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: [email protected]

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 [email protected]

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 discussions 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 interprets 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 additional 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 question. 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 questions 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 Committee, 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! Christine Waasdorp Hurtado, MD, MSCS, FAAP 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 pediatric 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 gastroenterology 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 gastroenterologist, 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 ambitious 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 Imad Absah, MD Maisam Abu-El-Haija, MD Arun Aggarwal, MD Sabina Ali, MD Razan Alkhouri, MBBS Naim Alkouri, MD Ammar Al-Rikabi, MD Dina Al-Zubeidi, MD Julia L. Anderson, MD Shruti Arya, MD Katherine Atienza, DO Ruba Azzam, MD Susan S. Baker, MD, PhD Jane Balint, MD Barbara Bambach, MD Julie Bass, MD Vince F. Biank, MD Anas Bitar, MD Samra S. Blanchard, MD Ellen Blank Brendan Boyle, MD Julia Bracken, MD Gia Bradley, MD Herbert Brill, MD David Brumbaugh, MD Luis Caicedo, MD Carolina S. Cerezo, MD Jorge Chavez-Saenz, MD Anupama Chawla, MD Edaire Cheng, MD Lay Har Cheng, MD, MSPH Rebecca Cherry, MD Ashish Chogle, MD, MPH Lillian Choi, MD Jose Cocjin, MD Conrad Cole, MD, MPH, MSc Steven Colson, MD Emily Contreras, MD Carmen Cuffari, MD James Daniel MD Adam Davis MD Amy R. DeFelice, MD Karen DeMuth, MD Jolanda Denham, MD Nirav K. Desai, MD

Sonal S. Desai, MD Edwin deZoeten, MD, PhD Molly Dienhart, MD Frank DiPaola, MD Jennifer L. Dotson, MD Chelly, Dykes, MD Dawn Ebach, MD Mounif El-Youssef, MD Karan McBride Emerick, MD Steve Erdman, MD Rima Fawaz, MD Lina M. Felipez, MD Minela Fernandez, MD Laurie Fishman, MD Thomas Flass, MD, MS Deb Freese, MD Juliana Frem, MD Joel Friedlander, DO, MBE Craig Friesen, MD Yonathan Fuchs, MD Katryn Furuya Megan E. Gabel, MD Kriston Ganguli, MD Jennifer Garcia, MD Cheryl Gariepy, MD Lynette Gillis, MD Vi Lier Goh, MD Roberto Gomez, MD Mariana Gomez-Nájera, MD Alka Goyal, MD Alex Green, DO Leana Guerin, MD Nitika Arora Gupta, MD Michael S. Halata, MD Alfredo Larrosa Haro, MD, PhD Jeri E.F. Harwood, PhD Solange Heller, MD Lina Maria Hernandez, MD James Heubi, MD Meredith Hitch, MD Edward Hoffenberg, MD Anna Hunter, MD Christine Waasdorp Hurtado, MD, MSCS, FAAP Paul E. Hyman, MD David Israel Daniel Kamin

Jess L. Kaplan, MD Aubrey J. Katz, MD Ajay Kaul, MD Melissa Kennedy, MD Julie Khlevner, MD Crystal Knight Debora Kogan-Liberman, MD Robert Kramer, MD Ben Kuhn, MD Joel E. Lavine, MD, PhD Daniel H. Leung, MD Henry C. Lin, MD Simon Ling, MD Cheryl A. Little, MD Mark E. Lowe, MD Brandy Lu, MD Ying Lu, MD Sarah Shrager Lusman, MD Cara Mack, MD Nisha Mangalat, MD Maria Mascarenhas, MD Elizabeth M. McDonough, MD Maireade McSweeney, MD, MPH Khyati Mehta, MD Jeremy Middleton, MD Elizabeth Mileti, DO Steve Min, MD Aminu Mohammed, MD Javier J. Monagas, MD Christopher J. Moran, MD Brigitte Moreau, MD Véronique Morinville, MD Michael Narkewicz, MD Catherine Newland, MD Samuel Nurko, MD, MPH Stephanie Page, MD Pablo J. Palomo, MD Raza A. Patel, MD, MPH Tiffany Patton, MD Adam Paul, DO Maria E. Perez, DO David Piccoli, MD John Pohl, MD Carol Potter, MD Jaya Punati, MD Phil Putnam, MD Ruben E. Quiros-Tejeira, MD Riad Rahhal, MD Ramya Ramraj, MD Meenakshi Rao, MD, PhD Sara Rippel, MD Yolanda Rivas, MD Leonel Rodriguez, MD, MS Norberto Rodriguez-Baez, MD

Isabel Rojas, MD Rachel Rosen, MD Philip Rosenthal, MD Thomas Rossi, MD Robert Rothbaum, MD Gary Russell, MD Sabina Sabharwal, MD Rina Sanghavi, MD William San Pablo, MD Miguel Saps, MD Ahmed Sarkhy, MD, FRCPC Meghana Sathe, MD Cary Sauer, MD Ann Scheimann, MD, MBA Kathleen B. Schwarz, MD Steven M. Schwarz, MD Jeffrey B. Schwimmer, MD Timothy Sentongo, MD Thomas J. Sferra, MD Ala K. Shaikhkhalil, MD Darla R. Shores, MD Michelle Sicard, MD Lesley Smith, MD Aliza Solomon, MD Inbar Spofford, MD Arvind Srinath, MD Janis Stoll, MD Carolyn Sullivan, MD Jillian S. Sullivan, MD Shikha S. Sundaram, MD, MSCI Pornthep Tanpowpong, MD, MPH Sharon Taylor, MD Kelly Fair Thomsen, MD Justine M. Turner, MD Aliye Uc, MD Paul Ufberg, MD Charles Vanderpool, MD Alexandra B. Vasilescu, DO, MS Preeti Viswanathan, MD Ghassan Wahbeh, MD Mei-Lun Wang, MD Sheree Watson, MD Jessica Wen, MD Lisa Wheelock, MD Asha Willis, MD Harland S. Winter, MD Desale Yacob, MD Lillienne Yoon, MD Elizabeth L. Yu, MD Shamila B. Zawahir, MD Garrett C. Zella, MD Zili Zhang, MD, PhD Monica M. Zherebtsov, 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 observed 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 upper 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 information 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

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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 circular 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 difficult d. Significant overlap between different pain receptors (chemical, mechanical, temperature), making types of sensation difficult to separate 5. Visceral hyperalgesia a. Prolonged acid exposure in the esophagus causes altered sensory perception and sensitization 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 vagalmediated relaxation of LES

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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: Pathophysiology, Diagnosis, Management. 5th ed. Lewiston, NY: BC Decker; 2008. Sengupta JN. Esosphageal sensory physiology. GI Motility Online. 2006. doi: 10.1038/gimo16.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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 inflammatory 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

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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 (exterior) 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 thickened smooth muscle fibers that extend approximately 2 cm above and 3 cm below the diaphragmatic 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

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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 procedures. Neurogastroenterol Mot. 2002 (14): 411-420. Section 1 - Mouth and Esophagus

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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 procedures. 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 during swallow, and elevated resting LES pressure I. Treatment 1. Balloon dilation of LES—Good results in 60%. Complications include perforation, fever, pleural 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 8

The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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 consensus 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, Sanderson IR, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, and Management. 4th ed. Hamilton, Ontario: BC Decker; 2004:55-69. Di Lorenzo C, Hillemeier C, Hyman P, Loening-Baucke V, Nurko S, Rosenberg A, Taminiau J. Manometry studies 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.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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, volume, 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 pharyngeal 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

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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 malformation, 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, Diagnosis, and Management. 5th ed. Hamilton, Ontario: BC Decker; 2008.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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, gagging, 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. Odynophagia—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 swallowing 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, myelomeningocele, Chiari malformation, dysautonomia b. Neuromuscular disorders: myotonic dystrophy, myasthenia gravis, Guillain-Barré syndrome, poliomyelitis, spinal muscular atrophy C. Esophageal phase 1. Stricture—caustic ingestion, peptic esophagitis, eosinophilic esophagitis, epidermolysis bullosa, 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 Section 1 - Mouth and Esophagus

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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 compresses 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 obstruction 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.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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. Esophageal 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 atresia 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 Section 1 - Mouth and Esophagus

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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%), gastrointestinal (25%), and musculoskeletal (20%), as well as VACTERL association (10%) c. Right-sided aortic arch occurs in 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 suspected 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 impaction 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 Section 1 - Mouth and Esophagus

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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) 2. One study demonstrated symptomatic and histological improvement in 74% of patients D. Elemental Diet 3. One study demonstrated symptomatic and histological improvement in 98% of patients 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 Research 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.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

1H-2. Infectious Esophagitis Kelly Fair Thomsen, MD

Esophageal infections are rare in children. Herpes simplex virus is the most common in an immunocompetent 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 illness, 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

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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 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, suggesting a perforation 2. Upper GI contrast study can detect ulceration, radiolucent foreign bodies, and duplication cysts Section 1 - Mouth and Esophagus

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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 coiling/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 hemodynamically 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, facilitating 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 controlled, 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.

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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 accidental 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 seconds 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

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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 III-A

Circumferential ulceration, areas of 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 gastrostomy and pulled retrograde up the esophagus 4. Retrograde traction dilation has lower risk of perforation than antegrade dilation with balloon 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 caustic 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/contents/caustic-esophageal-injury-in-children.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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, dysphagia D. Oropharyngeal/proximal esophageal perforation: neck swelling and/or erythema, tenderness, crepitus 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 radiopaque 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 objects 5. If radiographic assessment shows no foreign body, persistent symptoms related to the esophagus require endoscopic evaluation

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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 secretions 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 impaction in the esophagus is unknown D. Blunt objects such as coins located beyond the esophagus can be observed for spontaneous passage. 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 visualized 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 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 unless there are significant gastrointestinal signs or symptoms—severe pain, bleeding, obstruction 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 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 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

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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.

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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 lymphocyte 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 Section 2 - Stomach

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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 infection f. Prevention of NSAID gastropathy by concomitant use of PPI or misoprostol (cytoprotectant) 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/vomiting 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

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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 24hour 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

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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 infiltrate 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

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The NASPGHAN Fellows Concise Review of Pediatric Gastroenterology, Hepatology and Nutrition

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 mucosal 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

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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.

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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 organisms 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 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 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 characterized 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 contractions. 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 administered 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 (hypercontractility) 4. Lack of fed response (Figure 3) B. Myopathic disorders are characterized by low amplitude contractions of 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, gastric surgery, chronic intestinal pseudo-obstruction, idiopathic dysmotility, IBS, etc. Section 3 - Small Bowel

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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 available 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 manometry. A normal Phase III front originating in the antrum and migrating aborally along the duodenum into the jejunum can be observed. 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 irregular contractions (Phase II).

Figure 3. Antroduodenal manometry in a patient with neuropathy. The tracing shows abnormalities in Phase III of the MMC. Some uncoordinated clusters, as well as isolated irregular phasic contractions, can be observed. Throughout the study, there was no organized activity, and irregular phasic contractions were seen. No Phase III could be observed, even after provocative medications.

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Figure 2. Normal postprandial pattern in a small bowel manometry. There are irregular persistent phasic contractions in the antrum and small bowel

Figure 4. Antroduodenal manometry in a patient with visceral myopathy. The tracing shows a normal Phase III of the interdigestive motor complex, although the amplitude is much lower than normal (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 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) A. Mode of transmission: 1. Vertical, parenteral, or sexual 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 B. Incubation period: 30–150 days

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C. Clinical features: 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) A. Mode of transmission: 1. Vertical, parenteral, or sexual 2. Carrier state and chronic infection exist 3. HDV cannot replicate without a coexisting infection with hepatitis B B. Incubation period: 20–90 days 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) A. Mode of transmission: 1. Fecal-oral (foodborne, waterborne). Reports of contaminated blood products 2. There is no carrier state or chronic infection B. Incubation period: 15–40 days C. Clinical features: 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

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Table 1. The Hepatitis Viruses: Characteristics and Terminology of Associated Antigens and Antibodies Marker

Definition

Significance of Marker

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

HBsAg

Hepatitis B surface antigen; found on surface of intact virus and in serum as free particles

Active HBV infection

HBcAg

Hepatitis B core antigen; found within virus core

Detectable in liver tissue

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

Anti-HCV

Antibody (IgG) to HCV

Exposure to HCV; Not protective

HCV RNA

RNA of HCV (PCR test)

Active HCV infection

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

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

Serologic Markers of HAV

Serologic Markers of HBV

Serologic Markers of HCV

Serologic Markers of HDV

Serologic Markers of HEV

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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 combination 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.

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6K-3. Infectious and Inflammatory Diseases— 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

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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 contaminated 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

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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 Section 6 - Liver

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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 Gastrointestinal 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.

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6K-4. Infectious and Inflammatory Diseases— 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 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 progress. 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.

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6K-5. Infectious and Inflammatory Diseases— 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 multinucleated 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 tuberculosis and infections associated with acquired immunodeficiency syndrome (AIDS). Schistosomiasis, 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 granulomas, particularly sulfonamides and isoniazid

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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 transaminases, 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 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 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

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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 aminotransferase. Hyperkeratosis of palms and soles, corneal thickening, developmental delay with normal hepatic and renal functions Recommended Reading Hansen K, Horslen S. Metabolic liver disease in children. Liver Transplantation. 2008;14:391-411. 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. Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2006: Chapter 61.

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6N-5. Metabolic/Genetic 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 traverse the mitochondrial membrane without conversion to acylcarnitines

ACS = acyl-CoA synthtase; CACT = carnitine acylcarnitine translocase; CoA = coenzyme A; CoASH = unacylated 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. Section 6 - Liver

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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

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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

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Table1. Differential Diagnosis Ammonia

Metabolic Acidosis

Anion Gap {Na- (Cl- Bicarb)}

Ketones

Urea Cycle Disorders

High

No

N/A

N/A

FAO Disorders

High

Yes

Elevated

Too Low

Organic Acidemias

High

Yes

Elevated

Too High

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. Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2006: Chapter 60.

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6N-6. Metabolic/Genetic 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, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, & Management. 4th ed. Hamilton, Ontario: BC Decker Inc; 2004: Chapter 55, section 2, pages 1257-1274. 2004; Chapter 55, section 2, page 1282. Section 6 - Liver

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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 (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 considered 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

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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.

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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

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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, microcephaly, 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. Adrenoleukodystrophy. 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 disorders: the main facts.

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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 diagnosis based on the presence of hepatocellular cholestasis, low serum levels of gammaglutamyl 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 profiles. The specific genes involved in all subtypes of PFIC code for various bile canalicular transporters 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 BRIC-1

normal

ATP8B1 FIC1

18q21-22

ATP-dependent amino-phospholipid transport

PFIC-2 BRIC-2

normal

ABCB11 BSEP

2q24

ATP-dependent bile-acid transporter

PFIC-3

high

ABCB4 MDR3

7q21

ATP-dependent translocation of 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 (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

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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

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C. Management/Treatment 1. Adequate nutrition is crucial: a high-calorie diet with a high proportion of fat from medium-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 hereditary 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 progressive 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 progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 1994;18(2):134-141.

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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 encephalopathy. The incidence is decreasing. A. Epidemiology/Pathogenesis 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 B. Clinical Features 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 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 (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

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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 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 V. Treatment/Management 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 336

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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.

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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

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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 containing T cells. However, it can occur with transfer of any tissue containing T cells (blood products, 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

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Table 1. Acute GVHD Grading Criteria Stage

Skin

Liver (Bilirubin)

GI Tract (Stool Output/d)

0

No GVHD rash

30 mL/kg/d

4

Generalized erythroderma with bullous formation

>15 mg/dL

Severe abdominal pain with or 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% Section 6 - Liver

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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 Allergy 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.

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6P. Systemic Diseases Affecting the Liver Sheree Watson, MD Christine Waasdorp Hurtado, MD, MSCS, FAAP 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 engorgement, 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

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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 maintain 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 manifestations 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, cardiovascular, 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 findings. Biopsy may provide useful prognostic information, e.g., extensive necrosis or fibrosis portends poor prognosis 344

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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 B.  Juvenille Rheumatoid Arthritis (JRA) JRA is an autoimmune disorder characterized by particular 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 associated 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 D.  Ankylosing Spondylitis (AS) Ankylosing spondylitis is an inflammatory arthropathy of the 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

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IV. Granulomatous Diseases A. The liver is a common associated site for various granulomatous diseases. Granulomas are a discrete 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, original 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)

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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 phagocytose 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 100 days s/p HSCT. 2. Liver abnormality: small bile duct damage (see section on GVHD vs VOD)

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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 sequestration 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, clinical 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 Gastroenterol. 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;15:153164. Youssef WI, Tavill AS. Connective Tissue Diseases and the Liver . J Clin Gastroenterol. 2002;35(4):345-349.

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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

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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 incorporates 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

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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 symptoms 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

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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;32:913929. Spada M, Riva S, Maggiore G, Cintorino D, Gridelli B. Pediatric liver transplantation. World J Gastroenterol. 2009;15:648-674.

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7A. Normal Anatomy, Development, and Physiology 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 epithelium 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 digestive 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

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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

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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 Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th ed. Philadelphia, PA: Saunders Elsevier; 2010:909-930. Kleinman RE, Goulet O-J, Mieli-Vergani G, Sanderson I, Sherman P, Shneider B. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker, Inc.;2008:1185-1201. Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2006:1005-1021.

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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 pancreas). B. Hedgehog proteins (signaling molecules) regulate pancreatic morphogenesis by promoting cellular 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, zymogens 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 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

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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. Wyllie R, Hyams JS. Pediatric Gastrointestinal and Liver Disease. 3rd edition. Philadelphia, PA: Saunders 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.

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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

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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 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