterior and
posterior parts
a. Posterior part = external anal sphincter
b. Anterior part = superficial transverse perineal, bulbospongiosus, and
ischiocavernosus muscles
8. At the end of the 8th week, anal membrane ruptures
a. At this point, the anal canal communicates with amniotic cavity
C. Anal canal
1. Superior 2/3 is derived from hindgut
2. Inferior 1/3 is derived from proctodeum
D. Pectinate line is the junction of proctodeum ectoderm and hindgut endoderm
E. Anocutaneous line is ~2 cm superior to anus
1. Anal columnar epithelium changes to stratified squamous
F. Superior 2/3 of the anal canal
1. Supplied by superior rectal artery
2. Drained by superior rectal vein
3. Lymphatic drainage goes to inferior mesenteric lymph nodes
4. Nerve supply
a. Autonomic nervous system
5. Tumors here generally are of columnar epithelium etiology, and are painless
G. Inferior 1/3 (from proctodeum, not from the hindgut)
1. Supplied by inferior rectal arteries
2. Drained by inferior rectal vein
3. Lymphatic drainage goes to superficial inguinal lymph nodes
4. Nerve supply
a. Inferior rectal nerve
1) Sensitive to pressure, pain, touch, and temperature
5. Tumors here are generally from squamous epithelium, and are painful
H. Dentate line
1. Divides hindgut (endoderm) from distal anal canal (ectoderm)
IV. Normal Anatomy of Colon

A. Large intestine
1. Ileocecal valve to anus
a. Divided into colon, rectum, anal canal
B. Colon
1. Junction of terminal ileum and cecum until rectum (3–5 feet)
2. 5 layers of colon and rectal wall:
a. Mucosa, submucosa, inner circular muscle, outer longitudinal muscle, serosa
b. Colonic outer longitudinal muscle is separated into three taenia coli that
converge at the appendix and rectum
c. Rectosigmoid junction: where three taenia coli coalesce, forming a longitudinal
smooth muscle layer of rectum
d. Distal rectum: inner smooth muscle layer forms internal anal sphincter
e. Colon that is intraperitoneal and proximal 1/3 rectum is covered by serosa
3. Cecum
a. Widest and thinnest part of colon
4. Ascending colon
a. Fixed to retroperitoneum
5. Transverse colon
a. Starts at hepatic flexure until splenic flexure
b. Intraperitoneal and mobile
c. Attached to colonic mesentery and gastrocolic ligament
d. Greater omentum is attached to the superior anterior edge
6. Descending colon
a. Starts at the splenic flexure
b. Lineocolic ligament attaches the spleen with splenic flexure
c. Fixed to retroperitoneum
7. Sigmoid colon
a. Narrowest portion
b. Very mobile
C. Vascular supply of colon
1. Highly variable
2. Ileocolic artery, as a branch of superior mesenteric artery, provides the blood supply
a. Absent in 20%
b. Supplies TI and the proximal ascending colon
3. Right colic artery
a. Supplies ascending colon
4. Middle colic artery
a. Supplies transverse colon
5. Left colic arterial branch of inferior mesenteric artery
a. Supplies descending colon
b. Sigmoidal branches supply sigmoid
6. Superior rectal artery
a. Supplies proximal rectum
D. Nerve supply to the colon
1. Sympathetic T6–T12 and L1–L3 (inhibitory)
2. Parasympathetic (stimulatory)
a. Vagus nerve to right and transverse colon
b. Sacral nerves S2–S4 to left colon
V. Normal Anatomy of Anorectum

A. Rectum
1. 12–15 cm long
2. Valves of Houston
a. 3 submucosal folds in lumen
3. Dentate line
a. Transition from columnar rectal mucosa to squamous anoderm
b. 1–2 cm proximal
1) Anal transition zone with columnar, cuboidal and squamous
epithelium.
c. Columns of Morgagni
1) Longitudinal mucosal folds surrounding dentate line
4. Distal rectum
a. Internal anal sphincter
1) Thickened inner smooth muscle.
2) Innervated by sympathetic and parasympathetic nerves
3) Both inhibit contraction of sphincter
VI. Colonic Physiology

A. Functions
1. Absorption of water/electrolytes
2. Mucous secretion
3. Fecal material formation/propulsion/storage
4. Residence of microbes
B. Passage of food to the rectum
1. Initial ingested food reaches the cecum in ~4 hours (all by 8–9 hours)
2. Average transit time first 1/3 of the colon = 6 hours
3. Second 1/3 of the colon = 9 hours
4. Reaches the sigmoid in 12 hours
C. Digestion in the colon is generally a result of colonic microbes
1. Microbial fermentation of carbohydrates leads to release of short-chain fatty acids (FA)
acetate, butyrate, proprionate
a. Short-chain FA are an important energy source for colonic cells and for mainte-
nance of a healthy colonic epithelium
b. Metabolism of short-chain FA by colonocytes provides energy for active Na+
transport

D. Water absorption
1. Up to 5 L water/day absorbed in colon
a. Removes 90% of fluid from the digested food bolus
1) 1–2 L isotonic chyme that enters colon is converted to 200–250 mL
semisolid feces
E. Electrolyte absorption
1. Colon absorbs sodium against gradient via Na-K ATPase
a. Can absorb up to 400 mEq of Na+/day
b. With volume depletion, aldosterone increases sodium conductance in colon
2. Potassium
a. By active secretion into lumen and passive absorption
3. Chloride
a. By active transport through exchange with bicarbonate
4. Ammonia
a. Result of bacteria degrading protein and urea
b. Absorbed (influenced by lumen pH) and then transported to liver
F. Secretion
1. Mainly mucin, which lubricates lumen and forms barrier to microbes/pathogens
G. Bacteria
1. 30% of the fecal dry weight
2. 1011–1012 bacteria/g feces
3. Mainly consists of anaerobes, especially Bacteroides
4. E coli is the most common aerobe
5. Endogenous bacteria
a. Important for metabolism of bilirubin, bile acids, estrogen, cholesterol, and
breakdown of carbohydrates and proteins in the colon
b. Produce vitamin K
H. Flatus production
1. 400–1200 mL/day, depending on diet
I. Colonic motility (see colonic motility section for further description)
1. Contractions
a. No migrating motor complexes/cyclic activity like small bowel
b. The colon is rarely inactive
c. Segmental
1) Predominate contraction, occurs throughout the day, isolated/bursts,
rhythmic/arrhythmic
2) Mainly mixes contents of colon, thus facilitating absorption
3) Maximizes intestinal mucosa exposure to luminal contents to enhance
absorption of water, electrolytes, bacterial products
d. Rectal motor complex
1) Rhythmic contractions in cycles of 3–6 per minute (independent
of small bowel MMCs) that help maintain fecal continence
2. Propagated
a. High vs low amplitude contractions, but likely continuum
b. To move feces and gas rapidly over long distances
3. Cholinergic activity increases motility in colon
4. Mass action contraction
a. Unique to colon
b. Simultaneous smooth muscle contraction over large areas, propelling feces
along colonic segments or into rectum
5. Gastrocolic reflex
a. Colonic mass peristalsis after meal, and contraction of rectum in response to
distension of stomach by food
6. Gastroileal reflex
a. Cecum relaxes and chyme goes through ileocecal valve when food leaves the
stomach
VII. Anorectal Physiology
A. The anorectum maintains fecal continence and allows defecation
1. Continence requires puborectalis muscle and anal sphincter contraction
2. Defecation requires puborectalis relaxation by sacral parasympathetic nerves
B. Reflex sympathetic relaxation of internal (involuntary) and external sphincters occurs in
response to rectal distension
C. Defecation pattern
1. Involves coordination of internal and external anal sphincters, abdominal muscles,
pelvic floor
a. High-amplitude propagating contractions deliver stool to rectum
b. Rectal distension reflexively relaxes internal anal sphincter due to
excitation of sympathetic nerve supply (rectoanal inhibitory reflex)
c. External sphincter and pelvic floor muscles contract
d. Feces contact the anal canal, and the sensory epithelium distinguishes
solid/liquid stool and gas, providing the urge to stool
e. If stool is not released, the rectum relaxes and the urge subsides (accommoda-
tion response) and the stool is retained until a bowel movement occurs
1) The bowel movement is a coordination of increased abdominal pressure
by Valsalva, contractions of rectum, relaxation of puborectalis muscle,
and opening of the anal canal (initiated voluntarily, and then spinal
reflexes take control)
Recommended Reading
Moore KL, Persaud TVN. Before We Are Born: Essentials of Embryology and Birth Defects. Philadelphia, PA:
WB Saunders Company; 1998.
Mills JC, Stappenbeck TS, Bunnett N. Gastrointestinal Disease. In: McPhee SJ, Hammer GD. Pathophysiology
of Disease. Available at http://www.accessmedicine.com/content.aspx?aID=5369402.
Barrett KE, Barman SM, Boitano S, Brooks H. Gastrointestinal Motility. In: Barrett KE, Barman SM, Boitano
S, Brooks H. Ganong’s Review of Medical Physiology. Available at http://www.accessmedicine.com/content.
aspx?aID=5242514.
Bullard Dunn KM, Rothenberger DA. Colon, Rectum, and Anus. In: Brunicardi FC, Andersen DK, Bil-
liar TR, et al. Schwartz’s Principles of Surgery. Available at http://www.accessmedicine.com/content.
aspx?aID=5014922.

4B. Microanatomy
Ahmed Sarkhy, MD, FRCPC
Ammar Al-Rikabi, MD
I. Normal Colon Histology

A. The colon has four layers: mucosa, submucosa, muscularis externa, and serosa (Figure 1)
II. The mucosa of the colon

A. Formed by epithelium, lamina propria, and muscularis mucosae (Figure 2)
1. The mucosal thickness increases as it goes from the cecum to the rectum. It contains numer-
ous straight tubular glands or crypts of Lieberkűhn
2. The surface epithelium
a. No villi, thus it has a smooth surface epithelium which is lined with simple columnar
epithelial cells
b. A mixture of absorptive cells at the luminal surface and mucous-secreting goblet
cells at the base of the glands
c. The number of goblet cells are increased compared to small intestine cells, which
increase in number distally
1) Goblet cell depletion can be seen in chronic inflammation
d. The absorptive cells have shorter and less abundant microvilli than found in the
small intestine
1) Like the brush border enzymes, they have no role in digestion
2) The main function of these absorptive cells is to absorb electrolytes and
water
e. The crypts are longer and straighter than those in the small intestine
f. Low concentration overall of enteroendocrine cells in the large intestine
1) Need special immunohistologic stains for proper visualization
g. Paneth cells are seen scattered only in cecum
3. Muscularis mucosa
a. Several thin layers of smooth fibers oriented in different directions
1) Layers are penetrated by nerve twigs from the submucosa plexus, which
extend vertically into the lamina propria
4. Lamina propria is a highly cellular layer which contains lymphocytes, plasma cells, macro-
phages and scattered eosinophils. Lymphoid follicles are also present in colonic mucosa, and
may extend through muscularis mucosae into submucosa (part of Gut Associated Lymphoid
Tissues [GALT]). Neutrophils are seen occasionally in lamina propria, however, their presence
in excess in the surface epithelium or crypts may indicate an active infection or inflammation
III. Submucosa
A. Composed of a loose connective tissue, with collagen and elastic fibers that connects mucosa
and muscularis externa layers closely together.
1. Also composed of blood vessels, lymphatics, and nerves
a. Contains specialized nerve ganglions (Meissner’s plexus), defined below
2. No glands in the submucosa
IV. Muscularis externa

A. Thin smooth muscle layer that has inner circular and outer longitudinal layers of smooth muscles
1. The outer layer is primarily condensed into three muscular bands called taenia coli (seen
throughout the colon except the rectum)
a. Contraction of the taenia coli and circular muscle layer draws the colon into
sacculations called haustra, which are characteristic for the colon
2. Muscularis externa is responsible for the propulsive force of the large intestine
3. Large intestine peristalsis is mediated by intrinsic (myenteric plexus) and extrinsic
(autonomic innervation) neural control
a. Meissner’s plexus resides at the base of submucosa

1) Consists of two neural networks
2) Auerbach’s plexus lies between the inner circular and the outer longitu-
dinal muscle layers of the wall
V. Serosa
A. Outer layer of the colon
1. Single layer of avascular, flat, nucleated cells, simple squamous epithelial cells
a. Lubricates by producing serous fluid
VI. Appendix and rectum

A. Different in some aspects from the other parts of the colon
B. Appendix
1. Thin, finger-like extension of the cecum. Characterized by long crypts without villi
2. There is a large accumulation of lymphoid tissue in the lamina propria and submucosa.
Inflammation in this area leads to hyperplasia of these lymphoid follicles, causing ob-
struction of its lumen, bacterial proliferation, and subsequent appendicitis
3. Appendices epiploicae
a. Adipose structures protruding from the serosal surface of the colon
1) Lobulated masses of pericolic fat, usually 2–5 cm long
a) Can undergo a spontaneous torsion, leading to infarction,
which produces symptoms similar to appendicitis
C. Rectum
1. The dilated terminal portion of the intestinal tract that does not have mesentery
2. Divided into two segments; the upper part (rectum proper), and the lower part
(anal canal), which extends from the anorectal junction to the anus
3. Rectal mucosa is thicker compared to other parts of the colon, with more prominent
veins
a. The crypts are longer than those in the small intestine, and are lined predomi-
nantly by goblet cells
b. At the level of the anal canal, the crypts gradually disappear
4. The rectum is distinguished from the other parts of the colon by:
a. The absence of taenia coli in its muscularis externa
b. The presence of transverse rectal folds in its submucosa (columns of Morgagni),
each ending in a small valve called anal valve
1) Between columns of Morgagni are depressions called anal sinuses,
which contain anal glands. The anal sinuses end at the lower part of
the anal columns, called the dentate line or pectinate line (Figure 3)
a) When the canal is distended with stool, the columns, sinuses,
and valves flatten, and mucus is discharged from sinuses to
lubricate the passage of the stool
b) The valves and sinuses prevent leakages from the anus
5. Beyond the dentate line
a. The simple columnar epithelium of the rectum abruptly changes to a stratified,
squamous, nonkeratinized epithelium (Figure 4)
b. Becomes keratinized in the anus, which contains sebaceous glands and apo-
crine sweat glands
6. The inner circular layer of the muscularis externa thickens to form the internal sphincter
at the level of the anus
7. The outer longitudinal layer becomes the fibroelastic septum
8. The external anal sphincter is formed by skeletal muscle and lies inside the levator ani
muscle
Figure 1. Colonic wall segment Figure 2. Mucosa layer of the colon.
shows the different layers of the colon. Adapted from the University of
Adapted from the University of West- Western’s Blue Histology Web page.
ern’s Blue Histology Web page.
Figure 3. Anatomy of the anus. From Ryan DP, Figure 4. Anorectal junction area shows
Compton CC, Mayer RJ. Carcinoma of the anal canal. the transition area and the different
N Engl J Med. 2000;342:792-800.) Reprinted with mucosa between them. Adapted from
permission. the University of Western’s Blue
Histology Web page.
Recommended Reading
Kierszenbaum AL. Histology & cell biology, an introduction to pathology. 2nd ed. Toronto, Ontario: Mosby;
2007: 477-481.
Stevens A, Lowe JS. Human Histology. 3rd ed. Toronto, Ontario: Mosby; 2005:219-222.
Young B, Lowe J, Stevens A, Heath J. Wheater’s Functional Histology: A Text and Colour Atlas. 5th ed. Lon-
don, England: Churchill Livingstone; 2007: 283-285.
The University of Western, Blue Histology. Available at http://www.lab.anhb.uwa.edu.au/mb140/CorePages/

GIT/git.htm. Accessed July 17, 2011.

4C. Normal and
Abnormal Motility
Jeremy Middleton, MD
Cary Sauer, MD
I. Normal Physiology
A. Nervous System of the Colon
1. Intrinsic innervation = enteric nervous system
a. Ontogeny of enteric nervous system
1) Majority of bowel neurons are derived from vagal segment neural crest
cells of the fetal CNS
2) 20% of bowel neurons are from the sacral segment of the fetal CNS
3) Myenteric plexus develops first
4) Submucosal plexus is derived from myenteric nerve cells that migrate
across the muscle layer
b. Myenteric (Auerbach plexus)
1) Regulates smooth muscle function
2) Has a net inhibitory influence
c. Submucosal (Meissner plexus)
1) Regulates the mucosal ion transport and absorption
B. Extrinsic innervation = autonomic nervous system
1. Parasympathetic
a. Excitatory pathways lead to increased colonic contractions
1) Proximal colon innervated by vagus nerve
2) Distal colon innervated by S2–S4 of pelvic plexus
b. Main excitatory neurotransmitters include:
1) Acetylcholine
2) Substance P
2. Sympathetic
a. Inhibitory pathways lead to increased sphincter muscle tone and relaxation of
nonsphincter muscle
1) Proximal colon innervated by splanchnic nerves
2) Distal colon innervated by lumbar nerves
b. Main inhibitory neurotransmitters
1) α2 adrenergic
C. Colonic Contractions
1. Segmental contractions
a. Occur throughout the day
b. Act to mix intraluminal contents and increase contact with mucosa, leading to
maximized water and electrolyte absorption
c. Rectal motor complexes are specialized segmental contractions that occur more
frequently at night, and are thought to aid in nocturnal continence
D. Propagated contractions
1. High-amplitude peristaltic contractions are responsible for movement through colon
a. Occur several times a day
b. Can be associated with defecatory stimulation
2. Low-amplitude peristaltic contractions are not completely understood
3. Increased high-amplitude peristaltic contractions are seen after a meal and upon
awakening
4. Rectal distention leads to decreased propagated contractions
E. Anorectal Motility
1. Nervous system
a. Internal anal sphincter
1) Parasympathetic innervation

a) Activation leads to relaxation
b) Supplied by pelvic nerves
2) Sympathetic innervations
a) Activation leads to constriction
b) Supplied by hypogastric nerves
b. External anal sphincter
1) Somatic innervation of striated muscle by the pudendal nerve
c. Rectoanal inhibitory reflex
1) With distention of the rectum, there is relaxation of the internal anal
sphincter and contraction of the external sphincter
F. Modalities to Measure Colonic and Anorectal Motility
1. Radiopaque marker studies
a. Ingestion of radiopaque markers, with follow-up abdominal x-ray on Day 4
1) Delayed transit is described as >20% retention of markers after
96 hours
2. Radionuclide scintigraphy
a. Ingestion of radiolabeled indium, with follow-up gamma camera scans at 6, 24,
48, 72, and 96 hours
1) No standardized values for pediatrics
2) Not commonly used
3. Wireless capsule
a. Location of the ingested pill is monitored as it passes from different areas of the
GI tract, as identified by changes in pH
1) No pediatric data available
4. Colonic manometry
a. Manometry catheters can be placed endoscopically or radiographically
b. Indications for manometry
1) Medically refractory constipation
2) Persistent symptoms after surgical repair of Hirschsprung’s disease
3) Evaluation for pseudoobstruction
4) Evaluation of colonic function prior to intestinal transplant
5) Determination of the utility of antegrade enemas
6) Evaluate colonic function prior to reanastomosis of diverting ileostomy
c. Typical observations demonstrating abnormal motility
1) Decreased frequency of high-amplitude propagating sequences
2) Decreased colonic response to ingestion of meals
3) Decreased colonic response to awakening
4) Abnormal colonic response to chemical stimulation or rectal distention
5. Anorectal manometry
a. Placement of manometry catheter into rectum
1) Measures internal and external anal sphincter contraction and
relaxation upon stimulation with rectal distention from a balloon
2) Determines volume of rectal distention necessary to elicit the rectoanal
inhibitory reflex
3) Can evaluate defecatory dynamics of straining
II. Diseases Causing Abnormal Colonic/Anorectal Motility, and the Finding on Motility Study
A. Constipation/encopresis
1. Delayed colonic transit time
B. Chronic intestinal-pseudoobstruction
1. Absent colonic response to a meal as measured by colonic manometry
C. Hirschsprung’s disease
1. Absent relaxation of the internal sphincter with rectal dilation
D. Spinal cord injury
1. Absent contraction of the external anal sphincter with no urge to defecate
with rectal dilation
E. Anismus or paradoxic puborectalis contraction
1. Contraction of the external anal sphincter and puborectalis with attempted defecation
Recommended Readings
Beck D, Wolff B, Fleshman J, Pemberton J, Wexner S, eds. The ASCRS Textbook of Colon and Rectal Surgery.
Springer Online: 2007; Chapter 2.
Dinning PG, Di Lorenzo C. Colonic dysmotility in constipation. Best Pract Res Clin Gastroenterology.
2011;25(1):89-101.
Dinning PG, Smith TK, Scott SM. Pathophysiology of colonic causes of chronic constipation.
Neurogastroenterol Motil. 2009;21:20-30.
Walker W, Goulet O, Kleinman R, Sherman P, Shneider B, Sanderson I, eds. Pediatric Gastrointestinal Disease.
4th edition. Hamilton, Ontario: BC Decker Inc; 2004: Chapters 4, 46.
2006:Chapter 5.

4D. Hirschsprung Disease
Ashish Chogle, MD, MPH
Miguel Saps, MD
Hirschsprung disease (HD) is a developmental disorder of the enteric nervous system, characterized by a
congenital absence of ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexus of the
distal bowel extending proximally from the internal anal sphincter. The extent of the aganglionic segment is
variable.
A. Affects about 1 in 5,000 live births
B. Male to female ratio is 4:1 for short-segment disease
C. Male to female incidence approaches 1:1 as the length of the affected segment increases
D. Short segment or classic HD is limited to the rectum and sigmoid colon in 75%–80% of cases
II. Genetics
A. More than 11 susceptibility genes have been implicated in the pathogenesis of HD
1. Genetic factors that predispose to HD are heterogeneous, and there is no clear
pattern of inheritance
2. A familial incidence of 15%–21% has been reported. This incidence increases to about
50% in cases of total intestinal aganglionosis
3. Risk of recurrence of HD in the sibling of a proband is 4% (relative risk of 200)
B. RET (receptor tyrosine kinase) is the major susceptibility gene for HD. Approximately 50% of
familial and 15%–20% sporadic cases of HD have been attributed to mutations of RET gene
C. 70% of HD cases occur as an isolated malformation (nonsyndromic HD)
D. 30% of cases have associated anomalies
1. Malformations of other neural crest derivatives—such as cardiac conotruncal derivatives,
melanocytes, craniofacial musculature, skeleton, and rarely, irides—may be present
E. Chromosomal anomalies are associated in 12% cases with trisomy 21 occurring in 2%–10% of
HD cases
F. HD has been reported along with several syndromes, such as MEN2, Waardenburg syndrome,
Smith-Lemli-Opitz syndrome, X-linked hydrocephalus, congenital hypoventilation syndrome,
and neurofibromatosis
III. Pathogenesis
A. Failure of normal migration of vagal neural crest cells between the 5th and 12th weeks of
gestation
1. The earlier the arrest of migration, the longer the aganglionic bowel segment
B. Upon distension of the normal rectum, mechanoreceptors are stimulated and activate inhibitory
neurons in the myenteric plexus, resulting in relaxation of the internal anal sphincter. Nitric oxide
is the main inhibitory neurotransmitter in this reflex
1. Abnormal innervations in HD result in absence of relaxation of affected bowel segments,
impaired propagation of peristaltic waves, and lack of recto-anal inhibitory reflex (RAIR)
on distension of the rectum
IV. Diagnosis
A. Clinical Presentation
1. 80%–90% of patients with HD are diagnosed in the neonatal period
2. 95% of healthy infants pass meconium on Day 1 of life. 60%–90% of neonates with
HD fail to pass meconium on the first day of life
3. HD should be suspected in any patient with difficulty passing stools in the newborn
period
4. Presenting with:
a. Constipation with abdominal distension (63%–91% cases)
b. Bilious vomiting (19%–37% cases)
c. Encopresis is not typically seen in patients with HD

d. Stools are of thin or normal caliber
e. Patients can present with failure to thrive
f. One-third of patients with HD can present with diarrhea without any other
symptoms
5. Rectal exam of a HD patient may reveal a tight anus, with an empty collapsed
rectal vault
6. In a patient with HD, foul-smelling, explosive diarrhea, with fever and abdominal
distension, can indicate enterocolitis
a. Enterocolitis is associated with high morbidity and mortality
b. Can progress to potentially fatal toxic megacolon, which is associated with
dehydration and shock
B. Evaluation
1. Tests available for assessment of patients suspected of having HD include:
a. Contrast enemas done in an unprepared bowel may show a caliber change
between the small or normal-sized distal aganglionic segment and dilated
proximal segment
1) Can assist in estimating the length of aganglionic segment
2) An abnormal mucosal pattern can be seen with contrast enema in
some patients with enterocolitis
b. Rectal suction biopsy is used in infants with no anesthesia and minimal risk
1) Several posterior rectal biopsies are taken above 2 cms and <4 cms
above the anal margin
c. Full thickness rectal biopsy
1) The gold standard for diagnosis is a full thickness rectal biopsy,
although it is a more invasive test requiring general anesthesia
2. Rectal biopsies demonstrating the absence of ganglion cells and presence of acetyl
cholinesterase (AChE) with positive hypertrophic nerve fiber is confirmatory for HD
3. In patients with HD, anorectal manometry is used, with rectal distention using a balloon,
to demonstrate lack of RAIR
4. Rectal suction biopsy (even without AChE staining) has been shown to be more sensitive
and specific than contrast enema and anorectal manometry in diagnosing HD
V. Differential Diagnosis
A. Hypo/hyperganglionosis
B. Intestinal neuronal dysplasia
C. Meconium plug syndrome
D. Meconium ileus (secondary to cystic fibrosis)
E. Anorectal malformation
F. Hypoplastic left colon syndrome
G. Intestinal atresia
H. Intestinal malrotation (volvulus)
I. Maternal infections
J. Maternal intoxications
K. Drugs
L. Congenital hypothyroidism
M. Sepsis
VI. Treatment/Management
A. Basic principle of surgical treatment of HD is to reconnect the ganglionic bowel to the anus
B. Many surgical techniques have been described for HD
1. Swenson’s procedure: Rectosigmoidectomy
2. Duhamel’s procedure: Retrorectal-transanal approach
3. Soave: Endorectal procedure
C. Most commonly encountered postoperative problems include constipation, encopresis, and
enuresis. Rarely, obstruction and fistulae formation may occur
D. Prompt recognition of enterocolitis and treatment with fluids, antibiotics, and rectal irrigations
decrease associated risk of mortality. There is a risk of enterocolitis, even after surgery
Recommended Reading
de Lorijn F, Boeckxstaens GE, Benninga MA. Symptomatology, pathophysiology, diagnostic work-up, and
treatment of Hirschsprung disease in infancy and childhood. Curr Gastroenterol Rep. 2007;9(3):245-253.
Kapur RP. Practical pathology and genetics of Hirschsprung’s disease. Semin Pediatr Surg. 2009;18(4):212-
223.

4E. Chronic Constipation
Emily Contreras, MD
Rebecca Cherry, MD
Constipation is a common problem in childhood, accounting for 3% of general pediatrician visits and 25%
of pediatric GI consults. While functional constipation is the most common, there are several other conditions
that lead to constipation, including celiac disease, hypothyroidism, cystic fibrosis, and structural anomalies.
I. Background
A. Most common cause is functional (aka idiopathic constipation, functional fecal retention, fecal
withholding)
B. Normal stool frequency varies (~4 stools/day as infant, 1.2 stools/day at 4 years old and older,
with range of 3/day to 3/week)
1. Healthy breastfeeding babies can have infrequent stools after 2 months of age due to
almost complete absorption of breastmilk with little residue for stool formation
C. Normal defecation mechanics:
1. Anatomy: Internal and external anal sphincters surrounding the anal canal form an angle
with the puborectalis muscle (85°–105° at rest)
a. Stool is propelled into the anorectum during defecation, where rectal distension
results in reflex relaxation of the internal anal sphincter (IAS) with simultaneous
external anal sphincter (EAS) contraction until defecation is socially appropriate
b. At the time of defecation, increased intrarectal pressure moves feces toward the
anal canal; the puborectalis muscle relaxes, straightening the anorectal angle,
thus inhibiting the external anal sphincter and allowing fecal evacuation
c. Voluntary contraction of the puborectalis muscle and external anal sphincter
decreases the anorectal angle <85°–105°, which prevents defecation
II. Evaluation
A. History:
1. Timing of first bowel movement after birth, parent’s definition of constipation, duration
of symptoms, frequency of stools, presence of blood or pain with stools, toilet training
history, abdominal pain, presence of withholding symptoms (see below), medical history,
medications, previous treatments, allergies, surgeries, hypothyroid symptoms, urinary
continence, neurologic deficits
2. Developmental and nutritional history
3. Family history: GI disease (especially Hirschsprung disease (HD), constipation, celiac
disease), cystic fibrosis, and thyroid disease
4. Psychosocial: family/household structure, interaction with peers, temperament, toilet
habits at school
5. Red flags concerning for organic disorder
a. Fever, abdominal distension, anorexia, nausea, vomiting, weight loss or poor
weight gain, bloody diarrhea (worrisome for enterocolitis seen with HD)
B. Physical Exam:
1. General physical exam, including vitals and growth parameters
2. Abdomen: distension, fecal masses, tenderness, bowel sounds
3. Back: signs of spinal abnormalities such as sacral dimple, tuft of hair
4. Neuro exam: Lower extremity tone and strength, cremasteric reflex, deep tendon
reflexes
5. Perineum, perianal, and digital rectal exams:
a. Position of anus
b. Fissures or fistulas
c. Perianal sensation
d. Anal sphincter tone
e. Size of rectum, presence of polyps, hemorrhoids
f. Presence of anal wink
g. Size and consistency of stool and location within rectum

h. Presence of soiling
i. Test for occult blood if indicated
j. Findings concerning for HD
1) Rectum devoid of stool (though not seen in short-segment HD)
2) Explosive discharge of foul-smelling liquid stool when finger withdrawn
If there are no red flags in history and/or physical exam, patient most likely has functional constipation and
does not require further evaluation.
C. Other tests to consider if constipation is refractory to medical management:

1. Thyroid function tests
2. Serum calcium level
3. Serum lead level
4. Sweat test if clinically indicated
5. TTG IgA, serum IgA (or prometheus celiac panel if 2 years of age)
6. MRI of lumbosacral spine: if clinically indicated to evaluate for tethered cord, tumors,
sacral agenesis, and other intraspinal problems
D. Anorectal or colonic manometry: more advanced testing used in situations of constipation
refractory to medical therapy. Evaluate for myopathy and neuropathy, including HD
E. Rectal biopsy: detect HD, neuronal intestinal dysplasia, other myenteric abnormalities
F. Barium enema: detect anatomic abnormality (should be unprepped if evaluating for possible HD)
G. Psychological evaluation
Management of organic causes of constipation will not be further discussed in this section.
III. Functional Constipation

A. Definition: Constipation without objective evidence of a pathologic condition
B. Most commonly caused by painful stools → voluntary withholding of feces→ prolonged fecal
stasis with resorption of fluids, increased size/consistency of stools → Rectal dilation →Larger
amounts of stool needed to activate rectal stretch receptors → Urge to defecate disappears,
stool withholding becomes automatic
1. Causes of painful stools include:
a. Difficult or stressful toilet training
b. Changes in routine or diet
c. Stressful events
d. Illness causing dehydration
e. Unavailability of toilets
f. Withholding while busy or playing
2. Withholding behaviors that may be observed by family:
a. Tiptoeing
b. Rocking back and forth, fidgeting
c. Stiffening buttocks and legs, sitting on edge of seat
d. Hiding in a corner, often with unusual postures
C. Patients can present with hard stools, painful stools, bright red blood in stools, abdominal pain,
cramps, abdominal distension, decreased oral intake, irritability, encopresis
D. Encopresis:
1. When large stool volumes stretch the rectum, the IAS relaxes and anal canal is
shortened. The EAS is eventually unable to function adequately to prevent defecation
and stool leakage occurs
2. Rarely occurs in patients < 3 years old, usually resolves before late adolescence
E. Management:
1. Determine whether fecal impaction is present
a. Fecal impaction defined as:
1) Hard mass in lower abdomen (abdominal exam)
2) Dilated rectum filled with large amount of stool (rectal exam)
3) Excessive stool in colon (KUB)
a) KUB not needed to establish impaction if above findings seen
on exam
b) Of note, a recent JPGN article (Pensabene 2010) reports that
KUBs may have very limited value in assessing functional
constipation due to low sensitivity and low interobserver
reproducibility
c) Having stool in the colon is not abnormal
2. Treat the impaction if present
a. Oral and/or rectal approach may be used. Choice of treatment best determined
after discussing options with family and child
1) Oral route is noninvasive and empowers children with management of
their problem
a) Below approaches can be used in initial disimpaction alone or
in combination
(1) Mineral oil
(2) Magnesium hydroxide
(3) Magnesium citrate
(4) Lactulose
(5) Sorbitol
(6) Senna or bisacodyl
(7) Polyethylene glycol 3350 (e.g., Miralax) or
polyethylene glycol with electrolytes (e.g., Golytely)
2) Rectal disimpaction is faster than oral approach, but is invasive, and
can be more emotionally draining and difficult to administer. May be
helpful to do rectal disimpaction prior to starting oral laxative
a) Saline enemas
b) Mineral oil enemas
c) Suppositories usually not as effective, but may be helpful
adjunctively
(1) Glycerin suppositories for infants
(2) Bisacodyl suppositories in older children
3. Maintenance therapy:
a. Goal is to pass 1–2 soft stools daily and allow rectal vault to approach normal
size (may take several months to years)
b. Dietary interventions
1) Increase fluid intake
2) May use small amounts of absorbable carbohydrates (e.g., sorbitol in
prune, pear, and apple juice)
3) Nonabsorbable carbohydrates (fiber)
a) Titrate gradually towards goal
b) Excessive intake may worsen constipation
c. Behavioral modification
1) Unhurried time on toilet 30 minutes after meals, in order to work with
peristaltic contractions
2) Appropriate toileting hygiene: feet flat on the floor, no prolonged toilet
time (rule of thumb is 1 minute for every year of age up to age 15)
3) If behavioral/motivational problems interfere with treatment, consider
referral to mental health care provider
d. Oral medications
1) Stool softeners
a) Mineral oil (lubricant): not recommended in children <1 years
old or with other aspiration risk
b) Docusate sodium
2) Osmotic laxatives
a) Magnesium hydroxide
b) Lactulose
c) Sorbitol
d) Polyethylene glycol 3350 (Miralax)
e. ± stimulant laxative for rescue therapy for short periods (<30 days)
1) Senna
2) Bisacodyl

f. Biofeedback therapy
1) Sensory retraining, learning how to relax EAS during defecation
2) More likely to be useful in patients with abnormal defecation dynamics
on anorectal manometry
g. Surgical treatment (rare)
1) Malone appendicocecostomy for antegrade colonic enemas (MACE):
appendix used as conduit to cecum; appendix used as stoma through
which colon can be irrigated in antegrade fashion
a) Can also use cecostomy buttons in place of
appendicocecostomy
2) Proctocolectomy: in a small number of cases with debilitating
symptoms, persistently abnormal colonic manometry, and
nondilated colon
4. Educate patient and family
a. Explain pathophysiology
b. Remove negative attributions with soiling
c. Promote consistent, positive supportive attitudes with treatment. Forceful
adherence to treatments is NOT helpful
d. Advise parents that treatment can be prolonged and difficult, with relapses
common
e. Patient should not stop treatment abruptly, as this may lead to relapse
5. Close follow-up
a. If refractory to medical treatment:
1) Consider laboratory work-up as above, and HD evaluation with at least
unprepped barium enema and/or anorectal manometry
2) Consider trial of cow’s milk-free diet
a) There is a clear association between cow’s milk consumption
and constipation in more than one-third of children, likely non-
IgE–mediated
b. Prognosis
1) Long-term outcome is not well established
2) Predictors of poor outcome include:
a) Early onset of constipation
b) Family history of constipation
c) Long duration of symptoms prior to referral to a pediatric
gastroenterologist
Recommended Reading
Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology
and Nutrition. Evaluation and treatment of constipation in infants and children: recommendations of the
North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol
Nutr. 2006;43:e1-e13.
Croffie JM, Fitzgerald JF. Hypomotility disorders: idiopathic constipation. In: Walker W, Goulet O, Kleinman R,
Sherman P, Shneider B, Sanderson I, eds. Pediatric Gastrointestinal Disease. 4th edition. Hamilton, Ontario: BC
Decker Inc; 2004:1000-1015.
Irastorza I, Ibanez B, Delgado-Sanzonetti L, Maruri N, Vitoria JC.Cow’s-milk-free diet as a therapeutic option

in childhood chronic constipation. J Pediatr Gastroenterol Nutr. 2010;51:171-176.
Pensabene L Buonomo C, Fishman L, Chitkara D, Nurko S.Lack of utility of abdominal x-rays in the evaluation
of children with constipation: comparison of different scoring methods. J Pediatr Gasroenterol Nutr.
2010;51(2):155-159.
4F. Rectal Prolapse
Brigitte Moreau, MD
Véronique Morinville, MD
Rectal prolapse refers to either a mucosal or full-thickness protrusion of the rectum through the anus, and
presents as concentric rings of mucosa on examination. Affects males more than females.
Figure 1.
I. Etiology
A. The most common underlying condition: chronic constipation
B. The next most frequent etiology is acute diarrhea
C. One must consider cystic fibrosis as a possible cause
D. Other causes include increased intraabdominal pressure, parasitosis, juvenile polyps, malnutrition,
and conditions predisposing to pelvic floor weakness
E. Pathophysiology is not completely understood; some theorize this is due to sliding hernia or
result of an intussusception
II. Clinical Presentation and Diagnosis

A. Usually self-limited and intermittent during the period of toilet training
B. History of constipation or other underlying condition, as mentioned above
1. Often no underlying cause is identified
C. If recurrent and pronounced, and no anatomic abnormality is identified, children should have a
sweat chloride test and possibly a screen for intestinal parasites
III. Treatment
A. Initial management: manual reduction and the treatment of the primary inciting factor
B. If persistent: surgical intervention may be required, such as injection of a sclerosant
submucosally or submuscularly above the dentate line, using D50W (1 cc/kg), phenol in oil,
or hypertonic saline
C. For prolapse that fails sclerotherapy and in children with pelvic anatomic distortion caused by
previous surgery: more aggressive surgical efforts may be needed, but there is no consensus on
the operation of choice. Regardless of the approach, the prognosis is generally good
Recommended Reading
Gourgiotis S, Baratsis S. Rectal prolapse. Int J Colorectal Dis. 2007;22:231-243.
Walker W, Goulet O, Kleinman R, Sherman P, Shneider B, Sanderson I, eds. Pediatric Gastrointestinal Disease.
4th edition. Hamilton, Ontario: BC Decker Inc; 2004:Chapter 35.
Wu JS. Rectal prolapse: a historical perspective. Curr Probl Surg. 2009;46:602-716.

4G. Hemorrhoids
Imad Absah, MD
Mounif El-Youssef, MD
I. History and Prevalence in the United States

A. Hemorrhoidal venous cushions are normal structures of the anorectum
B. Hemorrhoids are more common in adults, and rarely seen in children
C. They are common causes of anal pathology due to their rich vascular supply, highly sensitive
location, and tendency to engorge and prolapse
D. Prevalence in the United States is 4%
E. Peak incidence is between ages 45–65 years
F. Equal between both genders
G. Hemorrhoids generally cause symptoms when they become enlarged, inflamed, thrombosed, or
prolapsed
II. Features of hemorrhoidal disease include:

A. Bleeding
B. Anal pruritus
C. Prolapse
D. Pain due to thrombosis
III. Risk factors:

Pregnancy Colon malignancy Loss of rectal muscle tone
Lack of erect posture Hepatic disease Rectal surgery
Familial tendency Obesity Episiotomy
Higher socioeconomic status Elevated anal resting pressure Anal intercourse
Chronic diarrhea Spinal cord injury
IV. Anatomy
A. Hemorrhoids arise from a plexus of dilated veins arising from the superior and inferior
hemorrhoidal veins
B. Located in the submucosal layer in the lower rectum
C. There are three primary cushions (left lateral, right anterior, and right posterior) corresponding to
the end branches of the middle and superior hemorrhoidal veins
D. Internal and external hemorrhoids communicate and drain into the internal pudendal veins and,
ultimately, the inferior vena cava
E. Hemorrhoids have direct communication with the portal system. However, they are not more
common in patients with portal hypertension
V. Anatomical Classification: Hemorrhoids are classified by their anatomic origin within the anal
canal and by their position relative to the dentate line
A. Internal hemorrhoids develop above the dentate line from embryonic endoderm. They are
covered by the simple columnar epithelium of anal mucosa, and lack somatic sensory innervation
and are therefore painless
B. External hemorrhoids develop from ectoderm and arise distal to the dentate line. They are
covered by stratified squamous epithelium, and receive somatic sensory innervation from the
inferior rectal nerve, rendering them painful when irritated
C. Both types of hemorrhoids often coexist

VI. Internal Hemorrhoids Staging: There is no classification for external hemorrhoids, whereas
internal hemorrhoids are staged according to the degree to which they prolapse from the anal
canal, as follows:
A. Stage I: Internal hemorrhoids that bleed
B. Stage II: Internal hemorrhoids that cause bleeding and prolapse with straining, but return to their
resting point by themselves
C. Stage III: Internal hemorrhoids that bleed and prolapse with straining, requiring manual effort for
replacement into the anal canal
D. Stage IV: Internal hemorrhoids that do not return into the anal canal
VII. Pathogenesis
A. The cause of symptomatic internal hemorrhoids is not completely understood, but may be due
to multiple factors:
1. Low-fiber diets
2. Decreased venous return
3. Prolonged sitting on a toilet
4. Aging causes weakening of the support structures, which facilitates prolapse and/or
swelling of the hemorrhoidal cushions
VIII. Clinical Presentation

A. Bleeding
1. Usually painless bleeding with bowel movements
2. Bright red blood typically coats the stool at the end of defecation
3. Blood may also drip into the toilet or stain toilet paper
4. Chronic blood loss can induce iron-deficiency anemia
B. Pruritus
1. Common symptom results from combination of:
a. Prolapse of internal hemorrhoids may permit leakage of rectal contents
b. Skin tags associated with external hemorrhoids may be difficult to clean,
resulting in prolonged contact of fecal material with the perianal skin and
leading to local irritation
c. Patients with leakage may clean aggressively, irritating the perineum and also
allowing contact of fecal material with denuded skin
C. Pain
1. Usually results from thrombosis
2. Occurs in both internal and external hemorrhoids
3. Thrombosis of external hemorrhoids may be associated with excruciating pain
4. The thrombosed external hemorrhoid is an easily visible, purple mass extending from
the anal to the perianal skin. It is extremely painful to palpation, and a thrombus may be
appreciated
5. Thrombosed internal hemorrhoids may cause pain, but to a lesser degree than external
hemorrhoids; except when internal hemorrhoid strangulation leads to gangrene, which
is life-threatening if not immediately treated surgically
IX. Diagnosis
A. Detailed clinical history
B. Careful examination of the rectum and anus
C. Further diagnostic procedures such as anoscopy or proctosigmoidoscopy may be needed to
confirm the diagnosis
X. Differential Diagnosis
A. Many anorectal disorders may present like hemorrhoids:
1. Anal fissures
2. Condyloma
3. Rectal prolapse
4. Anal cancer
5. Inflammatory bowel disease
XI. Treatment: Treat hemorrhoids only if they cause problems for the patient
XII. Conservative Management
A. Treatment of all first- and second-degree internal hemorrhoids and non-thrombosed external
hemorrhoids consists of:
1. Sitz baths (BID/TID)
2. High-fiber diet
3. Adequate fluid intake
4. Stool softeners
5. Topical and systemic analgesics
6. Proper anal hygiene
7. Short course of topical steroid cream, as the prolonged use of topical steroids
should be avoided
XIII. Nonoperative Treatments

A. First-line treatment of all first- and second-degree internal hemorrhoids that do not respond to
conservative therapy. Nonoperative methods include:
1. Rubber band ligation—Most widely used procedure for Grade II and Grade III
hemorrhoids and is the standard to which other methods are compared
a. No anesthesia is required
b. Successful in approximately 70%–80% of patients
c. Complications are uncommon and usually benign
2. Laser, infrared, or bipolar coagulation may be as effective as banding, with fewer and
less severe complications
a. Laser therapy is more costly, and provides no advantage over other methods
3. Sclerotherapy is less effective than rubber band ligation
4. Radiowave ablation followed by suture ligation could prove to be a safe, cost-effective,
and convenient way to treat prolapsing hemorrhoids
XIV. Surgical Management

A. Hemorrhoidectomy is the most effective treatment, and is indicated in the following situations:
1. Nonsurgical treatment fails (persistent bleeding or chronic symptoms)
2. Grade III and IV hemorrhoids with severe symptoms
3. Presence of concomitant anorectal conditions (e.g., anal fissure or fistula) requiring
surgery
4. Patient preference
5. 5%–10% of people with hemorrhoids eventually require surgical hemorrhoidectomy
6. Postoperative pain remains the major complication, with most patients requiring
2–4 weeks before returning to normal activities
Recommended Reading
American Gastroenterological Association. Medical position statement: diagnosis and treatment of

hemorrhoids. Gastroenterology. 2004;126(5):1461-1462.
Jayaraman S, Colquhoun PH, Malthaner RA. Stapled versus conventional surgery for hemorrhoids.
Cochrane Database Syst Rev. 2006;(4):CD005393.
Yuksel BC, Armagan H, Berkem H, et al. Conservative management of hemorrhoids: a comparison

of venotonic flavonoid micronized purified flavonoid fraction (MPFF) and sclerotherapy. Surg Today.
2008;38(2):123-129.

4H. Lower GI Bleeding
Shamila B. Zawahir, MD
Samra S. Blanchard, MD
I. Definition: Bleeding distal to the ligament of Treitz.
II. Presentation: Dark black or red blood in the stool, with or without pain (see Table 1).
Table 1. Etiology by Age Group
Neonatal Infants Younger Children Adolescents
Swallowed maternal blood Anal fissure Juvenile polyps Infectious colitis
Anal fissure Allergic colitis Anal fissure Polyps
Allergic colitis Infectious colitis Infectious colitis Inflammatory bowel
Infectious colitis Intussusception Henoch-Schönlein disease
Necrotizing enterocolitis Volvulus purpura Hemorrhoids
Coagulopathy Meckel diverticulum Lymphonodular Anal fissure
Meckel diverticulum Juvenile polyps hyperplasia Meckel diverticulum
Volvulus Vascular malformation Intussusception Hemolytic uremic
Intussusception Intestinal duplication Meckel diverticulum syndrome
Hirschsprung disease Pseudo membranous Inflammatory bowel Henoch-Schönlein
Intestinal duplication colitis disease purpura
Ischemic colitis Hemolytic uremic Pseudomembranous
Vascular lesion syndrome colitis
Pseudomembranous Ischemic colitis
colitis AV malformation
Ischemic colitis Vasculitis
Vasculitis Vascular lesions
Vascular lesions
III. Initial Evaluation

A. Test for blood in the stool
1. Hemoccult
a. The reagent contains peroxide, which interacts with peroxidases in hemoglobin
to cause a color change
2. False negatives can be caused by large amounts of ascorbic acid in the diet, or if
intestinal bacteria degrade hemoglobin to porphyrin
3. False positives can be caused by large amounts of rare red meat and certain vegetables,
including broccoli, cauliflower, turnips, radishes, and cantaloupe
B. Foods and medicines that can make stool appear bloody
1. Red licorice
2. Red soda, Kool-Aid® and Jell-o®
3. Beets
4. Iron
5. Pepto-Bismol
6. Red Hot Cheetos
C. Upper vs lower intestinal tract bleeding
1. If there is blood on the surface of the stool, this is usually of anal-rectal origin
2. Bright red blood mixed in with stool is usually from below the ligament of Treitz, but
could be from above if massive
3. Melanotic stools are usually from above the ligament of Treitz
D. Evaluation of bleeding
1. History
a. Amount of blood and appearance of stool (bright red blood vs tarry stools)
b. How long has there been bleeding?

c. Associated symptoms of fever, weight loss, diarrhea, vomiting, constipation,
pain, change of appetite
d. Diet
e. Travel
f. Family history
g. Growth
2. Physical exam
a. Pallor
b. Rashes, petechiae, purpura, hemangiomas, jaundice, telangiectasias
c. Mouth lesions
d. Abdominal exam for masses, tenderness
e. Rectal exam
f. Vital signs
g. Jaundice (hepatic failure) or cutaneous bruising
IV. Initial Management

A. Assess the airway, breathing, and circulation (ABC’s)
B. Hemodynamic stabilization
1. Isotonic crystalloid and PRBCs
2. Tachycardia indicates >10% loss of intravascular blood volume
3. Positive orthostatics indicates 20% loss
4. Prolonged capillary refill indicates 25% loss
5. Mental status changes indicates 30%–40% loss
C. Place NG and assess aspirate if melanotic stools are the concern
1. Be cautious if there are signs of portal hypertension
D. Monitor HR, BP, and urine output
E. Correct coagulopathies and electrolyte abnormalities
1. If active bleeding and PT is >1.5 x control value, infuse FFP
2. If platelets <50,000, transfuse
F. Endoscopy once stabilized
G. Surgical emergencies: volvulus, nonreducible intussusception, Meckel diverticulum, vascular
lesions and malformations
H. Capsule endoscopy: if unidentified bleed despite endoscopy, do UGI with SBFT prior
I. Consider CT angiography if capsule does not define etiology
V. Specifics on selected causes of lower intestinal bleeding

A. Intussusception
1. Part of the intestine invaginates into another section of intestine
2. Early symptoms can include nausea, vomiting, pulling legs to the chest area, and
intermittent, moderate-to-severe, cramping abdominal pain. Later signs include rectal
bleeding, often with red currant jelly stool
3. Treatment
a. Air or water soluble contrast enema
b. If unable to reduce the intussusceptions, surgery is required
B. Meckel diverticulum (see Meckel Diverticulum chapter)
1. The etiology of GI bleeding is ileal ulceration caused by acid secretion from the ectopic
gastric mucosa
a. Erosion into small arterioles leads to painless, brisk rectal bleeding
b. The site of ulceration is generally at the base of the diverticulum, where the
ectopic mucosa and the normal ileum join
Recommended Reading
Leung AK, Wong AL. Lower gastrointestinal bleeding in children. Pediatr Emerg Care. 2002 Aug;18(4):319-
23. Review.
Arain Z, Rossi TM. Gastrointestinal bleeding in children: an overview of conditions requiring nonoperative
management. Semin Pediatr Surg. 1999 Nov;8(4):172-80. Review.
4I-1. Inflammatory Bowel
Disease—Crohn’s Disease
Steven Colson, MD
Edwin deZoeten, MD, PhD
I. Presentation
A. Common presenting features of Crohn’s disease (CD):
1. Abdominal pain (67%–75%)
a. RLQ (terminal ileum, cecum), periumbilicial (colon, diffuse), epigastric
(stomach, duodenum)
b. Persistent, severe, awakes patient from sleep
c. Odynophagia, dysphagia (esophagus)
2. Diarrhea (30%–65%)
a. Severe, frequently nocturnal
b. Gross blood: more frequent with colonic disease and severe small
bowel ulceration
3. Weight loss (55%–65%)
4. Growth failure (30%): Decreased height and/or weight velocity, delayed puberty
Etiology: Deficient nutritional intake, poor digestion and absorption, increased metabolic
demand, corticosteroid use
5. Nausea/vomiting (6%–25%): With any bowel involvement, especially severe colitis
6. Perirectal disease (25%): Tag, fissure, abscess (painful), fistula
7. Hematochezia (20%–43%)
8. Fever: Low grade or waxing and waning
9. Fatigue (13%–27%)
10. Anorexia
B. Extraintestinal manifestations (EIM) (anywhere between 25%–35%)
1. Arthralgia (17%–40%), arthritis (1%–10%): axial or peripheral joints, colon > small
bowel disease
a. May precede GI symptoms, often improves as IBD is treated
b. Type I: <5 joints, larger joints, brief, associated with Crohn’s flares
c. Type II: multiple small joints, independent of Crohn’s activity
2. Aphthous stomatitis (5%–20%): tends to parallel IBD activity
3. Skin
a. Perianal disease (common) - abscess, fistulae, tags, and fissures
b. Erythema nodosum (1.5%-10%): active disease
c. Pyoderma gangrenosum (<1%–2%): may be unrelated to disease activity
d. Metastatic Crohn’s disease: granulomatous lesions, independent of
disease activity
4. Hepatobiliary/pancreas: often asymptomatic with liver disease
a. Elevation of aminotransferases (10% at diagnosis)
b. Primary sclerosing cholangitis (<1%–1%), autoimmune hepatitis (<1%),
and overlap syndrome
c. Pancreatitis (<1%)
5. Ankylosing spondylitis (<1%): seronegative vertebral arthropathy, associated with
HLA-B27, sacroiliitis and progressive fusion of vertebral column
6. Eye: often with other EIM
a. Uveitis (<1%–6%): slit lamp, often asymptomatic and independent of IBD
activity
b. Episcleritis: often parallels IBD activity
c. Iritis
7. Clubbing: particularly with small bowel involvement
8. Hypercoagulable state: deep vein thrombosis, pulmonary emboli, neurovascular disease;
higher risk with active disease

9. Renal: ureteral obstruction and hydronephrosis (due to phlegmon), enterovesicular
fistula, perinephric abscess, nephrolithiasis (oxalate, urate, phosphate)
10. Bone:
a. Osteopenia: malnutrition, inadequate calcium intake or absorption, vitamin D
deficiency, proinflammatory cytokines, corticosteroids
b. Bone loss: fractures, loss of height, severe pain and disability
11. Anemia: iron, vitamin B12 and folic acid deficiency, autoimmune hemolysis, suppression
of erythrocyte production by cytokines
12. Granulomatous inflammation at any body site
C. Distribution:
1. Ileocolitis (40%–60%), gastroduodenal (up to 30%), small bowel alone (20%–30%)
2. Under 5 years old: higher likelihood of isolated colonic involvement
D. Physical exam features of CD
1. Short stature, low BMI; RLQ tenderness, fullness, and/or mass; clubbing; pallor
(if anemic); oral aphthous ulcers; perianal disease (tag, fissure, ulceration, fistula,
abscess); scleral injection; skin rashes; joint pain
II. Diagnosis
A. History of common presenting features and consistent physical exam
B. Lab testing
1. Evaluate for infection: Salmonella, Shigella, Campylobacter, E coli O157:H7, Yersinia,
Aeromonas, Clostridium difficile, Cryptosporidium, Giardia
2. Elevated ESR and CRP (85%–100%), thrombocytosis (85%), anemia (16%–77%),
leukocytosis, hypoalbuminemia (35%–64%), guaiac-positive stool (35%), elevated
aminotransferases (10%)
3. May have decreased iron, zinc, magnesium, calcium, phosphorus levels
4. ASCA (specificity 88%–97%), pANCA, anti-OmpC, and anti-CBir may be positive,
although these markers can vary significantly in pediatrics from year-to-year and thus
may not be considered a reliable marker for this population
5. Stool lactoferin and calprotectin (markers of neutrophil inflammation): elevated
(>7.25 μg/dL and >100 μg/g respectively)
C. Radiologic evaluation
1. Plain abdominal radiograph (abnormal in 2/3): mural thickening, dilatation, abnormal
gas and stool
2. Contrast studies: upper GI series with small bowel follow-through (differentiates UC
from CD, strictures, fistulae) and barium enema
3. Abdominal CT scan: bowel wall thickening, luminal narrowing and obstruction,
mesenteric involvement, abscess, fistulae
4. MRI: has the advantage of avoiding radiation, good soft tissue visualization, good
abscess visualization
5. Ultrasound: abscess, wall thickening, hyperemia, very operator dependent
D. Perianal fistula evaluation (diagnostic accuracy): examination under anesthesia (91%), MRI
(87%), endoscopic ultrasound (91%), any two (100%)
E. Endoscopy:
1. Early: focal aphthous ulcers
2. Later: ulcers enlarge and become deep, linear transverse ulcers, with skip lesions.
3. Severe: cobblestone appearance, strictures, stenosis
4. Terminal ileum: most commonly involved (exudates, thickening, and stenosis)
5. Upper intestinal endoscopy:
a. Esophagus: erythema, small erosions to transmural disease and fistula,
polypoid lesions, pseudomembranes, strictures
b. Stomach and duodenum: ulcers (superficial, aphthous, linear, and serpigenous),
nodularity, cobblestoning, rigidity
F. Histology: transmural inflammation, cryptitis, focal crypt abscesses, increased lamina propria
cellularity, some mucous depletion, deep granulomas, fissures and sinuses, submucosal fibrosis,
neuromatous hyperplasia
III. Management
A. Medical Therapy
1. 5-ASA (sulfasalazine, mesalamine)
a. Use: induction of remission in mild-to-moderate disease, maintenance of
remission. Lacking strong evidence in pediatrics
b. Mechanism: likely through anti-inflammatory action: inhibits prostaglandin,
leukotriene synthesis, other effects. Location of drug release dependent on
formulation. Drug is minimally absorbed
c. Side effects: headache, nausea, anorexia, diarrhea, joint pain, allergic reaction,
folic acid deficiency (sulfasalazine), interstitial nephritis, proteinuria, pancreatitis,
leukopenia, hepatitis
d. Monitoring: CBC, liver chemistries, BUN, creatinine, and urinalysis
2. Antibiotics (ciprofloxacin, metronidazole)
a. Use: induction of remission in mild-to-moderate disease, maintenance of
remission, perianal disease. Lacking evidence in pediatrics
b. Mechanism: reduction of luminal bacterial content, altering colon microflora,
reduction of bacterial invasion, and limiting bacterial translocation
c. Side effects: peripheral neuropathy (metronidazole), bone growth effects in
animals (ciprofloxacin)
d. Monitoring: none
3. Steroids (prednisone, methylprednisolone, budesonide)
a. Use: Induction of remission in mild-to-severe disease
b. Mechanism: immune suppression via gene transcription: proinflammatory
mediators (prostaglandins) suppressed, anti-inflammatory mediators
(IL-10) increased. Nongenomic mechanisms also exist (NO production).
Often leaves mucosal healing incomplete
c. Side effects: growth delay, bone loss/disease, hypertension, hyperglycemia,
acne, hirsutism, facial swelling (moon facies), weight gain, infection, mood
disturbance, insomnia, and cataracts
d. Monitoring: before starting therapy: PPD, chest x-ray if symptomatic, and
Varicella titer (if possible, immunize before therapy if negative).
During therapy: growth, eye exam
4. 6-MP/azathioprine
a. Use: maintenance of remission, perianal disease
b. Mechanism: antimetabolite actions leading to immunosuppression and
lymphocytotoxicity
c. Side effects: nausea, vomiting, diarrhea, allergic reaction, bone marrow
suppression (dose related), hepatotoxicity (dose related), pancreatitis
(idiosyncratic), infections (HSV, HPV), lymphoma including hepatosplenic T-cell
lymphoma (HSTCL), nonmelanoma skin cancer (NMSC)
d. Monitoring: TPMT phenotype or genotype before initiating therapy (adjust dose
with low activity and do not use with absent activity), CBC and liver enzymes at
0, 2, 4, and 8 weeks, then every 3 months. Varicella titer (if possible, immunize
before therapy if negative)
5. Methotrexate
a. Use: induction and maintenance of remission in moderate-to-severe disease
b. Mechanism: in lower doses (for IBD), mechanisms not fully known (possibilities:
induction of apoptosis, alteration of adenosine concentration and subsequent
adaptive immune response, direct effect on cytokines). In higher doses, blocks
DNA synthesis, leading to antiproliferative effects
c. Side effects: nausea and vomiting (may need antiemetics), stomatitis, anorexia,
diarrhea, bone marrow suppression, hepatotoxicity, upper respiratory infections,
pneumonitis, hypersensitivity skin reactions, teratogenicity, folate deficiency
d. Monitoring: CBC and liver enzymes at 0, 2, 4, and 8 weeks, then every 3
months. Varicella titer (if possible, immunize before therapy if negative).
Consider PFTs

6. Tacrolimus, cyclosporine
a. Use: induction of remission in moderate-to-severe disease, perianal disease
b. Mechanism: calcineurin inhibitors, leading to decreased production of IL-2 and IL-4, which
impairs T-cell > B-cell function
c. Side effects: hypertension, nausea, transaminitis, infection, nephrotoxicity, glucose intolerance,
hypomagnesemia, seizures, infection (PCP, Aspergillus), cosmetic (cyclosporine)—gingival
hyperplasia, hirsutism, coarsening facial features
d. Monitoring: Ca, Mg, Phos, BUN/creatinine, CBC, transaminases, lipids, cholesterol, fasting
glucose, drug trough levels, use PCP prophylaxis
7. Anti-TNF (infliximab, adalimumab-approved for use in children with JRA and adults with Crohn’s)
a. Use: induction and maintenance of remission in moderate-to-severe disease, perianal disease
b. Mechanism: monoclonal IgG1 antibody to TNFα (infliximab-chimeric, adalimumab-fully human),
neutralizes TNF, blocks leukocyte migration, induces apoptosis of T-cells and monocytes,
complement fixation, complement-dependent cytotoxicity, antibody-dependent cellular
cytotoxicity
c. Side effects: infusion reaction, nausea, fever/chills, hives, fatigue, lymphoma including HSTCL,
NMSC, TB, cytopenia, transaminitis, psoriasis, demyelination syndromes, lupus-like reactions
d. Monitoring before starting therapy: PPD, chest x-ray if symptomatic, and Varicella titer (if
possible, immunize before therapy if negative). CBC, transaminases, skin exams
IV. Non-medical Therapy

A. Surgery (70%–80% of patients during course of illness)
1. Indications include those listed in the Complications section below
2. NOD2/CARD15 variant alleles increase risk for surgery
3. Limited small bowel resection, ileocecectomy, ileostomy, colectomy (segmental, subtotal, or
proctocolectomy), stricturoplasty, fistulotomy, incision and drainage of abscess, transanal dilation
4. May result in surgical remission of disease, but post-op recurrence is common
B. Nutrition therapy:
1. Use: induction and maintenance of remission in moderate-to-severe disease
2. Mechanism unknown. Elemental and polymeric formulas with equivalent efficacy. Ideally 80%–100%
caloric intake through formula
3. Side effects: largely related to NG tube placement; may have diarrhea
V. Complications
1. Intestinal obstruction
2. Intestinal perforation
3. Phlegmon
4. Drug allergies
5. Perianal disease
6. Progression of disease
7. Bleeding
8. Fistula
9. Abscess
10. Drug resistance
11. Urologic complications
12. Growth failure
VI. Outcomes
A. Dependent in part on disease phenotype (inflammatory, stricturing, penetrating) – may change over time to latter
two
B. Relapse of disease activity is common after induction of remission
C. Though children often respond to steroids, dependence is common (31% at 1 year with immunomodulator use)
D. Drug-free maintenance of remission may be possible in small subset of patients
E. Young adults who develop CD often have short stature as adults (25% <5 percentile)
F. Cancer: risk unknown in children; increased in adults (colon, small bowel, lymphoma)
Recommended Reading
Dotson JL, Hyams JS, Markowitz J, et al. Extraintestinal manifestations of pediatric inflammatory bowel
disease and their relation to disease type and severity. J Pediatr Gastroenterol Nutr. 2010;51(2):140-145.
Mamula P, Markowitz JE, Baldassano, RN. Pediatric Inflammatory Bowel Disease. New York, NY: Springer;
2008.
Russo P, Ruchelli E, Piccoli DA. Pathology of Pediatric Gastroenterology and Liver Disease. New York, NY:
Springer; 2004.
Schwartz DA, Wiersema MJ, Dudiak KM, et al. A comparison of endoscopic ultrasound, magnetic resonance
imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology.
2001;121(5):1064-1072.
Stephens M, Rosh JR. A case-based monograph focusing on IBD: optimizing therapeutic safety in children
and young adults with IBD. NASPGHAN, CDHNF and TCL Institute, 2010.
2006.

4I-2. Inflammatory Bowel
Disease—Ulcerative Colitis
Steven Colson, MD
Edwin deZoeten, MD, PhD
I. Presentation
A. Common presenting features of ulcerative colitis (UC):
1. 40%–50%: mild disease; 35%: moderate disease; 10%–15%: acute, fulminant disease
2. Diarrhea (74%–98%)
a. Most common in the morning when arising, after eating, at night
b. Often tenesmus and urgency
3. Hematochezia (83%–96%): streaks of blood, clots or large blood
4. Abdominal pain (43%–88%): crampy, lower abdomen
5. Anorexia (6%–50%)
6. Nocturnal diarrhea (43%)
7. Weight loss (31%–42%)
8. Growth failure (5%–10%)
9. Fever (13%)
10. Vomiting (11%)
11. Fatigue (2%–12%)
B. Extraintestinal manifestations (EIM) (any 24%)
1. Arthralgia (15%–32%), arthritis (2%–20%)
a. Arthritis can be peripheral migratory of large joints, or monoarticular (knees and
ankles) and nondeforming
b. Often mirrors bowel disease activity
2. Hepatobiliary/pancreas: often asymptomatic with liver disease
a. Elevation of aminotransferases
b. Primary sclerosing cholangitis (PSC) (3%), autoimmune hepatitis (<1%) and
overlap syndrome
1) Appears before, during or after IBD diagnosis
2) PSC increases risk for colorectal cancer; risk decreased in adults by
using ursodeoxycholic acid
c. Pancreatitis (1%)
3. Aphthous stomatitis (3%)
4. Skin: present with active disease
a. Erythema nodosum (<1%): raised, painful, red nodules over tibia
b. Pyoderma gangrenosum (0%–2%): small, painful, sterile pustules → larger
sterile abscess
5. Eye: (iritis/uveitis <1%): uveitis may be asymptomatic, episcleritis
6. Hypercoagulable state: sites of thrombus are extremities, portal/hepatic vein, lung,
central nervous system; multiple potential etiologies described
7. Ankylosing spondylitis (rare): seronegative vertebral arthropathy, associated with
HLA-B27, sacroiliitis and progressive fusion of vertebral column
8. Bone: less risk of decreased bone mass than Crohn’s disease
9. Anemia: iron and folic acid deficiency, autoimmune hemolysis, anemia or chronic disease
C. Distribution:
1. Pancolitis (41%), left-sided (34%), proctitis/proctosigmoiditis (26%)
2. Can have esophageal disease (15%–50%) gastroduodenal inflammation (25%–69%)
and backwash ileitis
D. Physical exam features of UC:
1. Abdominal tenderness often in LLQ or mid-epigastric, without mass; pallor (if anemic);
perianal inspection usually normal; scleral injection; skin rashes; joint pain

II. Diagnosis
A. History of common presenting features and consistent physical exam
B. Lab testing
1. Evaluate for infection: Salmonella, Shigella, Campylobacter, E coli O157:H7, Yersinia,
Aeromonas, Clostridium difficile, Cryptosporidium, Giardia
2. Elevated ESR and CRP (23%–60%), thrombocytosis (70%), anemia (9%–67%),
leukocytosis, hypoalbuminemia (15%), guaiac-positive stool (35%), elevated
aminotransferases
3. pANCA (specificity 65%–95%), ASCA, anti-OmpC and anti-CBir may be positive,
although these markers can vary significantly in pediatrics from year to year and thus
may not be considered a reliable marker for this population
4. Stool lactoferin and calprotectin (markers of neutrophil inflammation): elevated (>7.25
μg/dL and >100 μg/g respectively)
C. Radiologic evaluation
1. Plain abdominal radiograph: nonspecific mucosal edema occasionally noted, marked
colon dilation in toxic megacolon
2. Contrast studies:
a. Upper GI series with small bowel follow-through: differentiate UC from CD
b. Barium enema: rarely used, but can help evaluate extent/severity of disease
and complications. Changes usually contiguous, circumferential and symmetric
without skip lesions. Findings include fine granular pattern (early), flask-
shaped or collar-button ulcers, inflammatory pseudopolyps and lead pipe colon
(longstanding disease)
3. Abdominal CT scan (oral and/or rectal contrast), ultrasound (to monitor disease activity
and assess response to treatment) and MRI (little value over CT in evaluating colonic IBD,
though this assists in avoiding radiation) are also options
D. Endoscopy
1. Early: diffuse erythema and dull-appearing vasculature with friability
2. Later: small to larger ulcers on background of diffuse, continuous inflammation
extending from rectum proximally
3. Longstanding: pseudopolyps
4. Terminal ileum: normal or backwash ileitis
5. Upper intestinal endoscopy: often normal, though may see mild gastritis
E. Histology: acute and/or chronic inflammation limited to mucosa and superficial submucosa,
cryptitis, extensive crypt abscesses, increased lamina propria cellularity, mucous depletion, villous
surface transformation, absence of deep granulomas
III. Management
A. Medical Therapy — For drug mechanisms, side effects and monitoring, see IBD, Crohn’s Disease
section.
1. 5-ASA (sulfasalazine, mesalamine)
Use: induction of remission in mild to moderate disease, maintenance of remission
2. Antibiotics
Use: few studies show efficacy in treating UC
3. Steroids (prednisone, methylprednisolone)
Use: induction of remission in moderate to severe disease
4. 6-MP/azathioprine
Use: maintenance of remission
5. Methotrexate
Use: less effective in UC than CD
6. Tacrolimus, cyclosporine
Use: induction of remission in severe disease
7. Anti-TNF (infliximab, adalimumab-neither approved in pediatrics)
Use: induction and maintenance of remission in moderate to severe disease
B. Surgical Therapy — 30%–40% of patients will require surgical therapy at some point.
1. Indications include those listed in Complications section below: urgent/emergent (1-6),
elective (7-10)
2. Types:
a. Proctocolectomy with ileal pouch-anal anastamosis (IPAA): current standard
of care, most often J-pouch, usually 2–3-stage procedure with temporary
ileostomy
b. Subtotal colectomy with closure of rectum (Hartmann procedure) and
ileostomy: for urgent operations
c. Proctocolectomy with end ileostomy: ileostomy is permanent
3. Complications (up to 50% of IPAA)
a. Postoperative period: wound infection, ileus, high ileostomy output,
anastamosis dehiscence
b. Adhesion and small bowel obstruction, parastomal hernia, pelvic abscess,
cuffitis (with residual rectal tissue)
c. Pouch: pouchitis (common, acute or chronic, metronidazole and/or
ciprofloxacin), anastamotic stricture (10%–15%, require dilation), irritable
pouch syndrome, mechanical pouch dysfunction
d. Ileostomy: prolapse, stenosis, retraction
C. Complications
1. Intractable bleeding
2. Toxic megacolon (increased risk with steroid, opiate use)
3. Persistent pain
4. Repeated sepsis
5. Colonic perforation
6. Colonic stricture
7. Refractory to medical management or complications
8. Chronic malnutrition leading to poor growth, delayed puberty
9. Steroid dependence
10. Dysplasia
D. Outcomes
1. Changing as diagnosis and therapy improves; data may differ in current biologic therapy
era
2. Recent data (1996): >80% resolution of symptoms by 6 months, 55% symptom-free at
yearly follow-ups
3. Corticosteroids used in 70% of moderate/severe disease by 1 year
4. Colectomy: at 1–5 years: 1%–8% initial mild disease, 8%–26% moderate-severe
disease
5. Cancer: mucosal dysplasia, although rare, can be found in children and warrants
colectomy. Colonoscopic surveillance should begin around 8 years postdiagnosis
Recommended Reading
Dotson JL, Hyams JS, Markowitz J, et al. Extraintestinal manifestations of pediatric inflammatory bowel
disease and their relation to disease type and severity. J Pediatr Gastroenterol Nutr. 2010;51(2):140-145.
Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in
children. J Pediatr. 1996;129:81-88.
Mamula P, Markowitz JE, Baldassano RN. Pediatric Inflammatory Bowel Disease. New York, NY: Springer;
2008.
Russo P, Ruchelli E, Piccoli DA. Pathology of Pediatric Gastroenterology and Liver Disease. New York, NY:
Springer; 2004.
Schwartz DA, Wiersema MJ, Dudiak KM, et al. A comparison of endoscopic ultrasound, magnetic resonance
imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology.
2001;121(5):1064-1072.
Stephens M, Rosh JR. A case-based monograph focusing on IBD: optimizing therapeutic safety in children
and young adults with IBD. NASPGHAN, CDHNF and TCL Institute, 2010.

4I-3. Other Inflammatory
Lesions of the Bowel
Ying Lu, MD
The differential diagnosis for bowel inflammation includes infection, inflammatory bowel disease, vasculitis,
Henoch-Schönlein purpura, hemolytic uremic syndrome, protein-losing enteropathy and Behçet’s disease.
I. Henoch-Schönlein Purpura (HSP)

A. Epidemiology
1. 90% of HSP patients are under 10 years old, most commonly between 3–7 years old
2. Typically occurs during autumn and winter
B. Etiology
1. Genetic predisposition (HLA-DRB1*01 and DRB1*11)
2. Infection, most often viral or Streptococcus
3. Mediated by IgA deposition in various sites
C. Clinical manifestations
1. Skin (first sign): painless palpable purpura on back, buttocks and legs, nonpitting edema
2. GI (small bowel most affected): colicky periumbilical and epigastric abdominal pain
worse after eating, nausea, vomiting, bleeding (occult > overt bleed, melena >
hematochezia), ileoileal intussusception, perforation, mesenteric vasculitis (which
may lead to bowel necrosis and massive GI bleed), protein-losing enteropathy (PLE),
cholecystitis, pancreatitis
3. Joints: symmetrical arthralgia or arthritis of large joints in legs
4. Renal (onset about 1 month after appearance of purpura): microscopic hematuria with
or without proteinuria, may develop rapidly progressive glomerulonephritis or ESRD
D. Histology
1. Leukocytoclastic vasculitis affecting capillaries, venules and arterioles
2. IgA and C3 deposits
E. Labs and imaging
1. UA—hematuria with or without proteinuria
2. Moderate leukocytosis
3. Mild elevation of acute phase reactants
4. Increased serum IgA
5. Elevated ALT and GGT
6. US—bowel wall thickening, intussusception, hepatomegaly, gallbladder wall thickening
7. Barium studies—mucosal fold thickening, separation of loops due to intramural edema
and bleeding, mucosal scalloping, thumb printing
8. CT—bowel wall thickening, engorged mesenteric vessels, target sign
9. Endoscopy—erythema, edema, petechiae, submucosal hemorrhage, purpura, erosions,
ulcerations, gastritis, duodenitis
F. Management
1. Supportive care
2. Maintain hydration, nutrition and electrolyte balance
3. Analgesics for joint pain
4. NSAIDs for severe arthritis (avoid in patients with GI and renal problems)
5. Antihypertensive medications and dialysis as needed
6. Steroids controversial and reserved for severe systemic manifestations and renal
involvement
a. In patients with glomerulonephritic disease, may treat with steroids with or
without cytotoxic agents
b. Abdominal pain will eventually resolve, but steroids will shorten its duration
c. Steroids may be effective for massive GI bleed and ischemic bowel from
widespread mesenteric vasculitis
d. Steroids may be used in children with painful cutaneous edema

e. Surgery for intussusception (if it does not reduce spontaneously over 24 hours),
infarction, perforation
G. Prognosis
1. Self-limited, usually lasts 1–4 weeks
2. Correlates with degree of renal pathology, defined as presence of crescents
3. 15%–40% have at least one recurrence within 4 months, which is usually milder and
shorter than the first episode
II. Hemolytic Uremic Syndrome (HUS)

A. Etiology
1. Triggers of vascular injury (eg, Shiga toxin, virus, immune complexes, drugs) and
predisposing conditions (such as disorders of complement system) lead to endothelial
cell damage and thrombotic microangiopathy
B. Clinical manifestations: hemolytic anemia, thrombocytopenia, acute renal failure
C. Diarrheal associated form (>90% of HUS cases)
1. Most common between 6 months and 5 years old
2. Triggered by intestinal infection with enterohemorrhagic E coli (EHEC) that produce
Shiga toxin (Stx)
3. Manifestations
a. GI: diarrhea (nonbloody > bloody), abdominal pain, dehydration
b. Neuro: seizures, coma, brain edema
c. Heme: pallor
d. Renal: hematuria (usually microscopic), edema, hypertension, renal insufficiency
4. Labs
a. Anemia with schistocytes, thrombocytopenia
b. High creatinine or low GFR
c. Increased LDH, decreased haptoglobin
d. Positive stool culture
e. Elevated amylase, lipase, transaminase, alkaline phosphatase, GGT
5. Self-limited course (1–3 weeks) with relatively good short-term outcome, but some may
develop renal sequelae
D. Nondiarrheal associated form (aka atypical HUS)
1. Not associated with diarrhea and Stx-producing E coli
2. Caused by various triggers (eg, infection, disorders of complement system, drugs,
malignancy)
3. Small percentage caused by streptococcus pneumonia, which presents with more severe
symptoms, higher risk of renal complications and higher mortality rate
4. Poorer prognosis
5. More likely to have severe HTN and chronic end-stage renal failure, and to recur
E. Management
1. Find cause of HUS
2. Maintain hydration, nutrition and electrolyte balance
3. Transfuse with PRBC and platelets prn (caution: platelets may lead to microthrombi)
4. Dialysis as needed
5. Antihypertensive and antiseizure medications prn
6. No antibiotics given for EHEC
III. Protein-losing Enteropathy (PLE) — (see section on protein-losing enteropathy)
IV. Behçet’s disease

A. Chronic relapsing multisystemic vasculitis
1. Starts around 2nd to 4th decade of life
2. Etiology unknown, but possibly secondary to autoimmune reaction triggered by
infection or antigen in a genetically predisposed person (HLA-B51)
3. Prevalent among Silk Route population from Eastern Asia to Mediterranean Basin
4. Diagnosis based on clinical criteria
B. Clinical manifestations
1. Mucocutaneous lesions (hallmark) often precede other manifestations
a. Multiple recurrent painful oral and genital ulcers similar to aphthae in
appearance
2. Eye: uveitis > retinal vasculitis
3. Vascular: systemic vasculitis (venous > arterial system) affecting vessels of all sizes
a. Thrombophlebitis, Budd-Chiari, pulmonary arterial aneurysm contributes to
mortality
4. Joints: nonerosive, nondeforming, monoarticular arthritis
5. GI: abdominal pain, GI bleed, fever, weight loss, diarrhea, constipation, perforation,
fistulas, ischemia, infarction, aphthous-like ulcers in ileocecal area, pancreatitis,
hepatobiliary complications, normal growth
6. Skin: erythema nodosum, pustules, acne-like lesions, positive pathergy test (pustule
develops 24–48 hours after needle prick to skin)
7. Neuro (rare but poor prognosis)
C. Studies
1. Barium studies: ulcers, thickening of surrounding mucosal folds
2. CT or MRI: bowel wall thickening
3. Colonoscopy: ulcers in ileocecal area, discontinuous bowel involvement with relative
sparing of rectum, no granulomas or cobblestoning
4. Capsule endoscopy: ulcers, pseudopolypoid lesions
D. Treatment
1. Topical treatment: corticosteroids, antimicrobial agents, sucralfate, silver nitrate,
anti-inflammatory agents
2. Systemic corticosteroids, colchicine, dapsone, thalidomide, methrotrexate, azathioprine,
cyclophosphamide, cyclosporine A, mycophenolate mofetil, interferon-alpha, anti-TNF
agents
Recommended Reading
Alpsoy E, Akman A. Behçet’s disease: an algorithmic approach to its treatment. Arch Dermatol Res.
2009;301:693-702.
Ebert EC. Gastrointestinal manifestations of Behçet’s disease. Dig Dis Sci. 2009;54:201-207.
Ebert EC. Gastrointestinal manifestations of Henoch-Schönlein Purpura. Dig Dis Sci. 2008;53:2011-2019.
Gonzalez LM, Janniger CK, Schwartz RA. Pediatric Henoch-Schönlein Purpura. Int Soc Dermatol.
2009;48:1157-1165.
Scheiring J, Rosales A, Zimmerhackl LB. Today’s understanding of the haemolytic uraemic syndrome. Eur J
Pediatr. 2010;169:7-13.

4I-4. Colitis Not Due to
Inflammatory Bowel Disease
Ghassan Wahbeh, MD
Infectious and noninfectious causes beyond chronic idiopathic inflammatory bowel disease.
I. Introduction
A. The right colon is tasked with absorption of residual intestinal fluid and salt
B. The left colon handles the storage and evacuation of stool
C. Abundant bacteria and yeast colonize the colon
D. The composition of the flora varies according to dietary factors and host-specific defenses and
susceptibilities
E. The term colitis is used to denote inflammation of the colon and/or symptoms thereof, namely
pain, diarrhea, tenesmus, passage of mucus and blood
F. At the microscopic level, colitis indicates a change in the number and makeup of immune cells
within the colonic wall or its structural architecture
II. Infectious Colitis

A. Symptoms of infectious colitis are generally acute
B. Macroscopically, acute infectious colitis can look like ulcerative colitis
C. Microscopically, there are no significant architectural changes and neutrophils are the
predominant immune cell type present
D. Most infections are self-limited in the immune-competent host
E. The most common agents include:
1. Clostridium difficile (Figure 1)
a. Gram-negative, anaerobic, spore-forming, toxin-producing bacteria
b. In nosocomial setting:
1) Rising cause of morbidity and mortality due to increasing strain
virulence, toxin novelty (binary toxin) and antibacterial resistance
c. Part of the normal flora
d. Very commonly colonizing the younger gut (immunity to toxins thought to be
due to absence of epithelial toxin receptors)
e. Alteration in the commensal flora is what drives C diff to turn from bystander
to pathogen
f. Risks factors
1) Antibiotics, hospitalization, older age, immune suppression and IBD
2) Association with acid suppression possible
g. Symptoms are variable and can be severe, with fever, leukocytosis and toxic
megacolon
h. Worth noting that frank bleeding with C diff (a noninvasive pathogen) is
uncommon and its presence should prompt suspicion for other underlying
causes
i. In the right clinical setting, demonstrating toxin presence (toxin assays, recently
PCR) is diagnostic
j. Gross appearance
1) Pseudomembranes are quite typical in moderate/severe
disease (Figure 1)
k. Treatment options include metronidazole, vancomycin, supplemental probiotics,
toxin binders and pooled immune globulin infusions
l. C diff can be detectable for weeks after therapy
m. Disease recurrence can be challenging to address

2. Yersinia enterocolitica
a. Ileocecal inflammation in younger children and infants
b. Causes pain and diarrhea with bleeding
c. Can be confused with Crohn’s disease
d. Course can be self-limited without need for antibiotic treatment
3. Campylobacter jejuni
a. The most common cause of colitis worldwide
b. (see section on Enteric Infections)
4. Salmonella typhi, Shigella and E coli O157:H7
a. Invasive pathogens that occur endemically or sporadically
b. (see section on Enteric Infections)
5. Amoebiasis
a. In endemic areas
b. Left-sided colitis and systemic symptoms
6. Cytomegalovirus (CMV) (Figure 2)
a. Causes colitis in immunocompromised host
b. Manifests with ulceration and edema
c. Can be a complicating infection in IBD, more so when steroids are used
III. Noninfectious Colitis

In this category, chronic idiopathic IBD is relatively common and will be reviewed separately.
Some less common causes are listed below.
A. Microscopic colitis
1. Grossly normal-appearing colon
2. Microscopic inflammation: lymphocyte predominant lymphocytic colitis and/or collagen
deposit–related “collagenous colitis” (Figure 3)
3. Presents with persistent watery diarrhea
4. Cause remains unknown, some association with celiac disease and NSAID has been
suggested
5. The inflammation can improve spontaneously. Therapies have not been extensively
evaluated, including bismuth salicylate, budesonide, cholestyramine and azathioprine
B. Behçet’s disease
1. Multiorgan disease that affects young adults
2. (see section on Other Inflammatory Lesions of the Bowel)
C. Eosinophilic colitis
1. Commonly a benign transient phenomenon
2. In infants attributed to cow’s milk protein (or other protein) allergy
3. Also found in exclusively breastfed babies
4. Beyond infancy, isolated eosinophilic colitis is rare (vs colitis as part of a systemic
eosinophilic syndrome like Churg-Strauss syndrome)
5. If at risk, parasitic infections should be ruled out as a cause
6. Seen in postorgan transplantation patients with immune suppression (eg, tacrolimus)
or other drug exposure
7. Manifestations are variable, including diarrhea, rectal bleeding, abdominal pain, anemia
and peripheral eosinophilia
8. Gross exam may show a normal colon or prominent lymph nodules, with eosinophils on
histologic exam
9. If symptomatic, medication withdrawal or allergy trigger elimination (when identified)
are indicated
10. Rarely, steroids are needed
D. Graft-vs-Host disease (GVHD)
1. One of the most common complications of hematopoietic stem cell transplantation
2. (see section on Graft Vs Host Disease)
E. Neutropenic colitis (typhlitis)
1. Presents with a triad of fever, abdominal pain and neutropenia
2. The colon wall is thickened when imaged
3. Conservative treatment is usually successful
4. Colonoscopy and surgery are not commonly indicated in this setting.
F. Nonsteroidal anti-inflammatory drugs
1. Cause intestinal injury by inhibiting the cyclooxygenase system and perhaps other
nonprostaglandin-related mechanisms
2. Similar to the upper gastrointestinal tract, NSAIDS can cause colonic ulceration,
inflammation and bleeding
3. Most NSAID effects on the lower intestines are asymptomatic
4. Degree of injury varies with the NSAID type. For example, some pass through the
enterohepatic circulation
5. The bacterial flora composition and concomitant antibiotic use may affect the degree of
NSAID injury as well
G. Solitary rectal ulcer
1. Uncommon condition
2. Localized ulceration in the anterior rectal wall, edema and, occasionally, polypoid lesions
are seen
3. It is attributed to straining and dysfunctional stooling dynamics that cause the anterior
rectal wall to face direct mucosal pressure against a nonrelaxing pelvic floor
4. Treatment lies in improving defecation pattern, including stool softeners and,
rarely, surgery
H. Radiation colitis
1. Acute or chronic
2. Appears months to years after radiotherapy
3. Symptoms are variable and can be severe
4. Last for months to years
I. Other causes of colitis occur less commonly
1. Ischemic colitis is rare in children
2. Diversion colitis is nonspecific in appearance macro- and microscopically, although
usually mild. This stresses the importance of the fecal stream and flora in the stability of
the colonic milieu
Figure 1. Clostridium difficile Figure 2. CMV
Figure 3. Microscopic colitis Figure 3B. Bechet’s

Recommended Reading
Felt-Bersma RJ, Tiersma ES, Cuesta MA. Rectal prolapse, rectal intussusception, rectocele, solitary rectal ulcer sSyndrome, and
enterocele. Gastroenterol Clin N Am. 2008;37:645-668.
Koutroubakis IE. Spectrum of non-inflammatory bowel disease and non-infectious colitis.. World J Gastroenterol.
2008;14(48):7277-7279.
Lanas A. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am.
2009;38(2):333-352.
Nielsen OH, Vainer B, Rask-Madsen J. Non-IBD and noninfectious colitis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(1):28-
39.
4J. Perianal Disease
Kriston Ganguli, MD
Gary Russell, MD
I. Rectal Fissure
A. Background
1. Superficial tears of the anoderm, inferior to the dentate line
2. Majority located at the posterior (90%)
3. Typically due to constipation, although this history is only elicited in 25% of cases
B. Classification
1. Primary fissures
a. Not related to underlying pathology
b. Sharply demarcated edges
c. Pathogenesis related to local trauma, typically with passage of a large-caliber,
hard stool in the context of:
1) Anal sphincter hypertonicity and/or
2) Poor andoderm perfusion in the posterior midline
3) The above two entities result in poor wound healing
d. Diarrhea is another possible etiology
2. Secondary fissures
a. Generally the consequence of systemic illness, such as Crohn’s disease
C. Presentation
1. Severe, sharp perianal pain may occur during defecation
2. Pain lasts minutes to hours after passage of stool
3. Associated passage of blood is also common
D. Diagnosis
1. Examination of the anal canal, which may require an anoscope
2. Acute fissures are typically small
3. Chronic fissures may be associated with anal papilla hypertrophy, fibrosis or a skin tag
4. Child abuse should be considered when a large fissure is associated with perianal
bruising
E. Management
1. Acute fissures
a. Three-fold:
1) Decreasing anal trauma associated with stooling using stool softeners,
lubricants or fiber supplementation
2) Reducing anal sphincter tone with warm baths/sitz baths
3) Increasing anal perfusion
b. >80% heal with conservative management
c. Failure to maintain good hygiene may prolong the healing process
d. Refractory cases may respond to a trial of cow’s milk restriction
e. Topical steroids/anesthetics have not been shown to be advantageous
2. Chronic fissures
a. Defined as a lesion persisting for at least 6 weeks after initial management
b. Uncommon in children
c. Despite underlying etiology, chronicity can lead to fibrotic edges or a sentinel
tag
d. Management includes:
1) Decreasing the resting tone of the anus
a) In infants, gentle, daily anal dilatation at home can diminish
anal spasm and pain
2) Other approaches include:
a) Nitric oxide, administered as 0.2% glyceryl trinitrate topically
3 times daily

b) Injectable botulinum toxin, which shows a higher rate of
healing, not adequately studied in children
e. Cases refractory to medical management may require anal dilatation and fissure
excision under general anesthesia
f. In older children and adolescents, lateral internal sphincterotomy without
fissure excision is the approach of choice
II. Anterior Ectopic Anus

A. Background
1. Part of the spectrum of anorectal developmental abnormalities, from high imperforate
anus to anteriorly displaced anus
2. Ectopic anus should not solely explain constipation unless severely displaced
B. Diagnosis
1. Documenting an anal opening not located in the center of the perineal pigmented area
2. Anal Position Index (API) can be used as a guide, to support a suspicion of ectopic anus:
a. Girls: Anus-fourchette/coccyx-fourchette
mean ± SD for API is 0.45 ± 0.08
b. Boys: Anus-scrotum/coccyx-scrotum
mean ± SD for API is 0.54 ± 0.07
C. Management
1. API <2 SD from the mean (eg, <0.29 in girls and <0.40 in boys) is consistent with
anteriorly displaced anus and identifies roughly 4% of infants with the most severe
lesions
2. Surgical consult should be considered if severe constipation is associated with and API
<2 SD from the mean
III. Acute Perianal Strep (Perianal Infectious Dermatitis)

A. Presentation
1. Typically between 6 months to 10 years of age
2. 70% of cases occur in boys
3. Cellulitis occurs in 90% and pruritis in 80% of cases
4. Majority of patients complain of rectal pain, often described as anal burning
during defecation
5. 33% of patients have blood-streaked stools
6. Fecal retention may occur due to pain associated with defecation
7. No fever, headache or malaise should be present, and if present would suggest
subcutaneous involvement
8. Familial spread is not uncommon, particularly between siblings who bathe together
9. Exam reveals a superficial, confluent, erythematous, well-demarcated rash without
induration, extending radially from the anus
10. In the acute stages, affected skin is moist, bright red, tender and may have an associated
white pseudomembrane
11. In chronic cases, painful fissures, dried mucoid discharge or psoriasiform plaques with
yellow peripheral crust may develop
12. Vulvovaginitis or penile involvement may occur
B. Diagnosis
1. Moderate to heavy growth of group A streptococcus (GABHS) from perianal culture
differentiates this from other possible etiologies:
a. Differential diagnosis: S aureus dermatitis psoriasis, seborrheic dermatitis,
candidiasis, pinworm infestation, sexual abuse, guttate psoriasis and IBD
2. Asymptomatic perianal colonization will show light GABHS growth on blood agar
3. Direct GABHS antigen is less sensitive than culture and false negatives are relatively
common early in the course
4. ASLO or anti-DNase B are not helpful
5. Index cases should be cultured
C. Management
1. A 10-day course of oral penicillin treats the majority of cases
2. 40%–50% recurrence rate, hence close follow-up is recommended
3. Erythromycin ES or erythromycin estolate excellent choice for:
a. Penicillin-allergic patients
b. Persistent positive cultures after penicillin
c. Patients infected with S aureus
4. Recurrent perianal dermatitis can be treated effectively with clindamycin or a macrolide,
with or without concurrent mupirocin
IV. Perirectal Abscesses

A. Background
1. Majority result from a crypt of Morgagni infection
2. Resultant fistula is due to spontaneous drainage of the abscess, which results in a
chronic inflammatory tract
3. Fistula in ano occurs in 20%–80% of patients
B. Classification
1. Determined by the anatomic location of the lesion relative to the levator ani and
sphincteric muscles
2. Lesions are located, in decreasing frequency, in the perianal, ischioanal, intersphincteric
and supralevator regions
C. Presentation
1. More common in males
2. 98% report persistent perirectal pain
3. History of a diarrheal illness or anal fissure may be elicited
4. Infectious process due to DM, Crohn’s disease, tuberculosis or AIDS is less common
5. Infants may present with crying or irritability especially with diaper change
6. Tender, indurated area may be appreciated early in the disease process, which may
become erythematous
7. Fevers possible, not necessary
8. Abscesses are identified in 95% of cases when an external perianal exam is combined
with a digital rectal exam
9. Fistulae typically traverse the lowest fibers of the interval sphincter and ultimately
connect to the rectum near the crypts of Morgagni
a. More common in the first 12 months of life
D. Management
1. Depends upon age
a. Infants
1) Uncomplicated lesions successfully managed with careful hygiene and
sitz baths, with or without concurrent antibiotics
2) Fistulae typically follow a self-limited course in healthy infants and are
safely managed with nonoperative approaches
3) Abscesses or Fistulae-in-ano, refractory to conservative management,
may require a surgical approach
b. Older Children
1) Often managed with surgical drainage and examination under general
anesthesia since lesions extend to involve deeper tissues in this age
group
2) Chronic fistulae persisting beyond 3 months despite medical
management with associated recurrent abscesses or persistent drainage
are an indication for surgery
3) Surgical options include fistulectomy, fistulotomy or the use of a seton
loop, which results in division and fibrosis of existing fistulous tracts
4) Patients with persistent or recurrent fistulae should be evaluated for
neutropenia, leukemia, HIV, immunosuppression, diabetes mellitus and
Crohn’s disease

Recommended Reading
Browning J, Levy M. Cellulitis and Superficial Skin Infections. In: Long SS, Pickering LK, Prober CG, ed. Principles and Practice
of Pediatric Infectious Diseases. 3rd ed. Hamilton, Ontario: Churchill Livingstone; 2008: Chapter 72.
Davari HA, Hosseinpour M. The anal position index: a simple method to define the normal position of the anus in neonate.
Acta Paediatr. 2006;95:877.
Ferry GD. Constipation in children: Etiology and diagnosis. Klish WJ, Hoppin AG, eds. Waltham, MA: UpToDate; 2010.
Available at www.uptodate.com. Accessed July 19, 2011.
Hendren WH. Constipation caused by anterior location of the anus and its surgical correction. J Pediatr Surg. 1978;13:505.
Langer M, Modi BP. Benign Perianal Lesions. In Kleinman RE, Goulet O, et al, eds. Pediatric Gastrointestinal Disease. 5th ed.
Hamilton, Ontario: BC Decker Inc; 2008: 368-369.
Leape LL, Ramenofsky, ML. Anterior ectopic anus: a common cause of constipation in children. J Pediatr Surg. 1978;13:627.
Morelli JG. Cutaneous Bacterial Infections. In Kliegman RM, Stanton BMD, St. Geme J, Schor N, Behrman RE. Nelson Textbook
of Pediatrics. 18th ed. Philadelphia, PA: Saunders; 2007: Chapter 664.
Pfefferkorn, MD, Fitzgerald JF. Disorders of the anorectum: fissures, fistulae, prolapse, hemorrhoids, tags. In: Wyllie R, Hyams
JS, eds. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders;2006: 801-806.
4K. Polyps
Shamila B. Zawahir, MD
Samra S. Blanchard, MD
Intestinal polyposis syndromes are rare. The polyps found in children can be classified by their histology into
hamartomatous, adenomatous, inflammatory and other. It is important to identify these children due to the
health risks associated with several polyposis syndromes.
I. Classification
A. Hamartomatous polyps
1. Solitary juvenile polyp
2. Juvenile polyposis syndrome
3. Peutz-Jeghers syndrome
4. Phosphatase and tensin homologue gene mutation (PTEN) hamartoma syndrome
a. Bannayan-Riley-Ruvalcaba syndrome
b. Cowden syndrome
c. Gorlin syndrome
B. Adenomatous polyposis syndromes
1. Familial adenomatous polyposis (FAP)
2. Gardner syndrome
3. Turcot syndrome
4. MYH-associated polyposis
C. Inflammatory polyps
D. Mixed polyposis syndromes
II. Solitary Juvenile Polyp

A. Presentation: painless rectal bleeding or polyp prolapse
B. Typical age: 2–6 years. Rare before 1 year or after 10 years
C. May be multiple: ≤5 by definition
D. No malignant potential
E. Appears as a pedunculated 1–3 cm in size, with smooth red surface
1. Microscopically: dilated cysts filled with mucin, abundant lamina propria with
inflammatory infiltrate
2. Present at any location in colon
III. Juvenile Polyposis Syndrome

A. Multiple hamartomatous polyps and increased risk of GI malignancies
B. By definition, >5 juvenile colonic polyps, extracolonic juvenile polyps or juvenile polyps with
positive family history of cancer
C. Three forms of the syndrome
1. Juvenile polyposis of infancy
a. Presents in infancy with anemia, rectal bleed, diarrhea, protein-losing
enteropathy (PLE), intussusception
b. Fulminant course, death often before 2 years of age despite colectomy due to
uncontrolled PLE, bleeding
2. Juvenile polyposis coli (JPC): multiple juvenile polyps only in the colon
3. Generalized juvenile polyposis
a. JPC and generalized juvenile polyposis with 50–200 polyps over a lifetime
b. At least 5 polyps required to make diagnosis (some say 3)
c. Present with chronic and acute GI bleed, anemia, prolapsed rectal polyps,
abdominal pain, diarrhea
d. Polyps found in stomach, small bowel, colon and rectum
` e. Associated findings: digital clubbing, macrocephaly, alopecia, cleft lip/palate,
congenital heart disease, GU abnormalities, mental retardation

D. Complications
1. Premalignant condition
a. 15% incidence of colorectal carcinoma <35 years of age
b. Neoplasias arise in polyps and in normal-appearing colonic mucosa
c. Higher risk of cancer in generalized form compared to colorectal form
E. Genetics
1. Fully penetrable, variable expression; 40% of mutations are sporadic
2. Germline mutations of SMAD4 (20% of JPS patients), BMPR1A (20%)
F. Treatment/Follow-up
1. After gene mutation identified in index patient, all at-risk family members should be
tested
2. If parent carries mutation, all children have a 50% chance of inheriting disease
3. Affected children should undergo colonoscopy every 2 years, or more frequently if
symptomatic
4. If no gene mutation identified, siblings of patient should have screening colonoscopy
starting at 12 years of age
5. Annual colonoscopy until all polyps are resected and then every 2–3 years for patient
6. Gastroscopy starting in mid-teens for patient
7. Colectomy indicated if patient develops dysplasia, cancer or high number of polyps with
uncontrollable symptoms
8. Screen first-degree relatives starting at 10 years of age if asymptomatic
IV. Peutz-Jeghers Syndrome (PJS)

A. Autosomal-dominant (1:50,000–200,000 live births)
B. Mucocutaneous pigmentation and hamartomatous polyps throughout the GI tract
1. Small bowel (jejunum) > stomach, and colon
2. Bleeding/anemia, intussusception/obstruction
C. Presumptive diagnosis made by positive family history and typical PJS freckling
D. Rarely polyps occur in renal pelvis, bladder, lungs, and nares
E. Pigmented macules
1. Arise in infancy
2. Located around mouth, buccal mucosa, nostrils, perianal area, fingers and toes, and
dorsal and volar aspects of hands and feet
3. May fade with puberty; however, buccal lesions tend to persist
F. Genetics :
1. STK11 (LKBq) gene on Chromosome 19p13.3
2. Identified in up to 90% of patients
G. Management and Complications
1. Midgut complications best dealt with polypectomy rather than resection because of
high reoperation rate
2. Upper and lower endoscopy, video capsule endoscopy ± patency capsule (to ensure
safety of passage of capsule) or magnetic resonance endoscopy to visualize small bowel
starting at age 8 years; if symptoms start earlier, need to start screening earlier
H. Malignancy risk:
1. In order of greatest risk: colorectal, breast, stomach, small bowel, and pancreas
2. Risk of malignancy at 20 years: 1%; risk at 40 years: 19%; risk at 70 years: 81%
3. Tumors of the GI tract: colorectal (38%), stomach (29%), small bowel (13%), pancreas
(11%–36%)
4. Extraintestinal tumors:
a. Females: breast (32%–54%), ovary (21%), cervical cancer (10%); benign
ovarian tumors (sex-cord tumors) cause hyperestrogenism and sexual precocity
b. Males: Sertoli cell testicular tumor (9%)
V. TEN – Hamartoma Tumor Syndrome

A. Three syndromes affiliated with a mutation in PTEN gene at 10q23.3
1. Bannaya-Riley-Ruvalcaba syndrome (BRRS)
2. Cowden syndrome
3. Gorlin syndrome
B. BRRS
1. Presents in childhood with polyps of the ileum and colon
2. Intussusception, rectal bleeding, hypoalbuminemia
3. Macrocephaly, developmental delay, lipomatosis, hemangiomatosis
4. Requires regular colonoscopy and small bowel surveillance
5. After age 18 surveillance for thyroid, renal and breast cancer is recommended
C. Cowden syndrome
1. Rarely presents in childhood
2. Macrocephaly, papillomatous papules, acral keratosis
3. 50% risk of breast cancer in women; 10% risk of epithelial thyroid cancer
4. 90% have polyps distal to hepatic flexure
D. Gorlin syndrome
1. Autosomal-dominant
2. Upper GI hamartomas and pink/brown macules on the face and hands
3. Frontal/parietal bossing, hypertelorism, skeletal abnormalities, intracranial calcification
4. Risk of medulloblastoma
VI. Familial Adenomatous Polyposis

A. Usually more than 100 colorectal adenomatous polyps
B. Appear in childhood/adolescence and multiply with age
C. Colorectal cancer by 5th decade unless colectomy is performed
D. Attenuated FAP: fewer adenomas, later presentation
1. Risk of cancer almost 100% by 45 years of age
E. Gastric fundic polyps and small bowel adenomas can occur with dysplastic changes, but rarely
progress to carcinoma
F. Adults at increased risk of cancer of duodenum, pancreas, thyroid and ampulla of Vater
G. Extracolonic manifestations of FAP in childhood/adolescence
1. Bone: osteomas (mandibular, maxillary), exostoses, sclerosis
2. Teeth: impacted/supernumerary teeth, unerupted teeth
3. Connective tissue: desmoid tumors, fibroma, subcutaneous cysts
4. Eyes: congenital hypertrophy of the retinal pigment epithelium (CHRPE)
5. CNS: glioblastomas (Turcot syndrome)
6. Adenomas: stomach, duodenum, small intestine, adrenal cortex, thyroid, ampulla of
Vater
7. Carcinomas: thyroid (papillary form reported in adolescence), adrenal
8. Liver: hepatoblastoma (seen under 5 years of age)
H. Genetics
1. Autosomal-dominant caused by mutation in APC gene
2. 1:10,000 births
3. 20%–30% due to spontaneous mutation with no family history
I. Surveillance and management of established FAP
1. Genetic tests for at-risk family members of those with >100 adenomas
2. Once colonic polyps are detected, one needs to do a full colonoscopy to determine
extent
3. Indications for colectomy: >1 cm adenomas, profuse polyposis or adenomas with villous
histology and/or high-grade dysplasia
4. Sparse or <5 mm adenomas: follow endoscopically yearly; schedule colectomy around
school schedule (ie, after finishing high school)
5. Even after colectomy, patients are still at risk for adenomas and adenocarcinomas
6. After total colectomy, patients still need regular surveillance of ileal pouch
7. Extracolonic tumors:
a. Screening EGD with side viewing (for papillary adenomas) and forward viewing
scopes when colonic polyps are diagnosed or at 20–25 years of age
b. Endoscopic removal of duodenal adenomas or those of ampulla of Vater
c. Biopsy of papilla if appears abnormal or has history of pancreatitis or biliary
obstruction
d. Gastric polyps:
1) Biopsy gastric fundic polyps to check for dysplasia
2) Antral polyps typically adenomas – remove completely endoscopically
e. Thyroid palpation yearly ± FNAC of nodules

J. Children in FAP families:
1. If child has a negative gene test in a family with a known genotype for FAP, there is no need for
colonoscopy
2. If gene test is positive, do annual sigmoidoscopy starting at age 10–14 years of age until rectal adenomas
are confirmed or negative until 35–40 years of age
K. Surveillance in Attenuated FAP (AFAP)
1. Annual colonoscopy starting 20–25 years of age for gene carriers or those in at-risk family with
inconclusive gene tests
2. Patient with AFAP needs colonoscopy with yearly surveillance if all polyps can be removed endoscopically
3. If there are too many polyps to remove endoscopically, consider prophylactic colectomy
L. Prognosis
1. Currently, most deaths from FAP are due to extracolonic disease because of increased use of prophylactic
colectomy
M. Desmoid disease
1. Locally aggressive, non-metastasizing myofibroblastic lesions
2. Majority located in the abdominal wall or intraabdominally
3. Risk factors: APC gene mutation site, mutation of CTNNBI, germline mutations, abdominal surgery,
family history of desmoids, estrogens
4. Within peritoneal cavity most common, and may cause small bowel, ureteral or vascular obstruction
5. Detected by CT and MRI
6. May progress rapidly or resolve spontaneously
7. Surgical resection associated with high morbidity and mortality and stimulates further growth
8. Nonsurgical treatment: NSAIDS and/or antiestrogens, chemotherapy, radiotherapy
N. Chemoprevention with NSAIDs
1. May reduce the number of polyps and slow the increase in number, but degree of prevention of
development of colorectal carcinoma is unknown
2. Sulindac:
a. Causes incomplete regression of colorectal adenomas
3. Celecoxib:
a. Decreases number of colorectal polyps
b. Decreases extent of duodenal polyposis
4. Use of NSAIDs: to slow development of adenomas prior to colectomy and to delay new polyp formation
in the rectum after subtotal colectomy
VII. Gardner Syndrome

A. Variant of FAP
B. Colonic adenomas, upper GI polyps
C. Extraintestinal manifestations:
1. Osteomas
2. Epidermal inclusion cysts, other benign skin tumors
3. Desmoid tumors of abdominal wall/abdomen
4. Fibrosis of mesentery
5. Dental abnormalities
6. Carcinoma of periampullary duodenum
7. Carcinoma of thyroid
VIII. Turcot Syndrome

A. Primary brain tumor (often glioblastoma multiforme) and multiple colorectal adenomas
B. Occurs in adolescence
C. Management of polyps similar to FAP
IX. MYH-associated Polyposis

A. Autosomal-recessive inheritance
B. Colorectal polyposis resembles FAP or attenuated FAP
X. Mixed Polyposis Syndromes

A. Dominant genetic syndrome
B. Mutation at 15q13-14 (CRAC-1) or in BMPR1A gene
C. Colorectal polyps of mixed histology (hyperplastic, serrated adenomas, atypical juvenile)
D. Progresses to colorectal carcinoma
XI. Inflammatory Polyps (Pseudopolyps)
A. Occur in areas of longstanding inflammatory colitis
B. Colon predominantly, rarely in rectum
C. No malignant potential
Recommended Reading
Burt RW. Gastric fundic polyps. Gastroenterology 2003; 125:43-49
Galiatsatos P, Foulkes WD. Familal adenomatous polyposis. Am J Gastroenterol. 2006;101:385-398.
Rubio CA. Jaramillo E, Lindbolm A, FOgt F. Classification of colorectal polyps: guidelines for the endoscopist.
Endoscopy. 2002;34:226-236.
Tomlinson IPM, Houlston RS. Peutz Jeghers syndrome. J Med Genet. 1997;34:1007-1011.
Vasen HFA, Möslein G, Alonso A. Guidelines for the clinical management of FAP. Gut. 2008;57:704-713.

4L. Intestinal
Pseudo-obstruction
Janis Stoll, MD
Samuel Nurko, MD, MPH
Pseudo-obstruction is a severe disabling disease characterized by repetitive episodes or continuous symptoms

and signs of intestinal obstruction, including radiographic documentation of dilated intestines and air-fluid
levels, in the absence of fixed lesion which is occluding the lumen of the intestine. It can be congenital,
acquired, primary, or secondary.
I. Presentation
A. Symptoms are variable and dependent on the length and location of involved bowel. Based on a
pediatric patient cohort with chronic intestinal pseudo-obstruction, the most common symptoms
included:
1. Abdominal distention (98%)
2. Nausea/vomiting/feeding intolerance (91%)
3. Constipation (77%)
4. Failure to thrive (62%)
5. Abdominal pain (58%)
6. Sepsis (34%)
7. Diarrhea (31%)
B. Prenatal
1. Ultrasound may show dilated bowel loops and/or bladder, with or without
polyhydramnios
C. Neonatal
1. Most common symptoms include delayed meconium passage, bilious vomiting,
abdominal distention, and constipation
2. Dilation and slow intestinal transit may lead to bacterial overgrowth and resulting
malabsorption, diarrhea, and malnutrition
3. 75% of congenital pseudo-obstruction patients present within the first year of life, and
the majority (67%) present within the first month of life
D. Syndromic
1. Including megacystis, microcolon, intestinal hypoperistalsis syndrome, mitochondrial
disorders, or autoimmune disorders
E. 25% of patients have associated intestinal disorders (malrotation, gastroschisis, and atresias)
F. Urinary problems are commonly found in cases of myopathy
II. Diagnosis
A. Based on clinical symptoms
B. Motility testing can confirm the diagnosis
C. Radiography and laboratory studies are primarily used to rule out other potential causes
D. Abdominal radiographs may show dilated loops of small bowel and air-fluid levels
E. Upper GI contrast studies (with water-soluble contrast) show dilated loops of bowel and slow
transit
F. Radiopaque markers may help in identifying an area of functional obstruction
G. Antroduodenal and colonic manometry can be used to distinguish myopathy from neuropathy or
mixed patterns
1. Myopathy: contraction amplitude is reduced by spatial and temporal relationship
is normal
2. Neuropathy: normal contraction amplitudes and abnormal spatial/temporal relationships
3. May be difficult to interpret with dilated colon
H. Manometry can help to determine areas of preserved motility, which can also help in determining
therapy
I. Pathology including light microscopy, electron microscopy, immunohistochemistry and enzyme
histochemistry, but it is not consistently used, and not recommended in routine cases

III. Management
A. Treatment is mostly supportive, and should focus on fluid and electrolyte balance, nutrition, and
preventing complications
B. Enteral nutrition is preferred
1. Low-fat, liquid supplemental diets are tolerated best
2. If enteral feeds are not tolerated, parenteral nutrition should be used
3. Frequently, a combination of feeding methods is used
C. Bacterial overgrowth is frequent, and should be treated aggressively, since it can worsen motility
D. Avoid medications which slow intestinal motility
1. Opioids and drugs with anticholinergic properties
E. Surgery
1. For IV access
2. To provide enteral routes for feeding or for decompression
3. Surgery should be avoided if possible, as adhesions can complicate future evaluations
and management
F. Prokinetics
1. Cisapride, erythromycin, amoxicillin, metoclopramide, and octreotide have been effective
G. Pain
1. Should be managed with non-narcotic agents, including tricyclic antidepressants,
gabapentin, SSRIs, and clonidine
2. Pain can also be managed with behavioral and relaxation therapy
H. Small intestinal transplantation
1. Only indicated in TPN-dependent patients with life-threatening complications or no
venous access
2. Survival after transplant may be lower than for other conditions
IV. Complications
A. High morbidity and mortality can occur
1. Related to the severity of intestinal abnormalities, concurrent infections from bacterial
translocation from the gut, parenteral nutrition–related side effects, line problems, and
the need for frequent hospitalizations because of pseudo-obstructive crises
Recommended Reading
Chumpitazi B, Nurko S. Pediatric gastrointestinal motility disorders: challenges and a clinical update.
Gastroenterol Hepatol. 2008;4(2):140-148.
Connor FL, Di Lorenzo C. Chronic intestinal pseudo-obstruction: assessment and management.

Gastroenterology. 2006;130:529-536.
Faure C, Goulet O, Ategbo S, et al. Chronic intestinal pseudoobstruction syndrome: clinical analysis,
outcome, and prognosis in 105 children. French-speaking group of pediatric gastroenterology. Dig Dis Sci.
1999;44:953-959.
Pandolfino JE, Howden CW, Kahrilas PJ. Motility-modifying agents and management of disorders of
gastrointestinal motility. Gastroenterology. 2000;118.
Rudolph CD, Hyman PE, Altschuler SM,. Diagnosis and treatment of chronic intestinal pseudo-obstruction in
children: report of Consensus Workshop. J Pediatric Gastroenterol Nutrit. 1997;24:102-112.
5A. Normal Anatomy,
Development, Physiology
and Microanatomy
Jessica Wen, MD
David Piccoli, MD
I. Development of Biliary Tree/Gallbladder

A. Primitive anlagen appears at end of 2nd month of gestation
1. Hepatic diverticulum gives rise to hepatic parenchyma, intrahepatic biliary tree and
common bile duct
2. Cystic diverticulum gives rise to cystic duct and the gallbladder
B. Gall bladder is initially solid, then becomes cystic during development
1. Congenital absence of gall bladder caused by failed development of cystic diverticulum
a. Usually of little clinical significance
b. May be associated with congenital heart disease, situs inversus, polysplenia,
asplenia, biliary atresia (splenic malformation syndrome)
2. Fetal cystic duct fuses with common bile duct. Abnormalities at this stage may produce
choledochal cyst anomalies
C. Bipotential hepatoblasts give rise to cholangiocytes and hepatocytes
1. Hepatoblasts in mesenchyme nearest the portal vein form a bilayered structure (ductal
plate)
2. Ductal plate cells remodel to form bile ducts in the intrahepatic portal tracts
3. Abnormal development of intrahepatic bile ducts due to ductal plate malformations are
likely the underlying cause of:
a. Congenital hepatic fibrosis with cystic kidney disease
b. Ciliopathies—Joubert syndrome, Meckel-Gruber and Ivemark syndrome
4. The smallest intrahepatic bile ducts (canaliculi) are formed from junction between
hepatocytes
5. Intrahepatic bile duct development starts at the hilum and progresses to the periphery
of the liver
a. At birth, the most peripheral intrahepatic bile ducts are immature with
persistence of ductal plate
b. Maturity of intrahepatic biliary tree achieved by 4 weeks of life
II. Anatomy and Physiology

A. Biliary ducts
1. Hepatocytes secrete bile into canaliculi
2. Bile passes from canaliculi to canals of Hering (lined by combination of hepatocyte and
cholangiocytes)
3. Canals of Hering empty into interlobular bile ducts
4. Interlobular biliary ducts join larger portal tract bile ducts
5. Portal tract bile ducts join to form right and left hepatic ducts, which form the common
hepatic duct at the porta hepatis
6. Cystic duct joins the common hepatic duct, forming common bile duct
7. Common bile duct and main pancreatic duct join at the ampulla of Vater at the 2nd por-
tion of the duodenum
B. Vascular supply
1. Vascular supply for the intrahepatic biliary ducts is the hepatic artery
2. In fetuses, the umbilical vein joins the portal vein to form the ductus venosus
3. The oxygenated blood from the placenta is largely shunted to IVC via the
ductus venosus
Section 5 - Bilary Tree - Intra and Extrahepatic Bile Ducts and Gall Bladder 207
4. At birth, functional closure of ductus venosus occurs within minutes, while the struc-
tural closure occurs slowly, over the 1st week of life, and may take longer in premature
infants
5. After closure, the ductus venosus becomes the ligamentum venosum
C. Gall bladder vasculature
1. Gall bladder supplied by cystic artery branch of the right hepatic artery
2. The cysto-hepatic triangle (Calot triangle) is composed of the cystic duct, cystic artery
and the common hepatic duct
D. Hepatic innervation
1. Hepatic plexus contains sympathetic fibers (celiac plexus) and parasympathetic fibers
(vagus nerve)
2. Hepatic nerve supply mediates hepatic vasoconstriction. Other functions are unclear
III. Histology
A. Biliary histology
1. Bile ducts lined by cuboidal epithelium
2. Loss of intrahepatic bile ducts occurs in
a. Chronic biliary tract obstruction
b. Primary sclerosing cholangitis
c. Primary biliary cirrhosis
d. Ischemia
e. Chronic graft vs host disease
f. Chronic graft rejection
3. Paucity of intrahepatic bile ducts is a feature of premature neonates and is more severe
in Alagille syndrome
B. Gall bladder histology and pathology
1. Three tissue layers: mucosa, muscularis propria and serosa. There is no muscularis mu-
cosa or submucosa
2. Surface epithelium composed of single layer columnar cell
3. Lamina propria contains
a. Loose connective tissue
b. Blood vessels, lymphatics
c. Occasional chronic inflammatory cells
4. Heterotopic tissue may occur in gall bladder wall
a. Gastric and hepatic most common
b. Also reported: adrenal, thyroid, pancreas
5. Cystic duct has mucosal folds with smooth muscle near gallbladder neck, functioning as
spiral valve of Heister
6. Aberrant bile ducts (Luschka ducts)
a. 10% of cholecystectomy specimens
b. Often buried in gallbladder wall
c. May communicate with intrahepatic bile ducts
Recommended Reading
Moore KL, Dalley AF. Clinically Oriented Anatomy. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins;
1999: Chapter 2.
Russo P, Ruchelli E, Piccoli D, eds. Pathology of Pediatric Gastrointestinal and Liver Disease. New York, NY:
Springer; 2004: Chapter 8.
Suchy F, Sokol R, Balistreri W, eds. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University
Press; 2007.
Young B, Lowe J, Stevens A, Heath J. Wheater’s Functional Histology. 5th ed. Philadelphia, PA: Elsevier; 2006:
Chapter 15.
5B. Gallstones
Jess L Kaplan, MD
Garrett C Zella, MD
Most gallstones are not chemically pure, but are mixtures of calcium, bilirubin, cholesterol and other
substances. For the purposes of this study guide, gallstones will be classified into three types: cholesterol
stones, black pigment stones and brown pigment stones
I. Cholesterol Stones
A. Formation requires the following conditions:
1. Increased secretion of cholesterol into bile causing supersaturation of bile has several
common causes:
a. ↑ cholesterol delivery to the liver via LDL and chylomicrons (increased dietary
cholesterol intake, estrogen, oral contraceptive use)
b. ↑ endogenous cholesterol production (obesity and hypertriglyceridemia)
c. ↓ conversion of cholesterol to bile acids (older age)
d. ↑ conversion of cholesterol to cholesterol esters (progesterone, clofibrate)
2. Nucleation of soluble cholesterol into solid crystals
3. Gallbladder stasis, allowing aggregation of cholesterol crystals into stones
4. ↑ mucin secretion by gallbladder provides a nidus for crystal formation
B. Clinical conditions associated with higher risk of cholesterol gallstones
1. Pregnancy
a. Estrogen induces cholesterol hypersecretion
b. Progesterone reduces bile acid production → decreased ability to solubilize
cholesterol
c. Progesterone decreases gallbladder motility → stone formation
2. Obesity
a. ↑ exogenous cholesterol intake
b. ↑ endogenous cholesterol synthesis (increased HMG-CoA reductase activity)
3. Hypertriglyceridemia
4. Oral contraceptive pills
a. Due to estrogen effects (cholesterol hypersecretion)
b. Risk appears to be 1.5–1.8:1 compared to controls
5. Female gender: female:male ratio during childbearing years approaches 3:1 and the
ratio decreases with advancing age
C. Other facts about cholesterol stones
1. Yellow/white in color
2. Cholesterol content is >50%
3. Not radio opaque on plain x-ray, due to minimal calcium salt content
II. Black Pigment Stones

A. Formation occurs when there is increased conjugated bilirubin secreted into bile
1. Endogenous glucuronidase activity in gall bladder releases free bilirubin anions into bile
with resulting supersaturation
2. Unconjugated bilirubin monohydrate precipitates with calcium in bile
B. Clinical conditions associated with black pigment stones:
1. Hemolytic disease (excess bilirubin load)
2. Dysfunctional erythropoiesis with increased bilirubin load
3. Ileal resection and/or ileal inflammation (↑ enterohepatic circulation of bilirubin and ↓
bile acid reabsorption causing ↓ bile acid pool)
4. Cystic fibrosis with pancreatic insufficiency (increased enterohepatic circulation of biliru-
bin and ↓ bile acid resorption)
5. Parenteral nutrition (↓ bile acid reabsorption and ↓ bile acid pool)
6. Cirrhosis (bile salt malabsorption)
C. Other characteristics of black pigment stones:
1. Black or brown color
2. 50%–75% of black pigment stones are radio opaque (high calcium content)
3. Often occur in multiples
4. Calcium carbonate, calcium phosphate, mucin and cholesterol account for <20% by
weight
5. No gender predominance
III. Brown Pigment Stones

A. Occur in the presence of the following risk factors:
1. Infection of bile (bacterial infection, parasitic infection)
2. Bile stasis (bile duct abnormalities)
3. Bile infection and stasis result in increased mucin production. Mucin is the nidus for
brown pigment stone formation
B. Clinical conditions associated with brown pigment stones:
1. Bacterial infections (often E coli but other enteric pathogens implicated) → bacteria can
be found/cultured from the stone core
2. Parasitic infections (eg, Ascaris)
3. Bile duct anomalies causing stasis, e.g. stricture
C. Other characteristics of brown pigment stones
1. Brown to orange in color (due to high calcium bilirubinate content)
2. Not radiopaque on plain film (calcium carbonate and phosphate content is too low)
3. Typically form in the common bile duct and intrahepatic bile ducts
IV. Risk Factors

Gallstones are rare in childhood but are increasing in frequency due mostly to ↑ prevalence of obesity.
Risk factors for gallstones in children include:
A. Obesity:
1. Excessive hepatic cholesterol secretion due to increased cholesterol synthesis
2. Prevalence of 2.0% in asymptomatic obese children (8–19 years old)
B. Female gender (only after puberty)
1. After puberty, prevalence ratio F:M is at least 4:1
C. Hemolytic disease
1. Sickle cell disease (prevalence 14%–36% in children 6–20 years old, prevalence
increases with age)
2. Hereditary spherocytosis
3. Thalassemias
4. Wilson disease
D. Reduced bile salt pool, etc
1. History of ileal resection (only after puberty when cholesterol secretion increases and bile
salt secretion declines)
2. Small bowel Crohn disease
3. Cystic fibrosis with pancreatic insufficiency (prevalence of 13.2% in children and increas-
es with age). Pancreatic enzyme supplements decrease the risk
E. Total parenteral nutrition (biliary stasis → gallbladder sludge → pigment stones)
1. Prevalence in children as high as 13% after 4 weeks of TPN
F. Medications:
1. Ceftriaxone (displaces bilirubin from albumin binding sites)
2. Furosemide (in patients with other risk factors like prematurity and sepsis)
3. Octreotide (induces gallbladder stasis)
4. Cyclosporine (especially in bone marrow and solid organ transplant patients; mechanism
is unknown)
G. Down syndrome (4.7% prevalence in 21 children in one study; etiology unknown)
H. Hypertriglyceridemia
I. Pregnancy
J. Some Native American tribes have very high risk of gall stones - Pima, Hopi, Araucan
V. Complications of Gallstone Disease
A. Cholecystitis
B. Choledocholithiasis
C. Pancreatitis secondary to cholecystitis or choledocholithiasis
D. Cholangitis
E. Gallbladder perforation
VI. Management of Symptomatic and Asymptomatic Gallstones

A. Asymptomatic gallstones in infancy:
1. Generally resolve spontaneously and do not require surgery
2. Gallstones identified on intra-uterine ultrasound are a common, normal finding not
requiring therapy
B. Asymptomatic gallstones in older children:
1. Spontaneous resolution is rare, but there is no consensus on whether they should
be removed
2. Parenteral nutrition–associated pigment gallstones that appear after short-term PN may
resolve spontaneously and should be monitored, unless they become symptomatic
3. Adult studies support watchful waiting in asymptomatic patients with incidental
gallstones, but this has not been studied in children
C. Symptomatic gallstones in older children:
1. Remove via cholecystectomy
2. Cholecystostomy tube for drainage is an option if patient is critically ill
3. ERCP before surgery is indicated in some situations
a. Suspicion of common bile duct stones
b. Dilation of intra- or extrahepatic bile ducts on ultrasound
c. Associated pancreatitis
D. Nonsurgical techniques for gallstone removal not well studied in children
1. Ursodeoxycholic acid and/or chenodeoxycholic acid inhibit HMG-Coa reductase,
reducing cholesterol synthesis. They also increase bile acid concentration in
bile, promoting dissolution of cholesterol stones
Recommended Reading
Broderick A. Gallbladder Disease. In: Kleinman RE, Sanderson IR, Goulet O, Sherman
PM, Mieli-Vergani G, Shneider BL, eds. Walker’s Pediatric Gastrointestinal Disease.
5th ed. Hamilton, Ontario: BC Decker, Inc; 2008:1173-1183.
Gilger MA. Diseases of the gallbladder. In: Wylie R, Hyams JS, eds. Pediatric
Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management. 3rd
ed. Philadelphia, PA: Saunders Elsevier; 2006:989-1001.
Kaechele V, Wabitsch M, Thiere D, et al. Prevalence of gallbladder stone disease in

obese children and adolescents: influence of the degree of obesity, sex, and pubertal
development. J Pediatr Gastroenterol Nutr. 2006;42(1):66-70.
Kumar R, Nguyen K, Shun A. Gallstones and common bile duct calculi in infancy and
childhood. Aust N Z J Surg. 2000;70(3):188-191.
5C. Cholecystitis
Jess L Kaplan, MD
Garrett C Zella, MD
I. Acute Calculous Cholecystitis

A. Essential features: fever, right upper quadrant abdominal pain, leukocytosis associated with gall-
bladder inflammation
B. Etiology/pathogenesis: gallbladder stasis is common to all
1. Cholelithiasis: responsible for vast majority of childhood cases
2. External compression of biliary tree with stasis (mass, lymph nodes)
3. Trauma
4. Structural duct abnormalities (choledochal cyst)
C. Risk factors for cholelithiasis and cholecystitis in childhood (see section on Gallstones)
D. Clinical features
1. Symptoms
a. RUQ/epigastric abdominal pain ± radiation to the right shoulder
b. Nausea and nonbilious emesis, anorexia
c. Fever
d. Murphy sign: inspiratory pause on deep palpation of the RUQ
2. Laboratory findings
a. Leukocytosis with left shift
b. Serum transaminases normal to slightly elevated
c. Serum amylase elevated in ~8% of cases, even in the absence of obstructive
pancreatitis
d. Direct and total serum bilirubin elevated in children
e. Marked elevations of γ glutamyl transferase, alkaline phosphatase and direct
bilirubin suggest choledocholithiasis
E. Diagnosis
1. Sonography findings
a. Gallstones
b. Gallbladder wall thickening >4–5 mm in adults and >3.0–3.5 in some
pediatric reports
c. Pericholecystic fluid
d. Sonographic Murphy sign – tenderness over the gallbladder from pressure of
the U/S transducer
e. Common bile duct dilation raises suspicion for choledocholithiasis
2. Cholescintigraphy (HIDA)
a. Technetium-99m labeled iminodiacetic acid (IDA) given via IV is taken up by the
liver and secreted into the bile. Concentrated in the gallbladder
b. Normal hepatic uptake of IDA with reduced concentration in gallbladder bile
after 60 minutes is consistent with cholecystitis
c. Morphine administration decreases false positives by increasing sphincter of
Oddi pressure, causing back pressure in the common bile duct and forcing more
radionuclide into the gallbladder
d. False-positive results on HIDA scan caused by:
1) Obstruction of the cystic duct by stone, inflammation or tumor
2) Hyperbilirubinemia (total bili >4.4 mg/dL)
3) Severe parenchymal liver disease decreases hepatic uptake of IDA
4) Prior biliary sphincterotomy decreases resistance to bile flow and
bypasses the gallbladder
5) Prolonged fasting or TPN (gallbladder already full resists further filling)
e. Results of HIDA are 94% sensitive and 65%–85% specific for acute
cholecystitis in adults
F. Management
1. Morbidity and mortality
a. Complications occur in up to 30% of patients
1) Gallbladder perforation
2) Abscess
3) Empyema
b. Surgery to remove stones prevents subsequent attacks
2. NPO
3. Intravenous fluid – more aggressive therapy needed in sickle cell hemoglobinopathies
4. Analgesics
a. Ketorolac
b. Morphine and derivatives were formerly avoided because of concern about
increase in sphincter of Oddi pressure
c. Morphine is now routinely used for analgesia with no adverse effects
on outcome
5. Antibiotics are universally used but clear evidence for benefit is lacking
a. Common regimens designed to combat enteric flora – cefoxitin or piperacillin/
tazobactam
6. Percutaneous cholecystostomy tube
a. Relieves biliary obstruction and allows for gallbladder irrigation and, sometimes,
removal of sludge and small stones
b. Reserved for critically ill patients
7. Cholecystectomy
a. Procedure of choice for calculous cholecystitis
b. Laparoscopic surgery preferred over open
c. Laparoscopy associated with shorter hospital stay, smaller incision and less post-
operative pain, but more common bile duct injury
d. Timing of surgery controversial
1) Patients too sick for surgery should have percutaneous cholecystostomy
2) Patients deteriorating after 24 hours of medical therapy should have
cholecystectomy
3) Patients with uncomplicated course and recovering on medical therapy
generally have cholecystectomy within 1–5 days
4) Patients with sickle cell disease benefit from transfusion of RBCs and
aggressive fluid resuscitation prior to cholecystectomy
e. Complications
1) Gangrene of the gallbladder
2) Perforation of gallbladder is rare in children
3) Pancreatitis – especially with cholelithiasis
f. Management of choledocholithiasis
1) Confirm presence of stones by imaging
2) ERCP with stone removal often performed prior to cholecystectomy
a) Endoscopic stone removal lowers the risk of retained common
bile duct stones
3) MRCP can be helpful in some cases to identify common duct stones
G. Acute Acalculous Cholecystitis (AAC)
1. Associated underlying conditions usually present
a. Sepsis
b. Gastroenteritis
c. Abdominal trauma or surgery
d. Extensive burns
e. Shock, cardiac resuscitation
f. IV nutrition and prolonged fasting
g. Systemic inflammatory diseases – SLE, Kawasaki disease, polyarteritis nodosa
h. Malignancy
i. Congestive heart failure
2. Pathophysiology – the root cause appears to be gallbladder stasis and/or ischemia
3. Clinical features
a. Fever
b. Abdominal pain typically RUQ
c. Vomiting
d. Leukocytosis in 70%–80% of children
e. Bilirubin and transaminase elevation in 60% of children
f. RUQ mass found in 25% of children in one pediatric study
4. Radiographic features
a. Ultrasound shows:
1) Gallbladder distension
2) Gallbladder wall thickening
3) Sludge but not stones
4) Pericholecystic fluid
5) Sonographic Murphy sign
6) Intramural gas sometimes occurs
7) Abscess and perforation rare
b. Cholescintigraphy (HIDA scan)
1) Normal hepatic uptake with failure to opacify the gall bladder
2) Increased pericholecystic radiotracer accumulation in the gallbladder
fossa (Rim Sign) is associated with gangrene
3) Leakage of tracer into fossa indicates perforation
5. Management
a. Antibiotics and serial ultrasounds to follow for progression and complications
b. Nonoperative management successful in 30%–75% of children
c. Percutaneous cholecystostomy with drainage in critically ill patients
d. Cholecystectomy
H. Chronic Acalculous Cholecystitis/Biliary Dyskinesia
1. Definition – abnormal gallbladder contractility as measured by decreased gallbladder
ejection fraction on HIDA scan
2. Clinical features
a. Chronic RUQ pain in absence of other findings with normal imaging of the
gallbladder
b. Fatty food causes abdominal pain
c. Normal liver function blood tests
3. 50%–93% of surgically resected gallbladders show chronic inflammatory changes
4. Diagnosis
a. HIDA scan before and after CCK or fatty meal stimulation is used to calculate
the gallbladder ejection fraction
b. Gallbladder ejection fraction is defined as the difference between the amount
of tracer in the gallbladder before and after the fatty meal or CCK, divided by
the amount of tracer in the gallbladder before CCK or fatty meal stimulation
c. Ejection fraction in adults <35% is considered abnormal. Norms not established
for children
d. Protocols for timing of the post-stimulation measurement are not established
5. Management
a. Cholecystectomy
b. Pediatric studies after cholecystectomy show short-term improvement in 85%
of patients
c. Long-term improvement is only 48%–70%
d. Preoperative ejection fraction does not predict postoperative outcome
Recommended Reading
Broderick A. Gallbladder Disease. In: Kleinman RE, Sanderson IR, Goulet O, Sherman PM, Mieli-Vergani G, Shneider BL, eds.
Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontarion: BC Decker, Inc; 2008:1173-1183.
Gilger MA. Diseases of the gallbladder. In: Wylie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease: Pathophysiol-
ogy, Diagnosis and Management. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2006:989-1001.
Haricharan RN, Proklova LV, Aprahamian CJ, et al. Laparoscopic cholecystectomy for biliary dyskinesia in children provides
durable symptom relief. J Pediatr Surg. 2008;43:1060-1064.
Imamoglu M, Sarihan H, Sari A, Ahmetoglu A. Acute acalculous cholecystitis in children: Diagnosis and treatment. J Pediatr
Surg. 2002;37:36-39.
Vengunta RK, Raso M, Pollock J, et al. Biliary Dyskinesia: The most common indication for cholecystectomy in children. Sur-
gery. 2005;138:726-733.
5D. Biliary Atresia
Inbar Spofford, MD
Sabina Sabharwal, MD
Biliary atresia, a process of bile duct obliteration, is on the differential diagnosis for neonatal cholestasis. Early
identification is vital to improve survival and delay liver transplantation. While there are several theories, the
etiology has not yet been identified.
I. Background
A. Inflammation of the bile ducts with progressive obliteration of the extrahepatic biliary tract in
newborn infants results in obstruction to bile flow
B. Types
1. BA without associated malformations (perinatal form)
a. Type I: obliteration of common bile duct
b. Type II: atresia of the hepatic duct
c. Type III (most common): atresia of the right and left hepatic ducts to the level of
the porta hepatis
2. BASM (embryonal form): BA with splenic malformation is associated with situs inversus,
asplenia, polysplenia, intestinal malrotation, annular pancreas and cardiac anomalies
C. Etiology is not completely defined
1. Animal model studies have focused on pre- or immediate postnatal infection of liver and
biliary tract in association with immune dysregulation. Most commonly cited organisms
possibly associated are CMV and rotavirus
2. The following genetic mutations have been identified in small numbers of patients with
biliary atresia, but none can be defined as the sole cause of biliary atresia: JAG 1, CFC1,
ICAM1, CD14 endotoxin receptor, hepcidin antimicrobial peptide gene
II. Presentation
A. Apparently healthy newborn with gradual onset of jaundice, hepatosplenomegaly, acholic stools
and dark urine between 6 and 12 weeks of age. Poor weight gain, frequent stools, bleeding
diathesis (vitamin K deficiency) are also reported
B. The embryonal form presents with cholestasis at birth
C. Laboratory findings: conjugated hyperbilirubinemia,mild to moderate elevation of transaminases,
more significant elevation of GGT and alkaline phosphatase
III. Diagnosis
A. Abdominal US may show absent or small, thick-walled gallbladder
1. Test is neither sensitive nor specific enough to make a diagnosis
2. Normal gallbladder is often hard to identify in newborns because of small size and high
frequency of postprandial contractions
3. False-positive diagnosis is common
4. Triangular cord sign (hyperechoic triangular area in the porta hepatis that corresponds
with the fibrous remnant of the hepatic duct) is 80% sensitive and 98% specific for BA
B. Hepatobiliary scintigraphy
1. Technetium-99 diisopropyl iminodiacetic acid is given intravenously
2. Scanning repeatedly over 24 hours shows good, prompt hepatic parenchymal uptake
but absent or reduced excretion into the intestine within 24 hours
C. Liver biopsy
1. To differentiate BA from other causes of intrahepatic cholestasis
a. Histologic changes are nonspecific, but in unoperated infants usually include
expanded portal tracts with edema and inflammation, bile duct proliferation,
and canalicular and bile duct bile plugs
IV. Complications
A. Ascending cholangitis after Kasai procedure (hepatic portoenterostomy)—incidence of 40%–
90%; increased risk due to abnormal anatomy and bacterial stasis; recurrent cholangitis can lead
to progressive cirrhosis
B. Portal hypertension due to biliary cirrhosis
V. Treatment
A. Kasai procedure is mainstay of management
1. Goal is to help restore bile flow from intrahepatic bile ducts to small bowel
2. 10-year survival rate of patients diagnosed and treated prior to 60 days of age is 73% vs
11% in those diagnosed and treated after 90 days of age
3. >50% of patients who undergo Kasai will require liver transplantation by 2 years of age
4. At 3 months postoperatively, a total serum bilirubin <2 mg/dL is associated with low
likelihood of requiring hepatic transplant within 2 years, whereas a total serum bilirubin
≥6 mg/dL is associated with failure of adequate bile flow and higher likelihood of need
for hepatic transplantation
B. Supportive care after Kasai procedure
1. Nutrition management of cholestatic liver disease; diet supplemented with medium-
chain fatty acids and fat-soluble vitamins (ADEK)
2. Prophylaxis against cholangitis with trimethoprim/sulfamethoxazole is recommended for
the first year after Kasai procedure
3. Prevention of fibrosis: ursodiol may be beneficial to prolong native liver survival and
delay liver transplantation in patients after Kasai
4. Treatment of portal hypertension
a. Variceal bleeding controlled with sclerotherapy or banding
b. If ascites develops, use diuretics, β-blockers, salt and/or water restriction
C. Liver transplant for patients who develop biliary cirrhosis
Recommended Reading
Chang M. Screening for biliary atresia. Chang Gung Med J. 2006;29(3):231.
Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet. 2009;14;374:1704.
Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the United
States, 1997 to 2000. J Pediatr. 2006;148(4):467.
Willot S, Uhlen S, Michaud L, et al. Effect of ursodeoxycholic acid on liver function in children after successful
surgery for biliary atresia. Pediatrics. 2008;122(6):e1236.
5E. Other Disorders
of the Bile Ducts
Inbar Spofford, MD
Sabina Sabharwal, MD
I. Differential Diagnosis of Bile Duct Disorders

A. Caroli disease
1. Congenital dilation of large intrahepatic ducts
2. Affects 1:100,000
3. Mode of inheritance is controversial
4. Caroli disease: bile ductular ectasia without hepatic abnormalities
5. Caroli syndrome (more common): bile duct dilatation associated with congenital hepatic
fibrosis (CHF)
a. Associated with autosomal recessive polycystic kidney disease (ARPKD)
b. Develop cholangitis and portal hypertension
c. Increased risk of biliary carcinoma
B. Sclerosing cholangitis
1. Primary sclerosing cholangitis: progressive chronic inflammation and fibrosis of intra-
and/or extrahepatic bile ducts of unknown etiology with eventual obliteration of periph-
eral bile ducts, development of bile duct strictures and resultant dilation
a. Associated with inflammatory bowel disease, mostly ulcerative colitis
2. Secondary causes include histiocytosis X, immunodeficiencies (HIV), bacterial cholangitis,
cancers, recurrent pancreatitis, choledocholithiasis and trauma
3. Diagnosis
a. Elevated serum alkaline phosphatase, GGTP, AST/ALT
b. 50% with modest increase in bilirubin
c. ERCP/MRCP shows beading (strictures and dilatation) of bile ducts
d. Classic liver biopsy finding is periductal, concentric, onion-skin fibrosis. Often,
histology is nonspecific and not useful to confirm diagnosis
4. Treatment
a. Ursodiol is used to promote bile flow. Adult studies have not confirmed efficacy
of this therapy
b. Vitamin ADEK for fat-soluble vitamin deficiency
c. Liver transplant indicated for recurrent bacterial cholangitis, jaundice refractory
to medical and/or endoscopic treatment, decompensated cirrhosis or complica-
tions of portal hypertension
5. Complications
a. Ascending cholangitis, portal hypertension, dominant stricture
b. Lifetime risk of cholangiocarcinoma is 10%–15%
c. Cancer screening includes yearly abdominal ultrasonogram and serum carbohy-
drate antigen 19-9 (CA19-9), but neither test is adequately sensitive or specific
C. Congenital hepatic fibrosis
1. Characterized by hepatic fibrosis, portal hypertension, and autosomal-recessive (ARPKD)
or autosomal-dominant (ADPKD) polycystic kidney disease
2. Etiology
a. Pathogenesis: abnormalities of the ductal plate during hepatic organogenesis
b. Genetics: ARPKD is caused by mutations in the polycystic kidney and hepatic
disease 1 (PKHD1) gene
3. Symptoms:
a. Most patients present with symptoms of portal hypertension, often a sudden
bleed from unsuspected esophageal varices
b. Large, hard liver on physical exam
4. Treatment
a. Treat symptomatic esophageal varices with banding/sclerotherapy/ligation/beta-
blockers
b. Transjugular intrahepatic portosystemic shunt (TIPS) if endoscopic and medical
management fails
c. Liver transplant for recurrent cholangitis or progressive hepatic dysfunction
despite medical/surgical care
D. Bile duct paucity
1. Alagille Syndrome (see section on Alagille Syndrome)
E. Choledochal cysts
1. Frequency 1:15,000 births in West and 1:1,000 in Japan
2. Female:male ratio 3–4:1
3. Five types classified by location:
a. Type I—cystic dilatation of the common bile duct (most common,
80%–90% of cases)
b. Type II—diverticulum of the extrahepatic bile duct proximal to the duodenum
c. Type III—cystic dilatation limited to the intraduodenal portion of the common
bile duct
d. Type IVa—multiple intrahepatic and extraheptic biliary cysts
e. Type IVb—multiple dilation of only extrahepatic bile ducts
f. Type V—multiple intraheptic biliary cysts (Caroli disease)
4. Symptoms
a. Infants: jaundice and acholic stools, often diagnosed during evaluation for sus-
pected biliary atresia
b. Children: intermittent biliary obstruction or recurrent bouts of pancreatitis
c. Mass in the right upper quadrant sometimes seen
d. Classic triad of jaundice, mass and abdominal pain is more common in adults
and only comprises 10%–20% of cases in infants and children
5. Diagnosis
a. Variable elevations of AST and ALT, direct bilirubin, alkaline phosphatase
and/or GGTP
b. Ultrasound: imaging of choice but effectiveness is operator dependent
c. MRCP is more sensitive and will give more anatomical detail of neighboring
structures
6. Treatment: surgical excision of cyst
7. Complications
a. Increased risk of cholangiocarcinoma (9%–28%) in any part of the biliary tree
Risk increases with age and is present even after excision of cyst
b. Screening for cholangiocarcinoma is recommended yearly. Ultrasound
and serum CA-19-9 are used but there are no evidence-based guidelines
in pediatrics
F. Choledocholithiasis (see section on Gallstones)
G. Bile duct stricture
1. Can be benign (trauma, iatrogenic, PSC) or malignant (cholangiocarcinoma or adjacent
compressing tumor of liver, gallbladder, pancreas); can be single or multiple
2. Symptoms
a. Varied presentation: asymptomatic; jaundice, fever and RUQ tenderness if
complicated by ascending cholangitis; symptoms of portal hypertension if
complicated by cirrhosis
3. Diagnosis
a. Direct bilirubin, alkaline phosphatase and GGT are usually elevated
b. Ultrasound: imaging of choice, but MRCP is more sensitive
4. Treatment: ERCP with dilatation and stenting
5. Complications
a. Ascending cholangitis
b. Liver abscess
c. Secondary biliary cirrhosis
H. Bile duct perforation
1. Etiology: usually a result of trauma or iatrogenic (eg, ERCP/surgery), although can occur
spontaneously
2. Symptoms: range from vague abdominal pain to peritonitis
3. Diagnosis: imaging (x-ray/ultrasound/CT/MRCP/HIDA) will show free air
in retroperitoneum
4. Treatment: surgical repair
Recommended Reading
Banani SA, Bahador A, Nezakatgoo N. Idiopathic perforation of the extrahepatic bile duct in infancy: patho-
genesis, diagnosis, and management. J Pediatr Surg. 1993;28:950.
Chapman R. Fevery J, Kalloo A. AASLD Practice Guidelines. Diagnosis and Management of Primary Sclerosing
Cholangitis. Hepatology. 2010;51(2):660.
Todani, T, Watanabe, Y, Toki, A, Morotomi, Y. Classification of congenital biliary cystic disease: special refer-
ence to type Ic and IVA cysts with primary ductal stricture. J Hepatobiliary Pancreat Surg. 2003;10:340.
6A. Normal Anatomy,
Development, Physiology
I. Introduction
A. The liver is divided into two lobes (right and left) by falciform ligament
B. The normal liver span is 7 cm in women and 10.5 cm in men. In infants, the normal liver span by
percussion is 4–5 cm
C. Embryonic development of the liver:
1. Liver is formed from endoderm
2. Liver bud emerges from cranioventral portion of the endoderm
3. Hepatocyte precursors—hepatoblasts—migrate into the septum transversum mesen-
chyme along with hematopoietic and endothelial precursors
a. Hepatoblasts become hepatocytes
b. Endothelial precursor cells develop into sinusoids
4. Liver grows in volume and then is encapsulated and lobulated by 6th week of human
gestation
5. Lymphatic system develops at 15th week
II. The Blood Supply of the Liver

A. The majority of the blood supplied to the liver is venous. 70%–80% of the blood entering the
liver is from the portal vein
1. Portal venous blood is coming from small intestines, stomach, pancreas and spleen, and
is rich in nutrients
B. Hepatic artery supplies the remaining 20%-30% of blood to the liver
1. Arises from celiac artery
C. Terminal branches of the hepatic portal vein and hepatic artery empty together and mix as they
enter sinusoids in the liver
1. Sinusoids are lined with highly fenestrated endothelial cells and bounded circumferen-
tially by hepatocytes
2. Blood flows through the sinusoids, resulting in a substantial volume of plasma filtered
into the space of Disse
D. Blood flows through the sinusoids to the central vein
1. Central veins coalesce into hepatic veins
2. Hepatic veins empty into the vena cava
III. Lymphatic Drainage

A. Lymph is created in the space of Disse
B. Lymphatics in portal tracts and wall of hepatic veins drain to lymph nodes in hilum and vena cava
C. Lymphatics in capsule drain across the diaphragm to esophageal lymph nodes
IV. Nerve Supply

A. Supplied by lower thoracic ganglia, celiac plexus, and vagus forming a plexus about hepatic
artery, portal vein and bile duct
B. Arteries are mainly sympathetic fibers
C. Bile ducts have both sympathetic and parasympathetic fibers
D. Individual hepatocytes with unmyelinated sympathetic fibers
V. Biliary System (see section 5A)
Section 6 - Liver 223

VI. Liver Functions
The liver has many different functions. The major responsibility of the liver is to provide a source of
energy for the entire body.
A. Carbohydrate metabolism (see section on Disorders of Carbohydrate Metabolism)
1. Glycogen storage
2. Gluconeogenesis – liver can produce 240 mg/day
a. Fructose and galactose metabolism
B. Synthesis and metabolism of fatty acids (see section on Disorders of Lipid Metabolism)
1. Fatty acid oxidation
2. Ketogenesis
3. Lipid transport
C. Bile acid synthesis (see section on Bile Acid Synthetic Disorders)
D. Protein synthesis
1. Protein metabolism—deamination of AA, formation of plasma proteins, interconversion
of AA
2. Synthesis of nonessential AA
3. Coagulation factors: Vitamin K–dependent
4. Complement
E. Filter/detoxify
1. Medication, toxin and xenobiotic elimination = first-pass metabolism
2. Hormone metabolism
3. Kupffer cells are macrophages and remove enteric organisms
F. Excretion of lipid-soluble waste products
1. Excreted in bile
G. Hematopoiesis peaks in 3rd trimester
1. Exocrine: secretion into biliary system
a. Bile acids
b. Cholesterol and phospholipids
Recommended Reading
The American Journal of Surgery. Volume 112, Issue 3, September 1966, Pages 337-347. Symposium on
diseases of the liver.
6B. Microanatomy
I. Normal Histology
A. Majority of cells are hepatocytes (60%)
B. Kupffer cells, endothelial cells, stellate cells and lymphocytes (40%)
C. Liver organization—two ways to conceptualize the organization
1. Lobules
a. Lobules consist of hepatocytes, hepatic sinusoids (blood spaces), intralobular
ducts and central vein (intralobular vein)
b. Central vein surrounded by six portal triad areas (hepatic arteriole, portal ven-
ule, bile ductile). Hexagonal shape with central vein in center and portal triads
at vertices
c. Portal triads mark the junction of three lobules
d. Lobules are separated by connective tissue
2. Acinus
a. Axis is two portal triads. Zone 1 is periportal with oxygen and nutrient rich
blood. Zone 2 receives blood lower in oxygen and nutrients
D. Hepatocytes are polygonal cells joined by anastomosing plate. Arranged in plates 1 cell thick
E. Sinusoids run between rows of hepatocytes (Figure 1)
1. Lined with fenestrated endothelial cells
2. Blood flows from terminal branches of hepatic artery and portal vein at the periphery of
lobules, and is delivered into central veins
F. Kupffer cells are phagocytic cells (resident macrophages)
G. Space of Disse is the area between endothelial cells and hepatocytes
1. Lymph collects in this space
2. Lymphocytes in this space
3. Stellate cells are star-shaped, lipid-storing cells. They function as fibroblasts following
cytokine stimulation
H. Bile secreted at base of hepatocytes collects in canaliculi and flows into bile ductules and to the
hepatic duct. Bile ducts have cuboidal epithelial cells (Figure 2)
Sinusoids Portal Tract
Central Vein
Figure 1. Used courtesy of Kelly Capocelli, MD. Children’s Hospital Colorado.

Figure 2. Adapted from the Tokyo Institute of Technology’s Department of Biomolecular Engineering Web site.
Recommended Reading
Histopathology of the Liver: 2 Volume Set Hardcover. Oxford University Press, USA; 1 edition (April 8, 1993)
6C. Jaundice
Rima Fawaz, MD
I. Overview
A. Jaundice is the yellow discoloration of tissue due to deposition of bilirubin. The degree of dis-
coloration is directly related the amount of bilirubin deposition. Jaundice may be physiologic in
infants or may be a sign of significant hemolysis, infection or liver failure
B. Jaundice refers to a yellowish pigmentation of the sclera, mucous membranes and skin occurring
when the plasma bilirubin exceeds 4–5 mg/dl in infants and 3 mg/dL in older children
1. Other body fluids such as tears, saliva and cerebrospinal fluids may also have a
yellowish hue
C. An elevated bilirubin should always be fractionated into unconjugated (indirect) or conjugated
(direct) bilirubin
1. Direct bilirubin includes both the conjugated bilirubin fraction and bilirubin bound to
albumin (delta bilirubin)
D. Cholestasis occurs when there is failure of bile formation and/or flow
1. Cholestasis and hyperbilirubinemia are not synonymous, although bile acid flux and
bilirubin excretion are linked events in cholestasis
II. Mechanisms
A. Jaundice can be broadly classified as prehepatic, hepatic or posthepatic
1. Prehepatic jaundice occurs when excess bilirubin overwhelms the hepatocyte’s ability to
conjugate bilirubin, as occurs in hemolysis
2. Hepatic jaundice occurs when there is failure of bile formation or excretion, ie, at the
cellular level
a. Therefore, elevations of conjugated bilirubin may be seen in any type of liver
disease
b. In most liver diseases, both conjugated and unconjugated bilirubin fractions of
the bilirubin are elevated
1. Posthepatic jaundice occurs when there is interruption of drainage of bile into the biliary
system, such as with a choledochal cyst
III. Bile Metabolism

A. Bile is primarily an aqueous solution that is iso-osmotic to plasma
1. It is the route of excretion of a range of endogenous compounds, including bile acids,
bilirubin, cholesterol, steroids, xenobiotics and divalent heavy metals such as copper,
iron, manganese and zinc
B. Bile formation is a major function of the liver
1. The major driving force for bile flow is the secretion and recirculation of bile acids
C. Bile formation is also dependent upon ion flux in both hepatocytes and cholangiocytes
1. In humans, up to 40% of bile is derived from bile ducts
2. A main determinant of bile flow is the secretion of chloride, mainly through the apical
CFTR gene product in cholangiocytes
D. Bile formation and metabolism can be divided into four phases
1. Hepatic uptake at the sinusoidal membrane (basolateral membrane)
a. Initial site of bile formation
b. Na-K ATPase is an inorganic ion transporter that creates a negative electric
potential in the cell that helps facilitate diffusion
c. Na-taurocholate cotransport peptide (NTCP) has a high affinity for bile acid
uptake from the portal circulation
d. The Solute Carrier Organic Anion Transport family, also known as Multispecific
Organic Anion Transport Polypeptides (OATP; SLC21), are sodium independent
carriers that facilitate uptake of a variety or organic compounds (both anions
and cations), as they have broad substrate specificity

1) SLC21A6 transports bilirubin
2) Other carriers transport most drugs and unconjugated bile salts
(Na-independent uptake system)
2. Hydroxylation
a. Hydroxylation of lipid soluble constituents (bile and bilirubin) are mediated by
cytochrome P450 (CYP) enzyme system
b. Bile acids are formed from cholesterol via CYP7A1 and CYP8B1
c. The majority of drugs are metabolized by CYP3A4
3. Conjugation
a. Conjugation of bile acids with taurine or glycine is carried out by bile acid-CoA
synthetase and bile acid Co-A amino acid N-acetyl transferase
b. Bile acid conjugation also occurs with glucouronides and sulfates during
cholestasis, which are substrates for the multidrug resistance–related protein 2
and 3
1) These reactions are mediated by uridine glucuronyl transferases
(UGT2B4) and sulfotransferases (SULT2A1)
c. Bilirubin is normally conjugated with glucouronides by UGT1A1
1) Mutations in the promoter region of UGT1A1 result in reduced enzyme
activity and Gilbert’s syndrome
2) Mutations in the gene itself result in complete loss or very low level of
enzyme activity and Crigler-Najjar syndrome
4. Canalicular excretion (apical membrane)
a. Bile salt export pump (BSEP, ABCB11) is an ATP cassette transporter, which ef-
ficiently secretes bile acids into the canalicular lumen
1) The secretion of the bile acids against a steep concentration gradient is
the rate-limiting step of bile secretion
2) Mutations in BSEP result in a variety of cholestatic diseases, including
progressive familial intrahepatic cholestasis (PFIC) Type 2, benign recur-
rent intrahepatic cholestasis (BRIC-2) and intrahepatic cholestasis of
pregnancy (ICP)
b. The multidrug resistance protein 3 (MDR3) gene product, a flippase, functions
as a phospholipid export pump
1) Mutations in MDR3 result in variable forms of PFIC type 3, ICP, low
phospholipid-associated cholelithiasis and adult biliary cirrhosis
2) Cholesterol is secreted by two combined half transporters, ABCG5/G8
a) Mutations of either half results in Sitosterolemia
c. Multidrug resistance–related protein 2 (MRP2) multispecific transporter (ABCC2)
excretes conjugated bilirubin
1) MRP2 exports glutathione and other organic anions into the bile (usu-
ally as conjugates with glutathione, glucuronide or sulfates)
2) Mutations in MRP2 lead to Dubin-Johnson syndrome, while polymor-
phisms may predispose to drug-induced cholestasis
IV. Differential Diagnosis

A. The differential diagnosis for jaundice is age-specific
B. See neonatal cholestasis and cholestasis in older child
V. Evaluation
A. Jaundice in the older infant and child is always pathologic and requires an investigation
B. History and patient age provide important clues as to the etiology of jaundice (Table 1)
1. A detailed physical exam may help direct the investigation by providing an assessment of
global health and nutrition, assessing for dysmorphic features, and stigmata of chronic
liver disease.
2. Initial laboratory might include a complete blood count with differential, chemistry, liver
enzymes, albumin, total and direct bilirubin, and evaluation of liver synthetic function.
More detailed testing can then be tailored according to suspected diagnoses.
3. Imaging evaluation might begin with an abdominal ultrasound as it noninvasive and
without radiation. Ultrasonography can measure hepatic size and consistency. It can
detect abnormal echotexture suggestive of fat, fibrosis or infiltration, and it can identify
masses, cysts, abscesses and biliary tree abnormalities. Absence of the gallbladder in
a fasting baby can be suggestive of biliary atresia, but is not diagnostic. Liver biopsy is
often needed for definitive diagnosis.
Table 1. Patient History and Associated Differential Diagnosis

History of: Differential Diagnosis:
Maternal infection TORCH infections, HIV, HBV
Abnormal fetal ultrasound Choledochal cyst, ciliopathies
Cholestasis of Pregnancy PFIC
Consanguinity or similar history in parents Autosomal recessive genetic or metabolic
or siblings diseases
History of feeding, irritability and vomiting Metabolic disorders, such as galactose
Acholic stools Obstruction or severe hepatocellular
disease
Blood products transfusions/organ Infectious hepatitis
transplant
Sexual activity/ intravenous drug use Hepatitis B, C, HIV, gonorrhea and syphi-
lis
Foreign travel Parasitic infections and/or liver abscesses
Shellfish ingestion Hepatitis A
Drug intake: prescription or recreational Vitamin A, Tylenol, hepatotoxic
drugs medications
Chronic illnesses Congenital heart disease, cystic fibrosis,
diabetes mellitus, hematologic diseases,
autoimmune diseases
Recommended Reading
Moyer V, Freese DK, Whitington PF, et al., Guideline for the evaluation of cholestatic jaundice in infants:
recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.
Boyer JL. New perspectives for the treatment of cholestasis: lessons from basic science applied clinically.
J Hepatol. 2007;46(3):365-371.
Karpen SJ. Mechanisms of Bile Formation and Cholestasis. In: Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in
Children. 3rd ed. New York, NY: Cambridge University Press; 2007.

6D. Elevated
Aminotransferases
Isabel Rojas, MD
I. Serum aminotransferases are liver chemistry tests used to assess for liver injury. These enzymes are found
in several different tissues. Increased levels of aspartate aminotransferase (AST) and alanine aminotrans-
ferase (ALT) can assist in the identification of the liver injury and direct additional evaluation.
A. AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are released from damaged
hepatocytes, indicating liver injury
B. AST is found in high concentrations in liver, heart muscle, skeletal muscle, kidney, brain, pan-
creas, lung, leukocytes and red blood cells
C. ALT is more specific for liver disease, due to its presence in low concentrations in other tissues
D. Elevation itself is not diagnostic of any disease, however, evaluated in conjunction with patient’s
history and physical exam, it can suggest a particular diagnosis and direct the evaluation
E. Differential diagnosis of marked elevated aminotransferases (>1,000 U/L) include: viral hepatitis
(A to E), toxic or drug-induced liver injury, ischemic hepatitis and, less commonly, autoimmune
hepatitis, Wilson’s and acute obstruction of biliary tract
F. A disproportionately isolated increase in AST suggests: hemolysis, acute rhabdomyolysis second-
ary to a viral illness, myopathic process, myocardial disease and recent vigorous physical activity
G. Although the value of the AST:ALT ratio is not well-documented in children, a ratio >4 in the ap-
propriate clinical setting is highly suggestive of fulminant Wilson’s disease
H. Increased aminotransferases may be the only manifestation of celiac disease
I. Nonalcoholic fatty liver disease may present with isolated increase in ALT
J. Differential diagnosis of elevated transaminases in a transplanted patient include: acute or
chronic cellular rejection, de novo autoimmune hepatitis, infection, and biliary or vascular compli-
cations
K. There is poor correlation between degree of elevation of aminotransferases and extent of liver
cell damage. A rapid decline in aminotransferases with increasing bilirubin and coagulopathy
reflect massive liver damage and poor prognosis in a child with acute liver failure
II. Causes
A. Chronic, mild elevation: ALT>AST (<150 U/L or <5X normal)
1. Hepatic origin:
a. α1-antitrypsin deficiency
b. Autoimmune hepatitis
c. Chronic viral hepatitis (B, C and D)
d. Hemochromatosis
e. Medications and toxins
f. Steatosis and steatohepatitis
g. Wilson’s disease
2. Nonhepatic origin:
a. Celiac disease
b. Hyperthyroidism
B. Severe, acute elevation ALT>AST (>1,000 U/L or >20–25 X normal)
1. Hepatic origin:
a. Acute bile ducts obstruction
2. Acute Budd-Chiari syndrome
3. Acute viral hepatitis
4. Autoimmune hepatitis
5. Hepatic artery ligation
6. Ischemic hepatitis
7. Medications/toxins
8. Wilson’s disease

C. Severe, acute elevation: (AST>ALT (>1,000 U/L or >20–25 X normal)
1. Hepatic origin:
a. Alcohol-related liver injury
b. Cirrhosis
a. Acute rhabdomyolysis
b. Myopathy
D. Chronic, mild elevation: (AST>ALT (<150 U/L, <5 X normal)
1. Hepatic origin:
a. Alcohol-related injury
b. Cirrhosis
a. Hypothyroidism
b. Macro-AST
c. Myopathy
d. Strenuous exercise
Recommended Reading
Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press;
2007.
Pennsylvania, PA: Saunders; 2010.
6E. Hepatomegaly
Rima Fawaz, MD
I. Increased liver size or hepatomegaly can be seen in many disorders, but is not a very reliable sign of liver
disease, because of the variability of the size and shape of the liver.
A. To determine if hepatomegaly is present, the liver span should be measured along the midcla-
vicular line, with palpation of the lower margin and percussion of the upper margin
B. In children <2 years of age, the liver edge can extend up to 3.5 cm below the right costal margin
in the midclavicular line. In older children, the liver edge rarely extends beyond 2 cm
C. The mean liver span is related to body weight, age and gender. At age 20, mean liver span for
men is 7.7 cm and for women 6.3 cm. A liver span 2–3 cm smaller or larger than mean is consid-
ered abnormal
D. Hepatomegaly may be a transient finding during systemic infection, but persistent hepatomegaly
should prompt a proper investigation
E. Mechanisms leading to hepatomegaly are similar to those leading to tissue growth and can be
the result of alterations in cell number (hyperplasia), cell growth (hypertrophy) and/or cell death
(apoptosis). In different disorders associated with hepatomegaly, many of all the above mecha-
nisms can be at work at the same time
II. Differential Diagnosis

A. See Table 1
III. Evaluation
A. Hepatomegaly should always be confirmed by a careful abdominal examination before extensive
testing is undertaken. A detailed history can help direct further laboratory testing (see Table 2).
If hepatomegaly is confirmed clinically further evaluation is recommended
B. A firm, enlarged liver may suggest a storage disease, infiltrative process, venoocclusive disease
or neoplasia. Assessment of the liver edge may reveal firmness, irregularity, or frank nodules,
suggestive of cirrhosis. Tenderness of an enlarged liver may indicate an inflammatory process
C. Laboratory evaluation should include a complete blood count with differential, comprehensive
metabolic panel, liver enzymes including transaminases, glutamyltranspeptidase, alkaline phos-
phatase, albumin, total and direct bilirubin, and evaluation of liver synthetic function. More
specialized testing can then be requested according to the suspected diagnosis
D. Imaging evaluation should always start with an abdominal ultrasound as it is the least
invasive. This will help guide the need for further investigation
E. Ultrasonography can measure hepatic size and consistency. It can detect abnormal echotexture
suggestive of fat, fibrosis or infiltration, and it can identify masses, cysts, abscesses and biliary
tree abnormalities. Further imaging modalities may be needed for further elucidation, such as CT
scan or MRI
F. Liver biopsy is often needed for definitive diagnosis.

Table 1. Differential Diagnosis of Hepatomegaly
Increased Number of Cells in Liver Increased Vascular Space Increased Biliary Space
Inflammation (hepatocyte or Kupffer cell Intrahepatic obstruction to Congenital hepatic fibrosis
enlargement, inflammatory cells) hepatic vein outflow
• Viral: Hepatitis A-E, Cytomegalovirus, • Venoocclusive disease Caroli disease
Epstein-Barr virus, Coxsackievirus •H epatic vein thrombosis
• Bacterial (sepsis, abscess, cholangitis) (Budd-Chiari) Idiopathic (benign?)
• Toxic • Hepatic vein web
• Autoimmune
Suprahepatic obstruction
Storage • Congestive heart failure
• Fat • Pericardial disease
oN onalcoholic fatty liver disease, Reye o T amponade, Constrictive
syndrome/mitochondrial disease, pericarditis
Malnutrition (kwashiorkor),
Hyperalimentation, Galactosemia,
Cystic fibrosis, Diabetes
• Glycogen storage diseases
• Gaucher disease
• Niemann-Pick disease
• Wolman disease
• Alpha one antitrypsin deficiency
• Wilson disease
• Hypervitaminosis A (Kupffer cell
hyperplasia)
Infiltration
• Extramedullary hematopoiesis
• Primary tumors
oH epatoblastoma, Hepatocellular
carcinoma, Hemangioma,
Focal nodular hyperplasia
• Secondary or metastatic tumors
o L ymphoma, Leukemia,
Neuroblastoma, Wilms tumor,
Hemophagocytic lymphohistiocytosis
Modified with permission from “Disorders of the Liver and Biliary System” in Oski’s pediatrics : Principles &
Practice of Pediatrics. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006: Chapter 367.
Table 2. History Intake for the Evaluation of Hepatomegaly
Historical Information Implication
Maternal infection Torch infections, HIV, HBV
Fetal ultrasound findings Choledochal cyst, ciliopathies
Consanguinity/similar problems with parents or Risk for autosomal-recessive inheritance, genetic
siblings diseases
Blood products transfusions/organ transplant Infectious hepatitis
Sexual activity/ intravenous drug use Hepatitis B, C, HIV, gonococcal and syphilis
Foreign travel Parasitic infections and/or liver abscesses
Shellfish ingestion Hepatitis A
Medication intake/nonprescription and recreational Vitamin A, Tylenol, hepatotoxic medications
drugs
Chronic illnesses Congenital heart disease, cystic fibrosis, diabetes
mellitus, hematologic diseases, autoimmune dis-
eases, obesity
Recommended Reading
Lawson EE, et al., Clinical estimation of liver span in infants and children. Am J Dis Child. 1978;132(5):474-
476.
Naveh Y, Berant M. Assessment of liver size in normal infants and children. J Pediatr Gastroenterol Nutr.
1984;3(3):346-348.
Novak D, Suchy FJ, Balistreri WF. In: Feigin RD, DeAngelis CD, Jones MD Jr. Disorders of the liver and biliary
system. Oski’s Pediatrics: Principles & Practice of Pediatrics. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2006: Chapter 367.
Squires R. Approach to the patient with hepatobiliary symptoms or signs. In: Rudolph AM, Rudolph CD, eds.
Rudolph’s Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2003.
Walker WA, Mathis RK. Hepatomegaly. An approach to differential diagnosis. Pediatr Clin North Am.
1975;22(4):929-942.

6F. Ascites
Alfredo Larrosa Haro, MD, PhD
Mariana Gómez-Nájera, MD
I. scites defined as the accumulation or retention of free fluid within the peritoneal cavity and it is one of
A
the most common complications of cirrhosis.
A. Ascites may also be associated with other diseases, such as cancer with peritoneum involvement,
primary infections, autoimmune diseases and chylous ascites due to disruption of the abdominal
lymphatics
B. Prevalence is unknown
II. P
athogenesis: The accumulation of fluid in the peritoneal cavity represents a breakdown of intravascular
volume homeostasis.
A. The Associated factors to ascites are:
1. Decreased plasma-colloid osmotic pressure
2. Increased capillary pressure
3. Increased colloid osmotic pressure of ascites fluid
4. Decreased ascites fluid hydrostatic pressure
III. Causes of Ascites

A. Portal hypertension
1. Presinusoidal causes, eg, portal vein thrombosis (usually ascites is mild if present at all)
2. Sinusoidal causes, eg, cirrhosis, vitamin A toxicity
3. Postsinusoidal causes, eg, venoocclusive disease, Budd-Chiari syndrome, constrictive
pericarditis, congestive heart failure
B. Neoplastic causes
1. Peritoneal carcinoma
2. Lymphoma
3. Hepatocellular cancer
C. Inflammatory causes
1. Infectious causes, eg, spontaneous bacterial peritonitis, tuberculosis
2. Chemical causes, eg, talc peritonitis
3. Immunologic disorders, eg, systemic lupus erythematosus, vasculitis
4. Allergic causes, eg, eosinophilic gastroenteritis
D. Miscellaneous causes
1. Nephrotic syndrome
2. Dialysis-associated ascites
3. Thoracic duct obstruction
IV. Diagnosis
A. Moderate and severe ascites may be detected on physical exam: fluid wave with percussion,
ballotable liver and spleen and development of hydrocele and/or inguinal hernias are frequent
findings
B. Mild ascites may be confirmed by ultrasound
C. An abdominal paracentesis is not necessarily indicated in a child with known chronic liver
disease. However, it is indicated to rule out spontaneous bacterial peritonitis (SBP) or other less
frequent etiologies
1. The ascitic fluid associated with cirrhosis contains protein of <2.0 g/dL, serum-ascites
albumin gradient (SAAG) is >1.1 g/dL (reflects portal hypertension) and the cell count is
<250 cells/mm3. Glucose concentration resembles serum levels
D. Paracentesis location: The left lower quadrant of the abdomen, two finger breadths cephalad
and two finger breadths medial to the anterior superior iliac crest, is the best location for para-
centesis because it has thinner abdominal wall and larger pool of fluid accumulation

E. Spontaneous bacterial peritonitis (SBP) is a primary bacterial infection of the ascites fluid
1. Fever, irritability, abdominal tenderness, tense distension and erythema of skin are com-
mon signs
2. >250 neutrophils/mm3 has the highest sensitivity for the diagnosis of SBP.
3. Peritoneal bacterial cultures are only positive in ~60% of cases of SBP
4. Bacterial organisms identified commonly include Gram-negative bacteria, Strep species,
Enterococcus
V. Treatment
A. Sodium restriction
1. Sodium plays a central role in the pathogenesis of ascites
2. Sodium restriction is the first step to treat ascites. However, this restriction should not
affect nutrient ingestion, particularly of infants receiving formulas with specific sodium
content. Children should have sodium restriction limited to 1,000 mg/day
B. Diuretics
1. The promotion of sodium excretion by means of diuretics is the second step
2. Spironolactone (1–5 mg/kg/d divided in 2–4 doses in infants or 100–200 mg/d in
two divided doses for children and adolescents) is a potassium-sparing diuretic
3. Furosemide is indicated when spironolactone fails to improve ascites (1–4 mg/kg/d in
infants or 40–240 mg/d in older children and adolescents).
4. Complications of diuretics may be hypovolemia and electrolyte disturbance (hyponatre-
mia for spironolactone and hyponatremia plus hypokalemia for furosemide)
C. Large-volume paracentesis is indicated in refractory ascites or in children with restrictive respira-
tory failure
Recommended Reading
Hardy S, Kleinman RE. Cirrhosis and chronic liver failure. In: Suchy FJ, Sokol RJ, Balistreri WF, ed. Liver Disease
in Children. New York, NY: Cambridge University Press; 2007:108-114.
Hou W, Sanyal AJ. Ascites:diagnosis and management. Med Clin North Am. 2009;93(4):801-817.
McDiarmid SV. End-stage liver disease. In: Kleinman R, Sanderson IR, Goulet O, Sherman PM, Mieli-Vergani G,
Shneider BL. Walker’s Pediatric Gastrointestinal Disease. Hamilton, Ontario: BC Decker Inc; 2008:1138-1141.
Sabri M, Saps M, Peters JM. Pathophysiology and management of pediatric ascites. Curr Gastroenterol Rep.
2003;5:240-246.
6G. Liver Masses
Jillian S. Sullivan, MD
Shikha S. Sundaram, MD, MSCI
Primary tumors of the liver are rare and represent 0.3%–4% of all pediatric solid tumors.
A. Two-thirds of liver tumors are malignant, with the most common being hepatoblastoma
B. The liver may also be the site of metastatic lesions from neuroblastoma, Wilms’ tumor, and
lymphoma
C. General signs and symptoms
1. Abdominal distention, palpable right upper quadrant mass, anemia
2. Jaundice and hepatic insufficiency are rare
3. May see symptoms associated with specific tumor types
a. Fever, thrombocytosis
b. Precocious puberty
c. High output cardiac insufficiency
d. Skin findings (hemangiomas)
4. Can occur within the presence of a genetic/metabolic syndrome
II. Benign Liver Tumors

A. Differential diagnosis varies by age
1. Infants: infantile hepatic hemangioma
2. Toddlers: mesenchymal hamartoma, Focal Nodular Hyperplasia (FNH)
3. School-aged children/adolescents: hepatic adenoma, FNH
4. Other benign tumors: non-neoplastic cystic masses (biliary/simple hepatic cysts),
hematoma, parasitic cysts, pyogenic/amoebic liver abscesses
III. Infantile Hepatic Hemangiomas (IHH)

A. Most common benign hepatic tumor in infancy
B. Vascular lesion, represents 12% of all childhood liver tumors
C. Most cases (85%) are diagnosed within the first 6 months of life
1. ~30% present within the first month
D. Slight female predominance (F:M 1.3–2:1)
E. Presentation
1. Asymptomatic abdominal mass; normal labs, including alpha-fetoprotein (AFP)
2. Cutaneous hemangiomas
3. High output cardiac failure
4. Coagulopathy
5. Jaundice, failure to thrive, fever
6. Hypothyroidism
F. Varying degrees of hepatic involvement
1. Focal: Well-defined, solitary, spherical tumor, usually asymptomatic
a. Rarely accompanied by cutaneous hemangiomas
b. Does not stain positive for glut-1
c. Lesions should spontaneously involute
2. Multifocal: Presence of, multiple individual spherical tumors with arteriovenous shunts
a. Usually asymptomatic
b. Accompanied by multiple cutaneous hemangiomas
c. Should spontaneously involute
3. Diffuse: Extensive hepatic involvement, near total replacement of hepatic tissue
by hemangiomas
a. More likely to have serious effects, including compression of inferior vena cava,
respiratory compromise from compression of thoracic cavity, abdominal com-
partment syndrome, severe hypothyroidism, and high output cardiac failure

G. Treatment may include: resection, embolization, medical therapy (vincrinstine, steroids,
management of hypothyroidism)
1. Transplant should be considered in severe cases
IV. Mesenchymal Hamartoma (MH)

A. Cystic/multicystic lesion, whose origin/biology are poorly understood
B. The second most common benign liver tumor in children
1. Accounts for 6% of all pediatric liver tumors
2. 85% of lesions occur in children <2 years old
C. Slight male predominance (M:F, 3:2)
D. Presentation
1. Abdominal distention, vomiting, anorexia, may have respiratory distress
2. May be diagnosed by prenatal ultrasound
3. May have increased AFP
E. Clinical course is variable
1. Tumor usually increases in size over first few months of life; then can stabilize, continue
to grow, or spontaneously regress
2. Small risk of malignant change into embryonal sarcomas
F. Management is controversial, but includes:
1. Nonoperative management in asymptomatic cases, as lesion will spontaneously regress
a. Must consider potential transformation risk to malignant embryonal sarcoma
2. Incision/drainage of individual cysts
3. Complete tumor resection
4. Transplantation in cases of unresectable lesions or severe symptoms
5. Prenatal intervention
V. Focal Nodular Hyperplasia (FNH)

A. Benign epithelial tumor, represents 2% of all pediatric liver tumors
1. Well-circumscribed, lobulated lesion with central stellate scar
2. Can vary in size from a few mm to 20 cm
3. Has been seen with hepatocellular carcinoma, prompting consideration of tissue
sampling to confirm diagnosis
B. Presentation
1. Usually diagnosed between 2–5 years, but can occur at any age
2. More common in females
3. Typically diagnosed on routine physical exam
4. Patients may have abdominal pain
5. Normal AFP
C. Management
1. Nonoperative management recommended for asymptomatic patients
2. Excision of tumor may improve abdominal pain associated with FNH
VI. Hepatic Adenoma

A. Usually occurs in young women on oral contraceptives or during pregnancy
B. Also associated with glycogen storage disease
C. Presentation
1. Usually an incidental finding
2. Larger lesions can present with pain or a right upper quadrant mass
3. May also present with hemorrhage/rupture of adenoma
D. Carries risk of transformation to hepatocellular carcinoma
E. May be difficult to diagnose
1. CT/MRI findings can be nonspecific (homogenous enhancement in arterial phase, hem-
orrhage, fat deposition, calcifications, lack of central scar)
2. Can look like hepatocellular carcinoma, although AFP may help to differentiate these
conditions
3. May need to rely on tissue sample for diagnosis
a. Histology: hepatocytes arranged in organized cords
b. May also look like well-differentiated hepatocellular carcinoma
F. Management
a. Surgical resection, radiofrequency ablation (RFA)
VII. Malignant Liver Tumors (See Table 1)
VIII.Hepatoblastoma (HB)
A. Most common malignant pediatric liver tumor
1. 79% of all liver tumors in patients <15 years
B. Male predominance (M: F, 6.1:1.2–3)
C. Five histologic subtypes
1. Fetal
2. Embryonal
3. Mixed epithelial
4. Mesenchymal/macrotrabecular
5. Small cell undifferentiated
D. Multiple known risk factors:
1. Birth weight <1,000 grams
2. Familial adenomatous polyposis syndrome
3. Beckwith-Wiedemann syndrome
4. Many other metabolic/genetic associations
E. Presentation can vary
1. Asymptomatic right upper quadrant mass that is firm, non-tender, irregular
2. Weight loss, anorexia, abdominal pain, vomiting, rarely jaundice
3. Precocious puberty resulting from HCG
4. Labs: anemia (70%), thrombocytosis (35%), elevated AFP (90%)
a. Normal and high AFP levels can be associated with poor outcome
b. Important to consider normal physiologic changes in AFP based on
postgestational age
1) Normal AFP: 25,000–50,000 ng/mL at birth (<25 ng/mL by 6 months)
5. In high-risk groups, such as those with familial adenomatous polyposis or Beckwith-
Wiedemann syndrome, screening with AFP and a liver ultrasound until age 4–5 years is
recommended
6. Biopsy needed to confirm diagnosis
7. Management: (based on PRETEXT score)
a. PRETEXT I/II: surgical resection followed by chemotherapy
b. PRETEXT III/IV: chemotherapy followed by delayed primary resection
c. Need to consider liver transplantation in patients with unresectable primary
tumors despite chemotherapy, assuming they do not have metastatic disease
1) Important prognostic factor: decreasing tumor size or reduction in AFP
levels after chemotherapy
2) Refer to liver transplant center if patients have multifocal PRETEXT IV
tumors or unifocal PRETEXT II/III tumors (involving main hilar structures
or all three hepatic veins)
3) Contraindications to transplant include persistence of extrahepatic
metastases despite chemotherapy
IX. Hepatocellular Carcinoma (HCC)

A. The 2nd most common malignant pediatric liver tumor
1. Represents <0.5% of all pediatric malignancies
B. Usually occurs in older children/teenagers
C. Most are de novo tumors, but can be associated with chronic liver diseases:
1. Viral hepatitis (particularly hepatitis B)
2. Inborn errors of metabolism (i.e., tyrosinemia)
3. Biliary atresia
4. Fanconi’s syndrome
D. Other risk factors: androgenic steroids, oral contraceptives, methotrexate
E. Presentation
1. Abdominal distention, dull pain/discomfort, weight loss, weakness, hepatomegaly
2. Often present with metastases at diagnosis (regional lymph nodes, lungs, bones)
3. Labs: elevated AFP in 60%–80% of cases

F. Management:
1. PRETEXT staging (similar to hepatoblastoma)
2. Relatively chemoresistant tumor (only partial response in ~50% of patients)
3. Surgical resection
4. Consider liver transplantation for unresectable HCC
Table 1. Liver Tumor Summary

Tumor Presentation Labs Imaging Management
IHH Palpable mass, distention, Normal Focal, multiple or Screening, ± /-
CHF, hemangiomas (infant) diffuse hemangiomas steroids; will likely
resolve (Glut-1 neg);
may need resection/tx
(diffuse)
MH Abd distention + prenatal Normal Single/multiple cysts; Resection if possible
u/s (infant/toddler) ±/- high AFP can look like solid (risk of malignancy)
tumor
FNH Asymptomatic Normal Homogenous mass Can occur with HCC
Can have pain with the with central scar If asymptomatic, no
larger lesions surgical intervention
Adenoma Incidental finding, Normal Nonspecific findings Resection vs ablation
pregnancy, OCPs, +/± high GGT (risk of malignancy)
rupture/RUQ mass
HB Asymptomatic mass, f/wt +AFP CT: solitary/multifocal Resection,
loss/pain, FAP, BWS, prec (10% with normal) mass; calcifications chemotherapy (high
pub, LBW risk may get
chemotheraphy,
?OLTx
HCC Hepatomegaly, weight loss, +AFP (60%-80%) Solid tumor with Chemotherapy,
pain, fatigue irregular margins resection/liver
transplant
Recommended Reading
Czauderna P. Hepatocellular carcinoma in children: results of the First Prospective Study of the International
Society of Pediatric Oncology Group. J Clin Oncology. 2002;2798-2804.
Emre S, McKenna GJ. Liver tumors in children. Pediatr Transplantation. 2004;8:632-638.
Meyers RL. Tumors of the liver in children. Surg Onc. 2007;16:195-203.
Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for hepatoblastoma: indications and contraindica-
tions in the modern era. Pediatr Transplantation. 2005;9:557-565.
Stocker JT. Hepatic tumors in children. Clin Liv Dis. 2001;5:259-281.
6H. Cirrhosis and
Portal Hypertension
Khyati Mehta, MD
Simon Ling, MD
Portal hypertension can be caused by a wide variety of conditions. It frequently presents with bleeding from
esophageal varices, which is the most common cause of serious gastrointestinal hemorrhage in children.
I. Definition
Portal hypertension is defined as an increase in portal pressure >5 mm Hg
II. Etiology
Portal hypertension in children may arise due to problems at three different levels (Figure 1)
A. Prehepatic disease
1. Portal vein thrombosis or occlusion by tumor and splenic vein thrombosis
B. Intrahepatic disease
1. Intrinsic diseases of the liver, including those causing severe fibrosis and cirrhosis; i.e.,
congenital hepatic fibrosis
2. Intrahepatic vascular or sinusoidal diseases, including schistosomiasis, veno-occlusive
disease, nodular regenerative hyperplasia, hepatoportal sclerosis
C. Posthepatic disease
1. Budd-Chiari syndrome, congestive heart failure, constrictive pericarditis
D. Other causes
1. Arterialization of the portal venous flow by an arteriovenous fistula (e.g., as a congenital
abnormality or acquired after liver biopsy)
III. Pathophysiology
A. Pressure gradient in the portal circulation (ΔP) is a function of portal flow (F) and resistance to
flow (R)
1. ΔP = F × R
B. Changes in portal flow and resistance originate from vascular and mechanical factors, which
may be fixed (e.g., fibrosis and architectural distortion) or dynamic (e.g., sinusoidal vascular tone)
(Figure 2)
IV. Vascular Factors

A. Raised intrahepatic vascular tone due to constriction of vascular smooth muscle cells, hepatic
stellate cells, and hepatic myofibroblasts in response to changes in vasoactive substances
(e.g., endothelin 1, reduced intrahepatic nitric oxide, increased thromboxane A2, reactive
oxygen species)
B. Increased portal venous inflow due to splanchnic vasodilatation that increases bloodflow to the
gut and spleen
C. Angiogenic mechanisms contributing to the development of portosystemic collaterals and varices
V. Mechanical factors
A. Fibrosis and nodularity of the cirrhotic liver, with distortion of the vascular architecture, causes
remodeling in systemic and splanchnic vasculature, due to increased flow and shear stress that
leads to a hyperdynamic circulatory state

VI. Clinical Presentation
A. Splenomegaly
1. On physical exam or ultrasound
B. Variceal bleeding
2. Presentation with hematemesis and/or melena
C. Prominent vascular markings
3. Caput medusa, spider hemangiomata
D. Ascites
E. Associated lab findings
1. Leukopenia and thrombocytopenia
VII. Complications of Portal Hypertension (Figure 3)

A. Variceal bleeding
B. Ascites
1. Peritoneal fluid collection resulting from the combined effects of circulatory changes,
including splanchnic dilatation, activation of the renin-angiotensin-aldosterone system,
increased vasopressin secretion, water and sodium retention, increased portal hydro-
static pressure, and reduced intravascular oncotic pressure due to hypoalbuminemia
(See section on Ascites)
C. Hepatic encephalopathy
1. Portosystemic shunting and liver dysfunction leads to delivery of blood to the brain
containing increased concentrations of neurotoxic substances, such as ammonia
D. Hepatopulmonary syndrome
1. Classically diagnosed by the triad of liver disease, hypoxemia and intrapulmonary vascu-
lar dilatations (identified by contrast-enhanced echocardiography or macroaggregated
albumin nuclear medicine scan), but also seen in other causes of portosystemic shunting
(e.g., congenital portosystemic shunt)
E. Portopulmonary hypertension: pulmonary hypertension in the setting of portal hypertension
F. Hepatorenal syndrome: renal failure in the setting of portal hypertension, primarily due to renal
vasoconstriction in the absence of renal parenchymal damage
G. Mucosal edema leading to malabsorption and FTT
VIII.Diagnosis
A. The presence of portal hypertension in children is usually a presumptive diagnosis based on find-
ings on clinical examination (splenomegaly in the setting of known liver disease) and/or imaging:
1. Abdominal US—confirms nonspecific features, such as abnormal hepatic echotexture,
large collateral veins, and splenomegaly. Doppler flow studies provide information on
direction and velocity of flow in the portal vein, hepatic veins, and vena cava, including
presence of thrombosis or cavernous transformation of portal vein. Reversal of blood
flow in the portal vein is usually a late finding
2. CT & MRI—both useful in confirming Budd-Chiari syndrome (absence or diminutive
hepatic veins, splenomegaly, ascites, patchy contrast enhancement of liver parenchyma,
caudate lobe hypertrophy)
3. Angiography—MR angiography is used to assess patency and caliber of veins through-
out the portomesenteric system, and is particularly important when considering porto-
systemic shunt surgery and/or liver transplantation
4. Endoscopy may be used to evaluate for gastroesophageal and anorectal varices, as well
as portal hypertensive gastropathy characterized by mucosal hyperemia and dilated
submucosal veins
a. Large varices (>5 mm Hg) and varices of any size with red signs (including red
spots, varices on varices, red wales) are at greater risk of bleeding
5. Hepatic venous pressure gradient (HVPG) is measured via the transjugular approach, and
is the difference between the wedged hepatic venous pressure (an indicator of portal
venous pressure) and free hepatic venous pressure. A value >12 mm Hg is predictive of
variceal bleeding. This measurement is rarely used in routine clinical practice in children;
however is the most accurate way to define portal pressure in the setting of cirrhosis
(but is inaccurate in other causes of portal hypertension)
6. Liver biopsy—may show mild periportal fibrosis in extrahepatic PVO
IX. Management
Evidence for the management of portal hypertension is primarily derived from adult studies, with most
pediatric studies consisting of a small, uncontrolled case series
A. Primary prophylaxis: in patients at high risk of bleeding, adult studies show effective preventative
therapy with either nonselective beta blockers or endoscopic variceal ligation (EVL). Endoscopic
screening of adults is therefore recommended
B. Emergency management of variceal bleeding
1. Airway, breathing, IV access and fluid resuscitation, NPO
2. Do not overtransfuse (aim to maintain Hb at approximately 8 g/dL)
3. Broad-spectrum antibiotic prophylaxis
4. Vitamin K 1–10 mg slowly IV
5. Intravenous proton pump inhibitor or ranitidine
6. Octreotide infusion: to reduce splanchnic blood flow and portal pressure with minimal
side effects
7. Urgent EGD within 24 hours to confirm source of bleeding and to treat varices
C. Endoscopic management of varices (see section on Therapeutic Endoscopy)
1. Endoscopic variceal ligation (EVL)
2. Endoscopic injection sclerotherapy
D. Surgery for portal hypertension: surgery for portal hypertension is mostly considered in children
with portal vein thrombosis, and only rarely in children with cirrhotic liver disease in whom crite-
ria for liver transplantation are not met (Figure 4). Indications for surgery include:
1. Esophageal variceal bleeding that is refractory to medical and endoscopic therapy in
children with portal venous occlusion, or in children with chronic liver disease who do
not fulfill criteria for liver transplantation
2. Bleeding gastric or ectopic varices that cannot be controlled endoscopically
3. Severe hypersplenism characterized by platelet count <10,000 and/or recurrent compli-
cations, including nonvariceal hemorrhage or infections
4. Medically refractory portosystemic encephalopathy
5. Hepatopulmonary syndrome or portopulmonary hypertension in children with portal
vein thrombosis, if bypass surgery can be achieved (see below)
6. Relative indications include symptomatic splenomegaly, restricted activity, large varices
and poor access to health care, portal biliopathy, and unexplained failure to thrive
E. Description of surgical procedures:
1. The mesenteric-left portal vein (“Rex”) bypass is used to treat portal vein thrombosis,
bypassing the thrombosed portal vein with a venous conduit from mesenteric vein to the
left portal vein
a. Restores portal venous blood flow to the liver and is therefore not complicated
by encephalopathy
2. The splenorenal shunt is the portosystemic shunt most often used in children because
there is a lower risk of postoperative hepatic encephalopathy compared to mesocaval
shunts
3. Transjugular intrahepatic portosystemic shunt (TIPS) is a less invasive interventional radi-
ology technique, in which a channel is created within the liver between a hepatic vein
and portal vein
F. Liver transplantation:
1. Transplantation is the treatment of choice for most children with variceal bleeding com-
plicating end-stage chronic liver disease (e.g., biliary atresia), in whom criteria for liver
transplantation are met
2. Previous portosystemic shunting does not compromise survival after liver transplantation,
although may complicate surgery and increase morbidity

Figure 1. Normal anatomy of the portal venous system.
Courtesy of Kelly D. Diseases of the Liver and Biliary System in Children.
3rd ed. Hoboken, NJ: Wiley-Blackwell; 2008
Cirrhosis
Resistance to Portal Blood Flow
Varices Portal Pressure Splanchnic Arteriolar

Resistance
Large > 5 mm
Hyperdynamic
Small < 5 mm Portal Pressure
Circulation
Figure 2. Association between circulatory changes, portal pressure, and development of varices
Figure 3. Sites of collaterals formed as a result of portal hypertension. Varices may also develop at surgical
sites, such as Roux-en-Y anastamosis created during the Kasai operation in children with biliary atresia or at
the site of a gastrostomy tube.
Shunt procedures for portal hypertension
1. Portosystemic shunts
A Distal splenorenal
B Proximal splenorenal
C Side-to-side splenorenal
D Mesocaval splenorenal
2. Mesenterico-left portal (Rex) shunt
3. Transjugular intrahepatic
portosystemic stent shunt (TIPSS)
Figure 4. Surgical procedures. Courtesy of Kelly DA. Diseases of the Liver and Biliary System in Children.
3rd ed. Hoboken, NJ: Wiley-Blackwell; 2008.
Recommended Reading
Bosch J, Abraldes JG, Berzigotti A, Garcia-Pagan JC. Sem Liver Dis. 2008;28:3-25.
Kelly DA. Diseases of the Liver and Biliary System in Children. 3rd ed. Hoboken, NJ: Wiley-Blackwell; 2008.
Shneider B, Emre S, Groszmann R, Karani J, McKiernan P, Sarin S. Expert pediatric opinion on the Report of
the Baveno IV Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.
Pediatr Transplantation. 2006;10: 893-907.
Superina R, Shneider B, Emre S, Sarin S, de Ville de Goyet J. Surgical guidelines for the management of extra-
hepatic portal vein obstruction. Pediatr Transplantation. 2006;10:908-913.

6I. Fulminant Liver Failure
Naim Alkouri, MD
Acute liver failure (ALF) is rare in the United States. ALF accounts for 10%–15% of pediatric liver transplants.
I. Definition
A. Onset of hepatic encephalopathy and coagulopathy within 8 weeks of the onset of liver disease
in absence of preexisting liver disease
B. In pediatrics, however, encephalopathy may be difficult to detect and liver failure may be first
presentation of a previously unrecognized disease
1. The Pediatric Acute Liver Failure Study Group defines acute liver failure (ALF) in children
as:
a. Biochemical evidence of liver injury
b. No history of known chronic liver disease
c. Coagulopathy not corrected by vitamin K
d. INR >1.5 if the patient has hepatic encephalopathy (HE), or >2.0 if the patient
does not have HE
II. Etiology
A. A specific etiology cannot be identified in about 50% of pediatric cases
B. Toxins and Medications:
1. Acetaminophen: dose-dependent hepatotoxicity. Conversion to highly reactive metabo-
lite NAPQI; diagnostic criteria include toxic level on the Rumack nomogram and acute
ingestion of 100 mg/kg within 24 hours. Aminotransferase levels are extremely high
2. Anticonvulsants (phenytoin, carbamazepine, valproic acid): Can be accompanied by
fever, skin rash, and eosinophilia. Valproic acid can induce ALF by unmasking a more
generalized mitochondrial disorder
3. Mushrooms
4. Isoniazid
5. Amiodarone
6. Ecstasy
C. Metabolic:
1. Wilson Disease: serum ceruloplasmin may be normal in ALF. Very low alkaline phos-
phatase, high bilirubin-to-alkaline phosphatase ratio, and hemolytic anemia are clinical
clues. Poor prognosis with fulminant presentation
2. Galactosemia
3. Hereditary Fructose Intolerance: problems with introduction of fruit/sucrose. Some drugs
and vitamins are in sucrose suspension
4. Tyrosinemia
5. Urea cycle defect: Ornithine transcarbamylase (OTC) deficiency is the most common and
is X-linked. Very high ammonia levels without acidosis
6. Fatty acid oxidation (FAO) defects: present with a Reyes-like syndrome and hypoketotic
hypoglycemia
7. Mitochondrial disorders: neurologic involvement, with severe hypotonia and myoclonus
epilepsy (e.g., Alpers’ disease). Elevated lactate/pyruvate >20
8. Neonatal hemochromatosis: affects the fetus and newborn. Severe coagulopathy, with
relatively normal transaminases, and high ferritin and AFP. Abdominal MRI to demon-
strate siderosis in the pancreas and liver or buccal mucosa biopsy
D. Immune:
1. Autoimmune hepatitis (AIH): histology shows severe hepatic necrosis with interface
hepatitis and plasma cell infiltration. Treatment with steroids may permit survival without
liver transplantation
2. Hematophagocytic lymphohistiocytosis (HLH)

E. Infections: viral hepatitis
1. Hepatitis A and E are the most common cause of ALF in endemic areas
2. HSV and EBV are more common in North America
3. Enterovirus adenovirus
4. Sepsis
F. Ischemic:
1. Shock
2. Budd-Chiari syndrome
3. Congenital heart disease
4. Cardiac surgery
G. Malignancy
H. Indeterminate (50%)
I. The etiologic agents vary by age, as seen in Figure 1 below:
Courtesy of Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348
patients in the pediatric acute liver failure study group. J Pediatr. 2006;148:652-658.
III. Clinical presentation: varies based on etiology

A. Hepatic dysfunction with hypoglycemia, coagulopathy, and encephalopathy, with jaundice as a
late feature
B. Typically a healthy patient who develops flu-like prodrome with malaise, myalgia, nausea,
vomiting, and jaundice
C. Laboratory tests: increased transaminases, hyperbilirubinemia, coagulopathy
1. Rapidly falling enzymes with worsening coagulopathy suggests exhaustion of hepato-
cyte mass
IV. Complications
A. Hypoglycemia: due to failure of synthesis and release, along with hyperinsulinemia due to failed
degradation
1. Maintain adequate glucose infusion rate
B. Hepatic encephalopathy (HE)
1. Increased intracranial pressure (ICP) and cerebral edema are the major causes
of mortality
2. Factors that play a central role in the pathogenesis of HE
a. Hyperammonemia, which is associated with increased levels of glutamine in
astrocytes → results in cell swelling
b. Increased cerebral blood flow may contribute to the development of
cerebral edema
c. Enhanced inflammatory response and inflammatory cytokines such as TNFα
3. Symptoms include personality changes, regression, irritability, apathy, insomnia,
disturbed sleep wake cycles, and poor oral intake
4. May result in cerebral edema: prevention is critical with fluid restriction
a. Mannitol and hyperventilation for temporary treatment
Table 1. A scale to Assess HE in Children <4 Years
Coma stage for children younger than 4 years

Stage Clinical Signs Reflexes Neurologic Signs
Early (I and II) Inconsolable crying, sleep reversal, Hyper-reflexic Untestable
inattention to task
Mid (III) Somnolence, stupor, combativeness Hyper-reflexic Most likely untestable
Late (IV) Comatose, arouses with painful stimuli Absent Decerebrate or decorticate
(IVa) or no response (IVb)
Courtesy of Bucuvalas J, Yazigi N, Squires RH Jr. Acute liver failure in children. Clin Liver Dis. 2006;10:149-
168, vii.
5. Coagulopathy; causes epistaxis, bleeding, hemorrhage

a. Factor levels may help differentiate form DIC
b. Treat with vitamin K, FFP, activated factor 7a
V. Management
A. Treat above noted complications
B. Specific therapy
1. Acetaminophen → N-acetylcysteine
2. Drug-induced → Remove offending drug
3. Galactosemia → Remove dietary lactose
4. Tyrosinemia → NTBC
5. FAO defects → IV glucose and avoid fasting
6. Wilson disease → Liver transplantation
7. AIH → Corticosteroids
8. Herpes → Acyclovir
9. Neonatal hemochromatosis → Antioxidant cocktail
VI. Supportive Care

A. Manage ICP and multiorgan failure while awaiting recovery of liver function or liver transplant
B. IV fluids with glucose to avoid hypoglycemia
C. Electrolyte replacement (hypokalemia, hypophosphatemia)
D. Encephalopathy: medical therapy with lactulose. Minimize sedation, treat sepsis, and decrease
protein intake. ICP monitoring is controversial. Consider mannitol, hyperventilation, hypothermia,
or barbiturate coma for cerebral edema
E. Coagulopathy: correct PT/INR with FFP or recombinant factor VII only in the setting of active
bleeding or in anticipation of an invasive procedure
F. Prophylactic acid-suppressive therapy
G. Patients may develop hepatorenal syndrome or acute tubular necrosis and require dialysis
or CVVH
H. Obtain blood cultures and start antibiotics if indicated
I. Consider acyclovir if suspecting infection with HSV
VII. Liver Transplantation

A. Children with ALF fare poorly compared to those with chronic end-stage liver disease (average
6-month survival of 60% vs 90%).
B. Indications for OLT include:
1. Grade 3–4 encephalopathy
2. Rising bilirubin (>20 mg/100 mL)
3. Falling transaminases
4. Coagulopathy with prolonged PT >100 seconds, and Factor II, V, VII decreased to
<20% of normal values
5. Acute renal decompensation

Recommended Reading
Bucuvalas J, Yazigi N, Squires RH Jr. Acute liver failure in children. Clin Liver Dis. 2006;10:149-168, vii.
Cochran JB, Losek JD. Acute liver failure in children. Pediatr Emerg Care. 2007;23:129-135.
Dhawan A. Etiology and prognosis of acute liver failure in children. Liver Transpl. 2008;14:S80-S84.
Lee WM, Squires RH Jr, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop.
Hepatology. 2008;47:1401-1415.
Squires RH, Jr. Acute liver failure in children. Semin Liver Dis. 2008;28:153-166.
Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the pedi-
atric acute liver failure study group. J Pediatr. 2006;148:652-658.
6J-I. Cholestatic Liver
Diseases — Newborn
David Brumbaugh, MD
Cara Mack, MD
I. Overview of Neonatal Cholestasis

A. Cholestatic jaundice in the neonatal period can be attributed to a variety of etiologies
B. All jaundiced infants >3 weeks of age require measurement of direct (or conjugated) bilirubin
C. Neonatal cholestasis is defined as a direct bilirubin of ≥2 mg/dL and ≥20% of the total
bilirubin level
D. In assessing the jaundiced infant, make sure to visualize the stool color, as acholic stools are
associated with biliary atresia as well as other causes of biliary stasis
E. All patients with cholestasis should be worked up for the underlying cause as expediently as
possible. The most important reason for this urgency is based on the fact that the success of
the Kasai portoenterostomy surgical procedure for biliary atresia is dependent on an early age
at diagnosis
F. Patients with neonatal cholestasis should have further liver evaluation, including serum AST, ALT,
GGT, alkaline phosphatase, total protein, and albumin
G. An abdominal ultrasound should be performed in order to rule out a choledochal cyst, biliary
stones, sludge formation, or a tumor compressing the extrahepatic bile duct
H. Other abdominal abnormalities found in <20% of biliary atresia patients includes polysplenia,
intestinal malrotation, discontinuous inferior vena cava, and preduodenal portal vein
II. Differential Diagnosis of Neonatal Cholestasis

A. The causes of neonatal cholestasis include anatomic abnormalities, metabolic disorders,
infections, genetic syndromes and endocrinopathies
B. Anatomic abnormalities:
1. Choledochal cyst—five subtypes
a. Most common are Type 1: saccular dilation of extrahepatic bile duct only;
and Type 4: saccular dilations of intra- and extrahepatic biliary tree
b. Jaundice, acholic stools, and a palpable mass; may present with
cholangitis picture
c. Diagnosis by US
d. Surgical resection
e. Increased risk of cholangiocarcinoma if untreated
2. Spontaneous perforation of the bile duct
a. Jaundice, poor weight gain, ascites, acholic stools, and vomiting
b. Ill-appearing child with peritonitis
c. Ultrasonography typically reveals ascites and fluid around the gallbladder
d. Bile-stained ascitic fluid is a hallmark finding
e. Alert surgery immediately
3. Inspissated bile syndrome
a. Stagnant flow of bile leading to cholestasis
b. Often seen in the setting of intestinal disease and parenteral nutrition in the
neonate
c. Precipitation of cholesterol and calcium salts within bile can result in the forma-
tion of sludge
d. Bile sludge can be detected by ultrasound
e. Managed conservatively with ursodeoxycholic acid, a bile salt that acts as a
choleretic agent to promote bile flow
f. Bile sludge may be identified at cholangiogram, and saline flushes of the biliary
tree at that time can improve flow

4. Biliary atresia
a. Diagnostic workup includes ultrasound (US), liver biopsy, and intraoperative
cholangiogram. Rule out A1AT definitely
b. Ultrasound: to screen for associated anomalies (i.e., polysplenia)
1. Ultrasound: the size of the gallbladder by ultrasound is variable in bili-
ary atresia (from absent to normal caliber)
c. Percutaneous liver biopsy—liver histology consistent with biliary atresia—
fibrosis, bile duct proliferation, bile plugs in intrahepatic bile ducts
d. Alert surgery: intraoperative cholangiogram is the gold standard in the
diagnosis of biliary atresia
e. Kasai portoenterostomy: it is generally regarded that effective bile drainage
with resolution of jaundice can be achieved in up to 70% of biliary atresia
patients if the portoenterostomy is performed prior to 60 days of life, as
compared to 40%–50% of patients if performed at 60–90 days of life;
25% of patients at 90–120 days; and only 10%–20% of patients at 120 days
f. Complications post-Kasai:
1) Growth problems (see below)
2) Fat-soluble vitamin deficiencies (see below)
3) Cholangitis: fever, increase in bilirubin and other liver tests, acholic
stools, RUQ abdominal tenderness, bacteremia; Rx - antibiotics
4) Pruritis: due to excess circulating serum bile acids;
Rx - antibiotics: ursodiol ± rifampin
5) Portal hypertension is common: splenomegaly with hypersplenism,
variceal bleeding, ascites
6) Bile lakes that may become infected
7) Cirrhosis with synthetic dysfunction (coagulopathy, hypoalbuminemia,
hyperammonemia)
g. ~80% of cases lead to liver transplant in childhood
C. Metabolic disorders
1. Alpha-1 antitrypsin (A1AT) deficiency
a. 10%–15% of patients with A1AT deficiency present with neonatal cholestasis
b. Defect in the ATZ molecule that results in abnormal accumulation of A1AT in
the endoplasmic reticulum of hepatocytes
c. Diagnosed based on the serum A1AT level and phenotype (normal MM;
abnormal ZZ, SZ, SS; heterozygote MZ or MS)
d. Important to obtain A1AT laboratory test early on in the evaluation of
cholestasis, because if A1AT deficiency is confirmed, then there is no need
for further workup
e. No known therapies
2. Inborn errors of metabolism (IEOM)
a. Enzyme deficiencies (usually autosomal-recessive transmission) involving
multiple steps within metabolism of lipid, carbohydrate or protein
b. Examples include:
1) Galactosemia: part of the newborn screen and if suspected can be
confirmed with the galactose-1-phosphate uridyl transferase
serum level
2) Tyrosinemia: diagnosed with the urine succinylacetone level
3) Other IEOM can be screened for with serum amino acid and urine
organic acid studies
3. Bile acid synthesis defects (BASD)
a. Defects in a number of enzymatic steps within the bile acids pathway results in
abnormal bile acid synthesis and cholestasis
b. Screening test for BASD is total serum bile acids; this will be below normal in
BASD as compared to elevated in all other cholestatic diseases
c. GGT also usually not elevated
d. Total serum bile acids are low, then BASD are confirmed with measurement of
individual bile acid levels by fast atom bombardment (urine specimen)
e. Bile acid synthesis defects can generally be effectively treated by oral bile acid
supplementation
D. Genetic disorders
1. Cystic fibrosis (CF)
a. Cholestasis often associated with meconium plug syndrome
b. Newborn screen (serum immunoreactive trypsinogen)
c. Confirmed by sweat chloride test or genetic testing (CFTR gene
mutation analysis)
2. Alagille syndrome
a. Autosomal-dominant mutation of Jagged 1 gene on chromosome 20;
variable penetrance of disease
b. Constellation of physical findings, including cholestasis due to bile duct paucity,
congenital heart disease such as peripheral pulmonic stenosis, abnormal facies,
ophthalmologic abnormalities (posterior embryotoxon), and bony defects
(butterfly vertebrae)
c. Cholestatic neonates are screened for Alagille syndrome with an
echocardiogram (if a murmur is detected), ophthalmologic exam, spine
film, liver biopsy
d. Characteristic findings on liver histology include paucity of bile ducts (may have
bile duct proliferation early on in disease process, prior to paucity)
e. Clinical course of liver disease in infancy is highly variable, with some children
experiencing a gradual improvement in cholestasis in childhood, while others
progress to cirrhosis, requiring liver transplant
3. Progressive familial intrahepatic cholestasis (PFIC)
a. Specific transporter proteins on apical surface of the hepatocyte which are
responsible for trafficking of bile components into the bile canaliculus. Defects
in these proteins are associated with cholestatic disease
b. PFIC type 1 (PFIC1): mutation in the gene coding for FIC1, a canalicular
surface protein
1) Clinically can present with cholestasis, diarrhea, and growth failure
2) Low/nl GGT
c. PFIC type 2 (PFIC2): mutation in the gene coding for BSEP interferes with bile
salt trafficking into the canaliculus, leading to reduced bile flow and the toxic
accumulation of hydrophobic bile acids within hepatocytes
1) Clinical phenotype of cholestasis and pruritus in the first year of life
2) Low/nl GGT
3) Pruritus, a dominant clinical feature of both PFIC1 and PFIC2, is typically
not problematic until after 6 months of age
d. PFIC type 3 (PFIC3): mutation in the gene coding for the transporter MDR3,
which is responsible for phosphatidylcholine secretion into the bile canaliculus
1) The onset of cholestasis is variable in PFIC3, but is typically later than
seen in PFIC1 and PFIC2
2) High GGT
E. Infections:
1. TORCH infections: toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes-virus can
all lead to a similar pattern of cholestasis and growth restriction
a. Obtain a maternal history for TORCH infections, and perform diagnostic
workup if history or physical exam warrants
b. Screen for exposure to CMV with a urine CMV culture
2. Acquired infections after birth, in particular, Gram-negative sepsis
3. Urinary tract infections
F. Endocrinopathies:
1. Hypothyroidism
2. Panhypopituitarism
a. Hypoglycemia often present
b. Screening includes TSH, total and free T4, early morning cortisol level, and brain
MRI (to assess pituitary gland)
c. Associated with optic nerve hypoplasia, septo-optic dysplasia, microphallus

III. Management of Neonatal Cholestasis
A. Growth failure. Etiology:
1. Increased metabolism
2. Decreased fat absorption: reduced bile flow results in poor solubilization of dietary fats
in mixed micelles, leading to fat malabsorption and steatorrhea
3. Treatment: high medium-chain triglycerides (MCT)-containing formula/supplement
(MCTs do not require bile for intestinal absorption)
a. Consider nasogastric feeds for adequate caloric delivery
B. Fat-soluble vitamin deficiencies
1. Pervasive in infants with chronic cholestasis, and should be aggressively managed
2. Frequent monitoring of serum vitamin levels (PT- for Vitamin K, Vitamin E, Vitamin A,
Vitamin D)
3. Use of oral fat-soluble vitamin supplements
C. Ursodeoxycholic acid
1. Hydrophilic bile acid that stimulates bile flow and displaces more toxic bile acids from
the hepatocyte, thus potentially lessening the hepatocyte injury
2. Ursodeoxycholic acid can decrease pruritus
Table 1. Neonatal Cholestatic Diseases

Disease Diagnostic Workup
Biliary atresia Abdominal US, liver biopsy, cholangiogram
Choledochal cyst Abdominal US
A1AT deficiency A1AT level and phenotype
IEOM Newborn screen (galactosemia)
Urine succinylacetone (tyrosinemia)
Serum amino acids, urine organic acids (others)
BASD Total serum bile acids; urine bile acid FAB
TORCH Urine CMV culture; others as warranted
UTI Urine bacterial culture
Sepsis Based on history, clinical picture, cultures
Cystic fibrosis Newborn screen, sweat chloride test
Alagille syndrome Echocardiogram (if murmur present), spine film,
ophthalmology exam, liver biopsy
Hypothyroidism Newborn screen, TSH, total and free T4
Panhypopituitarism TSH, total and free T4, early a.m. cortisol, glucose,
brain MRI (assess pituitary gland)
Recommended Reading
Emerick KM, Whitington PF. Neonatal liver disease. Pediatr Ann. 2006 Apr;35(4):280-286.
Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts.
Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University
Press, 2007. Chapters 9,12.
Emerick KM, Whitington PF. Neonatal liver disease. Pediatr Ann. 2006 Apr;35(4):280-286.
Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts.
6J-2. Cholestatic Liver
Diseases — Older Child
Ramya Ramraj, MD
Daniel H Leung, MD
The causes of cholestasis in the older child are varied, and the evaluation requires a judicial amount of labora-
tory testing, imaging, and other invasive studies to maximize diagnostic accuracy. Most of the metabolic and
storage disorders present in early infancy; however, it is important to recognize that some of them have late
presentations or may manifest as a result of decompensation during illnesses (Figure 1).
I. Causes of Cholestasis
A. Infections
1. Hepatitis A, B, C, D, E viruses
2. Adenovirus
3. EBV, CMV, herpes viruses
4. Influenza
B. Immunological
2. Primary sclerosing cholangitis
C. Bile duct obstructions
1. Cholelithiasis
2. Caroli’s disease
3. Autosomal-recessive polycystic kidney disease (ARPKD)
D. Inherited cholestatic/hyperbilirubinemia syndromes
1. Progressive familial intrahepatic cholestasis (PFIC) 1, 2
2. Gilbert’s syndrome, Dubin-Johnson, Rotor syndrome, Crigler–Najjar syndrome
E. Metabolic
1. Alpha 1 antitrypsin deficiency
2. Wilson disease
3. Cystic fibrosis
F. NAFLD
G. Storage disorders
1. Glycogen storage disorders (types 1, 4)
2. Lipid storage disorders
H. Urea cycle disorders
I. Mitochondrial disorders
J. Peroxisomal disorders
K. Drug-induced liver injury
L. Vascular
1. Hepatic outflow obstruction (Budd–Chiari, myeloproliferative disorders)
2. Portal vein thrombosis
M. Systemic
1. Malignancies
2. Immunodeficiency syndromes
II. History
A. Eliciting a complete history with the relevant details is important in ruling out important diagno-
ses. Below are some of the most pertinent questions to be asked and their possible etiologies
B. H/o Medications (Tylenol, amoxicillin, OCPs, steroids, testosterone, etc) – drug-induced liver injury
C. H/o IV drug use, blood transfusions, travel – Viral hepatitis
D. H/o Neuropsychiatric symptoms – Wilson disease

III. Physical Exam
A. A full physical exam is mandatory, and certain characteristic features, if present, point to specific
diagnoses
B. Presence of KF rings (best seen with a slit lamp) and neurological signs like chorea will point to a
diagnosis of Wilson disease
C. Presence of hepatomegaly and splenomegaly
D. Ascites in patients with portal hypertension
IV. Laboratory Testing

A. A full liver panel, with coagulation studies and hepatitis serology, needs to be drawn as part of
the initial evaluation
B. Total and fractionated bilirubin to distinguish between the unconjugated hyperbilirubinemia vs
conjugated hyperbilirubinemia
C. Creatine kinase levels to rule out muscular pathology
D. Based on the initial results and results of imaging, further labs looking for specific etiology such
as AIH or Wilson disease need to be drawn
E. Check vitamin levels as part of nutritional assessment in chronic cholestasis
F. Low white blood cell counts and platelet count, especially thrombocytopenia, can be the first
sign of chronic liver disease
V. Imaging
A. A full abdominal ultrasound with Doppler is very essential in the initial workup, to determine
abnormalities in the hepatic architecture, as well as for the presence of any intrahepatic mass,
ascites, or splenomegaly
B. The Doppler exam is a valuable diagnostic tool when there is a strong suspicion for abnormalities
in the vasculature, or to determine portal venous blood flow
C. When there is strong suspicion for biliary tract disease (e.g., strictures, dilatations), choledocholi-
thiasis, or previous evidence of biliary obstruction (presence of sludge in the gall bladder), further
diagnostic evaluation with MRCP is warranted
VI. Biopsy
A. A core liver biopsy is often the gold standard in the diagnosis of cholestatic disorders in
the older children
B. Biopsy can be delayed if the serological tests are positive for any of the viral hepatitis infections
Biopsy can also be delayed in patients who are overweight or obese, with a mild-to-moderate
elevation of the liver enzymes, no other features of cholestasis, negative laboratory testing for
metabolic disorders, and high suspicion for NASH
Figure 1. Algorithm for evaluation of cholestasis in the older child.
VII. Clinical Scenarios
A. An 11-year-old boy develops episodes of jaundice during viral illnesses. There is no history of
pruritus, bleeding, or fatigue, and he is otherwise well. There is no history of medication use.
1. Labs including transaminases, prothrombin time, ammonia, and complete blood count
are normal, except for unconjugated bilirubin, which is 3 mg/dL, with a conjugated
bilirubin of 0.5 mg/dL
1. Most likely diagnosis – Gilbert’s syndrome
2. A benign form of inherited hyperbilirubinemia, and often manifests after puberty, espe-
cially during periods of illnesses and dehydration
3. The history and the presence of elevated levels of unconjugated bilirubin (it is essential
to get a fractionated bilirubin in the initial workup) establish the diagnosis, and no
treatment is necessary
4. It is important to recognize this condition while evaluating a child for jaundice, and thus
avoid unnecessary testing
B. A 13-year-old girl presents with a few weeks history of fatigue and conjunctival icterus. She has
no recent history of travel. She has a history of hypothyroidism, and is on hormone replacement
therapy. A liver panel shows moderate elevation of transaminases and conjugated hyperbilirubi-
nemia. Prothrombin time is normal. A liver US is unremarkable. Additional tests reveal an elevat-
ed IgG, elevated F actin level, and normal ceruloplasmin and MM alpha 1 antitrypsin phenotype.
Liver biopsy shows interface hepatitis with plasma cell infiltration, confirming the diagnosis of
autoimmune hepatitis
1. Autoimmune hepatitis is one of the most common causes of cholestasis in older
children, especially in females, and can occur in association with other autoimmune
disorders. The presentation is often insidious, and hence it is important to recognize
and make the diagnosis
2. There are two types – Type 1 is characterized by antinuclear or smooth muscle
antibodies, and type 2 is characterized by antiliver kidney microsomal type 1 antibodies
C. A 10-year-old boy is referred for elevation of transaminases. There is a history of declining school
performance and occasional fatigue. No history of medication use. Liver panel shows moderate
elevation of transminases and conjugated hyperbilirubinemia. Physical exam is unremarkable
except for mild tremor of the hands. Laboratory testing shows a normal ceruloplasmin level and
an elevated 24-hour urinary copper excretion. A liver biopsy shows ballooning degeneration of
hepatocytes, and total quantitative copper content of the liver is elevated (>250/Gm), confirming
the diagnosis of Wilson disease
1. Wilson disease is a rare autosomal-recessive disorder caused by excess accumulation of
copper. Mutations in the ATP7B gene leads to defective copper transport, resulting in
accumulation in liver, CNS, cornea, skeletal system, and other organs
2. Wilson disease can present with nonspecific neurological or systemic symptoms, and
hence it is essential to recognize the clinical spectrum and establish the diagnosis
D. A 3-year-old girl is seen for a WCC, and hepatomegaly is noted on exam. Liver panel shows mild
elevation of transaminases and conjugated bilirubin. The history is otherwise unremarkable,
except for episodes of sweating in the early mornings and mild developmental delay. There is
no family history of liver disease. Imaging is unremarkable. Further laboratory testing is
unremarkable. A liver biopsy is obtained, and shows ballooning of the hepatocytes with glyco-
gen accumulation as detected by the PAS stain. The diagnosis is most likely GSD, and the liver
tissue is sent for enzyme analysis to determine the subtype
1. GSD (except for the infantile form of GSD 4) often presents in early childhood as
organomegaly, asymptomatic elevation of transaminases, or intermittent periods of
hypoglycemia
2. A liver biopsy often establishes the diagnosis, and a multisystem evaluation with referral
to genetics is essential

E. An 8-year-old boy presents to the ER with intense pruritus for a few weeks. He recently was
diagnosed with a viral illness, that has since resolved. Physical examination is unremarkable
except for mild scleral icterus. Liver panel shows elevated transaminases and conjugated
hyperbilirubinemia. GGT is within normal limits, and US of the abdomen is unremarkable.
Serum bile acids are elevated to 5x the upper limit of normal. A liver biopsy is performed,
which shows features of intrahepatic cholestasis. EM shows granular bile, and the diagnosis
is highly suspicious for BRIC 1 (benign recurrent intrahepatic cholestasis)
1. BRIC 1 is caused by missense or splice mutations in the ATP8B1 gene that codes for
the FIC 1 protein. Severe mutations can lead to a complete absence or complete loss
of function of the protein, leading to the more severe form of the disease, progressive
familial intrahepatic cholestasis (PFIC1)
2. Patients affected by BRIC 1 present with episodic cholestasis during illnesses, character-
ized by periods of intense itching, which can last for a few months
3. The characteristic history and the presence of low or normal GGT with cholestasis are
important clues to the diagnosis
F. An obese teenager presents to the ER with severe right upper quadrant pain. An US of abdomen
is obtained, which shows a dilated common bile duct of 6 mm, with sludge in the gallbladder.
A liver panel shows elevated GGT with conjugated hyperbilirubinemia. An ERCP is performed on
the patient, which shows choledocholithiasis, followed by removal of the stones
1. In patients with abnormal ultrasound findings and signs of acute obstruction, it is essen-
tial to proceed to ERCP without need for further imaging. The likelihood of finding bile
duct stones in such clinical scenarios is high, and it is essential to relieve the obstruction
to avoid further morbidity
G. A 7-year-old boy is seen in the clinic for fatigue and jaundice. His family has recently emigrated
from Cambodia. Past medical history and family history are unremarkable. Liver panel shows
elevated transaminases, and hepatitis serology is positive for HBs Ag and HBe Ag
1. Hepatitis B is an important cause of elevated transaminases and jaundice in children,
and it is important to recognize the diagnosis, even in the absence of clear-cut risk
factors
H. A 16-year-old teenager is referred to the clinic for abnormal liver panel and cholestasis. Imag-
ing is unremarkable, and laboratory testing for most common etiologies as AIH, A1AT, and viral
hepatitis is negative. Further questioning of the patient when alone revealed the use of hormone
supplements for the past several months. The diagnosis is most likely hepatic injury secondary to
steroid use. Liver biopsy is performed, which shows nonspecific hepatocellular damage
1. Drug-induced liver injury (DILI) is an important cause of cholestasis, and it is essential to
recognize the entity through proper elicitation of history and maintaining a high suspi-
cion for the diagnosis, especially when initial laboratory testing and imaging offer no
clue to the diagnosis
Recommended Reading
Bezzera et al. Cholestatic Syndromes of infancy and childhood. Semin Gastrointest Dis. 2001;12(2):54-65.
Kelly et al. Metabolic liver disease in the pediatric patient. Clin Liver Dis. 1998;2(1):1-30.
Press, 2007.
6K-1. Infectious and Inflammatory
Diseases — Congenital Infections
of the Liver
Charles Vanderpool, MD
I. Bacterial Infections
A. Both Gram-positive and Gram-negative infections can cause liver injury, including hepatomegaly
and jaundice
1. Gram-negative infections are most common
2. Hepatotoxicity is caused in part by endotoxin, including lipopolysaccharide complex
(LPS), which causes cholestasis by diminishing bile flow
3. Escherichia coli is the most common bacteria that causes neonatal hepatitis
a. Galactosemia should be considered in infants with cholestasis and Gram-nega-
tive (especially E coli) bacteremia
4. Urinary tract infections are a common route of bacteremia, and can result in hepatitis
and cholestasis
a. Rarely have fever or urinary symptoms
b. Often have irritability, lethargy, poor oral intake, and hyperbilirubinemia, with
mildly elevated aminotransferases
B. Congenital Toxoplasmosis
1. Maternal infection acquired by exposure to oocytes in cat feces or uncooked meat
2. 70%–90% of affected patients are asymptomatic at birth, with hepatitis as the only sign
3. In symptomatic patients, hepatic and neurologic effects predominate
a. Hepatomegaly is common; jaundice is variable
4. Liver biopsy shows nonspecific, generalized hepatitis and necrosis
a. Toxoplasma organisms may be seen with immunofluorescence
5. PCR or IgG/IgM testing of infant helps confirm diagnosis
C. Congenital Syphilis
1. Transmission to fetus as high as 60%–100% with primary and secondary
syphilis infections
a. Up to 40% of infections result in fetal death
2. Hepatomegaly, elevated aminotransferases, and conjugated hyperbilirubinemia are seen
3. Liver biopsy classically shows intralobular dissecting fibrosis with centrilobular
mononuclear inflammation
a. Silver stain may highlight spirochetes
4. Extrahepatic manifestations include skin lesions, snuffles, lymphadenopathy, anemia,
thrombocytopenia
5. Mother and infant should be tested with the same nontreponemal syphilis test
(VDRL, RPR) to compare titers
6. Primary treatment is parenteral penicillin
II. Viral Infections

A. Cytomegalovirus
1. May be acquired transplacentally, at delivery, or postnatally
2. Approximately 10% of infants manifest clinically apparent infections
a. Hepatosplenomegaly and conjugated hyperbilirubinemia are common
b. Extrahepatic manifestations include microcephaly, low birth weight, purpura,
and thrombocytopenia
3. Liver biopsy often shows nonspecific giant cell transformation, in addition to large
characteristic intranuclear inclusions in bile duct epithelium or intracytoplasmic inclusion
bodies in hepatocytes

4. Diagnosis is supported by culture of virus from urine, nasopharynx, or saliva
a. Culture of liver tissue may be positive, but PCR has higher yield
5. Treatment options include ganciclovir and CMV immunoglobulin
B. Rubella
1. Risk of infection - related birth defects is dependent upon timing of maternal infection
a. Up to 85% of infants are affected if infection occurs during first 12 weeks of
gestation, and this number decreases to 25% if infection occurs after second
trimester
2. Hepatomegaly is common, and is often associated with splenomegaly
3. Elevated aminotransferases and conjugated hyperbilirubinemia are seen
4. Extrahepatic findings include ophthalmologic (cataracts, chorioretinitis), hematologic
(thrombocytopenia), dermal (blueberry muffin rash), cardiac (patent ductus arteriosus,
septal defects), auditory (deafness), and neurologic (microcephaly, encephalitis) defects
5. Liver biopsy has portal mononuclear infiltrates, giant cell transformation, focal necrosis,
ductular proliferation
6. Diagnosis is made by viral culture from the nose or throat, or IgM viral titer
7. Treatment is supportive
a. Majority of infants recover from hepatic disease without liver failure
b. Morbidity/mortality associated with other organ system involvement
C. Herpes Simplex
1. May be congenital, or present 4–8 days after birth, consistent with herpes virus
incubation period
2. Neonatal infections often occur from asymptomatic infection of mother, primarily
from HSV 2
a. 1/3 of infections are disseminated (with liver involvement), 1/3 of infections
are limited to the cranial nervous system, and 1/3 are limited to skin, eyes, and
mouth
3. Clinical liver disease can result from either HSV 1 or 2
a. May be quite mild and range to fulminant hepatitis with jaundice,
hepatosplenomegaly and coagulopathy
b. Liver biopsy shows multinucleated giant cells, multifocal or generalized necrosis,
and characteristic intranuclear acidophilic inclusions
4. Diagnosis is made by culture of mouth, nasopharynx, conjunctiva, and rectum
a. Cultures of skin, urine, blood, and CSF specimens are also helpful
b. Direct fluorescent antibody staining or immunoassay of antigens are specific,
but are less sensitive than culture
5. Treatment with IV acyclovir should be given to infants with any degree of symptomatic
disease
a. Approximately 25% of infants with disseminated disease die despite therapy
b. Liver transplantation should be considered
D. Enteroviral Hepatitis
1. Includes infections with coxsackievirus, echovirus, and enterovirus
2. Transmission may occur during prenatal, intrapartum, or perinatal periods
3. Maternal history of fever or viral syndrome just prior to birth may be elicited
4. Clinical symptoms in newborn include poor feeding, fever, lethargy, diarrhea,
and skin rash
5. Liver involvement may be mild or can be severe, with jaundice, hepatomegaly, elevated
aminotransferase levels, and coagulopathy with liver failure
6. Diagnosis is made using culture from nasopharynx or rectum, or biopsy material from
sites of involvement
a. PCR testing is available and often used for CSF analysis
7. Treatment is supportive, with no specific therapy options
b. IVIG has been used in severe neonatal infections
E. Hepatitis A, B, C, D, and E are covered in the section on Viral Hepatitis
Recommended Reading
American Academy of Pediatrics. Red Book 2006: Report of the Committee on Infectious Diseases. 27th ed.
Elk Grove Village, IL: American Academy of Pediatrics; 2006.
Banatvala JE, Brown DWG. Rubella. Lancet. 2004;363:1127-1137.
Rosenthal P. Neonatal hepatitis and congenital infections. In: Suchy FJ, Sokol RJ, Balistreri WF, eds.
Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press; 2007: 232-246.
Verma A. Neonatal herpes simplex virus infection presenting as acute liver failure: prevalent role of herpes
simplex virus type 1. J Pediatr Gastroenterol Nutrition. 2006;42(3):282-286.
Woods CR. Congenital Syphilis – Persisting Pestilence. Ped Infectious Dis J. 2009;28(6):536-537.

6K-2. Infectious and
Inflammatory Diseases—
Viral Hepatitis
Brandy Lu, MD
Cara Mack, MD
I. Hepatitis A: single-stranded RNA hepatitis A virus (HAV)

A. Mode of transmission:
1. Fecal-oral (foodborne or waterborne)
2. There is no carrier state or chronic infection
B. Incubation period: 15–40 days (mean 28)
C. Clinical features:
1. HAV infection is often asymptomatic (especially under the age of 6 years); only 30% of
infants and preschool-aged children exhibit symptoms
2. Acute, self-limited condition may be associated with anorexia, malaise, fevers, headache,
emesis, diarrhea, and jaundice
3. Acute HAV is characterized by clinical improvement with the onset of jaundice and a
normalization of bilirubin and transaminases within 4–6 weeks
4. Acute liver failure due to HAV is possible
a. Consider hospital admission for any child with HAV and evidence of liver syn-
thetic dysfunction (i.e., INR ≥2.0)
D. Diagnosis:
1. Confirmed with the presence of anti-HAV IgM antibody in serum
2. Laboratories: check liver panel, PT/INR, and HAV-IgM
E. Prevention:
1. HAV vaccine:
a. Universally recommended for all children between 12–24 months of age
b. Catch up immunizations for older, unimmunized children
c. Offer HAV vaccine to HAV-exposed family members or close contacts
2. HAV immune globulin indications for use:
a. Travel to endemic areas
b. Postexposure prophylaxis within 14 days after exposure to food handled by
someone with HAV, or persons exposed to family member with HAV
II. Hepatitis B: double-stranded DNA hepatitis B virus (HBV)

1. Vertical, parenteral, or sexual
2. Perinatal transmission rates vary from 20%–90%, depending on maternal HBsAg titer
and HBeAg status
3. Carrier state and chronic infection state
a. A carrier state is a persistent infection with presence of HBsAg, but without
biochemical or clinical signs of ongoing hepatic injury
b. HBV carriers are infectious
4. Special at-risk populations:
a. Infants born to HBV-infected women
b. Infants/children living in community groups with endemic HBV
c. Immigrants/adopted children from regions of world with high
prevalence of HBV
d. Household contacts of individuals with chronic HBV
e. Adolescents engaging in high-risk behaviors

5. The development of chronic disease varies based on age of HBV acquisition: infants have
a 90% chance of developing chronic disease, children 1–5 years have 30% chance, and
children >5 years have 6% chance
B. Incubation period: 50–180 days
1. Perinatal HBV acquisition is usually asymptomatic; however, if mother is HBeAg positive
at birth, ~6% of infants will develop acute liver failure by 2–3 months of age
2. Chronic active hepatitis is associated with persistence of HBsAg >6 months and elevated
ALT and AST levels
3. Of the neonates who become chronic carriers, many will develop an immune tolerant
phase, represented by a normal ALT/AST despite high HBV DNA levels and persistent
HBsAg & HBeAg positivity (and negative antibodies)
4. Acute liver failure has been reported, with the highest incidence in neonatal period
5. Co-morbidities: Gianotti-Crosti syndrome (acrodermatitis of face, trunk, and extremities;
and lymphadenopathy); polyarteritis nodosa and glomerulonephritis
D. Diagnosis: see Table 1 at end of section for details
1. Confirmed with detection of HBV surface antigen (HBsAg) on two separate testings at
least 6 months apart
2. Laboratories: check liver panel, HBV: sAg, sAb, eAg, eAb
a. Positive HBsAg represents active infection
b. Positive HBeAg represents high infectivity
c. HBeAg negative and HBeAb positive reflects seroconversion, with clearance of
actively replicating virus
d. HBsAb is rare, but represents protective immunity
3. Annual rate of spontaneous clearance (convert to HBeAg negative and HBeAb positive):
0-3 years of age <2%; >3 years of age ~5%
4. Check HBV DNA if considering treatment
5. Check liver histology if considering treatment; classic finding of HBV infection is ground
glass appearance of hepatocytes
E. Treatment:
1. Subcutaneous weekly pegylated interferon-alpha injections for 24 weeks
2. Treatment response: nondetectable HBV DNA and seroconversion to HBeAb positive
(HBeAg negative)
3. Pegylated interferon therapy approved for ≥3 years of age
F. Prevention:
1. HBV vaccine:
a. Universally recommended for all infants; series of three doses over 6–9 months
b. Catch up immunizations for older, unimmunized children
c. HBV-exposed family members or close contacts
2. HBV immune globulin indications for use:
a. Infants born to HBsAg positive mothers
b. Postexposure prophylaxis within 24 hours after exposure (if no history of
vaccination in past)
3. Household contacts: avoid sharing of tweezers, shavers, toothbrush, nail clippers
4. Universal precautions for handling abrasions, bleeding, etc
5. Screening for hepatocellular carcinoma (HCC): increased risk for HCC in setting of
chronic HBV hepatitis. Screening modalities include annual alpha fetoprotein,
liver ultrasound
III. Hepatitis C: single-stranded RNA hepatitis C virus (HCV)

2. Carrier state and chronic infection exist
3. Perinatal transmission rates are ~5%, and increase to 15%–20% if the mother is
coinfected with HIV
1. Chronic infection will develop in 60%–80% of exposed children
2. Majority of patients are asymptomatic in childhood
3. End-stage liver disease with decompensated cirrhosis has been described in children
with chronic HCV hepatitis
4. Acute liver failure from HCV infection in immunocompetent patients has not
been reported
5. Comorbidities: glomerulonephritis, cryoglobulinemia, autoimmune hepatitis, and
Sjorgren’s syndrome
D. Diagnosis:
1. Laboratories: check liver panel, screen with HCV IgG antibody (after 18 months of age)
and HCV RNA (after 2 months of age)
a. Positive anti-HCV antibody (IgG) after >18 months of age reflects exposure
to HCV
b. Active infection can only be confirmed with positive HCV RNA
2. HCV genotype analysis indicated if treatment is being considered
3. HCV RNA testing in the first 2 months of life is problematic: both false positives (due
to transient viremia) and false negatives (low levels not detectable) have been reported;
wait until after 2 months of age to check HCV RNA, and repeat test 6 months later
4. Variable rates of spontaneous clearance after perinatal acquisition have been reported
E. Treatment:
1. Subcutaneous weekly pegylated interferon-alpha injections for 48 weeks (genotypes 1
or 4) or 24 weeks (genotypes 2 or 3), plus oral ribavirin
2. Treatment response: nondetectable HCV RNA by 24 weeks of age
3. Pegylated interferon/ribavirin therapy approved for ≥3 years of age
F. Prevention:
1. HCV vaccine: none available
2. HCV immune globulin: none available
3. Household contacts : avoid sharing of tweezers, shavers, toothbrush, nail clippers
4. Universal precautions for handling abrasions, bleeding, etc
5. Screening for hepatocellular carcinoma (HCC): increased risk for HCC in setting of
chronic HCV hepatitis. Screening modalities include annual alpha fetoprotein and liver
ultrasound
IV. Hepatitis D: defective RNA hepatitis D virus (HDV)

2. Carrier state and chronic infection exist
3. HDV cannot replicate without a coexisting infection with hepatitis B
C. Clinical features: coinfection with hepatitis D is more severe than hepatitis B alone, and can
progress more rapidly to liver failure and cirrhosis
D. Diagnosis: confirmed with the presence of anti-HDV antibody
E. Prevention: HDV vaccine or immune globulin. Not available
V. Hepatitis E: single-stranded RNA hepatitis E virus (HEV)

1. Fecal-oral (foodborne, waterborne). Reports of contaminated blood products
2. There is no carrier state or chronic infection
1. Acute, self-limited condition may be associated with anorexia, malaise, fevers, headache,
emesis, diarrhea and jaundice
2. Infection can be very severe in pregnant women (3rd trimester), with 20% mortality
D. Diagnosis:
1. Confirmed with the presence of anti-HEV IgM antibody in serum
2. Laboratories: check liver panel, PT/INR, and HEV-IgM
E. Prevention: no HEV vaccine is available

Table 1.
The Hepatitis Viruses: Characteristics and Terminology of Associated Antigens and Antibodies
Marker Definition Significance of Marker
Serologic Markers of HAV
Anti-HAV IgM Antibody (IgM) directed against HAV Current or recent infection
Anti-HAV IgG Antibody (IgG) directed against HAV Previous infection/vaccine and
protective immunity
Serologic Markers of HBV
HBsAg Hepatitis B surface antigen; found on Active HBV infection
surface of intact virus and in serum as
free particles
HBcAg Hepatitis B core antigen; found within Detectable in liver tissue
virus core
HBeAg Hepatitis B e antigen; soluble antigen High infectivity
produced during self-cleavage of HBcAg
HBV DNA DNA of HBV (PCR test) Active HBV replication
Anti-HBs IgG Antibody (IgG) to HBsAg Protective Immunity
Anti-HBc IgM Antibody (IgM) to HBcAg Early infection
Anti-HBc IgG Antibody (IgG) to HBcAg Indicates infection
Anti-HBe Antibody to HBeAg Resolution of active viral
replication
Serologic Markers of HCV
Anti-HCV Antibody (IgG) to HCV Exposure to HCV; Not protective
HCV RNA RNA of HCV (PCR test) Active HCV infection
Serologic Markers of HDV
HDVAg Hepatitis D antigen HDV infection
Anti-HDV Antibody (IgM/IgG subclass) to HDV Exposure to HDV
HDV RNA RNA of HDV (PCR test) Active HDV replication
Serologic Markers of HEV
HEVAg Antigen associated with HEV Stool test; recent infection
HEV RNA RNA of HEV (PCR test) Early HEV infection
Anti-HEV Antibody (IgM) to HEV Early HEV infection
Anti-HEV Antibody (IgG) to HEV Protective immunity
Recommended Reading
Hsu EH, Murrary KF. Hepatitis B and C in children. Nat Clin Pract Gastroenterol Hepatol. 2008;5:311-320.
Jonas MM, Block JM, Haber BA, et al; for the Hepatitis B Foundation. Treatment of children with chronic
hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology.
2010;52(6):2192-205.
Narkewicz MR, Cabrera R, Gonzalez-Peralta RP. The “C” of viral hepatitis in children. Semin Liver Dis.
2007;3:295-311.
Schwarz KB, Gonzalez-Peralta RP, Murray KF, et al; for the Peds-C Clinical Research Network. The combina-
tion of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with
chronic hepatitis C. Gastroenterology. 2011;140(2):450-458.
Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Diseases in Children. 3rd ed. New York, NY: Cambridge University
Press; 2007.
HAV, hepatitis A virus; HBV, hepatitis B virus; HBcAg, hepatitis B core antigen; HBeAg, hepatitis B e antigen;
HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; PCR,
polymerase chain reaction.
Modified from Hochman JA, Balistreri WF. Acute and chronic viral hepatitis. In: Suchy FJ, Sokol RJ, Balistreri
WF, eds. Liver Disease in Children. New York, NY: Cambridge University Press; 2007: 370.

Bacterial, Parasitic, and
Other Infections of the Liver
Sabina Ali, MD
I. Pyogenic Hepatic Abscess

A. Overview:
1. It is a life-threatening condition
2. Delay in or failure to recognize this condition results in high mortality and
3. morbidity
4. Liver abscess often occurs in patients with underlying medical conditions:
a. Perforated appendicitis
b. Crohn disease
c. Immunodeficiency
d. Sickle cell disease
e. Neonates with UVC catheter and necrotizing enterocolitis
f. Patients with VP shunts and with penetrating injuries
B. Pathogenesis:
1. Biliary disease
2. Infection via the portal system
3. Hematogenous (via the hepatic artery)
4. Cryptogenic
C. Microbiology:
1. Cultures from blood and/or abscess contents are mostly positive
2. Lesions can be polymicrobial
3. E coli is the most commonly reported single bacteria
4. Anaerobic accounts for 30%–50% of cases
5. Other usual organisms: Salmonella, Haemophilus, andYersinia
6. Fungal liver abscesses are seen in patients with neutropenia and in patients
with leukemia
7. Patients with AIDS are at increased risk for mycobacterium-related infections.
Tuberculous liver abscess is uncommon, but should be considered in patients when
other organisms are not recovered
8. Amebiasis: should be considered in patients who are from or have traveled to
an endemic area within the past 6 months
D. Clinical Features:
1. Fever 79%–90%
2. Chills
3. Abdominal pain
4. Nausea
5. Vomiting
6. Chest pain
7. Weight loss
8. Cough and dyspnea
9. Diarrhea
10. In neonates, it appears to have similar features as neonatal sepsis

E. Laboratory Findings:
1. Anemia
2. Leukocytosis
3. Abnormal transaminases are common
4. Elevated ESR 100%
5. Elevated prothrombin time
6. Hypoalbuminemia is a poor prognostic sign
7. Diagnostic imaging
8. Chest x-ray
9. Elevated hemidiaphragm, right pleural effusion, atelectasis
10. Ultrasound
11. Round, oval, or elliptoid lesion
12. Irregular margin
13. CT scan
14. Sensitivity 94%
15. Lesions show reduced attenuation, and may enhance with contrast
16. MRI: Sensitive for smaller lesions
F. Management and Prognosis:
1. Antibiotic therapy as a sole treatment modality has been successful
2. Treatment should not be delayed pending the abscess drainage procedure
3. Blood culture should be taken prior to initiation of antibiotic therapy
4. Surgical intervention may be required if the patient fails to respond to antibiotic therapy
G. Complications:
1. Septicemia
2. Septic shock
3. ARDS
4. Renal failure
5. Liver abscess rupture is rare and is more commonly reported with amoebic liver
abscesses, at a rate of 5%–20%
6. Metastatic abscess
II. Other Bacterial Infections

A. Typhoid fever
1. Fever, diarrhea, abdominal pain, and hepatosplenomegaly
2. Patients can also present with encephalopathy, seizures, myocarditis, and
circulatory failure
B. Brucellosis: consumption of infected unpasteurized milk or milk product
C. Perihepatitis (Fitz-Hugh-Curtis syndrome):
1. Occurs as a complication of PID
2. Can occur both with N gonorrhea and Chlamydia
3. Acute sharp RUQ pain, fever, mimics acute cholecystitis
4. Serum hepatic enzymes and bilirubin may be normal
5. Laproscopic finding: violin sign – adhesions from the liver to the right costal margin
D. Weil syndrome: severe form of leptospirosis associated with hepatic dysfunction, renal failure,
hemorrhagic manifestations, and pulmonary involvement
III. Amebic Liver Abscess

A. Overview:
1. Caused by Entamoeba histolytica
2. Transmission occurs via the fecal-oral route, either directly by person-to-person contact
(e.g., diaper changing, sexual practices), or indirectly by eating or drinking fecally con-
taminated food or water
3. Commonly reported in the tropical regions such as Africa, Asia, and Central and
South America
4. 7%–20% have contiguous pulmonary infection
5. Liver abscess is 10x more common in men, and rare in children
Humans
Cysts and Trophozoites inhabit
the large bowel
Penetration of bowel results in trophozoites being

transported to liver, lungs, etc. by blood stream
Ingestions of Cysts by faecal-oral route Cysts and Trophozoites are excreted in faeces
Figure 1. Lifecycle of E histolytica
B. Clinical Features:
1. May have preceding amoebic colitis (10%–30%)
2. Fever, malaise, rigors, diaphoresis
3. Right upper quadrant pain: sharp, constant, relieved by lying on left side
4. Radiating to shoulder tips and scapulae
5. Pleuritic component
6. Hepatomegaly
7. Chronic presentations: weight loss and vague abdominal discomfort
C. Diagnosis:
1. Hyperbilirubinemia – uncommon
2. Leukocytosis
3. Anemia
4. Abnormal transaminases
5. Abnormal ESR
D. Imaging:
1. Ultrasound or CT can provide anatomic verification
2. Usually solitary in the right hepatic lobe (75%). Amebic abscess has a better defined
margin with a peripheral halo
3. Aspiration of abscess: The abscess contains sterile pus, and reddish-brown “anchovy
paste” liquefied necrotic liver tissue
E. Serological Tests:
1. Indirect hemagglutination assay (IHA)
2. Combination of a positive immunofluorescent antibody test (IFTA) and positive cellulose
acetate precipitin test (CAP) correlates 100% invasive amebic disease
F. Treatment:
1. Usually with drugs alone: metronidazole, tinidazole, or chloroquine
2. Luminal amebicides must always be used following the above regimens
3. Diloxanide furoate or paromomycin
IV. Hydatid Disease of Liver

A. Overview:
1. Worldwide distribution
2. It is a chronic and potentially dangerous condition
3. Echinococcus granulosis is the most common form of hydatid disease in humans
4. Host: dog
B. Clinical Features:
1. May be asymptomatic
2. Right upper quadrant pain and/or mass
3. Fever
4. Jaundice

5. Anorexia
6. Weight loss
7. Vomiting
8. Pruritis
9. Cysts may rupture and anaphylaxis may occur
10. Eosinophilia
11. Abnormal liver enzymes
12. Ultrasound is useful in diagnosis: cyst may be anechoic, round, and septated
13. IHA and ELISA are 75%–94% sensitive
C. Complications:
1. Rupture and leakage of cyst
2. Cholangitis
3. Secondary infection
D. Management:
1. Surgery remains as the mainstay treatment. Complications of surgery are high
2. Drug therapy includes: albendazole or mebendazole
Recommended Reading
Hughes MA, Petri WA Jr. Amebic liver abscess. Infect Dis Clin North Am. 2000;14(3):565-582.
Johannsen EC, Sifri CD, Madoff LC. Pyogenic liver abscesses. Infect Dis Clin North Am. 2000;14(3):547-563.
Kleinman R, Goulet O-J, Mieli-Vergani G, Sanderson I, Sherman P, Schneider B. Walker’s Pediatric Gastrointes-
tinal Disease. Vol 2. 5th ed. Hamilton, Ontario: BC Decker Inc; 2008.
Mishra K, Basu S, Roychoudhury S, Kumar P. Liver abscess in children: an overview. World J Pediatr.
2010;6(3):210-216.
Chronic Hepatitis
Deb Freese, MD
Autoimmune hepatitis is an idiopathic chronic inflammatory disorder involving the liver is often associated
with autoimmune inflammation of other organs.
I. Basics
A. Autoimmune hepatitis (AIH) is found in all ethnic groups
B. There are two major types of autoimmune hepatitis—Type 1 and Type 2. Each is recognized by
distinct serological markers and characterized by subtle differences in presentation and clinical
course
C. Overall incidence in North America is 2/100,000 and AIH can present at all ages
D. 60%–75% of patients are female
II. AIH in Children

A. 40% of patients present at <20 years of age
B. In children, mean age at presentation is 10–14 years, though it has been described in infants
C. 5% of children with chronic liver disease have AIH
D. 3.5% of children undergoing transplant have AIH
III. Presentation
A. Acute hepatitis is most common presentation, approximately 40%
B. 20%–25% present with features of chronic liver disease
C. Fulminant failure is an uncommon presentation
D. 20% are asymptomatic, and AIH is discovered serendipitously at routine exam
E. 5%–10% are diagnosed in course of evaluation of other autoimmune diseases
IV. Etiology
A. Thought to occur in genetically susceptible individuals in response to a variety of triggers via
molecular mimicry. These triggers include:
1. Drugs, viruses—hepatitis A, EBV, CMV, HCV among others, and possible environmental
factors
B. Genetic factors include MHC class II antigens, such as:
1. Type 1 AIH—DR3, 4 in Europe, N. America, and Japan; and DR13 in South America and
India (especially associated with HAV)
2. Type 2—DR7 and DQ2
C. Also polymorphisms in a variety of cytokines and in the complement system
V. Diagnosis
(Codified by International Autoimmune Hepatitis Group)
A. Exclude metabolic disease—e.g., Wilson, alpha-1-antitrypsin deficiency
B. Exclude infectious causes
C. Exclude alcohol or drugs
D. Demonstrate hepatitic process—e.g., elevated transaminases
E. Demonstrate immune process—e.g., elevated gamma globulin, autoantibodies
F. Describe characteristic histological features
G. Normal cholangiogram

VI. Characteristic Histology
A. Interface hepatitis
B. Mononuclear cell infiltrate
C. Piecemeal necrosis
D. Plasma cells
E. Multilobular (bridging) collapse
VII. Characteristic Autoantibodies

Titers in children are typically lower than adults—1:10 is significant
A. Type 1 AIH
1. Antinuclear antibody (ANA)
2. Antismooth muscle antibody (SMA)
3. p-ANCA
4. Antiactin antibody
B. Type 2 AIH
1. Antiliver kidney microsomal antibody (LKM)
2. Antiliver cytosol antibody
C. Soluble liver antigen (SLA) may be present in both types and may connote a worse prognosis
D. Very rarely, no antibodies are found—seronegative AIH
VIII.Type 1 AIH
A. 70%–95% of all cases
B. May present at any age
C. ANA, SMA, and pANCA are the most common antibodies, and are nonpathogenic
D. Target antigen unknown
E. Genetic associations—DR3 more severe than DR4; DR13 often associated with HAV
IX. Type 2 AIH

A. 5%–30% of cases—much more common in Europe than North America
B. Most patients are children
C. LKM antibodies are pathogenic—ANA, SMA, pANCA are absent
D. Target antigen—CYP2D6
E. Initial presentation may be more severe, and fulminant failure more common than Type 1
F. Response to treatment is similar, although these patients may be less likely to be taken off
medications altogether
G. 25% of patients with autoimmune polyendocrinopathy have Type 2 AIH
1. Target antigen different
2. More severe disease, less responsive to treatment
X. Treatment—Standard Regimen
A. Prednisone 2 mg/kg/day; azathioprine (AZA) 1–2 mg/kg/day
B. After liver tests near/normalize, then begin slow steroid taper over several weeks. Goal is to
eventually stop steroids if possible; patients may need continuous low-dose prednisone; azathio-
prine at therapeutic levels
1. Endpoints—normal LFTs for two years without flares, and normal biopsy
C. Labs should be monitored biweekly initially, and then every 1–3 months as treatment progresses
D. Consider d/c therapy (AZA ± prednisone) only if inflammation has resolved on biopsy
(histologic remission)
E. Biochemical remission in 80% by 18 months, histological remission in 90% by 48 months
F. Flares of disease activity occur in 40% during treatment, and require transient increase in steroid
doses. Consider noncompliance, especially in teenagers
G. Worse long-term outcome with any recurrence—some now recommend only one or no attempts
to stop all therapy
H. 15%–20% Type 1 and fewer Type 2 patients can stop treatment permanently
XI. Treatment Failure
A. Relapse despite Rx or inability to taper steroid to acceptable levels
B. 11% adults, 17% children
C. Again, consider noncompliance
D. Indication for other treatment
1. MMF as substitute for AZA, not as monotherapy
2. CSA, tacrolimus
3. Possible TNF ab, rituximab, IVIG, IL-2 ab—anecdotal reports only
XII. Transplant
A. 5%–15% patients require transplant, children > adults
B. Indications—disease progression to decompensation, despite treatment or fulminant failure
C. Type 2 has higher incidence of fulminant presentation compared to Type 1
D. Disease recurrence in up to 50%
XIII.Overlap Syndromes
A. AIH + characteristics of another liver disease, usually PSC or PBC
B. Seen in 20% of adults
C. 35%–40% children with PSC present with features of AIH
D. Antibody profile consistent with Type 1 AIH
E. UC commonly associated
F. Parenchymal inflammation improves with standard AIH therapy, but biliary lesions typically prog-
ress. Outcome worse than AIH, and transplant more common
Recommended Reading
Chai PF, Way SL, Brown RM, et al. Childhood autoimmune liver disease: Indications and outcome of liver
transplantation. J Pediatr Gastroenterol Nutr. 2010;50:295-302.
Czaja AJ. Autoimmune liver disease. Curr Opin Gastroenterol. 2005;21:293-299.
Czaja AJ, Freese DK. Diagnosis and treatment of autoimmune hepatitis. Hepatology. 2002;36:49-497.
Mieli-Vergani G, Heller S, Jara P, et al. Autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2009;49:158-164.
Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children. Clin Liver Dis. 2002; 6:335-346.

Granulomatous Hepatitis
Vi Lier Goh, MD
Vince F. Biank, MD
I. Hepatic granulomas are found in 2%–10% of livers biopsied for any indication. They are associated with
disorders of the liver outlined below, but may also be an incidental finding. Histologically, granulomas
consist of a central accumulation of mononuclear cells, mainly macrophages, with a surrounding rim of
lymphocytes and fibroblasts. When activated, macrophages may become epitheliod cells. These cells may
fuse under the influence of certain cytokines and become multinucleated giant cells.
II. Giant Cell Hepatitis

A. The giant cells seen in granulomatous hepatitis should not be confused with giant cell hepatitis,
such as in neonatal giant cell hepatitis, which is characterized by ballooning degeneration of
hepatocytes with fusion of hepatocyte membranes and nuclear transformation into multinucle-
ated giant cells. The etiology of these giant cells is unclear. A recent study has identified nuclear
proliferation markers in the hepatocytes of patients with giant cell hepatitis, suggesting that
nuclear proliferation contributes to the pathogenesis of these giant cells. Multinucleated giant
cells are also believed to be the response of immature hepatocytes to injury, as seen commonly in
neonatal giant cell hepatitis.
III. Autoimmune Disorders

A. Sarcoidosis
1. Systemic granulomatous disease of unknown etiology characterized by noncaseating
epithelioid granulomas
2. Gastrointestinal system involvement (usually hepatic) occurs in 0.1%–0.9% of patients
3. Hepatic manifestations include hepatomegaly (40%); less commonly elevated serum
aminotransferases; least common chronic liver disease, cirrhosis, cholestatic liver disease,
portal hypertension, and hepatic vein thrombosis
4. Liver pathology: noncaseating granulomas mainly in portal tracts and with increased
hepatic copper. Decreased number of interlobular bile ducts, with periportal fibrosis and
micronodular biliary cirrhosis, are long-term complications
5. Granulomatous phlebitis of the portal and hepatic veins occurs rarely
6. Serum angiotensin-coverting enzyme (ACE) level is high in 75% of untreated cases
7. Treatment: corticosteroids, ursodeoxycholic acid
B. Primary biliary cirrhosis (PBC)
1. Immunological attack on intralobular bile ducts that leads to cirrhosis and liver failure
2. Biochemical liver profile and hepatic histology may mimic sarcoidosis
3. Usually distinguished from sarcoidosis by presence of antimitochondrial antibodies
IV. Systemic Infections

A. The most common infections causing granulomatous liver disease in the United States are tuber-
culosis and infections associated with acquired immunodeficiency syndrome (AIDS). Schistoso-
miasis, leprosy, brucellosis, and Q fever also cause granulomatous liver disease
B. AIDS-related causes
1. Patients with AIDS are susceptible to infections associated with hepatic granulomas,
including Mycobacterium tuberculosis and Mycobacterium avium complex (MAC),
Cryptococcus neoformans, Cytomegalovirus (CMV), histoplasmosis, and toxoplasmosis
2. Some of the medications used to treat these infections also produce hepatic granulo-
mas, particularly sulfonamides and isoniazid

C. Tuberculosis – Mycobacterium tuberculosis
1. Hepatic granulomas occur in >90% of patients with miliary tuberculosis
2. Alkaline phosphatase levels are high in approximately 75% of cases, and
aminotransferase levels are high in 35%
3. Liver histology is variable. Most common findings are small hepatic granulomas in portal
areas. Early granulomas are composed of lymphocytes and epithelioid cells. Later, giant
cell formation and central necrosis (caseation) may predominate
4. Acid-fast bacilli can be identified in granulomas on histologic examination
5. Biliary obstruction may result from perihilar adenopathy
6. In congenital TB, the liver is the usual primary site of infection
D. Brucellosis – B melitensis, B abortus, B suis
1. 25% of affected children have hepatosplenomegaly. 84% have elevated serum trans-
aminases, but jaundice is rare
2. Lymphocytosis and elevated erythrocyte sedimentation rate are common
3. Liver histology: portal inflammation and focal hepatocyte necrosis in 90% of patients.
Noncaseating granulomas occur in 70%, primarily within the first 100 days of illness
4. Treatment: with tetracycline or doxycycline in conjunction with rifampin.
Trimethoprim-sulfamethoxazole may be used in children aged <9 years
E. Q fever – Coxiella burnetii
1. Liver usually involved in acute infections. 70%–85% have elevated serum transaminases;
11%–65% have symptoms referable to the liver; 5% present with jaundice
2. Liver histology: fibrin ring granulomas, characterized by a central clear space surrounded
by histiocytes and a fibrin ring. Early lesions may contain neutrophils. Giant cells appear
in later lesions. Steatosis, and mononuclear infiltration of portal tracts with Kupffer cell
hyperplasia, are nonspecific histologic findings. Fibrosis and chronic hepatitis are rare
3. Treatment: disease can be self-limited, but doxycycline is efficacious in shortening the
clinical course
V. Fungal Disease
A. Hepatosplenic candidiasis
1. Occurs almost exclusively in neutropenic oncology patients, often as a consequence of
seeding during generalized fungemia
2. Fever occurs in 85% of patients; abdominal pain in 57%, hepatomegaly in 44%, and
splenomegaly in 43%. Serum alkaline phosphatase is elevated in 60%. Leukocytosis is
present in 30%. Serum total and direct bilirubin may be very high, but aminotransfer-
ases are less frequently elevated
3. Computerized tomography early in infection often shows areas of variably enhancing di-
minished attenuation. Ultrasound examination is less sensitive, but so called “bull’s-eye”
lesions are characteristic
4. Liver pathology: early lesions are composed of pseudohyphae and yeast forms,
surrounded by neutrophils and an outer fibrous rim. Lesions progress to well-formed
granulomas, with giant cell change. Fungal organisms may be seen using periodic
acid-Schiff (PAS) or silver stains
5. Treatment: amphotericin B, often in conjunction with 5-fluorocytosine
B. Coccidioidomycosis – Coccidioides immitis
1. Endemic in southwestern United States, parts of Mexico, Central America,
and South America
2. Transmission usually via inhalation of arthrospores. Pulmonary infection is the most
common manifestation
3. Disseminated infection seen most often in immunocompromised patients
4. Hepatic involvement in 45%–60% of patients with disseminated disease. Hepatomegaly
occurs in conjunction with elevationed serum aminotransferases, and less commonly
with elevated serum alkaline phosphatase and bilirubin
5. Serology often useful for diagnosis disseminated disease
6. Liver pathology: granulomas and giant cells containing PAS or methenamine silver-stain-
ing spherules are seen, surrounded by normal-appearing hepatic parenchyma
7. Treatment: amphotericin B
C. Cryptococcus infection – Cryptococcus neoformans
1. Liver may be involved in disseminated disease. Primary hepatic infection is rare
2. Gross examination of the liver reveals white nodules
3. Liver pathology: granuloma formation surrounding fungal organisms
4. Treatment: usual agent is amphotericin B. Other agents include 5-fluorocytosine and
fluconazole
D. Histoplasmosis – Histoplasma capsulatum
1. Endemic in the Ohio and Mississippi River valleys in the United States
2. Inhalation of spores is the usual route of infection. The gastrointestinal tract is rarely the
portal of entry
3. Hepatic involvement occurs in conjunction with disseminated disease
4. Laboratory findings include pancytopenia, and mild-to-moderate elevations of serum
aminotransferase and alkaline phosphatase
5. Liver pathology: Kupffer cells loaded with fungal spores, prominent in sinusoids and
periportal areas, causing compression and necrosis of adjacent hepatocytes. Kupffer cell
infiltration of veins and arteries may be present. Granuloma formation most common in
chronic disease
6. Treatment: amphotericin B or itraconazole
E. Malignancy
1. Hodgkin lymphoma and, less commonly, non-Hodgkin lymphoma and renal cell carci-
noma have been associated with hepatic granulomas
2. Lesions are distinct from the primary lymphomatous tumor
3. Granulomas are not pertinent to the staging of Hodgkin and non-Hodgkin lymphomas
VI. Drugs
A. The most common drugs associated with hepatic granulomas are allopurinol, sulfa drugs,
chlorpropamide, and quinidine
VII. Idiopathic
A. Idiopathic granulomatous hepatitis is characterized by recurrent fever, weight loss, myalgia,
arthralgia, and vague abdominal pain, with granulomas in the liver when other causes of hepatic
granulomas have been excluded
B. Diagnosis is one of exclusion. Evaluations include clinical history, skin testing for fungal and
bacterial pathogens, and microbiological, serological and biochemical screening to rule out
other causes
C. Laboratory findings are usually nonspecific, with elevations of transaminases and bilirubin.
Sedimentation rate is often markedly elevated
D. Liver pathology: granulomas in all cases. A common finding is multiple lesions consisting of
typical focal nodular aggregations of lymphocytes, mononuclear cells and epitheloid cells.
Caseation is absent. Most granulomas are distributed randomly throughout the liver
parenchyma, although periportal granulomas are also seen
E. Treatment: some patients benefit from immunosuppression with corticosteroids or methotrexate
F. The natural history of the disease is chronic, with multiple remissions and exacerbations.
The condition can resolve spontaneously in some patients

Recommended Reading
Drebber U. Hepatic granulomas: histological and molecular pathological approace to diffential diagnosis- a
study of 442 cases. Liver Int. 2008;28:828.
Fang J, Gonzailez-Peralta R, Chong S, et al. Hepatic expression of cell proliferation markers and growth fac-
tors in giant cell hepatits: Implications for the pathogenetic mechanisms involved. Jour Ped Gastroenterol
Nutr. 2011;52:65-72.
Farrell MK. Systemic disease and the liver. In: Suchy FJ, Sokol RJ, Balisteri WF, eds. Liver Disease in Children.
3rd ed. New York, NY: Cambridge University Press; 2007:897-927.
Karagiannidis A et al. Hepatic sarcoidosis. Ann Hepatol. 2006; 5(4):251-256.
Novak DA, Lauwers GY, Kradin RL. Bacterial, parasitic, and fungal infections of the liver. In Suchy FJ, Sokol RJ,
Balisteri WF, eds. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press; 2007: 871-896.
6L. Congenital Hepatic
Fibrosis
Vi Lier Goh, MD
Vince F. Biank, MD
I. Congenital hepatic fibrosis (CHF) is characterized by ductal plate malformation, variable degrees of
periportal fibrosis, and irregularly shaped proliferating bile ducts, resulting in portal hypertension and
increased risk of ascending cholangitis.
II. Associated Anomalies

A. Autosomal-recessive polycystic kidney disease (ARPKD) is most common. Mutations of PKHD1,
which encodes the large, integral membrane protein; and fibrocystin that appears to be a ciliary/
basal body protein, although its role is not fully determined
B. Autosomal-dominant kidney disease (ADPKD). Mutations of PKD1 or PKD2. PKD1 accounts for
85% of ADPKD cases and is associated with more severe renal disease. The proteins encoded,
polycystin-1 and-2, are thought to play a role as a flow detector on primary cilia in kidney and
biliary ducts
C. Meckel-Gruber syndrome. Recessively inherited lethal condition with central nervous system
(occipital meningoencephlacele) abnormalities, bilateral large multicyctic kidneys, CHF, and
polydactyly. Gene loci: MKS1, MKS2, MKS3
D. Ivermark syndrome. Renal-pancreatic-hepatic dysplasia
E. Jeune syndrome. Asphyxiating thoracic dystrophy, rare, autosomal-recessive skeletal dysplasia
leading to respiratory insufficiency, with constricted thoracic cage
F. Bardet-Biedl syndrome. Retinal dystrophy; obesity, developmental delay, cystic renal disease
G. Bold Joubert syndrome. Hypoplasia of cerebellar vermis, retinal dystrophy, subset with medul-
lary cystic disease of the kidney and CHF. Gene: NPHP1
H. Caroli’s disease
I. von Meyenburg complexes
J. Choledochal cyst

A. Age of presentation and the severity of symptoms vary greatly, with patients usually being
diagnosed in childhood or early adulthood
B. Most patients are asymptomatic
C. Physical examination findings include hepatomegaly, predominantly left lobe; splenomegaly,
and nephromegaly
D. The liver is firm, with a mildly nodular surface
E. Four clinical forms have been defined:
1. Portal hypertension (most common, more severe with portal vein abnormalities)
2. Cholangitic: cholestasis and recurrent cholangitis
3. Mixed
4. Latent (presentation at a late age)
IV. Diagnosis
A. Mild elevation of liver enzymes
B. Patients with a predominant cholangitic clinical picture may have marked elevations in alkaline
phosphatase (ALP), γ-glutamyl transpeptidase (GGT) and bilirubin
C. Varying cytopenias secondary to hypersplenism
D. Abnormal renal function tests are associated with extensive cystic renal disease, which may prog-
ress to end-stage renal failure
E. Ultrasound: most informative, often reveals increased echogenicity of the liver, cysts in the he-
patic parenchyma, enlarged spleen, and accompanying fibrocystic changes in the kidneys.

F. Magnetic resonance cholangiopancreatography (MRCP) typically shows cystic or fusiform dila-
tations and irregularities of the intrahepatic bile ducts, abnormally large left lobe of the liver
extending anteriorly under the xiphoid and to the left over the spleen, fusiform dilation of the
extrahepatic bile ducts, elongation of the gall bladder, and enlarged spleen, which can be quanti-
fied by calculating volume and accompanying fibrocystic changes in the kidneys
V. Histopathology
A. Varying degrees of hepatic fibrosis with nodular formation, which may become extensive as the
disease progresses and may be mistaken for cirrhosis
B. Widened fibrous bands may be seen in the portal tract, containing an increased number of
irregularly shaped proliferating bile ducts lined by normal cuboidal epithelium
C. Signs of cholestasis may be observed in the settings of cholangitis
D. Other findings include cystic dilatation of the bile ducts (Caroli’s disease), and hypoplasia of the
portal vein branches in association with supernumerary hepatic artery branches
VI. Treatment
A. As yet, there is no treatment that has been shown to stop or reverse the process in CHF.
It remains a progressive debilitating condition
B. Endoscopic treatment is the mainstay for primary and secondary prophylactic management of
esophageal and gastric varices, as well as in the setting of acute bleeding
C. Portosystemic shunts are considered for patients with refractory bleeding. Liver transplantation is
the only known cure for CHF, and is indicated at the later stages of the disease, with the devel-
opment of liver failure
Recommended Reading
Jonas MM, Perez-Atayde AR. Fibrocystic liver disease. In: Suchy FJ, Sokol RJ, Balisteri WF, eds. Liver Disease in
Children. 3rd ed. New York, NY: Cambridge University Press; 2007: 929-931.
Shorbagi A. Experience of a single center with congenital hepatic fibrosis: A review of the literature. World J
Gastroenterol. 2010;16(6):683-690.
6M. Vascular Disease
of the Liver
Lina Maria Hernandez, MD
Lesley Smith, MD
I. Budd-Chiari Syndrome
A. Characterized by hepatic venous outflow tract obstruction in the absence of right heart failure or
constrictive pericarditis (which must be carefully excluded)
B. The obstruction can be located at the level of the small or large hepatic veins, or the suprahe-
patic portion of inferior vena cava (IVC)
C. Pathogenesis
1. Primary: hepatic expression of underlying prothrombotic conditions
a. Myeloproliferative diseases (MPD): mutation in the Janus Tyrosine Kinase-2
(JAK2) gene in myeloid cells
b. Inherited conditions: Factor V Leiden deficiency (accounts for 7%–25% of
Budd-Chiari Syndrome (BCS patients), G20210A prothrombin gene mutation,
deficiencies in protein C and S, and antithrombin
c. Other acquired conditions: Bechet’s disease, paroxysmal nocturnal
hemoglobinuria, antiphospholipid syndrome, hyperhomocysteinemia,
oral contraceptives, pregnancy, polycythemia vera
d. Systemic diseases: sarcoidosis, hypereosinophilic syndrome
2. Secondary: invasion or compression by a tumor, paracytic or non-paracytic cyst,
or abscess
3. Hepatic veno-occlusive disease must also be excluded
D. Presentation
1. Classic presentation: abdominal pain and distension with ascites
2. May be asymptomatic (15%), fulminant, or chronic (more common)
3. Common symptoms: abdominal pain, ascites, hepatomegaly, splenomegaly, portal
hypertension, prominent dilation of subcutaneous veins of the trunk, lower extremity
edema
4. Aminotransferases and bilirubin are minimally elevated
E. Diagnosis
1. Demonstration of an obstructed hepatic venous outflow tract or inferior vena cava
(IVC) obstruction
2. Doppler-ultrasound, triphasic CT scan, or MRI is usually sufficient to show
diagnostic features
3. Direct or retrograde venography rarely used
F. Treatment
1. Prompt recognition and treatment of underlying disease, and in all patients:
a. Initiate anticoagulation therapy
b. Refer to hematologist for paroxysmal nocturnal hemoglobinuria and MPDs
c. Stop oral contraceptives
d. Therapy for portal hypertension
e. Treat ascites with diuretics
2. Angioplasty (balloon dilatation), with or without stenting in patients with short length
stenosis in hepatic vein or IVC
3. Transjugular Intrahepatic Portosystemic Shunt (TIPS)
4. Liver transplantation if there is no improvement with above measures

II. Hepatic Veno-Occlusive Disease
A. Please refer to the section on venocclusive disease vs graft host disease
.
III. Hemangioma
A. Most common benign hepatic tumor
B. Lesions are usually focal, but can be multifocal or diffuse
C. May have estrogen receptors, resulting in accelerated growth during puberty, pregnancy,
oral contraceptive use, and with androgen treatment
D. Tumor consists of multiple, large vascular channels lined by a single layer of endothelial cells and
supported by collagenous walls, with blood supply arising from the hepatic artery
E. Clinical Presentation
1. Mostly asymptomatic, and diagnosed as an incidental finding on ultrasound
2. In symptomatic patients, right upper quadrant pain or fullness is common, and intermit-
tent symptoms may occur secondary to necrosis, infarction, or thrombosis of the tumor
3. May rarely present as a large abdominal mass, cardiac failure, spontaneous rupture, or
jaundice from compression of biliary ducts
4. Patients with giant hemangiomas may present with Kasabach-Merritt syndrome
5. Laboratory evaluation is usually unremarkable, including a normal alpha-fetoprotein, CA
19-9, and CEA, but may demonstrate thrombocytopenia or hypofibrinogenemia
6. Infantile hemangiomas may present with cardiac failure secondary to high-volume
shunting, hypothyroidism secondary to overproduction of type III iodothyronine deiodin-
ase, fulminant hepatic failure, respiratory compromise, and/or abdominal compartment
syndrome
F. Diagnosis
1. The majority of hemangiomas can be diagnosed accurately by imaging studies alone
a. Ultrasound shows a well-defined, lobulated, homogeneous hyperechoic mass
b. Findings inconsistent with this description are confirmed by triple phase
CT or MRI
2. Liver biopsy contraindicated in most circumstances because of increased risk of
hemorrhage, and should be used only when radiology study results and alpha
fetoprotein testing are equivocal
G. Management
1. Most hepatic hemangiomas may be safely left alone
2. Asymptomatic patients with focal or multifocal disease should be observed,
with follow-up ultrasonography to document regression
3. Indications for treatment include severe symptoms, complications, and inability to
exclude malignancy
4. Treatment includes surgical enucleation, resection, transarterial catheter
chemoembolization, hepatic irradiation, and transplantation
a. Surgical resection and enucleation are applicable for single hemangioma
b. Transplantation may be necessary in large unresectable lesions, multiple lesions,
or those involving the hepatic hilum
IV. Infantile Hemangioendothelioma

A. The 3rd most common hepatic tumor in childhood
B. It is usually detected before 6 months of age, with 85% detected by age of 2 months
C. 2:1 female predilection
D. These tumors are composed of vascular channels lined by a single layer of neoplastic endothelial
cells, often with entrapped hepatocytes, bile ducts, and areas of extramedullary hematopoiesis
E. Most tumors continue to grow during the 1st year of life, and then spontaneously regress,
probably due to thrombosis and scar formation
F. Clinical Presentation
1. Most common presenting signs of are hepatomegaly, abdominal mass, cutaneous
hemangiomata, and congestive heart failure
2. Patients may also have splenomegaly, jaundice, ascites, gastrointestinal bleeding,
anemia, feeding difficulties, failure to thrive, elevated transaminases, respiratory
difficulties, and hepatic bruit
3. Hemangiomas can be seen at distant sites, including skin, lung, pancreas, lymph nodes,
and bone
4. Serum alpha fetoprotein levels are normal or slightly elevated
5. Associations with chromosome 6q deletion, diaphragmatic hernia, Trisomy 21, transposi-
tion of the great arteries, extranumerary digits, and Kasabach–Meritt syndrome
6. Risk of degeneration into malignant hemangioendothelial sarcomas
a. Infantile hemangioendothelioma (IHE) in older children are at higher risk
for malignancy
G. Diagnosis
1. Ultrasound shows heterogeneous, septated lesion with iso- and hypoechoic areas, with
increased blood flow on Doppler
2. Biphasic contrast CT and dynamic gadolinium-enhanced MRI show rapid peripheral
enhancement during the arterial phase, with delayed central filling during the venous
phase
3. Liver biopsy should only be performed if there is doubt of the benign nature of a
vascular lesion
H. Management
1. Intervention is unnecessary for asymptomatic masses
2. Yearly ultrasound should be performed until complete resolution occurs
3. Options for medical therapy include steroids and interferon to accelerate the natural
involution of the mass, radiation therapy or chemotherapy, and supportive care for con-
gestive heart failure and coagulopathy
4. Hepatic artery embolization can be used to reduce tumor vascularity and arteriovenous
shunting. Surgical resection is indicated for life-threatening symptoms or if the mass
cannot be distinguished from a malignant tumor radiologically
a. Single lesions may be managed with hepatic lobectomy or local resection
b. Orthotopic liver transplantation should be considered if other therapies fail
Recommended Reading
Choi N. The diagnosis and management of benign hepatic tumors. J Clin Gastroenterology. 2005;395.
Christison-Lagay R. Hepatic hemangiomas: subtype classification and development of a clinical practice algo-
rithm and registry. J Pediatric Surg. 2007;42:62-68.
Deleve V. AASLD Practice Guidelines, Vascular Disorders of the Liver. Hepatology. 2009;49:5.
Hansen K, Horslen S. Metabolic liver disease in children. Liver Transplantation. 2008;14:391-411.
Kumar S, Deleve LD, Kamath PS, Tefferi A. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome)
after hematopoietic stem cell transplantation. Mayo Clin Proc. 2003;78.

6N-1. Metabolic/Genetic
Liver Diseases—Bile Acid
Synthetic Disorders
Khyati Mehta, MD
James Heubi, MD
I. Bile acids are synthesized by the liver from cholesterol through a complex series of reactions involving
multiple enzymatic steps in the bile acid synthetic pathway.
A. Chemistry and Physiology
1. The two primary bile acids synthesized by liver are cholic acid (3α, 7α, 12α, trihydroxy-5
β cholanoic acid) and chenodeoxycholic acid (3α, 7 α– dihydroxy-5β-cholanoic acid)
a. These bile acids are extensively conjugated to the amino acids glycine and
taurine
b. The primary bile acids enter the distal small intestine and colon, where a
portion are deconjugated and dehydroxylated by bacterial enzymes to produce
the secondary bile acids, deoxycholic and lithocholic acid
2. Bile acids perform several important functions
a. They are the major catabolic pathways for elimination of cholesterol
from the body
b. They provide the primary driving force for the promotion and secretion of bile,
and are essential to development of the biliary excretory route for the elimina-
tion of endogenous and exogenous toxic substances, including bilirubin and
drug metabolites
c. Within the intestinal lumen, the detergent action of bile acids facilitates the
absorption of fats and fat-soluble vitamins
1. There are nine identified defects in the bile acid synthetic pathway, resulting in blocked
production of normal bile acids, accumulation of unusual bile acids and intermediary
metabolites, reduced bile flow, and decreased intraluminal solubilization of fat and fat-
soluble
vitamins
2. Liver disease occurs as increased hepatotoxic bile acid intermediaries are created because
of blockage in pathways
3. Bile acid synthetic defects should be considered in all cholestatic infants. Clinical
suspicion should be raised in particular if:
a. Total serum bile acids are low or normal, as they are usually high in
cholestatic infants
b. GGT is normal or minimally elevated, as it is usually high in cholestatic infants
c. Pruritus, which is a common and distressing component of most cholestatic
disorders, is absent
C. Diagnosis
1. Requires high index of suspicion, as above
2. If serum bile acids are normal or low, urine bile acids should be measured by Fast Atom
Bombardment Ionization Mass Spectrometry (FABMS), which allows identification of a
profile of the bile acids in urine
3. FABMS can be complemented by Gas Chromatography-Mass Spectrometry (GC-MS) of
urine, bile, and serum, to establish absence or reduction of primary bile acids in conjunc-
tion with the presence of atypical bile acid and sterols that are synthesized as a result of
enzymatic deficiency
4. Liver biopsy may demonstrate suggestive features (see below)

D. General Treatment Principles
1. Down regulate hepatocyte bile acid synthesis by negative feedback inhibition, thereby
diminishing the toxic products of intermediate metabolism, such as monohydroxy bile
acids
2. Nutritional support, including fat-soluble vitamins and medium-chain triglyceride-con-
taining formula
3. Liver transplant may be an option in some cases
II. Specific Inborn Errors of Bile Aid Synthesis (BAS)

A. 3β Hydroxy C-27 Steroid Oxidoreductase/Dehydrogenase Deficiency (3βHSD)
1. Most commonly reported defect in BAS 3βHSD catalyzes the conversion of 7α hydroxy
cholesterol to 7α hydroxyl-4-cholesten-3-one
2. Presents in neonates with progressive jaundice, increased aminotransferases, normal
GGT, conjugated hyperbilirubinemia, and low/normal total bile acids
3. Hepatomegaly with or without splenomegaly, malabsorption with steatorrhea and
fat-soluble vitamin deficiency, rickets
4. Urine bile acid profile shows decreased primary bile acids and increased di- and
trihydroxy cholenoic acids
5. Liver biopsy: giant cell hepatitis/portal inflammation, perilobular fibrosis,
cannalicular bile plugs
6. Enzyme activity can be measured in fibroblasts and is undetectable in affected patients
7. Molecular techniques allow for genetic diagnosis
8. Treatment with cholic acid can improve liver function and resolve jaundice if fibrosis has
not yet occurred
B. Oxysterol 7 α Hydroxylase Deficiency
1. Only one reported case in literature
2. Clinical presentation of severe progressive liver failure, cholestasis, and hepatospleno-
megaly
3. Urine bile acids show absent primary bile acids, and increased sulfate and glycosulfate
conjugates of 3 beta-delta 5-monohydroxy bile acids
4. Liver biopsy shows lobular disarray, giant cell transformation, and moderate portal
inflammation
C. ∆4- 3 oxosteroid 5β Reductase Deficiency
1. ∆4-3 oxosteroid 5β reductase catalyzes conversion of the intermediates 7α hydroxy
4-cholesten – 3- one & 7α, 12α-dihydroxy-4-cholesten-3-one to their corresponding
3-oxo-5β (H) intermediates
2. Present with neonatal cholestasis, increased aminotransferases, conjugated hyperbilirubi-
nemia, coagulopathy, and normal GGT
3. Liver biopsy typical of neonatal hepatitis
4. Enzyme not expressed in fibroblasts or leukocytes. Diagnosis must be made by FABMS,
which shows increased 3-oxo-7α bile acids. Urine and serum concentration of normal
bile acids are low. Accumulated ∆4-3-oxo-7α bile acids cause hepatotoxicity
5. Treatment with cholic acid, as it suppresses endogenous synthesis of bile acids and
accumulation of toxic metabolites
D. Cerebrotendinous Xanthomatosis
1. A defect in bile acid side chain modification
2. Slowly progressive disease of lipid accumulation, characterized in adults by progressive
neurologic dysfunction, dementia, ataxia, cataracts, and xanthomata in the brain and
tendons
3. Liver disease is not generally a feature of this condition, but a self-limiting neonatal
cholestasis may occur, consisting of increased ALT, AST, conjugated bilirubin, and normal
GGTP and liver enzymes, and usually resolves by 6 months of age because of increased
cholic acid production by compensatory alterative 25 hydroxylation pathway
4. Treatment with chenodeoxychoic acid or cholic acid is recommended, with the addition
of a statin to suppress cholesterol synthesis. Without treatment, tendinous and CNS
xanthomata occur, with neurologic dysfunction in adulthood
E. Alpha Methylacyl-CoA Racemase Deficiency
1. Defect results in inhibition of cholesterol side chain oxidation
2. Key enzyme required for racemization of trihydroxycholestanoic acid and pristanic acid
into their stereoisomers
3. Present with cholestatic liver disease, severe fat-soluble vitamin deficiencies and coagu-
lopathy. If undiagnosed in infancy, may later present as adults with peripheral neuropa-
thy
4. Urine bile acids show decreased primary bile acids and increased trihydroxycholestanoic
and pristanic acids
5. Liver biopsy shows neonatal hepatitis with giant cell transformation. Electron microscopy
shows decreased numbers of peroxisomes
6. Treatment options include cholic acid and, with severe presentation, liver transplant
F. Bile Acid Conjugation Defects
1. Conjugation of cholic and chenodeoxycholic acid into taurine and glycine is the final
step in primary bile acid synthesis
2. The enzymes that catalyze this conjugation are the rate-limiting Co-A ligase and CoA:
amino acid N-acyltransferase
3. Patients have symptoms of malabsorption and fat-soluble vitamin deficiency. May have
conjugated hyperbilirubinemia, severe cholestasis, and liver failure
4. Diagnosis is based on urine FABMS, with complete absence of usual glycine and taurine
conjugated BA
5. Treatment with oral primary conjugated bile acids and fat-soluble vitamins
Recommended Reading
Bove KE. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol.
2004;7(4):315-334.
Hansen K, Horslen S. Metabolic liver disease in children. Liver Transpl. 2008;14(4):391-411. Review.
Heubi JE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27(3):282-294. Review.
Sundaram S. Mechanisms of disease; inborn errors of bile acid synthesis. Nat Clin Pract. 2008;5(8):456-468.

Liver Diseases—Disorders
of Bilirubin Metabolism
Asha Willis, MD
Stephanie Page, MD
James Daniel, MD
Fred Suchy, MD
I. The metabolism of bilirubin involves many enzymes and receptors. Defects in the bilirubin transport or
enzyme defects lead to jaundice, and are seen in several different scenarios.
Bilirubin is the end result of the breakdown of heme. Hemoglobin contributes 80% of the total amount
of heme in the body with smaller contributions by myoglobin, cytochromes, catalases, and tryptophan.
Heme oxygenase converts heme to biliverdin and biliverdin reductase changes biliverdin to bilirubin.
Bilirubin is bound to albumin within the bloodstream and upon uptake by hepatocytes, is conjugated by
UDP-glucuronosyltransferase to mono and di-glucuronides. These are then excreted into the lumen of
the intestines and some are changed by bacteria into urobilinogen and excreted in feces and some are
reabsorbed in the ileum via enterohepatic circulation (after deconjugation by intestinal enzymes).
In the neonate increased enterohepatic circulation is the likely cause of significant physiologic jaundice.
However, jaundice usually resolves unless there are other abnormalities as well. Evaluating the direct and
indirect components of bilirubin points the diagnostician in the appropriate direction for diagnosis.
II. Breast Milk Jaundice

A. The persistence of physiologic jaundice beyond the first week of life, due to an unknown factor
that promotes increased intestinal absorption of bilirubin
1. Beta-glucuronidase is one proposed substance: deconjugates intestinal bilirubin, increas-
ing its ability to be absorbed (i.e., increasing enterohepatic circulation)
B. Typically begins after the first 3–5 days of life, peaks within two weeks after birth, and progres-
sively declines to normal levels over 3–12 weeks
C. Severe in 2% of cases, where serum bilirubin levels can reach 15 mg/dL
D. Not associated with kernicterus
E. Different from breastfeeding jaundice, which occurs because of inadequate intake of breast milk,
leading to significant weight and fluid loss resulting in hypovolemia and hyperbilirubinemia
F. Cessation of breastfeeding for 24–48 hours will decrease bilirubin
III. Gilbert’s Syndrome

A. A defect in bilirubin glucuronidation resulting in chronic recurrent, mild, unconjugated
hyperbilirubinemia, with otherwise normal liver function tests
1. Inherited as autosomal-dominant or autosomal-recessive
2. Heterogeneous group of disorders, with at least a 50% decrease in hepatic bilirubin UDP
glucuronyl transferase (BUGT) activity
B. Clinical diagnosis in which mild, fluctuating, unconjugated hyperbilirubinemia occurs with other-
wise normal liver function tests and no evidence of hemolysis
C. Patients are often identified when elevated serum bilirubin is noted on screening blood chemistry
D. Mild jaundice or scleral icterus may occur during a period of fasting or viral illness
E. Most often clinically apparent after puberty
F. Serum unconjugated bilirubin levels usually range from 1–4 mg/dL

G. Genetic screening for UGT1A1 mutations is available
H. Benign condition, with affected patients not at increased risk of morbidity or mortality
related to condition
I. No specific treatment is required
IV. Crigler-Najjar Syndrome

A. Glucuronidation defect resulting in a severe unconjugated hyperbilirubinemia in the immediate
neonatal period, with a high risk of kernicterus
B. Autosomal-recessive condition
1. Type I: complete absence of functional UGT1A1 activity
2. Type II: markedly reduced but not absent UGT1A1 activity
3. Type I can be differentiated from Type II by response to phenobarbital, which can stimu-
late endoplasmic reticulum hyperplasia: those with Type II will decrease serum bilirubin,
while Type I will not
C. Patients with one normal allele have normal bilirubin metabolism
D. Evaluation begins in the immediate neonatal period, when serum bilirubin levels are >20 mg/dL,
without a conjugated fraction
1. Evaluation should include the exclusion of other causes of unconjugated
hyperbilirubinemia, such as hemolysis, hypothyroidism, infection
E. Neonates should be treated with phototherapy and/or exchange transfusion to prevent
kernicterus
F. Requires lifelong treatment with phototherapy, 6–12 hours daily, to maintain serum bilirubin
<20 mg/dL
G. Phenobarbital (4 mg/kg/d) may be used as an adjunct therapy in Type II patients
H. Oral administration of binding agents such as agar, cholestyramine, or calcium phosphate have
also been used to bind bilirubin in the intestinal lumen and prevent enterohepatic recirculation
I. Orthotopic liver transplantation is curative
V. Rotor Syndrome
A. Defect of intracellular binding of bilirubin and its conjugates
B. Autosomal-recessive defect of glutathion S-transferase (GST), though genetic defect is unknown
C. Chronic elevation of both conjugated and unconjugated serum bilirubin fractions
1. Total serum bilirubin concentrations range from 2–7mg/dL, with ≥50% conjugated
D. Consider diagnosis in individuals with elevations of both conjugated and unconjugated serum
bilirubin fractions, but otherwise normal liver function, and no hemolysis
E. The diagnosis made by measuring urinary coproporphyrin levels: 2.5–5x higher than in normal
individuals
1. Urinary coproporphyrin Isomer I will be <80% of the sum total of Isomer I and III
F. Jaundice is lifelong, but not associated with morbidity or mortality
G. No specific therapy is required
VI. Dubin-Johnson Syndrome

A. A defect of hepatic excretion of non-bile salt organic ions at the apical canalicular membrane by
the ABC transport system (cMOAT/MRP2/ABCC2)
B. Autosomal-recessive condition
C. Elevation of both conjugated and unconjugated serum bilirubin fractions
1. Total bilirubin levels range from 1.5–6 mg/dL, with >50% conjugated
2. Levels as high as 25 mg/dL may occur during intercurrent illness
D. Usually diagnosed after puberty, though may occur in neonates
E. Male predominance, with earlier age of presentation
F. Patients may have abdominal complaints
G. Hepatomegaly may occur, but liver function tests are otherwise normal
H. Jaundice may be worsened by pregnancy and oral contraceptives
I. Patients have an increase in the urinary excretion of coproporphyrin I (80%), with a decrease in
the excretion of coproporphyrin III
J. Liver has a brown-to-black discoloration, due to pigment in lysosomes
K. Jaundice is lifelong, but not associated with morbidity or mortality
L. No specific therapy is necessary
1. Avoidance of oral contraceptives is recommended
2. Anticipatory guidance regarding pregnancy should be provided
Recommended Reading
Bhutani VK. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyper-
bilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103(1):6-14.
Grunebaum E. Breast milk jaundice: natural history, familial incidence and late neurodevelopmental outcome
of the infant. Eur J Pediatr. 1991;150(4):267-270.
Suchy FJ.. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press; 2007 :287-294.
Walker AW. Pediatric Gastrointestinal Disease. 4th ed. Vol 2. Hamilton, Ontario: BC Decker Inc; 2004;
1347-1355.

Liver Diseases—Disorders of
Carbohydrate Metabolism
(Glycogen Storage)
Maria E. Perez, DO
Carol Potter, MD
I. Carbohydrate Metabolism
A. A central role of the liver is glucose homeostasis (See figure 1)
B. Glucose can be generated via pathways of gluconeogenesis and by degradation of
stored glycogen
C. Hormones such as insulin, glucagon, and epinephrine regulate the uptake and release of glucose
D. The majority of dietary carbohydrates are absorbed in the form of glucose, galactose,
and fructose
E. Glucose is stored primarily in the form of glycogen, a branched-chain glucose polymer
primarily located in liver and muscle
II. Common Features of Disorders of Carbohydrate Metabolism

A. Neonates and infants may present with hypoglycemia, vomiting, diarrhea, poor feeding,
poor weight gain, seizures, hepatomegaly, and liver failure
B. Older children may present with hepatomegaly, abnormal feeding behaviors such as sugar avoid-
ance, poor weight gain and growth, and developmental delay
C. May present after an acute illness or prolonged period of fasting
III. Disorders of Galactose Metabolism

A. Epidemiology/Pathogenesis
1. Most common defect of galactose metabolism is a deficiency of galactose 1-phosphate
uridyl transferase (GALT). This defect is responsible for classic galactosemia (See figure 2)
2. Occurs in 1 of every 30,000–50,000 live births
3. Autosomal-recessive condition
4. Other galactose metabolism defects include a defect of galactokinase (the enzyme
responsible for the first step in galactose metabolism)
B. Clinical Features
1. Failure to thrive, vomiting, diarrhea are most common
2. Patients may present with hypoglycemia and encephalopathy shortly after birth, and
then develop jaundice, ascites, hepatosplenomegaly, and liver failure
3. Hemolytic anemia can be seen
4. Cataracts can develop with galactokinase deficiency due to accumulation of toxic me-
tabolites (galactitol) in the lens
5. E coli sepsis should prompt an evaluation for galactosemia
6. Renal tubular dysfunction can also occur
7. Mental retardation is the most significant long-term effect. IQ is highly correlated with
adequate dietary control
8. Hypergonadotropic hypogonadic ovarian failure can also occur with GALT deficiency
C. Diagnosis
1. Most patients are detected via the newborn screen
2. Positive urinary reducing substances, without glucosuria
3. Decreased GALT activity in the red blood cells

D. Management/Treatment
1. Elimination of dietary galactose
a. Switch infants to soy or protein hydrolysate formula
b. Older children and adults should avoid products that contain milk and milk
products. Food labels must be read carefully to look for these ingredients
c. Legumes such as garbanzo and black beans should also be avoided because
they contain increased amounts of galactose
d. Calcium and Vitamin D supplementation is recommended
2. Annual ophthalmologic exams and neurodevelopmental assessments are recommended
Figure 1. Galactose metabolism. Galactose is

phosphorylated to galactose 1-phosphate, by
galactokinase (1). This is then further converted to
uridine diphosphate (UDP) galactose and glucose
1-phosphate by galactose-1-1phosphate uridyl
transferase (GALT) (2). UDP-galactose is converted
to UDP-glucose by uridine diphosphate galactose-
4-epimerase (3). UDP-glucose is converted to glu-
cose 1-phosphate by uridine diphosphate glucose
pyrophosphorylase (4). In the absence of GALT,
galactitol and galactonate are over-produced.
Adapted from Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 4th ed.
Philadelphia, PA: Saunders Elsevier; 2011: Chapter 73.
IV. Hereditary Fructose Intolerance

1. Caused by a deficiency of fructose-1,6-bisphosphate aldolase (aldolase B) (See figure 3)
2. Occurs in approximately 1 in 20,000 live births
3. Autosomal-recessive condition
1. Symptoms develop once fructose is introduced into the diet (switch to
sucrose-containing formula or the initiation of baby foods)
2. Most common symptoms include poor feeding, vomiting, diarrhea, and abdominal pain
3. Chronic exposure or large fructose loads can lead to seizures, failure to thrive, liver
failure, and renal tubular dysfunction
4. Older patients and adults may go undiagnosed, because these patients may purposefully
avoid fructose-containing foods
C. Diagnosis
1. Definitive diagnosis requires tissue enzyme assay
1. Complete avoidance of fructose and sucrose. Must take particular notice of food
additives, pill coatings, and medication suspensions
2. In acutely ill patients, correct hypoglycemia, metabolic acidosis, and coagulopathy
Figure 2. Fructose metabolism. Fructose is metabo-

lized to glycogen or to components of the Krebs cycle.
A deficiency in aldolase B, as in hereditary fructose
intolerance, results in the accumulation of fructose
1-phosphate.
Adapted from Wyllie R, Hyams JS. Pediatric Gastro-

intestinal and Liver Disease. 4th ed. Philadelphia, PA:
Saunders Elsevier; 2011: Chapter 73.
V. Fructose 1,6-Bisphosphatase Deficiency
A. An autosomal-recessive condition resulting in impaired gluconeogenesis
B. A slight female predominance (1.5:1) exists
C. Parental consanguinity has been reported in some cases
D. Symptoms develop when glycogen stores are low (such as in newborns or in periods of
prolonged fasting or illness)
E. Approximately 50% of affected patients will develop symptoms shortly after birth, including
hypoglycemia, hyperventilation, and metabolic acidosis
F. Definitive diagnosis is made by liver biopsy
G. Treatment includes avoidance of prolonged periods of fasting, and limitation of dietary fructose
and sucrose
VI. Glycogen Storage Diseases (GSDs)

1. Caused by deficiencies of enzymes in the pathways of glycogen metabolism.
ten different types of GSDs have been identified, with Types I, III, IV, and VI primarily
affecting the liver (See Table 1)
2. Autosomal-recessive conditions
3. Type Ia occurs in 1 of every 200,000 live births
Table 1.
Type Enzyme Defect Affected Tissues(s) Main Clinical features
Ia (Von Gierke disease) Glucose-6-phosphatase Liver, kidney Classic form of GSD;
hypoglycemia & metabolic
acidosis 3–4 hours post meal;
hepatomegaly with protuberant
abdomen and lordosis; elevated
triglycerides; doll facies and
xanthomas; impaired platelet
function/bleeding; elevated uric
acid
I b-c Glucose-6-phosphatase Liver Ib – neutropenia and recurrent
related transport infections; association with IBD
Ic – impaired insulin secretion
II (Pompe disease) Acid-α-glucosidase Heart, muscle Cardiorespiratory failure,
cardiomyopathy
III (Forbes disease) Debranching enzymes Liver, muscle Hepatomegaly, fasting hypogly-
cemia, hyperlipidemia, progres-
sive myopathy
IV (Andersen’s disease) Branching enzyme Liver Hypoglycemia is RARE; liver
(α-1,4-glucan 6 glucosyl- disease and cardiomyopathy are
transferase) common
Figure 3. Type 1 glycogen storage disease (A) Glycogen-filled hepatocytes seen on periodic acid-Schiff stain.
(B) Plantlike mosaic patter of hepatic lobules on hematoxylin stain. Courtesy of Dr. H. Melin-Aldana
Adapted from Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Saun-
ders Elsevier; 2011: Chapter 73.

B. Diagnosis
1. Liver biopsy: histological exam of GSD type I patients will demonstrate glycogen-filled
hepatocytes that are periodic acid-Schiff stain positive
2. Molecular genetic tests available for GSD types I through V
C. Management/Treatment
1. GSD Type I
a. Continuous glucose source (small frequent feeds in infants, continuous or
overnight enteric tube feeds, cornstarch)
b. Allopurinol and lipid-lowering agents are rarely needed
c. Recombinant G-CSF for neutropenia
2. GSD Type III
a. Continuous glucose source
b. Annual alpha-fetoprotein and ultrasound due to risk of
hepatocellular adenomas
c. Annual echo and EKG for patients with cardiomyopathy
3. GSD Type IV
a. Liver transplantation is the only effective therapeutic modality for these patients
Recommended Reading
Philadephia, PA: Saunders Elsevier; 2010: Chapter 57.
Walker A, Goulet O, Kleinman R, Sherman PM, Shneider BL, Sanderson IR. Pediatric Gastrointestinal Disease:
Pathophysiology, Diagnosis, & Management. 4th ed Hamilton, Ontario: BC Decker Inc; 2004: Chapter 55,
section 2, pages 1257-1274.
Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Saunders Elsevier;
2011: Chapter 73.
Liver Diseases— Disorders of
Amino Acid Metabolism
Maria E. Perez, DO
Carol Potter, MD
I. Tyrosine Metabolism
A. Degradation of tyrosine is catalyzed by a series of reactions yielding acetoacetate and fumarate.
The complete pathway only occurs in hepatocytes and renal proximal tubules. Conditions leading to
elevated serum tyrosine levels include: transient tyrosinemia of the newborn (most common cause
of hypertyrosinemia resulting from immaturity of the liver and the enzymes required for tyrosine
degradation); any severe hepatocellular dysfunction; congenital deficiencies or dysfunction of
enzymes related to tyrosine metabolism, hyperthyroidism and vitamin C deficiency.
Tryosine
4-OH phenylpyruvate
NTBC α-aminolevulinic
inhibitory
acid
Homogentisate
Maleylacetoacetate Succinylacetoacetate
Fumarylacetoacetate inhibitory
Succinylacetone
fumarylacetoacetate
hydrolase
Porphobilinogen
Fumarate + acetoacetate
NTBC: (20(20nitro-4-trifluoromethylbenzol)-3cyclohexendiome
Figure 1. Tyrosine degradation pathway demonstrating fumarylacetoacetate hydrolase, a defect of which is
responsible for tyrosinemia type 1. In addition, the inhibitory effect of abnormal metabolites on porphyrin
metabolism and the site of action of NTBC are also demonstrated.
Abbreviation: NTBC, 2-(2-nitro-4-trifluoromethylbenzol)-1, 3-cyclohexanedione
Adapted from Hansen K, Horslen S. Metabolic liver disease in children. Liver Transplantation. 2008; 14: 391-
411.
II. Hepatorenal Tyrosinemia (Hereditary Tyrosinemia Type 1)

1. Incidence of 1 in 100,000, with higher incidence in Northern Europeans (1 in 8,000) and
in Saguenay-Lac Saint-Jean region of Quebec, Canada (1 in 1,846)
2. Autosomal-recessive condition caused by defect in fumaryl acetoacetate hydrolase (the
last enzyme in tyrosine degradation), resulting in accumulation of fumarylacetoacetate
and maleylacetoacetate, and their derivatives succinylacetoacetone (SAA) and
succinylacetone (SA)
3. Maleylacetoacetate induces renal Fanconi syndrome
4. Maleylacetoacetate and fumarylacetoacetate are reactive unstable compounds that may
form glutathione adducts, which allow free radical formation. This may be the source of
DNA damage and the increased risk of hepatocellular carcinoma

5. Succinylacetone inhibits synthesis of porphobilinogen from δ-aminolevulinic acid
(δ-ALA). Accumulation of δ-ALA is the source of neurotoxicity as in acute intermittent
porphyria
1. Acute manifestations are those of acute liver failure with vomiting, diarrhea,
hepatosplenomegaly, edema, ascites, mild elevations of bilirubin and transaminases,
and severe hepatic synthetic dysfunction–producing coagulopathy, hypoglycemia and
hypoalbuminemia
2. Chronic Form
a. Growth failure
b. Renal tubular dysfunction from Fanconi syndrome with phosphaturia and renal
rickets resulting from maleylacetoacetate accumulation
c. Neurological crises, pain with paresthesias and posturing result from delta ami-
nolevulinic acid accumulation. Often precipitated by infection. Can last up to a
week and may progress to flaccid paralysis and respiratory failure
resembling acute intermittent porphyria
d. Main causes of death are liver failure, especially recurrent bleeding,
Hepatocellular carcinoma and neurological crises
3. Hepatocellular carcinoma (HCC) is usually a long-term complication occurring in less
than 1/3 of patients. Cases as young as 15 months have been reported. Abdominal
ultrasound or CT scan can identify HCC. Cirrhotic nodules may be a confounder, but are
not a reliable indicator of HCC
C. Diagnosis
1. Elevated urine succinylacetone is most diagnostic. Urine δ-ALA also elevated but is
elevated in other disorders. Serum α-fetoprotein elevation variable with or without HCC
2. Coagulopathy (with normal factors V and VIII), hypoalbuminemia and hypoglycemia out
of proportion to milder elevation of bilirubin and transaminases
3. Hemolytic anemia
4. Renal tubular dysfunction (hyperphosphaturia, glucosuria, proteinuria
and aminoaciduria)
5. Liver biopsy
a. Acute → fatty infiltration of liver, iron deposition and varying degrees of
hepatocyte necrosis
b. Chronic → multilobular cirrhosis, bile duct proliferation and
regenerative nodules
1. Coagulopathy is NOT responsive to Vitamin K
2. Dietary restriction of phenylalanine and tyrosine. In infants, Tyrex® or Tyros®
formula is used
3. NTBC (2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)
a. Inhibits 4-hydroxyphenylpyruvate dioxygenase (2nd step in tyrosine
degradation)
b. >95% of patients respond with significant hepatic and renal improvement
c. Need frequent monitoring, including LFTs and urine succinylacetone
d. Recurrent ophthalmological evaluations and abdominal imaging
e. Serum alpha-fetoprotein every 6–12 months
f. NTBC started early may decrease the incidence of HCC, but careful monitoring
is still required for all Type I cases
4. Liver transplantation
a. Reserved for those patients who do not respond to medical therapy
b. Reported 1-year survival is high: 88%–100%
c. Renal tubular dysfunction, renal rickets and poor growth may persist after
transplantation
III. Other Forms of Tyrosinemia
A. Liver failure: nonspecific elevation of many urine and serum amino acids, including tyrosine
B. Transient tyrosinemia of the newborn: immaturity of 4-hydroxyphenylpyruvate dioxygenase
(4HPPD) causes self-limited elevation of tyrosine. Treat with lower protein diet and vitamin C
C. Vitamin C deficiency: Vitamin C is a cofactor for 4HPPD
D. HP Type III: congenital defect in 4HPPD
E. HP Type II (oculocutaneous tyrosinemia) autosomal-recessive deficiency of tyrosine aminotrans-
ferase. Hyperkeratosis of palms and soles, corneal thickening, developmental delay with normal
hepatic and renal functions
Recommended Reading
Nitisinone: new drug. Type 1 tyrosinemia: an effective drug. Prescrire International. 2007;16(88):56-58.
Van Spronsen FJ, Thomasse Y, Smith GPA, et al. Hereditary tyrosinemia: A new classification with difference in
prognosis on dietary treatment. Hepatology. 1994;25:1187-1195.
2006: Chapter 61.

Liver Diseases—Disorders of
Lipid Metabolism
Maria E. Perez, DO
Carol Potter, MD
I. Physiology of Fatty Acid Oxidation

A. Mitochondrial β-Fatty acid oxidation (FAO) provides most of the energy needed in the heart and
muscle, and is an essential pathway to maintain blood glucose during periods of fasting
1. FAO leads to the production of ketone bodies, which are an important secondary
energy source for many tissues, including the brain, when glucose supplies are low.
This is particularly important in childhood when glycogen stores are limited
B. The initial step in fatty acid metabolism is lipolysis, in response to fasting, resulting in free fatty
acids (FFAs)
1. FFAs are transported across the plasma membrane and are esterified to coenzyme A
(CoA) by the enzyme acyl-CoA synthetase, to form acyl-CoA esters before entry into
the mitochondria for further metabolism
a. Long-chain fatty acids (LCFAs) require the carnitine cycle and transesterification
to acylcarnitines to cross the mitochondrial membrane
2. Within the mitochondria, the acyl-CoA esters enter the β-oxidation cycle, and carnitine
is reshuffled back across the inner mitochondrial membrane to bring more LCFAs across
the membrane
a. Medium-chain fatty acids (MCFAs) and short-chain fatty acids (SCFAs) can tra-
verse the mitochondrial membrane without conversion to acylcarnitines
ACS = acyl-CoA synthtase; CACT = carnitine acylcarnitine translocase; CoA = coenzyme A; CoASH = unacyl-
ated coenzyme A; CPT1 = carnitine palmitoyltransferase 1; CPT12 = carnitine palmitoyltransferase 2; FA =
fatty acid; FA-CoA = fatty acyl CoA; FATP = fatty acid transport protein; MCAD = medium-chain acyl-CoA
dehydrogenase; Mit = mitochondrial; M/SCHAD = medium-/short-chain 3-hydroxyacyl-CoA dehydrogenase;
SCAD = short-chain acyl-CoA dehydrogenase; SCEH = short-chain enoyl-CoA hydratase; SKAT = short-chain
ketoacyl-CoA thiolase; TFP = trifunctional protein; VLCAD = very-long-chain acyl-CoA dehydrogenase.
Figure 1. Overview of fatty acid import and metabolism. Adapted from Walker WA, Goulet O, Kleinman RE,
Sherman PM, Shneider BL, Sanderson IR. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, and
Management. 4th ed. Hamilton, Ontario: BC Decker Inc;2004. Chapter 55-3.

C. The β-oxidation cycle is a 4-step cyclical process. Each turn of the β-oxidation cycle results in the
cleavage of two carbon fragments from the original LCFA in the form of acetyl-CoAs that are
then directed into ketone body synthesis
1. An important byproduct of the β-oxidation cycle is the production of electrons for the
electron transport chain
2. There are four major enzyme families responsible for each turn of the β-oxidation cycle
a. Acyl-CoA dehydrogenases
b. Enoyl-CoA hydratases
c. 3-Hydroxyacyl-CoA dehydrogenases
d. 3-Ketoacyl-CoA thiolases
3. Enzymes responsible for long-chain metabolism (e.g., VLCAD, LCHAD, LKAT) are
associated with the inner mitochondrial membrane
4. Enzymes responsible for short- and medium-chain metabolism (e.g., MCAD, SCAD,
MCHAD, SCHAD, MCKAT) are associated with the mitochondrial matrix
5. The rate-limiting step in the β-oxidation cycle is the first reaction catalyzed by the family
of acyl-coA dehydrogenases. Riboflavin (Vitamin B2) is a precursor to these enzymes
D. The following are the recognized defects in fatty acid oxidation:
1. Fatty acid transporter
2. Carnitine transporter
3. Carnitine palmitoyltransferase 1 (CPT1)
4. Carnitine-acylcarnitine translocase
5. Carnitine palmitoyltransferase 2 (CPT2)
6. Very long chain acyl-CoA dehydrogenase (VLCAD)
7. Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
8. Mitochondrial trifunctional protein
9. Medium chain acyl-CoA dehydrogenase (MCHAD)
10. Short chain acyl-CoA dehydrogenase (SCHAD)
11. Short chain 3-hydroxyacyl-CoA dehydrogenase (3 types)
12. Multiple acyl-CoA dehydrogenases
13. Riboflavin-responsive multiple acyl-CoA dehydrogenase
14. 2,4 Dienoyl-CoA reductase deficiency
15. HMG-CoA synthase
16. HMG-CoA lyase
II. Epidemiology/Genetics
A. Autosomal-recessive inheritance, with an incidence of approximately 1 in 10,000 and a
recurrence risk of 25% in subsequent pregnancies by the same couple
B. MCAD deficiency is the most common and best studied FAO disorder, with 1 point mutation
accounting for approximately 80% of cases
III. Clinical Features/Associations

A. In general, the more proximal the defect in the FAO pathway, the earlier the clinical presentation
and the more severe the clinical course
B. Most symptoms appear after a period of fasting and/or vomiting, typically associated with an
acute infection or illness
C. Hypoketotic hypoglycemia is a hallmark of most FAO disorders
D. Symptoms at presentation include vomiting, lethargy, apnea, seizures, encephalopathy and
respiratory arrest
E. May also presence with a metabolic crisis, cardiac arrhythmia, skeletal or muscle myopathy
F. Physical exam can be significant for marked hepatomegaly but NO splenomegaly, hypotonia, and
a gallop rhythm and poor perfusion if the heart is affected. Jaundice is rare
G. One-third of patients will have a family history significant for SIDS, Reye syndrome, sudden
cardiac decompensation, or early infant death due to acute liver failure or sepsis. An estimated
1%–5% of SIDS cases are due to an underlying FAO disorder
H. SCHAD and SCAD deficiencies allow for multiple turns of the β-oxidation cycle, which allows for
the formation of ketones
I. Several case of LCHAD, CACT and MCKAT have presented in acute liver failure, although this is
an overall uncommon presentation for FAO disorders
J. Some patients with SCAD deficiency may have persistent vomiting, gastroesophageal reflux and
failure to thrive. Mild types of MCAD and SCAD may have a cyclic vomiting syndrome–like
presentation
K. Several cases of LCHAD and CPTII deficiencies have been linked to repeated episodes of
pancreatitis
L. Pregnancy and FAO Disorders
1. Acute fatty liver of pregnancy (AFLP)
a. Disorder with significant morbidity and mortality in women during the third
trimester of pregnancy
b. Women typically present with nausea, vomiting and abdominal pain,
and quickly progress to fulminant hepatic failure with coagulopathy and
encephalopathy
c. Liver histology reveals microvesicular hepatic steatosis and mitochondrial
disruption
d. Management includes prompt delivery
2. HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome
a. Complication of preeclampsia that occurs in the third trimester
b. Better prognosis than AFLP
c. Liver histology reveals periportal hemorrhage and fibrin deposition
d. Management includes prompt delivery
3. There is a well-documented association between FAO disorders and complications, such
as AFLP and HELLP syndrome, particularly in those women carrying LCHAD-deficient
fetuses. A common mutation in G1528C has been found
a. Offspring of women who develop these third trimester complications should be
screened for this mutation
IV. Diagnosis
A. Urine organic acids and serum acylcarnitine profile have the best diagnostic yield
B. Labs significant for elevated ammonia, mild elevation in transaminases, normal or very mild
elevation in bilirubin, and mild to moderate increase in BUN, uric acid and CPK
C. Urinary ketones during a metabolic crisis may be useful
D. Serum free fatty acids and β-hydroxybutyrate (increased FFA concentrations in FAO disorders)
E. Tissue assays (liver, muscle, skin fibroblasts) to measure enzyme activity
V. Management/Treatment
A. Acute
1. Reverse hypoglycemia with dextrose infusions
2. Dextrose also raises insulin levels and inhibits FAO and lipolysis
3. Avoid drugs that inhibit FAO (e.g., valproic acid, NSAIDs, and salicylate) and drugs that
increase the release of FFA (e.g., epinephrine)
4. Avoid IV propofol, IV fat emulsions and parenteral nutrition
5. Carnitine (IV or enterally) if there is no vomiting or diarrhea, particularly for those with
a carnitine tranport defect
B. Chronic
1. AVOID fasting. A low-fat, high-carbohydrate diet is recommended. Overnight NG or
gastrostomy tube feeding may be helpful. These patients often need to be admitted if
they are going to be NPO for a prolonged period of time (e.g., prior to surgery)
2. High carbohydrate load prior to cold exposure or prolonged aerobic activity
3. MCT supplementation for long-chain defects
4. Daily carnitine supplementation (100 mg/kg/day) for those with carnitine
transport defects
5. Riboflavin supplementation (100 mg/day) for those with defects in the first step of the
β-oxidation cycle
C. Prognosis
1. Those who present in neonatal period have a poor prognosis, with a mortality rate as
high as 60% (even before diagnosis is made)
2. If diagnosis can be made early, then appropriate measures can be taken to prevent acute
episodes

Table1. Differential Diagnosis
Ammonia Metabolic Acidosis Anion Gap {Na- (Cl- Bicarb)} Ketones
Urea Cycle High No N/A N/A

Disorders
FAO Disorders High Yes Elevated Too Low
Organic High Yes Elevated Too High
Acidemias
Recommended Reading
Kelly DA, ed. Diseases of the Liver and Biliary System in Children. 3rd ed. Hoboken, NJ: Wiley-Blackwell;
2008: Chapter 5.
Treem WR. Inborn defects in mitochondrial fatty acid oxidation. In: Suchy F, Sokal E, Balistreri W, ed. Liver
Disease in Children. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:735-785.
Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR. Pediatric Gastrointestinal
Disease: Pathophysiology, Diagnosis, and Management. 4th ed. Hamilton, Ontario: BC Decker Inc; 2004:
Chapter 55-3.
2006: Chapter 60.
Liver Diseases—Urea Cycle
Defects
Maria E. Perez, DO
Carol Potter, MD
I. Ammonia/Hyperammonemia
A. Ammonia is a degradation product from amino acid metabolism. Some is reused, but most is
detoxified by the urea cycle and excreted as urea
B. Hyperammonemia is toxic to the immature nervous system, and repeated prolonged episodes of
elevated ammonia can lead to permanent neurologic impairment
C. Differential Diagnosis of Hyperammonemia
1. Urea cycle defects (elevated ammonia, NO metabolic acidosis)
2. Fatty acid oxidation disorders (elevated ammonia, + metabolic acidosis, elevated anion
gap, NO ketones in urine)
3. Organic acidemias (elevated ammonia, + metabolic acidosis, elevated anion gap,
ELEVATED ketones in urine)
4. Transient hyperammonemia of the newborn (rapid neurological deterioration right after
birth, possibly due to decreased hepatic blood flow)
5. Reye’s syndrome (also have hypoglycemia and coagulopathy)
6. Liver failure
7. Severe systemic illness
II. Pathogenesis/Epidemiology
A. The urea cycle converts ammonia into urea and produces arginine
B. 6 different enzymes involved
1. Carbamyl phosphate synthetase (CPS)
2. Ornithine transcarbamylase transferase (OTC)
3. Argininosuccinate synthetase (AS)—citrullinemia
4. Argininosuccinate lyase (AL)
5. Arginase
6. N-acetylglutamate synthetase
C. All urea cycle disorders are inherited in an autosomal-recessive pattern, except for OTC
deficiency, which is inherited in an X-linked dominant pattern
D. OTC deficiency is the most common urea cycle disorder
E. Urea cycle defects occur in 1 of every 25,000–30,000 newborns
Figure 1. The urea cycle and associated defects. Adapted

from Walker WA, Goulet O, Kleinman R, Sherman PM, Shnei-
der BL, Sanderson IR, eds. Pediatric Gastrointestinal Disease:
Pathophysiology, Diagnosis, & Management. 4th ed. Ham-
ilton, Ontario: BC Decker Inc; 2004: Chapter 55, section 2,
pages 1257-1274. 2004; Chapter 55, section 2, page 1282.

III. Clinical Features
A. Infants → rapid sepsis-like deterioration after protein feeds, food refusal, vomiting, tachypnea,
seizures, lethargy, coma
B. Older children → vomiting, neurological changes
IV. Diagnosis
A. Elevated ammonia levels
B. Citrulline level (low in OTC and CPS deficiencies, high in AS deficiency)
C. Elevation in transaminases and prothrombin time during acute exacerbations
D. Diagnosis is confirmed by the measurement of tissue enzyme activity
E. OTC deficiency
1. Expressed in liver and intestinal mucosa
2. Males have virtually absent enzyme activity
3. Females are heterozygous
V. Management/Treatment
A. REDUCE serum ammonia levels
1. Discontinue all protein intake and supply sufficient glucose (IV or orally) to
limit catabolism
2. Provide alternatives for nitrogen excretion
a. Sodium benzoate (1 mole of nitrogen excreted for each mole of
benzoate given)
b. Phenylbutyrate (2 moles of nitrogen excreted for each mole
of phenylbutyrate given)
B. Dietary
1. Protein restriction (<700 mg/kg/day)
2. Cyclinex® (free nonessential AA formula)
C. Arginine supplementation (except for those with arginase deficiency)
D. Citrulline supplementation (excretes additional nitrogen) for OTC and CPS deficiencies
E. Some may require anticonvulsants
F. Regular monitoring of serum ammonia and amino acids
G. Caution during periods of fasting, illness, infections, anesthesia, or surgery
H. Transplantation reserved for those with recurrent or poorly controlled hyperammonemia,
but does NOT correct existing neurological injury
VI. Outcomes
A. Duration of hyperammonemia is related to subsequent intellectual ability of the patient
B. Severity of hyperammonemia is NOT related to subsequent intellectual ability of the patient
Recommended Reading
Philadelphia, PA: Saunders Elsevier; 2010:Chapter 57.
Walker WA, Goulet O, Kleinman R, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal
Disease: Pathophysiology, Diagnosis, & Management. 4th ed. Hamilton, Ontario: BC Decker Inc; 2004.
2006:Chapter 61.
Liver Diseases—Alpha-1
Antitrypsin Deficiency
Michael Narkewicz, MD
I. Alpha-1 antitrypsin deficiency (α-1 ATD)

A. A common metabolic liver disease in childhood. The diagnosis should be considered in all adults
and children with chronic hepatitis or cirrhosis of unknown etiology and in infants with cho-
lestasis. Alpha-1 antitrypsin deficiency is associated with chronic liver disease in 10% of affected
adults and 10%–15% of affected children.
II. Genetics and Function

A. Alpha-1 antitrypsin (AT) deficiency is an autosomal co-dominant disorder affecting 1 in 1,800 live
births encoded by a gene on the long arm of chromosome 14 q31-32.2
B. PiMM (PI = protease inhibitor), the normal phenotype which is present in 95% of the population
and is associated with normal serum levels of α-1 AT
C. The Z α-1 AT protein is caused by a single nucleotide substitution (glu to lys). The gene is most
common in those of northern European descendants. PiZZ and PiSZ phenotypes are associated
with severe deficiency and liver disease, while the PiMZ phenotype leads to an intermediate
deficiency without liver disease
D. There are more than 100 allelic variants of AT. Not all variants are associated with clinical disease
E. Alpha-1 antitrypsin is an inhibitor of neutrophil proteases and elastases
III. Clinical Presentation

A. α-1 ATD predisposes children and adults to pulmonary and liver disease
B. Liver involvement is often first identified in the newborn period due to persistent cholestatic-
jaundice. Affected infants tend to be small for gestational age. The jaundice generally clears.
10%–15% of PiZZ individuals present with liver disease in the first years of life
C. 10%–30% of those presenting with neonatal liver disease develop moderate to severe liver
disease with coagulopathy, poor growth, portal hypertension and ascites in childhood
D. Serum aminotransferase levels, alkaline phopsphatase and gamma glutamyl transpeptidase may
all be elevated
E. Emphysema develops in 60%–70% of α-1 ATD adults over the age of 25 years with the peak in
the 4th and 5th decades
IV. Pathogenesis and Diagnosis

A. Liver disease is associated with retention of abnormally folded Z protein in the endoplasmic
reticulum of hepatocytes
B. Far fewer patients exhibit liver and lung disease associated with α-1 ATD than estimated by
population human genetic estimations, suggesting involvement of unidentified genetic and
environmental factors and modifier genes in the development of tissue damage
C. The pathogenesis of α-1 ATD associated liver disease is not completely understood, with several
possible theories proposed
1. Accumulation of mutant protein in the endoplasmic reticulum, resulting in
hepatotoxicity
2. Autophagy, a cellular mechanism for disposal of accumulated proteins has been
suggested to be defective in those with liver disease
3. Other inherited traits for protein degradation and environmental factors (viral hepatitis,
alcohol) may increase accumulation of the defective protein and result in increased liver
injury

D. α-1 ATD is associated with liver injury in other disease process. Several studies suggest that the
PiMZ state may predispose to more severe liver injury in other hepatic disorders (HBV, HCV,
alcoholic liver disease, cystic fibrosis and NAFLD)
E. Diagnosis is established by a serum α-1 antitrypsin phenotype (PI typing) or genotype
1. Serum levels are generally significantly decreased in affected patients; however,
α-1 antitrypsin is an acute phase reactant and could be falsely elevated. Serum
concentrations are rarely above 50–60 mg/dL in patients with PiZZ phenotype
2. Liver histology demonstrates periodic acid-Schiff positive diastase-resistant globules in
the endoplasmic reticulum of periportal hepatocytes, but should not be used for
diagnosis, as some patients with PIMZ have this histology as well and this finding can
be absent in young infants
V. Treatment and Screening

A. There are no specific therapies for α-1 ATD–associated liver disease
B. Infants with cholestasis may benefit from fat-soluble vitamin supplements (vitamins A, D, E and
K) and infant formula containing medium-chain triglyceride oil. In addition, ursodeoxycholic acid
may increase bile flow and reduce liver injury associated with cholestasis, although there is no
evidence of direct long-term benefit
C. Avoidance of cigarette smoking (including secondhand smoke) and environmental pollution
exposure is mandatory in order to slow the progression of lung disease
D. Orthotopic liver transplantation (OLT) is the treatment for α-1 ATD–associated end-stage liver
disease and liver failure. The recipient assumes the donor PI phenotype and is no longer at risk
for emphysema
E. Screening is recommended for all relatives of patients with α-1 ATD to identify PiZZ or PiSZ family
members and is mandatory for siblings of affected patients. Newborn screening has not been
instituted
Recommended Reading
Bals R. Alpha-1-antitrypsin deficiency. Best Pract Res Clin Gastroenterology. 2010;24(5):629-633.
Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol.
2008;103(8):2136-2142.
Pietroangelo A. Inherited metabolic disease of the liver. Curr Opin Gastroenterol. 2009;25(3):209-214.
Liver Diseases—Wilson Disease
Isabel Rojas, MD
Degenerative disease of the central nervous system associated with cirrhosis due to copper toxicity. Clinical
manifestations vary between affected individuals, even within affected families. Children typically present
with hepatic disease and neurologic disease is seen in later onset.
I. Overview
A. Also known as hepatolenticular degeneration
B. Rare autosomal-recessive disease of copper metabolism with a prevalence of 1:30,000
C. Abnormal gene (ATP7B) found in chromosome 13, encodes for a P-type ATPase expressed mainly
in hepatocytes, which transports copper into bile and incorporates it into ceruloplasmin. Absent
or reduced function of this protein leads to decreased hepatocellular excretion of copper into bile
resulting in copper accumulation in the liver and decreased ceruloplasmin
D. As liver copper levels increase, it is released in the circulation and deposits in other organs, brain,
kidneys and cornea
II. Clinical Features

A. Usually manifests as liver disease in children and teenagers; and as neuropsychiatric illness
in adults
B. Classic 3 criteria: liver disease, decreased ceruloplasmin and Kaiser-Fleischer rings
C. Hepatic manifestations:
1. Can be highly variable from asymptomatic with abnormal laboratories to acute
liver failure
2. Patients may present with hepatomegaly, signs of chronic liver disease and cirrhosis,
splenomegaly, acute liver failure with Coombs-negative hemolytic anemia, coagulopathy
unresponsive to parenteral vitamin K, gallstones, or histological findings of steatosis
3. May be indistinguishable from autoimmune hepatitis. Patients with apparent autoim-
mune hepatitis that do not respond to therapy should be assessed for Wilson disease,
because elevated serum immunoglobulins and nonspecific antibodies may be found in
both conditions
D. Neurological manifestations:
1. Usually onset 10–30 years of age
2. Mainly affects the motor system, include changes in behavior, deterioration of school-
work and handwriting, or inability to perform activities requiring good hand-eye coordi-
nation, tremor, lack of motor coordination, drooling, dysarthria, dystonia and spasticity.
Due to pseudobulbar palsy, dysphagia may occur with risk of aspiration
3. Other behavioral changes include depression, anxiety and even frank psychosis
4. Sensory function and intelligence remain normal
E. Other manifestations: aminoaciduria and nephrolithiasis, skeletal abnormalities such as prema-
ture osteoporosis, spontaneous fractures, and arthritis, cardiomyopathy, EKG abnormalities,
pancreatitis, hypoparathyroidism, and infertility or repeated miscarriages
F. Kaiser-Fleischer rings:
1. Represent deposition of copper in Deçemet’s membrane of the cornea. It is seen only
under slit-lamp examination
2. Present in 50% of patients with liver disease and 95% of patients with neurologi-
cal symptoms, but usually absent in children. Other eye manifestations are sunflower
cataracts; represent deposits of copper in the lens. Both lesions usually disappear with
treatment, if reappearance it suggests noncompliance with therapy

III. Diagnosis
A. Combination of clinical findings and biochemical testing
B. Laboratory findings:
1. Aminotransferases are generally abnormal.
2. Ceruloplasmin is usually low (<20 mg/dL) but can be normal or mildly elevated, since it is
an acute phase reactant
3. Serum copper: usually decreased or normal, elevated in acute liver failure
4. Urinary copper excretion in 24 hours: >100 g, useful in diagnosis and monitoring of
treatment
C. Hepatic copper concentration >250 g/g dry weight: it is the best biochemical evidence for Wilson
Disease
D. Liver biopsy:
1. Mild steatosis, glycogenated nuclei in hepatocytes and focal hepatocellular necrosis
2. May have findings similar to autoimmune hepatitis
3. With progression of the disease fibrosis and cirrhosis occur. Apoptosis of hepatocytes is
a prominent feature with acute liver disease
4. Electron microscopy reveals mitochondria of varying shapes and size with increased
density of the matrix material, and numerous inclusions, including lipid and fine granular
material that may correspond to copper. Increased intracristal space with dilatation of
the tips of the cristae, creating a cystic appearance in absence of cholestasis, is consid-
ered pathognomonic of WD
E. Brain radiological studies: CT or MRI show abnormalities in the basal ganglia
F. Genetic studies: molecular testing looking for haplotypes or polymorphisms of ATP7B gene.
Useful in identifying affected first degree relatives.
IV. Treatment
A. Chelating agents:
1. D-penicillamine
a. Chelates copper and induces cupruria
b. Needs supplementation with pyridoxine
c. Side effects include fever, skin rash, lupus, lymphadenopathy, thrombocytopenia
and nephrotoxicity
2. Trientine
a. Chelates copper and induces cupruria
b. Safe during pregnancy
3. Tetrathiomolybdate
a. Blocks copper absorption
B. Zinc:
1. Interferes with the uptake of copper from the gastrointestinal tract and induces
enterocyte metallothionein that is an endogenous chelator
2. It could be used alone or with a chelating agent
C. Antioxidants: Vitamin E may have a role in the treatment of WD
D. Dietary avoidance of food with high copper content:
1. Shellfish, nuts, chocolate, mushrooms and organ meats
E. Liver transplant:
1. Patients with fulminant liver failure, decompensated liver disease unresponsive to
treatment, and patients with progressive neurological disease will benefit from liver
transplantation
V. Monitoring
A. Serum copper and ceruloplasmin, hepatic transaminases, PT/INR, CBC, urinalysis and physical
exam should be done at least every 6 months, especially for those on chelating therapy
B. A 24-hour urinary excretion of copper should be done at least once a year to monitor response
and compliance with treatment
VI. Screening
A. Asymptomatic siblings and other first-degree relatives should be screened for the disease after
age 3 or 4 years unless symptomatic before
1. History and physical examination, slit lamp examination, serum ceruloplasmin and
copper concentration, hepatic transaminases and 24-hour urinary copper excretion
should be performed
2. Liver biopsy is needed to confirm diagnosis
3. Alternative noninvasive approach is the genetic testing
Recommended Reading
AASLD Practice Guidelines for Wilson’s Disease. Hepatology. 2008;47:6.
Suchy F, Sokal E, Balistreri W, ed. Liver Disease in Children. 3rd ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2007.

6N-9. Metabolic/Genetic Liver
Diseases—Peroxisomal Disorders
Lynette Gillis, MD
I. Functions of peroxisomes include:

A. Beta-oxidation of very long-chain fatty acids (VLCFA) and related substances
B. Alpha-oxidation of 3-methyl fatty acids (e.g., phytanic acid)
C. Biosynthesis of etherlipids, isoprenoids, cholesterol and bile acids
II. General clinical features of peroxisomal disorder:

A. Neurological – encephalopathy, hypotonia, seizures, deafness
B. Skeletal – short limbs, calcific stippling, craniofacial abnormalities
C. Ocular – retinopathy, cataract, blindness
D. Hepatic – neonatal hepatitis, hepatomegaly, cholestasis, cirrhosis
E. Lab testing includes:
1. LFTs: abnormal ALT/AST with normal or elevated bilirubin
2. Serum cholesterol: normal or low (in setting of cholestasis)
3. Serum VLCFA: increased (C26 et al) with abnormal beta-oxidation of VLCFAs
4. Serum pristanic acid: increased in disorders of beta-oxidation of VLCFAs
5. Serum phytanic acid: increased in disorders of perixosome biogenesis, Refsum disease
6. Erythrocyte plasmalogens: decreased in disorders of ether lipid biosynthesis
7. Bile acid intermediates (urine/serum): abnormal intermediates
III. Zellweger syndrome (cerebro-hepato-renal syndrome): autosomal recessive

A. Clinical presentation:
1. Usually identified as newborns with hypotonia, feed poorly, distinct facies (wide
fontanelle, prominent forehead, midface hypoplasia, epicanthal folds), seizures and
hepatic dysfunction.
2. Older children: retinal dystrophy, sensorineural hearing loss, developmental delay with
hypotonia and liver dysfunction
3. Characteristic bony stippling (chondrodysplasia punctata) of the patella(e) and other
long bones may occur
4. Usually fatal in the first 2 years of life
B. Liver has decreased production of normal bile acids and increase in abnormal di- and trihydroxy
bile acids
C. Liver ultrastructure reveals absence of peroxisomes, usually overall intact pericanalicular tight
junctions with focal loss of integrity of pericanalicular tight junctions with dilation of the lateral
spaces
D. Diagnosis
1. Elevated plasma very-long-chain fatty acid (VLCFA) levels
2. Increased concentrations of phytanic acid, pristanic acid, and pipecolic acid in plasma
and fibroblasts
3. Reduced erythrocyte concentration of plasmalogen
4. Mutations in 12 different PEX genes that encode peroxins (proteins required for normal
peroxisome assembly) identified.
a. Mutations in PEX1, the most common.
b. Sequence analysis is available clinically for the following twelve genes: PEX1,
PXMP3 (PEX2), PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19
and PEX26
E. Management
1. Symptomatic therapy may include gastrostomy to provide adequate calories,
vitamin supplementation, reduce exposure to phytanic acid and genetic counseling is
very important

IV. Neonatal Adrenoleukodystrophy and Refsum Disease
A. Most have mutations in either the PEX1 or PEX6 genes that encode ATPases needed to import
protein into peroxisomes.
B. Clinical courses are variable and may include developmental delays, hearing loss, vision
impairment, liver dysfunction, episodes of hemorrhage and intracranial bleeding.
1. Slowly progressive.
C. Liver disease is usually mild or absent
D. Neonatal Adrenoleukodystrophy
1. Mid-face hypoplasia, adrenal insufficiency, behavioral problems
2. Neurologic features include weakness, hypotonia, seizures, progressive visual and
auditory dysfunction
3. Labs—same biochemical abnormalities as seen in Zellweger syndrome
4. Most children die by 5 years
E. Refsum Disease
1. Least severe presentation: typically at 1–6 months with dysmorphic features, hypotonia,
visual and auditory abnormalities, retinitis pigmentosa, polyneuropathy, cerebellar ataxia,
deafness, anosomia, ichthyosis, skeletal and cardiac symptoms, normal IQ
2. May not be diagnosed until later in life because of very mild features
3. May present with vomiting, diarrhea and malabsorption
4. Labs—same biochemical abnormalities as seen in Zellweger syndrome
V. Rhizomelic Chondrodysplasia Punctata

A. Clinical presentation includes proximal limb shortening, abnormal facies, small stature, micro-
cephaly, contractures, spasticity, cataracts, ichthyosis
B. Diagnosis: decreased plasmalogens, increased phytanic acid, decreased pristanic acid
C. Therapy: restrict phytanic acid (benefit in some)
VI. α-Methyl-acyl-CoA Racemase Deficiency

A. Clinical presentation includes diarrhea, liver disease, retinitis pigmentosa,
polyneuropathy, epilepsy
B. Diagnosis: elevated bile acid intermediates, elevated pristanic acid
C. Therapy: substitution of bile acids
Recommended Reading
Cappa M, Bizzarri C, Vollono C, Petroni A, Banni S. Endocr Dev. 2011;20:149-60. Epub 2010 Dec 16. Adre-
noleukodystrophy.
Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism.

Van Veldhoven PP. J Lipid Res. 2010 Oct;51(10):2863-95. Epub 2010 Jun 17. Review.
Fidaleo, M. Exp Toxicol Pathol. 2010 Nov;62(6):615-25. Epub 2009 Sep 9. Peroxisomes and peroxisomal disor-
ders: the main facts.
6N-10. Metabolic/Genetic Liver
Diseases—Familial Hepatocellular
Cholestatic Disorders
Karan McBride Emerick, MD
I. Progressive Familial Intrahepatic Cholestasis

A. Epidemiology and Pathogenesis
1. Progresssive Familial Intrahepatic Cholestasis (PFIC) was initially described as a clinical di-
agnosis based on the presence of hepatocellular cholestasis, low serum levels of gamma-
glutamyl transferase (GGT) activity and autosomal-recessive inheritance recognized in an
Amish kindred of Jacob Byler (known as Byler’s disease)
2. Subsequently, patients were clinically divided into two distinct subtypes: low GGT-PFIC
(PFIC-1 and PFIC-2) and high GGT-PFIC (PFIC-3)
B. PFIC has now become five separate diseases with specific gene defects and distinct clinical pro-
files. The specific genes involved in all subtypes of PFIC code for various bile canalicular trans-
porters involved in bile export. We now identify the diseases by their gene defect, i.e., PFIC-1 as
FIC1 disease (Table 1)
Table 1. Gene Defects

GGT Gene Locus Defect
PFIC-1 normal ATP8B1 18q21-22 ATP-dependent amino-phospholipid
BRIC-1 FIC1 transport
PFIC-2 normal ABCB11 2q24 ATP-dependent
BRIC-2 BSEP bile-acid transporter
PFIC-3 high ABCB4 7q21 ATP-dependent translocation of
MDR3 phosphatidylcholine
C. Clinical Features
1. There are many clinical similarities between the PFIC diseases. They are characterized by:
a. Chronic cholestasis in early childhood which usually progresses to cirrhosis
within the first decade of life. The average age at onset is 3 months
1) Pruritus is the dominant feature of cholestasis in the majority
of patients
b. Growth failure, with more than 95% of patients having short stature (<5%),
though their weight for height is often normal, giving a stocky appearance
c. Recurrent epistaxis in the absence of thrombocytopenia or coagulopathy and
perennial asthma-like disease are common problems
d. These patients do not have xanthomas
e. These patients have severe fat-soluble vitamin deficiency
f. All have near normal serum cholesterol but markedly elevated levels of serum
bile acids. Serum concentrations of alkaline phosphatase, aminotransferases,
bilirubin and bile salts are similar to that seen in seen in several other cholestatic
disorders
g. Hepatocellular and canalicular cholestasis with pseudoacinar transformation are
the most uniform histologic findings. Giant cell transformation and ballooned
hepatocytes are present. Portal to central bridging then develops in association
with lacy lobular fibrosis, and eventually leads to cirrhosis

D. Differences Between the PFIC Diseases
1. The laboratory findings in PFIC 1 and 2 are remarkable for the presence of low GGT,
whereas, in PFIC-3, the GGT levels are considerably elevated
2. Examination with electron microscopy shows subtle differences between PFIC-1 and
PFIC-2. Samples from patients with PFIC-1 show the retention of coarsely granular bile,
so called Byler’s bile, in canalicular spaces and canalicular cholestasis, whereas PFIC-2
patients have amorphous or finely filamentous bile and neonatal hepatitis
3. Patients with PFIC-1 are more likely to have associated watery diarrhea, some of which is
very severe
E. PFIC-1: FIC1 Disease
1. The gene for PFIC-1 (Byler’s disease) is FIC-1 and codes for an ATP-binding cassette
(ABC), which functions in flipping a phosphatidylcholine molecule from the inner plasma
membrane to the outer
a. The FIC-1 gene is present in liver, pancreas, intestine and lungs. Therefore,
mutations in this gene lead to multisystemic disease
2. FIC-1 disease is therefore associated with progressive liver disease as well as intractable
diarrhea, recurrent pancreatitis and, in some cases, hearing loss. Clinically, FIC-1 disease
appears to have a later onset and slower course than the other two forms of PFIC
F. PFIC-2: BSEP Disease
1. PFIC-2 is caused by a defect in a gene named FIC-2, located at 2q24. The FIC-2 gene is
an ABC bile salt transporter also called the bile salt export pump (BSEP)
a. Lack of staining for BSEP protein by immunohistochemistry in the liver tissue
from patients with gene defects in FIC-2 suggests that in the majority of PFIC-2
patients the gene defect is severe enough to produce no product/protein that
can be inserted into the canalicular membrane
2. BSEP disease has been associated with cholangiocarcinoma and hepatocellular
carcinoma in young children
G. PFIC-3 Multidrug Resistance gene-3 Deficient (MDR-3[-]) Disease
1. Patients with high serum GGT and familial intrahepatic cholestasis fit the category of
so-called high GGT PFIC. PFIC-3 is due to mutations in an export pump of the ABC
transporter family called multidrug resistance 3 (MDR-3) that is expressed on the
canalicular membrane
a. The MDR3 gene has been mapped to 7q21. It functions in the translocation
of phosphatidylcholine across the canalicular membrane and therefore in the
excretion of phospholipid into bile
b. The mechanism of damage in MDR3 disease is likely to be due to the absence
of phospholipid in bile, which then destabilize micelles and promotes lithogenic
bile with crystallized cholesterol. This lithogenic bile could produce the picture
of small bile duct obstruction
2. Liver biopsies show expanded portal areas with proliferation of interlobular bile ducts
plugged with bile, suggesting an obstructive disorder rather than a primary defect in bile
formation
3. These patients have aggressive disease that progresses toward hepatic failure in the first
few years of life
H. Benign Recurrent Intrahepatic Cholestasis (BRIC)
1. The condition benign recurrent cholestasis presents very similarly to PFIC with cholesta-
sis, pruritus, low GGT and high serum bile acids. However, the hallmark of this condition
is intermittent episodes of cholestasis, without progression to liver failure and later onset
than PFIC
2. Patients are totally asymptomatic, both clinically and biochemically in between the
episodes of cholestasis
3. BRIC shares the same locus with PFIC-1 (ATP8B1 mutation) and 2 (ABCB11 [BSEP]) but
the mutations cause only partially impaired protein synthesis
4. The cholestasis episodes have been treated by temporary biliary diversion using
nasobiliary tube drainage of bile during the episode with some success in relieving
the pruritus
I. Management/Treatment
1. Without intervention, PFIC is a progressive disease which results in cirrhosis. The disease
does not typically respond to medical therapy, although ursodeoxycholic acid (20–30
mg/kg/day), is recommended in all forms of PFIC to enhance bile flow
2. Supplemental fat-soluble vitamins treatment is required to prevent deficiencies
3. A surgical treatment, biliary diversion, in which bile salts are diverted from the
enterohepatic recirculation, may relieve pruritus and slow the progression of the
disease. The diversion may be performed in two ways
a. The first is called an ileal diversion, in which the small intestine is divided above
the terminal ileum and reconnected to the proximal intestine at the cecum,
thereby bypassing the receptors for bile acid reabsorption
b. The second is called a partial external biliary diversion (PEBD), in which gallblad-
der bile is diverted out of the body by way of a conduit, fashioned from small
intestine, connecting the gallbladder to the skin
c. The end result of both procedures is a diversion of bile salts, with liver disease
that improves in the majority of patients
4. Liver transplantation is indicated in patients with decompensated cirrhosis or failed
diversion with mutilating pruritus
II. Alagille Syndrome

1. Alagille syndrome (AGS) or arteriohepatic dysplasia, is an autosomal-dominant disorder
2. The traditional clinical diagnosis of AGS follows the guidelines of bile duct paucity plus
3 of 5 clinical criteria including cholestasis, cardiac murmur or heart disease, skeletal
anomalies, ocular findings and characteristic facial features
3. Anomalies of the vascular system and abnormalities of the kidney and pancreas are also
present in a significant number of AGS patients
4. The incidence of AGS believed to be at least 1:70,000 live births
5. Mutations in the JAG1 gene, which encodes a ligand in the Notch signaling pathway,
cause AGS. JAG1 and the Notch signaling pathway are crucial for the development of
the liver, bile ducts, heart, vasculature, kidneys and other organs affected in this
multisystem disorder
a. JAG1 mutations can be identified in up to 94% of patients who meet clini-
cal criteria for AGS, 60% of which are de novo. The majority of the mutations
(72%) are protein-truncating
b. No genotype-phenotype correlation has been identified in AGS. There is
tremendously clinical variability in individuals carrying the same JAG1 mutations
6. NOTCH2 mutations have also been identified in a small group of JAG1-negative
individuals
1. Hepatic manifestations of AGS
a. Neonatal cholestasis is the most common clinical presentation of AGS
1) Liver biopsy may be nondiagnostic in the neonatal period, due to
evolution of bile duct paucity over time
b. The chronic cholestatic liver disease in AGS causes significant pruritus,
malabsorption and xanthomas
c. Cholesterol levels may rise to the thousands, with the appearance of skin
xanthomas at levels >500 mg/dL
d. The pruritus in AGS can be extremely severe, interrupting sleep and daily
activities, and may require multiple medical interventions or may respond to
biliary diversion
e. A minority of AGS patients develops progressive liver disease leading to cirrhosis
and portal hypertension.
1) It is estimated that 20%–40% of AGS patients will eventually require
liver transplantation

2. Cardiac manifestations
a. Cardiac murmurs occur in 85%–98% of affected individuals
1) The most common abnormality is stenosis at some level in the
pulmonary arterial tree
b. Up to 24% of patients may have structural heart disease, such as tetralogy of
Fallot or ventricular septal defects
c. Mortality is dramatically higher in the group with structural heart disease
compared to those without, with a predicted 20-year survival of only 40%
3. Skeletal manifestations
a. Vertebral arch defects, the typical finding of butterfly vertebrae, is one of the
least common features
b. Other minor skeletal abnormalities identified in AGS patients include a
decreased interpedicular distance in the lumbar spine, and shortened distal
phalanges in the hands
c. Risk of recurrent and poorly healing bone fractures in AGS patients is a
significant source of morbidity in this population, and may be an indication for
liver transplantation in severe cases
4. Ocular manifestations
a. The most common ocular features of AGS are deepset hyperteloric eyes and
bilateral posterior embryotoxon
b. Posterior embryotoxon is thought to represent a prominent thickened or
hypertrophied Schwalbe’s line that is anteriorly displaced, visible through a
clear cornea as a sharply defined, concentric white line or opacity anterior to
the limbus
1) Found in 90%–95% of patients with AGS, it is also found in parents
of patients with AGS and in the normal population at a frequency
between 8%–15%
5. Facial features
a. Characteristic facial features are a highly penetrant manifestation of Alagille
syndrome, identified in 70%–98% of patients
b. During childhood, the facies are typically described as triangular, with a broad
forehead, deeply set eyes, a pointed chin and a straight nose with a bulbous tip
c. In adulthood, the facial appearance becomes less triangular, and the chin
becomes more angular and prominent
6. Renal involvement in AGS
a. Renal anomalies occur in 40%–50% of AGS patients, and renal involvement is
now considered one of the major criteria for the diagnosis
b. Structural abnormalities include solitary kidney, ectopic kidney, bifid renal pelvis
and multicystic or dysplastic kidneys
c. Functional abnormalities include renal tubular acidosis, neonatal renal
insufficiency, nephronophthisis, lipidosis of the glomeruli and tubulointerstitial
nephropathy
7. Vascular involvement in AGS

a. Vascular anomalies in AGS involve the aorta, renal arteries and cerebral vessels
b. Intracranial vessel aneurysms, internal carotid artery aneurysms and moyamoya
disease occur in up to 9% of AGS patients studied
1) Intracranial bleeding is a major cause of morbidity and mortality in the
AGS population, accounting for 25% of the overall mortality
8. Growth
a. Growth failure is multifactorial in etiology, including a genetic contribution,
chronic cholestasis, fat malabsorption, congenital heart disease and limited
oral intake
C. Management/Treatment
1. Adequate nutrition is crucial: a high-calorie diet with a high proportion of fat from medi-
um-chain triglycerides is recommended in the neonatal period
2. Ursodeoxycholic acid (20 mg/kg/day), is recommended to enhance bile flow
3. Supplemental fat-soluble vitamins treatment is required to prevent deficiencies
4. Biliary diversion may relieve pruritus and slow the progression of the disease
5. Liver transplantation is indicated in patients with decompensated cirrhosis or failed
diversion with mutilating pruritus
Recommended Reading
Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of heredi-
tary cholestasis. Nat Genet. 1998;18(3):219-224.
de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic
cholestasis. Proc Natl Acad Sci U S A. 1998;95(1):282-287.
Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92
patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829.
Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients
with progressive familial intrahepatic cholestasis. Gastroenterology. 1999;117(6):1370-1379.
Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of
morbidity and mortality. Circulation. 2004;109(11):1354-1358.
Keitel V, Burdelski M, Warskulat U, et al. Expression and localization of hepatobiliary transport proteins in
progressive familial intrahepatic cholestasis. Hepatology. 2005;41(5):1160-1172.
Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome:
a study of 163 patients. Gut 2001;49(3):431-5.
Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in pro-
gressive familial intrahepatic cholestasis. Nat Genet. 1998;20(3):233-238.
Whitington PF, Freese DK, Alonso EM, Schwarzenberg SJ, Sharp HL. Clinical and biochemical findings in pro-
gressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 1994;18(2):134-141.

6O-1. Other Acquired Liver
Diseases—Reye Syndrome
Vi Lier Goh, MD
Vince F. Biank, MD
I. Reye’s syndrome is an extremely rare, acute syndrome resulting in hepatic dysfunction and encephalopa-
thy. The incidence is decreasing.
1. Typically occurs in the fall and winter, concurrent with influenza season
2. Affects children at peak ages of 5–15 years
3. Symptoms develop several days after the onset of a viral infection (influenza A/B
or varicella)
a. There is a strong association between use of aspirin during these illnesses and
development of Reye syndrome
4. Postulated to be a secondary mitochondrial hepatopathy, due to injury from a virus or
drug that results in an acquired abnormality of mitochondrial respiration
5. The incidence of Reye syndrome has decreased dramatically following aggressive public
education warning against salicylate use in children
1. Affected children appear to be recovering from a viral illness and then develop persistent
vomiting along with irritability and listlessness
a. Encephalopathy progresses with evidence of cerebral edema
1) Direct involvement of CNS mitochondria may be responsible
for encephalopathy
b. Hepatic dysfunction is universal if vomiting is present
1) Markedly elevated aminotransferases, serum ammonia, but
normal bilirubin
2) Variable hypoglycemia
3) Mild to moderate prolonged prothrombin time
c. Liver biopsy
1) Microvesicular steatosis without concurrent hepatic inflammation
or necrosis
2) On electron microscopy: characteristic swelling and pleomorphism
of mitochondria
d. Liver makes full recovery despite progressive and sometimes fatal
cerebral edema
C. Management
1. High mortality rate due to risk of cerebral herniation
a. Management aimed at controlling cerebral edema while maintaining cerebral
perfusion pressure, in a manner similar to patients with acute liver failure
2. High morbidity rate if disorder is unrecognized and appropriate management is not
initiated promptly
II. Reye Syndrome vs Fatty Acid Oxidation Defects

A. Some patients diagnosed with Reye syndrome actually have a fatty acid oxidation defect (FAO),
a primary mitochondrial hepatopathy
1. The most commonly diagnosed FAO defects associated with Reye syndrome are medium
and long-chain acyl coenzyme A dehydrogenase deficiencies
2. All children diagnosed with Reye syndrome should be evaluated for FAO defects. Clinical
clues may include:
a. Recurrent Reye, family history of Reye or SIDS, or age <2 years
b. Viral prodrome and vomiting universal in Reye and less common in
FAO defects
c. Low carnitine levels in FAO defects, not in Reye
3. Histologically may appear similar, but electron microscopy will be different

Recommended Reading
Gosalakkal J. Reye Syndrome and Reye-like Syndrome. Pediatr Neurol. 2008;39:198-200.
Pugliese A. Reye’s and Reye’s-like syndrome. Cell Biochem Funct. 2008; 26:741-746.
Sokol RJ. Mitochondrial Hepatopathies. In: Suchy FJ, Sokol RJ, Balisteri WF, eds. Liver disease in Children. 3rd
ed. New York, NY: Cambridge University Press;2007: 816-817.
6O-2. Other Acquired Liver
Diseases—Drug-induced
Liver Injury
Henry C. Lin, MD
Adam Davis, MD
Drug-induced liver injury is rare in children. Of all drug-related deaths, only 1/6 are due to acute liver failure.
Antiepileptic and antineoplastic drugs are the most likely drugs to cause liver injury.
I. Hepatic Drug Metabolism

A. Phase I → Activation: creates unstable and reactive metabolite, generally polar
1. Cytochrome P450 enzymes perform most of phase I reactions
2. Cytochrome P450 are monoxygenases, inducible and have overlapping substrate
specificity
3. Cytochromes P450 in the 1A, 2B, 2C, 2D, 2E and 3A subfamilies are important in
human drug metabolism
B. Phase II → Detoxification: transforms a hydrophobic chemical to a hydrophilic one for excretion
in urine or bile
1. Phase II enzymes include sulfotransferases, glucuronosyltransferases, epoxide hydrolase,
acetyltransferases and glutathione S-transferases
C. Polymorphisms in above enzymes can make individuals rapid or poor metabolizers
II. Classification of Drug-induced Liver Injury into three Types

A. Intrinsic hepatotoxins: true poison, causes predictable injury in all persons in dose-dependent
fashion
B. Contingent hepatoxins: causes hepatotoxicity in susceptible individuals under unfavorable
conditions (genetic or acquired)
C. Immunoallergic responses: this includes drug hypersensitivity reaction, hepatic granulomatosis,
autoantibodies and chronic active hepatitis
III. Overview of Drug Hepatotoxicity/Epidemiology

A. Drug induced liver disease is rare in children
1. Accounts for ~10% of acute hepatitis
B. Most drug-induced liver disease is cytotoxic and targets hepatocytes
1. Zonal hepatocellular necrosis suggests that toxic metabolites are involved in the
pathogenesis of the hepatotoxicity
a. Hepatocytes in zone 3 of the Rappaport acinus have the highest concentration
of cytochromes P450
C. Classification of drug hepatotoxicity by duration (classical 1993 definition)
1. Hyperacute <7 days
2. Acute 8–28
3. Subacute 4–12 weeks
4. Chronic >12 weeks
D. Drug hepatotoxicity by clinical features (3 clinical and 2 systemic syndromes)
1. Hepatic → elevated AST/ALT, symptoms of hepatitis
2. Cholestatic → elevated bilirubin/GGT, jaundice
3. Mixed → hepatic and cholestatic symptoms
4. Drug hypersensitivity syndrome → fever, lymphadenopathy, eosinophilia, atypical
lymphocytosis, inflammation of organ systems (Stevens–Johnson syndrome,
renal dysfunction)
5. Chronic active hepatitis → subacute or chronic course with fatigue, anorexia, presence
of nonspecific autoantibodies, elevated serum immunoglobulin G, and variable systemic
changes (rash, arthralgias)
IV. Selected Drugs Associated With Liver Injury
A. Acetaminophen
1. Leading drug-related cause of acute liver failure
2. Doses > 350 mg/kg likely to develop severe liver toxicity
a. Acute Ingestion → Minimum toxic dose 150 mg/kg or >12 g in 24 hours
b. Chronic Ingestion → Minimum toxic 150–175 mg/kg over 2–4 days
3. Histopathology
a. Hepatocellular necrosis in a zonal, centrilobular pattern with minimal
inflammatory infiltrate
4. Clinical Course
a. Stage 1 (<24 hours): nausea, vomiting, diaphoresis, pallor, lethargy followed by
an asymptomatic interval
b. Stage 2 (24–72 hours): jaundice, abnormal transaminases, coagulopathy
c. Stage 3 (72–96 hours): peak LFT abnormalities, can progress to hepatic failure
d. Stage 4 (4–14 days): recovery phase → resolution of symptoms and labs
5. Treatment
a. N-acetylcystine → acts by providing substrate to make more glutathione to
minimize toxic intermediate of acetaminophen
1) Most effective if given within 10 hours of ingestion
2) Two regimens → 72-hour regimen of oral vs 20-hour intravenous
b. Good prognosis if after 48 hours of treatment, PT and LFTs are all normal
B. Antiepileptic Drugs
1. Usually presents with hepatitis with a drug hypersentivity reaction
a. Primarily with phenobarbital, phenytoin, carbamazepine
2. Phenobarbital
a. Can lead to fulminant hepatitis characterized by jaundice within 8 weeks of
starting medication, generalized rash, fever and eosinophilia
3. Phenytoin
a. Fever, rash, lymphadenopathy, eosinophilia, atypical lymphocytosis
b. Histopathology → spotty necrosis of hepatocytes, cholestasis in severe cases,
occasional granulomas
c. Treat with corticosteroids in severe cases
4. Carbamazepine
a. Hepatotoxicity is rare
1) Children → hepatitis with drug hypersensitivity reaction
2) Adults → can see ductopenia
5. Valproic Acid
a. Two different types of hepatotoxicity
1) Dose-responsive effect that resolves with stopping drug
2) Progressive liver failure that starts with hepatitis-like prodrome
a) Malaise, anorexia, nausea, vomiting
3) Can lead to coagulopathy and hypoglycemia (sign of poor prognosis)
b. Histopathology → hepatocellular necrosis, microvesicular fat
C. Anti-neoplastic Drugs
1. Commonly see asymptomatic elevation of aminotransferases with no other evidence
of severe liver toxicity
a. Drugs: 6-mercaptopurine, cis-platinum, cytosine arabinoside,
dacarbazine, nitrosoureas
2. Veno-occlusive disease
a. Acute onset of tender hepatomegaly, ascites, jaundice, elevated transaminases
b. Drugs: 6-thioguanine, busulfan, cytosine arabinoside, dactinomycin,
dacarbazine
3. L-asparaginase
a. Associated with severe steatosis, fibrosis, hepatocellular necrosis
D. Immunosuppressant Drugs
1. Azathioprine
a. Histopathology → centrilobular hepatocyte ballooning, canalicular cholestasis,
endothelial cell damage
2. Methotrexate
a. Histopathology → hepatic (periportal) fibrosis, macrovesicular steatosis
E. Antibiotics
1. Tetracyclines (minocycline)
a. Histopathology → features of chronic active hepatitis
1) Chronic inflammatory cell infiltrate (plasma cells), interface hepatitis,
bridging necrosis and fibrosis
b. Clinical course can lead to hepatic failure without discontinuation of drug
1) Can result in autoimmune hepatitis and may need treatment
V. Other Patterns of Injury

A. Steatohepatitis
1. Steatosis, lobular inflammation, fibrosis, hepatocellular ballooning
2. Drugs: amiodarone, irinotecan
B. Hepatic vein thrombosis
1. Presents clinically as Budd-Chiari syndrome
2. Drugs: oral contraceptives, dacarbazine
C. Granulomatous hepatitis
1. Present in portal tracts or parenchyma, lack of necrosis
2. Drugs: isoniazid, penicillin, phenytoin, diazepam, carbamazepime
D. Stellate cell lipidosis
1. Hepatic stellate cells are modified fibroblasts that store lipids and vitamin A
2. Drugs: retinoids (isotretinoin, etretinate) → due to hypervitaminosis A
E. Ground glass cytoplasmic inclusions
1. Ground glass change in cytoplasm (pale eosinophilic cytoplasmic inclusions) reflects
hypertrophy of smooth endoplasmic reticulum
2. Drugs: diazepam, insulin, steroids, tacrolimus, mycophenolate mofetil
F. Lipofusion pigment deposits
1. Lysosomal pigment in centrizonal hepatocytes
2. Drugs: phenothiazine, phenacetin
G. Drug-related neoplasms
1. Oral contraceptives associated primarily with hepatic adenomas, but also with focal
nodular hyperplasia and hepatocellular carcinoma
2. Anabolic steroids associated with hepatic adenoma
Recommended Reading
Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathology. 2009;62:481-
492.
Roberts EA. Drug-induced liver disease. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 3rd
ed. New York, NY: Cambridge University Press;2007:478-512.
Roberts EA. Drug-induced liver injury. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB,
eds. Pediatric Gastrointestinal Disease. 3rd ed. Hamilton, Ontario: BC Decker Inc.;2000:1015-1033.
Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference.
Hepatology. 2006;43:618-631.

6O-3. Other Acquired
Liver Diseases—Iron Storage
Disorders
Nitika Arora Gupta, MD
I. There are many disorders that can lead to iron overload. The primary forms include hereditary
hemochromatosis, neonatal hemochromatosis, aceruloplasminemia, atransferemia and heavy-chain
ferritin disease. The secondary forms are primarily transfusion associated.
II. Hereditary Hemochromatosis

A. Autosomal-recessive disorder of iron overload
1. Occurs secondary to reduced synthesis or activity of hepcidin, which downregulates
iron entry into the bloodstream
B. Predominant mutation is in the HFE gene, which regulates hepcidin synthesis
1. Identified mutations in HFE gene include: C282 Y mutation (a change from cysteine to
tyrosine at position 282) and H63D (a change from histidine to aspartate at position 63)
C. Majority of patients with classic hereditary hemochromatosis are homozygous for C282Y
mutation, with 5% compound heterozygous (C282Y/H63D)
D. Clinical Features/Presentation
1. C282Y homozygosity present in 1 of 200–400 Caucasians of North European descent
2. Rare in African Americans, Asians and Pacific Islanders
3. Although increased iron absorption begins in childhood, clinical symptoms typically do
not occur until adulthood
a. Most pediatric patients are asymptomatic, but may be diagnosed based on
clinical or family risk factors
4. Common symptoms include: chronic liver disease (elevated liver tests, fibrosis,
cirrhosis), skin pigmentation, arthritis, cardiac problems (heart failure, arrhythmias,
cardiomyopathy), diabetes, gonadal dysfunction
a. Classic presentation of bronze skin, diabetes and joint inflammation rarely seen
because of early screening
b. Most common presentation is fatigue, malaise, arthralgias and hepatomegaly
5. Spectrum of the disease ranges from mild (genetic predisposition with a mildly elevated
serum transferrin saturation) to iron overload without symptoms (2–5 gs of iron), overt
iron overload ( >5 gs of iron) with early symptoms of fatigue and joint pains and the
severe form leading to organ damage
6. Heterozygotes generally do not have clinically important iron overload
E. Diagnosis and Screening
1. In adults, serum transferrin saturation >45% in men and >42% in premenopausal
women warrants further investigation
a. Elevated serum ferritin indicates iron accumulation
b. Consider genetic testing
2. Although asymptomatic, many affected children will have an elevated transferrin
saturation, but normal ferritin
3. Indications for liver biopsy include elevated liver tests, hepatomegaly or serum ferritin
>1,000, which allows for evaluation of fibrosis and other concurrent diseases
a. Liver biopsy will show increased Prussian blue staining and total hepatic iron
index (calculated by iron concentration (in µmol/grams of liver) ÷ age (in years)
4. MRI of the abdomen can be used to quantify hepatic iron stores
5. Other disorders associated with iron overload should be excluded, such as alcoholic and
nonalcoholic liver disease, cystic fibrosis, porphyria cutanea tarda and chronic viral
hepatitis

F. Treatment: Goal is to reduce total body iron stores and prevent reaccumulation
1. Iron depletion: weekly phlebotomy of roughly 1 unit of blood over 1–2 years, until
ferritin <50 and transferrin saturation is <30%
2. Maintenance therapy: phlebotomy 2–4 times per year to maintain ferritin
between 50–100.
3. In symptomatic children: weekly phlebotomy of 5–8 cc/kg until ferritin <300,
then 2–4 times per year
G. Management of Children With an Affected Parent
1. Genotype affected parent and spouse
2. If both have at least one mutation, then genotype children
3. If child has positive genotype: annual fasting transferrin saturation and serum ferritin
4. Initiate phlebotomy when abnormal
III. Neonatal Hemochromatosis

A. Introduction
1. The most common identified cause of acute liver failure in the neonate
2. Associated with hepatic and extrahepatic deposition of iron (such as in the thyroid,
pancreas, heart and salivary glands) without involvement of the reticuloendothelial
system
3. Proposed theories of pathogenesis are: 1) Fetal alloimmune disorder; 2) Primary disorder
of fetoplacental iron handling
4. Unrelated to hereditary or juvenile hemochromatosis
5. Extremely rare in first pregnancies, but late fetal loss in sibships is common
1. Liver failure within hours of life, with hypoglycemia, coagulopathy and edema
2. Illness develops in utero, with resultant intrauterine growth retardation,
oligohydramnios, placental edema or stillbirth
C. Diagnosis
1. Laboratory studies:
a. Serum aminotransferases disproportionately low considering degree of hepatic
dysfunction.
b. Hypersaturation of transferrin, with hypotransferrinemia.
c. Hyperferritinemia (>800 n/mL)
d. Elevated alpho-fetaprotein (100,000–600,000 ng/mL)
2. Magnetic resonance imaging of the abdomen for evidence of extrahepatic deposition of
iron in the pancreas and myocardium.
3. Buccal biopsy of the lip to show deposition of iron in the minor salivary glands
is diagnostic
4. Liver biopsy is neither required nor advisable for diagnosis because of severe coagulopa-
thy. If performed, it shows evidence of giant cell transformation, siderosis, bile ductular
proliferation and fibrosis, nodular regeneration, cirrhosis and massive loss of hepatocytes
D. Management
1. Consider transfer to liver transplant center
2. Supportive regimen for acute liver failure
3. Antioxidant cocktail is commonly used, but controversial and consists of N-acetyl cyste-
ine, selenium, prostaglandin E and alpha tocopherol
4. Exchange transfusion or IVIG may be beneficial
5. Liver transplantation should be considered
Recommended Reading
Knisley AS. Neonatal Hemochromatosis. Gastro Clin North America. 2003;877-889.
Pietrangelo A. Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment. Gastroenterology.

2010;139:393-408.
Press;2007:478-512.
Weiss G. Genetic mechanisms and modifying factors in hereditary hemochromatosis. Nat Rev Gastroenterol
Hepatol. 2010;7:50-58.
Whitington PF. Fetal and infantile hemochromatosis. Hepatol. 2006;43:654-660.

6O-4. Other Acquired Liver Diseases—
Non-alcoholic Fatty Liver Disease and
Steatohepatitis (NAFLD/NASH)
Elizabeth L. Yu, MD
Jeffrey B Schwimmer, MD
Joel E Lavine, MD, PhD
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in childhood and adoles-
cence.
A. NAFLD encompasses a spectrum of liver pathology:
1. Isolated steatosis or macrovesicular fat accumulation within hepatocytes,
without inflammation
2. Non-alcoholic steatohepatitis (NASH), fat accumulation associated with inflammation
and/or evidence of cellular injury
3. Cirrhosis
B. Natural history and progression of disease in children remains undetermined
C. NAFLD in children and adults predisposes to Type 2 diabetes, hypertension and dyslipidemia
D. True prevalence of NAFLD is difficult to assess, as liver biopsy needed for definitive diagnosis,
although an autopsy study demonstrated a 9.6% overall prevalence of NAFLD in children
ages 2–19.
E. Factors associated with increased risk of NAFLD:
1. Obesity
2. Male sex
3. Older age
4. Hispanic ethnicity
5. Asian race (especially those of Chinese or Filipino descent)
F. ~10% of NAFLD patients are of healthy weight
II. Pathogenesis
A. Pathophysiology of NAFLD thought to be multifactorial
B. Hyperinsulinemia and hepatic insulin resistance important in development of fatty liver
C. Two-hit hypothesis is a commonly agreed-upon theory of pathophysiology:
1. 1st hit: insulin resistance → leads to hepatic steatosis
2. 2nd hit: oxidative injury required for progression to necroinflammatory steatohepatitis
D. Obesity, especially increased visceral adiposity, is correlated with dyslipidemia and increased insu-
lin resistance.
1. Visceral adiposity with increased risk of steatosis given presence of increased free fatty
acids (FFA) in combination with anatomical ease of transport of FFAs directly to portal
vein for conversion to triglycerides (TG) in liver
2. Presence of obesity in NAFLD patients increases risk of development of fibrosis
three-fold as opposed to nonobese NAFLD patients
3. Adolescent males more likely to develop NAFLD secondary to greater degree of insulin
resistance in adolescents compared to children and adults; estrogen may be protective
against progression of steatosis to NASH
E. Insulin resistance a key pathophysiological component in NAFLD
1. Enhances peripheral lipolysis, increases TG synthesis and increases hepatic uptake of
fatty acids leading to an overall increase in hepatic FFA accumulation
2. Associated with decreased beta oxidation of FFAs, impairment of apolipoprotein B and
decreased TG secretion → net excess of hepatic TG storage
F. Steatosis: increased quantities of FFA contribute to a cycle of deteriorating function and hepato-
toxicity by downregulating beta-oxidation and activating proinflammatory pathways

G. Oxidative injury (second hit) sources:
1. Hepatic iron (reactive oxygen species (ROS) produced in reduction of Fe3+ → Fe2+)
2. Antioxidant deficiency
3. Hypoxia
4. Intestinal bacteria
H. Increased amounts of ROS → lipid peroxidation, inflammation, hepatocellular apoptosis
and fibrosis
1. ROS induces expression of proinflammatory cytokines: TGF-β, TNF-α, Fas ligands
III. Diagnosis
A. Average age of presentation: 10–14 years
B. Clinically, most children asymptomatic, though some may complain of vague abdominal pain in
the RUQ
1. Acanthosis nigricans found in >50% of patients with NAFLD
C. Initial screening labs: CBC, AST/ALT, GGT, lipids and fasting glucose, insulin
1. Lab findings that may indicate NAFLD: elevated serum aminotransferases with ALT >
AST, elevated GGT and alkaline phosphatase, low HDL and elevated fasting triglycerides
D. Family history important in terms of viral hepatitis, autoimmune diseases, which may be
risk factors
E. Imaging: hepatic ultrasound and MRI
1. Ultrasound is readily available and inexpensive, but this is balanced by a lack of
sensitivity to milder degrees of steatosis, operator dependence, and inability to
adequately quantify the degree of steatosis, fibrosis or inflammation
2. MRI is more sensitive, but concurrently more expensive
F. Liver biopsy and histological examination of the liver required for definitive diagnosis
1. For diagnosis, at least 5% of hepatocytes must contain macrovesicular fat
2. Two distinct histological subtypes of NASH found in children:
a. Type 1 NASH: steatosis with ballooning degeneration of hepatocytes and
perisinusoidal fibrosis
b. Type 2 NASH: steatosis with portal inflammation and/or portal fibrosis without
evidence of ballooning degeneration
3. Type 1 NASH is consistent with the typical adult pattern
4. Type 2 NASH unique to children
5. Children with type 2 NASH generally younger and more severely obese than those
with type 1 NASH
a. Males and Asian or Native Americans more likely to have type 2 NASH
b. Type 2 NASH more often associated with severe (bridging) fibrosis
IV. Differential Diagnosis

A. Infections: hepatitis B and hepatitis C
B. Autoimmune disease: autoimmune hepatitis, insulin-dependent diabetes mellitus
C. Wilson’s disease
D. Alpha-1-antitrypsin deficiency
E. Drug-induced liver injury: prednisone, amiodarone, tetracycline, valproate, methotrexate
F. Chronic use of total parenteral nutrition (TPN)
G. Nutritional deficiencies: refeeding syndrome, rapid weight loss, starvation
H. Following bypass surgeries
A. Weight loss through lifestyle modification
1. Nutritional goals:
a. Eliminated foods high in saturated fats, trans fats and simple sugars
2. Increased aerobic exercise
3. Decreasing sedentary behaviors
B. Amount of weight loss required to induce a significant change in NAFLD unknown
C. Pharmacological treatments still undergoing trials, no definitive evidence to support their use
1. Metformin has been utilized in trials to increase insulin sensitivity and decrease hepatic
glucose production.
2. Vitamin E trial recently completed, with goal of slowing progression of simple steatosis
to NASH
Recommended Reading
Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998;114:842-845.
Lavine JE, Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clin Liver Dis
2004;8:549-558.
Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric non-alcoholic fatty liver disease.
Hepatology. 2005;42:641-649.
Schwimmer JB, Deutsh R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and
adolescents. Pediatrics. 2006;118:1388-1393.
Van der Poorten D, Milner KL, Hui J, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver
disease. Hepatology. 2008;48:449-457.

6O-5. Acute Graft vs
Host Disease and
Veno-occlusive Disease
Preeti Viswanathan, MD
Debora Kogan-Liberman, MD
I. Veno-occlusive Disease
A. Clinical syndrome characterized by jaundice, painful hepatomegaly and fluid retention
B. Among the spectrum of organ injury syndromes that occurs after high-dose chemotherapy
(alkylating agents) used for hematopoietic stem cell transplant (HSCT)
1. Typically occurs by day 35 post-HSCT, although can occur later
C. May also occur with other toxins including alcohol, radiation, terbinafine, oral contraceptives,
azathioprine, herbal teas made with pyrrolozidine alkaloids and solid organ transplantation,
including liver and kidney
D. Pathogenesis
1. Initial injury occurs to sinusoidal endothelial cells
2. Hepatic Zone 3 involved, where there is both a high concentration of cytochrome
P450 and glutathione S transferase
a. Cytochrome P450 enzymes metabolize chemotherapeutic agents,
e.g., cyclophosphamide
b. Glutathione is needed to detoxify metabolites. Depletion of glutathione may
play a role in sinusoidal injury and leads to hepatic necrosis
3. Dilation of sinusoids and ongoing hepatic necrosis lead to collagen deposition in the
sinusoids and venules, sclerosis of venular walls and fibrosis of venular lumens
4. Activated stellate cells secrete plasminogen activator inhibitor type 1 and other
vasoactive mediators
5. The coagulation cascade is activated by endothelial injury, with resultant low
antithrombin, and protein C and consumption of Factor VII and platelets
E. Histology
1. Injury to hepatic venules is first histological change
2. Subendothelial edema, red cell extravasations and fibrin deposition also occur
F. Risk factors
1. Pretransplant factors include: female gender, prior radiation, preexisting liver disease,
elevated transaminases, exposure to amphotericin B, vancomycin, acyclovir
2. Post-transplantation factors include: high-dose conditioning regimens, allogenic
transplantation, HLA mismatch, use of Busulfan for conditioning, use of
cyclophosphamide, GVHD prophylaxis
G. Diagnosis
1. Mainly clinical
2. Criteria for diagnosis include the development, prior to day 30, of jaundice,
hepatomegaly with right upper quadrant pain, ascites or unexplained weight gain
3. CT and ultrasound with Doppler may be useful in excluding Budd-Chiari and
constrictive pericarditis
4. Transvenous liver biopsy (percutaneous is contraindicated due to risk of bleeding) and
measurement of hepatic venous pressure gradient (HVPG) remain gold standard of
pathologic diagnosis. HVPG represents the gradient between pressures in the portal
vein and the intraabdominal portion of inferior vena cava. A gradient of >10 mmHg has
91% specificity for VOD

H. Prognostic factors
1. Rates of bilirubin rise and weight gain are significantly higher in those with
severe disease
2. Hepatic venous pressure gradient >20 mmHg—poor prognosis
3. Multiorgan failure is a key indicator of poor prognosis—these patients die of renal or
cardiac failure rather than hepatic insufficiency.
I. Treatment
1. Defibrotide: an adenosine receptor agonist. It has local antithrombotic effect, without
systemic anticoagulant properties. Appears to modulate endothelial cell injury without
enhancing systemic bleeding, and protects sinusoidal epithelium without compromising
the antitumor effects of cytotoxic therapy
2. TIPS—likely not of long-term benefit and not shown to change the course of VOD
3. Transplant—limited by patient’s clinical status, especially presence of multiorgan failure,
and finding suitable liver graft
II. Graft vs Host Disease

A. Incidence of graft vs host disease (GVHD) is directly related to HLA disparity
B. Generally, there are three requirements for development of GVHD
1. Graft must contain immunologically competent cells ( T cells )
2. Recipient must express antigens that are not present in the donor
3. Recipient must be incapable of mounting an effective response to eliminate the
transplanted cells
C. Allogenic HSCT is the most common setting for the development of GVHD, in which recipients
receive immunoablative chemotherapy or radiation before hematopoietic stem cell infusion con-
taining T cells. However, it can occur with transfer of any tissue containing T cells (blood prod-
ucts, solid organs)
D. Two types: acute and chronic. Previously classified based on timeframe of occurrence (before and
after 100 days from transplantation), now classified based on constellation of symptoms,
including an overlap syndrome where features of acute and chronic GVHD may be present
III. Acute GVHD

A. Exaggerated response of normal inflammatory mechanisms that involves donor T cells
and multiple innate and adaptive cells and mediators
B. Clinical features:
1. The three main organs involved in acute GVHD are the skin, liver and GI tract
2. The extent of involvement of the three principal target organs determines the overall
severity of acute GVHD. The overall grades are defined as I (mild), II (moderate)
and III (severe)
3. Skin is generally the first and most commonly affected organ, generally coinciding with
donor cell engraftment
a. Characterized by an erythematous, maculopapular rash that is often pruritic,
with blisters and ulcerations in severe cases
4. Liver GVHD initially presents with jaundice or an increase in alkaline phosphatase
a. May be difficult to distinguish from other causes of jaundice posttransplant
(drug toxicity, VOD, infections, parenteral nutrition–associated cholestasis), and
a biopsy is often required
b. Histology demonstrates endothelialitis, lymphocytic infiltration of the portal
areas, pericholangitis and bile duct destruction
5. GI tract involvement may present with nausea, vomiting, anorexia, abdominal pain
or diarrhea
a. Gastric involvement causes postprandial vomiting that is not always preceded
by nausea
b. The diarrhea of GVHD is secretory
c. Mucosal ulcerations may cause GI bleeding and is a predictor of poor outcome
d. Histological features include patchy ulcerations, apoptotic bodies, crypt
abscessesand loss and flattening of epithelial surface
Table 1. Acute GVHD Grading Criteria
Stage Skin Liver (Bilirubin) GI Tract (Stool Output/d)
0 No GVHD rash <2 mg/dL Adult: <500 mL/d
Child: <10 mL kg/d
1 Maculopapular rash 25% BSA 2-3 mg/dL Adult: 500-999 mL/d
Child: 10-19.9 mL/kg/d or persistent
nausea, vomiting,or anorexia, with a
postive upper GI biopsy
2 Maculopapular rash 25%-50% BSA 3.1-6 mg/dL Adult: 1000-1500 mL/d
Child: 20-30 mL/kg/d
3 Maculopapular rash >50% BSA 6.1-15 mg/dL Adult: >1500 mL/d
Child: >30 mL/kg/d
4 Generalized erythroderma with >15 mg/dL Severe abdominal pain with or
bullous formation without ileus
Modified from Carpenter PA, Macmilian ML. Management of acute graft vs host disease in children.
Pediatr Clin N Am. 2010;57:273-295.
IV. Chronic GVHD

A. Major cause of late non-relapse death following allogenic HSCT
B. It is associated with decreased quality of life and impaired physical and functional status
C. Can occur between 6–18 months after transplant with median time at diagnosis of 4.5 months
D. It is a complex multisystem disorder that involves many organ systems, characterized by immune
dysregulation, immunodeficiency, impaired organ function and decreased survival
E. The clinical manifestations are similar to autoimmune diseases, suggesting a similar
pathophysiology
1. Mainly involves skin, eyes, oral cavity, GI tract, liver and lungs, but unlike acute GVHD,
can involve any other organs
2. Clinical manifestations may be inflammatory (rash, mucositis, diarrhea) or fibrotic and
sclerotic (lichen planus, bronchiolitis obliterans, sica syndrome, esophageal strictures)
3. Increased levels of nonspecific auto (vs allo) antibodies have been described, including
ANA, antiSMA, antineutrophil antibody, antiplatelet antibody
F. One of the most important risk factors is severity of previous acute GVHD
V. Treatment
A. Prevention is an important component
B. Most widely used acute GVHD prophylaxis is a combination of calcineurin inhibitor
and methotrexate
1. Calcineurin inhibitors impede the function of cytoplasmic enzyme calcineurin, which is
critical to the activation of T cells
2. The most important predictor of long-term survival in patients with acute GVHD is the
primary response to the first line of treatment
3. Mild skin GVHD can be treated with topical corticosteroids, more severe skin or visceral
GVHD requires systemic corticosteroids, typically starting at 1–2 mg/kg/day. Gradual
dose reduction is attempted after 7 days or more of high-dose corticosteroids
4. Nonabsorbable corticosteroids like oral budesonide are also commonly used for GI
GVHD
C. Steroid-refractory GVHD is defined as disease progression or lack of response following
3–7 days of systemic therapy with corticosteroids and a calcineurin inhibitor
D. No effective prophylaxis regimen exists for chronic GVHD
E. Definitive treatment of chronic GVHD in pediatrics is highly variable. The general approach is
high-dose corticosteroid plus calcineurin inhibitor, with gradual steroid taper to lowest allowable
dose to prevent GVHD flare
1. The mean duration of therapy for chronic GVHD is 3 years
2. Approximately 90% of patients who ultimately respond do so within 3 months.
F. Extracorporeal photopheresis is increasingly used in the management of acute and chronic GVHD
to minimize steroid exposure. Response rate varies from 52%–83%

VI. VOD vs GVHD
A. May be difficult to distinguish between the two entities, as well as other cause of jaundice
posttransplant
1. Absence of fluid retention and weight helps distinguish VOD from GVHD
2. Hyperacute GVHD can be confused with VOD
a. As GVHD progresses, alkaline phosphatase levels increase (unusual in VOD)
b. When ascites, pleural effusions, renal failure and sepsis are present, VOD is by
far the most common cause
c. The histological hallmark of GVHD-induced cellular injury is apoptosis with
lymphoid infiltration. In VOD, inflammatory cells are absent and hepatocyte
necrosis is seen.
Recommended Reading
Baird K, Cooke K, Schultz KR. Chronic Graft-versus-Host Disease (GVHD) in children. Pediatr Clin N Am.
2010;57 : 297-322.
Bayraktar UD, Seren S, Bayraktar Y. Hepatic venous outflow obstruction: three similar syndromes. World J
Gastroenterol. 2007; 13(13):1912-1927.
Carpenter PA, Macmilian ML. Management of acute graft vs host disease in children. Pediatr Clin N Am.
2010;57:273-295.
Choi SW, Levine JE, Ferrara JLM. Pathogenesis and management of graft-versus-host disease. Immunol Al-
lergy Clin N Am. 2010;75-101.
Senzolo M, Germani G, Cholongitas E, Burra P, Burroughs AK. Veno-occlusive disease: Update on clinical
management. World J Gastroenterology. 2007;13(29):3918-3924.
Wadleigh M, Ho V, Momtaz P, Richardson P. Hepatic veno-occlusive disease: pathogenesis, diagnosis and

treatment. Curr Opin Hematol. 10:452-452.
6P. Systemic Diseases
Affecting the Liver
Sheree Watson, MD
I. The liver is often involved in systemic disease as an innocent bystander. Elevated transaminases may be
the first sign of systemic disease. Rheumatologic diseases in particular have systemic involvement, with
43% of patients demonstrating transient liver transaminase abnormalities. In a small percentage, these
abnormalities are persistent and most often represent coexisting primary liver disease (i.e., autoimmune
hepatitis, NAFLD, viral hepatitis or primary biliary cirrhosis) or medication-related liver toxicity.
II. Cardiac Diseases

A. Constrictive Pericarditis, Pulmonary atresia, Tetralogy of Fallot, and s/p Fontan for single ventricle
heart diseases.
1. Liver abnormality: hepatic congestion
2. Pathophysiology: increased right atrial and ventricular pressures cause sinusoidal en-
gorgement, which leads to modest elevations in transaminases. May sometimes see
unconjugated hyperbilirubinemia. Alkaline phosphatase is usually normal
3. Histopathology:
Figure 1.
-Gross appearance- ‘nutmeg liver - red central area (due to sinusoidal congestion and
bleeding into atrophic regions surrounding enlarged hepatic veins) intermixed with a yellow
area of either normal or fatty liver.
-Microscopic appearance- sinusoidal dilation around the central vein, engorged with
erythrocytes, no inflammation.
-Congestive hepatopathy. Liver tissue showing sinusoidal dilatation and congestion in the
perivenular zone.
Adapted from Malnick S, Melzer E, Sokolowski N, Basevitz A. The involvement of the liver in
systemic diseases. J Clin Gastroenterol. 2008;42(1):69-80.
4. Clinical Features
a. Early tender hepatomegaly
b. Late hypoalbuminemia with PLE, ascites, cirrhosis and portal hypertension
c. Diagnosis: If constrictive pericarditis, cardiac catherization may be necessary
5. Differential for hepatic congestion: Budd-Chiari syndrome, veno-occlusive disease,
tuberculous pericarditis
6. Management: diuretics, treatment of underlying heart disease

III. Autoimmune/Connective Tissue Diseases
A. Systemic Lupus Erythematosus (SLE) SLE is a multisystem immune-mediated disease.
Liver involvement can be difficult to differentiate from autoimmune hepatitis.
1. Liver abnormality: variable fatty liver, chronic active hepatitis, liver failure,
Budd-Chiari syndrome, nodular regenerative hyperplasia (NRH), hepatic infarction
2. Pathophysiology:
a. Fatty liver likely related to corticosteroid therapy
b. Budd Chiari syndrome – antiphospholipid antibodies lead to hepatic venous
thromboembolism causing obstruction, portal hypertension, cirrhosis and
subsequent ascites
c. Nodular Regenerative Hyperplasia (NRH) – antiphospholipid antibodies lead to
focal ischemia induced liver injury, and subsequent liver regeneration to main-
tain liver functional capacity. Majority with NRH are asymptomatic, but NRH
may lead to noncirrhotic portal hypertension with ascites and variceal bleeding
3. Histopathology: variable
a. Hepatic steatosis: micro- and macrovesicular fat in hepatocytes
b. Chronic active hepatitis/lupus hepatitis, nonspecific lymphocytic infiltration of
periportal areas
Figure 2.
Liver biopsy in a SLE patient showing active interface hepatitis with prominent plasmacytic
infiltrates. This is consistent with lupus hepatitis (H&E 200X)
Adapted from Mok CC. Investigations and management of gastrointestinal and hepatic mani-
festations of systemic lupus erythematosus. Best Practice & Research Clinical Rheumatology.
2005;19(5):741-766.
4. Clinical features of SLE are variable, but typically involve skin, joints, kidneys, cardiovas-
cular, CNS and hematologic systems. Other organs, including the liver, may be involved
5. Clinical hepatic features: elevated transaminases, cholestasis, pruritis, ascites,
non-specific increased immunoglobulin subclasses, acute liver failure (rare)
a. Liver laboratory tests are abnormal at some point in disease course in up to
50% of patients
b. Hepatomegaly is found in up to 2/3 of patients
c. Few patients have primary liver disease; however, a Japanese registry did
demonstrate chronic hepatitis in 2.4%, cirrhosis 1.1%, and liver fibrosis in 1%.
6. Liver disease is also seen in 10% of neonatal SLE with three patterns
a. Liver failure at birth or in utero
b. Transient hyperbilirubinemia
c. Transient elevate aminotransferases
7. Diagnosis: see American College of Rheumatology diagnostic criteria
a. Lupus-related liver disease may resemble AIH. ANA may be seen in both, but
antismooth muscle and antimitochondrial antibodies (AMA) are rare in SLE.
Antiribosomal P protein antibodies are present in SLE
b. Liver biopsy not very useful in diagnosis due to wide range of nonspecific find-
ings. Biopsy may provide useful prognostic information, e.g., extensive necrosis
or fibrosis portends poor prognosis
c. SLE is the attributable cause of approximately 20% of liver abnormalities
d. Liver biopsy with mild lobular inflammation without piecemeal necrosis
e. Degree of liver enzyme elevation correlates with disease activity and improves
with steroid treatment
8. Management: treat the underlying SLE with NSAIDs, steroids, azathioprine
Liver disease in SLE may be associated with inflammation in other organs — fibrosing
alveolitis, pericarditis, autoimmune gut disease
Juvenille Rheumatoid Arthritis (JRA) JRA is an autoimmune disorder characterized by particu-
B.
lar joint inflammation. Extraarticular involvement can include the lungs, heart, liver and blood.
1. Liver involvement is variable with abnormal liver tests reported in 5%–77% of patients
a. Elevated alkaline phosphatase and gamma glutamyl transferase (GGT) is the
most common liver finding
b. Levels are a reflection of disease activity and correlate with elevated ESR
2. Liver involvement may also be due to therapy
a. Salicylates are currently used less often, but can be hepatotoxic
b. Methotrexate may cause elevated transaminases, and less frequently,
hepatic fibrosis
3. Liver biopsy demonstrates a nonspecific periportal collection of inflammatory cells and
Kupffer cell hyperplasia.
4. Felty’s syndrome (long-standing JRA with splenomegaly and leukopenia) is associated
with hepatomegaly and elevated transaminases. The liver injury is due to obliteration of
portal venules resulting in portal hypertension
C. Sjogren’s- autoimmune disorder mainly affecting salivary and lacrimal glands
1. Liver abnormality: chronic nonsuppurative cholangitis
2. Histopathology: inflammation and/or abnormal connective tissue confined to
the portal areas
3. Clinical features:
a. Keratoconjunctivitis, xerostomia, salivary gland inflammation and often
Raynaud’s phenomenon, achlorohydria, alopecia and splenomegaly
b. In children, Sjogren’s syndrome typically accompanies another connective
tissue disease
c. In children with JRA and Sjogren’s syndrome, 40% will have subclinical
liver disease
d. Children with antimitochondrial antibodies may develop liver injury that
resembles primary biliary cirrhosis
e. Elevated alkaline phosphatase, AST and ALT
f. Positive antimitochondrial antibody (AMA) titers are also seen and are associ-
ated with histopathologic abnormalities similar to those seen in stage I PBC
g. Liver histopathology is present even when transaminases are normal
4. Diagnosis: AMA is a sensitive indicator of underlying liver pathology
5. Management: geared toward treatment of the other disease manifestations
Ankylosing Spondylitis (AS) Ankylosing spondylitis is an inflammatory arthropathy of the
D.
sacroiliac joints and the spine.
1. Clinical presentation involves back pain and worsening spinal stiffness
2. Laboratory findings may include elevated alkaline phosphatase
a. Gel electrophoresis can be used to identify liver or bone etiology
b. 5-nucleotidase (5-NT) and GGT typically increase in parallel if liver is source
c. Increases correlate with elevation in ESR and respond to disease treatment

IV. Granulomatous Diseases
A. The liver is a common associated site for various granulomatous diseases. Granulomas are a dis-
crete aggregate of specialized immune cells which fuse to form large epithelioid multinucleated
giant cells which are surrounded by fibroblasts and lymphocytes (see section on Granulomatous
Liver Disease).
Figure 3. A large hyalinized granuloma in a well-established case of sarcoidosis (hematoxylin-eosin, original

magnification x 4). Note the lack of cellular debris in the areas of hyalinization (inset; hematoxylin-eosin, origi-
nal magnification x 40). This lack of cellular debris is one of the useful features in differentiating hyalinization
(pseudonecrosis) from true necrosis. (B) A truly necrotic granuloma in a patient who had positive acid-fast
bacilli (AFB) staining (hematoxylin-eosin, original magnification x 10). Note the ample cellular debris in the
necrotic region. Adapted from Lagana SM, Moreira RK, Lefkowitch JH. Hepatic Granulomas: Pathogenesis
and Differential Diagnosis. Clin Liver Dis. 2010;14:605-617.
B. Sarcoidosis
1. Systemic granulomatous disease, unknown etiology.
a. Liver abnormality: non-caseating epithelioid granulomas (see section on
Granulomatous Liver Disease)
C. Chronic Granulomatous Disease
1. Primary immunodeficiency, incidence 1/200,000, X-linked recessive, occasionally
autosomal-recessive.
2. Liver abnormality: liver abscesses; ascites (see section on Immunodeficiency States)
V. Endocrine Diseases
A. Type I polyglandular autoimmune syndrome (Hypoparathyroidism, adrenal insufficiency,
mucocutaneous candidiasis)/APECED (autoimmune polyendocrinopathy- candidiasis-ectodermal
dysplasia).
B. Liver abnormality: chronic active hepatitis (15%–18%) (see section on Autoimmune Enteropathy)
VI. Renal Diseases
A. Infantile Polycystic Disease
B. Liver abnormality: congenital hepatic fibrosis (see section on Congenital Hepatic Fibrosis)
Figure 4. Congenital hepatic fibrosis and ARPKD in a newborn girl. The bile ducts (arrows) are
concentrated at the edge of the portal triad. Normally, bile ducts are found in the center of portal
triads. In congenital hepatic fibrosis, bile ducts are tortuous, dilated with irregular contours and are
in the periphery of portal triads (PV portal vein; H&E, original magnification×200). Adapted from
Veigel MC, Prescott-Focht J, Rodriguez MG, Zinati R, Shao L, Moore CAW, Lowe LH. Fibropolycystic
liver disease in children. Pediatr Radiol. 2009;39:317-327.
VII. Hematologic Diseases
A. Hemophagocytic Lymphohistiocytosis (HLH)
1. Liver abnormality: acute liver failure
2. Etiologies: sporadic, viral (EBV, parvo, B19, echovirus), familial (autosomal-recessive,
occasionally X-linked)
3. Pathophysiology:
a. Macrophages (including Kuppfer cells) become excessively activated and phago-
cytose neighboring cells (e.g., RBCs and WBCs) secrete inflammatory cytokines
b. Patients have NK cell function defect that results in overexpression of
proinflammatory cytokines; 80% with primary immune defect
c. Familial forms are heterogenous, but all demonstrate mutations in intracellular
killing (i.e. granzyme)
B. Histopathology: Erythrophagocytosis in liver or bone marrow; in familial HLH atypical
lymphocytes or histiocytes are seen in CSF.
C. Clinical Features:
1. Fever, cytopenia, lymphadenopathy, and liver dysfunction including hepatosplenomegaly,
ascites, jaundice, fulminant hepatic failure with coagulopathy; mortality 75%
2. Clinical features may also involve skin infiltrates, respiratory failure and CNS involvement
D. Diagnosis
1. Laboratory finding include hypofibrogenemia, hyperferitinemia, elevated triglycerides
and serum lactate dehydrogenase in addition to cytopenia
2. Liver or bone marrow biopsy showing erythrophagocytosis
E. Management:
1. Supportive care for liver failure
2. Cytotoxic therapy with etoposide
3. Methylprednisolone and methotrexate (yields remission in 1/3)
4. Allogeneic BMT or SCT in high-risk populations (age <2 years or familial pattern)
VIII.Oncologic Diseases
A. Post-HSCT (Hematopoietic stem cell transplant)
B. Graft versus Host Disease (GVHD)
1. Systemic immunologically mediated reaction of immune competent donor cells against
the recipient’s HLA. Involves skin, gut, lung, eye, pancreas and liver (40% of cases).
Acute: 100 days or less s/p HSCT. Chronic: >100 days s/p HSCT.
2. Liver abnormality: small bile duct damage (see section on GVHD vs VOD)

C. Veno-occlusive Disease (VOD) or Sinusoidal Obstructive Syndrome (SOS)
3. Liver abnormality: hepatic congestion, portal hypertension (see section on GVHD vs
VOD)
D. Hepatobiliary infections (see section on Viral Hepatitis and Bacterial and Parasitic Infections)
IX. Multisystemic disorders

A. Sepsis
1. Liver abnormality: liver failure
2. Histopathology: hyperplasia in the reticuloendothelial system; fatty change
3. Clinical features:
a. Early: jaundice, hepatomegaly, nonspecific elevation in transaminases
b. Late: coagulopathy due to liver failure or DIC
4. Diagnosis: ultrasound to identify abscess, fluid collections or an obstructed biliary tree
due to sludge. Most common ultrasound finding is an echo-bright liver
5. Management: treat sepsis; supportive care for the liver failure
B. Hypoxia/ischemia
1. Liver abnormality: diffuse hepatic injury
2. Pathophysiology: occurs after interruption of hepatic blood supply due to hypotensive
episode, coronary bypass surgery if bypass time >2 hours, sickle cell hepatic sequestra-
tion crisis, hepatic artery or portal vein thrombosis.
3. Histopathology:
a. Hepatocyte necrosis and a variable degree of architectural collapse in zone 3
(around the central vein, i.e., furthest from arterial blood supply)
b. If severe and prolonged ischemia, necrosis may extend to mid-zonal
hepatocytes
4. Clinical features: transaminases rise 24–48 hours post-op. Range may be >10,000.
Transaminases return to normal within 1–2 weeks. LDH also significantly elevated.
Bilirubin rises after aminotransferases begin to decline. Normal to slightly impaired liver
synthetic function
5. Diagnosis: clinical presentation consistent with hypoxia/ischemia
6. Management: correction of circulatory disturbance
X. Kawasaki syndrome
A. Kawasaki syndrome is an autoimmune vasculitis typically affecting heart, skin, lymph nodes and
mucus membranes.
1. Gallbladder hydrops and hepatobiliary dysfunction have been reported
2. Hepatomegaly is seen in 14% and liver laboratory studies are abnormal in 30%
3. Liver pathology demonstrates portal inflammation, vasculitis, sinusoidal infiltrates,
Kupffer cell hyperplasia and congestive changes presumed to be from cardiac disease
Recommended Reading
Beath SV. The Liver in Systemic Illness. In: Kelly D, ed. Diseases of the Liver and Biliary System in Children. 3rd
ed. New York, NY: Blackwell Publishing; 2008:381-403.
Hedrich CM, Zappel H, Straub S, et al. Early onset systemic lupus erythematosus: differential diagnoses, clini-
cal presentation, and treatment options. Clin Rheumatol. 2011;30:275-283.
Malnick S, Melzer E, Sokolowski N, Basevitz A. The Involvement of the Liver in Systemic Diseases. J Clin Gas-
troenterol. 2008;42(1):69-80.
Mok CC. Investigations and management of gastrointestinal and hepatic manifestations of systemic lupus
erythematosus. Best Practice & Research Clinical Rheumatology. 2005;19(5)741-766.
Schlenker C, Halterman T, Kowdley KV. Rheumatologic disease of the liver. Clin Liver Disease. 2011;15:153-
164.
Youssef WI, Tavill AS. Connective Tissue Diseases and the Liver . J Clin Gastroenterol. 2002;35(4):345-349.
6Q. Liver Transplantation
Naim Alkouri, MD
P ediatric liver transplantation has an increasing number of indications. Recent advances in preoperative care,
posttransplant care and immunosuppression have improved survival.
I. General Indications for Liver Transplantation in Children

A. Cholestatic Liver Diseases: leading to chronic liver disease with complications secondary to
hepatic decompensation
1. Most common indication for pediatric liver transplant (54%)
2. Biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC),
primary sclerosing cholangitis
B. Chronic Non-cholestatic Liver Diseases
1. Chronic hepatitis B and C, autoimmune hepatitis
C. Metabolic Diseases
1. Primary liver diseases: Alpha-1-antitrypsin deficiency, tyrosinemia, glycogen storage
disease, cystic fibrosis, Wilson’s disease
2. Primary non-liver disease: Urea cycle defects, primary hyperoxaluria, organic acidemias,
bile acid synthesis defects
D. Acute Liver Failure
1. 11% of pediatric liver transplants
2. Indeterminate etiology in up to 49% of pediatric patients with ALF
3. Consider drugs, toxins, acetaminophen, viral etiologies
4. Outcome after liver transplantation is not as good as with chronic liver disease
E. Liver Tumors
1. Hepatoblastoma is the most common primary liver tumor in children
a. If complete resection is not possible, liver transplantation is performed when
maximum benefit of chemotherapy has been obtained
b. Children presenting with metastatic hepatoblastoma with lung metastases that
clear with chemotherapy have favorable outcomes as well
c. Outcomes following liver transplantation for this indication are comparable to
transplantation for other diagnoses
d. Ideal transplant candidates include children with tumors that are completely
confined to the liver, but which are unresectable, despite a definite response
to chemotherapy
2. Hepatocellular carcinoma is rare in children
F. Cirrhosis not otherwise specified, despite complete evaluation
1. Cirrhosis is an indication for liver transplantation when there is evidence of functional
hepatic decompensation (coagulopathy, ascites, frequent or massive gastrointestinal
hemorrhage, malnutrition and growth failure, and frequent severe bacterial infections)
G. Miscellaneous: congenial hepatic fibrosis, Caroli’s disease, TPN-related cirrhosis,
neonatal hemochromatosis, nonalcoholic steatohepatitis
II. Contraindications to Transplant

A. Absolute contraindications
1. Extrahepatic malignancy
2. Uncontrolled sepsis
3. AIDS
4. Irreversible and severe brain injury
5. Uncorrectable congenital anomalies affecting major organs (e.g., severe cardiac disease
or pulmonary hypertension)
B. Relative contraindications
1. Progressive extrahepatic disease
2. Substance abuse

III. Referral to a Transplant Center
A. Ideally as soon as the patient is identified as having a condition that will require transplantation
1. Patients with chronic liver disease, including infants with biliary atresia who remain
jaundiced post-Kasai procedure
2. Patients with metabolic disease poorly controlled by medication, and patients with
cirrhosis for any reason
3. Early referral allows the transplant center to have a maximum input into the
pretransplant management strategy
a. Aggressive ascites treatment
b. Variceal bleeding management
c. Management of hepatorenal syndrome
d. Aggressive nutritional management: fat-soluble vitamins, supplemental enteral
or parental nutrition
e. Immunizations
IV. The MELD/ PELD Scoring System

A. Designed to prioritize patients by acuity of illness rather than waiting time
B. The MELD score (Model for End-Stage Liver Disease) and the PELD score (Pediatric End-Stage
Liver Disease) are disease severity scales that are predictive of the risk of dying from liver disease
within 3 months for patients who are listed for transplant
C. The MELD score incorporates a patient’s bilirubin, INR and creatinine levels with a mathematical
equation. A score from 6 to 40 is calculated
D. A PELD score is calculated for pediatric patients who are less than 12 years of age and incorpo-
rates a patient’s bilirubin, INR, albumin, growth failure and age
V. Postoperative Complications
A. Primary Non-function (PNF): 5%
1. Characterized by encephalopathy, coagulopathy, minimal bile output, and progressive
renal and multisystem failure with increasing serum lactate level and rapidly rising liver
enzymes
2. Histologic evidence of hepatocyte necrosis in the absence of any vascular complication
3. Donor risk factors include prolonged cold ischemia time, unstable donor, high level of
steatosis in the liver allograft, older donor, high serum sodium level in the donor and
recovered organ from DCD (donation after cardiac death/non-heartbeating) donors
B. Hepatic Artery Thrombosis (HAT): 4%–6 % in children
1. Presents with markedly escalating transaminases and coagulopathy
2. Urgent retransplantation is necessary
3. May present as biliary leak, as hepatic artery is sole blood supply for biliary system
4. Late HAT: multiple biliary strictures, late complication
5. Diagnosis: Doppler ultrasonography or arteriography used to confirm HAT
C. Portal Vein Stenosis/Thrombosis
1. May present as recurrent variceal bleeding, enlarging spleen/liver, ascites or liver
allograft dysfunction
2. Doppler ultrasound may be diagnostic or may require venogram
3. Treatment: surgical intervention in the early posttransplantation period for portal vein
thrombosis. In the late posttransplant period, portal vein angioplasty ± stenting
D. Biliary Complications (Biliary Leak and Biliary Obstruction): 10%–30%
1. Range from early anastamotic leak to late stricture and obstruction, both in the
extrahepatic or intrahepatic biliary system
2. Biochemical abnormalities with elevation of bilirubin and canalicular enzymes (alkaline
phosphatase and gamma-glutamyltransferase) are not specific, these indicators of biliary
obstruction are also seen in ischemic graft injury, rejection, recurrent HCV and sepsis
3. Bile leaks tend usually within 1–2 weeks of transplant and result from a technically poor
anastomosis or a thrombosed hepatic artery
a. Immediate exploration is required to control or repair the leak
4. Strictures at the anastomosis may occur months to years after transplantation
a. ERCP and/or Percutaneous transhepatic cholangiogram (PTC) with dilatation
and stenting are the usual first-line treatment
b. Surgical revision reserved for lesions refractory to interventional approaches
VI. Rejection
A. Acute Rejection: 20%–50% of patients within the first 3 months post-transplant
1. Clinical manifestations: fever, graft enlargement and tenderness, and reduced bile flow
2. First manifestation however is elevation of AST and/or ALT
3. Diagnosis requires histological confirmation with liver biopsy
a. Classical biopsy findings include: 1) portal inflammation, 2) bile duct damage
and 3) venular endothelialitis.
B. Chronic Rejection
1. Histologically: loss of small bile ducts and an obliterative vasculopathy affecting large
and medium-size arteries
2. Bile duct loss is generally considered to be the most important diagnostic feature, the
term ductopenic rejection is widely used as an alternative to chronic rejection
3. Clinically characterized by progressive jaundice accompanied by progressive rise in GGT,
alkaline phosphatase and bilirubin
4. Most cases are due to medication noncompliance
VII. Infection
A. Early Infections (0–30 Days):
1. Usually caused by either bacteria or yeast
2. Bacterial infections are most often caused by Gram-negative organisms, enterococci or
staphylococci
3. Re-exploration of the abdomen is associated with increased risk for fungal infections
B. Intermediate Period (31–180 Days):
1. Donor-related infections (peak incidence of CMV infection especially in seronegative
recipients receiving seropositive donor organs)
2. Reactivated viruses (EBV-associated PTLD)
3. Opportunistic infections (PCP)
C. Late Infections (>180 Days):
1. Recurrent bacterial cholangitis and PTLD
2. Use of CMV prophylaxis may delay the onset of this infection to the late period
VIII.Immunosuppressive Therapy (see section on Immunosuppressive and Transplant Therapy)

A. Corticosteroids: Inhibit the synthesis of cytokines, such as IL-2 and interferon-γ → reduction in
the proliferation of lymphocytes and the migration and activity of neutrophils
B. Calcineurin Inhibitors (CNI): Bind to intracellular proteins called immunophilins.
The immunophilin-drug complex inhibits the activity of calcineurin → blocks the transcription of
IL-2 which regulates the proliferative T-cell response
1. Side effects include nephrotoxicity, neurotoxicity, hypertension, hyperglycemia/diabetes
(more with tacrolimus) and dyslipidemia
2. Tacrolimus and cyclosporine
C. Mycophenolate Mofetil: Inhibits the enzyme inosine monophosphate dehydrogenase, which is
essential for purine synthesis → arrested lymphocytes replication. Side effects include GI symp-
toms and bone marrow suppression.
D. Sirolimus: A macrolide antibiotic that blocks T-cell activation by way of IL-2R post-receptor
signal transduction. Used as a rescue treatment in chronic rejection and CNI toxicity. A common
side effect is dyslipidemia
IX. Post-Transplant Lymphoproliferative Disorder (PTLD)

A. Broad range of lymphoproliferative disorders that result from primary EBV infection in the setting
of immunosuppressive therapy
B. Most frequent tumor in children following OLT and usually occurs in the first 2 years after
transplantation
C. Risk factors
1. High total immunosuppression load
2. EBV-naïve recipient
3. Intensity of active viral load
D. Clinical presentation may include fever, lymphadenopathy, tonsillar enlargement, anemia,
splenomegaly or masses

E. Treatment options depend on the presence of architectural distortion on lymph node, tissue or
tonsil biopsy and includes:
1. Immediate decrease or withdrawal of immunosuppression, taking into account the
increased risk of rejection
2. Anti-CD20 monoclonal antibody, rituximab, if the tumor expresses the B-cell
marker CD20
3. Severe cases: the combination of cyclophosphamide + prednisone + rituximab
X. Long-term Outcomes
A. 1-year patient survival around 85%–90%
B. 5-year patient survival around 75%–80%
C. Common non-immune complications of immunosuppressive therapy include chronic kidney
disease, hypertension, hyperglycemia and dyslipidemia
Recommended Reading
Bucuvalas J. Long-term outcomes in pediatric liver transplantation. Liver Transpl. 2009;15:S6-S11.
Halasa N, Green M. Immunizations and infectious diseases in pediatric liver transplantation. Liver Transpl.
2008;14:1389-1399.
Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation.
Hepatology. 2005;41:1407-1432.
Rand EB, Olthoff KM. Overview of pediatric liver transplantation. Gastroenterol Clin North Am. 2003;32:913-
929.
Spada M, Riva S, Maggiore G, Cintorino D, Gridelli B. Pediatric liver transplantation. World J Gastroenterol.
2009;15:648-674.
7A. Normal Anatomy,
Gia Bradley, MD
Ann Scheimann, MD, MBA
I. Development of the Pancreas

A. Pancreatic development is influenced by both signaling and transcription factors
1. Hedgehog proteins—signaling molecules that both stimulate and inhibit pancreatic
growth
2. Other factors influencing development—pancreatic duct primary cilia, fibroblast growth
factor, transforming growth factor-β, vascular endothelial growth factor and homeobox
transcription factor
B. At 4–5 weeks’ gestation, distinct dorsal and ventral pancreatic buds arise from the endoderm of
the caudal foregut (the primordial proximal duodenum)
1. The dorsal bud is larger than and slightly cranial to the ventral bud
2. Each bud communicates with the foregut through a duct
C. Rotation of the duodenum causes the ventral pancreatic bud to rotate clockwise to the left of
the duodenum, and brings it posterior and inferior to the dorsal pancreatic bud
D. During the 7th week of gestation, the two buds fuse to form the pancreas
1. The ventral pancreatic bud forms the inferior part of the head of the pancreas and the
uncinate process
2. The dorsal pancreatic bud forms the superior part of the head, the body, and the tail of
the pancreas
E. During the 8th week of gestation, the ductal systems of the two buds anastomose
1. The longer dorsal duct drains into the proximal part of the ventral duct to form the main
pancreatic duct (duct of Wirsung), which enters the duodenum at the major duodenal
papilla (ampulla of Vater)
2. If the proximal portion of the dorsal duct remains, it forms an accessory duct (duct of
Santorini) that opens into a minor accessory papilla located about 2 cm above the main
duct
a. The accessory duct opens into a minor papilla in 33% of people and ends blindly
in 8% of people, while about half of individuals do not have one
F. At about 8 weeks’ of gestation, groups of endocrine cells (islets) originating from ductal epithe-
lium are identifiable
1. From 10–14 weeks’ gestation, the islets form clumps and detach from the ducts
G. At about 12 weeks’ gestation, exocrine cells appear along the pancreatic ducts
1. Exocrine pancreatic development continues after birth with maturation of specific diges-
tive enzymes, including pancreatic amylase and lipase
II. Anatomy
A. Arterial supply
1. Pancreatic head—supplied by the superior pancreaticoduodenal artery (a branch of the
gastroduodenal artery), and the inferior pancreaticoduodenal artery (a branch of the
superior mesenteric artery)
2. Remainder of pancreas is supplied by the pancreatic branches of the splenic artery
B. Venous drainage
1. Head of the pancreas is drained by superior mesenteric and portal veins
2. Body and neck of pancreas are drained by splenic vein
C. Innervation
1. Acini, islets and ducts innervated by the vagus nerve
2. Blood vessels innervated by sympathetic nervous system
Section 7 - Pancreas 353

D. Endocrine cells
1. These cells are distributed within the islets of Langerhans
2. There are 4 four types:
a. A cells: produce glucagon
b. B cells: produce insulin
c. D cells: secrete somatostatin
d. F cells: secrete pancreatic polypeptide
3. These hormones enter systemic circulation via pancreatic blood flow
E. Exocrine cells
1. The exocrine pancreas consists of lobules that contain acini and ductal system
a. Each acinus contains ~6–8 pyramidal cells, with their apical poles facing a lumen
that empties into an intercalated duct
b. Intercalated ducts fuse to form intralobular ducts that drain into interlobular
ducts
c. Interlobular ducts empty into the main pancreatic duct which enters the
duodenum
2. The acinus synthesizes, stores and releases pancreatic enzymes
a. The basal region of the acinar cell contains the nucleus and endoplasmic
reticulum where proteins are synthesized
b. Enzymes are packaged in secretory (zymogen) granules in the Golgi complex
c. Secretory granules are stored in the apical region of the cell
d. Acinar basolateral membrane has multiple receptors for secretagogues
(e.g., cholecystokinin) and neurotransmitters (e.g., acetylcholine and
vasoactive intestinal peptide)
F. Duct cells
1. Centroacinar (proximal ductular) cells that empty into the acinar lumen and pancreatic
duct cells both modify pancreatic juice by secretion of water and bicarbonate
III. Physiology
A. The adult human pancreas delivers ~2.5 L of fluid to the duodenum daily
1. The fluid is composed of digestive enzymes, bicarbonate to ensure an optimal pH for
enzyme activity, and water
2. At rest, pancreatic secretion rate is 0.2 mL/min, with bicarbonate concentration equal to
that of plasma
3. After stimulation, secretion rate increases to ~4 mL/min, and bicarbonate concentration
increases to a maximum of 140 mEq/L, creating a pH of ~8.2 in pancreatic fluid
B. Regulation of pancreatic secretion
1. Hormones that stimulate pancreatic fluid secretion
a. Secretin
1) Major mediator of hydrogen ion-stimulated bicarbonate and water
secretion
2) Released by S-type enteroendocrine cells in the proximal small intestine
in the presence of duodenal acidification (pH threshold 4.5), bile, and the
products of protein and fat digestion
b. Cholecystokinin
1) Major mediator of meal-stimulated enzyme secretion
2) Secreted primarily by intestinal I cells in response to the products of
protein and fat digestion
2. Interdigestive pancreatic secretion
a. There is a cyclic secretion of pancreatic juice that closely follows the pattern of
the migrating myoelectric complex in the intestine
b. Interdigestive secretion is important in the digestion of residual food, cellular
debris and pathogens in the duodenum
c. Regulation occurs via motilin, pancreatic polypeptide and the autonomic nervous
system
3. Postprandial pancreatic secretion
a. Cephalic phase: vagus nerve mediates pancreatic secretion at the sight, smell,
taste and thought of food
b. Gastric phase: distension of the stomach produces vasovagal cholinergic reflex
that causes increased pancreatic secretion
c. Intestinal phase: chyme in the duodenum leads to pancreatic secretion via
secretin, cholecystokinin and the vagus nerve
4. Hormones that inhibit pancreatic secretion
a. Pancreatic polypeptide: released from the islets of Langerhans in response to
food and duodenal acidification
b. Peptide YY: released in response to fat in the distal ileum and colon
c. Somatostatin: produced in mucosa of stomach and duodenum and in islets of
Langerhans. Released in response to fat and amino acids in the intestinal tract
C. Pancreatic exocrine function (see section on Exocrine Function)
Recommended Reading
Philadelphia, PA: Saunders Elsevier; 2010:909-930.
Kleinman RE, Goulet O-J, Mieli-Vergani G, Sanderson I, Sherman P, Shneider B. Walker’s Pediatric Gastrointes-
tinal Disease. 5th ed. Hamilton, Ontario: BC Decker, Inc.;2008:1185-1201.
2006:1005-1021.

7B. Exocrine Function
John Pohl, MD
I. Exocrine Pancreatic Development

A. The pancreas forms during the 4th week of gestation, developing from the endodermal lining
of the duodenum as ventral and dorsal outpouchings. By Week 6 of gestation, the dorsal aspect
develops a nodular pattern resembling the basic acinar pancreatic anatomy, while the ventral
aspect develops a connection with the early common bile duct. The ventral and dorsal elements
fuse at Week 7 of gestation, and the main pancreatic duct attaches to the common bile duct
(which forms from the fusion of the common bile duct, pancreatic duct and the ventral pan-
creas).
B. Hedgehog proteins (signaling molecules) regulate pancreatic morphogenesis by promoting cel-
lular proliferation and differentiation. Indian hedgehog protein appears to be the sole hedgehog
protein involved in pancreatic growth. Pancreatic acini are present by the 3rd month of gestation.
Zymogen granules appear by the 12th week of gestation. By the 20th week of gestation, zymo-
gens identical to those in adult pancreas are observed. Infants have exocrine pancreatic function
similar to adults at term, although zymogen size and enzyme content may differ.
II. Tests for Exocrine Pancreatic Insufficiency

A. 72-hour fecal fat collection is the gold standard indirect measure of lipolytic enzyme activity
1. Requires accurate estimate of dietary fat intake for 72 hours
2. Requires complete collection of stool for 72 hours
3. Total fats are extracted from stool and weighed
4. Total fat excreted as fraction of fat intake calculated
5. Normal fat excretion is <7% of intake in children over 2 years. May be higher in young
children, especially those infants younger than 6 months of age
6. Very accurate measure of lipase activity, but difficult because of poor compliance with
stool collection and diet record
B. Stool trypsin/chymotrypsin measures proteolytic activity in stool
1. Indirect measure of pancreatic proteolytic enzyme secretion
2. Trypsin in stool is prone to bacterial degradation, producing false low values (poor
sensitivity)
C. Breath hydrogen excretion
1. Using starch as substrate, an increase in breath hydrogen excretion of 20 ppm over
baseline after oral administration roughly indicates insufficiency of pancreatic amylase
activity
2. Positive tests occur in patients with small bowel bacterial overgrowth and
monosaccharide transport defects who may be inaccurately diagnosed with pancreatic
exocrine insufficiency
D. Serum immunoreactive trypsinogen measures trypsin precursor in serum
1. In true exocrine pancreatic insufficiency, serum immunoreactive trypsinogen will be very
low
2. In newborns with cystic fibrosis, serum IRT is elevated because of obstruction of
pancreatic ducts and regurgitation of IRT into bloodstream
3. In newborns with cystic fibrosis and distal intestinal obstruction at birth (meconium
ileus), IRT is usually low because of extensive prenatal destruction of pancreatic acini

E. Secretin/CCK infusion test is the gold standard direct measurement of pancreatic exocrine
enzyme secretion
1. IV infusion of secretin and/or cholecystokinin is followed by aspiration of duodenal
contents (biliary and pancreatic secretions) by nasoduodenal tube for 15 minutes to 1
hour
2. Aspirated pancreatic secretions tested for pH, bicarbonate concentration and lipase,
amylase and proteolytic activity
3. Test is expensive and invasive
4. Test accuracy is increased by simultaneous perfusion of the duodenum with a
nonabsorbed marker, so that total volume of secretion following stimulation can be
determined
F. Fecal elastase measures amount of pancreatic neutrophil elastase in stool
1. Low fecal elastase concentration indicates pancreatic exocrine insufficiency
2. Test is easy to perform
3. Patients with pancreatic sufficient Shwachman-Diamond syndrome may have falsely low
fecal elastase
4. Patients with short bowel syndrome have falsely low fecal elastase
5. Falsely low results occur in patients with large volume diarrhea due to dilution
III. Diagnoses Associated With Exocrine Pancreatic Insufficiency

A. Acquired pancreatic exocrine insufficiency may occur as a complication of chronic pancreatitis.
Causes of chronic pancreatitis include:
1. Trauma, after endoscopic retrograde cholangiopancreatogram (ERCP)
2. Medication use (eg, isoniazid)
3. Infections (eg, ascariasis)
4. Biliary disease
5. Pancreas divisum
6. Metabolic causes (eg, hypercalcemia, hypertriglyceridemia, malnutrition)
7. Associated with systemic diseases (hemolytic uremic syndrome or Kawasaki disease)
B. Cystic fibrosis is the most common inherited cause of exocrine pancreatic insufficiency
(approximately 1 in 2,000 live births)
1. Dysfunction of the cystic fibrosis transmembrane conductance regulatory protein (CFTR)
2. Most common CFTR gene mutation is ΔF508
3. Measuring exocrine pancreatic function is not the recommended means of making a
diagnosis of cystic fibrosis. Knowing the extent of exocrine insufficiency may assist in
management. Recommended diagnostic tests include:
a. Sweat chloride
b. Nasal mucosal potential difference
c. Cystic fibrosis gene (CFTR) mutation analysis
C. Second most common cause of pancreatic insufficiency is Shwachman-Diamond syndrome (1 in
75,000 live births)—exocrine pancreatic insufficiency, bone marrow abnormalities, metaphyseal
dysostosis, growth retardation and immune dysfunction (see section on Shwachman-Diamond
Syndrome)
D. Other causes of pancreatic exocrine insufficiency
1. Hereditary pancreatitis (autosomal dominant) typically presents in 2nd decade of life,
associated with pancreatic malignancy. Can be seen with PRSS1 mutation or SPINK1
mutation affecting cationic trypsinogen gene
2. Pearson’s bone marrow syndrome: pancreatic exocrine insufficiency, sideroblastic
anemia, bone marrow vacuolization
3. Congenital rubella due to cell loss, possibly from molecular mimicry/immune destruction
4. Pancreatic agenesis/hypoplasia: 10 cases reported
5. Isolated pancreatic enzyme defects: very rare (lipase deficiency, colipase deficiency,
enterokinase deficiency)
6. Johanson-Blizzard syndrome: pancreatic exocrine insufficiency, failure to thrive, deafness,
hypothyroidism, microcephaly, abnormal hair pattern, nasal cartilage hypoplasia, small or
absent permanent teeth
Recommended References
Beharry S, Ellis L, Corey M, et al. How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic
disease? J Pediatr. 2002;141: 84-90.
Casellas F, Guarner L, Vaquero E, et al. Hydrogen breath test with glucose in exocrine pancreatic insufficiency.
Pancreas. 1998;16:481-486.
Philadelphia, PA: Saunders Elsevier; 2010.
Pohl JF, Easley DJ. Pancreatic insufficiency in children. Pract Gastro. 2003;27(10):38-48.
Weintraub A, Blau H, Mussaffi H, et al. Exocrine pancreatic function testing in patients with cystic fibrosis and
pancreatic sufficiency: a correlation study. J Pediatr Gastro Nutr. 2009;48:306-310.

7C. Congenital Anomalies
of the Pancreas
Maria E. Perez, DO
Cheryl Gariepy, MD
I. Pancreatic Divisum
A. Most common congenital anomaly of the pancreas
B. Failure of fusion of the dorsal and ventral pancreatic buds off the foregut (typically Weeks 7–8 of
gestation) causes formation of two separate drainage systems
1. Head of the pancreas is drained through the major papilla
2. Neck and tail of the pancreas (majority of the pancreatic tissue) is drained through the
minor papilla
C. Clinical significance is controversial
1. Normal variant vs possible cause of recurrent pancreatitis
2. Possible cause of recurrent pancreatitis
a. High volume of pancreatic secretions through the smaller papilla allows activated
pancreatic enzymes to inflame the papilla, leading to stasis, stenosis and
pancreatitis
D. Diagnosis — ERCP and MRCP
E. Treatment — Endoscopic enlargement of the minor papilla, sphincteroplasty, stent placement
II. Ectopic Pancreas

A. Also known as pancreatic rest
B. Pancreatic tissue with no vascular or physical continuity with the pancreas
C. Most common locations: prepyloric stomach, duodenum, Meckel diverticulum
D. Clinical signs/symptoms:
1. Usually causes no symptoms
2. May be the source of abdominal pain, dyspepsia, GI bleed, pyloric obstruction
3. Ectopic pancreatitis is rare, but it has been documented in the adult and pediatric
population
E. Diagnosis — usually an incidental finding on upper GI series or upper endoscopy; appears as a
round, slightly raised, smooth, submucosal mass with a central umbilication
F. Treatment — usually requires no treatment. Surgical resection only if the rest is thought to be
causing serious symptoms
III. Annular Pancreas

A. Ventral portion of the pancreas encircles the second portion of the duodenum and fuses with
the dorsal aspect of the developing pancreas
B. Most common presentation is neonatal duodenal obstruction
C. 75% associated with other congenital anomalies
1. Anomalies of the GI tract are most common, including malrotation; duodenal web,
atresia or stenosis; TE fistula, imperforate anus and Hirschsprung disease
2. Congenital heart disease
3. Increased incidence in trisomy 21
D. Clinical signs/symptoms
1. Infancy: UGI obstruction, vomiting (may or may not be bilious), pancreatitis
2. Adolescents/adults: duodenal obstruction, chronic pancreatitis
E. Diagnosis
1. Double bubble on plain abdominal x-ray
2. MRCP/ERCP provide best view
F. Treatment — surgical bypass of lesion with duodenoduodenostomy
Recommended Reading
Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 3rd edition. Philadelphia, PA: Saunders
Elsevier; 2006: Chapter 68.

7D. Acute Pancreatitis
Maria E. Perez, DO
Cheryl E. Gariepy, MD
I. Incidence
The incidence of acute pancreatitis in children has increased in the past decade as a result of increased
physician awareness of pathophysiology and improved diagnostic methods. In adults, alcohol use and
gallstones account for most cases. In children, there are multiple etiologies and many cases remain
idiopathic. Management is supportive, and most patients recover without complications.
II. Three Phases in Pathophysiology of Pancreatitis

A. An event triggers pancreatic injury
B. Acinar cell injury occurs through the activation of digestive enzymes, such as trypsinogen
C. Cell injury produces a local inflammatory response with the release of inflammatory mediators
III. Etiology
A. Systemic illnesses associated with pancreatitis
1. Hemolytic uremic syndrome
2. Systemic lupus
4. Sickle cell disease
5. Kawasaki disease
6. Shock/hypoperfusion injury
7. Cystic fibrosis
B. Biliary disease—cholelithiasis, choledochal cyst, biliary sludge
C. Trauma—motor vehicle accidents or bike handle injuries
D. Medications
1. Valproic acid and L-asparaginase are drugs most commonly associated with pancreatitis
at therapeutic doses
2. Azathioprine, mercaptopurine, mesalamine and metronidazole have also been associated
with acute pancreatitis
E. Anatomic—pancreas divisum, annular pancreas
F. Obstruction—duodenal ulcer, tumor of the papilla, duodenal Crohn disease
G. Infections—below are major pathogens
1. Mycoplasma
2. Coxsackie virus
3. Mumps virus
4. Varicella, HSV, CMV
5. Rubeola
6. Hepatitis A & B
7. Influenza A & B
8. HIV
H. Genetic—PRSS1 mutations, CFTR mutations, SPINK-1 mutations
I. Metabolic—hypercalcemia, hyperlipidemia, malnutrition
J. Toxins—acetaminophen overdose, organophosphates, alcohol, spider venom, heroin, amphet-
amines
IV. Clinical Manifestations/Diagnosis

A. Diagnosis of acute pancreatitis requires at least two of the following three criteria:
1. Abdominal pain consistent with pancreatitis
2. Elevation of serum amylase and/or lipase of at least three times the upper limit of normal
3. Radiographic evidence of pancreatitis (ultrasound, CT scan, etc)

B. Indicators of disease severity at presentation: age <7 years, lower body weight, elevated WBC,
and LDH >2,000 associated with more severe disease
C. Predictors of severe disease at 48 hours
1. Low serum calcium
2. Low serum albumin
3. Elevated BUN
4. High fluid requirements
D. Signs and symptoms of acute pancreatitis are listed in Table 1. These vary based on the age of
the child at presentation
1. Turner sign—bluish discoloration of the flank
2. Cullen sign—bluish discoloration of the periumbilical region
3. Turner and Cullen signs indicate hemorrhagic pancreatitis and are late signs in the clinical
course of pancreatitis
Table 1. Signs and Symptoms

Common Uncommon
Symptoms Abdominal pain Back pain
Irritability (infants) Jaundice
Nausea Fever
Vomiting Feeding intolerance
Anorexia Respiratory distress
Signs Abdominal tenderness Turner sign
Abdominal distension Cullen sign
Evidence of dehydration Evidence of ascites
Evidence of pleural effusion
Table adapted from Lowe ME. Pancreatitis. In: Wyllie R, Hyams JS, Kay M, eds. Pediatric
Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Elsevier Saunders; 2011: Chapter 82.
E. Laboratory Findings
1. Serum amylase
a. 33%–45% from the pancreas, remainder from the salivary glands
b. Increases in 2–12 hours and remains increased 3–5 days
c. Can be elevated in other conditions such as diabetic ketoacidosis, renal failure,
burns, mumps, anorexia and bulimia
2. Serum lipase
a. Increases in 4–8 hours and remains increased 8–14 days
b. More sensitive indicator of pancreatic injury than amylase
3. Other evaluation to determine underlying etiology
a. Elevated transaminases and GGT suggest possible underlying biliary obstruction
b. Electrolytes may reveal an elevated calcium level
c. Elevated triglycerides suggest an underlying hyperlipidemia
d. Genetic testing for PRSS1, CFTR, SPINK-1 mutations if there is a significant family
history or patient history of recurrent pancreatitis
F. Imaging
1. Ultrasound
a. Very good initial test
b. Available, inexpensive, no radiation exposure
c. High sensitivity for gallstones
d. Limited by obesity and bowel gas
2. CT scan with IV and enteral contrast
a. Not necessary in most cases of acute pancreatitis
b. Helpful in patients with a prolonged course because it can identify possible
etiologies and/or complications
c. Radiation exposure is a drawback
3. Magnetic resonance cholangiopancreatography (MRCP)
a. Helpful in patients with recurrent episodes of acute pancreatitis
b. Can reveal anatomic abnormalities and obstructive etiologies, such as pancreatic
divisum, gallstones and choledochal cyst
c. Requires anesthesia in younger children
4. Endoscopic retrograde cholagiopancreatography (ERCP)
a. Limited role in initial evaluation of acute pancreatitis
b. Most helpful for interventional procedure (stone removal, stent placement, etc)
5. Esophagogastroduodenoscopy (EGD)
a. Not routine in the evaluation of acute pancreatitis
b. May reveal duodenal ulcer, tumor of the papilla or duodenal Crohn disease
6. Endoscopic ultrasound
a. Not in widespread use yet
b. Helpful for gallstones and microlithiasis
c. Limited data in children
A. Fluid Management
1. Early aggressive fluid resuscitation improves outcome and prevents severe disease in
animal and human studies, by maintaining cardiovascular stability and decreasing the
incidence of pancreatic necrosis
B. Pain Control
1. Parenteral narcotics are preferred
2. All opiates increase sphincter of Oddi pressure, but this action does not affect outcome
or clinical course
C. Nutrition
1. Pancreatic rest (nothing by mouth) is standard in treatment of acute pancreatitis, but no
clear evidence supports this practice
2. Early enteral nutrition is recommended
a. Associated with lower infection risk, reduced surgical interventions and shorter
hospital stay
b. Jejunal feeds may be helpful, since there is less stimulation of the exocrine
pancreas
c. No evidence-based guidelines in children. Adult studies suggest oral nutrition
be resumed when pain and nausea resolve in mild cases. In severe pancreatitis,
enteral nutrition within the first 48 hours has been associated with a better
outcome
3. No evidence that clear liquid or a low-fat diet improves outcome
VI. Complications/Outcomes
A. Most cases resolve in 7–10 days without complications
B. 13%–20% of children have prolonged courses with complications
C. Mortality rate ranges from 2%–10%, and in children is typically associated with systemic illness
D. Peripancreatic fluid collections and pseudocyst
1. Most common complication in children (13%–16% of cases)
2. Trauma often associated with pancreatic pseudocyst formation in children
3. Suspect pseudocyst if acute episode is not resolving, abdominal mass develops or pan-
creatitis recurs
4. Ultrasound or CT scan aid in diagnosis (Figure 1)
5. Pseudocyst can be managed conservatively. Some require surgical drainage (endoscopic
or surgical, often into the stomach) and long-term antibiotics
E. Other local complications
1. Fat necrosis
2. Pancreatic necrosis, pancreatic abscess
3. Abscess extension to adjacent organs

F. Systemic complications
1. Electrolyte abnormalities
2. Sepsis
3. Pleural effusions
4. Acute renal failure
5. Coagulopathy
6. Shock
Figure 1. Pseudocyst (between white arrows) near the distal body and tail of the pancreas.
Figure adapted from Lowe ME. Pancreatitis. In: Wyllie R, Hyams JS, Kay M, eds. Pediatric
Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Elsevier Saunders; 2011: Chapter
82.
Recommended Reading
Kandula L, Lowe ME. Etiology and outcome of acute pancreatitis in infants and toddlers. J Peds.
2008;152:106-110.
Lowe ME, Greer JB. Pancreatitis in Children and Adolescents. Curr Gastroenterol Reports. 2008;10:128-135.
Teh SH, Pham TH, Lee A, Stavlo PL, Hanna AM, Moir C. Pancretic pseudocyst in children: the impact of
management strategies on outcome. J Pediatr Surg. 2006;41: 1889-1893.
Wyllie R, Hyams JS, Kay M, eds. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Elsevier
Saunders; 2011: Chapter 82.
7E. Chronic Pancreatitis
Razan Alkhouri, MBBS
Susan Baker, MD, PhD
I. Chronic pancreatitis
Chronic pancreatitis is the continuous destruction of the pancreatic gland with irreversible scarring
of acinar and ductal cells. Each exacerbation leads to additional damage. Fortunately, the pancreas
has significant reserves and is able to function with as little as 10% of the gland functioning. The
etiology of chronic pancreatitis can be divided into obstructive (ductal anomalies, strictures, trauma and
autoimmune), calcific (hereditary, hyperlipidemia and hypercalcemia) and idiopathic.
II. Genetic causes of chronic pancreatitis

A. Hereditary pancreatitis (PRSS1)
1. Most common genetic cause of chronic pancreatitis
2. Mutation in cationic trypsinogen gene (serine protease 1) located on chromosome 7q35,
autosomal dominant
3. R112H is the most prevalent mutation followed by N291
4. Recurrent bouts of pancreatitis starting at 10–20 years of age
5. Family history usually positive for recurrent pancreatitis
6. Long-term risk of diabetes and pancreatic adenocarcinoma
B. SPINK-1 gene produces pancreatic trypsin inhibitor
1. Mutations cause uninhibited activation of trypsin in pancreatic ducts
2. Mutations may be autosomal dominant, autosomal recessive or multigenic
3. Family history usually absent
C. Cystic fibrosis transmembrane conductance regulator gene (CFTR)
1. Heterozygous mutations of this autosomal recessive gene found in 20%–40% of
patients with chronic pancreatitis
a. Gene expressed in pancreatic ductal tissue of Type 1 is cystic fibrosis with a
CFTRsev/CFTRsev
b. Type 2 is atypical cystic fibrosis with a CFTRsev/CFTRm-v
c. Type 3 is CFTRsev or CFTRm-v plus a second pancreatitis modifier or
susceptibility gene in a polygenetic condition
d. Type 4 is CFTRsev or CFTRm-v plus a strong environmental risk factor,
such as alcohol
III. Causes of chronic obstructive pancreatitis

A. Pancreas divisum
1. 25 % of patients with pancreatic divisum develop obstructive pancreatitis
2. Diagnosed by MRCP or ERCP (see Figure 1)
3. Optimum therapy not established
a. Endoscopic sphincterotomy or surgical sphincteroplasty
b. Stent of minor papilla
B. Idiopathic fibrosing pancreatitis
1. Very rare
2. Presents with obstructive jaundice or abdominal pain and pancreatitis
3. Diffuse pancreatic fibrosis ± inflammation
4. Can be associated with PRSS1, SPINK-1 and CFTR 5T
C. Abdominal trauma may cause obstructive pancreatitis if there is duct damage and stricture
formation
D. Congenital anomalies associated with chronic pancreatitis: choledochal cyst, pancreatic ductal
duplication, anomalous pancreaticobiliary ductal union

E. Autoimmune pancreatitis
1. Primary: isolated pancreatic involvement may require biopsy diagnosis
2. Associated with lupus erythematosis, autoimmune hepatitis, Sjögren disease
3. Histology shows ductal and periductal infiltration by lymphocytes, plasma cells and
granulocytes with irregular narrowing of pancreatic duct and pancreatic enlargement
4. Associated increase in IgG4 (most commonly in adults)
5. Responsive to steroids
IV. Other causes of chronic pancreatitis

A. Hypertriglyceridemia syndromes
1. Type I hyperlipidemia—30% develop pancreatitis
2. Type IV—15% of patients develop pancreatitis
3. Type V—30%–40% of patients develop pancreatitis
4. Common features include triglyceride levels >1,000 mg/dL
B. Tropical chronic pancreatitis
1. Disease with young onset
2. Occurs in tropics
3. Associated with large intraductal calculi, steatorrhea and diabetes
C. Hypercalcemia
D. Organic acidemia
V. Clinical presentation of chronic pancreatitis

A. Repeated bouts of pancreatitis
B. Acute and chronic abdominal pain
C. Chronic abdominal pain may improve in longstanding disease due to loss of pancreatic tissue
D. Some patients present with diabetes, exocrine pancreatic insufficiency and obstructive jaundice
without obvious pain
VI. Diagnostic testing

A. Elevated serum amylase and lipase almost always present during acute episodes but may not be
dramatic as disease progresses
B. Biochemical markers of protein and fat malabsorption occur late in disease due to exocrine
insufficiency
C. Pancreatic stimulation test helpful to evaluate exocrine function (see section on Pancreatic
Function Testing)
D. Fecal elastase (see section Pancreatic Function Testing) is a noninvasive method to document
pancreatic exocrine insufficiency
E. Functional MRCP obtained after intravenous secretin improves definition of pancreatic
duct anatomy
F. Other imaging studies to clarify duct structure, cysts, masses, ductal stricture or dilation
1. Endoscopic ultrasound—head of pancreas
2. Abdominal CT
3. MRCP
G. Genetic testing to clarify causation (see above)
VII. Treatment
A. Treat acute episodes – (see section on Acute Pancreatitis)
B. Acute and chronic pain management
C. Nutrition
1. Low-fat diet, although evidence is lacking
2. Nasoduodenal feeds
D. Surgical therapies
1. Puestow procedure—pancreas and main pancreatic duct are sectioned longitudinally
and oversewn with a segment of jejunum to directly drain pancreatic secretions into
bowel
2. Partial pancreatectomy may relieve pain
3. Complete pancreatectomy with islet cell transplantation in recalcitrant disease
4. Celiac sympathectomy in recalcitrant disease with pain
368 The Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition
Figure 1. Typical pancreatic divisum. Small ventral duct (arrows) drains via major papilla. Larger dorsal duct
(open arrows) drains via minor papilla. Adapted from Yu J, Turner MA, Fulcher AS, Halvorsen RA. AJR.
2006;187:1544-1553. Reprinted with permission from the American Journal of Roentgenology.
Recommended Reading
Kochlef A, Ben Yaghlane L, Kharrat J, et al. Chronic pancreatitis in the ventral pancreas in pancreas Divisum.
Medicine. 2002;80(2):90-93.
Walker A, Goulet O-J, Kleinman RE, Sherman P, Shneider B, Sanderson I. Pediatric Gastrointestinal Disease.
3rd ed. Hamilton, Ontario: BC Decker, Inc.; 2006.
Elsevier; 2006.
Yu J, Turner MA, Fulcher A, Halvorsen R. Congenital anomalies and normal variants of the pancreaticobiliary
tract and the pancreas in adults: Part 2, Pancreatic duct and pancreas. AJR. 2006; 187:1544-1553.

370 The Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition
7F. Shwachman-Diamond
Syndrome
Maria E. Perez, DO
Cheryl E. Gariepy, MD
I. Overview/ Epidemiology
A. Autosomal recessive condition characterized by the triad of exocrine pancreatic insufficiency,
bone marrow dysfunction and skeletal abnormalities
B. Prevalence is 1:50,000
1. SDS the 2nd most common inherited cause of pancreatic insufficiency after cystic
fibrosis
2. SDS is the 3rd most common inherited bone marrow failure syndrome
C. Variable clinical presentation with gastrointestinal and hematologic abnormalities in almost all
patients
D. Median survival for all patients is 35 years. Severe bacterial infection and leukemia are the major
causes of morbidity and death
II. Pathogenesis
A. Biallelic mutations in the SBDS gene on chromosome 7 occur in 90% of cases The remaining
10% have the clinical picture of SDS but no identified mutations
B. The SBDS gene product seems to participate in ribosome biogenesis, RNA processing, stabilizing
the mitotic spindle and neutrophil chemotaxis
C. Mutation causes failure of normal development of pancreatic acinar tissue in utero with fatty
replacement of acini
D. Bone marrow abnormalities
1. Abnormal myeloid clones in bone marrow with mutations of chromosome 7 (eg,
monosomy) and dysmyelogenesis
2. Leukemia or aplastic anemia are long-term complications
3. Impaired neutrophil function
E. Skeletal abnormalities
1. No correlation between genotype and skeletal phenotype
2. Delayed secondary ossification
3. Variable widening, thickening, and irregularity of the metaphyses and growth plates
4. Generalized osteopenia
III. Comparison of Pancreatic Function in CF and SDS

A. Sweat chloride
1. Normal sweat chloride concentration in SDS
2. Elevated sweat chloride in CF
B. Histology
1. Normal ductal elements in SDS. Fatty replacement of the acinar tissue
2. Duct obstruction, fibrosis and ectasia in CF
C. Pancreatic enzyme output
1. Increased pancreatic volume and enzyme output in SDS patients over time with normal
fat absorption in approximately 50% of patients by 4 years of age
2. No increased risk of pancreatitis in SDS
3. Enzyme output in CF is dependent on genotype, whereas in patients with SDS it is NOT
dependent on genotype

IV. Laboratory Diagnosis of SDS
A. Low pancreatic secretion of lipase, amylase and trypsin in response to secretin and CCK
stimulation
B. Low serum immunoreactive trypsinogen and low serum isoamylase in children <3 years of age
C. Serum immunoreactive trypsinogen and fat absorption may normalize in older children/adults.
D. Low serum isoamylase levels and starch malabsorption persist to adulthood
E. Cyclic or persistent neutropenia. Additional cytopenias may also be present. Anemia has been
reported in 42%–66% of patients, and thrombocytopenia has been reported in 24%–60%
F. Imaging
1. Abdominal CT scan or ultrasound shows a fatty pancreas of normal size
2. Skeletal x-ray findings include clinodactyly, syndactyly, genu and cubitus valgus, tooth
enamel defects, metaphyseal dysostosis
V. Clinical Manifestations
A. Diarrhea, steatorrhea, failure to thrive
B. Hematology
1. Recurrent neutropenia is most common abnormality (>90%)
2. Impaired neutrophil chemotaxis
3. Pancytopenia (in approximately 10%–25%) carries the worst prognosis
4. 1/3 of patients with severe chronic neutropenia develop myelodysplastic syndrome
(MDS)
5. 10%–25% of patients with severe chronic neutropenia develop acute myeloid leukemia
(AML)
C. Skeletal abnormalities
1. Progressive metaphyseal dysostosis in approximately 45% of patients
2. Thoracic cage abnormalities in approximately 1/3 of patients
3. Short stature, usually remaining at less than the 5th percentile for life
4. May be at higher risk for slipped capital femoral epiphysis (SCFE)
D. Others
1. Dental caries, enamel abnormalities, delayed dentition
2. Hepatomegaly and elevated transaminases are common in infancy and usually resolve by
5 years of age. Histologic abnormalities may include microvesicular and macrovesicular
steatosis, periportal and portal inflammation, bridging fibrosis and glycogenosis
3. Learning difficulties including weaknesses in higher-order language skills, perceptual
skills and perceptual reasoning are more common in patients with SDS compared to
both healthy controls and patients with CF
4. Behavioral issues and social problems are also more common in patients with SDS
compared to healthy siblings, healthy unrelated controls and patients with CF
VI. Treatment/Management
A. Oral pancreatic enzyme supplementation. Steatorrhea typically resolves in approximately 50% of
patients by 4 years of age. Fecal fat measurement should be repeated to determine the need for
continued supplementation
B. Fat-soluble vitamin supplementation
C. Serial CBC (at least every 4–6 months)
D. Bone marrow biopsy (every 1–3 years)
E. Transfusions as needed
F. Timely evaluation of fever and neutropenia, including physical exam, cultures and prophylactic
antibiotics
G. Granulocyte colony-stimulating factor (G-CSF) for those patients with ANC <500 and with
repeated infections. The French Neutropenia Registry has documented an 80% response with
G-CSF, but there has been no association between G-CSF use and the subsequent risk of AML
H. Bone marrow transplant is the only curative therapy for bone marrow failure
VII. Differential Diagnosis
A. Cystic fibrosis: sweat chloride and genetic testing will differentiate. In addition, high
immunoreactive trypsinogen in most infants with CF
B. Johanson-Blizzard syndrome
1. Exocrine pancreatic insufficiency
2. Multiple congenital abnormalities: deafness, imperforate anus, urogenital
malformations, dental anomalies
3. Endocrine abnormalities: hypothyroidism, GH deficiency, diabetes, panhypopituitarism
4. Typical facies: nasal hypoplasia with beak-shaped appearance, small misshapen teeth,
sparse hair
C. Pearson Marrow-Pancreas syndrome
1. Rare mitochondrial disorder
3. Bone marrow involvement
a. Profound sideroblastic anemia
4. Lactic acidosis is very common
5. Early death is very common
D. Jeune syndrome
1. Rare autosomal-recessive disorder
3. Respiratory difficulties, asphyxiating thoracic dystrophy
Recommended Reading
Philadelphia, PA: Saunders Elsevier; 2010:Chapter 57.
Ginzberg H, et al. Shwachman syndrome: Phenotypic manifestations of siblings sets and isolated cases in a
large patient cohort are similar. J Peds. 1999;135:81-88.
Kerr EN, Ellis L, Dupuis A, Rommens JM, Durie PR. The behavioral phenotype of school-age children with
Schwachman Diamond syndrome indicates neurocognitive dysfunction with loss of Schwachman-Bodian-
Diamond syndrome gene function. J Pediatr. 2010;156:433-438.
Lacaille F, Mani TM, Brunelle F, Lallemand D, Schmitz J. Magnetic resonance imaging for diagnosis of
Schwachman’s syndrome. J Pediatr Gastroenterol Nutr. 1996; 23(5):599-603.
Shimamura A. Shwachman Diamond syndrome. Semin Hematol. 200643: 178-188.

Elsevier; 2006:Chapter 68.

7G. Cystic Fibrosis
Alex Green, DO
Steve Erdman, MD
I. Description
Cystic fibrosis is the most common lethal genetic disease in Caucasians. Cystic fibrosis affects many organ
systems, including the gastrointestinal tract (meconium ileus, distal intestinal obstruction syndrome),
hepatobiliary system (neonatal cholestasis, steatosis, biliary cirrhosis, biliary sludge) and pancreas
(exocrine dysfunction).
II. Carrier Rate/Inheritance/Diagnosis

A. Autosomal recessive with carrier rate in Caucasians of 1 in 25
B. Disease prevalence
1. Caucasians 1 in 2,500
2. African Americans 1 in 15,000
3. Asians 1 in 31,000
C. Of more than 1,500 mutations now described, DF508 accounts for 66%
1. Deletion of the three nucleotides comprising the codon for phenylalanine
at position 508
D. Most cases of CF are diagnosed by newborn screen with high values of immunoreactive
trypsinogen (IRT)
1. False positive (high) IRT may be produced by:
a. hypoxia, respiratory or physiologic stress
b. low Apgar scores, organ damage
c. trisomies 13, 18, 21
d. renal dysfunction
e. hypoglycemia
f. contamination of filter paper
g. carrier status
h. early specimen collection
2. False negative (low) IRT results seen in:
a. CF genetic variant with normal pancreatic function
b. Older affected infant with pancreatic insufficiency
c. Meconium ileus (severe pancreatic insufficiency)
E. Gold standard of CF testing remains sweat chloride.
1. Normal <40 mmol/L
2. Abnormal ≥60 mmol/L
3. Borderline readings between 40–60 require repeat sweat chloride test, CFTR mutation
analysis or nasal potential difference to confirm diagnosis
4. False positive sweat chloride test caused by
a. Anorexia nervosa, Addison disease, nephrogenic diabetes insipidus and
hypothyroidism
5. False negative sweat chloride test caused by
a. Edema
III. CFTR:Structure and Function (See Figure 1)

A. Localized in the epithelial cells of the airway, pancreatic and hepatic ducts, intestine, sweat gland
and vas deferens
B. CFTR opens channels in the cell membrane which transport chloride ions out of the cells
C. Six classes of mutations with increasing severity
1. Mutations of lower class (I-IV) involve mutation, with effect closer to the transcription
and processing phase of the CFTR protein with complete loss of function
a. More serious complications of the lower classes include pancreatic insufficiency
(PI), meconium ileus and hepatic complications
2. Mutations of higher class (V-VI) have reduced function once CFTR reaches the surface
membrane (see Figure 1)

Figure 1. CFTR structure and function.
Adapted from Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 4th edition. Philadelphia, PA:
Saunders Elsevier; 2010: Figure 81-2.
IV. Meconium Ileus (see section on Miscellaneous Cystic Fibrosis)

A. One of the earliest manifestations of cystic fibrosis occurs in 15% of CF neonates
B. 50% of cases resolve without complication
1. Gastrografin enema can be both diagnostic and therapeutic
2. In cases unresponsive to gastrografin enema, T-tube ileostomy with instillation of
n-acetylcysteine, gastrografin or surgical decompression is possible
C. Complications of meconium ileus (MI)
1. Meconium peritonitis from in utero perforation, gangrene, volvulus and atresia often
require surgical intervention
2. CF patients with meconium ileus have ↑ neonatal mortality, ↑ incidence of distal
intestinal obstructive syndrome (DIOS) and ↑ incidence of surgical complications
3. Relationship between MI and later CF liver disease is unclear
D. Overall survival rate, nutritional status and pulmonary function of CF patients with and without
MI are similar
V. Hepatic complications of cystic fibrosis

A. Prevalence of significant liver disease in CF children estimated at 13%–25%
B. 30% of CF children have hepatomegaly
C. Mechanism of hepatobiliary disease:
1. CFTR mutations lead to defective CFTR function in the biliary tree
2. Focal biliary obstruction by viscous secretions leads to focal periportal inflammation and
biliary cirrhosis
3. Portal inflammation causes decreased bile flow, increased toxic (deconjugated) bile and
increased bile precipitation
4. Long-term outcome may be multilobular cirrhosis, hepatosplenomegaly, portal
hypertension and hypersplenism
5. More severe liver disease may be modulated by other genetic and/or environmental
factors
D. Prolonged neonatal cholestasis occurs in 35% of CF neonates
1. The hepatic prognosis is favorable, with only a small percentage progressing to cirrhosis
2. There is no therapy that will alter the course of progression to cirrhosis in CF
3. Ursodiol has been shown to improve bile flow and biochemical parameters of liver injury
in CF
E. Hepatic steatosis is common in CF patients of all ages
1. It is a reflection of malnutrition and/or deficiency of essential fatty acids, carnitine or
choline
2. In older children, the development of diabetes can also contribute to steatosis
3. Ultrasonography and computed tomography show increased hepatic fat
4. Steatosis does not progress to serious focal biliary cirrhosis
F. Focal biliary cirrhosis
1. Usually presents in teen years or later
2. CF patients are generally asymptomatic until late in the disease course
3. Hepatomegaly or splenomegaly can be present along with elevated serum transaminases
4. Elevated serum bilirubin usually a late finding
5. CF patients with high transaminases for 3–6 months should have Doppler US to assess
hepatic blood flow and possible esophageal varices
6. MRCP can be used for checking biliary tree and gallbladder
7. Liver biopsy is another option
8. Treatment includes ursodiol and nutritional improvement
G. Portal hypertension
1. Pace of progression is unpredictable
2. The incidence of portal HTN and variceal bleeding in CF patients is <5%
H. Cholelithiasis and biliary sludging
1. Incidence ranging from 1%–10% of CF patients
2. CF patients usually have radiolucent gallstones rich in calcium bilirubinate and proteins;
therefore, ursodiol does not help dissolve the stones
3. Symptomatic patients require cholecystectomy with intraoperative cholangiogram to as-
sess intrahepatic biliary tree
I. Microgallbladder is found in 20% of CF patients
1. It is a relatively benign condition
2. Bile duct stenosis requiring dilation occurs in <1% of CF patients
J. Liver transplantation
1. Almost all patients with cystic fibrosis have some evidence of liver disease, but only
3%–7% develop the degree of cirrhosis that progresses to end-stage liver disease
2. In 2002 Milkiewicz reported that among CF patients requiring liver transplant, the
average age was 13 years. Recommendation is that liver transplant be performed before
lung transplant if both are needed
H. CF patients have an increased risk of malignancies including esophagus, stomach, small and
large intestine, rectum, liver, biliary tract and pancreas. Greatest risk for malignancy is 20–29
years of age
VI. Nutritional Complications

A. Pancreatic insufficiency (PI)
1. Exocrine pancreatic insufficiency occurs in 60% of infants and in 90% by 1 year of age
2. Protein-calorie malnutrition due to maldigestion and increased energy requirements
occurs in untreated patients
3. An acute Marasmic-Kwashiorkor-like presentation can occur with growth failure,
anemia, hypoproteinemia, edema and ascites
B. Fat-soluble vitamin deficiencies occur in up to 50% CF infants by 2 months of age
1. Even when supplemented with standard ADEK, there can still be a deficiency, especially
vitamin E
C. Electrolyte abnormalities
1. NaCl loss can occur with increased sweating (environmental, fever)
2. Salt supplementation at 2–4 mmol/kg/day
3. Most common presentation is hypochloremic alkalosis and dehydration
4. Very low urinary sodium is a good indicator that salt supplementation is needed

VII. Pancreatic Exocrine Function Association With Genotypes/Abnormalities
A. CFTR genotypes are more closely related to the severity of pancreatic exocrine dysfunction than
they are to the severity of lung disease
B. Fecal fat excretion is more accurate than fecal elastase or serum IRT for classifying the extent of
pancreatic exocrine insufficiency
C. The most accurate test of pancreatic exocrine function is direct pancreatic stimulation with
exogenous hormones (i.e., cholecystokinin or secretin) (see section on Pancreatic Function)
D. Pancreatic insufficiency occurs when <10% of normal pancreatic exocrine function remains
Recommended Reading
Messick J. A 21st-century approach to cystic fibrosis: optimizing outcomes across the disease spectrum.
JPGN. 2010;51:S1-S17.
Wilschanski M, Durie PR. Patterns of GI disease in adulthood associated with mutations in the CFTR gene.
Gut. 2007;1153-1163.
Borowitz D, Durie PR, Clarke LL, et al. Gastrointestinal outcomes and confounders in cystic fibrosis. JPGN.
2005; 273-285.
Weintraub A, Blau H, Mussaffi H, et al. Exocrine pancreatic function testing in patients with cystic fibrosis
and pancreatic sufficiency: a correlation study. JPGN. 2009;306-310.
Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulmonary Med. 2007; 529-536.
Dodge JA, Turck D. Cystic fibrosis: nutritional consequences and management. Best Pract Res Clin
Gastroenterol. 2006;531-546.
Wilschanski M. Patterns of gastrointestinal disease associated with mutations of CFTR. Curr Gastroenterol
Rep. 2008;316-323.
Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 4th edition. Philadelphia, PA: Saunders
Elsevier; 2010.
8A. Nutritional Requirements
of Preterm and Term Infants,
Children, and Adolescents
Julie Khlevner, MD
Anupama Chawla, MD
Children have different nutritional requirements at different ages. Caloric requirements are highest in infancy
and decrease with age (Table 1).
Table 1. Caloric Requirements/kg Body Weight

Age kcal
0–6 months 108
6–11 months 98
1–3 years 102
4–6 years 90
7–10 years 70
Males 11–14 years 55
Males 15–18 years 45
Females 11–14 years 47
Females 15–18 years 40
Adapted from Brandt L. Clinical Practice of Gastroenterology. Vol 2. Philadelphia, PA:
Current Medicine Inc; 1999: Chapter 182.
I. Preterm infant: goal weight gain is 15–20 g/kg/day

A. Optimal nutrition is critical
B. Preterm infants should be given early aggressive enteral/parenteral nutrition (Table 2)
Table 2. Enteral and Parenteral Intake

ENTERAL INTAKE PARENTERAL INTAKE
ELBW (<1,000 g) VLBW –LBW ELBW (<1,000 g) VLBW–LBW
(1,000-1,500 g) (1,000-1,500 g)
per kg/day per kg/day per kg/day per kg/day
Energy 130–150 kcal 110–130 kcal 105–115 kcal 90–100 kcal
Protein 3.8–4.4 g 3.4–4.2 g 3.5–4.0 g 3.2–3.8 g
Carbs 9–20 g 7–17 g 13–17 g 9.7–15 g
Fat 6.2–8.4 g 5.3–7.2 g 3–4 g 3–4 g
Vit A 700–1500 IU 700–1500 IU 700–1500 IU 700–1500 IU
Vit D 150–400 IU 150–400 IU 40–160 IU 40–160 IU
Ca 100–220 mg 100–220 mg 60–80 mg 60–80 mg
P 60–140 mg 60–140 mg 45–60 mg 45–60 mg
Adapted from Kleinman R. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American
Academy of Pediatrics; 2009: Chapter 4.
Section 8 - Nutrition 379

C. Enteral Nutrition
1. Preterm infant formula and preterm human milk fortifiers for breastmilk are required for
appropriate weight gain and bone mineralization
2. Preterm formulas meet the special requirements of preterm infants for:
a. Protein content
1) Higher content results in increased protein accretion and weight gain
2) Whey predominant, cow milk–based
b. Fat
1) Fat blends consist of 40%–50% MCT (MCT delivers adequate fat calories
despite low intestinal lipase or bile salt concentration)
2) Preterm formula fat blends also contain essential fatty acids
c. Carbohydrate
1) Contain carbohydrate blends of lactose and glucose polymers
2) 40%–50% of calories come from carbohydrates
d. Minerals
1) Calcium and phosphorus: preterm formulas contain 165–180 mg of
Ca/100 kcal and 82–100 mg of P/100 kcal (term infant formulas contain
53–76 mg of Ca/100 kcal and 42–57 mg of P/100 kcal)
2) Magnesium content higher than in term formulas
3) Iron: provides 2–4 mg/kg until 12 months of age
e. Vitamins
1) Vitamin content is higher than standard formula and is such that no
additional MVI supplementation is necessary
D. Parenteral nutrition as a supplement to gradual introduction of full enteral feeding
1. Protein
a. Should be provided within 24 hours of birth at a minimum of 1.5–2 g/kg per day
due to rapid loss of protein stores with glucose infusion alone
2. Carbohydrate
a. Glucose infusion rates should start at 6 mg/kg/min and slowly increased to
11–12 mg/kg/min
3. Fat
a. 20% intralipid preparation is superior to the 10% solution because of the lower
phospholipid emulsifier content
b. Administer lipid emulsion continuously over 24 hours at initial dose of 1–2 g/kg,
increasing 3 g/kg maximum
c. Requires close monitoring of serum triglyceride to keep serum levels <200 mg/dL
4. Trace Minerals
a. Additional selenium, zinc, manganese, copper and cobalamin are essential
b. Copper and manganese should be cautiously administered in the presence of
obstructive jaundice
II. Term Infant

A. Caloric requirement:
1. 95–115 kcal/kg/day for the first 6 months of life
2. 40%–60% from carbohydrate
3. 30%–50% from fat
4. 8%–12% from protein
B. Ideal weight gain:
1. 25–30 g/d for the first 3 months
2. 15–20 g/d for the second 3 months
3. 10–15 g/d for the next 6 months
C. Infant formulas in the US are standardized to contain adequate minerals and vitamins to meet
the needs of healthy infants in the first year of life
1. Calcium: 210 mg/day for first 6 months. 270 mg/day 7–12 months
2. Vitamin D: RDA for infants is 400 IU/day
3. Iron: RDA for infants 0–6 months 0.27 mg/day, for infants 7–12 months is 11 mg/day
4. Zinc: RDA for infants 2 mg/day
5. Fluoride: 0.25 mg daily supplementation recommended in infants over 6 months of age
consuming nonfluoridated water
380 The NASPHGAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition
III. Prepubertal Children
A. Caloric requirement 70–90 kcal/kg/day
B. Protein: normally 1–1.2 g/kg/day
C. Fat: 30%–40% of total calories for children 1–3 years. From age 3 to adulthood, no more than
25%–35% of total daily calories
IV. Adolescent (Pubertal)

A. Increased energy requirements:
1. Estimated energy requirement for girls and boys ages 11–14 years is 45 and
55 kcal/kg/day, respectively
2. Requirement decreases to 40–45 kcal/kg/day between 15–18 years
B. Protein requirement estimated at 0.85 g/kg/day
C. At risk for inadequate Ca and vitamin D intake
1. Recommended intake of Ca for both males and females (ages 9–18 years) is
1,300 mg/day
D. Females are at increased risk of iron deficiency due to menstrual losses
Recommended Reading
Brandt L. Clinical Practice of Gastroenterology. Vol 2. Philadelphia, PA: Current Medicine Inc; 1999: Chapter
182.Corkins M. The A.S.P.E.N. Pediatric Nutrition Support Core Curriculum. ASPEN; 2010.
Kleinman R. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2009: Chapter 4.Samour P, King K. Handbook of Pediatric Nutrition. 3rd ed. Sudbury, MA: Jones and Bartlett
Publishers; 2005.

382 The NASPHGAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition
8B. Comparison of
Human Milk and Cow
Milk–based Formula
Lay Har Cheng, MD, MSPH
Conrad Cole, MD, MPH, MSc
I. Human Milk—Nutrition and Production

Nutritional content of human milk is variable, between women as well as between feeds in the same
individual. All outlines of nutritional content of human milk are averages
A. Stages of human milk production
1. Colostrum is the fluid secreted by the mammary glands in the first few days after birth
a. Higher in protein than transitional or mature milk
2. Transitional milk is produced starting 2–5 days postpartum for 10–14 days
b. Higher in fat than colostrum or mature milk
3. Mature milk is produced starting 10–14 days postpartum
a. Higher concentration of lactose than colostrum or transitional milk
b. Foremilk is the milk first sucked by the baby and is thinner and lower in fat,
providing hydration. This is followed by hindmilk, which is richer in fat content
and high in calories
II. Proteins
A. Mature human milk
1. Produced after term infant delivery
a. Contains 70% whey and 30% casein
b. Peak total protein content of term birth colostrum is approximately 2.3 g/dL
c. Protein content of mature milk is approximately 1g/dL
2. Produced after preterm infant delivery
a. Contains 70% whey and 30% casein
b. The more immature the infant at birth, the higher the protein level in maternal
milk at same number of weeks postpartum for at least the first 8 weeks
1) Protein content of preterm human milk is still considered inadequate
for growth in the preterm infant
3. Whey protein in human milk consists of ~99% α-lactalbumin, but also includes
lactoferrin, lysozyme and secretory IgA. The latter three are resistant to intraluminal
digestion and thus aid in infant immune defenses
B. Standard cow milk protein-based formula (20 kcal/oz)
1. Whey-to-casein ratio ranges from 18:82 (resembling ratio in whole cow milk) to 100:0
2. Total protein concentration is approximately 1.4–1.7 g/dL
3. Whey protein in cow’s milk is ~65% β-lactoglobulin, ~25% α-lactalbumin and ~8%
albumin. β-lactoglobulin is the major antigen responsible for cow milk protein allergy
III. Lipids
1. Produced after term infant delivery
a. Lipid content variable between individuals, diurnally and day-to-day, but is
~3.5 g/dL
b. Lipid content increases throughout a feed from foremilk to hindmilk, and also
increases over the total duration of lactation in months
c. Lipids account for ~50% of the calorie content of human milk
d. Lipid content of breast milk is unrelated to maternal diet

2. Produced after preterm infant delivery
a. Higher fat content than milk produced after full-term delivery
b. Lipid composition – 98% triglyceride, 0.8% phospholipid and 0.5% cholesterol
1) Majority of triglyceride is long-chain fatty acids—palmitic, oleic, linoleic
and linolenic
2) Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are also long-
chain fatty acids in milk
3) Medium-chain fatty acids make up <12% of the total fatty acids
B. Standard intact cow milk protein-based formula
1. Total fat content is similar or greater than human milk, ranging 3.4–3.8 g/dL
2. Lipids account for 40%–50% of calories in formula
3. Increased proportion of passively absorbed medium-chain fatty acids and decreased
long-chain fatty acids than human milk to better match the absorption of human milk
4. Composition of fats varies by brand, but generally consists of various vegetable oils
5. ARA and DHA added to most formulas
IV. Carbohydrate
1. Main carbohydrate is lactose, approximately 7 g/dL
2. Contributes 40% of total calories
B. Standard intact cowmilk, protein-based formula (Table 1)
1. Usual carbohydrate is lactose, but some brands use combinations of glucose, corn syrup
solids, rice starch and maltodextrin, with or without lactose
2. Carbohydrate content is fairly standard at 7 g/dL
3. Contributes 40% of total calories
V. Minerals
Table 1. Estimated Micronutrient Content of Preterm, Term and Standard Cow Milk Formula
Mineral (per L) Mature preterm milka Mature term milkb Standard cow milk
formula (20 kcal/oz)b
Iron (mg) 0.9 0.3–0.9 10–12.2
Calcium (mg) 220 200–250 420–570
Magnesium (mg) 40 30–35 41–54
Phosphorous (mg) 125 120–140 255–380
Zinc (mg) 2.8 1–3 5–6.8
Copper (mg) 0.63 0.2–0.4 0.47–0.61
Values from Butte NF, Garza C, Johnson CA, Smith EO, Nichols BL. Longitudinal changes in milk composition
a
of mothers delivering preterm and term infants. Early Human Development. 1984;9:153-162. Values in italics
calculated from Mendelson RA, Anderson GH, Bryan MH. Zinc, copper and iron content of milk from mothers of
preterm and full-term infants. Early Human Development. 1982;6:145-151.
Values from Kleinman R. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of
b
Pediatrics; 2009.
A. Mature Human Milk

1. Although the concentrations of most minerals in human milk are lower than those in
cow milk, mineral bioavailability is higher from human milk
2. Iron: Iron in breastmilk is highly bioavailable; however, exclusively breastfed infants
absorb only ~0.15 mg of iron daily, relying on their own iron stores to meet the daily
need of 0.75 mg. Iron stores are typically exhausted by 5–6 months postpartum in term
infants. Infants require complementary foods to provide the additional 0.6 mg absorbed
iron after 6 months
3. Calcium and magnesium content constant in mature milk and adequate to meet term
infant needs
4. Phosphorous declines during lactation but is still adequate to meet nutritional needs of
term infants
5. Zinc and copper content of breast milk are highest in colostrum, but quickly decline to
stable levels in mature milk that are adequate for nutritional needs until about 6 months
postpartum
B. Preterm Milk
1. Preterm milk is inadequate to meet iron, calcium, phosphorous and zinc needs of
premature infant, and must be fortified or the infant must receive supplements
C. Standard intact cowmilk, protein-based formula
1. If manufactured in the U.S. must meet guidelines for nutrient content set in The U.S.
Infant Formula Act of 1980
VI. Vitamins
A. Human milk
1. Vitamin D
a. Per Institute of Medicine (IOM), recommended dietary allowance (RDA) is
10 µg/day or 400 IU/day
b. Mature milk contains ~ 0.33 µg/L vitamin D (13.2 IU/L) which is inadequate for
nutritional needs. Supplementation required
2. Vitamin K
a. Per IOM, adequate intake is 2.0–2.5µg/day.
b. Mature milk contains ~ 2–3µg/L. Infants do not achieve adequate serum levels
until ~6 weeks after birth if exclusively breastfed
c. Subcutaneous or intramuscular injection of 0.5–1.0 mg phytonadione (Vitamin
K1) at birth prevents Vitamin K deficient bleeding in healthy newborns
B. Cow milk formula
1. Vitamin D and K are adequate to meet nutritional needs by law. However, minimum
volume required to meet RDA varies by formula from 800 mL to 1 liter/day
VII. Substances found only in human milk

A. Digestive enzymes
1. Amylase aids in digestion of starches. Infant pancreas does not secrete amylase until
approximately 6 months of age
2. Bile-salt stimulated lipase aids in digestion and absorption of lipids in infants fed human
milk. Heating or pasteurization of expressed breast milk destroys lipase and decreases
absorption of lipids
B. Host defenses
1. Secretory IgA provides passive immunity to antigens to which mother is exposed
2. Human milk has small amounts of IgM, IgD, IgG and IgE
3. Lactoferrin in human milk has bacteriostatic and bacteriocidal effects
4. Human milk lysozyme – bacteriocidal and antiinflammatory
5. Human milk macrophages aid in protection against gut pathogens
C. Growth factors – higher concentrations in colostrum than in mature milk
1. Epidermal growth factor – cytokine stimulates growth of intestinal mucosa and
epithelium, strengthening barrier function
2. Human milk growth factor promotes growth of intestinal mucosa
3. Insulin-like growth factor promotes growth of intestinal tract
D. Hormones
1. Thyroxine and thyrotropin-releasing hormone – may mask congenital hypothyroidism in
the first few months of life
2. Cortisol – correlates with maternal serum cortisol levels
3. Cholecystokinin – enhances digestion, sedation and satiety
4. Prostaglandins – cytoprotection of gastrointestinal epithelium

Recommended Reading
Bauer J, Gerss J. Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants.
Clinical Nutrition. 2010. [Epub ahead of print].
Butte NF, Garza C, Johnson CA, Smith EO, Nichols BL. Longitudinal changes in milk composition of mothers delivering preterm
and term infants. Early Human Development. 1984;9:153-162.
Gross SJ, David RJ, Bauman L, Tomarelli RM. Nutritional composition of milk produced by mothers delivering preterm.
J Pediatrics. 1980;96:641-644.
Institute of Medicine. 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies
Press; 2011.
Kleinman R. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
Moltó-Puigmartí C, Castellote AI, Carbonell-Estrany X, López-Sabater MC. Differences in fat content and fatty acid proportions
among colostrum, transitional, and mature milk from women delivering very preterm, preterm, and term infants. Clinical
Nutrition. 2011;30(1):116-123.
Wojcik KY, Rechtman DJ, Lee ML, Montoya A, Medo ET. Macronutrient analysis of a nationwide sample of donor breast milk.
J Am Dietetic Assoc. 2009;109(1):137-140.
Kleinman R. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
Moltó-Puigmartí C, Castellote AI, Carbonell-Estrany X, López-Sabater MC. Differences in fat content and fatty acid proportions
among colostrum, transitional, and mature milk from women delivering very preterm, preterm, and term infants. Clinical
Nutrition. 2011;30(1):116-123.
Wojcik KY, Rechtman DJ, Lee ML, Montoya A, Medo ET. Macronutrient analysis of a nationwide sample of donor breast milk.
J Am Dietetic Assoc. 2009;109(1):137-140.
8C. Special Formulas
Jorge Chavez-Saenz, MD
Solange Heller, MD
I. The use of special infant formulas should be justified by a specific diagnosis

A. Prematurity
B. Lactose intolerance
C. Protein allergy
D. Congenital metabolic disorders
E. Short bowel syndrome
F. Inflammatory disease associated with malabsorption
G. Pancreatic insufficiency
H. Hepatobiliary disorders
II. Special formulas

A. Formula for premature infants
1. Usually contains more protein than standard cow milk-based formulas
2. Caloric concentration is often increased
3. Fat content is enriched with medium-chain triglycerides to improve fat and calcium
absorption (usually 40%–50% MCT)
4. Carbohydrates usually in the form of lactose, maltodextrin and glucose polymers
a. Preterm infants have lower intestinal lactase activity than term infants
b. Carbohydrate polymers allow osmolality to remain <300 mOsm/kg of water
5. Contain more calcium than standard cow milk-based formulas (up to 2.5x) with
calcium:phosphorus ratio usually ~2:1
6. 2–2.5 times more vitamin A and D
B. Soy-based formula
1. Soy protein isolate must be supplemented with L-methionine and taurine
2. Carbohydrates are sucrose, corn syrup solids and/or maltodextrin
3. Nonmedical indications include vegetarian parents and parents with religious beliefs
that forbid use of animal-based formulas
4. Infants with galactosemia can safely drink soy-based formula
5. 30%–64% of patients with cow milk protein-induced enteropathy are sensitive to soy
protein and may require hydrolyzed protein or amino acid–based formulas
6. Soy-based formulas are not recommended for premature infants, infants <1,800 grams,
patients with renal disease (soy-based formulas contain aluminum) and infants with
fructose intolerance
C. Protein hydrolysate formula (semielemental)
1. Protein hydrolysate formulas contain casein and/or whey which have been heat-treated
and enzymatically hydrolyzed into short peptide chains and free amino acids
2. Protein hydrolysate formulas are recommended for infants who are intolerant to intact
cow milk and soy proteins
a. Partially hydrolyzed formulas (i.e., Alfare®, Althera®, Good Start®) usually
contain bigger peptides (1,500 kDa), and can induce allergic reactions
b. Extensively hydrolyzed formulas (i.e., Pregestimil®, Nutramigen®, Alimentum®,
Nutren junior®, Peptamen junior®) usually contain only free amino acids and
peptides <1,500 kDa (at least 96% of peptides are <1,000 kDa, and no more
than 4% of peptides between 1,000 and 2,000 kDa)
c. Extensively hydrolyzed formulas are still immunogenic, but do not provoke
reactions in 90% of infants or children with confirmed cow’s milk allergy

3. Uses:
a. Short bowel syndrome
b. Food protein allergy
c. Autoimmune enteropathy
d. HIV-associated enteropathy
e. Pancreatic insufficiency and hepatobiliary disorders
4. Formulas derived from whey require supplemental L-cysteine, L-tyrosine and
L-tryptophan to increase their biological value
5. The carbohydrates are sucrose or glucose polymers (lactose free)
6. Contain medium-chain triglycerides as they bypass the lymphatic system, and require
less pancreatic lipase and bile salts for absorption (usually no more than 55% MCT, as it
increases the formula osmolarity)
7. Indications for high content of medium-chain triglycerides include: liver disease, cystic
fibrosis, lymphangiectasia and chylothorax
D. Free amino acid formula (elemental)
1. The protein precursors in these formulas (i.e., Neocate®, Vivonex pediatric®, Elecare®)
are 100% free amino acids and are designed for infants with food allergy and short
bowel syndrome
2. These formulas are considered hypoallergenic
3. Have a higher osmolarity than hydrolyzed formulas
4. Lipids are a mixture of safflower, sunflower, coconut (medium-chain triglycerides)
or soy oil
5. Carbohydrates in these formulas are corn syrup and/or maltodextrin
6. Some brands that contain soy oil may be contaminated with soy protein
Recommended Reading
Duggan C, Watkins J, Walker W. Nutrition in Pediatrics. 4th ed. Lewiston, NY: BC Decker Inc; 2008: Chapter
67.
Kleinman R. Pediatric Nutrition Handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2004: Chapter 4.
Kleinman R, Sanderson I, Goulet O, Sherman P, Mieli-Vergani G, Shneider B. Walker’s Pediatric

Gastrointestinal Disease. 5th ed. Lewiston, NY: BC Decker Inc; 2008: Chapter 15, 21 and 35.
8D. Nutritional Assessment
Monica M. Zherebtsov, MD
Sharon Taylor, MD
I. Assessment Requirements
The assessment of an infant or child for malnutrition requires objective measures, including anthropomet-
rics measurements, BMI and biochemical measures of malnutrition. The assessment should also incorpo-
rate calculation of energy expenditures to understand the degree to which the child is not meeting their
nutritional goals.
II. Anthropometric Measurements

A. Weight, length, head circumference
1. Infant weight: nude weight to the nearest gram
2. Length <2 years of age requires length board with movable footboard
3. Length >2 years of age requires stadiometer for erect height
4. Head circumference is measured from birth to 3 years of age
B. Underweight children
1. Stunting: body weight proportional to length, but small for age. May be the result of
chronic under-nutrition
2. Wasting: low body weight in reference to length. May be the result of acute or subacute
nutritional deprivation
III. Waterlow Criteria for Malnutrition (Table 1)

A. Acute malnutrition
1. Described as the percent of the ideal body weight for the patient’s height
2. Divide current weight by 50th percentile weight for patient’s height x 100
B. Chronic malnutrition
1. Described by the index of linear growth
2. Divide current height by ideal height for age x 100
Table 1. Waterlow Classification of Malnutrition

Normal Mild Moderate Severe
Height for age (%) 95 90-95 85-90 85
Weight for age (%) 90 80-90 70-80 70
Decreased height for age suggests chronic malnutrition (stunting);
Decreased weight for age suggests acute malnutitrition (wasting).
Adapted from Waterlow (1973).
C. Z score
1. Number of standard deviations (SD) that a height or weight value differs from the mean
height and weight for child’s age
D. BMI—Body mass index (kg/m2)
1. Best anthropometric indicator of adiposity
2. Overweight: BMI 85-95 percentile for age
3. Obese: BMI >95 percentile for age

IV. Body Composition Methodologies
A. Skinfold thickness: direct measurement of fat. Method not fully validated in children
B. Mid-Arm Circumference (MAC): indicator of lean body mass. Measurement of fat, muscle and
bone at the mid upper arm
C. Bioelectrical impedance: measurement of lean body mass based on the principle that bioelectrical
conductance of fatty tissue is lower than the conductance of fat-free tissue
D. Hydrodensitometry: based on the principle that fat-free mass has a higher density than fat. Fat
density can be estimated by comparing body weight in air vs weight in water
V. Biochemical Measurements of Malnutrition

A. Delayed type hypersensitivity—depressed cell-mediated immune response in children with
protein-calorie malnutrition results in delayed or absent response to intradermal antigens
1. Decreased reactivity to Candida albicans skin testing
2. Seen in moderate to severe malnutrition
3. Associated with increased surgical complications
B. Lymphopenia
1. Thymic atrophy and a decrease in T-cell numbers have been observed in malnourished
children
C. Nitrogen balance—reflection of the adequacy of dietary protein
1. Negative nitrogen balance may indicate inadequate protein intake
2. Negative nitrogen balance may indicate increased catabolic stress, leading to lean
mass breakdown. High nitrogen losses can be seen in burn patients and in those with
inflammatory bowel disease for example
3. Positive nitrogen balance can be seen in anabolic states (e.g., states of growth and
tissue repair). A goal of zero balance is used when a patient has adequate visceral
protein stores.
D. Visceral protein levels
1. Blood concentrations of visceral proteins (C-reactive protein, fibrinogen, ferritin,
ceruloplasmin, alpha-1-antitrypsin, albumin, prealbumin, retinol binding protein,
transferrin and alpha-1-acid glycoprotein) synthesized by the liver can be a reflection of
protein nutrition. Decreased levels may reflect decreased stores of amino acid precursors
and/or visceral mass. Levels may vary with infection or catabolic illnesses
a. Blood concentrations of the following visceral proteins increase with catabolic
stress, such as fever or infection: C-reactive protein, fibrinogen, ferritin,
ceruloplasmin, alpha-1-antitrypsin and alpha-1-acid glycoprotein
b. Blood concentrations of the following visceral proteins decrease with catabolic
stress: albumin, prealbumin, retinol binding protein and transferrin
2. Albumin is the most abundant serum protein. Half-life is 20 days
3. Prealbumin is a more useful measurement of protein recovery. Half-life is 2 days
4. Retinol Binding Protein (RBP): rapid response to protein-energy depletion and repletion.
Half-life is 12 hours. RBP is metabolized by the kidney; high levels may develop in renal
failure
5. Transferrin: binds iron for delivery to the tissues. Half-life is 8 days. Increased
concentrations seen in iron deficiency anemia, pregnancy, and with oral contraceptive
use. Decreased transferrin levels found in iron overload, anemia of chronic disease, and
steroid therapy
E. Total energy expenditure (TEE)
1. TEE is the sum of the energy required for BMR (REE) + energy required for activity (EER)
+ energy required for growth + energy lost in urine and stool
2. Estimate the energy required for basal metabolic rate (REE) by the Harris Benedict
Equation in adolescents and adults—see below
3. Basal Energy Expenditure for Children (see Table 2)
Table 2. Schofield Equations for Basal Energy Expenditure for Children
Age Male Female
0–3 year (.167 x wt) + (15.174 x ht) – 617.6 (16.252 x wt) + (10.232 x ht) – 413.5
3–10 years (19.59 x wt) + (1.303 x ht) + 414.9 (16.969 x wt) + (1.618 x ht) + 371.2
10–18 years (16.25 x wt) + (1.372 x ht) + 515.5 (8.365 x wt) + (4.65 x ht) + 200
4. Resting energy expenditure (REE): Used as an approximation of BMR. The difference

between BMR and REE is thought to be <10%. Indirect calorimetry is used to measure
REE
5. Estimated Energy Requirement (EER): Average dietary energy intake required to main-
tain current weight and activity in healthy individuals with normal physical activity
Recommended Reading
Ekvall SW, Ekvall VK. Pediatric Nutrition in Chronic Diseases and Developmental Disorders. Prevention,
Assessment, and Treatment. 2nd ed. New York, NY: Oxford University Press; 2005.
Kleinman RE, ed. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2009.
Preedy V, Grimble G, Watson R. Nutrition in the Infant. Problems and Practical Procedures. London, England:
Greenwich Medical Media; 2001.

8E. Growth Failure
Stephanie Page, MD
Craig Friesen, MD
I. Incidence
10% of children seen in the primary care setting have signs of growth failure. The etiology is most often
multifactorial. Laboratory screening is typically low yield with the majority of diagnoses coming from a
complete history and physical exam.
II. Overview/Epidemiology
A. 1%–5% of referrals to children’s hospitals are for growth failure
B. 15%–30% of children in inner-city emergency departments have signs of growth failure
C. Occurs more frequently in children living in poverty
D. ~20%–33% of cases are undiagnosed
III. Definition
A. The term “failure to thrive” is falling out of favor. Many advocate for using less pejorative terms,
such as growth failure, poor weight gain or undernutrition
B. Growth failure is multifactorial in origin. It is the final common pathway of many medical,
psychosocial and environmental processes
C. Current definition for children younger than 2–3 years of age
1. Weight <3rd/5th percentile for age on more than one occasion
2. Weight <80% of ideal weight for age
3. Weight crosses two major percentiles on standardized growth curve over time
IV. Pathogenesis
A. Organic vs Nonorganic vs Mixed
1. Organic: attributed to major/chronic illness
2. Nonorganic: environmental/psychosocial factors
3. Mixed: combination of illness and psychosocial factors
B. Inadequate Caloric Intake
1. Maternal/infant dysfunction resulting in poor intake
2. Mechanical problems impairing infant feeding
a. Sucking/swallowing dysfunction
b. Inappropriate feeding technique
3. Inappropriate diet
4. Insufficient lactation in mother
5. Economic factors
C. Inadequate Caloric Absorption
1. Malabsorption
a. Cystic fibrosis or other pancreatic insufficiency
b. Milk allergy with intestinal damage
c. Lactose intolerance usually does not result in calorie deprivation in
young infants
d. Celiac disease
e. Chronic liver disease with fat malabsorption
2. Vomiting that produces excess losses or prevents adequate intake
3. Inflammatory bowel disease may cause malabsorption ± increased expenditure due to
inflammation and anorexia with inadequate intake
4. Chronic renal disease

D. Excessive Caloric Expenditure
1. Hyperthyroidism
2. Congenital/acquired cardiac disease
3. Cystic fibrosis, bronchopulmonary dysplasia and other pulmonary disease
4. Cerebral palsy and other hypertonic muscle disease
5. Malignancy
6. Metabolic disease and mitochondrial disease with abnormal intermediary energy
metabolism
V. Diagnosis
A. History
1. Feeding behaviors
2. Dietary history—detailed!
3. Social history—documented observations of maternal/child interactions and parental/
physician interactions
4. Thorough review of systems to detect red flags for organic disease
5. Physical exam
a. Plot weight, height and head circumference
b. Wasting defined as decreased weight for height signals acute malnutrition
c. Stunting defined as decreased height for age signals chronic malnutrition
VI. Evaluation
A. Only 1.4% of laboratory studies performed in evaluating children with growth failure are useful
diagnostically. Most diagnoses are suggested by history and physical examinations
B. Usual screening examinations include:
1. CBC, basic metabolic panel, liver functions
2. Urine analysis
3. Stool examination for blood, fat and infection
C. Occasionally useful screening tests depending on age: thyroid panels, celiac screening and
sedimentation rate
D. Document intake with 2–3-day diet record
E. Monitor growth measurements over time
VII. Therapy/Treatment
A. Determine contributing factors and address them
B. Create positive interactions and a positive feeding environment
C. Dietary supplementation
1. Increase caloric density for infants
2. Add high-calorie foods such as sour cream, butter, peanut butter, cheese for older
children
D. Behavior Modification
1. Reduce snacking/grazing
2. Turn off TV while eating
3. Eat as a family
E. Multiple vitamins with iron and zinc may be needed in children with inflammatory disease and
malabsorption syndromes
F. Appetite stimulants: zinc and cyproheptadine have been used, with no proven long-term effect
G. Monitor for refeeding syndrome in severely malnourished children (see section on Malnutrition)
H. Provide calories for catch-up growth
1. Defined as weight gain needed to return child to previous normal growth trajectory and
percentiles
2. Catch-up weight gain is 2–3x greater than normal rate for age
3. Estimate ~150 kcal/kg/day for child aged 0–1 years to induce catch-up growth
4. Severe FTT may need >200 kcal/kg for catch-up growth
5. Usually some acceleration of weight gain occurs afters 2 days–2 weeks of
increased calories
6. 6–12 months needed to restore height and weight to genetically appropriate level
Recommended Reading
Boswinkel J, Mamula P. Failure to thrive. Pediatr Case Rev. 2003;3(1): 20-29.
Careaga M, Kerner J. A gastroenterologist’s approach to failure to thrive. Pediatr Ann. 2000;29:558-567.
Gahagan S. Failure to thrive: a consequence of undernutrition. Pediatr in Review. 2006;27:e1-e11.
Gahagan S, Holmes R. A stepwise approach to evaluation of undernutrition and failure to thrive. Pediatr Clin
North Am. 1998;45(1):169-187.
Reif S, Belor B, Villa Y, et al. Long-term follow-up and outcome of infants with non-organic failure to thrive.
Isr J Med Sci. 1995;31:483-489.
Stephens M, Gentry B, Michener M, et al. What is the clinical workup for failure to thrive? J Fam Pract.
2008;57(4).
Tolia V. Failure to thrive. In: Wyllie R, Hyams JF, eds. Pediatric Gastrointestinal and Liver Disease 3rd ed.
Philadelphia, PA: Saunders; 2006: 193-202.

8F. Malnutrition
Sarah Shrager Lusman, MD
Amy R. DeFelice, MD
I. Incidence
44% of children presenting to gastroenterology (inpatient and outpatient combined) have evidence of
malnutrition, growth failure, or are overweight. Of the affected children, 20% are acutely malnourished
and 31% are chronically malnourished. Infants and toddlers are at the highest risk for malnutrition.
Chronic malnutrition appears to be equally distributed amongst all pediatric age groups. Acute
malnutrition is seen more often in adolescents.
II. Indications for Nutritional Assessment

A. Any child with height-for-age <10th percentile
B. Child <2 years with weight-for-height <15th percentile. Child >2 years with BMI <15th
percentile
C. Child >2 years with BMI >85th percentile (obesity)
D. Failure of appropriate growth during a 6-month to 1-year interval
E. Child >2 years with height velocity <5 cm/year (chronic malnutrition)
F. Prepubertal weight velocity <1 kg/year or pubertal weight velocity <1 kg/6 months (acute
malnutrition)
G. Hospitalized children or children with chronic medical conditions, especially recurrent febrile
illness or malignancy (the more complex the medical or surgical problem, the higher risk of
nutritional disorders)
H. Children with very limited dietary habits, feeding behavior issues, and abnormal activity levels
I. Children who are taking medication, developmentally delayed, anemic, allergic or intolerant to
certain foods, on a special diet, formula, prescribed or self-imposed fad diet, using supplemental
foods or vitamins, difficult to feed or have dental problems, not ambulatory, sedentary or overly
active
III. Goal of Nutritional Assessment

A. To prevent nutritional disorders and the increased morbidity and mortality that accompany them
IV. Components of Nutritional Assessment

A. Dietary, medical and medication history
B. Physical examination
C. Growth, anthropometric and body composition measurements
D. Laboratory tests
E. Intervention and monitoring
V. Types of Nutritional Disorders

A. Stunting (low height for age) is caused by long-term insufficient nutrient intake and frequent
infections. Usually occurs before the age of 2. Also referred to as chronic malnutrition. Cognitive
effects are largely irreversible
B. Wasting (weight for height more than 2SD below the mean) is caused by acute significant food
shortage and/or disease. Also referred to as acute malnutrition
C. Overweight (BMI 85th–95th percentile for age) or obesity (BMI >95th percentile for age)

Table 1. Classifying Malnutrition
Guidelines adapted from JC Waterlow and AA Kanawati (1970s):
0 1 2 3
Method Normal Mild Moderate Severe
Weight-for-height, % expected ≥90 <90 <80 <70
Height-for-age, % expected ≥95 <95 <90 <85
Mid-arm-circumference/fronto-occipital-circumference ≥0.31 <0.31 <0.28 <0.25
Guidelines from the World Health Organization:

Moderate Severe (type)
Symmetrical edema No Yes (edematous malnutrition)
Weight-for-height −3≤SD-score<–2 (70%–79%) SD-score<–3 (<70%) (severe
wasting)
Height-for-age −3≤SD-score<–2 (85%–89%) SD-score<–3 (<85%) (severe
stunting)
SD score = deviation of the value for an individual from the median value of the reference population,
divided by the standard deviation of the reference population
VI. Types of Malnutrition

A. Severe protein and calorie malnutrition without nutritional edema = marasmus
B. Severe protein malnutrition with nutritional edema = kwashiorkor
VII. Biochemical, Hematologic and Radiologic Evaluation of Malnutrition

A. Laboratory evaluation for specific diseases as directed by the history and physical
B. Hemoglobin and red blood cell indices
1. May identify children with nutritional deficiencies of iron, folate or vitamin B12 or with
anemia of chronic disease
2. Iron deficiency anemia (hypochromia and microcytosis) is the most common nutritional
deficiency in children, presents with low serum iron, high serum iron-binding capacity,
low serum ferritin
3. Causes of microcytic anemia include deficiencies of iron, vitamin E, lead toxicity and
Thalassemia minor
4. Ferritin measures body iron stores, also an acute phase reactant
5. Macrocytic anemia: suggests deficiency of folic acid or vitamin B12 especially when
hypersegmented neutrophils are seen
6. Anemia of chronic disease is normochromic, normocytic and hypoproliferative. May see
low iron, low iron-binding capacity and normal to increased ferritin
C. Prealbumin and albumin
1. Prealbumin: indicator of adequacy of short-term nutrition, synthesized in liver, half-life is
2 days. Falls rapidly with poor dietary intake, rises within 10 days of adequate nutrition.
Falls in the presence of infection. Threshold defining low levels is 13 mg/dL in children
and 4 mg/dL in neonates
2. Albumin: indicator of adequacy of long-term nutrition, synthesized in liver, half-life is
14–20 days, so reflects intake in past 3 weeks. May take up to 3 weeks to normalize
following initiation of nutritional therapy
D. Effects of nutritional disorders on cellular immunity: low lymphocyte count and depressed
delayed-type hypersensitivity testing
E. Vitamin levels: fat-soluble vitamins A, D, E and K may be low in malabsorptive disorders, such as
cystic fibrosis, cholestasis, inflammatory bowel disease and celiac disease
F. Specific mineral levels may be useful in certain types of chronic illness. Example: zinc deficiency
in IBD, copper deficiency in patients on PN without mineral supplementation
G. Serum potassium and phosphorus should be monitored during refeeding of chronically
malnourished patients. Intracellular ion shifts lead to hypokalemia and hypophosphatemia, which
may cause serious cardiac arrhythmias and muscle weakness
H. Radiologic evaluation includes bone age in children with short stature, bone density for those at
risk of osteopenia, e.g., IBD, anorexia nervosa, cholestasis, cystic fibrosis
VIII.Management of Acute Malnutrition
A. First response: in a resource-rich environment, consider chronic condition or illness. In a resource-
poor environment, malnutrition secondary to inadequate dietary intake is most likely
B. Decision to treat in hospital or home: depends on clinical presentation and resources available. If
uncomplicated, manage at home. If complicated, proceed with facility-based care
1. Children who have severe wasting or symmetrical edema involving at least the feet are
severely malnourished and should be admitted to a facility (see WHO guidelines for
details)
2. Clinical features associated with complicated malnutrition: fever related to systemic
infection, respiratory distress, heart failure, electrolyte derangements, marked anorexia,
anemia, profuse diarrhea and shock
C. Acute moderate malnutrition: add a nutrient-rich supplemental food that provides the RDA of all
micronutrients and 75 kcal/kg/day
D. Uncomplicated acute severe malnutrition: manage at home with ready-to-use therapeutic food,
provide 175 kcal/kg/day
1. Examples of therapeutic foods: F-75 and F-100. Both contain dried skimmed milk, sugar,
cereal flour, vegetable oil, mineral mix, vitamin mix and water
E. Complicated acute severe malnutrition: inpatient treatment with liquid food every 2 hours,
100 kcal/kg/day, treat for sepsis and monitor for shock. Do not give IV fluids except in profuse
diarrhea or hypovolemic shock, because IV fluids can stress the organs and precipitate heart
failure
F. Causes of death in severe malnutrition: hypoglycemia, hypothermia, cardiac failure from over
hydration and electrolyte imbalance, and infection
G. Standardized protocol based on WHO guidelines: slower rehydration, avoidance of IV fluids,
routine use of antibiotics, immediate feeding, greater use of tube feeding, supplementation of
potassium, magnesium and micronutrients. Slow advancement to prevent refeeding syndrome
(see section on Eating Disorders)
Recommended Reading
Manary M, Sandige H. Management of acute moderate and severe childhood malnutrition. BMJ.
2008;337:a2180.
World Health Organization. Management of severe malnutrition: a manual for physicians and other senior
health workers. Geneva: World Health Organization; 1999. Available at http://www.who.int/nutrition/
publications/severemalnutrition/9241545119/en/. Accessed July 26, 2011.

8G. Obesity
David Brumbaugh, MD
I. Incidence
Childhood obesity is epidemic in the United States. The number of affected, the number of affected
children continues to increase. There are multiple factors involved, but the majority of cases can be
explained by excess calorie intake and inadequate expenditure.
II. Epidemiology
A. Obesity defined as BMI >95% for age using CDC growth charts from 2000
B. Prevalence by age in the United States (NHANES report 2007–2008)
1. 10.4% in 2–5 years old
2. 19.6% in 6–11 years old
3. 18.1% in 12–19 years old
C. Hispanic boys of all age groups have higher risk of obesity (OR 1.80) than non-Hispanic white
boys
D. Non-Hispanic black girls have higher risk of obesity (OR 1.70) than non-Hispanic white girls
III. Gastrointestinal Complications

A. Non-Alcoholic Fatty Liver Disease (NAFLD)
1. Single-center study of autopsy specimens estimates NAFLD prevalence of 38% in obese
children
2. Progression to hepatic dysfunction in childhood is rare, but fibrosis (67%) and
steatohepatitis (30%) are common
B. Functional abdominal disorders
1. Higher prevalence of obesity in children with functional GI disorders than in controls
C. Cholelithiasis
1. A particular risk in women with extreme obesity (up to 7-fold increase in risk in adult
women with extreme obesity)
D. Abnormal lipid profile
1. Defined as any combination of the following: elevated total cholesterol, elevated
low-density lipoprotein cholesterol (LDL-C), elevated triglyceride or low high-density
lipoprotein cholesterol (HDL-C)
E. Pancreatitis
1. Obesity is an independent risk factor for severity of pancreatitis in adults, perhaps due to
circulating inflammatory adipocytokines
IV. Non-gastrointestinal complications

A. Insulin resistance and Type 2 Diabetes Mellitus (Type 2 DM)
1. Impaired glucose tolerance in 21% and Type 2 DM in 4% of asymptomatic obese
adolescents
2. Risk of obstructive sleep apnea increases 3.5-fold for every standard deviation increase in
BMI z-score in adolescents with snoring
B. Hypertension—prevalence is 34% in children with BMI >95% for age
C. Polycystic Ovarian Syndrome: 30%–70% of women with PCOS are obese
D. Slipped Capital Femoral Epiphysis (SCFE)
1. Increased mechanical load across proximal femoral physis
2. Increasing incidence over last 2–3 decades
3. BMI in SCFE is higher than in general population
E. Blount disease (bowing of tibia)
1. Disordered ossification of proximal tibial physis; can lead to limb shortening. Obesity
produces excessive compressive force on physis, inhibiting growth

F. Idiopathic Intracranial Hypertension (Pseudotumor Cerebri)
1. Increased intracranial pressure of unknown cause can lead to permanent visual loss
2. Weight loss associated with improvement in symptoms
G. Psychological problems
1. A meta-analysis in adults showed that obesity increases risk of depression (OR 1.55)
Also, depression is predictive of developing obesity (OR 1.58)
V. Etiology
A. Obesity is almost always multifactorial, including genetic, epigenetic, environmental and
behavioral factors
1. The strongest genetic association with obesity are variants in the FTO gene (fat mass
and obesity-related gene). These variants only explain 0.5% of variance in BMI
B. Syndromic and Monogenic Forms of Obesity
1. Monogenic (rare): leptin, leptin receptor, melanocortin 4 receptor
2. Syndromic: Prader-Willi syndrome, pseudohypoparathyroidism type 1A, Bardet-Biedl
syndrome
VI. Management
A. Workup should include thyroid studies, fasting plasma glucose concentration, serum insulin
levels, serum lipid concentrations and serum aminotransferase levels
B. Nutritional and behavioral management
1. Portion reduction
2. Avoidance of sugar-containing beverages, restaurant meals and fast food,
calorie dense snacks and eating in front of television
3. Decrease time spent infront of television and increase activity levels
C. Drugs
1. Orlistat: lipase inhibitor reduces fat absorption by 30%
a. Modest weight loss (<10%) in placebo-controlled trial
b. Side effects: steatorrhea, abdominal pain, flatulence
2. Metformin: reduces hepatic glucose production and increases insulin sensitivity
a. Modest weight loss (<10%) in multiple trials
3. Sibutramine: centrally acting serotonin and norepinephrine reuptake inhibitor
a. Pooled results from four studies in adolescents showed mean BMI reduction of
2.2 kg/m2
b. Withdrawn from use in U.S. in 2010 because of risk of heart attack and stroke
in adults
D. Weight Loss Surgery (WLS) (bariatric surgery)
1. Patient selection: recent expert panel recommendations:
a. Adolescents with BMI ≥35 and one of the comorbidities below
1) Type 2 diabetes mellitus
2) Moderate-to-severe obstructive sleep apnea
3) Pseudotumor cerebri
4) Severe steatohepatitis
b. In the absence of complications, only adolescents with BMI >40 are candidates
for weight loss surgery
c. Compliance with medical treatment and monitoring must be demonstrated
prior to WLS
d. Patients must be Tanner stage IV or V
e. Skeletal maturation of 95% if diversion procedure is planned
2. Laparoscopic Roux-en-Y Gastric Bypass (RYGB)
a. Percent decline in BMI at 1 year postoperatively is 36%–37%
b. Metabolic improvement (insulin sensitivity) occurs independent of weight loss
and BMI improvement for unclear reasons
c. Immediate postoperative complications
1) Bowel obstruction
2) Wound infection
3) Dehydration
4) Intestinal leakage
d. Micronutrient deficiencies post-RYGB: iron, vitamin D, vitamin B12,
calcium and thiamine
3. Laparoscopic Gastric Band (Lap Band)
a. Randomized trial comparing gastric band to lifestyle intervention in obese
adolescents showed significantly greater weight loss and improvement in insulin
sensitivity in lap band after two years
b. Multiple studies show persistence of weight loss after lap band
c. Reoperation (band removal, band replacement or adjustment) occurs in 10% or
more of adolescent patients
d. Risk of vitamin deficiency is less than that after RYGB
Recommended Reading
Catoira N, Nagel M, Di Girolamo G, Gonzalez CD. Pharmacological treatment of obesity in children and
adolescents: current status and perspectives. Expert Opin Pharmacother. 2009;11:2973-2983.
Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence of high body mass index in US children
and adolescents, 2007-2008. JAMA. 2008;303:242-249.
Pratt JS, Lenders CM, Dionne EA, et al. Best practice updates for pediatric/adolescent weight loss surgery.
Obesity (Silver Spring). 2009;17:901-910.
Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and
adolescents. Pediatrics. 2006;118:1388-1393.
Teitelbaum JE, Sinha P, Micale M, Yeung S, Jaeger J. Obesity is related to multiple functional abdominal
diseases. J Pediatr. 2009;154:444-446.

8H. Normal Digestion
and Absorption
Carolina S. Cerezo, MD
Lina M. Felipez, MD
I. Process
Digestion and absorption of food is a complex process that begins in the mouth and continues through
to the colon with water and salt absorption. Fats, carbohydrates and protein all have specialized digestion
and absorption processes. These processes evolve from the neonate to child, reflecting the dietary intake
at different stages.
II. Phases of Digestion and Absorption

A. Cerebral:
1. Initial phase of the digestive process
2. Salivary and gastric secretory responses are triggered by sight, smell and thought of
food. Mediated by autonomic nervous system via the vagus nerve
B. Oral:
1. Limited digestion of starch by salivary amylase
2. Lingual lipase produced by von Ebner glands on the dorsum of the tongue provide up to
50% of total lipolytic activity in neonates
C. Gastric:
1. Pepsin initiates protein digestion by preferentially cleaving hydrophobic and aromatic
amino acids and may account for up to 20% of proteolysis
2. Gastric lipase does not require bile or colipase for maximal activity, and may provide up
to 30% of lipolysis
D. Intestinal: duodenum initially enhances gastric activity to process chyme in the stomach
1. As chyme arrives in the duodenum, gastric secretion and motility are suppressed to
allow for intestinal digestion and absorption
III. Satiety Signals (see Table 1)

Satiety signals are relayed to the hindbrain indirectly via the vagus nerve and direct to the hindbrain via
mediators in the blood.
Table 1. Satiety Signals

Mediator Source Receptor Action
CCK I cells in the mucosal CCK receptors in CNS Suppresses appetite by inhibition of
(Cholecystokinin) epithelium of the gastric emptying and secretion
small intestine
GRP (Gastrin Secreted by post Antral G-cells Gastrin induces satiety by increasing
Releasing ganglionic vagal fibers gastric acid secretion and delaying
Peptide) in the antrum gastric emptying
APO IV Intestinal mucosa CNS receptors Centrally mediated appetite suppression
(apolipoprotein in response to fat absorption
a-IV)
Leptin Adipocytes Hypothalamus Decrease appetite
PYY (peptide L cells in ileum and NPY (neuropeptide Y) Reduces appetite by slowing gastric
tyrosine- colon receptors in the CNS emptying and inhibition of pancreatic
tyrosine) and ANS secretion
PP (pancreatic Pancreatic endocrine PP receptors in Inhibits pancreatic exocrine secretion,

polypeptide) cells (F cells) pancreas, GI tract and gallbladder contraction and gut motility
CNS

Table 1. Satiety Signals
Mediator Source Receptor Action
GLP (glucagon- Ileal L cells GLP-1 receptors in Inhibits gastric motility; contributes
like peptide) the pancreas to satiety by delaying absorption of
carbohydrates
Oxyntomodulin Oxyntic cells in the GLP-1 and glucagon Suppresses appetite by binding to the
colon receptor in the GLP1 receptors
pancreas
Ghrelin “hunger D cells in the stomach Ghrelin receptor in Stimulates hunger and growth hormone
hormone” and epsilon cells in the hypothalamus secretion
pancreas and pituitary gland
IV. Gastric Emptying

A. Gastric factors controlling gastric emptying are:
1. Rate of gastric emptying is proportional to the volume of chyme
2. Gastric distension triggers increased gastric motility through direct effects on gastric
stretch receptors and via the vagus and intrinsic nerves of the stomach wall
B. Duodenal factors controlling gastric emptying are:
1. Particle size/consistency – pylorus retains particles >2 mm
2. pH – acid pH of antral contents delays gastric emptying
3. Osmolality – hypertonicity of gastric contents stimulates osmoreceptors and
chemoreceptors in the duodenum that delay gastric emptying
4. Increased fat content of chyme slows emptying
5. Duodenal mucosal receptors for fatty acids, amino acids and carbohydrates are triggered
by increase in size or energy density (not osmolality) of a meal and lead to increased
emptying and rate of delivery
6. Ileal brake – unabsorbed nutrients in the ileum and colon stimulate secretion of
hormones PYY, GLP-1 and GLP-2. These slow gastric emptying
V. Effects of Chyme in the Duodenum

A. Serotonin, released from intestinal enterochromaffin cells and nerve terminals of the enteric
nervous system (ENS) mediate CCK and secretin secretion into portal circulation, where they bind
to receptors in the gallbladder and pancreas
1. CCK promotes gall bladder contraction and pancreatic enzyme, water and ion secretion
2. Secretin stimulates pancreatic enzyme and bicarbonate secretion
B. Exocrine pancreatic secretion is controlled by coordination of cephalic (vagus), gastric (acid,
pepsin and gastric emptying) and intestinal (CCK/secretin) mechanisms
C. Enteropeptidase (enterokinase) secreted from duodenal crypts of Lieberkuhn, in response to
chyme, activates pancreatic trypsinogen to trypsin. Trypsin activates other pancreatic enzymes
D. Ingestion of a meal stimulates water and salt secretion in the jejunum to maintain fluid state of
luminal contents
E. Intestinal motor response is altered in the presence of distention, and pH and osmolality of
chyme. Repetitive pattern of interprandial resting motor activity seen in fasting changes to the
disrupted/disordered pattern post-prandially to allow mixing of luminal contents
VI. Intestinal Conservation and Recycling

A. Acid-base balance is maintained by neutralization of gastric acid
B. Nitrogen is absorbed from metabolized digestive enzymes and mucous
C. Bile acids are preserved via active reabsorption from the ileum and uptake by the liver
D. Water and salt are preserved via colonic reabsorption
E. Dietary fibers are broken down to short-chain fatty acids by colon bacteria and absorbed in the
colon
VII. Fat Digestion/Absorption
A. Lipids supply about 40% of adult energy requirements
B. Polyunsaturated fatty acids (PUFA), linoleic and linolenic acid, are not synthesized by humans and
are essential
C. Most lipids absorbed in the upper 2/3 of the jejunum
D. Soluble dietary fiber reduces fat absorption by binding to bile acids
E. Steps in fat digestion
1. Hydrolysis of triglycerides liberates fatty acid, glycerol and some di- and monoglycerides
2. 20%–30% occurs in stomach via gastric lipase and lingual lipases at pH optimum 4.5,
and 70%–80% in the duodenum via pancreatic lipase and co-lipase at pH optimum
>6.0
3. Optimal function of pancreatic lipase also requires bile salts
4. Products of lipolysis are stabilized (emulsified) by phospholipids and bile salts in micelles.
Hydrophobic region of bile salts forms the core of micelle, with hydrophilic region to the
exterior
5. Phosphatidylcholine (lecithin), the major dietary phospholipid, is hydrolyzed by
pancreatic phospholipase A2
6. Cholesterol esters are hydrolyzed by carboxyl ester lipase or pancreatic cholesterol
esterase in the presence of bile salts and calcium
F. Fat absorption
1. Transfer of fatty acids, monoglycerides and phospholipid across the brush border
membrane of enterocytes is by passive diffusion of micelles and transfer to lymphatic
vessels in the core of the villus
2. Other lipid containing particles transfer lipids to the mucosa via formation of liquid
crystals on the surface of the shrunken emulsion droplet. It is not clear how significant
this mechanism of absorption is
3. The unstirred water layer on the luminal surface of epithelial cells may be rate-limiting
for uptake of long-chain fatty acids, but is not a factor in absorption of short- and
medium-chain fatty acids
4. Transfer of LCFA across the brush border membrane
a. Extracellular: long-chain fatty acid (LCFA) binds to fatty acid transport protein
complex on the enterocyte surface
b. Intracellular: LCFAs are coupled to Coenzyme A by LCFA acyl Coa synthetase to
prevent efflux from the enterocyte
c. Fatty acid-binding protein acts as a cytoplasmic buffer for incorporation of LCFA
into the cell
G. Intracellular processing of lipids
1. Absorbed intracellular fatty acids bind to fatty acid-binding proteins for transport to the
endoplasmic reticulum (ER)
2. In the ER, triglyceride is resynthesized by two processes
a. Monoglyceride pathway in which triglycerides are resynthesized from absorbed
fatty acids and monoglycerides
b. Microsomal triglyceride transfer protein (MTP) transfers resynthesized TG,
phospholipids and cholesterol to apolipoproteins A1 A4 and B48. Deficiency of
MTP is the cause of abetalipoproteinemia
c. Triglycerides and phospholipids are synthesized via the α-glycerophosphate
pathway, in which α-glycerophosphate is acylated with formation of phosphatidic
acid and triglyceride (or phospholipid)
d. Absorbed cholesterol is transported as esterified cholesterol almost exclusively by
the lymphatic system
e. After resynthesis, TG, cholesterol, cholesterol esters and phospholipids are
exported as chylomicrons and very low-density lipoproteins (VLDL)
f. During fasting, VLDL is the major triglyceride-containing lipoprotein. After
feeding, chylomicrons predominate
H. Disorders of fat absorption (See Table 2)

Table 2. Disorders of Fat Absorption
Stage of Fat Defect Clinical Condition Findings, Diagnosis
Digestion/
Absorption
Emulsification/ Defect in fatty Hyperacidity, ie, Zollinger- Gastrinomas in pancreas or duodenum
Formation of acid ionization Ellison syndrome Increased serum gastrin
Micelles Rare in children
Hydrolysis Deficiency of Pancreatic insufficiency Fecal elastase <200 mcg/g
pancreatic Cystic fibrosis Sweat CL test >70 mEq/L
lipase, colipase
or bicarbonate Isolated lipase and colipase
ion deficiency
Schwachman syndrome Neutropenia and pancreatic insufficiency
Johanson-Blizzard syndrome Dysmorphic facies and pancreatic insufficiency
Pearson syndrome Sideroblastic anemia, mitochondrial cytopathy
and pancreatic insufficiency
Solubilization Deficiency of Biliary obstruction Cholestasis, increase direct bilirubin, serum
bile salts bile acids, e.g., TPN cholestasis, Biliary atresia,
Alagille syndrome, PFIC
Impaired synthesis Deficient or missing serum bile acids
Terminal Ileal disease or loss Resection of the terminal ileum, e.g., short
bowel syndrome, post-surgery in Crohn
disease, gastric bypass surgery
Small bowel bacterial Positive hydrogen breath test
overgrowth, blind loop
syndrome deconjugates
bile acids
Mucosal Cell Enteropathy Celiac disease Histology: villous atrophy
Tropical sprue
Giardia lamblia Giardia on biopsy, watery fatty stools + O/P
stool, + Giardia antigen in stool
Deficiency of Abetalipoproteinemia Deficient or absent plasma LDL and apo B,
lipoproteins Histology: lipid-filled enterocytes
Anderson disease Deficiency of apo-B48, autosomal recessive
Chylomicron Lymphatics Lymphangiectasia Distorted villi with ectatic lymphatics
Transport obstruction of Hennekam syndrome Lymphedema, lymphangiectasia and mental
malformation retardation
Protein-losing enteropathy Increased fecal alpha 1-antitrypsin
s/p Fontan operation
Post small bowel Tx Transient chylous ascities
VIII. Carbohydrate Digestion/Absorption

A. Carbohydrate is the major source of calories in humans. Half of the digestible carbohydrate in western
diets is starch
B. Amylose (linear α 1, 4 links) and amylopectin (branched α 1,6 links) are long chain polymers of
glucose
C. Other sources of carbohydrate: milk (lactose), cells of fruits and vegetables (fructose, sucrose and
glucose), purified cane/beets (sucrose)
D. Sorbitol is a sugar alcohol with slow rate of absorption and minor impact on blood sugar
E. Glycogen is the major storage form of carbohydrate in animals with a structure similar to amylase
F. Non-starch polysaccharides are unavailable, e.g., cereals, peas, beans, carrots, peanuts, pectin, gums,
alginates and lignin
G. Cellulose and hemicellulose are resistant to human enzymes
H. Fiber delays the absorption of sugars and curtails insulin response to carbohydrate load
I. Intraluminal carbohydrate digestion
1. Salivary amylase activity promoted by slow chewing, prolonging the oral phase
2. Salivary amylase rapidly inactivated by gastric acid
3. Human milk contains amylase
4. Pancreatic amylase is the major starch hydrolyzing enzyme
5. Amylases produce oligosaccharides, maltotriose, maltose and alpha limit dextrins
(short branched chain oligosaccharides), NOT glucose monomers
J. Brush border membrane hydrolases (see section on Disaccharidase Deficiency)
1. Lactase: lactose → glucose and galactose
2. Maltase: alpha 4 linked oligosaccharides→glucose
3. Sucrase: sucrose→glucose and fructose
4. Isomaltase (debrancher): alpha limit dextrin and alpha 1,6 and 1,4→glucose
5. Trehalase: trehalose (α-linked glucose-glucose found in shrimp, baker’s yeast,
mushrooms)→glucose
K. Enterocyte monosaccharide transport:
1. Monosaccharides are transported by saturable carrier systems in the brush border
membrane of the enterocyte in proximal and mid-small intestine
2. Glucose and galactose are actively transported by sodium glucose co-transporter
(SGLT 1)
a. Active glucose transport is driven by Na + gradient across the apical membrane
b. Each glucose molecule brings with it 2 Na + ions and 2 accompanying anions. This
movement drives water molecules across the BBM to maintain cellular
iso-osmolality
c. Congenital glucose-galactose malabsorption caused by mutations in the SGLT1
gene – severe neonatal diarrhea with carbohydrate-containing feedings
3. Fructose absorbed via facilitated diffusion uses a carrier protein GLUT5
a. Fructose minimally metabolized in the enterocyte
b. Transported across the basolateral membrane by GLUT5 and rapidly metabolized
by the liver
4. Monosaccharides exit epithelial cells by way of the basolateral membrane
a. Depends on facilitated diffusion mediated by specific carrier: GLUT2 for glucose
and GLUT5 for fructose
b. Fanconi-Bickel syndrome: congenital defect in GLUT2
1) Patients exhibit tubular nephropathy, fasting hypoglycemia, rickets,
stunted growth and hepatomegaly due to glycogen accumulation
c. 20% of starch is undigested and delivered to the colon, where it is metabolized
by colon bacteria to SCFA which provides energy
IX. Protein Digestion/Absorption

A. Protein makes up 10%–15% of Western diet
B. Deficiency states are rare even with intakes as low as 0.5 g/kg
C. Plant protein less digestible than animal protein
D. Quality of protein depends on amino acid composition. High quality proteins are rich in essential
amino acids (AA)
E. Digestion and absorption of protein is complete with only 3%–5% lost in the stool
F. Secretory IgA, intrinsic factor and alpha-1-antitrypsin in gut lumen are resistant to proteolysis
G. Intraluminal digestion of protein
1. Pepsinogen release from gastric chief cells is stimulated by gastrin, histamine and
cholinergic nerves
2. Pepsin is released from pepsinogen by autoactivation in an acid pH
3. Enterokinase liberated from epithelial membranes by bile acids activates trypsinogen to
trypsin
4. Trypsin activates other pro-enzymes and trypsinogen
5. Pancreatic proteases
a. Endopeptidases (trypsin, chymotrypsin and elastase) cleave peptide bonds
b. Exopeptidases (carboxy peptidase A and B) remove single amino acids from
C-terminus
c. Final products of intraluminal protein digestion are 30% neutral and basic amino
acids (AA) and 70% short peptides (2-6 AA in length)

6. Protein digestion at the brush border
a. Peptidases are present in gut lumen and epithelium
b. Peptidases produce free amino acids, di- and tripeptides
c. Active absorption of peptides at the brush border is more efficient than active
absorption of amino acids
d. Amino acid based formulas have no absorptive advantage over hydrolysates with
respect to efficiency of protein absorption
e. Cystinuria and Hartnup disease have defects in transport of basic and neutral
AAs. No protein deficiency state occurs in either condition because peptide
absorption is normal
H. Absorption of proteins
1. Di- and tripeptides utilize a separate transport system from single AAs
2. Kinetic studies have shown greater absorption rate for peptides than AA
3. Peptide absorption occurs via
a. Na + -H + exchanger (maintains intracellular alkaline pH) in the BBM
b. Na + -K+ ATPase in the basolateral membrane, maintains inside negative membrane
potential
c. Cytoplasmic peptidases prevent intracellular accumulation of absorbed peptides
I. Protein exit from the epithelium
1. Major mechanisms are active transport and passive diffusion across the basolateral
membrane
2. Glutamine is the major energy source for the enterocyte with NH3 as byproducts
3. Basolateral membrane has different transport proteins for AA and peptides
4. Oligopeptides and AA are released to the portal circulation
5. Majority of absorbed protein that reaches the portal circulation is in the form of AA
X. Vitamin and Mineral Absorption (See Table 3)
Table 3. Vitamin and Mineral Absorption

Water-soluble Vitamin Transport Mechanism
Ascorbic acid Active; sodium dependent at the BBM
Folic acid Hydrolysis of dietary polyglutamates at BBM;
sodium dependent active transport
Cobalamin Binds to R protein from the saliva which is hydrolyzed by
pancreatic enzymes in the duodenum; binds to intrinsic fac-
tor (IF) in the duodenum; uptake of IF-B12 complex at BBM
in the ileum by a specific receptor
Thiamine Sodium dependent active transport; absorption includes
hydrolytic and phosphorylation steps
Riboflavin Absorption includes hydrolytic and phophorylation steps
Niacin ?
Pantothenic acid ?
Biotin ?
Pyridoxine Simple diffusion
Adapted from Farrell JJ, Friedman LS and Brandt LJ, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver
Disease. 8th ed. Philadelphia, PA: Saunders; 2006: Chapter 97; p2172.
A. Fat-soluble Vitamins A, D, E, K are all polar and insoluble lipids
1. Vitamins A, D and E absorbed via passive diffusion
2. Vitamin K1 (phytomenadione) absorbed via a carrier-mediated uptake
3. Vitamin K2 (menaquinone) absorbed by passive diffusion
B. Calcium absorption
1. Plant phytate, oxalate and fiber bind calcium and reduce its availability
2. Dietary lactose enhances calcium absorption
3. Duodenum is major site for active transport (transcellular)
a. Calcium enters cell via specific channels across the apical membrane and binds
with calbindin in the cytoplasm
b. Maximal transport rate correlates with calbindin concentration regulated by
1, 25-dihydroxyvitamin D3 (rate-limiting step)
c. Calbindin transports calcium to basolateral membrane, where calcium dependent
ATPase drives calcium uphill against the electrochemical gradient
4. Passive (paracellular) calcium transport occurs throughout the small intestine. The
jejunum absorbs calcium faster than the ileum and absorption rates are increased by
vitamin D
C. Magnesium absorption
1. Absorption is greater in the ileum than jejunum
2. Jejunal absorption increased by vitamin D
3. Ileal transport by both diffusion and carrier-mediated process
D. Iron absorption
1. Average iron ingestion in meat eating societies is 20–30 mg/day
2. Only 10% of dietary iron is absorbed
3. Most absorption occurs in the proximal small intestine
4. Ferrous (Fe2+) form is absorbed better than ferric (Fe3+) form, which is highly insoluble
and the predominant dietary form
5. At the BBM, ferric iron reduced to ferrous form before cell entry
6. Heme iron is transported into the cell by a separate mechanism
7. Intracellular iron binding proteins transfer iron to basolateral membrane for delivery
across cell membrane and subsequent binding to transferrin
XI. The Neonatal Intestine

A. >50% of the calorie requirement is provided by fat in milk (95% in the form of triglycerides)
B. Neonates have low pancreatic lipase activity
C. Transporters for bile salts are not programmed to appear on ileal enterocytes until after weaning
D. Triglyceride digestion mostly by milk derived and gastric lipase
E. Protein digestion is incomplete
1. Pancreatic proteases do not reach adult levels until after weaning
2. Trypsin and elastase are present in breast milk
F. Gastric acid and pepsin are secreted at birth and reach adult levels by 3–4 months of age
G. Brush border membrane glucose and amino acid transporters are present in fetal intestine, well
before birth, along the entire crypt-villus axis
H. Trigylceride digestion in neonates
1. Milk triglycerides, packaged in small emulsion droplets, are surrounded by trilaminar
membrane that includes phospholipid and proteins (albumin and betalactoglobulin)
2. Since neonatal pancreatic lipase activity is low, digestion is carried out mostly by gastric
lipase produced by the gastric chief cells. This lipase has activity at lower pH (4–6) and
releases fatty acids and diglycerides
I. Carbohydrate digestion in neonates:
1. Minimal need for amylase since the major carbohydrate in milk is lactose
2. Glucosidases/disaccharidases are present at birth in high concentrations
3. Starch digestion in first 2–3 months of life relies on salivary amylase, mucosal
α-glucosidases and colonic salvage by bacterial fermentation of undigested carbohydrate

J. Protein digestion in neonates:
1. Pancreatic proteolytic enzymes are secreted at birth but at a slower rate than the adults
until weaning
2. Enterokinase present at birth and capable of activating trypsinogen
3. Despite immaturity of protein digestion, infants can cope with as much as 3–4 grams of
protein per kg body weight of casein
a. Breast milk proteases (e.g., plasmin) assist in protein digestion
b. Infant intestine can absorb intact macromolecules
c. Whole proteins, such as immunoglobulins, are absorbed via pinocytosis and
endocytosis
Recommended Reading
Bronner F, Pansu D. Nutritional aspects of calcium absorption. J Nutrition. 1999; 129;9.
Farrell JJ. Digestion and absorption of nutrients and vitamins. In: Feldman M, Friedman L, Brandt L, eds.
Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. Vol 2. 8th ed. Philadelphia, PA: Saunders Elsevier;
2006: 2147-2197.
Kleinman RE, ed. Pediatric Nutrition Handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2004: Section III Micronutrients and Macronutrients, Chapters 14-21; 229-359.
Wessling-Resnick M. Iron transport. Annu Rev Nutr. 2000;20:129.
Woods SC. Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake.
Am J Physiol Gastrointest Liver Physiol. 2004; 286:G7.
8I. Disaccharidase Deficiency
Rebecca Cherry, MD, MPH
I. Disaccharidases—Definition
Disaccharidases are glycoproteins located in the apical portion of the microvillus membrane of entero-
cytes. They are responsible for the breakdown of α-glycosidic linkages between monosaccharides allow-
ing for transport across the brush border.
II. Disaccharidases
A. Four types
1. Sucrase-isomaltase – hydrolysis products of sucrose are fructose and glucose
2. Lactase-phlorizin hydrolase – hydrolysis products of lactose are galactose and glucose
3. Maltase-glucoamylase – hydrolysis products of maltase activity are glucose and glucose
oligosaccharides
4. Trehalase – hydrolysis product is glucose
B. Symptoms of disaccharidase deficiencies are nonspecific but usually coincide with ingestion of
the particular disaccharide and do not occur in the absence ingesting the specific disaccharide.
1. Nausea and abdominal pain
2. Vomiting
3. Diarrhea (both osmotic and fermentative)
4. Abdominal distension and flatulence
III. Etiology
A. Primary genetic
1. Isolated sucrase deficiency is the most common
2. Isolated congenital lactase deficiency rare
3. Multiple disaccharidase deficiency rare
4. Intestinal biopsy usually appears normal
B. Secondary
1. Usually a result of intestinal mucosal damage from infection, inflammation, drug toxicity,
radiation, celiac disease and malnutrition
2. Intestinal biopsy may reveal findings leading to specific diagnosis
3. Multiple disaccharidase deficiency is common in secondary deficiency
IV. Sucrase-isomaltase (SI) deficiency

A. Sucrase hydrolyzes α-1,2 and α-1,4 glucosidic bonds in sucrose
B. Isomaltase hydrolyzes α-1,6 bonds in starch/glucose polymers, such as amylopectin (found in
wheat and potatoes)
C. Genetics/prevalence
1. At least 12 mutations known in sucrase-isomaltase gene (chromosome 3q25-q26)
2. Prevalence is <0.2% of North Americans but 2%–10% of Greenland Eskimos
D. Presentation: see symptoms listed above, also can see growth failure
1. On enzyme studies: essentially no sucrase activity but can have trace-to-normal
isomaltase activity
2. Symptom severity may be modified by presence of other disaccharidase deficiency,
sucrose content of diet, GI motility, colon flora, and age (symptoms generally worse in
first 3 years of life)

E. Diagnosis
1. Sucrose hydrogen breath test
a. 2 g/kg sucrose bolus given orally (up to 50 g)
b. Increase in breath hydrogen of >20 ppm in 2 hours after ingestion indicates
sucrase deficiency
c. Increase in breath hydrogen is a result of colon bacterial fermentation of
unhydrolyzed and unabsorbed sucrose
d. False negative results occur with abnormal motility and failure to deliver
unhydrolyzed disaccharide to the colon in a normal interval
e. False negative results occur when colon flora is suppressed by antibiotics—no
fermentation of unabsorbed disaccharide
2. Disaccharidase activity in duodenal biopsies
3. Oral sucrose tolerance tests not generally used. In SI deficiency, blood glucose rises less
than 20 mg/dL above fasting in the hour after oral sucrose administration
F. Treatment
1. Low-sucrose/low starch diet (avoid peas, beets, onions, potatoes, wheat)
2. Lyophilized Saccharomyces cerevisiae provides intact sucrase enzyme
3. Liquid yeast sucrase: sacrosidase (Sucraid™ or Isogest™)
V. Lactase-phlorizin hydrolase (LPH) deficiency

A. Lactase breaks down lactose into glucose and galactose
B. Lactase enzyme is complexed with phlorizin hydrolase, which digests beta-glycosylceramides.
Physiologic role in humans unknown
C. Prevalence
1. Adult type hypolactasia occurs in 75% of the world’s population
2. Northwestern Europeans where the lactase gene is an autosomal-dominant have lower
rate of hypolactasia
3. Adult type hypolactasia affects 100% of Asians, Alaskan natives and Native Americans
4. Adult type hypolactasia affects from 60%–85% of African Americans
5. Hypolactasia starts to develop in childhood after 4 years of age and may develop as late
as adolescence with a decrease in lactase activity to 5%–10% of newborn values
6. Congenital lactase deficiency is rare (autosomal recessive; protein-folding defect, lactase
enzyme accumulates in ER)
7. Preterm infants have a relative lactase deficiency which resolves with age
8. Lactase may be inducible by steroids in preterm infants, but not in term infants
9. May also be induced by enterocyte hypoxia and by keratinocyte growth factor (in vitro)
10. In patients with intestinal injury causing secondary disaccharidase deficiency, lactase is
usually the first disaccharide affected
D. Presentation
1. Colicky abdominal pain, flatulence, and/or diarrhea
2. Most people with lactase deficiency do not have clinical symptoms of lactose intolerance
3. Symptoms occur usually within 3–4 h of lactose ingestion
4. Symptoms can be worse in the setting of rapid intestinal transit (e.g., IBS)
5. Most people with lactase deficiency can tolerate up to 12 g of lactose (about the
amount in 1 cup of milk) without difficulty
E. Diagnosis
1. Breath hydrogen testing after lactose ingestion (see sucrase diagnosis)
2. Small bowel biopsy with direct measurement of lactase activity in tissue
3. Trial of lactose-free diet is adequate for diagnosis in most clinical settings
F. Treatment
1. Low-lactose diet
2. Yeast-derived lactase supplements taken with milk products
3. Supplement Ca and Vitamin D if dairy foods are restricted from the diet
VI. Maltase-glucoamylase
A. Alternate pathway for starch digestion
B. Deficiency can lead to starch malabsorption
C. Roughly 2% of chronic childhood diarrhea may be due to this deficiency
D. Diagnosed by enzyme activity on small intestinal biopsy
E. Treatment: avoidance of dietary starches and short glucose polymers
VII. Trehalase
A. Breaks down trehalose, found in some mushrooms, algae and insects
B. Deficiency is autosomal recessive
C. Present in 8% of Greenlanders and essentially no other populations
D. Treatment: avoidance of trehalose
Recommended Reading
Heyman MB. Lactose intolerance in infants, children and adolescents. Pediatrics. 2006;118(3):1279-1286.
Robayo-Torres CC, Quezada-Calvillo R, Nichols BL. Disaccharide digestion: clinical and molecular aspects. Clin
Gastroenterol Hepatol. 2006 ;4(3):276-287.

8J. Congenital Enzyme
and Transport Defects
Meghana Sathe, MD
I. Transport Defects
Several rare medical conditions are due to congenital defects in enzyme synthesis, or defects in the
transport of electrolytes or nutrients across the bowel wall.
II. Abetalipoproteinemia
A. Defective MTP gene (microsomal triglyceride transfer protein) prevents synthesis of
ß-lipoproteins. Failure to transport absorbed triglycerides and cholesterol esters into the
portal circulation with deficiency of triglycerides and cholesterol esters. Triglycerides and
apolipoproteins B-100 and B-48 are important to the formation of VLDLs and chylomicrons
B. Inheritance: autosomal recessive
C. Clinical Manifestations
1. Profound fat malabsorption in the neonate causes diarrhea, emesis and failure to thrive
2. Untreated patients develop irreversible neurologic abnormalities starting with loss of
deep tendon reflexes (vitamin E deficiency)
3. Other neurologic problems: retinitis pigmentosa, ataxia and spinocerebellar
degeneration
4. Patients may develop fatty food aversion
D. Diagnosis
1. Low to absent ß-lipoproteins in plasma
2. Plasma triglyceride concentration <10 mg/dL
3. Serum cholesterol concentration 25–40 mg/dL
4. Red blood cell acanthocytosis reflects defects in structural lipids of the red cell
membrane
5. Small bowel surface grossly yellow/white from fat. Biopsies show fat-laden enterocytes
in the upper portion of the villus. Electron microscopy shows fat droplets in enterocyte
cytoplasm (see Figure 1)
E. Treatment:
1. Diet low in long-chain triglycerides and cholesterol can effectively reduce steatorrhea
2. The diet should be supplemented with medium-chain triglycerides that can be directly
absorbed into the portal circulation without micellar formation
3. Fat-soluble vitamin supplementation including high doses of vitamin E to minimize
neurologic symptoms
Figure 1. Electron microscopy demonstrating fat droplets in the enterocyte.

Red blood cell smear with acanthocytosis due to cell membrane defect from
defect in structural lipids.
Adapted from Pautler D, Easley D, Pohl JF. Abetaliproteinemia: Image of the
month. JPGN. 2008;46(4):355.

III. Primary Bile Acid Malabsorption
A. Impairment of bile acid reabsorption caused by defective or absent apical sodium co-dependent
bile acid transporter (ASBT) of ileal enterocytes and cholangiocytes
B. ASBT is essential in the enterohepatic circulation of bile acids, which preserves 95% of the bile
acids secreted into the intestine
C. Inheritance: autosomal recessive
D. Clinical Manifestations
1. Secretory diarrhea in infancy is driven by two mechanisms
a. Fat malabsorption
b. Stimulation of colonocyte secretion of ions and fluids by unabsorbed bile acids
2. Steatorrhea and failure to thrive
3. Low serum LDL cholesterol secondary to loss of cholesterol in bile acids
E. Diagnosis
1. Small intestine architecture is normal
2. Diarrhea may improve with trial of cholestyramine (see Treatment for further details) and
low-fat diet
3. Bile acid absorption can be detected by measuring bile acid analogue 75 Se-homocholic
acid-taurine test
F. Treatment
1. Cholestyramine binds bile acids and may prevent secretory diarrhea
2. Cholestyramine does not prevent fat malabsorption and may even exacerbate it by
binding bile acids, preventing micellar formation
3. Low-fat diet with supplemental medium chain triglyceride (MCT). MCTs do not require
bile acids for emulsification, as they can be directly absorbed into the portal system
4. Fat-soluble vitamin deficiencies should be monitored and supplemented
IV. Congenital Chloride Diarrhea (see Diarrhea)

A. Most common cause of congenital secretory diarrhea results from mutation in the SLC26A3
gene causing abnormality of Cl-/HCO3 exchange in the ileum and colon
B. Diagnosis
1. Fecal chloride concentration exceeds the sum of fecal sodium and potassium
2. Metabolic alkalosis, hypochloremia, hypokalemia and hyponatremia
C. Treatment
1. Oral and/or parenteral KCl supplementation
V. Congenital Sodium Diarrhea

A. Very rare impairment of intestinal sodium-hydrogen exchanger results in net sodium excretion by
enterocyte
1. There are 3 Na + -H + transporters in the GI tract including NHE-2, NHE-3, NHE-4. NHE-
2 and NHE-3 are expressed in the small intestine and NHE-4 is mainly in the gastric
mucosa. A defect in NHE-3 is the possible primary cause of congenital sodium diarrhea
1. Polyhydramnios due to in-utero diarrhea
2. Dilated small bowel detectable on prenatal ultrasound suggest distal intestinal atresia
3. Life-threatening diarrhea in the 1st week of life. Diarrhea is alkaline with high sodium
concentration
4. Hyponatremia and metabolic acidosis. Urine shows low-to-normal levels of sodium
5. Association with choanal atresia has been noted
D. Diagnosis
1. Fecal stool sodium >90 mEq/L of stool water. Stool bicarbonate levels are also increased
2. Hyponatremia and metabolic acidosis
3. Normal or low urinary sodium
4. Intestinal biopsies usually normal. Some show partial villous atrophy and decreased
villus-to-crypt ratio
E. Treatment
1. Maintain fluid–electrolyte balance with oral and/or parental supplements
VI. Acrodermatitis Enteropathica
A. Primary acrodermatitis enteropathica: mutation of ZIP4 gene on chromosome 8q24.3 causes
abnormal zinc transport through the apical membrane of gastric, intestinal, colonic and renal
epithelium
1. SLC39 proteins are members of the ZIP family of metal ion transporters that export into
cell cytoplasm
2. SLC39A4 has been implicated in the uptake of dietary zinc into intestinal enterocytes
1. Presents earlier in patients who are exclusively breastfed, as breast milk is not an
adequate source of zinc
2. Anorexia, steatorrhea and failure to thrive
3. Acral dermatitis on hands and feet. There is also a rash around the orifices, specifically,
the mouth, anus, ears and nares (See Figure 2)
4. Alopecia is seen in long-term zinc deficiency
5. Other manifestations include poor wound healing and abnormalities of humoral and
cell-mediated immune system. Neurologic manifestations include mental slowness and
neurosensory problems
6. Secondary zinc deficiency due to chronic diarrhea can present similar to primary acroder-
matitis enteropathica
D. Diagnosis
1. Low serum level of alkaline phosphatase, a zinc-dependent metalloenzyme
2. Low serum and urinary zinc
3. Small bowel histology: loss of villous architecture with increased cellular infiltration in
the lamina propria. Enterocyte nuclei enlarged with chromatin
Figure 2. Dermatitis associated with primary acrodermatitis enteropathica.
4. Skin histology: nonspecific inflammation with intracellular edema and pallor of the upper
third of the epidermis
E. Treatment
1. Large doses of zinc supplementation
VII. Congenital Glucose-Galactose Malabsorption

A. Mutation in SGLT (sodium coupled glucose transporter) gene
1. In homozygous state, inability to transport glucose and galactose in the intestinal and
renal tubular epithelial cells
2. SGLT couples the transport of two molecules of sodium with 1 molecule of glucose or
galactose
B. Inheritance: autosomal recessive. Heterozygotes have mild clinically insignificant impairment of
renal and intestinal glucose transport. Most common in Greenland Eskimos
1. Life-threatening neonatal diarrhea, dehydration and metabolic acidosis. Diarrhea stops
when feedings are withheld

D. Diagnosis
1. Diarrhea resolves on diet absent of glucose and galactose
2. Breath hydrogen test positive after glucose by mouth
3. Stool pH <5.3 due to bacterial fermentation of unabsorbed carbohydrate to acetate, butyrate and propio-
nate
4. Stool osmolality increased
5. Stool Clinitest positive
6. Small intestine histology and disaccharidase activity are normal
E. Treatment
1. Carbohydrate-free formula with fructose as the carbohydrate source
2. Patients must be monitored carefully, as fructose absorption early in life may be limited
3. Older patients tolerate some dietary glucose. Generally, patients require a high-fat, high-protein diet
throughout life
VIII. Fructose Malabsorption

A. Fructose malabsorption is a feature of 2 distinct clinical circumstances
1. Toddler’s diarrhea due to increase ingestion of fruit juices
2. GLUT 5 responsible for absorption of fructose across enterocyte brush border. In animals, GLUT 5
expression increases slowly during weaning
3. Perhaps relative deficiency is causative in human children drinking copious fruit juice
4. Isolated fructose malabsorption (IFM)—rare disorder resulting from mutations in the GLUT 5 gene causes
lifelong fructose malabsorption
B. Inheritance: IFM is autosomal recessive
1. Toddler diarrhea: fruits and fruit juices produce abdominal cramping and osmotic diarrhea. Symptoms are
dose-dependent
2. IFM: malabsorption of fructose is severe and not dose-dependent
D. Diagnosis
1. Usually clinical – improved symptoms with fructose-free diet
2. Fructose breath hydrogen test
3. Small intestinal histology is completely normal
E. Treatment
1. Fructose-free diet for toddler diarrhea can be titrated to tolerance. Need for strict fructose elimination
improves with age
2. IFM patients: lifelong fructose elimination diet
IX. Hereditary Fructose Intolerance

A. Rare inborn error of metabolism often confused with fructose malabsorption
1. Disease results from deficiency of aldolase-B in liver, kidney and intestine
2. Aldolase B
a. Critical in gluconeogenesis. Deficiency causes hypoglycemia
b. Aldolase B mediates conversion of fructose-1-phosphate to dihydroxy-acetone-phosphage (DHAP)
and glyceraldehyde. Enzyme deficiency blocks fructose metabolism at the formation of fructose-
1-phosphate, preventing release of free phosphates needed in the metabolism of glycogen to
glucose
c. Fructose-1-phosphate accumulation and fructokinase inhibition allows free fructose in blood with
eventual change in ATP-adenosine monophosphate (AMP) cellular ratio secondary to decreased
free phosphate. The result is increased production of uric acid, with episodes of hyperuricemia and
lactic acidosis. Hepatic and renal dysfunction is also seen
1. May be difficult to differentiate clinically from IFM. Most patients naturally avoid fructose-containing
foods, including fruits
2. Patients with hereditary fructose intolerance are much sicker than patients with IFM after consumption
of fructose with abdominal pain, nausea, hypoglycemia and weakness, which may progress to vomiting,
irritability, lethargy, jaundice, seizures (from hypoglycemia) and liver failure
3. Patients may have scleral icterus and hepatomegaly ± splenomegaly during an acute episode
D. Diagnosis
1. Dietary history and symptoms give the best clue to diagnosis
2. Clinitest positive non–glucose-reducing sugar in the urine
3. Renal Fanconi syndrome with glucosuria, proteinuria and aminoaciduria. Serum electrolytes indicate renal
tubular acidosis
4. Hepatic dysfunction
5. Dietary elimination of fructose causes improved symptoms
6. Liver biopsy may show focal necrosis, fatty degeneration in peripheral lobules, bile duct proliferation, and
late changes of portal and biliary cirrhosis
E. Treatment
1. Eliminate fructose and sucrose from diet
2. Supportive care during acute episode
3. Avoiding triggers that cause acute episodes decreases risk of developing cirrhosis from repetitive insults
X. Lysinuric Protein Intolerance

A. Sole disorder of amino acid and peptide absorption causing GI symptoms
1. Mutation of SLC7A7 gene which encodes for the cationic amino acid transporter y+LAT-1 located on
basolateral membrane of enterocyte, renal tubules and respiratory epithelium
a. Responsible for transport of dibasic amino acids (lysine, arginine and ornithine) in exchange for
Na + and neutral amino acids
b. Decreased absorption of arginine and ornithine results in urea cycle dysfunction and
hyperammonemia
1. Failure to thrive, diarrhea and vomiting
2. Many patients have history of self-imposed restriction of protein intake
3. Chronic ingestion of protein enriched diet can result in irreversible mental retardation
4. Patients also present with marked hepatosplenomegaly and frequent bone fractures
D. Complications
1. Alveolar proteinosis is common possibly due to alterations in the immune system and accumulation of
lipoprotein deposits in the alveoli
2. Osteoporosis due to decrease in essential amino acid lysine
3. Arginine deficiency may also be associated with vascular endothelial dysfunction, increasing risk of vascu-
lar abnormalities throughout life
4. Deficiency of total and antigen-specific immunoglobulin, resulting in increased risk of infections (T-cell
function is normal)
5. Increased risk for hemophagocytic histiocytosis and systemic lupus
E. Diagnosis
1. Decreased plasma concentration of diamino acids
2. Urine organic acids show elevated lysine and orotic acid
F. Treatment
1. Systemic administration of the essential amino acid, lysine, has not improved clinical symptoms
2. Supplemental citrulline (200 mg/kg/d) and dietary protein restriction (not to exceed 1.5 g/kg/d). Citrulline
is absorbed by neutral amino acid transporters and can subsequently replenish the urea cycle. Mealtime
doses of citrulline are readily absorbed and decrease rates of postprandial hyperammonemia by providing
needed substrate for the urea cycle

Recommended Reading
Martin MG, Wright EM. Congenital Intestinal Transport Defects. In: Walker WA, Kleinman RE, Sherman PM, Shneider BL,
Sanderson IR. Pediatric Gastrointestinal Disease. 4th ed. Hamilton, Ontario: BC Decker, Inc.: 2006; Chapter 43, Part 2: 898-
921.
Pautler D, Easley D, Pohl JF. Abetaliproteinemia: Image of the month. JPGN.

2008;46(4):355.
Wyllie R, Hyams JF, eds. Pediatric Gastrointestinal and Liver Disease 3rd ed. Philadelphia, PA: Saunders; 2006.
8K. Vitamin and Mineral
Absorption, Function, and
Deficiency States
Tiffany Patton, MD
Vitamins are essential organic compounds required in small amounts as cofactors in a wide range of meta-
bolic functions of an organism. Deficiency typically results in specific symptoms and laboratory findings.
Similarly, excessive levels may be toxic with characteristic presentations. Most vitamins and minerals can be
assessed with laboratory testing.
Fat-soluble Absorption Function Deficiency Toxicity Laboratory

Vitamins Measurement
Vitamin A Location: - F orms retinol for Etiology: - Alopecia - Retinol
(retinoid) -U
pper small low light and -Fat - Ataxia - Retinol
intestine color vision malabsorption -M uscle and binding
- Carbohydrate (pancreatic insuf- bone pain protein
Dietary source: transfer to ficiency, choles- - Cheilitis
Green leafy veg- glycoprotein tatic liver disease, - Conjunctivitis
etables, carrots, - Maintains malabsorption) - Headache
sweet potatoes, epithelial -Dietary - Hepatotoxicity
liver, fish oil, kid- integrity insufficiency - Hyperlipidemia
ney, dairy products - R equired for cell
and eggs proliferation Symptoms:
-Night
blindness
- Xerophthalmia
- Bitot spots
- Keratomalacia
Vitamin D Location: - Regulates Etiology: - Hypercalcemia - 25-OH
(Ergocalciferol = - Synthesis in skin calcium and -Fat (N/V, weakness, Vitamin D
D2, (D3) phosphate malabsorption fatigue, - Calcium
Cholecalciferol - Absorbed from levels through -Inadequate sun diarrhea, - Phosphorous
= D3) food in duode- impact on exposure anorexia,
num and distal absorption, -Dietary headache,
small intestine but also renal insufficiency confusion,
excretion and psychosis and/or
Dietary source: bone mobiliza- Symptoms: tremor)
Fortified milk, liver, tion - Rickets/osteo- - Hypercalcuria
oils, sunlight, egg malacia
yolks - Dental caries
- Hypocalcemia/
hypophospha-
temia
- Increased alka-
line phosphatase
- Phosphaturia,
aminoaciduria
(Continued)

Fat-soluble Absorption Function Deficiency Toxicity Laboratory
Vitamin E Location: - Cell membrane Etiology: - Impaired - Plasma
- Nonsaturable antioxidant -Fat neutrophil Alpha-tocoph-
passive diffusion - Free radical malabsorption function erol
in jejunum scavenger -Inadequate - Coagulopathy
- Inhibits intake (breastfed - Thrombocyto-
Dietary source: polyunsaturated infants) penia
Oil containing fatty acid -Chronic - Cerebral
grains, plants and oxidation antibiotic therapy hemorrhages
vegetables
Symptoms:
- Anemia/hemo-
lysis
-N eurologic defi-
cit (ocular palsy,
wide-based gait,
decreased DTR’s)
- Altered
prostaglandin
synthesis
Vitamin K Location: - Carboxylation Etiology: -N
ot well - PT
- Saturable, and activation of - Fat understood - Inadequate
energy clotting factors malabsorption levels of vitamin
dependent - Affects bone - Inadequate K dependent
absorption in formation intake (breastfed clotting factors
jejunum infants) (II, VI, IX, X)
- Chronic - Plasma
Dietary source: antibiotic phylloquinone
Leafy vegetables, therapy
soybean oil, fruits,
seeds, cow milk, Symptoms:
liver - Coagulation/
prolonged PT
- Abnormal bone
matrix synthesis
Water-soluble Absorption Function Deficiency Toxicity Laboratory
Vitamin C Location: - Antioxidant Etiology: -V ery high doses - P lasma ascorbic
(Ascorbic acid and - Predominantly reacts directly - Inadequate cause gastric acid
dehydroascorbic ileum via with superoxide, intake irritation and
acid) saturable, hydroxyl radicals - Cigarette renal dysfunc-
sodium - energy and singlet smoking tion
dependent active oxygen - Supplementa-
transport -R equired for Symptoms: tion should
synthesis of MILD be avoided in
Dietary source: collagen, DEFICIENCY: renal failure,
Citrus fruits, carnitine and - Anorexia kidney stones,
papaya, tomatoes, neurotransmit- - Fatigue iron overload
cabbage, pota- ters - Muscle pain disease, and/or
toes, cantaloupe, - Enhances individuals re-
strawberries intestinal SEVERE ceiving heparin
absorption of DEFICIENCY: or warfarin
nonheme iron - scurvy: anemia,
- Cholesterol bleeding gums,
hydroxylation petechiae,
into bile acids perifollicular
-R eduction of hemorrhage,
toxic transition impaired wound
metals healing, joint
- Immune-mediat- effusions,
ed and fatigue,
antibacte- depression,
rial functions of and/or
white blood cells weakening
of collagen in
bone, teeth,
and connective
tissue, sudden
death
Vitamin B See following page
Biotin Location: - Coenzyme for Etiology: - No toxicity - S erum biotin
-A
bsorbed in carboxylases, - Raw egg or 24-hour
jejunum and transcar- consumption urine collection
boxylases - Prolonged (most valid)
Dietary source: antibiotic – decreased
Oats, swiss chard, therapy urinary excretion
eggs, soy - TPN of biotin and
- Anticonvulsant increased
therapy excretion of
3-hydroxyisova-
Symptoms: leric acid
- Multiple
carboxylase
deficiency
- Organic
acidemia/
acidosis
- Dermatitis/
alopecia
- CNS: seizures/
ataxia/
depression

B Vitamins
• Vitamin B1 (Thiamine)
o Coenzyme in metabolism of carbohydrates and branched AAs
o Absorption in the proximal jejunum by carrier mediated mechanisms at low concentra-
tions and passive diffusion at high concentrations
o Deficiency results in calf tenderness, hyporeflexia, severe lethargy, irritability, restlessness
along with wet and/or dry Beriberi
• Wet Beriberi – primarily cardiac involvement (dilated cardiomyopathy, edema,
cardiac failure)
• Dry Beriberi – primarily damage to nerves (Wernicke encephalopathy, Korsakoff
psychosis, paresthesias, weakness, ophthalmoplegia, nystagmus)
• Infantile Beriberi – occurs in undeveloped countries related to breastfeeding
mother with inadequate intake of thiamine (primarily due to polished rice-
based diet), usually between 2–3 months of age. Chronic form characterized
by lethary, anorexia, vomiting, constipation or diarrhea, with hypotonia. In the
acute form, cardiac enlargement, generalized edema and tachycardia rapidly
develops after these initial symptoms, followed by aphonia, severe weakness,
loss of reflexes, coma and death
o Laboratory measurement utilizes erythrocyte transketolase activity with and without in
vivo addition of thiamine pyrophosphate
• Vitamin B2 (Riboflavin)
o Involved in metabolism of carbohydrates, fats, ketone bodies and AAs
o Absorption in the proximal small intestine via Na-dependent carriers
o Deficiency results in angular stomatitis, cheilosis, glossitis, seborrheic dermatitis, normo-
cytic anemia, reduced growth in children
o Infants on prolonged phototherapy may be at risk for deficiency
o Laboratory measurement utilizes erythrocyte glutathione reductase activity. 24-hour
urinary riboflavin <30 mcg/day
• Vitamin B3 (Niacin)
o Precursor of NAD+/NADH and NADP+/NADPH which are involved in cellular metabolism,
DNA repair and the production of steroid hormones
o Absorption in stomach and intestine by active transport and passive transport at high
concentrations
o Deficiency occurs where corn is a staple food and results in pellagra – classic signs are
the 4 D’s (dermatitis, diarrhea, dementia, death)
• Hartnup disease is a hereditary nutritional disorder caused by abnormal trypto-
phan (a precursor of niacin) absorption and metabolism. Infants present with
failure to thrive, photosensitivity, ataxia, nystagus and tremor. Symptoms may
not begin until early adulthood with a pellagra-like dermatosis on sun-exposed
skin. Treatment includes a high-protein diet, sun avoidance and niacin supple-
mentation
o Toxicity – vasodilation, itching, sensitization to heat, headache, GI irritation, hepatitis,
glucose intolerance and myopathy
o Laboratory measurement of urine excretion of niacin-methylated metabolites
• Vitamin B5 (Pantothenic Acid)

o Required for the synthesis of coenzyme A (CoA), which is important for energy metabo-
lism and acetylation of alcohol and amines
o Absorption is by both passive diffusion and by Na-dependent active transport
o Deficiency results in postural hypotension, anorexia and vomiting, and hyperreflexia
o Toxicity is very rare
o Laboratory measurement is by levels in whole blood or 24-hour urine collection
• Vitamin B6 (Pyridoxine)
o Required for Hgb synthesis, maintenance of sodium/potassium balance, immune and nervous function,
and maintenance of glucose homeostasis
o Absorption by passive diffusion in the jejunum
o Deficiency results in dermatitis, glossitis, depression, confusion, seizures and anemia. Deficiency is most
commonly associated with use of isoniazid
o Toxicity occurs with excessive vitamin supplementation and results in reversible ataxia and severe sensory
neuropathy
o Laboratory measurement utilized plasma pyridoxal phosphate and 24-hour urine excretion
• Vitamin B9 (Folate/Folic Acid)

o Involved in synthesis, repair and function of DNA, helps in RBC production, helps with neural
tube formation
o Absorption by passive diffusion in the jejunum
o Deficiency results in increased risk of low birth weight and prematurity, increased risk of neural tube de-
fects, anemia, delayed growth, diarrhea, headaches, weakness
o Patients with alcohol abuse or with chronic use of anticonvulsants are at risk for deficiency
o Methotrexate interferes with the biosynthesis of folic acid, so patients on this medication should be
supplemented
o Laboratory measurement of plasma folate levels
• Vitamin B12 (cyanocobalamin)

o Catalyzes reactions required for formation of methyl donor DNA and RNA, and reactions required for
Hgb synthesis and fat/protein metabolism
o Absorption in ileum is dependent on intrinsic factor
o Deficiency results in megaloblastic anemia and neurological symptoms, such as weakness, paresthesias
and confusion
o Pernicious anemia
• Autoimmune disorder resulting in destruction of parietal cells, achlorydia, and failure to
produce intrinsic factor
o Vitamin B12/Folate Deficiency
• Treat with Vitamin B12 first! This will address both anemia and neurological symptoms
o Who is at risk for deficiency?
• Celiac disease, Crohn disease, post-bariatric surgery, post-ileal resection, vegetarians/vegans
o Laboratory measurement by serum B12 levels

Mineral and Absorption Function Deficiency Toxicity Laboratory
Trace Elements Measurement
Calcium Location: - Bone structure Etiology: - E arly: Fatigue, - Serum levels
- Duodenum - Important - Inadequate nausea, vomit- - In hypoalbu-
- Mobilization metabolic intake ing, constipa- minemia adjust
from bone stores regulator - Vitamin D tion, anorexia, with following
when serum - Maintains nerve deficiency and confusion formula or get
levels low excitation - L ate: Cardiac ionized level
threshold Symptoms: arrhythmia,
Dietary source: - Bone bradycardia Corrected total
Milk, yogurt, demineralization Ca (mg/dL) =
cheese - Tetany/seizures measured Ca +
- Cardiac 0.8 [4.0 –
arrhythmias albumin (g/dL)]
Chromium Location: - Glucose Etiology: - T rivalent Cr -N
o accurate
- Soluble in tolerance factor - Pregnancy and potentially toxic: tests due to very
stomach, -M etabolism of lactation rhabdomyolysis, low levels in
absorbed via nucleic acids liver dysfunc- body
nonmediated - ? Iodine/thyroid Symptoms: tion, renal – Can use serum,
passive diffusion function - Glucose failure erythrocyte, and
in jejunum - Important in intolerance urine values if
lipid metabolism - Neuropathy/ necessary
Dietary source: encephalopathy
Whole grains, - Altered nitrogen
cheese, lean metabolism
meats, fruits and - Increased serum
vegetables fatty acids
Copper Location: - Essential Etiology: - Nausea - S erum copper,
- Stomach and component of - Inadequate - Vomiting ceruloplasmin
small intestines several oxidative intake - L iver and kidney - Liver biopsy
- Transported to enzymes (super- damage - Estimate
the liver bound oxide dismutase, Symptoms: abnormal
to albumin and cytochrome oxi- - Neurologic - Recommend storage of Cu
incorporated into dase, catalase) abnormalities omit from in - Superoxide
ceruloplasmin - Involved in en- - Anemia TPN of choles- dismutase
ergy production, - Osteoporosis tatic infants activity
Dietary source: bone strength, - Brittle hair
Liver, veal, shell Hgb synthesis,
fish protection of
cell membranes
from oxidative
damage, and
neurological
development
Iodide Location: - Component Etiology: - Rare - Physical exam of
- Stomach and of thyroid - Inadequate thyroid
upper SI hormones intake - 24-hour urine
or random urine
Dietary source: Symptoms: level of iodine
Sea vegetables, - Goiter
milk, eggs, fish - Hypothyroidism
(Continued)
Iron Location: - Heme synthesis Etiology: - Wide range - Hemoglobin,
- Duodenum and -C omponent of - Inadequate from acute plasma iron,
jejunum cytochromes intake poisoning with iron-binding
- Ferrous iron - Parasitic worms overdose to capacity, fer-
is most easily -C hronic blood chronic iron ritin, transfer-
absorbed loss overload and rin, erythrocyte
- Vitamin C, HCl, - PICA subsequent protoporphyrin,
lactic acid, and organ damage transferrin
amino acids, Symptoms: receptor and
aspartic and - Hypochromic MCV
glutamic acid microcytic
promote ferrous anemia
form -A ltered oxidative
phosphorylation
Dietary source: - Diminished
Meat, fish and concentrative
poultry ability
- Decreased
exercise
tolerance
Magnesium Location: - Cofactor of Etiology: - Nausea, vomit- - Serum levels
-D
istal jejunum hexokinase and - Inadequate ing, diaphore-
and ileum phosphokinase intake sis, flushing,
- Alters ribosomal - Malabsorption depressed
Dietary source: aggregation in - Diuretic use mental function-
Whole greens, protein synthesis - Pregnancy ing, drowsi-
nuts and green - Increases nerve ness, muscular
leafy vegetables excitation Symptoms: weakness,
threshold - Cardiac hypotension,
dysrhythmias bradycardia
- Neuromuscular
excitability
-D ecreased PTH
level/activity
- Hypocalcemia/
hypokalemia
- Convulsions
Manganese Location: - Enzyme Etiology: - CNS abnormali- - Whole blood
- T hroughout SI activator Very rare in those ties: hyperir- levels
with quickly - Mucopolysac- with enteral nutri- ritability, violent - MRI of brain
saturable state charide synthesis tion acts, hallucina- looking at basal
- Cholesterol tions and ataxia ganglia if con-
Dietary source: synthesis Symptoms: - Deposition in cern for toxicity
Green leafy veg- - Cartilage/bone - Dermatitis basal gan-
etables and maple formation - Decreased clot- glia produces
syrup - Pyruvate ting factors Parkinson-like
carboxylase - Decreased nail/ syndrome
cofactor hair growth - Immune dys-
- Superoxide - Ataxia function
dismutase - Growth - Nephritis, pan-
cofactor retardation creatitis, hepati-
- Abnormal bone tis, orchitis
and cartilage
growth
- Defects in car-
bohydrate and
lipid metabolism
(Continued)

Phosphorus Location: Bone structure Etiology: - Diarrhea - Serum
Small intestine Cell membrane - Inadequate - Calcification of phosphorous
structure intake organs and soft levels
Dietary source: Energy storage - TPN tissue
Meats, eggs, Acid-base bal- - Hypoparathy-
legumes and milk ance: buffering roidism
Oxygen release - Renal losses
(2,3-DPG) - Refeeding
syndrome
Symptoms:
- Tissue hypoxia
- Respiratory
failure
(ventilatory
dependence)
- Rickets
- CNS
abnormalities
Selenium Location: - P revent cellular Etiology: - Hair loss - Serum selenium
Small intestine damage from Inadequate intake - Muscle cramps - Nail and hair
free radicals - Diarrhea selenium
Dietary Source: - Regulates Symptoms: - Nausea - Glutathione
Nuts, meats, tuna thyroid function - P oor cardiac - Vomiting peroxidase
-R ole in immune function activity
function - Osteoarthropa-
thy
- Hypothyroidism
Zinc Location: - Catalytic activ- Etiology: - Nausea - Serum zinc
Small intestine ity of over 100 Inadequate intake - Vomiting - Alkaline
enzymes - Decreased phosphatase
Dietary source: - Immune Symptoms: immune -R BC zinc
Oysters, beef, function - Delayed growth, function concentrations
pork, lobster - Protein synthesis hypogonadism -A ltered copper
- Wound healing - Hair loss, skin and iron
- DNA synthesis lesions function
and cell division - Impaired - Reduced HDL
immune
function
- Diarrhea
Recommended Reading
ASPEN. Nutrition Support Core Curriculum: A Case-Based Approach - The Adult Patient.
Baker SS, Baker RD, Davis AM, eds. Pediatric Nutrition Support. Sudbury, MA: Jones and Bartlett Publishers;
2007: Chapter 25.
Gottschlich MM, ASPEN. Nutrition Support Core Curriculum: A Case-Based Approach - The Adult Patient.
2nd ed.
Kappy M, Misra M, Pacaud D, Petryk A, Collett-Solberg PF. Vitamin D Deficiency in children and its manage-
ment: review of current knowledge and recommendations. Pediatrics. 2008;122:398-417.
Walker WA, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR. Pediatric Gastrointestinal Disease. 4th ed.
Hamilton, Ontario: BC Decker, Inc.: 2006.Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease.
3rd ed. Philadelphia, PA: Saunders Elsevier; 2006.
8L. Essential Amino Acids
Justine M. Turner, MD
I. Indispensible amino acids

20 amino acids that cannot be synthesized by humans in sufficient amounts for needs (also called dietary
essentials)
A. Conditionally indispensable amino acids are normally synthesized in sufficient amounts, but
during rapid growth or unusual metabolic needs, amount synthesized becomes insufficient for
needs
1. Table 1 shows the amino acids required for protein synthesis, indicating which are
indispensable and which are conditionally indispensable
2. Protein constitutes ~20% of adult body weight, 2% of infant body weight, <2% in
preterm infants
II. Protein turnover
A. Protein turnover is a continuous process of endogenous protein breakdown and synthesis
1. Amount of daily protein turnover far exceeds daily amino acid intake
B. Protein turnover provides constant flux of amino acids through all body compartments
C. Measurable free plasma amino acid represents a small percentage of the whole body amino acid
content
D. Table 2 shows the body organ systems of importance in essential amino acid metabolism
III. Amino acid toxicity

A. Occurs with genetic defects of amino acid metabolism
B. Occurs with damage or bypass of major organ systems involved in amino acid metabolism
1. Parenteral nutrition bypasses the regulatory influence of the intestine
2. Intestinal bypass for obesity prevents absorption
C. Table 3 shows common indispensable amino acids that can be toxic in excess and the typical
signs and symptoms
IV. Amino acid deficiency

A. Amino acid deficiency is a much more important global nutritional problem than amino acid
toxicity
B. Growth restriction is the most important sign of an amino acid deficiency in childhood
C. Additional signs of amino acid deficiency:
1. anorexia
2. decreased plasma concentration of the most limiting amino acid
V. Principle of amino acid metabolism

A. Rate of protein synthesis and rate of growth are determined by the first limiting amino acid
B. Protein synthesis is optimal when all amino acids are present at or above their requirement
C. Deficiency of a single amino acid may cause suboptimal protein synthesis and restricted growth,
even when other amino acids are available in excess
D. Normal amino acid metabolism requires vitamin cofactors. Cofactor deficiency may mimic certain
amino acid deficiencies
1. Vitamin B6 – histidine, methionine, phenylalanine, tryptophan, branch chain amino acids
2. Folate and vitamin B12 – methionine, phenylalanine
3. Nicotinic acid/B3 – tryptophan
4. Biotin/B7 – lysine

VI. Specific amino acid deficiency syndromes
A. Phenylalanine deficiency syndrome in infants receiving therapy for PKU presents with failure to
thrive, neurological signs and eczema
B. Isoleucine deficiency in infants receiving branch chain amino acid-free formula for MSUD may
cause failure to thrive and acrodermatitis enteropathica
Table 1. indispensable, Dispensable and Conditionally Dispensable Amino Acids in the Human Diet
Conditionally
Indispensable Dispensable Dispensable Scenario
Histidinea Alanine Arginine Intestinal bypass – as crucial site for synthesis
Trauma and critical illness – increased demand beyond synthesis
Prematurity (hyperammonia observed with arginine free TPN)
Isoleucineb Aspartate Cysteined Liver disease – site of transulfuration from methionine
Prematurity – low cystathionase activity
Leucineb Asparagine Glutamine Trauma and critical illness – increased demand and also
shunting away from muscle to visceral compartments
Lysine Glutamate Glycine Prematurity – increased demand during rapid growth
Methionine c
Serine Proline Intestinal bypass – as crucial site for synthesis
Critical illness – increased demand beyond synthesis
Phenylalanined Tyrosine Prematurity – low phenylalanine hydroxylase activity
Renal disease – uremia inhibits phyenylalanine hydroxylase activity
Threonine
Tryptophand
Valineb
a
Deficiency states with growth failure have not been described, but chronic deficiency in adults has shown a fall in
plasma level, with improved nitrogen balance if supplemented.
b
Known as the branched chain amino acids.
c
Known as the sulfur amino acids.
d
Known as the aromatic amino acids.
Table 2. Organ Sites Important in Indispensable Amino Acid Metabolism

Indispensable Amino Acid Major Organ Sites of Metabolism
Histidine skin, intestine, liver, kidney
Isoleucine muscle, kidney
Leucine muscle, kidney
Lysine liver, intestine
Methionine intestine, liver, muscle
Phenylalanine liver, central nervous system, kidney
Threonine intestinea, liver
Tryptophan central nervous system, liver
Valine muscle, kidney
a
Mucin formation
Table 3. Toxic Indispensable Amino Acids in Excess
Indispensable Potential Causes of
Amino Acid Toxicity/Excess Signs and Symptoms
Methioninea Implicated in parenteral Potential to cause liver disease and elevate
nutrition associated liver plasma homocysteine levels, with risk of
disease; high plasma level thrombosis or atherogenesis
in chronic liver disease
with malnutrition
Phenylalanine Phenylketonuria – inborn Neonatal death, mental retardation, growth
error of phenylalanine impairment
hydroxylase
Tryptophan Food supplements Serotonergic, nausea, drowsiness, appetite
suppression, MAOI interaction
Leucine, Maple Syrup Urine Neonatal death, mental retardation, high
isoleucine and Disease – inborn error of plasma and urine leucine level
valineb branch chain ketoacid
dehydrogenase
a
Theoretical or animal data.
b
Theoretically could compete for membrane transport of tryptophan and tyrosine with potential
for neurotoxicity (observed in animals).
Recommended Reading
Furst P, Stehle P. What are the essential elements needed for determination of amino acid requirements in
humans? J Nutr. 2004;143:1558S-1565S.
Harper AE, Benevenga NJ, Wohihueter RM. Effects of ingestion of disproportionate amounts of amino acids.
Phys Rev. 1979;50(3):428-558.
Institute of Medicine. Dietary Reference Intakes for Protein and Amino Acids. Washington DC: National Acad-
emies Press; 2005.
Reeds PJ. Dispensable and indispensable amino acids for humans. J Nutr. 2000;130: 1835S-1840S.

8M. Nutritional Therapy
Sarah Shrager Lusman, MD
Amy R. DeFelice, MD
Several medical conditions require modification of nutritional intake as an integral part of therapy. Some
common conditions requiring nutrition therapy include refractory seizures, cystic fibrosis, cholestasis,
diarrhea, celiac disease, disaccharidase deficiency, food allergy, malnutrition and obesity. Each condition
has specific indications for initiation of nutrition therapy. It is important to monitor children for
complications associated with a restricted diet.
I. Ketogenic Diet
A. Overview and Pathophysiology
1. Ketogenic diet consists of 3 or 4 parts (by weight) fat to one part protein and/or
carbohydrate
2. High fat and low carbohydrate diet produces persistent ketosis
3. Ketosis has a direct antiseizure effect
B. Indications
1. Refractory partial or generalized seizures
2. Symptomatic generalized epilepsy syndromes i.e., infantile spasms, Lennox-Gastaut,
GLUT-I deficiency, pyruvate dehydrogenase deficiency, myoclonic-astatic epilepsy,
tuberous sclerosis, Rett syndrome
3. Intractable focal epilepsy
4. Contraindications:
a. Absolute—defects in fatty acid oxidation, porphyria, pyruvate carboxylase
deficiency
b. Relative—certain mitochondrial cytopathies, carnitine deficiencies, other
disorders of fat metabolism
C. Implementation and Monitoring
1. Usually done in the inpatient setting
2. Patients fast except for sugar-free fluids for 24 hours, blood glucose is checked q6h
3. Feeding is then gradually started and increased to full caloric intake over 2–3 days
4. Modification of the diet from 4:1 to 3:1 lipid:nonlipid ratio improves tolerability for older
children but may lessen ketosis and allow recurrence seizures
5. The level of ketosis is monitored in urine or serum
6. The nutritional content of all meals must be calculated and each item weighed and
measured
7. Ketocal® and Ross carbohydrate-free are commercially available formulas which can be
used
8. Supplementation with a multivitamin, minerals and carnitine is recommended
9. Clinical response occurs within a few weeks to 2 months
10. The diet should be gradually discontinued after 2 years
D. Complications
1. Dehydration usually during initial fasting phase
2. GI complaints: diarrhea, gastroesophageal reflux, nausea, vomiting, constipation
3. Pancreatitis
4. Cardiomyopathy due to selenium deficiency
5. Metabolic complications: acidosis, hyperuricemia, hypoproteinemia, hypomagnesemia
and hyponatremia
6. Renal stones
7. Osteopenia and decreased height velocity

II. Cystic Fibrosis
A. Overview
1. Better nutritional status in patients with CF is associated with improved FEV1 and
improved survival
2. Malnutrition results from discrepancy between energy and micronutrient requirements
and food intake modified by malabsorption
3. Higher energy intake results in better weight gain
4. Energy needs in CF are 110%–200% of energy needs for the healthy population of
similar age, sex and size
B. Pathophysiology
1. Loss of CFTR function limits fluid secretion in the pancreas, resulting in a more viscous
and acidic fluid in the pancreatic ducts
2. Lower pH prematurely activates trypsin and other zymogens, which cannot be flushed
from the pancreas
3. Results in recurrent injury, progressive fibrosis and chronic pancreatitis
4. Insufficient production and secretion of pancreatic enzymes causes malabsorption of fat,
protein and micronutrients, especially fat-soluble vitamins A, D, E and K
5. 85%–90% of patients have pancreatic insufficiency
6. Other gastrointestinal abnormalities may contribute to malnutrition: CF-related liver
disease, bile salt abnormalities, CF-related diabetes mellitus, altered motility, small bowel
bacterial overgrowth, gastroesophageal reflux disease, distal intestinal obstruction
syndrome and constipation
7. Progressive lung disease and increased work of breathing increases caloric requirements.
Chronic and recurrent infections, may reduce appetiti and cause cytokine-induced
catabolic state
C. Recommendations
1. BMI percentile is a more sensitive predictor of pulmonary outcomes than % of ideal
body weight for age or for height
2. Children diagnosed before age 2 years should reach a weight for length >50th
percentile by age 2 years
3. For older children and adults, the goal is BMI ≥50th percentile for age
4. For growth deficits, the first line is intensive treatment with behavioral intervention,
nutritional counseling and use of oral nutritional supplements
5. When oral nutrition fails, enteral tube feeding should be used
6. Pancreatic enzyme replacement therapy should be given just prior to each meal, with
half the dose given for snacks (see section on Pancreatic Enzymes)
7. Blood tests to evaluate nutritional status should be done at least annually: vitamin A,
D and E levels, calcium, phosphorus, PTH, dexa scan, CBC, serum sodium, albumin and
blood glucose
D. Dietary Supplementation
1. Vitamin supplementation in international units/day
Vitamin Infants < 1 year 1–3 years 4–8 years >8 years
A 1,500 5,000 5,000–10,000 10,000
D 400 800 800 800
E 40–50 80–150 100–200 200–400
K 0.3–0.5 mg/day for all ages
2. Because of sodium losses in sweat, patients with CF are prone to hyponatremic dehydra-
tion in heat stress and may need sodium chloride supplementation
III. Cholestasis (see section on Nutritional Consequences of Cholestasis)
A. Overview
1. Causes of cholestasis: biliary atresia, intestinal failure–associated liver disease (IFALD),
Alagille syndrome, alpha-1-antitrypsin deficiency, progressive familial intrahepatic
cholestasis, metabolic conditions
2. Nutritional goals for children with cholestasis: meet caloric needs, correct nutritional
deficiencies, and minimize hepatotoxicity
B. Causes of Malnutrition in Pediatric Chronic Liver Disease
1. Abdominal distension and early satiety
2. GERD and caloric loss
3. Poor palatability of semielemental diet
4. Restriction of protein, water and calories
5. Fat malabsorption
6. Poor duodenal alkalinization leading to zinc and calcium malabsorption
7. Portal hypertension and bleeding
8. Ascites and protein loss
9. Liver dysfunction and impaired protein synthesis
C. Dietary Recommendations
(see section on Nutritional Consequences of Cholestasis)
D. Strategies for prevention of intestinal failure-associated liver disease (see intestinal failure)
1. Maximize enteral tolerance and stimulation, with both oral and tube feedings
2. Consider use of fish oil–based fat emulsions
3. Limit the total amount of lipid infusion
4. Alternate high and low protein formulations to prevent toxicity due to concentrated
amino acids
5. Ursodeoxycholic acid protects against hepatotoxicity from toxic bile acids, stimulates bile
flow, increases levels of glutathione (an antioxidant) and inhibits hepatocyte apoptosis
IV. Diarrhea — Acute

A. Overview
1. Defined as diarrhea with duration <3 weeks
2. Usually self-limiting, most often infectious
B. Dietary Recommendations
1. First step is repletion of fluid deficit and ongoing fluid losses
2. Once rehydration is complete, resume a balanced diet per ADA guidelines for age
3. Breastfeeding during oral rehydration appears to reduce the number, volume and
duration of diarrheal stools
4. Full-strength cow’s milk and other nonhuman milks usually can be tolerated without
problems. Dilution and substitution of lactose-free formulas usually is unnecessary
5. Foods containing high levels of fats and simple sugars are less well tolerated than are
those with complex carbohydrates, lean meats, yogurt, fruits and vegetables
6. Use of the BRAT diet (banana,rice,applesauce,toast) or clear liquid diets (pediatyte and
juices) should not be used for more than 24 hours. They provide suboptimum nutrition
and there is little proof of efficacy in acute diarrhea
V. Diarrhea — Chronic
A. Overview
1. Defined as: diarrhea with duration of 4 weeks or more
2. Differential diagnosis:
a. Bacterial, viral or parasitic agents
b. Carbohydrate intolerance
c. Milk or soy allergy
d. Anatomic abnormalities, inflammatory bowel disease, celiac, cystic fibrosis
e. Rare congenital disorders
f. Immunodeficiency states

B. Interventions Based on Suspected Causes
1. Chronic nonspecific diarrhea of childhood: reassurance, high fiber, high fat, avoid intake
of fluids containing fructose and sorbitol
2. Inflammatory bowel disease: exclusive enteral nutrition using hypoallergenic liquid diet
may suppress intestinal inflammation and promote mucosal healing. Enteral nutrition can
also be used as a supplement to increase caloric intake and promote growth. Patients
should be monitored for micronutrient deficiencies with replacement as needed
3. Short bowel syndrome: young children may require a protein hydrolysate or elemental
formula. Fiber supplementation enhances adaption via increased short chain fatty acid
production and retention of stool water. Medium-chain triglycerides are used in patients
with cholestasis
4. Celiac disease: gluten-free diet
5. Allergic enteropathy—elimination of some or all of the following highly allergenic foods:
milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat and soybeans
6. Autoimmune enteropathy/IPEX: hydrolyzed, hypoallergenic formula to reduce antigen
exposure
7. Congenital chloride diarrhea: high chloride intake to prevent volume depletion
8. Glucose-galactose malabsorption: fructose-based formula, lifelong dietary restriction of
glucose and galactose
9. Congenital sucrase-isomaltase deficiency: elimination of sucrose, use of yeast based
sucrase (sacrosidase) enzyme replacement therapy
Recommended Reading
A 21st century approach to cystic fibrosis: optimizing outcomes across the disease spectrum. JPGN.
September 2010.
Baker A. Guidelines for nutritional care for infants with cholestatic liver disease before liver transplantation.
Pediatric Transplantation. 2007;11:825-834.
Cowles RA. Reversal of intestinal failure-associated liver disease in infants and children on parenteral nutrition:
experience with 93 patients at a referral center for intestinal rehabilitation. J Pediatric Surgery. 2010;45:84-
88.
Hartman AL, Vining EPG. Clinical aspects of the ketogenic diet. Epilepsia. 2007;48(1):31-42.
Stallings VA. Evidence-based practice recommendations for nutrition-related management of children and
adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Dietetic Assoc.
2008;108(5):832-839.
Young RJ, Philichi L. Clin Handbook of Pediatr Gastroenterol. 2008.
8N. Nutritional
Supplementation: Enteral
and Parenteral Nutrition
Jennifer Garcia, MD
I. Nutritional Supplementation
A. Indications for Enteral Nutrition/Parenteral Nutrition
1. Preexisting nutritional deprivation
2. Anticipated or current inadequate energy intake by mouth
a. Unable to take PO 3–7 daysor sooner in the presence of weight loss or catabolic
stress and in preterm/LBW infants
3. Significant multiorgan system disease
a. GI, renal, hepatic, cardiac, hematologic, pulmonary, burns
B. Enteral nutrition by mouth or tube is always preferable to IV nutrition if possible. Contraindica-
tions include:
1. Ileus
2. Bowel ischemia
3. Persistent or bilious emesis
4. Intestinal obstruction
C. Parenteral Nutrition (PN)
1. Indications
a. Premature, LBW Infants
b. Intestinal Failure
1) Congenital and acquired lesions of the GI tract (short bowel syndrome)
a) NEC, intestinal atresia, gastroschisis
2) Intractable GI dysmotility/malabsorption
a) Chronic intestinal pseudoobstruction, microvillus inclusion disease,
tufting enteropathy, total aganglionic Hirschsprung disease
2. Definition
a. Nutrition given intravenously, bypassing the usual process of eating and digestion
b. Provides macronutrients (carbohydrates, protein, fat) and micronutrients
(minerals, vitamins, trace elements)
3. Intravenous access may be central or peripheral
a. Peripheral: IV or PICC
1) Appropriate for patient with normal nutritional status without fluid restric-
tion, likely to tolerate enteral nutrition (EN) in <2 weeks
2) Limited nutrient concentration due to osmolarity restriction (300–900
mOsm/L)
a) Osm= (Dex x 50) + (%AA x 100) + 2 (Na + K + Ca + Mg mEq/L)
b) usual concentration of dextrose is 10-12.5 g/dL and usual
concentration of protein is 2 g/dL
b. Central catheter: PICC, Broviac, Hickman, Port
1) Placed in large central vein to reduce damage to veins from the catheter
and infusate (thrombophlebitis)
a) High blood flow in central veins rapidly dilutes
concentrated solutions
2) Appropriate for patient with intolerance for more than 2 weeks regardless
of initial nutritional status

4. Complications of PN
a. Infection of line
1) Interrupt PN infusion as little as possible
2) Staph epidermidis, Staph aureas, Candida are the most common
infecting organisms
b. Technical complications of line placement
1) Extravasation of fluid into pericardial or pleural space
a) Usually presents with severe hemodynamic instability
2) Pneumothorax
3) Brachial plexus injury
4) Air Emboli
5) Venous thrombosis and thrombophlebitis
6) Subcutaneous infiltration of PN solution causing with infection,
pain and slough
c. Bone disease (Insufficient Ca, Phos)
d. PN-Associated Liver Disease (see below)
5. Components of PN
a. Carbohydrate
1) Given as glucose (D5-25%)
2) Provides majority of total (55%) and non-protein calories (60%) for energy
expenditure
3) Primary energy source for brain
4) Caloric density: 3.4 kcal/g of dextrose
5) Glucose infusion rate (GIR)
a) GIR (mg/kg/min) = IV rate (ml/hr) x Dex conctrn (g/dL) x 0.167
Weight (kg)
b) Start at GIR of 3–5 mg/kg/min
c) Advance by 1–1.5 mg/kg/min or by D2.5% daily to max GIR
12–14 mg/k/min
d) Make adjustments based on Total Fluid Volume (TFV)
i) Fluid restricted (PDA, Renal failure, Cardiac): Increase
Dextrose % to maintain same GIR
ii) Higher fluid volumes (ostomy, short bowel syndrome):
decrease dextrose % to maintain same GIR
e) Consider insulin if not meeting nutritional goal because of
hyperglycemia
i) Increases cellular glucose uptake → Provides appropriate
non-protein calories and prevents glucose conversion to fat
b. Protein
1) Amino Acids: Given as trophamine
a) Neonatal form based on amino acid composition of breast milk
i) Older formulations caused metabolic acidosis due to high
concentration of nonessential AA
b) Provides protein calories to attain positive nitrogen balance,
prevent catabolism and stimulate growth
c) Allows lower dextrose concentration preventing hyperglycemia
d) Caloric density: 4 kcal/g of protein
e) In NICU, can start from 1st day of life
i) If no AA given, lose 1% body protein stores per day
ii) 3.5 g/kg/day needed to meet intrauterine accretion rate
(a) Can start at 2.5 g/kg/day and advance by 0.5 g/kg/
day
(b) Tolerated well, without adverse effects
(1) No increase BUN/Cr, replaces urinary losses
c. Fats
1) Lipids: Provided as intralipid (IL) 20%
a) Omega 6, Soybean oil-based
b) Other formulations not approved in US: Fish oil, SMOF
(mixture of soybean oil, MCT, olive oil, fish oil)
c) Intralipid 10 vs 20%
i) 10% more volume needed to provide same amount of fat
ii) 10% higher phospholipid to TG ratio, which interferes with
TG clearance
d) Provides non-protein calories (40%) for energy expenditure
e) Allows lower dextrose concentration, preventing hyperglycemia
f) Most caloric dense macronutrient = 9 kcal/ g
g) Usually started at 0.5–1 g/kg/day and increase by 0.5 g/kg/day
daily to goal
i) Monitor TG level when advancing
(a) Keep triglyceride serum level <150 mg/dL
(1) May have to decrease for a few days
(2) Can add carnitine (see below)
h) Discontinue lipid infusion in the setting of infection
i) Fats impair the macrophage activation system
i) Essential Fatty Acid Deficiency
i) Deficiency of Linoleic and Linolenic acids (Omega 6)
(a) Cannot be synthesized by humans
ii) Presents with:
(a) Dermatitis
(b) Thrombocytopenia
(c) Susceptibility to infection
(d) Failure to Thrive
(e) ? Abnormal brain and eye development
iii) Can present as early as 1 week without fat supplementation
iv) Minimum requirement 0.5 g/kg/day of fat
d. Vitamins (MVI)
1) Pediatric MVI given based on weight
2) Vitamin A
a) Important for vision, normal lung development,
immunocompetency
b) Lost by binding to PN bag/tubing and exposure to light
c) Vitamin A can be given by intermittent IM injection
3) Vitamin E
a) Free radical scavenger/antioxidant
i) Prevents peroxidation of cell membrane (PUFA)
b) May reduce incidence and severity of BPD and retinopathy
of prematurity
4) Vitamin D
5) Vitamin K
6) Water-soluble vitamins
e. Electrolytes
1) Na, K, Cl
a) In NICU, not generally required first 24 hours
b) Add after 1st 24–48 hours (diuresis occurs)
c) Adjust thereafter based on laboratory testing
d) usual requirements for Na, K, and Cl are 2-4 mEq/Kg/day.
Take into account electrolyte content of other intravenous
fluids and medications
2) Acetate
a) Metabolic acidosis common in:
i) Pre-term infants
(a) Acidosis very common during sepsis,
heart failure, PDA
(b) Decreased renal reabsorption of HCO3 in the
immature kidney
ii) Short Bowel Syndrome
(a) Increased losses of HCO3 (stools)
iii) Trophamine contains AA which may be acidic (cysteine)

3) Calcium
a) Hypocalcemia is a significant problem in preterm infants
i) Maternal to fetal transfer of Ca occurs last trimester
ii) Impaired response to PTH
iii) Increased urinary loss
b) In chronic PN patients, calcium supplementation is important to prevent metabolic
bone disease
4) Phosphate
a) Can be elevated in preterm infants, but usually corrects with increasing GFR
b) In chronic PN patients, important to prevent metabolic bone disease
c) Ca:Phos ratio of most PN solutions should be 1.7
5) Magnesium
a) preterm infants whose mothers have received magnesium during labor may
be hypermagnesemic. Withhold Mg from PN solutions until serum level is normal
f. Other Additives
1) Trace elements: selenium, zinc, chromium, manganese and copper
2) Preterm infants have very low stores of trace elements at birth as accretion usually
occurs in the 3rd trimester
3) Cysteine
a) Conditionally Essential AA especially in preterm infants
b) Cysteine precipitates on standing so is added to PN just before administration
c) Cysteine lowers the pH of PN solutions and making Ca and Phos more soluble
and potentially causing metabolic acidosis
d) Cysteine solutions contain chloride and add to total daily chloride intake
4) Carnitine
a) Conditionally Essential AA in preterm infant, and in, liver and metabolic disease
b) Intermediary of fat metabolism
i) Shuttles LCFA into mitochondria for b-oxidation
c) Crucial for energy production in tissues dependent on fatty acid oxidation
i) Cardiac and skeletal muscle
ii) Not available in PN formulations
d) Consider supplementation 10–20 mg/kg/day in preterm infants,
PN >2 weeks, high TG, hypoglycemia, low serum carnitine level
e) No study has shown positive effects of additive, but no ill effects
5) Medications
a) Some meds are not compatible with PN. Hold PN during their infusion.
i) Acyclovir, amphotericin B, flagyl, bactrim
b) Some meds can be added directly to PN bag
i) Ranitidine/Famotidine, vitamin K, iron dextran, albumin
6. PN-Associated Liver Disease
a. Etiology
1) Thought to be multifactorial including characteristics of PN (composition, delivery) and
characteristics of the patient
a) Lipids currently heavily investigated: specifically, phytosterols in omega-6 formula-
tions
i) Phytosterols alter biliary canalicular membrane
ii) Proinflammatory
b) High dextrose concentration → steatosis
c) Enteral starvationreduces bile flow and secretion of GI hormones
b. Manifestations depends on age
1) Infants: cholestasis
2) Children/Adults: steatosis/steatohepatitis
3) Both: biliary sludge, cholelithiasis
c. Presentation
1) Mild hepatomegaly → Increased Bili within 2–3 weeks
2) Transaminitis, Alk Phos/GGT elevation later
3) Can lead to cirrhosis
d. Histology
1) Nonspecific
a) Intracellular and canalicular cholestasis
b) Interlobular bile duct proliferation
c) Portal and lobular inflammation (minimal)
d) Portal Fibrosis→ Lobule→ Bridging → Cirrhosis
e. Treatment
1) Wean PN as soon as possible
2) Decrease intralipid volume
3) Consider Omegaven
a) Fish oil (omega-3) based formulation
b) Composed of long-chain polyunsaturated fatty acids
i) DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid)
c) Initially made as an additive due to minimal quantities of essential
fatty acid
d) Discovered to improve cholestasis
e) Not FDA approved
4) Cycling of intralipids
5) Actigall 10 mg/kg/day QD-TID
II. Monitoring Laboratory Parameters (see Table 1)
Table 1. Monitoring Frequency

Parameters Early Later Chronic
Weight, I/Os., TFV Daily Weekly Biweekly-Monthly
Urine dip, Dex q6 Daily N/A
BMP 3x/week Weekly Biweekly-Monthly
Ca, Mg, Phos Weekly Weekly Biweekly-Monthly
Serum Protein/Albumin Weekly Weekly Biweekly-Monthly
LFT, DB Weekly Weekly Monthly
TG/Chol 2–3x/week Weekly Monthly
Calories Daily Monthly Biweekly-Monthly
III. Monitoring Anthropometric Measurements (see Table 2)
Table 2. Measuring Frequency

Measurement Interval
Weight 7 days
Length/Stature 4/8 weeks
Head Circumference 7 days (Infant)/4 weeks (up to 4 years old)

IV. Caloric Requirements
A. Caloric recommendations are based on maintenance
1. May need more for catch up
B. PN caloric requirement is ~85% of enteral requirements
1. Less fecal loss, bypass digestion
C. Preterm: to continue Intrauterine Growth Accretion
1. EN= 100–130 kcal/kg/day, including 3–3.5 g/kg/day Fat
2. PN= 80–90 kcal/kg/day, including 3–3.5 g/kg/day Protein
D. Children: can use general guidelines and/or metabolic equations
1. General Guidelines
a. Total Non Protein Calories= 60% CHO, 40% Protein
b. Total Calories= 55% CHO, 30% Protein, 15% Fat
c. >5 years old 1,500 cal/d (1st 20 kg) + 25 cal/kg/day for each additional kg
d. By age: (Table 3)
Recommended Reading
Forchielli ML, Walker WA. Nutritional factors contributing to the development of cholestasis during total
parenteral nutrition. Adv Pediatr. 2003;50:245-267.
Schutzman DL, Porat R, Salvador A, Janeczko M. Neonatal nutrition: a brief review. World J Pediatr.
2008;4(4):248-253.
Wessel JJ, Kocoshis SA. Nutritional management of infants with short bowel syndrome. Semin Perinatol. 2007
Apr;31(2):104-11.
8O. Nutritional Consequences
of Cholestasis
Juliana Frem, MD
I. Overview
Protein energy malnutrition occurs in about 60% of children with chronic cholestatic liver disease.
Manifestations include growth failure, wasting and specific nutritional deficiencies resulting from
anorexia, malabsorption of fat and fat-soluble vitamins, abnormal intermediary protein and carbohydrate
metabolism, and increased metabolic demands associated with chronic disease and recurrent infection.
Nutritional assessment should be a part of every medical encounter in cholestatic children including
weight and height for age, weight for height and BMI. In some children with cholestasis and/or chronic
liver disease with portal hypertension, body weight does not accurately reflect nutritional status. Serial
measurements of triceps skinfold thickness and mid-arm circumference can be used to estimate body fat
and muscle bulk, respectively. Clinicians should obtain a detailed feeding history and screen for signs and
symptoms of vitamins and trace element deficiencies.
II. Etiologies of malnutrition in chronic cholestasis

A. Decreased food intake:
1. Anorexia results from altered amino acid metabolism and elevated plasma tryptophan
levels
2. Altered taste perception results from zinc, magnesium and/or vitamin A deficiency
3. Early satiety may result from mechanical compression of the viscera by ascites and/or
organomegaly
4. Nausea and vomiting may be caused by inflammatory cytokines or medications
5. Frequent intercurrent illnesses decrease intake
B. Impaired nutrient digestion and absorption
1. Reduced luminal bile concentration causes impaired intraluminal lipolysis, solubilization
and absorption of long-chain triglycerides with resultant malnutrition and fat-soluble
vitamin deficiency
2. Vascular congestion secondary to portal hypertension can result in an edematous
enteropathy that produces nutrient malabsorption
3. Small bowel bacterial overgrowth in patients with previous Kasai portoenterostomy
causes bile salt deconjugation and abnormal micelle formation
C. Increased energy requirements result from:
1. Underlying liver disease processes such as inflammation
2. Recovery from major insults such as infection or surgery
3. Increased respiratory effort secondary to ascites or organomegaly
D. Altered fuel consumption
1. May produce negative protein balance
2. May decrease hepatic glycogen stores
3. May cause an increased used of fat stores as a substrate for metabolism, a pattern seen
in starvation
III. Nutritional consequences of chronic cholestasis

A. Carbohydrates
1. Fasting hypoglycemia: abnormal hepatocyte function and reduced hepatocyte mass
results in impaired gluconeogenesis and reduced glycogen stores
2. Postprandial hyperglycemia and reduced glucose utilization may be caused by impaired
catabolism of insulin in the liver
B. Proteins
1. Negative nitrogen balance results from impaired hepatic protein synthesis and increased
use of amino acids for gluconeogenesis in the presence of disordered carbohydrate
metabolism
2. Reduced synthesis of insulin-like growth factor-1 and its binding protein results in
growth hormone resistance

C. Fats
1. Reduced fat stores occur secondary to increased fat oxidation and fat malabsorption
2. Impaired micelle formation results in malabsorption of long-chain triglycerides, fat-
soluble vitamins (A, D, E and K) and essential fatty acids
3. Linoleic and linolenic acids are essential fatty acids used in synthesis of long-chain
polyunsaturated fatty acids (LCPUFAs). LCPUFAs such as arachidonic acid and
docosahexaenoic acid are essential for neurologic development and growth in children
4. Medium-chain triglycerides (MCT) are more water soluble than long-chain triglycerides
and are readily absorbed by the intestinal mucosa, making them a better source of fat
calories in cholestatic children
D. Vitamin A
1. Retinyl palmitate and carotenoids are derived from animal and plant sources, respectively
2. Deficiency in vitamin A results in night blindness, xerophthalmia and keratomalacia
3. Vitamin A may play a role in immune function as suggested by decreased morbidity of
diarrheal illnesses, measles, and HIV infection with vitamin A supplementation
4. Serum retinol level is a convenient, clinically practical measure of vitamin A nutrition.
Retinol dose response is more reliable and is based on a sharp increase of retinol level in
response to vitamin A administration in patients who are deficient in vitamin A
5. Treatment: refer to Table 1.
E. Vitamin D
1. There are two major prohormones of vitamin D—vitamin D2 (ergocalciferol) and
vitamin D3 (cholecalciferol). Prohormones first undergo 25- hydroxylation in the liver
(25-hydroxy vitamin D) and then further hydroxylation in the kidney, producing 1,25
dihydroxy vitamin D or 24, 25 dihydroxy vitamin D
2. Food rich in vitamin D include fish oils and fortified dairy products, although adequate
amounts can be synthesized in the skin when cholesterol is exposed to sufficient
ultraviolet B light
3. Deficiency results in defective bone mineralization
4. Measurement of serum 25-hydroxy vitamin D is the most accurate means of assessment
of vitamin D status. Half-life of 1,25 dihydroxy vitamin D is so short that it is a poor
reflection of chronic vitamin D status
5. Treatment: refer to Table 1.
F. Vitamin E (α-tocopherol)
1. Group of tocopherols of which α-tocopherol is the most studied. Vitamin E is found in
nuts, green leafy vegetables and vegetable oils
2. Deficiency associated with progressive neuromuscular syndrome with areflexia,
cerebellar ataxia, posterior column dysfunction and peripheral neuropathy. Hemolytic
anemia occurs due to oxidative damage to red blood cells
3. In cholestasis, total serum vitamin E levels may be artificially elevated even in deficient
children, because vitamin E concentrates in the increased lipid fraction of serum
4. The most reliable index of vitamin E status is the ratio of serum vitamin E (mg/dL) to
total serum lipids (g/dL). In infants and children <12 years of age, vitamin E to total
serum lipid ratio <0.6 mg/g indicates vitamin E deficiency
5. Treatment: refer to Table 1
G. Vitamin K
1. Vitamin K1 is abundant in green leafy vegetables, dairy products, and liver. Vitamin K2
is derived from bacterial metabolism in the gut. Bacterial production of vitamin K2 is not
sufficient in the absence of dietary vitamin K1
2. Deficiency causes abnormal coagulative function. Vitamin K is required for carboxylation
of glutamic acid residues on coagulation factors II, VII, IX, X and proteins C and S in the
liver
3. Osteocalcin requires vitamin K-dependent carboxylation, hence the link between vitamin
K deficiency and bone disease
4. Confirmation of vitamin K deficiency can be made by noting the improvement of a
prolonged prothrombin time after a parenteral dose of vitamin K
5. The PIVKA (or proteins induced in vitamin K absence)-II assay is a more sensitive but not
widely available measure of vitamin K status
6. Treatment: refer to Table 1
H. Folic acid
1. In severe hepatic insufficiency, the liver cannot methylate folic acid, resulting in deficien-
cy of the active vitamin
I. Trace elements
1. Calcium and magnesium metabolism are closely related to vitamin D status. Depletion
of minerals occurs in cholestasis because of reduced vitamin D-stimulated intestinal
absorption. Both also become bound to unabsorbed fatty acids in the gut, further
reducing absorption
2. Iron deficiency can occur in the presence of reduced intake or overt losses from
gastrointestinal bleeding in patients who have portal hypertension
3. Elevated levels of copper and manganese may occur, because these metals are primarily
excreted in bile
IV. Nutritional management

A. The goal for caloric intake should be 125%–150% of recommended dietary allowance based
on ideal body weight (50th percentile of weight-for-height measurement). Anthropometric
measurements may be more appropriate to guide nutritional therapy
B. Adequate protein intake is necessary (2.0–3.0 mg/kg/d in small infants) while delivering optimal
energy intake
C. Infants should be started on a formula containing MCT oil. The formula may be concentrated to
provide 24 kilocalories per ounce
D. Older children can add calorie-dense nutritional supplements to their usual diet. Glucose
polymers or MCT oil can be added to solid food
E. If oral intake is not sufficient, patients may be started on supplemental enteral feedings
F. Essential fatty acid deficiency must be suspected in the cholestatic child with poor growth,
dry scaly rash, or thrombocytopenia. Corn oil, safflower oil, or lipid emulsions can be added to
formula to provide additional linoleic acid, if needed
G. Refer to Table 1 for specific vitamins supplementation. Vitamin status should be monitored every
3–6 months and supplementation should continue at least 3 months after resolution of jaundice
Table 1. Vitamins and Trace Elements

Vitamin/trace element Treatment/prevention
Vitamin A 5,000–25,000 U/d of water-soluble preparation
Vitamin D Vitamin D3 3,000–5,000 U/d
Vitamin E 15–25 IU/kg per day of a water-soluble form of vitamin E,
d-α-tocopherol polyethylene glycol 1000 succinate (TPGS)
Vitamin K 2.5–5.0 mg 2–7x per week
Zinc 1–2 mg/kg/d of elemental zinc
Calcium 25–100 mg/kg/d of elemental calcium
Recommended Reading
Ng VL, Balistreri WF. Treatment options for chronic cholestasis in infancy and childhood. Curr Treat Options
Gastroenterol. 2005;8(5):419-430.
Nightingale S, Ng VL. Optimizing nutritional management in children with chronic liver disease. Pediatr Clin
North Am. 2009;56(5):1161-1183.
Henkel AS, Buchman AL. Nutritional support in patients with chronic liver disease. Nat Clin Pract Gastroen-
terol Hepatol. 2006;3(4):202-209.
Squires RH. End-stage liver disease in children. Curr Treat Options Gastroenterol. 2001;4(5):409-421.

See Page 687 for 8P- Carbohydrate Malabsorption
9A. Endoscopy
Roberto Gomez, MD
I. Procedures
Esophagogastroduodenoscopy (EGD) and colonoscopy allow for obtaining mucosal tissue to assist with
diagnosis. In addition, these procedures allow for access for therapeutic treatment of varices, GI bleeding,
strictures, polyps and removal of foreign bodies.
II. Esophagogastroduodenoscopy
A. Indications: vary with the age of the patient and include dysphagia, odynophagia, abdominal
pain, GI bleeding (hematemesis and hematochezia), intractable GERD, vomiting, anorexia, weight
loss, failure to thrive, anemia of unclear etiology, diarrhea, and ingestions (foreign body and
caustic). Therapeutic EGD indications include foreign body removal, stricture dilation, varices
treatment and control of upper GI bleeding
III. Colonoscopy
A. Indications: vary with age and include gastrointestinal bleeding, suspected inflammatory bowel
disease, cancer surveillance in both polyposis syndrome and IBD, anemia of unclear etiology,
weight loss, failure to thrive and chronic diarrhea. Therapeutic colonoscopy indications include
polypectomy, foreign body removal, decompression of toxic mega colon, dilatation of stricture
and control of bleeding lesions
B. Contraindications of EGD and Colonoscopy
1. Absolute contraindications include suspected perforation and peritonitis in a toxic
patient
2. Relative contraindications include recent bowel surgery, coagulopathy, thrombocytope-
nia, neutropenia, connective tissues disorders such as Ehlers-Danlos with increased
risk of perforation. Bowel obstruction and toxic dilation also hold an increased risk
for perforation
3.
IV. Preparation and Bowel Cleanout for Colonoscopy
A. Several regimens have been described to be effective for colonoscopy cleanout
1. Polyethylene glycol and stimulant laxative
2. Magnesium citrate and stimulant laxative
3. Phosphate enema, bisacodyl and clear liquid diet
V. Complications of EGD and Colonoscopy

A. Complications following EGD are rare, occurring in <2% of patients and include hypoxia sec-
ondary to sedation, bleeding, hematoma, perforation, missed lesions and infection. The risk of
bleeding following EGD with biopsy is 0.3%. Perforation occurs in less than 0.3% of cases and
infection is rarely reported
B. Complications of colonoscopy are equally infrequent, occurring in <2% of patients, and include
hypoxia secondary to sedation, bleeding, hematoma, perforation, missed lesions and infection.
Bleeding and perforation are the most likely complications occurring <0.3% and 0.3%,
respectively
C. Identification of complications typically occurs in the first 24 hours after the procedure. Bleeding
presents with hematemesis or bloody output from a gastrostomy tube in EGD patients and
with hematochezia following colonoscopy. Repeat endoscopy is recommended for identification
of the bleeding site and treatment with the appropriate therapy. Perforation is identified due
to patient discomfort, fever, and tachycardia, with extraluminal air visualized on a radiograph.
Conservative therapy with antibiotics and gut rest is the typical treatment
Section 9 - Diagnostic Tests 449

VI. Findings of EGD and Colonoscopy
A. Sufficient training and experience are required to allow for identification of normal and abnormal
gross findings. The EGD allows for visual identification of inflammation, ulcers, foreign bodies
and hiatal hernia. Obtaining biopsies is vital to diagnosis. Similarly, colonoscopy can identify
inflammation, ulcers, polyps and foreign bodies, but biopsies are paramount to diagnosis
Recommended Reading
Geboes K, Ectors N, D’Haens G, et al. Is ileoscopy with biopsy worthwhile in patients presenting with symp-
toms of inflammatory bowel disease? Am J Gastroenterol. 1998;93(2):201-206.
Wyllie R, Kay MH. Gastrointestinal endoscopy in infants and children. Pediatr Rev. 1993;14(9):352-359.
9B. Intestinal Biopsy
Steve Min, MD
Carolyn Sullivan, MD
I. Intestinal Biopsy in Infectious Diarrhea

A. Bacterial
1. V cholera; minimal or no histologic change
2. Shigella species: large bowel typically affected (mostly left-sided); hemorrhagic mucosa
with exudates that may form pseudomembranes, ulcers can be present; histologic
features include cryptitis, crypt abscesses acutely, and may develop mucosal destruction
with neutrophils and other inflammatory cells in lamina propria
3. E coli (EHEC): right side colon usually most severely affected, colonic edema, erosions,
ulcers and hemorrhage; histologic findings include edema and hemorrhage in lamina
propria/submucosa, mucosal acute inflammatory cells and necrosis; microthrombi may
also be seen within small vessels
4. Salmonella (typhoid fever): may involve any level of GI tract (most prominent ileum,
appendix, colon); thickened bowel wall, raised nodules (hyperplastic Peyer’s patches),
ulcerations and necrosis; histological findings mostly involve hyperplasia of Peyer’s
patches, with acute inflammation of the overlying epithelium
5. C difficile: classic pseudomembranous colitis findings include yellow-white
pseudomembranes that are most commonly found in the left colon, with patchy
distribution, often sparing the rectum; classic histologic findings involve the presence
of volcano lesions (intercrypt necrosis and ballooned crypts give rise to the laminated
pseudomembrane, and often with loss of superficial epithelial cells)
6. M tuberculosis: ileocecal and jejunoileal areas most commonly involved, followed by
appendix and ascending colon; ICV may be deformed and gaping; strictures, ulcers,
along with thickened mucosal folds, and inflammatory nodules; characteristic histologic
finding is the caseating, often confluent granuloma which can be present at any level of
the wall of the gut; acid-fast stains may demonstrate organisms within the granuloma
7. Yersinia: preferentially involves ileum, right colon, appendix; responsible for many cases
of isolated granulomatous appendicitis
B. Viral
1. Most enteric viruses that cause diarrhea (adenovirus, rotavirus, coronavirus, echovirus,
enterovirus, astrovirus, and Norwalk virus) are detected in stool samples and, rarely, by
surgical pathology
2. CMV: may involve any part of the GI tract; most common gross lesion is ulceration,
which may be single or multiple, and either superficial or deep; also may find mucosal
hemorrhage, pseudomembranes and obstructive inflammatory masses; histologic
findings vary, but may include minimal inflammation, deep ulcers with prominent
granulation tissue; classic owl’s eye inclusions may be seen, usually in endothelial cells
3. Adenovirus may cause similar findings as CMV; however, the inclusions are usually
crescent-shaped, and generally within the epithelium
C. Parasitic
1. Many protozoal infections are also diagnosed by stool sample examination
2. Giardia lamblia: endoscopic exam is generally unremarkable; biopsies may demonstrate
mild villous blunting, with increased lamina propria inflammatory cells; may find
trophozoites (resembling pears cut lengthwise that contain 2 ovoid nuclei) at luminal
surface
3. Entamoeba histolytica: coalescing small ulcers, which may form large, geographic ulcers;
cecum most commonly involved, but can affect any level of colon or appendix; histo-
logically, deep ulcers extending into submucosa found in advanced disease; organisms
resemble macrophages with foamy cytoplasm – presence of ingested red blood cells are
pathognomonic of E histolytica (hemophagocytosis)

II. Immunodeficiency-related Diarrheal Disease
A. Common variable immunodeficiency (CVID)
1. Findings consistent with chronic infections can be found in CVID, most commonly from
Giardia
2. Gastric mucosa with nonspecific increase in lamina propria lymphocytes
3. Small bowel may include sprue-like lesions with villous blunting
4. In contrast to celiac disease, the villous atrophy in CVID lacks crypt hyperplasia and
plasma cells are decreased in number
5. Granulomatous enteropathy has been reported with CVID; poorly formed non-
necrotizing granulomas can be found in multiple sites throughout GI tract
6. Nodular lymphoid hyperplasia found in up to 60% of patients with CVID
7. Some may develop chronic inflammatory process involving small or large bowel, similar
to IBD
B. Graft-vs-host disease (GVHD)
1. GI tract involvement occurs during acute GVHD
2. Endoscopic findings include mucosal edema and erythema, as well as ulcers and
mucosal sloughing
3. Histologic features are epithelial cell apoptosis and relatively sparse mononuclear
inflammatory cell infiltrate; apoptotic cells in the colon are also known as exploding
crypt cells
4. In stomach, granular eosinophilic necrotic cellular debris may be present in the lumen of
gastric glands; villous blunting can be seen in small bowel
III. Other Types of Diarrheal Disease

A. Ulcerative colitis
1. Crypt distortion with villous surface, goblet cell depletion and prominent crypt abscesses
2. Diffuse, predominantly plasma cell, infiltrate of lamina propria
B. Crohn disease
1. Granulomas present in 25%–28% biopsies
2. Crypts are generally well-aligned, despite moderate inflammatory infiltrate
3. Crypt abscess and cryptitis are less constant than UC or infectious colitis
4. Patchy inflammatory infiltrates
C. Celiac
1. Loss of normal architecture with decrease in height of villi; crypt elongation or
hyperplasia; increased number of intraepithelial lymphocytes is characteristic; lamina
propria also typically shows an increase in plasma cells
2. Important to note that all findings are nonspecific and may also be found in variety of
other disease (i.e., tropical sprue, bacterial overgrowth, food allergies and CVID)
D. Cow’s milk protein allergy
1. Mild-to-severe intraepithelial or lamina propria eosinophils, associated with epithelial
injury and edema; usually found in the colorectum, but may be found throughout the
GI tract
E. Autoimmune enteropathy
1. Variable flattening of villi with increase in number of lamina propria plasma cells; without
increase in intraepithelial lymphocytes
2. Colon histology may range from normal to severe inflammation
F. Bacterial overgrowth syndrome
1. May be histologically normal
2. May reveal mild-to-moderate villous blunting with chronic inflammation in lamina pro-
pria and epithelium
3. Changes are patchy, and may vary from segment to segment
G. Microvillous inclusion disease
1. Grossly, mucosa appears scalloped or atrophic; duodenal biopsies reveal
moderate-to-severe villous blunting, and no increase in either lamina propria
inflammation or intraepithelial lymphocytes (unlike celiac)
2. Electron microscope findings are pathognomonic and reveal markedly decreased surface
microvilli, which are shortened and disorganized in appearance
3. Intracytoplasmic vacuoles can be detected with PAS stain or with carcinoembryonic
antigen immunostaining
H. Megaloblastic anemia – radiation and chemotherapy effect
1. Variable villous abnormality with or without megaloblastic epithelial changes
2. Focal necrosis of epithelial cells (apoptosis) and increased inflammatory cells within
mucosa/submucosa (similar to changes associated with folate/vitamin B12 deficiency)
I. Whipple’s disease
1. Caused by Tropheryma whipplei, a rod-shaped micro-organism
2. Diagnosis based on identification of PAS-positive, diastase-resistant bacilli within lamina
propria in small bowel biopsy specimens
J. Eosinophilic gastroenteritis
1. Scattered intramucosal eosinophils are normal in the GI tract (except the esophagus)
2. Diagnostic histology for EG in the appropriate clinical setting includes:
a. Collections of eosinophils not associated with other inflammatory cells
b. Groups of eosinophils associated with cryptitis or crypt abscesses
c. Eosinophilic infiltration of the muscularis mucosae
K. Intestinal lymphangiectasia
1. Histologic appearance in both primary and secondary forms involves dilated lymphatics
located in otherwise normal tissue
L. Tufting enteropathy
1. Small bowel biopsies demonstrate variable villous abnormality, usually not associated
with epithelial lymphocytosis, and a distinctive surface epithelial change consisting of
epithelial crowding, disorganization and focal tufting
IV. Risk Associated With Biopsies

A. General
1. Complications associated with cold biopsy forceps in patients without coagulopathy are
very rare
a. Risk of bleeding and perforation are both approximately 0.7%
2. Complications from hot biopsy forceps or electrocautery snare resection include
hemorrhage, perforation and postcoagulation syndrome
a. Risk of significant hemorrhage from monopolar hot biopsy of a polyp is 0.39%
b. Frequency of perforation from hot biopsy is 0.5%
3. Incidence of hemorrhage during colonoscopic polypectomy is 0.77%–2.24%, while
perforation during colonoscopy occurs 0.11%–0.42%
4. In graft-vs-host disease, given the potential for desquamation, ulcerations and
vesicobullous lesions, performing EGD and biopsy (particularly in duodenum) carries
higher than normal risk of bleeding and perforation
B. Perforation
1. Predisposing factors for perforation in the upper GI tract include presence of anterior
cervical osteophytes, Zenker’s diverticulum, esophageal strictures and malignancies
2. Though uncommon, esophageal perforations are associated with a relatively high
mortality rate (approximately 25% in adult population)
C. Bleeding
1. More likely in individuals with thrombocytopenia and/or coagulopathy
2. In patients with platelet counts <20,000, biopsies should be performed with caution and
platelet transfusion should be considered prior to biopsy
3. In general, standard biopsy techniques may be used in anticoagulated patients
D. Infection
1. Transient bacteremia may occur during endoscopy, but is generally clinically insignificant
in pediatric patients
2. Antibiotic prophylaxis for prevention of infective endocarditis (IE) is not indicated for any
endoscopic procedure, regardless of the cardiac condition, based on most recent ASGE/
AHA guidelines
3. However, for patients with established GI tract infections in which enterococci may
be part of the infecting flora, antibiotic prophylaxis may be considered for those with

cardiac conditions associated with the highest risk of adverse outcomes from IE. These
include those with prosthetic valves, previous IE, cardiac transplant and subsequent
valvulopathy, unrepaired cyanotic congenital heart disease and repaired CHD with
prosthetic material
Recommended Reading
Standards of Practice Committee; ASGE. Antibiotic prophylaxis for GI endoscopy. Gastrointestinal Endoscopy.
2008;67:6.
Standards of Practice Committee; ASGE. Complications of upper GI endoscopy. Gastrointestinal Endoscopy.

2002;55:7.
Technology Assessment Committee; ASGE. Update on endoscopic tissue sampling devices. Gastrointestinal
Endoscopy. 2006;63:6.
Walker WA, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR. Pediatric Gastrointestinal Disease. 3rd ed.
Hamilton, Ontario: BC Decker, Inc.; 2004: 1670-1671.
Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders
Elsevier; 2006: 343.
9C. Liver Biopsy
Yonathan Fuchs, MD
I. Indications for Liver Biopsy

A. Diagnosis
1. Alcoholic liver disease
2. Nonalcoholic steatohepatitis
4. Hemochromatosis-index patient
5. Wilson disease
6. Cholestatic liver disease
a. Biliary atresia
b. Primary sclerosing cholangitis
c. Primary biliary cirrhosis (in adults)
7. Liver mass
8. Liver rejection s/p transplant
B. Grading and staging
1. Chronic hepatitis B and C (if treatment is a consideration)
C. Evaluation
1. Abnormal liver biochemical tests following inconclusive workup
2. Evaluation of fever of unknown origin, including tissue culture
II. Equipment and Sonography

A. Suction-type devices (Jamshidi, Menghini)
B. Spring-loaded cutting devices (Manopty)
C. Suction needles generally produce larger specimens than spring-loaded needles
D. Ultrasonography prior to a liver biopsy defines the anatomy of the liver and the relative positions
of the gallbladder, lung and kidney
III. Risks:
A. Minor complications: transient localized discomfort at the biopsy site and pain sufficient to
require analgesia. Referred pain to the right shoulder
B. Major complications:
1. Perforation
a. Pneumothorax and hemothorax
b. Bowel perforation
c. Biliary perforation
2. Intraperitoneal hemorrhage
3. Bile peritonitis
4. Infection
5. Inadvertent renal puncture/biopsy
IV. Histologic Features

A. Neonatal Cholestasis
1. Critical role in the diagnosis of extrahepatic biliary atresia
2. Biopsy in biliary atresia will reveal
a. Bile ductular proliferation, canalicular and cellular bile stasis, and portal and
perilobular edema and fibrosis
b. Bile plugs in bile ducts are relatively specific but are found in only 40% of biopsy
specimens
3. Biopsy in neonatal hepatitis will reveal
a. Little or no bile duct alteration. Liver parenchyma abnormalities include giant cell
ballooning/degeneration, neutrophil infiltration, intralobular inflammation and
Kupffer cell hyperplasia

B. Acute Hepatitis
1. Inflammation is predominantly within the lobule. Hepatocellular injury is more
pronounced (edema and necrosis of individual hepatocytes, macrophages are enlarged
and numerous)
C. Chronic Hepatitis
1. Inflammation is within the portal tracts. Variable degree of parenchymal loss, scarring,
parenchymal regeneration and cirrhosis
D. Acute Liver Failure
1. Massive confluent or multilobular necrosis
E. Autoimmune Hepatitis
1. Dense mononuclear and plasma cell infiltration of the portal areas, which expands into
the liver lobule; destruction of the hepatocytes at the periphery of the lobule, with
erosion of the limiting plate (interface hepatitis) and hepatic regeneration with rosette
formation
F. Drug-induced Hepatitis
1. Prominence of neutrophils and eosinophils among inflammatory cells. Hepatocellular
injury can be spotty, affecting single hepatocytes, or it can be confluent, affecting
groups of hepatocytes. Confluent necrosis can be zonal or non-zonal, depending upon
the offending agent
2. Zonal necrosis is characteristic of compounds with predictable, dose-dependent, intrinsic
toxicity, such as halothane (zone 3), carbon tetrachloride (zone 3), and acetaminophen
(zone 3)
G. PSC
1. Obliterative atrophy of septal or trabecular ducts proximal to sites of large duct scarring
(progressive ductal lesions)
2. Focal concentric edema and fibrosis (onion skinning) around interlobular bile ducts
H. NASH
1. Ballooning degeneration of hepatocytes, macrosteatosis and perisinusoidal fibrosis
I. Wilson Disease
1. Early stages marked by steatosis of hepatocytes, mild chronic hepatitis, portal tract fibro-
sis and scant stainable copper
2. Characteristic ultrastructural lesions seen via EM: hepatocellular mitochondria are pleo-
morphic and abnormally large, and show widened intracristal spaces, increased matrix
density and large granules
J. Reye Syndrome
1. Caused by the interaction of a viral infection and salicylate use or some underlying
undefined metabolic-genetic predisposition
2. Liver biopsy demonstrates microvesicular steatosis in the absence of hepatic
inflammation or necrosis and characteristic swelling and pleomorphism of mitochondria
under EM
K. α1-AT deficiency
1. Periodic acid-Schiff-positive, diastase-resistant globules in the endoplasmic reticulum of
hepatocytes. Variable degrees of hepatocellular necrosis, inflammatory cell infiltration,
periportal fibrosis or cirrhosis may be present
L. Portal Hypertension
1. Portal vein thrombosis
a. Portal venules are small in caliber
b. Parenchymal atrophy, especially in centrilobular regions
2. Congenital hepatic fibrosis
a. Portal tracts are expanded by fibrosis and contain increased numbers of dilated
bile ducts at the limiting plate
V. Post-Transplant Rejection
A. Histologic changes are variable
B. The classic triad for acute cellular allograft rejection is: mixed portal tract inflammation, portal
venule endothelialitis and inflammatory-mediated bile duct damage
C. May present with necrosis in the pericentral vein (zone 3) and lymphocytic infiltration in the
central vein as central venulitis, or lymphocytic infiltration in the portal zone either in bile ducts
or portal vein as portal venulitis
D. Involvement of vascular system is usually suggestive of more severe rejection
Recommended Reading
Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press;
2007.
Van Thiel DH, Gavaler JS, Wright H, Tzakis A. Liver biopsy. Its safety and complications as seen at a liver
transplant center. Transplantation. 1993;55:1087.
Hamilton, Ontario: BC Decker, Inc.; 2006.
Wyllie R, Hyams S, Kay M. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Elsevier
Saunders; 2011: 859-860.

9D-1. Additional Studies—
Esophageal pH and
Impedance Monitoring
Lillienne Yoon, MD
Rina Sanghavi, MD
I. Esophageal pH Monitoring
A. Esophageal pH monitoring is a way to study acid reflux (pH <4) in patients and correlate with
symptoms (an event marker)
1. Can quantify the amount of reflux:
a. # of episodes with a drop in pH <4.0
b. # of episodes of certain duration of pH <4.0
c. Duration of intraesophageal pH <4.0.
B. Traditionally, it is the standard test for diagnosing GERD
C. Esophageal pH can be monitored by a transnasal catheter or wireless pH capsule (Bravo)
1. Transnasal flexible catheter is positioned with the distal pH sensor 5 cm above the LES
in adults and 13% of the esophageal length in children. Reproduceability of results
depends on comparable placement of the pH sensor
a. How to verify position of catheter
1) Esophageal manometry: optimum method but not ideal for pediatrics
(time consuming and invasive)
2) Fluoroscopy, calculating esophageal length according to Strobel’s formula
(distance from the nose to the cardia) and endoscopy have been used
instead in pediatrics
b. The two most common pH electrodes are glass and antimony
1) Glass is considered the best sensor but it is expensive, large in diameter
2) Antimony has smaller diameter (more comfortable) can hold multiple
pH sensors
3) pH sensors need a reference electrode, which can be external or internal
a) External electrodes—less reliable due to problems with high body
temperature or sweat, which can lead to inaccurate pH values
b) Internal reference is more difficult to make but it is more reliable
4) The data from glass sensors vs antimony sensors do not correlate, so one
cannot reference normal ranges with each other
5) In-vitro 2-point calibration of the pH sensors is performed prior to the
study and when the test is complete
c. Dual channel (proximal and distal esophagus) can be used to evaluate patients
with GERD off therapy, or dual channel (distal esophagus and gastric) can be
used to evaluate patients with GERD on therapy (Figure 1B)
2. Bravo pH capsule has antimony electrode, internal reference, and is placed by
endoscopy at 6cm above the Z line in adults
a. Advantages: more comfortable, can record 48–72 hours, no risk of slipping into
the stomach
b. Disadvantages: expensive, invasive (need endoscopy), single location
3. Interpreting pH monitoring
a. Can use scoring system like Johnson and DeMeester Score system, or refer to
normal ranges created below

Table 1. Catheter-based Dual-probe (distal and proximal) Esophageal pH Monitoring
Variable Normal
Proximal (%) Distal (%)
Time pH <4.0 (%)
Total period < 0.9 < 4.2
Upright period < 1.2 < 6.3
Recumbent period < 0.0 < 1.2
Distal = 5 cm above manometric – defined proximal border of the LES.
Proximal = 20 cm above manometric – defined proximal border of the LES.
Catheter free distal esophageal pH monitoring17
Variable Normal
Distal (%)
Time pH <4.0 (%)
Total period < 5.3
Upright period < 6.9
Recumbent period < 6.7
Distal = 6 cm above endoscopic – defined gastroesophageal junction
Adapted from Tutuian R, Castell DO. Gastroesophageal reflux monitoring: pH and impedance. GI
Motility Online. 2006.
4. Most relevant parameters are the acid exposure time or reflux index (the % of time of
the entire duration of the investigation during which the pH is <4)
a. reflux index <3 is normal
b. reflux index 3–7 is indeterminate
c. reflux index >7% abnormal
II. Impedance
A. Impedance can monitor the resistance to current flow (impedance) between two electrodes from
either liquid or gas bolus
FIGURE 2 . The esophagus starts at a resting value at

baseline (A) that represents the collapsed esophageal
walls on the catheter. When a swallow is initiated,
air is also swallowed. Air enters in the first measuring
segment causing an increase in impedance (B). After
the passage of air, the bolus causes a decrease in
impedance due to its conductivity and its effect on
luminal dilatation (C). The bolus enters, traverses,
and exits the measuring segments (C, D, and E,
respectively). After the passage of the bolus, the
lumen-occluding contraction (F) causes an increase in
impedance. If the contraction wave completely clears
the bolus from the segment, then a return to the
original impedance baseline is seen (G).
Adapted from Di Pace M, Caruso A, Catalano P, Casuccio A, De Grazia E. Evaluation of esophageal

motility using mulitchannel intraluminal impedance in healthy children and children with
gastroesophageal reflux. J Ped Gastroenterol Nutrition. 2011;52:26-30.
B. There is a combined MII-pH catheter for esophageal monitoring for GERD
1. It has become the preferred method of testing patients with persistent symptoms on
acid suppressive therapy, as it can clarify whether symptoms are associated with acid or
nonacid reflux or not associated with reflux
2. A recent consensus report provided a detailed nomenclature for the reflux patterns
detected by impedance-pH monitoring
a. Reflux is defined as either pure liquid or a mixture of liquid and gas detected by
impedance
b. Liquid-only reflux is defined as a retrograde 50% decrease in impedance from
the baseline in the 2 distal impedance sites
c. Gas reflux is defined as a simultaneous increase in impedance >3,000 Ω in any 2
consecutive impedance sites with 1 site having an absolute value >7,000 Ω
d. Mixed liquid gas reflux is defined as gas reflux occurring during or immediately
before liquid reflux
3. Transnasal catheter design:
a. It has 1 pH sensor that is placed above the LES
b. It has impedance sensors 3, 5, 7, 9, 15, 17 cm above the LES
4. Principles of the MII-pH catheter:
a. Reflux frequency
b. Esophageal height and duration of reflux episodes
c. Detect nonacid reflux
d. Detect gas vs liquid reflux
5. There are no normal ranges in impedance but there are some guidelines: (see Table 2)
6. In general, impedance will detect more reflux episodes, since it can detect nonacid
reflux compared to pH probe alone
Table 2. Liquid GER and Gas Reflux

Liquid GER Gas Reflux
- Drop in impedance to less than 50% of baseline - Rapid and pronounced rise in impedance (low
values electrical conductivity)
Acid GER
1. pH falls <4 for at least 4 secs or
2. p
H already <4, decreases by at least 1 pH unit for
more than 4 secs
Nonacid GER
-Weakly acidic and alkaline GER
Weakly acidic reflux
-pH drop of at least 1 pH unit sustained for more than
4 secs with basal pH remaining between 7 and 4
Alkaline
-pH does not drop below 7
Adapted from Vandenplas Y. Esophageal pH and Impedance Measurement. In Kleinman R, Sanderson I,
Goulet O, Sherman P, Mieli-Vergani G, Shneider B, eds. Walker’s Pediatric Gastrointestinal Disease. Vol 2.
Hamilton, Ontario: BC Decker Inc; 2008:1393-1400.
III. Preparation/Performing pH Monitoring

A. Patient preparation rule of thumb:
1. Fasting for 3–5 hours prior to procedure
2. Sedation should not be used because it can interfere with swallowing and influences LES
pressures
3. Histamine and proton pump inhibitors should be stopped at 3 or 7 days, respectively
(the exception would be to see the acid-blocking effect of the drug)
4. Antacids are fine up to 6 hours prior to the start of the recording
5. Prokinetics should be stopped at least 48 hours prior to test
6. For radiology studies, pH monitoring can be done at least 3 hours after barium or
nucleotide gastric/esophageal study

B. Duration: at least 18–24 hours spanning day and night
1. GERD and esophageal acid exposure is highest during the day
2. There is substantial evidence that there are more reflux episodes during the day than at
night (likely due to eating and physical activity)
3. In general, it is noted that there are more acid reflux during fasting and more nonacid
reflux during feeding
IV. Recording Conditions Influenced by Patient-related Factors

A. Diet
1. Debate: during the test, the diet is restricted (nonacidic foods/drinks, etc). However, if
the diet is restricted, then it is not the norm for the patient, so it may lead to non-realis-
tic results.
2. Rule of thumb:
a. Avoid hot or ice cold beverages and foods (electrodes are temperature sensitive)
b. Avoid chewing gum and hard candy (increases saliva production, which increases
peristalsis and swallowing, which tends to normalize results)
c. If drinking alcohol or smoking, it should be noted in diary
d. Fatty foods prolong postprandial gastric antiacidity and delay gastric emptying
3. With infants, it is suggested to replace one of the feedings with apple juice to solve the
problem of gastric buffering after a milk feeding
B. Position
1. There are data that prone sleeping is the preferred position for infants with GER (the
problem is SIDS)
2. There is data suggesting that prone anti-Trendelenburg 30o sleeping position reduces
GER in normal subjects (difficult for infants)
C. Physical activity can also precipitate reflux
Recommended Reading
Di Pace M, Caruso A, Catalano P, Casuccio A, De Grazia E. Evaluation of esophageal motility using

mulitchannel intraluminal impedance in healthy children and children with gastroesophageal reflux.
J Ped Gastroenterol Nutrition. 2011;52:26-30.
Hirano I, Richter J; Practice Parameters Committee of American College of Gastroenterology. ACG Practice
Guidelines: Esophageal Reflux Testing. Am J Gastroenterol. 2007;102:668-685.
Vandenplas Y. Esophageal pH and Impedance Measurement. In Kleinman R, Sanderson I, Goulet O, Sherman

P, Mieli-Vergani G, Shneider B, eds. Walker’s Pediatric Gastrointestinal Disease. Vol 2. Hamilton, Ontario: BC
Decker Inc; 2008:1393-1400.
Gastric Function Tests
Leonel Rodriguez MD, MS
I. Evaluation
Evaluation of gastric function focuses on ability to accommodate and empty, motility, electrical activity
and acid secretion.
II. Gastric Acid Secretion

A. Quantitation of total gastric acid secretion at rest and after stimulation
B. Most commonly used to evaluate conditions with abnormally low secretion (atrophic gastritis,
Menetrier disease, pernicious anemia) or high acid secretion (Zollinger-Ellison syndrome)
C. Nasogastric tube used to aspirate gastric juice in 15-minute aliquots
D. Basal acid output (BAO)
1. 15 minute aspirate of fasting gastric juice is titrated with NaOH to neutrality
2. Normal BAO in children is 0.03–0.05 mEq/kg/hour
3. Suspect Zollinger-Ellison syndrome if BAO is >15 mEq/hour
E. Pentagastrin stimulation performed when BAO is low or absent
1. Pentagastrin (6 mcg/kg) given IV and 15 minute aspirations performed for 45–60
minutes to calculate the maximal acid output (MAO)
F. Normal values for MAO are 18–28 mEq/h in men, 11–21 mEq/h in women
G. 0.031 mEq/kg/h at 1 month of age
H. 0.122 mEq/kg/h at 3 months
I. 0.218 mEq/kg/h at 20 months with no significant change thereafter
III. Gastric Myoelectrical Activity

A. Electrogastrography (EGG)
1. Noninvasive external electrodes record gastric myoelectric activity
2. Normal rhythm is 3 contractions per minute (cpm) corresponding to gastric pacemaker
generated gastric slow waves
3. Does not correlate to gastric emptying by scintigraphy and ultrasonography
4. May help differentiate children with normal and abnormal antroduodenal manometry
5. Limited application because of lack of standardization and significant motion artifacts
6. EGG can be an adjunct in the evaluation of patients with functional and motility
gastrointestinal disorders
IV. Gastric Emptying Studies

A. Scintigraphy
1. Evaluates gastric emptying of a meal labeled with Tc99 sulfur colloid and/or Indium-111
2. Simultaneous estimates of solid and liquid phase emptying using two labels
3. Area over the stomach scanned intermittently for up to 120 minutes after administration
of labeled meal, and amount of tracer remaining used to calculate % emptying
4. Most studies estimate 50% emptying in 1 hour is normal, >60% emptying at 2 hours
and >90% emptying at 3 hours
5. Important drawback—lack of pediatric standards, lack of standard test meal both type
and volume, radiation
B. Breath test
1. Measures ratios of C12 and C13 in breath after a meal enriched in C13 and compares to
known ratios in atmosphere
2. Amount of C13 enrichment in breath hydrogen on serial measurements is related to
gastric emptying rate

3. C13 octanoic acid used to label solids. C13 sodium acetate used to label liquids
4. Breath test has poor correlation with scintigraphy and poor relationship to dyspeptic
symptoms
5. In children the ½ emptying of C13-sodium acetate correlates with gastric emptying
measured by scintigraphy in children with gastroparesis, and discriminates healthy
volunteers from children with gastroparesis symptoms
6. Useful when radiation must be avoided (pregnancy) and in patients with aspiration risk
and patient unable to be moved to radiology
7. Advantage: noninvasive, low cost
8. Most important limitation is that test requires normal intestinal, hepatic, and pulmonary
functions, and reproducibility is poor
C. Ultrasonography (US)
1. Most common technique—serial measurements of antral area (related to antral volume)
after a meal to estimate the time to return to baseline area or 50% baseline area
2. Good correlation with scintigraphy for gastric emptying of liquids in healthy and diabetic
adults
3. In children, correlates well with scintigraphy but limited by the overlapping of duodenum
and shadowing of the gastric antrum by air
4. US particularly useful in patients on a liquid diet (preterm infants)
5. Advantage: noninvasive
6. The test is limited by its poor reproducibility, lack of standard protocols, operator depen-
dency and interference by intestinal air
V. Gastric Receptive Accommodation Tests

A. Gastric barostat
1. Gold standard for evaluating gastric accommodation to distension
2. Utilizes an intragastric balloon manometer inflated to varying degrees
3. Not available for clinical practice
B. Ultrasonography
1. An attractive, noninvasive alternative to the barostat
2. Measures the gastric area or volume during and after a test meal to evaluate the
percentage of emptying over time and also gastric accommodation. No significant
intra and interobserver variability, but moderate day-to-day variability in healthy adult
volunteers
3. Reliable to evaluate accommodation in subjects with functional dyspepsia and in children
with recurrent abdominal pain
Recommended Reading
Abell TL. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American
Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol.
2008;103(3):753-763.
Di Lorenzo C. Is electrogastrography a substitute for manometric studies in children with functional gastroin-
testinal disorders? Dig Dis Sci. 1997;42(11):2310-2316.
Rao SS. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European
Neurogastroenterology and Motility Societies. Neurogastroenterol Motil. 2001;23(1):8-23.
Motility Testing
Meenakshi Rao, MD, PhD
Samuel Nurko, MD
I. Anorectal Manometry (ARM)
II. Indications for ARM

A. To diagnose a nonrelaxing internal anal sphincter—as found in Hirschsprung’s disease and IAS
achalasia (patients with normal rectal biopsy and abnormal sphincter)
B. To diagnose pelvic floor dyssynergia
C. To evaluate patients with fecal incontinence
D. To decide if the patient is a candidate for biofeedback therapy
E. To evaluate postoperative patients after imperforate anus repair
F. To evaluate postoperative patients with Hirschsprung’s that have obstructive symptoms, and to
evaluate the effect of botulinum toxin
III. ARM Procedure

A. Rectal distension with a balloon catheter to assess for the presence of the rectoanal inhibitory
reflex (RAIR), the reflexive relaxation of the internal anal sphincter (IAS) upon distention of the
rectum (Figure 1). This relaxation is absent in patients with Hirschsprung’s disease (Figure 2)
1. Good screening test (sensitivity 91%, specificity 98%)
2. Higher probability of false negative result in neonates, especially preterm infants
3. May require sedation in patients unable to cooperate
Figure 1. Normal IAS relaxation (RAIR) after Figure 2. Non-relaxing internal anal sphincter (IAS).
balloon distention.
Rodriguez L, Nurko, S Gastrointestinal motility procedures. In Wyllie et al editors: Pediatric Gastrointestinal
and Liver Disease. 4th edition. Elsevier, 2011; pp686-698.
IV. Antroduodenal (AD) Manometry

A. Measures intraluminal pressures of antrum and duodenum, providing information on contraction
patterns of upper GI tract

V. Indications for AD Manometry
A. Establish the presence or absence of chronic intestinal pseudo-obstruction (CIPO)
B. Classify pattern of dysfunction in patients with CIPO (myopathic vs neuropathic) and provide
prognostic information (likelihood of successful enteral feeding)
C. Exclude a motility problem as the basis of the patients’ symptoms (i.e., show normal findings in
children with apparent intestinal failure)
D. Evaluation of unexplained nausea and vomiting
E. Distinguish between rumination and vomiting
F. Exclude generalized motility dysfunction in patients with dysmotility elsewhere. For example, as-
sess small bowel motility prior to colectomy for intractable constipation
G. Assess motility in patients with CIPO being considered for intestinal transplantation. May suggest
unexpected obstruction
VI. AD Procedure
A. A motility catheter is placed across the antrum and into the duodenum, either by endoscopy or
fluoroscopy
B. Medications that affect motility should be discontinued at least 48 hours prior to testing
C. Catheters should be tailored to patient size and information needed (minimum 1 antral and 3
small bowel recording sites; with a distance of 3 cm between ports)
D. Distance for duodenal and jejunal ports varies depending on the age of the patient, with a range
from 3– 10 cm between ports. In most children, a distance of 3 cm is sufficient
E. The position of the catheter needs to be checked frequently by fluoroscopy during the
performance of the test to ensure the correct position across the antroduodenal junction
F. Compared to stationary tests, ambulatory tests cannot be used reliably to assess postprandial
antral activity due to frequent catheter displacement
G. Antroduodenal contraction is then monitored for at least 3 hours in fasting state, and 1 hour
after ingestion of a standardized meal
1. Type and size of meal should be adjusted according to patients’ age and preference (at
least 10 kcal/ kg or 400 kcal; >30% kcal from lipids)
2. Meal should be administered by mouth or into the stomach if possible
H. If no motor migrating complex (MMC) seen in fasting state, then stimulated with erythromycin
1 mg/kg IV over 30 minutes
I. If no MMC observed despite erythromycin stimulation, then octreotide given SQ
VII. Interpreting Results of AD Manometry

A. During fasting, the stomach and small bowel show a cyclic pattern, known as the motor
migrating complex (MMC) which has three phases: I, II and III
1. Phase I is the most characteristic and consists of regular rhythmic peristaltic contractions
that start proximally and migrate down to the ileum
2. Phase II shows regular contractions that occur in the antrum at a rate of 2–3/min and in
the small bowel at 11–12/min
3. Phase III is followed by a period of quiescence (Phase I) that is interrupted by irregular
motor activity (Phase II) (Figure 3)
B. After the ingestion of nutrients, the fasting pattern is interrupted by what has been termed the
fed pattern
1. Fed pattern is characterized by an irregular occurrence of contractions with various
amplitudes in the antrum and duodenum (Figure 4)
C. Normal physiology: if Phase III MMC is present in fasting state or induced with erythromycin,
enteric neurons are likely intact
VIII. Abnormal Motility Patterns
A. CIPO
1. Neuropathic – antral hypomotility, absence of Phase III activity or abnormal propagation
of Phase III MMC activity, bursts of uncoordinated activity (hypercontractility) and lack
of fed response (Figure 5)
2. Myopathic – normal Phase III activity, but markedly low amplitude of contractions (<20
mm Hg) (Figure 6)
B. Postprandial antral hypomotility: seen in gastroparesis. Reduced motility index of postprandial
distal antral contractions correlates with impaired gastric emptying of solids
C. Rumination: simultaneous contractions or R waves are associated with regurgitation
D. Mechanical obstruction: postprandial clustered contractions lasting >30 minutes, separated by
quiescence or prolonged contractions
Figure 3. Normal fasting antroduodenal manometry. Figure 4. Normal fed antroduodenal manometry.
First 3 ports are in the antrum and lower 5 ports are First port is in the antrum, lower 7 ports are in the
in the duodenum. Ibid. duodenum. Id.
Figure 5. Neuropathic pseudobstruction. Id. Figure 6. Myopathic pseudobstruction. Id.

Recommended Reading
De Lorijn F, Reitsma JB, Voskuijl WP, et al. Diagnosis of Hirschsprung’s disease: a prospective, comparative
accuracy study of common tests. J Pediatr. 2005;146(6):787-792.
De Lorijn F, Kremer LC, Reitsma JB, Benninga MA. Diagnostic tests in Hirschsprung disease: a systematic
review. J Pediatr Gastroenterol Nutrition. 2006;42(5):496-505.
Evaluation and treatment of constipation in infants and children: recommendations of the North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutrition.
2006;43(3):e1-13.
Meunier P, Marechal JM, Mollard P. Accuracy of the manometric diagnosis of Hirschsprung’s disease. J Pediatr
Surg. 1978;13:411-415.
Nurko S. Gastrointestinal Manometry. Methodology and Indications. In: Kleinman RE, Goulet O-J,Mieli-
Vergani, Sanderson IR, Sherman PM, eds. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Lewiston, NY:
BC Decker Inc.; 2008; 1375-1391.
Rodriguez L, Nurko S. Gastrointestinal motility procedures. Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal
and Liver Disease. 4th ed. Philadelphia, PA: Saunders Elsevier; 2011: 686-698.
Pancreatic Function Tests
Gia Bradley, MD
Ann Scheimann, MD, MBA
I. Indications for Pancreatic Function Tests

A. Differentiate pancreatic malabsorption from other causes of malabsorption
B. Serial assessment of pancreatic exocrine function in diseases affecting the pancreas
C. Assess efficacy of pancreatic enzyme replacement in children with malabsorption secondary to
exocrine pancreatic dysfunction
II. Direct tests—Exogenous hormonal stimulation

A. Description
1. Secretin, cholecystokinin, or both administered intravenously to stimulate pancreatic
secretion
a. The combination of secretin and cholecystokinin provides the most information
about pancreatic exocrine function
2. The stomach and duodenum are intubated
a. Gastric intubation required to remove gastric secretions that would interfere with
measurement of water and bicarbonate secretion from the pancreas
b. Duodenal tube used for infusion of a nonabsorbable marker and for collection of
pancreatic secretions
3. Measurements obtained on aspirated duodenal fluid
a. Bicarbonate concentration
b. Amylase, trypsin, chymotrypsin and lipase activities
c. Concentration of the nonabsorbable marker
1) Enzyme activities and ion concentration are corrected for percent recovery
of the nonabsorbable marker
B. Advantages
1. Most accurate assessment of exocrine pancreatic function
2. Test allows classification of mild, moderate or severe pancreatic exocrine dysfunction
C. Disadvantages
1. Requires duodenal intubation and intravenous administration of hormones
2. No standard method for secretin/CCK stimulation
III. Indirect tests of Pancreatic Exocrine Function

A. Lundh test meal
1. Description
a. Subject ingests a 300-mL liquid test meal composed of dried milk, vegetable oil
and dextrose (6% fat, 5% protein and 15% carbohydrate)
b. Duodenum is aspirated for a defined time after ingestion
c. Fluid analyzed for enzyme activity (usually only trypsin is measured)
2. Advantages
a. More physiologic than exogenous hormone stimulation
b. Does not require intravenous administration of hormones
c. Allows for detection of moderate or severe exocrine pancreatic dysfunction when
a direct test cannot be done

3. Disadvantages
a. Requires duodenal intubation, a test meal, and normal anatomy, including normal
small intestinal mucosa
1) Test relies on endogenous hormones to stimulate pancreatic secretion, so
conditions like celiac disease can lead to poor physiological stimulation of
the pancreas
b. Less sensitive than direct tests in detecting mild exocrine pancreatic dysfunction
1) Only enzyme concentrations rather than enzyme output can be
determined because a marker is not used
2) Increased potential for acid and pepsin to enter the duodenum, which can
prevent accurate measurements of enzyme concentrations
B. Measurement of fecal fat
1. Description
a. The patient consumes a diet adequate in fat intake for 3 days
b. Some experts recommend giving a nonabsorbed marker (charcoal, methylene
blue) at start and end of 72 hours
c. All stool output collected for 72 hours (or all stools passed from appearance of
first marker to the appearance of the second marker in stool)
d. Fat extracted from homogenized stool collection and weighed
2. Advantages
a. Quantitative measurement of steatorrhea
1) Steatorrhea does not occur until stimulated pancreatic lipase output is less
than 5%–10% of normal
2) Normal fat excretion is 7% or less of ingested fat; infants may excrete up
to 15% of dietary fat
3. Disadvantages
a. Requires sufficient dietary fat intake and accurate collection of stool
b. Only detects severe pancreatic dysfunction
C. Measurement of fecal chymotrypsin and elastase 1
1. Description
a. Chymotrypsin
1) Reliably differentiates between pancreatic-insufficient and pancreatic-
sufficient patients
2) There is a good correlation between the 72-hour fecal output of
chymotrypsin and the CCK secretin–stimulated duodenal output of
chymotrypsin
3) Patients receiving pancreatic enzyme supplements should discontinue
them at least 5 days prior to measurement
b. Elastase 1
1) More sensitive and specific than fecal chymotrypsin in detecting pancreatic
insufficiency
2) A decline in fecal elastase concentration precedes fat malabsorption in
patients with pancreatic-sufficient cystic fibrosis, who become pancreatic
insufficient
3) The measurement is not altered by pancreatic enzyme supplements
a) The ELISA is specific for human elastase, so exogenous pancreatic
enzyme supplements, which are of porcine origin, have no effect
on the results
4) False-positive results may occur if there is villous damage
a) These patients may have a secondary pancreatic insufficiency due
to the impairment of mucosal release of pancreatic secretagogues
5) False-negative results may occur with the following
a) Diarrheal disease and short bowel syndrome—secondary to a
dilutional effect, which can be overcome by lyophilization of stool
samples to remove the water content
b) Occasionally in pancreatic-sufficient patients with Shwachman-
Diamond syndrome
2. Advantages
a. Noninvasive
b. Does not require administration of oral substrates
3. Disadvantages
a. Only detects severe pancreatic dysfunction
D. NBT-PABA and fluorescein dilaurate tests
1. Description
a. Requires oral ingestion of the synthetic peptide NBT-PABA (N-benzoyl-L-tyrosyl-
p-aminobenzoic acid) or fluorescein dilaurate with a meal and subsequent
measurement of PABA or fluorescein in the serum or urine
b. NBT-PABA is specifically cleaved by chymotrypsin to NBT and PABA; PABA is then
absorbed in the intestine, conjugated in the liver and excreted in the urine
c. Fluorescein dilaurate is hydrolyzed by pancreatic carboxylesterase into lauric acid
and free water-soluble fluorescein; fluorescein is absorbed into the intestine,
partially conjugated in the liver and excreted in the urine
2. Advantages
a. Simple indicator of severe pancreatic dysfunction
3. Disadvantages
a. Tests do not detect mild or moderate pancreatic dysfunction
b. Prior gastric surgery, small bowel disease, liver disease and renal insufficiency may
interfere with the measurements
IV. Blood tests
A. Serum amylase
1. Non-specific test of the amount of pancreatic amylase secretion; most clinical
laboratories do not distinguish between salivary and pancreatic isoenzymes
B. Serum lipase
1. After 5 years of age, the test is 95% sensitive and 85% specific for the detection of
pancreatic insufficiency in cystic fibrosis
2. There is no information about the usefulness of the test in delineating pancreatic
insufficiency in other pancreatic diseases of childhood
C. Serum immunoreactive trypsinogen (IRT)
1. In infants <1 year of age, elevated IRT is a sensitive diagnostic screening test for cystic
fibrosis with a detection rate of 90%
a. IRT levels may be lower in cystic fibrosis infants with meconium ileus compared to
other infants with cystic fibrosis, which can lead to a false-negative screen
2. In patients over the age of 7 with cystic fibrosis, decreased serum levels of IRT are highly
predictive of pancreatic insufficiency
a. Below 7 years of age, a fecal fat determination is recommended
3. In patients with other pancreatic diseases of childhood, this test is useful in
distinguishing pancreatic steatorrhea from nonpancreatic steatorrhea
a. In Shwachman-Diamond Syndrome, IRT values are low because pancreatic failure
is due to hypoplasia and reduced acinar enzyme production
Recommended Reading
Philadelphia, PA: Saunders Elsevier;2010:909-930.
Kleinman RE, Goulet O-J,Mieli-Vergani, Sanderson IR, Sherman PM, eds. Walker’s Pediatric Gastrointestinal
Disease. 5th ed. Lewiston, NY: BC Decker Inc.; 2008:1401-1410.

Breath Tests
Julia Bracken, MD
Jose Cocjin, MD
I. Hydrogen breath testing

Hydrogen breath testing is a safe, noninvasive method to evaluate for sugar malabsorption (lactose,
fructose, sucrose, sorbitol, d-xylose) and small bowel bacterial overgrowth.
II. Testing for Sugar Malabsorption

A. Method
1. While NPO a test dose of specified sugar is administered orally
a. Lactose is dosed 2 g/kg with max dose of 25 g
2. Exhaled breath hydrogen content is measured at baseline and every 30 minutes for 3
hours
B. Interpretation
1. Pre and post test-sugar hydrogen concentrations are compared
a. Breath hydrogen change of <10 parts per million (ppm) is considered normal
b. Breath hydrogen change of >20 ppm is considered diagnostic of sugar
malabsorption
C. Additional Consideration
1. False-positive results: inadequate fasting time, recent smoking
2. False-negative results: recent antibiotic use, restrictive lung disorders
III. Testing for Small Bowel Bacterial Overgrowth (SBBO)

A. Method
1. While NPO a test dose of a carbohydrate solution is administered orally
a. Lactulose is most commonly used (2 g/kg, max 50–75 g)
b. Glucose may be used as an alternative substrate
2. Exhaled breath hydrogen content is measured at baseline and every 30 minutes for 3–5
hours
B. Interpretation
1. Patients with SBBO demonstrate an early peak in breath hydrogen concentration
a. Lactulose should normally be metabolized by colonic bacteria only
2. In SBBO, small bowel bacteria metabolize the substrate prematurely leading to an early
rise (within the first 2 hours) in hydrogen concentration, followed by the expected (and
larger) colonic peak
C. Additional Considerations
1. Methane-producing bacteria may give false-negative breath hydrogen test results as
hydrogen is converted to methane
a. Methane concentrations can be measured concurrently with exhaled hydrogen to
improve sensitivity and detect methane producing bacteria
b. Most updated equipment has the capability to measure both gases
2. Short bowel syndrome or fast transit time may give false positive results
Recommended Reading
Hamilton LH. Breath Tests and Gastroenterology. 2nd ed. QuinTron Instrument Company; 1998.
Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-
based review of indications and pitfalls in interpretation. Am J Gastroenterol. 2000;97:1113.

9E-1. Laboratory Evaluation—
Alkaline Phosphatase
Emily Contreras, MD
Rebecca Cherry, MD
I. Alkaline phosphatase
Alkaline phosphatase (AP) is a group of isoenzymes that hydrolyze organic phosphate esters at alkaline
pH. Serum AP may have many different tissue sources, including liver, bone, placenta and, less often,
intestine. The function in the serum is unknown. Levels are often obtained in the evaluation of
cholestasis.
II. Background
A. Found in several different tissues:
1. Canalicular membrane of hepatocytes – unknown function but may be involved in
transport processes
2. Bone osteoblasts – involved in calcification
3. Brush border of small intestine enterocytes – involved in cholesterol breakdown and
calcium absorption, can be increased after a fatty meal
4. Proximal convoluted tubules of the kidney
5. Placenta
6. White blood cells
B. Isolated elevated AP does not indicate hepatic or biliary disease if other liver biochemical tests are
normal
1. Polyacrylamide gel electrophoresis (not routinely available in all clinical labs) can be used
to differentiate between liver, bone, intestinal and placental isoenzymes
C. Level varies with age and sex
1. In children, serum AP activity is elevated in both sexes, correlating with rate of bone
growth
2. Healthy adolescent males can have AP values >3x normal without underlying
hepatobiliary disease
3. From ages 15–50, AP is slightly higher in males
4. Over age 60, AP activity is greater in women
III. Alkaline Phosphatase and Hepatobiliary Disease

A. If AP is elevated, should check gamma glutamyltransferase (GGT) or 5’-nucleotidase (5’NT) to
confirm hepatic origin
1. GGT and 5’NT are both present in liver and multiple other organs, but not in bone,
intestine or placenta
B. Elevated hepatic AP is due to increased de novo synthesis of AP in the liver induced by bile acids
and subsequent leakage into the serum
C. In 75% of patients, biliary obstuction lead to >4x normal AP levels
1. But 25% of adults with viral hepatitis without biliary obstruction can also have AP levels
>4x normal
D. AP levels up to 3x normal are nonspecific
E. AP levels do not differentiate between extrahepatic or intrahepatic obstruction or between
different etiologies of biliary obstruction
F. Markedly increased AP levels are predominantly seen in infiltrative liver disorders (such as primary
or metastatic liver tumors) or with biliary obstruction
1. However, AP may be normal despite extensive hepatic metastasis or large biliary
obstruction
G. Elevated intestinal AP can be caused by liver disease, such as alcoholic cirrhosis

IV. Non-hepatobiliary Diseases Associated With Elevated AP
A. Pregnancy: due to increased placental activity
B. Familial inheritance
C. Chronic renal failure
D. Patients with the following hematologic characteristics have increased intestinal AP:
1. Blood groups type B and type O
2. ABH red blood cell antigen
3. Lewis antigen positive
E. Transient hyperphosphatasemia of infancy and childhood: a benign condition characterized by
marked increase in serum AP (often >10x normal) lasting up to 8–12 weeks in absence of any
clinical, radiologic or biochemical evidence of bone or liver pathology
F. Malignant tumors without any liver involvement
1. Regan isoenzyme is produced and indistinguishable from placental AP
V. Low Serum Alkaline Phosphatase

A. Zinc deficiency: because Zn is a cofactor for AP, AP activity is low when zinc is deficient
B. Wilson disease: AP can be low in fulminant Wilson disease, mechanism unknown
Recommended Reading
Kaplan MM. Alkaline Phosphatase. New Engl J Med. 1972;62:200-202.
Kaplan MM. Alkaline phosphatase and other enzymatic measures of cholestasis. In: Chopra S, ed. UpToDate.
Waltham, MA: 2010.
Ng VL. Laboratory Assessment of Liver Function and Injury in Children. In: Suchy FJ, Sokol RJ, Balistreri WF,
eds. Liver Diseases in Children. 3rd edition. New York, NY: Cambridge University Press; 2007: 165-166.
Hematologic Manifestations
of GI Disease
Megan E. Gabel, MD
Thomas Rossi, MD
I. Complete Blood Count (CBC)

Changes in the CBC can be seen related to chronic or acute disease, due to blood loss or due to chronic
medications.
II. Basic Review of Anemia

A. Etiology
1. Decreased production of erythrocytes
a. Normocytic: nutritional deficiency, chronic disease
b. Macrocytic: vitamin B12 deficiency, folate deficiency, drug related (trimethoprim-
sulfamethoxazole, methotrexate, 6-mercaptopurine), chronic disease
c. Microcytic: iron deficiency, chronic disease
2. Acute blood loss. Usually normocytic
3. Chronic blood loss. Usually microcytic
4. Increased destruction/consumption
a. Immune mediated, red cell membrane defects, hypersplenism
B. General Laboratory Evaluation for Anemia
1. CBC with platelets and differential (includes MCV, RDW), reticulocyte count, blood
smear
a. If Microcytic: iron, TIBC, transferrin saturation, ferritin, lead level
b. If Macrocytic: vitamin B12, folate, TSH
c. If Hemolysis: T/D bili, LDH, Coombs, PT, PTT, haptoglobin, fibrinogen
III. Anemia of Chronic Disease

A. Most often a mild, normocytic, normochromic anemia associated with a myriad of chronic
illnesses
1. In 20% of cases anemia is severe (Hgb <8 g/dL)
B. Characterized by:
1. Low serum iron
2. Low serum transferrin (TIBC)
3. Normal or increased ferritin level (acute phase reactant)
4. Low reticulocyte count
C. Pathogenesis is complex and multifactorial
1. Increased macrophages production of IL-6 leads to increase in hepatic hepcidin
production
2. Hepcidin inhibits intestinal iron absorption and decreases release of iron from
macrophages
3. Decrease in erythropoetin production relative to degree of anemia also complicates
some chronic disease
4. Decreased RBC survival may play minor role
D. First principle of treatment is control underlying disease
1. Rule out other contributing factors such as blood loss or deficiency of iron, B12 or folate
2. Erythropoietin administration may be effective in some cases

IV. Medications Associated With Macrocytic Anemia
A. Trimethoprim-sulfamethoxazole
1. Trimethoprim inhibits dihydrofolic acid reduction to tetrahydrofolate
2. Sulfamethoxazole interferes with bacterial folic acid synthesis by inhibition of dihydrofolic
acid formation from para-aminobenzoic acid
3. Coadministration of folinic acid can mitigate antifolate activity without interfering with
antimicrobial action
B. Methotrexate
1. Methotrexate irreversibly binds to dihydrofolate reductase, inhibiting production of
reduced folates
2. Usual finding is macrocytosis, rarely pancytopenia
3. Monitor CBC every 4–8 weeks
4. Folic acid can be given if cytopenia develops, but folic acid may decrease methotrexate
efficacy
C. 6-Mercaptopurine
1. 6-MP: purine antagonist which inhibits DNA and RNA synthesis
2. May cause lymphopenia, anemia, thrombocytopenia
3. Recommended screening: CBC weekly for 1 month, biweekly for 1 month, then every
1–2 months during therapy
4. Dose should be decreased or discontinued if bone marrow suppression occurs
V. Changes in CBC Due to Inflammatory Bowel Disease

A. Anemia commonly present at time of IBD diagnosis (78%)
1. May be due to iron deficiency (58%), folic acid deficiency, vitamin B12 deficiency,
hemolysis (drug-induced or autoimmune) or chronic disease
2. Complete correction of anemia is associated with significant improvement in quality of
life
B. Recommended evaluation of anemia includes total body iron status, transferrin saturation and
ferritin
C. Bone marrow suppression may be seen (leukopenia) with 6-Mercaptopurine or methotrexate
D. Immune activation may result in suppression of erythrocyte production and thrombocytosis
VI. Hematologic Abnormalities Associated With Liver Disease

A. Bleeding disorders
1. Liver synthesizes clotting factors II, V, VII, VIII, IX, X
2. Vitamin K dependent proteins include factors II, VII,IX, X; protein C, S
3. Hypersplenism associated with portal hypertension produces thrombocytopenia
4. Diagnosis: prolongation of PT, INR, specific factor assay, platelet count
5. Treatment/Management
a. Vitamin K administration, FFP, cryopreciptate and platelets
b. Recombinant-activated factor VII can be used to correct INR prior to invasive
procedures
B. Hypercoagulopathy occurs due to decrease hepatic synthesis of anticoagulant factors (protein C,
S, antithrombin)
1. This is not reflected in the PT, PTT, INR
2. Specific factor analysis necessary
C. Portal Hypertension
1. Hypersplenism can result in pancytopenia
a. Up to 90% of platelets can be sequestered in the spleen
b. Diagnosis based on thrombocytopenia, enlarged spleen
D. Morphologic changes in RBCs (acanthocytes, echinocytes, target cells) can be seen in liver
disease
1. Abnormal high density lipoprotein binds to receptors on the RBC membrane and induces
conformational change
VII. Other GI Causes of Abnormalities in the CBC
A. Vitamin B12 malabsorption with megaloblastic anemia
1. Due to intrinsic factor deficiency, bacterial overgrowth, pancreatic insufficiency, or ileal
resection or disease
B. Celiac disease
1. May present with microcytic anemia unresponsive to iron therapy
2. May present with pernicious anemia, autoimmune thrombocytopenia
C. H pylori
1. Unexplained iron deficiency anemia may be presenting feature
2. H pylori infection can result in hypochlorhydria and decreased gastric ascorbic acid levels
that impair bioavailability of dietary iron
D. Shwachman Diamond syndrome
1. Pancreatic insufficiency, neutropenia and metaphyseal dysotosis
2. Recurrent neutropenia is the most common (>90%), pancytopenia occurs in 10%–25%
of cases
3. 1/3 develop myelodysplastic syndrome
4. 10%–25% develop acute myeloid leukemia
E. Wilson disease
1. Severe hemolytic anemia may occur as hepatocellular necrosis, resulting in the release of
copper ions into the circulation
F. Abetalipoproteinemia
1. Very low serum cholesterol
2. Near absence of apolipoprotein B containing lipoproteins in the plasma
3. Red cell takes the form of acanthocytes (in severe cases up to 90% of RBCs)
4. Patients are not anemic and have no evidence of hemolysis
G. Vitamin E deficiency
1. Echinocytosis
Recommended Reading
Pels L. Slow hematologic recovery in children with IBD-associated anemia in cases of expectant management.
J Pediatr Gastroenterol Nutrition. 2010; 51(6):708-713.
Elsevier; 2006: Chapters 26,33,38,40.

Testing for Micro-organisms
Sonal S. Desai, MD
Susan S. Baker, MD, PhD
I. Laboratory evaluation
Can be used to identify bacterial, viral and parasitic pathogens
A. Helicobacter pylori (see section on Helicobacter Pylori)
1. IgG antibodies indicate past or ongoing infection
2. H pylori antigen in stool by ELISA very sensitive indicator of ongoing infection
3. Gastric mucosal biopsy
a. Warthin Starry or H&E stain shows organisms on surface of gastric mucosa
b. CLO test (Campylobacter-like organism) – mucosal biopsy placed in urea-
containing medium. Urease activity of H pylori rapidly produces NH3, which
raises pH and produces pink color when positive
4. C13 urea breath test – labeled urea given by mouth, labeled CO2 detected in exhaled
breath. Positive test indicates urease producing H pylori
B. Bacterial diarrheas
1. Salmonella and shigella: stool culture on blood, MacConkey, EMB* or XLD* agar
2. E coli – Stool culture on MacConkey, EMB or SM* agar
3. Campylobacter jejuni – stool culture on Skirrow agar
4. Yersinia enterocolitica – stool culture on CIN* agar. Can be isolated from throat, lymph
nodes, urine and bile
5. C dificille
a. Culture on CCFE* agar
b. ELIZA for toxin A and B
c. Cell culture of monkey kidney cells with ultrafiltrate of stool reveals characteristic
cytopathic changes caused by toxin B on microscopic examination
d. Immunoassay for glutamate dehydrogenase in stool is rapid and accurate
C. Protozoal
1. Giardia lamblia
a. Detect trophozoites in duodenal aspirate
b. Detect cysts in stool (least sensitive)
c. Detect trophozoites on surface of duodenal biopsy
d. Detect giardia antigen in stool (most sensitive)
2. Cryptosporidium spp
a. Stool acid-fast stain
b. Direct fluorescent antibody on stool
c. ELIZA on stool
d. Stain of intestinal biopsy
3. Entameba histolytica
a. Detect in stool or stool concentrate after staining
b. Detect in biopsy from edge of colon ulcers
c. PCR and ELIZA on stool possible
4. Blastocystis hominis
a. Detect stool hematoxylin or trichrome stain
5. Balantidium coli
a. Detect by stool exam
b. Detect by biopsy
6. Isospora belli
a. Detect by O&P
b. Detect in duodenal aspiration

D. Nematodes
1. Enterobius vermicularis (pinworm)
a. Direct observation of adult worms on perianal skin
b. Detect ova microscopically on scotch tape swab of perianal skin
c. Stool examination for ova
2. Ascaris lumbricoides, Trichuris trichura, Strongyloides stercoralis, Ancylostoma duodenale
(hookworm), Cestoides and Necator americanus (hookworm) – direct stool examination
for ova and/or adult forms
3. Cestodes (tapeworm)
a. Direct stool examination for proglottids (section of tapeworm) and ova
b. Purged stool increases sensitivity of test
4. Trematodes
a. Fasciola – stool for ova or ELIZA on blood
b. Schistosomes
1) S mansoni and S japonicum – stool of ova
2) S hematobium – urine for ova
3) Serology also used in light infestations
E. Hepatic infections and infestations – (see section on Viral Hepatitis)
*CCFE – cycloserine-cefixitin-fructose-egg agar; CIN – cefsuladin-irgasan-novobiocin agar;

EMB – e-methyline blue agar; SM Sorbitol-MacConkey agar; XLD – xylose-lysine-deoxycholate agar.
Recommended Reading
Centers for Disease Control. Available at www.cdc.gov.
Committee for Infectious Diseases. Red Book 2009. Elk
Grove Village, IL: American Academy of Pediatrics; 2009.
Stool Analysis
Paul Ufberg, MD
I. Stool Analysis
Analysis of stool can be helpful in narrowing the differential diagnosis in patients with diarrheal
disease and children with poor growth. Laboratory testing is currently available for fecal fat, stool pH,
electrolytes, α-1-antitrypsin, trypsin elastase, reducing substances, fecal blood, WBC, and culture and ova
and parasite analysis. Many laboratories now offer fecal calprotectin testing to evaluate for inflammation
(see section on IBD).
II. Fecal Reducing Substances

A. Use of Benedict’s reagent (Clinitest tablets) on liquid feces is the most common qualitative
method to assess carbohydrate malabsorption
B. Reducing substances are generated by colonic bacterial fermentation of unabsorbed
dietary carbohydrates
III. Limitations of Fecal Reducing Substances

A. The test assumes that the patient’s diet includes reducing sugars, including glucose, lactose and
fructose, but not sucrose
B. Malabsorbed sucrose can be degraded by colonic bacteria to glucose and fructose, resulting in a
positive test
IV. Fecal pH Evaluation

A. Stool pH less than 5.5 is indicative of carbohydrate malabsorption (reference range is
typically 6.5–7.5)
V. Limitations of Fecal pH Evaluation

A. Stool volume and transit time affect accuracy of the pH
B. Bacterial fermentation may give falsely acidic results if the specimen is not analyzed within 1 hour
of collection or properly stored prior to analysis
VI. Microscopic Fecal Fat Evaluation (see section Pancreatic Function Test)
A. Helpful in qualitative detection of fat malabsorption and monitoring the efficacy of pancreatic
enzyme supplementation therapy in patients with pancreatic insufficiency
B. A rapid screen can be done via steatocrit or sudan red/black staining
VII. Stool Electrolyte Evaluation

A. Stool electrolytes are useful in determining osmotic vs secretory diarrhea
B. Fecal osmolarity is approximately 290 mOsm/kg and is isotonic with plasma
C. Carbohydrate malabsorption increases osmolarity due to colonic bacterial metabolism of
undigested sugars
D. Equation for stool osmolarity is:
1. Stool osmolarity = 2[(stool Na + in mEq/L) + (stool K+ in mEq/L)]
2. Normal is <50
3. Osmotic diarrhea = Osmotic gap >100
a. Osmotic diarrhea is caused by maldigestion and/or malabsorption of one or more
nutrients. This creates an osmotic force, which drives water across tight junctions
into the lumen
b. If stool Na + is <60 mOsm and the gap is >125, the diarrhea is likely osmotic

4. Secretory diarrhea = Osmotic gap <100
a. Secretory diarrhea results from active secretion from epithelial cells. Most acute
causes are from bacterial infections. After colonization, enteric bacteria may
adhere to the epithelium and produce enterotoxins or cytotoxins. Cytotoxins
attract inflammatory cells contributing to secretion
b. If stool Na + is >90 and the gap is <50, diarrhea is likely secretory
5. In mixed osmotic and secretory diarrhea and cases of modest carbohydrate
malabsorption the osmotic gap is between 50–100 and the stool Na is between 60-90
mEq/L
Table 1. Features of Diarrhea

Osmotic Secretory
Stool Volume moderate increase very large
Response to Fasting stops continues
Stool Osmolarity normal to increase normal
Osmolarity >100 mOsm/kg <100 mOsm/k
E. Fecal electrolytes may be useful in differentiating congenital diarrheas, but are only completely
diagnostic in congenital chloride diarrhea
1. Normal Stool:
a. Stool Na + = 20-50 mmol/L
b. Stool K+ = 83-95 mmol/L
c. Stool Cl− = 5-25 mmol/L
d. Osmotic Gap = 50-100 mmol/L
2. Microvillous Inclusion Disease:
a. Stool Na + = 79 mmol/L
b. Stool K+ = 19 mmol/L
c. Stool Cl− = 70 mmol/L
d. Osmotic Gap = <84 mmol/L
3. Intestinal epithelial dysplasia:
a. Stool Na+ = 70–120 mmol/L
b. Stool K+ = 22 mmol/L
c. Stool Cl- = 33 mmol/L
4. Congenital Chloride Diarrhea:
a. Stool Na + = 55 ± 27 mmol/L
b. Stool K+ = 56 ± 20 mmol/L
c. Stool Cl− = 158 ± 16 mmol/L
d. Fecal Na + K is less than fecal Cl
5. Congenital Sodium Diarrhea:
a. Stool Na + = 98–190 mmol/L
b. Stool K+ = NOT REPORTED
c. Stool Cl− = 84–109 mmol/L
d. Fecal K + Cl is less than fecal Na
F. Genetic testing is available
1. Microvillus inclusion: Mutation in myosin promoter gene MY05B
2. Congenital chloride diarrhea: SCL26A3 gene mutation
3. Congenital sodium diarrhea: SPINT2 gene mutation
4. Intestinal epithelial dysplasia: Mutation in 2p21 epithelial adhesion molecule
VIII. Limitations of Stool Electrolytes

A. Bacterial fermentation following stool collection results in increased stool osmolarity
B. Healthy children may ingest nonabsorbable sugars, resulting in increased osmolarity
IX. Other Stool Tests
A. Stool α-1-antitrypsin
1. Screening for protein-losing enteropathy
a. Increased risk after Fontan procedure (4%–13% will get PLE)
2. Levels >5 mg/gm (dry sample) stool is abnormal
B. Stool elastase (see section on Pancreatic Function Test)
1. Screen for pancreatic exocrine insufficiency
C. Stool Hemoccult evaluation
1. Identifies occult blood in the stool
2. Rely on the oxidative conversion of a colorless compound to blue color in the presence
of pseudoperoxidase activity of hemoglobin
3. False-positive with ingestion of raw meat and vegetables with peroxidase properties
4. False-negative with citrus and vitamin C ingestion
D. Stool WBC
1. Presence of WBC may indicate invasive bacterial infection
E. Stool microbiologic evaluation
1. Stool culture for bacteria
a. Place stool on agar or in broth for culture
b. Most labs test for Campylobacter, Escherichia coli O157:H7, salmonella, and
shigella
c. Special request for Yersinia and non-O157:H7 Shiga toxin–producing E coli,
Vibrio, Aeromonas and Pleisiomonas
2. Stool O&P for parasites
a. Wet mount microscopic exam
b. Identify Giardia lamblia, Cryptosporidium parvum and Entamoeba histolytica and
helminths
3. Stool electron microscopy for viral particles
4. Stool viral culture
F. Stool testing for C difficile
1. Enzyme immunoassay for toxin A and B
2. Multiple specimens do not increase the yield
G. Please see Helicobacter Pylori chapter for stool testing
Recommended Reading
Lindquist BL, Wranne L. Problems in Analysis of faecal sugar. Arch Dis Child. 1976;51:319-321.
Miller JM, Holmes HT. Specimen Collection, Transport, and Storage. In: Murray PR, ed. Manual of Clinical
Microbiology, 7th ed. Washington DC: American Society for Microbiology; 1999: 33-104.
Hamilton, Ontario: BC Decker, Inc.; 2006:1820.
Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia, PA: Saunders
Elsevier; 2008: 116.

9F. Radiology Evaluation
Pablo J. Palomo, MD
Ruben E. Quiros-Tejeira, MD
Lisa Wheelock, MD
I. Introduction
Radiology studies play a crucial role in the diagnosis of some conditions. Imaging studies are also used
to direct management in the treatment of other conditions. A clear understanding of the risks and
benefits of each modality is vital prior to ordering a specific study. When the optimal testing is unclear,
a discussion with a radiologist can be critical to obtaining the correct imaging studies to provide the
needed information.
A. Plain abdominal radiograph
1. Advantages: low cost, quick, available
2. Essential first examination for suspected intestinal obstruction or perforation
3. Useful to localize radiopaque foreign bodies
4. Evaluation of plain radiographs
a. Identify position of liver, gastric air bubble and cardiac apex to assess for
abnormal situs or heterotaxy syndromes
b. Identify abnormal calcifications
c. Assess gas pattern – air fluid level, pneumoperitoneum, pneumatosis intestinalis,
sentinel loops, mass effect
1) Differentiation of small and large bowel gas is difficult in neonates
d. Assess bony structures for segmentation anomalies, dysraphisms, sacral
dysplasias, fractures
e. Assess diaphragms for hernia, eventrations, paralysis
f. Estimate liver and spleen size
B. Abdominal radiographs in specific conditions
1. Congenital obstruction
a. Esophageal atresia – gasless abdomen in some forms, coiling of NG tube in
esophagus
b. Duodenal atresia – double bubble sign with air in distended stomach and
proximal duodenum
c. Jejunal atresia and ileal atresia – dilated loops of small bowel with absence of
colon gas
d. Meconium ileus – dilated loops of small bowel with ground glass appearance of
stool in right lower quadrant
e. Colon obstruction – dilated loops of colon proximal to obstruction with/without
small bowel distension
2. Ileus – non-mechanical obstruction. Air fluid levels and usually less massive bowel
distension than mechanical obstruction
3. Viral enteritis – ileus with multiple short air fluid levels, especially in infants. Rarely,
pneumatosis occurs in viral enteritis
4. Intraabdominal abscess may produce mass effect, air fluid levels, ileus and obstruction
5. Necrotizing enterocolitis – pneumatosis, pneumoperitoneum, persistent fixed and dilated
bowel loops, portal venous and hepatic pneumatosis may be present
6. Ischemia and inflammation cause bowel wall thickening (thumb printing) – inflammatory
bowel disease, shock bowel, infection, lymphoma, GVH, lymphangiectasia, Henoch-
Schönlein purpura, hemolytic uremic syndrome, necrotizing enterocolitis and
pseudomembranous colitis
7. Hernia may cause bowel gas to appear in abnormal locations – chest, scrotum, umbilicus
and inguinal canal

8. Calcifications
a. Adrenal – old hemorrhage, neuroblastoma and Wolman syndrome
b. Renal – calculi and Wilms tumor (15% are calcified)
c. Pancreas – CF and chronic pancreatitis
d. Liver – hepatoblastoma (50%), hemangioendothelioma, hepatocellular carcinoma
and granuloma
e. Spleen – granulomata
f. Appendix – fecalith
g. Mesentery – calcified lymph nodes
9. Intussusception – plain radiograph may be normal. Gasless right lower quadrant. Prone
film may reveal abnormal cecal gas
C. Barium contrast studies
1. Single contrast (without air), most often used in children, prevents close evaluation of
mucosal abnormalities
2. Common indications – congenital and acquired structural GI anomalies, stricture, situs
anomalies, aspiration and inflammatory disease
3. Technical points
a. Use water-soluble contrast when investigating possible perforation
b. Use nonionic contrast when tracheal aspiration is possible
c. Use air or water-soluble contrast to evaluate and reduce intussusception
4. Risks
a. Swallowing studies performed under direct vision can evaluate all phases of
deglutition. Risk of prolonged fluoroscopy time and radiation exposure
b. Upper GI series with small bowel follow through – long duration fluoroscopy
adds to radiation exposure
D. Abdominal ultrasound
1. Utilizes frequencies from 1–20 MHz depending on depth of region of interest
2. Advantages
a. No ionizing radiation
b. Little need for sedation
c. Immediate results
d. Widely available and inexpensive
e. Doppler technique allows assessment of blood flow volume and direction
f. Improving technology with micro bubble and other contrast is expanding
indications – intraendoscopic, bowel wall anatomy, examination of complex
structures, better mucosal detail, better resolution of small structures
3. Disadvantages
a. Poor penetration of air-containing or bony structures
b. Less resolution than CT or MRI
c. Operator dependent, time consuming
d. Transducer may cause pain over abscess or other painful lesions
e. Distal body and tail of pancreas sometimes hard to see
4. Common indications
a. Modality of choice for pyloric stenosis
b. Liver masses, liver vascular anatomy and flow dynamics, gall bladder disease
c. Pancreatic parenchymal, ductular or malignant disease (both extracorporal U/S
and endoscopic ultrasound)
d. Bowel wall edema and intussusception
e. Prenatal U/S for duodenal atresia and other anomalies
f. Fluid collections and cysts
g. Modality of first choice for scrotum, testes, ovaries, inguinal hernias
h. Arterial and venous thrombosis – use duplex Doppler ultrasound
E. Computerized tomography (CT)
1. Advantages
a. Excellent spatial resolution and tissue differentiation (fluid, soft tissue, calcium,
air, fat and iron)
b. Can assess small structures – common bile duct, pancreatic ducts and fistulae
c. Can assess bowel wall with use of luminal and intravenous contrast
d. Good in suspected abdominal trauma, abdominal masses
2. Disadvantages
a. Very high radiation
b. Sedation may be required
c. Expensive
d. Oral and intravenous contrast may be contraindicated in renal disease, bowel
obstruction and dehydration
e. No possibility of therapeutic intervention, i.e., stone removal, papillotomy,
stricturoplasty
3. Technical points
a. No longer recommended as first diagnostic tool in suspected appendicitis (CT
with rectal contrast) because of high radiation. Ultrasound is safer
F. Magnetic resonance imaging (MRI)
1. Advantages – no radiation with excellent contrast resolution
2. Disadvantages
a. May require anesthesia or sedation because of long scan times
b. Expense similar to CT
c. Contraindicated with some implantable devices or with unstable patient
d. Gadolinium-based contrast contraindicated in renal insufficiency
e. Full identification of masses may require multiphase contrast sequences with
lengthy exam time
3. Indications
a. Biliary and pancreatic duct anatomy and flow are well described
b. Good substitute for ERCP if intervention is not immediately required
c. Excellent for pancreatic abnormalities – divisum, mass, abscess, cyst
d. MRA/MRV excellent for assessment of vascular anomalies
e. MR Enterography
1) Uses gadolinium based IV contrast and luminal contrast
2) Dynamic imaging may differentiate active vs inactive disease
3) Excellent localization of structural bowel lesions
4) Good mucosal detail
G. Percutaneous transhepatic cholangiography (PTC)
1. Requires needle puncture of bile duct – contraindicated in intractable bleeding disorders
2. Requires anesthesia for most children
3. Helps differentiate surgical from medical causes of cholestasis – choledochal cyst,
choledocolithiasis, stricture (especially if ERCP not possible)
4. Used to clarify biliary disease after liver transplant
5. Complications – biliary leak, sepsis, cholangitis, hemobilia, fistula
6. Some centers routinely give prophylactic antibiotics for Gram-negative and anaerobic
organisms before study
H. Magnetic retrograde cholangiopancreatography (MRCP)
1. Improved MRCP techniques are making endoscopic retrograde
cholangiopancreatography ERCP less desirable for diagnosis of biliary disease
2. Advantages – no radiation
3. Disadvantages
a. Technical problems in small children
b. Requires anesthesia in young children
c. Diagnostic, but not therapeutic
4. Indications – diagnosis and therapy
a. Biliary and pancreatic duct strictures, leaks, plugs, stones, cysts and pseudocyst
b. Evaluation of unexplained pancreatitis and pancreatic trauma
5. Risks: none

I. Radionuclide studies
1. Most use compound labeled with Technetium 99m (Tc99m)
2. Provides functional information without detailed anatomic evaluation
3. Tc99m sulfur colloid used for gastric emptying studies, evaluation of pulmonary aspira-
tion of gastric contents, and motility studies of esophagus
4. Tc99m iminodiacetic acid (IDA)
a. Measures amount of hepatic uptake and extent of biliary excretion
b. Delayed uptake seen in parenchymal disease
c. Delayed excretion seen in biliary obstruction, biliary hypoplasia, focal biliary
disease of CF, neonatal hepatitis, paucity syndromes, and alpha-1 antitrypsin
deficiency
d. Technical details
1) Patient must be fasting
2) CCK may be used to stimulate gallbladder contraction if there is no risk of
obstructive disease
3) Several radionuclides used – IDA, di-isopropyl-IDA (DIPIDA)and
trimethylbromo-IDA (TSIDA)
4) Tc99m DIPIDA has >70% hepatic extraction with bilirubin >2mg/dL,
making it the radionuclide of choice in liver disease
5) Unclear whether premedication with phenobarbital improves extraction
6) Region of interest drawn over gallbladder to serially assess excretion
fraction
5. Leukocyte Scintigraphy – tagged WBCs accumulate in areas of inflammation; limited
experience in pediatric GI diseases
6. Tc99m albumin – protein-losing enteropathy
7. Tc99m pertechnetate for Meckel diverticulum
a. Radionuclide concentrates in gastric mucosa contained in Meckel diverticulum
b. Technical details
1) Antihistamines and H2 blockers may prevent excretion of Tc99m, but may
also enhance uptake
2) Glucagon reduces peristalsis which improves retention of radionuclide
3) Pentagastrin may enhance visualization of diverticulum by enhancing acid
secretion
c. False positives – renal and bladder retention of radionuclide, gastric duplication or
cyst, vascular malformations, intussusception
d. False negatives
1) Poor blood supply to diverticulum
2) Insufficient gastric mucosa in diverticulum to concentrate radionuclide
3) Idiopathic – repeat examination may be required in difficult cases
8. Tc99m labeled red cell study
a. Indications – obscure GI bleed
b. Requires active bleeding to detect site
c. Bleed volume required 0.1 mL/minute to be seen
d. May require imaging for up to 2 hours in slow bleeds
J. Radiation risks of radiologic exams
1. Radiation is greater concern in pediatric medicine relative to adult medicine
a. Tissues are more radiosensitive
b. Longer life expectancy to develop radiation induced cancers
c. Each exam and radiation dose is cumulative
d. Children are 2–10 times more radiosensitive than adults
2. Measures to reduce radiation risk to pediatric patients
a. Assure necessity of test and ideal timing of image acquisition
b. Replace high radiation exposure exams with lower radiation exposure exams or other modalities,
such as MRI or ultrasound
c. Discuss case with radiologist to plan optimal exam to address both clinical concerns and to
minimize radiation exposure
d. Order based on medical concerns and not on legal or parental pressure
e. Assess need for general anesthesia or sedation to decrease need for repeat imaging secondary to
motion
f. Be specific in ordering examination to decrease risk of performing incorrect exam and to increase
likelihood that radiology staff may recognize need for specific imaging protocols or possibility of
exam with a less radiation exposure
g. Information and data obtained from Image Gently web site through the Society of Pediatric
Radiology
Table 1. Diagnostic Procedures

Effective Number of chest Time period for equivalent
radiation dose x-rays to give effective dose from estimated
in mSva equivalent dose natural back-ground radiation
in the US
Chest (PA) film .02 1 2.4 days
Upper GI series 3.0 150 1.0 years
Barium Enema 7.0 350 2.3 years
CT of the abdomen 10.0 500 3.3 years
a
mSv – millisevert

10A. Fluid Therapy
Emily Contreras, MD
Rebecca Cherry, MD
I. Assessment of Dehydration
A. Several schemes using clinical diagnostic criteria to evaluate dehydration have been created by
WHO, AAP, and MMWR. Validity and reliability depend on the presence of several clinical indica-
tors. Individual indicators of dehydration lack reliability
B. Clinical history must include:
1. Onset, frequency, estimated quantity of diarrheal and vomiting fluid losses, character of
symptoms (Table 1)
2. Urine output
3. Fever
4. Mental status
5. Acute weight change is the gold standard for estimating degree of dehydration, but pre-
illness weight often not available
Table 1. Symptoms Associated with Dehydration

Minimal or No
Dehydration Mild to Moderate
(<3% Loss of Body Dehydration Severe Dehydration
Symptom Weight [BW]) (3-9% loss of BW) (>9% Loss of BW)
Mental status Well, alert Normal, fatigued or Apathetic, lethargic, unconscious
restless, irritable
Thirst Drinks normally or might Thirsty; eager to drink Drinks poorly; unable to drink
refuse liquids
Heart rate Normal Normal to increased Tachycardia; bradycardia in most
severe cases
Quality of pulses Normal Normal to decreased Weak, thready, or impalpable
Eyes Normal Slightly sunken Deeply sunken
Tears Present Decreased Absent
Mouth and tongue Moist Dry Parched
Breathing Normal Normal to fast Deep
Skin fold Instant recoil Recoil in <2s Recoil in >2s
Capillary refill Normal Prolonged Prolonged or absent
Extremities Warm Cool Cold; mottled; cyanotic
Urine output Normal to decreased Decreased Minimal
II. Labs
A. No single lab value has great accuracy in predicting the degree of dehydration in children with
gastroenteritis
B. Serum electrolytes are mainly useful to guide replacement therapy, not as a predictor of
hydration status
C. Serum electrolytes for most previously healthy children with AGE and dehydration are NOT
recommended
Section 10 - Therapy 493

III. Oral vs IV Rehydration
A. IV fluids (IVFs) are the therapy of choice for severe dehydration (Table 2)
B. Oral rehydration solution (ORS):
1. ORS should be first-line therapy of mild to moderate dehydration
2. ORS contains sodium, potassium, chloride, carbohydrates (usually glucose) and a base.
Can be given orally or by NG
3. Highly effective, safe and inexpensive. Rates of successful rehydration at 2 hours and 4
hours after initiation are similar to IV rehydration
4. Requires diligent and willing caregiver
5. Avoids pain of IV placement
6. Highly underutilized due to (1) unfamiliarity with guidelines, (2) misperception of longer
ER stay and (3) misperception of contraindication if patient is vomiting
7. The few contraindications to ORT include(1) hemodynamic instability, (2) suspected ileus,
and (3) impaired airway protection
Table 2. Therapy Based on Degree of Dehydration

Degree of Dehydration Rehydration Therapy Replacement of Losses
No dehydration to minimal None <10 kg: 60–120 mL oral
rehydration solution (ORS) per
vomiting or diarrheal episode
>10 kg: 120–240 mL ORS per
vomiting or diarrheal episode
Mild to moderate dehydration ORS, 50–100 cc/kg body weight over 3 to 4 h As above
ORS therapy is initiated with 5 cc (1 teaspoon)
every 1 to 2 min
If not improving with ORS, consider intravenous
(i.v.) fluid therapy
Severe dehydration normal saline or lactated ringers 20 cc/kg As above
i.v. until mental status and perfusion If unable to tolerate oral fluids,
improve, followed by 5% dextrose ½ nor- administer through nasogastric
mal saline i.v. at twice maintenance rates tube or administer 5% destrose
½ normal saline with 20 mEq/L
potassium chloride i.v.
Source: King CK, Glass R, Bresee JS, Duggan C. Managing acute gastroenteritis among children: oral rehydration, mainte-
nance, and nutritional therapy. MMWR Recomm Rep 2003 Nov 21;52(RR-16):1–16.
Table 3. Composition of Commercial Oral Rehydration Solutions and Commonly Consumed Beverages
Sodium Carbohydrate Potassium Chloride
Solution (mEq/L) (g/dL) (mEq/L) (mEq/L) mOsm/kg H2O
World Health Organization 90 2 20 80 310
Pedialyte ®
45 2.5 20 35 250
Rehydralyte 75 2.5 20 65 250
Infalyte 50 3 25 45 200
CeraLyte 70 4 20 60 220
Gatorade ®
21 5.9 2.5 1.7 377
Apple juice 0.4 11.9 26 __ 700
Sources: Colletti JE. Diarrhea. In: Hendey GW, Hendry PL, Linden CH, Rosen CL, Schaider J, eds. Harwood-Nuss’
Clinical Practice of Emergency Medicine, 4th ed. Philadelphia: Lippincot Williams and Wilkins; 2005:1221. Stone B.
Fluids and electrolytes. In: Robertson J, Shilkofski N. The Johns Hopkins Hospital: The Harriet Lane Handbook, 17th ed.
St. Louis, MO: Mosby; 2005.
Table 4. Oral Replacement Therapy Dosing Based on Weight and Age
Age Weight Initial Dosing Volume/h First Advance Next Advance
0–6 mo 8 kg 5 cc every 5 min 60 cc (10 cc/kg) 15 cc every 15 min 30 cc every ½ hr
2–3 yrs 15 kg 10 cc every 5 min 120 cc (10 cc/kg) 30 cc every 15 min 60 cc every ½ hr
Courtesy of Mark Hostetler MD, University of Chicago, Illinois
IV. Treatment of Dehydration

A. Three phases: (1) rehydration appropriate for degree of dehydration, (2) replacement of ongoing
losses, (3) continuation of normal feeding. See Tables 3 and 4 for guidelines
B. IV and oral replacement of deficits and ongoing losses should be based in part on suspected
etiology and knowledge of likely stool sodium content
1. Cholera and secretory diarrhea – high sodium content 90–120 mEq/L stool water
2. Most viral gastroenteritis – low sodium content 20–40 mEq/L stool water
3. Bacterial colitis – depending upon amount of blood and transudate in stool, Na content
may be higher than viral gastroenteritis
V. Feeding
A. Breastfed children should continue breastfeeding
B. Other patients should eliminate food high in simple sugars, but otherwise continue usual diet
C. Patients should not get diluted or special formula
All tables were derived or copied from Colletti J. The management of children with gastroenteritis and dehy-
dration in the emergency department. J Emerg Med. 2010;38(5):686-698.
Recommended Reading
Colletti J. The management of children with gastroenteritis and dehydration in the emergency department.
J Emerg Med. 2010;38(5):686-698.
Gorelick M. Validity and reliability of clinical signs in the diagnosis of dehydration in children. Pediatrics.
1997;99(5):e6-e12.
Hartling L, Bellemare S. (Oral versus intravenous rehydration for treating dehydration due to gastroenteritis in
children. Cochrane Database Syst Rev. 2006; 3: CD004390.

10B. Blood Replacement
Katherine Atienza, DO
Yolanda Rivas, MD
I. Blood Transfusion in Patients With GI Bleeding

A. One unit of packed red blood cells (pRBCs) has a volume of 250–300 ml and a hematocrit of
65%–80%
B. Expected rise in hemoglobin after pRBC transfusion
1. In adults, expect an increase of 1 g/dL for each unit of pRBCs
2. In children, expect an increase of 2.5 g/dL for each 10 ml/Kg pRBCs
3. In children, Hct will increase 10% for each 10 ml/Kg pRBCs
C. Children have higher blood volumes than adults (Table 1)
Table 1. Blood Volume by Age

Age Estimated blood volume
Premature 90–100 ml/kg
Newborn 80–90 ml/kg
3 months–1 year 70–80 ml/kg
>1 year 70 ml/kg
Adult 55–60 ml/kg
D. Hematocrit immediately after onset of bleeding may not accurately reflect blood loss
1. Equilibration between intravascular space, extravascular space, and hemodilution
requires up to 72 hours
2. HCT will fall as extravascular fluid enters vasculature to restore volume
E. GI bleeding in otherwise healthy children usually has no major impact on vital signs until a
HCT of 30% is reached. HCT 20%–25% may be tolerated if the circulating blood volume
is maintained
1. Begin with initial fluid resuscitation 20 ml/kg NS, then pRBCs if needed
2. Indications for transfusion depend on clinical signs and symptoms, hemodynamic status,
H/H and ongoing blood loss
3. Consider fresh frozen plasma, 15–20 ml/kg, in children who have received significant
blood volume replacement or have prolonged coagulation profile
4. Consider platelet transfusion as needed depending on the child’s medical history,
platelet count, and if there is any active bleeding
Recommended Reading
Cote CJ. Pediatric Anesthesia. In: Miller RD, Erikkson LI, Fleisher LA, Weiner-Kronish JP, Young WL. Miller’s
Anesthesia. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:2583.
Kupfer Y, Cappell MS, Tessler S. Acute gastrointestinal bleeding in the intensive care unit: the intensivist’s
perspective. Gastroenterol Clin North Am. 2000;29:275-307.
Miller RD. Transfusion Therapy. In: Miller RD, Erikkson LI, Fleisher LA, Weiner-Kronish JP, and Young WL.
Miller’s Anesthesia. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:1740-1741.
Pediatric Anesthesia. In: Morgan GE, Mikhail MS, Murray MJ, .Larson CP. Clinical Anesthesiology. Chicago, IL:
McGraw Hill; 2006:896-897.

10C-1. Drugs—Anti-rejection
and Anti-inflammatory
Preeti Viswanathan, MD
I. Anti-rejection agents
The immune response can be broken down into several processes. Each of the processes listed below is a
potential target for therapeutic anti-rejection agents.
A. Antigen recognition: currently there are no approved agents that directly interact with the T-cell
receptor, in part due to variations in the antigen recognition site
B. Gene activation, transcription and translation: steroids, calcineurin inhibitors
C. Modulation of the immune response by cytokines, chemokines and growth factors: Rapamycin/
sirolimus
1. Cytokines are small peptide molecules produced by immune cells that bind to cell surface
receptors through autocrine or paracrine mechanisms to drive DNA replication and
functional differentiation
2. The action of cytokines is pivotal in determining the extent and character of an immune
response in both T and B cells
D. DNA replication and clonal expansion: azathioprine, mycophenylate mofatil (MMF)
E. Migration of T cells to effector site/modulation of effector activity: thymoglobulin, basiliximab,
daclizumab, OKT3
F. Limitation of immune response by induction of apoptosis: efforts to build Fas-Fas ligand therapies
for apoptosis are still experimental
G. Memory induction and maintenance: no agents yet identified to influence this stage
II. Corticosteroids
A. Mechanism of action
1. Corticosteroids are complexes with intracellular receptors that bind intranuclear
regulatory elements and prevent activation of genes needed for immune responses,
particularly IL-2 and interferon-gamma
2. Suppress proliferation of helper and cytotoxic T cells and B cells
3. Inhibit migration and activity of neutrophils
B. Adverse effects of corticosteroids
1. Increased bacterial, fungal and viral infections
2. Increased risk of malignancy, especially lymphoma and skin cancer
3. Hyperglycemia
a. Secondary to increased hepatic gluconeogenesis, degradation of proteins to free
amino acids in muscle and lipolysis
b. Decreased peripheral insulin sensitivity with decreased pancreatic insulin secretion
4. Hyperlipidemia
a. Incidence is 45% after liver transplant
b. Glucocorticoids increase the activity of acyl coenzyme A carboxylase, fatty acid
synthase and HMG CoA reductase
c. Glucocorticoids decrease activity of lipoprotein lipase (LPL)
d. Increased hepatic very low density lipoprotein (SLDL) synthesis and down
regulation of low density lipoprotein (LDL) receptor activity causes increased
serum VLDL, cholesterol and triglycerides with decreased high density lipoprotein
(HDL) levels
5. Suppression of pituitary-adrenal axis occurs rapidly. Shorter acting steroids (prednisone,
cortisol or prednisolone) suppress the pituitary-adrenal axis less than dexamethasone
6. Acne, hirsutism
7. Skeletal growth retardation, osteopenia, fractures, avascular necrosis of the femoral
head

III. Calcineurin Inhibitors
1. See major mechanism in Figure 1
2. Cyclosporine (CYA) and tacrolimus also inhibit prolactin, an immune activator, thereby
providing a synergistic effect on immune modulation
B. Dosing and metabolism
1. CYA and tacrolimus are lipophilic and are extensively distributed in body fat. Both are
absorbed in the small intestine. Peak plasma concentration occurs 1–8 hours after
ingestion
2. Absorption of CYA, but not tacrolimus, is dependent on bile salts
3. CYA absorption is increased when ingested with a fatty meal
4. Tacrolimus absorption is decreased when administered with meals
5. Calcineurin inhibitors are metabolized by the cytochrome p450A enzyme system.
Metabolites are excreted in bile
6. Oral bioavailability is poor for both drugs (~20% for tacrolimus) as a result of poor
absorption, partial metabolism by enzymes in the intestinal mucosa and first-pass
hepatic metabolism
7. The most important drug interactions are caused by drugs that increase or decrease the
cytochrome p450 system
Figure 1. Calcineurin inhibitor mechanism of action. Antigen stimulation of the T-cell

receptor (TCR) leads to generation of inositol triphosphate (IP3), which increases cytosolic
calcium and allows formation of activated calcineurin. Calcineurin is a phosphatase which
dephosphorylates transcription factors for the nuclear factor of activated T cells (NF-AT).
This allows NF-AT to translocate to the nucleus and induce expression of cytokine genes.
Cyclosporine (CYA) and tacrolimus (T) bind to their respective immunophilins (I) to block the
phosphatase action of calcineurin and prevent the expression of cytokine genes induced
by NF-AT, particularly IL-2 which regulates the proliferative T cell response. Adapted from
Adkinson NF Jr, Busse WW, Bochner BS, Holgate ST, Simons FER, Lemanske RF Jr. Middleton’s
Allergy: Principles and Practice. 7th ed. Philadelphia, PA: Mosby Elsevier; 2008: Chapter 94;
Figure 94.3.
C. Cyclosporine A (CYA)
1. Form, bioavailability and dosing
a. Microemulsion preparation maximizes absorption
b. Bioavailability is lower in younger patients, but metabolism is higher. Childhood
doses are higher than adult
c. Recommended oral dose 5 mg/kg BID starting within 12 hours of transplant
d. Recommended IV dose 1 mg/Kg BID given as slow infusion over 2–6 hours
e. CYA trough level is a poor predictor of efficacy. Serum concentration 2 hours
after dosing is a better predictor
2. Adverse effects
a. Dose dependent hypertension: activates the sympathetic nervous system,
upregulates endothelin, and inhibits inducible nitric oxide, all of which cause
potent vasoconstriction
b. Nephrotoxicity: by reducing effective renal plasma flow and glomerular filtration
rate
c. Neurotoxicity: possibly by interfering with mitochondrial function, vasospam
induced axonal swelling and generation of reactive oxygen species in the brain
d. Decreased insulin secretion and abnormal glucose tolerance
e. Hypertrichosis
f. Gingival hyperplasia
g. Hyperuricemia and gout
h. Hyperlipidemia possible causes
1) Inhibition of mitochondrial steroid 26-hydroxylase that mediates bile
acid synthesis from cholesterol. Inhibition of bile acid synthesis causes
elevated hepatic cholesterol, down-regulation of LDL receptor and
hypercholesterolemia
2) CYA can bind to the LDL receptor, producing elevated LDL levels
3) Increased hepatic lipase activity and decreased LPL activity results in
impaired VLDL and LDL clearance
4) Inhibition of prednisone metabolism by CYA worsens lipid abnormalities
induced by glucocorticoids
3. Increased CYA levels may occur with simultaneous use of the following drugs:
a. Diltiazem
b. Nicardipine
c. Verapamil
d. Fluconazole
e. Itraconazole
f. Ketoconazole
g. Clarithromycin
h. Erythromycin
i. Lansoprazole
j. Rabeprazole
k. Cimetidine
l. Methylprednisolone
m. Allopurinol
n. Bromocriptine
o. Metoclopramide
p. Colchicine
q. Amiodarone
r. Danazol
s. Grapefruit juice
4. Decreased CYA levels may occur with simultaneous use of the following drugs:
a. Nafcillin
b. Rifabutin
c. Rifampin
d. Carbamazepine
e. Phenobarbital
f. Phenytoin
g. Octreotide
h. Orlistat
i. St. John’s wort
D. Tacrolimus
1. More potent immunosuppressant activity than CYA
2. Dosing
a. Recommended starting dose 0.05–0.1 mg/Kg orally in first 12 hours after
transplant
b. Subsequent dose adjusted to maintain trough concentration at recommended
range
1) 0–3 months posttransplant= 10–15 ng/ml

c. Trough level is widely used for monitoring tacrolimus dose
d. Drug clearance is 2–4 times faster in children than adults. Children’s doses
higher than adults
3. Adverse effects
a. Dose dependent nephrotoxicity, neurotoxicity and hypertension
b. Hypertrophic cardiomyopathy with chronic high dose tacrolimus
c. Reversible, dose-dependent cytotoxicity to beta cell with decreased insulin
secretion. Coadministration of steroids can worsen tacrolimus-induced
hyperglycemia. Tacrolimus more likely than CYA to produce hyperglycemia
d. Tacrolimus produces less hyperlipidemia and cardiovascular effects than CYA
e. Combination therapy with glucocorticoids produces increased cholesterol and
triglyceride levels
f. Hyperkalemia and hypomagnesemia occur via effects on renal tubular function
g. Hyperuricemia and gout are less common with tacrolimus than CYA
4. Drugs that increase tacrolimus levels
a. Antifungals, especially azoles
b. Calcium channel blockers
c. Metronidazole
d. Grapefruit juice
e. Macrolide antibiotics
f. Proton pump inhibitors
g. Isoniazid: by inhibiting CY3A4, may decrease its metabolism
5. Drugs that lower tacrolimus levels
a. Phenytoin – increases rate of metabolism
b. High fat meals decrease absorption
c. Rifampin – increases its metabolism by inducing CY3A4
IV. Mycophenylate Mofitil (MMF)

1. Active metabolite is mycophenolic acid (MPA)
2. Selective inhibitor of inositol monophosphate (IMP) dehydrogenase, an essential enzyme
in de novo synthesis of purines. Inhibition depletes guanosine nucleotides and arrests
lymphocyte replication
3. Lymphocytes become sensitive to MMF because they lack a salvage pathway for purines
and rely on de novo synthesis
4. Used as alternative therapy in chronic rejection, refractory rejection or severe calcineurin
inhibitor toxicity
B. Metabolism
1. Converted to MPA by esterases in the gut wall, blood and liver
2. MPA undergoes glucuronidation to MPAG in the liver. MPAG is then excreted in the
urine and bile
3. MPAG is then converted back to MPA by gut flora and undergoes enterohepatic
circulation. This phenomenon is responsible for its secondary peak in blood and
maintenance of therapeutic levels
C. Suggested dose after pediatric liver transplant is 15 mg/kg BID
D. Adverse effects
1. Dose dependent bone marrow suppression
2. Diarrhea is a major dose-limiting side effect
3. No effect on glucose metabolism
4. Antibiotics, cholestyramine, antacids, CYA and high tacrolimus levels reduce MMF levels
a. Antibiotics reduce gut flora and thereby reduce enterohepatic circulation
b. Cholestyramine binds to MPAG and reduces enterohepatic circulation (this can
decrease bioavailability by up to 50%)
c. Antacids decrease the absorption of MMF
d. Cyclosporine also thought to indirectly affect enterohepatic circulation by inhibit-
ing the excretion of MPAG into bile
e. Tacrolimus also decreases enterohepatic circulation by inhibiting glucuronidation,
but its effect on MMF levels is much less than that seen with cyclosporine
V. Sirolimus
1. Macrolide antibiotic blocks T-cell activation by IL-2R post receptor signal transduction
2. Used with calcineurin inhibitors to reduce acute rejection and facilitate steroid
withdrawal
3. Used in rescue therapy of chronic rejection and calcineurin toxicity
4. Not used as a single agent—very high rejection rate
B. Dosing
1. Drug half life is 40–86 hours
2. Daily monitoring not required
3. Trough level twice weekly at onset, then decreased frequency
4. Target trough level 1–15 ng/ml
5. Serum levels increase with simultaneous administration of CYA
VI. Antibody Preparations

A. Directed against specific or multiple antigen targets in or on immune cells
B. Indications
1. Induction therapy directly after transplant
2. Adjunct therapy to allow decreasing the dose of nephrotoxic maintenance therapy in
patients with delayed graft function
C. Antibodies may be lymphocyte depleting (thymoglobulin/anti-lymphocyte globulin) or non-
lymphocyte depleting (IL-2 receptor antibodies)
D. Most of the monoclonal antibody is the human sequence with only the hypervariable antigen-
specific regions containing murine or other animal characteristics
E. Polyclonal anti-lymphocyte and anti-thymocyte antibodies are produced by harvesting serum
from animals inoculated with human thymocytes or lymphocytes. Mechanism of action is
lymphocyte depletion
F. IL-2 receptor antibodies
1. Used primarily in children as induction agents in double or triple immunosuppression
protocols
2. IL-2 receptor antibodies prevent T-cell activation and expansion, but are not effective in
the treatment of acute rejection
3. These antibodies are well tolerated in part because they are partially humanized and
because they have no effect on the resting T cell population, but rather target activated
T cells displaying cell surface CD25
4. Basiliximab – first dose is given within 6 hours of organ reperfusion
5. Daclizumab – various dosing regimens used. Dual regimen of 1 mg/kg on days 0 and 4
provides receptor saturation for up to 21 days
G. OKT3
1. Mouse anti-human CD3 specific antibody
2. Targets the CD3 complex of T cells, causing endocytosis of its constituent peptides and
impairment of T-cell activation and proliferation
3. Induces a cytokine release syndrome with fever, rigors and sometimes hypotension and
pulmonary edema
4. Due to side effect profile, use as induction agent has declined and OKT3 is more
commonly used for rescue therapy in rejection
H. Adverse effects of antibody preparations
1. Increased incidence of posttransplant lymphoproliferative disease (PTLD)
2. Mechanism of PTLD is probably reactivation of Epstein-Barr virus, either in the recipient
or in passenger lymphocytes that originate in the donor and are transplanted with the
graft. <1% of transplant recipients develop PTLD, but mortality is high
3. Incidence of PTLD increases in direct proportion to the amount of therapeutic antibody
used
4. Other adverse effects – fever, anaphylaxis, tachyarrhythmia, hypotension, hypertension

Recommended Reading
Mangray M, Vella JP. Hypertension after kidney transplant. Am J Kidney Dis. 2011; 57(2):331-341.
Padiyar A. Induction antibody therapy in kidney transplantation. Am J Kidney Dis. 2009;54: 935-944.
Pediatric Liver Transplantation. World J Gastroenterology. 2009;14:648-674.
Pidwell DJ, Burns C. The immunology of composite tissue transplantation. Clin Plastic Surg. 2007; 34:303-
317.
Serkovans NJ, Chritians U. Biochemical Mechanisms of cyclosporin neurotoxicity. Mol Interv. 2004;2:97-107.
Staatz CE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant
recipients. Clin Pharmacokinet. 2007;46(1):13-58.
Subramanian MD. Immunosuppressive Agents: Effects on Glucose and Lipid Metabolism. Endocrinol Metab
Clin N Am. 2007;36:891-905.
10C-2. Drugs—Biologics
Joel Friedlander, DO, MBE
Zili Zhang, MD, PhD
I. Biological Therapies
Defects in innate immunity and aberrant adaptive immune responses are major contributors to the
production of Inflammatory Bowel Disease (IBD). The role of a number of inflammatory mediators and
other immune molecules in IBD have also been defined. Understanding of these immune mechanisms has
led to the development of new biological therapies, specifically targeting the molecules and mechanisms
involved in the intestinal inflammatory process.
II. Inhibition of TNF-α

A. TNF-α is an inflammatory cytokine produced chiefly in monocytes and lymphocytes. It is initially
synthesized as a membrane-bound precursor, and then processed and released from the cell
surface by TNF-α–converting enzyme (TACE)
B. Numerous studies have implicated this cytokine in the pathogenesis of IBD
C. There are increased numbers of TNF-α–secreting cells in the intestinal mucosa of individuals with
IBD
D. TNF-α exacerbates immune responses by activating NF-κB, releasing inflammatory mediators and
upregulating adhesion molecules
III. Infliximab
A. Drug Characteristics, Indications and Efficacy
1. Infliximab is a chimeric IgG1 monoclonal antibody against TNF-α, in which 25% of the
molecule is a mouse peptide sequence
2. Infliximab is effective in induction and maintenance of steroid-refractory and steroid-
dependent Crohn disease, particularly fistulizing disease and perianal disease
3. The usual pediatric regimen includes an induction phase (5 mg/kg IV on weeks 0, 2 and
6) followed by a maintenance phase of infusions every 8 weeks. Up to 10 mg/kg/dose at
4-week intervals has been used to achieve effective trough or tissue concentrations
4. REACH pediatric clinical trial has shown a clinical remission rate of 50%–68% to
infliximab, with sustained response at 1 year of 56%–64% using the standard infliximab
dose
5. Hyams et al demonstrated efficacy of infliximab in childhood ulcerative colitis, with 38%
and 21% of patients in steroid-free remission at 1 year and 2 years, respectively. Turner
and Griffiths report up to 75% pooled success in avoiding colectomy when used as
rescue therapy
B. Side Effects
1. Infliximab is generally well tolerated in pediatric patients
2. Serious side effects include infections (abscess, viral and fungal infections, reactivation
of latent herpes virus or tuberculosis), allergic reactions, gradual loss of efficacy and
malignancy
a. Very rapid healing of surface tissues around fistulas has been reported to produce
walled off abscess, constipation and intestinal stricture
b. Reactivation of tuberculosis: patients should have a PPD test or chest x-ray prior
to infliximab therapy. If negative originally, the PPD should be repeated every 1–2
years while the patient receives anti-TNF-α therapy
c. Reactivation or new infection with herpes or CMV may produce intestinal
symptoms similar to those of Crohn disease. Patients with reactivation of Crohn
disease require organism specific diagnostic testing
d. Life-threatening hepatosplenic T-cell lymphoma has been reported in patients
with concomitent exposure to 6-mercaptopurine or azathioprine
e. Development of human anti-chimeric antibodies (HACA)

1) Immunogenicity of infliximab is attributed to the murine component
of the molecule
2) Reactions can be immediate (infusion reactions, anaphylaxis) or delayed
(serum sickness)
3) HACA increases the risk of infusion reactions. Reduced drug efficacy is a
result of immune clearance of infliximab and subtherapeutic levels
4) Concomitant immunosuppressive therapy and premedication with
steroids are reported to reduce the incidence of HACA formation
and infliximab-related reactions
5) Regularly scheduled infusion (as opposed to waiting for symptom
recurrence) during maintenance therapy is associated with reduced HACA
formation
6) Increased infliximab dose, decreased interval between infusions and
concomitant immune-suppression therapy may improve clinical efficacy
7) Patients with HACA may benefit from a switch to adalimumab (see below)
IV. Adalimumab
A. Humanized anti-TNF-α monoclonal IgG1 antibody that is 95% human. The antibody is as effica-
cious as infliximab in patients who have never received anti-TNF-α therapy
B. Alternative therapy for the patients who either lose responsiveness or develop intolerance to
infliximab because of HACA
C. Therapeutic Regimen
1. The usual regimen for individuals >40 kg is adalimumab (160 mg by subcutaneous
injection), followed by 80 mg SQ in 2 weeks, followed by 40 (SQ) mg every 2 weeks
2. Adalimumab is approved for the patients 16 years or older
3. Inadequate data on therapy of patients <40 Kg. Uncontrolled clinical studies have used
40 mg SQ as induction followed by 20 mg SQ every 2 weeks as maintenance
D. Side Effects
1. The side effects of adalimumab are similar to those of infliximab. In 2007, Sandborn
studied adalimumab in adult subjects non-responsive and/or intolerant to infliximab and
demonstrated safety and efficacy
V. Certolizumab Pegol
1. Certolizumab Pegol is a pegylated Fab fragment of humanized anti-TNF monoclonal anti-
body, currently approved for use in adults with moderate to severe Crohn disease
2. Theoretically, less immunogenic than infliximab
3. Clinical trials in adults have shown rapid and long-lasting therapeutic effect
VI. Inhibition of Adhesion Molecules

A. Recruitment of leukocytes is a critical step for eliciting local inflammatory responses
B. Adhesion molecules, such as integrins, mediate selective binding between leukocytes and
vascular endothelial cells, the first step in the migration of leukocytes into inflamed sites
C. T cells express tissue-tropic molecules, enabling them to migrate to specific target organs
D. α4-integrins, predominantly expressed on lymphocytes, in combination with a β subunit, interact
with adhesion molecules on endothelium
1. α4β7-integrin binds to mucosal addressing cell adhesion molecule-1 (MAdCAM-1)
2. Interaction between α4β7-integrin and MAdCAM-1 mediates homing of lymphocytes to
the intestinal mucosa
E. Integrins are upregulated in IBD
F. Blocking homing molecules prevents the entry of inflammatory lymphocytes into the
gastrointestinal tract
VII. Natalizumab
A. Indications and Efficacy
1. Humanized IgG4 anti-α4-integrin monoclonal antibody inhibits both α4β7-integrin/
MAdCAM-1 interaction and α4β1/VCAM-1 binding, thereby interrupting lymphocyte
trafficking into the intestine
2. Natalizumab is superior to placebo in producing remission in Crohn disease and
ulcerative colitis
3. Used in therapy of multiple sclerosis
4. FDA approved for pediatric patients with severe IBD refractory to standard therapies
B. Side Effects
1. Progressive multifocal leukoencephalopathy (PML) is a rare complication of natalizumab
and other adhesion molecule inhibitors
a. Infection with human polyomavirus (JC virus) causes lytic infection of
oligodendrocytes. Most commonly occurs in immune-suppressed patients
b. PML presents with neuropsychological deficits, subcortical dementia, apraxia,
retrochiasmal visual deficits and motor difficulties
c. Often progressive and fatal
d. One case as of 2010 reported in a patient with Crohn disease
VIII. Inhibition of Cytokines Promoting T-cell Differentiation

A. Anti-IL-12p40/p23 antibody
1. Indications and Efficacy
a. Activated antigen-presenting cells produce cytokines, such as IL-12 and IL-23
1) IL-23 promotes Th17 differentiation
b. Anti IL-12p40/p23 binds to the p40 subunit of IL12 and IL-23, decreasing or
normalizing IL12 and IL-23 mediated signaling, cellular activation and cytokine
production (all elevated in Crohn disease and psoriasis)
1) Recent multicenter adult trial showed moderate efficacy for anti-IL-
12p40/-23 antibody in Crohn disease
Recommended Reading
Clark M, Colombel JF, Feagan BC, et al. American gastroenterological association consensus development
conference on the use of biologics in the treatment of inflammatory bowel disease, June 21-23, 2006.
Gastroenterology. 2007;133(1):312-339.
Mamula P, Mascarenhas MR, Baldassano RN. Biological and novel therapies for inflammatory bowel disease in
children. Pediatr Clin North Am. 2002;49(1):1-25.
Rutgeerts P, Van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease.
Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases.
Gastroenterology. 2009;136(4):1182-1197. Erratum in: Gastroenterology. 2009;136(5):1844.
Sandborn WJ. Current directions in IBD therapy: what goals are feasible with biological modifiers?

10C-3. Drugs—Acid Control
Jennifer L. Dotson, MD
Jolanda Denham, MD
I. Antacids
A. Pharmacology/Mechanism of Action
1. Usual compounds are carbonate and bicarbonate salts and alkaline complexes of
aluminum or magnesium
2. Chemically neutralizes gastric acid
3. Rapid onset of action, but limited duration of effect
4. Liquid or tablet antacids do not alter the course of GER
5. Examples: magnesium hydroxides, aluminum and magnesium phosphates, sodium
bicarbonates
B. Indications and Side Effects
1. Mainly used to treat occasional symptoms of heartburn and esophagitis in adults
2. Should not be given to infants and toddlers (limited experience with use)
3. Can cause elevated magnesium levels
4. Chelates and impairs absorption of certain medications (i.e., tetracycline, azithromycin
quinolones)
5. Absorbed magnesium and sodium require renal excretion. Use with caution in renal
impairment
6. Diarrhea may occur with magnesium-based antacids
II. Histamine 2 (H2) Receptor Antagonist

1. Reversibly inhibits parietal cell H2 receptors
2. Decreases gastric acid secretion 50%–80%
3. Decreases pepsin activity due to higher gastric pH
4. Decreases gastrin-stimulated gastric acid secretion
5. Does not affect gastric emptying or intestinal motility
6. May prevent heartburn if taken prior to meals
7. Onset of action within 60 minutes. Effects last up to 12 hours
8. Examples: Zantac® (ranitidine), Axid® (nizatidine), Pepcid® (famotidine),
Tagamet® (cimetidine)
B. Indications
1. Symptomatic relief of gastroesophageal reflux disease and dyspepsia
2. Treatment of ulcers
3. Used as an adjunct in treating systemic allergic reactions because of histamine
antagonism
4. Less effective than proton pump inhibitors for treatment of erosive esophagitis or
Helicobacter pylori gastritis
5. Main action is reduced basal acid secretion of the parietal cell
C. Side Effects
1. 1%–6% of patients experience fatigue, dizziness, headaches, dyspepsia, nausea,
abdominal pain, flatulence, constipation or diarrhea
2. Ranitidine use is associated with increased risk of pneumonia in ICU patients. Probable
mechanism is reduction in antibacterial effect of gastric acid and alterations in intestinal
flora. Risk is lower than that associated with PPIs
3. Cimetidine blocks activity of cytochrome P-450 (more so than other H2 blockers),
leading to higher risk of drug interactions
4. Can alter heart rate
5. Patients may experience nocturnal breakthrough of symptoms
6. Limited long-term use: rapid development of tachyphylaxis or tolerance

7. Cimetidine can cause reversible gynecomastia via binding to androgen receptors
8. Renal excretion of drug requires reduced dosing for renal insufficiency
III. Proton Pump Inhibitors (PPIs)

1. Irreversible binding to the final common pathway of gastric acid secretion, parietal cell
H+/K+ ATPase
2. Produces >90% decrease in total daily gastric acid secretion
3. Most effective when given 15–30 minutes prior to meal
4. Delayed onset of action (2–5 days) and longer duration (24 hours–3 days) than H2
receptor antagonists
5. When enteric coated, absorption begins at higher pH of duodenum, but it is primarily
absorbed in the small bowel
6. Dosing is usually a single morning dose. Young children >6months to 10 years may
benefit from twice daily dosing because of a higher rate of drug metabolism
7. Chewing or dissolving capsules reduces potency secondary to reduced absorption with
exposure to gastric acid
8. Capsules can be opened and mixed with an acidic substance (yogurt, juice, applesauce)
9. Metabolized by cytochrome P450 to inactive metabolites which are excreted in the urine
10. Examples: Nexium® (esomeprazole), Prevacid® (lansoprazole), Prilosec® (omeprazole),
Protonix® (pantoprazole), Aciphex® (rabeprazole), Dexilant® (dexlansoprazole)
B. Indications
1. More effective acid suppression than that obtained with H2 antagonists
2. Indicated and effective for treatment of moderate-severe GERD symptoms, acute or
chronic esophagitis, erosive esophagitis or complicated GERD (stricture, ulcers, Barrett
esophagus)
3. Adjunctive therapy (as a continuous intravenous infusion) for severe upper GI bleeding
4. Peptic ulcer disease – H pylori, burns, multiorgan failure, sepsis, drug related
5. Zollinger-Ellison syndrome – may require significant increase in recommended dose
6. Must be used in conjunction with antibiotics to treat Helicobacter pylori infection
C. Side Effects
1. No dose-dependent side effect profiles
2. Metabolized in the liver (use with caution in patients with severe liver disease) and
excreted via urine
3. Can alter the metabolism of other medications
4. Headaches (3%), neurologic/psychiatric (fatigue, dizziness, confusion, rash/urticaria,
gynecomastia, GI (4% – constipation, abdominal pain, diarrhea, flatulence, or 2%
nausea and dyspepsia), vomiting, abdominal pain, transaminitis, urinary sodium loss
5. Prolonged hypochloridia increases gastric bacterial overgrowth
6. Increased nosocomial and community acquired pneumonias (risk increases with
increased dose)
7. N-nitrosamine metabolites are generated secondary to gastric bacterial overgrowth (can
be carcinogenic)
8. B12 deficiency
9. Hypergastrinemia, fundic polyps/nodules
10. Rebound hypersecretion warrants gradual dose reduction/weaning
11. Drug interactions: decreased absorption (ketoconazole, itraconazole, iron salts, vitamin
B12, griseofulvin), increased absorption (digoxin, nifedipine), prilosec increases drug levels
(CYP 450) of some antiepileptics, warfarin and methotrexate
Recommended Reading
Flockhart DA, Desta Z, Mahal SK. Selection of drugs to treat gastro-oesophageal reflux disease: the role of
drug interactions. Clin Pharmacokinet 2000; 39(4):295-309.
Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman’s The Pharmacological Basis of Therapeutics.
10th ed. New York, NY: Mc-Graw Hill; 2001.
Kelly DA. Do H2 receptor antagonists have a therapeutic role in childhood? J Pediatr Gastroenterol.
1994;19(3):270-276.
Wyllie R, Hyams JF, eds. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders; 2006.
Zimmerman AE, Walters JK, Katona BG, Souney PE, Levine D. A review of omeprazole use in the treatment
of acid-related disorders in children. Clin Ther. 2001; 23(5):660-679.

10C-4. Drugs—Prostaglandins
Mazen I. Abbas, DO, MPH
Minela Fernandez, MD
I. Physiologic Role/Mechanism of Action

A. Gastric mucosa secretes prostaglandins of the E and I series
B. Effects of prostaglandin E and I enhance gastric mucosal protection by multiple mechanisms
1. Inhibition of gastric acid and pepsin secretion
2. Stimulation of mucous and bicarbonate secretion
3. Increasing mucosal blood flow
4. Stabilization of tissue lysozymes and vascular endothelium
5. Increased mucosal regenerative capacity
C. Misoprostol – synthetic analog of prostaglandin E1
1. Direct stimulation of prostaglandin receptors on parietal cells inhibits G protein secretion
and prevents activation of adenylate cyclase
2. This mechanism inhibits gastric acid secretion, enhancing mucosal protection
3. Significantly more effective than placebo, sucralfate or H2 receptor antagonists in pre-
vention of NSAID-induced ulceration
4. Prospective studies in children report the same benefits as adult studies
II. GI Indications
A. Treatment of peptic ulceration (duodenal and/or gastric) in children
1. Dose of 800 mcg daily divided in 2 or 4 doses for 4 weeks
B. Prophylaxis and treatment of NSAID-induced peptic ulceration
1. Dose of 200 mcg orally QID
III. Side Effects

A. Dose-dependent diarrhea (13%–40% of patients)
1. Secondary to stimulation of cyclic adenosine monophosphate system and increased
intestinal secretion
2. Life-threatening diarrhea has been reported in patients with inflammatory bowel disease
B. Abdominal pain and cramping (7%–20% of patients)
1. Probably secondary to intestinal contractions
C. Rupture of uterus, abortion, premature birth, birth defects
1. Misoprostol is used therapeutically to induce labor and decrease postpartum
hemorrhage
2. Prostaglandins stimulate uterine smooth muscle contraction and cervical ripening
3. Women of childbearing age should not take misoprostol, as it may cause miscarriage
and birth defects when used during pregnancy
D. Other reported side effects
1. Headaches
2. Gastrointestinal hemorrhage (infrequent)
3. Cardiac dysrhythmia, mainly tachyarrhythmias (infrequent)
4. Anemia secondary to bleeding (infrequent)
5. Chest pain/myocardial infarction (infrequent)
6. Thromboembolic disorder
7. Anaphylaxis (infrequent)
8. Deafness (infrequent)

Recommended Reading
Gazarian M, Berkovitch M, Koren G, Silverman ED. Experience with misoprostol therapy for NSAID
gastropathy in children. Ann Rheuma Dis.1995;54:277-280.
Lanza FL, Chan FK, Qugley EM; Practice Parameters Committee of the American College of
Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol.
2009;104:728-738.
Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: Why doesn’t the stomach digest itself?
Physiol Rev. 2008;88:1547-1565.
10C-5. Drugs—Sucralfate
Monica M. Zherebtsov, MD
Lillian Choi, MD
I. Overview
A. Mucosal barrier agent
B. Sulfated disaccharide linked to AL(OH)3
C. Effective in healing of single duodenal ulcers in children
II. Mechanism of Action

A. In an acid environment (pH <4), sucralfate undergoes cross-linking, producing a sticky polymer
adhering to positively charged protein molecules of the mucosa for up to 6 hours
B. Sucralfate increases hydrophobicity of the mucous gel
C. Increases local production and release of prostaglandins
III. Administration
A. Sucralfate should be taken on an empty stomach 1 hour prior to meals
B. Because sucralfate functions better in an acid environment, it should not be taken within 30
minutes of antacids
C. Dosing not established in children. Doses of 40–80 mg/kg/day divided every 6 hours have been
used
IV. Adverse Effects

A. Constipation is the most frequent adverse effect, affecting 2% of patients
B. Other side effects: diarrhea, nausea, vomiting, gastric discomfort, flatulence, indigestion, dry
mouth, pruritis, back pain, headache, dizziness, insomnia, sleepiness and vertigo
C. Aluminum salt is minimally absorbed but can accumulate in renal failure; use with caution in
premature patients, and in those with renal failure or on dialysis
D. Serum aluminum levels should be monitored in children with renal failure on sucralfate
E. Sucralfate may inhibit absorption of other drugs: phenytoin, digoxin, cimetidine, ketoconazole
and fluororoquinolone antibiotics
Recommended Reading
Brunton LL, Lazo JS, Parker KL. The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-
Hill Medical Publishing Division; 2006.
McEvoy GK. AHFS Drug Information. American Society of Health-System Pharmacists; 2003.
Reese WD. Mechanisms of gastroduodenal protection by sucralfate. Am J Med. 1991;91(24):585-635.

10C-6. Drugs—
Pancreatic Enzymes
Darla Shores, MD
Mark E. Lowe, MD
I. Purpose
Exogenous administration of pancreatic enzymes is required to promote normal digestion of complex
formulas and food in pancreatic exocrine deficient children. The major indication for the administration of
exocrine pancreatic supplements in pediatric patients is cystic fibrosis. As of 2010, all pancreatic enzymes
preparations must be FDA approved. The three approved commercially available preparations—Creon,
Pancreaze and Zenpep—are extracts of porcine pancreas containing lipase, amylase and proteases (in a
roughly 1:5:3 ratio) as well as numerous other porcine proteins.
II. Packaging/Preparation
A. Most efficacy is preserved by enclosing enzymes in microspheres inside gelatin capsules; this is
the only formulation currently recommended
B. Powdered preparations are no longer being manufactured
C. Capsule protects enzymes from gastric acid
D. Microsphere dissolves in alkaline environment of duodenum
E. A non-porcine preparation using a recombinant lipase, protease and amylase is under FDA review
currently (Liprotamase)
III. Factors With Impact on Efficacy

A. Gastric acid inactivates enzyme activity
B. Residual proteolytic activity in duodenum degrades enzymes
C. Poor mixing of enzymes with duodenal chyme prevents adequate contact between food and
enzymes
D. Insufficiently alkaline duodenal juice prevents release of enzymes from microspheres;
administration of H2 blockers or PPIs may overcome this problem
IV. Dosing
A. Varies with age, body mass and amount of ingested fat
B. Dosing is based on the need for lipolytic activity, as steatorrhea is the most symptomatic and
quantifiable macronutrient malabsorption
C. The current recommendation is 500–2,500 lipase units/kg body weight/meal, not to exceed
2,500 lipase U/kg/meal or 10,000 lipase U/kg/day
D. Supplements should be taken before all meals, formula (polymeric and elemental), breastmilk
and snacks
E. For continuous feeds or slow eaters, supplements should be given before and during feeds
V. Monitoring Efficacy
A. Monitor weight gain
B. Monitor fecal fat excretion as a fraction of intake over 72 hours (see section on Pancreatic Func-
tion Test)
C. Monitor serum concentrations of exogenously acquired fat-soluble indicators: carotene, vitamin
D, vitamin E
D. Monitor functions dependent on fat-soluble vitamins: vitamin K dependent prothrombin time,
INR. These indirect tests are not very sensitive
VI. Complications of Pancreatic Enzyme Replacement

A. Fibrosing colonopathy
1. Prolonged use of high dose lipase (>2,500 U/Kg/meal: >10,000 U/Kg/day)
2. Submucosal fibrosis, inflammation and sometimes stricture of cecum and ascending
colon
3. This problem is not reversible
B. Allergic reactions—more common in older powdered preparations
1. Cough and bronchospasm
2. Anaphylaxis
C. Hyperuricemia/hyperuricosemia from high purine content of porcine preparations has been
reported, but may actually be a result of other mechanisms associated with CF
1. May be asymptomatic, or develop crystals and renal tubular damage
2. Treat with increased fluid intake and allopurinol
D. Oral, perioral, perianal rashes and ulcers from contact with active enzymes. Most commonly seen
with powdered preparations and in children who chew capsules or hold them in the mouth
Recommended Reading
Borowitz D. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol
Nutr. 2002;35(3):246-259.
Caliari S. Pancreatic enzymes are necessary for the absorption of elemental and polymeric enteral diets in
severe pancreatic insufficiency. Scand J Gastroenterol. 1993;28(8):749-752.
DiMagno E. Gastric acid suppression and treatment of severe exocrine pancreatic insufficiency. Best Pract Res
Clin Gastroenterol. 2001;15(3):477-486.
FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pancreatic-enzyme supplements and fibrosing
colonopathy in children with cystic fibrosis. N Engl J Med. 1997;336(18):1283-1289.
10C-7. Drugs—Motility Agents
Alex Green, DO
Jaya Punati, MD
I. Motility Agents
A. Esophagus/Stomach
1. Prokinetics
a. Metoclopramide
1) Pharmacology: receptor antagonist that binds to dopamine D2 receptors
and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist
2) Site of action
a) Antiemetic activity: D2 receptors in the chemoreceptor trigger zone
b) Prokinetic activity: muscarinic activity mediated by D2 receptor
inhibition and 5-HT4 receptor stimulation
3) Side effects
a) Common: restlessness, drowsiness, dizziness, dystonic reactions
b) Uncommon: headache, extrapyramidal effects, oculogyric
crisis, hypertension, hypotension, hyperprolactinemia leading to
galactorrhea, diarrhea, constipation and/or depression
c) Rare: agranulocytosis, supraventricular tachycardia,
hyperaldosteronism, neuroleptic malignant syndrome, akathisia,
tardive dyskinesia
b. Domperidone
1) Pharmacology: blocks action of dopamine, especially at D2 and D3
receptors
2) Site of action
a) Antiemetic activity: D2/D3 receptors in the chemoreceptor trigger
zone, poor CNS penetration
b) Prokinetic activity: limited to esophagus, stomach and duodenum
3) Side effects: headache, somnolence, diarrhea, abdominal pain
Extrapyramidal effects rare
c. Erythromycin
1) Pharmacology: mimics the effect of motilin
2) Site of action: motilin receptors in the gastric antrum and proximal
duodenum
3) Side effects
a) Common: nausea/vomiting, crampy abdominal pain, diarrhea,
anorexia, rash, elevated transaminases, jaundice
b) Uncommon: hepatotoxicity, erythema multiforme, Stevens-Johnson
syndrome
d. Cisapride (Removed from market)
1) Pharmacology: promotes acetylcholine release from postganglionic nerve
endings in myenteric plexus longitudinal muscles of the GI tract. Also an
agonist for 5-HT4 receptors and antagonist for 5-HT3 receptors
2) Site of action: Acts as both an agonist and antagonist at serotonin
receptors throughout the GI tract. Increases lower esophageal sphincter
pressure and esophageal motility, accelerates gastric emptying of liquids
and solids, and decreases colonic transit time
3) Side effects: Headache, nausea/vomiting, abdominal pain, rhinitis,
diarrhea. Serious side effects include QT prolongation, ventricular
arrhythmias and torsade de pointes

2. Other agents with some motility effects
a. Cyproheptadine
1) Pharmacology: antagonizes central and peripheral H1 receptors along with
serotonin receptors
2) Site of action: competitively antagonizes histamine at the H1-receptors
of the GI tract, uterus, large blood vessels and bronchial smooth
muscle. Competes with serotonin at intestinal smooth muscle receptors.
Antagonism of serotonin on the appetite center of the hypothalamus
3) Side effects: sedation, anticholinergic effects, appetitie stimulation and
weight gain
b. Octreotide
1) Pharmacology: somatostatin receptor agonist
2) Site of action: prolongs gastric emptying time by resetting the migrating
motor complex to the fasting level
3) Side effects: abdominal pain, diarrhea, nausea/vomiting, ileus, abdominal
distention, epigastric pain, abdominal tenderness, bradycardia, growth
retardation, cholelithiasis, gallbladder sludge
c. Botulinum toxin
1) Pharmacology: prevents acetylcholine release from motor neurons
2) Site of action: at injection site; in GI tract used at anal sphincter, pylorus,
and lower esophageal sphincter
3) Side effects: rare when used as local injection, but could cause paralysis of
surrounding gastric wall
Recommended Reading
Di Lorenzo C, Youssef NN. Diagnosis and management of intestinal motility disorders. Semin Pediatr Surg.
2010;19(1):50-58.
Hasler WL. Management of Gastroparesis. Expert Rev Gastroenterol Hepatol. 2008;2(3):411-423.
Karamanolis G, Tack J. Promotility agents now and in the future. Dig Dis Sci. 2006;24(3-4):297-307.
10C-8. Drugs—Laxatives
and Stool Softeners
Alex Green, DO
Jaya Punati, MD
I. Dietary Fiber
A. Pharmacology: soluble fiber absorbs water to become a gelatinous, viscous substance and
is fermented by bacteria in the digestive tract. Insoluble fiber has bulking action and is not
fermented
B. Mechanism of action: absorbs liquid in the GI tract, thereby altering intestinal fluid and
electrolyte transport. Absorption of liquid also causes expansion of the stool, and the resultant
bulk facilitates peristalsis and bowel motility. Provides substrate for bacterial growth with increase
of colonic flora
C. Indications: chronic constipation
D. Side effects: abdominal pain, diarrhea, flatulence, GI obstruction, nausea and vomiting
II. Medications
A. Long-term
1. Milk of magnesia
a. Pharmacology: converted to magnesium chloride in stomach. Magnesium is
in the ionic form in the small intestine
b. Mechanism of action: osmotic laxative. Magnesium draws water into the intes-
tine, causing an increase in intraluminal pressure. This increased pressure exerts a
mechanical stimulus that increases intestinal motility
c. Indications: severe constipation with hard stools. Can be used in children >1
month old
d. Side effects: anorexia, dehydration, diarrhea, hypermagnesemia, hypotension,
nausea/vomiting
2. Mineral oil
a. Pharmacology: onset of action is usually 6–8 hours, and it works in the colon
b. Mechanism of action: retards colonic absorption of fecal water and softens the
stool. Mineral oil retards colonic absorption of fecal water and softens the stool
c. Indications: constipation/hard stools. Use only in children >12 months of age
because of risk of aspiration
d. Side effects: concerns of interfering with fat-soluble vitamins, largely unfounded
Anal leakage, diarrhea, nausea/vomiting, perianal irritation, abdominal cramps,
lipid pneumonia if aspirated
3. Lactulose
a. Pharmacology: synthetic derivative of lactose, is a disaccharide sugar containing
one molecule of galactose and one molecule of fructose
b. Mechanism of action: cannot be hydrolyzed by any gastrointestinal enzyme until
it reaches the colon where colonic bacteria can break down lactulose. This break-
down increases osmotic pressure, causing fluid accumulation that softens the
stool and distends the colon, enhancing peristalsis
c. Indications: constipation/hard stools. Use in children >1 month old
d. Side effects: abdominal pain, diarrhea, flatulence, hypernatremia, hypokalemia,
metabolic acidosis, nausea/vomiting
4. PEG 3350
a. Pharmacology: oligomer or polymer of ethylene oxide. Not absorbed nor de-
graded by bacteria
b. Mechanism of action: binds water and causes water to be retained within the
stool. Does not change colonic transit time
c. Indications: constipation. Use in children >1 month
d. Side effects: abdominal pain, diarrhea, fecal urgency/incontinence, flatulence

B. Short-term
1. Senna
a. Pharmacology: anthraquinone derivative that causes changes in fluid balance and
electrolyte absorption
b. Mechanism of action: it alters permeability of cell walls in the colon because
it increases cyclic AMP, which regulates active ion secretion → increased fluid
accumulation in the colon
c. Indications: Stimulant laxative. Use in children >1 year old
d. Side effects: abdominal pain, melanosis coli, physical dependence, vomiting,
weakness
2. Glycerin enemas
a. Mechanism of action: Local irritant effect on rectal mucosa and
hyperosmotic action.
b. Indications: constipation. Use in >10 years old
c. Side effects: griping, diarrhea, rectal bleeding with chronic use, nausea/vomiting,
perianal irritation, abdominal cramps, weakness, dizziness, syncope
d. Small volume glycerine suppositories safe for occasional use in infants
3. Bisacodyl suppositories
a. Mechanism of action: directly stimulating peristaltic movement of the intestine
via local mucosal irritation. Also thought to alter intestinal fluid and electrolyte
absorption and thus promoting peristalsis. Stimulates enteric nerves to cause
colonic mass movements
b. Indications: constipation. Use in children >10 years old
c. Side effects: abdominal pain, diarrhea, nausea/vomting, physical dependence,
hypokalemia
C. Clean-out
1. Phosphate enema
a. Pharmacology: draws additional water from the bloodstream into the colon and
acts as a mechanical stimulant
b. Mechanism of action: increase the amount of water present in the bowel due
to the hyperosmotic effect of sodium within the large intestines. Excess water
in the colon stimulates bowel stretch receptors and stimulates the release of
cholecystokinins. Distention causes peristalsis increasing and stimulating a
purgative effect
c. Indications: constipation
d. Side effects: seizures, hyperphosphatemia and hypocalcemic tetany, abdominal
pain, fecal incontinence/urgency
2. Magnesium citrate
a. Pharmacology: action primarily in the small intestine
b. Mechanism of action: hyperosmotic effect from magnesium and stimulation of
stretch receptors and peristalsis through retention of water
c. Indications: constipation
d. Side effects: abdominal cramps, diarrhea, flatulence, hypotension,
hypermagnesemia, respiratory depression, electrolyte disorders
Recommended Reading
Blackmer AB, Farrington EA. Constipation in the pediatric patient: an overview and pharmacologic
considerations. J Pediatr Health Care. 2010;24(6):385-399.
Walia R, Mahajan L, Steffen R. Recent advances in chronic constipation. Curr Opin Pediatr. 2009;21(5):661-
666.
10C-9. Drugs—
Anti-pruritic Agents
Elizabeth Mileti, DO
Philip Rosenthal, MD
I. Pathophysiology of pruritus in cholestasis

A. Bile acids, bilirubin and cholesterol in the skin previously thought to cause pruritus
B. Recent data suggest pruritus is centrally mediated by opioid neurotransmission
1. Opioid peptides cause mast cells to release histamine
2. Exogenous opioids can cause pruritus relieved only by opioid antagonists
a. Cirrhotic adults have increased endogenous opioids, such as enkephalins
b. Opioid antagonists in cholestatic individuals may cause a withdrawal response
similar to that of opioid abusers, suggesting that cholestatic individuals have
chronically increased circulating opioids
II. Treatment
A. First principle – treat the cause of cholestasis if possible
B. Antihistamine – diphenhydramine
1. Dose – 5 mg/kg/day divided in 4 doses (not to exceed 300 mg/day)
2. Mechanism – H1 receptor blocker competes with histamine for H1-receptor sites
3. Blocking H1 receptors on peripheral nociceptors decreases sensitization and reduces
itching
4. Side effects – blurred vision, dry mouth, paradoxical excitement, sedation
5. Contraindications – hypersensitivity to diphenhydramine, asthma, encephalopathy
C. Ursodeoxycholic acid (UDCA)
1. Drug properties – hydrophilic bile acid stimulates hepatic bile production and protects
hepatocytes against cytotoxicity by hydrophobic bile acids
2. Dose – 15–30 mg/kg/day in 2–3 divided doses
3. Mechanism of action – reduces toxicity of endogenous bile acids by competitively
inhibiting intestinal absorption
4. Side effects – abdominal pain, diarrhea, nausea, may worsen pruritus at start of therapy
5. Contraindications – hypersensitivity reaction
6. UDCA is not effective for dissolving radiopaque stones, bile pigment stones and calcified
cholesterol stones
D. Cholestyramine
1. Drug properties – bile-binding resin
2. Dose – 240 mg/kg/day in 3 divided doses; maximum 16 g/day
3. Mechanism – binds bile acids in the intestine, forming nonabsorbable complex,
preventing enterohepatic reuptake of bile salts
4. Side effects – nausea, vomiting, abdominal pain, constipation
5. Contraindications – hypersensitivity reaction, complete biliary obstruction, bowel
obstruction
6. Cholestyramine interferes with absorption of many medications and should be given
2 hours before or after administration of other drugs

E. Rifampin
1. Bactericidal antibiotic
2. Dose – 10 mg/kg/day orally (1 hour prior to meals or 2 hours after meals to decrease GI
distress)
3. Mechanism – unknown. Rifampin may inhibit toxic bile acid uptake and induce
cytochrome P450 system to degrade enkephalins and bile acids, preventing hepatocyte
injury
4. Side effects
a. Orange discoloration of urine, sweat, tears
b. Elevated transaminases (monitor LFTS every 2–4 weeks while on medication)
c. Idiosyncratic hypersensitivity – hemolytic anemia, renal failure, thrombocytopenic
purpura
5. Contraindications – hypersensitivity reaction
F. Naloxone, naltrexone
1. Opiate antagonists have not been evaluated in children
2. Mechanism – bind competitively with opioid receptors with high affinity but without
activating the receptors
3. Side effects
a. Anxiety, headache, insomnia, withdrawal symptoms
b. Black box warning for naltrexone prohibits use in patients with liver failure
4. Contraindications: hypersensitivity reaction, concurrent use of opioid analgesics, opioid
withdrawal or dependency
Recommended Reading
Bergara N. Treatment of the pruritus of cholestasis. Curr Treat Options Gastroenterol. 2004; 7: 501-508.
Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic implications of
opioids. Gastroenterology. 1995;108:1582-1588.
Cies JJ, Giamalis JN. Treatment of cholestatic pruritus in children. Am J Health-Syst Pharm. 2007; 64:1157-
1162.
Ng VL, Balistreri WF. Treatment options for chronic cholestasis in infancy and childhood. Curr Treat Options
Gastroenterol. 2005;8:419-430.
Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. BMJ. 1988; 297:1501-1504.
10C-10. Drugs—Prebiotics/Probiotics
Thomas Flass MS, MD
Robert Kramer, MD
I. Definitions
A. Probiotics: Live microorganisms that, when consumed in adequate numbers, confer a health
benefit to the host
B. Prebiotics: Nondigestible substances that promote the growth of limited strains of (probiotic)
bacteria in the human body, eg, fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS)
and lactulose
C. Synbiotics: Mixtures of pro- and prebiotics
D. Metagenomics: Bacterial identification using small subunit rRNA genes carried by all cellular
organisms. The technology can characterize the phylospecies and population densities of an en-
tire microbial community using PCR amplified 16S rDNA extracted from bacteria in a sample and
uses primers targeting highly conserved regions of rDNA (high throughput sequencing)
E. Microbiome: All microbes in or on the human body. Or, alternatively, the resident microbial
community in a defined biologic/anatomic area.
F. Human Microbiome Project (HMP): NIH program to completely characterize the human
microbiome and its role in health and disease. Work currently underway to define the human
intestinal microbiome and alterations in the microbiome (dysbiosis) that occur in disease
II. Forms (species) of Probiotics

A. Lactobacillus rhamnosus GG (LGG)
B. Lactobacillus spp (acidophilus, paracasei, rhamnosus, casei, lactis, plantarum, reuteri,
salivarius, fermentum, bulgaricus)
C. Streptococcus thermophilus, salivarius
D. Bifidobacteria spp (infantis, longum, breve, lactis, animalis, bifidum)
E. Saccharomyces boulardii (yeast)
F. Mixed species (VSL#3 is a mixed preparation containing species bolded above)
G. E coli Nissle 1917
H. FDA approved the use of B lactis and S termophilus in infant formula in 2002
III. Physiologic Importance/Mechanisms of Action

A. Colonization of the infant gut
1. Occurs during birth and breastfeeding
2. Initial colonization by facultative maternal vaginal and fecal species (Streptococcus,
Enterococcus, Coliform)
a. C-section infants more likely to be colonized by Klebsiella, Enterobacter and
Clostridia
b. Breastfed infants have more Bifidobacteria and Lactobacillus, and fewer
Bacteroides, C difficile, E coli in stools than formula-fed infants.
3. After 1 week, anaerobic bacteria are established (Bifidobacterium, Bacteroides,
Clostridium)
4. Bifidobacteria are the dominant species through the first year
B. Development and maintenance of intestinal tight junctions and mucosal integrity
1. VSL#3 and other probiotics improve mucosal barrier function and tight junction protein
expression
2. Bifidobacterium reduces the intestinal permeability of preterm infants and children with
atopic dermatitis
3. Probiotic supplementation reduces bacterial translocation and intestinal permeability in
adults after colorectal surgery
C. Increase Mucin Production
1. VSL#3 enhances expression of mucin-related genes and increases mucus production in
rat colonic epithelium

2. Probiotics may enhance the protective mucous layer of the gut in humans, decreasing
contact of luminal contents with epithelium to limit immune reactivity
D. Secrete/Stimulate antimicrobial substances
1. Lactobacilli and VSL#3 enhance secretion of antimicrobial β-defensin by human
enterocytes
2. Lactobacilli produce bacteriocins, antimicrobial substances which inhibit growth of
pathogenic bacterial species
E. Displace pathogenic species
1. Addition of probiotic bacterial strains significantly lowered the adherence of pathogenic
bacteria to pig intestine and to intestinal mucus in human models
F. Decrease pH (lactic acid production):
1. Probiotic bacteria produce lactic acid and short chain fatty acids, lowering intestinal pH
2. Environment created is less supportive of pathogenic species
G. Short-chain fatty acid (SCFA) production:
1. SCFA (butyrate, acetate, propionate) are produced from probiotic fermentation of di-
etary fiber and prebiotics
2. SCFA provide 60%–70% of the energy needs of colonocytes
3. Decreased colon pH is less favorable for pathogenic species
4. Butyrate has antiproliferative effects on cells, and is thought to be protective against
colon cancer
5. SCFA stimulate intestinal motility
H. Manufacture vitamins
1. Several vitamins are byproducts of probiotic organisms: riboflavin, folate, B12 and some
vitamin K
I. Aid in digestion
1. Probiotic bacteria contain α and β-galactosidase activity that break down nondigestible
carbohydrate in the colon, creating SCFA.
2. Probiotic supplementation increases β-galactosidase activity in intestine and decreases
symptoms of lactose intolerance
J. Increase stool bulk
1. Bacteria comprise 30%–50% of the dry weight of stool promoting regular defecation
K. Promote motility
1. Probiotic bacteria interact with the enteric nervous system impacting motility
2. Germ-free and postinfectious animal models have intestinal motility disturbances, which
resolve with probiotic administration
3. Bifidobacterium supplementation has been shown to reduce colonic transit times in
adults
L. Detoxify toxic compounds
1. Probiotic bacteria decrease NH3 production in the intestine by displacing urease-produc-
ing species and increasing NH3 excretion
2. Probiotics help prevent hepatic encephalopathy in this manner
3. S boulardii is an effective treatment and preventive for C difficile infection. It secretes a
protease that cleaves C diff toxin A, and prevents binding to toxin receptor, as well as
increasing host anti-toxin immunoglobulin production
M. Promote humoral immunity and production of IgA
1. Probiotic supplementation increases IgA production in the infant
2. Higher intestinal IgA levels are associated with decreased risk of developing atopic
disease
3. LGG supplementation increases IgA production in children with atopic disease and with
acute gastroenteritis
4. LGG supplementation enhances immunogenicity of rotavirus and salmonella vaccines
N. Promote immune tolerance/decrease inflammation
1. The response to intestinal flora is immunologic tolerance
2. In the healthy host, there exists a balance of T-cell subtype mediated responses.
Excessive response of either subtype may lead to disease, with excess Th1 activity
promoting autoimmune disease and excess Th2 activity promoting atopic disease
3. In vitro and in vivo models show that probiotic bacteria increase the antiinflammatory
cytokines IL-10 and TGF-β, and increase the number of Treg cells in animal and human
subjects. IL-10 specifically ↑ Treg activity and promotes immune tolerance and suppresses
inflammation
IV. Clinical Applications
A. IBD
1. In newly diagnosed, relapsing or refractory ulcerative colitis, VSL#3 has been effective in
reduction of disease scores and achievement and maintenance of remission
2. DBPCT of VSL#3 as adjunct to standard therapy shown to be effective in induction and
maintenance of clinical and endoscopic remission in UC
3. Efficacy in Crohn disease not proven
B. Pouchitis
1. Strong evidence for effectiveness of VSL#3 in prevention and treatment of pouchitis in
children with ileal pouch anal anastomosis
2. Cochrane database review supported use of VSL#3 in prevention and treatment of
pouchitis
C. Antibiotic-associated diarrhea
1. Cochrane Review (2007) showed benefit of Lactobacillus and S boulardii in preventing
antibiotic-associated diarrhea in adults, but not children
D. Recurrent C difficile infection
1. S boulardii is effective in prevention of recurrent C difficile infection in adults, but
meta-analysis of all literature (2007) showed insufficient evidence to recommend use
2. To date, there are very limited data in children
E. H pylori
1. Meta-analysis of S boulardii as adjunct to triple therapy for eradication of H pylori in
adults showed small, statistically significant increase in eradication rates and decrease in
side effects
F. Prevention/treatment of infectious gastroenteritis
1. Meta-analysis looking at four randomized controlled trials (RCT’s) of S boulardii in
treatment of acute diarrhea showed small but significant reduction in duration of
diarrhea in healthy infants and children
2. Similar results were found in a meta-analysis LGG supplementation in reduction of
diarrhea duration in healthy children
G. Prevention of NEC
1. Meta-analysis on the use of probiotics for prevention of NEC in preterm infants showed
very significant reduction of NEC incidence and mortality in infants receiving probiotics
(mostly bifidobacteria)
2. No increased in sepsis in patients on probiotics, and no adverse events
H. Irritable bowel syndrome
1. A single RCT on LGG use in children with IBS showed efficacy in reduction of symptoms
2. Several RCTs in adults have shown improvement in IBS symptoms with lactobacilli and
bifidobacterium species
3. A recent DBPCT crossover trial of VSL#3 in 59 children with IBS yielded significant
improvements in symptom score over placebo after 6 weeks
I. Constipation
1. Three RCTs in adults showed B lactis, L casei Shirota, and E coli Nissle 1917 improved
defecation frequency and stool consistency in constipated adults
2. No valid results in children
J. Allergies/atopic dermatitis
1. Meta-analysis (2008) showed some evidence supporting probiotic both pre- and post-
natal as a preventive for development of atopic disease, with a risk reduction as large as
61%
2. The evidence insufficient to recommend probiotics as treatment for active atopic derma-
titis
3. Recent RCT of 90 children atopic dermatitis found that a mixture of L acidophilus and B
lactis with FOS for 8 weeks improved disease scores

V. Contraindications
A. Probiotics are generally considered safe for healthy children
B. Bacteremia and fungemia have occurred in immunocompromised patients and/or patients with indwelling central
venous catheters
C. Rare cases of lactobacillus sepsis are reported in the neonate but none have been tied to use of probiotics
D. Fungemia has occurred in immunocompromised patients receiving S boulardii. Distinguishing between S cerevisiae
and S boulardii may be difficult and absolute verification of infectious species could be questioned
Recommended Reading
Collado MC, Meriluoto J, Salminen S. Role of commercial probiotic strains against human pathogen adhesion to intestinal
mucus. Lett Appl Microbiol. 2007;45(4):454-460.
Floch MH. Recommendations for probiotic use--2008. J Clin Gastroenterol. 2008;42:S104-S108.
Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev
Gastroenterol Hepatol. 7(9):503-514.
Holubar SD. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane
Database Syst Rev. 6:CD001176.
Michail S. Clinical efficacy of probiotics: review of the evidence with focus on children. J Pediatr Gastroenterol Nutr.
2006;43(4):550-557.
Montalto M. Management and treatment of lactose malabsorption. World J Gastroenterol. 2006;12(2):187-191.
Ng SC. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis. 2009;15(2):300-310.
Penders J. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006; 118(2):511-521.
Rosenfeldt V. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic
dermatitis. J Pediatr. 2004;145(5):612-616.
Ruemmele FM. Clinical evidence for immunomodulatory effects of probiotic bacteria. J Pediatr Gastroenterol Nutr.
2009;48(2):126-141.
Schlee M. Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2. Clin Exp Immunol. 2008;151(3):528-535.
Verdu EF. Probiotics effects on gastrointestinal function: beyond the gut? Neurogastroenterol Motil. 2009;21(5):477-480.
Wallace B. Clinical use of probiotics in the pediatric population. Nutr Clin Pract. 2009;24(1):50-59.
10C-11. Drugs—Anti-diarrheal Drugs
Adam Paul, DO
Samra Blanchard, MD
I. Overview
A. The use of anti-diarrheal agents should be considered with caution in pediatric patients:
1. Anti-diarrheal/anti-motility agents are not recommended for any child at any age with
an acute infectious diarrhea
2. Avoid using anti-diarrheal/anti-motility drugs in infectious colitis. There are rare reports
of toxic megacolon
3. Anti-motility agents have been suspected (but not proven) to increase the risk of
hemolytic-uremic syndrome in children with E coli O157-H7 infection
II. Peripheral Opioid Agonists

A. Loperamide (Immodium®)
1. Mechanism: Mu opioid receptor agonist active in the myenteric plexus of the colon with
anti-nociceptive and anti-motility effects
2. Prolongs intestinal transit time, increases stool viscosity, reduces fecal volume and
increases anal sphincter tone
3. Pediatric dosage: Not recommended under 2 years of age (fatal paralytic ileus reported)
a. 13–20 kg 1 mg TID
b. 20–30 kg 2 mg TID
c. >3 kg 2 mg TID
4. Side effects: lethargy, respiratory depression, ileus
B. Diphenoxylate-atropine (Lomotil®, Elmotil®, Lo-Quel®)
1. Opioid-anticholinergic combination
a. Atropine added to decrease abuse potential
b. Not recommended in children <4 years because of serious toxicities: respiratory
depression, cerebral edema, aspiration pneumonia and death
2. Actions
a. Decreases smooth muscle contractions of the stomach and intestines
b. Prolongs intestinal transit time
3. Pediatric dosage: 0.3–0.4 mg/kg/day divided in 4 doses
III. Anti-secretory Agents

A. Octreotide – Somatostatin analog
1. Action
a. Inhibits release of vasoactive intestinal polypeptide, thereby inhibiting secretion of
electrolytes and water in the pancreas, small and large bowel
b. May also increase intestinal absorption
c. Some inhibition of motor activity in stomach, small intestine and gallbladder
2. Used in diarrhea secondary to ileostomy losses, congenital microvillus atrophy, idiopathic
secretory diarrhea, Zollinger-Ellison syndrome, AIDS-related diarrhea, and multiple
endocrine neoplasia-2A
3. Adverse effects: may effect growth (inhibits release of growth hormone) and increase
incidence of gallstones, by inhibiting gallbladder and sphincter of Oddi motility
4. Pediatric patients tolerate doses of 3–40 mg/kg/day SQ, IM or IV
B. Anticholinergics: Scopolamine, Hyoscyamine, Dicyclomine
1. Mechanism: blocks action of acetylcholine in smooth muscle by competitive inhibition
2. Action: reduces amplitude of gastrointestinal contractions
3. Use is limited due to side effects: dry mouth, blurred vision, tachycardia, urinary
retention, somnolence
4. Reports of toxicity in children: seizures, coma, death
C. Clonidine: Alpha-2-Adrenergic Agonist
1. Action: stimulates intestinal alpha-2 adrenergic receptors and increases mucosal
absorption

2. Cardiovascular and central nervous systems side effects, including hypotension and
autonomic neuropathy, limit usefulness
3. Limited benefit in patients with diabetic diarrhea and diarrhea related to opioid
withdrawal
4. No current pediatric studies determining efficacy and safety
D. Bismuth Subsalicylate
1. Exact mechanism not been determined:
a. May stimulate absorption of fluid and electrolytes across the intestinal membrane
b. When hydrolyzed to salicylic acid, may inhibit production of prostaglandin
responsible for intestinal inflammation and hypermotility
2. Dose: 100 mg/kg/24 hours divided in five equal doses for 5 days. Maximum daily dose
is 4 g/24 hours
3. Side effects: constipation, vomiting, gray-black discoloration of stool
4. Concurrent use of bismuth subsalicylate and methotrexate may result in methotrexate
toxicity (hemorrhage, anemia, septicemia) due to decreased renal elimination
5. Not recommended in children with flu-like symptoms or chicken pox due to increased
risk of Reye syndrome. Use with caution in patients with bleeding disorders or impaired
renal function
E. Cholestyramine
1. Useful in diarrhea associated with bile acid malabsorption
2. Action: binds with bile salts in the intestine, leaving them unable to promote secretion
of water and electrolytes in the colon
3. Dose:
a. Child: 240 mg/kg/24 hours divided TID; doses normally do not exceed 8 g/24
hours
b. Adult: 3–4 g BID-QID
4. Adverse effects: abdominal discomfort, constipation, flatulence, nausea and vomiting.
Possible electrolyte disturbances
F. Racecadotril (Acetorphan)
1. Enkephalinase inhibitor
a. Enkephalins are endogenous opioid peptides that act on gamma-opiate receptors
in the gut, reducing hypersecretion of water and electrolytes
b. Enkephalins also act on mu opioid receptors and inhibit peristalsis
c. Enkephalins are rapidly degraded by enkephalinases.(endopeptidases)
2. Action: racecadotril is diesterified into thiorphan, which inhibits enkephalinase A
3. Optimal dosing for children has not been determined
a. Usual effective dose in clinical trials is 1.5 mg/kg TID until resolution (not to
exceed 5 days)
Recommended Reading
Custer J, Rau R, eds. The Harriet Lane Handbook. 18th ed. Philadelphia, PA: Elsevier Mosby; 2009.
Huijghebaert S. Racecadotril versus loperamide. Dig Dis Sci. 2003;48:239-250.
Thomas T. Are one or two dangerous? Diphenoxylate-atropine exposure in toddlers. J Emerg Med.
2008;34:71-75.
10D. Therapeutic Endoscopy
Robert Kramer, MD
I. Purpose
Endoscopy can be used to locate and treat gastrointestinal lesions including strictures, varices, ulcers,
foreign bodies and polyps. In addition, endoscopy can be used to place or modify the position of enteral
feeding devices.
II. Variceal Bleeding

A. Esophageal variceal bleeding accounts for 5%–11% of gastrointestinal bleeding in children (see
section on Portal Hypertension)
1. Esophageal varices grading
a. Grade I : disappear with air insufflation
b. Grade II: nonconfluent varices remain unchanged with insufflation
c. Grade III: large, tense varices protrude into the esophageal lumen
d. Grade IV: varices with near complete obstruction of the lumen, impending
hemorrhage, cherry red spots
B. Portal hypertensive gastropathy is seen in both cirrhotic and noncirrhotic portal hypertension.
Cirrhosis accounts for >90%. Portal hypertensive gastropathy can be treated with argon plasma
coagulation (see section on Ulcer Treatment)
1. Endoscopic findings vary with severity of hypertension, from a mosaic pattern of
erythematous patches separated by a white lattice to cherry red spots or diffuse
hemorrhage
III. Endoscopic Treatment of Variceal Bleeding

A. Current endoscopic therapy techniques allow for control of bleeding in 85%–90% of cases
B. Bleeding varices should be treated with therapeutic endoscopy when they are not responding the
conservative clinical management
C. Patients with a recent history of upper GI bleed or known varix progression should have prophy-
lactic treatment to prevent additional bleeding events
1. Sclerotherapy:
a. Sclerosants: polidocanol, sodium morrhuate, ethanolamine oleate and hypertonic
saline. Ethanolamine is most readily available and commonly used
b. Flexible catheter with a 25-gauge needle is used for the injections
c. Where to inject:
1) First injection of 1–2 ml should be placed intravariceal with the needle
held in place for hemostasis
2) Up to 10 mls of the solution divided into 4–5 injections may be used
d. Timing: sclerotherapy can be used in an acute bleeding situation or for treatment
of known varices
e. Mechanism: thrombosis of varix and inflammation in the surrounding mucosa
f. Advantages:
1) Injection catheter fits in diagnostic and neonatal endoscopes
2) Recurrent intubation with endoscope is not required
3) Rapid thrombus formation
g. Disadvantages:
Section 10 -Therapy 531

1) Dysphagia
2) Ulceration can be seen in up to 20%
3) Bacteremia may occur in 35%
4) May result in strictures, perforation, mediastinitis, motility disorders
2. Endoscopic band ligation:
a. Band: elastic bands are placed on the varices to cause thrombosis. Typically,
the maximum number is 4–5 per session. Single and multiple band devices are
available
b. Where: start with the distal varices and progress to proximal
c. Timing: at the time of the bleed or to treat known varices. May repeat every 2–4
weeks to reduce risk of rebleeding
d. Mechanism: necrosis of the mucosa resulting in superficial ulceration and scar
formation
e. Advantages:
1) Fewer side effects than sclerotherapy
2) Technically easier to perform
f. Disadvantages:
1) Dysphagia and chest pain
2) May require multiple intubations
3. Balloon Tamponade
a. Pneumatic compression of the fundus and lower esophagus stops bleeding in
85% of adults
b. Sengstaken-Blakemore tube
1) Pediatric and adult sizes are available
2) Maximum pressure for Pediatric SBT is 35 mm Hg
a) Should not be kept in place for prolonged periods due to risk of
ischemic injury (max 24 hours)
c. Recurrence at deflation is high. Risks of aspiration pneumonia and perforation
are high
IV. Nonvariceal Bleeding

A. Ulcers can be primary or secondary to systemic illness. Primary peptic ulcers may be due to peptic
ulcer disease, H pylori and Zollinger-Ellison syndrome (see section on Gastritis)
B. The endoscopic appearance of the ulcer provides prognostic information on rebleeding and
mortality
1. High risk: active bleeding, non-bleeding visible vessel
2. Moderate risk: adherent clot, oozing ulcer
3. Low risk: pigmented flat spots
C. Therapeutic endoscopy should be used to treat nonvariceal bleeding when adequate hemostasis
is not acquired with conservative medical therapy or in high-risk lesions (actively bleeding and
non-bleeding visible vessel)
D. Endoscopic techniques: injection therapy, thermal therapy and mechanical therapy
1. Injection
a. Injection of a sclerosing agent at 3 or 4 sites around an exposed bleeding vessel
and then directly at the site of the vessel
b. Sclerosing agents include epinephrine, hypertonic saline, absolute ethanol and
thrombin. Use a single agent to reduce complications
c. Combination of normal saline and 1:1,000 epinephrine (9 ml saline:1 ml epi)
combined with thermal therapy is most effective
d. Advantages: most effective treatment when used with thermal therapy
e. Disadvantages: complications include ulcer with necrosis, bleeding, ischemia and
perforation. Injection can be technically challenging
E. Thermo-coagulation
1. Thermo-coagulation options include heater probe, monopolar and bipolar coagulators
a. Heater probe is a Teflon-coated hollow cylinder with an interior heater coil. Heat
is delivered via conduction. Applied around bleeding site and then directly on it
1) Advantage: water perfused to prevent tissue adhesion
2) Disadvantage: can cause ulceration
b. Monopolar probes provide a continuous current from the probe tip to the
grounding pad. The current generates heat and results in coagulation. Vessels <1
mm may be directly coagulated. Vessels >1 mm should first be approached with
circumferential coagulation followed by placement on the vessel or base of the
ulcer
1) Advantage: direct or tangential contact
2) Disadvantage: diffuse tissue injury, difficult to control depth, tissue
adherence
c. Bipolar probes do not require a grounding pad. The energy is transmitted from
one electrode to another at the tip of the probe. First tamponade the vessel, then
apply current around the area and then again directly to the vessel or ulcer base
1) Advantage: no grounding plate, tangential or direct contact, lower
temperature than monopolar, Teflon tip avoids adherence to mucosa
2) Disadvantage: risk of perforation
2. Argon plasma coagulation
a. High-frequency monopolar current is conducted via ionized argon gas. This
modality allows for treatment of large areas. A grounding pad is required to
complete the circuit
b. Depth is dependent on power setting, argon flow rate, duration of application,
and distance from probe to target tissue
c. Useful for superficial ectasia, postpolypectomy bleeding, hemostasis of bleeding
ulcers and tissue ablation
1) Advantage: superficial injury, use for large areas
2) Disadvantage: can inflate submucosa with argon gas, resulting in
pneumatosis; can’t use if large volume of fluid at site
F. Endoscopic hemostatic clips are used primarily for hemostasis. They also have uses for anchoring
feeding tubes and catheters to the bowel wall, fistulae closure. For ulcer closure, the first clip
is placed directly on the bleeding vessel, and then several others can be deployed into the
surrounding tissue
1. Advantage: theoretical advantage in patient with coagulopathy, minimal risk of perfora-
tion
2. Disadvantage: difficult to place
V. Gastrointestinal Stricture
A. Dilation
1. Esophageal strictures are often very debilitating. Stricture dilation can provide prompt
resolution of symptoms, but has a significant risk for perforation (1%–3%)
2. Indications for therapeutic esophageal stricture dilation include ability to directly visualize
stricture, allowing for proper selection of equipment and evaluation for tissue disruption
following dilation
a. Three modalities: bougie, pneumatic, and stents
b. Bougie dilators: a series of tapered, flexible rods that are either blindly passed
through the esophagus or passed over a guidewire
1) Savary-Gilliard dilators are advanced over a wire that is first placed under
direct endoscopic visualization
2) Maloney dilators are weighted and do not require a guidewire
3) Serial dilations are performed with increasing bougie size. The bougie
dilators apply longitudinal shearing forces, as well as radial force to dilate
the stricture. These are appropriate for single, distal strictures than can be
traversed by the endoscope
c. Pneumatic balloon dilators are passed through the endoscope
1) As the balloon is inflated with radiopaque dye, it applies isolated radial
forces, allowing for dilation
2) The dilation can be monitored with fluoroscopy. Most balloons have three
dilation diameters, depending on the amount of pressure applied during
dilation
3) Balloon dilators vary in terms of length of balloon and presence of a
guidewire
4) Pressure typically held for 60 seconds at each dilation diameter

5) Useful for eosinophilic esophagitis, epidermolysis bullosa, esophageal
atresia postoperative strictures, achalasia and strictures of recent onset
d. Expandable covered stents are implantable devices designed to provide constant
dilation pressure for the duration of their placement
1) Available as plastic mesh or metal alloy (Nitinol)
2) Placed under endoscopic and fluoroscopic guidance across stricture
3) Covered with silicon to prevent ingrowth of tissue into mesh
4) Endoscopically removed after 1–4 weeks
5) Attempt to recast scar tissue of stricture into a larger diameter
3. Esophageal perforation appears to be more related to the underlying medical condi-
tion than the technique used (eosinophilic esophagitis or caustic ingestion higher risk vs
peptic stricture lower risk)
B. Endoscopic therapy adjuncts
1. Corticosteroid injection: injection of triamcinalone into four quadrants of stricture
using sclerotherapy needle has been effective in decreasing the frequency or need for
subsequent dilations
2. Mitomycin–c application to esophageal strictures has been shown to decrease need for
dilations in refractory cases
VI. Intestinal Polyps (see section on Polyps)

A. Most polyps in the pediatric population are juvenile polyps with no potential for malignancy, but
with an association with iron deficiency anemia
B. Indications for polypectomy include screening for dysplasia in familial polyposis syndromes and
removal of juvenile polyp associated with anemia and hematochezia
C. Technique by size
1. Small polyps of 5 mm or less can be removed with biopsy forceps
a. Routine forceps followed by coagulation or hot biopsy forceps may also be used
2. Polyps of >5 mm are removed with snare electrocautery. The snare should be placed
closer to the polyp head than the bowel wall
3. Polyps of >2 cm will need to be removed piecemeal
4. Power settings on electrocautery generator may be adjusted for polyps in different areas
of GI tract (i.e., lower settings for small bowel and right colon)
5. Use of cutting and coagulation settings for the snare results in decreased bleeding. The
cutting current, when used alone, is more likely to result in bleeding
6. Placement of a hemostatic clip may be the most effective way to achieve hemostasis
from a bleeding stalk
VII. Gastrointestinal Foreign Body (see section on Esophageal and Gastric Foreign Body)
A. Gastric FBs may often be allowed to pass spontaneously if they are relatively small (<2 cm in
diameter or <5–7 cm in length) or smooth (i.e., most coins)
1. Sharp or pointed objects (i.e., nails, pins) will generally travel with the heavier, blunt end
first, making perforation risk small
2. Toothpicks can be particularly dangerous, as they are not visualized radiographically, can
harbor large numbers of bacteria, and have been known to perforate the intestine and
migrate out of the bowel
3. Benign objects that have not spontaneously passed after 1–2 weeks may be removed
endoscopically, though a repeat X-ray immediately prior to endoscopy is advised
VIII. Enteral Feeding Tube Placement

A. Endoscopy can be used for initial placement or revision of previously placed enteral feeding
devices
B. Percutaneous Endoscopic Gastrostomy (PEG) Placement
1. Utilized for primary placement of a gastrostomy tube
a. Relative contraindications: abnormal abdominal anatomy (malrotation, adhesions,
severe scoliosis, etc), significant reflux/need for fundoplication, obesity/thick
abdominal wall
C. Conversion of gastrostomy to transpyloric/gastrojejunostomy tube
1. Various methods exist, but often best accomplished by passing neonatal scope through
prior gastrostomy tract (> 15 Fr) and into small bowel under fluoroscopy, passing
guidewire through scope, pulling scope off guidewire, then threading new GJ tube over
wire
D. Placement of nasojejunal feeding tube
1. NJTs that cannot be placed by radiology may be placed endoscopically
2. Attaching suture to end of NJT and dragging it along with scope into small bowel is
fairly easily accomplished. Challenge is removal of endoscope without dislodging tube
a. Consider small scope to decrease drag on tube
b. Consider clipping device to affix tip of tube in place
Recommended Reading
Cardenas A. Management of acute variceal bleeding: emphasis on endoscopic therapy. Clin Liver Dis.
2010;251-262.
Draganov PV. Colonoscopic polypectomy and associated techniques. World J Gastroenteroly 2010;3630-
3637.
Kay MH, Wyllie R. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. J Pediatr Gastroenterol
Nutr. 2007;157-171.

11A. GI Manifestations of
Psychologic Disorders
Meredith Hitch, MD
Robert Rothbaum, MD
I. Psychogenic Associations
Many psychological disorders have associated gastrointestinal manifestations. While evaluating a child
for chronic abdominal pain, it is important to consider psychologic as well as organic etiologies for the
symptoms
II. Mood Disorder and Anxiety—Chronic Abdominal Pain

A. There is a vicious cycle involving chronic pain, depression, and anxiety, each provoking the other
B. Anxiety disorder is found in 80% of children with recurrent abdominal pain (RAP) in
some studies
C. Depressive symptoms found in 40% of children with RAP
D. Possible explanations
1. Pain evokes mood and anxiety disorders
2. Affective disorders cause or exacerbate pain
3. A common biological predisposition underlies both problems
4. Common characteristics of both include somatization, social stress, and poor coping
E. Life stressors provoke
1. Physiologic stress response with increased ccorticotropin-releasing factor (CRF)
2. CRF causes ↑ intestinal motility, hyperalgesia, psychoemotional inflammatory responses
F. Typical life stresses
1. Maternal separation
2. Conflicting maternal relationships
3. Abusive environments – sexual or physical
4. Traumatic events – death, major illness, geographic dislocation
5. Marital discord
6. Peer pressure
7. Perfectionism
III. Pathologic Aerophagia—Abdominal Distension

A. Symptoms: eructation, abdominal cramping, flatulence, chronic diarrhea
B. Tympanitic abdomen with very hyperactive bowel sounds
C. Plain abdominal film showing uniform gassy distension from esophagus to rectum, without air
fluid levels
D. Hallmarks:
1. Increasing abdominal distension throughout the day
2. Increased flatus at night
E. Visable air swallowing is often subtle and hard to detect
F. Signs of abuse or stress
IV. M
ental Retardation/Anxiety/Obsessive Compulsive Disorder (OCD) —
Solitary Rectal Ulcer Syndrome
A. Presentation:
1. Recurrent rectal bleeding
2. Mucous discharge from the anus
3. Prolonged straining to pass stool
4. Tenesmus
Section 11 - Psychologic Considerations 537

5. Perineal pain
6. Rectal prolapse
a. Secondary to excessive straining during defecation
b. Intraabdominal pressure forces the anterior rectal mucosa firmly into the
contracting puborectalis muscle
c. The anterior rectal mucosa is frequently forced into the anal canal, and as a
consequence becomes strangulated, causing congestion, edema, and ulceration
B. Differential Diagnosis
2. Infectious proctocolitis
3. Intussusception
4. Hemorrhoids
5. Prolapsing rectal polyp
6. Sexual abuse
C. Diagnosis
1. History – straining, constipation, prolapse, self-digitization to induce stools
2. Proctosigmoidoscopy and histology
D. Histology
1. Fibromuscular obliteration of the lamina propria with disorientation of muscle fibers
2. Mucous-laden macrophages
3. Histologic changes are secondary to chronic mechanical and ischemic trauma,
inflammation by hard stools, and intussusception of the rectal mucosa
E. Self-digitization maneuver to reduce a rectal prolapse or to evacuate an impacted stool may also
cause direct trauma and ulceration
1. Behavioral aspect
2. Self-stimulating
3. Habitual
4. Associated with obsessive compulsive disorder
5. Associated with Prader-Willi syndrome
F. Treatment is conservative
1. Fiber, stool softeners and retraining to avoid straining
2. Rectal medications with local anti-inflammatory effect - sucralfate, 5-ASA,
corticosteroid, mesalazine, topical fibrin
3. Behavior modification therapy by biofeedback in adults is associated with symptom
improvement in 75% of patients with uncoordinated defecation habits, excessive
straining, and high rectal sensory threshold
V. Trichotillomania—Abdominal Pain, Vomiting and Abdominal Mass

A. Usually associated with underlying psychiatric disorders
B. Most commonly age of presentation is adolescence
C. 1% of patients with trichophagia develop a trichobezoar
D. Association with early childhood neglect or abuse, psychiatric conditions, mental retardation or
bereavement
E. Presentation
1. Abdominal pain
2. Nausea, vomiting, halitosis
3. Obstruction
4. Peritonitis
5. Less common: weight loss, anorexia, hematemesis, and intussusception
6. Complications by a large eroding or obstructing bezoar
a. Gastric ulceration
b. Obstructive jaundice
c. Acute pancreatitis
d. Gastric emphysema
7. Malabsorption-related complications: protein-losing enteropathy, iron deficiency, and
megaloblastic anemia
F. Pathophysiology
1. Trichobezoars form when slippery hair strands escape peristaltic propulsion and are
retained in the stomach
2. As hair accumulates, peristalsis causes it to be enmeshed into a ball
3. If the ball becomes too large to exit the stomach, gastric atony may result
4. Hair ball assumes shape of stomach
5. Rapunzel syndrome: trichobezoar extending from the stomach to the small intestine
G. Treatment
1. Surgical removal
2. Pharmacotherapy: fluoxetine or other serotonin reuptake inhibitors
3. Parental counseling
4. Long-term prognosis good when medication is combined with behavioral therapy
Recommended Reading
A rare and often unrecognized cause of hematochezia and tenesmus in childhood: solitary rectal ulcer syn-
drome. Pediatrics 2002;110;e79.
Psychosocial functioning in children and adolescents with gastrointestinal complaints and disorders. J Clin
Psychol Med Set. 2010;17(2):159-166.
Rapunzel Syndrome: A Comprehensive Review of an Unusual Case of Trichobezoar. Clin Med Res. 7;3:99-
102.
Solitary rectal ulcer syndrome in children. Eu J Gastroenterol Hepatol. 2008;20: 2.

11B. Rumination
Meredith Hitch, MD
Robert Rothbaum, MD
I. Definition
Rumination is a syndrome characterized by repeated regurgitation of gastric contents followed by spitting
or re-swallowing. Rumination may be difficult to differentiate from true vomiting
II. Rumination
A. Clinical definitions
1. Infant rumination– repetitive contractions of abdominal muscles, diaphragm, and tongue
that produce regurgitation of gastric contents into the mouth, after which oral contents
are rechewed, reswallowed, or expectorated
a. Onset 3–8 months
b. No nausea or distress
c. Does not occur during sleep
d. Not responsive to acid suppression, anticholinergics, formula change,
gastrostomy, or gavage
e. Infant rumination often occurs in the setting of child neglect or sensory
deprivation, and is thought to represent a self-stimulatory behavior
2. Adolescent rumination–repeated painless regurgitation with rechewing, or expectora-
tion of gastric contents occurring soon after eating, in the absence of retching
a. Does not occur during sleep
b. Usually begins within 30 minutes of a meal, and ceases when gastric acidity is
restored (usually within 90 minutes of a meal)
c. Unresponsive to acid suppression
d. No organic basis determined on radiologic or endoscopic evaluation–no
obstruction
e. Motility studies show normal postprandial antral activity. May reveal marked
increase in intraabdominal pressure just before regurgitation caused by voluntary
contraction of abdominal musculature
f. Episodes often preceded by burping
g. Adolescents may have a combination of true reflux and ruminative behavior
which makes diagnosis difficult
B. Statistics
1. Mean age of diagnosis in adolescent rumination is 15 years
2. Average duration of symptoms prior to diagnosis is 2 years
3. 73% miss school or work
4. 46% have been hospitalized
5. 11% have had surgery for the complaint before diagnosis
6. 16% have a comorbid psychiatric diagnosis
C. Abnormal motility findings associated with rumination that may promote rumination, but are not
the sole etiologic mechanism
1. Gastric sensitivity to distension is higher than normal
2. Frequency of relaxations of the lower esophageal sphincter after distension is higher
than normal
3. Postprandial gastric accommodation is decreased
D. Treatment
1. Identify triggers for the behavior
2. Exclude affective disorders
3. Infants often respond to increased parental attention and stimulation. No medical or
behavioral therapy is needed

4. Therapeutic options in adolescents
a. Cognitive behavioral therapy with biofeedback
b. Relaxation techniques
c. Distraction
d. Antidepressants, anxiolytics if indicated
Recommended Reading
Chial H. Rumination syndrome in children and adolescents: Diagnosis, treatment and prognosis. Pediatrics.
2003;111:158-162.
Van den Plas Y. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the Eu-
ropean Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol
Nutrition. 2009;49:498-547.
11C. Feeding Refusal and
Psychogenic Dysphagia
Meredith Hitch, MD
Robert Rothbaum, MD
I. Overview
Feeding refusal is a challenging diagnosis that is associated with several underlying organic conditions.
There are specific behaviors that are associated with feeding refusal, and when present they assist
with diagnosis. Psychogenic dysphagia should also be considered in the diagnosis of feeding refusal,
particularly in older children.
II. Feeding Refusal

A. Definitions
1. Child refuses to eat most foods, resulting in failure to meet nutritional needs
2. Specific behaviors associated with food refusal
a. Head turning, mouth closure, tongue thrust, spitting out food
b. Food packing
c. Excessive dawdling
d. Gagging, vomiting during feeding
e. Anticipatory gagging
f. Requires distraction to be fed (TV, video)
g. Shows no interest in food
B. Common associated organic conditions
1. GE reflux
a. Found by testing in 53%–69% of patients with food refusal
b. Although found frequently in association with food refusal, it is rare that GE
reflux is the cause of food refusal
2. Pseudo-obstruction, achalasia, cricopharyngeal achalasia, and GI dysmotility
3. TEF, laryngopharyngeal cleft, or other lesions causing aspiration
4. Cardiopulmonary conditions, especially congenital heart disease
5. Bronchopulmonary dysplasia
6. Neurologic conditions
a. Cerebral palsy – increased or decreased tone delays acquisition of feeding skills
and produces fear of eating
b. Autism – heightened texture and taste sensitivity limits food choices
7. Anatomic anomalies causing aspiration or other negative experiences with eating
a. Cleft lip and palate
b. Microgastria
c. Duodenal web, gastric outlet obstruction, duodenal stenosis
d. Vascular ring
8. Traumatic experience – choking, aspiration, forced feeding by caregiver
C. Development of feeding behavior
1. There is a critical window during, newborn period to establish oropharyngeal
coordination with deglutition. If normal deglutition is not established during this critical
time, food refusal may result
2. Normal feeding behavior depends on successful integration of both physical and
emotional factors. Disruption in either may precipitate feeding refusal
3. 25%–45% of normal children and up to 80% of developmentally delayed children
experience some feeding disorder

D. One authority suggests the diagnosis of feeding refusal disorder can be made based on three
criteria below in the absence of organic disease
1. History of food refusal
2. Pathological feeding
a. Able to feed only when child is somnolent
b. Persecutory feeding – unrelenting parental attempts to feed
c. Forceful feeding
d. Mechanistic feeding – rigid schedule and quantity unrelated to hunger cues
e. Use of distraction as only means to accomplish feeding (TV, video)
3. Anticipatory gagging
E. Treatment of food refusal
1. Multidisciplinary approach involving primary care doctor, pediatric GI, developmental
pediatrician; speech, physical, and occupational therapy; nutritionist, psychologist, family
counselor
2. Supervised behavior modification for child
3. Modification of caregiver responses
a. Eliminate parental coaxing, pleading, yelling
b. Ignore child’s negative behaviors
c. Reward child’s appropriate behaviors
4. Techniques
a. Positive rewards for good behavior – utensil use, eating, quiet behavior
b. Consistency, e.g., re-presenting of food that has been spit out or thrown by child
c. Hunger provocation by spacing out meals, or supervised temporary calorie
restriction or limitation of milk
d. Swallow induction – limiting tongue thrust and packing
e. Smaller meals to increase chances of success
III. Psychogenic Dysphagia

A. Common characteristics
1. Fear of swallowing, particularly solid or lumpy food
2. Globus sensation before or during swallowing
3. Fear of gagging or vomiting leads to verbal and physical food refusal
4. No abnormal body image, as in anorexia nervosa or bulimia
5. Often, a traumatic event precedes onset
6. Occurs in older children with previously normal eating behavior
B. Clinical diagnosis of psychogenic dysphagia
1. Normal physical examination
2. Normal neurological examination
3. Normal swallowing of saliva
4. Compatible history
5. Some imaging studies may be helpful – modified barium swallow, upper endoscopy – to
rule out physical obstruction
C. Treatment
1. Cognitive behavioral therapy is most often effective
2. Pharmacologic therapy for associated depression, anxiety disorder may be required
Recommended Reading
Feeding and eating disorders in childhood. Int J Eating Dis. 2010;43:90-111.
Levine E. Screening criteria for diagnosis of infantile feeding disorders as a cause of poor feeding or food
refusal. JPGN. 2011;52:563-568.
Williams KE. Food refusal in children: A review of the literature. Res Devel Disab. 2010;31:625-633.
11D. Eating Disorders
Meredith Hitch, MD
Robert Rothbaum, MD
I. Overview
The pediatric gastroenterologist is often the first subspecialist to see a patient with an eating disorder.
Winsted and Willard reviewed the GI complaints in patients admitted for eating disorders, and found
that 62% had seen a gastroenterologist or primary care physician for GI complaints. Of these, 46% had
sought treatment for the gastrointestinal complaint before the diagnosis of eating disorder was made,
and 38% had undergone endoscopy and imaging studies for GI complaints.
II. DSM IV-TR Criteria for Anorexia Nervosa

A. Refusal to maintain body weight at or above lower normal limits of weight for age and height
B. Weight loss producing body weight <85% of expected, or failure to gain sufficient weight during
period of growth leading to body weight <85% of expected
C. Intense fear of gaining weight or becoming fat
D. Disturbance in body image. Undue influence of body weight or shape on self evaluation. Denial
of seriousness of low body weight
E. Amenorrhea (at least three consecutive cycles) in postmenarchal patients
F. Types of eating disorder
1. Restricting type: anorectic patient whose current underweight condition is a result of
caloric restriction not binge-eating or purging behaviors such as self-induced vomiting,
laxatives, diuretics or enemas
2. Binge eating purging type: anorectic patient who is currently regularly engaged in binge
eating or purging behaviors listed above
III. DSM IV-TR Criteria for Bulimia

A. Recurrent episodes of binge eating characterized by both:
1. Eating in a discrete period of time an amount of food larger than most people would eat
under similar circumstances
2. A sense of lack of control over eating during the episode
B. Recurrent inappropriate compensatory behavior to prevent weight gain
1. Self-induced vomiting
2. Misuse of laxatives, diuretics, enemas, or other medications
3. Fasting
4. Excessive exercise
C. Binge eating and compensatory behavior occur at least twice a week for three months
D. Self-evaluation is unduly influenced by body shape and weight
E. The disturbance does not occur exclusively during episodes of anorexia nervosa
F. Types
1. Purging type: During the current episode of bulimia nervosa, patient regularly uses
purging techniques: self-induced vomiting, laxatives, diuretics, or enemas
2. Nonpurging type: During the current episode of bulimia nervosa, patient uses
inappropriate compensatory behavior, but has not regularly engaged in
purging behaviors

IV. Medical Complications of Extreme Weight Loss and Undernutrition by System
A. Skin (all Eating Disorders)
1. Xerosis (dry scaly skin) secondary to decreased dietary fat
2. Lanugo-like body hair
3. Telegen effluvium (hair loss secondary to poor nutrition)
4. Acne secondary to hormonal imbalances
5. Carotenemia – carotene deposits in skin from increased ingestion of carotene containing
vegetables
6. Acrocyanosis – increased dilatation of efferent capillaries in extremities
7. Stomatitis or chelitis
B. Endocrine:
1. Type I diabetics who have bulimia often will abuse insulin for weight loss and can de-
velop hypoglycemic comas
2. Thyroid dysfunction
C. Gastrointestinal:
1. Anorexia nervosa
a. Gastric dilatation
b. Spontaneous gastric rupture
c. Mucosal necrosis (binge eating)
d. Delayed gastric emptying
e. Gastric motor dysfunction
f. Impaired sense of hunger/satiety
g. Delayed small bowel transit
h. Constipation
i. Pancreatitis
j. Necrotizing colitis
k. Perforated ulcer
2. Bulimia
a. Parotid gland hypertrophy
b. Gastritis
c. Acute liver damage
d. Enamel erosion
D. Cardiovascular/Pulmonary
1. Arrhythmias secondary to prolonged QTc interval and hypokalemia
2. Hypotension and orthostatic hypotension
3. Pneumomediastinum caused by vomiting
4. Anorexia: QT/RR slope is enhanced secondary to autonomic imbalance; can result in life-
threatening arrhythmia
5. Bradycardia:
a. Low Resting Energy Expenditure
b. Problematic with extreme exercise
6. Ampullary cardiomyopathy: akinesis of the apical region of the heart with compensatory
hypercontraction of the basal ventricular components
7. Myocardial atrophy
8. Mitral valve prolapse
9. Pericardial effusion
10. Sudden cardiac death
E. Skeletal: Osteopenia: etiology, course and effective treatments are uncertain
1. Osteopenia - etiology and outcome are uncertain
2. Treatment of osteopenia
a. Not recommended during acute phase of management
b. Bisphosphonates can improve bone density
c. Calcium and vitamin D supplements recommended
F. Mortality:
1. Marked risk of premature death in anorexia nervosa
2. Mean mortality risk is 10.5 (95% Confidence Interval= 5.5–15.5)
V. Medical Complications of Disordered Eating by Activity
A. Purging
1. Abnormal colonic motility
2. Arrhythmias
3. Cardiac and other myopathies
4. Dehydration
5. Dental caries
6. Electrolyte abnormalities caused by vomiting, laxatives, or diuretics
7. Gastrointestinal irritation, bleeding, or reflux
8. Parotid hypertrophy
9. Secondary renal failure
B. Appetite suppressant abuse
1. Anxiety
2. Hypertension
3. Tachyarrhythmia
4. Tremors
C. Metabolic complications of therapy – Refeeding syndrome
1. Onset within four days of refeeding
2. Etiology
a. Sudden increase in serum insulin after refeeding
b. Phosphorylated carbohydrate compounds in liver and skeletal muscle deplete
intracellular ATP and 2,3 diphosphoglycerate in red blood cells, causing
dysfunction and inadequate oxygen delivery
c. Increased basal metabolic rate
d. Intracellular movement of electrolytes, with associated decrease in serum
concentration
1) Hypophosphatemia
2) Hypokalemia
3) Hypomagnesemia
4) Hypoglycemia
5) Reduced serum thiamine
D. Clinical features of refeeding syndrome
1. Intracellular electrolyte shift and increased intravascular fluid increases cardiac workload
and heart rate. Heart failure and pulmonary edema may occur
2. Hypovolemia and hemoconcentration
a. Oxygen consumption increases, which increases the demand on the respiratory
system
b. Significant risks from refeeding syndrome – confusion, coma, seizures, death
E. Treatment monitoring in refeeding syndrome
1. A high index of suspicion in the early phase of refeeding syndrome is critical. Medical
therapy is most effective at this time
2. Correct electrolyte imbalances and monitor frequently
3. Supplement with multiple vitamin preparations, especially thiamine and
vitamin B complex
4. Maintain energy intake at 50%–70% of normal for the first 3–5 days
VI. Psychiatric Considerations in Eating Disorders

A. Family dysfunction
1. Overcontrolling parents
2. Parental substance abuse
3. Parental eating disorder
4. Sexual abuse by family member (15%)
B. Most patients have comorbid psychiatric conditions:
1. Depression
2. Anxiety
3. Personality disorders
4. Self-mutilation behaviors
5. Substance abuse

VII. Treatment
A. The chronicity and complexity of the comorbid conditions associated with eating disorders
makes treatment and management of these patients more appropriate for adolescent medicine
physicians, psychologists, and psychiatrists. The role of the pediatric gastroenterologist is to
recognize the condition, initiate appropriate evaluation, involve appropriate subspecialists for
ongoing management, and consult on GI comorbidities during therapy. The greater the patient’s
insight into the disorder, the better the chance of improvement at 6–12 months of therapy
B. Anorexia nervosa
1. Medication is less successful in anorexia nervosa than in bulimia nervosa. It is most often
used after weight has been restored, but may begin earlier when indicated
2. Selective serotonin reuptake inhibitors (e.g., fluoxetine) often used for depressive,
obsessive, or compulsive symptoms that persist in spite of or in the absence of weight
gain
C. Bulimia nervosa
1. Antidepressants are used primarily to reduce the frequency of disturbed eating, and
treat comorbid depression, anxiety, obsessions, and impulse-disorder symptoms
2. Medication can reduce binge episodes, but are not sufficient as sole therapy
3. The only medication approved by the US FDA for bulimia nervosa is the SSRI fluoxetine
4. Higher doses of fluoxetine may be needed to treat bulimia nervosa
Recommended Reading
Casiero D, Frishman, WH. Cardiovascular complications of eating disorders. Cardiol Rev. 2006;14: 227-231.
Mitchell JE, Crow S. Medical complications of anorexia nervosa and bulimia nervosa. Curr Opin Psychiatry.
2006;19:438-443.
Winsted NS, Willard SG. Frequency of physician visits for GI complaints by anorexic and bulimic patients. Am J
Gastroenterol. 2001; 96:1667-1688.
11E. Munchausen
Syndrome by Proxy
Javier J. Monagas, MD
Paul E. Hyman, MD
I. Overview
Munchausen syndrome by proxy (MSBP) is a factitious disorder in which the person caring for a child or
an adult with special needs, acts as if that child has a medical illness. This is considered a form of child
abuse. Factious disorders such as MSBP are mental illnesses.
II. Definition
A. Parent or caregiver fabricates symptoms of illness on behalf of an unsuspecting or helpless victim,
thereby causing the victim to be regarded as ill by others
B. Defining characteristics
1. Child’s symptoms produce repetitive or persistent interactions with health care providers,
often associated with multiple diagnostic and therapeutic procedures
2. Caregiver denies he/she is the cause of the child’s illness
3. Symptoms abate when the child is separated from the caregiver
III. Epidemiology
A. Prevalence unknown
B. Equal prevalence in male and female children
C. Average age at diagnosis 48 months
D. Average interval from onset of symptoms to diagnosis is 21 months
E. Some studies estimate mortality as high as 6%–10%
IV. Presentation
A. Usually presents with a recurrent symptom that has not been explained through testing—
e.g., vomiting, diarrhea, hematemesis, hematochezia, hematuria, multiple infections, apnea
spells, seizures
B. Patients with central lines or other indwelling medical appliances may have a history of frequent
infections or malfunctions
C. Specific diagnoses frequently made to explain symptoms include: intestinal pseudo-obstruction
or gastroesophageal reflux disease, seizures, malabsorption syndrome, immune deficiency,
urinary tract infection, epilepsy, bleeding disorder, metabolic disease
D. Successive siblings may be at risk
V. Characteristics of the Caregiver

A. Perpetrator is the biologic mother in 70% of cases
B. Perpetrator is knowledgeable about details of child’s symptoms and previous evaluations
C. If patient is hospitalized, caregiver rarely leaves the hospital
D. Caregiver is unusually comfortable with risky procedures or treatments, and calm despite
setbacks or inability of physician to find the correct diagnosis
E. Frequently, caregiver demonstrates an interest in health care profession or is a medical
professional or paraprofessional, or claims to be one
F. When caregiver is the mother, the father is often emotionally or physically unavailable
G. There is no consistent comorbid psychiatric diagnosis in the perpetrator

VI. Characteristics of the Physician Facilitator
A. The physician, by ordering tests and therapies, may perpetuate or aggravate MSBP
B. The role and the importance of a physician facilitator in MSBP is currently under active study
C. Preliminary descriptions of the physician facilitator include:
1. Subspecialist with an interest in unusual diagnoses, challenged by complex medical
mysteries
2. Subspecialist with tendency to use diagnostic testing
3. Physician may become defensive when approached with the possibility of MSBP
4. Physician may develop a very strong bond with the caregiver over the investigation and
care of the patient
VII. Diagnosis/Management
A. Document the patient’s symptoms. The diagnosis of MSBP must be added to the differential
diagnostic considerations if the history does not point to a specific diagnosis after preliminary
screening tests, and if characteristics of patient, caregiver, and symptoms are as outlined above
B. Order specific tests to confirm suspicions of abuse and maintain the chain of evidence: if a
specific cause is suspected, such as poisoning (e.g., insulin, salt, sedative, laxatives, emetics),
obtain confirmatory toxicology. If suffocation is considered, video surveillance should be initiated.
Failure to evaluate may result in continued dangerous abuse
C. Obtain information from previous evaluators in writing and in person: written records may not
contain the candid opinion by previous medical providers that MSBP has been suspected
D. Psychiatric or psychological assessment of the suspected perpetrator and family. Identification
and documentation of warning signs in caregiver and family members will be important in
validating concerns and putting the pieces together
E. Systematically assess the child’s condition. For example, if the child has “problems eating” or
“vomits all his food”, the child should be fed under direct supervision. If the child’s problems
have been fabricated, the child may improve dramatically upon separation from the caregiver
F. Be cautious about requests for performing new tests or repeating old tests
G. The Department of Children’s Protective Services must be notified if a diagnosis of MSBP is
suspected. Because this is a dangerous form of child abuse, separation from the caregiver may be
needed. Supervised foster care placement may be needed to prove that a child is healthy
H. Hospital admission for observation, review of medical records, and sequential withdrawal of
unnecessary medical therapies
VIII. Special Situations for Pediatric Gastroenterologists

A. Laxative abuse
1. Produces chronic diarrhea that can be hard to differentiate from organic causes
2. Examinations for fecal pH, osmolarity, electrolytes, blood, WBC, culture, and parasites
are usually normal or negative
3. Stool content of magnesium may be elevated if magnesium salts are used
4. Phenolphthalein may be detected by alkalinizing stool water (pink color develops).
Phenolphthalein is no longer used in commercially available laxatives in the US, but is
available elsewhere
5. Colonoscopy may show melanosis coli (dark submucous pigmentation seen with
anthracine derivatives)
6. Medical complications of laxative abuse include malnutrition, renal calculi, renal failure,
hypokalemia
B. GI bleeding
1. Caregiver complains of bright red blood per rectum
a. Monitor vital signs
b. Check hematocrit
c. Check the blood in the diaper by Hemoccult. Red dyes and tomato juice
may be used
d. Check excreted blood microscopically to determine source (caregiver, animals)
e. In some cases, blood may be drawn from a child’s vein or indwelling IV and
placed in the diaper
C. Vomiting
1. Exaggeration and fabrication of spit up or vomiting should be suspected:
a. If symptom reports are dramatic or inconsistent with the physical exam
b. If the medical history does not make sense
c. If the caregiver is the only one who witnesses the child vomiting
Recommended Reading
Bursch B, Hyman P. Gastrointestinal features of pediatric illness falsification. In: Kleinman RE, Goulet O-J,
Mieli-Vergani G, et al, eds. Walker’s Pediatric Gastroenterology Disease. 5th ed. Hamilton, Ontario: BC Decker
Inc.; 2008:1485-1492.
Galvin HK, Newton AW, Vandeven AM. Update on Munchausen syndrome by proxy. Curr Opin Pediatr.
2005;17:252-257.
Hyman PE, Bursch B, Beck D, et al. Discriminating pediatric condition falsification from chronic intestinal
pseudo-obstruction in toddlers. Child Maltreat. 2002;7:132-137.
Sheridan MS. The deceit continues: an updated literature review of Munchausen syndrome by proxy. Child
Abuse Negl. 2003;27:431-451.
Squires JE, Squires R. Munchausen syndrome by proxy: ongoing clinical challenges. J Pediatr Gastroenterol
Nutr. 2010;51:248-253.

12A. Abdominal Pain
Laurie Fishman, MD
I. Acute vs Chronic Abdominal Pain

A. Acute:
1. Acute abdominal pain is one of the most common childhood complaints
a. Often self-limited
b. Need to rule out life-threatening causes (i.e., intestinal obstruction, perforation or
hemorrhage)
c. Consider nongastrointestinal causes (i.e., genitourinary tract, infection or
extraintestinal conditions)
2. Obtain thorough history of symptoms and perform physical exam:
a. Is there emesis? If so, assess quality of emesis (bilious vs non-bilious; bloody vs
non-bloody)
1) Bilious emesis: consider obstruction (anatomic or functional)
2) Coffee ground or blood tinged emesis: consider some form of esophagitis,
gastritis, gastric or duodenal ulcer, Mallory-Weiss tear
b. What are the quality and frequency of patient’s stools? (hard vs soft vs watery;
bloody vs acholic vs melanotic)
1) Watery: consider infectious diarrhea etiologies or bowel inflammation
2) Harder stool (or decreased frequency): consider constipation
3) Melena: assess for an upper gastrointestinal bleeding lesion (i.e., gastric or
duodenal ulcer)
4) Bloody stools: assess for an anal fissure, hemorrhoid, inflammatory or
allergic colitis, polyp lesion, ischemic injury (NEC), intussusception (currant
jelly stools)
5) Acholic stools: assess for biliary or hepatic disease
3. Acute gastroenteritis is most common gastrointestinal inflammatory process in children
a. Often a viral process
4. Appendicitis is the most common surgically treated source of abdominal pain in children
Table 1. Differential Diagnosis of Abdominal Pain by Location

Epigastric: Right Upper Quadrant: Left Upper Quadrant:
-Gastroesophageal reflux -Hepatitis -Splenic injury
-Esophagitis -Cholecystitis -Left lower lobe pneumonia
-Gastritis -Cholelithiasis/biliary colic -Kidney disease
-Gastroduodenal ulcer -Cholangitis
-Pancreatitis -Right lower lobe pneumonia
-Gastric or small bowel volvulus -Kidney disease
-Cholelithiasis/biliary colic
Hypogastric: Left Lower Quadrant: Right Lower Quadrant:
-Constipation -Constipation -Constipation
-Colon spasm or colitis -Colon spasm or colitis -Mesenteric adenitis
-Bladder disease -Ovarian disease/torsion -Crohn disease
-Uterine conditions -Ectopic pregnancy -Appendicitis
-Pelvic inflammatory disease -Testicular torsion -Intussusception
-Hernia -Ovarian disease/torsion
-Sigmoid volvulus -Ectopic pregnancy
-Testicular torsion
-Hernia
Section 12 - Miscellaneous 553

Periumbilical: Diffuse Pain: Location Varies:
-Constipation -Gastroenteritis -Trauma
-Gastroenteritis -Celiac disease -Ischemic bowel disease
-Early appendicitis -Perforation -Allergic disease
-Pancreatitis -Constipation
-Small bowel volvulus -Functional abdominal pain
-Incarcerated umbilical hernia -Streptococcal pharyngitis
-Inflammatory bowel disease
-Henoch-Schonlein purpura
-Diabetic ketoacidosis
-Porphyria
-Sickle cell crisis
-Volvulus
-Abdominal migraine
-Cyclic vomiting syndrome
-Toxic ingestion
-Familial Mediterranean fever
-Angioneurotic edema
-Venomous bites
Adapted from Ross A, LeLeiko NS. Acute abdominal pain. Pediatr Rev. 2010;31: 135-144.
5. Evaluation:
a. Consider laboratory evaluation: CBC, electrolytes, urinalysis, inflammatory
markers, liver enzymes, pancreatic enzymes, urine pregnancy, infectious studies if
indicated (i.e., rapid strep Ag)
b. Consider abdominal x-ray and/or ultrasonography
II. Recurrent or Chronic Abdominal Pain:

A. Now referred to as Pain-related functional gastrointestinal disorders (FGID) involves a
combination of chronic or recurrent abdominal symptoms not explained by known biochemical
or structural abnormalities (see section on Functional Abdominal Pain)
1. Review Rome III criteria 2006
2. Prevalence in Western world 0.3%–19%
3. Evaluate for chronic infectious, inflammatory, metabolic, autoimmune, or anatomic
disorders leading to a patient’s chronic abdominal pain
a. Consider non-gastrointestinal causes of chronic pain (i.e., genitourinary tract,
infectious or extraintestinal conditions)
b. Assess patient for alarm signals for pathologic chronic abdominal pain syndromes
1) Involuntary weight loss
2) Growth retardation
3) Delayed puberty
4) Significant vomiting
5) Significant diarrhea
6) Gastrointestinal blood loss
7) Extraintestinal symptoms
8) Unexplained fever
9) Family history of IBD
10) Consistent RUQ or RLQ abdominal pain
11) Abnormal physical exam
III. Innervation and Mechanisms of Pain

A. Broken down into visceral, parietal or referred pain
B. Visceral pain: abdominal pain secondary to nonmyelinated pain receptors located in muscles,
mucosa of organs, mesentery and serosal surfaces
1. These pain receptors respond to stretching (i.e., bowel distension). Visceral pain is not
well localized and often dull, diffuse, crampy or burning in nature
2. Lower esophagus, stomach and duodenum → felt in epigastric area
3. Small intestine → felt around the umbilicus
a. Example: nonspecific periumbilical pain often felt in early appendicitis
4. Colonic visceral pain→ felt in lower abdomen
5. Not evoked from all viscera, especially liver and kidney
6. Often accompanied by motor and autonomic reflex responses (i.e., nausea, vomiting)
C. Parietal pain: abdominal pain secondary to myelinated pain receptors, in the parietal
peritoneum, muscle and skin
1. Pain receptors respond to stretching, tearing or inflammation
2. Gives a localized pain and often sharp in nature
a. Example: once there has been parietal peritoneal inflammation from acute
appendicitis, a patient often localizes pain to his/her RLQ pain
3. Movement often increases pain
D. Referred pain: abdominal pain often associated with visceral pain, which leads to activity
of nerve fibers from cutaneous dermatomes entering spinal cord/CNS at the same level; get
activation of nerve pathways distant to the affected site
1. Acute cholecystitis → often leads to referred right scapular pain
2. Acute pancreatitis → often leads to mid-back pain
Recommended Reading
Cervero F, Laird JM. Visceral pain. The Lancet. 1999;353:2145-2148.
McCollough M, Sharieff GQ. Abdominal pain in children. Pediatr Clin North Am. 2006;53(1):107-137.
Nurko S, Di Lorenzo C. Functional abdominal pain: time to get together and move forward. J Pediatr
Gastroenterol Nutr. 2008;47: 679-680.
Ross A, LeLeiko NS. Acute Abdominal Pain. Pediatr. Rev. 2010. 31: 135-144.
Vlieger AM, Benninga MA. Chronic abdominal pain including functional abdominal pain, irritable bowel
syndrome, and abdominal migraine. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC
Decker Inc.,;2008: 715-727.

12B. Irritable Bowel Syndrome
Meredith Hitch, MD
Arvind Srinath, MD
Robert Rothbaum, MD
Alka Goyal, MD
I. Irritable bowel syndrome (IBS) is a diagnosis that should be considered in children with chronic ab-
dominal pain. The diagnosis can be made in children who are able to provide a history of abdominal pain
lasting for more than 3 months. The evaluation leading to the diagnosis does not identify any underlying
organic disease.
II. IBS is a clinical diagnosis, a condition of unknown etiology characterized by episodes of abdominal
pain or discomfort more than once per week accompanied by changes in bowel habit
A. Subtypes based on predominant symptoms
1. Diarrhea predominant (IBS-D)
2. Constipation predominant (IBS-C)
3. Mixed (IBS-M)
4. Pain predominant (IBS-P)
B. Prevalence of each subtype is equal
III. ROME III Criteria (www.romecriteria.org)

A. Currently the best clinical definition of IBS must include:
1. Recurrent abdominal pain or discomforta at least 3 days/month in the last 3 monthsb
associated with 2 or more of the following at least 25% of the time:
a. Improvement of discomfort with defecation
b. Onset associated with a change in frequency of stool
c. Onset associated with a change in form (appearance) of stool
2. No evidence of inflammatory, anatomic, metabolic or neoplastic process
a
Discomfort means an uncomfortable sensation not described as pain.
b
Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
IV. Typical GI Symptoms

A. Abnormal stool frequency (≥4/day or ≤2/week)
B. Abnormal stool form: lumpy/hard or loose/watery
C. Passage of mucous with or without stool
D. Bloating/sensation of abdominal distension
V. Epidemiology
A. Female to male ratio is 2–2.5:1
B. Between 3%–20% of North American adults are affected
C. Similar prevalence for pediatric patients with recurrent abdominal pain
VI. Pathophysiology: not well understood

A. Genetic factors may play a role
1. Family clusters of affected patients
2. Mothers of children with recurrent abdominal pain are more likely to have a lifetime
history of IBS than controls
3. Concordance for IBS is greater in identical than fraternal twins
4. No mutations proven, but polymorphisms in G-proteins have been found in dyspepsia
and polymorphisms in IL10 and serotonin transporter gene in other forms of IBS
B. Chronic stress has a likely role
C. Infection may be the initiating event with chronic changes in motility and flora
1. Giardiasis particularly associated with subsequent IBS
D. Both high and low socioeconomic groups are affected
E. Food allergy unproven as cause

VII. Comorbid Non-GI Conditions
A. 48%–60% of patients have psychological comorbidities: depression, anxiety, abuse, somatic
attribution and hypochondria
B. Central pain processing disorders: fibromyalgia, chronic fatigue syndrome and chronic pelvic pain
C. Other somatic complaints associated with IBS
1. Headache
2. Fatigue
3. Myalgias
4. Dyspareunia/menstrual pain
5. Urinary frequency or dysuria
6. Dizziness/syncope
VIII. Economic impact of irritable bowel syndrome is high

A. Health care costs recently estimated to be
1. Direct costs: US $348–$8,750 per patient per year
2. Indirect costs: US $355–$3,344 per patient per year
B. Impaired work productivity and quality of life
IX. Alarm signs and symptoms demanding further investigation

A. New onset IBS after 50 years of age
B. Unintentional weight loss, growth failure
C. Nocturnal diarrhea
D. Anemia
E. Hematochezia
F. Family history of colon cancer, celiac disease or inflammatory bowel disease
G. Constitutional symptoms
X. Diagnostic Testing
A. American College of Gastroenterology (ACG) IBS Task Force recommends that routine diagnostic
testing should not be performed in patients with typical IBS symptoms who have no alarm
features
B. Colonoscopy is not recommended unless alarm signs and symptoms accompany pain
C. IBS and celiac disease may co-exist
1. Testing for celiac disease may be warranted for patients with IBS-D and IBS-M subtypes
2. 4-fold increase in IBS symptoms in patients with biopsy proven celiac disease over
healthy controls
D. Lactose Intolerance
1. Prevalence of lactose intolerance in IBS is about 35%
2. ACG IBS Task Force recommends lactose breath testing if suspicion is high after lactose
restricted diet trial
E. Fructose intolerance may cause IBS-like symptoms
1. Incompletely absorbed fructose is fermented in the colon producing H2, CO2 and short-
chain fatty acids. The osmotic load and gas cause diarrhea, flatulence and pain similar to
IBS-D
2. Short-chain carbohydrates and sugar alcohols have a similar effect
3. Exclusion diets lead to an improvement in 80% of patients with fructose intolerance
F. Fermentable oligo-, di-, and monosaccharides and polyols also cause symptoms
1. Fructan-containing vegetables – onions, asparagus, artichokes
2. Sorbitol – plums, cherries and chewing gum
3. Raffinose – cabbage and lentils
G. Small bowel bacterial overgrowth rarely mimics IBS
1. ACG IBS Task Force recommends lactulose or glucose breath test for bacterial over-
growth only in cases with severe diarrhea and nocturnal diarrhea
XI. Management
A. Team approach develops rapport with patient in nonjudgmental atmosphere
1. Mild disease – education, reassurance and dietary and lifestyle modifications
2. Moderate disease – add pharmacotherapy and psychological treatments
3. Severe disease – to the management above, consider adding referral to pain treatment
center
B. Diet
1. 70% of IBS patients think that diet provokes their symptoms
2. Some dietary changes that benefit some IBS patients
a. Smaller meals
b. Avoid fatty food
c. Decrease dairy, lactose and total carbohydrates
d. Decrease caffeine and alcohol
e. Increase dietary fiber
3. The ACG IBS Task Force does not recommend exclusion diets for IBS
C. Global treatment options
1. Cognitive behavioral therapy to modify maladaptive behaviors and thinking
2. Hypnotherapy
3. Alternative medicine therapies have not been subjected to trial, including acupuncture,
herbal therapy
D. Common pharmacologic treatments for IBS-C
1. Psyllium, methylcellulose to improve straining and hard stools
2. Osmotic laxatives – milk of magnesia, lactulose syrup, PEG
3. Stimulant laxatives – senna, diphenylmethane derivatives (biscodyl)
4. Emollients – docusate, mineral oil
5. Serotonin (5HT4) agonists – tegaserod only available by special release because of
cardiac side effects
6. Chloride channel activators – lubiprostone (prostaglandin derivative is FDA approved for
IBS-C in women and adults with idiopathic constipation)
E. Common pharmacologic treatments of IBS-D
1. Antidiarrheals – loperamide, diphenoxylate
2. 5HT4 antagonists – alosetron available only for severe IBS-D in women. Severe side
effects include constipation and ischemic colitis
3. Tricyclic antidepressants – amitriptyline, doxepin, imipramine, clomipramine, desipramine,
nortriptyline
a. Treatment must be preceded by screening EKG because of potential long QTc
syndrome and cardiac arrhythmia
b. Doses are usually lower than those used for mood elevation
F. IBS-D and IBS-M
1. Rifaximin has been associated with global improvement in IBS-D and IBS-M with
decreased bloating
G. IBS-M and IBS-P
1. Antispasmodics (hyoscamine sulfate and dicyclomine) are often used and may improve
postprandial symptoms.
2. Tricyclic antidepressants (see above)
3. Selective serotonin reuptake inhibitors – fluoxetine, citolopram, paroxetine, sertraline,
escitalopram
a. Limited controlled studies
b. Some global improvement
4. Probiotics
a. Bifidobacterium infantis may improve gas-related symptoms
b. VSL #3

Recommended Reading
Bahar RJ, Collins BS Steinmetz Bm, Ament ME. Double blind placebo controlled trial of amitriptyline for
treatment of irritable bowel syndrome in adolescents. J Pediatr. 2008;152:685-689.
Campo JV. citolopram treatment of pediatric recurrent abdominal pain and comorbid internalizing disorders:
an exploratory study. J Am Acad Child Adolesc Psychiatry. 2004;43:1234-1242.
Dhroove B, Chogle A, Saps M. A million dollar work up for abdominal pain: is it worth it? J Pediatr
Gastroenterol Nutr. 2010;51:579-583.
diLorenzo C. Chronic abdominal pain in children: a technical report of the American academy of Pediatrics
and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr
Gastroenterol Nutr. 2005;40: 249-261.
Khan S, Chang, L. Diagnosis and management of IBS. Nat. Rev Gastroenterol Hepatol. 2010;7:565-581.
Youssef NN. Treatment of functional abdominal pain in childhood with cognitive behavioral strategies. J
Pediatr Gastroenterol Nutr. 2004;39:192-196.
12C. Abdominal Masses
Laurie Fishman, MD
I. Differential Diagnosis
The differential diagnosis for abdominal masses is large and includes both benign and malignant lesions.
A. Epidemiology
1. Primary gastric neoplasms are rare
a. GI malignancies account for ~1.2% of all childhood malignancies
b. Gastric neoplasms are a very small subset of primary GI malignancies
2. Non-Hodgkin lymphomas and sarcomas are most common gastric neoplasms
B. Benign gastric tumors
1. Adenomatous polyps (see section on Colon Polyps)
a. Familial adenomatous polyposis (FAP) may have multiple gastric polyps (fundic
gland type > adenomatous)
b. Fundic gland polyps in the setting of FAP may have neoplastic potential and
require regular screening endoscopy every 1–3 years
2. Fundic gland tumors and polyps are often seen in familial adenomatous polyposis
syndrome and more frequently in patients on long-term PPI therapy
a. PPI-related polyps are a result of hyperplasia of parietal cells and have been re-
ported within 10–48 months of starting PPI therapy
1) PPI-related gastric changes are currently not thought to have significant
risk for cancer
2) No definitive guideline for monitoring these polyps in children has been
developed. One widely quoted authority suggests endoscopic monitoring
for fundic gland polyps in children on long-term PPI
3. Juvenile/hamartomatous polyp (see section on Colon Polyps)
a. Peutz-Jeghers syndrome: 40% patients have gastric hamartomas, most
commonly in the antrum
b. Juvenile polyposis: hamartomas with inflammatory cells in the lamina propria.
Juvenile polyps occur in the stomach in generalized juvenile polyposis syndrome
or juvenile polyposis of infancy (usually fatal). Gastric juvenile polyps have lower
risk of malignant transformation than colon polyps
4. Gastric pseudopolyps: may be seen with Crohn disease, allergic gastritis, or other
inflammatory polyps
5. Teratomas:
a. Rare tumor composed of mesodermal, endodermal and ectodermal elements
(gastric teratomas comprise only 0.75% of all childhood teratomas)
b. Almost all patients are male and <2 years old (majority <3 months).
Excision is curative
c. May produce irregular soft tissue mass with both solid and cystic components,
as well as calcifications on abdominal imaging
d. Mostly benign; because there are rare case reports of malignant gastric
teratomas, all teratomas require complete resection

C. Malignant lesions
1. Adenocarcinomas:
a. Very rare in children
b. Can be associated with: IgA deficiency, common variable immunodeficiency,
ataxia-telangiectasia, as well as FAP and Peutz-Jeghers syndrome (usually later
in life)
c. Also associated with familial diffuse gastric carcinoma syndrome (germline
mutations in E-cadherin/CDH2 gene)
d. H pylori infection is mostly associated with non-cardia adenocarcinomas
1) Currently, no definite recommendations for screening for H pylori in
asymptomatic children to prevent gastric cancer
2) Testing for H pylori should be considered if there is a family history of
gastric cancer
e. Symptoms: pain, anorexia, vomiting, GI bleeding, upper abdominal mass and
weight loss
2. Gastric Lymphomas
a. Small proportion of all intestinal non-Hodgkin lymphomas in children
b. Most are Burkitt lymphomas
c. MALT (mucosa-associated lymphoid tissue) lymphoma has been associated with
H pylori infection
1) If diagnosed with MALT lymphoma, patient should be tested for H pylori,
as treatment of H pylori may help regression/remission of gastric MALT
lymphoma
d. Primary immunodeficiencies are a risk factor for this tumor
e. Treatment: surgical resection and adjuvant chemotherapy and radiotherapy if
metastases are present
3. Gastrointestinal stromal tumor (GIST):
a. Spindle or epithelioid mesenchymal neoplasm arising from interstitial cells of Cajal
b. ↑ incidence in females
c. Cells express C-Kit and CD34
d. Extremely rare in children (only 1% present in children, most often occur in 2nd
decade of life), but 60%–70% occur in stomach
e. Common presentation is GI bleeding and intestinal obstruction
D. Miscellaneous tumors:
1. Gastric hemangioma: often associated with vascular skin lesions and vascular
involvement of intestinal tract
a. Hematemesis: frequent symptom
b. Benign, but if symptomatic may require surgical therapy
2. Gastric lipoma: slow-growing tumors composed of adipose tissue
3. Inflammatory myofibroblastic tumor or inflammatory pseudotumors: made up of spindle
cells, myofibroblasts, plasma cells and histiocytes
a. Thought to be an aberrant response to tissue injury
b. Treatment is by surgical resection; recurrence and metastases are common
4. Carcinoid tumor: has been reported in stomach (but most likely found in appendix)
a. Treatment: full resection of tumor
5. Gastric Hamartoma
a. Bengin lesions with histologic variation (a mixture of components of the gastric
wall)
6. Gastric leiomyosarcoma and leiomyomas: soft tissue tumors of smooth muscle origin
that involve gastric wall
a. Often present with GI hemorrhage, obstruction and perforation
7. Ectopic pancreas (or pancreatic rest): accessory pancreatic tissue, most often found in
prepyloric gastric antrum
a. Pancreatic tissue with no ductular connection to pancreatic gland
b. Usually asymptomatic and discovered incidentally, although there have been
reports of clinical symptoms if >1.5 cm (abdominal pain, dyspepsia, GI bleeding)
c. On endoscopy, appear as round, smooth submucosal mass with central
umbilication
d. Treatment: observational; due to submucosal location of pancreatic rests,
endoscopic removal has high risk of perforation
Recommended Reading
Alkhouri N, Franciosi JP, Mamula P. Familial adenomatous polyposis in children and adolescents. JPGN.
2010;51:727-732.
Attard TM, Yardley JH, Cuffari C. Gastric polyps in pediatrics: an 18-year hospital-based analysis. Am J Gastro-
enterol. 2002;97:298-301.
Curtis JL, Burns RC, Wang L, Mahour GH, Ford HR. Primary gastric tumors of infancy and childhood: 54-year
experience at a single institution. J Pediatr Surg. 2008; 43:1487-1493.
Ladd AP, Grosfeld JL. Gastrointestinal tumors in children and adolescents. Semin Pediatr Surg. 2006;15:37-47.
Graeme-Cook F, Lauwers G. Tumors of the Pediatric Esophagus and Stomach. In: Walker’s Pediatric
Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker Inc.,;2008: Chapter 10; 175-185.Ladd AP,
Grosfeld JL. Gastrointestinal tumors in children and adolescents. Semin Pediatr Surg. 2006;15:37-47.
Ooi CY, Lemberg DDA, Day AS. Other causes of gastritis. In: Walker’s Pediatric Gastrointestinal Disease. 5th
ed. Hamilton, Ontario: BC Decker Inc.,;2008: Chapter 9; 165-174.

12D. GI Manifestations
of Immunodeficiency
Christopher J. Moran, MD
Harland S. Winter, MD
I. T here are more than 80 primary and secondary immunodeficiency syndromes that affect children. IgA
deficiency is the most common primary immune deficiency. Many of the immunodeficiency states have
associated gastrointestinal manifestations.
II. IgA deficiency is the most common human immunodeficiency

A. Prevalence 1:300 to 1:700
B. Severe deficiency – IgA levels repeatedly <7 mg/dL with normal IgG and IgM
C. Mild deficiency/probable diagnosis – IgA >7 mg/dL but <2 SD below the mean for age
D. Diagnosis should not be made until child is 4 years or older because of normally low levels of IgA
in younger children
E. Many IgA deficient children are asymptomatic
F. IgA deficiency may be associated with
1. Autoimmunity (systemic lupus, juvenile rheumatoid arthritis) found in 20%–30% of
deficient individuals
2. Anaphylaxis to blood products (40% have IgG antibodies against IgA
3. Infections
a. Sinopulmonary infections more common than GI infections
b. Chronic giardiasis
c. Other GI infections not common
4. Lymphoid nodular hyperplasia of the small and large intestine is common
5. Celiac disease
a. 2% of celiac disease patients are IgA deficient
b. 10%–30% of IgA deficient patients have celiac disease
c. Histology and response to diet are identical in IgA deficient and sufficient
patients
G. Treatment of IgA deficiency is directed at managing clinical manifestations rather than correcting
IgA deficiency
III. Chronic granulomatous disease (CGD)

A. Caused by defect in the NADPH oxidative burst pathway
1. Prevents neutrophil oxidation and killing of catalase+ organisms
2. Mutation may be in 1 of 4 genes (gp91, p47, p67, p22)
B. X-linked recessive disease (gp91): ~67% of cases
1. Mean age at diagnosis: 4.9 year
C. Autosomal recessive: ~33% (p47 more common than p67 and p22)
1. Mean age at diagnosis: 8.8 year
D. Found in 1/250,000 live births
E. GI related presentations are common especially in X-linked CGD
1. Infection – 48%
2. Oral aphthae – 11%
3. Perirectal abscess (16%–21%)
4. Gastric or esophageal obstruction by granulomas
5. Hepatic abscess (30%) due to Staphylococcus or Pseudomonas
6. Colitis (11%–17%) occurs at similar rates in X-linked vs AR

F. Other infections in CGD - pneumonia>abscess>adenitis
1. High risk for catalase + organisms
2. Bacteria – Staphylococcus aureus, Gram-negative rods (E coli, B cepacia, Serratia spp)
and Nocardia
3. Fungi – Aspergillus, Candida
G. Autoimmune disease is less common in CGD than CVID
H. Diagnosis
1. Preferred test is dihydrorhodamine reductase (DHR) assay to measure oxidative burst
2. Nitroblue tetrazolium test is less reliable
3. Genetic testing is available
I. Therapy
1. Prophylaxis with antifungal (itraconazole) and antimicrobial (TMP-SMX) agents
2. Interferon-γ to reduce frequency of serious infections
3. Stem cell transplantation and gene therapies are available in some centers
4. Colitis usually responds to steroids and/or Interferon-γ
5. Colitis may be treated with anti-TNF and antimicrobials
IV. Common variable immunodeficiency (CVID)

A. Hypogammaglobulinemia with poor response to immunization – B cells do not differentiate into
plasma cells
B. Multiple genes implicated (80% are sporadic mutations)
C. Incidence 1:50–200,000
D. Usually presents during adolescence or later
E. Diagnostic criteria – two IgG subclasses > 2 SD below normal with poor titers after vaccination
with tetanus (IgG1) or Hemophilus/pneumococcus (IgG2)
F. Most common infectious manifestation is pneumonia
G. GI related infections
1. Giardia most common
2. Bacterial: Salmonella, Campylobacter, Yersinia
3. Viral: CMV
H. Hepatosplenomegaly sometimes present
I. GI histology
1. Gastritis with apoptosis similar to that in acute GVHD
2. Duodenitis: 30%–60% have increased intra epithelial lymphocytes, villous blunting and
deficiency of plasma cells in lamina propria
3. Mild colitis with increased apoptosis
J. >25% of patients with CVID have autoimmune disease
K. Therapy is IgG replacement
V. Severe combined immunodeficiency

A. Lack of functional T cells (and sometimes lack of NK and B cells)
B. Multiple genes implicated (ADA, PNP, JAK3)
C. Occurs in 1:50–75,000 live births
D. Manifestations
1. Respiratory infection, diarrhea and failure to thrive in first months of life
2. Hepatosplenomegaly, lymphoid hyperplasia
3. Intractable diarrhea with shedding of viruses that cause self-limited infections in normal
children
4. Recurrent oral, cutaneous and GI candidiasis
5. Death from viral sepsis, especially EBV, varicella, herpes, CMV
E. Intestinal biopsy shows villous blunting, absent plasma cells
F. Therapy: IVIG replacement, antimicrobial prophylaxis and prompt therapy for infections
G. Bone marrow transplant is curative
VI. Bruton agammaglobulinemia – X-linked agammaglobulinemia
A. Mutation in Bruton tyrosine kinase gene results in defective B cell development
B. Incidence is 1:100,000–200,000 live male births.
C. Manifestations
1. Recurrent sinopulmonary infections in first year after maternal antibody levels fall
2. Recurrent GI infections with Campylobacter and Giardia – less commonly Salmonella
and Shigella
3. Chronic GI enteroviral infection may seed CNS
4. Some develop Crohn-like disease
D. Diagnosis
1. Markedly low Ig levels and paucity of B cells
2. May be confused with SCID but T cell numbers are normal
3. Genetic screening for Bruton tyrosine kinase gene
E. Therapy
1. Prompt treatment of infection
2. IVIG infusion
VII. Wiskott-Aldrich syndrome

A. X-linked disorder due to mutation in WAS protein (WASP)
B. 1 in 250,000 live male births
C. Triad of immunodeficiency, eczema, thrombocytopenia with small platelets
D. Wide spectrum of disease although thrombocytopenia present in nearly all
E. Mild mutations may cause only thrombocytopenia
F. Autoimmune phenomena: IBD in 3%, hemolytic anemia, vasculitis
G. Diagnosis:
1. High IgA, low IgM, normal IgG
2. Diagnosis confirmed with genetic testing
H. Treatment: Bone marrow transplant curative
VIII. IPEX Syndrome (see section on Autoimmune Enteropathy)

A. X-linked immune dysregulation, polyendocrinopathy, enteropathy
B. Mutation in FoxP3 gene causes minimal or absent FoxP3+ regulatory T cells
C. Typical presentation is failure to thrive and secretory diarrhea
IX. Graft vs host disease

A. Occurs when donor T cells (and potentially other immune cells) recognize host antigen and
initiate reaction against host
B. Acute GVHD – occurs in the first 100 days after bone marrow transplant. Rarely can occur after
liver transplants (<1%)
C. GI Symptoms: nausea, anorexia, abdominal pain, weight loss, diarrhea (watery becoming bloody)
D. Skin involvement is most common
E. Gastrointestinal involvement can be severe
1. Hallmark finding is epithelial cell apoptosis leading to crypt degeneration/loss
2. Upper GI involvement often occurs before colonic
3. Duodenal biopsy often shows villous blunting
F. Initial therapy is steroids (50% effective)
G. No definitive second-line therapy, may use calcineurin inhibitor, mycophenolate, anti-thymocyte
globulin

X. Hepatic GVHD is 2nd most common form of GVHD
A. Occurs in 25% of pediatric bone marrow transplants compared to <1% in pediatric
liver transplants
B. Obstructive jaundice more common than transaminitis
C. Diagnosis requires liver biopsy – showing portal fibrosis with cholestasis with no infectious
diagnosis
D. Therapy similar to non-hepatic GVHD with addition of Ursodiol
XI. Chronic GVHD – occurs >100 days after BMT

A. Complicates 20%–50% of pediatric BMT (adults 50%–70%)
B. Can involve any organ (as opposed to specific organs in acute GVHD)
1. Often affects esophagus causing strictures
C. Diagnostic criteria are less definitive
D. May be confused with infection or autoimmune conditions (lupus, scleroderma)
E. Initial therapy is steroids ± calcineurin inhibitor
XII. HIV – Acquired immunodeficiency syndrome

A. RNA retrovirus infects CD4 cells and macrophages
B. Inversion of CD4/CD8 ratio to <1
C. Viral reverse transcriptase converts RNA to DNA, then cell machinery synthesizes viral RNA
D. Most common manifestations
1. Opportunistic infections
2. Weight loss
3. Malignancy – leiomyoma/myosarcoma in children. Kaposi sarcoma in adults
E. Primary acute retroviral infection
1. Fever, lymphadenopathy, myalgia, oral ulcers
2. No antibody response
3. Viral RNA positive, very high viremia
4. Virus found in lymph nodes
F. AIDS-defining infections
1. CMV, HSV, Cryptosporidia, Isospora, Giardia, Mycobacterium avium complex, Candida
G. GI manifestations of HIV
1. Infections with CMV are common – esophagitis, hepatitis, colitis
2. Gastritis, duodenitis
3. Chronic diarrhea
H. Diagnosis
1. Screen for HIV antibody with enzyme-linked immunoassay
2. Confirm with Western blot
I. Current therapy is highly active antiretroviral therapy (HAART)
1. Consists of 2 nucleoside reverse transcriptase inhibitors (NRTI) and
1 non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor
2. Children treated with HAART have better growth
XIII. Hereditary angioedema

A. C1 inhibitor dysfunction in 20%. Deficiency of C1 inhibitor in 80%
B. 0.4% of all urticaria cases in children are hereditary angioedema
C. Often diagnosed in first decade but worsens at puberty
D. Edema occurs because of vascular leak
E. Clinical manifestations
1. Recurrent angioedema and urticaria lasting 2–3 days
2. Often initiated by trauma
3. Swelling of proximal and distal extremities common
F. Most common GI symptom is recurrent severe abdominal pain
G. Treatment
1. Mostly supportive
2. C1 inhibitor replacement with danazol or fresh frozen plasma
3. Aminocaproic acid may prevent spread of edema
XIV. Immunodeficiency due to medications used to treat GI disorders (see section on Anti-inflammatory/
Transplant Medications)
A. Hypogammaglobulinemia may accompany the use of
1. Sulfasalazine
2. Anti-convulsants
3. Anti-TNFα (see section on Major Biologic Medications)
B. Complications of 6-MP/azathioprine
1. Dose-dependent bone marrow suppression causes leucopenia and sometimes thrombocytopenia
2. Leucopenia risk can be decreased by evaluating thiopurine methyl transferase enzyme before therapy
3. Repeat TPMT evaluation may be warranted while on therapy, as 6-MP/azathioprine induces enzyme
activity
4. 5-ASA and infections may affect TPMT activity
5. Increased risk of CMV, varicella and severe EBV infections
C. Methotrexate in low dose rarely causes pancytopenia
D. Corticosteroids
1. Increased risk of respiratory, urinary tract and liver infections
2. Increased risk for infection with Herpes simplex and Pneumocystic jeroveci
3. Children on >2 mg/kg or >20 mg/day of corticosteroids for >14 days should not receive live-attenuated
vaccines until 1 month after cessation of therapy
Recommended Reading
Agarwal S. Gastrointestinal manifestations in primary immune disorders. IBD. 2010;16(44):703-711.
Guerrerio AL. Recognizing gastrointestinal and hepatic manifestations of primary immunodeficiency diseases. JPGN.
2010;51(5):548-555.
Marks D. Inflammatory bowel disesases in patients with adaptive and complement immunodeficiency disorders. IBD.
2010;16(11):1984-1992.

12E. Cystic Fibrosis
Ala Shaikhkhalil, MD
Desale Yacob, MD
I. ystic fibrosis (CF) is the most common lethal genetic defect in the Caucasian population. The gastroin-
C
testinal tract can be affected. Meconium ileus is the earliest gastrointestinal manifestation of cystic fibro-
sis. Distal intestinal obstruction syndrome is a gastrointestinal complication that can be seen at any time,
but is more common in adolescence.
II. Meconium ileus

A. Overview/Epidemiology
1. Meconium ileus (MI) is an early clinical manifestation of CF, characterized by partial or
complete intestinal obstruction in the neonate
2. MI occurs in 10%–20% of patients with CF
3. Prognosis for MI has improved over the years, but delayed diagnosis still causes
significant mortality
B. Pathogenesis/Pathophysiology
1. MI occurs in utero almost exclusively in patients with complete exocrine pancreatic
insufficiency. Other risk factors for MI have not been defined
2. Meconium in patients with CF is thick and likely to become inspissated in the intestinal
lumen. Thickness of meconium is caused by increased concentration of albumin and
minerals, increased mucous and decreased water content
3. Inspissation usually occurs in the terminal ileum, producing partial or complete small
bowel obstruction
4. Bowel distal to inspissated meconium is usually of small caliber (unused micro-colon)
5. Bowel proximal to inspissated meconium is usually dilated
6. Dilated proximal bowel is at risk for volvulus and perforation
7. Antenatal intestinal perforation causes meconium peritonitis, with peritoneal
calcifications
8. Antenatal volvulus causes ileal atresia
C. Diagnosis
1. Evaluation
a. The results of neonatal serum immunoreactive trypsinogen (IRT) will be falsely
negative in patients with meconium ileus because of the profound pancreatic
insufficiency
b. In patients with MI, a mutation analysis for CF should be obtained, not IRT
2. Imaging
a. Diagnosis suggested by increased echogenicity of bowel on ultrasound in the first
trimester (questionable reliability)
1) Plain film
a) Dilated bowel loops with ground glass appearance (no air within
meconium) in the right lower quadrant
b) Air-fluid levels are generally not seen because of inconsistency of
bowel contents
c) Calcification of intraluminal contents suggests prenatal perforation
and peritonitis
2) Contrast enema usually shows microcolon with filling defects caused by
pellets of mucous and meconium

D. Clinical Manifestations
1. Signs and symptoms of intestinal obstruction in the newborn period: bilious emesis,
distension, and failure to pass meconium within the first 2–48 hours of life
2. Filled loops of bowel may be palpable. The rectum is tight on digital examination
3. Nearly 50% of cases have complicated MI, where in addition to MI there is malrotation
with volvulus, intestinal perforation, peritonitis, necrosis, meconium cysts or intestinal
atresia requiring laparotomy
4. Most cases have microcolon in association
5. MI can be distinguished from other forms of neonatal gut obstruction by the lack of air
fluid levels in erect or lateral radiographs in addition to the ground glass appearance
6. Diagnosis of MI should be suspected if there is a family history of CF. When an infant
develops MI, the recurrence risk for siblings with CF significantly increases
7. Prognosis: children with CF born with MI go on to have more clinically significant lung
disease and shorter life expectancy
E. Treatment/Management
1. Current surgical and nutritional modalities have significantly decreased the formerly high
mortality rates in infants with MI
2. In uncomplicated MI, a gastrografin enema by a skilled pediatric radiologist not only
helps establish the diagnosis, but, because it is hypertonic, it can also be therapeutic in
washing out the insipissated meconium
3. Contrast radiography should be avoided in those with perforation or intraabdominal
calcification
4. Great care is needed to avoid the perforation, shock and dehydration associated with
the use of the hypertonic enemas
5. Secure IV access, adequate hydration and close monitoring are essential in a center
where neonatal surgery is available
6. Failure to resolve the obstruction with gastrografin necessitates surgical intervention
7. The standard procedure is to milk out the insipissated material to wash out the
residue with saline or solutions containing n-acetylcystine. Intraoperative infusions of
n-acetylcysteine or hyperosmolar contrast have been shown to decrease the need for
surgical resection
8. There may be late complications from loss of resected intestine or development of
stricture or band at the site of surgery. Persistent bowel symptoms despite adequate
pancreatic enzyme therapy should be thoroughly investigated in any CF patient,
especially in case of neonatal surgery
F. Differential Diagnosis
1. Hirschsprung disease
2. Intestinal volvulus
3. Intestinal atresia
4. Meconium plug syndrome (MPS): seen in infants with CF, Hirschsprung disease,
hypotonia, and prematurity. Presentation similar to MI but the obstruction is distal
(at the level of the colon rather than the ileum). Contrast enema shows a normal
caliber colon with filling defects from insipissated meconium and is usually diagnostic
and therapeutic. Surgery is rarely indicated
III. Distal intestinal obstruction syndrome (DIOS)

A. Overview/Epidemiology
1. DIOS replaces the vague term of meconium ileus equivalent
2. ESPGHAN CF Working Group defined DIOS and defined complete and incomplete DIOS
(see Table 1)
3. Incidence is variable depending on definition used
4. 17%–24% of patients with CF experience DIOS. The diagnosis is being made more fre-
quently now that the ESPGHAN guidelines are being used
5. Can occur at all ages but is more common in adolescents and adults. Patients with prior
meconium ileus are at increased risk of developing DIOS
Table 1. ESPGHAN CF Working Group definition for DIOS in cystic fibrosis
No. 1 Complete intestinal obstruction as evidenced by vomiting of bilious
material and/or fluid levels in small intestine on an abdominal radiography
No. 2 Fæcal mass in ileo-cæcum
No. 3 Abdominal pain and/or distension
Complete DIOS: 1, 2, and 3
Incomplete/impending DIOS: 2 and 3 without 1
CF = cystic fibrosis; DIOS = distal intestinal obstruction syndrome; ESPGHAN =
European Society for Pædiatric Gastroenterology, Hepatology, and Nutrition.
B. Pathogenesis/Pathophysiology
1. Believed to result from a combination of retained mucofeculent material, abnormal
intestinal secretions and abnormal intestinal motility, leading to impaction of stool in the
terminal ileum, cecum and proximal colon
2. Symptoms are complete or partial intestinal obstruction
3. Occurs almost exclusively in patients with pancreatic insufficiency
4. Risk factors for developing DIOS
a. Patients on insufficient pancreatic enzyme replacement therapy – iatrogenic or
noncompliance
b. Opiates, anticholinergic agents
c. Dehydration
d. Change in diet (high fat)
e. CFTR dysfunction (certain genetic factors are believed to play a role, although
not fully understood)
5. Insipissated intestinal contents in the distal ileum and proximal colon can often be pal-
pated as masses in the right iliac fossa
C. Diagnosis
1. Diagnosis rests on history and physical examination. Imaging studies are helpful in
confirming the diagnosis, ruling out other conditions, and following up on response to
treatment
2. Clinical Picture
a. Symptoms: crampy lower abdominal pain, abdominal distension, vomiting, bil-
ious vomiting and anorexia
b. Signs: palpable mass in the lower right quadrant sometimes present
3. Imaging
a. Ultrasound and CT scan can help confirm the diagnosis and rule out concomitant
pathology
b. Abdominal radiography shows air fluid levels in small bowel and retained stool in
the ileum and cecum appearing as bubbly granular opacities
c. The diagnosis is initially achieved with obtaining supine and erect abdominal
films. If there is obstruction, one should suspect concomitant pathology
D. Treatment/Management
1. In DIOS without complete intestinal obstruction, GI lavage with balanced isotonic
solution containing polyethylene glycol (Go-LytleyTM ), which can be administered orally
or through an NG tube
2. Endpoint of lavage is to relieve the partial obstruction manifested by passage of stool,
resolution of pain and mass
3. Enemas using water-soluble contrast or N-acetylcysteine are used less frequently due to
success of antegrade lavage
4. After resolution of acute episode, optimize enzyme dose or improve compliance with
enzyme replacement, increase fluid intake, add dietary fiber and use regular osmotic
laxatives to prevent recurrence

5. In DIOS with intestinal obstruction (distension and bilious emesis), it is mandatory to
exclude other complications
a. In presence of obstruction or if washout therapy fails, gastrografin enemas can
help outline the colonic pathology and can be useful to relieve impaction
b. In resistant cases of obstruction, US should be done to rule out intussusceptions
c. Persistent obstruction despite therapy may necessitate laparotomy, although this
is rare in the absence of appendicitis or intussusceptions
6. In patients with recurrent DIOS, appendecostomy placement for routine administration
of osmotic agents is an option
E. Differential Diagnosis
1. In the presence of fever and peritoneal signs, high index of suspicion should be present
for inflammatory conditions. DIOS can occur in association with the conditions listed
below adding to the complexity of this condition.
a. Appendicitis
b. Purulent mucocele of the appendix
c. Intussusception
d. Volvulus
e. Constipation
f. Crohn’s disease
g. Small bowel perforation or fistula
h. Colonic stricture
i. Pancreatitis
j. Ovarian conditions
F. Some CF patients will have chronic fecal retention and an acquired mega colon syndrome.
They will have reduced bowel frequency and sometimes even rectal overloading, resulting in
incontinence. Fecal retention is differentiated from DIOS by the fact that the fecal loading is
distal. Treatment is with laxatives and ensuring adequate pancreatic supplements.
Recommended Reading
Houwen RH. Defining DIOS and Constipation in Cystic Fibrosis With a Multicenter Study on the Incidence,
Characteristics, and Treatment of DIOS. J Pediatr Gastroenterol Nutrition. 2010;50(1):38-42.
Littlewood JM. Gastrointestinal complications of cystic fibrosis. Brit Med Bull. 1992;48(4):847-859.
Raia VF, Staiano A. The ESPGHAN Cystic Fibrosis Working Group: Defining DIOS and Constipation in
Cystic Fibrosis With a Multicenter Study on the Incidence, Characteristics, and Treatment of DIOS. J Pediatr
Gastroenterol Nutrition. 2010;50(1).
Walker A, Kleinman R, Sherman P, Shneider B, Sanderson I, Pediatric Gastrointestinal Disease. 4th ed. Vol 1.
Hamilton, Ontario: BC Decker Inc.; 2004.
12F. Chronic Diarrhea
Alex Green, DO
Jane Balint, MD
I. hronic diarrhea is defined as diarrhea lasting >14 days. The differential is extensive and varies with the
C
age of onset. History and physical exam are vital to identifying the correct diagnosis.
II. Antibiotic-associated diarrhea (AAD)

A. Definition
1. Unexplained diarrhea (2 unformed stools per day for 2 or more days) occurring between
2 hours and 2 months after starting antibiotics
B. Prevalence
1. 11% of children have AAD starting on average 5 days after starting antibiotics and
lasting 4 days
2. Most common antibiotics involved are amoxicillin/clavulanic acid (23%) and
erythromycin (16%)
3. Most common in children less than 2 years old
C. C difficile colitis is associated with 15%–20% of all cases of AAD
D. Treatment
1. Discontinuation or changing of antibiotics
2. Anti-motility agents should be avoided
3. Metronidazole or oral vancomycin for C difficile colitis diarrhea
E. Prevention
1. Probiotics (Saccharomyces boulardii or Lactobacillus GG) may have some benefit
III. Chronic nonspecific diarrhea of childhood

A. Definition
1. Stool volume of >10 grams/kg/day in infants and toddlers, or >200 grams/day in older
children for more than 14 days
B. Manifestations
1. Chronic diarrhea, normal growth and exam, no weight loss or bleeding per rectum.
Usually pass stools only during waking hours
C. Potential causes
1. Low-fat diet
2. High osmolality carbohydrate intake especially sorbitol and fructose
3. Possible fast motility due to prostaglandin effect
D. Treatment
1. Decrease carbohydrates, increase fat in diet
2. May use loperamide if necessary
IV. Protracted diarrhea of infancy

A. Sucrase and lactase deficiency
1. Autosomal recessive
a. Sucrase-isomaltase deficiency (SI deficiency)
1) Prevalence is 1 in 5,000 people of European descent
2) More prevalent in Native populations of Greenland, Alaska and Canada
b. Congenital lactase deficiency
1) Extremely rare
2. Diagnosis
a. Hydrogen breath test, + stool reducing substances, response to clinical challenge,
and eventually biopsy and dissacharidase testing
3. Treament
a. Avoid sucrose in patients with SI deficiency and lactose in lactase deficiency
b. Treat with sucrase or lactase depending on the deficiency

B. Congenital glucose-galactose malabsorption
1. Autosomal recessive
2. Mutations in Sodium-Glucose Luminal Co-Transporter (SGLT-1)
3. Marked osmotic diarrhea in neonatal period with lactose, glucose or glucose polymer
containing feeds
4. Mild renal glucosuria
5. Infants should receive fructose based formula
C. Electrolyte malabsorption
1. Congenital chloridorrhea
a. Presentation
1) Echogenic loops of bowel can be seen on antenatal ultrasound
2) Diarrhea and dehydration at birth
3) Abdominal distention and fluid-filled loops
4) Metabolic alkalosis (↓Na +, ↓Cl-)
5) Stool Cl- level >90 mmol/L
b. Etiology
1) Caused by a defect in the DRA gene
a) Adjacent to CFTR
2) Due to defective chloride-bicarbonate exchange in the enterocyte brush
border
3) DRA encodes a chloride transporter in the chloride-bicarbonate exchange
c. Treatment
1) Replacement of NaCl and KCL
D. Primary epithelial defects –
1. General onset in 1–2 weeks from birth
2. Microvillous inclusion disease
a. Presentation
1) Severe secretory diarrhea and additional osmotic diarrhea after oral intake
a) Severe diarrhea begins in first week
i) 50–300 ml/kg if NPO
ii) 100–500 ml/kg if taking orally
iii) High sodium content (100 mmol/L)
b) Causes profound intestinal failure
b. Prevalence and etiology
1) Most are of Turkish descent
2) Likely due to a major defect in membrane trafficking in intestinal epithelial
cells
a) Gene recently defined - MYO5B
c. Pathology (see Figure 1)
1) Intracellular inclusions and secretory granules
2) Microvilli are depleted on the apical epithelial surface
3) Microvilli are present in intracellular inclusion bodies
4) Crypt epithelium show secretory granules
5) Light microscopy shows villous atrophy
6) No marked crypt hypertrophy
7) PAS shows PAS+ material in upper crypt and villous epithelium with
absent brush boarder staining
8) Treatment
a) TPN
b) Intestinal transplantation has had variable success
c) Past unsuccessful therapies include Corticosteroids, somatostatin,
epidermal growth factor
3. Tufting enteropathy (TE)
a. Presents with moderate to severe diarrhea in the first day of life
b. Differential includes microvillus inclusion disease
c. Pathogenesis
1) Recently discovered to be due to mutations in the EpCAM gene (an
epithelial cell adhesion molecule)
d. Pathology (Figure 2)
1) Presence of tufts of extruding epithelial cells
2) These tufts are usually seen after 2 years
3) Total or partial villus atrophy, crypt hyperplasia and normal or slightly
increased density of inflammatory cells in the lamina propria
4) Tufting may be due to abnormal adhesion of enterocytes to the basement
membrane
5) Rounded epithelial cells at the tips of the villi and are no longer attached
to the basement membrane
e. Treatment
1) TPN
2) Possible small bowel transplant
3) General facts
a) Tufting can be seen in the colon but without inflammation
b) Severe GERD and malabsorption are associated
f. Other primary epithelial defects
1) Intestinal a6b4 integrin deficiency
2) Enterocyte heparan sulfate deficiency
3) Syndromic diarrhea (unknown cause with multiple abnormalities)
4. Enterokinase deficiency (EK deficiency)
a. Presentation
1) Diarrhea at birth
2) Failure to thrive
3) Hypoproteinemia
4) Vomiting in 50% of patients
b. Pathogenesis
1) Enterokinase is secreted by the enterocytes of the intestinal mucosa
2) Without enterokinase, trypsinogen is not adequately activated and
protein absorption is impaired
3) Thought to be a genetic disease but no gene identified currently
c. Treatment
1) Pancreatic enzyme replacement
5. Autoimmune enteropathy (See autoimmune enteropathy)
6. IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked)
(See section on Autoimmune Enteropathy)
E. Villous atrophy
1. Differential diagnosis
a. Total – Celiac disease if intraepithelial lymphocytes present
b. Partial – dermatitis herpatiformis, Giardia infection, absence of HLA expression/
immunodeficiency status, bacterial overgrowth, food protein sensitization,
protracted diarrhea, post-infectious diarrhea
2. Diagnosis – TTG/antiendomysial Ab/antigliadin Ab (Celiac disease), dermal IgA deposits
(dermatitis herpatiformis), Giardia in stool or biopsy (Giardiasis), HLA typing (absence of
HLA), duodenal bacterial counts/H2 breath tests (bacterial overgrowth), food challenge
(protein sensitization), clinical history (protracted diarrhea)

Figure 1. Microvillus inclusion disease.
Severe villous atrophy, absent microvilli.
Figure 2. Tufting enteropathy. Severe

villous atrophy, tufts of rounded tear-drop
shaped enterocytes.
Figure 3. Autoimmune enteropathy.

Severe villous atrophy, Inflammatory
destruction of the crypts, extensive
apoptosis.
Recommended Reading
Canani RB, Terrin G, Cardillo G, et al. Congenital diarrheal disorders: improved understanding of gene defects
is leading to advances in intestinal physiology and clinical mManagement. J Pediatr Gastroenterol Nutr.
2010;50:360-366.
Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the causes of protracted diarrhea of
infancy. J Pediatr Gastroenterol Nutr. 2004;38:16-26.
Turck D, Bernet JP, Marx J, et al. Incidence and risk factors of oral antibiotic-associated diarrhea in an
outpatient pediatric population. J Pediatr Gastroenterol Nutr. 2003;37:22-26.
12G. Food Allergy
Aminu Mohammed, MD
Karen DeMuth, MD
I. F ood allergies are adverse immune responses to food proteins. Allergy can be IgE or non-IgE mediated.
Diagnosis can be challenging, particularly in non-IgE–mediated allergy.
II. Overview/Epidemiology
A. IgE-mediated food allergy
1. Affects 6%–8% of children <4 years of age and 2% of the general population
2. IgE-mediated allergic reactions are rapid in onset and are most common in young
children, with about 50% of reactions occurring in the first year of life
3. Milk, soy, egg, wheat, fish and peanut account for more than 90%of IgE-mediated food
allergy in children
4. Because there is little homology between milk and soy proteins, people with
IgE-mediated milk allergy are able to tolerate soy and vice versa
5. Early IgE-mediated food allergy is associated with later atopic respiratory illness
6. Diagnosis of IgE mediated food allergy is based on typical history with confirmatory skin
prick or RAST testing
a. Routine broad testing for food allergy is not recommended
b. Titer of IgE food antibodies does not predict severity of reactions
7. IgG antibodies against food proteins are not adequate for confirming food allergy
B. Non-IgE or cell-mediated food allergy
1. Insidious onset
2. Includes dietary protein-induced or eosinophilic protocolitis, eosinophilic esophagitis and
allergic eosinophilic gastroenteritis
3. High degree of cross-reactivity between milk and soy protein in sensitized individuals
with food protein–induced enteropathy syndrome (FPIES). Reported prevalence
15%–50%
4. FPIES is a severe cell-mediated, GI food hypersensitivity typically seen with cow’s milk
and soy protein
a. Has been described with many food proteins
b. Presentation: from mild vomiting and/or diarrhea, to hematochezia, dehydration,
lethargy and shock (hypovolemic)
c. Diagnosis is clinical. Skin prick and RAST testing not useful to identify offending
protein. Skin patch testing may have a role in diagnosis
d. Management: avoidance of inciting protein and use of protein hydrolysate or
elemental formula
III. Manifestations
A. IgE-mediated food allergies
1. Signs and symptoms are caused by mediator release from tissue mast cells and
circulating basophils
2. Extra-GI manifestations common in IgE-mediated food allergic reactions: urticaria,
angioedema, rhinoconjunctivitis, gastrointestinal anaphylaxis and generalized anaphylaxis
3. Other presentations
a. Oral allergy syndrome (oropharyngeal pruritus)
b. Food-dependent, exercise-induced anaphylaxis
B. Non-IgE–mediated and mixed food allergies:
1. Diarrhea, hematochezia, increased mucus production
2. Vomiting, abdominal pain, dysphagia
3. Eczema
4. Anemia
5. Poor weight gain/malnutrition

C. Diagnosis
1. Positive responses on in vitro and in vivo tests do not always predict clinically relevant
reactions in blinded food challenges
2. History is key to diagnosis for both IgE and non-IgE–mediated reactions
3. Confirmatory testing for IgE-mediated reactions
a. RAST tests for food specific IgE
b. Skin prick test – more specific than RAST
c. Oral food challenge performed in setting equipped to treat anaphylaxis
4. Associated lab tests present in some non-IgE–mediated reactions
a. Elevated eosinophil count
b. Stool WBC, eosinophils, culture, ova and parasites and C difficile toxin to exclude
infectious causes
c. Celiac serology
d. Flexible sigmoidoscopy may demonstrate colitis in FPIES with increased lamina
propria eosinophils and normal crypt architecture
e. Upper endoscopy useful for diagnosis of eosinophilic esophagitis, eosinophilic
gastroenteritis and celiac disease
IV. Treatment/Management
A. IgE-mediated food allergies
1. Dietary restriction
2. Subcutaneous epinephrine, corticosteroids, anti histamines and H2 blockers for
anaphylaxis
3. Epinephrine auto-injectors (EpiPen) for management of accidental exposure
B. For non-IgE–mediated food allergies:
1. Dietary restrictions
2. Protein-hydrolysate or elemental formula
3. Majority of children are able to tolerate the inciting food protein by age 1–3 years
V. Role of Breastfeeding
A. Breastfeeding infants at high risk of allergic disease for ≥4 months may prevent or delay
occurrence of cow’s milk allergy and eczema during the first 2 years
B. Current evidence does not support any role for maternal dietary restriction during pregnancy or
lactation to prevent allergy
C. Insufficient data to recommend any dietary intervention beyond 4–6 months of age in effort to
prevent atopic disease
D. Current recommendations allow any food after 6 months of age, except those likely to cause
aspiration or choking
VI. Influence of Age

A. Majority of childhood food allergies diminish with time
B. Timing of resolution varies among patients and foods
C. IgE-mediated food allergies:
1. Cow’s milk and egg allergies usually outgrown during childhood and adolescence
2. Peanut, tree nut and shellfish allergies more likely to persist into adulthood (20% of
patients with peanut allergy lose sensitivity with time)
3. Food-specific IgE levels decrease with time in most patients with food allergies. This loss
is the best-known predictor of the development of clinical tolerance
4. Non-IgE–mediated food allergies usually resolve by 1 year of age
VII. Mast Cells
A. Derived from hematopoietic progenitor cells in bone marrow
B. Maturation and differentiation occurs in tissues under the influence of growth factors
C. Found in all vascularized tissues and abundant in host-environment interfaces of skin and
mucosal surfaces
D. Mast cells classified by protease content
1. Tryptase-containing mast cells found in mucosal tissues of intestine and respiratory tract
2. Tryptase and chymase-containing mast cells found in connective tissues of skin,
submucosa and muscularis propria of GI tract
E. Mast cells are active in both IgE and non-IgE–mediated food allergy
F. Antigen cross-linking of high affinity IgE receptors (FcεR1) on surface of mast cells causes
degranulation and mediator release→allergic reactions
G. Eosinophil-derived proteins also induce mast cell degranulation and probably mediate changes
seen in eosinophilic esophagitis
Recommended Reading
American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma
Immunol. 2006; 96:S1.
Furuta GT, Atkins D, eds. Eosinophilic Gastrointestinal Diseases. Immunology and Allergy Clinics of North
America. 2009.
Greer FR. Effects of early nutritional interventions on the development of atopic disease in infants and
children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary
foods, and hydrolyzed formulas. Pediatrics. 2008;121:1.
Wood RA. The natural history of childhood food allergy. Uptodate Article. May 2010.

12H. GI Manifestations
of Endocrine Disorders
Elizabeth M. McDonough, MD
Julia L. Anderson, MD
I. any endocrine disorders have gastrointestinal manifestation and complications. The underlying etiology
M
for the gastrointestinal symptoms is not always known, but is likely due to hormone interactions with the
organs of the digestive system. Thyroid dysfunction and diabetes are the most common endocrine
disorders causing GI symptoms in children.
II. Hypothyroidism:
A. Esophageal dysfunction
1. Decreased LES pressure and low amplitude peristalsis cause dysphagia and reflux
2. Local esophageal compression from goiter causes dysphagia
B. Gastric dysfunction
1. Pernicious anemia and hypochlorhydria secondary to parietal cell antibodies
2. Delayed gastric emptying due to smooth muscle dysfunction, incoordination of antrum
and duodenum, and/or pylorospasm
C. Small bowel dysmotility
1. Small intestine bacterial overgrowth. Improves with antibiotics but not with treatment
of thyroid disease
D. Colon dysfunction
1. Delayed colon transit time. Oro-cecal transit time is usually normal
2. Diminished motility of all hollow viscera occurs in myxedema. Usually reverses with
treatment. Can result in paralytic ileus, megacolon, pseudo-obstruction, volvulus and
ischemia
E. Other
1. Ascites may be associated with pleural and pericardial effusion. Due to increased
capillary permeability
III. Hyperthyroidism
A. Gastric Dysfunction
1. Gastric emptying can be rapid, normal or delayed. All improve with treatment
2. Reduced gastric acid secretion in 33%–37% of patients with thyrotoxicosis due to
antiparietal cell antibodies
3. Hypergastrinemia
a. Possibly due to hypersensitivity of beta-receptors
b. Response to low acid production
B. Small Bowel Dysfunction
1. Diarrhea due to low trypsinogen, bile acid output and rapid orocecal transit
IV. Cushing syndrome

A. Main complications are central or generalized obesity, failure of longitudinal growth, hirsutism,
weakness, nuchal fat pad, acne, striae and hypertension due to glucocorticoid excess. Patients
may develop gastrointestinal complications of diabetes mellitus

V. Adrenal insufficiency (Addison disease)
1. Symptoms: anorexia, weight loss, nausea, vomiting, diarrhea and abdominal pain
2. May be associated with cyclic vomiting syndrome
3. Associated with atrophic gastritis, achlorhydria and pernicious anemia
B. Small Bowel Dysfunction
1. Malabsorption, diarrhea, FTT due to functional defects in enterocyte
2. Reversed with glucocorticoid therapy
C. Liver dysfunction – Chronic elevation of aminotransferases
VI. Hypoparathyroidism
A. Small bowel dysfunction
1. Steatorrhea and malabsorption may be earliest sign of hypoparathyroidism.
Hypocalcemia causes CCK release, gallbladder contraction and pancreatic
enzyme release
2. Diarrhea normalizes with correction of hypocalcemia and vitamin D therapy
3. Must rule out magnesium deficiency which can also present with malabsorption and
functional hypoparathyroidism
VII. Hyperparathyroidism – Sporadic adenoma, MEN type 1 or 2

1. Colonic or gastric atony secondary to increased serum calcium and reduction in
neuromuscular excitability cause nausea and vomiting
2. Peptic ulcer disease due to gastric acid hypersecretion
B. Colon Dysfunction
1. Constipation due to colon or gastric atony secondary to increased serum calcium
C. Acute pancreatitis occurs in 1.5% of patients with primary hyperparathyroidism
VIII. Diabetes Mellitus

A. Pathogenetic factors in GI symptoms
1. Autonomic neuropathy
2. Hyperglycemia
3. Neurovascular insufficiency
4. Autoimmune damage
5. Neurohormonal growth factor deficiency
B. Gestational Diabetes
1. Increases risk of abortion, macrosomia with increased heart and liver size, IUGR,
hypoglycemia, jaundice secondary to polycythemia, and cardiomyopathy
2. Neonatal small left colon syndrome produces postnatal obstructive symptoms
C. Esophageal Dysfunction: Rare
1. LES pressure, peristaltic amplitude and simultaneous a peristaltic contraction attributed
to diabetic autonomic neuropathy (DAN) of vagus and motor nerves
2. Increased risk of GERD
3. ↑ risk of candida esophagitis
D. Gastroparesis – rare in children, but occurs in 58% of adults
1. Solid emptying most frequently impaired
2. Due to antral dysrhythmia, abnormal gastroduodenal pressure, prolonged pyloric
contractions limiting gastric outflow. Exacerbated by hyperglycemia
3. Symptoms – postprandial epigastric discomfort, bloating, nausea, vomiting, indigestion,
early satiety and weight loss
a. Some medications worsen gastroparesis – anticholinergics, TCAs, benzodiaz-
epines and ganglionic-blocking agents
4. Management
a. Improve glycemic control
b. Medical therapy
1) Antiemetics
2) Low-dose tricyclic antidepressants (reduce visceral hypersensitivity)
3) Promotility agents – metoclopramide, domperidone, erythromycin
4) Grehlin
c. Gastric pacing for refractory gastroparesis
E. Acute erosive gastritis occurs in diabetic ketoacidosis
F. 15%–20% of patients with DM 1 have antiparietal cell antibodies, autoimmune chronic gastritis
with pernicious anemia, iron deficiency anemia, hypochlorydia and hypergastrinemia
G. Small bowel dysfunction – diarrhea is the main symptom
1. Due to coexistent celiac disease, pancreatic insufficiency, bacterial overgrowth, drug
therapy, islet cell tumor or fecal incontinence
2. Drugs causing diarrhea - metformin, acarbose and miglitol (inhibit breakdown of of oligo
and disaccharides to monosaccharides in brush border)
3. Diarrhea worse with poorly controlled type 1 DM with DAN
H. Colon Dysfunction
1. Incontinence
a. Usually in the setting of diabetic diarrhea
b. Steatorrhea in 30% of patients
c. Autonomic dysfunction – impaired internal anal sphincter resting tone and
reflexive internal sphincter relaxation
2. Constipation
a. Related to DAN. Complicated by megacolon, pseudo-obstruction, stercoral ulcer,
perforation, volvulus and overflow diarrhea
I. Biliary tree and liver
1. Increased risk of cholelithiasis, cholecystitis, cholangitis
2. Elevated transaminase levels
3. Mauriac syndrome: hepatomegaly with increased glycogen, hypoglycemia, dwarfism
and cushingoid appearance. Results from chronic elevation of serum glucose and excess
hepatic glycogen
4. Nonalcoholic fatty liver disease
J. Pancreas
1. Increased prevalence of acute pancreatitis and exocrine pancreatic insufficiency
2. New onset DM may be first sign of pancreatic cancer
Recommended Reading
Ebert E. The Parathyroids and the Gut. J Clin Gastroenterol. 2010;44 (7):479-482.
Ebert E. The Thyroid and the Gut. J Clin Gastroenterol. 2010:44 (6):40-406.
Feldman Ml. Gastrointestinal and hepatic manifestations of systemic diseases. Sleisenger and Fordtran’s
Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. Philadelphia, PA: Elsevier
Saunder; 2010.
Jospe N. Endocrinology. In: Kliegman R, ed. Nelson Essential of Pediatrics. Philadelphia, PA: Elsevier Saunders;
2006: 820-823.

12I. Secretory Tumors
Affecting the GI Tract
Christopher J. Moran, MD
Brigitte Moreau, MD
Aubrey Katz, MD
I. Zollinger-Ellison syndrome (ZES)

A. Syndrome of hypergastrinemia and gastric acid hypersecretion usually secondary to gastrin-
secreting tumor
1. Prevalence 1–3 per million
2. Usually diagnosed in adults, but cases as young as 7 years old are reported
3. 20% of mutations are inherited; 80% are de novo mutations
4. Responsible for <1% of peptic ulcer disease
B. Typical clinical findings
1. Medically refractory peptic ulcer disease (usually duodenal) in 90%
2. Most common finding is small solitary ulcer in proximal duodenum
3. 80% have diarrhea due to acid interference with fat absorption and high-volume gastric
secretions
4. Suspect ZES in cases of recurrent ulcers or ulcers in abnormal locations
5. 90% have prominent gastric folds
6. Gastric histology shows gastritis and enterochromaffin cell hyperplasia
C. Primary gastrinoma
1. Located in duodenal wall (70%), pancreas (20%) or lymph nodes (10%)
2. Pancreatic tumors are usually larger than tumors in other sites with highest malignant
potential and highest gastrin levels
3. Gastinomas also secrete smaller amounts of VIP and glucagon
4. Metastasis occurs in >60%, most commonly to liver
D. Diagnosis (See Figure 1)
1. Diagnostic: fasting gastrin level >1,000 pg/mL (basal or after pentagastrin) or 10x upper
limit of normal
2. Suggestive: gastrin level between 15–1000
a. Hypergastrinemia secondary to PPI use may produce elevations between 15–
1000. Re-evaluate after discontinuing PPI
3. Secretin stimulation helps clarify the source of intermediated gastrin elevation
a. Secretin causes dramatic rise in serum gastrin in ZES
b. Secretin inhibits gastrin secretion in normal individuals
4. Elevated chromogranin A is suggestive of gastrinoma
a. Chromogranin A is secreted from enterochromaffin cells and is a measure of
enterochromaffin cell mass
b. Hypergastrinemia induces enterochromaffin cell hyperplasia
c. Chromogranin A may be elevated in other neuroendocrine tumors
5. Radiographic localization recommended
a. Somatostatin receptor scintigraphy is most sensitive
b. CT or MR have poor sensitivity especially for small lesions
c. Endoscopic ultrasound may reveal tumors in bowel wall or head of pancreas
E. Treatment:
1. Very high-dose PPI (60–80 mg/day) is usually effective for ulcer healing and prevention
2. Because of the risk of malignancy, resection is recommended for localized tumors

At least 8 h fast
Eliminate other
possible diagnosis
Figure 1. Evaluation for Gastrinoma
Causes of hypergastrinemia
I. Achlorhydria with compensatory hypergastrinemia

a. Pernicious anemia
b. Atrophic gastritis
c. Gastric ulcer
d. Vagotomy
e. H pylori infection
f. PPI therapy
II. Hypergastrinemia with gastric hypersecretion

a. Gastrinoma
b. Renal failure
c. Retained antrum
d. Antral G cell hyperplasia
e. Pheochromocytoma
f. Hypercalcemia
g. Duodenal ulcer
h. Pyloric obstruction with gastric retention
II. Multiple endocrine neoplasia Type 1
A. Syndrome with parathyroid (95%), anterior pituitary and pancreatic tumors
B. ZES occurs in 60% of MEN 1 cases
1. It is presenting symptom in 40% of those cases
2. Associated with duodenal gastrinomas
C. Pancreatic tumors include gastrinoma, insulinoma, non-secreting tumors
D. Autosomal-dominant inheritance
E. Surgical resection of gastrinomas associated with MEN 1 is less effective than resection of gastri-
nomas not associated with MEN
1. MEN gastrinomas are usually multifocal and difficult to eradicate
2. Malignant potential of MEN gastrinomas is less than that of sporadic gastrinomas
III. VIPoma
A. Neuroendocrine islet cell tumor produces vasoactive intestinal peptide
1. VIP secretion is under neural control, which is lost in VIPoma
2. Extrapancreatic VIP-secreting tumors include ganglioneuromas, ganglioneuroblastomas,
neurofibromas and neuroblastoma
3. VIP hypersecretion causes cAMP-mediated secretory diarrhea
4. VIP also blocks gastric acid secretion causing hypokalemia and hypochlorhydria
B. Incidence in adults is 1–10 per million. Incidence in childhood not established.
C. In childhood cases, average age of onset <5 years old (adult onset near 40 years old)
1. No sex predominance in children
2. 75% of adult patients are female
D. Rarely is found in patients with MEN
E. 90% of VIPomas in adults are found in tail of pancreas
1. Other sites: sympathetic ganglia, colon, bronchus, adrenals, liver
2. Common locations for children: adrenals and sympathetic ganglia
a. Children are more likely than adults to have extrapancreatic tumors
3. 60% of adult VIPomas have metastasized at diagnosis
a. Metastasis at diagnosis rare in children
F. Symptoms: secretory diarrhea, hypokalemia, facial flushing (20%)
1. 20–50 mL/kg/day of stool when kept NPO
2. Hypercalcemia occurs due to a PTH-like effect by VIP
G. Diagnosis:
1. Serum VIP level >75 pmol/L (nl <20). Most VIPomas have serum levels ~200 pmol/L
2. Testing must be done while patient is symptomatic, as serum levels vary widely
3. Should screen for primary tumor and metastases with MR or CT
H. Treatment:
1. Increased fluids
2. Octreotide highly effective due to inhibition of neuroendocrine protein secretion
3. Glucocorticoids may slow diarrhea although mechanism unclear
4. Consider surgical resection if no metastasis
IV. Carcinoid tumors

A. Incidence: 1.5 per million
B. 50% of all GI neuroendocrine tumors
C. Commonly found in GI tract (67%)
1. Ileum 28%
2. Appendix and rectum are minor sites
D. Can secrete many hormones (serotonin, histamine, gastrin, insulin, secretin, dopamine, VIP)
E. Carcinoid syndrome
1. Occurs in <10% of GI carcinoid tumors
2. Rarely occurs when tumor limited to GI tract, because secreted hormones enter portal
circulation and are inactivated in the liver
3. Carcinoid syndrome occurs when there are hepatic metastases

4. Symptoms of carcinoid syndrome
a. Flushing in 85% starting on face and neck lasting <30 seconds
b. diarrhea
c. bronchospasm
d. GI mass effects – obstruction, perforation
e. Carcinoid crisis – severe diarrhea, hypotension and flushing
f. Peptic ulcer if tumor secretes histamine
F. Diagnosis:
1. Elevated plasma chromogranin A or serotonin
2. Elevated urinary 5-HIAA (24-hour collection)
3. Bananas, pineapples, walnuts, tomatoes may elevate 5-HIAA
4. Localization by CT or octreotide scintigraphy
G. Treatment:
1. Surgical excision for isolated tumor
2. If diffuse, octreotide is effective for flushing and diarrhea
3. Carcinoid crisis: octreotide and volume resuscitation
4. Avoid catecholamines as they provoke further mediator release from tumors
V. Systemic mastocytosis
A. Elevated histamine levels secondary to increased mast cell numbers
B. Activating mutation in c-kit tyrosine kinase receptor that regulates mast cell proliferation
C. Non-GI symptoms: flushing, reactive airways wheezing, pruritus, neuropsychiatric
1. Urticaria pigmentosa is the most common skin manifestation
2. Worsens with hot showers, stress, certain foods, local trauma, medications
D. Ulcers in 23% (GI complaints in 50%–80%, pain and diarrhea common)
1. Duodenitis or duodenal ulcer is the most common finding
2. Ulcers most likely due to histamine-induced acid hypersecretion
E. Patients do not always have typical skin findings
F. Can have urticarial nodules (mast cell infiltrates, edematous)
G. Treat with acid blockade and antihistamine
1. Trigger avoidance
2. Steroids or mast cell stabilizers may be used in patients with malabsorption
Recommended Reading
Modlin IM. Current status of gastrointestinal carcinoids. Gastroenterology. 2005; 128(6):1717-1751.
Osefo N. Gastric acid hypersecretory states: recent insights and advances. Curr Gastro Rep. 2009;11(6): 433-
441.
Sokol H. Gastrointestinal involvement and manifestations in systemic mastocytosis. IBD. 2010;16(7):1247-

1253.
Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances.
12J. Graft Versus
Host Disease
Raza A. Patel, MD, MPH
Barbara Bambach, MD
I. raft-vs-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation.

G
It is a clinical syndrome that requires synthesis of clinical, laboratory, and histopathologic findings for
diagnosis.
II. Acute Graft vs Host Disease (aGVHD)

A. Definition: Occurs before day post transplant 100
B. Risk: Between 8%–85%
C. Pathogenesis: Transplanted donor T lymphocytes recognize antigenic disparities between
host and donor. Activation of T-cells is one step in complex process. Effect is mediated by
dysregulated cytokine (IL-2, IFN-γ) release by other cells, which leads to tissue damage. Finally,
activated T-cell mediate cytotoxic damage against host cells
D. Findings/Progression: Skin to liver to GI tract (Table 1)
1. Skin: Most common involved organ
a. Manifestation: maculopapular rash, usually occurring at or near the time
of the white blood cell engraftment (Figures 1 and 2). In severe GVHD, the
maculopapular rash forms bullous lesions with toxic epidermal necrolysis
2. Liver: second most commonly involved organ (see VOD vs GVHD)
a. Manifestation: abnormal liver function tests, with the earliest and most common
finding being a rise in the serum levels of conjugated bilirubin and alkaline
phosphatase
b. Pathology: damage to the bile canaliculi, leading to cholestasis
c. Histology: Extensive bile duct damage (e.g., bile duct atypia and degeneration,
epithelial cell dropout, lymphocytic infiltration of small bile ducts), leading to
occasionally severe cholestasis5 (Figures 3 and 4)
3. Luminal tract: third most common organ, described as a distinct entity initially in older
patients
a. Upper GI Tract: more responsive to immunosuppressive treatment than lower
tract aGVHD
1) Manifestations: anorexia, dyspepsia, food intolerance, nausea and
vomiting
2) Diagnosis: upper GI tract endoscopy and biopsies (Figures 5a and 5b)
b. Lower GI Tract: the most severe and difficult to treat and may involve any
location throughout the lower gastrointestinal tract
1) Manifestations: Profuse secretory diarrhea and ileus
c. Endoscopy/Colonoscopy: Findings do not correlate well with histopathologic
findings and range from apparently normal mucosa to severe ulceration
(Figure 6)
1) Visible endoscopic lesions are found in a minority of cases (16%–32%)
but when present, the most frequently described endoscopic findings
are mucosal edema, erythema and friability; erosions and ulcers are less
frequently encountered
d. Histopathology:
1) Apoptosis in the regenerative compartment of gland or crypts containing
intracytoplasmic vacuoles filled with nuclear dust and other karyorrhectic
debris and have been described as exploding crypt cells
2) Scattered eosinophils and neutrophils in more severely affected tissue
3) Cystic dilatation of glands or crypts, crypt abscesses, frank epithelial
destruction has been noted (Figure 7)

E. Prevention/Treatment: immune suppression
1. Steroids: 55% response rate
2. Nonresponders receive second-line therapy, which includes high-dose steroids,
cyclosporine, FK506 and mycophenolate mofitil
III. Chronic Graft vs Host Disease (cGVHD)

A. Definition: after 100 days or as an extension of aGVHD, following resolution of aGVHD, or can
occur de novo
B. Risk: 10%–30% with related donor and 40%–50% with an unrelated donor. 25%–40% of
long- term bone marrow transplant develops cGVHD 3–12 months after engraftment
C. Pathophysiology: poorly understood and may be due to both allo- and autoreactive T cells
D. Findings (Table 2)
1. Skin: lichen planus (Figure 8) and sclerodermatous-like (Figure 9) manifestations
2. Liver: biopsy usually shows extensive damage to small bile ducts (Figure 10)
and, in severe cases, ductopenia; in patients receiving no, or tapering doses of,
immunosuppression, liver GVHD may also present as an acute hepatitis
3. Luminal: multisystemic and proceeded by acute GVHD (88%)
a. Upper GI tract: sclerodermatous-like findings/symptoms
b. Lower GI tract: chronic diarrhea, malabsorption, fibrosis of the submucosa and
sclerosis of the intestine may be observed
1) Often requires parenteral nutrition to maintain growth and nutritional
status
E. Treatment: combination therapy with prednisone and either cyclosporine or FK506 (see section
on VOD vs GVHD)
Table 1. Typical Findings Associated With aGVHD

Skin Liver Gastrointestinal Tract
Clinical Lab Clinical
• Maculopapular rash • Hyperbilirubinemia • Secretory diarrhea
(distal to proximal progression) • Elevated alkaline phosphatase • Vomiting
• Erythroderma • Elevated liver transaminases • Anorexia
• Bullae • Abdominal pain
• Desquamation Histology • GI bleeding
• Lymphocytic infiltration • Ileus
• Damage to interlobular bile • Protein-losing enteropathy
ducts (dilatation of the ducts,
flattening, vacuolization of the Radiology
duct epithelium) • Mucosal/submucosal edema
• Intraepithelial lymphocytes • Rapid barium transit time
in the absence of portal • Loss of haustral folds
inflammation • Ileus
• Occasional apoptotic cells and
canalicular cholestasis within Colonoscopy
the lobules • Non-bleeding ulcers
Histology
• Epithelial cell apoptosis
Table 2. Typical Findings Associated With cGVHD
Skin Liver Gastrointestinal Tract
Clinical Lab Clinical
• Lichenoid eruption • Hyperbilirubinemia • Anorexia
(erythematous, papular) • Elevated alkaline phosphatase • Mouth/esophagus
• Sclerodermatous-dermis and/ • Elevated liver transaminases o Xerostomia
or fascia (thickened, tight, o Pseudomembrane
fragile) Other o Dysphagia
• Joint contractures, severe • Portal hypertension o Odynophagia
disability o Sclerodermatous-like
• Hypo or hyperpigmentation Histology symptoms
• Blister from poor lymphatic, • Lobular hepatitis • Pancreatic insufficiency
ulcers from trauma • Occasional apoptotic cells and • Lower GI tract
• Hyperkeratosis pilaris canalicular cholestasis within o Diarrhea
• Hair loss, destruction of sweat the lobules Histology
glands • Epithelial cell apoptosis
• Premature graying of hair,
eyebrows, lashes
• Nails: vertical ridges, cracking
Figure 1. Painful red to violacious maculopapular rash

consistent with aGVHD in a 2-year-old girl involving the
sole of the foot 11 days after HLA-nonidentical BMT.
Figure 2. Erythema and desquamation before

treatment for aGVHD, day 27.

Figure 3. Hepatic GVHD, day 35. Portal spaces have
extensively damaged bile ducts (arrows) with focally
necrotic epithelium, nuclei of irregular size and shape,
segmental loss of nuclei, shrinking of ductular lumens and
an eosinophilic syncytium of cytoplasm.
Figure 5a. Gastric biopsy with GVHD, day 35.

Of all upper endoscopic biopsy sites, the most
frequently showing histologic changes of GVHD is
the stomach. In the area shown here, large numbers
of lymphoctyes infiltrate the lamina propria and
the basilar portions of the gastric crypts. There is
Figure 4. Liver Histology: The graft versus host disease apoptosis of crypt epithelial cells and frank early
(GVHD) here is affecting the liver, and marked by yellow- crypt destruction. Inflammation and apoptosis of this
brown collections of bile within the canaliculi, as well as intensity are not required for the diagnosis of GVHD.
chronic inflammatory cells within the liver parenchyma.
Figure 5b. Gastric GVHD in which the severe mucosal erythema, edema, and erosion seen endoscopically on the left are
more striking than the focal, mild, epithelial apoptosis (arrow) in the histological section on the right. Although a lymphocytic
infiltrate is absent, apoptosis in multiple crypts is consistent with GVH activity. Inflammation may have been partially controlled
by immunosuppressive therapy.
Figure 6. (Left) aGVHD lower GI tract: Endoscopic photograph
of several linear, non-bleeding ulcers located in the distal colon.
These ulcers represent findings in a patient, status post-bone
marrow transplantation, who developed graft versus host
disease.
Figure 7. (Below) aGVHD lower GI tract. A: Colonic biopsy with GVHD. Focal crypt abnormalities (crypt size
variation and irregular crypt distribution) with decreased mucosal thickness [x]. Inset: Ectatic vessels [y] and
slightly dilated crypt [z] with mild decrease in number of lymphocytes in LP. B: Colonic biopsy with GVHD,
crypt abnormalities with focal ulceration [A], focal reactive surface epithelium [b], focal fibrosis [C], and many
apoptotic cells in crypts [d].
Figure 8. Lichen planus-like chronic GVHD before treatment, day 220.

Figure 10. Chronic GVHD at day 184
post-transplant: high-power view of a
portal area, with damaged small bile
ducts (arrows) infiltrated by lymphocyes.
Figure 9. Generalized scleroderma with atrophy, sclerodactyly, and

joint contracture, day 540 after HLA-identical BMT.
Recommended Reading
Washington K, Jagasia M. Pathology of graft-versus-host disease in the gastrointestinal tract. Hum Pathol. Jul
2009;40(7):909-917.
Ball LM, Egeler RM. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. 2008;41:S58-
S64.
Blood and Marrow Transplantation. Paper presented at: BMT Tandem Meetings2007; Keystone, Colorado.
Castilla C, Perez-Simon JA, Sanchez-Guijo FM, et al. Oral beclomethasone dipropionate for the treatment of
gastrointestinal acute graft-versus-host disease (GVHD). Biol Blood Marrow Transplant. 2006;12(9):936-941.
Colon GVHD: NASPGHAN.org; 2010.
Higman MA, Vogelsang GB. Chronic graft versus host disease. Brit J Haematology. 2004;125(4):435-454.
Jacobsohn DA, Chan GW, AR C. Current Advances in the Treatment of Acute and Chronic Graft-versus-Host
Disease. Blood Marrow Transplant Rev. 2007;17(4):4-14.
Klatt EC. Immunopathology, Graft versus Host Disease Liver Cholestasis Microscopic: University of Utah;
2010.
12K. Drug-induced
Bowel Injury
Razan Alkhouri, MBBS
Susan S. Baker, MD, PhD
I. Introduction
Drugs can cause bowel injury via different mechanisms, including mechanical injury, as seen in pill
esophagitis, by cell death as seen in chemotherapy, by reduction in protective prostaglandins as is seen
with NSAIDS, by changes in motility as is seen with erythromycin, chemotherapy and opiods, and by
changes to bowel flora.
II. P
ill Esophagitis refers to damage to the esophageal mucosa caused by impaction of a swallowed tablet
or capsule with subsequent release of concentrated drug. The majority of injuries occur without underly-
ing esophageal disease.
A. Incidence 10,000 cases/year in the United States
B. Symptoms include dysphagia, odynophagia, and acute onset retrosternal chest pain. Rarely
perforation and stricture
C. Drugs most commonly associated with esophageal injury:
1. Antimicrobials (Doxycycline, Tetracycline, Oxytetracycline, Minocycline, Penicillin,
Ampicillin, Zidovidine)
2. NSAIDs and Salicylates
3. Others ( Bisphosphonates, Potassium chloride, Ferrous sulfate, Corticosteroids,
Theophylline, Quinidine)
D. Risk factors for esophageal ulcer or esophagitis include large capsules, assumption of supine
position immediately after ingestion, inadequate liquid taken with medication causing slow
passage of medication
E. Diagnosis confirmed by upper endoscopy
F. Differential includes herpetic or other acute esophageal infection, unrecognized foreign body
G. Treatment
1. Stop the offending medication
2. Carafate or gastric antisecretory medication may relieve pain until spontaneous healing
occurs
H. Complications
1. Severe, but rare complications include eosophageal stricture, esophageal perforation
with massive hemorrhage or mediastinitis
III. Chemotherapy
A. Chemotherapeutic agents cause mucosal ulceration and inflammation throughout the
gastrointestinal tract by causing death of rapidly dividing cells of the mucosal surface
B. Most common agents to cause mucosal damage are methotrexate, vinca alkaloids, dactinomycin,
doxorubicin and bleomycin
C. Symptoms include abdominal pain, diarrhea, vomiting, melena and protein-losing enteropathy
D. Treatment is mostly supportive. Folinic acid rescue (leucoverin) can be used during or after
treatment with methotrexate to prevent some toxicity
IV. Nonsteroidal Anti-Inflammatory Drug (NSAID) Ulceration

A. Ulcers induced by NSAIDs occur anywhere in the GI tract, but are most common in the stomach,
duodenum and small bowel
B. Slow release NSAIDs shift the target site of damage from stomach to distal intestinal tract. Distal
intestinal ulcers may cause intestinal perforation in adults
C. NSAIDS cause damage by inhibiting cytochrome oxidase (COX) in the mucosa of GI tract, thus
reducing synthesis of protective prostaglandins
D. Risk factors: old age, previous history of ulcers, high-dose NSAID and concomitant use of steroids
or anticoagulants. Among pediatric patient, preterm neonates are at highest risk of NSAID-
associated intestinal perforation

E. COX-2 inhibitors reduce the risk of mucosal damage, but are not effective in treating NSAID-
associated dyspeptic symptoms in adults
F. Misoprostol, proton pump inhibitors, H2 blockers and nitrous oxide are used to counteract the
ulcerogenic effects in the stomach and duodenum
V. Nonsteroidal Anti-Inflammatory Drug (NSAID) Strictures

A. Reported in adults only in the small intestine and colon after prolonged NSAID
B. Occurs in the absence of prior ulceration or perforation
VI. Nonsteroidal Anti-Inflammatory Drug Enteropathy

A. Poorly defined entity with variable disturbance of the small intestinal function in the absence of
macroscopic lesions
B. Mechanism unclear, but inflammation and increase in intestinal permeability may be causative
C. Symptoms of NSAID enteropathy result from chronic blood loss, protein-losing enteropathy and
lipid malabsorption
VII. Nonsteroidal Anti-Inflammatory Drug Colitis

A. Watery or bloody diarrhea associated with NSAID use >6 months
B. Colon biopsies may show eosinophilic, collagenous or pseudomembranous colitis
C. NSAIDS may activate inflammatory bowel disease, especially ulcerative colitis, possibly via
inhibition of COX, which produces a shift in the arachidonic pathway toward the production of
proinflammatory cytokines
VIII. Prostaglandin E1 (PG E1)

A. PG E 1 is used to sustain circulation dependent on ductus arteriosus in neonates with heart
disease
B. Causes diarrhea and antral hyperplasia without pyloric stenosis. Gastric outlet obstruction may
occur
IX. Erythromycin
A. Erythromycin is a gastrointestinal prokinetic that stimulates motilin receptors, causing
contractions of stomach and intestines
B. Erythromycin administration within the first 2 weeks of life increases the risk of pyloric stenosis
by 7–10-fold
C. Maternal use of erythromycin during pregnancy or lactation does not increase the risk of pyloric
stenosis
D. No other macrolide is linked to pyloric stenosis
E. Most common symptom associated with erythromycin is crampy abdominal pain
X. Dexamethasone
A. Associated with gastric and small intestinal perforation in premature infants
B. Dexamethasone used with indomethacin may increase the risk of intestinal perforation
XI. Antibiotic-associated diarrhea

A. Most antibiotic-associated diarrhea is watery, nonspecific and self-limited
B. Clostridium difficile
1. Causes ~20% of antibiotic-associated diarrhea
2. Onset from 4–18 days after first dose of antibiotic
3. Bloody diarrhea with fever, leukocytosis, abdominal pain and, rarely, signs of peritonitis
may occur
4. Causative agents are cytotoxins A and B produced by this organism. Toxins A and B can
be detected in stool by immunoassay or observation of cytotoxic effect on cultured cells.
Organisms can be cultured from stool
5. Colonoscopy shows patchy adherant plaques of white cells and fibrin with apparently
normal intervening mucosa
6. Histology shows cryptitis with microscopic volcano eruptions of white cells. Most likely
mechanism is a change in bacterial flora caused by antibiotics or other drugs. Stasis
caused by drugs or surgery is another risk factor
7. Mild pseudomembranous colitis resolves on discontinuing offending antibiotic. Severe
cases require fluid resuscitation and intravenous metronidazole or oral vancomycin.
Relapse occurs in up to 67% of cases
8. Diarrhea with Clostridium difficile may be the first manifestation of underlying
inflammatory bowel disease
9. Infants under 12 months may have Clostridium difficile or its toxins in stool, but do not
develop pseudomembranous colitis
XII. Drug-induced intestinal hypomotility

A. Most common agents are vincristine, anticholinergics or drugs with anticholinergic properties
(tricyclic antidepressants, opioids)
B. Symptoms of intestinal hypomotility – nausea, emesis, constipation, bloating occur within 2–3
days of therapy
C. Vincristine causes hypomotility by damaging the myenteric plexus. The impact is aggravated by
simultaneous use of itraconazole
D. Anticholinergics cause hypomotility by interfering with nerve conduction in the bowel
E. Discontinuation of drug usually effective within 2 weeks, but vincristine sometimes causes
prolonged symptoms
XIII. Neutropenic enterocolitis: typhlitis and ileocecal syndrome

A. Severe inflammation leading to necrosis in cecum, ascending colon and terminal ileum most
commonly in oncology patients receiving chemotherapy
B. Severe granulocytopenia, fever, nausea, vomiting, diarrhea and abdominal pain
C. Perforation, peritonitis and sepsis can occur
D. Imaging shows fluid-filled lumen, pneumatosis or cecal wall thickening
E. Treatment: triple antibiotics, supportive measures and surgery in case of complications
perforation
Recommended Reading
Kikendall JW. Pill esophagitis. J Clin Gastroenterology. 1999;28:298-305.
Non-steroidal anti-inflammatory drug-induced small bowel injuries identified by double-balloon endoscopy.

World J Gastroenterology. 2005;11(31):4861-4864.
Wallace JL. Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract. Mechanisms of protection
and healing: current knowledge and future research. Am J Med. 2001;110(1A):19S-23S.
Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker Inc.;2008: Chapter 8.

12L. Radiation-induced Injury
Ala Shaikhkhalil, MD
Brendan Boyle, MD
A. Radiation therapy for abdominal malignancies in children is rarely used. Current indications
include: leukemia, intracranial malignancy, Wilms tumor and preparation for bone marrow
transplant
B. The incidence of radiation enteritis in adults receiving abdominal radiation therapy is 2.5%–25%
C. Children are more prone to the acute effects of radiation therapy because of actively growing
tissues. In one study of children with total body irradiation and chemotherapy, 74% developed
GI symptoms acutely and 36% developed GI symptoms chronically
II. Pathogenesis/Pathophysiology
A. Radiation induced injury is described as either acute or chronic
B. Intestinal injury is related to the physical characteristics of radiation exposure: dose rate, total
dose and fractionation, field size and type of irradiation
C. Acute injury contributes to the chronic effects of radiotherapy by several mechanisms
1. Radiation produces free radicals in tissue water disrupting DNA and causing cell death
2. The earliest impact of radiation on gut epithelium is in crypt cells (most rapidly dividing
cells)
3. Cellular response to radiation is influenced by the phase of division cycle. Cells are most
sensitive to radiation in mitotic (cell division) and G2 (DNA synthesis) phases
4. Other modifiers of intestinal radiation injury are tissue perfusion (hypoxic cells are
resistant), pancreatic secretions (exacerbate radiation-induced damage), cellular
expression of different molecules (that can be cytoprotective against programmed cell
death) and platelet adherence to vascular wall (resulting in occlusion of the vascular
lumen)
D. Late complications of radiotherapy are related to vascular and connective tissue changes (these
cells are less mitotically active and less radiosensitive, hence the later effects). Obliterative
endarteritis causes ischemia. Vasculopathy causes progressive fibrosis leading to strictures
E. Microscopic abnormalities in radiation damaged bowel:
1. Increased apoptotic bodies
2. Decreased mitotic bodies
3. Shortened villi with concomitant loss of disaccaridases
4. Crypt abscesses (containing high eosinophils suggesting an allergic-type response)
III. Clinical features

A. Classified as early, chronic and very late
B. Location of radiation determines GI tract involvement
1. Thoracic irradiation causes esophageal symptoms
2. Abdominal irradiation causes small bowel involvement
3. Pelvic irradiation leads to damage in distal small bowel and colon
C. Some chemotherapeutic agents increase the risk of enteritis
1. 5-fluorouracil, methotrexate and actinomycin D
2. These agents are generally avoided in current radiation therapy
D. Small bowel is relatively protected by its constant mobility. Intestinal damage is increased if bowel
is fixed by adhesions or scars
E. Symptoms of acute radiation injury
1. Symptoms and extent of tissue injury are dose related
2. Mostly mild. Respond to supportive management

3. 30% of children develop electrolyte imbalances due to vomiting and diarrhea
4. Symptoms usually improve within 2 weeks of cessation of radiotherapy
5. Patients with severe early enteritis are at greater risk of chronic enteritis
6. Early injury symptoms may develop within hours of exposure but usually begin after
7–10 days
IV. Specific syndromes of radiation injury—Thoracic irradiation (esophageal injury)

A. Esophageal epithelium is radiotherapy resistant; symptoms tend to be mild and reversible
B. Proximal esophagus is most commonly affected
C. Epithelial regeneration starts within 2 weeks after standard radiotherapy but complete epithelial
recovery may take 3–24 months
1. Symptoms typically start within 2 weeks and resolve in about 1 month of cessation of
therapy
2. Symptoms include odynophagia, dysphagia and chest pain
3. Rare complications include tracheo-esophageal fistula, perforation or GI bleeding
4. Radiographic findings in radiation-induced esophageal injury include abnormal
esophageal motility, stricture and ulceration
V. Specific syndromes of radiation injury—Radiation-induced gastritis

1. Uncommon in children
2. Radiotherapy injures mucosal cells and disrupts normal gastric secretion
3. Radiation-induced gastritis occurs within a week of radiotherapy with histological
recovery usually 3 weeks after completing therapy
4. In adults, even low-dose radiation is associated with long-term reduction in stomach
acid production
5. Acute symptoms include anorexia, nausea, fatigue and abdominal cramping and occur
3–4 weeks into standard radiotherapy
6. With modern radiation techniques, the rate of severe gastric injury (ulceration) is about
5% in adults
VI. Specific syndromes of radiation injury—Abdominal irradiation (small bowel injury)

A. Most patients receiving abdominal radiotherapy develop early symptoms consisting of vomiting,
diarrhea and dehydration
B. Diarrhea is caused by loss of absorptive capacity (inflammation, shortened villi, loss of
disaccharidases and bile salt malabsorption)
C. Vomiting and nausea are common. Radiotherapy stimulates 5-HT3 receptors centrally and
peripherally. 5-HT3 receptor antagonists are used in treatment
D. Radiation enteritis is rarely life-threatening, except during concomitant chemotherapy
E. Majority of acute symptoms resolve 2–6 weeks after radiotherapy
F. Acute radiation enteritis largely due to depletion of crypt epithelium, mucositis and damage to
the mucosal barrier. There is dense infiltration of leukocyte and plasma cells, with shortened villi
and decreased total surface area for absorption
G. Acute changes are generally reversible but increase the risk of chronic radiation enteritis
VII. Specific syndromes of radiation injury—Pelvic irradiation (colon injury)

A. Uncommon in pediatric population. Affects distal ileal loops and colon
B. Proctosigmoiditis, mucoid rectal discharge, rectal bleeding and tenesmus
C. Rectal bleeding is difficult to treat but is self-limiting in about 80% of adults. Need for
transfusion is a poor prognostic indicator in adults
VIII. Specific syndromes of radiation injury—Chronic radiation enteritis

A. Affects about 10% of children, usually appearing within 2 months of completion of radiotherapy
B. Most patients have antecedent acute enteritis as well
C. Symptoms—vomiting, diarrhea, abdominal distension, malabsorption, vitamin B12 deficiency
(terminal ileal involvement)
D. Intestinal lesions—adhesions, fibrosis, obstruction, fistula, abscess
E. Most cases affect both small and large intestine and damage is often more extended than
expected
F. Chronic complications tend to progress over time
G. Pathophysiology of delayed reactions is related to persistent villous atrophy, malabsorption,
protein-losing enteropathy (lymphatic damage) and bacterial overgrowth
H. Prognosis is poor; mortality is 10%
IX. Very late effects of radiation therapy

A. Most delayed effects occur 6 months to 5 years after therapy, but may occur up to 20 years later
B. Effects are dose related and affect anatomically fixed parts of the GI tract more often
C. Esophageal symptoms: progressive dysphagia, stricture formation and abnormal motility
D. Small intestinal symptoms: subacute small bowel obstruction, vomiting, abdominal pain,
constipation, diarrhea, bleeding, anemia, anorexia, fatigue and wasting
E. Most children have loose stools for years but it tends to not interfere with daily activities
F. Colonic involvement is rare and manifests as proctosigmoiditis
G. Secondary malignancy is rare
X. Diagnosis of radiation injury

A. Early symptoms
1. Minor symptoms early in therapy do not require formal evaluation. Treat symptomatically
2. Endoscopy especially in pelvic irradiation is helpful shows hyperemia, friability, erosions
and sometimes ulcerations of affected mucosa
3. Perforation risk is high in acute stage disease
4. Biopsies reveal villous atrophy and inflammatory changes
5. Imaging studies rarely helpful in acute injury
B. Delayed symptoms
1. Barium upper or lower GI x-rays helpful in stricture formation, but localization is difficult
in small bowel injury
2. CT and MRI are helpful for diagnosis of abscess and obstruction
3. CT enteroclysis may help diagnose site of obstruction or occult bleeding
4. Common radiographic findings are dilatation of bowel loops, wall edema and loss of
normal motility
5. Endoscopy is rarely helpful in delayed symptoms, as involved areas are often outside the
reach of the scope
6. Testing for malabsorption and bacterial overgrowth can be clinically helpful
XI. Treatment
A. Most symptoms improve with supportive care and resolve within 2 weeks of cessation of
radiotherapy
B. Occasionally changes to the radiotherapy regimen are needed for severe symptoms
C. Management of chronic radiation enteritis is challenging because of the progressive nature of the
condition and the variation in the clinical manifestations
D. Medications
1. Antispasmodic and anti-motility agents are used for abdominal cramping
2. Antidiarrheal agents—loperamide
3. Cholestyramine helpful in bile salt malabsorption–related diarrhea
4. Octreotide may be beneficial as an antidiarrheal agent in patients who fail to respond to
other agents
5. 5HT3 receptor antagonists used for nausea, vomiting and might improve small bowel
dysmotility
6. NSAIDs used for nausea, vomiting and diarrhea
7. Prokinetic agents, sucralfate, acid suppression, NSAIDs and local anesthetics are used
empirically for radiation esophagitis. No controlled studies
8. Sulfasalazine may reduce acute radiation injury when given orally during radiation
therapy. Proposed mechanism is reduced synthesis of eicosanoids (prostaglandins,
leukotrienes, etc)
9. Proctitis treatment includes sucralfate enemas in methylcellulose vehicle, hyperbaric
oxygen and argon laser for coagulation. Steroids and mesalamine not helpful
10. Antibiotics for treatment of bacterial overgrowth
11. Methyl prednisone sometimes used in patients with chronic enteritis and malnutrition

E. Dietary modifications:
1. Assessment of nutritional status and nutritional support essential for all stages of
radiation
2. Lactose free, low fat diet commonly prescribed
3. In severe acute or chronic enteritis, elemental diets and TPN sometimes used
a. Lactose-free, gluten-free, and low-fat low-fiber diet is often helpful in children
with chronic enteritis
4. Dietary supplementation with fat-soluble vitamins and vitamin B12 may be required
F. Surgical/endoscopic intervention:
1. Surgery may be hazardous in an irradiated field; risk of postoperative fistula, perforation
and abscess
2. Resection of affected bowel is preferable to bypass due poor quality of anastomoses
using irradiated bowel
3. Low-grade strictures should be managed conservatively if possible
4. Resection of the rectum may be needed for severe proctitis
5. Factors that contribute to poor surgical outcome:
a. Poor nutritional status
b. Previous surgeries
c. Interval of <12 months between radiation and surgery
6. Argon plasma coagulation often used for hemorrhagic GI tract lesions
7. Esophageal strictures may require repeat dilations
G. Other interventions:
1. Cytokines such as filgrastim shorten the duration of associated neutropenia and may
accelerate recovery
2. Hyperbaric oxygen recently used in adults to create an O2 gradient that stimulates new
blood vessel growth and reduces ischemia. Dosage and administration remain unclear
XII. Prevention
A. Highly focused therapy prevents widespread tissue injury
B. Scale dose to size of child
C. Use of elemental diet or TPN associated with decreased diarrhea during acute phase of
abdominal radiation
D. Prophylactic NSAIDs may ameliorate radiation enteritis. Sucralfate has been shown to reduce
acute and chronic radiation side effects in patients receiving pelvic irradiation
E. Amifostine is cytoprotective in adults against radiation mucositis; it is a prodrug that protects
normal cells against ionizing radiation likely through scavengering free radicals
F. In a large adult-based trial, amifostine failed to reduce the incidence or severity of esophagitis
Recommended Reading
Bismar MSF. Radiation enteritis. Current Gastroenterol Rep. 2002;4(5):361-365.
Bolling T, Ernst I. Late effects of abdominal irradiation in children: A review of the literature. Anticancer Res.
2010;30:227-232.
Feldman M, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders
Elsevier; 2006.
Walker A, Kleinman R, Sherman P, Shneider B, Sanderson I. Pediatric Gastrointestinal Disease. 4th ed. Vol 1.
Hamilton, Ontario: BC Decker Inc.; 2004.
12M. Ostomy Care
Edaire Cheng, MD
I. T ubes for feeding are placed in both the stomach and the jejunum. The complications, advantages and
disadvantages of the tubes differ.
II. Gastrostomy
A. Insertion Methods
1. Endoscopic: Percutaneous Endoscopic Gastrostomy (PEG)
2. Radiological: with fluoroscopic guidance
3. Surgical
B. Advantages
1. Allow long-term access and are easily cared for
2. Can be easily replaced
3. Bolus feeding and administration of medication are possible due to large caliber of the
tube
C. Disadvantages
1. Can increase reflux by altering contour of stomach and allowing larger volume feedings
D. Complications
1. Aspiration, bleeding, tube occlusion, dislodgment, pneumoperitoneum, stomal leakage,
tube deterioration, wound infection
III. Jejunostomy
A. Insertion Methods
1. Endoscopic
a. Percutaneous Gastrojejunostomy (JET-PEG, jejunal extension through a PEG)
—jejunal tube is placed via a matured gastrostomy site
b. Primary Percutaneous Endoscopic Jejunostomy (PEJ)—tube placed with the PEG
technique directly into the small intestine.
2. Radiological—can insert a small feeding tube through the stomach and fluoroscopically
guide it through the pylorus to the duodenojejunal flexure
3. Open surgery
B. Advantages
1. Decrease the risk of tube feeding–related aspiration
2. Early postoperative feeding is possible
C. Disadvantages
1. Infusion pump is required
2. Administration of medication is dependent on the size of the tube
3. Invasive procedures are required for placement
4. Outside connectors are prone to break and may require replacement of the entire tube
5. The tubes are difficult to replace unless a mature tract has developed
D. Complications
1. Pneumatosis intestinalis, bowel obstruction/intussuception, bleeding, tube occlusion,
dislodgment, stomal leakage, tube deterioration, wound infection and volvulus

IV. Proper care for gastrostomy and jejunostomy tubes
A. Checking placement
1. For traditional gastrostomy and jejunostomy tubes, document the external length of the
device to monitor for migration of the internal stabilizing balloon or other device
2. Gastrostomy tubes with internal bumpers ought to allow 360° of rotation. If this is not
possible, a buried bumper may be developing
3. Low profile devices (LPD) should also be monitored daily. The tube should have some
movement. LPDs should be gently pushed in approximately 0.5 inch and rotated 360°
daily to prevent the balloon or internal bumper from adhering to the gastric wall
B. Care of exit site and tube
1. Check exit site for erythema, edema, warmth and exudate. Foul-smelling drainage is a
sign of infection
2. Monitor site for skin breakdown, pressure necrosis, hypergranulation (keep site dry),
gastric leakage (identify the cause)
3. A decrease in exterior length of G tube >1 inch in adults and >0.25 inches for infants
and small children indicates possible tube migration
4. Immediate postplacement skin care. Clean the exit site with diluted hydrogen peroxide
5. After healing, clean the site daily with soap and water. Clean and inspect under external
bumpers or disks to check for excessive pressure. External bumpers and disks should be
just above skin level and not tight against the skin
C. Tube stabilization. Stabilizing a tube can reduce the risk of tube displacement, pain and
enlargement of the tract
1. Sutures or T-fasteners may be used to secure gastrostomy or jejunostomy tubes. Most
jejunostomy tubes require a secure suture
2. Anchoring devices can secure the tube and protect against stoma enlargement and
protect the skin from trauma of frequent dressing changes
3. If the tube has a balloon, check the water in the balloon weekly
D. Maturation of the tract generally occurs in 2–3 weeks in the adult patient and 6 weeks in the
pediatric patient. Longer for PEGs (up to 12 weeks)
1. If the tube is inadvertently removed, it should be replaced as soon as possible; the tract
can close within hours of the incident
Recommended Reading
Kirby DF, Opilla M; American Society for Parenteral and Enteral Nutrition. Nutrition Support Practice. Manual.
2nd Ed.
2006.
13A. Study Design and Statistics
Nisha Mangalat, MD
Sara Rippel, MD
I. REGRESSION TO THE MEAN and SURVIVAL ANALYSIS

A. Regression to the mean refers to the phenomenon that a value in an extreme distribution on first
measurement will tend to be closer to the center of the distribution on a later measurement
B. Survival analysis estimates survival of a cohort over time, making the best use of all available data
from each patient in a cohort. The usual method is Kaplan-Meier analysis. Survival analysis can
be applied to any outcomes that are dichotomous and occur only once during follow-up (e.g.,
time to develop lymphoma after initation of Remicade).
C. On the Kaplan-Meier survival curve, the vertical axis represents the estimated probability of
surviving, and the horizontal axis represents the time from the beginning of the observation
D. The chance of survival is 100% until there is a death (an event). At that time, the probability of
surviving at that point is calculated. The probability of survival, is the number of patients who
have survived divided by the number of patients at risk of dying. Patients who have dropped out
or already died are not included in the denominator
E. To interpret a survival curve, remember that the vertical axis is the estimated probability of
survival for a hypothetical cohort, not the percent surviving in the actual cohort
II. SYSTEMATIC REVIEWS AND META-ANALYSES

A. Systematic reviews are reviews of specific clinical questions. They are systematic because they
summarize the original research pertaining to the clinical questioning, following a specific
scientifically based plan that is formulated in advanced, and described at every step. The result
is that the readers can assess the strength of the evidence for the conclusions that are reached,
and check the validity of the results. The results of a systematic review are usually presented as
a forest plot. A forest plot shows the point estimate and the confidence interval for each of the
included studies
B. A meta-analysis refers the practice of combining the results of individual studies when the
studies are similar enough to be combined. This has the benefit of providing more precise
estimates of effect size than are available in any of the individual studies alone. To ensure that
the studies included are similar enough, a statistical test for homogeneity may be used. Another
approach is to make an informed decision about whether the patients, interventions, outcomes,
etc., are similar enough to be pooled together to answer the same questions
III. PRINCIPALS OF EPIDEMIOLOGY AND CLINICAL RESEARCH DESIGN

A. Case control study: Two samples are selected – patients who have developed the study disease
vs. similar people who have not developed disease. Researchers look backward to measure the
frequency of exposure to a possible risk factor in the two groups
B. Cross-sectional study: People are studied at a cross-section of time. This is a prevalence
study – meaning that the people in a population at a given moment in time are examined for
presence of the condition of interest
C. Case series: Descriptions of groups of patients with a disease. These are particularly useful in
describing early experience with new or rare diseases
D. Longitudinal Study/Cohort Study: Patients are followed over time. Cohort studies are also called
“prospective studies” to denote the “forward” direction in which the patients are followed.
Cohort studies measures incidence, which measures the development of new disease events
over time
E. Randomized-controlled trial: Similar to cohort study, except that treatment is assigned by
randomization rather than physician/patient choice. The “experimental” group is exposed to an
intervention that is believed to be better than the current alternative. The “control” group
is treated in all same ways as the experimental group except that its members are not exposed
to the experimental intervention
F. Before-after study: This may also be called an “uncontrolled” trial. It describes the course of a
disease in a single group of patients before and after exposure to an intervention.
Section 13 - Study Design and Statistics 607

G. Crossover study: Refers to the event when one group of patients in a cohort moves to another
group during their follow-up
H. Open-label study: A trial when there is no attempt at blinding
I. Post-hoc analysis: Refers to looking at the data after the experiment has concluded for patterns
that were not specified previously
J. Subgroup analysis: Process of analyzing a subgroup of patients who have particular outcomes
or special characteristics, beyond the main results of the study. This is of benefit in that clinicians
can tailor care to individual patients. However, there is increased risk of false positive (finding a
difference when there is none) or even false negative (as there is a marked decreased in the data
available)
IV. BIAS AND CONFOUNDING

A. “Bias” refers to any part of data gathering, analysis, interpretation, publication, or review of data
that is systemically different from the truth. Bias includes selection bias (i.e. – volunteer bias),
detection bias (i.e. – recall bias), intervention bias (i.e. – withdrawal or contamination bias)
B. Bias can be prevented by conducting clinical investigations properly, or can be corrected through
proper data analysis. Randomization of subjects helps to insure that groups are comparable.
Blinding is another important tool used to minimize bias
V. CAUSATION
A. Two factors (the suspected cause and the effect) must be associated if they are thought to be
causal. However, not all associations are causal. To determine cause between two factors, several
other reasons for association must be excluded, such as 1) bias (selection or measurement)
2) chance, 3) confounding factors
VI. COST-BENEFIT, COST-EFFECTIVENESS, AND OUTCOMES

A. With cost-benefit analysis, both costs and benefits are evaluated in dollars and compared. In
cost-effectiveness analysis, the costs of alternative means of achieving some benefit are com-
pared. In cost-effectiveness analysis the benefit itself is not measured in dollars
B. The quality-adjusted life-year is a measure of disease burden, including both the quality and the
quantity of life lived. It is used in assessing the value for money of a medical intervention
VII. SENSITIVITY ANALYSIS

A. Sensitivity analysis is a method used to test the robustness of analyses, to see how they vary with
different assumptions. It is used in a variety of analysis types, including meta-analysis, multivari-
ate analysis, cost-effective analysis, decision analysis, and modeling. It is used across a variety of
fields, including engineering, medicine, agriculture, politics, and finance. Sensitivity analysis is
also referred to as “uncertainty analysis”. It is often used in the statistical model building process,
as it allows the modeler to assess uncertainty and see how dynamically the model behaves. If
uncertainty remains after sensitivity analysis, it may prompt changes to be made. The limitations
of sensitivity analyses are that they tend not to challenge the form of the models, the underlying
distribution of errors, or the link between the model and error distribution
B. In meta-analysis, it is used to assess the impact of excluding small trials. In multivariate analysis,
it may assess the impact of excluding different variables. It can also be used to assess the influ-
ence of some of the assumptions used in a model. Estimates of inputs or variables used to make
statistical models are based upon our best guess, and are usually not known with complete cer-
tainty, even in large studies. The goal of sensitivity analysis is to assess to what extent the viability
of a model is influenced by variations in quantifiable input. Basically, a one-way sensitivity model
changes one input to assess the outcome. There can be simultaneous changes made to multiple
input variables as well, which is called n-way sensitivity analysis. Another method is to compare
the model’s answer to the “true” answer when that is known a priori
C. The following is an example of a sensitivity analysis performed for a decision analysis affecting
cost-effectiveness: “As an example, the cost of colonoscopy may be cheaper in some institutions
or health care delivery settings compared with others; thus, to determine the cost-effectiveness
of screening colonoscopy, the cost of a colonoscopy is varied over a range to determine the
maximal cost at which it remains cost-effective. This process (termed “sensitivity analysis”) allows
for a reasonable appraisal about the parameters that are most important in the analysis, and the
stability of the reference case results (Bonis, UptoDate).”
VIII.MEASUREMENT
A. Validity is an indicator of whether a measurement is measuring what was intended. There are
two types of study validity. Internal validity is a measure of how close what you measured was to
what you intended to measure. External validity is a measure of how much your results can be
generalized to a larger population
B. Reliability is the extent to which a measure gives the same result on a repeated trial. It is a
measure of reproducibility or dependability. When a measurement is repeated, reliability is a
way to evaluate the stability
C. In research, accuracy refers to how close the study measurements are to the actual value of the
phenomenon being studied or their exactness. Precision refers to how close repeated study
measurements under similar conditions of the same item are to one another, or their reproduc-
ibility
D. The interobserver κ (kappa) is a measure of agreement between two people rating an item, with
1.0 indicating perfect agreement. It is a measurement of reliability
E. Cronbach’s alpha (Cronbach α, coefficient alpha) is a measure of the internal consistency of
a questionnaire or test. This is often used for a psychological test. It is an index used to test
whether reliability is satisfactory in a multi-item scale
IX. ASSESSMENT OF STUDY DESIGN, PERFORMANCE, AND ANALYSIS (INTERNAL VALIDITY)

A. Internal validity is a measure of how close what you measured was to what you intended to
measure. Proper study design, execution, and analysis are needed to obtain internal validity
B. A control group includes participants in a study who did not receive the study drug or interven-
tion, and are used as a comparison with the cases. The control group may receive placebo or
standard treatment. The control group should be similar to the treatment group, except that
they did not receive the intervention. This should be accomplished with randomization if done
properly
C. In intention to treat analysis, participants are analyzed according to their original group assign-
ment. This is regardless of the intervention they actually received and whether or not they ac-
cepted and/or adhered to the intervention. The advantage of intention to treat analysis is that it
avoids the possibility of bias associated with loss, misallocation, or nonadherence of participants.
ITT analysis contrasts to per protocol analysis, where the analysis is based on actual intervention
received
D. Sample size estimation is the number of study participants needed for the study to have suf-
ficient power. It is based on quantifying study parameters, including the desired size of the
increased/decreased risk or difference, standard deviations of the distributions (based on previous
studies or best estimate), if 1 or 2-tailed, significance level (or P-value), and power of the study.
After the sample size calculation is made, it needs to be adjusted for estimated loss to follow-up.
Statistical power is the measure of the ability of a study to detect a statistical significance, if it
truly exists. Researchers typically use a power of at least 80%. The sample size increases as the
power increases
X. ASSESSMENT OF GENERALIZABILITY (EXTERNAL VALIDITY)

A. External validity is a measure of how much your results can be generalized to a larger popula-
tion. This is also known as generalizability. The study population needs to be reflective of all
patients with the disease in question. Many factors may affect this measure, including geography
and drop-out. Characteristics of the patients who chose not to participate or are lost to follow-
up should be assessed, to ensure generalizability. The study design is key to optimize external
validity
Recommended Reading
Armitage P, Colton T, eds. Encyclopedia of Biostats. Vol 5.
Bonis P. A short-primer on cost effectiveness analysis. Uptodate.com
Byrnes D. Glossary for Vanderbilt’s 2009 Biostats I Course

.
Fletcher R, Fletcher S. Clinical Epidemiology: The Essentials. 4th ed. Lippincott
Kirkwood B, Sterne J. Essential Medical Statistics. 2nd ed.

13B. Research Methods:
Evaluation of the Data
Jeri E.F. Harwood, PhD
I. Variable Types:
A. Continuous: Quantitative variable, with infinite number of possible values without gaps
Blood pressure and blood sugar are examples
B. Categorical: Qualitative variable that is distinguished by some non-numerical characteristic such
as sex, male vs female. Separate the data set into different categories
C. Nominal: A type of categorical variable that cannot be ordered, such as blood type. Nominal
variables tend to have both qualitative and absolute character, making measurement simple
D. Ordinal: A type of categorical variable that can be arranged in some order, but differences
between data values can’t be determined. An example is course grades – A, B, C, D;
or economic status – low, medium, high
II. Data Distribution:

A. The data distribution determines the shape of the data – bell-shapes, uniform or skewed
1. Normal: Data are symmetric, with equal volumes to the right and left. A bell-shaped curve
is an example of a normal distribution
Skewed: If the data are not symmetric, they will extend more to one side than the other.
2.
A skew to the right is described as a positive skew with a long right tail. The mean and
median will be to the right of the mode
B. Mean: Average value. Sensitive to extreme values

1. = Sum of all values/# of values
C. Median: The middle value when data are arranged in increasing or decreasing value
1. = For odd # data set, the median is the middle value
2. = For even number data set, the median is the mean of the middle 2 numbers
D. Mode: The value that occurs most frequently
1. If two numbers occur equally, the distribution is bimodal
2. If more than two occur equally, the distribution is multimodal
3. If no numbers repeat, there is no mode
E. Standard Deviation: Measure of variation of values about the mean (xbar)
1. S = Square root of ∑(x-xbar)2/n-1
Standard error of the mean: Measure of the differences (or distances) between the observed
F.
sample values and the predicted values (mean)
1. Can be calculated from a sample or a regression
2. Se = standard deviation/square root of sample size

III. Diagnostic Tests
A. Incidence: Proportion of population initially free of disease, in whom disease develops over time
1. Incidence per 1,000 = # of new cases of disease occurring during a specified time
period, divided by the sum of time periods of observation of each person who has
been observed
B. Prevalence: Proportion of population with disease at one point in time
1. Prevalence per 1,000= # cases of disease present in population at specified time,
divided by the # persons in population at specified time
C. Sensitivity: Proportion of diseased people who were correctly identified with a positive test
1. Sensitivity = A/A+C = # of true positive (TP) /# with disease (TP + false negatives (FN))
D. Specificity: Proportion of nondiseased people who are correctly identified with a negative test.
1. Specificity = D/B+D = # of true negatives (TN)/# without disease (TN + false positives
(FP))
E. Positive predictive value: Probability patient will have the disease if the test is positive.
PPV determined in a sample will only be representative of the PPV in the target population
if they share the same disease prevalence
1. PPV = A/A+B = TP/TP+FP
F. Negative predictive value: Probability patient will not have the disease if the test is negative.
NPV determined in a sample will only be representative of the NPV in the target population if
they share the same disease prevalence
1. NPV= D/C+D = TN/TN+FN
G. As prevalence of a disease changes, the sensitivity and specificity of a test remains constant. As
prevalence increases, the PPV increases and the NPV decreases. As prevalence decreases, the PPV
decreases and the NPV increases. This is why screening programs are best targeted in high-risk
populations
Mausner JS, Kramer S. Mausenr and Bahn Epidemiology: AN introductory test. Philadelphia, PA:
WB Saunders; 1985:221.
IV. Likelihood Ratios:
A. Positive likelihood ratio: Ratio between the probability of a positive test result, given the pres-
ence of the disease; and the probability of a positive test result, given the absence of the disease
1. Positive Likelihood ratio= TP rate / FP rate = Sensitivity / (1-Specificity)
B. Negative likelihood ratio: Ratio between the probability of a negative test result, given the
presence of the disease, and the probability of a negative test result, given the absence of the
disease.
1. Negative Likelihood ratio = FN rate / TN rate = (1-Sensitivity) / Specificity
C. ROC curves:
1. A tool for diagnostic test evaluation that provides a graphical plot of the sensitivity (true
positive rate) vs the false positive rate (1 − specificity). It is a graphic representation of
the trade-off between sensitivity and specificity. The plot shows the false positive rate on
the X axis and the false-negative rate on the Y axis
Figure from Obuchowski Radiology 2003: 229:3-8
V. Hypothesis testing:
A. Hypothesis: Claim or statement about a property of a population
B. Hypothesis test (test of significance): Procedure to test claim about a property of a population
C. Null hypothesis: Statement that there is no association between the predictor and outcome
variables in the population (i.e., there is no difference in frequency of obesity between subjects
who were breastfed and those who were not). The null hypothesis can be directly tested to
determine whether there is adequate evidence to reject the null
D. Alternative hypothesis: Statement that there is an association between predictor and outcome
(the frequency of obesity is different between subjects who were breastfed and those who were
not). The alternative hypothesis cannot be directly tested, but is accepted by default if the null
hypothesis is rejected
VI. Statistical tests:

A. Chi-Square (X2): Used when data are categorical (i.e., sex). Compares the proportion of
subjects in two groups with a dichotomous outcome. For example, the proportion of children
who develop disease while being treated with a medication compared with the proportion who
develop disease while taking a placebo
B. t Test (Student’s t-test): Used when data are continuous (i.e., age), with a normal or symmetric
distribution. Compares whether the mean value of a continuous outcome variable in one group
differs significantly from that in another group
1. Paired: Paired t-tests have greater power than unpaired tests when the paired units are
similar in collection. Paired t-tests can be used to reduce the effects of confounding.
T-tests typically consist of a sample of matched pairs data
2. Non-paired: Used when two separate sets of independent samples are obtained,
one from each of the two populations being compared, such as a treatment and
control group
3. 1 vs 2-tailed: 1-sided only tests one direction while 2-sided tests both directions.
1-sided should only be used when only one direction has clinical or biological signifi-
cance or plausibility.

C. ANOVA: Used to compare the mean of a continuous outcome between more than two groups
(i.e., blood pressure). The ANOVA takes into account the variability from being part of different
groups (placebo vs treatment) and random variability due to sampling error and individual differ-
ences. The question that ANOVA tests is this: can a significant proportion of the overall variability
found in the results be attributed to the known differences between groups or not? If the vari-
ance between groups is large in comparison to the random fluctuations within groups, it must
be a result of differences between the groups (i.e., treatment)
D. P-value: Probability of getting a value of the test statistic that is at least as extreme as the one
representing the sample data, assuming the null hypothesis is true. The null hypothesis is rejected
if the P value is very small (P ≤0.05)
E. Confidence Interval: Range of values about a sample mean or proportion that reports the
precision of a sample estimate. The value is set by the investigator, such as 95% or 99%.
An interval with greater confidence (99%) is wider, and therefore more likely to include the true
mean or proportion in the population. The interpretation is that we are 99% confident that the
true mean (or proportion) is captured by the interval. The interval is dependent on sample size
with a larger population, allowing for a smaller confidence interval
Type 1 (alpha) error: Accepting the alternative (experimental) hypothesis when it is false. Infer-
F.
ring a difference or association when it is not present
G. Type 2 (beta) error: Rejecting the alternative hypothesis when it is true. A difference in groups
is present, but not detected
True State of Nature

Ho True Ho False
Ho Accepted Correct decision
Type II error: _
Statistical (not rejected) 1-_: Confidence
Decision Ho Rejected Type 1 error: _, Correct decision
(Ha accepted) significance level 1-_; power
VII. Measures of Association

A. Relative risk:
1. Relative risk evaluates if there is an association between exposure to a factor and
development of disease. It can be defined as the ratio of risk of disease in exposed
compared to unexposed, or as the probability of an event (disease formation) occurring
in an exposed people compared to unexposed, or as the ratio of the two probabilities
a. RR = incidence in exposed/incidence in nonexposed
1) =P(disease/exposed)/P(disease/unexposed)
b. Interpretation of RR
1) RR = 1 indicates an association between exposure and disease unlikely
to exist
2) RR >1 indicates an increased risk of disease among those that have
been exposed (possibly causal)
3) RR <1 indicates a decreased risk of disease among those that have been
exposed (possibly protective)
B. Absolute risk reduction:
1. The difference between the control group’s event rate and the experimental group’s
event rate
C. Odds Ratio (Relative Odds):
1. The odds ratio is a measure of whether exposure is associated with a specific disease.
The RR can’t be calculated in a case control study, and thus OR is used in these stud-
ies. OR can be used as an approximation of RR when the cases are representative of all
people with disease, and the controls are representative of all people without disease
and when the disease is rare
2. OR =odds that a case was exposed/odds that a control was exposed
3. Interpretation of OR
a. OR=1 indicates a person with disease is no more likely to have an exposure than
a person without disease. The risk factor is not related to disease
b. OR>1 indicates a person with disease is more likely to have an exposure
c. OR<1 indicates a person with the disease is less likely to have been exposed.
This implies the risk factor may be protective
D. Hazard Ratio:
1. Hazard Ratio is the slope of the survival curve, and compares two groups. For example,
if the hazard ratio is 3.0, then the rate of deaths (or event of interest) in one group is
three times the rate in the other group
E. Number needed to treat (NNT):
1. A measure with clinical significance that allows for comparison of different treatment
effectiveness
2. NNT = 100/absolute risk reduction
3. Interpretation of NNT
a. NNT = 100; One-hundred people would need to be treated to save one life.

14. Principles of
Teaching and Learning
Aliza Solomon, MD
I. Principles of Adult Learning Theory

A. Professional development activities should be created with consideration for principles of how
adults learn best. This enables the instructor to become an effective educator.
II. Principles of Adult Learning

A. Assess the level of the learner
B. Actively involve the learners in the learning process
C. Encourage mutual feedback
D. Teach information in the context within which it will be applied
E. Encourage self-directed learning
F. Adults learn better in an informal, non-threatening environment – the environment
should be fun
G. Adults learn better when they want or need to learn something. This integrates with demands of
their own life
H. Adults learn better when their individual learning needs and styles are met
I. Adults learn better when their previous knowledge and experience are valued and used
J. Adults learn better when there are opportunities for them to have some control over the
learning content and activities
K. Adults learn better through active mental and physical participation in the learning activities
L. Adults learn better when sufficient time is provided for the assimilation of new information,
practice of new skills, or development of new attitudes
M. Adults learn better when they have opportunities to practice or to apply successfully what they
have learned
N. Adults learn better when there is a focus on relevant and realistic problems and the practical
application of learning
O. Adults learn better when there is guidance and some measure of performance, so that learners
have a sense of progress toward their goals
III. Effective Learning Environment

A. Learning is an active process. An effective learning environment relies on the educator to take
into account the following principles:
1. The objectives and expectations are clear to both the educator and learner
2. The focus is on the development of problem-solving skills and attitudes
3. The teaching level is appropriate for the learner
4. There is active participation of the learner
5. There is adequate supervision and provision of feedback to the learner
6. There is the opportunity for reflection and discussion
7. There is respect for privacy and dignity of patients
8. There is continuity with the rest of the curriculum
Section 14 - Principles of Teaching and Learning 617

IV. Teaching Methods:
A. Teaching can occur in many different locations, from the classroom to the bedside. Classic
teaching occurs in lectures, allowing for a large volume of information to be distributed to many
students. Small group discussions, bedside teaching, and simulation all provide excellent teach-
ing opportunities, each with strengths and weaknesses. Time for reflection between learning
opportunities is an important part of teaching.
B. “Learning is the process whereby knowledge is created through the transformation of experi-
ence.” (Kolb). The theory by Kolb is represented by cyclical model which consists of four stages :
C. Reflection– Reflection is the process of critically assessing and giving meaning to an experience.
The “Reflective Practitioner” is able to critically analyze a situation using a theoretical back-
ground and practical experience (Schon). Consideration of the larger context is crucial. This type
of reflection is necessary for lifelong self-directed learning.
V. Feedback and evaluation

A. Feedback is a crucial part of the learning process. Feedback should be given after a learner
actively experiences an activity, so that when the learner consciously reflects on that experience,
the evaluation may be incorporated to improve their future performance and ensure success.
1. Formative Evaluation – A formative evaluation is a method of providing feedback while
the activity is happening. This type of assessment is good for setting short-term goals. It
is usually performed in an informal manner, and provides opportunity for improvement.
Potential methods of formative evaluation include:
a. Direct Observation – Feedback provided in an ‘on the spot’ situation (procedural
skills, lectures, written patient care notes, and informal oral presentations)
b. Self Assessment Form – A method of critically assessing the learner’s own skills
c. Semiannual Evaluation – Critical assessment of competency periodically
throughout the learning experience/time period
d. Competence forms for procedural skills
2. Summative Evaluation – A summative evaluation provides information about the overall
effectiveness of the education program on the learner. It defines how the learner did.
The summative evaluation is a means to assess the accomplishment of long-term goals.
It can be more formal, and reflects the previous formative evaluations.
a. Verification of Competence form as specified by the American Board
of Pediatrics
1) 6 ACGME competencies
2) Scholarly activity
Recommended Reading
Hafferty FW. Beyond curriculum reform: confronting medicine’s hidden curriculum. Acad Med. 1998;73:403-
407.
Kolb DA. Experiential Learning: Experience as the Source of Learning and Development. Englewood Cliffs, NJ:
Prentice-Hall, Inc.; 1984.
Schon D. The Reflective Practitioner: How Professionals Think In Action. USA: Basic Books Inc; 1983.
Sheal PR How to develop and present staff training courses. New York, NY: Nichols Publishing; 1989.
Spencer J. Learning and teaching in the clinical environment. BMJ. 2003; 326(7389):591-594.
Section 14 - Principles of Teaching and Learning 619

15. Ethics
Herbert Brill (subcommittee chair)
Ellen Blank
Katryn Furuya
David Israel
Daniel Kamin
Crystal Knight
Steve Schwarz
I. Basic Concepts:
A. Ethics: a body of knowledge and expertise that explains why actions or thoughts are morally
right or wrong. Ethical analysis seeks to explain why some actions or thoughts may be more or
less morally right or wrong than others
B. Ethical principles provide a framework for decision making by physicians and their communica-
tions with patients and colleagues
C. An ethical dilemma is a situation in which potential solutions involve a conflict between two or
more of the basic ethical principles
II. Belmont Report

A. 1979 NIH statement of basic principles and guidelines is recommended as a guide for evaluating
and solving ethical issues surrounding the conduct of research in human subjects and the con-
duct of direct patient care. The report lists four cornerstone tenets (B-E below) that serve as the
framework for establishing an ethical physician-patient and physician-study subject relationship
B. Autonomy is present when the patient has both Liberty and Agency
1. Liberty – freedom from controlling influences. This condition requires that physicians
preserve patient liberty by avoiding coercion, i.e., compelling a decision by using
financial, emotional, or other inducements
2. Agency—ability to perform intentional action
a. Competent adults have the right to self-determination
b. Self determination requires that a patient be “capable”, but there are no
accepted criteria for defining capacity or incapacity. Determination of compe-
tence/capacity is a judgment based on evidence, which can always be disputed
c. Level of evidence for determining capacity/competence should vary directly with
the level of risk
d. Standards of incompetence, from least to most stringent (after Beauchamp and
Childress, 2009)
1) Inability to express or communicate a preference
2) Inability to understand one’s situation and its consequences
3) Inability to understand relevant information
4) Inability to give a rational reason for a decision
5) Inability to give risk/benefit-related reason
6) Inability to reach a reasonable decision (as judged by a reasonable
person standard)
3. In the case of children or adults who are incapacitated, there is a need to involve sur-
rogate or substitute decision makers
a. Parent/Guardian or Guardian/Health Care Power of Attorney must represent
patient’s interests
1) Give permission on behalf of children or the never-before competent –
standard is best interest of the child
2) Guardians give consent on behalf of incapacitated patients who were
once competent – standard is substituted judgment (what would this
person want if he/she could speak for him/herself?)
Section 15 - Ethics 621

3) Parents are considered the decision makers for their minor
children unless:
a) They are deemed unfit (e.g., child abuse, mental illness,
inadequate cognitive capacity). Then a guardian is appointed
b) The child is deemed by a court to be a mature minor and able
to make a specific health care decision (e.g., being a bone
marrow donor)
c) The child is deemed an emancipated minor (e.g., living
independently, married, serving in the military)
b. Physician must at all times represent the patient’s best interests
4. Assent before receiving treatment
a. Children should participate in decision making to a degree commensurate
with their abilities
b. Parents must still give permission
c. Treatment may be provided even while children object, yet assent should be
attempted unless refusal of treatment is clearly detrimental to the child’s health
and well-being
5. Emancipated minors
a. Certain conditions are considered indicative of adulthood—pregnancy, financial
independence, parenthood
b. Certain conditions, cannot be effectively treated if parental oversight were
required (e.g., sexually transmitted diseases)
c. Laws determine that emancipated minors are able to make independent medi-
cal decisions, provided they have the capacity to do so
6. Principles of adequate informed consent
a. Threshold elements
1) Competence
2) Voluntariness
a) Respect refusal
b) In the case of children, parental refusal must not present a
certain danger to the child. Society has an obligation to protect
the vulnerable
b. Informational elements required of the physician
1) Disclosure of material information
2) Present all alternatives
3) Best recommendation
c. Consent elements
1) Decision to choose a plan
2) Authorization to enact the plan
d. Children at a cognitive level of age 8 years are required to give their assent,
along with parental consent, to participate in human research protocols
e. Patient Self-determination Act of 1990: At the time of admission or treatment,
information regarding the patient’s right to refuse care or create an advance
directive must be given to the decision maker
C. Beneficence
1. Positive beneficence means to do good or to provide benefit to others
2. Obligations of beneficence
a. Rescuing persons in danger
b. Removing conditions that cause harm to others
c. Preventing harm from occurring to others
d. Protecting and defending the rights of others
e. Promoting the welfare of others
3. Paternalism almost always creates a conflict between the principles of autonomy
and beneficence
a. Definition: The intentional overriding of one person’s preferences or actions by
another person, where the person who overrides justifies this action by ap-
peal to the goal of benefiting, or preventing or mitigating harm, to the person
whose preferences or actions are overridden
b. Justification: As a person’s autonomy interests increase and prospects for ben-
efit decrease, the justification of paternalism decreases. As a person’s autonomy
interests decrease and the possibility of benefit increases, justification for pater-
nalism increases
c. Much larger role for paternalism in pediatrics
1) Children cannot make autonomous choices, so parents give permission
2) Pediatrics promotes children’s best interests as well
3) Shared decision-making occurs over a reasonable spectrum of some
options, but not all
4. Utility refers to beneficence towards groups and populations, in contrast to the individu-
al patient
a. Utility seeks to find the best balance of benefits, risks, and costs to produce the
best overall result to the population
b. Methods used to determine utility include cost-effectiveness and cost-benefit
analysis
c. Determination of outcomes is critical to improving utility. One measure of
outcome is quality-adjusted life years (QALYS)
D. Non-maleficence – Primum non nocere (First, do no harm)
1. Differs from beneficence in that the obligation to do no harm is generally stricter than
the obligation to do good
2. Concepts of importance in determining the nature and magnitude of harm
a. Has there been negligence?
b. Killing vs letting die
c. Intending vs foreseeing bad outcomes
d. Optional vs obligatory treatments
1) Futile treatments—no obligation to continue or offer treatments that
have no/little hope of benefiting patients
2) Contraindicated treatments—obligation not to treat
e. Withdrawing or withholding treatment should be considered equivalent ethi-
cally
E. Justice
1. What is fair? Is the physician treating equals equally, and unequals unequally?
2. Allocation of scarce resources, such as access to health care, should be distributed so
that everyone benefits equally. Allocation must be fair and according to need, and
independent of culture, ethnicity, and ability to pay
3. Physicians should not make bedside or direct patient care decisions regarding individuals
based upon societal needs
III. Principles Guiding Confidentiality/Disclosure

A. The Principles of Confidentiality apply to both clinical care and research protocol environments,
and may be breached only under specific, defined situations
B. Current NIH policies on confidentiality/disclosure include the following statement (from NIH
policies on human subjects research):
1. …persons engaged in biomedical, behavioral, clinical, or other research (must) protect
the privacy of individuals who are the subject of such research, by withholding from all
persons not connected with the conduct of such research the names or other identifying
characteristics of such individuals. Persons so authorized to protect the privacy of such
individuals may not be compelled in any federal, state or local civil, criminal, administra-
tive, legislative, or other proceedings to identify such individuals.*
* Public Health Service Act §301(d), 42 U.S.C. §241(d)
Section 15 - Ethics 623

C. The Principles of Confidentiality are also relevant to the care of subjects not involved in a
research study, according to the following tenets:
1. The physician is obligated to maintain information in strict confidence
2. This confidentiality must be balanced against duty to warn. The physician may have to
breach strict confidentiality to avoid harm to society or persons
3. Confidentiality principles must also be balanced against the risk that failure to disclose
data to appropriate agencies may result in greater societal harm
4. Disclosure: the information one ought to share before an informed decision can be
reached
5. Care provider has duty to inform patient/family of an unexpected adverse event
IV. Ethical Considerations Specific to Human Subjects Research (NIH principles)

A. The obligation of the IRB (Committee for the Protection of Human Subjects) includes protocol
assessment to assure the following:
1. The research plan must be sound
a. What are the underlying objectives of the project?
b. Are these objectives clearly formulated?
c. Is study design sufficient to achieve stated goals?
d. Are researchers competent to carry out study?
e. How will data be analyzed?
f. How will results be disseminated?
B. The risks must be in proportion to the benefits/knowledge gained from research
C. Safety must be maximized
D. Subject selection must be equitable
E. Privacy and confidentiality must be adequate, and informed consent must be obtained
F. Investigators’ conflicts of interest must be identified and resolved/managed
G. Pediatric Risk Categories - Subpart D of 45 CFR (Code of Federal Regulations) 46:
1. In every proposed research protocol involving minor subjects, a major obligation of the
IRB includes an assignment of risk that takes into consideration all aspects and all study
groups involved in a planned study. The obligation of risk assignment is unique to the
evaluation of research in subjects <18 years of age. Risk determination is based upon
that component of study, irrespective of study group, which is associated with the great-
est risk to individual subjects in the study
16. Questions and Answers
1. Which of the following is not associated with esophageal webs?
A. Plummer-Vinson syndrome
B. Epidermolysis bullosa
C. Lupus
D. Psoriasis
E. Stevens-Johnson syndrome
2. An 11 year old boy complains that occasionally a bite of hotdog “gives mild pressing pain in his
chest” and that “it takes a while before he can take another bite.” If it happens again, he discards
the hotdog but sometimes he can finish it. The most helpful diagnostic information would come
from
A. Family history of Schatzki rings

B. Eosinophil counts
C. UGI
D. Time-phased MRI
E. Technetium 99 salivagram
3. 12 year old boy previously healthy with one-month history of difficulty swallowing both solid and
liquids. He sometimes complains food is getting stuck in his retrosternal area after swallowing. His
weight decreased approximately 5% from last year. He denies vomiting, choking, gagging, drooling,
pain during swallowing or retrosternal pain. His physical examination is normal.
What would be the appropriate next investigation to perform in this patient?
A. Upper Endoscopy
B. Upper GI contrast study
C. Esophageal manometry
D. Modified Barium Swallow (MBS)
E. Direct laryngoscopy
4. A 12 year old male presents to the ER after a recent episode of emesis. The parents are concerned
because undigested food 3 days old was in his vomit. He admits to a sensation of food and liquids
“sticking” in his chest for the past 4 months, as he points to the upper middle chest. Parents relate a
10 lb (4.5 Kg) weight loss over the past 3 months. Past medical history and family history are unre-
markable. Vital signs are stable, and physical exam is unremarkable. The ER physician obtains a chest
X-ray AP and lateral that shows dilatation of the esophagus with an air fluid level. What is the best
diagnostic test for this patient’s condition?
A. Endoscopy
B. 24 hour PH monitoring
C. Barium swallow
D. Esophageal manometry
Section 16 - Questions and Answers 625

5. A 26 month old female is referred to the GI clinic with a history of spitting up since 10 month of age.
Mom noticed that symptoms began after the introduction of table food. The pediatrician diagnosed
GERD and started the patient on an H2 blocker. Medication was changed to a proton pump inhibi-
tor without improvement and the patient continued to spit up and have difficulty swallowing with
solids but not with liquids. She was in the 50%ile for height and the 25%ile for weight. Her diet was
mainly liquid. The pediatrician was concerned because in the last month she did not gain weight. Af-
ter your history and physical exam you ordered a barium swallow which showed a posterior impres-
sion of the upper-middle esophagus. Which of the followings is the next step in management?
A. Esophagoscopy
B. 24 hours PH monitoring
C. Barium swallow
D. Esophageal manometry
D. Chest MRI
6. Eosinophilic Esophagitis is associated with the following diseases except:
A. Atopic Dermatitis
B. Asthma
C. Helicobacter Pylori
D. Allergic Rhinitis
7. You are seeing an 8 year old male in clinic as a follow-up from a recent EGD you performed for the
sensation of “things getting stuck” while swallowing. A distal esophageal biopsy showed 10 eosino-
phils/HPF. The EGD was otherwise endoscopically and histologically normal, which included a total of
6 esophageal biopsies. What is the most appropriate next step:
A. Start oral fluticasone.

B. Start proton pump inhibitor therapy
C. Start elemental diet
D. Refer to an allergist
8. You have diagnosed a 1 year old child with eosinophilic esophagitis. All of the following are treat-
ment options except:
A. Oral fluticasone.
B. Directed food elimination diet based on food allergy testing (skin prick and patch testing)
C. 6-food elimination diet (eliminating milk, soy, egg, wheat, peanut, and fish/shellfish)
D. Elemental diet
E. Lactose-free diet
9. A 10 year old African-American female presents with complaints of several months of intermittent
symptoms including trouble keeping eyelids open, inability to brush her hair, and trouble getting out
of chairs at school. Her speech is sometimes slurred. She complains of double vision occasionally. Her
symptoms are usually worse in the evening after school. On exam, she has bilateral ptosis. When
asked to raise both extended arms over her head, she can raise them only 3-4 times before tiring. On
laboratory evaluation, she is acetylcholinesterase receptor antibody positive. Which of the following
structures is most likely to be affected?
A. Duodenal villi chloride channels

B. Colonic motility
C. Bile canaliculi
D. Upper esophageal sphincter
E. Pancreatic duct
10. The ER calls you at 7 PM to see a 2 year old who swallowed an unknown quantity of vanilla scented
hair relaxer. You ask about the presence of facial or oral lesions and you are told none are evident
but the patient is not fully cooperative for a complete exam. You know the endoscopy suite is only
on emergency status so you
A. Request the ER attending to call the ENT service.

B. Request the ER attending to notify the endoscopy suite for an emergent study.
C. Proceed to the ER for your own assessment and finding no lesions or respiratory distress,
you recommend sending the patient home on bismuth subsalicylate to return for F/U in one
week.
D. Proceed to the ER for your own assessment and finding no lesions you or respiratory distress,
you recommend symptomatic treatment and endoscopy the following morning
11. The patient with achalasia may have:
A. Incomplete relaxation of the lower esophageal sphincter

B. Ineffective peristalsis
C. Absent peristalsis
D. Dysphagic chest pain
E. A and C
F. All of the above
12. Bloody emesis in a 2 day old healthy full term neonate is likely to be secondary to:
A. Mallory-Weiss tear
B. Esophageal varices
C. Foreign body aspiration
D. Swallowed maternal blood
13. Which of the following statements is true regarding reflux:
A. Thickening formula reduces reflux episodes

B. Proton pump inhibitors have been found to improve infant irritability
C. Treatment with PPI’s for three months is indicated in patients with endoscopically proven
reflux esophagitis
D. Acute life threatening events have definitively been linked to gastroesophageal reflux disease
E. Erythromycin has been proven to be beneficial in patients with GERD
14. Nissen fundoplication is indicated for all except:
A. Institutionalization
B. Intractable pain
C. Recurrent bleeding
D. Recurrent aspirations
E. Neurological impairment
15. ENT complications of GERD may include all of the following except:
A. Sinusitis
B. Otalgia
C. Laryngitis hoarseness
D. Glue ear
E. Recurrent epistaxis

16. An older sibling finds his 18m/o brother has taken apart a small non-functioning LED flashlight and
the lithium battery is missing. He informs his parents who then bring the toddler to the ER. The ER
attending calls and informs you that by x-ray the battery in the stomach. You proceed to the ER,
review the history, examine the child and find he is in no distress. You then:
A. Call the endoscopy suite to set up for immediate removal

B. Tell the parents since the battery size is <10mm there is no need for concern or follow-up
C. Tell the parents a “dead” battery will not cause tissue damage
D. Arrange to follow the course of the battery with daily radiographs
E. Discharge the patient for F/U in one week but ask the parents to notify you if pain or vomit-
ing evolves and to examine diaper stools for the battery over the next 2-4 days
17. A one week old male infant has crying after feeds that last 2 hours. He spits up and often calms
down after passing gas. He stools after each feed. He takes a standard cows’ milk formula. Mother
recently noted small flecks of blood in the stools. The most likely etiology is
A. Malrotation
B. Pyloric stenosis
C. Hirschsprung’s Disease
D. Milk-protein intolerance
E. Mild ulcerative colitis
18. Which statement is false?
A. E. histolytica infections are asymptomatic in 90% of patients.

E. histolytica liver abscesses tend to occur only in those children
B.
who develop severe dysentery
C. G. lamblia can be zoonotic.
D. B. hominis produces diarrhea, bloating and eosinophilia
E. G. lamblia is predominantly contracted through water.
A. Salmonella infections can result from contaminated eggs, chicken, salads and cheese.
B. Campylobacter and Shigella sp infection can be very similar in presentation.
C. Yersinia infection of the terminal ileum can mimic appendicitis
D. Bacillus cereus constitutes a major component of probiotic therapy
Bacillus bifidum and Streptococcus thermophilus constitutes major components of probiotic
E.
therapy
20. Which is a common association found amongst gastric polyps?
A. Peutz-Jeghers syndrome and juvenile polyps

B. H. pylori infection and hyperplastic polyps
C. Juvenile polyposis syndrome and fundic gland polyps
D. Familial adenomatous polyposis syndrome and hamartomas.
21. With respect to gastric tumors in childhood, which statement is false?
A. Fundic gland polyps associated with familial adenomatous polyposis may undergo
malignant transformation
B. Fundic gland polyps associated with long-term PPI use rarely appear before six years
C. Fundic gland polyps associated with long-term PPI require surveillance for
malignant transformation
D. Nearly all patients with Peutz-Jeghers syndrome require surveillance for gastric hamartomas
E. Gastric teratomas with fetal elements occur exclusively in females
22. During a fraternity initiation, a 18y/o is forced to swallowed two live minnows. Three days later he
presents to the ER with severe abdominal cramps, nausea and blood tinged vomitus. Physical exami-
nation reveals diffuse abdominal tenderness. You decide to consult a surgeon because you suspect
A. A perforated duodenal ulcer

B. Outlet obstruction by a minnow
C. Gastritis from schistosomiasis
D. Gastritis and perforation by Eustrongylides
23. Regarding H pylori which statement is true?
A. The natural reservoir for H pylori is zoonotic

B. Once gastritis becomes chronic it is usually irreversible
C. 90% of children with duodenal ulcer have antral H pylori infection
D. Approximately 15-20% of children with GERD response to H pylori eradication
C. H Pylori
24. Regarding H pylori infection which statement is false?
A. Patients with MALT lymphoma experience regression of the tumor with

eradication of H pylori
B. H pylori gastric “cobblestoning” is more common in children
C. Biopsy for H pylori is best obtained from the antrum
D. H pylori grows best on chocolate agar medium
25. The metabolic disturbance most typical of pyloric stenosis is:
A. Hypochloremic acidosis
B. Hyperchloremic acidosis
C. Hypochloremic alkalosis
D. Hyperchloremic alkalosis
26. Which object(s) is LEAST likely to require endoscopic removal from the stomach?
A. 8 cm metal rod
B. A toy with known lead paint
C. 4 magnet balls
D. A nickel from a 9 year old boy
27. Which items is MOST likely to need endoscopic removal from the stomach?
A. A 3 cm-long pen cap in a 14 year old boy

B. A closed safety pin
C. A quarter ingested 4 weeks ago.
D. A 1 cm long toy piece
28. Which of the following is matched with its major site of injury?
A. Acid ingestion → stomach

B. Alkali ingestion → stomach
C. Doxycycline → duodenal bulb
D. Ibuprofen → colon

29. An 8 year old female comes to the ER with 12 hours of abdominal pain, vomiting, and low grade
temperature of 100.2. On exam, she has diffuse tenderness with guarding in the right lower quad-
rant and rebound tenderness. The next best step in management is:
A. Oder a CBC, blood culture, and urine culture

B. Order an abdominal CT without contrast
C. Order a surgical consult
D. Order a pelvic ultrasound
30. A 14 year old male has had diarrhea and vomiting for 3 days with fevers up to 102. Today he has
right-sided lower abdominal pain with rebound tenderness. Laparoscopy only shows mild periappen-
diceal involvement. Which of the following is most likely to yield the correct etiology:
A. Blood culture for gram negative sepsis

B. Stool culture for yersinia
C. WBC to look for immunosuppression
D. Colonoscopy for inflammatory bowel disease
31. 3 month old male infant is referred to you because of secretory diarrhea and hypoglycemia. His work
up included normal CBC, and normal Immunoglobulin levels except for elevated IgE. You are sus-
pecting autoimmune enteritis (AIE) as a diagnosis. Which one of the following is true about AIE?
A. IPEX usually presents later in childhood.

B. It only affects boys.
C. Histology is significant for intraepithelial T cell infiltration.
D. Patients usually have normal lymphocyte count.
E. Only the IPEX form has extra-intestinal manifestations.
32. In you discussion with the parents of the above patient, which of which statement is correct?
A. Most of these cases will resolve by adolescence.

B. Diarrhea will decrease with bowel rest.
C. Immune suppression with monotherapy is effective.
D. BMT helps control diabetes and eczema in patients with AIE.
33. Appendicitis is usually characterized by periumbilical pain which moves to the RLQ within the first
12-24 hours. In what situation may a patient not experience the “classic” RLQ pain associated with
appendicitis?
A. A long appendix
B. A fecalith impacted appendix
C. A perforated appendix
D. A retrocecal appendix.
34. Which of these would be most likely to cause pain in the LLQ?
A. Sigmoid volvulus
B. Pancreatitis
C. Acute Cholecystitis
D. Peptic ulcer
35. A full-term neonate has nonbilious emesis after each feed since birth. An abdominal radiograph
shows a dilated stomach and you suspect possible gastric outlet obstruction. The next diagnostic test
performed should be:
A. Nuclear medicine gastric emptying study

B. Barium contrast upper gastrointestinal series
C. Magnetic resonance imaging of the abdomen
D. Nuclear medicine biliary scan
E. Left lateral decubitus radiograph
36. A 2 year old male undergoes an abdominal ultrasound to evaluate the kidneys after an abnormal
urinalysis is discovered. A gastric duplication cyst is an incidental finding on the ultrasound. The cyst
is not large enough to cause compression and the child has no vomiting. The recommended timing
of treatment is:
A. Emergent surgery the same day

B. Surgical excision soon after the lesion is discovered
C. Surgical excision after 5 years of age
D. Surgical excision during adolescence
E. No surgical excision because the child is asymptomatic
37. A 14 m/o male presents with a three month history of chronic diarrhea, anorexia and a fall from the
75th to the 25th percentile in weight. His height however remains on track. There is no vomiting,
but he does have increased foul and rancid flatulence and hydrogen sulfide eructations. This patient
merits
A. Serum tTG antibodies screening

B. IgA/IgG antigliadin antibodies screening
C. Stool analysis for giardiasis
D. DQ2-DQ8 screening
E. A trial of a milk-free diet
38. With respect to celiac disease which statement is false?
A. It is the most common non-surgical cause of asplenia

B. It can be associated with Down syndrome and idiopathic pericarditis
C. The biopsy reveals intraepithelial lymphocytosis
D. African-Americans are at increased risk if they are lactose intolerant
E. Up to 6% of patients with irritable bowel syndrome turn out to have celiac disease.
39. Most duplication cysts arise in:
A. Stomach
B. Colon
C. Ileocecal region
D. Jejunum
40. Most duplication cysts present in:
A. Early adulthood
B. Puberty
C. Neonatal period
D. Before age 2
41. The best treatment option for enteric duplication cysts is:
A. Percutaneous drainage
B. Medical management
C. Surgical excision
D. Establish communication with main intestinal lumen

42. Which of the following neonates has the greatest risk potential of developing
necrotizing Enterocolitis?
A. Stable 1 day old, full term, female infant with no significant medical findings consuming
breast milk enterally.
B. 2 week old, 32 week gestation, male infant with a birth weight of 1200 grams on hyperos-
molar formula.
C. 3 week old, large for gestational age full term male infant of a diabetic mother.
D. 3 week old, 36 week gestation, male infant with birth weight of 2000 grams and a menin-
gomyelocele
43. A 10 day old, ex- 28 week premature female is confirmed to have Stage IIB NEC. You would expect
this infant to display all of the following signs and symptoms except:
A. Temperature instability, lethargy and abdominal distension

B. Pneumatosis intestinalis on abdominal radiograph
C. Severely perforated bowel
D. Thrombocytopenia, diminished bowel sounds and grossly bloody stool
44. Most patients with malrotation present:
A. After one year of age

B. In the first month of life
C. In adolescence
D. Immediately after birth
45. The best modality for diagnosis of malrotation in a child is:
A. Barium enema
B. Upper GI series
C. Abdominal Ultrasoound
D. Upper endoscopy
46. On an UGI series the location of the duodenal-jejunal flexure ( Ligament of Treitz) is found:
A. Upper right of the spine

B. Upper left of the spine
C. Midline
D. Lower left of the spine
47. You will be following a patient who is s/p successful surgical repair of a gastroschisis.
Your long term concerns will be for:
A. Evolving intestinal dysmotility

B. Cantrell pentalogy defects
C) Development of GERD
D) All of the above
E) A and C
48. Newborns with surgically corrected omphalocele or gastroschisis are both at risk for:
A. Adhesions
B. GER and dysmotility
C. Atresias
D. Bowel ischemia
E. All of the above
49. Which of the following laboratory findings is NOT likely to be found in a patient presenting with
Small Bowel Bacterial Overgrowth?
A. Elevated D-lactate
B. Macrocytic Anemia
C. Microcytic Anemia
D. Elevated Stool pH
E. Hypocalcemia
50. Which of the following pairings of anatomic location and bacterial concentration is INCORRECT?
A. Colon: <1011 – 1012 CFU/mL

B. Ileum: <108-1010 CFU/mL
C. Duodenum and Proximal Small Bowel: <106-108 CFU/mL
D. Stomach: <103 CFU/mL
51. A 4 year old male presented to the ED with a 5d h/o diarrhea, which became bloody for the past 2
days. He was admitted overnight. Labs on admission include WBC 17,000 Hgb 12.5, Plts 195; Na
142, K 4, Creat 1.5 BUN 30. Which of the following organisms is most likely?
A. Yersinia
B. Toxigenic E. Coli
C. Norwalk-like virus
D. C. difficile
E. E. Coli O157:H7
52. A 2yo girl, who attends daycare, is brought to your outpatient clinic with a 3 day history of watery,
nonbloody diarrhea. Mom reports that she had low-grade fever, not checked; since yesterday the
stools have become bloody. She has not received any recent antibiotic therapy. On exam the pa-
tient’s vital signs reveal temperature 40 deg C, blood pressure 85/63, pulse 110, respiratory rate 20,
oxygen saturations 100% room air; she has dry mucous membranes; stool testing reveals multiple
leukocytes. The most likely cause of this girl’s illness is:
A. Salmonella typhi
B. C difficile
C. Enteroinvasive E coli
D. Shigella
E. Giardia
53. What is the most common cause of diarrhea in children worldwide?
A. Rotavirus
B. Norwalk virus
C. Enterotoxigenic E. Coli
D. Salmonella
E. Shigella
54. You were called to evaluate a 48-hr-old male in the newborn nursery for a 12 hr history of bilious
emesis. The patient was born full-term vaginally without complication. A prenatal ultrasound exami-
nation revealed polyhydramnios during the third trimester. On physical exam, the patient is mildly
jaundiced, with a slight abdominal distension and hypoactive bowel sounds. There is no abdominal
tenderness, respiratory distress, or signs of dehydration. He passed meconium 24 hrs after delivery.
You order an abdominal radiograph that shows dilation of the stomach and proximal duodenum and
absence of distal gas. The most appropriate next study for this newborn is:
A. Fetal Karyotyping
B. Upper gastrointestinal radiograph
C. Echocardiography
D. Renal Ultrasound
E. Abdominal CT scan

55. Which of the following statements about tropical sprue (TS) are true?
A. Tropical sprue (TS) is seen only in visitors to the tropics

B. TS does not occur in epidemic form
C. TS has a uniform geographical distribution in all tropical regions
D. Patients can present with nutritional deficiencies in the absence of diarrhea.
56. Which of the following statements about TS are true?
A. Bacterial colonization of the small intestine is rare in patients with TS

B. Colonic absorption of water remains unaffected in TS
C. Morphological changes in the mucosa in patients with TS resemble those of celiac disease
D. Small bowel transit is reduced in TS.
57. Which of the following is true regarding Clostridium difficile?
A. It’s presence always indicates active infection

B. Primarily causes watery diarrhea
C. Prevalence increases with age
D. Retesting should be done after 2 weeks of treatment
58. Which of the following causes of colitis presents as focal lesions without surrounding inflammation
A. Crohn’s colitis
B. Microscopic colitis
C. Eosinophilic colitis
D. Behçet ‘s disease
59. Of the following, which best describes graft vs. host disease of the gut?
A. Exclusively involved the upper gastrointestinal tract

B. Significant involvement of the lamina propria
C. Apoptosis is commonly seen
D. Precipitated by food or drug allergies
60. A 14 year old female presents with lower abdominal pain for the past 4 months, diarrhea, weight
loss and intermittent fevers. Blood work shows a hematocrit of 10.2, mean cell volume of 65%,
platelet count of 525, and sedimentation rate of 45. Colonoscopy reveals moderate chronic, active
colitis and ileitis with granuloma. You decide to begin medical therapy for Crohn’s disease. A week
later, her mother calls and informs you she has developed pain in her legs. Which of the following
medications is most likely the cause of her new symptom?
A. Prednisone
B. Mesalamine
C. Metronidazole
D. Infliximab
E. Lactobacillus
61. An 8 year old male presents with chronic diarrhea and abdominal pain waking him from sleep at
night. His school performance has been declining due to frequent absences and inability to concen-
trate. Upper intestinal endoscopy and colonoscopy reveal active esophagitis and linear ulcerations in
the colon. The most common extraintestinal manifestation of this disorder is which of the following:
A. Iritis
B. Erythema nodosum
C. Arthritis
D. Arthralgia
E. Aphthous stomatitis
62. Which of the following medications for ulcerative colitis works by inhibition of prostaglandin and
leukotriene synthesis?
A. Azathioprine
B. Mesalamine
C. Tacrolimus
D. Infliximab
E. Cyclosporin
63. A 14 year old male comes to your office with 6 weeks of persistent diarrhea containing streaks of
blood and crampy lower abdominal pain. Perianal inspection reveals no lesions, and occult blood
testing confirms the presence of blood. His height is at the 45 percentile for his age. You suspect
ulcerative colitis. Which of the following findings on colonoscopy would most strongly support this
diagnosis?
A. Inflammatory pseudopolyps
B. Areas of normal colon mucosa between inflamed regions
C. Inflammation of the terminal ileum
D. Nodularity of the colon mucosa.
E. Linear ulcerations
64. A child with Hirschsprung’s disease would have the following finding on anorectal manometry after
rectal dilation with the balloon:
A. Increased internal sphincter tone and decreased external sphincter tone.

B. Increased internal sphincter tone and increased external sphincter tone.
C. Decreased internal sphincter tone and decreased external sphincter tone.
D. Decreased internal sphincter tone and increased external sphincter tone.
65. The most common cause of constipation in childhood is:
A. Celiac disease
B. Inflammatory bowel disease
C. Hirschsprung disease
D. Functional constipation
E. Cystic fibrosis
66. A 4 year old otherwise healthy male has large-caliber, painful bowel movements, which occur every
5-7 days. On physical exam, there is a hard palpable mass in the left lower quadrant of his abdo-
men. His exam is otherwise normal. He is taking no medications. Which of the following is the
most appropriate next step?
A. Obtain an abdominal x-ray to confirm presence of fecal impaction

B. Start this patient on daily maintenance oral laxative
C. Treat fecal impaction with oral and/or rectal therapies, followed by a maintenance regimen
and close followup.
D. Encourage increased fiber in his diet and close followup.
E. Order a barium enema.
67. Encopresis typically occurs when:
A. The external anal sphincter is no longer able to function to prevent defecation

B. The internal anal sphincter is no longer able to function to prevent defecation
C. The puborectalis is no longer able to function to prevent defecation
D. The external anal sphincter is contracted.
E. The anal canal is lengthened.

68. Which of the following is the correct statement about hemorrhoids?
A. Internal hemorrhoids cause painful bleeding.

B. Hemorrhoids develop later in life due to chronic straining.
C. Bleeding from hemorrhoids can cause anemia.
D. Patients with portal hypertension have higher risk of developing hemorrhoids.
69. Which statement is incorrect about the management of Hemorrhoids?
A. Acute thrombosed external hemorrhoids can be excised within 24-48 hr.

B. High fiber diet helps shrink hemorrhoids and decrease bleeding.
C. Sclerotherapy is more effective than rubber banding.
D. 5-10 % of patients with hemorrhoids will need surgical treatment.
70. Which of the following statements regarding Hirschsprung disease is TRUE?
A. HD is commonly associated with other congenital malformations.

B. Presence of recto-anal inhibitory reflex is characteristic.
C. Early diagnosis is important to avoid development of enterocolitis and subsequent toxic
megacolon.
D. Surgery for HD is usually performed between 2 and 3 years of age.
71. Which of the following is a common manifestation of HSP?
A. Painful palpable purpura

B. Colicky abdominal pain and occult GI bleed
C. Arthritis of large joints in the arms
D. Proteinuria
72. What of the following is part of the pathophysiology of E coli in HUS?
A. It produces Shiga toxin

B. It produces cholera toxin
C. It produces C diff toxin
D. It is enteroinvasive and ulcerogenic
73. Which of the following is the appropriate diet for an infant with primary intestinal lymphangiectasia?
A. Low protein and low fat diet

B. Low protein and high fat diet
C. High protein and low fat diet
D. High protein and high fat diet
74. You follow a 6 y/o boy with juvenile polyposis coli. Part of your care involves
A. Screening all at risk family members

B. Colonoscopy performed annually with polypectomies PRN
C. Gastroscopy of the index patient beginning at adolescence
D. Only B and C
E. A, B and C
75. A 9 year old girl with presumed Peutz Jeghers syndrome lacks the STK11 mutation on chromosome
number 11. In this patient:
A. The risk of malignancy is greatest in the small bowel over the colorectal area
B. There is no risk for precocity
C. Her risk for breast tumor is under 25%
D. All statements are true
E. All statements are false
76. 12 month old girl present with her third episode of rectal prolapse during the last 2 months. No
constipation reported by the parents but was prescribed lactulose in the last month with a good
response. Physical examination normal.
Which investigation should be the next step?
A. colonoscopy
B. barium enema
C. sweat test
D. abdominal series
77. An 8 month-old male infant presents to your clinic with 6 weeks of crying with stooling. The parents
have noted small steaks of blood in the diaper after he stools. His nutrition consists of breast milk
and a variety of fruits, vegetables and cereal. He has had no vomiting, signs of abdominal pain, fe-
vers or diarrhea. He was passing hard-consistency stools at the beginning of this course, but this has
improved with daily MiraLax prescribed by his primary physician. Currently, he is passing three softly
formed stools daily. On your physical exam, you note a fissure in the posterior midline, an associated
small non-inflamed skin tag and hypertonicity of the anal sphincter. In addition to careful hygiene,
what is the best management approach?
A. As 0.2% nitric oxide preparation topically three times daily

B. Daily anal dilatation at home
C. Cow’s milk restriction
D. Increased dietary fiber
E. Lateral internal sphincterotomy
78. A 2-year old female has had a three week history of decreased stooling frequency. Her stools have
become hard in consistency and require straining. Her parents have not noted blood in her stools,
but are concerned with the amount of discomfort she has with defecation. She has become ex-
tremely apprehensive with diaper changes and is exquisitely tender to the touch in the diaper area.
On your physical exam, you note a well-demarcated and moist area of erythema in her perineum,
radiating from the anus without induration. She has not had a similar perineal rash in the past. What
is the most appropriate diagnostic test?
A. Direct GABHS antigen

B. ASLO or anti-DNase B
C. Perianal swab culture
D. Sigmoidoscopy with biopsies
E. Stool ova & parasites
79. A previously healthy 7-year-old male was diagnosed with a perirectal abscess by his primary physi-
cian. Initial management of oral antibiotics and sitz baths has been initiated. Which of the following
is considered an indication for surgical management?
A. Persistent perineal pain despite antibiotics

B. Persistent drainage despite 3 months of medical management
C. Underlying inflammatory bowel disease
D. The presence of fistula in ano at initial presentation
E. Current immunosuppressive medications for JIA

80. A 2-year-old female presents with distended abdomen, feeding intolerance, vomiting, and chronic
severe constipation since infancy. One year ago she had been at the 40% weight for age on the
CDC growth curves and she is now on the 10% weight for age. Past medical history is significant
for multiple urinary tract infections which have required antibiotic prophylaxis. Previous abdominal
ultrasound showed megaureters and hydronephrosis. An abdominal radiograph is notable for a
distended small bowel with multiple air fluid levels and stool-filled colon. Previous home clean-outs
prescribed with osmotic and stimulant laxatives have not helped to resolve her symptoms. She has no
abnormalities in thyroid studies, metabolic problems, celiac testing, or hematocrit. She had a previ-
ous normal anorectal manometry. Exam in your office was notable for distended abdomen which is
tympanic to percussion with mild abdominal pain on palpation throughout. Rectal exam was normal
without stool mass noted.
What next study would give the most diagnostic yield?
A. Upper gastrointestinal contrast study with small bowel follow through

B. Radio-opaque marker study
C. Colonoscopy with biopsies for histopathology
D. Antroduodenal and colonic manometry
81. The hepatic lobule is centered on
A. Bile duct
B. Central vein
C. Portal vein
D. Hepatic artery
82. You follow an eleven year old boy with ulcerative colitis and he comes in for a routine evaluation. He
claims his symptoms have been well controlled with mesalamine and at this visit he says his stools
are formed with no blood, but he has had new tenderness in his abdomen, occasional nausea, new
fatigue and itching. He denies recent trauma, fever or new medications. On physical examination you
note mild hepatomegaly and tenderness, and subtle conjunctival icterus. You are concerned he may
have acquired hepatitis or is evolving primary sclerosis cholangitis. You order all the following studies
except one.
A. Hepatitis serologies
B. JAG-1 and NOTCH-2 mutational studies
C. Fresh liver function studies
D. Blood cultures
E. MRCP
83. Findings in a patient with Alagille syndrome may include all of the following findings except which?
A. Posterior embryotoxon
B. Hemivertebra
C. Periductal hyperplasia
D. Peripheral pulmonary stenosis
E. Portal tracts with bile duct ratio of less than 0.5
84. During his routine one month check-up a four week old African American male is found to have
woody hepatomegaly and a conjunctiva suggestive of icterus. His mother is concerned he is not gain-
ing weight and that his suck is poor. Your initial studies reveal conjugated hyperbilirubinemia, moder-
ate increase of transaminases but a 4-fold increase of GGT. You order an ultrasound which reveals a
small gallbladder but the sonographer is unable to measure the hepatic ducts. Hepatic scintography
shows normal uptake but delayed and diminished excretion at 24 hours. Your next step is to order
A. A repeat ultrasound to locate the “triangular cord sign.”

B. Schedule a liver biopsy
C. Repeat scintography with a double dose of Phenobarbital
D. Order serologies for CMV, HBV, HCV and Cocksackie B
E. Order a bone marrow for hemophagocytosis
85. You are following a five month old male who is status post Kasai. His liver is firm but not hard and
he has no splenomegaly. He is slowly gaining weight and his nutrition appears adequate. There is no
diarrhea but both his stools and urine are dark. He is on ADEK supplementation and ursodeoxycholic
acid. At this visit, his total bilirubin is 6.4 mg/dL and his stools are guaiac positive. You should at this
point:
A. Schedule endoscopy for possible varices

B. Increase his dose of ADEK and ursodeoxycholic acid
C. Change his antibiotics for possible ascending cholangitis
D. Request a HIDA scan to assess Kasai function
E. Refer the child to the transplant team for preliminary assessment and registration.
86. A 16-year-old female has a 6-month history of intermittent epigastric and right upper quadrant ab-
dominal pain. Her BMI is 35. The pain is often worse after fatty meals and it has not improved with
8 weeks of appropriate proton pump inhibitor therapy. Laboratory testing for pancreatitis, hepatitis,
liver function and celiac disease have been unrevealing. Her WBC is normal. An abdominal ultra-
sound with focus in the right upper quadrant showed a normal appearing gallbladder without any
evidence of gallstones or sludge. The liver parenchyma and pancreas appeared normal. The com-
mon bile duct diameter was 3mm. You suspect that she may suffer from chronic acalculous chole-
cystitis/biliary dyskinesia. Which of the following is the best next step in establishing that diagnosis?
A. Magnetic resonance cholangiopancreatography (MRCP)

B. Endoscopic retrograde cholangiopancreatography (ERCP) with sphincter of Oddi manometry
C. Abdominal CT scan
D. Upper endoscopy with bile sampling for analysis
E. HIDA scan with fatty meal stimulation
87. The risk of childhood cholelithiasis is increased in all these circumstances except:
A. Cystic fibrosis with the mutation of ΔF508 or ΔI507

B. Crohn’s disease limited to the terminal ileum
C. Total abdominal situs inversus
D. Thalassemia and hereditary spherocytosis
E. A pregnant Pima Indian adolescent

88. A 2-day-old otherwise healthy full-term male infant undergoes an abdominal ultrasound for surveil-
lance of pelviectasis initially diagnosed on a prenatal ultrasound. The kidneys appear normal but the
ultrasound reveals a 3mm, mobile echogenic mass in the gallbladder consistent with a gallstone. No
other gallbladder or liver abnormalities are seen and there is no pericholecystic fluid noted. The child
has a transcutaneous bilirubin consistent with a value of 4.3 mg/dl and is feeding well. What is the
most appropriate next step in the management/evaluation of the gallstone?
A. Start Ursodeoxycholic Acid therapy

B. Consult pediatric surgery for cholecystectomy
C. Order a magnetic resonance cholangiopancreatography (MRCP) to assess for
bile duct anatomy
D. No further evaluation if the gallstone does not cause symptoms
E. Technetium 99m–hepatic iminodiacetic acid (HIDA) scan
89. A 7-year-old boy with nephrotic syndrome who has been hospitalized for 3 weeks for the manage-
ment of edema develops intermittent right upper quadrant abdominal pain. An abdominal ultra-
sound shows the presence of a mobile, 6mm stone in the gallbladder. Which of his medications is
most likely to have played a role in the development of the gallstone.
A. Hydralazine
B. Omeprazole
C. Furosemide
D. Lisinopril
E. Dalteparin
90. Which of the following is a risk factor for the development of black pigment gallstones?
A. Hereditary Spherocytosis
B. Obesity
C. Pregnancy
D. Bile infection
E. Hyperlipidemia
91. 17 year old male has ALF. He was well until 2 wks before admission, when jaundice developed. One
week later he was hospitalized because of progressive confusion. He has slight asterixis. Labs: Hemo-
globin 9.8, ALK PHOS 60, T bilirubin 40, D bilirubin 12, UA 1.1, AST 300, ALT 170, INR 2.5. SMA and
ANA neg. Ceruloplasmin 24 (22-43). Which of the following is true?
A. Normal value for ceruloplasmin excludes Wilson

B. Slit-lamp examination should be done to look for KF rings
C. He is too ill to be considered for OLT
D. Liver Bx should be the next study
92. 20 year old female was admitted for “Liver Transplant”. Three months ago she began gaining wt
(16 lbs). Two mo ago she had dark urine and yellow skin. Tests for HBsAg, HB core AB, HAV IgM,
HCV AB, CMV IgM and IgM to VCA for EBV were all negative. PE showed jaundice, shifting dullness,
hepatomegaly. LABS: AST 624, T Bilirubin 12, TP 8.5, Alb 2, INR 2, ANA 1:40. Tests for SMA and LKM
were neg. What is the next step in her treatment?
A. OLT
B. Observation for 3 mo
C. IFN and Ribavirin
D. Prednisone 60 mg daily
93. A 15 year old female is admitted to the ICU following intentional acetaminophen overdose. She is
unresponsive, mildly hypotensive and has no stigmata of chronic liver disease. She is most likely to
die of:
A. Cerebral herniation
B. Coagulopathy with bleeding
C. Liver synthetic failure
D. Renal failure
94. A 12 year old boy is seen for FTT, episodic irritability, lethargy, and refusal to eat animal protein (milk,
eggs, and meat). Which of the following abnormalities is most characteristic of OTC deficiency?
A. Elevated ammonia
B. Elevated plasma citrulline
C. Metabolic acidosis
D. Aminotransaminase levels more than 1000
95. A 5 day old breastfed infant is admitted to the hospital because of lethargy and a poor suck. The
infant appears jaundiced. The total bilirubin is 12 with 25% conjugated. The metabolic disease most
likely to cause jaundice in this infant is:
A. A HFI
B. B Galactosemia
C. C Hypothyroidism
D. D PKU
96. A 2 month old infant who presents with a 1 wk h/o intermittent vomiting appears jaundiced on
PE. At 4 weeks of age the exclusively breastfed baby was gaining wt well and was not icteric. The
mother subsequently returned to work and the infant has been receiving supplements of formula
and apple juice. A urine test for reducing substance is positive.
A. alpha-1-antitrypsin deficiency
B. Biliary atresia
C. hereditary Fructose Intolerance
D. Cystic Fibrosis
97. Which of the following statements about pyogenic abscess of the liver is true?
A. The right lobe is more commonly involved than the left lobe.
B. Appendicitis with perforation and abscess is the most common underlying cause
of hepatic abscess.
C. Mortality is not determined by the underlying disease.
D. Mortality from hepatic abscess is currently greater than 80%.
98. You follow a 7 m/o cholestatic male with biopsy proven non-syndromic paucity of bile ducts. At this
visit the mother is pleased to report he is no longer scratching himself and is gaining weight. Surveil-
lance LFT reveal persistent cholestasis, elevated AlkP, progressive increase in ALT/AST, but a progres-
sive drop in GGT. You next order
A. Urinary bile acid profile

B. Repeat liver sonography
C. Repeat liver biopsy
D. A followed by B if the profile is abnormal
E. A followed by C if the profile is abnormal

99. ou receive a request for a second opinion on a 4 wk/o male with hepatomegaly, increased LFTs with
Y
low GGT, evidence of steatorrhea, and a liver biopsy revealing giant cell transformation, fibrosis and
bile lakes. You suggest as a primary next step to:
A. Seek a hematology consult to r/o a hemophagocytosis syndrome

B. Obtain a urinary bile acid profile
C. Begin an empiric trial of Phenobarbital at 3 mg/kg/day
D. Begin an empiric trial of ursodeoxycholic acid at 15 mg/kg/day
E. Seek a infectious disease consult to r/o enterovirus infection
100. A 5- month old baby presents to the ER with vomiting, diarrhea and poor weight gain for the past
month. He is a full term baby born to a healthy mother with no prenatal or perinatal complications.
There have been no sick contacts. No fevers, rashes, or recent antibiotic use. He has been solely
breastfed, and one month ago he started eating jarred baby foods, but has not been taking them
well. A deficiency in which enzyme should be considered in this case?
A. Aldolase B
B. Galactokinase
C. Fumarylacetoacetate hydrolase
D. Glucose-6-phosphatase
D. Galactose-1-phosphate uridyl transferase
101. A 3-day old female develops a fever prior to discharge home. She undergoes a complete sepsis
evaluation including blood, urine, and CSF cultures. Urine and blood cultures are both positive for
E Coli. Which of the following should be the initial next step for this patient?
A. Check thyroid studies

B. Obtain an abdominal ultrasound
C. Switch to a soy-based formula
D. Check PT, PTT, INR
E. Obtain chest x-ray
102. Which of the following chemotherapy medications is NOT associated with veno-occlusive disease?
A. 6-thioguanine
B. Busulfan
C. Cytosine arabinoside
D. Dactinomycin
E. L-asparaginase
103. Ground glass cytoplasmic inclusions are typically seen in which types of drug-induced liver injury?
A. Amiodarone
B. Isoniazid
C. Isotretinoin
D. Mycophenolate mofetil
E. Oral Contraceptives
104. A
two-year old boy develops URI symptoms 2 days prior to admission. His pediatrician diagnoses
him with a viral pharyngitis. The boy drinks minimal fluids over the next two days. On the day of
admission, parents note that he is pale and extremely sleepy. They drive him to the ER, and the boy
has a seizure in the car on the way there. In the ER, his serum glucose is 25 mg/dL. Blood gas re-
veals pH 7.29, pCO2 31, and HCO3 of 15. Electrolytes reveal Na 131, K 4.4, and Cl 99. Ammonia
is elevated at 95. Urinalysis demonstrates no glucose, no protein, and 1+ ketones. The most likely
diagnosis is:
A. Sepsis
B. Urea cycle defect
C. Congenital heart defect
D. Organic acidemia
E. Fatty acid oxidation disorder
105. A 27-year old woman at 33 weeks gestation presents to the emergency room with nausea, vomiting,
and abdominal pain. She is found to have a mild elevation in her transaminases, and is subsequently
admitted for IV fluid hydration and observation. Over the next 3 days, she develops worsening
elevation in her transaminases and a coagulopathy, and progresses to fulminant liver failure. An
emergency cesarean section is scheduled and the baby is delivered. Both mom and baby go on to do
well. Screening for which of the following mutations should be considered for the baby?
A. MCAD mutation
B. G1528C mutation
C. Trifunctional protein deficiency
D. SCAD mutation
106. A 16-year-old white female presented with a few weeks history of low-grade-fever and arthritis. On
physical exam, she was noted to have erythema nodosum on both her shins, arthritis of her ankles,
and hepatomegaly. Chest radiograph showed bilateral hilar adenopathy. Liver biopsy revealed non-
caseating granulomas mainly in the portal tract. Skin tuberculin test was negative. What is the most
likely diagnosis:
A. Tuberculosis
B. Sarcoidosis
C. Coccidioidomycosis
D. Histoplasmosis
107. The oncology service consults you for a febrile 12 y/o with hepatomegaly, splenomegaly, hyperbili-
rubinemia, elevated alkaline phosphatase and leucocytosis Ultrasound reveals “bull’s eye” lesions in
the hepatic parenchyma most likely caused by
A. Systemic candidiasis
B. Coccidiomycosis
C. Histoplasmosis
D. Coxiella infection
108. With regards to hepatic granuloma, which statement is false?
A. Up to 10% of all liver biopsies reveal granulomas

B. Brucellosis, Q-fever and Hansen’s disease may cause hepatic granulomas
C. Granulomas occur in about 10% of patients with miliary tuberculosis
D. Acid-fast bacilli can actually be seen in TB granulomas
109. All of the following are associated with NAFLD EXCEPT:
A. Increased TGF-beta
B. Increased adiponectin levels
C. Increased hepatic Fe stores
D. Increased reactive oxygen species
E. Increased free fatty acids

110. The most common area of presentation of PTLD in pediatric liver transplant recipients include;
A. The kidneys
B. The pancreas
C. The liver
D. The pharyngeal and cervical lymphatic chain
111. Which of the following statements are true regarding the outcome of liver transplantation in children
A. Expected one year patient survival is approximately 99%

B. Chronic rejection results in graft loss in approximately 5% of children
C. Primary non-function has been virtually eliminated as a clinical problem
D. All of the above
112. Nephrotoxicity secondary to calcineurin inhibitors causes the following
A. Afferent arteriole vasoconstriction

B. Endothelial cell damage
C. Interstitial fibrosis
D. Tubular atrophy
E. All of the above
113. In the setting of acute liver failure it is appropriate to proceed with transplantation:
A. Before establishing the etiology of the liver injury

B. When patients exhibit clinical signs of stage II encephalopathy
C. When patients have clinical signs of irreversible neurologic injury
D. Only if some form of bridge therapy is not available
E. None of the above
114. Accepted contraindications to liver transplantation in children include all except the following:
A. Alpers syndrome
B. Cystic fibrosis
C. Advanced pulmonary hypertension
D. Uncontrolled systemic infection
E. The above are all accepted contraindications
115. As compared to patients receiving tacrolimus, patients receiving cyclosporine are less likely to:
A. Develop DM
B. Develop hypertension
C. Dyslipidemia
D. Seizures
116. Primary bile acid therapy with cholic acid is effective in which of these peroxisomal disorders?
A. Zellweger syndrome
B. Adrenoleukodystrophy (ALD)
C. Refsum disease
D. Methylacyl-CoA racemase deficiency
E. Rhizomelic chondrodysplasia punctata
117. An eight month old infant presents with cholestasis, poor growth and chronic diarrhea. He had
negative TORCH serologies, normal alpha 1 antitrypsin, and normal metabolic screening. His labora-
tory tests revealed GGT 23, Bilirubin 6.0/4.0 and ALT 350. His most likely diagnosis is:
A. PFIC-1, FIC-1 disease

B. PFIC-2, BSEP disease
C. PFIC-3, MDR3 disease
D. BRIC
118. Match the finding or symptoms to the gene defect:
A. MDR3 disease 1. Bile duct proliferation

B. BSEP disease 2. Episodes of severe pruritus which resolve
C. FIC-1 disease 3. Associated with liver tumors
D. BRIC 4. Recurrent pancreatitis
119. The family of a child newly diagnosed with AGS asks you what is the risk of their older child or future
children also being affected with AGS. You advise them that:
A. The majority of mutations in AGS occur for the first time in the identified individual
B. If there is a family history then the chance is 50% of a sibling being affected
C. The sibling could carry the same gene mutation as the newly diagnosed child and yet have a
very different range and severity of clinical symptoms
D. All of the above
120. A child with AGS is likely to have:
A. A lifetime risk of needing a Liver transplant of 90%

B. Poor growth
C. Severe itching
D. All of the above
E. B and C only
121. Graft-versus-host disease (GVHD) is caused when:
A. Host lymphocytes are depleted

B. Immunosuppressive therapy is increased
C. Donor lymphocytes attack host tissues
D. Host granulocytes attack donor tissues
122. After bone marrow transplantation, ________ present in the graft, either as contaminants or inten-
tionally introduced into the host, attack the tissues of the transplant recipient after perceiving host
tissues as antigenically foreign.
A. T Cell
B. T Helper Cell
C. Cytotoxic T Cell
D. Regulatory T Cell
123. The progression of disease in GVHD goes in which order?
A. GI Tract → Liver → Skin

B. GI Tract → Skin → Liver
C. Liver → GI Tract → Skin
D. Liver → Skin → GI Tract
E. Skin → GI Tract → Liver
F. Skin → Liver → GI Tract

124. During an upper endoscopy where are you most likely to find histologic changes
associated with GVHD?
A. Esophagus
B. Stomach
C. Duodenum
D. Rectum
E. Liver
125. When looking at a histologic sample, what finding is most suggestive of GVHD?
A. Crypt abnormalities
B. Epithelial cell apoptosis
C. Focal fibrosis
D. Focal reactive surface epithelium
E. Lymphocytic infiltrate
126. A 14 year old boy is referred to you for conjunctival icterus. He feels well and has no complaints.
He volunteers that has noted his eyes “yellow” when he has a cold. At the visit, there is no icterus
evident, no visceromegaly and all his liver function tests and hemogram are normal. You next:
A. Schedule a liver biopsy

B. Order an ultrasound
C. Order hepatitis serologies
D. Order a 10 day course of low dose phenobarbital
E. Request a screen from UGT1a1 mutation
127. A 15 year old boy with sickle cell disease presents with jaundice and fatigue. Review of systems
reveals intermittent dark urine and icteric conjunctiva over the last month. Physical exam is unremark-
able except for scleral conjunctiva. Differential diagnosis includes the following except:
A. Hemolysis related to his sickle cell disease

B. Hepatocellular dysfunction
C. Obstruction due to biliary stones
D. Acute cholecystitis
128. A three month-old infant of Canadian descent presents with irritability, mild jaundice and hepa-
tomegaly. Labs are concerning for AST of 130, ALT 170, PT 28, INR 2.4, and serum glucose of 40.
Which of the following tests would be most helpful in confirming the underlying diagnosis?
A. CBC with differential

B. Urine succinylacetone
C. Factor 5 level
D. Serum alpha-fetoprotein level
E. Serum albumin
129. Which condition or syndrome is NOT associated with hepatoblastoma?
A. Beckwith-Wiedemann Syndrome
B. Familial Adenomatous Polyposis Syndrome
C. Glycogen Storage Disease 1a
D. Biliary Atresia
E. Cleft Palate
130. A 3-week old full term, otherwise healthy formula-fed infant presents with new-onset poor feeding
and fever to 38.3°C. Laboratory findings at presentation are significant for leukocytosis, as well as
a mild transaminase elevation (approximately 1.5 times upper limits of normal). Total bilirubin is el-
evated to 6.7 mg/dL with conjugated bilirubin of 2.3 mg/dL. A bacterial infection is found on culture
analysis. What is the most likely bacterial cause and route of infection?
A. Staphylococcus aureus infection from skin

B. Streptococcus pyogenes infection from throat
C. Escherichia coli infection from urine
D. Listeria monocytogenes infection from blood
131. 1-week old infant is noted to have fulminant liver failure with coagulopathy after presenting with
A
vesicular rash and seizures. Disseminated herpes simplex virus infection is confirmed by nasopharyn-
geal culture and PCR analysis of CSF. Which of the following is true regarding this infection?
A. Parenteral acyclovir is indicated only in instances of disseminated disease

B. Liver transplantation is contraindicated due to the presence of active viral infection.
C. Mortality rate is high even with acyclovir therapy
D. The majority of mothers of infants with disseminated HSV will have symptomatic
infection at time of delivery
E. Both C and D.
132. Which serologic profile best reflects the “immune tolerant” state of chronic Hepatitis B infection?
A. HBsAg positive, HBsAb positive, HBeAg positive, HBeAb positive

B. HBsAg positive, HBsAb negative, HBeAg positive, HBeAb positive
C. HBsAg positive, HBsAb negative, HBeAg positive, HBeAb negative
D. HBsAg negative, HBsAb positive, HBeAg negative, HBeAb positive
133. Which of the following individuals should receive HBV immune globulin therapy?
A. All infants and children

B. Asymptomatic children with chronic HBV infection
C. Post-HBV exposure, within 24 hours after exposure
D. All household contacts of HBV infected child
134. True or False: Serum Hepatitis C antibody (IgG) is protective and will prevent recurrent infection
upon re-exposure of HCV.
135. All of the following hepatitis viruses can result in a chronically infected state, except:
A. HEV
B. HCV
C. HDV
D. HBV
136. 6 week old presents with neonatal jaundice, direct hyperbilirubinemia, markedly elevated GGT and
pale-colored stools. Possible diagnoses include all of the following, except:
A. Biliary atresia
B. PFIC2
C. PFIC3
D. A1AT deficiency

137. Cholestatic infants should be monitored for deficiencies in many vitamins, including:
A. Vitamin K
B. Folic acid
C. Vitamin A
D. Iron
E. A and C
F. All of the above
138. Which of the following is true regarding autoimmune hepatitis?
A. Children represent a very small subset of patients diagnosed with autoimmune hepatitis
B. Acute hepatitis is the most common presentation
C. Giant cell transformation is a classic histological feature
D. In children, the incidence is equal in males and females
E. HLA A2 is a common association.
139. Patients with Type 1 autoimmune hepatitis:
A. Typically exhibit anti-perinuclear antibody (pANCA)

B. Present at an earlier age than do patients with Type 2 disease
C. Do not have other autoimmune disorders
D. Typically progress to liver transplant in 5-8 years
E. Often demonstrate mildly abnormal cholangiograms
140. An 8 year old girl is being treated for Type 2 AIH with a standard prednisone/azathioprine regimen.
She responded readily with ALT falling from a high of 650 IU/l consistently. A slow prednisone taper
is in progress. With the most recent dosage decrease, ALT was noted to jump from 75 to 180 with
6-MP metabolites in the normal range. The appropriate response should be:
A. This is a treatment failure. Consider addition of CSA

B. Consider overlap syndrome and order MRCP
C. Stop current regimen and start MMF
D. Refer for transplantation
E. Increase prednisone temporarily and resume taper when labs improve
141. Which of the following arteries contributes to the blood supply of the pancreas?
A. Left gastric artery

B. Right gastric artery
C. Proper hepatic artery
D. Superior mesenteric artery
E. Inferior mesenteric artery
142. The major mediator of meal-stimulated pancreatic enzyme secretion is:
A. Secretin
B. Cholecystokinin
C. Pancreatic polypeptide
D. Peptide YY
E. Somatostatin
143. A ten-year-old male presents to the emergency room with a one day history of vomiting, decreased
appetite, and abdominal pain after falling off his bicycle the day before. Labs reveal an elevated
lipase of 3500 and abdominal ultrasound reveals peripancreatic fluid and pancreatic fullness. Patient
is admitted with a diagnosis of acute pancreatitis. He is initially managed with bowel rest, IV fluids,
and IV pain medications. Within 4 days, he is no longer requiring IV pain medications, is tolerating a
regular diet, and his lipase has decreased to 485. He is subsequently discharged home. Two weeks
later at his follow-up visit, he complains of mild to moderate diffuse abdominal pain and decreased
appetite. He is noted to have epigastric fullness on physical exam. Lipase is rechecked and is now
1205. Which of the following steps should be taken next in the evaluation of this patient?
A. Follow serum lipase on a daily basis for the next week

B. Repeat abdominal ultrasound
C. Admit the patient for bowel rest and IV fluids
D. Send genetic testing for CFTR mutations
E. Schedule for an upper endoscopy
144. 2-year old male presents with a cough and diarrhea. Weight is below the 5th percentile and
A
height is at the 10th percentile on the CDC growth curve. His mother states his stool is very foul-
smelling. Stool culture for bacteria and examination for ova and parasites are negative. The parents
want the fecal elastase test performed to rule out pancreatic insufficiency. Which statement is correct
to tell the parents?
A. No sweat test is necessary in this child.

B. A 72-hour fecal fat test is easy to perform.
C. Fecal trypsin testing is more specific than fecal elastase testing
D. Fecal elastase can be artificially lowered if the child has short bowel syndrome.
145. You are giving a medical student lecture regarding the embryology of pancreatic development.
What statement is correct to present to the students?
A. The ventral and dorsal pancreatic segments fuse at the 4th week of gestation.
B. Pancreatic function occurs at the 12th week of gestation.
C. Sonic hedgehog protein is the hedgehog protein necessary for pancreatic
cellular differentiation.
D. The dorsal aspect of the pancreatic segment contains the connection to the
common bile duct.
146. A 2 year old female comes to your office with failure to thrive, steatorrhea, small teeth, nasal ab-
normalities, and microcephaly. An outside lab test reveals hypothyroidism. You suspect pancreatic
insufficiency due to what diagnosis?
A. Johansson-Blizzard syndrome
B. Homozygous ΔF508 mutation cystic fibrosis
C. Shwachman-Diamond syndrome
D. Congenital Rubella
147. Pancreas divisum:
A. Results from lack of fusion of the ventral and dorsal pancreatic ducts
B. Is easily diagnosed with ultrasound
C. Is associated with ectopic pancreatic tissue
D. Is treated with duodenoduodenostomy
148. Annular pancreas
A. Is best diagnosed by ultrasound

B. Results from the failure of atrophy of the ventral bud
C. Is not associated with congenital malformations
D. Occurs at the third portion of the duodenum

149. Which of the following statements regarding Shwachman-Diamond Syndrome is TRUE?
A. Exocrine pancreatic insufficiency is a universal manifestation in all patients with SDS

B. Exocrine pancreatic insufficiency in SDS arises from ductular inflammation
C. Few SDS patients exhibit intermittent neutropenia
D. SDS adolescents commonly have hepatomegaly
150. How would you assess for vitamin D deficiency in a child in whom you suspected inadequate intake/
inadequate sun exposure?
A. Serum 25 (OH) D level

B. Serum phosphorus
C. Serum 1, 25 (OH) D
D. Serum calcium
E. Urinary 1, 25 dihydroxy D
151. A 4-year-old child with biliary atresia, status post Kasai, presents with a direct bilirubin of 3.0, an ALT
of 230, AST of 340 and GGT of 850. Recently his mother noticed that he was walking ‘funny’. On
examination he is jaundiced, has a large spleen and liver. You note that his gait is wide and irregular.
What vitamin deficiency is the most likely cause of his ‘funny’ walking?
A. Vitamin A
B. Vitamin D
C. Vitamin E
D. Vitamin K
E. Carnitine
152. You are seeing a family who just moved to the US from Greenland. A family brings in a 1 year old
infant who has failure to thrive, diarrhea, and abdominal distension. The baby has been breastfed ex-
clusively till 6 months of age when solid foods were introduced. Between 6 and 12 months of age,
the weight decreased from the 50th to the 5th percentile, while the height remained at the 50th per-
centile. On physical examination, the alert but thin infant has a distended abdomen and a perianal
rash. The stool is watery and foul-smelling and has a pH of 3. No parasites are identified in the stool.
Fecal fat and fecal alpha-1-antitrypsin measurements are both within normal limits. Of the following,
the MOST likely diagnosis is:
A. Congenital lactose intolerance

B. Cystic fibrosis
C. Hereditary fructose intolerance
D. Intestinal lymphangiectasia
E. Sucrase-isomaltase deficiency
153. A 15 month old female with history of failure to thrive and a mild, persistent diarrhea is brought to
your clinic for further evaluation of a 2 week history of “being wobbly” and “running into things,
especially at night”. Laboratory analysis reveals the abnormality shown below. What is the patient’s
diagnosis?
A. Acrodermatitis enterohepatica
B. Congenital chloride diarrhea
C. Abetalipoproteinemia
D. Syndromic diarrhea
E. Vitamin E deficiency
http://www.wadsworth.org
154. Which is the only amino acid malabsorption disorder that presents with gastrointestinal manifesta-
tions of diarrhea, failure to thrive, and possible hyperammonemic coma with ingestion high protein
diet?
A. Cystinuria
B. Lysinuric protein intolerance
C. Hartnup disease
D. Iminoglycinuria
E. Renal tubular acidosis
155. An 18 month old presents to your clinic with history of or diarrhea since about 9 months of age.
Dietary history is positive for 3-4 servings of fruit daily and at least 16 to 24 ounces of juice daily. In
addition, he drinks 16 ounces of whole milk and eats a variety of food including chicken, pasta, and
vegetables. Parents have noticed some relationship to fruit and juice intake. What is likely cause of
his diarrhea and the treatment you would recommend?
A. Congenital Glucose –Galactose malabsorption requiring him to be on Ross Carbohydrate

Free formula supplemented with Fructose as his sole source of carbohydrate
B. Acrodermatitis enterohepatica requiring treatment with zinc
C. Abetalipoproteinemia requiring supplementation with medium chain triglycerides and
fat-soluble vitamins (with especially high doses of vitamin E)
D. Fructose malabsorption requiring them to take fructose in the form of fruit and fruit juice
out of his diet. They can reintroduce in small amounts when he is school-aged.
E. Load dependent lactose intolerance with secondary disaccharide deficiencies.
156. In chronic pancreatic insufficiency, which of the following is absorbed normally?
A. Fat
B. Folic acid
C. Vitamin B12
D. Protein
E. amylopectin
157. Medium chain triglycerides account for 40-50% of the fat content of formulas fed to low-birth
weight infants. Of the following, the BEST explanation for this practice is that
A. Absorption of MCT is similar to that of butterfat

B. Low-birth weight infants have a large pool of bile acids
C. Low-birth weight infants have normal capacity to synthesize bile acids
D. MCT cause less steatorrhea
E. MCT require micelle formation for absorption
158. Lactose enhances the intestinal absorption of which one of the following nutrients?
A. Calcium
B. Chloride
C. Lipid
D. Potassium
E. Sodium
159. Of the following, the most beneficial formula for patients with gastrointestinal allergy, short gut or
cystic fibrosis is:
A. Protein hydrolysate
B. Carbohydrate free
C. Lactose free
D. Low iron
E. Soy based

160. Of the following fatty acids, which must be added to cow milk-based infant formula?
A. Arachidonic acid
B. Linoleic acid
C. Oleic acid
D. Palmitic acid
E. Stearic acid
161. In regards to gastric emptying, which of the following statements is TRUE?
A. Solids empty faster after vagotomy

B. Proteins delay emptying more than lipids
C. Solids are emptied in an exponential pattern
D. Liquids are emptied faster than solids
E. Cholecystokinin accelerates emptying
162. An Asian-American family is concerned that their 2-month-old infant’s abdominal distention is due to
lactose intolerance. She is intermittently fussy, with frequent vomiting and poor weight gain, but no
diarrhea. She takes a standard cow’s-milk based infant formula. Which of these options is the most
appropriate first intervention?
A. Trial of a soy-based formula

B. Trial of lactase supplementation
C. Upper GI series
D. IgE RAST testing for cow’s milk
E. Stool pH and reducing substances
163. An adolescent patient with recurrent abdominal pain has a duodenal biopsy showing low lactase
activity, but lactose breath hydrogen test is normal. What is one likely explanation for these conflict-
ing results?
A. His pain is strictly functional in nature.

B. He recently completed a course of antibiotics.
C. He suffers from sucrase-isomaltase deficiency.
D. He ate a high-fiber meal prior to breath testing.
E. He has cow’s-milk protein intolerance.
164. After three weeks of nursing a new mother develops fissured nipples and has to use a breast pump.
At the baby’s one month check-up the mother expresses concerns that when she begins the pump-
ing process the milk seems watery and she is worried about the baby’s nutrition. You assure her that:
A. Foremilk is normally thinner and primarily serves to assure the baby’s hydration
B. The milk has the normal whey : casein ratio of 30 : 70
C. Consuming a diet higher in fat will increase the lipid concentration and nutrition of her milk
D. Consuming more cow milk in her diet will increase the carbohydrate content of her milk
E. It provides sufficient vitamin D for her baby
165. Which of the following statements regarding nutritional evaluation in children is TRUE?
A. Marasmus is defined as severe malnutrition with nutritional edema

B. Prealbumin is a sensitive marker of chronic malnutrition
C. Iron deficiency anemia is the most common nutritional deficiency in children
D. Folate and vitamin B12 deficiency cause microcytic anemia
E. The first step in management of acute moderate malnutrition is always aggressive hydration
with intravenous fluids
166. A 10 year old female and her mother present to your office with dietary questions. The patient has
just recently decided to follow a vegetarian diet and her mother is concerned that this diet will be
inadequate for her. Supplementation of which vitamin is recommended for this patient?
A. Vitamin C
B. Thiamine (Vitamin B1 )
C. Folate (Vitamin B9 )
D. Cobalamin (Vitamin B12 )
E. Niacin (Vitamin B3 )
167. A 12 year old male with Crohn’s disease obtains a chest x-ray prior to the start of Remicade therapy.
CXR reveals cardiomegaly. Patient is referred to cardiologist, and Echo reveals cardiomyopathy.
Deficiency of which of the following micronutrients has been associated with cardiac complications?
A. Selenium
B. Iron
C. Copper
D. Vitamin C
E. Zinc
168. What is the most appropriate IV formulation within the first 24 hrs of life for a patient born at
28 week gestation weighing 1,100 grams?
A. Normal Saline
B. 5% Dextrose with electrolytes
C. 5% Dextrose with amino acids
D. 5% Dextrose
169. What is the caloric requirement for a healthy 13 year old male?
A. 100-110kcal/kg/day
B. 70-90 kcal/kg/day
C. 20-30 kcal/kg/day
D. 45-55 kcal/kg/day
170. A 16 year old boy with a Body Mass Index (BMI) of 47, Obstructive Sleep Apnea, and Type 2 Diabetes
Mellitus is interested in a laparoscopic Roux-en-Y Gastric Bypass surgery for weight reduction. A true
statement regarding this procedure is:
A. Patients undergoing Roux-en-Y Gastric Bypass may experience paradoxical weight gain
B. Post-surgery follow-up pediatric care should be limited to a single office visit
C. Roux-en-Y Gastric Bypass may lead to iron deficiency and other micronutrient deficiencies
D. A post-surgical decrease in insulin resistance is not seen until the BMI decreases by 30%
E. The stomach is removed completely during the Roux-en-Y Gastric Bypass
171. Which of the following statements regarding the ketogenic diet is FALSE?
A. The ketogenic diet is high in fat content and low in protein and carbohydrates.
B. Ketones have a direct anti-seizure effect on the brain.
C. The ketogenic diet is recommended for children with disorders of fatty acid oxidation.
D. Patients following a ketogenic diet require vitamin and mineral supplementation.

172. A twelve-year-old girl who was diagnosed with cystic fibrosis and pancreatic insufficiency as an infant
presents for her annual evaluation. Her BMI has fallen from the 60th percentile to the 40th percentile
for age. She is receiving pancreatic enzyme replacement therapy at a dose of 2,500 units of lipase
per kg per meal. Which is the most appropriate next step in management?
A. Reassure the patient and family that a BMI at the 40th percentile is adequate.
B. Provide oral nutritional supplements and conduct a full nutritional and behavioral evaluation.
C. Increase her dose of pancreatic enzymes to 3,000 units of lipase per kg per meal.
D. Refer the patient for surgical gastrostomy tube placement.
173. A three-year-old boy presents for evaluation of diarrhea. His mother states that he has had up to 6
watery bowel movements per day for one week. He also has a fever and nasal congestion. Which of
the following is the most appropriate recommendation?
A. Restrict the patient’s diet to clear liquids until the diarrhea resolves.
B. Remove all sources of lactose from the patient’s diet until the diarrhea resolves.
C. Begin a diet consisting of only bananas, rice, applesauce, and toast.
D. Encourage oral rehydration with fluids followed by an unrestricted, age-appropriate diet.
174. A 2 year old with history of short bowel syndrome (secondary to necrotizing enterocolitis), TPN
dependence, and TPN induced liver disease presents to your clinic with a history of persistent anemia
over the last 6 months. On exam, he is afebrile, pale, and significantly jaundiced. He has hepato-
splenomegaly. He has a Mickey button in place and well-healed incision from his previous surger-
ies. Labs are significant for a total bilirubin of 8 mg/dL and a direct bilirubin of 4 mg/dL. His AST
54 units/L and ALT 68 units/L, Albumin 2.5 g/dL, INR 1.5. His hemoglobin is 7.5 g/dL and MCV 70.
What micronutrient deficiency has resulted in his persistent anemia?
A. Selenium
B. Copper
C. Niacin
D. Folate
175. A 6 year old male develops a duodenal hematoma after routine endoscopy for evaluation of his
chronic diarrhea and failure to thrive. Biopsies shows subtotal villous atrophy, atrophic villi, enlarged
crypts with large amounts of inflammatory cells. The patient is diagnosed with celiac disease Marsh
3b. What vitamin deficiency contributed to the formation of the duodenal hematoma during the
endoscopy?
A. Vitamin A
B. Vitamin D
C. Vitamin E
D. Vitamin K
176. A healthy 1 week old male presents to your clinic for evaluation of a questionable anal abnormality
noted by the pediatrician at 2 days of age. In turns out, everything is normal – however, the mother
asks you about vitamin supplementation, specifically of vitamin D, as she is completely breastfed
infant. When should vitamin D supplementation begin and how much?
A. Immediately, 200 IU till patient is 2 months old then 400 IU.

B. Immediately, 400 IU.
C. Not till 2 months of age, 400 IU.
D. Never, as long as patient is breastfed he will get all the vitamin D he needs from mom.
177. Which of the following patients does not require folate supplementation?
A. A 10 year old male with inflammatory bowel disease on methotrexate for

maintenance therapy.
B. A 2 year male with seizure disorder on phenytoin.
C. A 6 year old female with cystic fibrosis.
D. A 12 year old female with eosinophilic colitis being tried on sulfasalazine therapy.
178. A 6 month old male develops a weepy, crusted dermatitis around the eyes, nose, mouth, diaper area,
hands and feeds about 4 weeks after being weaned from breast milk to formula. He recently devel-
oped a watery diarrhea and has stopped gaining weight over the last month. On exam, he appears
listless. His hair is sparse. What is there is fine and lightly pigmented. What nutritional deficiency has
resulted in this patient’s current condition?
A. Copper
B. Aluminum
C. Zinc
D. Molybdenum
179. A 6 month old female with a history of short bowel syndrome secondary to multiple intestinal atre-
sias presents with complaints of increased work of breathing, poor feeding, and cough over the last
week. She is diagnosed with RSV. It is noted on chest x-ray that her heart size is significant enlarged
and that on exam her heart rate seems irregular. Further evaluation is concerning for evolving car-
diomyopathy. The ICU physician is concerned that the patient receives her TPN from a new, small
emerging pharmaceutical company by her home in rural Texas. What micronutrient deficiency is the
ICU physician concerned about?
A. Selenium
B. Copper
C. Pyridoxine
D. Iodine
180. A 2 year old male with diagnosis of abetalipoproteinemia moves to your area. He has recently been
diagnosed and comes to your office for establishment of care. The mother’s chief complaint for
this visit is that he stumbles while walking despite walking with a wide-gait. The stumbling is much
worse at night. In addition to a single supplementation with AquaDEK – which of the following
vitamins should be supplemented further that the standard dosage in AquaDEK.
A. Vitamin A
B. Vitamin D
C. Vitamin E
D. Vitamin K
181. Considered one of three major nutrient deficiencies in the world by the World Health Organization,
this deficiency is the primary cause of blindness in children in the developing world.
A. Iodine
B. Iron
C. Zinc
D. Vitamin A
182. A 16 year old adolescent male has undergone resection of the terminal ileum because of an ileal
stricture. Of the following nutrients, which is MOST likely to become deficient in this patient?
A. Folic acid
B. Thiamin
C. Pantothenic acid
D. Cyanocobalamin
E. Vitamin K

183. A 15 year old boy with well–controlled ulcerative colitis is noted to have a hemoglobin of 10.2 gm%.
He denies any symptoms of bowel disease. He has a good appetite and eats a varied diet. He takes
sulfasalazine and azathioprine for maintenance therapy. Which of the following vitamin levels is likely
to be abnormally low.
A. Folate
B. Thiamine
C. Vitamin C
D. Cobalamin
184. A healthy 13 y/o male is referred to GI clinic due to elevated alkaline phosphatase which is 2-3 times
the upper limit of normal. Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and
albumin are normal. What should be your next step to assess for cholestatic disease?
A. Nothing. This is definitely not hepatobiliary disease as this patient is a rapidly growing male
and elevated alkaline phosphatase is due to increased bone activity.
B. Liver Ultrasound
C. Obtain gamma glutamyltransferase or 5’-nucleotidase
D. Repeat Alkaline Phosphatase, AST,ALT, and total bilirubin in 6 months
E. HIDA scan
185. The endoscopic definition for hiatal hernia involves:
A. Ascension of the Z line more than 2 cm above the hiatus

B. Ascension of the Z line 3 cm above the hiatus
C. Presence of folds in the distal esophagus
D. Open an incompetent hiatus.
186. Six hours after an upper endoscopy a 6 year old develops abdominal pain and vomiting.
Upper abdomen is tender, KUB is unremarkable. Best next step:
A. Pain medication and antiemetic

B. Imaging study
C. Surgery consult
D. Reassure mom and follow patient in 1 week
187. A 5 year old with abdominal pain and diarrhea is undergoing combined breath hydrogen/methane
testing. A standard dose of lactulose is given while the patient is NPO. Results from the study show
an increase in hydrogen production and peak 3 hours after ingestion of the test dose. No change in
methane production is noted.
The most correct interpretation of these results is:
A. The results indicate small bowel bacterial overgrowth

B. The results indicate lactose intolerance
C. The results are normal
D. The results are inadequate for interpretation
E. The results indicate fast intestinal transit time
188. Which of the following represents the most distinctive feature of the duodenum, as compared to the
rest of the small bowel?
A. Generally taller and more slender villi

B. Increased proportion of goblet cells within the epithelium
C. Abundance of lymphoid aggregates localized within the lamina propria
D. Predominance of tubuloalveolar glands known as Brunner’s glands throughout the
mucosa and submucosa
E. The plicae circularis are the tallest and most numerous within the small bowel
189. Which of the following could distinguish celiac disease from autoimmune enteropathy on small
bowel biopsies?
A. The degree of villous blunting is far less in autoimmune enteropathy

B. An increased number of plasma cells in the lamina propria in autoimmune enteropathy
C. The lack of increased intraepithelial lymphocytes in autoimmune enteropathy
D. The patchy nature of scalloped and ulcerated mucosa seen in autoimmune enteropathy
E. The increased presence of submucosal eosinophils in autoimmune enteropathy
190. Fecal elastase may be used to diagnose chronic pancreatitis. Which of the following conditions does
not result in abnormal levels of fecal elastase?
A. Celiac disease
B. Crohn’s disease
C. Diarrheal illness
D. Primary sclerosing cholangitis
E. Short bowel syndrome
191. Which of the following tests can detect mild pancreatic dysfunction?
A. Lundh test meal

B. Fecal elastase
C. Secretin stimulation test
D. Serum immunoreactive trypsinogen
E. Fecal fat measurement
192. An contrast UGI reveals a corkscrewed duodenum ending blindly suggesting the
possible diagnosis of:
A. Duodenal web
B. Duodenal protein enteropathy
C. Malrotation
D. Congenital microcolon of disuse
E. Annular pancreas
193. The radiological signs of necrotizing enterocolitis can include
A. pneumatosis intestinalis, pneumoperitoneum and hepatic pneumatosis

B. Colonic “thumb printing”
C. Punctate adrenal calcification
D. A and B
E. A and C
194. You see in follow-up a 12 y/o boy who sustained a bicycle handlebar injury 6 weeks prior. He reports
he is feeling well with no fever, vomiting or pain, but on physical examination, you notice he
grimaces when you palpate a smooth fullness just to the left of the umbilicus. You next order:
A. Plain film of the abdomen

B. Contrast UGI
C. US of the abdomen
D. CAT scan
E. Tc99m scan

195. A 5 year old boy is referred to your clinic for the evaluation of chronic diarrhea and failure to thrive.
You would like the parent to perform a 3 day collection for fecal fat. Which of the following is NOT
true regarding this test?
A. Steatorrhea is present in a child or adult if more than 7% of ingested fat is excreted.

B. It allows one to determine whether fat malabsorption is pancreatic or nonpancreatic
in nature.
C. The test involves the meticulous weighing of food and careful dietary records in order
to calculate mean daily fat intake.
D. Every single stool during a 3 day period should be collected.
196. Limitation of stool electrolyte testing include:
A. Can only be done on solid stool

B. Special media are needed
C. Subjects often ingest non-absorbable sugars
D. No standard exists for electrolytes in stool therefore results must be used in a comparative
values to prior or future stools
E. There are few genetic tests available for differentiation of congenital causes of diarrhea
197. A 3 year old male with a past medical history significant for small bowel resection including the
terminal ileum following necrotizing enterocolitis at 2 weeks of age presents with perianal
excoriation and diarrhea. Which antidiarrheal agent would be most appropriate?
A. Bismuth subsalicylate
B. Cholestyramine
C. Loperamide
D. Octreotide
E. Clonidine
198. All of the following are true EXCEPT:
A. Pruritus related to cholestatic liver disease is thought to be due to centrally mediated causes
related to endogenous opioid neurotransmission.
B. Diphenhydramine can help ameliorate pruritus in cholestatic liver disease
C. Opiate antagonists is the first line treatment for pruritus associated with cholestasis
in children
D. Cholestyramine is a hydrophilic, water insoluble anion-exchange resin that binds bile acids,
preventing their absorption through the enterohepatic circulation
199. Regarding blood transfusions in children, which statement is false?
A. Blood volume in children varies more dramatically in the first year of life than in latency
B. A unit of pRBCs has a hematocrit of 90%
C. Transfusion in children raises hemoglobin approximately 2 to 2.5 g/dL for every 10 ml/kg
of pRBCs given.
D. Hematocrit equilibrium post transfusion is generally evident within 24 hours
E. Newborns have a blood volume of about 85 ml/kg
200. What is the gold standard for measuring dehydration?
A. Serum electrolytes
B. BUN/Cr
C. Urine specific gravity
D. Percent loss of body weight
E. Heart rate
201. A 7 month old boy with biliary atresia underwent liver transplantation. His medications include tacro-
limus and prednisone. Two months postoperatively he is noted to have elevated transaminases. An
infectious work up is initiated and a liver biopsy is performed, which shows dense periportal lympho-
cytic and eosinophilic infiltration with endotheliitis and bile duct damage. One week after starting
high dose steroids his transaminases are still elevated. Which of the following agents may be consid-
ered in this situation?
A. Tacrolimus at an increased dose

B. Cyclosporine
C. MMF
D. OKT3
202. A 13 year old girl has a liver transplantation for autoimmune hepatitis and is started on prednisone
and tacrolimus in the post operative period. Her hospital course is complicated by a central line infec-
tion and adenovirus infection. She is discharged home on Prednisone, tacrolimus and MMF. Several
months after discharge she develops pharyngitis and is treated with an antibiotic.
One week later, her labs are as follows: Albumin - 4.1 mg/dL; total protein - 6.3 mg/dL; total biliru-
bin – 2.0 mg/dL; direct bilirubin - 1.0 mg/dL; ALT – 35 IU/L, AST – 22 IU/L, GGT – 45 IU/L; Na: 135
mEq/L; K: 6.8 mEq/L; CL – 110 mEq/L; CO2 – 24 mEq/L; glucose – 120mg/dL, BUN – 45 mg/dL; Cr -
2.3 mg/dL; Mg – 1.1
Which antibiotic is most likely to be the cause of these abnormal laboratory findings?
A. Penicillin
B. Amoxicillin
C. Erythromycin
D. Ceftriaxone
203. A 3 year old girl underwent liver transplantation for hepatoblastoma. Her post operative course is
complicated by biliary leak and multiple episodes of ascending cholangitis. She receives 10 days of
parenteral antibiotics with one week of fluconazole. She is discharged home on Tacrolimus, Predni-
sone and Multivitamins.
Two weeks later laboratory assessment shows Albumin – 3.5 mg/dL; total protein - 6.8 mg/dL, total
bilirubin - 5.0 mg/dL, direct bilirubin 3.2 mg/dL, ALT – 375 IU/L, AST – 450 IU/L, ALP – 315 IU/L. A
liver biopsy is suggestive of rejection.
Which of the following factors may be responsible?
A. Tacrolimus toxicity
B. Discontinuation of Fluconazole
C. Intercurrent viral infection
D. Incorrect HLA typing of donor
204. A twelve year old male who was diagnosed with Crohn disease 3 years ago has been on q8 wk Inf-
liximab infusions for one year. The parents reported that he developed erythematous, vesicular, skin
lesions in the right posterior rib cage area. The patient was afebrile but complained of skin tingling
sensation. According to above history, your recommend is:
A. Observation
B. Start 3rd generation cephalosporin
C. Discontinue Infliximab
D. Start p.o acyclovir
E. Admit for IV acyclovir

205. A 16 year old female has been on maintenance Infliximab mono therapy for 3 years. She was previ-
ously treated with 6-mercaptopurine. She presents with night sweats and splenomegaly.
What rare life threatening tumor must you be concerned about:
A. Burkitt’s Lymphoma
B. Hepatosplenic T-cell Lymphoma
C. Acute Myelogenous Leukemia
D. Hodgkin’s Lymphoma
E. Signet Ring Carcinoma
206. A 13-year-old female has a draining peri-rectal fistula. You choose to use infliximab therapy to heal
the fistula. What problem with using the therapy must you think about before starting therapy?
A. Walled off abscess formation

B. Systemic infection
C. Increased pain
D. Alternative site of fistulization
E. Constipation
207. A 17-year-old male has Crohn disease and has responded to Infliximab monotherapy for two years
without complication. He has been on 5 mg/kg/dose every 8 weeks. He develops 6 bloody stools per
day at 7 weeks and a trough level is obtained. It is undetectable. Stool studies for infection and CMV
PCR of colonic tissue is negative. Your best choice to treat this patient is:
A. Change to Adalimumab
B. Obtain a HACA
C. Increase to 10 mg/kg/dose or change interval to 4 weeks
D. Start prednisone
E. Start methotrexate or 6-mercaptpurine
208. A 7 year old female with cystic fibrosis is seen in follow up. She has not lost weight but has had
little weight gain over the last six months despite adequate caloric intake. She has 2 stools per day,
and sometime sees oil droplets. She has no other symptoms. She takes 2000 units/kg of pancreatic
enzymes with all meals. The next best step in management is:
A. Increase the pancreatic enzyme dose to 4000 units/kg before each meal
B. Offer reassurance that no intervention is needed unless there is weight loss
C. Add loperamide to her daily medications
D. Add a PPI to her daily medications
209. You are interested in assessing the possibility that a child has steatorrhea. What question would you
not ask the parents?
A. Are the stools hard to wipe off during a diaper change?

B. Do the stools float?
C. Do the stools smell rancid?
D. Are the stools difficult to flush?
E. Are the stools loose and oily?
210. A 4 month old infant presents to the emergency department with a four day history of progressive
lethargy, bradycardia, loose stools, and diminished deep tendon reflexes. She is afebrile and has no
rhinorrhea or exanthema. History revealed that her parents were mixing antacids into her bottles to
help with reflux symptoms. Her symptoms are MOST likely explained by
A. Hypermagnesemia
B. Hypomagnesemia
C. Hyperkalemia
D. Hypokalemia
E. Hypoglycemia
211. In a 12 year old boy with Zollinger-Ellison Syndrome, which of the following is the BEST
medical therapy?
A. Sodium bicarbonate
B. Nizatidine
C. Lansoprazole
D. Famotidine
E. Calcium carbonate-ranitidine compound
212. Probiotics have been shown to be of benefit in
A. Ulcerative colitis
B. Crohn’s disease
C. Both
D. Neither
213. In regard to the colonization of the newborn gut, which statement is false?
A. It is initially colonized by facultative maternal vaginal and fecal flora consisting of
Streptococcus, Enterococcus and Coliform genera
B. C-section babies are initially colonized by Klebsiella, Enterobacter and Clostridia genera
C. Breast fed babies have higher concentrations of Bifidobacterium and Lactobacillus genera
D. Formula fed babies have higher concentrations of Bifidobacterium and Lactobacillus genera
E. After 10 days both vaginal and C-section babies share the same flora
214. Probiotics are live microorganisms, that when consumed in adequate numbers, confer a health ben-
efit to the host. They also:
A. Lower intestinal pH and decrease the adherence of pathologic bacteria

B. Increase the production of short chain fatty acids and increase motility
C. Contribute to the production of riboflavin and folate
D. All above statements are false
E. All above statements are true
215. Misoprostol is thought to treat and prevent NSAID-associated peptic ulcers by which of
the following mechanisms:
A. Decreasing gastric acid secretion

B. Increasing mucosal resistance to injury by decreasing bicarbonate secretion
C. Providing mucosal protection by decreasing mucosal blood flow
D. Blocking histamine receptors
E. Activating adenylate cyclase in parietal cells.
216. Which of the following is true concerning the properties and action of Sucralfate on gut mucosa?
A. Sucralfate is a sulfated aluminum hydroxide that selectively binds to ulcers and erosions.
B. Sucralfate is a sulfated magnesium hydroxide that selectively binds to ulcers and erosions.
C. Sucralfate binds to ulcers and erosions and is activated by non-acidic conditions.
D. Sucralfate should be taken together with antacids for optimal binding activity.
217. A dialysis patient being treated for a gastric ulcer presents with bone pain, mental status changes
and proximal muscle weakness. Which medication was responsible for these side effects?
A. Ranitidine
B. Cimetidine
C. Sucralfate
D. Terfenadine

218. Which one of these drugs have reduced bioavailability when co-administered with Sucralfate?
A. Ciprofloxacin
B. Erythromycin
C. Aspirin
D. Prednisone
219. You are called at 3 am from the ER about a 3 year old female who has a history of severe constipa-
tion. The ER physician performed a history and a physical exam and there is no evidence of constipa-
tion or any acute problem but the mother demanded an X-ray of the abdomen to be taken since
“that is how her doctor diagnosed the constipation”. The X-ray showed scattered stool around the
colon. Thereafter the mother insisted on an admission for a clean-out. The ER physician is asking you,
would you admit this patient under your service for a Go-Lytely clean-out?
A. The abdominal X-ray and the history/physical exam are enough evidence that this patient has
constipation and needs a clean-out.
B. Parental insistence on admission may be reasonable given what appears to be a knowledge-
able parent.
C. The history/physical exam and X-ray do not support a diagnosis of constipation. You will
request history of admissions, ER visits and test results before deciding.
D. You recommend no admission; there is no indication to admit the patient. Refer the patient
and the mother to a psychiatrist.
E. You Recommend a CT scan of the abdomen since is more reliable than X-ray to diagnose
constipation.
220. You are consulted for admission of a 5 year old male who has G-tube issues. The patient has a his-
tory of severe recurrent asthma and is followed by the pulmonology service. He was diagnosed with
GERD for which he received a Nissen-fundoplication and G-tube. Recently, he started spitting up
again at home but it has not been witnessed by nurses. Mother believes the vomiting is caused by
fundoplication failure and a blocked G-tube and that an endoscopy is the best test to diagnose failed
fundoplication. At the end of the interview she gives you a gift and thanks for your time and asks
when you would do the scope and if you can also change her G-tube to a G-J tube since this will
help with the vomiting. The next best course of action is:
A. Accuse mother of Munchausen Syndrome by Proxy and call hospital security to protect the
child and the mother
B. Ask the mother to go out of the room to interview the child alone and ask him questions
about child abuse
C. Immediately leave the room and call Child Protective Services to take him into custody.
D. Call physicians and staff involved in his care to get details of the history. Obtain medical
records and document details of the encounter.
E. Schedule upper endoscopy and G-J tube placement as soon as possible. Consult surgeon for
repeat fundoplication.
221. Infant rumination best responds to
A. Anticholinergics
B. Soy formula
C. NG tube feedings
D. Frequent holding and social interaction
E. PPI therapy
222.
Clostridium difficile colitis is found in what percentage of children with antibiotic associated diarrhea:
A. 5%-10%
B. 15%-20%
C. 25%-30%
D. Greater than 30%
223. Which of the following statements regarding congenital chloridorrhea is true?
A. Stool Cl- level less than 90 mmol/L

B. Results in metabolic alkalosis
C. Results in metabolic acidosis
D. First detected after the patient first gets solid food
E. Due to defective chloride-bicarbonate exchange in the colon
224. Which of the following conditions is usually suspected after protracted diarrhea begins after the first
few weeks of life?
A. Microvillous inclusion disease

B. Tufting enteropathy
C. Congenital chloridorrhea
D. Autoimmune enteropathy
E. Enterocyte heparan sulfate deficiency
225. Erythromycin when used as a prokinetic:
A. Stimulates motilin
B. If given to a one week old increased the risk of pyloric stenosis
C. Can safely be given to a nursing mother
D. All are true
226. Pill esophagitis is commonly associated with these medications except:
A. Doxycycline
B. Tetracycline
C. Bismuth subsalicylate
D. Theophylline
E. KCl
227. What is the most common finding in a 15 year old male with IgA deficiency?
A. Recurrent infections with E. histolytica

B. Celiac disease
C. Inflammatory bowel disease
D. None of the above
228. Which immunodeficiency should be suspected in a 6yo male with recurrent infections and perianal
disease with gastric granulomas?
A. Leukocyte adhesion defect

B. Severe combined immunodeficiency
C. X-linked chronic granulomatous disease
D. IgA deficiency
229. Regarding IgA deficiency, which statement is false?
A. IgA deficiency is the most common form of immunodeficiency.

B. Most patients with confirmed IgA deficiency are asymptomatic.
C. There is variable penetrance of the IgA deficiency defect but all cases have <2 SD of normal
IgA levels for age.
D. Sinopulmonary infection is the most common manifestation, followed by recurrent gastroin-
testinal parasitosis of various genera including protozoa, flagellate, nematodes and platyhel-
minthes.
E. The diagnosis is most accurate after the age of four years.

230. You are consulted for a jaundiced 9 y/o male who is 3 weeks post bone marrow transplant. He is
afebrile and has right upper quadrant tenderness. All viral serology is negative except HBsAg. ALT is
78, AST is 59, TB is 8.2 with a direct of 3.9. AP is 181. His coagulation studies are normal. His RUQ
ultrasound report is unremarkable. You suspect hepatic GVHD and advise beginning with
A. Treatment with steroids

B. Treatment with steroids plus ursodeoxycholic acid
C. Liver biopsy to confirm the diagnosis
D. HIDA scan
E. Bone marrow aspiration for culture.
231. A 14 year old female with poorly controlled hyperthyroidism is evaluated for diarrhea. Which is the
following is not a possible cause for diarrhea is in this patient?
A. Decreased bile output

B. Decreased trypsinogen levels
C. Small intestinal bacterial overgrowth
D. Lactase deficiency
E. Accelerated oral to cecal transit
232. Nonalcoholic steatohepatitis is associated with which one of the following conditions?
A. Autoantibodies against liver antigens

B. Chronic hepatitis C
C. Insulin-dependent diabetes mellitus
D. Iron overload
E. Copper overload
233. Which of the following is not associated with hypothyroidism?
A. Ascites
B. Esophageal compression
C. Delayed gastric emptying
D. Delayed small bowel transit
E. Pernicious anemia
234. Graft-versus-host disease (GVHD) is caused when:
A. Host lymphocytes are depleted

B. Immunosuppressive therapy is increased
C. Donor lymphocytes attack host tissues
D. Host granulocytes attack donor tissues
235. The ethical precepts described in the Belmont Report include adherence to the principles of
Autonomy, Beneficence, Non-maleficence and:
A. Consent
B. Self-determination
C. Justice
D. Morality
236. In human subjects research involving minors, ethical considerations include:
A. Assent must be obtained from all children.

B. Clinical trials may not involve a greater than a minor increase
over minimal risk to individual subjects.
C. Investigator conflicts of interest are permissible, as long as they are reported to the local IRB.
D. A subpart D (Code of Federal Regulation) determination is required for all studies.
237. Choose the technique used to assess a statistical models assumptions:
A. Specificity
B. Cost-effective analysis
C. Sensitivity analysis
D. Validity
238. Match each word with the corresponding answer choice:
Validity A. Measure of agreement

Reliability B. Measurement of what is intended
Accuracy C. Measure gives same results on repeated trials
Precision D. Measure of the internal consistency of a test
Kappa statistic E. How close measurement is to actual value
Cronbach’s alpha F. How close repeated measures are to each other
239. If a researcher wants to increase the power of the study from 80% to 90% but keep all other
parameters the same, the original sample size will:
A. Decrease
B. Stay the same
C. Increase
D. Unable to tell
240. A control group compared to the intervention group should vary by:
A. Gender
B. Age
C. Education
D. None of the above
241. Analysis of variables by the original group assignment regardless if they remained or
adhered to that group is called:
A. Intention to treat analysis

B. Per protocol analysis
C. Post-hoc analysis
D. Cost-effectiveness analysis
242. The measure of how results of a study can be generalized to the population as a whole:
A. External validity
B. Accuracy
C. External variation
D. Power
243. A 17-year-old boy who has evidence of Crohn’s disease in the terminal ileum develops severe
radiating inguinal and scrotal pain.
The MOST likely visceral source for the referred pain in this patient is the
A. Appendix
B. Diaphragm
C. Gallbladder
D. Small bowel
E. Ureter

244. Which of the following represents the MOST likely mechanism for peptic injury associated with
chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDS)?
A. Generalized ischemia of the gut

B. Genetic predisposition
C. Inhibition of prostaglandin
D. Promotion of growth of Helicobacter pylori
E. Topical caustic injury
245. A 6 year old girl has had abdominal pain and nonbilious vomiting for 8 hours. History reveals cough
and fever for the past 3 days. Findings on physical examination include temperature, 39°C (102.2°F);
tachypnea; toxic appearance; diffuse, voluntary guarding; and quiet bowel sounds.
Of the following, the examination MOST likely to establish the etiology of the abdominal pain and
fever in this patient is a(n):
A. Abdominal radiograph
B. Chest radiograph
C. Complete blood count
D. Rectal examination
E. Upper gastrointestinal series
246. A 9-year-old girl has the height age of a 7-year-old and the bone age of a 6-year-old.
Among the following, the MOST likely cause of her short stature is
A. Achondroplasia
B. Hypothyroidism
C. Malnutrition
D. Normal variant short stature
E. Silver-Russell syndrome
247. An antral or pyloric web (diaphragm) is considered in the differential diagnosis of a 6-month-old girl
with failure to thrive syndrome and nonbilious vomiting.
The MOST specific study for diagnosing this condition is
A. Gastric emptying study

B. Plain abdominal radiography
C. Ultrasonography
D. Upper gastrointestinal contrast study
E. Upper gastrointestinal endoscopy
248. A 10-year-old child has had intermittent diarrhea and weight loss over the past year.
A TRUE statement regarding testing with guaiac or orthotolidine for occult blood in
this patient’s stool is:
A. Microscopic examination of the stool is a better test for detecting occult blood
B. Negative results exclude lower gastrointestinal bleeding
C. Positive results confirm the presence of occult blood
D. These tests detect peroxidase activity in hemoglobin
E. These tests quantitate the amount of hemoglobin in the stool
249. An 18-year-old girl who is taking tolmetin for juvenile rheumatoid arthritis develops gastritis.
Which of the following medications would have been MOST likely to prevent the development of
peptic disease in this patient?
A. Antacids
B. Corticosteroids
C. H2-blockers
D. Misoprostol
E. Sucralfate
250. A 3 year old boy with acute lymphoblastic leukemia in hematologic remission is receiving vincristine,
methotrexate, and 6-mercaptopurine. He develops abdominal pain and distention and nausea with-
out fever or diarrhea.
These findings are MOST likely caused by
A. Escherichia coli gastroenteritis due to granulocytopenia

B. Intestinal candidiasis due to lymphopenia
C. Intestinal mucosal ulcerations due to methotrexate toxicity
D. Necrotizing enterocolitis due to 6-mercaptopurine toxicity
E. Reduced intestinal motility due to vincristine toxicity
251. A term infant is born with gastroschisis that is repaired at birth. The infant is placed on total
parenteral nutrition.
The serum level of which of the following is likely to become abnormal FIRST?
A. Alkaline phosphatase activity

B. Bile salt concentration
C. Direct bilirubin concentration
D. Indirect bilirubin concentration
E. Transaminase activity
252. A previously healthy 12-year-old boy is icteric. Physical examination reveals a noncommunicative,
moderately ill-appearing boy who has an enlarged, soft, tender liver and ascites; there is no sple-
nomegaly. Pitting edema of the ankles and sacral area and scattered bruising of the extremities are
noted.
Among the following, the MOST critical set of studies to include in the initial laboratory evaluation is
A. Hepatitis A and B serologies

B. Hepatocellular enzyme activities
C. Prothrombin time and partial thromboplastin time
D. Total and fractionated serum bilirubin levels
E. Total serum protein and albumin concentrations
253. A 2 year old girl has a history of recurrent pneumonia, short stature, and failure to thrive. Studies
reveal absolute neutropenia and thrombocytopenia, normal sweat chloride concentration, and me-
taphyseal dysplasia of the head of the left femur. The MOST likely diagnosis for this patient is:
A. Alagille-Watson syndrome
B. Shwachman-Diamond syndrome
C. Sideroblastic anemia
D. Trypsinogen deficiency
E. Wiskott-Aldrich syndrome

254. f the following, which condition is the MOST common presentation of infection with
O
enterotoxigenic Escherichia coli?
A. Dysentery-like illness with fever

B. Hemolytic-uremic syndrome
C. Hemorrhagic colitis
D. Self-limited illness with watery stools and cramps
E. Severe diarrhea and dehydration
255. A 7-day-old breastfed infant born at term has had decreased appetite, irritability, and vomiting for
24 hours. On physical examination, the infant appears listless. Respiratory rate is 40/min; heart rate,
160/min; and blood pressure, 68/38 mm Hg. The skin and conjunctiva are icteric but no other abnor-
malities are noted. Laboratory studies reveal: hemoglobin, 12 gm/dL; total bilirubin, 16 mg/dL; and
direct bilirubin, 8 mg/dL. Urinalysis is negative for reducing substances.
Of the following, the MOST likely diagnosis is
A. Bacterial sepsis
B. Blood group incompatibility
C. Breast milk jaundice
D. Hypothyroidism
E. Intrauterine infection
256. Which of the following metabolic alterations is most commonly seen with re-feeding syndrome?
A. Hyperlipidemia secondary to increased serum ketone bodies

B. Wernicke’s encephalopathy secondary to thiamine deficiency
C. Severe hypophosphatemia affecting myocardial and respiratory function
D. Hypernatremia and hypertonic dehydration affecting mental status
257. A 29 year old male is referred from an optometrist for evaluation. The patient’s liver profile shows
AST 78 IU/L, ALT 92 IU/L, Bili 1.4 mg/dL, Alk Phos 88 IU/L, and albumin 3.4 g/dL. The photo of the
patient’s eyes is below. All of the following statements are true except:
A. The patient’s diagnosis is Wilson’s disease if the ceruloplasmin is low.

B. This finding on the eye exam can be seen in primary biliary cirrhosis and
autoimmune hepatitis.
C. The pigmentation will disappear with effective therapy.
D. Neurologic symptoms typically do not occur in the absence of this finding.
E. The mechanism that causes the disorder associated with this finding occurs
as a result of over-absorption of copper.
258. A 10-old male with HIV on HART therapy is evaluated for elevated liver enzymes (ALT 119 IU/L, AST
101 IU/L, bilirubin 1.3 mg/dL, Alk Phos 390 IU/L). A liver biopsy showed numerous blood-filled cysts
that do not have an endothelial lining. This liver biopsy finding is most likely secondary to:
A. Cytomegalovirus
B. Protease inhibitors
C. Rochalimaea henselae
D. Caroli disease
E. Congenital factors (e.g., cystic Von Meyenburg complexes)
259. An infant boy does not pass stool during the first 36 hours of life. Following rectal examination, he
passes a meconium plug. During the next 2 weeks, he has intermittent episodes of both watery and
hard, pellet-like stools. Barium enema reveals dilation of the large bowel with narrowing immediately
proximal to the rectum.
The MOST appropriate management of this patient’s problem is to
A. Add table sugar to the present formula

B. Arrange for a rectal biopsy
C. Change to a soy-based formula
D. Observe without intervention
E. Order an upper gastrointestinal series
260. Lactose enhances intestinal absorption of which ONE of the following nutrients?
A. Calcium
B. Chloride
C. Lipid
D. Potassium
E. Sodium
261. A 2 week old boy has short-bowel syndrome following surgery for severe necrotizing enterocolitis.
Management has included total parenteral nutrition. Clinical findings include a wasted appearance;
dry, flaky skin; a poorly healing abdominal incision; and thrombocytopenia.
The patient MOST likely has a deficiency of
A. Calories
B. Essential amino acids
C. Essential fatty acids
D. Iron
E. Vitamin E
262. A 14 month old African-American infant, exclusively breastfed since birth, has just begun walking.
Physical examination reveals prominence of the costochondral junctions. Radiographs reveal widen-
ing of the distal end of the radii. The laboratory test MOST likely to confirm the diagnosis is measure-
ment of the serum concentration of:
A. Albumin
B. Lactate dehydrogenase
C. Phosphorus
D. Vitamin A
E. Vitamin C

263. A 6 year old boy who has had a relapse of acute lymphoblastic leukemia has had a 4.8 kg (10 lb)
weight loss during a course of combination chemotherapy with prednisone, vincristine, and high-
dose methotrexate. He has had a poor appetite but no vomiting or diarrhea.
Of the following, the MOST appropriate next course of management would be
A. Administration of anabolic steroids

B. Administration of intravenous gamma globulin
C. Discontinuation of methotrexate
D. Enteral hyperalimentation
E. Parenteral hyperalimentation
264. The basal energy or metabolic requirement for children is calculated MOST accurately by considering
A. Body surface area

B. Creatinine-height index
C. Serum protein concentration
D. Total lymphocyte count
E. Triceps skinfold thickness
265. An infant boy born at term is delivered at home without medical supervision. At 48 hours of age, he
is brought to the emergency room because of a bloody discharge from the umbilical cord and bloody
stools. Until the results of laboratory studies are available, the BEST initial management is to adminis-
ter intravenous:
A. Ampicillin and gentamicin

B. Cryoprecipitate
C. Factor VIII concentrate
D. Fresh frozen plasma
E. Vitamin K
266. A 3 1/2 year old boy with chronic diarrhea and failure to thrive is diagnosed with cystic fibrosis.
Neurologic examination reveals absent deep tendon reflexes, truncal ataxia, and muscle weakness.
A nutrient deficiency is suspected. Given this constellation of findings, what additional physical sign
is MOST likely to be present in this child?
A. Desquamating skin lesions

B. Ophthalmoplegia
C. Positive Trousseau sign
D. Purpura
E. Stooped posture
267. Which of the following BEST explains why solutions containing 1.2 to 2.5% glucose, rather than
5% glucose, are used for oral rehydration?
A. Absorption of sodium and water in the gut is maximized

B. Glomerular filtration rate is enhanced
C. Hyperglycemia and glycosuria are less likely to occur
D. Potassium absorption is decreased
E. Stomach distention with vomiting is less likely to occur
268. A TRUE statement about the sugar content of infant formulas is:
A. All lactose-containing formulas are cow milk-based

B. All cow milk-based formulas contain only simple sugars
C. All soy-based formulas are corn syrup-free
D. All soy-based formulas contain lactose
E. Proprietary formulas do not contain sucrose
269. Shortly after birth, a 3,500 g term newborn is found to be jittery and to have a high-pitched cry.
Physical examination reveals tachypnea and a liver edge that is palpable several centimeters below
the umbilicus. Blood glucose concentration is 14 mg/dL. Among the following, the MOST likely cause
of the hypoglycemia in this newborn is:
A. Galactokinase deficiency
B. Glycogen storage disease
C. Insulinoma
D. Maternal diabetes mellitus
E. Prolonged maternal labor
270. A breastfed infant who appeared healthy at birth develops chronic diarrhea, failure to thrive, and
hepatomegaly during the first few weeks of life. Ultrasonography reveals adrenal enlargement and
calcification.
Of the following, the MOST likely explanation for these findings is:
A. Cystic fibrosis
B. Glucose-galactose malabsorption
C. Glycogen storage disease
D. Niemann-Pick disease
E. Wolman disease
271. Among the following, the gastrointestinal disease MOST likely to respond to treatment with anti-
cholinergic medications is:
A. Constipation
B. Dysentery
C. Gastroesophageal reflux
D. Irritable bowel syndrome
E. Poor motility
272. Examination of a developmentally normal 7-month-old boy reveals moderately enlarged cervical
lymph nodes; a hemorrhagic seborrhea-like rash on the forehead, scalp, and trunk; and hepato-
splenomegaly. Laboratory findings include: hemoglobin, 12.0 g/dL; mean corpuscular volume, 82
fL; white blood cell count, 10,700/mm³, with 40% neutrophils and 60% lymphocytes; and platelet
count, 260,000/mm³.
These findings are MOST consistent with
A. Acute lymphoblastic leukemia

B. Aplastic anemia
C. Langerhans cell histiocytosis
D. Neuroblastoma
E. Niemann-Pick disease
273. A 14 year old boy is being evaluated for jaundice that was first noted 1 week ago following an upper
respiratory tract infection. He reports not feeling very hungry for the past month. Physical examina-
tion reveals a firm liver, an enlarged spleen, and an intention tremor.
Among the following, the test that would be MOST helpful for making a definitive diagnosis
in this patient is a:
A. Liver biopsy for copper content

B. Serum bilirubin concentration
C. Serum ceruloplasmin level
D. Serum transaminase activity

274. A 3 month old infant girl is admitted to the hospital for evaluation of recurrent episodes of hypogly-
cemia. Physical examination reveals hepatomegaly. After 2 hours of fasting, she develops hypoglyce-
mia. Measurement of which of the following would be MOST helpful in determining the etiology of
this patient’s hypoglycemia?
A. Ammonia in the serum and the arterial pH

B. Cortisol and growth hormone in the serum
C. Insulin and glucose in the serum
D. Ketones and reducing substances in the urine
E. Organic acids in the urine and lactate in the serum
275. The mother of a 3 month old infant reports that the boy is demanding frequent feedings and has
a noticeably protuberant abdomen. Physical examination reveals doll-like facies and marked hepa-
tomegaly. Laboratory findings include a serum glucose level of 20 mg/dL and an elevated venous
lactate level of 44 mg/dL (normal, <18 mg/dL).
Of the following, the most appropriate INITIAL management of this infant is:
A. Administration of a formula that has high concentrations of fructose and galactose

B. Daily injections of glucagon
C. Insertion of a portacaval shunt
D. Nocturnal infusion of glucose via a nasogastric tube
E. Referral for liver transplantation
276. The mother of a 3 month old boy reports that he has a poor appetite and constipation. Findings
on physical examination, when compared to those 2 months ago, include poor interim growth,
increased lethargy, hoarse cry, decreased tone, large fontanelles, and a more pronounced umbilical
hernia.
Of the following, the MOST likely cause of this infant’s problem is
A. Agenesis of the thyroid gland

B. Endemic goitrous hypothyroidism
C. End-organ unresponsiveness to thyroid hormone
D. Inborn error of thyroxine synthesis
E. Thyroid gland unresponsiveness to thyrotropin
277. Which of the following is the most common cause of pancreatitis in childhood?
A. Viral
B. Drug induced
C. Idiopathic
D. Familial
E. Abdominal trauma
278. Which of the following is not part of the Currarino triad characterizing caudal regression syndrome
which can present as infantile constipation?
A. Dysplastic sacrum
B. Anal abnormalities
C. Tethered cord
D. Pre-sacral mass
279. Which of the following is NOT associated with Wilson’s Disease:
A. Fatty liver
B. High serum uric acid
C. Low serum zinc level
D. Low serum alkaline phosphatase
E. High serum bilirubin
A. 90% of Vitamin A is stored within the liver

B. Vitamin A deficiency Xerophthalmia is irreversible
C. Can cause a hypochromic microcytic anemia with low Fe but normal Fe stores
D. Hypervitaminosis A is associated with head aches
281. Which of the following is NOT a common feature of BOTH kwashiorkor and marasmus:
A. Irritability
B. Decreased serum lipoproteins
C. Markedly Depressed serum albumin
D. Increased susceptibility to infection
E. Anemia
282. Tyrosinemia is associated with:
A. Boiled cabbage smell

B. Mousey smell
C. Blue Cheese Vinaigrette smell
D. Maple syrup
E. All of the above except D
283. Which statement about Hepatitis A is true?
A. Leading cause of fulminant hepatitis in Pediatrics

B. Has been associated with chronic hepatitis
C. Recurrence of the disease can occur up to 6 months after primary infection
D. Treatment for non-fulminant hepatitis A includes Lamivudine for 4 weeks
E. Severity of disease decrease with increasing age
284. Acute lower GI hemorrhage in HIV infected patients is most often caused by:
A. CMV colitis
B. Lymphoma
C. Kaposi’s sarcoma
D. Idiopathic chronic colitis
E. Nonspecific colitis
285. First line of treatment of esophageal candidiasis in HIV infected patient is:
A. Clotrimazole
B. Ketoconazole
C. Fluconazole
D. Amphotericin B
286. Organism causing intestinal microsporidiosis in AIDS patients is:
A. Encephalitozoon intestinalis
B. Cryptosporidium
C. Isospora Belli
D. Enterocytozoon Bieneusi

287. A 7 year old girl who had undergone a surgical repair for long-segment Hirschsprung’s disease in
early infancy presents with a fever, abdominal distention, and bloody diarrhea for 2 days. Which of
the following is the most likely diagnosis?
A. Diversion colitis
B. Enterocolitis
C. Ulcerative colitis
D. Colonic stricture
E. Viral gastroenteritis
288. A 6 year old boy just arriving from Eastern Europe has had malodorous diarrhea since early infancy,
even though he was breast-fed. He is small, has some bruises from bumping into furniture going
to the bathroom at night, and has recently developed some difficulty walking. Physical examination
shows that he is small and undernourished, with depleted subcutaneous fat. He has a protuber-
ant abdomen and 1+ edema in his lower extremities. He has no deep tendon reflexes in his lower
extremities. Which one of the following explains the finding on the small intestinal biopsy from this
patient?
A. Gluten enteropathy
B. Congenital lactase deficiency
C. Abetalipoproteinemia
D. Glucose-galactose transport defect
E. Chronic nonspecific diarrhea of childhood
289. A 5 year old boy is referred for evaluation of liver disease after presenting to his primary physi-
cian with chronic pruritus. His evaluation reveals a small child (below the fifth percentile for height;
weight for height tenth percentile) with excoriations on his trunk and extremities. He has no icterus.
A grade 2/6 systolic murmur is heard at the left upper sternal border. His liver is soft, about 1 cm
below the right costal margin and nontender. Spleen was not palpable. He has diminished but sym-
metric deep tendon reflexes in his lower extremities. Laboratory studies reveal:
Hemoglobin 12.8
Platelet count 239,000
AST 129
ALT 134
Alkaline phosphatase 678
GGTP 948
Total bilirubin 0.7
Prothrombin time 13.9
INR 1.2
Which one of the following is the most likely diagnosis?
A. Progressive familial intrahepatic cholestasis (e.g., Byler’s disease)

B. Sclerosing cholangitis
C. Niemann-Pick disease, type A
D. Alagille syndrome
E. Alpha-1-antitrypsin deficiency
290. All of the following statements about hepatitis E are true, except
A. Outbreaks of hepatitis E tend to be very large because of the high rate of secondary
(case-to-case) spread
B. Cases of hepatitis E in the United States are rare
C. Infection with hepatitis E virus (HEV) in pregnancy is associated with high mortality rate
D. Anti-HEV appears to be protective, and prospects for developing a vaccine are good
E. HEV is not closely related in structure or function to any of the other viral hepatitis agents
291. All of the following agents are effective for both induction of remission and maintenance of
remission in patients with ulcerative colitis except
A. Oral mesalamine formulations including Asacol and Pentasa

B. Sulfasalazine
C. Olsalazine (Dipentum)
D. Rectal mesalamine (Rowasa enemas and suppositories)
E. No exception
292. Which one of the following statements is false with respect to the use of cyclosporine in patients
with inflammatory bowel disease?
A. Cyclosporine administered as a continuous intravenous infusion at a high dose of 4 mg/kg/d

is effective for severely active ulcerative colitis
B. Cyclosporine administered orally at a dose of 5 mg/kg/d is ineffective for the induction of
improvement or remission in patients with active Crohn’s disease
C. Cyclosporine administered orally at a dose of 5 mg/kg/d is ineffective for maintenance of
remission in patients with Crohn’s disease
D. Cyclosporine is slow acting and thus is not useful as a bridge therapy to other slower acting
medications such as 6-mercaptopurine, azathioprine, or methotrexate
E. None of the above
293. A young adult with a life-long history of mild jaundice, but no bilirubinemia or evidence of chronic
hepatitis or hemolysis is likely to have a genetic defect in:
A. Sinusoidal bilirubin uptake pump

B. MRP2 (canalicular multispecific organic anion transporter)
C. Bilirubin-UGT
D. UDP glucuronic acid synthetase
E. Cholesterol 7-á-hydroxylase
294. Alpha- l-antitrypsin deficiency leads to liver injury by way of
A. Uncontrolled proteolytic enzyme activity in the portal tracts

B. Chronic pancreatitis and focal biliary cirrhosis
C. Inability to transport divalent cations into the endoplasmic reticulum
D. Accumulation of abnormal glycoprotein in the liver cells
E. Pulmonary fibrosis and the development of cardiac cirrhosis
295. Which serological test is most commonly abnormal in autoimmune hepatitis?
A. Anti-nuclear antibody (ANA)

B. Anti-smooth muscle antibody
C. Anti-LKM antibody
D. Anti-SLA
E. Anti-HCV
296. A patient with photosensitivity is referred to you because of abnormal transaminases (ALT=120,
AST=150). Physical examination shows pigmentation and blisters on the dorsa of the hands. What
results of laboratory testing is the least likely to be found?
A. Positive hepatitis C antibody

B. High levels of excretion of ALA (aminolevulinic acid) and porphobilinogen (PBG)
C. Serum ferritin of 300 ng/mL
D. Elevated MCV (mean corpuscular volume)
E. Elevated gamma glutamyl-transpeptidase

297. Crigler-Najjar syndrome type II is typically treated by:
A. Liver transplantation
B. Lifelong phototherapy
C. Ursodeoxycholic acid
D. Gene transfer of UGT using adenovirus vectors
E. Phenobarbital
298. A 15 year old boy with decompensated cryptogenic cirrhosis presents with a 2 week history of
increasing anorexia and weakness. Four weeks prior to presentation he was treated for an episode
of spontaneous bacterial peritonitis and was discharged after 5 days of IV antibiotics on prophylac-
tic Bactrim, spironolactone and furosemide. Physical examination is remarkable for jaundice and
ascites. Laboratory data reveal a serum creatinine of 3.1 mg/dl (4 weeks prior: 0.8 mg/dl), and BUN
of 52 mg/dl (4 weeks prior: 14 mg/dl). At the present time, all of the following are appropriate steps
except:
A. Decrease diuretics by half, liberalize sodium intake and obtain follow-up blood studies.
B. Obtain urinalysis, urine sodium measurement, and urine eosinophil count
C. Renal ultrasound
D. Discontinue diuretics and give saline or colloid challenge
E. Repeat diagnostic paracentesis
299. Hepatitis A occurs in cyclical outbreaks in the United States.

These outbreaks spread largely because of:
A. HAV infection among injection drug users

B. Promiscuous sexual behavior
C. Infected food handlers
D. Widespread vaccination programs
E. Close personal contact with infected but asymptomatic individuals, particularly children
300. A previously healthy two year old boy is referred to you for elevation of liver function tests. When a
liver profile was drawn during an episode of fever, his serum alkaline phosphatase concentration was
elevated. He has no recent history of fractures. His growth and development have been normal. He
did not have neonatal liver disease. Review of symptoms is negative for pruritus, chronic diarrhea, or
acholic stools. His physical examination is normal. Laboratory studies at your institution confirm the
biochemical findings. Serum 25-hydroxy vitamin D levels are within the normal range.
Which of the following is the most appropriate next step to manage this child?
Patient’s results Normal range

Calcium 9.2 mg/dL 8.8-10.7 mg/dL
Phosphorus 4.2 mg/dL 3.0-5.0 mg/dL
Blood urea nitrogen 8 mg/dL 5-20 mg/dL
SGOT 28 IU/L 20-60 IU/L
SGPT 18 IU/L 5-45 IU/L
GGT 12 IU/L 6-20 IU/L
Conjugated bilirubin 0.1 mg/ dL < 0.3 mg/dL
Alkaline phosphatase 2800 IU/L 65-525 IU/L
A. Abdominal ultrasound
B. Liver biopsy
C. Radiographs for rickets survey
D. 1,25 dihydroxy vitamin D level
E. No further laboratory tests
301. The following statements regarding the management of foreign bodies in the stomach
are true EXCEPT:
A. The clinician should consider removing objects that are more than 2 cm in diameter or
more than 5 cm in length, because they are unlikely to pass through the duodenum.
B. In the case of battery ingestion, levels of heavy metal in the blood and urine
should be measured.
C. Batteries that have passed through the esophagus to the stomach should always
be removed.
D. Between 80% to 90% of ingested foreign bodies that reach the stomach will pass
without specific therapy.
302. Which of the following metabolic alterations is most commonly seen with re-feeding syndrome?
A. Hyperlipidemia secondary to increased serum ketone bodies

B. Wernicke’s encephalopathy secondary to thiamine deficiency
C. Severe hypophosphatemia affecting myocardial and respiratory function
D. Hypernatremia and hypertonic dehydration affecting mental status
303. Which of the following statements concerning hereditary hemochromatosis (HH) is false?
A. The phenotypic expression in the United States is 1/200-1/250.

B. HH is one of the most common, identified, genetic disorder in Caucasians.
C. The genetic defect causes an excessive absorption of iron.
D. Compound heterozygosity (C282Y, H63D) accounts for 3-5% of cases.
E. HH should be considered in any male patient with transferrin saturation greater
than 30 percent.
304. What is not a result of ascorbic acid deficiency?
A. Perifollicular hemorrhage
B. Subperiosteal hemorrhage
C. Hyperkeratotic hair follicles
D. Cheilosis
305. An asymptomatic duplication cyst that is found incidentally should be
A. Watched expectantly
B. Excised in a patients under the age of three years
C. Excised regardless of age
D. Undergo MRI and if it communicates with intestinal lumen, then excise
E. Undergo MRI and if it does not communicate with intestinal lumen, then watch
306. With respect to candidal esophagitis which statement is false?
A. It results in dysphagia, substernal pain and odynophagia

B. It can be treated with oral fluconazole
C. It is highly unlikely in the absence of thrush
D. It can be mimicked by cryptococcosis
E. Patients with AIDS may have candidal esophagitis with thrush
307. With respect to herpetic esophagitis which statement is false?
A. It is highly unlikely in the absence of herpetic stomatitis

B. It may be accompanied by drooling, fever and generalized malaise
C. Esophageal biopsy may show multinucleated giant cells
D. It can occur in children with normal immunity
E. Ulcerations may resemble CVM esophagitis

308. A previously healthy 2-month-old infant suddenly develops bilious vomiting. Physical examination
reveals an ill-appearing child with abdominal distention and diminished bowel sounds. Which of the
following is the MOST likely diagnosis?
A. Antral web
B. Cholelithiasis
C. Duodenal atresia
D. Malrotation with midgut volvulus
E. Peptic ulcer disease
309. Meckel’s diverticulum
A. Can be lined by ileal mucosa with external serosa but no muscularis layers
B. Can be lined by ileal mucosa, ectopic gastric mucosa and muscularis – serosa layers (*)
C. Can be lined with total gastric mucosa
D. Often has pancreatic rest which ulcerate
E. Can be lined with non-HCL secreting gastric mucosa
310. A toddler presents with edema of the hands, feet, and scrotum. Hypoproteinemia, lymphocytopenia,
and decreased levels or serum albumin, immunoglobulins, transferrin, and ceruloplasmin are noted.
Small bowel contrast study shows thickened mucosal folds. Characteristic histopathology will most
likely reveal
A. Eosinophilia in the lamina propria

B. Dilated lymphatics in the villous tips
C. Neutrophils invading the crypts
D. Basal lymphocytosis
E. Haloed inclusions bodies within the enterocytes
311. You are consulted on a 19 m/o with corrected tricuspid atresia and moderate anasarca. Upon hearing
the history and performing a physical examination you ask for a screening stool alpha-1-antitrypsin
level because you suspect
A. Hypoproteinemia secondary to alpha-1-antitrypsin liver disease

B. Protein losing enteropathy from heart surgery
C. Pulmonary hypertension secondary to alpha-1-antitrypsin deficiency fibrosis
D. Chaperon disease of enterocytes
E. Neutrophil elastase enteropathy
312. Which of the following laboratory findings is NOT likely to be found in a patient presenting with
Small Bowel Bacterial Overgrowth?
A. Elevated D-lactate
B. Macrocytic Anemia
C. Microcytic Anemia
D. Elevated Stool pH
E. Hypocalcemia
313. A 9-year-old girl with no previous illness is admitted with RLQ abdominal pain of one month dura-
tion, worsening over the last few days. Her pain is constant, non-radiating, moderate to severe
in intensity, and associated with nausea and vomiting. She has suffered a weight loss of10 lb. On
examination, she has RLQ tenderness without abdominal rigidity, guarding or rebound pain. Bowel
sounds are normal. She has no fever. CBC, serum chemistries, CRP, amylase and lipase were normal
except for mild normocytic anemia and moderately elevated CRP. Abdominal CT scan with contrast
reveals mesenteric adenopathy measuring 3 cm maximum and an irregular filling defect involving the
terminal ilium. EGD and colonoscopy reveals 3 polypoidal mucosal lesions in the cecum measuring
2.5 cm maximum. The ileocecal valve is edematous and the ileum is hard to intubate. Biopsies reveal
mild focal active cecitis and normal mucosa in the rest of the colon and upper GI tract. The most ap-
propriate next step is:
A. Small Bowel Series

B. Start Treatment with Steroids
C. Diagnostic laparoscopy
D. TB skin Test
E. Send IBD panel
F. Abdominal/Pelvic Ultrasound
314. Gastric acid secretion is inhibited by
A. Gastrin
B. Secretin
C. Motilin
D. CCK
E. Histamine
315. Which ethnic group has the lowest prevalence of primary hypolactasia?
A. Hispanics
B. Non-Hispanic Caucasians
C. Blacks
D. Asians
316. A 3 day old infant presents with severe life-threatening diarrhea and dehydration.
What is the most likely disorder?
A. Congenital trehalase deficiency

B. Fructose malabsorption
C. Glucose-galactose malabsorption
D. Sucrase-isomaltase deficiency

Answers for Board Review
1. C (Congenital Anomalies of the Esophagus)

2. C (Congenital Anomalies of the Esophagus)
3. B (Deglutition)
4. A (Dysphagia)
5. E (Dysphagia)
6. C (Eosinophilic Esophagitis).
7. B (Eosinophilic Esophagitis).
8. E (Eosinophilic Esophagitis).
9. D (Esophageal Anatomy, Development and Physiology)
10. D (Esophageal Caustic Injury)
11. F (Esophageal Motility)
12. D (Upper GI Bleed)
13. C (Gastroesophageal Reflux and Gastroesophageal Reflux Disease)
14. A (Gastroesophageal Reflux and Gastroesophageal Reflux Disease)
15. E (Gastroesophageal Reflux and Gastroesophageal Reflux Disease)
16. E (Esophageal Caustic Ingestions)
17. D milk-protein intolerance (Colic)
18. B (Food and Waterborne Illness)
19. D (Food and Waterborne Illness)
20. B (Abdominal Masses)
21. A (Abdominal Masses)
22. D (Gastritis)
23. D (H Pylori)
25. C (Pyloric Stenosis)
26. D (Gastric Foreign Body)
27. C (Gastric Foreign Body)
28. A (Gastric Foreign Body)
29. C (Appendicitis)
30. B (Appendicitis)
31. D (Autoimmune Enteropathy)
32. D (Autoimmune Enteropathy)
33. D (Abdominal Pain)
34. A (Abdominal Pain)
35. B (Stomach Congenital Anomalies)
36. B (Stomach Congenital Anomalies)
37. A (Celiac Disease)
38. D (Celiac Disease)
39. C (Small Intestine – Congenital Anomalies)
40. D (Small Intestine – Congenital Anomalies)
41. C (Small Intestine – Congenital Anomalies)
42. B (Necrotizing Enterocolitis)
43. C (Necrotizing Enterocolitis)
44. B (Small Intestine – Congenital Anomalies)
47. E (Small Intestine – Congenital Anomalies)
48. E (Small Intestine – Congenital Anomalies)
49. D (Small Bowel Bacterial Overgrowth)
50. C (Small Bowel Bacterial Overgrowth)
51. B (Enteric Infections)
52. D (Enteric Infections)
53. A (Enteric Infections)
54. B (Small Intestine – Obstruction)

55. D (Tropical Sprue)
56. C (Tropical Sprue)
57. B (Colitis not due to inflammatory bowel disease)
58. D (Colitis not due to inflammatory bowel disease)
59. C (Colitis not due to inflammatory bowel disease)
60. C (Inflammatory bowel disease – Crohn’s Disease)
61. C (Inflammatory bowel disease – Crohn’s Disease)
62. B (Inflammatory bowel disease – Ulcerative Colitis)
63. A (Inflammatory bowel disease – Ulcerative Colitis)
64. B (Colonic Motility)
65. D (Constipation)
66. C (Constipation)
67. A (Constipation)
68. C (Hemorrhoids)
69. C (Hemorrhoids).
70. C (Hirschsprung Disease)
71. B (Other inflammatory lesions of the bowel)
72. A (Other inflammatory lesions of the bowel)
73. C (Other inflammatory lesions of the bowel)
74. E (Polyps)
75. E (Polyps)
76. C (Rectal Prolapse)
77. B (Perianal Disease)
80. D (Pseudo Obstruction)
81. B (Biliary Tree Normal Microanatomy)
82. B (Other disorders of the bile ducts)
83. C (Other disorders of the bile ducts)
84. B (Biliary Atresia)
85. E (Biliary Atresia)
86. E (Cholecystitis)
87. C (Cholecystitis)
88. D (Cholecystitis)
89. C (Cholecystitis)
90. A (Cholecystitis)
91. B (Fulminant liver failure)
92. D (Fulminant liver failure)
93. A (Fulminant liver failure)
94. A (Fulminant liver failure)
95. B (Fulminant liver failure)
96. C (Fulminant liver failure)
97. A (Bacterial, parasitic and other infections of the liver)
98. E (Bile acid synthetic defects)
99. B (Bile acid synthetic defects)
100. A (Carbohydrate Metabolism)
101. C (Carbohydrate Metabolism)
102. E (Drug Induced Liver Injury)
103. D (Drug Induced Liver Injury)
104. E (Disorders of Lipid Metabolism)
105. B (Disorders of Lipid Metabolism)
106. B (Granulomatous hepatitis)
107. A (Granulomatous hepatitis)
108. C (Granulomatous hepatitis)
109. B (Non alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH))
110. D (Liver transplantation)
111. B (Liver transplantation)
112. E (Liver transplantation)
113. A (Liver transplantation)
114. B (Liver transplantation)
115. A (Liver transplantation)
116. D (Peroxisomal Disorders)
117. A (Familial hepatocellular cholestatic disorders)
118. A = 1, B = 3, C = 4, D = 2 (Familial hepatocellular cholestatic disorders)
119. D (Familial hepatocellular cholestatic disorders)
120. E ( Familial hepatocellular cholestatic disorders)
121. C (Acute graft vs Host disease and veno occlusive disease)
122. A (Acute graft vs Host disease and veno occlusive disease)
123. F (Acute graft vs Host disease and veno occlusive disease)
124. B(Acute graft vs Host disease and veno occlusive disease)
125. B (Acute graft vs Host disease and veno occlusive disease)
126. E (Disorders of bilirubin metabolism)
127. A (Jaundice)
128. B (Disorders of amino acid metabolism)
129. D (Liver masses)
130. C (Congenital hepatic infections)
131. E (Congenital hepatic infections)
132. C (Viral hepatitis)
133. C (Viral hepatitis)
134. F (Viral hepatitis)
135. A (Viral hepatitis)
136. B (Neonatal Cholestasis)
137. E (Neonatal Cholestasis)
138. B (Chronic hepatitis - Autoimmune Hepatitis and Crossover Syndromes in Children)
139. A (Chronic hepatitis - Autoimmune Hepatitis and Crossover Syndromes in Children)
140. E (Chronic hepatitis - Autoimmune Hepatitis and Crossover Syndromes in Children)
141. D (Pancreas - Normal anatomy, development and physiology)
142. B (Pancreas - Normal anatomy, development and physiology)
143. B (Acute Pancreatitis)
144. D (Pancreas – Exocrine Function)
145. B (Pancreas – Exocrine Function)
146. A (Pancreas – Exocrine Function)
147. A (Congenital anomalies of the pancreas)
148. B (Congenital anomalies of the pancreas)
149. A (Shwachman-Diamond syndrome)
150. A (Nutritional consequences of cholestasis)
151. C (Nutritional consequences of cholestasis)
152. C (Congenital enzyme and transport defects)
153. C (Congenital enzyme and transport defects)
154. B (Congenital enzyme and transport defects)
155. D (Congenital enzyme and transport defects)
156. B (Normal digestion and absorption)
157. D (Normal digestion and absorption)
158. A (Normal digestion and absorption)
159. A (Normal digestion and absorption)
160. B (Normal digestion and absorption)
161. D (Normal digestion and absorption)
162. C (Disaccharidase deficiency)
163. B (Disaccharidase deficiency)
164. A (Comparison of human milk and cow-milk based formulas)
165. C (Malnutrition)
166. D (Vitamin and mineral absorption, function and deficiency states)
167. A (Vitamin and mineral absorption, function and deficiency states)
168. C (Nutritional requirements of pre-term and term infants, children and adolescents)
169. D (Nutritional requirements of pre-term and term infants, children and adolescents)
170. C (Obesity)
171. C (Nutritional Therapy)
172. B (Nutritional Therapy)
173. D (Nutritional Therapy)
174. B (Vitamin and mineral absorption, function and deficiency states)

176. B (Vitamin and mineral absorption, function and deficiency states)
177. C (Vitamin and mineral absorption, function and deficiency states)
184. C (Alkaline phosphatase)
185. A (Endoscopy)
186. B (Endoscopy)
187. C (Breath tests)
188. D (Intestinal Biopsy)
189. C (Intestinal Biopsy)
190. D (Pancreatic Function Testing)
191. C (Pancreatic Function Testing)
192. C (Radiologic Evaluations)
193. D (Radiologic Evaluations)
194. C (Radiologic Evaluations)
195. B (Stool Testing)
196. C (Stool Testing)
197. B (Anti-diarrheals)
198. C (Anti-pruritic agents)
199. B (Blood Replacement)
200. D (Fluid Therapy)
201. D (Anti-rejection and anti-inflammatory)
202. C (Anti-rejection and anti-inflammatory)
203. B (Anti-rejection and anti-inflammatory)
204. E (Biologics)
205. B (Biologics)
206. A (Biologics)
207. C (Biologics)
208. D (Pancreatic Enzymes)
209. B (Pancreatic Enzymes)
210. A (Acid Control)
211. C (Acid Control)
212. A (Prebiotics/Probiotics)
213. D (Prebiotics/Probiotics
214. E (Prebiotics/Probiotics)
215. A (Prostaglandins)
216. A (Sucralfate)
217. C (Sucralfate)
218. A (Sucralfate)
219. C (Munchausen by proxy syndrome)
220. D (Munchausen by proxy syndrome)
221. D (Rumination)
222. B (Chronic Diarrhea)
223. C(Chronic Diarrhea)
224. D (Chronic Diarrhea)
225. D (Drug induced bowel injury)
226. C (Drug induced bowel injury)
227. D (GI manifestations of immunodeficiency).
228. C (GI manifestations of immunodeficiency)
229. D (GI manifestations of immunodeficiency)
230. C (GI manifestations of immunodeficiency)
231. C ( GI manifestations of endocrine disorders)
232. C (GI manifestations of endocrine disorders)
233. D (GI manifestations of endocrine disorders)
234. C (Graft versus host disease)
235. B C (Ethics)
236. D (Ethics)
237. C (Study Design and Statistics)
238. Validity- B; Reliability- C; Accuracy- E; Precision- F; Kappa statistic-A;
Cronbach’s alpha- D (Study Design and Statistics)
239. C (Study Design and Statistics)
240. D (Study Design and Statistics)
241. A (Study Design and Statistics)
242. A (Study Design and Statistics)
243. E (Abdominal Pain)
244. C (Prostaglandins)
245. B (Abdominal Pain)
246. B (GI Manifestations of Endocrine Disease)
247. E (Endoscopy)
248. D (Stool Testing)
249. D (Prostaglandins)
250. E (Drug Induced Bowel Injury)
251. B (TPN)
252. C (Acute Liver Failure)
253. B (Schwachman Diamond Syndrome)
254. D (Enteric Infection)
255. A (Neonatal Cholestasis)
257. E (Wilson’s Disease)
258. C (GI Manifestations of Immune Deficiency)
259. B (Hirschsprung Disease)
260. E (Normal Digestion and Absorption)
261. C (Essential Fatty Acids)
262. C (Vitamin and Mineral Absorption, function and deficiency states)
263. D (TPN)
264. E (Nutritional Assessment)
265. E (Vitamin and Mineral Absorption, function and deficiency states)
266. B (Vitamin and Mineral Absorption, function and deficiency states)
267. A (Normal Digestion and Absorption)
268. A (Infant Formula)
269. B (Glycogen Storage Disease)
270. E (Disorders of Lipid Metabolism)
271. D (Irritable Bowel Syndrome)
272. C (Hematologic Manifestations of GI Disease)
273. A (Wilson’s Disease)
274. E (Hepatomegaly)
275. D (Glycogen Storage Disease)
276. D (Constipation)
277. E (Acute Pancreatitis)
278. C (Constipation)
279. B (Wilson’s Disease)
280. B (Vitamin and Mineral Absorption, function and deficiency states)
282. A (Tyrosinemia)
283. C (Viral Hepatitis)
284. A (GI manifestations of Immunodeficiency)
285. C (GI manifestations of Immunodeficiency)
286. C (GI manifestations of Immunodeficiency)
287. B (Hirschsprung Disease)
288. C (Abetalipoproteinemia)
289. D (Alagille syndrome)
290. A (Viral Hepatitis)
291. E (IBD – Ulcerative Colitis)
292. D (IBD – Crohn’s Disease)
293. C (Disorders of bilirubin metabolism)

294. D (Alpha-1-antitrypsin deficiency)
295. A (Chronic Hepatitis)
296. B (Porphyria)
297. E (Bilirubin Metabolism disorders)
298. A (Liver Transplant)
299. E (Viral Hepatitis)
300. E (Alkaline Phosphatase)
301. B (Gastric Foreign Body)
303. E (Iron Storage Disease)
304. D (Vitamin and Mineral Absorption, function and deficiency states)
305. C (Congenital Anomalies of Small Intestine)
306. C (Infectious Esophagitis)
307. A (Infectious Esophagitis)
308. D (Congenital Anomalies of Small Intestine)
309. B (Congenital Anomalies of Small Intestine)
310. B (Protein-losing Enteropathy)
311. B (Protein-losing Enteropathy)
312. D (Small bowel bacterial Overgrowth)
313. C (Abdominal Mass)
314. B (Stomach Anatomy, Development and Physiology)
315. B (Carbohydrate Malabsorption)
Non-Hispanic Caucasians have a 15-25% prevalence of primary hypolactasia. Asians have the highest
prevalence at 90%.
316. C (Carbohydrate Malabsorption)
Glucose-galactose malabsorption typically presents in the first 2 weeks of life with severe life-threat-
ening diarrhea. Trehalase deficiency presents later in life when exposed to mushrooms or food addi-
tives containing trehalose. Fructose malabsorption and sucrase-isomaltase deficiency typically present
between 3 and 6 months of life.
8P. Carbohydrate Malabsorption
Catherine Newland, MD
I. Overview
A. Carbohydrates provide 50%-60% of calories consumed by Americans
B. Most absorption is in the jejunum and ileum
C. Carbohydrates not absorbed in small intestine are fermented to short chain fatty acids by colonic
bacteria and absorbed
D. Simple Carbohydrates (sugars)
1. Monosaccharides – glucose, galactose, fructose
a. Enter enterocytes through carrier-mediated transporters
1) SGLT1 – Sodium-glucose linked transporter – actively transports glucose
and galactose
a) 2 Na molecules absorbed for every glucose
b) Glucose can also be passively absorbed
2) GLUT 1 (glutamate transporter) – actively transports glucose and galactose
3) GLUT 2 – releases monosaccharides across basolateral membrane
4) GLUT 5 – passive absorption of fructose
2. Disaccharides – lactose, sucrose, maltose, and trehalose
a. Broken down to monosaccharides by brush border enzymes – sucrase-isomaltase,
lactase, and glucoamylase
b. Brush border disaccharidases located on villous tips in the jejunum and most
of ileum
1) Sucrase-isomaltase
a) Maltose and isomaltose → glucose
b) Sucrose → glucose + fructose
2) Lactase
a) Lactose → glucose + galactose
3) Glucoamylase
a) Glucose polymers → glucose
E. Complex Carbohydrates (starches, storage carbohydrate of plants)
1. Polysaccharides – >10 glucose units (amylase, amylopectin)
2. Oligosaccharides – short chain starches of 3-10 glucose units
3. Complex carbohydrates require digestion by salivary and pancreatic amylases to yield
disaccharides
4. Amylase cleaves amylase and amylopectin into maltriose, maltose, and α–limit dextrans
5. Starch malabsorption is rare in infants due to glucoamylase activity on brush border
II. Causes of Carbohydrate Malabsorption

A. Extensive inflammatory disease of the small intestine
1. Autoimmune enteropathy
2. Celiac Disease
3. Radiation enteritis
4. Post viral enteritis
B. Congenital intestinal transport or enzyme deficiencies (see table)
C. Inherited abnormalities of the brush border - Congenital microvillus atrophy, tufting enteropathy
D. Pancreatic exocrine insufficiency - Cystic fibrosis, Shwachman syndrome
E. Excessive ingestion of juices containing malabsorbed sugars like sorbitol
F. Short bowel syndrome
G. Ingestion of disaccharidase inhibitors e.g., Ascorbase, Miglitol (used for control of postprandial
hypyerglycemia)

III. Diagnosis
A. Symptoms – include osmotic diarrhea, abdominal pain, increased flatus, failure to thrive
B. Stool pH <5.5 indicates carbohydrate fermentation to short-chain fatty acids
C. Stool osmotic gap >50 mosm/kg and diarrhea symptoms improving with fasting
D. Stool osmotic gap = measured stool osmolality – estimated stool osmolality
E. Estimated stool osmolality = 2 x (Nastool + K stool)
F. Stool reducing substances – indicates presence of malabsorbed reducing sugars (usually glucose)
G. Positive breath hydrogen test after carbohydrate ingestion
Table 1. Brush Border Enzymes Deficiencies Causing Carbohydrate Malabsorption

Disorder Abnormal Inheritance Symptoms Diagnosis Treatment
Gene/Protein
Sucrase-Isomaltase Sucrase-isomaltase AR Presents - Primarily Sucrose
deficiency between 3-6 clinical restriction
months - Abnormal SI
activity with
normal histology
- All lack sucrase,
but varying
isomaltase activity
Glucose-galactose Na-glucose- AR Severe life- Primarily clinical Glucose and
malabsorption galactose threatening (Very rare) galactose
cotransport diarrhea and restriction
(SGLT1) dehydration (use fructose
in neonatal containing
period (Day of formula)
life 1-14)
Congenital Lactase AR Diarrhea and Clinical Lactose
lactase deficiency severe malnu- Confirmation with restriction
(Alactasia) trition starting a duodenal biopsy
at birth with abnormal
Hypercalcemia lactase activity
Nephrocalci-
nosis
Congenital Trehalase AR Diarrhea Duodenal biopsy Trehalose

trehalase after ingesting with abnormal restriction
deficiency young trehalase activity
mushrooms
(also a food
additive)
Fructose Facilitative AR Presents Improvement Diet free of
malabsorption glucose transport between 3-6 on fructose fructose
months elimination diet
Fructose breath
hydrogen test
Adult-type Lactase AD, Presents at Clinical Hydrogen Avoidance of
hypolactasia Acquired 3-15 years, breath test lactose, use
symptoms Rarely – confirma- of lactase
increase with tion by duodenal pills prior to
age biopsy ingestion of
lactose
I. Lactase deficiency
A. Primary lactase deficiency (congenital lactase deficiency) - very rare
B. “Adult onset” hypolactasia is most common carbohydrate malabsorption
1. Lactase activity decreases with age and varies with ethnicity
2. Decreased activity starts between 3-7 years – thought to be a genetically controlled
“switching off” of lactase gene
3. Prevalence – 15-25% Non-Hispanic Caucasians, 50% Hispanics, 80% Blacks, 90%
Asians
C. Secondary lactase deficiency – due to mucosal injury in small intestine, lactase is the brush bor-
der enzyme most sensitive to injury
1. Viral gastroenteritis
2. Resolves after resolution of illness, can last 1-2 weeks
D. Symptoms – due to undigested lactose fermented in colon to organic acids, hydrogen, carbon
monoxide, and methane
E. Symptoms occur based on amount of residual lactase activity, amount of lactose ingested, com-
position of meal
F. Unabsorbed sugar and acids cause osmotic diarrhea
II. Sucrase-isomaltase deficiency

A. Most common congenital enzyme deficiency causing carbohydrate absorption
B. Sucrase-isomaltase is cleaved into sucrase and isomaltase by pancreatic proteases
C. Rare, but occurs in ~5% of Greenlanders
D. Symptoms – diarrhea, bloating, cramps when sucrose containing fruits are introduced,
usually presents between 3 and 6 months
E. Diagnosis – Histologically normal duodenal or jejunal biopsy has deficient
sucrase-isomaltase deficiency
F. Treatment – strict avoidance of sucrose or use of sucrase before sucrose ingestion
Recommended Reading
Ammoury R, Croffie J. Malabsorptive disorders of childhood. Pediatr. Rev. 2010;31;407-416.
Kleinman R, Goulet O, Mieli-Vergani G, Sanderson I, Sherman P, Shneider B. Walker’s Pediatric

Gastrointestinal Disease, 5th edition. People’s Medical Publishing House, Shelton, CT. 2008. Chapter 15.
Corkins M. The A.S.P.E.N. Pediatric Nutrition Support Core Curriculum. American Society for Parental and
Enteral Nutrition. 2010. Chapter 3.
Kleinman, R. Pediatric Nutrition Handbook, 6th edition. American Academy of Pediatrics. 2009. Chapter 15.
Felipez L, Sentongo TA. Drug induced nutrient deficiencies. Pediatr Clin N Am, 2009;56:1211-24

Index
A adipocytes, 405
abdominal masses, 561-563 adiponectin, 643
abdominal pain, 553-555 adrenal glands, 201, 208, 318, 346, 488, 499,
abetalipoproteinemia, 68, 407-408, 417, 422, 584, 589, 657, 671
479, 650-651, 655, 674, 685 adrenoleukodystrophy, 318, 644
ablation by radiowave, 173, 241-242, 533 aeroallergens, 23
abortion, 513, 584 aeromonas, 102, 178, 184, 485
abscess, 84, 99-100, 102, 122, 177-178, 180, aerophagia, 45, 537
183, 185, 197, 214-215, 220, 229, 234, African-American, 83, 117, 331, 375, 414, 626,
271-274, 285, 348, 365, 452, 487-489, 505, 631, 639, 669
565-566, 602-604, 628, 637, 641, 660 aganglionosis, 118, 127, 137, 161, 439
acalculous cholecystitis, 214-216, 639 agranulocytosis, 519
acanthocytes, 417, 478-479 AIDS, acquired immune deficiency, 197,
acanthosis nigrans, 336 271, 279, 349, 529, 568
acarbose, 585 AIE, autoimmune enteritis, 115-116, 630
aceruloplasminemia, 331 AIH, autoimmune hepatitis, 249, 251, 258,
acetaminophen, 249, 251, 328, 349, 363, 456, 260, 275-277, 344, 648
641 akathisia, 519
acetorphan, 530 akinesis, 546
acetylcholine, 9 alacrimia, 8
acetylcholinesterase, 626 Alagille syndrome, Alagille-Watson
acetylcysteine, 251, 328, 376, 572-573 syndrome, 208, 220, 255-256, 321-323, 349,
achalasia, 2-3, 7-8, 12-13, 19-20, 25, 36 408, 437, 638, 667, 674, 685
achlorhydria, 51, 105, 345, 427, 584, 588 albendazole, 110-112, 274
acholic stools, 217, 220, 229, 253-254, 553, 676 albumin, 97-98, 130, 210, 227, 229, 233, 237,
achondroplasia, 666 244, 253, 293, 350, 364, 383, 390, 398, 411,
acidemia, organic, 308-309, 349, 368, 425, 643 428, 436, 442-443, 490, 571, 646, 654, 656,
acidophilus bacteria, 525, 527 659, 667-669, 673, 678
aciphex, 510 alcohol, 45, 48, 118, 232, 275, 311, 339, 363,
acne, 179, 189, 499, 546, 583 367, 408, 426-427, 462, 559
acral dermatitis, 146, 201, 419 aldolase, 298, 420, 642
acrocyanosis, 546 aldosterone, 150, 244
acrodermatitis, 266, 419, 432, 650-651 alemtuzumab, 138
ACTH, 8 alimentum, 387
actinomycin-D, 601 alkaline phosphatase, 475-476
acupuncture, 559 alkalosis, metabolic, 41, 43, 377, 418, 576,
acute liver failure, 249-252 629, 663
acyclovir, 26 allergens, 23
adalimumab, 180, 184, 506, 660 allergy, 19, 24
adaptation, 95, 127-129, 131, 135 Allgrove syndrome, 8
Addison disease, 375, 584 allopurinol, 281, 300, 501, 518
ADEK vitamins, 218-219, 377, 639 alopecia, 90, 199, 345, 419, 423, 425
adenitis, 100, 107, 553, 566 Alpers syndrome, 249, 644
adenocarcinoma, 51, 53-54, 92, 141, 145, 201, alpha-1-antitrypsin, 98, 231, 234, 254, 257,
367, 562 259, 275, 311-312, 336, 349, 390, 408-409,
adenoid, 13, 31 437, 483, 485, 490, 641, 645, 650, 674-675,
adenomas, 141, 144, 146, 201-202, 239-240, 678, 686
242, 300, 329 ALTE, 19
adenovirus, 101, 109, 140, 250, 257, 451, 659, aluminum, 387, 509, 515, 655, 661
676 alveoli, 110, 112, 345, 421
adenylate cyclase, 513, 661 amebiasis, 271
adhesion, 81, 131, 185, 206, 272, 484, 505-507, amebicides, 273
528, 532, 576-577, 601-602 amenorrhea, 545
Index 691
amifostine, 604 antienterocytes antibodies, 115-116
aminoaciduria, 302, 313, 421, 423 antimony, 459
aminocaproic acid, 568 aphonia, 426
aminolevulinic acid, 301-302, 675 aphthous, 49, 177-178, 183, 189, 634
amiodarone, 249, 329, 336, 501, 642 apoferritin, 63
Amish kindred, 319 apolipoprotein, 335, 405, 407, 417, 479
amitriptyline, 559-560 apoptosis, 50, 139, 179-180, 233, 314, 336, 342,
ammonia, 33 437, 452-453, 499, 566-567, 578, 591-594, 601,
amniotic cavity, 61, 81, 148 634, 646
amoebic infection, 102, 192, 239, 272-273 appendectomy, 100
amoxicillin, 56, 106, 130, 135, 206, 257, 575, appendicitis, 51, 75, 84, 99-100, 107-108, 119,
659 154, 271, 451, 489, 553-555, 574, 628, 630,
amphetamines, 363 641, 681
amphotericin, 25 appendix, 61-62, 99, 141, 147-148, 154, 168,
ampicillin, 106, 142, 597, 670 451, 488, 562, 574, 589, 630, 665
ampulla of Vater, 201, 207, 353 appetite, 57, 95, 176, 394, 405-406, 433, 520,
amylase, 139, 188, 213, 353, 357-358, 363-364, 547, 649, 656, 668, 670, 672
368, 372, 385, 405, 408-409, 411, 469, 471, applesauce, 437, 510, 654
517, 679 apraxia, 507
amyloidosis, 14 arabinoside, 328, 642
amylopectin, 408, 413, 651 arachidonic acid, 384, 446, 598, 652
amylose, 408 arginine, 309-310, 421, 432
anaphylaxis, 274, 503, 506, 513, 518, 565, Argininosuccinate, 309
579-580 argon, 531, 533, 603-604
anasarca, 678 Arnold-Chiari malformation, 2, 9, 12-13
anastomosis, 144, 350, 527-528 arrhythmias, 306, 331, 399, 428, 519, 546-547,
ANCA, 276 559
ancylostoma, 482 arthralgia, 90, 177, 183, 187, 281, 327, 331, 634
anencephaly, 11, 13 arthritis, 90, 107, 134, 177, 183, 187, 189, 313,
anesthesia, 51, 125, 162, 173, 178, 181, 185, 331, 345, 565, 634, 636, 643, 667
196-197, 310, 365, 489, 491, 497 arthropathy, 177, 183, 345
angioedema, 118, 568, 579 asacol, 675
angiofibroma, 144 ascariasis, 110-111, 117, 210, 358, 482
angiography, 32, 123, 176, 244 ascites, 84, 138, 218, 237-238, 244, 253-254,
anisakiasis, 47, 50 258, 285-286, 297, 302, 311, 328, 339,
anismus, 158 342-344, 346-347, 349-350, 364, 377, 437, 445,
ankylostoma, 111 583, 664, 667, 676
annular pancreas, 43, 117, 217, 361, 363, 649, ascorbic acid, 64, 175, 410, 425, 479, 677
657 asparaginase, 328, 363, 642
anorexia, 50, 79, 90, 94, 99, 103, 106, 110, 112, aspergillosis, 25, 113, 180, 556
118, 165, 177, 179, 183, 213, 240-241, 265, aspiration, 8-9, 13-14, 20, 35
267, 274, 327-328, 340-341, 364, 393, 399, aspirin, 48, 325, 662
419, 423, 425-426, 428, 431, 445, 449, 519, asplenia, 42, 207, 217, 631
521, 538, 544-546, 548, 562, 567, 573, 584, asterixis, 640
591-593, 602-603, 631, 676 asthma, 20-21, 23
anorexia nervosa, 118, 375, 399, 544-546, 548 astrocytes, 250
antacids, 48, 105, 461, 502, 509, 515, 660-661, astrovirus, 451
667 ataxia, 90, 134, 290, 318, 417, 423, 425-427,
anthracine, 550 429, 446, 562, 670
anthracycline, 142 atopic disease, 525-528, 579-581, 626
anthraquinone, 522 atresias, 15, 17, 80-81, 127, 205, 632, 655
anthropometric measurements, 70, 389, 397, atrophic gastritis, 47, 51, 93, 343, 452, 463,
443, 447 584, 588, 654
anticolonocyte antibodies, 115-116 Auerbach plexus, 2, 39, 62, 67, 154, 157, 161
anticonvulsants, 249, 310, 427 autism, 543
antidepressants, 206, 542, 548, 559, 584, 599 autoimmune disorders, 8, 51, 68-69, 89-91,
antidiarrheal, 559, 603, 658 115-116, 118, 137, 177-178, 183, 188, 205,
antidiarrheals, 529 229, 231, 234-235, 237, 249, 257, 259, 267,
antiemetics, 109, 179, 519, 565, 584 275-277, 279, 313-314, 329, 336, 341, 343-346,
348-349, 367-368, 388, 427, 438, 452, 455-456, biliary stasis/sludge, 210, 363, 377
478-479, 526, 554, 566-568, 577-578, 584-585, bilious vomiting, 43, 46, 49, 77, 83, 87, 119,
630, 648, 657, 659, 663, 668, 675, 681, 683 161, 205, 361, 439, 553, 572-574, 633, 678
autoimmune enteropathy, 115-117 biliverdin, 293
autonomic nervous system, 62, 148, 153, 157, binge eating, 545-546, 548
354, 405, 530, 546, 555, 584-585 biofeedback therapy, 168, 465, 538, 542
azathioprine, 116, 179, 184, 189, 192, 276, 329, biopsy, intestinal, 451-454
339, 345, 363, 499, 505, 569, 635, 648, 656, 675 biopsy, liver, 455
azithromycin, 106, 509 biotin, 410, 425, 431
aztreonam, 107 bird beak deformity, 8
azygos, 2 bisacodyl, 167, 449, 522, 559
bismuth, 56, 192, 530, 627, 658, 663
B bisphosphate, 298
bacteremia, 106, 130-131, 135, 254, 261, 453, bisphosphonates, 546, 597
528, 532 blastocystis, 102-103, 481
bacteroides, 133, 150, 525 blastomycosis, 25
bactrim, 106, 108, 442, 676 bleach ingestion, 33
balantidium, 102-103, 481 bleomycin, 597
balloon dilatation, 285, 533 blindness, 94, 134, 317, 423, 446, 655
ballooning degeneration, 259, 279, 329, 336, bloating, 93, 103, 134, 557, 559, 584, 599, 628
455-456 blunting of villi, 451-452, 566-567, 657
bananas, 437, 590, 654 bombesin, 64
Bannayan-Riley-Ruvalcaba, 145, 199-200 bone marrow, 25, 51, 63, 116, 134, 178-179,
barbiturate, 251 183, 201, 210, 286, 322, 345, 347, 351, 358,
bariatric surgery, 402, 427 371-373, 380, 390, 399, 421, 423-425, 428-430,
barium studies, 8, 14, 16, 19, 25, 43, 57, 77, 94, 440, 442, 446, 475-476, 478, 502, 546,
145, 166, 168, 178, 184, 187, 189, 461, 488, 566-569, 581, 592, 595-596, 601, 622, 639,
491, 544, 592, 603, 625-626, 630, 632, 635, 645, 656, 661, 664, 666
637, 669 borborygmi, 31
barley, 89-90 botulinum, 3, 9
Barrett esophagus, 16, 20, 151, 510 bowel infarction, 51, 145, 154, 188-189, 286,
basiliximab, 138, 499, 503 344, 513
battery ingestion, 33, 36-37 bowel ischemia , 47, 77, 82, 118, 120, 137-139,
Bechet disease, 193, 285 189, 208, 214, 344, 348, 350, 439, 487, 532,
Beckwith-Wiedeman syndrome, 82, 241, 646 583, 601, 604, 632, 666
beclomethasone, 596 bradycardia, 83-84, 428-429, 493, 520, 546, 660
Behçet disease, 187-189, 192, 634 brainstem, 19
benign recurrent cholestasis, 320 breast milk jaundice, 293
benzodiazepines, 584 breastmilk/breastfed, 45-46, 84, 109, 145-146,
beriberi, 426 165, 200-201, 293, 295, 383, 385-386, 411-412,
betablockers, 220 419, 440, 517, 525, 580-581, 632, 636-637,
betalactoglobulin, 411 652, 655, 661, 668, 674
bethanechol, 3, 20 breath test, 45, 55, 134, 357, 359, 408, 414, 420,
bezoar, 57, 538 463-464, 473, 481, 558, 575, 577, 652, 656, 684
bicycle injury, 58, 649, 657 bromocriptine, 501
bifidobacterium, 133, 525-527, 559, 661 bronchiolitis, 341
biliary ascariasis, 111 bronchodilators, 81
biliary atresia, 207, 217, 241, 245-247, 253-254, bronchospasm, 518, 590
258, 350, 408 brucellosis, 272, 279-280, 643
biliary carcinoma, 219 Budd-Chiari syndrome, 189, 231, 234, 237,
biliary cirrhosis, 218, 345, 377 243-244, 250, 257, 285, 329, 339, 343-344
biliary cysts, 220, 283 budesonide, 24
biliary development, 207 bulimia, 118, 364, 544-546, 548
biliary diversion, 321-333 Burkitt lymphoma, 141, 562, 660
biliary ducts, 207 busulfan, 328, 339, 642
biliary dyskinesia/colic, 215, 553, 639 butterfly vertebrae, 255, 322
biliary obstruction, 201, 214, 280, 350, 408, Byler disease, 319-320, 674
455, 475 bypass surgery, 245, 336, 348, 361, 408,
biliary reconstruction, 138 431-432
biliary sphincterotomy, 213
Index 693
C cesarean, 82, 643
cadherin, 63, 562 cestoides, 482
caffeine, 559 Chagas disease, 8, 14, 118
calbindin, 411 cheilosis, 94, 426, 677
calcineurin, 180, 341, 351, 499-500, 502-503, chenodeoxycholic acid, 211, 289, 291
567-568, 644 chewing, 13, 409, 462, 510, 558
calcitonin, 1 CHF - congenital hepatic fibrosis, 97, 219,
calcium channel blocker, 9, 14 242, 283-284
calcium metabolism, 8, 14, 64, 118, 131, 166, chilomastrix, 102
178, 209-210, 253, 294, 298, 364, 377, 380, chlamydia, 272
384-387, 402, 407, 411-412, 423, 428, 436-437, chloridorrhea, 576, 663
442, 447, 475, 489, 500, 502, 546, 584, chloroquine, 273
650-651, 661, 669, 676 chlorpropamide, 281
calcivirus, 110 choanal atresia, 12-13, 418
calprotectin, 98, 178, 184, 483 choking, 13, 16, 35
campylobacter, 101, 103, 107, 142, 178, 184, cholangiocarcinoma, 219-220, 253, 320
192, 481, 485, 566-567, 628 cholangiogram, 253-254, 256, 275, 350, 377
candida, 25, 47, 112, 390, 440, 566, 568, 584 cholangitis, 107, 177, 183, 208, 211, 218-221,
candidiasis, 25, 29 234, 253-254, 257, 274, 283-284, 345, 349,
caput medusae, 31 351, 455, 489, 553, 585, 638-639, 657, 659, 674
carafate, 597 cholecalciferol, 423, 446
carbamazepine, 249, 328, 501 cholecystectomy, 208, 211, 214-216, 377, 640
carboxylase, 425, 429, 435, 499 cholecystitis, 51, 131, 187, 211, 213-217, 272,
carcinoid, 141, 562, 589-590 553, 555, 585, 630, 639, 646, 682
carcinoma, 34, 47, 49, 54, 141, 146, 155, cholecystokinin, 354-355, 358, 378, 385, 405,
200-202, 219, 234, 237, 240-242, 266-267, 281, 469, 648, 652
301-302, 320, 329, 349, 488, 562, 660 choledochal cyst, 207, 213, 220, 227, 229, 235,
cardiomyopathy, 299-300, 313, 331, 426, 435, 253, 256, 283, 363, 365, 367, 489
502, 546, 584, 653, 655 choledocholithiasis, 211, 213-214, 219-220,
carnitine, 118, 305-307, 325, 377, 425, 435, 258, 260
441-442, 650 cholelithiasis, 213-214, 228, 257, 363, 377, 401,
Caroli diseae, 219-220, 234, 257, 283-284, 349, 442, 520, 553, 585, 639, 678
669 cholera, 451, 495, 636
carotene, 517, 546 choleretic, 253
carotenoids, 446 cholestasis, 129, 134, 217, 227-229, 253-261,
casein, 383, 387, 412, 652 283-284, 290-291, 311-312, 314, 317, 319-323,
catalase, 428, 565-566 328-329, 340, 344, 349, 375-376, 398-399, 408,
cataracts, 179, 262, 290, 297, 313, 318 435, 437-438, 442-447, 455, 475-476, 489,
caustic ingestion, 13-14, 31, 33-34, 36, 57-58, 523-524, 568, 591-593, 596, 641, 645, 658,
449, 534, 666, 681 674, 683, 685
CCK, 64, 215, 358, 372, 405-406, 469-470, 490, cholestasis, newborn, 253-256
584, 679 cholestasis, nutritional consequences,
cecostomy, 168 445-447
cefixitin, 482 cholestasis, older child, 257-280
cefotaxime, 106 cholestyramine, 192, 294, 418, 502, 523, 530,
cefoxitin, 214 603, 658
cefsuladin, 482 chondrodysplasia, 317-318, 644
ceftriaxone, 106, 210, 659 chorea, 258
celecoxib, 144, 202 chorioretinitis, 262
celiac disease, 24, 39, 49-50, 68-69, 89-94, chromium, 428, 442
97-98, 115-116, 118, 135, 142, 165-166, 192, chronic constipation, 165-168
208, 223, 231, 368, 393-394, 398, 408, 413, chronic diarrhea syndromes, 575-578
427, 435, 437-438, 452, 470, 479, 554, 558, chronic granulomatous disease, 565, 663
565, 577, 580, 585, 631, 634-635, 638-639, chronic hepatitis, 275-277
654, 657, 663, 681 Churg-Strauss syndrome, 24
cephalosporin, 107, 659 chylomicrons, 209, 407, 417
cerebral edema, 250-251, 325, 529 chylothorax, 388
certolizumab, 506 chymotrypsin, 357, 409, 469-471
ceruloplasmin, 98, 249, 259, 313-315, 390, 428, ciliopathies, 207, 229, 235
640, 668, 671, 678 cimetidine, 501, 509-510, 515, 661
ciprofloxacin, 108, 130, 179, 185, 662 cortisol, 255-256, 385, 499, 672
cisapride, 20 Cowden syndrome, 143, 145-146, 199-201
citolopram, 559-560 coxiella, 280, 643
citrulline, 310, 421, 641 coxsackie virus, 109, 234, 262, 363
clarithromycin, 56, 501 creatinine, 139, 179-180, 188, 350, 670, 676
clavulanate, 130 crepitus, 35
cleft lip/palate, 1, 12-13, 199, 543 cricoid, 1, 6
clindamycin, 197 cricopharyngeus, 1-2, 11, 13, 35
clinodactyly, 372 Crigler-Najjar syndrome, 228, 257, 294, 676
clofibrate, 209 Crohn disease, 29-31, 49, 69, 94, 100, 117-118,
clomipramine, 559 137, 141, 177, 180-181, 183-185, 192, 195,
clonidine, 206, 529, 658 197, 210, 271, 363, 365, 408, 427, 452,
clostridium, 97, 102-103, 133, 178, 184, 191, 505-507, 527, 553, 561, 567, 574, 634, 639,
193, 525, 598-599, 634, 662 653, 657, 659-661, 665, 675, 682, 685
clotrimazole, 673 cryoglobulinemia, 267
CMV, 26, 29 cryopreciptate, 478, 670
coagulopathy, 31-32 cryptitis, 139, 178, 184, 451-453, 598
coarctation, 82 cryptococcosis, 25, 279, 281
cobalamin, 134, 380, 410, 653, 656 cryptosporidium, 47, 68-70, 94, 103, 112, 178,
coccidian, 103 184, 481, 485, 568, 673
coccidioides, 113, 280 CSF, 262, 300, 347, 372, 642, 647
cocksackie virus, 639 cupruria, 314
coin ingestion, 35-36, 57, 534 currant jelly stools, 87, 119, 176, 553
colchicine, 189, 501 cyanoacrylate, 32
colectomy, 144, 180, 185, 199-202, 466, 505 cyanocobalamin, 427, 655
colipase, 358, 405, 408 cyclohexanedione, 301-302
colistin, 108 cyclophosphamide, 189, 339, 352
collagen vascular disease, 9 cyclospora, 112
colon, anatomy, 147-150 cyclosporine, 180, 184, 189, 210, 351, 500, 502,
colon, histology, 153-155 592, 644, 659, 675
colon, motility, 157-159 cyproheptadine, 394, 520
colon, physiology, 151 cystathionase, 432
colonic intraposition, 9, 34 cysteamine, 51
colonocytes, 149, 418, 526 cysteine, 102, 331-332, 388, 441-442
colostrum, 383, 385-386 cystic fibrosis, 375-378, 571-574
coma staging, 251 cysticercosis, 111
condyloma, 172 cystinosis, 51
congenital anomalies of esophagus, 15-17, cystinuria, 410, 651
25, 35 cytarabine, 142
congenital hepatic fibrosis, 283-284 cytomegalovirus, 47, 138, 192, 234, 255, 261,
congenital malformation, 2, 9, 12-13, 15, 35, 279, 669
79, 81, 119, 127, 255, 349, 361, 385 cytosine, 328, 642
congestive heart failure, 214, 234, 237, 243,
286-287, 348 D
conjunctiva icterus, 262, 639, 646, 668 dacarbazine, 328-329
conjunctivitis, 111, 423 daclizumab, 138, 499, 503
constrictive pericarditis, 234, 237, 243, 285, dactinomycin, 328, 597, 642
339, 343 danazol, 501, 568
contraceptives, 209, 240-241, 285, 294, 329, dapsone, 189
339, 390, 642 deafness, 8
copper, 227, 259, 279, 313-315, 380, 384-385, defecation physiology, 151, 158, 165-166, 168
398, 428, 430, 442, 447, 456, 479, 653-655, defensin, 526, 528
664, 668, 671 defibrotide, 340
coproporphyrin, 294 deglutition, 11-13
corkscrew duodenum, 657 dementia, 290, 426, 507
corneal defects, 94, 259, 303, 313, 322 demyelination, 180
cornstarch, 300 dental disease, 90-91, 144, 202, 372-373, 397,
coronavirus, 451 423, 547
corticosteroids, 98, 178, 185, 189, 251, 279, dermatomyositis, 9
281, 328, 341, 351, 499, 569, 576, 580, 597, 667 desipramine, 559
Index 695
desmoid tumors, 137, 144, 201-202 dysentery, 102-103, 105-106, 628, 668, 671
dexamethasone, 48, 499, 598 dyslipidemia, 335, 351-352, 644
dexlansoprazole, 510 dysmotility, 7, 9, 34, 36
Deçemet membrane, 313 dyspareunia, 558
diabetes mellitus, 14, 71, 91, 115, 118, 197, dysphagia, 7, 9, 12-15, 23, 25-26, 34-35
229, 235, 336, 364, 401-402, 436, 464, 530, dystocia, 82
583-584, 653, 664, 671 dystonia, 13
dialysis, 112, 187-188, 237, 251, 515, 661 dystrophy, 9, 12-13
diaphragm, 1, 5-6, 15
diatrizoate, 8 E
diazepam, 329 eating disorders, 543-548
dicyclomine, 529, 559 EBV - Epstein-Barr virus, 47, 118, 140,
dientamoeba, 102 142-143, 250, 257, 275, 347, 351, 566, 569, 640
diffuse esophageal spasm, 3, 7, 14, 19 echinococcus, 273
digestion and absorption, 405-412 echocardiogram, 255-256
digoxin, 510, 515 echocardiography, 244, 633
dihydrofolate, 478 echovirus, 109, 262, 347, 451
dihydrofolic, 478 ectopic anus, 196
dihydrorhodamine, 566 ectopic gastria, 41, 61, 75-76, 79, 176
dihydroxyvitamin, 64, 411 ectopic pancreas, 361, 562
dilation therapy, 9, 14-16, 24, 34 ectopic pregnancy, 553
diloxanide, 273 Ehlers-Danlos syndrome, 117, 449
diltiazem, 501 eicosanoids, 603
dipentum, 675 electrogastrography, 463-464
diphenhydramine, 523, 658 elemental diet, 24, 129, 180, 388, 438, 447,
diphenoxylate, 529-530, 559 517-518, 579-580, 604, 626
diphenylmethane, 559 elimination diet, 20, 24, 70, 420
diphyllobothrium, 111 ELISA, 274, 470, 481
disaccharidase deficiency, 413-415 embryology, 42, 65, 75, 151, 649
disaccharidases, 133-134, 409, 413-414, 420, embryotoxon, 255, 322, 638
435, 683 emesis, 16, 23, 25, 31
disk batteries, 36 emphysema, 311-312, 538
dismutase, 428-429 encephalopathy, 56, 117-118, 133, 244-245,
Disse space, 223, 225 249-251, 272, 297, 306-307, 317, 325, 350,
diuretics, 218, 238, 285, 343, 545, 547, 676 426, 428, 523, 526, 644, 668, 677
diverticulitis, 75 endocarditis, 453
docosahexaenoic, 384, 443, 446 endocrine disorders, 583-585
docusate, 167, 559 endocrinopathies, 89, 253, 255
domperidone, 20 endolimax, 102
dopamine, 519, 589 endoscopic biopsies, 24, 26, 29-30
Doppler, 244, 258, 285, 287, 339, 350, 377, 488 enema, 77, 87, 145, 162, 166, 168, 176, 178, 184,
doxorubicin, 597 376, 449, 491, 522, 571-572, 632, 635, 637, 669
doxycline, 95 enkephalins, 65, 523-524, 530
doxycycline, 108, 280, 597, 629, 663 entamoeba, 102, 112, 272, 451, 485
drooling, 12-13, 26, 33, 35 enteric infections, 105-113
drugs, antacids, 509-511 enterobacter, 105-106, 139, 525, 661
drugs, antipruritics, 523 enterobius, 482
drugs, biologicals, 505-507 enterocolitis, 83-85, 105, 127, 131, 137, 162,
drugs, pancreatic enzymes, 517 165, 175, 271, 487, 599, 632, 636, 654,
drugs, pre/probiotics, 525 657-658, 667, 669, 674, 681
drugs, prostaglandins, 513 enteropathy, 47, 68-69, 89, 92, 94-95, 97, 112,
Dubin-Johnson syndrome, 228, 257, 294 115, 142, 187-188, 199, 346, 387-388, 408,
Duchenne dystrophy, 117 438-439, 445, 452-453, 485, 490, 538, 567,
ductopenia, 328, 351, 592 576-579, 592, 597-598, 603, 657, 663, 674,
duodenitis, 187, 566, 568, 590 678, 681, 686
duodenoduodenostomy, 361, 649 enterostomy, 84, 129
duodenum, 35-36 enterovirus, 109, 140, 250, 262, 451, 642
duplication anomalies, 15 enzyme transport defects, 417-421
duplication cysts, 15, 31 eosinophilic esophagitis, 13, 16, 19, 23-24,
dysautonomia, 12-13 27, 29-30, 36
epidermolysis bullosa, 13-14, 16 famotidine, 442, 509, 661
epilepsy, 90, 111, 249, 318, 435, 549 Fanconi syndrome, 241, 301-302, 409, 421
epimerase, 298 fasciola, 482
epinephrine, 32 Fe (iron), 63-64, 336, 411, 643, 673
epiPen, 580 fecalith, 75, 99-100, 488, 630
episcleritis, 177, 183 Felty syndrome, 345
episiotomy, 171 femoral epiphysis, 372, 401, 499
epistaxis, 31, 251, 319, 627 ferritin, 63-64, 249, 331-332, 390, 398, 477-478,
ERCP, 111, 211, 214, 219-221, 260, 350, 358, 675
361, 365, 367, 489, 639 fetoprotein, 81-82, 144, 239, 266-267, 286-287,
ergocalciferol, 423, 446 300, 302, 646
erosions, mucosal, 47-51, 54, 133, 178, 187, fibrin, 280, 307, 339, 538, 598
451, 591, 603, 661 fibrinogen, 98, 390, 477
eructation, 537, 631 fibroids, 146
erythromycin, 20 fibromas, 144, 146, 201
erythrophagocytosis, 347 fibromyalgia, 558
erythropoetin, 477 fistula, 1, 12-13, 15-17, 35
escherichia, 107, 139, 261, 485, 647, 667-668 fistulectomy, 180, 197
escitalopram, 559 flagellates, 102
Eskimos, Greenland, 413, 419 flagyl, 442
esomeprazole, 510 flatulence, 45, 110, 134, 402, 413-414, 509-510,
esophagectomy, 34 515, 521-522, 530, 537, 558, 631
esophagitis, 13-14, 19-20, 23-27, 29-31, 36 fluconazole, 25
esophagus, 1-2, 5-8, 11, 14-17, 19-20, 23-25, 27, fluid therapy, 493-496
29, 33-37 fluorescein, 471
esophagus anatomy, 1-2 fluoride, 48, 380
esophagus atresia, 12-13, 15-17 fluorocytosine, 280-281
esophagus carcinoma, 34 fluororoquinolone, 515
esophagus congenital anomalies, 15 fluoroscopy, 8, 459, 466, 488, 533, 535
esophagus dysmotility, 7, 9 fluorouracil, 601
esophagus embryology, 1 fluoxetine, 539, 548, 559
esophagus ennervation, 1, 5 fluticasone, 24
esophagus histology, 5-6 folate, 70, 94-95, 179, 398, 427, 431, 453, 477,
esophagus manometry, 7-8 526, 652-654, 656, 661
esophagus motility, 3, 7, 9 Fontan proceedure, 97-98, 343, 408, 485
esophagus obstruction, 8 fontanelle, 46, 317
esophagus perforation, 9 food allergy, 579-581
esophagus physiology, 1-2, 7, 9 food/water-borne diseases, 101-104
esophagus ring, 16 foregut, 1, 15
esophagus sphincters, 1-2, 6-7, 11, 13, 19 foreign bodies, 31, 35-37
esophagus vasculature, 2 foremilk, 383, 652
esophagus, web, 16 formulas, 129, 180, 238, 380, 384, 387-388, 410,
essential amino acids, 431 435, 437, 517, 581, 651, 670, 683
estrogen, 150, 209, 286, 335 foscarnet, 26
ethanolamine, 531 fractures, 122-123, 178, 313, 322, 421, 487, 499,
ethics, 621-624 676
eustrongylides, 47, 629 friability, mucosal, 23, 49, 58, 184, 591, 603
eventration of diaphragm, 487 fructan, 558
evisceration, 125 fructokinase, 420
exopeptidases, 409 fructose, 224, 249, 297-299, 387, 408-409, 413,
exostoses, 201 420-421, 438, 473, 482-483, 521, 558, 575-576,
extramedullary hematopoeisis, 234, 286 641, 650-651, 672
extrapyramidal, 519 fulminant liver failure, 249-252
fundoplication, 20
F fungal esophagitis, 25
facies, syndromic, 146, 179, 255, 299, fungemia, 280, 528
317-318, 322, 373, 408, 589, 672 furazolidone, 108
failure to thrive, 393 furoate, 273
falciform ligament, 223 furosemide, 210, 238, 640, 676
Fallot tetralogy, 322, 343
Index 697
G gonorrhea, 229, 235, 272
gabapentin, 206 Gorlin syndrome, 199-201
gadolinium, 287, 489 gout, 501-502
galactokinase, 297-298, 642, 671 graft vs host disease, 14, 29, 50, 140, 192, 208,
galactorrhea, 519 286, 339-342, 452-453, 567, 591-596
galactosemia, 234, 249, 251, 254, 256, 261, granulocytopenia, 599, 667
297, 387, 641 granuloma, gastric, 49
galactosidase, 526 granuloma, hepatic, 279-282, 328, 346
gallstones, 209-211, 213, 220, 313, 363-365, granuloma, intestinal, 69, 178, 184, 452, 565
377, 529, 639-640 grapefruit, 501-502
GALT, 62, 153, 297-298 Greenland eskimos, 413, 415, 419, 575, 650
ganciclovir, 26 grehlin, 584
ganglioneuroblastomas, 589 griseofulvin, 510
ganglioneuromas, 142-143, 589 guaiac positive stools, 178, 184, 639, 666
gangrene, 172, 214-215, 376 Guillain-Barre syndrome, 13, 107, 118
Gardner syndrome, 202 gums, 31, 425
gastrectomy, 41 gunshot trauma, 121, 125
gastric emptying, 162, 207, 223, 354, 463, 515, gynecomastia, 510
652
gastric function tests, 463 H
gastrin, 3 H pylori, 5, 53-56
gastrinoma, 408, 587-589 HAART, 568
gastritis, 19, 31 hair anomalies, 33, 57, 94, 165, 358, 373,
gastrografin, 122, 376, 572, 574 428-430, 538-539, 546, 593, 626-627, 655, 677
gastrojejunostomy, 535, 605 halitosis, 538
gastroparesis, 73, 464, 467, 520, 584 halothane, 456
gastropathy, 47-52, 244, 514, 531 hamartomas, 145-146, 199-201, 239-240, 561,
gastroschisis, 61, 81-82, 118-120, 127-128, 137, 628
205, 439, 632, 667 hand lesions, 200-201, 259, 322, 419, 655, 675,
gastrostomy, 34 678
Gaucher disease, 234 Hansen disease, 643
gavage, 11 Hartnup disease, 410, 426, 651
gentamicin, 108, 670 HAV, 265, 268-269, 275-276, 640, 676
GER, 5, 19-20 HBcAg, 268-269
GERD, 5, 19-20, 23-25, 29 HBeAb, 266, 647
ghrelin, 406 HBeAg, 265-266, 268-269, 647
Gianotti-Crosti syndrome , 266 HBsAb, 266, 647
giardia lamblia, 68, 70, 94, 97, 102-103, 110, HBsAg, 265-266, 268-269, 640, 647, 664
112, 135, 178, 184, 408, 451-452, 481, 485, HBV, 229, 235, 265-266, 268-269, 312, 639, 647
566-568, 577, 633 HCC, 241-242, 266-267, 302
Gilbert syndrome, 228, 257, 259, 293 HCV, 266-269, 275, 312, 350, 639-640, 647, 675
gingival hyperplasia, 180, 501 HDV, 267-269, 647
gliadin, 90-91 heartburn, 19-20, 23
glioblastoma, 202 hedgehog proteins, 62, 353, 357, 649
glomerulonephritis, 187, 266-267 helicobacter, 52-53, 56, 481, 485, 509-510, 626,
glossitis, 16 666
glucagon, 297, 354, 406, 490, 587, 672 Heller myotomy, 9
glucoamylase, 413, 415 HELLP, 307
glucocorticoids, 47, 499, 501-502, 583-584, 589 hemangioendothelioma, 286-287, 488
gluconeogenesis, 224, 297, 299, 420, 445, 499 hemangiomas, 31, 143, 176, 234, 239, 242,
glucosidases, 299, 411 286-287, 562
glucosuria, 297, 302, 421, 576 hemangiomatosis, 145, 201
glutathione, 228, 301, 327-328, 339, 426, 430, hematemesis, 31, 33
437 hematochezia, 46, 119, 134, 177, 183, 187, 449,
gluten, 50, 89-92, 438, 604, 674 534, 539, 549, 558, 579
glycocalyx, 67 hematoma, 51, 59, 117, 122, 124, 239, 449, 654
glycogen, 224, 234, 240, 257, 259, 297-300, hematopoiesis, 62-63, 192, 223, 287, 339-340,
305, 349, 408-409, 420, 445, 585, 646, 671, 685 347, 581, 591
glycogen storage diseases, 297 hematuria, 187-188, 549
goiter, 51, 146, 428, 583, 672 hemidiaphragm, 122, 272
hemobilia, 31 hydronephrosis, 178, 638
hemoccult, 175, 485, 550 hymenolepis, 111
hemochromatosis, 231, 249, 251, 331-333, hyoscyamine, 529, 559
349, 455, 677 hyperaldosteronism, 519
hemoglobinopathies, 214 hyperalgesia, 2
hemoglobinuria, 285 hyperammonemia, 250, 254, 309-310, 421
hemolytic processes, 106, 175, 178, 183, hypercalcemia, 51, 358, 363, 367-368, 423,
187-188, 209-210, 227, 231, 249, 293, 297, 588-589
302, 307, 313, 358, 363, 424, 446, 479, 487, hypergastrinemia, 48, 51, 129, 510, 583, 585,
524, 529, 567, 668 587-588
hemolytic uremic syndrome, 188 hyperinsulinemia, 250, 335
hemoperitoneum, 123, 125 hyperkalemia, 502, 660
hemophagocytosis, 234, 347, 421, 451, 639, hyperkeratosis, 303, 593, 677
642 hyperlipidemia, 299, 363-364, 367-368, 423,
hemophilus, 271, 566 499, 501-502, 640, 668, 677
hemorrhoidectomy, 173 hypermagnesemia, 521-522, 660
hemorrhoids, 165, 171-173, 175, 198, 538, 636, hypernatremia, 109, 521, 668, 677
682 hyperoxaluria, 349
hemothorax, 455 hyperparathyroidism, 51, 584
Henoch-Schönlein, 31, 56, 175, 187, 189, 487, hypertelorism, 201, 322
554 hyperthyroidism, 231, 301, 394, 583, 664
heparan, 577, 663 hypertrichosis, 501
heparin, 97-98, 425 hypertriglyceridemia, 209-210, 358, 368
hepatoblastoma, 144, 201, 234, 239, 241-242, hyperuricemia, 420, 435, 501-502, 518
349, 488, 646, 659 hyperventilation, 250-251, 299
hepatopulmonary syndrome, 244-245 hypervitaminosis, 234, 329, 673
hepatorenal syndrome, 244, 251, 301, 350 hypoalbuminemia, 47, 98, 115, 178, 184, 201,
hepatosplenomegaly, 46, 217, 261-262, 272, 244, 254, 272, 302, 343
280, 290, 297, 302, 347, 376, 421, 566, 654, 671 hypocalcemia, 134, 423, 429, 442, 584, 633, 678
hepatotoxicity, 179, 249, 290, 311, 327-328, hypochloremia, 41, 43, 53, 377, 418, 479, 583
335, 423, 437, 519 hypogammaglobulinemia, 70, 98, 566, 569
hepcidin, 217, 331, 477 hypoglycemia, 249-251, 255, 259, 297-299,
herpes, 25-26, 251, 255, 257, 262-263, 505, 566, 302, 306-307, 309, 325, 328, 332, 375, 399,
569, 647 409, 420, 442, 445, 547, 584-585, 630, 660,
HEV, 267-269, 647, 674 671-672
hiatal hernia, 48, 450, 656 hypokalemia, 94, 238, 251, 399, 418, 429,
HIDA scan, 213, 215, 221, 639-640, 656, 664 521-522, 546-547, 550, 589, 660
hindgut, 61, 147-148 hypolactasia, 414
hindmilk, 383 hypomagnesemia, 94, 180, 435, 502, 547, 660
Hirschsprung disease, 8, 84, 137, 158, 161, hypomotility, 71, 73, 168, 467, 599
163, 165, 175, 361, 439, 465, 468, 572, 628, hyponatremia, 238, 418, 435
635-636, 674, 682, 685 hypoparathyroidism, 313, 346, 584
histamine, 20 hypopharynx, 2, 11, 31
histidine, 331, 431-432 hypophosphatemia, 251, 399, 423, 547, 668,
histology of esophagitis, 29-30 677
histopathology, 141, 226, 284, 328-329, 337, hypoproteinemia, 94, 377, 435, 577, 678
343-345, 347-348, 591, 638, 678 hypotension, 84, 121, 125, 426, 429, 503, 519,
histoplasmosis, 25 521-522, 530, 546, 590
HIV, 26, 29 hypothalamus, 405-406, 520
hoarseness, 19, 35 hypothermia, 251, 399
Hodgkin disease, 92, 141, 281, 561-562, 660 hypothyroidism, 51, 115, 162, 165, 232,
homocysteine, 433 239-240, 255-256, 259, 286, 294, 358, 373,
hookworm, 111-112, 482 375, 385, 428, 430, 583, 641, 649, 664, 666,
Hopi natives, 210 668, 672
human milk, 383 hypovolemia, 77, 87, 101, 118, 238, 293, 379,
HUS, hemolytic uremic syndrome, 106, 108, 547, 579
188, 636 hypoxemia, 12-13, 47, 244, 601
hydatid, 273
hydrocephalus, 161
hydrogen breath test, 473
Index 699
I isoniazid, 249, 279, 329, 358, 427, 502, 642
IBD, inflammatory bowel disease, 24, 29, isosorbide, 9
177-181 isospora, 94, 102-103, 112, 481, 568, 673
IBS, 71, 90, 414, 527, 557-560 isotretinoin, 329, 642
ibuprofren, 58, 629 itraconazole, 25
ichthyosis, 318
ICP, intracerebral pressure, 250-251 J
IgA, 53, 55, 62-63, 70, 83, 89, 91, 98, 102, 142, JAG mutation, 217, 321, 638
166, 187, 383, 385, 409, 526, 562, 565, 567, JAK mutation, 285, 566
577, 631, 663 Jamshidi needle, 455
IgD, 385 jaundic, 31
IgE, 23 jaundice, 31, 227-229, 253, 350, 633, 641, 650,
IgG, 53, 55, 91, 98, 180, 259, 261, 267-268, 368, 654, 664
385, 481, 505-507, 565-567, 579, 631, 647 Joubert syndrome, 207, 283
IgM, 50, 55, 98, 261-262, 265, 267-268, 385, JRA, juvenile rheumatoid arthritis, 180, 345
565, 567, 640 juvenile polyps, 144-145, 169, 175, 199, 534,
ileitis, 183-184, 634 561
ileocecectomy, 180
ileostomy, 129, 138, 158, 180, 185, 376, 529 K
ileus, 83-84, 117, 123, 162, 185, 341, 357, Kaposi sarcoma, 143, 568, 673
375-376, 439, 471, 487, 494, 520, 529, Kasabach-Merritt syndrome, 286-287
571-572, 583, 591-592 Kasai proceedure, 218, 246, 253-254, 350, 445,
iminodiacetic acid, 213, 217, 490, 640 639, 650
imodium, 529 Kawasaki syndrome, 118, 214, 348, 358, 363
impaction, 23, 35-36 keratoconjunctivitis, 345
imperforate anus, 196, 361, 373, 465 kernicterus, 293-294
incarcerated hernia, 554 ketoacidosis, 364, 433, 554, 585
indomethacin, 48, 598 ketoconazole, 112, 501, 510, 515, 673
infantile colic, 45-46 ketogenic, 435, 438, 653
infectious esophagitis, 25-26 ketorolac, 214
infliximab, 180, 184, 505-506, 634-635, 659-660 klebsiella, 139, 525, 661
influenza, 47, 257, 325, 363 koilonychias, 16
insipissated meconium, 253, 572-573 Korsakoff psychosis, 426
insomnia, 179, 250, 515, 524 KUB, 166, 656
insulinoma, 589, 671 Kupffer cells, 224-225, 234, 280-281, 345, 348,
integrin, 506-507, 577 455
interferon, 189, 266-267, 287, 351, 499, 566 kwashiorkor, 234, 377, 398, 673
interlobular bile ducts, 207, 279, 320, 354,
443, 456, 592 L
intracranial bleeding, 318, 322 lactalbumin, 383
intracranial pressure, 19, 250, 402 lactase, 110, 387, 409, 413-414, 575, 652, 664,
intussusception, 51, 68, 75, 87-88, 107-109, 674
117, 119, 141-145, 169, 175-176, 187-188, 194, lactation, 383, 385, 393, 428, 580, 598
199-201, 488, 490, 538, 553, 574 lactobacillus, 109, 133, 525, 527-528, 575, 634,
iodamoeba, 102 661
iodine, 428, 655 lactobezoars, 57
IPEX syndrome, 115-116, 438, 567, 577, 630 lactoferrin, 178, 184, 383, 385
iritis, 177, 183, 634 lactoglobulin, 383
iron deficiency anemia, 16, 57, 63, 91, 112, lactose, 106-107, 109, 134-135, 251, 380,
172, 178, 183, 447, 477-479, 585 383-384, 387-388, 393, 408-409, 411, 413-415,
iron physiology, 63-64, 93, 380, 384, 390, 398, 437, 473, 483, 521, 526, 528, 558-559,
411, 425, 429 575-576, 604, 626, 631, 650-652, 654, 656,
iron storage disease, 331-333 669-670
irradiation injury, 601-604 lactulose, 134, 167, 251, 473, 521, 525, 558-559,
irritable bowel syndrome, 87, 133, 135, 185, 637, 656
493, 527, 555, 557-558, 560, 631, 671, 685 Ladd bands, 77, 117, 563
islet cells, 115, 353-355, 368, 585, 589 lamblia, 47, 68, 70, 97, 102-103, 110, 408, 451,
isoamylase, 372 481, 485, 628
isoleucine, 432-433 lamivudine, 673
isomaltase, 409, 413, 438, 575, 650, 652 lansoprazole, 501, 510, 661
laparoscopy, 100, 123, 214, 216, 402-403, 653 lysine, 421, 431-432, 482
laparotomy, 84, 108, 123-125, 145, 572, 574 lysozyme, 68, 383, 385, 513
laryngomalacia, 12
larynx, 2, 11, 13, 19 M
lavage, 58-59, 123, 125, 573 macrocephaly, 46, 145-146, 199, 201
laxatives, 167, 521, 545, 547, 550, 559, 573-574, macrocytic anemia, 134, 477-478, 633, 678
638 macrolide, 118, 197, 351, 502-503, 598
LCFA, 128, 306, 407, 442 macrosomia, 584
LDL, 209, 401, 408, 418, 499, 501 maculopapular dermatitis, 340-341, 591-593
leiomyoma, 141, 562, 568 magnesium, 130, 167, 178, 380, 384, 399, 411,
leiomyosarcoma, 142, 562 429, 442, 445, 447, 449, 509, 521-522, 550,
lens deposits, 297, 313 584, 661
leprosy, 279 magnet ingestion, 36, 57-58
leptin, 402, 405 maleylacetoacetate, 301-302
leptospirosis, 272 malformation, 2, 9, 12-13, 15, 35, 161-162, 175,
LES, 1-3, 7-9, 19 207, 217, 283, 408
leucine, 432-433 Mallory-Weiss tear, 31, 48, 553, 627
leukemia, 197, 234, 271, 371-372, 479, 601, malnutrition, 25, 397-399
660, 667, 670-671 malrotation, 42, 61, 77, 81-82, 84, 117, 119-120,
leukocytosis, 83, 119, 139, 178, 184, 187, 191, 127, 162, 205, 217, 253, 361, 534, 572, 628,
213, 215, 272-273, 280, 598, 647 632, 657, 678
leukopenia, 25, 179, 244, 345, 478 MALT, 47, 54-55, 142, 562, 629
leukotriene, 179, 635 maltase, 409, 413, 415
levamisole, 111-112 maltodextrin, 384, 387-388
lichen dermatitis, 341, 592, 595 mandible, 12, 142, 201
licorice, 175 manganese, 227, 380, 429, 442, 447
Lieberkuhn crypts, 67, 153, 406 mannitol, 250-251
ligament of Treitz, 31 mannose, 98
linoleic, 384, 407, 441, 446-447, 652 manometry, 7-9, 14
linolenic, 384, 407, 441, 446 Manopty needle, 455
lipase, 51, 139, 188, 353, 357-358, 363-364, 368, maple syrup disease, 34, 429, 433, 673
372, 380, 385, 388, 402, 405, 407-408, 411, marasmus, 377, 398, 652, 673
469-471, 499, 501, 517-518, 649, 654, 679 mastocytosis, 51, 68, 590
lipolysis, 305, 307, 335, 405, 407, 445, 499 MCAD, 305-307, 643
lipomatosis, 145, 201 measles, 47, 97, 446
lipoprotein, 401, 407, 421, 478, 499 mebendazole, 111-112, 274
lisinopril, 640 Meckel diverticulum, 61, 75-76, 87, 117,
listeria, 647 175-176, 207, 283, 361, 490, 678
lithium battery ingestion, 36, 49 meconium ileus, 61, 117, 119, 161-162, 205,
liver, anatomy, 223 255, 357, 375-376, 471, 487, 571-572, 633, 669
liver, biopsy, 435 mediastinitis, 16
liver, function tests, 231 mediterranean fever, familial, 554
liver, histology, 225 medulloblastoma, 201
liver, metabolic disorders, 289-315 megacolon, 102, 107, 162, 184-185, 191, 529,
liver, toxicity, 327-329 583, 585, 636
liver, transplantation, 349-352 megacystis, 117, 205
liver, tumors, 239-242 megaloblastic anemia, 94-95, 427, 453, 479,
Loffler syndrome, 111 538
lomotil, 529 megaureters, 638
loperamide, 529-530, 559, 575, 603, 658, 660 Meissner plexus, 39, 62, 67, 153, 157, 161
lower GI bleeding, 175-176 melanosis, 522, 550
lubiprostone, 559 melanotic, 31, 175-176, 553
lymphangiectasia, 70, 97-98, 388, 408, 453, melatonin, 39
487, 636, 650 MELD scoring system, 350
lymphangiomas, 143 menaquinone, 411
lymphohistiocytosis, 234, 249, 347 Menetrier disease, 47, 49-50, 463
lymphoma, 47, 49-50, 54-55, 70, 87, 92, 94, Menghini needle, 455
141-142, 179-180, 234, 237, 239, 281, 487, meningitis, 15
499, 505, 562, 607, 629, 660, 673 meningoencephlacele, 283
lymphonodular hyperplasia, 175 meningomyelocele, 632
Index 701
mercaptopurine, 328, 363, 477-478, 505, 660, mucocele, 574
667, 675 mucormycosis, 113
mesalamine, 179, 184, 363, 603, 634-635, 638, multinucleated giant cells, 26, 262, 279, 346,
675 677
mesentery, 77, 79, 121, 141, 147-148, 154, 202, multiorgan failure, 192, 251, 340, 439, 510
488, 554 mumps, 363-364
metalloproteinases, 90, 97 Munchausen syndrome, 549, 551, 662, 684
metaphyseal dysostosis, 358, 372, 479 mupirocin, 197
metformin, 336, 402, 585 muromonab, 139
methane, 473, 656 mushrooms, 249, 314, 409, 415
methionine, 387, 431-432 myalgia, 250, 281, 558, 568
methotrexate, 142, 179, 184, 241, 281, 329, myasthenia, 12-13
336, 341, 345, 347, 427, 477-478, 510, 530, mycobacterium, 27
569, 597, 601, 654, 660, 667, 670, 675 mycophenolate, 138, 189, 329, 351, 504, 567,
methylprednisolone, 139, 179, 184, 347, 501 592, 642
metoclopramide, 20 mycoplasma, 363
metronidazole, 56, 102-103, 110, 130, 135, 142, myelodysplastic syndrome, 372, 479
179, 185, 191, 273, 363, 502, 575, 599, 634 myelomeningocele, 13
Meyenburg complexes, 283, 669 myocardial dysfunction, 231, 513, 546, 668,
microabscesses, 23, 29 677
microangiopathy, 188 myocarditis, 272
microcephaly, 12-13 myoelectric, 354, 463
microcolon, 117, 205, 571-572, 657 myoglobin, 293
microcytic anemia, 134, 398, 429, 477, 479, myopathy, 72, 117, 166, 205, 232, 299, 306,
633, 652, 673, 678 426, 547
microgallbladder, 377 myosarcoma, 568
microgastria, 42, 543 myosin, 484
micrognathia, 13 myxedema, 583
microsporidium, 112 Ménétrier disease, 47, 49-50
microvilli, 67, 153, 452, 576, 578
midesophagus, 2, 16 N
midgut, 61-62, 77, 117, 147, 200, 678 nadolol, 50
migraine, 90, 554-555 nafcillin, 501
milk of magnesia, 521, 559 NAFLD, 257, 312, 335-336, 343, 401, 643, 682
minocycline, 329, 597 nails, 16, 266-267, 429, 534, 593
miralax, 167, 637 naloxone, 524
miscarriage, 313, 513 NASH, 258, 335-336, 456, 682
misoprostol, 48, 513-514, 598, 661, 667 nasogastric tube, 31, 41, 48, 84, 122, 256, 463,
mitochondrial disorders, 14, 117-118, 205, 494, 672
234, 249, 257, 305-308, 325-326, 373, 394, nasojejunal tube, 42, 535
408, 435, 442, 456, 501 natalizumab, 507
mitomycin, 534 NEC, necrotizing enterocolitis, 47, 83-85,
MMC, migrating motor complex, 71-72, 97, 102, 117, 127, 137, 175, 271, 439, 487, 527,
150, 466-467 546, 553, 632, 654, 657-658, 667, 669, 681
mofetil, 138, 189, 329, 351, 502, 592, 642 necator, 111, 482
molybdenum, 655 nematodes, 482, 663
monoglycerides, 407 neocate, 388
monosaccharides, 357, 409, 413, 558, 585 neomycin, 135
Morgagni columns, 149, 154, 197 nephritis, 179, 429
morrhuate, 531 nephrolithiasis, 178, 313
motilin, 45, 64, 71, 354, 519, 598, 663, 679 nephromegaly, 283
motility, 9, 12-14, 25 nephronophthisis, 322
motility agents, 519 nephrotic syndrome, 237, 640
motility testing, 465-468 nephrotoxicity, 180, 314, 351, 501-502, 644
moyamoya disease, 322 neuroblastoma, 234, 239, 488, 589, 671
MRCP, 111, 214, 219-221, 258, 284, 361, 365, neurofibroma, 141, 143, 161
367-368, 377, 489, 638-640, 648 neuropathy, 72, 90, 134, 166, 179, 205, 291,
MRI, 79, 82, 166, 178, 184, 189, 202, 233, 240, 427-428, 446, 530, 584
244, 249, 255-256, 272, 285-287, 314, 331, neurotoxicity, 302, 351, 433, 501-502, 504
336, 429, 488-489, 491, 603, 625-626, 677
neutropenia, 83-84, 112, 115, 192, 197, 271, ornithine, 249, 309, 421
299-300, 372, 408, 449, 479, 604, 650, 667 oropharynx, 11-12, 33
nexium, 510 osteomas, 144, 201-202
nicardipine, 501 osteomyelitis, 105-106
nifedipine, 9 osteopenia, 90-91, 178, 371, 399, 435, 499, 546
Nissen fundoplication, 20, 627 osteoporosis, 90-91, 313, 421, 428
nitazoxanide, 103 ostomy care, 605
nitisinone, 303 otalgia, 627
nitrazoxanide, 103 otitis, 19
nitrogen metabolism, 310, 390, 406, 428, 432, ovarian, abdominal pain, 100, 200, 297, 401,
440, 445, 676 553, 574
nitroglycerine, 3 oxytetracycline, 597
nitrosamine, 510
nizatidine, 509, 661 P
nocardia, 566 PABA, 471
nociceptors, 1, 14, 529 palmitic acid, 384, 652
nonalcoholic fatty liver disease, 335-337 palmitoyltransferase, 305-306
noncaseating granulomas, 279-280, 643 pANCA, 178, 184, 276, 648
nonrotation of intestines, 77 pancreas, anomalies, 361
norepinephrine, 402 pancreas, exocrine, 357
noroviruses, 110, 140 pancreatectomy, 368
nortriptyline, 559 pancreatic function tests, 469-471
Norwalk virus, 110, 451, 633 pancreatitis, 41, 51, 94, 131, 133, 177, 179, 183,
novobiocin, 482 187, 189, 201, 211, 213-214, 219-220, 307,
NSAID, 48, 192-193, 202, 307, 345, 513-514, 313, 320, 358, 361, 363-369, 371, 401,
597-598, 661 435-436, 488-489, 538, 546, 553-555, 574,
nutcracker esophagus, 7, 9, 14 584-585, 630, 639, 645, 649, 657, 672, 675,
nutramigen, 387 683, 685
nutritional assessment, 389 pancreatitis, acute, 363
nutritional requirements, 379 pancreatitis, chronic, 367
nuts, 314, 430, 438, 446 pancytopenia, 281, 372, 478-479, 569
nystagmus, 426 Paneth cells, 65, 67-69, 153
nystatin, 112 panhypopituitarism, 255-256, 373
panreas, anatomy/development, 353-355
O pantoprazole, 510
obesity, 20, 100, 124, 171, 209-211, 235, 283, pantothenic, 410, 426, 655
335, 364, 397, 401-403, 431, 435, 534, 583, para-aminobenzoic acid, 471, 478
613, 640, 683 paracentesis, 84, 237-238, 676
obstruction, bile ducts, 208, 214, 220, paraneoplastic syndrome, 8, 14
257-258, 280, 320, 350, 371, 408, 475 parasitoses, 24, 47, 49, 70, 102, 110, 169, 192,
obstruction, gastric, 41, 48-49, 57 210, 229, 235, 239, 271, 282, 348, 429, 437,
obstruction, intestinal, 75, 77, 87, 99, 108, 451, 481, 485, 550, 580, 637, 649-650, 663, 682
117-120, 122, 128, 131, 139, 141, 180, 185, parathyroid, 585, 589
200, 361, 363, 375, 402, 439, 571-573, 603 paratyphi, 105, 113
OCD, obsessive compulsive disorder, 537 parenteral nutrition, 439-444
octapeptide, 32 paromomycin, 102-103, 273
octreotide, 32 parotid gland, 546-547
ocular signs, 111, 317, 321-322, 424 paroxetine, 559
oculogyric, 519 paucity of bile ducts, 208, 220, 255, 321, 490,
Oddi sphincter, 64, 213-214, 365, 529, 639 641
odynophagia, 7, 13-14, 25-27 PBC, primary biliary cirrhosis, 277, 279, 345
Ogilvie syndrome, 118 PCP, Pneumocystis carinii pneumonia, 180,
oligosaccharides, 105, 409, 413, 525 351
olsalazine, 675 PDA, 48, 440-441
omeprazole, 510-511, 640 peginterferon, 269, 606
omphalocele, 61, 81-82, 127, 137, 632 pegylated, 266-267, 506
ophthalmoplegia, 426, 670 pellagra, 426
opiate, 185, 365, 524, 530, 573, 658 penicillamine, 314
orchitis, 429 penicillin, 196-197, 261, 329, 597, 659
orlistat, 402, 501 pentagastrin, 463, 490, 587
Index 703
pentasa, 675 platyhelminthes, 663
pepsin, 83, 405-406, 409, 411, 470, 509, 513 pleisiomonas, 485
pepsinogen, 39-40, 409 Plummer-Vinson syndrome, 16, 625
peptides, 64-65, 90, 102, 387, 409-410, 503, pneumatosis, 83-84, 119, 487, 533, 599, 605,
523-524, 530 632, 657
pepto-bismol, 175 pneumococcus, 566
perforation, 9, 24, 31, 33-36, 57, 84, 271, 453, pneumocystis, 139, 569
546, 629-630, 632 pneumomediastinum, 546
perianal disease, 195-198 pneumonia, 16, 35, 510
pericarditis, 97, 234, 237, 243, 285, 339, 343, pneumonitis, 16, 33
345, 631 pneumoperitoneum, 84, 87, 122, 125, 487,
pericholangitis, 340 605, 657
perihepatitis, 272 pneumothorax, 440, 455
perineum, 165, 172, 637 poliomyelitis, 12-13, 109
peristalsis, 2, 7-9, 13, 16, 19 polyacrylamide, 475
peritonitis, 57, 83-84, 87, 99, 107, 112, 122, polyarteritis, 214, 266
139, 221, 237-238, 253, 376, 449, 455, 538, polycystic kidney disease, 219, 257, 283, 347,
571-572, 598-599, 676 401
periumbilical pain, 99, 177, 187, 364, 554-555, polydactyly, 283
630 polyendocrinopathy, 115-116, 276, 346, 567,
perixosome, 317 577
peroxidase, 430, 485, 666 polyethylene, 167, 447, 449, 573
peroxide, 49, 58, 175, 606 polyhydramnios, 16
peroxisomal disorders, 257, 317-318, 644, 683 polymerase, 103, 138, 140, 269
pertechnetate, 490 polymyositis, 9
petechiae, 31, 176, 187, 425 polyneuropathy, 118, 318
Peutz-Jeghers syndrome, 31 polypectomy, 144, 200, 449, 453, 534-535
pH monitoring, 459-462 polypeptide, 354-355, 405, 529, 648
pharyngitis, 13, 107, 554, 643, 659 polyposis, 97, 137, 141, 144-145, 199, 201-203,
phenacetin, 329 241, 449, 534, 561, 563, 628, 636, 646
phenobarbital, 294, 328, 490, 501, 639, 642, polyps, 50, 87, 141-142, 144-145, 165, 169, 175,
646, 676 199-203, 449-450, 510, 531, 534, 561, 563,
phenol, 169 628, 682
phenolphthalein, 550 polysaccharides, 408
phenothiazine, 329 polysomnography, 19
phenylalanine, 302, 375, 431-433 polysplenia, 207, 217, 253-254
phenylketonuria, 433 Pompe disease, 299
phenytoin, 249, 328-329, 501-502, 515, 654 porphobilinogen, 301-302, 675
pheochromocytoma, 588 porphyria, 118, 302, 331, 435, 554, 686
phlebitis, 279 portal hypertension, 243-247
phlegmon, 178, 180 portoenterostomy, 218, 253-254, 445
phlorizin, 413-414 posttransplant, 340, 342, 349-350, 501, 503
phosphatidylcholine, 255, 319-320, 407 potassium, 49, 63, 129-130, 150, 238, 399, 418,
phosphaturia, 302, 423 427, 494, 597, 651, 669-670
phosphorus, 178, 380, 384, 387, 399, 423, 430, potatoes, 413-414, 423
436, 650, 669, 676 pouchitis, 185, 527-528
photosensitivity, 426, 675 poultry, 101, 105, 107, 429
phototherapy, 294, 426, 676 PPI, 20, 25, 29
phycomytosis, 113 praziquantel, 111
phylloquinone, 424 prealbumin, 390, 398, 652
phytanic acid, 317-318 prebiotics, 135, 525-526, 684
phytobezoar, 57 precocious puberty, 200, 239, 241, 636
picornaviridae, 109 prednisone, 179, 184, 276, 336, 352, 499, 501,
Pima natives, 210, 639 592, 603, 634, 640, 648, 659-660, 662, 670
pinocytosis, 412 preeclampsia, 307
pinworm, 196, 482 pregestimil, 387
piperacillin, 100, 214 pregnancy, 45, 171, 209-210, 228-229, 240, 242,
pituitary, 255-256, 406, 499, 589 285-286, 294, 307, 314, 390, 428-429, 464,
platelets, 31, 48, 245, 258, 299, 453, 478, 497, 476, 513, 553-554, 580, 598, 622, 640, 674
601, 634, 671, 674
prenatal ultrasound, 81-82, 205, 240, 418, 488, pyloromyotomy, 43
633 pylorospasm, 43, 49, 583
pretransplant, 339, 350 pylorus, 31, 36
prevacid, 510 pyoderma gangrenosa, 177, 183
prilosec, 510 pyridoxine, 314, 410, 427, 655
probiotics, 56, 109, 135, 191, 525-528, 559, 575, pyrrolozidine, 339
628, 661, 684
proctitis, 183, 603-604 Q
proctocolectomy, 180, 185 quinidine, 281, 597
proctocolitis, 538 quinolones, 108, 509
proctosigmoiditis, 183, 602-603
progesterone, 209 R
proglottids, 111, 482 rabeprazole, 501, 510
progressive familial intrahepatic racecadotril, 530
cholestasis, 319-320 racemase, 291, 318, 644
prokinetic, 20, 42, 49, 118, 120, 135, 206, 461, radiation injury, 601-604
519, 598, 603, 663 radiotherapy, 193, 202, 562, 601-603
prolactin, 500 raffinose, 558
prolapse, rectal, 48, 108, 112, 144, 169, Ramstedt proceedure, 43
171-172, 185, 194, 198-199, 538, 546, 637, 682 ranitidine, 245, 442, 509, 661
propranalol, 50 rapamycin, 499
prostaglandins, 48, 179, 385, 513-515, 597, Rapunzel syndrome, 539
603, 684-685 Raynaud phenomenon, 345
proteases, 111, 311, 367, 409, 411-412, 517, rectal prolapse, 169
526, 568, 581, 669 rectosigmoidectomy, 162
protein losing enteropathy, 97-98 rectum, 42, 87, 125, 147-151, 153-154, 158, 161,
proteinosis, 421 165-166, 169, 171-172, 184-185, 189, 197, 199,
proteinuria, 179, 187, 302, 421, 636 202-203, 262, 377, 451, 465, 537, 550, 572,
prothrombin, 259, 272, 285, 310, 325, 446, 517, 575, 589, 604, 646, 669
667, 674 refeeding syndrome, 336, 394, 399, 430, 547
protonix, 510 reflux, 2, 7, 9, 16, 19-21, 23, 29-30
protoporphyrin, 429 Refsum disease, 317-318, 644
protozoal, 94, 102-103, 451, 481, 663 regurgitation, 19-20
pruritus, 171-172, 196, 255-256, 259-260, 274, Reiter syndrome, 107
289, 319-321, 323, 344, 515, 523-524, 579, remicade, 607, 653
590, 645, 658, 674, 676 renografin, 8
PSC, primary sclerosing cholangitis, 183, retching, 42, 48, 541
220, 277, 456 retinal anomalies, 144, 189, 201, 283, 317
pseudo-obstruction syndrome, 7-8, 71, 120, retinitis, 111, 318, 417
135, 137, 175, 205-206, 466, 543, 549, 551, retinol, 390, 423, 446
583, 585, 682 retinopathy, 317, 441
pseudocyst, 365-366, 489 retroperitoneal, 62, 99-100, 122-124, 147
pseudomembranous colitis, 84, 108, 175, 451, retroperitoneum, 123-124, 148, 221
487, 598-599 Rett syndrome, 435
pseudomonas, 565 Reye (Reye-Johnson) syndrome, 234, 306,
psoriasis, 16 309, 325-326, 456, 530
psychologic manifestations of GI disease, rhabdomyolysis, 231-232, 428
537, 539, 541, 543, 545, 547, 549, 551 rheumatoid arthritis, 345, 565, 667
psychosis, 313, 423, 426 rhinitis, 23
psyllium, 559 rhinoconjunctivitis, 579
PTLD, post-transplant lympoproliferative rhinorrhea, 660
disorder, 140, 351, 503, 644 ribavirin, 110, 267, 269, 640
puborectalis, 151, 158, 165, 538, 635 riboflavin, 306-307, 410, 426, 526, 661
Puestow proceedure, 368 rice, 102, 384, 437, 654
PUFA, polyunsaturated fatty acids, 407, 441 rickets, 290, 302, 409, 423, 430, 676
punctata, rhizomelic chondrodysplasia, rifabutin, 501
317-318, 644 rifampin, 254, 280, 501-502, 524
purine, 351, 478, 502, 518 rifaximin, 135, 559
pyloric atresia, 41 rituximab, 277, 352
pyloric stenosis, 8, 43-44, 117-119, 598 Robin sequence, 12
Index 705
rochalimaea, 669 senna, 167, 522, 559
Rome criteria, 557 sepsis, 47, 84, 100, 121-122, 131, 137, 162, 185,
rotashield, 109 205, 210, 214, 234, 250-251, 255-256, 271,
rotateq, 109 297, 306, 310, 342, 348-350, 366, 399, 441,
rotavirus, 101, 109-110, 113, 217, 451, 526, 633 489, 510, 527-528, 566, 599, 630, 642-643, 668
Rotor syndrome, 257, 294 serine, 367, 432
Roux-en-Y proceedure, 49, 246, 402, 653 serotonin, 402, 406, 519-520, 539, 548, 557,
rowasa, 675 559, 589-590
Rozycki syndrome, 8 serratia specie, 566
rubella, 255, 262-263, 358, 649 sertoli cell tumor, 200
rubeola, 363 sertraline, 559
rumination, 466-467, 541-542, 662, 684 sessile polyp, 50, 142
rye, 89-90 seton, 197
shellfish, 24, 229, 235, 314, 438, 580, 626
S shigella, 101, 106, 108, 113, 178, 184, 192, 451,
saccharomyces, 414, 525, 575 481, 485, 567, 628, 633
sacroiliitis, 177, 183 Shwachman-Diamond syndrome, 358, 371,
sacrosidase, 414, 438 373, 408, 471, 479, 649-650, 667, 683
safflower oil, 388, 447 sibutramine, 402
salicylates, 192, 307, 325, 345, 456, 530, 597 sickle cell disease, 105, 210, 214, 271, 348,
saliva, 16, 35 363, 554, 646
salivagram, 625 sideroblastic anemia, 358, 373, 408, 667
salmonella, 101, 103, 105, 107, 113, 178, 184, siderosis, 249, 332
192, 271, 451, 481, 485, 526, 566-567, 628, 633 SIDS, 20
Santorini duct, 353 sigmoidoscopy, 112, 202, 580, 637
sapoviruses, 110 silo tenting, 81-82
sarcocystis, 102 simethicone, 45
sarcoidosis, 8 sinopulmonary infection, 565, 567, 663
sarcoma, 143, 240, 287, 561, 568, 673 sinusoidal, 227, 237, 243, 287, 339-340, 343,
sashimi, 47 348, 675
satiety signals, 385, 405-406, 412, 437, 445, sinusoids, 12-13, 19, 154, 178, 223, 225, 281,
546, 584 339
SBBO, short bowel bacterial overgrowth, sirolimus, 138, 499, 503
130, 133-135, 473 sitz bath, 173, 195, 197, 637
SBP, spontaneous bacterial peritonitis, Sjögren syndrome, 267, 345, 368
237-238 skinfold measurement, 390, 445, 670
SCAD, short chain acyl CoA SLE, systemic lupus erythematosus, 50-51,
dehydrogenase, 305-307, 643 97, 117, 214, 344-345
SCFA, short chain fatty acids, 129, 305, 409, sleeping and GER, 2, 20, 462
526 slipped capital femoris epiphysis, 372, 401
SCFE, 372, 401 slit-lamp examinations, 177, 258, 313, 315,
Schatzki ring, 16, 625 640
schistocytes, 188 sludge, gallbladder/biliary, 210, 214-215,
schistosomiasis, 243, 279, 629 253, 258, 260, 348, 363, 375, 442, 520, 639
schwannomas, 142-143 small bowel, anatomy/development, 61-62
scintography, 20, 639 small bowel, bacterial overgrowth, 133-135
sclerodactyly, 596 small bowel, cysts, 79
scleroderma, 9, 14, 25 small bowel, histology, 67-70
sclerotherapy, 32 small bowel, motility, 71-73
scoliosis, 7 small bowel, obstruction, 117-120
scopolamine, 529 small bowel, physiology, 63-65
scrotum, 196, 487-488, 678 small bowel, transplant, 137-140
scurvy, 425 small bowel, trauma, 121-125
seborrheic dermatitis, 196, 426, 671 small bowel, tumors, 141-146
secretagogues, 354, 470 smoking, 45, 312, 425, 462, 473
secretin, 64, 354-355, 358, 368, 372, 378, 406, Soave proceedure, 162
469-470, 587, 589, 648, 657, 679 somatostatin, 39, 50, 64, 354-355, 520, 529,
secretory tumors, 587-590 576, 587, 648
selenium, 332, 380, 430, 435, 442, 653-655 sonography, 59, 123, 213, 455, 641
Sengstaken-Blakemore tube, 32 sorbitol, 167, 408, 438, 473, 482, 558, 575
soy, 24, 49, 298, 387-388, 425, 437, 579, 626, sulindac, 202
642, 651-652, 662, 669-670 sunflower oil, 313, 388
spergillus, 47 sushi, 47
spherocytosis, 210, 639-640 swallowing, 2, 7-8, 13-14, 145, 460, 544,
sphincter, 1-2, 6-7, 11, 13-15, 19, 35 625-626
sphincterotomy/plasty, 196, 213, 361, 367, 637 sweat test, 166, 169, 255, 358, 371, 373, 375
SPINK mutation, 358, 363-364, 367 Swenson proceedure, 162
SPINT mutation, 484 syndactyly, 372
spirochetes, 261 systemic lupus erythematosus, 14, 237, 344,
spironolactone, 238, 676 348, 368
splenomegaly, 25
splenorenal shunt, 245, 247 T
spondylitis, 177, 183, 345 tachycardia, 119, 121, 176, 426, 449, 493, 519,
sporozoites, 103 529
staphylococcus, 101, 103, 133, 139, 351, tachypnea, 100, 310, 666, 671
565-566, 647 tacrolimus, 116, 138-139, 180, 184, 192, 277,
starch, 128, 357, 372, 384, 405, 408-409, 411, 329, 351, 500-502, 635, 644, 659
413-415 taenia, 111, 148, 153-154
statin, 290 tagamet, 509
statistics/research, 607-615 tamponade, 32
steatocrit, 483 tapeworm, 111, 482
steatohepatitis, 231, 329, 335, 337, 349, tardive dyskinesia, 519
401-402, 442, 455, 664, 682 tarry stools, 31, 175
steatorrhea, 103, 133-134, 256, 290, 368, 372, taurine, 228, 289, 291, 387, 418
402, 417-419, 470-471, 517, 584-585, 642, 649, taurocholate, 227
651, 658, 660 tazobactam, 100, 214
steatosis, 231, 280, 307, 313-314, 325, 328-329, teaching principles, 617-619
335-336, 344, 350, 372, 375, 377, 442, 456 technetium, 75-76, 213, 217, 490, 625, 640
stellate cells, 225, 240, 243, 329, 339 TEF, 1, 15-16
stenosis, 8, 12-13, 15 tegaserod, 559
stenting, 220, 247, 285, 350, 361, 367, 533 telangiectasia, 31, 176
steroids, 24-25, 34 tenesmus, 102, 106, 112, 183, 191, 537, 539, 602
stillborn, 82, 332 teratomas, 561, 628
stomach, anatomy, 39 terbinafine, 339
stomach, anomalies, 41 testicular, 200, 553
stomach, trauma, 57 tetany, 134, 428, 522
stomatitis, 90, 94, 177, 179, 183, 426, 546, 634, tetracycline, 56, 95, 103, 142, 280, 329, 336,
677 509, 597, 663
stool softeners, 167, 173, 193, 195, 521, 538 tetralogy of Fallot, 322, 343
stool tests, 483-486 tetrazolium, 566
straining at stools, 71, 158, 172, 193, 537-538, thalassemia, 210, 398, 639
559, 636-637 thalidomide, 189
strangulation, 118-119, 172, 538 theophylline, 3
streptococcus, 133, 187-188, 196, 238, 525, thermophilus, 525, 628
554, 628, 647, 661 thiamine, 402, 410, 426, 547, 653, 656, 668, 677
striae, abdominal, 583 thioguanine, 328, 642
stricture, 12, 14, 23-25, 34, 36 thiolase, 305
stricturoplasty, 180, 489 thiopurine, 569
strongyloidiasis, 70, 94, 482 threonine, 432
stunting of growth, 389, 394, 397-398 thrombocytopenia, 31, 524
subsalicylate, 530, 627, 658, 663 thrombocytosis, 178, 184, 239, 241, 478
succinylacetone, 254, 256, 301-302, 646 thrombophlebitis, 189, 439-440
sucralfate, 20, 32 thrombosed hemorrhoids, 171-173
sucrase, 409, 413-414, 438, 575, 650, 652 thromboxane, 243
sucrose, 249, 298-299, 387-388, 408-409, thrush, 25
413-414, 421, 438, 473, 483, 575, 670 thymoglobulin, 499, 503
sulcralfate, 32 thymoma, 118
sulfamethoxazole, 130, 218, 280, 478 thymus, 13
sulfasalazine, 179, 184, 569, 603, 654, 656, 675 thyroiditis, 51, 89, 115
sulfonamides, 279 thyrotoxicosis, 583
Index 707
thyrotropin, 385, 672 TSH, 255-256, 477
thyroxine, 385, 672 ttg, 70, 90-92, 166, 577, 631
tinidazole, 273 tuberculosis, 27, 29, 108, 271, 343
TIPS, transjugular intrahepatic tufting enteropathy, 439, 453, 576-578, 663
portosystemic shunt, 220, 245, 247, 285, 340 Turcot syndrome, 144, 199, 201-202
TLESR (transient LES relaxation), 2, 19 tylenol, 229, 235, 257
TNF, 180, 184, 189, 277, 336, 505-507, 566 typhlitis, 100, 192, 599
tocopherol, 332, 446-447 typhoid, 113, 272, 451
tolmetin, 667 tyrosine, 161, 285, 301-303, 331, 388, 405,
tomatoes, 425, 550, 590 432-433, 567, 590
tomography, 42, 123-124, 280, 377, 489 tyrosinemia, 241, 249, 251, 254, 256, 301, 303,
tongue, 2, 11-12, 405, 493, 541, 543-544 349, 673, 685
tonsil, 13, 31, 352
toxoplasmosis, 255, 261, 279 U
TPN, 84, 115-116, 206, 210, 213, 336, 349, 408, UES, 1-2, 7, 9, 11
425, 428, 430, 432, 576-577, 604, 654-655, 685 UGI, 15-16, 19, 31-32, 34
trachea, 15-16 UGI bleeding , 31-32
tracheoesophageal fistula, 1, 12, 15, 17 ulcer, 19, 26, 31-32
tracheomalacia, 16 ulcerative colitis, 183-185
transaminitis, 90, 180, 442, 510, 568 ultrasonography, 43, 123, 229, 233, 253, 286,
transcarbamylase, 249, 309 350, 377, 455, 463-464, 554, 666, 671
transcriptase, 568 umbilicus, 61, 75, 81, 487, 555, 657, 671
transcription, 62, 179, 351, 353, 375, 499-500 urea, 50, 54-55, 133, 150, 249, 257, 308-309,
transferrin, 63, 98, 331-332, 390, 411, 429, 349, 421, 481, 643, 676
477-478, 677-678 urease, 55, 481, 526
transpeptidase, 283, 311, 675 uremia, 50, 118, 175, 187-188, 358, 363, 432,
transplantation, 131, 137-138, 140, 192, 206, 487, 529, 668
217-218, 240-242, 244-245, 247, 249, 251, 262, ureter, 125, 178, 202, 665
277, 284-287, 294, 300-303, 310, 312, 314, uric acid, 299, 307, 420, 672
321-323, 332, 339-340, 349-352, 368, 377, 438, uridine, 228, 298
457, 466, 504, 566, 576, 591, 595-596, ursodeoxycholic acid, 183, 211, 218, 253, 256,
644-645, 647-648, 659, 672, 676, 682-683 279, 312, 321, 323, 437, 523, 639-640, 642,
trehalose, 409, 415 664, 676
Treitz ligament, 31, 62, 77, 121, 175, 632 ursodiol, 218-219, 254, 376-377, 568
triamcinalone, 534 urticaria, 51, 54, 110, 510, 568, 579, 590
trichilemmomas, 146 uveitis, 107, 111, 177, 183, 189
trichobezoars, 57, 538
trichophagia, 538 V
trichuris, 112, 482 vaccination, 56, 266, 566, 676
trientine, 314 vaccine, 106-107, 109, 265-268, 674
trifluoromethylbenzol, 301 VACTERL, 16
triglycerides, 127, 129, 256, 299, 323, 335-336, vagotomy, 588, 652
347, 364, 387-388, 401, 407, 411, 417, 438, vagus, 1-2, 11, 15
445-446, 499, 502, 651 valproic acid, 48, 249, 307, 328, 363
trihydroxycholestanoic, 291 vancomycin, 191, 339, 575, 599
trimethoprim, 130, 218, 280, 478 varicella, 26
trimethylbromo, 490 varices, 2, 31
trinitrate, 195 vasculitis, 31
trophamine, 440-441 vasopressin, 32
Tropheryma whipplei, 68, 453 Vater sphincter, 201, 207, 353
trophozoites, 102, 110, 273, 451, 481 vegans, 427
tropical sprue, 93-95 vegetables, 105, 108, 175, 384, 399, 408, 424,
Trousseau sign, 670 428-429, 437, 446, 469, 485, 546, 558, 637, 651
trypsin, 109, 357, 367, 372, 406, 409, 411, 436, vegetarian, 387, 427, 653
469, 483, 649 venoocclusive disease, 233-234, 237, 286, 339
trypsinogen, 255, 357-358, 363, 367, 372-373, venulitis, 457
375, 406, 409, 412, 471, 571, 577, 583, 657, verapamil, 501
664, 667 vinblastine, 118
tryptase, 581 vincristine, 240, 599, 667, 670
tryptophan, 293, 388, 426, 431-433, 445 VIP, 64, 587, 589
VIPomas, 589
visceromegaly, 646
vitamins, 130, 133, 218, 249, 289-291, 312, 321,
323, 350, 380, 385, 394, 397-398, 411-412,
423-426, 436, 439, 441, 445-447, 517, 521,
526, 604, 648, 651, 655
vitamins and minerals, 423-430
vitiligo, 8
vivonex, 388
VLCAD, 305-306
VLCFA, 317
VOD, veno-occlusive disease, 339-340, 342,
347-348, 591-592
volvulus, 41-42, 58, 75, 77, 79, 82, 84, 117,
119-120, 127, 137, 162, 175-176, 376, 553-554,
571-572, 574, 583, 585, 605, 630, 678
W
walnuts, 590
warfarin, 425, 510
web, 12-13, 16
Wernicke encephalopathy, 426, 668, 677
wheat, 24, 49, 89-90, 92, 413-414, 438, 579, 626
wheezing, 16, 35
Whipple disease, 68, 453
whipworm, 112
Wilms tumor, 234, 239, 488, 601
Wilson disease, 82, 210, 231, 234, 249, 251,
257-259, 275, 313-315, 336, 349, 455-456, 476,
479, 640, 668, 672, 685
wireless capsule endoscopy, 72, 158, 459
Wirsung duct, 353
Wiskott-Aldrich syndrome, 116, 567, 667
Wolman syndrome, 234, 488, 671
worms, 110-112, 429, 482
X
xanthomas, 290, 299, 319, 321
xerophthalmia, 423, 446, 673
xerostomia, 345, 593
Y
yeast, 191, 280, 351, 409, 414, 438, 525
yersinia, 100, 102, 106, 113, 178, 184, 192, 451,
481, 485, 566, 628, 630, 633
yogurt, 428, 437, 510
Z
zantac, 509
Zellweger syndrome, 317-318, 644
zidovidine, 597
zinc, 49, 58, 68, 130, 178, 227, 314, 380,
384-385, 394, 398, 419, 430, 437, 442, 445,
447, 476, 651, 653, 655, 672
Zollinger-Ellison syndrome, 51, 408, 463,
510, 529, 532, 587, 661
zoster, 26
zygomycosis, 113
zymogen, 39, 354, 357
Index 709

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The NASPGHAN Fellows Concise Review of

Christine Waasdorp Hurtado, MD, MSCS, FAAP

NASPGHAN and Castle Connolly Graduate Medical Publishing, Ltd.

The NASPGHAN Fellows Concise Handbook of Pediatric Gastroenterology is a product of discus-

Christine Waasdorp Hurtado, MD, MSCS, FAAP

Very best wishes,

Kathleen B. Schwarz, M.D.

Mazen I. Abbas, DO, MPH Sonal S. Desai, MD

1. Mouth and Esophagus

I. Developmental Stages of the Esophagus

Section 1 - Mouth and Esophagus 1

Section 1 - Mouth and Esophagus 3

II. Squamous epithelium of the esophagus

III. Histology of the gastroesophageal junction (GEJ)

IV. Lamina Propria of the esophagus

Section 1 - Mouth and Esophagus 5

VI. Submucosa of the esophagus

VII. Muscularis Propria of the esophagus

VIII. Adventitia of the esophagus

I. Physiology of Esophageal Motility

II. Esophageal Manometric Evaluation

Section 1 - Mouth and Esophagus 7

IV. Diffuse Esophageal Spasm

VII. Neurologic disorders producing esophageal dysmotility

Di Lorenzo C, Hillemeier C, Hyman P, Loening-Baucke V, Nurko S, Rosenberg A, Taminiau J. Manometry stud-

Section 1 - Mouth and Esophagus 9

I. Three phases of deglutition

II. Changes in components of oral and pharyngeal cavities during development

III. Neurology of deglutition

Section 1 - Mouth and Esophagus 11

VI. Historical features in evaluation of dysphagia

VII. Physical examination

Section 1 - Mouth and Esophagus 13

II. Testing for Dysphagia

Kahrilas P, Smout A. Esophageal disorders. Am J Gastroenterol. 2010;105:747-756.

II. Esophageal Stenosis

III. Esophageal Atresia/Tracheoesophageal Fistula (TEF)

Section 1 - Mouth and Esophagus 15

IV. Esophageal Web

Section 1 - Mouth and Esophagus 17

II. Natural History

III. Differential Diagnosis

IV. Clinical Diagnosis

Section 1 - Mouth and Esophagus 19

Section 1 - Mouth and Esophagus 21

IV. Clinical Symptoms

VI. Histologic Findings Consistent with EoE

Section 1 - Mouth and Esophagus 23

II. Other, much less common causes of fungal esophagitis

Section 1 - Mouth and Esophagus 25

C. Endoscopic and histological findings

B. Endoscopic and histological findings

C. Treatment: ganciclovir or foscarnet

III. Less common viral infections

I. Peptic esophagitis, eosinophilic esohagitis, pill esophagitis, foreign body

Section 1 - Mouth and Esophagus 27

II. Tips for Best Biopsy Yield

III. Grading of Esophagitis

Section 1 - Mouth and Esophagus 29

Genevay M, Rubbia-Brandt L, Rougemont A-L. Do eosinophil numbers differentiate eosinophilic esophagitis

Section 1 - Mouth and Esophagus 31

Section 1 - Mouth and Esophagus 33

I. Impacted foreign bodies

II. Signs and symptoms of impacted foreign body