Aga Spring 2015 PDF

2 0 1 5 A G A S p r i n g P o s t g r a d u at e C o u r s e r e s o u r c e s
Evidence That Will Change Your Practice:
2 0 1 5 A G A S p r i n g P o s t g r a d u at e C o u r s e
New Advances for Common Clinical Problems
ONLINE SESSIONS
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advancements. Maximize your experience
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Combo
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the online session/DVD combo.
Combined purchase will save you $20.
DVD*
Watch the presentations when your

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Will ship fall 2015.
SYLLABUS*
Review comprehensive details of all sessions

with either the eSyllabus or book format.
Will ship June 2015.
* Does not offer CME.
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2200-080EDU_15-1
SYLLABUS 2015 AGA Spring Postgraduate Course
One Course, Four Options
Evidence That Will

Change Your Practice:
New Advances for Common
Clinical Problems
May 16 & 17, 2015

Walter E. Washington Convention Center
Washington, DC
Held in conjunction with DDW
Course Director
Douglas Corley, MD, PhD, MPH
Co-directors
Jacqueline OLeary, MD, MPH, AGAF
Christopher Thompson, MD, MSc, FACG, FASGE
Todays Case:
Improve Patient
Outcomes
AGA SpriSpringng Postgraduate

PostgraduateCourse
Course
Putting
First:
Actionable
Evidence for Clinical Practice
EvidencePatients
That Will
Change
Your Practice:
New Advances for Common Clinical Problems
May 18-19, 2013
Orange County Convention Center

May 16 &
Orlando,
FL 17, 2015
Walter E. Washington Convention Center

WASHINGTON, DC
Course Director: Brennan Spiegel, MD, MSHS, AGAF, FACG

Co-Directors:
Neena
Abraham,
MD,PhD,
MSCE,
AGAF, FASGE and Corey Siegel, MD, MS
Course Director:
Douglas
Corley, MD,
MPH
Co-Directors: Jacqueline OLeary, MD, MPH, AGAF and Christopher Thompson, MD, MSc, FACG, FASGE
AGA Spring Postgraduate Course, May 16-17, 2015
Preface
Welcome to the 2015 AGA Spring Postgraduate Course Evidence That Will Change Your Practice: New Advances for Common
Clinical Problems. This years course will address whats on the horizon for the diagnosis and treatment of digestive diseases
and how you can incorporate the latest advances into your practice. In addition, you will obtain practical information on how
to handle difficult clinical problems. This course will focus on six major topics: functional bowel disorders, inflammatory bowel
disease, esophageal and upper GI updates, pancreatic and biliary issues, hepatology, and colon concerns.
The course syllabus provides comprehensive details of each lecture. Each section contains the presenters slide materials and
detailed text, expanding on the topic. A DVD and access to an online version of the course will also be available for purchase
as a review after the course. Thank you for choosing to attend the AGA Spring Postgraduate Course. We appreciate the opportunity to share and discuss this information with you.

Jacqueline G. OLeary, MD, MPH, AGAF
Accreditation and Designation

The AGA Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AGA Institute designates this live activity for a maximum of 12 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In accordance with the ACCMEs Standards for Commercial Support of Continuing Medical Education, all faculty and planning partners must disclose
any financial relationship(s) or other relationship(s) held within the past 12 months. The AGA Institute implements a mechanism to identify and resolve
all conflicts of interest prior to delivering the educational activity to learners.
Statements, opinions, and results of studies presented at the AGA Spring Postgraduate Course are solely those of the presenters and do not reflect the
policy or position of AGA Institute. The material in this syllabus was presented at the AGA Institute Spring Postgraduate Course, May 16-17, 2015. This
publication was prepared from materials submitted by the course faculty.
AGA Institute does not provide any warranty as to the accuracy or reliability of information presented either verbally or in writing by presenters. No
responsibility is assumed by AGA Institute for any injury and/or damage to persons or property resulting from any use of such information.
Copyright 2015 by the AGA Institute. All rights reserved.
Table of Contents
Preface and CME Statement
Course Program
Course Faculty
Financial Disclosures
Walter E. Washington Convention Center Floor Plan
Claiming CME and MOC Credit for the 2015 AGA Spring Postgraduate Course
Presentation Summaries Saturday, May 16, 2015

Session I All Diseases Begin in the Gut
The Problem of Abdominal Pain: How to Work Up, Evidence on Effective Treatments
Lin Chang, MD, AGAF
NASH and Obesity: Whats Needed for Diagnosis, Role of the Microbiome and How to Treat?
Anna Mae Diehl, MD
Fecal Microbiota Transplantation: When Does it Work (C.diff and Beyond)? How to Do it? What Are the Restrictions?
Lawrence J. Brandt, MD, AGAF, MACG, FASGE
Bloating, Functional Bowel Disease and Food Sensitivity: Non-Celiac Gluten-Sensitivity, the Low-FODMAP Diet and Beyond?
Peter Gibson, MD
Session II Inflammatory Bowel Disease
Initiating Therapy for IBD: When to Start What, How to Adjust and Monitor?
Bruce Sands, MD, MS, AGAF
What is the Endpoint: Can You Stop Treatment, When to Switch Agents and to What?
David Rubin, MD, AGAF
When All Else Fails: Alternative Agents, Clinical Trials and Upcoming Treatments?
William Sandborn, MD, AGAF
Blood, Bones, Eyes and Nutrients: How to Monitor for and Prevent Complications of IBD?
Maria Abreu, MD, AGAF
Session III Esophagus / Upper GI

Cough, Wheeze, Sore Throat and More; What is Related to GERD and How to Approach?
Nicholas J. Shaheen, MD, MPH
Dealing with Dysphagia: How to Test, How to Treat?
John Erik Pandolfino, MD, AGAF
Eosinophilic Esophagitis: Distinguishing from Other Disorders? Best Short and Long-Term Management Strategies (Diet,
Steroids and Beyond)?
Rhonda Souza, MD, AGAF, FASGE
Barretts Esophagus Conundrums: How to Manage Low Grade Dysplasia? Ablation When and With What Follow-Up?
Amitabh Chak, MD
Functional Heartburn: What Works When PPIs Dont?
Ronnie Fass, MD, AGAF, FASGE
Session IV Pancreatic-biliary
The Cystic Pancreas: What Tests to Order? How to Follow Long-Term?
Linda S. Lee, MD, AGAF
The Possibly Malignant Biliary Stricture: Deciding if Benign? Treatment if Benign? If Malignant?
Grace Elta, MD, AGAF, FASGE
Prickly Problems in Acute Pancreatitis: How Can it be Prevented? How to Treat Necrosis and Complications (Endoscopy,
Antibiotics and Beyond)?
Bechien Wu, MD, MPH
Challenges in Chronic Pancreatitis: Diagnosis, Monitoring and Treatment (Short-Term and Long-Term)
Darwin L. Conwell, MD, MS
Presentation Summaries Sunday, May 17, 2015

Session V Hepatology
The Wild New World of Hepatitis C Treatment: How to Choose the Right Drug Cocktail?
Norah Terrault, MD
New Developments in Hepatitis B: Treat All or Only Some? When to Switch or Add Medications? When Can You Stop
Treatment?
Anna S.F. Lok, MD, AGAF
Non-Invasive Markers of Liver Fibrosis: Can They Replace Biopsy? Which to Use and When?
Sumeet Asrani, MD, MSc
Evidence That Will Change Your Practice
The Failing Liver in an Outpatient: When to Refer Whom, Changes to MELD, Pre-Transplant Management
Lorna Dove, MD, MPH
Infections in Cirrhosis: Prevalence, Prognostication, and Proactive Management
Jasmohan S. Bajaj, MD, MS, FACG, AGAF
Session VI Colon
The Family History Conundrum: What to Test, When to Bring Back and When to Refer?
Sapna Syngal, MD
Evolving Truths About Diverticulitis: Roles of Fiber, 5-ASA Agents, Rifaximin, NSAIDs and Diet?
Neil Stollman, MD, AGAF, FACP, FACG
Mastering the Difficult Colonoscopy and Polypectomy: What Are the Best Evidence-Based Methods? Should I Try
Something New?
Douglas K. Rex, MD, AGAF, FASGE
Constipation and Colon Motility: How to Diagnose? How to Manage?
Charlene M. Prather, MD, MPH, AGAF, FACP
GI Quality Indicators: What Should I Do in My Practice? What are the Requirements?
Brennan Spiegel, MD, MSHS, AGAF
Practical GI Practice: Top Take Home Points from the Meeting to Bring to Your Practice
Luncheon Breakout Sessions

Anti-Thrombotic Therapy: Management Peri-Procedure and in the Bleeding Patient.
Neena S. Abraham, MD, MSc, AGAF
Autoimmune Hepatitis: Monitoring and New Treatments.
Edward Krawitt, MD
Bariatric Surgery: Managing Before and After the Operation
Edward H. Livingston, MD, AGAF, FACS
Celiac and Non-Celiac Gluten Sensitivity: Diagnosis, Management and Monitoring
Ciaran Kelly, MD, AGAF
Digital Health for the Gastroenterologist: What You Need to Know about Apps, Wearable Sensors, and EHRs
Brennan Spiegel, MD, MSHS, AGAF
Evaluating Obscure Bleeding: Capsule, Enteroscopy and Beyond
Lauren B. Gerson, MD, MSc, AGAF
Gastroparesis, Nausea and Vomiting.

Michael Camilleri, MD, AGAF
Genetic Liver Diseases: Hemochromatosis and Wilsons Disease.
Bruce R. Bacon, MD, AGAF
HCV New Treatments: Sorting Out Current Options and Those Coming Soon.
Kris Kowdley, MD, AGAF, FASGE
Helicobacter Pylori in the Modern Age: How to Find, How to Treat
William D. Chey, MD, AGAF
New Therapies in Liver Disease: FXR Agonists, Antifibrotics and More.
Scott Friedman, MD, AGAF
Optimizing Colonoscopy: Getting the Prep, Sedation and Post-Procedure Follow-Up?
Ph, Manometry and Impedance Monitoring: When to Use Which?
Pregnancy and IBD: How to Manage, Meds to Use/Avoid?
Sunanda Kane, MD, MSPH, AGAF
The Lumpy Liver: Sorting Out the Lumps, Nodules, and Masses
Clinical Challenge Sessions

Alternative Therapies in Inflammatory Bowel Disease.
Josh Korzenik, MD and William Sandborn, MD, AGAF
Barretts Dysplasia: What to Do, When and How?
Jacques Bergman, MD, PhD and Nicholas Shaheen, MD, MPH
Case Studies in Microscopic Esophagitis: Reflux or Eosinophilic? How to Discern, How to Treat?
Edaire Cheng, MD and Fouad J. Moawad, MD, FACP, FACG
Challenges in Endoscopic Ultrasound: Intriguing Images and Techniques.
Kenneth J. Chang, MD, FACG, FASGE and Craig Munroe, MD
Collagenous and Lymphocytic Colitis: What to Use and When?
Derek R. Patel, MD and Sunanda Kane, MD, MSPH, AGAF
Constipation and Diarrhea: Case Studies on Approaches and What to Do When it Doesnt Work.
Anthony Lembo, MD and Charlene M. Prather, MD, MPH, AGAF, FACP
Endoscopic Management of Obesity.

Christopher Thompson, MD, MSc, FACG, FASGE and Shelby Sullivan, MD
Hepatocellular Carcinoma: Case Challenges and Treatment Approaches
Anna S.F. Lok, MD, AGAF and Sandy Feng, MD, PhD
HCV Treatment: Optimizing Outcomes with Direct Acting Antivirals
Josh Levitsky, MD, MS and Elizabeth Verna, MD, MS
Managing the Complicated IBS Patient
Lin Chang, MD, AGAF and Peter Gibson, MD
Monitoring and Biomarkers in IBD: Do They Change Management?
Brian G. Feagan, MD, FRCPC and Uma Mahadevan, MD, AGAF
Optimizing Outpatients with Cirrhosis: Encephalopathy, Ascites and Preventing Bleeding and Infection
Florence Wong, MBBS, MD, FRACP, FRCPC and K. Rajender Reddy, MD
Quality and Colonoscopy: How to Improve Adenoma Detection Rates.
Michael B. Wallace, MD, MPH, AGAF and Stacy B. Menees, MD, MS
The Big Bile Duct Stone: What to Do?
Grace Elta, MD, AGAF, FASGE and Michael Levy, MD
The Post-Op IBD Patient: Preventing Pouchitis and Recurrence
David T. Rubin, MD, AGAF and Maria Abreu, MD, AGAF
Course Program
Saturday, May 16
Session I All Diseases Begin in the Gut
Moderator: Naga Chalasani, MD
Time
8:158:20 a.m.
8:208:25 a.m.
8:25-8:43 a.m.
8:45-9:03 a.m.
9:05-9:23 a.m.
9:25-9:43 a.m.
Session Name
Presidents Welcome
Course Overview
The Problem of Abdominal Pain: How
to Work Up, Evidence on Effective
Treatments
NASH and Obesity: Whats Needed for
Diagnosis, Role of the Microbiome and
How to Treat?
Fecal Microbiota Transplantation:
When Does it Work (C.diff and Beyond)? How to Do It? What Are the
Restrictions?
Bloating, Functional Bowel Disease and
Food Sensitivity: Non-Celiac GlutenSensitivity, the Low-FODMAP Diet and
Beyond?
Speaker
John Allen, MD, MBA, AGAF
Room
Lin Chang, MD, AGAF
Anna Mae Diehl, MD

Hall D
Lawrence Brandt, MD, AGAF,
MACG, FASGE
Peter Gibson, MD
Refreshment Break
9:45-10:05 a.m.
Session II Inflammatory Bowel Disease
Moderator: Uma Mahadevan, MD
Time
10:05-10:23
a.m.
10:25-10:43
a.m.
10:45-11:03
a.m.
11:05-11:23
a.m.
Session Name
Initiating Therapy for IBD: When to
Start What, How to Adjust and Monitor?
What is the Endpoint: Can You Stop
Treatment, When to Switch Agents and
to What?
When All Else Fails: Alternative
Agents, Clinical Trials and Upcoming
Treatments?
Blood, Bones, Eyes and Nutrients: How
to Monitor for and Prevent Complications of IBD?
Speaker
Room

David Rubin, MD, AGAF, FACG,
FACP
Hall D
Maria Abreu, MD, AGAF
11:45 a.m.12:45 p.m.

L101
L102
L103
L104
L105
L106
L07
L108
L109
L110
L111
L112
L113
L114
L115
Luncheon Breakout Sessions

Anti-Thrombotic Therapy: Management Peri-Procedure and in the Bleeding Patient.
Autoimmune Hepatitis: Monitoring and
New Treatments.
Bariatric Surgery: Managing Before
and After the Operation.
Celiac and Non-Celiac Gluten Sensitivity: Diagnosis, Management and
Monitoring.
Digital Health for the Gastroenterologist: What You Need to Know About
Apps, Wearable Sensors, and EHRs.
Evaluating Obscure Bleeding: Capsule,
Enteroscopy and Beyond.
Gastroparesis, Nausea & Vomiting.
Genetic Liver Diseases: Hemochromatosis and Wilsons disease.
HCV New Treatments: Sorting Out Current Options and Those Coming Soon.
Helicobacter Pylori in the Modern Age:
How to Find, How to Treat.
New Therapies in Liver Disease: FXR
Agonists, Antifibrotics and More.
Optimizing Colonoscopy: Getting the
Prep, Sedation and Post-Procedure
Follow-Up?
Ph, Manometry and Impedance Monitoring: When to Use Which?
Pregnancy and IBD: How to Manage,
Meds to Use/Avoid?
The Lumpy Liver: Sorting Out the
lumps, Nodules, and Masses.
Neena Abraham, MD, MSc, AGAF,

FACG, FASGE
143ABC
Edward Krawitt, MD
140
Edward Livingston, MD, AGAF,

FACS
152
159
Brennan Spiegel, MD, MSHS
145B
Lauren Gerson, MD, MSc, AGAF
151A
146C
Bruce Bacon, MD, AGAF
150A
150B
146AB
Scott Friedman, MD, AGAF
151B
207A
207B
201
Jacqueline OLeary, MD, MPH,

AGAF
Ballroom A
Session III Esophagus / Upper GI

Moderator: Nicholas Shaheen, MD, MPH, AGAF
Time
12:45-1:03 p.m.
1:05-1:23 p.m.
1:25-1:43 p.m.
1:45-2:03 p.m.
2:05-2:23 p.m.
Session Name
Cough, Wheeze, Sore Throat and More;
What is Related to GERD and How to
Approach?
Dealing with Dysphagia: How to Test,
How to Treat?
Eosinophilic Esophagitis: Distinguishing from Other Disorders? Best Short
and Long-Term Management Strategies
(Diet, Steroids and Beyond)?
Barretts Esophagus Conundrums: How
to Manage Low Grade Dysplasia? Ablation When and With What Follow-Up?
Functional Heartburn: What Works
When PPIs Dont?
Speaker
Room
Nicholas J. Shaheen, MD, MPH,

AGAF
Hall D
Amitabh Chak, MD
Session IV Pancreatic-biliary
Moderator: Jacques Bergman, MD, PhD
Time
Session Name
Speaker
The Cystic Pancreas: What Tests to
2:25-2:43 p.m.
Order? How to Follow Long-Term?
The Possibly Malignant Biliary Stric2:45-3:03 p.m.
ture: Deciding if Benign? Treatment if Grace Elta, MD, AGAF, FASGE
Benign? If Malignant?
Prickly Problems in Acute Pancreatitis: How Can it Be Prevented? How
3:05-3:23 p.m.
Bechien Wu, MD, MPH
to Treat Necrosis and Complications
(Endoscopy, Antibiotics and Beyond)?
Challenges in Chronic Pancreatitis:
3:25-3:43 p.m.
Diagnosis, Monitoring and Treatment
(Short-Term and Long-Term)
3:45-4 p.m.
Refreshment Break
4-5:30 p.m.
Clinical Challenge Sessions
Alternative Therapies in Inflammatory Josh Korzenik, MD and William
C101
Bowel Disease.
Sandborn, MD, AGAF
Barretts Dysplasia: What to Do, When Jacques Bergman, MD, PhD and
C102
and How?
Nicholas Shaheen, MD, MPH
Room
Hall D
159
146C
C103
C104
C105
C106
C107
C108
C109
C110
C111
C112
C113
C114
C115
Case Studies in Microscopic

Esophagitis: Reflux or Eosinophilic?
How to Discern, How to Treat?
Challenges in Endoscopic Ultrasound:
Intriguing Images and Techniques.
Collagenous and Lymphocytic Colitis:
What to Use and When?
Constipation and Diarrhea: Case
Studies on Approaches and What to Do
When it Doesnt Work.
Edaire Cheng, MD and Fouad

Moawad, MD, FACP, FACG
Kenneth J. Chang, MD, FACG,
FASGE and Craig Munroe, MD
Derek R.Patel, MD and Sunanda
Kane, MD, MSPH, AGAF
151A
151B
140
Anthony Lembo, MD and Charlene

207A
M. Prather, MD, MPH, AGAF, FACP
Christopher Thompson, MD, MSc,

Endoscopic Management of Obesity.
FACG, FASGE and Shelby Sullivan,
MD
Hepatocellular Carcinoma: Case
Anna Lok, MD, AGAF and Sandy
Challenges and Treatment Approaches Feng, MD, PhD
HCV Treatment: Optimizing Outcomes
Josh Levitsky, MD, MS and
with Direct Acting Antivirals
Elizabeth Verna, MD, MS
Lin Chang, MD, AGAF and Peter
Managing the Complicated IBS Patient.
Gibson, MD
Monitoring and Biomarkers in IBD: Do Brian Feagan, MD, FRCPC and Uma
They Change Management?
Mahadevan, MD, AGAF
Optimizing Outpatients with Cirrhosis: Florence Wong, MBBS, MD,
Encephalopathy, Ascites and Preventing FRACP, FRCPC and K. Rajender
Bleeding and Infection
Reddy, MD
Quality and Colonoscopy: How to
Michael Wallace, MD, MPH, AGAF
Improve Adenoma Detection Rates.
and Stacy B Menees, MD, MS
Grace Elta, MD, AGAF, FASGE and
The Big Bile Duct Stone: What to Do?
Michael Levy, MD
The Post-Op IBD Patient: Preventing
David Rubin, MD, AGAF and Maria
Pouchitis and Recurrence
Abreu, MD, AGAF
145B
150B
201
207B
143ABC
146AB
150A
152
Ballroom A
Sunday, May 17
Session V Hepatology
Moderator: Lorna Dove, MD, MPH
Time
Session Name
Speaker
The Wild New World of Hepatitis C Treat8:30-8:48 a.m.
ment: How to Choose the Right Drug CockNorah Terrault, MD
tail?
New Developments in Hepatitis B: Treat All
8:50-9:08 a.m.
or Only Some? When to Switch or Add Medi- Anna Lok, MD, AGAF
cations? When Can You Stop Treatment?
Non-Invasive Markers of Liver Fibrosis: Can
9:10-9:28 a.m.
They Replace Biopsy? Which to Use and
When?
The Failing Liver in an Outpatient: When to
9:30-9:48 a.m.
Refer Whom, Changes to MELD, Pre-TransLorna Dove, MD, MPH
plant Management
Infections in Cirrhosis: Prevalence, Prognosti- Jasmohan Bajaj, MD, MS, FACG,
9:50-10:08 a.m.
cation, and Proactive Management
AGAF
10:10-10:30 a.m.
Refreshment Break
Room
Hall D
Session VI Colon
Moderator: Michael Wallace, MD, MPH, AGAF
Time
Session Name
The Family History Conundrum: What to
10:30-10:48 a.m.
Test, When to Bring Back and When to
Refer?
Evolving Truths About Diverticulitis: Roles
10:50-11:08 a.m.
of Fiber, 5-ASA Agents, Rifaximin, NSAIDs
and Diet?
Mastering the Difficult Colonoscopy and
Polypectomy: What Are the Best Evidence11:10-11:28 a.m.
Based Methods? Should I try Something
New?
Constipation and Colon Motility: How to
11:30-11:48 a.m.
Diagnose? How to Manage?
GI Quality Indicators: What Should I Do in
11:50 a.m.-12:08 p.m.
My Practice? What Are the Requirements?
Practical GI Practice: Top Take Home
12:10-12:28 p.m.
Points from the Meeting to Bring to Your
Practice
12:30-12:35 p.m.
Conclusion
Speaker
Room
Sapna Syngal, MD
Neil Stollman, MD, AGAF,
FACP, FACG
Douglas Rex, MD, AGAF,
FASGE
Charlene M. Prather, MD,
MPH, AGAF, FACP
Brennan Spiegel, MD, MSHS,
AGAF
Hall D
Course Faculty
Course Director:
Gastroenterologist
Kaiser Permanente San Francisco Medical Center
Research Scientist III
Kaiser Permanente Division of Research
Co-Directors:
Medical Director, Hepatology Research
Medical Director, Inpatient Liver and Transplant Unit
Baylor University Medical Center
Director of Therapeutic Endoscopy
Brigham and Womens Hospital
Associate Professor
Harvard Medical School
SPGC 2015 Faculty:
Neena S. Abraham, MD, MSc, AGAF, FACG, FASGE
Professor of Medicine
Mayo Clinic College of Medicine
Arizona Associate Medical Director
Kern Center for the Science of Healthcare Delivery
Maria T. Abreu, MD, AGAF
Chief, Division of Gastroenterology
Professor of Medicine, and Microbiology and Immunology
University of Miami Miller School of Medicine
Liver Consultants of Texas-Dallas
Bruce R. Bacon, MD, AGAF
James F. King M.D. Endowed Chair in Gastroenterology
Professor of Internal Medicine
Division of Gastroenterology and Hepatology
Saint Louis University Liver Center

Associate Professor, Internal Medicine
Division of Gastroenterology, Hepatology and Nutrition
Virginia Commonwealth University and
McGuire VA Medical Center
Jacques Bergman, MD, PhD
Professor of Gastrointestinal Endoscopy
Department of Gastroenterology and Hepatology
Academic Medical Centre
Emeritus Chief, Gastroenterology
Montefiore Medical Center
Professor of Medicine and Surgery
Albert Einstein College of Medicine
President-Elect, AGA Institute
Professor of Medicine, Pharmacology, and Physiology
Mayo Clinic College of Medicine
Amitabh Chak, MD
Head, Section of Gastrointestinal Endoscopy
University Hospital of Cleveland
Naga Chalasani, MD
Associate Professor of Medicine
Program Director, GI Fellowship
Indiana University
Kenneth J. Chang, MD, FACG, FASGE
Professor and Chief, Division of Gastroenterology
University of California, Irvine
Lin Chang, MD, AGAF
Program Director, UCLA GI Fellowship Program
Co-Director, Gail and Gerald Oppenheimer Family Center for
Neurobiology of Stress
Director, Digestive Health and Nutrition Clinic
David Geffen School of Medicine at UCLA
Edaire Cheng, MD
Assistant Professor of Pediatrics
UT Southwestern Pediatric Gastroenterology
Professor, Internal Medicine
Director, GI Physiology Laboratory
Co-Director of the Michigan Bowel Control Program
University of Michigan Health System
The Ohio State University College of Medicine
Director, Division of Gastroenterology, Hepatology and
Nutrition
Co-Director, The OSUWMC Digestive Disease Center
The Ohio State University Wexner Medical Center
Anna Mae Diehl, MD
Chief, Gastroenterology Division
Duke University Medical Center
Lorna M. Dove, MD, MPH
Columbia University Medical Center
Medical Director, Adult Liver Transplant
Grace Elta, MD, AGAF, FASGE
Division of Gastroenterology
University of Michigan
Chairman, Division of Gastroenterology and Hepatology
MetroHealth Medical Center
Brian G. Feagan, MD, FRCPC
Professor of Medicine, Epidemiology and Biostatistics
University of Western Ontario
Sandy Feng, MD, PhD

Professor of Surgery in Residence
Director, Abdominal Transplant Surgery Fellowship
University of California San Francisco
Scott L. Friedman, MD, AGAF
Fishberg Prof. of Medicine
Dean for Therapeutic Discovery
Chief, Division of Liver Diseases
Icahn School of Medicine at Mount Sinai
Director of Clinical Research
GI Fellowship Program
California Pacific Medical Center
Peter Gibson, MD
Professor and Director of Gastroenterology
The Alfred and Monash University
Mayo Clinic, Rochester
Joshua Korzenik, MD
Director, BWH Crohns and Colitis Center
Director, Liver Care Network
Swedish Medical Center
Clinical Professor of Medicine
University of Washington
Edward Krawitt, MD
Adjunct Professor of Medicine, Geisel School of Medicine
Dartmouth College

Assistant Professor of Medicine
Director, Endoscopic Education and Womens Health in GI
Anthony Lembo, MD
Beth Israel Deaconess Medical Center
Joshua Levitsky, MD, MS
Associate Professor of Medicine and Surgery
Program Director, Gastroenterology and Transplant
Hepatology Fellowships
Comprehensive Transplant Center
Northwestern University Feinberg School of Medicine
Michael J. Levy, MD
Mayo Clinic
Deputy Editor, JAMA
Professor of Surgery and Biomedical Engineering
University of Texas Southwestern School of Medicine
Professor of Surgery
Northwestern University
Anna S. F. Lok, MD, AGAF
Alice Lohrman Andrews Research Professor in Hepatology
Director of Clinical Hepatology
Associate Chair for Clinical Research
Uma Mahadevan, MD, AGAF
Co-Medical Director Center for Colitis and Crohns Disease
University of California, San Francisco
Stacy B. Menees, MD, MS

Fouad J. Moawad, MD, FACP, FACG
Major, Medical Corps, US Army
Assistant Chief of Gastroenterology
Walter Reed National Military Medical Center
Uniformed Services University
Craig A. Munroe, MD
General Gastroenterology and Therapeutic Endoscopy
Advanced Therapeutic Endoscopy
Kaiser Permanente
Chief, Division of Medicine-Gastroenterology and
Hepatology
Derek R. Patel, MD
Associate Clinical Professor of Medicine
University of California, San Diego
Saint Louis University School of Medicine
K. Rajender Reddy, MD
Professor of Medicine in Surgery
Director of Hepatology
Director, Viral Hepatitis Center
University of Pennsylvania

Director of Endoscopy
Indiana University Medical Center
David Rubin, MD, AGAF, FACG, FACP
Joseph B. Kirsner Professor of Medicine
Chief, Section of Gastroenterology, Hepatology and Nutrition
Co-director, Digestive Diseases Center
The University of Chicago Medicine
William J. Sandborn, MD, AGAF
Director, UCSD IBD Center
University of California San Diego
Dr. Burrill B. Crohn Professor of Medicine
Chief of the Dr. Henry D. Janowitz Division of
Gastroenterology
Nicholas J. Shaheen, MD, MPH, AGAF
Professor of Medicine and Epidemiology
Chief, Division of Gastroenterology & Hepatology
University of North Carolina School of Medicine
Rhonda F. Souza, MD, AGAF, FASGE
Co-Director, Esophageal Diseases Center
UT Southwestern Medical Center
VA North Texas Health Care System
Brennan Spiegel, MD, MSHS, FRR, AGAF, FACG
Director of Health Services Research, Cedars-Sinai Health
System
Director, Cedars-Sinai Center for Outcomes Research and
Education (CS-CORE)
Professor of Medicine and Public Health in Residence
University of California, Los Angeles

Chairman, Department of Medicine
Alta Bates Summit Medical Center
Shelby Sullivan, MD
Washington University School of Medicine
Sapna Syngal, MD, MPH
Director, Gastroenterology
Dana-Farber/Brigham and Womens Cancer Center
Norah Terrault, MD
Center for Liver Disease and Transplantation
Division of Digestive and Liver Diseases
Columbia University College of Physicians and Surgeons
Michael B. Wallace, MD, MPH, AGAF
Mayo Clinic
Florence Wong, MBBS, MD, FRACP, FRCPC
Clinician Scientist in Hepatology
Toronto General Hospital
Bechien Wu, MD, MPH
Program Director, Gastroenterology Fellowship KPSC
Kaiser Permanente
Los Angeles Medical Center
Financial Relationship Disclosure

In accordance with the Accreditation Council for Continuing Medical Educations (ACCME) Standards for Commercial Support
for Continuing Medical Education, all faculty and planning partners must disclose any financial relationship(s) or other
relationship(s) held within the past 12 months relevant to the content presented. The AGA Institute identifies and manages
all conflicts of interest prior to delivering the educational activity to learners.
Faculty
Neena S. Abraham, MD, MSc
Disclosed no relevant financial relationships

Maria T. Abreu, MD
Advisory Committees or Review Panels: GI Health
Foundation
Consultant: AbbVie Laboratories, Prometheus Labs, Sanofi
Aventis, Takeda, UCB, Pfizer, Janssen, WebMD Health, Focus
Medical Communication, Prova Education, Inc, GSK Holding
Americas, Inc.

Consultant: Ferring Pharmaceuticals Inc., Ironwood
Pharmaceuticals Inc., Takeda Pharmaceutical Company
Ltd, Synergy Pharmaceuticals, Inc, Bio-kier, AstraZeneca,
Shire Pharmaceuticals Inc., NPS Pharmaceuticals, Salix
Pharmaceuticals, Inc.
Grant/Research Support: Tsumura & Co., National Institutes
of Health, RHYTHM
John I. Allen, MD, MBA, AGAF

Consultant: gMed, Pentax, Olympus, AbbVie
Bruce R. Bacon, MD
Advisory Committees or Review Panels: Janssen, AbbVie,
ISIS, Gilead
Consultant: Merck
Grant/Research Support: AbbVie, ISIS, Gilead Sciences,
Merck
Speaking and Teaching: Janssen, Salix, AbbVie, Gilead
Sciences
Advisory Committees or Review Panels: Merz, Otsuka, Salix,
Grifols
Grant/Research Support: Grifols
Jacques Bergman, MD, PhD
Consultant: Boston scientific, Covidien
Grant/Research Support: Olympus Japan, Covidien,
Cook, Inc., Spectra Science, C2 medical, Boston Scientific
Corporation, ninepoint medical, Erbe, Cernostics
Amitabh Chak, MD
Advisory Committees or Review Panels: Xlumena
Consultant: US Endoscopy
Naga Chalasani, MD
Consultant: Abbott Laboratories, Aegerion, Eli Lilly &
Company, Salix Pharmaceuticals, Inc.
Grant/Research Support: Merck & Co, Cumberland, Intercept
Pharmaceuticals, Inc., Gilead Sciences Inc
Kenneth J. Chang, MD, FACG, FASGE
Advisory Committees or Review Panels: Mauna Kea
Consultant: Olympus Japan, Cook Medical, Inc.
Lin Chang, MD, AGAF
Advisory Committees or Review Panels: Entera Health,
Salix Pharmaceuticals, Inc., QOL Medical, Forest, Ironwood
Pharmaceuticals Inc.
Grant/Research Support: Ironwood Pharmaceuticals Inc.,
Salix
Edaire Cheng, MD
William D. Chey, MD
Advisory Committees or Review Panels: My Total Health
Consultant: Ardelyx, Astra Zeneca, Forest, Ironwood,
Prometheus, Nestle, Salix, QOL Medical, Takeda, Sucampo
Grant/Research Support: Ironwood, Prometheus, Nestle,
Vibrant
Douglas Corley, MD, PhD
Grant/Research Support: Pfizer Pharmaceuticals
Anna Mae Diehl, MD
Lorna M. Dove, MD, MPH
Grace Elta, MD, FASGE
Consultant: Olympus America, Inc.
Consultant: Takeda, Vecta, GSK, Tulip
Grant/Research Support: Ironwood
Brian G. Feagan, MD, FRCPC
Consultant: Abbott/AbbVie, ActoGenix, Amgen, Astra
Zeneca, Avaxia Biologics, Axcan, Baxter Healthcare Corp,
Boehringer-Ingelheim, Bristol-Myers Squibb Celgene, Elan/
Biogen, EnGene, Ferring, Roche/Genentech, GiCare Pharma,
Gilead, Given Imaging, GSK, Ironwood Pharma, Janssen
Biotech, Kyowa Kakko Kirin Co, Lexicon, Lilly, Merck,
Millennium Pharma
Sandy Feng, MD, PhD
Scott L. Friedman, MD, AGAF
Consultant: Capsovision,Inc. ,EndoGastricSolutions, Gerson
Lehrman Group, Guidepoint Global
Speaking and Teaching: Takeda
Peter Gibson, MD
Advisory Committees or Review Panels: Abbvie, Janssen,
Ferring, Takeda, Danone
Consultant: Nestle
Grant/Research Support: Ferring, Abbvie, Janssen, Shire,
Orphan Australia
Speaking and Teaching: Abbvie, Janssen, Takeda,
AstraZeneca, Pfizer
Advisory Committees or Review Panels: ABIM
Consultant: AbbVie, UCB, Inc.
Grant/Research Support: Shire Pharmaceuticals Inc.
Advisory Committees or Review Panels: Alba Therapeutics,
Alvine, Merck & Co, MedImmune, Seres Health,
ImmunoSanT, Cubist
Consultant: Stellar Biotech, Synthetic Biologics, CSL Behring,
Pfizer
Grant/Research Support: Sanofi Pasteur
Joshua Korzenik, MD
Advisory Committees or Review Panels: Shire, Janssen,
Merck, Roche, Corrona
Grant/Research Support: Takeda, Pfizer, Abbvie
Major Stock Shareholder: Vithera, Colonary Concepts
Advisory Committees or Review Panels: BMS, Achillion,
Gilead, Merck, Trio Health
Consultant: Up-To-Date
Grant/Research Support: Abbvie, Beckman, BMS, Boeringer
Ingelheim, Gilead, Intercept, Janssen, Merck, Novartis,
Vertex
Speaking and Teaching: Abbvie
Edward Krawitt, MD
Anthony Lembo, MD
Advisory Committees or Review Panels: Salix
Pharmaceuticals, Astra Zeneca, Forest Research Institute
Consultant: Ironwood Pharmaceutical, Prometheus
Laboratories Inc.
Derek R. Patel, MD
Joshua Levitsky, MD, MS

K. Rajender Reddy, MD
Advisory Committees or Review Panels: Janssen, BMS,
Gilead, Abbvie, Merck, Genentech-Roche
Grant/Research Support: Janssen, BMS, Gilead, Abbvie,
Merck
Michael J. Levy, MD


Consultant: EndoAid, Ltd.
Advisory Committees or Review Panels: Given Imaging,
Anna S. F. Lok, MD, AGAF
American BioOptics, CheckCap, Epigenomics, EXACT
Advisory Committees or Review Panels: MYR, Tekmira,
Sciences
Gilead Sciences, GlaxoSmithKline
Grant/Research Support: Given Imaging, Olympus America,
Grant/Research Support: Gilead Sciences Inc, Idenix, AbbVie, Inc., Braintree Laboratories Inc.
Merck & Co, Bristol-Myers Squibb
Speaking and Teaching: Olympus America, Braintree
Laboratories Inc., Boston Scientific Corporation
Uma Mahadevan, MD, AGAF
Advisory Committees or Review Panels: Janssen-Cilag,
David Rubin, MD, AGAF
Abbvie, Taleda, UCB Pharma, Genentech Inc.
Consultant: Prometheus Laboratories, Abbvie, UCB Pharma,
Grant/Research Support: Prometheus Laboratories Inc.,
Janssen, Takeda, Ironwood, Emmi, Santarus/Salix, Genetech
Takeda Pharmaceutical Company Ltd, GlaxoSmithKline
Grant/Research Support: Prometheus Laboratories, Abbvie,
Shire, Elan Pharmaceuticals
Stacy B. Menees, MD, MS
Major Stock Shareholder: Cornerstones Health, Inc
William J. Sandborn, MD
Fouad J. Moawad, MD, FACP, FACG
Consultant: ActoGeniX NV, Amgen, AM-Pharma BV,
Boehringer-Ingelheim Inc, Bristol Meyers Squibb, Celgene,
Cosmo Technologies, Coronado Biosciences, Eisai Medical
Craig A. Munroe, MD
Research Inc., Elan Pharmaceuticals, Eli Lilly, Ferring
Pharmaceuticals, Genentech, Gilead Sciences, Glaxo
Smith Kline, Ironwood Pharmaceuticals, Janssen, Lexicon
Pharmaceuticals, Millennium Pharmaceuticals, Nisshin
Consultant: Jansen, Abbvie, Novartis
Kyorin Pharmaceuticals Co., Ltd, Novo Nordisk A/S, Orexigen
Speaking and Teaching: Gilead, Asellas
Therapeutics, Inc., Pfizer, Prometheus Laboratories, Receptos
Consultant: Given
Grant/Research Support: Given Imaging
Given, AstraZeneca Pharmaceuticals, Takeda

Consultant: Luitpold Pharmaceuticals, AbbVie, Pfizer Inc.,
Forest Research institute, Salix, MedImmune, Vedanta,
Shire, Millennium Pharmaceuticals, Inc., Janssen Biotech,
ETX Pharma, Takeda Pharmaceutical Company Ltd
Grant/Research Support: Pfizer, Janssen Biotech,
MedImmune, Takeda
Major Stock Shareholder: Avaxia Biologics
Speaking and Teaching: Catrille & Associates, Creative
Educational Concepts, Focus Medical Communications,
Strategic Consultants International, American Academy of
CME, IMEDEX
Norah Terrault, MD
Advisory Committees or Review Panels: Roche/Genetech
Consultant: BMS, Merck, UptoDate, Achillion
Grant/Research Support: Biotest, Eisai, Gilead Sciences,
AbbVie

Consultant: Oncoscope, Inc., NeoGenomics
Grant/Research Support: Covidien Medical, Takeda
Pharmaceutical, CSA Medical Inc., Oncoscope, Inc., Takeda
Pharmaceutical Company Ltd, Shire Pharmaceuticals Inc.

Rhonda F. Souza, MD, AGAF, FASGE

Advisory Committees or Review Panels: Ironwood
Pharmaceuticals Inc., Prometheus Laboratories Inc.
Grant/Research Support: Ironwood Pharmaceuticals Inc.,
Shire Pharmaceuticals Inc., Amgen, Theravance
Consultant: PureFlora
Speaking and Teaching: Otsuka America, Optimer
Pharmaceuticals, Quest Labs, Aptalis Pharmaceuticals
Shelby Sullivan, MD
Consultant: USGI Medical, EnteroMedics, Obalon
Grant/Research Support: Aspire Bariatrics, ReShape
Medical, GI Dynamics, USGI Medical
Sapna Syngal, MD

Consultant: Boston Scientific, Olympus America, Beacon
Endoscopic, Valentx, Apollo Endosurgery Inc, Vysera, Iralnd
Grant/Research Support: Olympus America, Inc., Apollo
Endosurgery
Major Stock Shareholder: GI Windows
Michael B. Wallace, MD, MPH, AGAF

Grant/Research Support: Siemens, Olympus, BSCI, US
Endoscopy
Florence Wong, MBBS, MD, FRACP, FRCPC
Grant/Research Support: Grifols
Bechien Wu, MD, MPH
Planning Committee Disclosures

Andrew C. Barta, PA-C
Arthur J. DeCross, MD, AGAF
Thomas W. Faust, MD, MBE
Mark H. Flasar, MD
Grant/Research Support: Janssen, Inc, Given Imaging, Inc.
Eric M. Goldberg, MD
Consulting: Olympus Inc, Boston Scientific
Avlin B. Imaeda, MD, PhD
Kim L. Isaacs, MD, PhD, AGAF
Consulting: INC Research
Grant/Research Support: Given Imaging, AbbVie, Janssen
Pharmaceuticals, Elan Pharmaceuticals, Millenium
Pharmaceuticals, UCB, Takeda Pharmaceuticals
Speaking and Teaching: GI Health foundation
Geoffrey S. Jensen, MD
Denise Kalmaz, MD
Michelle K. Kim, MD, MSc, AGAF
Jan-Michael A. Klapproth, MD
Nicole M. Loo, MD
Jane E. Onken, MD, MHS, AGAF

Member: BMS DMC
Major Stock Shareholder: Merck
Richard M. Peek, Jr., MD, AGAF
Kimberly M. Persley, MD
Sheryl A. Pfeil, MD, AGAF
Advisory Committees or Review Panel: Alpha Omega Alpha
Daniel S. Pratt, MD
Suzanne Rose, MD, MSEd, AGAF
Major Stock Shareholder: Abbott Labs, Baxter International,
Johnson & Johnson, Novo Nordisk, Perrigo
Advisory Committees or Review Panels: AAMC
AGA Staff
Maura H. Davis
Natalie Foster
Lori N. Marks, PhD
Sandra Megally
exhibit Halls A, B & C
(LeveL L)
Lower Level
exhibit Halls A, B & C
(LeveL C)
Concourse
Grand Lobby/Registration/Salons AI
Meeting Rooms 101103 & 140160
Loading Dock entrance
(LeveL 1)
Street Level
RETAIL
exhibit Halls D & e

Meeting Rooms 201210
east and West Overlook
(LeveL 2)
Level Two
GRAND LOBBY BRIDGE
Ballroom
Meeting Rooms 301306
Kitchen
(LeveL 3)
Level Three
(LeveL 1)
Salons
RETAIL
PARTNERS
W I T H
P U R P O S E
Looking Forward: Giving Back

Campaign Honor Roll of Donors
The AGA Research Foundation recognizes our contributors* of $100,000 or more. We are pleased to pay special
tribute to their philanthropic leadership and vision. Their gifts have made an immediate difference in the careers of
young scientists and in the lives of countless patients who will benefit from their work.
Ferring Pharmaceuticals
John I. Allen, MD, MBA, AGAF

& Carolyn Allen
Gastric Cancer Foundation
Sumner and Susan Bell
Ironwood Pharmaceuticals
AGA-Caroline Craig Augustyn & Damian

Augustyn Award in Digestive Cancer
Athena Blackburn
Boston Scientific
Braintree Laboratories, Inc.
Farron and Martin Brotman, MD

Covidien
Gilead Sciences, Inc.
Colin and Jackie Howden
Alan and Louise MacKenzie

Salix Pharmaceuticals, Inc.
Bernard Lee Schwartz Foundation

Shire Pharmaceuticals
Takeda Pharmaceuticals U.S.A., Inc.
Donor names are listed according to donor preference. *As of March 9, 2015.
To learn how you can support GI research go to www.gastro.org/foundation.
2200-080EDU_15-1
ARE YOU READY
FOR ICD-10?
HHS has mandated replacement
of ICD-9 code sets with ICD-10
code sets by Oct. 1, 2015, to
report health-care diagnoses
and inpatient procedures. If you
do not transition, payors will not
reimburse you.
Dont lose revenue. Plan ahead and
easily transition your practice and
ASC to ICD-10. Learn how by visiting
the AGA ICD-10 Resource Center. AGA
members can download free AGAAAPC translation guides for the top 50
GI diagnosis codes.
The AGA In
ICD-9-CM to ICD stitute and AAPC
-10-CM Transl
ation Guide
Top 50
ICD-9-CM
Code
Gastroenterology
Codes
By Alphabetical Dise
ase
Description
789.06
Abdominal pain,
epigastric
789.00
Abdominal pain, unspe
State
ICD-10-CM Code
(s)
ICD-9-CM
Code
R10.13 Epigastric pain
211.4
cified site
ICD-10-CM
Codes
ICD-10-CM
Codes
R10.9 Unspecified
abdominal pain
* There are more speci
fic code choice selec
ICD-10-CM. These
tions available in
include:
R10.0 Acute abdo
men
R10.10 Upper abdo
minal pain, unspecified
R10.11 Right uppe
r quadrant pain
R10.12 Left upper
quadrant pain
R10.13 Epigastric pain
R10.2 Pelvic and perin
eal pain
R10.30 Lower abdo
minal pain, unspecified
R10.31 Right lower
quadrant pain
R10.32 Left lower
quadrant pain
R10.33 Periumbilic
al pain
R10.84 Generalize
d abdominal pain
571.2
Alcoholic cirrhosis
ICD-10-CM
Codes
285.9
535.1
D64.9 Anemia, unspe

cified
ICD-10-CM. These
tions available in
include:
D64.81 Anemia due
to antineoplastic chem
otherapy
D64.89 Other speci
fied anemias
Atrophic gastritis (with
out hemorrhage)
530.85
Barrett's esophagus
ICD-10-CM
Codes
211.3
Benign neoplasm
of
stomach
Blood in stool
ICD-10-CM
Codes
K92.1 Melena
R19.5 Other fecal
Chest pain, unspe
ICD-10-CM
Codes
K29.40 Chronic atrop

hic gastritis
without bleeding
K22.70 Barretts esoph

agus without dyspl
asia
K22.710 Barretts
esophagus with low
grade dysplasia
K22.711 Barretts
esophagus with high
grade dysplasia
K22.719 Barretts
esophagus with dyspl
asia, unspecified
Benign neoplasm
colon
D12.6 Benign neop

lasm of colon, unspe
cified
10-CM. These includ fic code choice selec tions available
in ICDe:
D12.0 Benign neop
lasm of cecum
D12.1 Benign neop
lasm of appendix
D12.2 Benign neop
lasm of ascending
colon
D12.3 Benign neop
lasm of transverse
colon
D12.4 Benign neop
lasm of descending
colon
D12.5 Benign neop
lasm of sigmoid colon
Copyright 2013
AAPC all rights reserv
ed 2480 S. 3850
W. Suite B. Salt Lake
Chronic hepatitis C
without hepatic coma
Cirrhosis of liver witho
564.00
K80.50 Calculus of
bile duct without
cholangitis or chole
cystitis
without obstructio
n
cified
70.54
B18.2 Chronic viral
577.2
Cyst and pseudocyst
K86.2 Cyst of pancr

eas
K86.3 Pseudocyst
of pancreas
787.91
(B15-B19)
cified
K59.00 Constipati
on, unspecified
ICD-10-CM. These
tions available in
include:
K59.01 Slow transi
t constipation
K59.02 Outlet dysfu
nction constipatio
n
K59.09 Other const
ipation
ICD-10-CM
Codes
553.3
hepatitis C
ut alcohol
K74.60 Unspecifie
d cirrhosis of liver
K74.69 Other cirrho
sis of liver
** Code also, if applic
able, viral hepatitis
(acute) (chronic)
Constipation, unspe
ICD-10-CM
Codes
lasm of stomach
R07.9 Chest pain,

unspecified
ICD-10-CM. These
tions available in
include:
R07.1 Chest pain on
breathing
R07.81 Pleurodyn
ia
R07.89 Other chest
pain
571.5
ICD-10-CM
Codes
D13.1 Benign neop
abnormalities
Calculus of bile duct

without cholecystit
is
without obstructio
n
Anemia, unspecified
ICD-10-CM
Codes
ICD-10-CM
Codes
of liver
canal
D12.7 Benign neop
lasm of rectosigmo
id junction
D12.8 Benign neop
lasm of rectum
D12.9 Benign neop
lasm of anus and anal
canal
211.1
786.50
ICD-10-CM Code
(s)
of rectum and anal
578.1
574.5
K70.30 Alcoholic
cirrhosis of liver witho
ut ascites
K70.31 Alcoholic cirrho
sis of liver with ascite
s
** Use additional code
to identify: alcohol
dependence (F10-)
abuse and
Description
Benign neoplasm
of pancreas
Diaphragmatic herni
a
without obstructio
n or
gangrene
Diarrhea
City, Utah, 84120
800-626-CODE (2633)
K44.9 Diaphragm
atic hernia
obstruction or gang without
rene
R19.7 Diarrhea, unspe
www.aapc.com/ic
d-10/
cified
Page 1
Visit www.gastro.org/ICD10 to download your guide.
A PROGRAM OF THE AGA INSTITUTE

2200-080EDU_15-1
A G A
R O A D M A P
T O
T H E
F U T U R E
O F
G I
THE AGA DIGESTIVE HEALTH RECOGNITION PROGRAMTM
Demonstrate Quality
and Avoid CMS Penalties
The AGA Digestive Health Recognition Program (DHRP) enables clinicians to
demonstrate superior quality of care in the treatment of various digestive diseases.
The program can be used to qualify for CMS Physician Quality Reporting System
(PQRS) and to complete an ABIM self-directed practice improvement modules (PIM).
Qualify for CMS PQRS Incentives
As of 2013, Medicare Part B providers are penalized for nonparticipation in the CMS PQRS. DHRP offers eligible professionals
a simple and cost-effective online tool for collecting and reporting
quality measures data under the CMS PQRS incentive program.
Gain Maintenance of Certification (MOC) Points
NOW SUPPORTING:
Inflammatory Bowel
Disease (IBD)
Hepatitis C
Colorectal Cancer
The data you collect as part of DHRP can also be used to gain ABIM
MOC points. The program will provide you with the pre- and postintervention data necessary to complete your ABIM self-directed PIM.
How to Participate
Participation in DHRP is simple: register and submit data for a sample
of 20 patients for the HCV or IBD modules and/or for 50 percent of
patients for the CRC screening and surveillance module.
Screening and Surveillance

AGA Members:
$300 per disease state
Nonmembers:
$550 per disease state
PROGRAM MADE POSSIBLE BY SUPPORT FROM ABBVIE INC., SALIX PHARMACEUTICALS, INC., AND SHIRE.
CMYK
Register today or learn more by visiting www.agarecognition.org

or contacting recognition@gastro.org.

2200-080EDU_15-1
ROADMAP
TO THE
FUTURE OF GI
How to Thrive in the New World of Accountable Care
As reimbursement shifts from fee-for-service to value-based, physicians must focus on the
quality rather than the quantity of services provided. AGAs Roadmap to the Future of GI will help you
make the most of health-care reform and implement changes in your practice so you can not only
survive but thrive in the new accountable-care environment.
DELIVER DEMONSTRATE MAXIMIZE

HIGH-VALUE
QUALITY
REVENUE
CARE
CMYK
Visit www.gastro.org/practice. Read the Practice Management:
The Road Ahead section in Clinical Gastroenterology and Hepatology.
AGA INSTITUTE
2200-080EDU_15-1
DENT
RESI
ICAL
MED
STUD
ENT
CORP
ORAT
SSIO
ROFE
NUR
SE/A
LLIED
HEAL
TH P
MAN
TICE
PRAC
NP/P
A
NEE
SCIE
TRAI
PHYS
ICIAN
NTIS
AGER
NAL
AGA MEMBERSHIP
Join AGA today to gain access to the tools you need

to succeed in your chosen field.
Youll be able to take advantage of members-only content and discounts on
publications, educational products and professional development resources
that will help you take your career to the next level.
Join AGA at DDW and the application fee will be waived, plus you will
receive a small gift. Visit the AGA Membership Booth (in the Registration Area),
the AGA Resource Center (Concourse B) or the AGA Booth (#2227, Exhibit Hall).
Learn more at www.gastro.org/membership.
2200-080EDU_15-1
Principles of Gastroenterology for the Nurse Practitioner and Physician Assistant
Cutting-Edge Gastroenterology:
What You Need to Know
AUG. 1416, 2015
CHICAGO MARRIOTT DOWNTOWN MAGNIFICENT MILE, IL
Addressing the needs of GI nurse practitioners and physician assistants, this course
offers a comprehensive program that focuses on best practices and evidence-based
medicine. Attendees have an exceptional opportunity to develop and enhance
diagnostic and therapeutic skills to help improve their overall delivery of patient care.
CMYK
Early registration ends June 8, 2015. Register online at www.gastro.org/nppa15.
2200-080EDU_15-1
DDSEP7
Digestive Diseases Self-Education Program
Enhance Your knowledge,

Build Expertise and Improve
Patient Care.
For more than 15 years, DDSEP has been the go-to, selfeducation resource for gastroenterologists in all stages of
their careers. It helps physicians stay current on the latest
advances in the fields of gastroenterology, hepatology and
nutrition and prepare for the ABIM GI board certification
and recertification examinations. DDSEPs flexible format
is also ideal for obtaining continuing medical education
credits conveniently and efficiently.
New section on how to plan for, study for and take
the GI boards.
n 17 chapters, including new information on small
bowel disease.
n More than 800 exam-style questions.
n Combined print/online format, including a portable
USB flash drive.
n Earn up to 102 CME credits.*
n
CMYK
*This activity has been approved for 102 AMA PRA Category 1 CreditsTM.
Order online at www.gastro.org/ddsep.

2200-080EDU_15-1
Claiming CME and MOC Credit for the

2015 AGA Spring Postgraduate Course
To claim CME for the 2015 AGA Spring Postgraduate Course:
1. Return your completed evaluation to an AGA staff member or place it in one of the
designated boxes.
2. Starting May 16, 2015, you can claim CME through the DDW system website,
www.ddw.org any time until November 30, 2015.
3. Email Education@gastro.org if you have any questions.
To claim MOC for the 2015 AGA Spring Postgraduate Course:
If you are board certified and intend to claim MOC for the course:
1. Please email MOC@gastro.org with your first name, last name, and ABIM number.
2. You will receive further instructions upon the return of AGA staff to the national office
following DDW 2015.
The Problem of Abdominal Pain: How to Work Up,

Evidence on Effective Treatments
Lin Chang, MD, AGAF Professor of Medicine

Program Director, UCLA GI Fellowship Program
Co-Director, Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress
Director, Digestive Health and Nutrition Clinic
The Problem of Abdominal Pain: How to

Work Up, Evidence on Effective Treatments
2015 Spring Postgraduate Course
Lin Chang, M.D., AGAF
Oppenheimer
pp
Familyy Center of Neurobiology
gy of Stress
Division of Digestive Diseases
Diagnostic Algorithm for

Functional Abdominal Pain
Patient with constant or

f
frequently
recurring
abdominal pain for at
least 6 months:
Not associated with
y
disease
known systemic
With loss of daily
function including work
and socializing
Referral to mental health

care professional to
exclude malingering
yes
Is pain associated with

bowel movements,
eating or menses?
no
yes
3
Consider IBS, EPS and

other painful FGIDs, or
mesenteric
t i iischemia.
h i
Other possible
diagnoses include
painful gynecologic
disorders, for example
endometriosis
Alarm features
identified on history or
physical examination?
no
yes
5
Do appropriate
g
work-up
p for
diagnostic
alarm features
Sperber AD, Drossman DA, Am J Gastroenterology 2010; 105(4):770
Suspicion that
pain is feigned?
no
Functional abdominal
pain syndrome
p
y
Chronic or Recurrent Abdominal Pain:

Specific Characteristics
Pain related
to BMs
IBS
Pain related
to meals
Functional
Dyspepsia
(FD)
Pain related
to menses
Endometriosis
Chronic mesenteric
ischemia (older, CV or
PVD)
Other
gynecologic
causes
Chronic or Recurrent Abdominal Pain: Location

Epigastric/RU
Q areas
Functional Dyspepsia
(Epigastric Pain
y
)
Syndrome)
Gallbladder
disease or
SOD
Lower
abdomen
bd
IBS
Pelvic pain
di d
disorders
Periumbilical
P
i bili l
or diffuse
Functional
Abdominal
Pain
Abdominal
migraine
Suprapubic
Painful bladder
syndrome/Interstiti
al cystitis
y
Gynecologic
disease


f
frequently
recurring
least 6 months:
Not associated with
y
disease
known systemic
With loss of daily
and socializing

exclude malingering
yes

bowel movements,
eating or menses?
no
yes
3

mesenteric
t i iischemia.
h i
Other possible
diagnoses include
painful gynecologic
endometriosis
Alarm features
no
yes
5
Do appropriate
g
work-up
p for
diagnostic
alarm features
Suspicion that
pain is feigned?
no
pain syndrome
p
y
Physical Exam:
Differentiating Abdominal Wall
vs. Visceral Pain
Carnetts sign
Pain or tenderness increases with intentional
tensing of the abdominal muscles
Positive sign
g is suggestion
gg
of abdominal wall
pain
May
y be positive
p
in Functional Abdominal Pain
due to central sensitization with hypervigilance
differentiates central vs. visceral mechanism
Physical Exam with Abdominal Palpation:

Differentiating Acute vs
vs. Functional
Abdominal Pain Syndrome (FAPS)
PE Finding
Acute Abdominal Pain
Closed eyes sign
Keep eyes open in

anxious anticipation
Stethoscope sign Increase pain behavior
FAPS
Wince with their eyes
May reduce behavioral
p
response
Alarm Features for Organic Disorders

Unintended weight loss (> 10% in 3 months)
Blood in the stools not caused (confirmed) by
hemorrhoids or anal fissures
Abnormal labs: anemia, hypoalbuminemia, liver
tests, elevated CRP or ESR
Fever
Family history of GI cancer,
IBD, or celiac disease
If alarm features are present,
investigate and treat
appropriately
FM 31
Avoid Unnecessary Tests in Absence of

Alarm Signs
No further diagnostic testing
Unnecessary excessive testing: CT, MRI, EGD,
colonoscopy,
co
o oscopy, US, capsu
capsulee endoscopy,
e doscopy, EUS,
US, ERCP
C
Increased risk to patient
Excessive health care costs
Reinforces patient
patientss inclination to think another
cause is being missed
www.choosingwisely.org
www.choosingwisely.org


f
frequently
recurring
least 6 months:
Not associated with
y
disease
known systemic
With loss of daily
and socializing

exclude malingering
yes

bowel movements,
eating or menses?
no
yes
3

mesenteric
t i iischemia.
h i
Other possible
diagnoses include
painful gynecologic
endometriosis
Alarm features
no
yes
5
Do appropriate
g
work-up
p for
diagnostic
alarm features
Suspicion that
pain is feigned?
no
pain syndrome
p
y
Symptom severity
Psych distress
Di bili
Disability
Previous therapy
Severity
y
R d Flags
Red
Fl
Mental Health Consultation
Severe depression /
suicidal
Difficulties in physician
patient interaction
Chronic refractory pain
Idiosyncratic health beliefs
Severe disability
Other identifiable
psychological difficulties
Maladaptive illness
behavior
(somatization disorder, PTSD, severe

anxiety,
y, abuse))
CNS Contribution to GI Pain

Chronic abdominal pain (FAPS)
Functional GI disorders
IBS
Functional dyspepsia
Chronic GI disorders
GERD
IBD
Acute GI episodes
p
Bowel obstruction
Cholecystitis
Functional Dyspepsia: Diagnostic Criteria*

One or more of
Epigastric pain
Epigastric burning
Early satiation
Postprandial fullness
AND
No evidence of structural disease (including
at upper endoscopy) that is likely to explain
the symptoms
*Criteria fulfilled for the last 3 months with symptom onset at least 6
months prior to diagnosis
Tack J, et al.. Gastroenterology. 2006;130:1466-1479
Rome III Diagnostic Criteria for IBS*

Recurrent abdominal pain or discomfort
att lleastt 3 days/mo
d /
i the
in
th llastt 3 mo
associated with 2 of the following
Improvement
with
ih
defecation
Onset associated
with
i h a change
h
iin
frequency of stool
Onset associated
with
i h a change
h
iin
form of stool
months prior to diagnosis
Longstreth GF et al. Gastroenterol. 2006;130(5):14801491
Functional Abdominal Pain Syndrome:

Diagnostic Criteria
Criteria*
Must include all of the following:
Continuous
C ti
or nearly
l continuous
ti
abdominal
bd i l pain
i
No (or only occasional) relationship of pain with
physiological events (eating,
(eating defecation
defecation, menses)
Some loss of daily functioning
The pain is not feigned
Insufficient symptoms to meet criteria for another
functional GI disorder that would explain the pain
prior to diagnosis
g
months p
Clouse RE et al. Gastroenterology; 2006; 130:1492.
Clinical Spectrum: IBS and FAPS

Mild/Mod
Mild/M
d Severe
S
FAPS
IBS
IBS
Population Frequency
5-10%
1-5%
<1%
Abdominal Pain
+/++
++/+++
++/+++
Bowel Dysfunction
+/++
++/+++
0/+
Psychosocial Distress
0/++
++/+++
+++
Somatic Symptoms
0/+
+/+++
++/+++
Health Care Utilization
0/++
++/+++
++/+++
Treatment Method
Bowel>CNS CNS>Bowel
CNS
Biopsychosocial Conceptual Model
Early Life
Genetics
Environment
Psychosocial
Factors
Life stress
Psychologic
state
t t
Coping
Social support
CNS
ENS
Physiology
Motility
M tilit
Sensation
Drossman DA et al. Gastroenterology 2002;123:2108-2131
Biopsychosocial Conceptual Model

Anxiety
Depression
Early Life
Genetics
Environment
Lack of family or friends

Catastrophizing
Psychosocial
Factors
Life stress
Psychologic
state
t t
Coping
Social support
CNS
Abdominal pain
Constipation
Somatic pain
Poor sleep
Decreased QOL
Medications
Many MD visits
ENS
Physiology
Motility
M tilit
Sensation
Positive FH
Early life adversity
Visceral hypersensitivity/ Enhanced perception

Dysmotility
Drossman DA et al. Gastroenterology 2002;123:2108-2131
AGA Technical Review and Guidelines for

Pharmacotherapy for IBS
Indication
Medication
IBS-D
IBS-C
IBS
Recommendation
Quality of
Evidence
Abdominal
Pain Relief
Alosetron
Conditional
Moderate
Yes
Rifaximin
Conditional
Moderate
Yes*
L
Loperamide
id
C diti
Conditional
l
V
Very
low
l
Y
Yes
Linaclotide
Strong
High
Yes
p
Lubiprostone
Conditional
Moderate
Yes*
PEG-Laxatives
Conditional
Low
No
Antispasmodics
Conditional
Low
Yes*
Tricyclics (TCAs)
Conditional
Low
Yes*
Conditional against
Low
No
SSRIs
* Rated down for potential risk of bias

bias, imprecision and/or indirectedness
Chang, Sultan, Lembo. Gastroenterology 2014;147:1149-1172
Weinberg, Smalley, Heidelbaugh, Sultan. Gastroenterology 2014;147:1146-1148
Linaclotide Phase 3 IBS-C Trial

CSBMss a
CS
and
d Abdominal
bdo
a Pain
a Ove
Over 26
6 Wee
Weekss
4
CSBMs
Lin 290 g
Placebo
Abdominal Pain
-10
3
% -20
Change
abdominal
bd i l
pain -30
Weekly
3
CSBMs
-40
1
-50
0
B 2 4 6 8 1 1 1 1 1 2 2 2 2
L
0 2 4 6 8 0 2 4 6
Trial week
60
-60
BL2 4 6 8 10 12 14 16 18 20 22 24 26
Trial week
p< 0.0001 for each of the 26 Weeks in the Treatment Period for both SBMs and CSBMs
ITT Population,
P
l ti
mean weekly
kl rates
t presented,
t d p-values
l
based
b d on ANCOVA att each
h weekk (observed
( b
d cases))
Chey W, et al. Am J Gastroenterol 2012; 107(11):1702
Antispasmodics in IBS
Cause smooth-muscle relaxation by either
Direct effect ((e.g.,
g mebeverine, p
pinaverium))
Anticholinergic or antimuscarinic properties (e.g.,
dicyclomine, hyoscamine)
Practical
P ti l approach
h
Give 30 min ac as needed for postprandial symptoms
Not optimal choice for chronic or severe abdominal pain
Side effects
Dry mouth
mouth, constipation,
constipation urinary retention,
retention visual
disturbances
Lesbros-Pantoflickova D et al. Aliment Pharmacol Ther. 2004; 20:1253
Antidepressants for IBS: Clinical Considerations
Consider specific symptoms treated1-3

TCAs in IBS-D, SSRIs in IBS-C
SSRI/SNRI for anxiety
profiles1,2
Consider side effect p
SSRIs may be better tolerated than TCAs
Consider previous use of psychotropic agents3
Start with low dose3
Titrate slowly (every 1-2 weeks)3
Follow up to assess side effects, adherence,
and efficacy3
Poor response3
1ACG
Switch to different class

antidepressant
tid
t
Combine treatments as
augmentation
Obtain psychiatry consultation
Satisfactory response3
Continue at minimum effective

dose
for
d
f 6 to
t 12 months
th
Long-term therapy may be
warranted for some patients
SNRI=serotonin-norepinephrine
SNRI=serotonin
norepinephrine reuptake inhibitor
Task Force on IBS. Am J Gastroenterol. 2009; 104(suppl 1):S1-S35

AC, et al. Gut. 2009; 58:367
3Grover M, Drossman A. Curr Opin Pharmacol. 2008; 8:715
2Ford
Antidepressant Treatment in IBS

TCAs
SSRIs
SNRIs
Agents
Amitriptyline,
Imipramine,Desipramine,
Nortriptyline
Fluoxetine, Sertraline,
Paroxetine, Citalopram
Duloxetine, Venlafaxine
Desvenlafaxine
Dose range
10-200 mg
10-100 mg
30-90 mg (duloxetine)
75-224 mg (venlafaxine)
Adverse
effects
Sedation
Constipation
Dry mouth/eyes
Weight gain
Hypotension
Sexual dysfunction
y
Insomnia
Diarrhea
Night sweats
Weight loss
Agitation
Sexual dysfunction
y
Nausea
A i i
Agitation
Dizziness
Fatigue
Liver dysfunction
Time to
action
Few days to 2 weeks (low

doses)
2-6 weeks (high doses)
3-6 weeks
3-6 weeks
Efficacy
Good
Moderate
Not adequately studied
Dose
adjustments
Common
Usually not needed
Common
TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;

SNRI=serotonin-norepinephrine reuptake inhibitor
Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.
Treatment
Severity
Combined
AD + psych
Psychiatric
referral
Augmentation
2 drugs
4-6 wks*
Increase dose
4-6 wks*
Low dose
TCA or SNRI or SSRI
CBT
Hypnosis
IP p
psychotherapy
y
py
Stress
management
S
Symptomatic
t
ti medical
di l ttreatment
t
t
Stress reduction
Exercise, yoga, etc.
Patient - Physician Relationship

* Monitor side
effects
Mental health
referral
ACG 2014 Meta-analysis for Psychological Therapy in IBS

Therapy
Trials
RR
(95% CI)
NNT
(95% CI)
Cognitive behavioral therapy (CBT)
610
0.66 (0.44-0.83)
3 (2-6)
Self-administered or minimal contact

CBT
144
0.53 (0.17-1.66)
N/A
Internet CBT
140
0.75 (0.48-1.17)
N/A
Relaxation therapy
255
0.77 (0.57-1.04)
N/A
Hypnotherapy
278
0.74 (0.63-0.87)
4 (3-8)
Multicomponent psychological therapy
335
0.72 (0.62-0.83)
4 (3-7)
Dynamic psychotherapy
273
0.60 (0.39-0.93)
3.5 (2-25)
Stress management
59
0 63 (0.19-2.08)
0.63
(0 19 2 08)
N/A
1 each
188
75
0.78 (0.64-0.93)
0.57 (0.32-1.01)
N/A
Multicomponent (telephone or
mindfulness meditation
Ford et al. AJG 2014;104
ACG 2014 Meta-analysis for Psychological Therapy in IBS

Therapy
Trials
RR
(95% CI)
NNT
(95% CI)
Cognitive behavioral therapy (CBT)
610
0.66 (0.44-0.83)
3 (2-6)
Self-administered or minimal contact

CBT
144
0.53 (0.17-1.66)
N/A
Internet CBT
140
0.75 (0.48-1.17)
N/A
Relaxation therapy
255
0.77 (0.57-1.04)
N/A
Hypnotherapy
278
0.74 (0.63-0.87)
4 (3-8)
Multicomponent psychological
therapy
335
0.72 (0.62-0.83)
4 (3-7)
Dynamic psychotherapy
273
0.60 (0.39-0.93)
3.5 (2-25)
Stress management
59
0.63 (0.19-2.08)
N/A
1 each
188
75
0.78 (0.64-0.93)
0.57 (0.32-1.01)
N/A
Multicomponent (telephone or
mindfulness meditation
Ford et al. AJG 2014;104
Teaching points
Clinical characteristics and physical exam can help
differentiate organic and functional abdominal pain
Avoid
A id unnecessary and
d repetitive
i i tests to work
k up chronic
h i or
recurrent abdominal pain
Apply
pp y the biopsychosocial
p y
approach:
pp
both p
physiologic
y
g and
psychologic factors that contribute to having chronic
abdominal pain
Help
e p patients
pat e ts u
understand
de sta d tthat
at p
physiologic
ys o og c abnormalities
ab o a t es
without anatomic disease cause real symptoms
General measures can help reduce GI symptoms and improve
overall well-being
well being
Use pharmacotherapy while trying to institute behavioral
therapies
NASH and Obesity: Whats Needed for Diagnosis,

Role of the Microbiome and How to Treat?
Anna Mae Diehl, MD

Chief, Gastroenterology Division
Duke University Medical Center
Learning Objectives
Upon completion of this session, the participant should be
able to:
1 Understand the factors that influence NAFLDs heterogeneous prognosis, and the utility of current diagnostic
approaches for determining this
2 Appreciate controversies regarding which NAFLD
patients to treat, as well as the impact of available
treatments on NAFLD prognostic factors
3 Summarize new developments in microbiome/gut-liver
axis research that might improve future diagnosis and
treatment of NAFLD.
NAFLD is a common disease with heterogeneous

outcomes
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and the metabolic syndrome. Like obesity and
the metabolic syndrome, NAFLD has become highly prevalent.
Population based studies suggest that at least 25% of American adults have NAFLD. There are two main types of NAFLD:
non-alcoholic fatty Liver (NAFL) and non-alcoholic steatohepatitis (NASH). Fat accumulates within hepatocytes in both
NAFLD subtypes. Population based studies in the US and other
countries suggest that most individuals with NAFLD (i.e., 75%
or more) have NAFL. Thus, NASH occurs in ~5% of the general
population.
The prognoses of NAFL and NASH are very different. NAFL has
a generally indolent course and benign liver prognosis. NASH
is characterized by increased liver cell death and associated
liver inflammation. Thus, NASH is a more serious form of liver
damage than NAFL. The risk for cirrhosis and primary liver
cancers are increased significantly in NASH. Never-the-less,
NASH is not inevitably progressive. For example, about 20%
of NASH patients enrolled in the placebo arms of prospective
clinical trials demonstrated regression/resolution of NASH
over 1-2 years. Conversely, natural history studies suggest that
about 30% of NASH patients ultimately develop cirrhosis. By
extrapolation, this suggests that ~2% of the general population has NAFLD-related cirrhosis. The prevalence of NAFLD
cirrhosis far exceeds that of most other chronic liver diseases
in the US. It will soon surpass HCV cirrhosis as our leading
indication for liver transplantation. Once NAFLD cirrhosis develops, the annual incidence of cancer is ~1%. NAFLD-related
hepatocellular carcinoma (HCC) is already the second leading
cancer-related indication for liver transplantation in the USA.
Liver fibrosis is the only independent predictor of
bad NAFLD outcomes
Because NAFLD is so common, and the clinical outcomes of

NAFLD are highly variable, considerable effort has been devoted to identifying factors that predict which NAFLD patients
will eventually develop liver-related morbidity and mortality.
This work is necessary in order to optimize management of individual NAFLD patients, as well as utilization of general health
care resources. Two recent natural history studies (together
comprising over 800 patients who were followed for an average of about 20 years) demonstrated that liver fibrosis was the
only factor that independently predicted all-cause mortality,
liver-specific mortality, liver transplantation, and liver-specific morbidities (e.g., ascites, varices, etc) in NAFLD patients.
Somewhat surprisingly, other histologic features (e.g., steatosis, ballooning, inflammation) and generally accepted bad risk
factors (age, BMI, obesity, type 2 diabetes) were not independent predictors of these important clinical endpoints. Upon
further reflection, this finding should not be surprising, and it
does not mean that the other factors are unimportant. Rather,
the data simply indicate that no liver injury is truly mild if it
triggers fibrosis; conversely even severe liver injury is really
not bad in the long run unless progressive fibrosis results.
Stated another way, human epidemiologic data demonstrate

conclusively that the outcomes of NAFLD depend upon how effectively the liver can repair injury (i.e., regenerate). Progressive fibrosis reflects defective repair. Defective repair results
when liver injury outstrips regeneration, and can occur either
because injury is particularly extreme and overwhelms normal repair responses, or because regenerative responses are
compromised and unable to repair even mild injury. Viewed
from this perspective, fibrosis itself is an outcome of NAFLD.
Earlier studies showed that the risk for fibrosis increases with
the severity of liver cell injury (e.g., hepatocyte ballooning)
and inflammation (but not steatosis). Certain clinical factors
correlate with/predict fibrogenic repair, particularly older
age and type 2 diabetes. Genetic and epigenetic factors that
regulate regenerative responses to tissue injury (e.g., transdifferentiation of hepatic stellate cells into myofibroblasts)
are also likely to be important.
The objective of NAFLD diagnosis is to determine
patient prognosis
Treatment for NAFLD is most important for individuals with

the greatest risk for having bad clinical outcomes (death, liverrelated morbidity, liver transplantation). Because these outcomes mainly occur in individuals with advanced liver fibrosis,
the primary goal of NAFLD diagnosis is to stage fibrosis severity. The tendency for fibrogenic repair can be estimated (e.g.,
family history of cirrhosis, older age, diagnosis of type 2 diabetes or PCOS) and evidence of advanced fibrosis acquired by
physical exam, routine blood testing, and abdominal imaging.
Accurate assessment of sub-clinical fibrosis severity has
proven to be challenging, however. Composite algorithms
that weight various blood tests are somewhat helpful, but
imperfect (diagnostic accuracy about 75-80% at best). Liver
biopsy remains the gold standard but is invasive and suffers
from sampling error. Imaging modalities (fibroscan and MRI
elastography) are promising, but as yet unvalidated in NAFLD
patients (in whom high BMI/extensive hepatic steatosis might
confound data interpretation). Given all of this, providers
must decide which combination of tests would be most helpful
in identifying staging fibrosis in individual patients. Other potentially informative data for estimating fibrosis risk include
establishing whether or not a patient has NASH. This is helpful because certain histologic features of NASH (especially hepatocyte ballooning and the intensity of the ductular reaction)
correlate with fibrosis severity.
NASH and Obesity: Whats Needed for Diagnosis, Role of the Microbiome and How to Treat?
Patient prognosis guides NAFLD treatment

Most treatments for NAFLD have been tested in subjects with
relatively low risk for developing progressive liver fibrosis
(i.e., non-diabetics with relatively mild fibrosis at enrollment).
Evaluation of true efficacy has been further complicated by the
fact that most studies have included improvement in steatosis as a measure of treatment success. However, recent data
demonstrates that steatosis severity and its predictors (i.e., insulin resistance and obesity) have no independent impact on
NAFLD progression or clinical outcomes of NAFLD. In addition, few treatment responders have been followed prospectively to determine if/how the intervention impacted fibrosis
progression or fibrosis-dependent clinical outcomes.
Among the potential NAFLD therapies that have been investigated in prospectively randomized, placebo-controlled clinical
trials, very few have proven to decrease liver fibrosis. Both
lifestyle modification and bariatric surgery seem to improve
NASH fairly reproducibly but effects on fibrosis are far less
consistent, with only rare studies documenting that either
intervention reduced fibrosis. A recent trial showed that a
72 week course of the FXR agonist, obeitocholic acid, was superior to placebo for improving liver fibrosis (and NASH) in
patients with NASH and fibrosis stage 3 or less. This study
included subjects with type 2 diabetes. In an earlier study, vitamin E improved certain fibrosis risk factors (i.e., hepatocyte
ballooning) in non-diabetic NASH subjects without advanced
liver fibrosis. Chronic coffee consumption and social alcohol
ingestion also associate with reduced liver fibrosis in crosssectional studies.
Safety is a concern for all NAFLD interventions, particularly
when treatments are being considered for patients who are at
low risk for liver fibrosis. Life style modifications and bariatric
surgery seem to positively impact NAFLD co-morbidities. In
contrast, both vitamin E and obeticholic acid may enhance the
risk for adverse outcomes of the metabolic syndrome. Chronic
vitamin E therapy increases the risk for prostate cancer and
all-cause mortality. Obeticholic acid acutely increased serum
cholesterol and worsened insulin resistance in the trial that
demonstrated its benefits for NASH and liver fibrosis, prompting concern that it might accelerate CVD and promote type 2
diabetes.
Microbiome/gut-liver axis offers novel opportunities
to prevent progressive NAFLD
Efforts to uncover the basis for the heterogeneous outcomes

of obesity-related liver disease revealed a possible role for the
intestinal microbiome in that process. The intestinal microbiome is complex and highly heterogeneous among individuals.
It regulates how efficiently hosts harvest and store energy
from dietary sources. Conversely, host factors modulate characteristics of the intestinal microbiota. For example, obesity
alters the intestinal microbiome in both rodents and humans,

and transfer of the microbiome from an obese individual to a
lean individual provokes recipient obesity.
Recent studies in animal models of NAFLD demonstrate that

the intestinal microbiota convey susceptibility to NAFL, NASH,
liver fibrosis, and liver cancer. In one study, mice that were
fed high fat diets demonstrated heterogeneous susceptibility
to NAFLD some mice were diet responders, developing hepatic steatosis (NAFL), hyperglycemia and insulin resistance,
while others did not (diet non-responders). Transfer of stool
from responder mice into germ free mice enhanced the severity of high fat diet-induced steatosis, hyperglycemia and
insulin resistance compared to germ free mice that received
stool transferred from non-responder mice. These results
suggest that the fecal microbiota transfer susceptibility to
diet-induced steatosis and insulin resistance.
Another study demonstrated that the fecal microbiota can

also transfer susceptibility to NASH. When fed methionine
choline deficient (MCD) diets, mice with targeted disruption
of either the NLRP6 or NLRP3 inflammasome exhibited more
severe NASH than wild type mice. The inflammasome-deficient mice also exhibited an altered intestinal microbiome, increased influx of intestinally-derived TLR4 and TLR9 agonists
into the portal circulation, and increased hepatic expression
of the pro-inflammatory cytokine, TNFalpha. Wild type mice
that were co-housed with the inflammasome- deficient mice
were also more susceptible to MCD diet-induced NASH than
standard wild type mice. Treating the inflammasome-deficient mice with oral antibiotics reduced the severity of dietinduced NASH in those mice. It also abolished the transfer of
the NASH-susceptible phenotype to co-housed wild type mice.
These results demonstrate that the intestinal microbiota can
transfer susceptibility to NASH.
A third study showed that gut microbiota can transfer susceptibility to liver fibrosis. In this study, mice fed high fat diet
(HFD) before bile duct ligation (BDL) developed more severe
liver fibrosis than mice that were fed standard chow before
BDL. HFD feeding caused a dysbiosis. When stool from HFDfed mice were transferred to control mice before BDL, the
recipient mice developed worse liver fibrosis post-BDL than
BDL recipient mice that received stool from chow-fed mice.
A fourth study linked the gut microbiome to NAFLD-related
HCC. Mice that were exposed to a carcinogen and then fed a
HFD developed HCC. Treating the mice with oral antibiotics
reduced HCC formation and lowered HFD-related increases in
deoxycholic acid (DCA), a secondary bile acid that is produced
by certain gut bacteria. Adding back DCA restored HCC formation in antibiotic-treated, HFD-fed mice, proving that this
gut-derived product played a critical role in the pathogenesis
of HCC in this NAFLD model.
Taken together, these studies in rodent models of NAFL/NASH

suggest that changes in the microbiome that increase intestinal permeability (e.g., depletion of bacteria that produce certain short chain fatty acids) and/or enhance production of
certain secondary bile acids (e.g., enrichment with bacteria
that are able to 7a-hydroxylate primary bile acids) promote
susceptibility to NASH, liver fibrosis and liver cancer. These
findings have potential importance for human NAFLD, but additional research is required to investigate this issue given inherent species-related differences in bacterial flora, diets, and
bile acid metabolism. At this point, it is premature to recommend treatment with prebiotics, probiotics, antibiotics, or fecal transplantation as a therapy for human NAFLD.
Key Points
1 NAFLD is a very common, but heterogeneous, disease.

Most NAFLD patients have a benign liver prognosis,
but some develop a more serious form of liver damage
(NASH) that may progress to cirrhosis and/or primary
liver cancer.
2 The severity of liver fibrosis is the only factor that
independently predicts bad clinical outcomes of NAFLD
(i.e., eventual mortality, liver-specific morbidity, liver
transplantation). Only age and the histologic severity of
liver cell death/inflammation are independent predictors
of fibrosis in adults with NAFLD.
3 NAFLD diagnosis should focus on staging fibrosis +/identifying fibrosis correlates (risk factors) in order to
determine an individuals prognosis and personalize
treatment.
4 Treatments must inhibit liver fibrosis (i.e., reduce liver
cell death/inflammation) or reverse it to prevent bad
clinical outcomes of NAFLD.
5 The anti-fibrotic efficacies of currently available NAFLD
treatments are not well-established because most randomized placebo-controlled trials have enrolled mainly
patients with little/no fibrosis, and long term follow-up
of treatment responders is generally lacking.
6 The microbiome might be a new NAFLD diagnostic/
therapeutic target because it conveys susceptibility to
liver cell death/inflammation, fibrosis, and liver cancer in
animal models of NAFLD, and the microbiome is heterogeneous in humans.
7 Research in pre-clinical models suggests that dangerous gut microbiomes are enriched with bacteria that
generate secondary bile acids (e.g., deoxycholic acid), as
opposed to bacteria that generate short chain fatty acids
that promote intestinal barrier function. More research

is necessary to determine if the same is true in people,
how best to detect dangerous microbiota, and how to
engineer a more benevolent microbiome.
References
1. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and
non-alcoholic steatohepatitis in adults. Alimentary pharmacology &
therapeutics. 2011;34(3):274-85. PubMed PMID: 21623852.
2. Grandison GA, Angulo P. Can NASH be diagnosed, graded, and
staged noninvasively? Clinics in liver disease. 2012;16(3):567-85.
PubMed PMID: 22824481; PubMed Central PMCID: PMC3405360.
3. Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N,
Younossi ZM. Pathologic features associated with fibrosis in nonalcoholic fatty liver disease. Human pathology. 2004;35(2):196-9.
PubMed PMID: 14991537.
4. Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to treatment. Frontline gastroenterology.
2014;5(4):277-86. PubMed PMID: 25285192; PubMed Central PMCID: PMC4173737.
5. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G, Cassard-Doulcier
AM, Gerard P. Intestinal microbiota determines development of
non-alcoholic fatty liver disease in mice. Gut. 2013;62(12):1787-94.
6. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss
CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman
GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated
dysbiosis regulates progression of NAFLD and obesity. Nature.
2012;482(7384):179-85. PubMed PMID: 22297845; PubMed Central
PMCID: PMC3276682.
7. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi
C, Trozzi L, Mingarelli E, Facinelli B, Magi G, Palmieri C, Marzioni
M, Benedetti A, Svegliati-Baroni G. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology.
2014;59(5):1738-49. PubMed PMID: 23959503.
8. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S,
Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara
E, Ohtani N. Obesity-induced gut microbial metabolite promotes liver
cancer through senescence secretome. Nature. 2013;499(7456):97101. Epub 2013/06/28. PubMed PMID: 23803760.
Fecal Microbiota Transplantation: When Does It

Work (C.diff and beyond)? How to Do It? What
Are the Restrictions?
Lawrence Brandt, MD, AGAF, MACG, FASGE

Fecal Microbiota Therapy (FMT)

Who, What, When, and How
Lawrence J.
L
J B
Brandt,
dt MD
Conflicts of Interest
Cipac: Advisory
Ad isor
Board
Cubist: Advisory Board
Recurrent C.difficile Infection (CDI)
15-20% of patients
relapse
re-infection
i f i
2nd
ddx: post
post-infection
infection IBS
recurrence: 30-45%; 3rd recurrence: 45-60%

Relapses can continue for years
No universal Rx algorithm
Rx recommendations are not evidence-based
Rx of Recurrent CDI: 2013 ACG Guidelines

1st Recurrence: Can use same Rx as for initial episode; if severe, use Vanco
2nd Recurrence : Pulsed vanco regimen
Cond recommend
recommend, low quality evidence
3rd Recurrence: Pulsed-tapered Vanco; (no robust data)
- 125 mg daily pulsed Q3D for 10 doses
- qid tid bid qd regimen
- qid interval dosing (q2d, q3d, q4d)
Consider FMT
Cond recommend, low quality evidence
IV immune globulin (IVIG) may be helpful in hypo-gammaglobulinemic pts
Strong recommend, low quality evidence
Am J Gastroenterol, 2013
Recurrent CDI: Why Do We Get It?

Impaired host-response
Altered intestinal microbiome
Decreased Diversity of the Fecal Micro ()biome

i Recurrent
in
R
t CDI
Patients with recurrent CDI have decreased phylogenetic richness

Bacteroidetes and Firmicutes are reduced in patients with recurrent CDI
nott iin patients
ti t with
ith just
j t one episode
i d off CDI
Chang JY, et al. J Infect Dis 2008:197;435-8
Fecal Microbiota Transplantation

p
((FMT))
Definition: Instillation of stool from a healthy person into a sick person to
c re a certain disease
cure
Rationale: An imbalance in our intestinal microbiota (dysbiosis) is
associated with or causes disease and can be corrected by re
re-introduction
introduction of
donor feces
Avoid p
prolonged,
g , repeated
p
courses of antibiotics
Re-establish normal diversity of the intestinal microbiome, restoring
colonization resistance
Early History of FMT

4th century: Ge Hong described use of human fecal
suspension by mouth for food poisoning or severe diarrhea
Zghou Hou Bei Ji Fang (Handy Therapy for Emergencies)
16th century: Li Shizhen detailed prescriptions of fermented
fecal solution, fresh fecal suspension, dry feces or infant feces
for abdominal diseases with diarrhea, abdominal pain, fever,
vomiting and constipation; yellow dragon soup
Ben Cao Gang Mu (Compendium of Materia Medica )
17th century: veterinary medicine:
transfaunation (transfer of cecal contents or fresh feces) to treat horses with chronic diarrhea
rumen transfaunation (transfer of rumen liquor) to treat ruminal acidosis in cows, sheep
Later History of FMT

1958: Eismann et al.
4 pts with pseudomembranous colitis (Micrococcus pyogenes)
R d with
Rxd
ith FMT enema
1983: Schwann, et al.

CDI Rxd with FMT enema
Other methods of FMT
1991: NG tube (Aas, Gessert, Bakken)
1998: gastroscopy and colonoscopy (Lund-Tnnesen)
2000:
2000 colonoscopy
l
(Persky,
k Brandt
d)
2010: self-administered enemas (Silverman, Davis, Pillai)
Protocol for FMT in Recurrent CDI

Choose donor
any healthy person
universal donor
stool bank product
D
Donor
exclusions
l i
antibiotic use within 3 months
diarrhea, constipation, IBS, IBD, colorectal CA, immunocompromise,
anti-neoplastic
anti
neoplastic drugs,
high-risk behaviors: MSMP, recent body piercing or tattoo
other: diabetes, obesity, atopy, ASCVD...
? psychologic or mood disorder, neurologic disease...
Donor testing
stool: culture (incl Listeria, Vibrios), O & P, C. difficile,
H. pylori Ag, Giardia Ag, cryptosporidium, isospora, norovirus
blood: hepatitis A,
A B,
B C,
C syphilis,
syphilis HIV 1,
1 2
Protocol for FMT in Recurrent CDI

Recipient
p
D/C antibiotics 2-3 days before procedure?
Large-volume colonoscopy prep the evening before procedure
Loperamide before procedure?
Donor
Gentle laxative (e.g., MOM) the night before the procedure?
Freshly passed stool is used within 6 hours?
Stool need not be refrigerated
Protocol for Colonoscopic FMT

i Recurrent
in
R
t CDI
Stool Transplant
Donor stool suspension with non-bacteriostatic saline
mix by hand
mix by blender
Filtered through gauze into canister
Use of a hood (stool is a level 2 biohazard)
60 cc catheter-tip
p syringe
y g connected to suction tubingg
Volume of ~300cc instilled into ascending colon
The importance of commas
Max Brenner Chocolates in Bryant Park, N.Y.
Meta-analysis of Clinical Resolution Rates

(11of 2709 reports,
reports 273 patients)
Resolution:
90% overall
- lower: 91%
- upper: 82%
No AEs
Kassam et al . Amer J Gastroenterol, 2013
FMT for Treatment of CDI:

A Systematic Review
Site
of FMT
Stomach
#
of Pts
Dose of FMT
(mean g/mls)
Success
Rate (%)
109
25/68
81
97
63/252
86
Cecum/Asc Colon
214
93/281
93
Distal Colon
116
58/272
84
Duod/Jejunum
Cammarota G, Ianiro G, Gasbarrini, A. J Clin Gastroenterol, 2014
Nasoduodenal FMT for Recurrent CDI: a RCT

Study terminated by DSMB
AEs: transient cramping
cramping, belching
SAEs: none
van Nood E , Vrieze A , Nieuwdorp M et al. N Engl J Med 2013;368:40715
The 1st RCT did not signal the arrival of FMT
it was the 1st televised fecal transplant shown on

Greyss Anatomy,
Grey
Anatomy 11/20/08
> 3 Months Follow-up of FMT:

a Multi-center of 77 Patients
Mean
duration of illness: 11 months

Symptomatic response after FMT
mean of 6 days
< 3 days in 74%
Primary cure rate: 91 %
S
Secondary
d
cure rate:
t 98
98.7%
7%
97% of patients would have another FMT for recurrent CDI
and 58.3 % would choose FMT as their preferred Rx
Brandt LJ, et al. Am J Gastroenterol, 2012
Cure Rates and AEs of FMT

in 146 Patients > 65 years of Age
CDI (n)
Primary
cure rate
Secondary cure
rate
Transient
AEs
Serious AEs
R-CDI
(89)
82%
94.4%
11.2%
2.2%
S-CDI
(45)
88 8%
88.8%
97 7%
97.7%
4 4%
4.4%
4 4%
4.4%
C-CDI
(12)
67%
100%
0%
16.6%
Total
(146)
82.8%
95.8%
7.5%
4.1%
Agrawal M, Aroniadis O, Brandt L, et al, DDW, 2014

Agrawal M, Aroniadis O, Brandt L, et al, DDW, 2014
FMT in Severe, Complicated CDI

13 patients
severe 11 (84%); complicated 12 (92%)
average age: 70 years (38
(38-89)
89)
Symptom response
cure
diarrhea
9/12 (75%)
tenderness 6/8 (75%)
improved
p
3/12 (25)
2/8 (75%)
1 Cure: 11/13 (84%)

2 Cure: 12/13 (92%); 1 pt: long-term vanco Rx
Aroniadis, et al. Gastroenterology, 2013
Severe C. difficile colitis
FDA Regulations
Early 2013
2013. Fecal microbiota falls within the definition of a biologic product and a drug
drug.
Since FMT has not yet been approved by the FDA for any specific clinical indication, it
constitutes an investigational agent and requires an Investigational New Drug application
(IND) from Center for Biologics Evaluation and Research (CBER) .
May, 2013. Public workshop on FMT
July, 2013. FDA intends to exercise enforcement discretion regarding the use of FMT
products to treat C.
C difficile infection unresponsive to standard therapies
therapies
March, 2014. Guidance document for comment purposes
http://www.fda.gov/BiologicsBloodVaccines/GuidanceCompliance
RegulatoryInformation/Guidances/default htm
RegulatoryInformation/Guidances/default.htm.
800-835-4709, 301-827-1800
ocod@fda.hhs.gov
FDA Guidance
Document
March, 2014. FDA intends to exercise enforcement discretion on an interim basis regarding
the use of FMT products to treat C. difficile infection unresponsive to standard
therapiesprovided
e p esp ov ded that
1. the licensed health care provider obtains adequate informed consent . Informed consent
should include, at a minimum, a statement that the use of FMT products to treat C. difficile
is investigational and a discussion of its potential risks.
2. The FMT product is obtained from a donor known to either the patient or the treating
licensed health care provider.
3 The stool donor and stool are qualified by screening and testing performed under the
3.
direction of the licensed health care provider for the purpose of providing the FMT
product
FMTthe next steps

A. Frozen fecal material from a universal donor*
Donor Materiall
N
Success**
Recurrence
Pt-identified donor
Std donor, fresh
Std donor, frozen
Total
10
12
21
43
7/10 (70%)
11/12 (92%)
19/21 (90%)
37/43 (86%)
3/10 (30%)
3/33 (9%)
6/43 (14%)
4 of 6 patients with RCDI had a 2nd FMT (std donor)

all cleared their infection final success rate of 41/43 (95%)
B. Synthetic stool (33 bacterial strains) from healthy donor

(Repoopulate) #
2 patients cured of RCDI
C. 3 strains of Bacteroides (ovatus, fragilis, thetaiotaomicron)

1 patient cured of RCDI
*Hamilton, et al. Am J Gastroenterol 2012; # Petrov,, et al. Microbiome 2013; Graham, ACG. 2013
FMTthe next steps

p
D. Poop pills*: 27 patients took 24-34 pills all cured of RCDI
E. Oral, Capsulized Frozen FMT for Recurrent CDI %
20 ppatients ((15 capsules
p
x 2 d)) 1 cure rate: 70%
overall cure rate: 90%
F. Stool Banking
*Thomas
Louie, Univ of Calgary; ID week, 2013; %Youngster, et al. JAMA, 2014
Anatomy of a Robogut
Petrof EO, Khoruts A. Gastroenterology 2014
Therapeutic unit of full-spectrum microbiota
Petrof EO, Khoruts A. Gastroenterology 2014
FMT capsules (Crapsules)

Author
Dose
Louie, et al
24-34 caps
Youngster, et al
15 caps
Pardi, et al
1.5x109
1.0x108
# pts
27
20
15
15
Cure
100%
70% (1)
90% (2)
100%
93%
Louie, et al. ID week, 2013; Youngster, et al. JAMA doi:10.1001/jama.2014.13875;

Pardi, et al. ICAAC, 2014
OpenBiome
Ball Publishing
Lactate
Producers
SCFA
Producers
Methanogens
Mucin
Degraders
Fecal Microbial Transplant
Consortium
Specificity
Single strain
Bioactive
Molecule
Ecosystem Effects
Modified from Olle, B. Nature Biotechnology, 2013
Disorders Associated with an Altered biome

Gastrointestinal
cholelithiasis
colorectal cancer
hepatic encephalopathy
idiopathic constipation*
IBS*
IBD*
familial mediterranean fever
gastric carcinoma and lymphoma
recurrent CDI*
Non-gastrointestinal
Non-gastrointestinal
arthritis
asthma
atopy
autism*
autoimmune disorders
chronic fatigue syndrome
syndrome*
diabetes mellitus and insulin
resistance*
eczema
fatty liver
liver, alcoholic *
fibromyalgia*
hay fever
hypercholesterolemia
idiopathic thrombocytopenic
purpura*
ischemic heart disease
metabolic syndrome
syndrome*
mood disorders
multiple sclerosis*
myoclonus dystonia*
obesity
oxalic acid kidney stones
Parkinson disease*
* indicates some reports on improvement or cure with FMT
An Approach to biota and

Disease
se se
Association
causation
?
Organism specific effect
Koch postulates:
1. the organism must be found in all organisms
suffering
ff i from
f
th
the disease
di
(b
(butt should
h ld nott be
b found
f
d
in healthy organisms).
2. the organism must be isolated from a diseased organism and grown in pure culture.
3. the cultured
organism
g
should cause disease when introduced into a healthy
y organism.
g
4. The organism must be re-isolated from the inoculated, diseased experimental host and identified
as identical to the original causative agent.
Safety and Ethical Concerns

Acute
infections
bacterial,
b
i l viral,
i l parasitic
ii
colonic, systemic
Acute allergic reactions
Long-term concerns
is it possible that we are predisposing the recipient to (some, all) of the diseases
or conditions that the donor will develop in his/her lifetime?
Future Areas of Investigation

g
Indications
CDI: severe, complicated disease? 1st occurrence?
other GI diseases: IBD, IBS, constipation
non-GI diseases: diabetes, obesity, Parkinson, MS, autism?
Route and means of administration
Safety concerns:
short-term: infections, allergies
long-term: new diseases, altered microbiota
Product development
processed stool spec strains bioactive molecules
Solutions
Use the safest product possible
stool is most problematic
stool-derived product from a volunteer population is probably safer
bioengineered (commercial) product is safest
Monitor results carefully
national registry for all FMT
Bloating, Functional Bowel Disease and

Food Sensitivity: Non-Celiac Gluten-Sensitivity, the
Low-FODMAP Diet and Beyond?
Peter Gibson, MD
Professor and Director of Gastroenterology
The Alfred and Monash University
Bloating, Functional Bowel Disease

and Food Sensitivity: NonCeliac
Gluten Sensitivity, the
LowFODMAP Diet and Beyond?
Peter Gibson
Monash University and Alfred
H i l
Hospital
Ingestion
g
of food and IBS
Can trigger or aggravate IBS symptoms; e.g.,
84% off 197 patients identified
d
f d 1 ffood
d off 5
56 specified
f d
food items
FODMAPs (70%), dairy (49%), biogenic amines (58%),
hi t i
histamine-releasing
l
i ffoods
d (43%)
Bohn et al, Am J Gastroenterol 2013
Diet is the 1o behavioural factor manipulated by

women with IBS
Jamieson et al Clin Nurse Spec 2007
Multiple potential mechanisms via:
stimulating of mechanoreceptors, chemoreceptors
inciting inflammation and/or damage
altering gut microbiota
Dietary
y strategies
g
Have changed from patient-initiated and
whole food, patient-focussed strategies
to attention to specific
p
components
p
Indigestible or slowly absorbed shortchain carbohydrates (FODMAPs)
Gl t and
Gluten
d wheat
h t
FODMAPs
ligo Dii & Mono-saccharides
ono saccharides And Polyols
Fermentable OligoFructose in excess
of glucose
y
Polyols
Lactose
Oligosaccharides
Galacto-oligosaccharides (GOS)
Fructans (fructo-oligosaccharides)
FODMAPs: absorption
p
p
patterns
Osmotic +
POORLY ABSORBED IN ALL
Fermentation +++
Oligosaccharides:
Oli
h id fructo- (FOS) & galacto- (GOS)
No small intestinal hydrolases
SLOWLY ABSORBED IN ALL

Free fructose (i.e., fructose in excess of glucose)
Polyols: sorbitol, mannitol .....
Osmotic +++
Fermentation +
Proportion
p
p
passively
y absorbed ((~30%))
POORLY ABSORBED IN ONLY SOME
Osmotic +++
Fermentation ++
Lactose
L
10-95% depending upon ethnicity, other factors
Recognise lactose malabsorption via breath H2 testing
Major mechanisms of action of FODMAPs
Polyol
CH4
Oligosaccharide
g Fructose Fructose
H2
P l l
Polyol
Lactose
CO2
water delivery
Luminal distension
gas production
Visceral
hypersensitivity
Diarrhoea and/or constipation,

pain, bloating, wind
Barrett et al APT 2010; Ong et al JGH 2010;
Marciani et al GE 2010; Murray et al AJG 2014
Low FODMAP diet: principles

1. Education (best by a dietitian)
Education on principles
Information on food composition
W
Ways
off choosing
h
i ffoods,
d cooking,
ki
recipes
i
.
2. Dietary structure:
Top-down exchange diet
Avoid all foods high in FODMAPs (unsafe)
R l
Replace
with
i h ffood
d llow iin FODMAP
FODMAPs (
(safe)
f )
3. Strict for 4-6 weeks

4. Step-down according to tolerance if efficacy
Evidence-base for efficacy

Clinically-relevant improvement in ~70% IBS
Observational cohort studies (retro- & prospective)
RCT cross-over rechallenge
RCT cross-over all food supplied
high vs low FODMAP diets

typical Aussie intake vs low FODMAP
RCT cross-over dietitian-taught

RCT low FODMAP vs habitual diet
Non-randomised comparative study
Multiple centres and countries
Overall symptoms IBS (n=30)
70% had overall

Blinded any bowel habit,
Blinded,
habit all food supplied symptoms
t
>20
20 mm
P<0 001
P<0.001
Mean 22
22.8mm
8mm 95%CI [16.7[16.7
[16 77-28
28.8]
8]
45.7mm 95%CI [37.2-54.3]
P<0.001; repeated measures ANOVA
Halmos et al Gastroenterology 2014
Effect on specific symptoms in IBS (n=30)
P<0.001
Repeated measures ANOVA
P<0.001
P<0.001
P<0.001
Key
y to the low FODMAP diet
Must know what foods should be avoided and
what
h are safe
f
program of measurement of food content using
a combination of HPLC and enzymatic assays
(including international foods)
Muir et al JAFC 2008, 2009; Biesiekierski et al JHND 2011; Yao et al JHND 2013
Available in booklet and App (Monash University Low

FODMAP Diet App)
http://www.med.monash.edu/cecs/gastro/fodmap/
Role of breath hydrogen

y
g testing
g
Definition of lactose malabsorption
Useful as accuracy of patients belief they are lactose
intolerant low
Lactose-containing dairy products are an important
source of dietary
y calcium& vitamin D
Definition of fructose or sorbitol malabsorption

Poor reproducibility
p
y in many
y
Small intestinal distension and symptoms occur
independently of whether some is malabsorbed
Does not dictate dietary approach
Sucrose malabsorption
extremely uncommon
Small bowel water content after fructose load

independent of its malabsorption (breath H2)
Murray et al, Am J Gastroenterol 2014
Gluten and wheat intolerance

Dominance of confusion, claims and
counter claims about gluten as an
counter-claims
important agent in inducing functional
gut symptoms
p
of wheat-free and g
gluten-free
Epidemic
diets across the Western world
M
Major
j iissue iis that
h wheat
h
contains
i gluten
l
and non-gluten proteins, and FODMAPs
(
(particularly
i l l fructans)
f
)
Australian wheat-avoiders = 11% adults

Coeliac
disease
8%
No
symptoms
12%
CSIRO Food
F d&
Health Survey
Dec 2010-Feb 2011

n = 1184 18 years old
ld
Bloating, abdominal pain,

fatigue
Symptom
relief
80%
Mostly female who

like the alternative
but
b t nott neurotic,
ti ill
illogical,
i l
hypochondriacal
40% strictly gluten
glutenfree
Golley et al, Pub Health Nutr 2014
FODMAPs and gluten coexist in cereal products
Biesiekierski et al, J Human Nutr Dietetics 2011
Wheat intolerance
Allergic responses to gluten
& nongluten
g
p
proteins
Bakers asthma,
dermatitis,, WDEIA
T cell mediated responses

Tcell
to gliadin (gluten) peptides
Coeliac disease
Epithelial/innate immune
responses to wheat protein
Wheat protein
sensitivity: NCGS
Luminal distension via

fructans (FODMAPs)
Functional GI
symptoms: IBS
Non-coeliac
Non
coeliac gluten sensitivity (NCGS)
Definition:
Gut & other symptoms that respond to a gluten
gluten-free
free diet
Do not fulfil criteria for celiac disease
Wheat allergy excluded
Catassi et al Nutrients 2013
Problems:
No way of determining that gluten is inducing symptoms
No biomarkers all based upon symptoms
Epidemiology
Prevalence 0.5-13%!
Some (~20%) will have celiac disease
M li I f t ett all APT 2015
Molina-Infante
Wheat protein (FODMAP-free) rechallenge in nonceliacs

l
with
h gluten-free
l
f
d
diet-responsive IBS (NCGS)
worst
P=0.047
Change in overall symptoms

n=19
n=15
(19)
(15)
*p=0.047
Independent Samples
t-test
none
Biesiekiesrki, et al Am J Gastroenterol 2011
Randomized, placebo-controlled, cross-over rechallenge

study of FODMAP-deplete wheat protein vs whey vs
placebo in NCGS (n=37)
All food provided

Low FODMAP
Only 3 subjects had a glutenspecific response

Biesiekierski et al Gastroenterology 2013
Overall symptom severity score during low

FODMAP run-in
run in (+ GFD)
Biesiekierski et al Gastroenterology 2013
Non-IgE-mediated hypersensitivity to wheat

proteins
t i
>900 consecutive IBS
Basophil activation
test +ve wheat in 80%
~30% +ve DB wheat challenge
Respond to
di
dietary
restriction
75% +ve milk/other

proteins
24% wheat
h
only
l
Respond to
di
dietary
restriction
90% IELs eosinophils in duodenum

75% intra-epithelial eosinophils in colon
Caroccio et al Am J Gastroenterol 2013
Confocal laser endomicrosocopy

(CLE) following food challenge
22/36 IBS +ve CLE lesions
wheat
h
13,
13 milk
ilk 9,
9 yeast 6,
6 soy 4
IEL count >25/100 EC in 70%
Fritscher-Ravens et al, Gastroenterology 2015
Conclusions wheat p
protein vs FODMAPs
Wheat protein sensitivity is real but not as
gg
common as many have suggested
FODMAPs are a major inducer of symptoms in
wheat intolerance
Low FODMAP diet greater symptom benefit than
wheat avoidance/gluten-free diet as empiric Rx
BUT
If we can identify minority with dietary protein
sensitivity,
iti it th
then might
i ht b
be able
bl tto correctt
pathophysiological abnormalities
Will not need a low FODMAP diet
Need reliable biomarker
Risks of dietary
y manipulation
p
Extra cost time, $$
Social consequences
Psychological consequences
Creation of the dietary
dietary cripple
cripple
Precipitation of an eating disorder (orthorexia nervosa)
Nutritional inadequacy
q
y
Inadequate intake of calcium when dairy restricted
Inadequate intake of dietary fibre when CHO restricted
Unfavourable effects on gut microbiota; e.g.,

Strict FODMAPs
absolute bacterial abundance
Butyrate-producing & mucus-associated bacteria associated with health
Halmos et al Gut 2015
Which dietary
y strategy?
gy
Management of IBS is multimodal
diet is only one possible parts of the strategy
for the individual
Depend upon the clinical scenario

Not interested in diet?
Major psychological co-morbidities
High risk of eating disorder
Already on gluten-free/other restrictive diet
Suggested clinical approach

New to dietary therapy
Celiac disease excluded
Psychological or
psychiatric
assessment first
yes
Risk of eating
disorder?
Interested in
dietary therapy?
no
no
Nondietary
therapy
yes
Low FODMAP
diet
Good
response
Stepdown
according to
tolerance
further
education
Poor
response
Cease
FODMAP
restriction
Other diets
?gluten-free
?low chemical
?exclusion
References/further
/
reading
g
FODMAPs
gy ((Suppl.)
pp ) May
y 2015
Gibson et al,, Gastroenterology
Tuck et al,. Expert Rev Gastroenterol Hepatol 2014;8:819-34
Halmos et al, Gastroenterology 2014;146:67-75
Halmos
H l
ett al,l Gut
G t 2015;64:93-100
2015 64 93 100
Murray, Am J Gastroenterol 2014;109:110-9.
Wheat/gluten
Golley et al, Public Health Nutr 2015;18:490-9
Catassai et al Nutrients 2013; 5:3839-53
Molina-Infante et al, Aliment Pharmacol Ther 2015 on line
Biesiekierski et al, Gastroenterology 2014;145:320-8.
al, Am J Gastroenterol 2013;108:1845
2013;108:1845-52
52
Caroccio et al
Fritscher-Ravens et al, Gastroenterology 2014;147:1012-20
Learning objectives
Upon completion of this session, the participant
should be able to understand:
That the recent focus of dietary manipulation to
reduce IBS symptoms & bloating has shifted to specific
food components.
The concept of manipulating slowly absorbed or
indigestible short-chain carbohydrates (FODMAPs).
The controversy around gluten and wheat proteins in
diagnosis and management.
The efficacy, implementation, limitations and risks of
such dietary strategies
Initiating Therapies for Inflammatory Bowel Disease:

When to Start What, How to Adjust and Monitor
Bruce E. Sands, MD, MS, AGAF

Chief of the Dr. Henry D. Janowitz Division of Gastroenterology
Mount Sinai Health System
New York, NY
Learning Objectives:

able to
1. Describe the appropriate indications for available
medical therapies to treat Crohns disease and ulcerative colitis
2. Incorporate the measurement of drug levels into the
management of inflammatory bowel disease
3. Outline risk-stratified approaches to treating patients
with Crohns disease who are newly diagnosed, have
perianal fistula or who have undergone ileocolonic
resection, or who have ulcerative colitis.
The goals of medical therapy in inflammatory bowel disease

(IBD) are to 1) induce symptomatic remission; 2) maintain steroid-free remission; 3) enhance quality of life; 4) prevent/treat
complications of disease; and 5) avoid short and long term
toxicity of therapy. Increasingly, we have come to understand
that achieving these goals requires a sophisticated approach
that tailors therapy to each patient, involving attempts to risk
stratify the patient, optimizing each therapy, and monitoring
for objective evidence of resolution of inflammation.
Although the number of medications available to treat Crohns
disease (CD) and ulcerative colitis (CD) has increased in the
last 15 years, with the important addition of biologic therapies,
including anti-TNF antbodies such as infliximab, adalimumab, certolizumab pegol (for CD) and golimumab (for UC), and
more recently, vedolizumab, an anti-47 integrin antibody,
the number of agents remains relatively small. Therefore, it is
essential that the clinician understand the appropriate indications for each class of agent, their expected efficacy and time to
onset of effect, and ways of optimizing treatment. Such optimization may include using combinations of medications as well
as therapeutic drug monitoring and dose modification.
5-Aminosalicylates
5-Aminosalicylates (5ASA) are effective in mild to moderate
ulcerative colitis, and may induce remission in 2 to 8 weeks.
Little, if any, clinical benefit has been described in Crohns
disease. In ulcerative colitis, the many different preparations
available are equally effective, with little difference noted in
rates of remission. Higher doses (in the range of 4 to 4.8 g/d)
are not more effective than doses in the range of 2 to 2.4 g/d,
but may be more effective in those with moderate disease, and
in those patients with previous exposure to other therapies.
It is useful to give 5ASAs once daily to improve adherence,
with no decrease in efficacy. Combining oral and rectal 5ASA
is more effective in both distal and extensive disease. Once
remission has been achieved, continuing 5ASA is effective in
maintaining remission.
Corticosteroids
Newer preparations of corticosteroids (controlled ileal release budesonide for CD, budesonide MMX for UC, and topical preparations such as budesonide foam) are useful in mild
to moderate CD and UC. For patients with moderate disease
that is refractory to these preparations, conventional oral
Figure 1. Medications used in the treatment of inflammatory corticosteroids such as prednisone may be effective, while
bowel disease. Medications are generally chosen according to for those who are severely ill or refractory to oral corticostethe severity of disease. Antibiotics are useful in Crohns disease roids, intravenous corticosteroids may prove effective. In UC,
in the treatment of penetrating disease and in post-surgical hydrocortisone enemas are less effective than mesalamine enprophylaxis, while cyclosporine may be used in severe acute emas. Systemic corticosteroids are neither safe nor effective
ulcerative colitis. Natalizumab is rarely used due to the risk for long term maintenance therapy, and preparations such as
of progressive multifocal leukoencephalopathy. It should be budesonide CIR should only be used as maintenance therapy
noted that, apart from antibiotics and 5-aminosalicylates at the in rare circumstances. Corticosteroids are generally rapidly
mild spectrum and cyclosporine and natalizumab at the severe effective, within a few weeks of initiation. The need for sysspectrum, the other classes of agents are used across a wide temic corticosteroids has been shown repeatedly to portend
spectrum
of disease activity,
necessarily
in the order in
an disease.
unfavorable
prognosis
ingenerally
both CD and
UC, and is associated
Figure 1. Medications
used inand
thenot
treatment
of inflammatory
bowel
Medications
are
chosen
which
they
are
depicted.
with
steroid
dependence
in
at
least
25%
of
according to the severity of disease. Antibiotics are useful in Crohns disease in the treatment of penetrating patients; therefore,
plans for
steroid
sparing therapy
should
be initiated early.
disease
and
in post-surgical
prophylaxis,
while
cyclosporine may be used in severe acute
Crohns Disease
Ulcerative Colitis
Immune modulators
ulcerative
colitis. Natalizumab is rarely used due
to
the
risk
of progressive
multifocal and azathioprine, and
Severe
The thiopurines,
mercaptopurine
Cyclosporine
Natalizumab
leukoencephalopathy.
It
should
be noted that, agents, and have
methotrexate are valuable as steroid-sparing
apart
from
antibiotics
and
5-aminosalicylates
at with biologInfliximab
Infliximab
also found a new role in combination therapy
Anti-TNF Abs
Adalimumab
Adalimumab
the
mild
spectrum
and
cyclosporine
and
ics to reduce immunogenicity. Measuring thiopurine methGolimumab
Certolizumab pegol
natalizumab
at(TPMT)
the severe
spectrum,
the otherprior to initiation
yltransferase
activity
or genotype
Anti-47 integrin Ab
Vedolizumab
Vedolizumab
classes
of agentswill
arereduce,
used across
a wide
of thiopurines
but not
eliminate, the risk of early
spectrum
of in
disease
activity,
and
necessarily
leukopenia
the roughly
9%
of not
individuals
with intermediate
?Methotrexate
Methotrexate
inTPMT
the order
in which
they serious
are depicted.
activity,
and more
bone marrow suppression in
Mercaptopurine/
Immune Modulators
Mercaptopurine/
Azathioprine
Azathioprine
the 1/300 Caucasians who are deficient, if dosing is reduced
or avoided altogehter. When appropriate weight-based dosing
Corticosteroids
Corticosteroids
Corticosteroids
of thiopurines does not achieve benefit in the 8 to 16 weeks
Budesonide MMX
Budesonide CIR
Budesonide foam
expected for onset of effect, measurement of the metabolites
6-thioguanine (6TGN) and 6-methymercaptopurine (6MMP)
5-Aminosalicylates
Antibiotics
Mild
will help to diagnose potential reasons for lack of efficacy.
6TGN greater than 235 is associated with higher likelihood of
5-Aminosalicylates
5-Aminosalicylates (5ASA) are effective in mild to moderate ulcerative colitis, and may induce remission in 2 to 8
weeks. Little, if any, clinical benefit has been described in Crohns disease. In ulcerative colitis, the many different
Initiating Therapies for Inflammatory Bowel Disease: When to Start What, How to Adjust and Monitor
response, while 6MMP/6TGN ratio >12 is associated with lack

of response due to shunting of drug to 6MMP. Low levels of
both metabolites indicates noncompliance with therapy.
Methotrexate is also useful as a steroid sparing agent in Crohns

disease, with some recent evidence also suggesting that patients with ulcerative colitis may also achieve steroid sparing.
Methotrexate is also used in combination with biologic therapy
to reduce immunogenicity, and may be considered in young
male patients (<35 years of age) who are concerned about the
very rare risk of hepatosplenic T cell lymphoma associated with
thiopurines alone or in combination with anti-TNF antibodies.
Biologic Therapies
Abundant evidence from clinical trials and observational studies demonstrates the efficacy of anti-TNF antibodies in a wide
variety of clinical situations. Generally reserved for moderate
to severe CD or UC, anti-TNF antibodies are also appropriate
for selected patients with CD who are at high risk of complicated or progressive disease. Evidence supports the efficacy
of infliximab and adalimumab as treatments for fistulizing CD,
and infliximab appears to have about the same efficacy as cyclosporine in the treatment of patients with severe UC refractory to intravenous corticosteroids. The use of TNF antagonists
in postoperative prophylaxis of CD remains controversial, with
clear benefit in reducing endoscopic recurrence, but without
clear demonstration of prevention of symptomatic recurrence
as yet.
Vedolizumab is effective in both UC and CD in patients who
have failed corticosteroids, immune modulators or anti-TNFs.
However, the rates of efficacy are diminished in patients with
prior anti-TNF antibody treatment. Particularly in patients with
CD who have had prior treatment with anti-TNF, time to onset
of effect is longer, and requires completion of the 3rd induction
dose at week 6, and waiting at least 10 weeks to assess benefit.
All biologic agents, whether chimeric, humanized or human,

have the potential to generate anti-drug antibodies, resulting
in decreased serum drug levels and loss of response. Therefore, all patients treated with biologics should be considered
for combination therapy with an immune modulator. Measurement of both serum trough levels and anti-drug antibodies appears to be most useful in the situation of inadequate response
or loss of response. When significant levels of anti-drug antibodies can be detected, switching to an alternate agent within
class is an effective and cost-effective strategy. Patients with
adequate serum trough levels, but demonstrable active inflammation, should switch out of class. Other patients may have low
serum trough levels but no significant antibodies, essentially
rapid clearance of drug through a variety of mechanisms. With
supratherapeutic levels of drug it may be possible to decrease
dose without reduced efficacy, with significant cost savings.
References
1: Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel
disease. J Gastroenterol Hepatol. 2005 Aug;20(8):1149-57. Review.
2: Vermeire S, Gils A. Value of drug level testing and antibody assays in optimising biological therapy. Frontline Gastroenterol. 2013
Jan;4(1):41-43. Epub 2012 Sep 5. PubMed PMID: 23293739; PubMed
Central PMCID: PMC3533399.
3: Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy
R, DHaens G, Ben-Horin S, Xu J, Rosario M, Fox I, Parikh A, Milch
C, Hanauer S. Effects of vedolizumab induction therapy for patients
with Crohns disease in whom tumor necrosis factor antagonist
treatment failed. Gastroenterology. 2014 Sep;147(3):618-627.e3.
doi: 10.1053/j.gastro.2014.05.008. Epub 2014 May 21. PubMed
PMID: 24859203.
4: Sandborn WJ, Hanauer S, Van Assche G, Panes J, Wilson S, Petersson J, Panaccione R. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J Crohns
Colitis. 2014 Sep 1;8(9):927-35. doi: 10.1016/j.crohns.2014.02.021.
Epub 2014 Apr 6. PubMed PMID: 24713173.
5: Antunes O, Filippi J, Hebuterne X, Peyrin-Biroulet L. Treatment
algorithms in Crohns - up, down or something else? Best Pract
Res Clin Gastroenterol. 2014 Jun;28(3):473-83. doi: 10.1016/j.
bpg.2014.05.001. Epub 2014 May 17. Review. PubMed PMID:
24913386.
6: Hashash JG, Regueiro MD. The evolving management of postoperative Crohns disease. Expert Rev Gastroenterol Hepatol. 2012
Sep;6(5):637-48. doi: 10.1586/egh.12.45. Review. PubMed PMID:
23061713.
7: Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and treatment of perianal fistulas in Crohn disease. Ann Intern Med. 2001
Nov 20;135(10):906-18. Review. PubMed PMID: 11712881.
8: Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle
G, Van Steen K, Simoens S, Rutgeerts P, Gils A, Vermeire S. Trough
Concentrations of Infliximab Guide Dosing for Patients with Inflammatory Bowel Disease.

Gastroenterology. 2015 Feb 24. pii: S0016-5085(15)00253-X. doi:

10.1053/j.gastro.2015.02.031. [Epub ahead of print] PubMed PMID:
25724455.
Initiating
g Therapies
p
for IBD:
When to start what, how to adjust
and monitor
Bruce E
E. Sands
Sands, MD,
MD MS,
MS AGAF
Chief of the Dr. Henry
y D. Janowitz Division of Gastroenterology
gy
Mount Sinai Health System
N
New
Y
York,
k NY
Overview
Key information about the medications
General approach and goals of therapy
Putting it together in clinical scenarios
Learning Objectives
Upon completion of this session
session, the participant should be
able to
1 Describe the appropriate indications for available
1.
medical therapies to treat Crohns disease and
ulcerative colitis
2. Incorporate the measurement of drug levels into the
management of inflammatory bowel disease
3. Outline risk-stratified approaches to treating patients
with Crohns disease who are newly diagnosed, have
perianal
i
l fifistula
l or who
h h
have undergone
d
il
ileocolonic
l i
resection, or who have ulcerative colitis.
Goals of Therapy
py
Induce symptomatic remission
Maintain steroid-free remission
Enhance quality of life
Prevent/treat complications of disease
Avoid
A id short
h t and
d llong tterm ttoxicity
i it off therapy
th
How to achieve g
goals of therapy?
py
Risk stratification
Optimize each medication
Monitor for and act upon objective evidence of
inflammation
Medications for IBD

Crohns Disease
Infliximab
Adalimumab
Certolizumab pegol
Vedolizumab
Methotrexate
Mercaptopurine/Azathi
oprine
i
Corticosteroids
Budesonide CIR
Antibiotics
Ulcerative Colitis
Biologics
Cyclosporine
Infliximab
Adalimumab
Golimumab
Anti-47 integrin Ab
Vedolizumab
Anti-TNF Abs
Immune Modulators
Corticosteroids
?Methotrexate
Mercaptopurine/Azathiop
ne
Corticosteroids
Budesonide MMX
Budesonide foam
y
5-Aminosalicylates
Medications for IBD

Crohns Disease
Infliximab
Adalimumab
Certolizumab pegol
Vedolizumab
Methotrexate
oprine
i
Ulcerative Colitis
Biologics
Cyclosporine
Infliximab
Adalimumab
Golimumab
Anti-47 integrin Ab
Vedolizumab
Anti-TNF Abs
Immune Modulators
Penetrating disease
Corticosteroids
Post-operative
operative Corticosteroids
Post
Budesonide
CIR
prophylaxis
Antibiotics
?Methotrexate
ne
Corticosteroids
Budesonide MMX
Budesonide foam
y
5-Aminosalicylates
Medications for IBD

Severe acute
UC
Ulcerative
Colitis
Crohns Disease
Infliximab
Adalimumab
Certolizumab pegol
Vedolizumab
Methotrexate
oprine
i
Biologics
Cyclosporine
Infliximab
Adalimumab
Golimumab
Anti-47 integrin Ab
Vedolizumab
Anti-TNF Abs
Immune Modulators
Penetrating disease
Corticosteroids
Post-operative
operative Corticosteroids
Post
Budesonide
CIR
prophylaxis
Antibiotics
?Methotrexate
ne
Corticosteroids
Budesonide MMX
Budesonide foam
y
5-Aminosalicylates
5-Aminosalicylates
Small clinical benefit in CD1
Effective for induction of remission2; generally in 2 to 8 weeks
No difference in rates of induction of remission among various
preparations2
High dose not more effective than moderate dose in mild disease;
possibly more effective in moderate disease and those exposed to
prior therapy3
Once daily as effective as split dosing and better adherence4
Combination of oral and rectal 5ASA more effective in distal and
extensive disease5,6
All doses effective for maintenance of remission2
1Clin
Gastroenterol Hepatol 2004;2:379-388

2Cochrane Database of Systematic Reviews, 17 OCT 2012 DOI: 10.1002/14651858.CD000543.pub3
3Sandborn WJ
WJ, et al
al. Gastroenterology 2009
4Lichtenstein GR, et al. Clin Gastroenterol Hepatol 2007
5Safdi M, et al. Amer J Gastroenterol 1997;92:1867
6Marteau P, et al. Gut 2005;54:960965
Corticosteroids: Topical and Budesonide

Steroid enemas, foam, suppositories effective for
induction of remission in mild to moderate UC
o Hydrocortisone enema less effective than mesalamine enema
Budesonide effective for induction of remission in mild to
moderate ileocolonic CD (CIR), UC (MMX),
proctitis/proctosigmoiditis (foam)
o Limited
Li it d role
l iin maintenance
i t
off remission
i i
Corticosteroids: Oral
Effective for induction of remission,
remission no role in
maintenance
Indicated for those failing 5ASAs
5ASAs, budesonide
budesonide,
moderately severe disease
Poor side effect profile
May be used in combination with an anti-TNF to induce
remission in moderate to severe CD
Doses >60 mg/d not more effective
Effective in 1 to 3 weeks
Anticipate steroid dependence in ~25% of patients
IV Steroids
Indicated for severe flare, not responding to oral
steroids,
id other
h therapies
h
i
No need to give more than 60 mg methylprednisolone or
300 mg h
hydrocortisone
d
ti
Can give once daily
Response generally occurs within 5-7 days!
~60% of patients completely respond to IV steroids
Truelove
T
l
SC
SC, Jewell,
J
ll DP.
DP Lancet
L
t 1974
Truelove SC et al. Lancet 1978
Jarnerot G, et al. Gastroenterology 1985
Gustavsson A, et al. Am J Gastroenterol 2007
Thiopurines: Mercaptopurine and

Azathioprine
Indications
o Steroid-dependence/refractoriness
o As part of combination therapy with biologics
o Post-operative
P t
ti prophylaxis
h l i (CD)
o Fistulas (CD)
TPMT testing advised before starting
Dosing
o Mercaptopurine: 1 1.5
1 5 mg/kg
o Azathioprine:
2 3 mg/kg
Onset of effect: 8 16 weeks
Metabolite testing helpful in inadequate response
Interpreting Thiopurine Metabolites
6TG
GN
450
235
Non-compliance
6MMP
Gearry RB et al. J Gastroetnerol Hepatol 2005; 20(8):1149-57
3,500
6TG
GN
450
235
Under-dosing
Under
dosing
6MMP
3,500
6TG
GN
450
Thiopurine Resistance
(if not responding)
235
6MMP
3,500
6TG
GN
450
Thiopurine resistance
6MMP:6TGN > 12
235
6MMP
3,500
6TG
GN
450
Li er Tox
Liver
To
235
6MMP
3,500
Methotrexate
Indications
o Steroid-dependence
o Steroid-refractory
o As
A partt off combination
bi ti therapy
th
with
ith biologics
bi l i
Dosing
o SC or IM:
25 15 mg weekly
o PO:
7.5 - 15 mg weekly
Onset of effect: 8 16 weeks
Anticipate nausea (folate, ondansetron)
Effective contraception needed
Monitor AST, ALT, bilirubin, albumin
Feagan BG, et al. N Engl J Med 1995;332:292-7.
Anti-TNF Antibodies
CD: infliximab
infliximab, adalimumab,
adalimumab certolizumab pegol
UC: infliximab, adalimumab, golimumab
Indications
o Moderate to severe disease
o Steroid
Steroid-dependent/refractory
dependent/refractory disease
o Refractory to immune modulators
o Severe, IV steroid-refractoryy UC
o Fistulizing CD
o Selected patients with early CD
o ?Post-operative prophylaxis of CD
Onset of effect: 2 -6 weeks
Therapeutic Drug Monitoring (TDM) of

Anti-TNF Antibodies
Minimum effective concentration roughly defined
o IFX trough ~3 g/mL1
2
o ADA trough
g ~5 g/mL
g
Role of TDM best established in assessing loss of
p
response
Growing interest in early TDM to dose optimize in severe
disease (especially UC)3,4
TDM appears to be cost effective when dose-reduction
incorporated into treatment algorithm, but will be highly
dependent upon cost and frequency of assay5
1Bortlik
M, et al. J Crohns Colitis 2013;7:736-743.

X ett al.
X,
l Am
A J Gastroenterol
G t
t
l 2014;109:1250-6.
2014 109 1250 6
3Murthy S, et al. Presented at DDW; May 19, 2012. Abstract Sa2047.
4Vande Casteele N, et al. Gastroenterology 2015, in press.
5Steenholdt C, et al. Gut 2014;63:919-27.
2Roblin
R bli
Management of loss of response to

anti-TNF antibodies
Symptoms
suggestive
of relapse
Trough
levels
detectable
Trough
levels
undetectable
Endoscopy
shows
inflammation
Endoscopy
shows no
inflammation
Antibodies high
No or low
antibodies
Switch to drug
with different
mode of
action
R/O stenosis,
consider
id
treating IBS
Switch within
class
Optimize within same

anti-TNF
ti TNF (d
(dose
intensify, add IMMOD)
Adapted from Vermeire S, Gils A. Frontline Gastroenterology 2013;4:4143
Vedolizumab
Indications
o
o
Active UC or CD despite corticosteroids, immune modulators, or antiTNF1,2

Effective in steroid sparing1,2
Dose: 300 mg IV weeks 0, 2, 6 and every 8 wk

Onset of effect
as early as 2 weeks
6 to 8 weeks more typical
at least 10 weeks needed in CD with prior anti-TNF3
Consider using in combination with immune modulator
1Sandborn
et al, N Engl J Med 2013;369:711-21

et al, N Engl J Med 2013;369:699-710
3Sands BE, et al. Gastroenterology 2014;147:618627
2Feagan
Putting it together in specific clinical

situations
Acute severe UC
New diagnosis CD: top-down?
Perianal fistulizing CD
Postoperative prophylaxis of CD
Prognostic factors in ulcerative colitis

Greater extent of disease
Failure of 5ASA/need for corticosteroids (especially for
first flare)
Deep ulceration
High CRP
CRP, ESR
Low albumin
Severe acute ulcerative colitis

Switch from oral to IV steroids may be effective
Stop 5ASAs
Decision for next steps in 3 days (not more than 5)
Cyclosporine and infliximab roughly same efficacy1
Infliximab:
I fli i b consider
id iinduction
d ti d
doses hi
higher
h th
than
standard 5 mg/kg at weeks 0, 2 and 6
1Laharie
D, et al. Lancet 2012; 380: 190915
Evolving
g treatment strategies
g
for Crohns disease
Sandborn WJ, et al. J Crohns Colitis. 2014;8:927-35.
Early disease: Who should get top-down?

Early Crohns Disease
(Moderate To Severe)
High risk for rapid progression to bowel
damage and disability
Potential predictors from literature
- Early onset (<40 yrs)
- Small bowel involvement
- Perianal
P i
l di
disease att diagnosis
di
i
- Endoscopic severe lesions
Potential predictors in clinical practice

- Diagnosis age <40 yrs
- Extensive anatomic involvement
- Perianal or severe rectal disease
- Deep ulcers
- Prior surgical resection
- Stricturing and/or penetrating behavior
NO
YES
Early top-down
IMM + TNF antagonist
i
Accelerated step-care
IMM + TNF antagonist
i
Fail to respond
TNF antagonist
t
i t IMM
Sandborn WJ, et al. J Crohns Colitis. 2014;8:927-35.
Management of Crohns disease:

from the start
Antues O, et al. Best Pract & Res Clin Gastroenterol 2014;28:473483
Management of Perianal Fistulzing CD

DIAGNOSTIC EVALUATION
Fistula Type?
Superficial
Not superficial
Tacrolimus
Failure
Noncutting Seton Abx

Antibiotics + AZA/6-MP
+/- Anti-TNF
Failure
Fistulotomyy
+ Short Course
of Antibiotics
Failure
Definitive Surgery
Failure
Maintenance Therapy With

AZA/6-MP or Anti-TNF
Adapted from Schwartz DA et al. Ann Int Med. 2001;135:906.
Observe
Postoperative Prophylaxis in CD
Low Risk
Moderate Risk
High Risk
No Meds
6MP or AZA
metronidazole
Anti-TNF
Colonoscopy 6-12
months post-op
Colonoscopy 6-12
months post-op
No
Recurrence
Recurrence
No
Recurrence
Recurrence
Colonoscopy
every 1-3 yrs
Immunomodulator
or anti-TNF
Colonoscopy
every 1-3 yrs
anti-TNF or
change biologics
Long-standing
<10yrs
Penetrating
CD, long
CD,
stricture
disease,
1st surgery,
or
> inflammatory
2 short
surgeries
stricture
CD
Adapted from Hashash JG, Regueiro MD. Expert Rev Gastroenterol Hepatol 2012;6:637-48.
Courtesy of Miguel Regueiro, MD
Conclusions
Know the indications/limitations of each therapy
Choose therapy according to individual risk
Set appropriate expectations for time to onset
Monitor for and act upon objective evidence of
inflammation; symptoms may be misleading
Optimize each medication
Contingency plan for lack of response after
adequate
d
t trial
ti l
New approach to treatment of IBD:

Treat to target
Active Symptoms
Periodic
reassessment
of symptoms
and
inflammation
Objective
evidence of
inflammation
No
Symptomatic
Treatment
Yes
New treatment begun
Reassess for symptoms
And objective inflammation
STOP
Treatment
t0
Appropriate
treatment
duration
t1
BNo
Optimi e
Optimize
dosing
ANo
Symptoms
resolved?
eso ed?
Inflammation
improved?
Yes
CONTINUE
Treatment
What is the Endpoint: Can You Stop Treatment,

When to Switch Agents and To What?
David Rubin, MD, AGAF, FACG, FACP

Chief, Section of Gastroenterology, Hepatology and Nutrition
Co-director, Digestive Diseases Center
The University of Chicago Medicine
What is the endpoint?

Can You Stop Treatment,
When to Switch Agents and to
What?
David T. Rubin,, MD,, FACG,, AGAF,, FACP
Chief, Section of Gastroenterology, Hepatology and
Nutrition
Co-Director, Digestive Diseases Center
Evolving Endpoints of IBD
Major Advances in Inflammatory Bowel Disease

in the Last 10 years
Great availability of novel therapies
approved by the FDA
Evidence of efficacy over placebo
Evidence of safety
Development of prognostic models

and tools to communicate risk of
disease and intervention of therapies
Movement off disease
d
management
goals from symptom-based to more
objective disease parameters
Comparative effectiveness studies
Movement to Objective Measures of Control and

Chronic Care Model of IBD: Improved Outcomes
Goal
Clinical parameters
Outcomes
Response
Improved symptoms
Improved QoL
Remission
No symptoms
Normal labs
Decreased
D
d
hospitalization
Deep remission
Normal endoscopy
Mucosal healing
Avoidance of surgery
Minimal/no disability
SUSTAINED DISEASE CONTROL
Achieving Deeper Remission

Achieving deeper remission possible
Enables more stable disease control
Implies that lower intensity maintenance therapy may be
possible
But in whom? And When?
Endoscopic Mucosal Healing is Associated with

Preferred Outcomes
Reduction in relapse
Increased steroid-free remission
Improved quality of life
Reduction in hospitalizations and surgeries
Neurath MF, et al. Gut. 2012;61(11):1619-35.

Sandborn WJ, et al. Gastroenterology. 2009;137(4):1250-60.
Froslie KF, et al. Gastroenterol. 2007;133(2):412-22.
Colombel JF, et al. Gastroenterol. 2011;141(4):1194-201.
Feagan BG, et al. Am J Gastroenterol. 2007;102(4):794-802.
Mucosal Healing Can Be Achieved with

Incremental Therapy Adjustments
Retrospective analysis of patients undergoing colonoscopy for UC:
1.
2.
Treated to target of mucosal healing: Dose adjustments in therapy.

Not treated to target of mucosal healing: No change in therapy.
Mucosal healing
Bouguen G et al. Inflamm Bowel Dis 2014;20(2):231-9.
Histologic healing
Introducing Deeper Remission

Histological Normalization is Possible in UC and Associated with Better
Outcomes
Histological quiescence vs. CHN: HR

3.37 [95% CI: 1.11-10.30, p = 0.033]
Histological activity vs. CHN: HR
5.63 [95% CI: 1.69-18.76, p = 0.005]
Christensen B, et al. Presented at ECCO; February 3, 2015.
Clinical Assessment of Disease Control

Routine inquiry regarding stability of disease
control (stable maintenance between doses)
Strict adherence to maintenance regimen
Ongoing laboratory assessment of clinical stability
Increasing utilization of surrogate markers of
inflammatory activity (fecal calprotectin)
Silent Crohns Patients (Asymptomatic with Elevated CRP)

Have 6
6-Fold
Fold Higher Risk of Hospitalizations
178 CD patients
ti t with
ith clinical
li i l
remission
Vargas et al. Presented at DDW; May 20, 2013. Abstract 557.
Majority of hospitalizations in asymptomatic

pts with elevated CRP occur within first 12
months of clinic visit
when CRP elevation was detected
Therapeutic Monitoring to
Pre emptively Adjust Dosing
Pre-emptively
C
Could
ld allow
ll
d
dose adjustment
dj t
t prior
i tto lloss off response to
t
drug and clinical relapse
Will identify patients at high risk of subsequent ADA and
loss of response1
May allow for dose reduction of anti
anti-TNF
TNF therapy
Less drug, less direct costs
Possibly avoiding AEs associated with high therapeutic
exposure (?)
1Vermeire
S et al. Gut. 2007;56(9);1226.
Prospective Therapeutic Drug Monitoring to

Optimize
Opt
e Infliximab
ab Maintenance
a te a ce Therapy
e apy in
IBD
Retrospective cohort of patients in clinical remission,

remission single physician practice
IFX dose optimization to trough concentrations 510ug/mL (n=48)
No IFX dose optimization (n=78)
Evaluated probability of remaining on IFX
IFX, up to 5 years
Probability
y on Inflixim
mab
100
80
P = 0.0006*
60
40
TCM
No TCM
20
0
0
100
200
300
400
500
600
Probability
y on Inflixim
mab
P < 0.0001*
P = 0.6
700
Dose optimization increases probability of remaining on IFX therapy up to 5 years
Vaughn BP, et al. Inflamm Bowel Dis 2014;20(11):1996-2003.
Tailoring
T
il i d
dose off T
Treatment
t
t tto M
Match
t h
Disease Burden
A Proposed Algorithm for Treatment of

IBD Focused on Target Goal
Baseline assessment of
disease activity by
endoscopy
d
paired
i d with
ith
surrogate marker
Choice of initial therapy

based on severity and
prognosis of patient
Treatment Escalated Until Goal Met, Patient Refuses,

or Run out of Options
3-6
months
Re-assessment of disease
activity directly or with
surrogate marker
De-escalation?
De
escalation?
TARGET
ACHIEVED?
No
Discussion with patient

treatment options
No
Clinical
f ll
follow-up
6-12
months
Yes
Clinical follow-up that includes

assessment of disease stability
Is patient willing to proceed

with your
recommendations?
Yes
Adjust
therapy
3-6
months
REACT Trial: Algorithm based treatment with early combined

i
immunosuppression
i reduced
d
d complications
li ti
iin C
Crohns
h Di
Disease
Centre-level cluster randomisation to

early combined immunosuppression
algorithm (ECI) or current best practice
(CM)
1982 patients recruited from 40 centres
Regular clinical review every 4 or 12

weeks
Used algorithm to treat to target
Primary end-point: Clinical Remission

(HBI <5 & no steroids)
High rate of compliance with the

protocol led to significant differences in
treatment between each group
Khanna R, et al. Presented at DDW, 2014 Abstract 342.
Therapeutic Algorithm for Crohns

Crohn s Disease
REACT Trial: Algorithm based treatment with early combined

pp
reduced complications
p
in Crohns Disease
immunosuppression
Results
Hospitalization, Surgery or Serious

Disease-Related Complication
HR = 0.73
(0.62, 0.86)
Conclusions:
There was no difference in clinical remission (primary endpoint).
There were significantly reduced rates of surgery and serious
complications in the ECI group (secondary endpoints).
A treat to target approach may modify the course of Crohns disease.
Khanna R, et al. Presented at DDW, 2014 Abstract 342.
Can you Stop Treatment?

De-escalation Considerations
Induction therapy continues at

same dose as maintenance
Maintenance therapy
decreased/de-escalated
How long?
Time
Drug
Drug
Theraapy inteensity
In
nflamm
matory b
burden
n
Therapy Adjustments Over Time

The Concept of Disease Burden
Examples of De-escalation of Therapy

Steroid induction steroid-sparing maintenance
therapy
h
Steroids withdrawn
Concomitant IMM + anti-TNF therapy

Maintained on combo therapy
Possibility of withdrawing IMM (IMM experienced)1
Possibility of withdrawing anti-TNF (Crohns disease)2
5-ASA?
MOMENTUM study shows 4
4.8
8 g/d 2.4
2 4 g/d IF complete
response3
1Van Assche,
et al. Gastroenterol. 2008 Jun;134(7):1861-8. 2Louis, et al. Gastroenterol. 2012;142(1):63-70.

3Rubin, DHaens, et al. ACG, Las Vegas, 2012.
Discontinuation of 1 agent during combination

Therapy in IBD
Author
Year
IBD Type
(N)
Stop IMM
Cont antiTNF
Stop antiTNF
Cont IMM
Cont ALL
Stop
Nothing
(index)
Overall
Chance:
Sustained
Remission
Van
V
Assche,
2008
CD
(n=40)
55% ~2yr
2
45%
Oussalah,
Oussalah
2010
CD
(n=48)
27% ~2yr
73%
Waugh,
2010
CD
(n=48)
50% 1 yr
50%
Louis,
2012
CD
(n=115)
50% 1 yr
50%
Van Assche, et al. Gastroenterol. 2008;134(7):1861-8. Oussalah , et al. Am J Gastroenterol 2010;105(5):1142-9. Louis, et al.
Gastroenterol. 2012;142(1):63-70. Waugh et al. Aliment Pharmacol Ther 2010;32:1129-1134.
Trough levels of IFX at discontinuation of IMM

are associated
i t d with
ith llong-term
t
response
Time of First IFX Dose escalation based

on Trough levels at withdrawal
Discontinuation of IFX as result of

LoR after withdrawal
Drobne D, et al. Clin Gastroenterol Hepatol. 2015;13(3):514-521.e4.
Withdrawal of therapy in IBD Patients on

Thi
Thiopurine
i Monotherapy
M
th
CD (n=129)
Kennedy et al. Aliment Pharmacol Ther. 2014;40(11-12):1313-23.
UC (n=108)
The Importance of Monitoring in Stable

Disease or When De-escalating
De escalating Therapy
Monitoring is periodic measurement
that guides the management of a chronic
or recurrent condition.
di i
It can be done by clinicians, patients, or
both.
both
Different phases of monitoring are based
g
y
you
on where in the treatment algorithm
are.
Once a target is reached monitoring for

disease drift or early relapse should
occur.
Glasziou P et al. BMJ 2005;330:6448.
Discontinuation of infliximab in patients in

clinical remission who remain on IMM
n=115
Louis, et al. Gastroenterol. 2012;142(1):63-70.
CRP
P (mean, 95% CI//g/g)
Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical

Relapse in Patients with CD in Remission after Infliximab Withdrawal: A
Sub-Analysis
Sub
Analysis of the STORI Study
CRP Evolution
30
P<0.001
25
20
Non-relapsers
15
Relapsers
10
CRP of 6.1mg/L
6 1mg/L and
calprotectin of 305mcg/g
best for prediction of
relapse
5
0
-14
N patients with
CRP measurement in
relapsers/non-relapsers
-12
-10
-8
-6
-4
-2
Time before relapse or end of follow-up (months)

3/33
6/36
5/34
12/39
14/44
27/45
31/49
41/50
Callpro (mean, 95% CI/g/g)
Calprotectin Evolution
1200
P=0.001
1000
800
Non-relapsers
600
Relapsers
400
200
0
-14
N patients with
Calpro measurement in
relapsers/non-relapsers
-12
-10
-8
-6
-4
-2
Time before relapse or end of follow-up (months)

4/35
6/39
6/39
9/41
Louis, et al. Gastroenterol. 2012;142(1):63-70.

De Suray N, et al. Presented at DDW; May 21, 2012. Abstract 864.
11/36
27/43
33/43
37/45
IFX, infliximab; IS, immunosuppressant
Fecal Calprotectin Predicts Postoperative CD

Endoscopic Recurrence
Prospective study of 135 patients (319

fecal samples)
Fecal calprotectin was correlated with

endoscopic recurrence (CRP or CDAI
were not).
Levels of FC >100
100 g/g indicated
endoscopic recurrence:
89% sensitivity
58% specificity
p
y
NPV 91%
Colonoscopy could have been avoided
for 47% of patients.
Wright EK, et al. Gastroenterology 2015 (epub ahead of print).
Median fecal calprotectin

p
levels
at 6 and 18 months combined
Patterns of Fecal Calprotectin in CD Patients After

Surgery
Endoscopy/beginning
py/ g
g of
Surgery
treatment
FC ((mg/kg)
No Recurrence
600
200
0
0
10 11 12 13 14 15 16 17 18
Recurrence No response to treatment
FC (mg/kg)
3000
800
600
400
200
0
0
10 11 12 13 14 15 16 17 18
FC (m
mg/kg)
Recurrence Response to infliximab
600
200
0
0
10 11 12 13 14 15 16 17 18
Months
Surgery
Sorrentino, et al. Dig Dis Sci. 2012;57:1341.
Endoscopy/beginning of
treatment
When to Switch Therapy?

And to What?
What we know and dont know about switching

Therapeutic drug levels and antibodies are helpful but not
always needed!
Can switch within class if
First agent worked and now patient losing response due to
anti-drug
ti d
antibodies
tib di
Some types of intolerance to one agent in the class
Should switch out of class if

Primary non-response to infliximab at escalated doses
CNS complication
p
of anti-TNF therapy
py
Most evidence is from infliximab to an injectable (ADA or
CZP). Unclear regarding the opposite, but possibly try IV
infliximab after primary non-response of injectable
What we know and dont know about switching,

continued
Should not switch from one agent to another electively
(especially true for anti
anti-TNF)
TNF)
Some limited evidence of elective switching from
natalizumab to vedolizumab appears safe1
Biosimilar switching is unclear at the current time

interchangeability is being studied and defined
1. Christensen B et al. Poster presentation DDW 2015 (Tuesday May 19th; Hall C).
Approach to patients receiving an anti-TNF

for the treatment of IBDs that experience loss
of response to therapy
Yarur A and Rubin DT. Inflam Bowel Dis. 2015 in press.
Summary: Whats the endpoint, can you

stop therapy,
therapy switch agents and to what?
Endpoints:
Evolving treatment endpoints of IBD should include objective outcomes:
Improved QoL, Decreased Hospitalization, Avoidance of Surgery, Minimal/No
Disability
Mucosal healing and histological normalization is possible in some patients
Stopping:
A subgroup of lower-risk patients might be able to safely discontinue
therapy:
A single agent (IMM or anti-TNF) in patients in remission on combination therapy
Patients maintained on thiopurine monotherapy for several years
Switching:
Account for prior response to class and/or side effects while switching of
agents
Try to prevent switching electively
@IBDMD
When All Else Fails: Alternative Agents, Clinical

Trials and Upcoming Treatments?

University of California San Diego
At the end of this presentation, the participant will be able
to:
1. Understand near-term and intermediate-term potential
treatment options for patients who are failing currently
available immunosuppressive and biologic therapy.
Take home points:

1. Many patients fail biologic therapy with anti-TNF
agents and anti-integrin therapy with vedolizumab
(anti-47 antibody), through a variety of mechanisms
including primary non-response, secondary lost response, and intolerance.
2. Treatment options switching within and out of class
with alternative selective anti-integrin agents, sphingosine 1 phosphate (S1P) receptor modulators, Janus
kinase (JAK) inhibitors, anti-interleukin 12/23 and antiIL 23, and Smad7 antisense.
Abstract
What are the future selective anti-integrin therapies in addition
to the currently available agent vedolizumab for the treatment
of ulcerative colitis and Crohns disease?
In addition to the approved agent vedolizumab, there are 3
selective anti-integrin agents in development, anti-MAdCAM1
(PF-00547,659, Pfizer), etrolizumab (anti-7, rhumab beta 7,
Genentech), anti-7 (AMG181, Amgen).1 PF-00547,659 blocks
MAdCAM-1 which is selectively expressed on the surface of the
vascular endothelium in the gut. MAdCAM-1 selectively binds
to gut-homing lymphocytes that express 47 integrin on
their surface. Etrolizumab and AMG181 both block 7 which
is expressed on the surface of gut-homing lymphocytes that
express 47 integrin on their surface as well as lymphocytes
that express E7on their surface. E7 binds to E-cadherin
on epithelial cells. A phase IIa study showed that anti-MAdCAM1 (PF-00547,659) showed greater rates of clinical and endoscopic remission in patients with active ulcerative colitis.2 A
recent Phase IIb study showed that anti-MAdCAM1 antibody
at doses of 22.5 and 75 mg was more effective than placebo
for active ulcerative colitis, with a greater effect in anti-TNF
nave patients.3 A Phase IIb study in patients with Crohns disease who failed anti-TNF therapy, failed to achieve its primary
endpoint, but there was a high placebo rate.4 A Phase IIb study
of etrolizumab in active ulcerative colitis showed efficacy for
doses of 100 mg and 300 mg.5
What are the future sphingosine 1 phosphate (S1P) receptor
modulators for the treatment of ulcerative colitis?
S1P receptor signaling on CCR7+ lymphocytes (central memory T cells) facilitate their exit from lymph nodes along an S1P
gradient. Ozanimod (RPC1063) induces S1P1R internalization
so lymphocytes do not respond to S1P and are retained in the
lymph node. Protective immunity is generally preserved since
CCR7- lymphocytes (effector memory T cells) do not circulate
through the lymph nodes. A Phase IIb study of ozanimod in patients with active ulcerative colitis showed that that ozanimod
was more effective than placebo, and that ozanimod 1 mg was
more effective than 0.5 mg.6
What are the future Janus kinase (JAK) inhibitors such as tofacitinib for the treatment of ulcerative colitis?
Tofacitinib is a JAK inhibitor which inhibits JAK1, JAK2, and

JAK3 in vitro with functional cellular specificity for JAK1 and
JAK3 over JAK2. Importantly, tofacitinib directly or indirectly
modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21. A Phase
IIb study of tofacitinib in patients with active ulcerative colitis
showed that tofacitinib was more effective than placebo, and
that doses of 10 mg and 15 mg bid were more effective than
0.5 mg and 3 mg bid.7
What are the future anti-interleukin 12/23 (p40) and anti-interleukin 23 (p19) antibodies for the treatment of Crohns disease?
Ustekinumab, a fully human IgG1 monoclonal antibody, binds
the p40 subunit of human IL-12/23. Ustekinumab prevents
IL-12 and IL-23 from binding IL-12Rb1, resulting in normalization of IL-12 and IL-23 mediated signaling, cellular activation, and cytokine production. Phase IIa and Phase IIb clinical trials in patients with Crohns disease who had primary
non-response, secondary loss of response, or intolerance to
anti-TNF agents demonstrated that intravenous ustekinumab
at doses of 1, 3, and 6 mg/kg were more effective than placebo for inducing clinical response and that subcutaneous
usekinumab 90 mg every 8 weeks was more effective than
placebo for maintaining response and remission.8, 9
Another Phase IIa clinical trial demonstrated that anti-interleukin 23 therapy with MEDI2070 was more effective than
placebo for inducing clinical response and a composite of clinical response and a reduction from baseline in CRP.10
What are the future Smad7 antisense oligonucleotides for the
treatment of Crohns diseases?
In the gut of healthy individuals (A), TGF-1, produced by

many cell types, binds to TGF- receptor type II (RII) thereby
promoting phosphorylation and activation of TGF- receptor
type I (RI). TGF-RI phosphorylates (p) and activates Smad2
and Smad3, followed by interaction of activated Smad2/3 with
Smad4 and translocation of the Smad2/3/4 complex to the
nucleus, with suppression of inflammatory gene expression.11
In the inflamed gut of patients with IBD (B), the inhibitor
Smad7 interacts with TGF-1R1 and prevents Smad2/3 phosphorylation (p), preventing TGF-1-mediated suppression of
inflammatory genes. A Phase IIb clinical trial demonstrated
that Smad7 antisense therapy with mongersen induced clinical remission and clinical response.12 Normalization of CRP
was less pronounced.
Conclusions
The pipeline for new treatments for IBD including anti-integrin therapy with anti-MAdCAM-1 antibody, anti-7 antibody
(etrolizumab, AMG 181), S1P receptor modulation (ozanimod), JAK inhibition with tofacitinib, anti-interleukin 12/23
antibody (ustekinumab), anti-interleukin 23 antibody, Smad7
antisense, and rifaximin EIR is very promising.
When All Else Fails: Alternative Agents, Clinical Trials and Upcoming Treatments?
References
1. Lobaton T, Vermeire S, Van Assche G, et al. Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol
Ther 2014;39:579-94.
2. Vermeire S, Ghosh S, Panes J, et al. The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study. Gut 2011;60:1068-75.
3. Vermeire S, Sandborn W, Danese S, et al. TURANDOT: a randomized, multicenter double-blind, placebo-controlled study of the safety
and efficacy of Anti-MAdCAM Antibody PF-00547659 (PF) in patients
with moderate to severe Ulcerative Colitis (UC). Gastroenterology
2015;Abstract (In Press).
4. Sandborn W, Lee S, Tarabar D, et al. Anti-MAdCAM-1 Antibody (PF00547659) for Active Refractory Crohns Disease: Results of the OPERA study. Gastroenterology 2015;Abstract (In Press).
5. Vermeire S, OByrne S, Keir M, et al. Etrolizumab as induction therapy
for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet
2014;384:309-18.
6. Sandborn W, Feagan B, Wolf D, et al. The TOUCHSTONE Study: A
Randomized, Double-Blind, Placebo-Controlled Induction Trial of an
Oral S1P Receptor Modulator (RPC1063) in Moderate to Severe Ulcerative Colitis. Gastroenterology 2015;Abstract (In Press).
7. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012;367:61624.
8. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of
Ustekinumab, a human interleukin-12/23 monoclonal antibody, in
patients with moderate-to-severe Crohns disease. Gastroenterology
2008;135:1130-41.
9. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and
maintenance therapy in refractory Crohns disease. N Engl J Med
2012;367:1519-28.
10. Sands BE, Chen J, Penney M, et al. OP025 A randomized, doubleblind placebo-controlled phase 2a induction study of MEDI2070 (antip19 antibody) in patients with active Crohns disease who have failed
anti-TNF antibody therapy. Journal of Crohns and Colitis 2015;ECCO
Abstract.
11. Zorzi F, Angelucci E, Sedda S, et al. Smad7 antisense oligonucleotide-based therapy for inflammatory bowel diseases. Dig Liver Dis
2013;45:552-5.
12. Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral
SMAD7 antisense oligonucleotide, and Crohns disease. N Engl J
Med 2015;372:1104-13.
Alternative Therapies in
I fl
Inflammatory
t
B
Bowell Di
Disease
William J. Sandborn MD
Case 1
Diagnosed with ulcerative colitis in 2011

Treated with MMX mesalamine and mesalamine enemas, no
improvement
Then treated with prednisone with resolution of symptoms,
prednisone dependent 10 mg/day
Colonoscopy January 2013 showed friability to the ascending
colon,
l
azathioprine
thi
i recommended,
d d patient
ti t declined
d li d
Prednisone discontinued, flare of symptoms, had another course
of prednisone
I J
In
July
l 2013 hospitalized
h
it li d for
f flare,
fl
low
l
albumin,
lb i llower extremity
t
it
edema, treated with IV steroids
August 2013 began infliximab 5 mg/kg at weeks 0, 2, and 6 as well
as azathioprine
Case 1 (continued)
October 2013 Clostridium difficile treated with oral vancomycin,
slow tapering regimen

November 2013 Staphylococcal pneumonia treated with
d
doxycycline,
li
azathioprine
thi
i stopped
t
d
December 2013 continued diarrhea, Clostridium difficile negative,
inflximab concentration at week 4 was 10 ng/mL and week 8
concentration was 0 ng/mL,
ng/mL infliximab dose increased to 10 mg/kg
Arthralgias following infliximab dose, no clinical improvement
March 2014 switched to adalimumab. Found to have pericarditis
(negative work up) and recurrent Clostridium difficile.
difficile Treated with
colchicine and prolonged oral vancomycin taper
May 2014 continued symptoms, adalimumab concentration 9
ng/mL. Adalimumab dose increased to 40 mg weekly and added
oral methotrexate and a course of prednisone, no improvement
What Would You Do Now?
Case 1 (continued)
August 2014 stopped adalimumab and methotrexated, started oral
tofacitinib 5 mg bid, and began to taper prednisone

January 2015, off prednisone, 1 stool per day without rectal
bl di
bleeding,
flexible
fl ibl sigmoidoscopy
i
id
showed
h
d mucosall healing
h li
Tofacitinib an Oral Janus Kinase (JK) Inhibitor
Cytokine
JAK
P
STAT
STAT
STAT
JAK
P
STAT
Tofacitinib blocks
phosphorylation of
STAT and
downstream
activation
mRNA
Cytokine
Effects on the immune system
IL-2
Stimulate the proliferation and differentiation of Th, Tc, B,

and natural killer (NK) cells
IL-4
Induce the differentiation of Th0 to Th2

Induce immunoglobulin switching
IL 7
IL-7
Promote the development,

p
,p
proliferation and survival of T,,
B, and NK cells
IL-9
Stimulate intrathymic T cell development
IL-15
5
Promote the proliferation, cytotoxicity and cytokine

production
d ti off NK cells
ll
IL-21
Enhance T and B cell function
Tofacitinib
T f iti ib (CP
(CP-690,550)
690 550) is
i a novel,l small-molecule,
ll
l l orall JAK iinhibitor
hibit
Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3
over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of
pro-inflammatoryy cytokines
p
y
includingg IL-2,, -4,, -7,, -9,, -15,, and -21
Sandborn W. New England Journal of Medicine 2012
Tofacitinib (Xeljanz
Xeljanz))
Approved for rheumatoid arthritis at a dose
g bid
of 5 mg
Indication is for the treatment of adults with
moderately to severely active rheumatoid
arthritis (RA) who have had an inadequate
response to or are intolerant of methotrexate
Tofacitinib for Moderately

y to Severely
y Active
Ulcerative Colitis: Clinical Response at Week 8
P<0.001
P=0.10
P=0.39
Sandborn W. New Engl J Med 2012.
Tofacitinib for Moderately

y to Severelyy Active
Ulcerative Colitis: Clinical Remission at Week 8
P<0 001
P<0.001
P<0 001
P<0.001
P=0.76
Tofacitinib for Moderately to Severely Active

Ulcerative Colitis: Endoscopic Response
P=.07
P=.001
P=0.64
P
0.64
Tofacitinib for Moderately to Severely Active

Ulcerative Colitis: Endoscopic Remission
P=.07
P=.001
P=0.64
Tofacitinib
Tofacitinib:: Adverse Events in
Rheumatoid Arthritis
Severe, sometimes fatal, infections have occurred. Tuberculosis
(TB) and other opportunistic infections have been reported.
11 solid cancers and 1 lymphoma were diagnosed among 3328
patients taking tofacitinib with or without a DMARD for 12
months, compared to no solid cancers or lymphoma in 809
patients
ti t ttaking
ki a placebo
l
b with
ith or without
ith t a DMARD ffor 3
3-6
6
months
perforation has been reported
p
during
g clinical
Gastrointestinal p
trials with tofacitinib; patients with a history of diverticulitis may
be at higher risk.
LDL and HDL cholesterol have increased in patients taking
tofacitinib; cholesterol levels should be checked 4-8 weeks after
starting treatment.
Tofacitinib
Tofacitinib:: Adverse Events in
Rheumatoid Arthritis (Continued)
Elevations in liver aminotransferase levels have occurred; liver
enzymes should be monitored regularly.
Lymphocytopenia,
Lymphocytopenia neutropenia and low hemoglobin levels can
develop in patients taking tofacitinib. Lymphocytes should be
monitored at baseline and then every 3 months. Neutrophils and
h
hemoglobin
l bi llevels
l should
h ld b
be monitored
it d att b
baseline,
li
after
ft 4
4-8
8
weeks of treatment, and then every 3 months.
g y C ((risk cannot be ruled out))
Tofacitinib is classified as category
for use during pregnancy. It is fetocidal and teratogenic in rats
and rabbits.
Case 2
1993 diagnosed with Crohn's ileitis

Initally no treatment after diagnosis
5 small bowel resections ((1993, 1995, 2004, 2009, 2010)) and a
perianal fistula requiring a seton in 2011
Infliximab for 6 months (discontinued in 2009 for angina and lack of
response)
p
)
Adalimumab for 6 months (discontinued in 2009 for lack of response)
Azathioprine of doses150-200mg/day without response
Cimzia and methotrexate
June 2011 colonoscopy showed apthous ulcers up to 30cm of neoterminal ileum
2012 hospitalized for SBO, found to have ulcerated narrowing of the
ileocolonic anastomosis and 14 cm of ileitis on colonoscopy and MRE
Case 2 ((Continued))
Treated with investigational therapy with anti-MAdCAM-1 antibody, no

response
July 2013 started on natalizumab (JC virus negative)
Able to discontinue prednisone, but still had abdominal pain
Small bowel resection for anastomotic stricture in May 2014,
natalizumab continued postoperatively
Abdominal p
pain and diarrhea p
post operatively.
p
y Colonoscopy
py in
November 2014 showed recurrently ileitis
Natalizumab discontinued
What Would You Do Now?
Case 2 ((continued))
Plan to start the patient on ustekinumab
Biology of Interleukins 12 and 23

IL-12
Stimulus
TLR?
IL-12R1
2
Ag
Antigen
Presenting
g Cell
MHCII
CD4+
TCR
IL-23R
IL-12R1
IL
12R1
p19
p40
IL-23
AntiIL 12/23
IL-12/23
p35 p40
AntiIL-12/23
Anti--ILAnti
IL-12/23
IFNg
(Th1)
IL-17
(Th17)
Ustekinumab and
briakinumab
b i ki
b are fully
f ll
human IgG1 monoclonal
antibodies
Bi d the
Bind
th p40
40 subunit
b it off
human ILIL-12/23
Prevent ILIL-12 and ILIL-23
from
f
binding
bi di IL
IL--12Rb1
Normalize ILIL-12 and ILIL23 mediated signaling,
cellular activation, and
cytokine production
In development in
Crohns disease and
psoriasis
Ustekinumab (Stelara
Stelara))
Approved for psoriasis at a dose of 45 mg
((90 mg
g for weight
g > 100 kg)
g) at weeks 0 and
4 and then every 12 weeks
Indication is for the treatment of adults with
moderate to severe plaque psoriasis who
are candidates for phototherapy or systemic
therapy
Ustekinumab (anti(anti-IL 12/23p40) for Induction of Clinical

Response
p
in Moderate to Severe Crohns Disease
80
60
40
P=.02
P=.019
P=.335
P=.337
20
0
4
6
Weeks
1.2
Median CRP
M
P (mg/dL)
Patients (%
%)
Placebo
Ustekinumab
100
Inflixiimab-Experrienced
Patients (%
%)
All Patients
100
Previously Treated with Infliximab
80
60 P=.046
P 001
P=.001
P=.004
P=.022
P 022
40
20
0
CRP in All Patients
Weeks
Week 0
Week 8
1.0
0.8
0.6
0.4
0.2
0
Subcutaneous
Intravenous
Placebo
Subcutaneous
Intravenous
Ustekinumab
Sandborn WJ. Gastroenterology 2008;135:1130-1141.
Ustekinumab (Anti(Anti-IL
IL--12/23p40) for Induction of Moderate to Severe
Crohn
Crohns
s Disease
Clinical Response
Clinical Remission
+
+
+
+
+
+ +
+p<0.05 vs. PBO by CMH test
Sandborn WJ. N Engl J Med 2012; 367:1519-1528
Change in CDAI Following Treatment with

Ustekinumab
Sandborn WJ, et al. N Engl J Med 2012;367:1519-28.
Change in CRP Following Treatment with

Ustekinumab
Ustekinumab ((Anti(Anti-ILIL-12/23p40)
p ) for Maintenance of
Moderate to Severe Crohns Disease
p<0.001
p=0.029
Sandborn WJ. N Engl J Med 2012; 367:1519-1528
Change in CDAI Score from 88-22 Weeks
Corticosteroid--free Remission at 22 Weeks

Corticosteroid
Blood, Bones, Eyes and Nutrients: How to Monitor

For and Prevent Complications of IBD?
Maria T. Abreu, MD, AGAF

Professor of Medicine, and Microbiology and Immunology
Blood,, bones,, eyes,

y , and
nutrients: How to monitor for and
preventt complications
li ti
off IBD
Maria T. Abreu, MD
Professor of Medicine, and Microbiology and
Immunology
Miami, Florida
Reasons for complications in the

established IBD patient
Complications of the disease
Complications of the treatment
IBD Systemic
IBD:
S t i Complications
C
li ti
E
Eye
inflammation*
Lower
o e
bone density*
Liver and
bile duct
inflammation
G
Gallstones
ll t
Skin lesions
*Higher incidence in women.
Growth failure
in children
d ey
Kidney
stones
Subfertility*
Ovaries
Uterus
Arthritis and
joint pains
Blood
Anemia, leukopenia,
hypercoagulability, NHL
Anemia in IBD
Anemia in IBD
Quality of Life
Hb
>12g/dl
Hb
<12g/dl
Cognitive Functions
Ability to Work
Ability
H
Hospitalization
it li ti
Comorbidity, Mortality (e.g. 7% Hep C)
Causes of Anemia in IBD

Common
Iron deficiency
Anemia of chronic disease
Occasional
Vitamin B12 deficiency

Folate deficiency
Drug-induced (sulfasalazine, thiopurines)
Rare
Gasche C et al. Inflamm Bowel Dis. 2007;13:1545-1553.
Hemolysis
Myelodysplastic syndrome
Aplasia (often drug-induced)
Innate hemoglobinopathies or disorders of
erythropoiesis
IDA and ACD Typically

yp
y Overlap
p
ACD
Serum ferritin
<30 g/L (no inflammation)
<100 g/L (inflammation)
Or: TSAT <16%
- Serum ferritin >100 g/L

- TSAT <16%
IDA
- Serum ferritin 30
100 g/L
- TSAT <16%
Iron Deficiency
y in IBD
The most common nutritional deficiency
(36-90%!!!)
Low intake
Impaired absorption
Crohns disease related (L4)
( )
Inflammation related
Continuous blood loss

Vi
Visible
ibl (ulcerative
( l
ti colitis)
liti )
Invisible (Crohns disease)
Lomer MC, Br J Nutr. 2004

Semrin G, Inflamm Bowel Dis 2006
Kulnigg S, APT 2006
An
nemia (%)
Prevalence of IDA in IBD
Goodhand JR et al. Inflamm Bowel Dis. 2012;18:513-519.
An
nemia (%)
Prevalence of IDA in Adults With IBD

b H
by
Hospitalization
it li ti St
Status
t
Gisbert JP, Gomollon F. Am J Gastroenterol 2008;103:1299-1307.
Consequences
q
of IDA in IBD
IDA in patients with IBD:
Associated with increased hospital visits1,2
,
Frequently delays hospital discharge1,2
Is associated with profoundly decreased quality

34
off life
l f 3,4
1. Kulnigg S, Gasche C. Aliment Pharmacol Ther. 2006;24:1507-1523; 2. Gasche C et al. Inflamm Bowel Dis. 2007;13:1545-1553;
3. Wells CW et al. Inflamm Bowel Dis. 2006;12:123-130; 4. Gasche C et al. Ann Intern Med. 1997;126:782-787
Stages of Iron Deficiency Anemia

(IDA)
Normal Iron Status
Storage Iron Compartment

T
Transport
t Iron
I
(serum
(
iron,
i
TSAT,
TSAT TIBC)
Functional Iron Compartment
p
(hemoglobin, myoglobin, cytochromes, etc.)
Changes in laboratory
indices
TSAT=transferrin saturation; TIBC=total iron binding

capacity; sTfR=soluble Transferrin Receptor; MCV=mean
corpuscular volume
Tussing-Humphreys L et al. J Acad Nutr Diet. 2012;112:391-400.

(IDA)
Normal Iron Status
Depletion
D
l ti off
Storage Iron
(Stage I)

T
Transport
t Iron
I
(serum
(
iron,
i
TSAT,
TSAT TIBC)
p
indices
Ferritin

corpuscular volume

(IDA)
Normal Iron Status
Depletion
D
l ti off
Storage Iron
(Stage I)
IIron Deficient
D fi i t
Erythropoiesis/
Iron Deficiency
(Stage II)

T
Transport
t Iron
I
(serum
(
iron,
i
TSAT,
TSAT TIBC)
p
indices
Ferritin

corpuscular volume
Ferritin
Serum iron
TSAT
TIBC
sTfR

(IDA)
Normal Iron Status
Depletion
D
l ti off
Storage Iron
(Stage I)
IIron Deficient
D fi i t
Erythropoiesis/
Iron Deficiency
(Stage II)
IIron Deficiency
D fi i
With Anemia
(Stage III)

T
Transport
t Iron
I
(serum
(
iron,
i
TSAT,
TSAT TIBC)
p
indices
Ferritin

corpuscular volume
Ferritin
Serum iron
TSAT
TIBC
sTfR
Ferritin
Serum iron
TSAT
TIBC
sTfR
Hemoglobin
MCV
Hepcidin inhibits iron absorption

and
d is
i increased
i
d with
ith inflammation
i fl
ti
FFe2+
Ferroportin
Stein J, Dignass AU. Ann Gastroenterol. 2012;26:1-10.

and
d is
i increased
i
d with
ith inflammation
i fl
ti
Ferroportin
Hepcidin

and
d is
i increased
i
d with
ith inflammation
i fl
ti
Hepcidin
H
idi
Iron export
through
ferroportin
Hepcidin
H
idi
Ferroportin
degradation:
Iron locked in cell
Ferroportin
Hepcidin
Hepcidin Levels Correlate With Presence of IBD

and Disease Activity
Enrolled patients with IBD and healthy controls
(N=202)
Median hepcidin levels were significantly higher in

patients vs healthy
y controls (P<.0001)
(
)
UC and CD p
Serum hepcidin correlated with disease activity
(UC: r=.36,
(UC
36, P=.009)
009) and
a dC
CRP ((r=.29,
9, P=.004)
00 )
Serum hepcidin levels negatively correlated with
ferritin
(P=.0008) and positively correlated with disease
activity (for UC, P=.004) in multivariate analysis
Oustamanolakis P et al. Eur J Gastroenterol Hepatol. 2011;23:262-268.
Hepcidin levels predict nonresponse to orall iron

Screening hemo
oglobin (gg/dL)
14
12
P=.0002 for correlation
between hepcidin levels
and nonresponse to
orall iron
i
10
8
6
4
Responder
R
d to Oral
O l Iron
I
Non-responder to Oral Iron
2
0
0
20
40
60
80
100
120
Screening hepcidin (ng/mL)
Bregman DB et al. Am J Hematol. 2013;88:97-101.
140
160
Laboratory
y Workup
p of Anemia in IBD
Initial evaluation:
CBC with differential
Serum ferritin
Transferrin saturation
CRP
Creatinine
Reticulocyte count
If cause of anemia
not identified:
Vitamin B12
Methylmalonic acid
Folic acid
Haptoglobin
Lactate dehydrogenase
Bone marrow aspirate
p
CBC=complete blood count; Hb=hemoglobin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume
Gasche C et al. Inflamm Bowel Dis. 2007;13:1545-1553.
Iron Supplementation IV Iron
IV iron
i
iis more effective,
ff ti
b
better
tt ttolerated
l t d and
d compliance
li
iis nott an iissue
Absolute indications for IV iron include

Severe Anemia (hemoglobin <10 g/dL)
Intolerance or inappropriate response to oral iron
Severe intestinal disease activity
Oral iron may not be able to compensate ongoing blood loss
Patient preference
Clinical comparative trials show faster response with IV iron
Gasche C et al. Inflamm Bowel Dis 2007;13:15451553
Intravenous vs Oral Iron: Response

p
Responders (%)
80
Iron sucrose
P=.07
Fe-sulfate
P=.04
60
Lindgren et al1
P=.007
Improved response
0% vs 24% AE-related
discontinuation
40
20
Reached mean
reference Hb
Hb increase
>2 g/dL
Anemic at end
of treatment
(13 or 15 g/dL; f/m)
Hb increase
i
2 g/dL
/dL
Respo
onders (%)
100
Kulnigg et al2
80
Faster response
60
Ferric
carboxymaltose
Fe-sulphate
40
20
1
1.5%
5% vs 7.9%
7 9% AE-related
AE related
discontinuation
0
2
10
12
Study week
1. Lindgren et al. Scand J Gastroenterol. 2009;44:838-845; 2. Kulnigg et al. Am J Gastroenterol 2008;103:1182-1192.
FCM vs IS: Response Rates at Week 12

P=.019
R
Responde
er (%)
P=.004
Ferric carboxymaltose
Iron sucrose
Hb increase 2 g/dL Hb increase 2 g/dL or

Normal Hb
Evstatiev R et al. Gastroenterology. 2011;141:846-853.
Diagnosis
g
and Management
g
of IDA in IBD
Hb <12 g/dL (women) or <13 g/dL (men)
Serum ferritin <100 ng/mL
Hb >10 g/dL
CRP normal
Hb <10 g/dL
CRP elevated
l
d
Oral Iron
30 to 50 mg per day
Intolerance
Incompliance
Inefficacy
IV iron
(1000 1500 mg)
Serum ferritin <100 ng/ml
IV Iron
(500 mg)
Adapted from Stein J et al. Nat Rev Gastroenterol Hepatol.

2010;7:599610.
IV iron
(
(1500
2000 mg))
Leukopenia
Medication related
Patients with Low TPMT Activity Have

Early Leukopenia
Median (Range) Time to Bone Marrow Toxicity
TPMTH/TPMTH
(N=30)
3 months (0.587)
TPMTH/TPMTL
(N=7)
4 months (118)
TPMTL/TPMTL
(N=4)
(N
4)
1 month (11.5)
0
Months
Colombel JF et al. Gastroenterology. 2000;118:1025-1030.
Utility
y of TPMT Genotyping
yp g In CD
WBC
C Count (x103/m
mm3)
Before AZA
10
At 2 weeks
At 3
months
th
8
6
P<0.001
<0 001
P=0.007
4
2
0
No patients developed acute

leukopenia
2-2.5mg/kg/d
2
2 5mg/kg/d
(N=45)
Initial AZA Dose
Regueiro M et al. J Clin Gastroenterol. 2002;35:240-244.
<2 mg/kg/d
(N=7)
1-1.5mg/kg/d
1-1
5mg/kg/d
(N=7)
Normal TPMT Intermediate TPMT
TPMT A
T
Activity (nmol/
/mL RB
BC/h)
TPMT activity is lower in patients

who
h develop
d l neutropenia
t
i
40
30
20
10
Mean TPMT activity lower in

neutropenic group than in
patients with other side effects
(P<0.05).
0
Neutropenia Pancreatitis Hepatitis Dermatological
(N=8)
(N=4)
(N=5)
(N=2)
Campbell S et al. Aliment Pharmacol Ther. 2002;16:389-398.
Other
(N=7)
6-TGN levels correlate with risk

off leukopenia
l k
i
1
What if you dont

don t measure
TPMT?
Can you monitor with CBCs?
Pattern of Monitoring and

Outcomes in Clinical Practice
Cohort study of IBD patients in Kaiser
Permanente Northern California
1997 new users of AZA or 6MP
Minimum 6 months in KP prior to first
thiopurine prescription
40% CD
CD, 35% UC
UC, 25% IBD NOS
Median starting dose 6-MP 48 mg/d
Lewis JD et al. Clin Gastroenterol Hepatol. 2009;7:1195-1201.
Severe Leukopenia More Common

in First 8 Weeks
Time since start
(weeks)
Number of
patients with
event
Incidence per 100

person-months
(95% CI)
Mild leukopenia
0 to 8
44
1.18 (0.83-1.53)
(WBC < 3.0)
9 to 26
49
0.80 (0.58-1.02)
> 26 weeks
100
0.38 (0.31-0.45)
Severe
leukopenia
0 to 8
0.16 (0.03-0.29)
(WBC < 1.0)
9 to 26
>26 weeks
0.01 (0-0.04)
% change in WBC
First CBC After Start of Therapy

Predicts Myelosuppression
5
0
-5
-10
10
-15
-20
-25
-30
-35
2
None
Mild
-18
18
Severe
-29
P<.001
< 001 Mild + Severe vs None
Thromboembolic Risk in
H
it li d IBD P
ti t
Hospitalized
Patients
Single
l center study:
d
173 patients experienced 200 thromboembolic events over an 11-year period
DVT 48%; PE 12%; thrombophlebitis 12%; mesenteric venous thrombosis 4%; coronary
i h i 6%
ischemia
6%; stroke/TIA
k /TIA 5%
Proportion of patients
Identified
Prothrombotic State
Number of patients,
total tested = 44 (%)
30% / 6%
Antiphospholipid Ab
3 (7)
Malignancy (past or current)
17%
Factor VIII mutation
3 (7)
Estrogen use
9%
Hyperhomocysteinemia
3 (7)
20% / 25%
Lupus anticoagulant
9 (20)
11%
Protein S deficiency
2 (5)
Risk Factor
Surgery (IBD related / unrelated)
Personal / family history of TE

Smoking
Prothrombotic state
12% (20 of 44 patients tested)
Total
20 (45)
Prophylaxis
h l
was documented
d
d in only
l 40%
0% off inpatients prior to the
h diagnosis
d
off the
h
thromboembolic event
Levy A, et al. Presented at DDW; May 20, 2013. Abstract Mo1242.
Lymphomas
Epidemiology of NHL
1960s-1990s: NHL
increased 2%-4%
2% 4%
annually
5th most common in US
10th most common
worldwide
38
Risk of Lymphoma Associated with

Immunomodulators
19,486 IBD patients
30
30.1%
1% currently receiving thiopurines
14.4% discontinued thiopurines
55.5% never exposed to thiopurines
Rate per 10,000

pt-years
95% CI
Current use
90
9.0
5 0 14 9
5.0-14.9
Discontinued
2.0
0.2-7.2
Never exposed
2.6
1.0-5.7
1.0
5.7
Exposure
Receiving thiopurines vs. never exposed

HR 5
5.28
28 (2
(2.01-13.9)
01 13 9)
Beaugerie et al, Lancet 2009;7:374.
Cesame
Trial
19 486 patients with IBD in a nationwide French cohort from 5/04-6/05
19,486
5/04 6/05
Multivariate Hazard Ratio for Lymphoproliferative Disorder From

Thiopurine
p
Use = 5.28 (2.01-13.9)
(
)
Beaugerie L et al. Lancet. 2009;374:1617-1625.
Risk of NH Lymphoma with anti-TNF + IM treatment

f Crohns
for
C h Disease
Di
Meta-analysis Results
8905 patients representing 20,602 pt-years of exposure

13 Non-Hodgkins lymphomas 6.1 per 10,000 pt-years
M
Mean
age 52
52, 62% male
l
10/13 exposed to IM* (really a study of combo Rx)
NHL rate
per 10,000
SIR
95% CI
SEER all ages
1.9
IM alone
3.6
Anti-TNF + IM vs SEER
6.1
3.23
1.5-6.9
Anti-TNF+ IM vs IM alone
6.1
1.7
0.5-7.1
Siegel et al, CGH 2009;7:874.

2
*not reported in
Risk of Lymphoma Returns to

N
l Aft
i Thi
i
Normal
After St
Stopping
Thiopurines
36,891 VA patients with UC with a median follow up of 6.7 years and a
median age of 60 years at inclusion
Thiopurine Use
Incidence Rate
4,734 p
patients usingg thiopurines;
p
median duration of exposure:
0.97 years
142 confirmed lymphoma cases
Khan N, et al. Presented at DDW; May 20, 2013. Abstract 641.
(per 1,000 p
(p
person-years)
y
)
Unexposed
0.6
During
2.3
Af stopping
After
i
03
0.3
VA, Veterans Affairs
Risk of Developing
p g NH Lymphoma
y p
Patient receiving anti-TNF + Immunomodulator Therapy for 1 year
IM monotherapy
medication
Risk without
with combination
therapy
Siegel et al, CGH 2009;7:874.
Serious Infection and Lymphoma Risk With Anti-TNF

Therapy for Pediatric IBD
IBD: Systematic Review
1,979 patients, more than
h 80% on concomitant immunomodulators
d l
Lymphoma rate of pediatric IBD patients exposed to anti-TNF agents: 2.3/10,000
patient-years of follow-up
Baseline incidence
(per 10,000 PY)
SIR for anti-TNF, P value,

(95% CI)
Lymphoma (general pediatric population)
0.58
3.88, P=0.15, (0.38-21.7)
Immunomodulators (pediatric use)
4.5
0.52, P=0.54, (0.04-7.1)
Pediatric Anti-TNF
(per 10,000
(p
,
PY))
Adults Anti-TNF
(per 10,000
(p
,
PY))
Serious infection
332
654
Lymphoma
2.3
6.1
Conclusion:
Death
58
5.8
21
Risk of serious infection, lymphoma, and death with anti-TNF in pediatric IBD is very low,
and much lower than in adults
Dulai PS, et al. Presented at DDW; May 20, 2013. Abstract 640.
Malignancies in Children Receiving IBD Therapies:

A Multicenter, Prospective, Pediatric (The DEVELOP)
Registry
Malignancy event rates from DEVELOP were compared with the expected event rates
usingg the SEER database; adjusted
j
for age,
g gender,
g
and race
4,343 patients enrolled
2,586 exposed to anti-TNFs (2,503 to IFX); 1,757 received non-biologic therapies
No malignancies in patients without prior immunomodulator exposure
Infliximab + immunomodulator
(N=2)
Infliximab Adalimumab +
Immunomodulator (N=2)
Basal cell carcinoma

Melanoma
Acute monocytic leukemia

Parotid gland adenocarcinoma
Medication use
Immunomodulator only (N=3)

Haematophagic histiocytosis
Hodgkins disease
Malignant lymphohistiocytosis
Observed Rate of Malignancies

(
(per
10,000
10 000 patients)
i
)
Standardized Incidence
R i (95% CI)
Ratio
Anti-TNF + immunomodulator combination
10.7
5.73 (1.56-14.70)
Immunomodulator monotherapy
12.4
7.12 (1.47-20.80)
Anti-TNF monotherapy
0 (0-21.40)
Neither Anti-TNF nor immunomodulator
0 (0-17.90)
Colletti RB, et al. Presented at DDW; May 20, 2013. Abstract 833.
Monotherapy with an anti-TNF

( d li
(adalimumab)
b) d
does nott iincrease risk
i k off
lymphoma
y p
or cancers
Osterman, M, et al. Gastroenterology. 2014 Apr;146(4):941-9. doi: 10.1053/j.gastro.2013.12.025.
It is a subgroup of patients at higher

risk
i k ffor iinfections
f ti
and
d lymphomas
l
h
Older
Average age = 63 (systematic review); 67
(Mayo)
Multiple co-morbidities
Concomitant steroids and/or narcotics
Long
Long-standing
standing disease
Young healthy patients are not in the
clear, but probably much less at risk
Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006; Toruner, Gastro 2008
Hepatosplenic T-Cell Lymphoma (HSTCL)

Used MedWatch reporting system of the US Food
and Drug Administration
36 cases of HSTCL in patients with IBD
Nearly all male

Nearly all dead
Nearly all <40 years old
90% had 3 years of AZA/6-MP
75% exposed to TNF- antagonists
Risk is likely to be < 1 in 22,000
Kotlyar DS, et al. Clin Gastroenterol Hepatol. 2011 Jan;9(1):36-41.e1. doi: 10.1016/j.cgh.2010.09.016.
Hepatosplenic T-Cell Lymphoma (HSTCL)
Kotlyar DS, et al. Clin Gastroenterol Hepatol. 2011 Jan;9(1):36-41.e1. doi: 10.1016/j.cgh.2010.09.016.
Bone disease in IBD
Scope of Problem
Dx
CD
UC
Osteopenia Osteoporosis
40-80%
20-40%
Fracture
risk
20-40%
40%
i
increase;
1515
20% silent
fractures
10-20%
Not
increased
Many studies
Good series: Siffiledeen JS et al. Inflamm Bowel Dis. 2004 May;10(3):220-8.
Bone Remodeling
g
Osteoclasts followed by osteoblasts

Act on the same bone surface
http://www.umich.edu/news/Releases/2005/Feb05/img/bone.jpg
Bone quality may be abnormal in

IBD
14-20% of CD patients have a
vertebral fracture
50% of fractures occur with
normal BMD
Bone
Density
Bone
Mineral
Bone
Bone
Architecture Turnover
Stockbrugger,et.al., Aliment PharmacolTher 2002;16:1519-27
IBD-related risk factors for bone

loss
Persistent disease activity;
Inflammatory cytokines
(IL-6, IL-1, TNF-)
Drug therapy
( t id CsA,
(steroids,
C A
MTX, heparin)
Osteope a/
Osteopenia/
Osteoporosis
Vitamin D
deficiency;
calcium
malabsorption
IL=interleukin; TNF=tumor necrosis factor; CsA=cyclosporine; MTX=methotrexate.

Valentine JF, et al. Am J Gastroenterol. 1999;94:878-883.
CTE Can Also Be Used to Diagnose

g
Osteoporosis
Biomechanical CT (BCT) can measure bone
mineral density (BMD) and bone strength from
non contrast CT images
i
Clinical CTE provides hip BMD, T-scores, &
p
to DXA
clinical classifications comparable
Density
distribution
For osteoporosis, CTE Sensitivity = 86%,

Specificity = 98%
Combined with BCT

BCT, CTE can identify patients
with osteopenia
Ancillary analysis of CTE exams for BMD & bone
strength could improve osteoporosis screening
rates in IBD patients and may alter management
plans
p
55 Weber NK, et al. Presented at DDW; May 19, 2013. Abstract 475.
Regions
of failure
Extent of bone loss in corticosteroid-nave

patients
ti t over 2 years
-0.4
04
P=.006
P=.007
P=.008
P=.011
T-S
Score
-0.5
-0.6
Budesonide EC
9 mg once daily
-0.7
Prednisolone
40 once daily
-0.8
-0.9
0
12
18
Time (months)
Mean BMD expressed as T score (with standard error of the mean) during the 22-year
study period in corticosteroidcorticosteroid-nave (N=98) patients.
Schoon EJ, et al. Clin Gastroenterol Hepatol 2005;3:113-21.
24
Change
e in BMD frrom Baseliine (%)
BMD improves
p
on maintenance
infliximab
4.5
4
35
3.5
3
2.5
2
1.5
1
0.5
0
Femoral trochanter
Femoral neck
Bernstein, M. et al. American J Gastroenterology 100:2005
Lumbar spine
Effect of infliximab in REACH

study
BSAP: Bone specific alkaline phosphatase
P1NP: N-terminal propeptide of type 1 collagen
CTX-1: C-telopeptide
p p
cross-links of type
yp I collagen
gen
DPD: Deoxypyridinoline
Thayu M et al. Clin Gastroenterol Hepatol 2008;6:137884
Risedronate 35mg OAW in osteoporotic postmenopausal IBD patients

Change
g in BMD - 1 yyear
*+
% Chan
nge in BMD from
m
Baseline
Placebo
Risedronate
*+
*+
4
2
0
-2
-4
-6
-8
8
Lumbar Spine
Trochanter
Femoral Neck
*p<0
p<0.001
001 vs
vs. placebo
Palomba S et al. Osteoporos Int. 2005 Sep;16(9):1141-9.
+p<0.05 vs. baseline
Palomba S et al. Menopause. 2008 Jul-Aug;15(4 Pt 1):730-6.
Risedronate 35mg OAW in osteoporotic post-menopausal

IBD patients
Vertebral Fractures 1 year
Incidence (%))
Placebo
40
35
30
25
20
15
10
5
0
*p<0.05 vs. placebo
Risedronate
34.1%
64% R
Relative
l ti
Risk Reduction
12 5%*
12.5%*
21.6% Absolute
Risk Reduction
14/41
5/40
Vertebral Fractures
Palomba S et al. Osteoporos Int. 2005 Sep;16(9):1141-9.
Palomba S et al. Menopause. 2008 Jul-Aug;15(4 Pt 1):730-6.
Oth therapies
Other
th
i for
f osteoporosis
t
i
Zoledronic Acid
4mg
4
IV over 15 minutes
i t
Increase BMD in post-menopausal women for 1 year
Teriparatide (rDNA origin) (Forteo)

very expensive
dailyy subq
q injection
j
so avoids g
gut absorption
p
Denosumab
Fully human antibody against RANKL (osteoclast
differentiation) subq q 3-6mo
Screening
g for bone disease
Check vitamin D 1, 25-OH levels in everyone
Testosterone
T t t
levels
l
l iin men
DXA for patients that are steroid-exposed more
than a cumulative of 3 months
Osteoporosis
p
warrants treatment with
bisphosphonates (or osteopenia and patient on
corticosteroids))
IV bisphosphonates available
Ocular manifestations of IBD
Anatomy
y of the eye
y
Anterior Uveitis ((Iritis)) in IBD

Inflammation of iris and/or ciliary body
Iritis/uveitis most common extraintestinal disease
of all 6 assessed in large, population-based study
Crohn's disease 1.5% and UC 2%
More common among UC women (3.8%)
Associated with pain, redness, blurred vision,

tearing, and photophobia
Slit lamp exam necessary for diagnosis
Acute form associated with HLA B27
Bernstein, C.N. et al. Am J Gastroenterol. 2001 Apr;96(4):1116-22.
Anterior uveitis/ Iritis
Other Ocular Complications

Episcleritis
Outer layers of eye

Eye burning or itching, erythema
Activity correlates to IBD activity
Topical corticosteroids
Scleritis
Severe, boring pain worse with eye movement
Dilation of the deep episcleral vessels and thinning of
the sclera;; the globe
g
is often tender to palpation
p p
Oral/ systemic steroids
Cataracts, glaucoma due to steroids
Episcleritis
p
Scleritis ((blue is bad))
Treatment of eye
y inflammation
Topical steroids, cycloplegic agents
Oral steroids for refractory cases or scleritis
Treat underlying disease
includes use of anti-TNFs
anti TNFs
Screening
g for ocular complications
p
Ask about red eyes

Is it painful to see bright light?
Is there a dull ache?
Is there vision loss?
For patients on corticosteroids greater
tthan
a 6 months,
o t s, need
eed eye e
exam
a for
o
cataracts
Nutrients
Vitamin D intervention studies
Plasma 25(OH)-Vitamin D Is Associated With a

Reduced Risk of Surgery in IBD
EMR-derived
d
d cohort
h off patients (n=3,217)
(
) assessed
d for
f association off 25(OH)5( )
Vitamin D status on subsequent surgery
Crohns
Initial Vitamin D Level
Surgery
UC
OR
Surgery
OR
>30 ng/dL
13%
10%
20-29 ng/dL
21%
1.54 (1.06 2.25)
12%
1.13 (0.68 1.86)
<20 ng/dL
24%
1.76 (1.24 2.51)
17%
2.10 (1.32 3.34)
Follow up Vitamin D examined for normalization and outcome in Crohns Disease

Surgery
Normalized
Not
Normalized
Normalized
1.0
0.51 (0.32 0.82)
1.0
0.64 (0.44 0.96)
1.0
0.56 (0.32 0.98)
1.0
0.78 (0.51 1.25)
Not
normalized
Unadjusted
Adjusted
Follow-Up Vitamin D Level
Hospitalizations
Crohnss disease
Crohn
Li it ti
Limitations:
no adjustment
dj t
t for
f severity/phenotype;
it / h
t
75 Ananthakrishnan AN, et al. Presented at DDW, May 18, 2013. Abstract 1.
What should you do when you get

home
home
Consider IV iron for iron-deficient anemic patients
p
TGN nucleotides and CBC every 3 months for patients
on thiopurines
Patients on corticosteroids should be on
bisphosphonates and have annual DXA
If you diagnose osteoporosis
osteoporosis, bisphosphonates are safe
Eye exams annually or for symptoms
Vitamin D supplementation in most patients
B12 in patients with ileal Crohns disease (IM and
g )
sublingual)
Cough, Wheeze, Sore Throat and More: What is

Related to GERD and How to Approach?

Professor of Medicine and Epidemiology
Chief, Division of Gastroenterology & Hepatology
University of North Carolina School of Medicine
Cough, Wheeze, Sore Throat and

More: What is Related to GERD
and How to Approach?
Nicholas J. Shaheen, MD, MPH, AGAF
University of North Carolina
Outline
What is the evidence linking these
symptoms to actual GERD?
What is the appropriate work up of putative
symptoms off extra-esophageal
h
l reflux?
fl ?
What response
p
rates of extra-esophageal
p g
symptoms can be expected acid suppressive
therapies
p and anti-reflux surgery?
g y
What are alternative treatment strategies
for these symptoms?
How Might Reflux Events be Related

t E
to
Extra-Esophageal
t E
h
l SSymptoms?
t
?
Three major possible mechanisms
Direct exposure of refluxate with possible
microaspiration
Reflux triggering pulmonary irritability by a
reflex arc mediated by the vagal nerve
Underlying pathophysiology triggers reflux
event
For instance, negative intrathoracic pressures
g
associated with asthma exacerbations might
exacerbate reflux
Aspiration
p
of Gastric Contents
Katz. Rev Gastroenterol Disord. 2005;5(3):126-134.
Neural Reflex Mechanisms
Katz. Rev Gastroenterol Disord. 2005;5(3):126-134.
Relationship Between GERD and Asthma
Yuksel ES, Vaezi MF. Gastroenterol Hepatol 2012.
Evidence Linking Reflux to LPR

S
Symptoms
t
Primarily
y epidemiological
p
g
and crosssectional
For instance,
instance
Patients with asthma are more likely to exhibit
pathological reflux on 24 hour pH study than
controls
Patients with chronic cough may have strong
association between cough and reflux episodes
on pH monitoring
Reference
Country
Study design
Patient
recruitment
Sontag et al 1990
USA
Cross-sectional
Consecutive
Suzuki et al 1997
Japan
Cross-sectional
Not reported
Vincent et al 1997
France
Cross-sectional
Consecutive
Kilj d ett all 1999

Kiljander
Fi l d
Finland
C
Cross-sectional
ti
l
N t reported
Not
t d
Carmona-Sanchez
et al 1999
Mexico
Cross-sectional
Consecutive
Compte et al 2000
Spain
Cross-sectional
Consecutive
Saudi Arabia Cross-sectional
Consecutive
Al-Asoom
Al
Asoom et al
2003
Kiljander and
L iti
Laitinen
2004
Leggett et al 2005
Finland
Cross-sectional
UK
Cross-sectional
Population
source
Secondary care,
asthma clinic
Secondary care
Secondary care,
asthma clinic
Secondaryy care,,
asthma clinic
Prevalence of
abnormal acid
exposure in
asthma
th
(%)
85/104 (81.8)
42/58 (72.4)
(72 4)
30/94 (31.9)
57/107 (53.3)
(53 3)
Secondary care,
45/60 (75.0)
asthma clinic
Secondary care,
12/81 (14.8)
asthma clinic
Secondary care
care,
22/50 (44.0)
asthma clinic
Random sample
of consecutive
Secondaryy care 32/90
/ ((35.6))
patients
Secondary care,
29/52 (55.8)
Not reported
asthma clinic
Havemann BD et al, Gut 2007.
GERD Will Be Present in Virtually

Any Chronic Disease Population
GERD
Asthma
Causes of Chronic Cough

g
Causes
s of Coug
gh (%)
100%
75%
50%
41%
24%
25%
21%
5%
4%
5%
0%
PND
Asthma
GERD
Chronic Bronchiect
Bronchitis
Causes of Cough
Irwin et al. Am Rev Respir Dis. 1990;141:640-647. Irwin et al. Am J Gastroenterol. 2000;95(suppl):S9-S14.
Misc
What is the Right Work

Work-up
up of
EERD Patients?
Diagnostic
g
Options for These Patients
Endoscopy
Ambulatory monitoring by impedance/pH
or pH
p
ENT exam w/ laryngoscopy
Hypopharyngeal
H
h
l pH
H monitoring
Sa
Salivary
va y peps
pepsin
Therapeutic trial of acid suppression
Endoscopy for Possible EERD

Less than 40% abnormal in studies of
patients with pulmonary symptoms
suggestive
gg
of GERD
ENT literature less well defined Given low
yield,
i ld endoscopy
d
is
i nott recommended
d d as
part of primary workup
SO WHY SO MUCH ENDOSCOPY?
pH or pH/Impedance Monitoring in
Possible EERD
Abnormal in 50% of those with suspected
ENT acid-related symptoms and as high as
82% of those with
ith suspected
s spected asthma related
to GERD
pH monitoring, even in combination with
laryngeal examination, is not specific for
establishing diagnosis
Specific Laryngeal Signs of GERD

ENT Si
Signs
N
Normals
l
GERD
(n = 105)a
(n = 34)
Posterior
cricoid wall
erythema
0%
Posterior
pharyngeal
y g
wall
cobble stoning
Interarytenoid
bar
True/false vocal
cord erythema /
edema
Arytenoid
medial wall
erythema /
edema
4-Month
4
M th
Treatment
Response
76%
<.001
.001
50%
21%
15%
0.8
20%
71%
76%
0.4
7%
2%
70%
< 001
<.001
60%
30%
82%
<.001
68%
Hicks et al. J Voice. 2002;16:564-579.
Laryngeal Signs Found in Normal Subjects

and
d More
M
Lik
Likely
l to B
Be LPR
LPR-Related
R l d
True/False vocal fold
erythema/edema
Posterior cricoid wall
erythema
Posterior commissure
erythema/edema
Posterior pharyngeal wall
erythema/edema
Vaezi et al. Clin Gastroenterol Hepatol. 2003;1:333-344.
Richter. Aliment Pharmacol Ther. 2005;22(suppl 1):70-80.
A diagnosis of reflux laryngitis

should not be made based solely
upon laryngoscopy findings.
findings
Could Pepsin Help Define those with Reflux?
Jamal O Hayat et al. Gut 2015;64:373-380
Receiver operating characteristics curve of the highest pepsin concentration between patients
with (A) gastro-oesophageal reflux disease (GORD) only and (B) GORD+Hypersensitive
Esophagus versus controls+FH patients.
Jamal O Hayat et al. Gut 2015;64:373-380
Is Heartburn Suggestive of Extra-Esophageal

GERD?
25
% Weekly
Heartburn
20
15
10
0
US Average
EERD
Koufman et al, OHNS, 2000
No Clinical
P
Presentation
t ti or
Sign is
Pathognomonic
for EERD
Pragmatic Issues About the First Visit

Patients are frustrated
You are doc #3 or 4 that they have seen for these
complaints
They present with strongly held

preconceptions
My ENT (PCP
(PCP, Pulmonary Doc) said this was all
reflux and that you would fix me
You are likely to let them down

They usually have tried PPI and failed
Maybe
Maybe it is not reflux!
reflux!
What You Can Do To Help on the 1st Visit

Check the completeness of their work-up
If they are a cougher or wheezer, have they had a
CXR?
If they are a cougher, has reactive airways disease
been considered (PFTs, maybe MCT)?
For coughers and hoarse people, has occult sinus
disease been considered?
Was the PPI trial adequate?

Educate, educate, educate
Explain possible pathophysiology and non-specific
nature of their symptoms
Explain
E l i results
l off treatment off their
h i symptoms with
ih
reflux medications
How Well Do These Patients

Respond to Acid Suppressive
Therapy?
BMJ 2005.
Change in Peak Expiratory Flow Rate
Arch Intern Med 2011;171:620-629.
Maybe
y We Are Just
J
Not Givingg Enough!
g
Not much difference in RFS scores, despite

4x normal dose of PPI!
J Voice 2014;28:369-77.
How About Surgery for ExtraEsophageal Symptoms?
Wright RC and Rhodes KP, Am J Surg 2003;185:455-61.
For the treatment of patients with

extraesophageal manifestations of
GERD symptoms,
y p
, no consistent benefit
could be attributed to either medication
or surgery.
AHRQ Publication No. 1111
EHC049-EF
S
September
b 2011
Asthma Recommendation
Empiric treatment is not helpful unless
patients are symptomatic for GERD
Especially helpful with nocturnal symptoms
Shoot for lowest effective dose
If not responsive perform additional workup
Chronic Cough Recommendation
Treat with BID PPI for 12 weeks and if no
improvement
p
Reassess for PND/Asthma/Bronchitis/etc.
Move forward with additional studies to
determine if reflux is present
p
Laryngitis Recommendations
BID PPI for 6 months
Plus or minus H2-blocker
Additional studies if patients do not respond
Esophageal Symptom Generation

Chemo-stimulation
Acid mediated
Heartburn
Reflux
Regurgitation
g g
Chest pain
Mechano-stimulation
Volume mediated
Cough
g
Kahrilas PJ 2007
Dealing with Dysphagia:

How to Test, How to Treat?

Chief, Division of Medicine-Gastroenterology and Hepatology
Dealing with Dysphagia:

H to
How
t Test
T t and
d Treat
T t
General Session III: Esophagus/Upper
p g
pp GI
John EE. Pandolfino
Pandolfino, MD,
MD MSCI
Feinberg School of Medicine,
Northwestern University
Chief, Division of Gastroenterology and Hepatology
N th
Northwestern
t
M
Medicine
di i
Northwestern Memorial Hospital
Dysphagia
Definition:
Dys=
Dys Disturbed or Disordered
phagia= to eat
IImpaired
i d transit
i off ffood
d ffrom the
h mouth
h to the
h
stomach
Oropharyngeal
Esophageal
Step 1: Watch people eat

eat.
Functional Elements of a Swallow

O l and
Oral
d Ph
Pharyngeall
a Nasopharyngeal closure
b Laryngeal vestibule closure
c UES opening
d Bolus propulsion
e Pharyngeal clearance
f Return to airway
GI Motility online (May 2006) doi:10.1038/gimo2
Diagnose and Treat the underlying Cause

Mechanical
Element
Biomechanical Mechanism
Evidence of Dysfunction
Typical Diseases
Nasopharyngeal
closure
Soft palate elevation
Nasopharyngeal regurgitation
Nasal voice
Myasthenia Gravis
Laryngeal closure
Laryngeal elevation
Arytenoid tilt
V l ffold
Vocal
ld closure
l
UES relaxation
Laryngeal elevation
Anterior hyoid traction
Sphincter distension
Lingual sensation and
control
Aspiration during bolus transit
CVA
Head Trauma
Dysphagia
Post-swallow
residue/aspiration
Diverticulum formation
Sluggish, misdirected bolus
Cricopharyngeal Bar
CVA
Parkinson's
UES opening
Tongue loading &

Bolus propulsion
Pharyngeal clearance
Pharyngeal shortening
Pharyngeal contraction
Epiglottic flip
Post-swallow
residue/aspiration
Parkinson's
Surgical defects
Cerebral palsy
p y
Polio
Post-polio
Oculopharyngeal
dystrophy,
dystrophy
CVA
Esophageal
p g
Symptoms
y p
Symptoms
Transit
T
it relatedl t d Antegrade
A t
d and
d Retrograde
R t
d
Food impaction
Regurgitation
Aspiration
Malnutrition
Perception related
Discomfort
Chest pain / pressure
Heartburn
Thermal
Patient with dysphagia/ food impaction

yes
Functional
yp g
Dysphagia
EGD biopsy
Abnormal?
no
High-Resolution Manometry
+/ esophagram
+/-
yes
Mechanical
Obstruction
Achalasia
EGJOO
Absent Contractility
Spasm
Jackhammer
yes
Primary Motor
Disorder
Normal
IEM
Fragmented
yes
Look for another

Cause
Treat GERD
I
Imaging
i
Etiologies of Mechanical Obstruction

Structural abnormality
(dysphagia- usually solid food)
Endoscopy
Ring
Stricture
Eosinophilic
p
esophagitis
p g
Infectious esophagitis
Pill or caustic esophagitis
Dermatologic disorders
Extrinsic compression
Primary or secondary tumor
Eosinophilic Esophagitis
Allergic esophagus infiltrative eosinophilia
Signs/symptoms:
D
Dysphagia,
h i ffood
d iimpaction,
ti
abdominal/chest
bd i l/ h t pain,
i
vomiting, regurgitation
Clinical characteristics
Male predominance (70%-80% of cases)
Family or personal history of allergy/atopy
Asthma, rhinitis, eczema, food allergy
Treatment
PPI
Steroids (fluticasone, prednisone)
Diet (wheat, egg, soy, milk, peanuts, and/or seafood)
Allergy evaluation?
Dilation
l
Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530.

Liacouras CA, et al. Clin Gastroenterol Hepatol. 2005;3:1198-1206.
Eos

yes
Functional
yp g
Dysphagia
EGD biopsy
Abnormal?
no
+/ esophagram
+/-
yes
Mechanical
Obstruction
Achalasia
EGJOO
Absent Contractiloity
Spasm
Jackhammer
yes
Primary Motor
Disorder
Normal
IEM
Fragmented
yes
Look for another

Cause
Treat GERD
I
Imaging
i
Line Plots (pressure vs time) of

Conventional and High
Resolution Manometry
Catheter
Configuration
HRM Plotted in
Esophageal Pressure Topography
0
Clouse Plots
UES
5
mmHg
1st
150
10
Proximal trough
40
mmHg
100
2nd
15
0
Middle trough
50
20
3rd
30
Distal trough
CDP
25
4th LES
EGJ
30
0
5
Time (seconds)
10
EGJ
relaxation
10 s
Chicago Classification 3.0

IRP upper limit of normal AND 100% failed
peristalsis or spasm
Disorders of EGJ
Outflow Obstruction
Yes
Achalasia
Type I: 100% failed peristalsis [no PEP]
Type II: 100% failed peristalsis [+ PEP]
Type III: >20% premature contractions
No
IRP upper limit of normal AND
sufficient evidence of peristalsis such that criteria for
type III achalasia are not met
Yes
EGJ Outflow Obstruction

Incompletely expressed achalasia
Mechanical obstruction
No
IRP is normal AND
reduced distal latency (DL)
OR DCI > 8,000 mmHg-cm-s
Major Disorders of Peristalsis

Entities not seen in normal
controls
Yes
No
IRP is normal AND
100% failed peristalsis
Yes
No
Minor Disorders of Peristalsis

Impaired bolus clearance
Distal esophageal spasm (DES)

20% premature contractions (DL<4.5s)
Jackhammer esophagus
20% of swallows with DCI >8,000
mmHg-s-cm and normal DL
IRP is normal AND

> 50% of swallows are ineffective based on DCI
values or large breaks
Yes
Absent Contractility
No scorable contraction by DCI and DL
criteria (should consider achalasia with
borderline IRP and/or bolus pressurization)
Ineffective Motility (IEM)
>50% ineffective swallows
Fragmented peristalsis
>50% fragmented swallows and not
meeting
ti criteria
it i for
f IEM ((mean DCI
>450 mmHg-s-cm)
No
Normal Esophageal Motor

Function
IRP is normal AND

> 50% of swallows are effective without criteria
for spasm or jackhammer
Yes
Rapid contraction and Hypertensive

peristalsis are not considered distinct
clinical-pathological entities in CC v3.0
Esophageal Physiology: Neuromuscular Control

C
Concept
t off IInhibitory
hibit
and
d EExcitatory
it t
B
Balance
l
A:EGJ Outflow Obstruction
B:Type
yp II Achalasia
30
C:Type
yp I Achalasia
Color Pressure scale (mmHg)

60
90
120
150
180
D:Type
yp III achalasia
B: Latency measured with EPT

Normal swallow
A:Latency described with

conventional manometry
21
19
Ax
xial position (cm)
17
mmHg
150
10
15
13
100
15
11
CFV
20
9
7
25
5
30
3
1
0s
0
35
C: DES: Rapid Premature Contraction

5
Bolus Escape
10
3.0 cm
15
25
30
35
CFV = 45
cm/s
2s
2s
Time (s)
30
0
CDP
Time (s)
E: Rapid Contraction with Normal latency
mmHg
150
1
cm/s
/
CFV =15
15
cm/s
cm/s
DL = 7.0 s
DL = 4
4.4
4s
DL = 3.0 s
DL
3
cm/s
CFV = 6
cm/s
30 cm/s
20
D: DES: Premature Contraction
Length alon
ng the
esophagus (cm)
Length along the esoph

hagus (cm)
10
10s
5s
5
50
5.5 cm
2
cm/s
2s
Time (s)
Time (s)
100
50
30
0
Utilizing HRM/EPT in the Management of Achalasia

Symptoms of dysphagia chest pain and bland regurgitation
Upper Endoscopy
Esophageal dilatation
EGJ resistance
Retained food
Diverticulum
Normal
Obstructive process: ring, stricture, etc.
High Resolution Manometry

*esophagram may be helpful when manometry
is technically difficult to perform
EPT Diagnosis
EGJ Outflow
Obstruction
EGD
EGD EUS/CT to
rule out obstructive
process
Potentially achalasia
phenotype with
preserved peristalsis
Absent
Peristalsis
If clinical scenario
c/w achalasia, a
timed barium
esophagram should
be performed
Potentially advanced
GERD or
scleroderma
Potentially achalasia
phenotype with
hypotensive LES
Achalasia I
Severe dilatation is
associated with poor
treatment response
Consider myotomy
as initial therapy
Achalasia II
Achalasia III
DES
Best treatment
response
Esophagram can be
normal without
barium retention or
esophageal
dilatation
Frequently
q
y
misdiagnosed with
conventional
manometry
Worst treatment
response
May benefit from
treatment directed at
spasm
Often diagnosed as
DES on esophagram
Extremely rare
Difficult to treat
Many cases are
misdiagnosed Type
III achalasia
Esophageal pressure Topography

Jackhammer EsophagusEsophagus Treatment
A: Jackhammer
standard swallowswallow no pain
B: Jackhammer- Normal
protocol swallow + sildenafil
30
C: Jackhammer-Spasm
during
d
i chest
h t pain
i eventt
Color Pressure scale (mmHg)

60
90
120
150
180
D: Jackhammer-Absent Contractility
After POEM
Absent peristalsis
1
Normal mean IRP

IRP, 100% of swallows with failed peristalsis
mmHg
150
Leength along th
he esophagus ((cm)
10
100
15
50
20
30
25
IRP= 4.6 mmHg
30
15 s
35
NU IRB
Pressure Topography of Esophageal Motility

The Chicago Classification 3
3.0
0
Minor Disorders of
Peristalsis
Impaired bolus
clearance
Absent Peristalsis
IRP is normal AND

> 50% of swallows are
ineffective based on DCI
values or large breaks
Absent/Failed Peristalsis
Yes
Weak Peristalsis- IEM
Ineffective Motility (IEM)

>50% ineffective swallows
Fragmented peristalsis
>50% fragmented swallows
and not meeting criteria for
IEM (mean DCI >450
mmHg-s-cm)
Fragmented- TZ Defect
Leng
gth along the esop
phagus (cm)
DCI= 7 mmHg-s-cm
DCI= 34 mmHg-s-cm
DCI= 325 mmHg-s-cm

DCI= 1121 mmHg-s-cm
10
1
15
20
25
30
10 s
35
10 s
10 s
10 s

yes
Functional
yp g
Dysphagia
EGD biopsy
Abnormal?
no
+/ esophagram
+/-
yes
Mechanical
Obstruction
Achalasia
EGJOO
Absent Contractiloity
Spasm
Jackhammer
yes
Primary Motor
Disorder
Normal
IEM
Fragmented
yes
Look for another

Cause
Treat GERD
I
Imaging
i
Medical Management: Functional Dysphagia

NOT FDA APPROVED
Anti-depressants
p
amitriptyline, nortriptyline, desipramine
10 to 25 mmg at bedtime with escalation of 10 to 25 mg increments to a target of 5075 mg
Trazadone
25mg QHs up to 100 mgHg
SSRIs
5HT agonists-antagonists- not currently available

Bethanecol and Metoclopramide too many side effects and
benefits not worth the risk in most
Gut-directed
Gut
directed Hypnotherapy
Are you getting sleepy?
Deep physical relaxation and deep
mental concentration
Alters focus of attention, changes
meaning about sensations arising from
the gut and encourages body to restore
itself to a healthier state
Shown to produce cognitive change and
improve pain tolerance
Modifies physiological arousal and
hypersensitivity over long
long-term
term
Initially performed in a doctors office but
can eventually be self-guided
The most scientifically supported nonnon
drug treatment for Functional GI
disorders
Key Clinical Take Home Points:

Watch people eat to determine etiology.
Modified videofluoroscopy cookie swallow is the best
test to help test and treat OP dysphagia
Endoscopy
py with biopises
p
is the first step
p followed
bymanometry if the endoscopy is negative or supportive
of a motility disorder
Barium Esophagram is an important complementary test
in equivocal cases
Reassurance and lifestyle modifications go along way in
improving quality of life
Hypnosis and
d neuromodulators
d l
may b
be h
helpful
l f l
Eosinophilic Esophagitis: Distinguishing From Other

Disorders? Best Short and Long-term Management
Strategies (Diet, Steroids and Beyond?)

VA North Texas Health Care System
Learning Objectives

able to:
1. Understand potential mechanisms for PPI-responsive
esophageal eosinophilia.
2. Appreciate the rationale for diet therapy in eosinophilic
esophagitis.
3. Formulate a management strategy for patients
with eosinophilic esophagitis.
In 2011, a task force on eosinophilic esophagitis (EoE) proposed this conceptual definition that EoE is a chronic, immune/antigen-mediated esophageal disease characterized
clinically by symptoms related to esophageal dysfunction
and histologically by eosinophil-predominant inflammation.
ADDIN EN.CITE ADDIN EN.CITE.DATA 1 In the United States,
the prevalence of EoE in the general population is estimated
at 50 to 100 per 100,000. For comparison, this is similar to
the estimated prevalence of ulcerative colitis. ADDIN EN.CITE
ADDIN EN.CITE.DATA 2 EoE is now the most common cause of
food impaction in patients seen in emergency rooms. ADDIN
EN.CITE ADDIN EN.CITE.DATA 2 The cost of diagnosing and
treating EoE in the United States has recently been estimated
at somewhere between .5 to1.4 billion dollars per year. ADDIN
EN.CITE ADDIN EN.CITE.DATA 2 These statistics are astounding for a disease that was essentially unknown just 20 years
ago.
A problem that confounds studies on the prevalence of EoE is
that there is no diagnostic gold standard for EoE. No single clinical, laboratory, endoscopic, or histological feature establishes
the diagnosis of EoE and this causes clinical confusion. We
identify patients with EoE when they come to us with symptoms. Dysphagia and food impaction are the most frequent
symptoms in adults, who often complain of chest pain, heartburn and upper abdominal pain which are not very specific because all these symptoms are very similar to gastroesophageal
reflux disease (GERD). In fact, these patients are often diagnosed with refractory GERD. These symptoms often result in
endoscopy. There has been the recent development of the EoE
endoscopic reference score known as EREFS, which stands for
the five main endoscopic findings, namely Exudates, which are
white plaques, Rings, also called trachealization of the esophagus, Edema, recognized by pallor and loss of vascular markings, Furrows, which are vertical lines, and Strictures. ADDIN
EN.CITE ADDIN EN.CITE.DATA 2 However, none of these findings are specific for EoE, and the esophagus can appear totally
normal in approximately 10% of cases. ADDIN EN.CITE ADDIN
EN.CITE.DATA 2 The key histological finding is the presence
of more than 15 intraepithelial eosinophils/high power field
(HPF) in esophageal biopsy specimens. Other typical findings include eosinophil microabscesses, basal zone hyperplasia, dilated intercellular spaces, and subepithelial fibrosis.
Even though 15 eosinophils per HPF is a requirement for the
diagnosis, 15 is an arbitrary number that has no established
biological importance. Furthermore, none of these histologic
findings are specific to EoE. A number of diseases are associated with esophageal eosinophilia. Besides EoE, you can find
large numbers of eosinophils in the esophagus of patients with
GERD, eosinophilic gastroenteritis, Crohns disease, infections,
connective tissue diseases, vasculitides, and hypereosinophilic
syndrome. ADDIN EN.CITE ADDIN EN.CITE.DATA 2 But the
disease on this list that causes the most diagnostic confusion
is GERD.
For patients who have esophageal symptoms and esophageal eosinophilia, a major problem for clinicians has been to
distinguish whether those patients have EoE or GERD and it
was thought that a response to proton pump inhibitors (PPIs)
means that your patient has GERD. ADDIN EN.CITE ADDIN
EN.CITE.DATA 1 This distinction was fine until studies reported that patients with upper GI symptoms and esophageal eosinophilia, but no evidence of GERD by endoscopy or pH monitoring, responded to PPIs. This condition is currently called
PPI-responsive esophageal eosinophilia. ADDIN EN.CITE
ADDIN EN.CITE.DATA 1 These patients have esophageal eosinophilia with typical EoE symptoms and histology, but they
have no evidence of GERD by endoscopy or pH monitoring,
and yet they show a clinical and histological response to PPIs.
There are at least two possible explanations for this condition. One is that these patients dont have an immune/antigen
mediated disease at all. What they have is acid reflux causing
esophageal eosinophilia, even though endoscopy and pH monitoring studies are normal. ADDIN EN.CITE ADDIN EN.CITE.
DATA 3 This is essentially NERD with eosinophils. The other
possibility is that these patients in fact have EoE that responds
to the anti-inflammatory effects of PPIs, independent of effects
on acid inhibition. ADDIN EN.CITE ADDIN EN.CITE.DATA 3 In
fact, a number of studies suggest that PPIs can do a lot more
than just inhibit gastric acid production. They have a number
of potential anti-inflammatory effects. PPIs have anti-oxidant
properties, they have been shown to have inhibitory effects
on neutrophil function that could decrease inflammation,
they decrease cytokine production by endothelial and epithelial cells and they decrease adhesion molecule production
by endothelial cells and neutrophils. ADDIN EN.CITE ADDIN
EN.CITE.DATA 3
If EoE is an immune/antigen mediated esophageal disease,
then how might an immune/antigen mediated esophageal
disease respond to the anti-inflammatory effects of PPIs? Every day, we ingest millions of antigens that have the potential
to evoke an immune response. If one of these antigens gets
the attention of an antigen presenting cell, and that cell presents the antigen appropriately, then it is possible to activate
the immune system, and this can stimulate the differentiation
of nave CD4+ T cells into Th 1 cells that secrete TNF- and
interferon- or the cells can differentiate into Th 2 cells that
secrete IL-4, IL-5, and IL-13. Overproduction of these Th2
cells is characteristic of a number of allergic disorders, and
appears to include EoE.
Using an RNA microarray, children with EoE have been found
to express a unique esophageal transcriptome compared to
children without EoE. Among the genes overexpressed in this
EoE transcriptome was eotaxin-3, which was increased more
than 50-fold. Eotaxin-3 is a potent chemoattractant for eosinophils that could draw them into the esophagus. Data from
Cheng et al. demonstrate how the PPI omeprazole might have
Eosinophilic Esophagitis: Distinguishing From Other Disorders? Best Short and Long-term Management Strategies (Diet, Steroids and Beyond?)
direct eosinophil-reducing effects in the esophagus. ADDIN

EN.CITE ADDIN EN.CITE.DATA 4 In two telomerase-immortalized esophageal squamous cell lines established from biopsy
specimens taken from EoE patients, baseline eotaxin-3 secretion was low and unaffected by treatment with omeprazole.
When the cells were stimulated with the Th2 cytokines, IL-13
and IL-4, their expression of eotaxin-3 increased dramatically.
However, that cytokine-stimulated eotaxin-3 secretion was
blocked by treatment with omeprazole. ADDIN EN.CITE ADDIN EN.CITE.DATA 4 Remember that eotaxin-3 is what draws
eosinophils to the esophagus, so if omeprazole blocks its production, that might decrease esophageal eosinophilia. In addition, these studies were performed on esophageal squamous
cells growing in a dish. There is no stomach in this system,
so this PPI effect was entirely independent of effects on gastric acid secretion. So a trial of PPI therapy is recommended
for patients with symptomatic esophageal eosinophilia, even if
the diagnosis of EoE seems clear cut. ADDIN EN.CITE ADDIN
EN.CITE.DATA 3 In fact, EoE cannot be distinguished from PPIresponsive esophageal eosinophilia based on clinical, histological or endoscopic findings probably because they are the
same disorder. ADDIN EN.CITE ADDIN EN.CITE.DATA 5 The
notion that EoE and PPI-responsive esophageal eosinophilia
are the same disorder has recently been supported by a study
comparing the esophageal transcriptome between adults with
EoE and those with PPI-responsive esophageal eosinophilia
(Figure 1) ADDIN EN.CITE ADDIN EN.CITE.DATA 6. The investigators used a RNA microarray that contained 59 specific EoE
genes. On this array (Figure 1), a blue color means that a gene
is downregulated, and red means that the gene is upregulated.
Based on the pattern of blue-red expression, the patients were
easily separated into those with EoE and those with a normal
esophagus. When they looked at the pattern of blue-red expression in the transcriptome of patients with untreated PPIresponsive esophageal eosinophilia, the investigators found
that it resembled that of EoE patients whereas the blue-red
expression pattern in the transcriptome of PPI-responsive
esophageal eosinophilia following treatment with PPIs resembled that of a normal esophagus. These findings demonstrate
that EoE and PPI-responsive esophageal eosinophilia are part
of the same spectrum of a Th2-mediated esophageal disease
ADDIN EN.CITE ADDIN EN.CITE.DATA 6 and suggest that EoE
and PPI-responsive esophageal eosinophilia are in fact the
same disorder.
If your patient responds to PPIs, it might not matter whether
this is GERD or EoE, unless you want to consider diet therapy.
EoE is a food allergy, GERD is not. PPIs are just covering up the
food allergy, similar to steroids. To really get to the heart of
the problem, diet therapy, to find the foods that are triggering
the esophageal eosinophilia, should be considered. There are
three general approaches to diet therapy. A directed elimination diet that is based on the results of skin prick testing for
food allergens can be prescribed. Recent meta-analysis found
that this approach has a success rate of about 46%. ADDIN

EN.CITE ADDIN EN.CITE.DATA 7 An empiric elimination diet,
in which formal allergy testing is not done, can be prescribed.
In this approach, the most common food allergens like milk,
soy, eggs, wheat, nuts and seafood are prohibited. The meta-analysis suggests that this approach has a success rate of
about 72%. ADDIN EN.CITE ADDIN EN.CITE.DATA 7 There
have been attempts to use less restrictive diets, for example,
a recent prospective multi-center study suggests that if you
prohibit 4 common food allergens (milk, wheat, eggs, and
legumes) the success rate is only 54%. Finally, an elemental
diet using amino acid-based formulas can be prescribed. The
meta-analysis suggests that this approach has an astounding
success rate of 91% but it seems unlikely that adult patients
will accept an elemental diet for this disorder. ADDIN EN.CITE
ADDIN EN.CITE.DATA 7 This meta-analysis describes short
term results. What happens in the long term?
Long-term results of the six-food elimination diet also appear
promising. ADDIN EN.CITE ADDIN EN.CITE.DATA 8 In those
50 patients who completed 6 weeks of the six-food elimination diet, 20 had foods reintroduced to identify which foods
were triggering the disease. Wheat and milk were the most
common food triggers, followed by soy, nuts and eggs. ADDIN
EN.CITE ADDIN EN.CITE.DATA 8 Interestingly, skin prick testing was found to be worthless for guiding the diet, because
skin prick testing predicted only 13% of the causal foods, and
two-thirds of patients who had a food trigger identified by reintroduction of the offending food had a negative skin prick test.
Among these 20 patients who had food triggers identified, 9
completed 1 year on a maintenance diet without the food triggers, and those patients all did well. When the offending food
was reintroduced, the peak eosinophil count in the esophagus
returned to pre-diet levels suggesting that diet therapy is effective at maintaining EoE remission in adults who have identified food triggers. ADDIN EN.CITE ADDIN EN.CITE.DATA 8
Now, what about topical steroids for EoE? We use topical steroid preparations like fluticasone and viscous budesonide to
avoid the side effects of systemic steroids. Randomized clinical trials have shown that topical steroids significantly reduce
esophageal eosinophil levels. Most patients in these trials
experienced some symptom relief with steroid treatment,
but not all studies have shown statistical significance in this
regard. For patients who get symptom relief, however, symptoms recur very frequently when the steroids are stopped and
we have very limited data on the safety and efficacy of longterm steroid therapy for eosinophilic esophagitis. (Reviewed
in ADDIN EN.CITE ADDIN EN.CITE.DATA 2) How about
treatments beyond diet and steroids? Montelukast and cromolyn have been studied but are not recommended in EoE.
Angiotension receptor blockers inhibit transforming growth
factor- (TGF-) signaling, which is pro-fibrotic. Early phase
clinical studies are being planned to examine their effective-
ness in EoE. (Reviewed in ADDIN EN.CITE ADDIN EN.CITE.

DATA 2) What about biologics? Antibodies against IL-5 have
shown mixed results in randomized controlled trials and further studies are in progress. Monoclonal antibodies against
IL-13, IL-4, and eotaxin-3 are currently under investigation.
(Reviewed in ADDIN EN.CITE ADDIN EN.CITE.DATA 2)
Finally, what is an adequate endpoint to judge the adequacy

of treatment for EoE. Is it good enough just to achieve a symptomatic remission or must physicians insist upon a histologic
remission, with biopsies showing that all of the esophageal
eosinophils are gone? To insist upon histologic remission
means that the patient has to undergo endoscopy with biopsies, which increases expense, inconvenience, and risk to the
patient. Investigators from Mayo Clinic and the UK have come
up with an interesting alternative to esophageal biopsy, the
cytosponge, for monitoring the extent of esophageal eosinophilia. ADDIN EN.CITE ADDIN EN.CITE.DATA 9 In their recent
study, 20 adults with EoE swallowed a capsule with a string
attached that was held at the mouth for 5 minutes to allow for
release of the cytosponge from the capsule. Then the sponge
was quickly withdrawn. Endoscopy with esophageal biopsy
was then performed. Both the biopsies and the epithelial cells
retrieved from the sponge were processed for eosinophil number and stained for eosinophil-derived neurotoxin (EDN). The
investigators found an excellent correlation of both eosinophil counts and EDN staining between the cytosponge and the
esophageal biopsies. Moreover, the cytosponge was well tolerated and safe with minimal to no esophageal abrasions seen on
endoscopy. Thus the cytosponge may be a minimally invasive
method to monitor histological response to treatment in EoE.
ADDIN EN.CITE ADDIN EN.CITE.DATA 9 The management
of patients with suspected EoE is shown in Figure 2. ADDIN
EN.CITE ADDIN EN.CITE.DATA 10

Figures:
Figure 1. Esophageal Transcriptome in Patients with EoE,

untreated and PPI-treated PPI-responsive esophageal eosinophilia (PPI-REE), and patients without any esophageal disease
(normal).
Figure 2. Management Strategy for Patients with Suspected

Eosinophilic Esophagitis
Eosinophilic Esophagitis: Distinguishing From Other Disorders? Best Short and Long-term Management Strategies (Diet, Steroids and Beyond?)
References
1. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy
Clin Immunol 2011;128:3-20.e6; quiz 21-2.
2. Dellon ES, Liacouras CA. Advances in clinical management of eosinophilic esophagitis. Gastroenterology 2014;147:1238-54.
3. Cheng E, Souza RF, Spechler SJ. Eosinophilic esophagitis: interactions with gastroesophageal reflux disease. Gastroenterol Clin North
Am 2014;43:243-56.
4. Cheng E, Zhang X, Huo X, et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic
oesophagitis and GORD. Gut 2013;62:824-32.
5. Dellon ES, Speck O, Woodward K, et al. Clinical and endoscopic
characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol
2013;108:1854-60.
6. Wen T, Dellon ES, Moawad FJ, et al. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin
Immunol 2015;135:187-197.e4.
7. Arias A, Gonzalez-Cervera J, Tenias JM, et al. Efficacy of dietary
interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology 2014;146:1639-48.
8. Gonsalves N, Yang GY, Doerfler B, et al. Elimination diet effectively
treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology 2012;142:1451-9.e1; quiz
e14-5.
9. Katzka DA, Geno DM, Ravi A, et al. Accuracy, safety, and tolerability
of tissue collection by Cytosponge vs endoscopy for evaluation of
eosinophilic esophagitis. Clin Gastroenterol Hepatol 2015;13:77-83.
e2.
10. Aceves SS, Furuta GT, Spechler SJ. Integrated approach to treatment
of children and adults with eosinophilic esophagitis. Gastrointest Endosc Clin N Am 2008;18:195-217; xi.
Eosinophilic Esophagitis:
Di ti
Distinguishing
i hi from
f
Other
Oth Disorders?
Di
d
?
Best Short and Long
Long--Term
Management Strategies (Diet,
Steroids and Beyond)?
Rhonda F. Souza, M.D., AGAF
Dallas VA Medical Center
A 29 year-old man presented to the hospital with a meat

impaction that occurred while eating chicken
chicken.
He had a history of heartburn and
dysphagia for 8 years, and a history of
asthma.
Endoscopy showed a ringed
p g with a meat bolus, which
esophagus
was removed.
Biopsies from both proximal and distal
esophagus showed >50 eosinophils
per hpf.
p
p
He was treated with a PPI BID, and his heartburn and

dysphagia resolved
resolved.
Repeat
p
endoscopy
py showed
persistent rings, but esophageal
biopsies showed <5 eosinophils per
hpf.
f
What is your diagnosis?
A GERD
A.
B. Eosinophilic Esophagitis
C PPI-responsive
C.
PPI
i esophageal
h
l esosinophilia
i
hili
D. Does it matter?
Eosinophilic
E
i
hili E
Esophagitis
h iti (E
(EoE)
E)
Conceptual Definition
EoE is a chronic,, immune/antigen-mediated
g
esophageal disease characterized clinically by
y p
related to esophageal
p g
dysfunction
y
and
symptoms
histologically by eosinophil-predominant
inflammation.
Liacouras CA et al. J Allergy Clin Immunol 2011;128:3-20.
EoE in the United States

Prevalence 50-100 per 100,000
- Similar to ulcerative colitis
Dellon E. Clin Gastroenterol Hepatol 2014;12:589.
Most common cause of food

impaction in patients seen in ER
Sperry S. Gastrointest Endosc 2011;74:985.
Health-care cost $0.5-1.4 billion per year

Jensen E. Am J Gastroenterol 2015 [Epub ahead of print].
There Is No Diagnostic Gold

Gold Standard
Standard
for Eosinophilic Esophagitis
No single clinical, laboratory,
endoscopic or histological feature
endoscopic,
establishes the diagnosis of EoE.
Common Symptoms
y p
of EoE
Dysphagia
Food Impaction
Chest pain
Heartburn
Abdominal Pain
Refractory GERD
EoE Endoscopic Reference Score (EREFS)

Exudates (plaques)
None off these

N
h
fifindings
di
are specific
ifi ffor E
EoE
E
Rings
(trachealization)
Esophagus
p g appears
pp
normal in ~10%
%
Edema (p
(pallor))
Furrows (vertical lines)
Strictures
Hirano I. Gut 2013;62:489.
Histological Findings
Eosinophilia
Esophageal Eosinophilia
(15 intraepithelial eos/HPF)
Eosinophil Microabscesses
Basal Zone Hyperplasia
Dilated Intercellular Spaces
Subepithelial
p
fibrosis
Epithelium
Subepithelial
Basal
zone
fibrosis
yp p
Hyperplasia
(>20%)
The finding of 15 eosinophils per HPF has no

established biological importance.
Histological findings are not specific.
Diseases Associated with Esophageal

Eosinophils
EoE
GERD
Eosinophilic gastroenteritis
Crohns disease
Infections
Connective
C
ti titissue di
diseases
Vasculitis
Hypereosinophilic syndrome
Major Problem for Clinicians
E E or GERD ?
EoE
Response to PPIs=GERD
Most Patients with UGI Symptoms and Esophageal

Eosinophilia Respond to PPIs
712 patients with UGI symptoms
4 biopsies from mid-esophagus
677 <15 eos/hpf
35 15 eos/hpf
Rabeprazole 20mg BID

9 (25%)
No Remission
26 ((75%))
Remission
24 GERD by endoscopy or
pH monitoring
2 no evidence of GERD
Patients who have EoE symptoms and histology but no

evidence
of GERDClin
can
respond Hepatol
to PPIs.
Molina-Infante.
Gastroenterol
2011;9:110.
PPI--Responsive Esophageal Eosinophilia

PPI
Eosinophilia
Reflux
Have typical EoE symptoms and histology

Do not have GERD by endoscopy or pH monitoring
Exhibit a clinical and histological response to PPIs
Liacouras et al. J Allergy Clin Immunol 2011.
PPI--Responsive Esophageal Eosinophilia

PPI
Eosinophilia
P
Possible
ibl Explanations:
E l
ti
1) Patients have GERD with acid reflux causing esophageal
eosinophilia, even though endoscopy and pH monitoring
are
a
e normal
o a.
Non-Erosive
NonR
Reflux
fl Di
Disease
(NERD)
2) Patients have EoE that responds to anti-inflammatory
effects
ff t off PPI
PPIs independent
i d
d t off effects
ff t on acid
id inhibition.
i hibiti
PPIs Do More Than Just Inhibit Gastric

Acid Production
Potential Anti-Inflammatory Effects
Anti-oxidant properties
Inhibitory effects on neutrophil function

Decrease cytokine production by
endothelial and epithelial cells
Decrease adhesion molecule production
by endothelial cells and neutrophils
Kedika, Souza, Spechler. Dig Dis Sci 2009;54:2312.
If EoE is an immune/antigen mediated

esophageal
p g
disease,, then how might
g an
immune/antigen mediated esophageal disease
respond
p
to PPIs?
Immune System Activation

Th1 and Th2 Differentiation
Antigen
g
Antigen Presenting Cell
Activate Immune System

Naive CD4+ T Cells
Th1
(T-helper 1)
(TTNF--, IFNTNF
IFN-
Allergic
Th2 Disorders
(T-helper 2)
(T-
IL--4, ILIL
IL-5, ILIL-13
RNA Microarray Analysis of

Esophageal Biopsies
230 Genes
Downregulated
344 Genes
Upregulated
Eotaxin 3
Eotaxin-3
( >50-Fold)
1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 10 11 12 13
Controls Pts. with EoE
Potent chemoattractant
for eosinophils
Blanchard. J Clin Invest 2006;116:536
Eosinophilic Esophagitis Pathogenesis

Model
(Genetically--Susceptible Individual)
(Genetically
eotaxin
eotaxin--3
Esophageal Epithelium
Mast Cells
Food Allergen
IL-13
IL-4
IL-5
APC
Th2 cell
Omeprazole Might Have Eosinophil

Eosinophil--Reducing
Effects Independent of Effects on Gastric Acid
E t i 3 iis a potent
Eotaxin-3
t t eosinophil
i
hil chemoattractant
h
tt t t
Eota
axin-3 (pg/ml/2
250K cells)
4000
3500
3000
2500
2000
PPI effect was
Baseline
entirely
ti l iindependent
d
d t
OME (50
(50M)
IL--13 (50ng/ml) of effects on gastric
IL
ILIL-4 (10ng/ml)
acid secretion
secretion.
IL--13+OME
IL
IL--4+OME
IL
1500
1000
500
*
PPI
EoE1-T
*p<0.05 compared to IL-13 alone

#p<0.05
compared to IL-4 alone
PPI
PPI
PPI
EoE2-T
Cheng , E. Gut, 62: 824-832, 2013.
A trial of PPI therapy

py is
recommended for patients with
symptomatic esophageal
eosinophilia, even if the diagnosis
of eosinophilic esophagitis seems
clear cut.
clear-cut
Cheng E, Souza RF, Spechler SJ. Gastroenterology Clinics of North America,
2014; 43:243-256.
EoE cannot be distinguished from PPIREE based on clinical, histological or

endoscopic
p findings.
g
P b bl b
Probably
because th
they are th
the same disorder.
di d
Dellon ES. Am J of Gastroenterol. 2013, 1854-1860; Schroeder S. J Pediatr

Gastroenterol Nutr. 2013, 166-172.
Similar Esophageal Transcriptome Between

EoE and PPI
PPI--REE
Esoph
hageal Transc
criptome
e
(59 EoE genes)
Normal
EoE
PPI-REE
PPI-REE
(Untreated) (PPI Treated)
Genes
Downregulated
o
egu
a
ed
EoE and PPI-REE
PPI REE are part of the
same spectrum of a Th2-mediated
esophageal disease.
disease
EoE and PPI-REE
are the
Genes
same disorder!
Upregulated
Wen T et al. J Allergy Clin Immunol 2014
A 29 year-old man presented to the hospital with a meat

impaction that occurred while eating chicken. He had a
history of heartburn and dysphagia for 8 years, and a
history of asthma. Endoscopy showed a ringed esophagus
with
ith a meatt bolus,
b l
which
hi h was removed.
d Bi
Biopsies
i ffrom
both proximal and distal esophagus showed >50
eosinophils per hpf
hpf. He was treated with a PPI BID,
BID and
his heartburn and dysphagia resolved. Repeat endoscopy
persistent rings,
g , but esophageal
p g
biopsies
p
showed
showed p
<5 eosinophils per hpf. What is your diagnosis?
A. GERD
B. Eosinophilic esophagitis
C. PPI-responsive esophageal eosinophilia
D It might not matter?
D.
Unless you want to consider diet therapy!
Approaches to Diet Therapy for EoE

Directed elimination diet
Based on skin prick testing
46% (95% CI
CI, 35-56%) success
Empiric elimination diet
Prohibit 6 most common food allergens
(milk, soy, eggs, wheat, nuts, seafood)
72% (95% CI
CI, 66-78%)
66 78%) success
Prohibit 4 foods 54% success
Molina-Infante
Molina
Infante et al.
al Rev Esp Enferm Dig 2015;107:29
2015;107:29.
Elemental diet
Use amino acid-based
acid based formulas
91% (95% CI, 85-96%) success
Arias et al. Gastroenterology 2014; 146:1639;
Long
Long--Term Results of Six
Six--Food Elimination Diet
(SFED) for Eosinophilic Esophagitis in Adults
50 pts completed 6 weeks SFED
20 pts had foods reintroduced to identify triggers

(wheat 60%, milk 50%, soy 10%, nuts 10%, egg 5%)
SPT predicted only 13%
of causal foods
67% of pts with food trigger

identified by reintroduction
had a negative SPT.
9 pts completed 1 year on maintenance diet without food

triggers
Gonsalves N. Gastroenterology 2012;142:1451.
Long
Long--Term Results of Six
Six--Food Elimination Diet
((SFED)) for Eosinophilic
p
Esophagitis
p g
in Adults
Peak
k Eosinophiils/HP
PF
160
140
Diet therapy is
effective at
maintaining EoE
remission in adults
with identified food
triggers
triggers.
120
100
80
60
40
20
0
Pre
SFED
Post
SFED
Reintro
Gonsalves N.
Gastroenterology
2012;142:1451.
Topical Steroid Therapy for EoE

(Fluticasone, Oral Viscous Budesonide)
RCTs show that topical steroids significantly

reduce esophageal eosinophil levels
Most patients experience symptomatic
relief during treatment with steroids
Symptoms recur frequently when steroids are
stopped
Limited data on efficacyy and safety
y of longg
term steroid therapy for EoE
Beyond Diet and Steroids

Montelukast and cromolyn not
recommended
Angiotension Receptor Blockers inhibit TGF-
signaling,
g
g, which is p
pro-fibrotic.
Early phase studies are being planned
to examine their effectiveness in EoE.
EoE
Biologics:
IL-5
IL 5 iinhibitors
hibit
h
have shown
h
mixed
i d results
lt
in RCTs; further studies are in progress.
IL-13,
IL 13 IL
IL-4,
4 and
d exotaxin-3
t i 3 inhibitors
i hibit
are under
d
investigation.
What to use as an endpoint to judge

the
h adequacy
d
off treatment?
?
Symptomatic remission?
Histological remission?
Esophageal biopsies showing that all of the
eosinophils are gone.
Endoscopy
py with biopsy
p y increases expense,
p
,
inconvenience, and risk
The Cytosponge
Be aeosinophil
Minimallycounts
Invasive
Excellent
correlationMay
of both
and
Method
to Monitor
Histological
to
EDN staining
g between
the cytosponge
y p Response
g and the
Treatmentbiopsies.
in EoE
esophageal
20 adults with EoE
swallowed a capsule with a string
attached and the string was held
attached,
at the mouth for 5 minutes to allow
y p g
release of the cytosponge
endoscopy with esophageal biopsy
was then performed
Biopsies and epithelial cells retrieved from the
sponge
were well
processed
for and
eosinophil
number
and
Cytosponge
tolerated
safe with
minimal
stained
t iesophageal
d for
f eosinophil-derived
i abrasions
hil d i seen
d neurotoxin
t i (EDN)
on endoscopy.
Kadri SR, BMJ 2010; 341:C4372; Katzka DA, Clin Gastro & Hep, 2015; 13:77; Images courtesy of D. Katzka.
Management of EoE 2015

Suspected EoE (15 eos/hpf)
Symptoms
Resolve Trial of PPI BID 4-8 weeks
Symptoms
Persist
Dx: GERD or PPIDx:

EoE
Responsive Eosinophilia
? t PPI,
?stop
PPI ?further
?f th testing
t ti
Continue PPI Rx
Empiric Elimination Diet
Symptoms
Resolve
Symptoms
Continue Diet Rx
Resolve
Symptoms
Persist
Topical Steroids 6-8 weeks

Symptoms
P i t
Persist
Rule Out Infection

Follow, Resume Steroids PRN
(Candida, HSV)
Dysphagia Persists
Esophageal Stenosis
Esophageal Dilation
Modified from Aceves, Furuta, Spechler. Gastrointest Endosc Clin N Am 2008;18:195
How To Manage Low Grade Dysplasia Ablation

When And With What Follow-up?
Amitabh Chak, MD
Head, Section of Gastrointestinal Endoscopy
University Hospital of Cleveland
Barretts esophagus (BE) is believed to progress from metaplasia to low grade dysplasia (LGD) to high grade dysplasia (HGD)
to cancer. Intervention, either endoscopic or surgical is warranted when HGD is detected during endoscopic surveillance
because the risk of progression to cancer is substantial. With
advances in endoscopic therapy, particularly ablative therapy,
it is natural to raise the question of whether and when it might
be appropriate to ablate LGD.
Definition of LGD LGD is defined histologically by the presence of nuclear hyperchromasia with stratification of the nuclei, generally confined to the lower half of the epithelium. An
increased number of mitotic figures are present and there is a
depletion of goblet cells. However, the epithelial architecture
is not disturbed, pleomorphism is limited, and full thickness
stratification of nuclei is not present. LGD can easily be confused with inflammatory changes and because the features
are subtle and subjective there is poor to only fair agreement
even among expert gastrointestinal pathologists in interpreting LGD.
Risk of Progression There are not many long-term prospective

follow-up studies of large cohort of LGD patients. Furthermore,
most retrospective studies report on the risk of progression of
prevalent LGD rather than incident LGD. Most studies also do
not use expert pathologists to define LGD. Another factor that
complicates folloq-up studies is the fact that nearly a third of
subjects with LGD will not have LGD detected on subsequent
surveillance endoscopies. Whether this phenomenon is related
to sampling error, misinterpretation of initial diagnosis, or true
regression of LGD is a subject of debate. In prospective multicenter study of 156 patients with LGD followed for a mean of 5
years, Sharma et al. found that the risk of progression to cancer
was 1 in 156 patient years, a rate that is not much higher than
that of non-dysplastic BE. A systematic review of 16 studies
found evidence for publication bias but reported the risk of
progression to cancer to be 1.7 per 100 patient years, about
three fold that of non-dysplastic BE. A population based Danish study reported a progression rate of 0.5% per patient year.
In contrast, a Dutch study that stratified LGD found that when
LGD was interpreted by 3 pathologists the risk of progression
to cancer was 3% per patient year.
Detection of LGD Novel imaging techniques such as high
resolution endoscopy, NBI, OCT, or even confocal endoscopy
detect dysplastic changes mainly by identifying architectural
changes or detecting nuclear polymorphism at the epithelial
surface. These techniques can detect HGD but are not able to
detect. Thus, LGD can only be detected by random biopsy sampling during surveillance endoscopies. The detection of LGD
depends on how many biopsies are obtained and is subject to
sampling error.
Surveillance of LGD The diagnosis of LGD should only be considered in subjects with no evidence for esophagitis at endoscopy. If a subject has erosive esophagitis at the time of surveillance endoscopy, the subject should be treated with PPIs and
the endoscopy should be repeated. Focal LGD on a pathology
report should not be interpreted as LGD. Guidelines recommend a repeat surveillance endoscopy 6 months following the
initial detection of LGD and subsequent surveillance endoscopies at yearly intervals until 2 consecutive endoscopies do not
detect LGD. The biopsy protocol during surveillance should
consist of biopsies of all visible abnormalities and random 4
quadrant biopsies at a minimum of 2 cm intervals.
Ablative Therapy LGD can be ablated by endoscopic therapies such as argon plasma coagulation, multipolar electrocoagulation, photodynamic therapy, and cryotherapy. A recent
multicenter randomized sham-controlled trial published
in the NEJM reported a 96% clearance of LGD and an 83%
complete clearance of all intestinal metaplasia with radiofrequency ablation. The SURF trial from Amsterdam randomized
consensus LGD patients (3 pathologists independently confirm LGD) to ablation versus surveillance and found that significantly more patients in the surveillance arm progressed to
HGD or Cancer. Endoscopic ablative therapy is generally safe
but it does have a small risk of complications such as stricture and bleeding. The long-term complications are unknown
and we do not know whether this therapy will reduce the risk
of progression to cancer nor how effective it will be in longterm follow-up. Thus, before offering endoscopic therapy to
a subject with LGD endoscopists have to struggle with much
uncertainty.
My personal approach is to have an informed discussion with
any patient who is interested in ablative therapy for LGD. The
discussion should include our lack of knowledge about the
risk of progression of LGD to cancer, our lack of knowledge
about the long-term efficacy of ablative therapy, and our lack
of knowledge about possible long-term complications of ablative therapy. It might be reasonable to consider therapy in
LGD subjects who have persistent LGD, multifocal LGD, younger patients, and patients with very long segments of BE because presumably the risk of progression to cancer is higher
in these patients. It is also wise to review biopsies of LGD with
an expert pathologist and confirm the presence of LGD lest
one ablate a subject with inflammatory esophagitis who was
misdiagnosed.
How to Manage
g Low Grade
Dysplasia? Ablation When and
With
i h What
h Follow-Up?
ll
?
Amitabh Chak, MD
University Hospitals Case Medical Center
Cleveland, OHIO
Case Presentations
Case One - 69 yo man with HTN, CAD.
LLong segmentt (8 cm)) BE di

diagnosed
d 1991.
1991
Ssurveillance with Seattle protocol identified
LGD in one jar in 1998; No LGD on 7
surveillance EGDs Seattle protocol detects
LGD again in one jar in 2009.
Case Two:
C
T
54 year old
ld man with
ith chronic
h i
GERD
Initial screening
sc eening EGD sho
showss 5 cm of BE with
ith
LGD in every jar
Questions
What is Low Grade Dysplasia (LGD)

definition, interpretation, agreement?
What is the risk of progression from
LGD to cancer?
What is the recommended management
of LGD? Should it be ablated?
How should ablated LGD be followed?
What is Low Grade Dysplasia

(LGD) definition,
definition
interpretation,
p
, agreement?
g
John Goldblum, MD Cleveland Clinic
John Goldblum, MD Cleveland Clinic
Low Grade Dysplasia
Preserved glandular architecture

Nuclear hyperchromasia
Nuclear stratification confined to lower
half of epithelium
Increased mitotic figures
Depleted mucin; decreased goblet cells
Difficult to interpret in presence of
inflammation
Pathology Interpretation
E. Montgomery, et al., 2001
12 expert GI pathologists submitted 250

slides containing BE, IND, LGD, HGD, and
cancer.
One set of 125 slides reviewed twice by
each
h pathologist
th l i t prior
i to
t consensus
meeting.
S
Second
d sett off 125 slides
lid reviewed
i
d by
b each
h
pathologist after consensus meeting.
Intra and Inter-Observer

Agreement
For Differentiating Non-dysplastic/IND/LGD vs.

HGD/Ca
Intraobserver Kappa = 0.82 0.80 (near perfect)

Interobserver Kappa = 0.66
0 66 0.70
0 70 (substantial)
For Diagnosing Specific Categories
Interobserver Kappa for HGD/Ca = 0

0.65
65
(substantial)
Kappa
pp for BE = 0.58 (moderate)
(
)
Kappa for LGD = 0.32 (fair)
What
h is
i the
h risk
i k off progression
i
from LGD to cancer?
Natural History of LGD
(Sharma, et al., Clin Gastro Hep 2006)
Multi-center followup of 618 BE

patients, mean F/U 4.12 years.
Risk of Progression
g
in LGD
(Sharma et al.)
BE to LGD incidence 1 in 25 patient

years = 4%
LGD to Cancer incidence was 1 in 156
patient years = 0.6%
Non-dysplastic BE to Cancer incidence
was 1 in 212 p
patient years
y
= 0.5%
Incidence of EAC
(Hvid-Jensen et al., NEJM 2011)
Risk of progression to EAC from Index endoscopy showing

LGD is 1 in 200 patient years (0.5%).
Amsterdam SURF Studyy

(Phoa et al. - JAMA 2014)
Three pathologists evaluated patients with

LGD Over half were re
LGD.
re-classified.
classified
140/511 = 27% patients with LGD
confirmed by 3 pathologists
pathologists. Randomized
to RFA vs. surveillance
27% in control vs.
vs 1.5%
1 5% in RFA arm
progressed to HGD or CA in ca. 3 year
followup,
p, p < 0.001
9% in control vs. 1.5% in RFA arm
progressed to CA, p = 0.03
What is the recommended

management of LGD? Should
it be ablated?
Guidelines for LGD
(Wang et al., AJG 2008)
Review biopsies with expert pathologist to

confirm diagnosis of LGD
Repeat EGD with surveillance in 6 months
to ensure there is no HGD or Cancer
Perform EGD every year if LGD persists or
3 years if there is no dysplasia on two
consecutive
ti surveillance
ill
endoscopies
d
i
Vid off RFA

Video
Response
p
to RFA
(Shaheen, et al. NEJM 2010)
SURF Studyy - Progression

g
to
HGD/Ca
Complications of RFA
NEJM Study 119 patients
4 SAE 1 GI bleed; 3 admissions for chest

pain/nausea
9 (8%) developed esophageal strictures
that responded to dilation
SURF Study 68 patients
3 SAE 1 GI bleed; 1 abd pain; 1 fever

8 (11.8%) developed esophageal strictures
tthat
at responded
espo ded to d
dilation
at o
Guidelines on RFA for LGD
AGA Guidelines are clear on RFA for HGD

b t do
but
d nott h
have a d
definite
fi it statement
t t
t on
LGD.
AGA Guidelines say RFA is a treatment
option but do not include it in their
recommendations.
d ti
ASGE Guidelines recommend surveillance
for LGD; ablation be considered in
select patients.
How should ablated LGD be

f ll
followed?
d?
Follow-up of Ablated LGD
BE recurs in up to 20% of subjects 5

years after ablation.
Buried subsquamous cancers have been
reported.
Follow-up of ablated LGD should be
similar to that of nonablated LGD
Must also survey gastric cardia
Guidelines for LGD
(Wang et al., AJG 2008)
Review biopsies with expert pathologist to

confirm diagnosis of LGD
Repeat EGD with surveillance in 6 months
to ensure there is no HGD or Cancer
Perform EGD every year if LGD persists or
3 years if there is no dysplasia on two
consecutive
ti surveillance
ill
endoscopies
d
i
Followup post ablation
Repeat EGD with surveillance in 6

months to ensure there is no HGD or
Cancer
Perform EGD every year until there is
no BE on ttwo consecutive
ti surveillance
ill
endoscopies then perform EGD every 3
years
Personal Approach
pp
to Patient
with LGD
Confirm diagnosis with second pathologist

Review current guidelines for surveillance
Reassure patients with LGD that their risk of
progression to cancer is similar to BE
Explain that two thirds will regress
spontaneously
Review data on efficacy, safety but also risk of
RFA
E l i that
Explain
th t surveillance
ill
is
i still
till necessary
Let patient decide about ablation
Case Patient Decision

Case One: 69 yo man with HTN, CAD.
BE diagnosed in 1991.
1991
LGD in 1998; then again in 2009
Elected to continue surveillance. Has had no

dysplasia in last four endoscopies over three
years
Case Two: 54 yo with multifocal LGD
Underwent
U
d
t abaltive
b lti therapy
th
with
ith complete
l t
remission. Still under surveillance
Functional Heartburn:
What Works When PPIs Dont?

Chairman, Division of Gastroenterology and Hepatology
MetroHealth Medical Center
Functional Heartburn: What

Works when PPIs Dont?
Ronnie Fass, MD
Case Western Reserve University
F nctional Esophageal Disorders

Functional
Rome III
F
Functional
ti
lE
Esophageal
h
l Di
Disorders
d
Functional heartburn
Functional chest pain of presumed esophageal
origin
Functional dysphagia
Globus
Drossman D, ed. Rome III: The Functional Gastrointestinal Disorders. Third Edition. 2006.
Functional Heartburn
(Rome III Criteria)
Must include all of the following criteria fulfilled for the last 3
months with symptom onset at least 6 months prior to diagnosis:
Burning retrosternal discomfort or pain
Absence of evidence that gastroesophageal reflux is the
cause off the
th symptom
t
Absence of histopathology-based esophageal motility
disorders
Patients with normal acid exposure and positive association
off symptoms
t
with
ith reflux
fl events
t (hypersensitive
(h
iti esophagus)
h
)
Excluded
Patients with normal acid exposure and negative symptom
index who are responsive to PPIExcluded
Who Falls Under the Category of Functional Heartburn?

Patient with heartburn
Endoscopy
Normal endoscopy
pH testing
(50%) abnormal
(50%) normal
Symptom
y p
index
Positive (37%)
Responsive
Negative (63%)
PPI ttreatment
eat e t
Not responsive
NERD
Hershcovici and Fass. J Neurogastroenterol Motil 2010;16(1):8-21
Common Mechanisms
for PPI Failure
Psychological comorbidity
Compliance
Improper dosing time
Eosinophilic esophagitis (?)
Weakly
W kl acidic
idi reflux
fl
Duodenogastroesophageal reflux
Residual acid reflux
Reduced PPI bioavailability

Rapid PPI metabolism
Delayed gastric emptying
PPI resistance
Others
Fass & Sifrim. Gut 2009;58(2):295-309
Concomitant functional bowel disorder
How Common is Functional Heartburn in

Patients with Heartburn Who Failed PPI bid?
Symptomatic
y
patients
172 (86%)
Nonacid reflux
61 (35%)
Acid reflux
13 (8%)
Mainie et al: Gut, 2006; 55:1398-1402
Symptoms not
associated with reflux
98 ((57%)) = Func. HB
Functional Heartburn and Esophageal

Hypersensitivity
Esophageal
p g Hypersensitivity
yp
y
The perception of nonpainful esophageal stimuli as being painful,
and painful esophageal stimuli as more painful
75% of FH
80% of FCP
86% of NERD
Trimble KC et al. Gut 1995;37:7-12.
Maradey Romero et al.CGH
Esophageal Hypersensitivity in Subtypes of

Gastroesophageal Reflux Disease
E
Esophageal
h
lS
Sensitivity
iti it
Exposure to noxious gastric content

Barretts
Esophagitis
NERD
FH
Pim W, Weijenborg, Bredenoord AJ, Res Clin Gastroenterology 2013; 27(3):353
Pain Modulators for the Treatment

of Functional Esophageal Disorders
Dickman R and Fass R. Neurogastroenterol Motil 2014;26:603 - 10
Esophageal Pain Modulators

Antidepressants
Tricyclic Antidepressants (TCAs)

Selective serotonin reuptake inhibitors (SSRIs)
Trazodone
Serotonin Norepinephrine reuptake inhibitors
(SNRIs)
Dickman R et al. Neurogastroenterol Motil 2014:26:603-10
Receptor activity and dosages

for TCA antidepressants
Sperber AD, Drossman DA. Aliment Pharmacol Ther 2011;33:514-524
H to
How
t U
Use TCA
TCAs iin P
Practice
ti
Main Principle: Low and slow
Start 10 mg at bedtime
Increase by
y 10 mg
g increments weeklyy
Goal of treatment 30 mg50 mg once daily
If side effects emerge:
Decrease to a lower dose
Can
C switch
it h tto another
th TCA
May combine with SSRIs

Fass R. Gastrointest Clin N Am 2009;19(1):23-33
TCAs - Low Dose

- Dosing: 5 10mg at bed time for 3-4
weeks before increasing the dose.
- Explain
p
p
patients that response
p
may
y
take time
Tricyclic
y
Antidepressants
p
Receptor Affinity Predicts Side Effects
Receptor Affinities*
3o
amines
Amitriptyline
2o
amines
Nortriptyline Desipramine
Imipramine
Doxepin
*F
For acetylcholine,
t l h li
histamine,
hi t i
and
d -adrenergic
d
i receptors
t
Receptor activity and dosages for

SSRI and SNRI antidepressants
p
AD, Drossman DA. Aliment Pharmacol Ther 2011;33:514-524
The Effect of Citalopram

p
20mg
g Once
Daily Vs. Placebo on Patients with the
H
Hypersensitive
iti E
Esophagus
h
A randomized, double-blind, placebo-controlled trial for 6 months.

% of patients who continued to report symptoms after full course of
treatment
80
%o
of Patientts
70
60
50
Citalopram 20mg
once daily
Placebo
40
30
20
*P=0
P 0.02
02
10
0
N=39
N=36
Viazis Am J Gastro 2012
Comparing Omeprazole with Fluoxetine for

T t
Treatment
t off P
Patients
ti t with
ith Heartburn
H tb
and
d Normal
N
l
Endoscopy who Failed Once Daily Proton Pump
Inhibitors: Double-Blind Placebo-Controlled Trial
Duration 6 weeks
Pp<0.001
Omeprazole 20mg
Fluoxetine 20mg
Ostovaneh MR et al. Neurogastroenterol Motil 2014;26:670-8
Placebo
Hierarchy of Antidepressants for

Esophageal Pain Reduction and
Global Health Improvement
Pain Reduction
Global Health Improvement
1. Venlafaxine
1. Venlafaxine
2. Sertraline
2. Sertraline
p
3. Imipramine
3. Trazodone
4. Trazodone
4. Imipramine
5. Paroxetine
5. Paroxetine
Nguyen TMT et al. Aliment Pharmacol Ther 2012;35:493-500
Efficacy
c cy of
o Ve
Venlafaxinee (75 mgg qhs)
q s) Vs.
Vs Placebo
cebo
on the Mean Intensity Symptom Score
N 43
N=43
Lee H et al. Am J Gastroenterol 2010;105:1504-1512
The Effect
ff off antidepressants
p
in FCP
Patients on pain as measured by pain
diary or VAS scoring system
Wang W et al. Pain Phys. 2012;15:E131-E142
Antidepressants With the Best

E id
Evidence
to
t Support
S
t Their
Th i Use
U in
i a
Functional esophageal Disorder
Esophageal
Disorder
Medication
Class
Dose
Functional chest
pain
imipramine
TCA
25-50mg
Sertraline
SSRI
50-200mg
Venlafaxine
SNRI
75mg
Hypersensitive
Esophagus
Citalopram
SSRI
20mg
Refractory
GERD
Fluoxetine
SSRI
20mg
Globus
Amitriptyline
TCA
25mg
Maradey-Romero and Fass, Clin Gastroenterol Hepatol 2015;13:260-2
Esophageal Pain Modulators
Adenosin agonists
(theophylline)
5-HT4 agonists
(tegaserod)
5-HT3 antagonists
(Octreotide)
Antiepileptics
(Pregabalin)
Peripheral neuropathy analgesics
(G b
(Gabapentin)
ti )
Somatostatin analog (Octreotide)
Dickman R, Maradey-Romero C, Fass R. Neurogastroenterol and Motil 2014;26:603-10.
The Effect of Oral Theophylline

p y
on the Number
of Painful Days in Each Subject
N = 24
Rao et al, Am J Gastroenterol 2007;102:930-938
The Role of Acupuncture in

Refractory GERD
Mean Daytim
me Heartburn
n Score
20
For acupuncture + PPI P < 0.001;

For double-dose PPI P = NS;
Between groups comparison P < 0
0.001
001
18
16
14
12
Acupuncture + PPI
Double-dose PPI
10
8
6
4
2
0
Baseline
Week 4
Dickman R et al. Aliment Pharmacol Ther 2007; 26;1333-1334
Psychological Interventions for

Functional Chest Pain
15 RCTs (803 pts)
Reports of chest pain first 3 ms
RR=0
RR
0.68
68 (95% CI 0
0.57
57 to 0
0.81)
81)
Maintained for 3 9ms RR = 0.59 (95%
CI 0
0.45
45 0.76)
0 76)
Cognitive behavioral therapy (CBT) and
hypnotherapy
Kisley SR et al. Cochrane Database Syst Rev 2012
The Cystic Pancreas: What Tests to Order? How to

Follow Long-term?

Director, Endoscopic Education and Womens Health in GI
The Possibly Malignant Biliary Stricture: Deciding

if Benign? Treatment if Benign? If Maligant?
Grace H. Elta, MD, AGAF, FASGE

1) Know the value of the various tissue sampling / imaging
techniques for biliary strictures that are indeterminate
between malignant and benign.
2) Understand the types of benign biliary strictures, their
treatment options, and their treatment outcomes.
3) Understand the evaluation and treatment of malignant
biliary strictures.
Take home points:
1) Indeterminate biliary strictures require multi-modal

evaluation / tissue sampling which may include brush
cytology with FISH, ductal biopsy, EUS +/- FNA, IDUS,
and cholangioscopy.
2) The most common causes of benign biliary strictures
are PSC, post-transplant, post-operative (cholecystectomy), and chronic pancreatitis. Endoscopic treatment
includes stricture dilation and placement of multiple
plastic stents with an evolving role for fully covered
metal stents.
3) ERCP can be avoided in patients with malignant
strictures who will go directly to surgery for a Whipple.
ERCP stenting with short bare metal or plastic stents is
indicated for patients who will have a delay to surgery.
4) Hilar cancers are best evaluated by MRI/MRCP; inoperable ones should be treated with unilateral or bilateral
SEMs for palliation.
Benign Biliary Strictures

The best diagnostic test for suspected benign biliary strictures
is MRI / MRCP unless the clinical suspicion is high when it is
reasonable to use ERCP directly. Endoscopic ultrasound is an
alternative but is considered less helpful if the diagnosis is
thought to be benign. The most common type of benign biliary strictures can be rank ordered in terms of their responsiveness to endoscopic therapy. Often the easiest strictures
to treat are in patients with primary sclerosing cholangitis
(PSC), indeed temporary stenting is not needed and is usually
contra-indicated due to the risk of subsequent stent clogging
and cholangitis. Brush cytology should be obtained although
strictures that respond easily to balloon dilation are usually
not cancer. Post-transplant strictures also have a high chance
of response to endotherapy (70-87%) although placement of
one or more plastic stents may help with long term stricture
response rates. Benign strictures that are more resistant to
dilation include post-cholecystectomy strictures and those
due to chronic pancreatitis. Post cholecystectomy strictures
should have as many plastic stents placed as the duct diameter
will allow and often require several treatment sessions. Distal
biliary strictures due to chronic pancreatitis are quite recalcitrant to therapy, especially in patients with calcific chronic
pancreatitis. Indeed if the patient is a good surgical candidate,
surgical biliary bypass (which is simpler / safer than a hepatico-jejunostomy) should be considered early. Other rare causes
of benign biliary strictures are autoimmune cholangiopathy /
pancreatitis, choledochocysts, possibly stone disease-induced,
and sphincter of Oddi stenosis (although these does not cause
high grade obstruction).
What is the role of covered self-expanding metal stents (SEMs)?
Partially covered stents cannot be removed in up to 12% of
patients and therefore have no role in benign strictures. Fully
covered SEMs are being used more frequently; they certainly
are easier to place than multiple plastic stents. Their comparable therapeutic efficacy to multiple plastic stents appears to
be at least as good as multiple plastics and they require less
ERCP procedures. The main downside is the complication of
distal migration occurring in 13-20% of patients (which may
be mitigated by flanges or by placement of a double pigtail
stent within), the possibility of cholecystitis and pancreatitis
due to blockage of those orifices, and the possibility of stent induced strictures. RCTs comparing efficacy and complications
of multiple plastic stents vs FCSEMs are in process.
When the etiology of a biliary stricture is unclear, it is called
indeterminate and requires aggressive evaluation methods,
best performed in tertiary medical centers. Brush cytology is
the simplest technique but unfortunately only has 30% sensitivity. The addition of fluorescent in situ hybridization (FISH)
to standard brush cytology specimens has been shown to increase cytology sensitivity by up to 20% with very little loss
of specificity. Direct ductal biopsy by passing a standard bi-
opsy forceps through an open biliary sphincterotomy under

fluoroscopic control significantly increase the diagnostic yield
with the combination of brush + biopsy reaching sensitivities
of 60-70%. EUS plus FNA is very useful for intra-pancreatic
biliary strictures. For strictures / masses higher in the bile
duct there continues to be debate about safety in patients
who may be transplant candidates for their cholangiocarcinoma. At many centers FNA is restricted to enlarged lymph
nodes and is not directed to the tumor due to fear of seeding the track in operable patients. Non-tissue sampling techniques that attempt to diagnose benign vs. malignant etiologies include cholangioscopy (with spyglass technology) and
intra-ductal ultrasound (IDUS). Although both are reportedly
very accurate in their diagnostic impression (75-90%) in case
series, these studies have not blinded the endoscopist to the
clinical presentation. Indeed, when blinded videos were reviewed by cholanagioscopy experts, the accuracy of differentiating between benign vs. malignant was 45%, less than a flip
of the coin. Spyglass cholangioscopy does have the advantage
of endoscopically directing biopsies to the lesion although the
small size of the forceps / specimen makes this less attractive
than standard biopsy forceps if the lesion can be reached by
standard forceps under fluoroscopic control.
Malignant Biliary Strictures
A pancreatic protocol CT scan is the most useful test in patients who present with painless jaundice and weight loss
and suspected malignant biliary obstruction. If the CT suggests inoperable cancer, ERCP can be performed for palliative
SEMS and tissue sampling. Due to the higher tissue yield of
EUS FNA, many experts perform both EUS FNA followed by
therapeutic ERCP in the same setting. The best choice of stent
in these inoperable patients are bare metal SEMs which have
similar long term patency to partially covered SEMS, are less
expensive and have less chance of complications, especially
migration. For patients who appear to have operable cancer
on CT scan, and have a bilirubin <12, going straight to surgery
is a reasonable strategy that can avoid ERCP in many patients.
However, if neoadjuvant therapy is planned pre-operatively,
which is common in many medical centers, temporary stenting with either plastic stents, FCSEMs, or short bare metal
SEMs (with top of stent left >2 cm from hilum to not interfere
with subsequent surgery) are options. If the initial CT scan
fails to show a mass and the diagnosis is uncertain, EUS with
FNA is the next step to take. If the initial CT (or US) suspects a
hilar cancer with intra-hepatic duct dilation and a non-dilated
CBD, a MRI / MRCP should be performed to assess operability.
If the hilar cholangiocarcinoma is inoperable, the MRCP can
help direct endoscopic stenting for palliation. For inoperable
hilar cholangiocarcinoma SEMS are superior to plastic stents.
There continues to be some debate about whether bilateral
SEMs using the stent through the stent technique allowed
by the open mesh variety is superior to unilateral bare metal
stent placement although many experts prefer this approach.
The Possibly Malignant Biliary Stricture: Deciding if Benign? Treatment if Benign? If Maligant?
References:
1) Anderson M, Appalaneri V, Ben-Menachem T, et al. The role of endoscopy in the evaluation and treatment of patients with biliary neoplasia. ASGE Guideline. 2013;77:167-174.
2) Moss AC, Morris E, Mac Mathuna P. Palliative biliary stents for obstructing pancreatic carcinoma. Update in Cochrane Database Sys
Rev 2006;2: CD 004200.
3) Baron TH, Mallery JS, Hirota WK, et al. The role of endoscopy in the
evaluation and treatment of patients with pancreaticobiliary malignancy. Gastrointest Endosc 2003;58:643-9.
4) Inui K, Miyosi H, Yoshino J. Bile duct cancers: whar can EUS offer?
Intraductal US, 3D-IDUS: FNA- is it possible: Endoscopy 2006;38(Supple 1):S47-9.
5) Wang W, Shpaner A, Krishna SG, et al. Use of EUS-FNA in diagnosing pancreatic neoplasm without a definitive mass on CT. Gastrointest Endosc 2013;78:73-80.
6) Kaffes AJ, Liu K. Fully covered self-expandable metal stents for treatment of benign biliary strictures. Gastrointest Endosc 2013;78:13-21.
7) Levy M, Oberg TN, Campion MB, et al. Comparison of methods to detect neoplasia in patients undergoing endoscopic ultrasound-guided
fine-needle aspiration. Gastroenterol 2012;142:1112-1121.
The Possibly Malignant Biliary Stricture:

D idi if Benign?
Deciding
B i ?
Treatment
eat e t if Benign?
e g If Malignant?
a g a t
Grace H
H. Elta
Elta, MD
Di i i off G
Division
Gastroenterology
t
t
l
Disclosure
Olympus consulting Feb, 2015
Indeterminate Bile Duct Strictures:

Ti
Tissue
A
Acquisition
i iti M
Methods
th d
Brush cytology alone: 30% sensitivity

FISH: increases cytology sensitivity by
20%*
M lti d l tissue
Multimodal
ti
(brush
(b
h + biopsy):
bi
) 70%
Standard biopsy forceps after ES
EUS-FNA:
EUS
FNA 77% S
S, NPV
NPV: 29%
? Contra-indicated due to seeding
g in
extra-pancreatic strictures
*Fritcher Gastro 2009
Indeterminate Bile Duct Strictures:

I
Image
Evaluation
E l ti Methods
M th d
MRCP
Cholangioscopic appearance
No tissue but can change suspicion

Blinded viewer accuracy: 45%*
Intra-ductal US non-blinded accuracy
71% (PSC) - 90% (non-PSC)

Problem: no tissue
*Sethi GIE 2012
What is the Value of

S
Spyglass
l
Ch
Cholangioscopy?
l
i
?
P
Pros:
Single operator, Two dials, wire guided

Channel for both water irrigation and device
Reported accuracy of visualization: 89%*
Cons:
Small biopsy forceps, less sensitive than
cytology
t l
plus
l FISH in
i one study**
t d **
Increases risk of cholangitis***
* Ramchandani GIE 2011 **Gonda

Gonda GIE 2013 ***Sethi
Sethi GIE 2011
Benign Biliary Strictures

Rank order of endoscopic Rx success:
1. Primary
y sclerosingg cholangitis
g
-Stricture Rx delays transplantation
-Balloon stent usually contra-indicated
-Balloon,
2. Post-transplant
- Balloon,
B ll
multiple
lti l stents
t t
-Stent-free patency: 73-90%
3. Post-operative
4. Chronic pancreatitis
p
Rare Causes of
B i Bili
Benign
Biliary Strictures
S i
Autoimmune cholangiopathy /
pancreatitis:
titi type
t
I (85% + IgG4)
I G4) & II
(rare + IgG4)
Choledochol cysts
? Previous stone disease
Sphincter
p
of Oddi stenosis not high
g
grade obstruction
L
Long
PSC St
Stricture
i t
3 month
th ffollow-up
ll
PSC Strictures:
- Must r/o cholangiocarcinoma
- Often
Oft quite
it responsive
i tto dil
dilation
ti
- Avoid stent placement
Post Transplant Strictures
Dilation, then10F stents: 1 for 4mm, 2 for 6

mm,, 3 for 8mm,, and 4 for 10mm
87% long term patency*
*Morelli GIE 2008
P t
Post-op
stricture
ti t
Present within 2 yrs of

cholecystectomy
Often complicated
cholecystectomy
h l
t t
Short CHD stricture
typical
Post-operative Stricture
Treatment
Endoscopic: dilation & stenting
Multiple plastic stents

Technical success: 80-90%
Morbidity: 30
30-40%
40% (stent occlusions)
Long-term patency: 50-75%
Multiple procedures required
Surgery: Roux-hepaticojejunostomy
Morbidity: 10-20%;
10 20%; mortality: 2
2-3%
3%
Stricture recurrence: 20-25%
Bile Duct Stricture due to

Ch
Chronic
i Pancreatitis
P
ii
Treatment indications: duct

>12mm or alk p
phos >3 X normal
Case series success rates: 10-44%
Better in non-calcific
non calcific
pancreatitis
Dil ti
Dilation,
multiple
lti l plastic
l ti stents
t t
Surgical bypass still good option
Is there a Role for Covered

SEMS in Benign Strictures?
Partially covered*: 12% fail to remove
Case series of 79 pts: success 75%

Not justifiable for benign strictures
Fully covered SEMS**
Simpler to use than multiple plastic stents

Requires fewer ERCPs
M be
May
b more effective
ff ti
*K h l h GIE 2008 **Kaffes
*Kahaleh
**K ff GIE 2013
FC-SEMS
FC
SEMS for Benign Strictures
60-90% stricture resolution

Limit to low strictures
? Cholecystitis risk with intact GB
Appears
pp
low in case series,, some avoid
Stent induced strictures: 8-16%
One Asian trial of placing them at hilum
? Due
D tto over-sized
i d stents
t t for
f d
ductt
Reports
p
of removal failure at >12 mos.
FC-SEMs
FC
SEMs for Benign Strictures
Migration risk: 4-40%, average 13-20%

Increased if no stricture
Mostly distal,
distal some proximal
Appears less risk with flanged FC-SEM
? Increase risk of duct ulcer, pancreatitis
Less risk if double pigtail within

within*
*Park AJG 2011
Suspected Malignant
Ob
Obstruction
i
Evaluation
E l i
Pancreatic protocol md CT:

Inoperable
p
cancer: ERCP for p
palliative SEMs
& tissue sampling
Operable:
p
EUS +/- FNA vs. Surgery
g y
Neoadjuvent
j
Rx p
planned pre-op:
p
p Short
SEMs, FCSEMs, or plastic stent
Diagnosis
g
uncertain: EUS FNA
Suspected hilar cancer: MRCP
Strategy avoids ERCP in up to 50%
Should a stent be placed prior to

surgical
i l resection
ti off pancreatic
ti cancer?
?
Van de
V
der G
Gaagg N
NEJM
J 2010
0 0
RCT: 206 pts, PBD

(stent) for 4
4-6
6 wks then
Whipple vs. Whipple
within 1 week of Dx
Complications higher in
PBD: 74% vs. 39%
Stent occlusion and
cholangitis in 26%
Stents for Palliation
Metal (SEMS): Ave. patency: 5-6 month
Not removable
Partially covered SEMS
No vs. slight longer patency

Migration (7-36%)*
+/- cholecystitis / pancreatitis
More expensive; No real role
Plastic: Ave. patency: 3 month
Removable
Cheaper
*Lee JH GIE 2013
S
Suspected
t d Hil
Hilar M
Malignancy
li
MRI / MRCP: Useful for determining

resectability and which side to stent
Only inject side where stent planned
Controversy over stent choice:
? Value of Dual stents

SEMS superior
p
to plastic*
p
*Perdue & Freeman 357 GIE 04
Hilar Cancer
Open mesh stents for stent

stent through stent
stent
Benign & Malignant Biliary Obstruction

C
Conclusions
l i
IIndeterminate
d t
i t strictures:
ti t
Multi-modal
M lti
d l tissue
ti
acquisition: brush cytology plus FISH,
bi
biopsy
(standard
( t d d vs spy),
) EUS FNA ffor iintrat
panc, ? outside pancreas
Benign strictures: Dilate, place multiple
plastic stents vs. FC-SEMs
Pre-Whipple biliary stent not indicated
unless bili> 14 or surgery
g y delay
y
Hilar cancer: Bilateral or unilateral SEMs for
palliation
Prickly Problems in Acute Pancreatitis: How

Can it Be Prevented? How to Treat Necrosis
and Complications (Endoscopy, Antibiotics and
Beyond)?
Bechien Wu, MD, MPH

Program Director, Gastroenterology Fellowship KPSC
Kaiser Permanente
Los Angeles Medical Center
Acute pancreatitis is a leading cause for hospitalization for digestive disease in the United States with over 280,000 hospitalizations on an annual basis1. While the majority of cases consist of self-limited disease, up to 15% of cases can evolve into
life-threatening illness2. A major determinant of the severity
of illness is the development of pancreatic necrosis as well as
organ failure.
A key to reducing the overall burden of acute pancreatitis has
been the development of effective primary and secondary prevention strategies. The most effective interventions for prevention of acute pancreatitis have been the use prophylactic
pancreatic duct stents3 and rectal indomethacin4 for patients
at high-risk of post-ERCP pancreatitis. For prevention of recurrent acute pancreatitis, evidence favors repeated 6-month
counseling compared to a single session in the setting of alcohol related acute pancreatitis5. A recently concluded multicenter trial has now also confirmed that early cholecystectomy
(within 72 hours of anticipated discharge or symptom resolution) leads to a significant reduction in recurrent pancreatitis
events as well as additional biliary complications compared to
delayed intervention (25-30 days) (ISRCTN72764151).
In 2006, the Atlanta classification was developed to characterize the severity of acute pancreatitis. This classification system
underwent revision in 2012 with implementation of more precise nomenclature for description of local complications related to acute pancreatitis as well as more specific definitions for
systemic complications that occur in acute pancreatitis6. Key
definitions to be familiar with include a distinction between
pancreatic pseudocyst (homogenous amylase-rich fluid filled
collection) and walled-off necrosis (well-circumscribed collection containing both fluid and necrotic debris). In the revised
Atlanta classification, severe acute pancreatitis is defined as
organ failure lasting more than 48 hours or the presence of necrosis. Necrosis may involve the pancreatic parenchyma or the
surrounding tissue (extra-pancreatic necrosis). The extent of
necrosis has not been associated with outcome.
The objective of the present syllabus is to apply definitions from

the revised Atlanta classification and recommendations from
current practice guidelines on management of necrotizing pancreatitis7 to the care of patients with necrotizing pancreatitis.
Upon completion of this session, the participant
should be able to:
1. Identify the appropriate clinical context for suspicion of infected necrosis

2. Recognize the indications for intervention on pancreatic necrosis
3. Implement evidence-based management for necrotizing
pancreatitis
Case scenario: a 26 year old man with history of chronic, heavy

alcohol use presents to the emergency department complaining of sharp epigastric abdominal pain radiating to the back. A
diagnosis of acute pancreatitis is made based on marked elevation in serum lipase. Liver function tests are normal. Vigorous fluid resuscitation is initiated with Ringers lactate. However, 24 hours later the patient develops fever, tachycardia and
leukocytosis. A contrast enhanced CT scan is obtained.
This
contrastenhanced
image
depicts areas of
non-enhancement
within the body of
the pancreas consistent with pancreatic necrosis. In
addition, there is
extensive stranding
surrounding
the
pancreatic parenchyma suggestive of possible extra-pancreatic necrosis. The
revised Atlanta classification identifies either pancreatic parenchymal necrosis or extra-pancreatic necrosis of surrounding fat tissue as necrotizing disease. There is no longer a distinction based on the extent of necrosis.
are
QuickTime and a
decompressor
needed to see this picture.
In this early stage of illness, infected pancreatic necrosis is

highly unlikely8. Based on the patients development of the
systemic inflammatory response syndrome (SIRS), a search
for additional underlying source of infection is warranted.
Case continued: Day 3
The patient develops respiratory distress and requires ventilator support. He is transferred to the intensive care unit.
Overnight, the patient subsequently develops hypotension
that requires vasopressor support.
This patient has developed multi-organ failure in the setting
of necrotizing pancreatitis. The most appropriate additional
intervention at this time is enteral nutrition. Enteral versus
parenteral nutrition in necrotizing pancreatitis has been evaluated in at least 8 randomized-controlled trials. A Cochrane
meta-analysis found evidence for benefit for enteral nutrition
in terms of reduced mortality, organ failure and systemic infection9. By contrast, prophylactic antibiotics have not been
demonstrated to be helpful in this setting10. In addition,
there does not appear to be an advantage with early (within 24
hours) initiation of enteral feeding in patients with predicted
severe acute pancreatitis11. The issue of nasogastric versus
nasojejunal feeding is the subject of an ongoing multi-center
Prickly Problems in Acute Pancreatitis: How Can It Be Prevented? How to Treat Necrosis and Complications (Endoscopy, Antibiotics and Beyond)?
randomized controlled trial; NCT00580749. Meanwhile, widespread availability of flanged, self-advancing nasojejunal catheters has greatly reduced the difficulty in initiation of enteral
nutrition as this can now be performed at the bedside without
endoscopic or fluoroscopic guidance.
Case continued: Day 28.
The patient continues to experience leukocytosis, fever and

tachycardia. A previous ventilator-associated pneumonia has
been treated and is no longer believed to be an active source of
infection. A repeat CT scan is obtained.
References
1. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease
in the United States: 2012 update. Gastroenterology 2012;143:117987 e1-3.
2. Wu BU, Banks PA. Clinical management of patients with acute pancreatitis. Gastroenterology 2013;144:1272-81.
3. Choudhary A, Bechtold ML, Arif M, et al. Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc 2011;73:275-82.
4. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial
of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J
Med 2012;366:1414-22.
5. Nordback I, Pelli H, Lappalainen-Lehto R, Jarvinen S, Raty S,
Sand J. The recurrence of acute alcohol-associated pancreatitis
can be reduced: a randomized controlled trial. Gastroenterology
2009;136:848-55.
This image depicts an example of walled-off necrosis. In the

revised Atlanta classification this is a distinct entity from pseudocyst. This distinction is important as it carries implications
for management. Specifically, pseudocysts can be addressed
by simple drainage whereas walled-off necrotic collections require more extensive debridement. In general, intervention is
only necessary if symptomatic. Common indications for intervention include infection or mass-effect related to the size of
an intra-abdominal collection. Risk of infected necrosis rises
sharply after two weeks from the onset of illness. Infection of
pancreatic necrosis should be suspected in the setting of sepsis
without alternative infectious etiology or findings of gas within
a peri-pancreatic collection.
The approach to symptomatic necrotic collections has shifted
in recent years based on the findings of several multi-center
randomized-controlled trials. Specifically, a step-up approach12 utilizing percutaneous drainage followed by either
minimally invasive surgery or endoscopic debridement has
demonstrated improved outcome compared to traditional
open surgical debridement. Delayed surgical or endoscopic
intervention to 4-6 weeks subsequent to onset of illness facilitates maturation of any necrosis and has been associated with
improved survival as well. In the setting of infected necrosis,
initial percutaneous drainage can serve as a temporizing measure until adequate maturation of the necrotic cavity can be
achieved. Ultimately, a multi-disciplinary approach including
gastroenterologists, surgeons, radiologists and nutritionists is
recommended to help manage complex patients with necrotizing pancreatitis.
6. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions
by international consensus. Gut 2013;62:102-11.
7. Freeman ML, Werner J, van Santvoort HC, et al. Interventions for
necrotizing pancreatitis: summary of a multidisciplinary consensus
conference. Pancreas 2012;41:1176-94.
8. Besselink MG, van Santvoort HC, Boermeester MA, et al. Timing and
impact of infections in acute pancreatitis. Br J Surg 2009;96:267-73.
9. Al-Omran M, Albalawi ZH, Tashkandi MF, Al-Ansary LA. Enteral versus parenteral nutrition for acute pancreatitis. Cochrane Database
Syst Rev 2010:CD002837.
10. Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis
against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev 2010:CD002941.
11. Bakker OJ, van Brunschot S, van Santvoort HC, et al. Early versus
on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J
Med 2014;371:1983-93.
12. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J
Med 2010;362:1491-502.
Prickly Problems in Acute Pancreatitis: How Can It Be Prevented? How

to Treat Necrosis and Complications (Endoscopy, Antibiotics and
Beyond)
Bechien U Wu, MD, MPH
Center for Pancreatic Care, Kaiser Permanente Los Angeles
Increasing hospitalizations for Acute Pancreatitis in the US

350,000
300,000
250,000
200,000
150,000
100,000
50,000
1993
1994
1995
1996
1997
Source: HCUP Nationwide Inpatient Sample
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
How to prevent acute pancreatitis and its recurrence

Post-ERCP
Post
ERCP
Pancreatic duct stent
Alcohol
Repeated counseling
Early cholecystectomy
Highg --risk
6---month intervals
72 hours
GRADE 1A
GRADE 1A
Mild, uncomplicated
Rectal indomethicin
High---risk
GRADE 1A
March 2, 2015
Gallstone
2011 Kaiser Foundation Health Plan, Inc. For internal use only.
GRADE 1A
Case
29 year old man with 1 day of acute onset epigastric pain
Risk Factors
Heavy alcohol history (3---4 whiskey/day)
Marijuana use (Class I agent)
BP 143/83 | Pulse 88 | Temp 97.6 F (36.4 C) | Resp 19 | Wt 170 lb | SpO2 97%
Pertinent Labs:
Lipase 3400
Normal liver function tests
White blood cell count 8.7 x 103 cells, Hematocrit 45.4%
Blood Urea Nitrogen 10 mg/dL
Transabdominal Ultrasound: no evidence of stones, sludge or duct dilatation
Case Continued0-- 15 hours

Emergency Department awaiting bed: 15 hours
Patient becomes agitated, tachycardic
Management for alcohol withdrawal initiated
OBJECTIVE:
Filed Vitals:
0723
BP:
136/95
Pulse: 148
Temp: 98.3 F
Resp: 20
SpO2: 93%
SpO
0853
0912
1206
136/89 142/92 146/93
143
142
142
98.1 F 98.2 F 99 F
20
22
24
90%
99%
94%
9
%
Bedside Index of Severity in Acute Pancreatitis

B Bun25 mg/dL
I Impaired mental status (GCS<15)
S SIRS
A Age 60
P Pleural effusion or pulmonary (hypoxemia)
Wu et al, Gut 2008
BISAP at 24 hours predicts mortality

B IS A P V a lid a t io n C o h o r t 2 0 0 4 - 2 0 0 5 ( N = 1 8 ,2 5 6 )
50
40
30
% P a ti e n ts
20
% M o r ta l i ty
10
0
0
B IS A P S c o r e
Singh et al., Am J Gastro 2009
Papachristou et al, Am J Gastro 2009
Systemic Inflammatory Response Syndrome (SIRS)
Temperature
Pulse
Respirations
WBC
Buter et al, Br J Surg 2002
Mofidi et al, Br J Surg 2006
<36 C (96.8 F) or >38 C (100.4F)

>90/min
>20/min
<4x109/L (<4K/mm3),>12x109(>12K/
mm3) or 10% bands
Wu et al, Gut 2008
Singh et al, Clin Gastro Hep 2009
Persistent SIRS: Severe Pancreatitis

35
30
25
20
Persistent OF
Necrosis ICU
15
Mortality
10
5
0
No SIRS
Singh et al, Clin Gastroenterol Hep 2009
SIRS<48
SIRS>48
p trend<0.0001
Ringers lactate resuscitation:

reduced SIRS at 24 hours
SIRS
p=0.90
Wu et al, Clinical Gastroenterol Hep 2011
p=0.035
THEAGA INSTITUTE
Prophylactic antibiotics?
Dellinger et al, DB-RCT, Ann Surg 2007
32 centers North America + Europe
N=100 ppts with necrotizingg ppancreatitis
Meropenem vs placebo
No impact on infected necrosis or mortality
Isenmann et al, DB-RCT, Gastroenterol 2004
N=114 pts with necrotizing or clinically severe AP
Ciprofloxacin + flagyl vs. placebo
No impact on infected necrosis or mortality
Cochrane Meta-Analysis 2010
No evidence of benefit for prophylactic antibiotics
Source: Dellinger et al, Ann Surgery 2007; Isenmann et al, Gastroenterology 2004, Cochrane Meta---analysis 2010
Enteral Nutrition
Cochrane Meta---Analysis 2010
8 randomized---controlled trials vs. TPN

Mortality RR 0.50 (95% CI 0.28 to 0.91)
Organ
g failure RR 0.55 ((95% CI 0.37 to 0.81))
Systemic Infection RR 0.39 (0.23 to 0.65)
Timing
PYTHON ISRCTN18170985
Location
SNAP study NCT00580749
Flanged nasojejunal tube:

enables bedside placement
When to suspect infected necrosis?

Persistent sepsis or clinical deterioration
Despite maximal supportive care
Absence of alternative infection
Gas within collection on contrast

g g
enhanced CT imaging
Positive gram stain or culture
IAP/APA Acute Pancrea ' ' s Guidelines, Pancreatology
RCT n=88 pts

Suspected
S
d or confirmed
fi
d infected
i f
d necrosis
i
Composite endpoint: new-- onset organ
failure perforation,
failure,
perforation bleeding or death
40% step-- up vs. 69% open necrosectomy (p=0.006)
Van Santvoort et al, NEJM 2010
Step-- up approach to infected necrosis

Step
Step 1: antibiotics + percutaneous drainage
Upsize catheters as needed
Daily irrigation
Step 2: video assisted retroperitoneal debridement (VARD)

Minimally invasive surgery for failure to respond within 72 hours
PANTER trial: 35% in step
step---up
up arm did not require
further debridement
Interventions for walled

walled-- off necrosis
Percutaneous Drainage
Endoscopic Debridement
Surgery
First line
Access dependent
Minimally invasive
Bridge or definitive
Technical expertise
Salvage/Rescue
THEAGA INSTITUTE
THEAGA INSTITUTE
Video
Courtesy Gyogy Vatakencherry MD, Interventional Radiology, Kaiser Permanente Los Angeles
THEAGA INSTITUTE
Video: endoscopic necrosectomy
Courtesy Kevin Kao, MD, Therapeutic Endoscopy, Kaiser Permanente Downey
Evidence for direct endoscopic necrosectomy

Multi---center RCT Netherlands
N=22 patients
p
Endoscopic vs. surgical necrosectomy (VARD) following
percutaneous drainage
Endoscopic
p necrosectomy:
y reduced IL---6and composite
p
clinical
outcomes
Multi---center US and German cohorts

US series,, n=104 with 95%
% success
German series, n=93 with 84% success
Complications: bleeding, cyst cavity rupture, mortality 1---7%
Bakker et al, JAMA 2012
Gardner et al, GIE 2011
Seifert et al, Gut 2009
Key Points: management of necrotizing

pancreatitis and its complications
Early stage necrosis
Failure to improve
Nutritional support
Step---up approach
Seek
Seek alternate sources of
infection
Percutaneous drainage
g
No role for prophylactic

antibiotics
Delay major intervention
Walled off necrosis

Intervention only when
symptomatic
Direct endoscopic
necrosectomy
Local expertise
Multi--disciplinary
approach
Challenges in Chronic Pancreatitis: Diagnosis,

Monitoring and Treatment (Short-term & Longterm)

Director, Division of Gastroenterology, Hepatology and Nutrition
Challenges
Ch
ll
i Ch
in
Chronic
i P
Pancreatitis:
titi
Diagnosis, Monitoring and Treatment:
Short-term & Long-term

P f
Professor
off M
Medicine
di i
Director, Division of Gastroenterology, Hepatology and Nutrition
Columbus, Ohio
25 year old female Small-duct Chronic Pancreatitis
Cambridge I-II imaging criteria (main duct normal)

Recurrent abdominal pain
Fluctuating pancreas enzymes
Chronic Abdominal Pain
19 year male old Big-duct Chronic Pancreatitis
Cambridge
C b id III
III-IV
IV imaging
i
i criteria(main
i i ( i d
duct iinvolvement)
l
)
Outline
Diagnosis
Exocrine Insufficiency
Metabolic Bone disease
Pain Management
Pancreas Cancer
Autoimmune Pancreatitis
Diagnosis
Pancreatic Center of Excellence

Diagnostic Tests Options
Definitive
f
Diagnosis
Patient profile + TIGAR-O Risk factors + Imaging + Physiology
Diagnosis in patients with Cambridge I / II criteria (side branch changes, no main duct involvement)
challenging
Radiology / Imaging
CT Pancreas protocol
MRI/sMRCP/DW MRI
Cambridge III / IV criteria (main duct involvement)
Advanced Endoscopy
EUS +/- PFT [30 min screen]
ERCP
EUS score >= 5
Cambridge III / IV criteria (main duct involvement)
Biochemical
Bi
h i l / Lab
L b evaluation
l i
CBC, CMP, Fecal elastase, serum trypsin
Pancreas Function Testing

Endoscopic / Dreiling Pancreas Function Test (ePFT): 30 min screen; 1 hour diagnostic
PFT peak bicarbonate > 75 (NPV 97%, PPV 45%)
Chronic Pancreatitis: CT Scan
STEP - CP Diagnostic Algorithm
Conwell, DL and Wu, B. Clin Gastro Hep 2012
finding urinary markers for chronic pancreatitis

Discovery
y
* p value < 0.05
** p value < 0.005
0 005
**
**
**
**
*
*
**
finding urinary markers for chronic pancreatitis

Discovery
y
E
Cluster 9
Cluster 11
Cluster 8
Fold c
changes
Cluster 7
Fold c
changes
Cluster 10
Fold ch
hanges
Fold ch
hanges
Cluster 6
Fold c
changes
Cluster 4
Cluster 12
Fold c
changes
Cluster 3
Fold c
changes
Fold c
changes
green:
gradual increase
E
Cluster 5
Fold c
changes
red:
specific for M
((moderate/severe))
Fold c
changes
blue:
specific
ifi ffor E
(equivocal/mild)
Cluster 2
Fold ch
hanges
Fold ch
hanges
Cluster 1
Exocrine Insufficiency
Indirect Tests for Exocrine Function
Sudan stain
Qualitative fecal fat
Fat droplets
Pancreatic elastase 1
>201
100-200
<100 Severe
80 mcg/g
Normal
Mild
Pancreas Exocrine Insufficiency
Pezzilli, R et al., World Journal Gastro 2013
Measuring Exocrine Function In Adults:

Why?
Recognition of exocrine insufficiency
Maldigestion associated morbidity / mortality
Malabsorption of fat-soluble vitamin

Eur
E JM
Med
d Res
R 2008
2008; 13:68-72
13 68 72
Pancreatology 2008; 8:583-6
Vitamin D
Osteopathy associated
Bone fractures associated with low fecal elastase-1
Pancreas 2007; 35:1-15.

Vitamin A - Night blindness, visual impairment
Vitamin E - Neurologic
l
symptoms
Vitamin K - Coagulopathy
Metabolic Bone Disease
Inflammation Induces an Imbalance between Osteoclast and

Osteoblast Activity
H Tilg, et al., Gut 2008 57: 684-694
Odds Ratio of Fracture Among CP was

comparable to other High Risk GI Disease
Odds Ratio
95% CI
Chronic Pancreatitis
4.4
(3.7, 5.2)
Crohns Disease **
2.6
(2.2, 3.0)
C li Di
Celiac
Disease
44
4.4
(3 4 5
(3.4,
5.6)
6)
Postgastrectomy
4.7
(2.8, 8.0)
Cirrhosis
4.4
(4.1, 4.7)
Duggan, SN et al., Am J Gastro 2015
Increased Bone Turnover markers in

Chronic Pancreatitis
Duggan, SN et al., Am J Gastro 2015
Enzyme Replacement Therapy
Forsmark, C Gastroenterology 2013
Algorithm Exocrine Insufficiency
Dose adjustment
40 80,000 IU / meal
Enteric coated
Protects enzymes
Rx: steatorrhea
Acid suppression
Acid neutralization
Lipase protection
New Drugs
NDA and FDA
Standardization
Pezzilli, R et al., World Journal Gastro 2013
Pain Management
Chronic pancreatic pain is a

complex, multi-level
Neuropathic pain
syndrome
Demir et al.,, Langenbecks
g
Arch Surgg 2011
Cerebral
Cerebral cortex - Level 3
Cortical reorganization
Central sensitization
Hyperalgesia
Allodynia
Spinal
S i l/P
Peripheral
i h l - Level
L l2
DRG and spinal cord
hypersensitivity
Intrapancreatic - Level 1
p
mechanisms
Neuropathic
Nociception
CP Pain is complex and

i
incompletely
l l understood
d
d
Unraveling the mystery of pain in chronic pancreatitis

Associated with a severe burden of disease.
Pathogenesis is poorly understood
Treatment has been largely empirical, often consisting of surgical or other
invasive methods, with an outcome that is variable and frequently
unsatisfactory.
Peripheral sensitization
Central sensitization.
Increased pancreatic nociception
Some of the specific molecules implicated in this process include the
vanilloid receptor, TRPV1, nerve growth factor, and the protease activated
receptor
p 2
Pasricha, J., Nat Rev Gastroenterol Hepatol. 2012 Jan 24;9(3):140-51.
There is Pain-Associated Adaptive Cortical

Reorganization in Chronic Pancreatitis
Healthy
Chronic
Pancreatitis
CP subjects respond differently to painful electrical stimulation of the sigmoid

Olesen, SS et al., Pancreatology, 2011
Non-Surgical Options for Pain Control
Lifestyle modification
Alcohol abstinence
Smoking cessation
Non-narcotic Management
Adjunctive agents
Pregabalin
Medical Evidence
Nordback I, Gastroenterology 2009
Yadav D,
D Arch Intern Med 2009
Olesen SS, Gastroenterology 2011
Bouwenese SH, Plos One 2012
Antioxidants
Patient population specific
Bhardwaj P, Gastroenterology 2009

Dhingra R,
R Pancreas 2013
Tramadol
Wilder-Smith CH et al. Dig Dis Sci 1999
Uncoated PERT
Slaff J, Gastroenterology 1984

Isaksson G, Dig Dis Sci 1983
Pancreatic rest
NJ feeding or TPN
Stanza G
G, et al
al., JPEN 2005
Narcotic analgesics
Pain Therapy Consultation: psychology, anesthesia, chemical dependancy
Detox / wean narcotic dose
19 year male old Big-duct Chronic Pancreatitis
Cambridge
C b id III
III-IV
IV imaging
i
i criteria(main
i i ( i d
duct iinvolvement)
l
)
Endoscopic therapy:
EHL, ESWL, CPB
Courtesy of David Leslie Carr-Locke, MD
Surgical Therapy:
Drainage versus Resection procedure
140 eligible patients

72 randomized to surgical vs. endoscopic therapy
Surgery
80 % resection / 20 % draiange
Endotherapy:
100% Sphincterotomy/Stent
/
23% with stone removal
Conclusion:
Endotherapy
d h
>Surgery
Short term relief (1 year)
51.6 versus 42.1 % complete relief
Surgery > Endotherapy
d h
Long term pain relief (5 year)
36.9 versus 14.3 % complete relief
Dite P., et al., Endoscopy. 2003 Jul;35(7):553-8.
25 year old female Small-duct Chronic Pancreatitis
Cambridge I-II imaging criteria (main duct normal)

EUS Guided Celiac Plexus Block:

Block the Pancreatic Nerves
50% response; short term benefit
Remove the Pancreatic Nerves
Narcotic Use:
90% iinitial
iti l
40% 1 year
15% 5 year
(Pancreas 2009;38: 1Y7)
Pain Management
Stevens T, www.clevelandclinicmeded.com
Smoking, alcohol cessation

Pancreatic Enzyme Replacement Therapy
Inhibits CCK-RF
CCK RF stimulation (trypsin)
Small duct disease
Antioxidant Trial
Tramadol
Pregabalin
Pancreatic Rest
Pain Characterization
Quantitative sensory testing
Nerve blockade (CPB or DNB)
Duct morphology
Surgical Therapy
Large duct
Total Pancreatectomy with Islet cell

p
transplantation
Small duct
More RCTs greatly needed

XRT, RFA, SCS, Secretin
Molecular targeted therapy TRPV1,
NGFs, Mast cells
Pancreas Cancer
CT Scan: Pancreas Adenocarcinoma

CT Report 2007
The pancreatic duct is diffusely
dilated up to 13mm in the head
to the level of coarse
calcifications in the head
There are additional coarse
calcifications within the pancreas
and within the pancreatic duct in
the upstream pancreas.
IMPRESSION: 1. Findings
consistent with chronic
pancreatitis
titi with
ith no evidence
id
off
acute pancreatitis.
CT 1/15/2009: Mass, malignant ascites,

Metastases, biliaryy dilation
Pancreatitis and Pancreas

Cancer: Meta
Meta-analysis
analysis
Cumulative Incidence of Pancreatic Cancer is

elevated in Chronic Pancreatitis
Approx 1% every 5 years
4-5% at 20 years
No screening guidelines
Better methods needed
Modify Risk Factors:
inflammation alcohol
inflammation,
alcohol,
SMOKING
Lowenfels, AB, et al., N Engl J Med. 1993 May 20;328(20):1433-7.
Histology: Lymphoplasmacytic Infiltrate
Pancreatic duct with a lymphoplasmacytic

infiltrate.
Pancreas biopsy
Plasma Cells and Lymphocytes
Clinical and surgical outcome: Autoimmune pancreatitis
Autoimmune: Responsive to steroids
Pancreas Carcinoma: Unresponsive to

Steroids
Pancreas Carcinoma: Unresponsive to

Steroids
Identification of a Novel Antibody Associated

with Autoimune Pancreatitis
Frulloni l, NEJM 2009; 361:2135-42.
Autoimmune Pancreatitis:
Treatment
Initial:
I iti l P
Prednisone
d i
40-60 mg x 4 weeks
taper 5 mg/week
1st Relapse: Prednisone

Maintenance prednisone 5-10 mg
Recurrent
R
t relapses
l
Refer to Pancreas Center of Excellence

Steroid sparing immunomodulators
Azothioprine
Methotrexate
Rituximab
Autoimmune Pancreatitis Relapse

p
Hart, PA Gut 2013
Algorithm Pancreas Mass vs. Pseudotumor vs. AIP
Pancreas CT scan?
Repeat if not
Ancillary data:
Outside film review with radiology staff
CA 19-9? Jaundice?
Duct morphology
Abdominal pain
Ask: Would MRI help?
EUS with
ith FNA
Cytology on site?
AMPULLARY BIOPSY (IgG4 stain)
5+ passes
Surgical versus Oncology Referral
2 week steroid trial suspected AUTOIMMUNE
When in doubt: SURGICAL RESECTION
Stevens T, Conwell DL., www.clevelandclinicmeded.com
Medical Therapy
Forsmark C. Gastroenterology 2013
Surgical Therapy
Forsmark C. Gastroenterology 2013
Conclusion
Diagnosis
Di
i
Challenging in Cambridge I-II imaging
Diagnostic biomarkers under investigation
Exocrine Insufficiencyy
Large dosages of enzymes
Gastric Acid [PPI; bicarbonate neutralization]
Metabolic Bone disease

DEXA Scan
Bone turnover markers elevated
Conclusion
Pain
P i M
Managementt
Patient selection
Endoscopy
Surgery drainage, resection, TPIAT
Pancreas Cancer
mimicks CP and AIP
Biomarker is needed
2 week steroid trial with close follow-up
SSteroid
id responsive
i
Referral to PCOE for relapses
The Wild New World of Hepatitis C Treatment:

How to Choose the Right Drug Cocktail?
Norah Terrault, MD, MPH

The Wild New

Th
N World
W ld Of Hepatitis
H
titi C Treatment:
T t
t
How To Choose The Right Drug Cocktail?
Norah Terrault, MD
Universityy of California San Francisco
Achievement of Viral Eradication Yields Many Benefits
Reduced risk of death

R d d risk
Reduced
i k off HCC
Prevention of liver decompensation
Reversal of liver decompensation
p
Reversal of hepatic fibrosis
Increased post-transplant survival
Improved
d quality
li off life
lif
Reduced frequency of extrahepatic complications
SVR and Reduction in All-Cause Mortality
Meta-analysis of 129 studies w/over 23,000 patients
Estimated relative reductions in risk of liver transplant, HCC, all-cause mortality for SVR vs non-SVR after antiviral
therapy
RR substantially reduced for all groups with SVR

20
%patientts after 5 years
18
16
General: 18 studies
n=29,269
Avg. FU=4.6 years
SVR
Cirrhotic: 9 studies
n=2,734
Avg. FU=6.6 years
HIV/HCV: 5 studies
n=2,560
Avg. FU=5.1 years
No SVR
14
12
11.3%
10.5%
10.0%
10
8
6
4.5%
3.6%
1.3%
2
0
General
Cirrho c
5-Year All Cause Mortality

Saleem, AASLD 2014, Abst# 44
Co-infected
Interferon-Free Therapy
A Game-Changer
G
Ch
High rates of cure across different patient populations, including

groups traditionally viewed as difficult to cure
African-Americans
HCV-HIV coinfection
Cirrhosis
Transplant recipients
Marked improvement
p
in safety/tolerability
y/
y
Fewer treatment contraindications
Simplicity of treatment regimen
All Oral Therapy Brings Providers and Patients Back into

T t
Treatment
t Arena
A
No injections
N
i j ti
Well-tolerated
Short duration
High success
Simplicity of treatment algorithms

Minimal pre-testing needed
Low intensity of monitoring
Side effects easily managed
Prioritization for Immediate Treatment*

Highest:
Advanced fibrosis (F3 or F4
Organ transplant
Type 2 or 3 mixed
cryoglobulinemia
l b li
i with
i h endd
organ manifestations
(vacuities)
Proteinuria, MPGN
*Reflecting
Reflecting risk of complications
AASLD-IDSA HCV Treatment Guideline
www.Hcvguidelines.org accessed March 13, 2014
Treatment with Intent to Prevent

T
Transmission
i i to
t Others
Oth
Men who have sex with men ((MSM)) with high-risk
g
sexual practices
Active injection drug users
Incarcerated persons
Persons on long-term hemodialysis
HCV-infected women of child-bearing potential wishing
to get pregnant
www.Hcvguidelines.org accessed March 13, 2014
Guiding Principles for

Use of Oral Regimens for HCV
Combine drugs from different classes:
Hit multiple targets to increase efficacy
ff
Diminish risk of viral resistance
Multiple
p drugs
g combined achieves superior
p
efficacyy than p
predicted byy individual
drug characteristics
Strategies:
Backbone/Anchor drug plus additional agent(s)
Anchor drug has high barrier to resistance does heavy lifting for regimen
Multiple drugs with high antiviral potency allow shorter duration therapy
Approved DAA Combinations Vary by Genotype

G1,4,6
G2,3
Sofosbuvir +
RBV
G1,4
Simeprevir +
Sofosbuvir
LedipasvirSofosbuvir RBV
OmbitasvirParitaprevir/r +
Dasabuvir RBV
G1,4
Drug Choices Need to Be Guided by Severity of

Liver and Renal Impairment
DAA
Primary Metabolic
Pathway
If Renal Impairment
If Hepatic
Decompensation
(CP-B or C)
Sofosbuvir
Renal
Not if CrCl
< 30 mL/min
Yes
Ledipasvir
Hepatic
Simeprevir
Hepatic
Not if CrCl
< 15 mL/min
No
Paritaprevir/r
Hepatic
No
Ombitasvir
Hepatic
Yes, but
not studied in HD patients
Dasabuvir
Hepatic
Ribavirin
Renal
Yes,, at reduced doses
Yes
Treatment Efficacyy is High:

g 90% for Most Patients
100
LDV-SOF
OBV-PTV/r+ DSB
SMV+SOF
SOF+RBV
90
80
70
60
50
G1
G2
G3
HCV Genotype
G4
G6
Safety of HCV DAAs

Well-tolerated
Paritaprevir/ritonavir
Simeprevir
Photosensitivity/pruritus, rash
Photosensitivity/pruritus
Fatigue
Nausea
Indirect hyperbilirubinemia, mild
(hepatic transporter inhibition)
Sofosbuvir
Fatigue
Nausea
Headache
Ledipasvir
Ombitasvir
Unknown
Side Effects of Ribavirin
Hemolytic anemia
R h
Rash
Insomnia
Irritability anxiety,
Irritability,
anxiety depression
Nausea
g
Teratogenic
Pregnancy category X
Increased if
renal
dysfunction
Recommended DAA Combinations by Genotype

G 1, 4
LDV-SOF
RBV
SMV+SOF
OBV
OBV-PTV/r
PTV/r
+ DSB
RBV
Prevalence
In US
HCV
Patients:
G1:70-75%
G4:1%
G 2, 3
SOF +RBV
LDV-SOF
RBV
G2: 15%
G3: 10%
G6: 1%
*No
IFN-free
DAA
combo
recommended
forfor
genotype
55
*No
IFN-free
DAA
combo
recommended
genotype
Manos MM, et al. J Med Virol. 2012;84(11):1744-1750.
G6
Treatment Algorithm: Genotype 2

SOF + RBV
SO
Nave
12 wks
Experience
d
Treatment Naive
SVR12
100
80
60
40
20
0
No
ccirrhosis
os s
12 wks
Cirrhosis
16 wks
98 91
www hcvguidelines org

www.hcvguidelines.org
Treatment Experienced
96
60
100 78
No cirrhosis
Cirrhosis
SOF+RBV
12 wks
SOF+RBV
12 wks
SOF+RBV
16 wks
Treatment Algorithm: Genotype 3

Nave
24 wks
SOF + RBV
SVR12
100
80
60
40
20
0
No
o cirrhosis
os s
24 wks
Experienced
Cirrhosis
12 wks plus
peg-IFN
Treatment Naive
Treatment Experienced
94 92
87
83 83
60
No cirrhosis
Cirrhosis
SOF+RBV
24 wks
SOF+RBV
24 wks
SOF+RBV+ Peg-IFN 12
wks
Potential Other Options for Genotype 3

Daclatasvir + SOF
+ RBV X 24wks
LDV/SOF + RBV X 12wks
100
89
73
SVR12
80
60
40
20
0
25/28
16/22
No Cirrhosis Cirrhosis
44% cirrhosis
All treatment experienced
Gane E, AASLD 2014
Approved DAA Combinations for Genotype 1

Ledipasvir-Sofosbuvir
RBV
Simeprevir + Sofosbuvir
OmbitasvirO
bit i
Paritaprevir/r +
Dasabuvir RBV
Renal dysfunction
Decompensation
HIV coinfection
Use of P450 active drugs
Tolerance of RBV
Need for high dose acid suppressive
th
therapy
Genotype 1 Treatment Options

Simeprevir + Sofosbuvir
Ombitasvir-Paritaprevir/r +
Dasabuvir
Duration of therapy
8 wk option for low stage and VL
12 wks
12 wks
Requirement for RBV
No
No
Yes, 1A treatment experienced
Cirrhosis with decompensation
OK
No
No
No, if CrCl <30
No, if CrCl <30
OK
OK, No DDIs
+ DDIs
+++ DDIs
Avoid
OK
OK
Renal dysfunction
On Meds with P450 activity
Need high dose acid suppressive
therapy
The majority of genotype 1 patients are

candidates
did t for
f treatment
t t
t with
ith any off the
th 3
approved DAA Combos
Provider preference
Patient preference
Monitoring
Side effect management
Ease of approval
Side effects
Pill burden
Lab frequency
Requirement
i
to change
h
other
h
medications
Insurer p
preference/Access
/
Cost
Factors Influencing Likelihood of Virologic Cure =

SVR12
HCV genotype and subtype
G
Genotype
t
3 iis mostt difficult
diffi lt tto cure with
ith currentt therapies
th
i
Genotype 1A more difficult to cure than genotype 1B
Presence of cirrhosis diminishes response rates

Decompensated
D
t d cirrhosis
i h i additional
dditi
l lose
l
off efficacy
ffi
Prior treatment failure with peg-IFN based therapies

Especially prior null responders
Tolerability
l bili off therapy
h
= tolerability
l bili off ribavirin
ib i i
Adherence
Missed doses = risk for resistance
Estimates of SVR in
Clinical Trials vs Real
Real Life
Life Cohorts
HCV TARGET Studyy
COSMOS Study
100
93%
80
60
40
20
0
SOF+SMVR
BV in F3/F4
12 Wk
Wks Regimen
R i
RBV Prior Null
Responders
Lawitz E, Lancet 2014;384:1756-65
100
89
85
89
85
80
60
40
20
0
No Cirrhosis
Cirrhosis
Naive
Experienced
12 Wk
Wks Regimen
R i
RBV
Jensen, AASLD, 2014, Oral #45
Real-Life Experience with DAA Therapy

TRIO Health: 119 Community and 31 Academic Practices
Discontinuation Rates
by Reason
Adverse Events
Non-Adherence
GT1
SMV + SOF RBV
N=547
1.4%
1.8%
GT1
SOF + PegIFN + RBV
N=384
2.0%
4.1%
HCV-TARGET: 18 Community and 38 Academic Practices
n (%)
Adverse Events
D/C Prematurely*
SOF+PegIFN+
RBV
n=384
1.6%
2.9%
SOF+SMV
RBV
n=228
2.2%
3.1%
SOF+SMV
n=784
SOF+RBV
n=667
2.0%
2.6%
2.5%
4.9%
High rates of treatment completion likely reflects safety of drugs and shorter duration of therapy
Dieterich, AASLD, 2014, Oral #46

Jensen, AASLD, 2014, Oral #45
Treatment Options for HCV Genotype 1B

Drug Combo
Treatment Eligible
Dose
Comments
All groups including

decompensated cirrhotics
1 pill daily for 12 wks
No ribavirin
Care with antacids
C Cl >30 ml/min
CrCl
l/ i needed
d d
R
Rx-experienced
i
d cirrhosis
i h i ((add
dd RBV or
extend to 24 wks)
Ombitasvir Paritaprevir/r +
Ombitasvir-Paritaprevir/r
Dasabuvir
All groups except cirrhotics with

decompensation
4 pills daily for 12 wks

Cirrhosis (add RBV)
Simeprevir-Sofosbuvir
Simeprevir
Sofosbuvir

decompensation

Cirrhosis (24 wks)
No ribavirin
No hemodialysis
Evaluate for DDIs
No ribavirin
CrCl >30 ml/min needed
Evaluate for DDIs
Treatment Options for HCV Genotype 1A

Drug Combo
Treatment Eligible
Dose
Comments
All groups including

decompensated cirrhotics
1 pill daily for 12 wks
No ribavirin
Care with antacids
CrCll >30 ml/min
l/
needed
d d
Rx-experienced
d cirrhosis
h
((add
dd RBV or
extend to 24 wks)
Ombitasvir-Paritaprevir/r +
Dasabuvir plus RBV

decompensation

Cirrhosis (24 wks)
Simeprevir-Sofosbuvir

d
decompensation
i

Cirrhosis (24 wks)
No ribavirin
No hemodialysis
Evaluate for DDIs
No ribavirin
CrCl
C
Cl >30
30 ml/min
l/ i needed
d d
Evaluate for DDIs
Paritaprevir-R/Ombitasvir + Dasabuvir + RBV in Cirrhotics
Pooled analysis of phase 3 trials Genotype 1A and 1B, Nave and experienced
Cirrhotics treated with 12 or 24 weeks of 3D + RBV
Cirrhotic GT 1a
3D + RBV 12 wks
3D + RBV 24 wks
Cirrhotic GT 1b
3D + RBV 12 wks
3D + RBV 24 wks
3DAA + RBV for 12 or 24 wks achieved generally similar, high rates of SVR across response types and with 12 or 24 weeks
Genotype 1A cirrhotic null responders may warrant 24 weeks

Colombo, AASLD 2014, Abst# 1931 and Everson, AASLD 2014, Abst # 83
Sofosbuvir-Ledipasvir in G1 Treatment Experienced Patients

With vs Without Cirrhosis
Cirrhosis
Without Cirrhosis
Treatment experienced cirrhotics need 24 wks LDV-SOF
100
95
86
100
82
99
100
99
100
83/87
19/22
89/89
18/22
86/87
22/22
88/89
22/22
SVR12 (%)
80
60
40
20
0
LDV/SOF
ION-2:
LDV/SOF + RBV
12 Weeks
LDV/SOF
/
LDV/SOF
/
+ RBV
24 Weeks
.
Afdhal et al. N Engl J Med 2014;370:1483-93 .
SOF/SMVRBV in Genotype 1 Patients with

Cirrhosis, N=261
100
80
79
87
83
85
G1A G1B
RBV
No
RBV
82
4
SVR4
SVR4
60
40
20
0
PI
Failure
Treatment duration 12 -24 weeks
Jensen D, AASLD, 2014, A45
Summary:
y Current HCV Treatment
Multiple options: high efficacy and excellent tolerability
Genotype 3, cirrhosis (especially decompensated) have lowest
SVR rates
Key patient influencing treatment choices:
Presence of renal and liver failure, DDIs, ability to tolerate RBV
Treatment is well-tolerated and treatment discontinuation is
infrequent
Prioritization of treatment by insurers means some patients will
remain untreated for now
The Future: Shorter Duration, High Efficacy and

Tolerability
C-SWIFT: MK-5172+MK-8742+Sofosbuvir in Treatment Nave Patients with HCV GT1

Optimized regimen of PI + NS5A + NUC
Evaluated 3 very short durations of therapy (4, 6, or 8 weeks)
Non-cirrhotics: 4-6 weeks; Cirrhotics: 6-8 weeks
Lawitz E, AASLD 2014, Abstr# LB-33
Continued Focus on Testing and Linkage to Care

Success of any eradication program requires identification of those infected
Estimated 170 million infected world-wide majority undiagnosed
In the U.S., at least 50% of infected persons are undiagnosed: mostly baby
boomers
100%
80%
60%
40%
20%
0%
50%
(1.6M)
Diagnosed
At least 3.2
3 2 million of U
U.S.
S population
pop lation with
ith chronic
hroni HCV
32-38%
(1.0-1.2M)
7-11%
(220,000360,000)
5-6%
(170,000200,000)
Referred to Care
Treated
Successfully
Treated
Screening and linkage to care are of highest priority

Holmberg, New Engl J Med. 2013;368:1859-1861z
New Developments in Hepatitis B:

Treat All or Only Some? When to Switch or Add
Medications? When Can You Stop Treatment?
Anna S.F. Lok, MD, AGAF

Alice Lohrman Andrews Research Professor in Hepatology
Associate Chair for Clinical Research
At the end of this presentation, the audience should have a

better understanding of
1. Efficacy and limitations of currently approved treatments for hepatitis B
2. When to start and when to stop treatment
3. What are the prospects for a cure
Efficacy and limitations of currently approved

treatments
There are 7 approved therapies: 2 formulations of interferon
and 5 nucleos/tide analogues: lamivudine, telbivudine, entecavir, adefovir and tenofovir [1,2]. Although these drugs are
effective in suppressing hepatitis B virus (HBV) replication,
the rates of clearance of hepatitis B e antigen (HBsAg) and
hepatitis B surface antigen (HBsAg) are low. Nevertheless,
antiviral therapy for hepatitis B had been shown not only to
reduce hepatic inflammation but also to reverse fibrosis and
even cirrhosis. Furthermore, antiviral therapy administered to
patients with advanced fibrosis or cirrhosis had been shown
to reduce the incidence of liver failure and hepatocellular carcinoma (HCC).
Interferon is associated with a higher rate of HBeAg and HBsAg loss than nucleos/tide analogues but it has to be administered parenterally and can be accompanied by a wide range
of adverse effects. Nucleos/tide analogues are administered
orally and have minimal adverse effects but viral relapse is
common when treatment is stopped. Antiviral drug resistance
is uncommon with tenofovir and entecavir with rates of 0-1%
after 5-6 years of treatment.
A major hurdle in eradicating HBV is the presence of covalently closed circular (ccc) DNA in the hepatocyte nucleus.
HBV cccDNA serves as a template for viral transcription and
translation. It has a long half-life and can be replenished by
recycling of HBV DNA from the hepatocyte cytoplasm without
the need for entry of new virus. Nucleos/tide analogues have
no effect on HBV cccDNA while interferon has some effect on
cccDNA degradation. Approximately 20% of patients will have
a durable virologic response after a 1-year course of pegylated
interferon therapy. Most patients receiving nucleos/tide analogue therapy will require many years treatment.
When to start and when to stop?
Treatment guidelines recommend that hepatitis B patients

with life threatening liver disease (acute liver failure, severe
exacerbations of chronic hepatitis, decompensated cirrhosis)
and those with high risk of liver failure or HCC in the near future (compensated cirrhosis and high viral load) to initiate
antiviral therapy. Guidelines also recommend HBsAg-positive
patients who require immunosuppressive therapy that are
associated with moderate to high risk of HBV reactivation to
initiate antiviral therapy. For non-cirrhotic patients, criteria
for initiating treatment are based on HBeAg status, viral load,
alanine aminotransferase (ALT) level, and liver histology when
available [1,2]. In essence, antiviral treatment is recommended for patients in the immune active phase (HBeAg positive or
negative) but not those in the immune tolerance or inactive
phase.
High viral load had been shown to be an independent predictor of cirrhosis, HCC and liver-related deaths prompting some
experts to recommend that antiviral treatment should be initiated based on viral load regardless of evidence of liver injury.
However, multiple studies showed that antiviral treatment
is less effective in patients who are in the immune tolerance
phase (HBeAg-positive with high viral load and normal ALT)
[3]. Currently, antiviral treatment is not recommended for patients in the immune tolerance phase except for women who
are pregnant where addition of a nucleos/tide analogue that
is safe in pregnancy had been shown to further reduce the risk
of perinatal transmission compared to hepatitis B immune
globulin and vaccine alone.
Pegylated interferon is administered for a finite duration: 48
weeks for both HBeAg-positive and HBeAg-negative patients.
Recent studies suggest that treatment may be stopped in patients with minimal or no response after 12 weeks. Stop rules
based on week 12 decline in HBsAg titer have better predictive
value than stop rules based on decline in HBV DNA but these
stop rules have not been validated and different rules have to
be applied based on HBeAg status and HBV genotype [4]. For
HBeAg-positive patients, guidelines recommend continuation
of nucleos/tide analogues until 12 months after achieving
HBeAg seroconversion. For HBeAg-negative patients, guidelines recommend continuation of nucleos/tide analogues
until HBsAg loss. Given the very low rate of HBsAg loss associated with nucleos/tide analogue treatment, most patients
will need to be on lifelong treatment. Recent studies suggest
that treatment may be stopped after 2-5 years treatment in
patients who have persistently undetectable HBV DNA [5,6].
However, these data need to be validated and patients must be
closely monitored if treatment is stopped such that treatment
can be resumed in patients with clinical relapse (reappearance of HBV DNA with accompanying ALT increase).
What are the prospects for a cure?
The existence of HBV cccDNA and integration of HBV DNA into

host genome make it difficult to achieve a cure for hepatitis B.
Indeed, even in patients who recovered from acute HBV infection with HBsAg to hepatitis B surface antibody (anti-HBs) seroconversion, HBV DNA persists in the liver and can be reactivated upon immunosuppression. However, it is possible that a
combination of antiviral therapy that targets multiple steps in
HBV life cycle plus immunomodulatory therapy may achieve
a functional cure durable suppression of HBV replication to
a level that is associated with negligible liver damage and risk
of HCC.
With the recent identification of the HBV entry receptor, several entry receptor inhibitors are being evaluated in vitro and
in clinical trials [7]. Other novel antiviral agents are designed
to target cccDNA, capsid assembly or virion secretion [8]. Of
New Developments in Hepatitis B
note, clinical trials with small interfering RNAs to block translation of viral proteins are in progress and preliminary results
are promising.
Patients with chronic HBV infection have weak immune response to HBV. Recent studies suggest that restoration of immune response to HBV is possible if HBV replication is suppressed and production of HBV proteins especially HBsAg is
decreased, and if the immunomodulatory approach combines
stimulation of T cell response with blockade of inhibitory pathways [9]. Clinical trials with toll-like receptor 7 and several formulations of therapeutic vaccines are in progress.
References:
1. Lok AS and McMahon BJ. Chronic hepatitis B: update

2009. Hepatology 2009; 50: 661-2. www.aasld.org
2. Yapali S, et al. Management of hepatitis B: our practice
and how it relates to the guidelines. Clin Gastroenterol
Hepatol 2014; 12: 16-26.
3. Chan HL, et al. Effects of tenofovir disoproxil fumarate
in hepatitis B e antigen-positive patients with normal
levels of alanine aminotransferase and high levels of
hepatitis B virus DNA. Gastroenterol 2014: 146: 1240-8.
4. Konerman MA and Lok AS. Is it more cost-effective for
patients with chronic hepatitis B to have a trial of interferon before considering nucleos(t)ide analogue therapy?
Clin Gastroenterol Hepatol 2015 (in press).
5. Hadziyannis S, et al. Sustained responses and loss of
HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
Gastroenterol 2012; 143: 629-36.
6. Jeng WJ, et al. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic
hepatitis B patients. Hepatology 2013; 58: 1888-96.
7. Lempp FA and Urban S. Inhibitors of hepatitis B virus
attachment and entry. Intervirology 2014; 57: 151-7.
8. Fletcher SP and Delaney WE. New therapeutic targets
and drugs for the treatment of chronic hepatitis B. Semin
Liver Dis 2013; 33: 130-7.
9. Bertoletti A and Ferrari C. Innate and adaptive immune
responses in chronic hepatitis B virus infections: towards
restoration of immune control of viral infection. Gut
2012; 61: 1754-64.
New Developments in
H
Hepatitis
titi B T
Treatment
t
t
Anna S. F. Lok, MD
Alice Lohrman Andrews Professor in Hepatology
Ann Arbor, MI, USA
Outline
Efficacy and limitations of current
treatment
When to start?
When to stop?
Prospects for a cure?
A
Approved
d HBV T
Treatments
t
t
Interferons (IFN)
Standard IFN alfa - 1992
Pegylated IFN alfa - 2005
Nucleos(t)ide analogues
Lamivudine (Epivir) - 1998
Adefovir
Ad f i (Hepsera)
(H
) - 2002
Entecavir (Baraclude) - 2005
Telbivudine (Tyzeka) - 2006
Tenofovir (Viread) - 2008
Decrease iin S
D
Serum HBV DNA after
ft 1
Year of Treatment
ADV
ETV
TBV
TDF
PEG-IFN
Log10 d
decrease
e in HBV
V DNA
LAM
Not head-to-head comparison, results from various trials combined

LAM=lamivudine, ADV=adefovir, ETV=entecavir, TBV=telbivudine, TDF=tenofovir, PEG-IFN=peginterferon
HBeAg
g
S
Seroconvers
sion (%)
HBeAg Seroconversion
after 1-5 Years of Treatment
At 1 Year
40
Peg = peginterferon
LMV = lamivudine
32
30
16-21
20
12-18
21
22
21
ETV = entecavir
10
0
Peg IFN
@
LMV
ADV
ADV = adefovir
ETV
TBV
TDF
TBV = telbivudine
TDF = tenofovir
@ 6 months off Rx
^ 3 years off Rx
# 5 years on Rx
* 4 years on Rx
HBsAg Loss after 2-5 Years of Treatment
HB
BsAg Los
ss
(%)
HBeAg+ Patients
12
10
8
6
4
2
0
Peg = peginterferon
11
10
3
Peg ^
LMV#
5
2
ADV #
TBV *
ADV = adefovir
ETV = entecavir
1.3
ETV #
LMV = lamivudine
TBV = telbivudine
TDF#
TDF = tenofovir
HBs
sAg Loss
s (%)
HB A Patients
HBeAgP ti t
12
10
8
6
4
2
0
^ 3 years off Rx
# 4-5 years on Rx
* 2 years on Rx
8
5
1
Peg ^
LMV#
NA
ADV #
ETV
0.5
NA
0.3
TBV *
TDF#
Reversal of Fibrosis and Cirrhosis

Tenofovir Phase III Trial: Biopsies at Year 0, 1 & 5
100%
Ishak Fibrosis Score

6
5
4
3
2
1
0
Perce
entage of P
Patients
Percentage
P
of Patient s
90%
80%
70%
60%
50%
40%
30%
20%
10%
0
Baselin e
Year 1
Year 5
348/641 (54%) had liver biopsy at baseline and Year 5

71/96
1/96 ((74%)
4%) with
i h cirrhosis
i h i (I
(Ishak
h k Score
S
5)
) at baseline
b
li no longer
l
had
h d
cirrhosis at Year 5
Marcellin, P, Lancet 2013; 381: 468
Antiviral Therapy Prevents Disease Progression

Bridging fibrosis or cirrhosis, HBeAg+ / HBV DNA >700,000 GEq/ml
% with
ith disease
di
progression
Increase CTP score, liver failure or HCC

21%
Placebo
P=0.001
9%
Lamivudine
Time to disease p
progression
g
((months))
Placebo (n=215)
ITT population
Lamivudine (n=436) p=0.001
Liaw YF, NEJM 2004; 351:1521
Limitations of Current HBV Treatment

Ultimate goals of
HBV treatment
Eradicate HBV
Reverse
R
li
liver damage
d
Prevent cirrhosis and
HCC
Efficacy of
g treatment
existing
Suppress but not eradicate
HBV
Low rate of HBsAg loss
Partial reversal of
inflammation and fibrosis
Decrease but not eliminate
risk of HCC
C
Covalently
C
Closed C
Circular ((ccc)) HBV DNA
Template for HBV transcription (pregenomic
RNA and messenger RNA) and translation (viral
proteins)
Long half-life,
half-life stable in quiescent cells
Persist at low levels even in patients with viral
suppression
i
after
ft many years off nucleos(t)ide
l
(t)id
analogue therapy
Interferon and Nucleos(t)ide Analogues

Block Only a Few Steps in HBV Life Cycle
X
Replenishment
of cccDNA
?
Nucleoside
analogues
X
IFN
D
Duration
ti off Nucleos(t)ide
N l
(t)id Analogue
A l
Therapy
Th
HBV Th
Therapy
Who Can Wait and Who Cant?
TREAT
NOW
TREAT NOW OR
MONITOR?
MONITOR
& DEFER
TREATMENT
UNTIL
INDICATED
Risk of Cirrhosis, Liver Failure and HCC
Clear Cut Cases in Which

Treatment Should be Initiated Now
Life-threatening liver disease
High risk of liver failure/HCC in the near future
Compensated
C
t d cirrhosis
i h i and
d high
hi h serum HBV DNA
HBsAg+ patients who will be starting
immunosuppressive therapy
Non
Non-cirrhotic
cirrhotic patients at high risk of progressive
liver disease
When to Initiate Treatment

in Non-Cirrhotic Patients?
Lok A & McMahon B, AASLD guidelines 2009; www.aasld.org
High Viral Load is Associated with

Increased Incidence of HCC
REVEAL Study (n=3,653), mean age 43
Cumulative incidence
e of HCC
(% subjects))
16
Baseline HBV DNA level, copies/mL
14
106 (n=627)
12
104<105 (n=643)
10
300<104 (n=1,161)
14 9%
14.9%
105<106 (n=349)
12.2%
<300 (n=873)
8
6
Log rank test of trend

p<0.001
3.6%
1.4%
1.3%
0
0
10
11
12
13
Year of follow-up
Chen CJ, et al. JAMA. 2006; 295:65
Tenofovir vs. Emtricitabine + Tenofovir

Patients in Immune Tolerance Phase
% of p
patients
HBeAg+,
g , HBV DNA 8 log10
g c/mL,, ALT ULN
Response at Week 192

Chan H, Gastroenterol 2014; 146: 1230
Is Treatment Necessary for Everyone with

Chronic HBV Infection?
Not all patients will progress to cirrhosis, HCC or
liver complications
Host immune response can result in spontaneous
remission which can be long-lasting
Current treatments do not eradicate HBV
g
treatment is associated with
Long-term
risks of drug resistance
potential adverse events
non-adherence
very high costs
Resistance Rates Through

g 6 Years
Among Nucleos(t)ide-Nave Patients
Y
Year
1
Y
Year
2
Y
Year
3
Y
Year
4
Y
Year
5
Y
Year
6
72
Weeks
LAM1
23%
46%
55%
71%
80%
0%
3%
11%
18%
29%
5%
25%
TDF4
0%
0%
0%
0%
0%
0%
ETV**5
<1%
<1%
ADV1
TBV3
1.2%
1.2%
1.2%
1.2%6
Patients with HBV DNA 400 copies/mL

p
at Week 72 could add FTC to TDF;
* Cumulative probabilities of resistance taken; Nave HBeAg (+); Nave HBeAg(-); N/A not available.
1. Lok AS, Gastroenterol 2003; 125: 1714. 2. Hadziyannis S, Gastroenterol 2006, 131: 1743.
3. Liaw YF, Gastroenterol 2009;136:486 . 4. Marcellin P, Lancet 2013 ; 381: 468. 5. Tenney D, Hepatology 2009;.49: 1503
Ad
Adverse
Effects
Eff t off HBV Treatment
T
t
t
Interferon
SC injections
flu- like symptoms, fatigue, mood changes,

depression, bone marrow suppression, unmask or
exacerbate autoimmune illnesses
Nucleos(t)ide analogs
Lactic
L ti acidosis,
id i rare
Adefovir and tenofovir nephrotoxicity
Tenofovir decrease bone mineral density
Telbivudine myopathy, peripheral neuropathy
Adherence
d e e ce to HBV Nucleos(t)ide
uc eos(t) de Analogs:
a ogs
Analysis of pharmacy claims database in 3 cohorts of patients
treated in the US in 2007, 2008 and 2009
New Patients
(n=458)
Existing Patients
(n=10,295)
20% patients <80% adherence

(% of days in that year in which patients have
medications in their hands)
W Chotiyaputta, J Hepatol 2011; 54: 12
Cost of HBV Treatment

Medications
Retail
R t il price
i ffor entecavir
t
i or tenofovir
t
f i
y $
$1000-1200
30 days:
5 years: $60,000-72,000
Physician visits
Monitoring labs
Wh to
When
t Stop
St Treatment?
T t
t?
PEG
PEG-IFN:
IFN 48 weeks
k ffor HB
HBeAg+
A + and
d HB
HBeAgA
patients
12 week stop rule for futility
Nucleos(t)ide analogues
Never because of high rate of relapse
HBeAg+
HBeAg+, after HBeAg seroconversion and 12
month consolidation therapy
HBeAg
HBeAg-, after HBsAg loss or after 4
4-5
5 years
treatment with persistently undetectable HBV
DNA
Week 12 Stop Rule in HBeAg+ and HBeAgPatients Treated with Peginterferon for 48 Weeks
Author (year)
HBeAg (n)
Genotype (%)
Stopping rule
NPV (%)
Sonneveld (2010)
+ve (202)
A (35), D (41)
No HBsAg decline
97
Piratvisuth (2011)
+ve (526)
B (32), C (56)
No HBsAg decline
82 (Ph 3)
71 (Neptune)
Sonneveld (2013)
+ve (779)
A (13), B (25),
C (48), D (14)
A/D: No HBsAg decline
100
B/C: HBsAg>20,000 IU/mL
Rijckborst (2012)
-ve (160)
D (66)
No HBsAg decline and

<2 log HBV DNA decline
95
M
Marcellin
lli (2013)
-ve (120)
A 910),
910) B (20)
(20),
C (46), D (22)
10% llog10
10 HBsAg
HB A
decline
87
Try interferon first if no contraindication and switch to nucleos(t)ide analogue if

unlikely to respond based on week 12 response?
Konerman M & Lok A, Clin Gastroenterol Hepatol 2015 (in press)
Lamivudine Maintenance Beyond 1 Year

after HBeAg Seroconversion Improves
Durability of Response
61.9%
8.7%
Retrospective study ,
178 patients
Independent predictors
of relapse:
age >40
<12 mo
consolidation
therapy
Lee HW, Hepatology 2010; 51: 415
Can Nucleos(t)ide Analogues Can

be Stopped in HBeAg- Patients?
95 patients (39 cirrhosis) treated with entecavir for
median of 2 (range 1-4)
1 4) years stopped treatment
Within 1 yr, 43 (45%) had clinical relapse, 1 patient with
cirrhosis decompensated
p
33 non-cirrhotic patients with undetectable HBV DNA

stopped treatment after 4-5 years of adefovir and
followed for 5.5 years
18 (55%) achieved sustained biochemical and virological
remission during continued follow-up
9 (27% of the entire cohort) lost HBsAg
Jeng WL, Hepatology 2013; 58: 1888 Hadziyannis S, Gastroenterol 2012; 143: 629
High Rate of Sustained Response and

HBsAg Loss After 4-5 Years Adefovir
Treatment in HBeAg
HBeAg- Patients
Hadziyannis S, Gastroenterol 2012; 143: 629
Is Virus Eradication a Realistic Goal?
Can treatment accomplish what nature cant?

HBV persists in persons who have recovered from
acute hepatitis B with HBsAg to anti-HBs
seroconversion
Functional cure: more realistic goal
Sustained suppression of HBV replication with a finite
course of treatment
HBsAg clearance
Elimination of risk of HCC over time
Combination Therapy Towards an HBV Cure

Viral targets
Entry inhibition
cccDNA
- formation
- stability / destruction
- epigenetic regulation
Viral core functions
Immune modulation
Stimulate innate responses
Specific ligands
Stimulate adpative responses
Co-inhibitory signals
Co stimulatory signals
Co-stimulatory
Therapeutic vaccination
Other viral targets
Functional cure / control
HBV Lifecycle:
Novel Approaches for Viral Targets
Kapoor R & Kottilil S. 2014. Future Virol;9:565-585
Inhibitors of HBV Attachment and Entry

Sodium taurocholate
cotransporting
polypeptide (NTCP)
identified as HBV
and HDV receptor in
2012
Myrcludex in phase
2 trials in chronic
HBV and chronic
HDV decrease in
HBV DNA and
d HDV
RNA
Yan H, Elife 2012; 1:e00049

Lempp RA, Urban S. Intervirol 2014; 57: 151
Restoration of Defective T
T-cells
cells
Patients with resolved HBV
Patients with chronic HBV
CD8 T cells
Granzyme
Perforin
INF-
TNF-
IL-2
Infected hepatocytes
Effective T-cells control virus
Infected hepatocytes
Exhausted T-cells lose control of

virus
Long-term virus suppression with nucleos(t)ide analogues

Modulation of innate and adaptive immunity
Nebbia G, Q J Med 2012;105:109; Freeman G, J Exp Med 2006;203::2223; Fisicaro P, Gastro 2012; 143: 1576 ;
Boni C, Gastro 2012; 143: 963
Antiviral Activity
y of a TLR7 Agonist
g
in HBV-infected Chimpanzees
Lanford R, Gastroenterology 2013
Cure will Only Benefit Patients Who Have

Been Diagnosed and Have Access to Care
Cohen C, J Viral Hepat 2010; 18: 377
Non-Invasive Markers of Liver Fibrosis:

Can They Replace Biopsy? Which to Use and When?

Liver Consultants of Texas-Dallas
Liver biopsy
The liver biopsy has long been considered the gold standard
in staging liver fibrosis. However, there are several limitations.
First, there is inter-observer variability with a reported 25%
discordance in staging. Second, there is sampling variability.
As an example, only 65% of biopsies that are 15mm in length
and only 75% of biopsies that are 25mm in length correctly
classify stage of fibrosis. Additionally, there is heterogeneity in
liver fibrosis with notable differences in fibrosis stage possible
between different parts of the liver (e.g. between right and left
lobe of the liver) and a sample of 1/50,000th of the liver may
not be representative.(1-3) Finally, there is an inherent risk
of morbidity associated with the invasive procedure. Over the
last decade, there has been tremendous progress and interest
in development of non-invasive markers of fibrosis. There are
two broad categories of non-invasive markers: serum and radiologic markers.
Serum markers
Serum markers can either be indirect or direct markers. Indirect markers are surrogate markers of liver function. These
include laboratory studies such as platelets, bilirubin, INR and
aminotransferases. Direct markers represent are primarily
components of matrix degradation as well as cytokines and
chemokines associated with fibrinogenesis. These include hyaluronic acid, type III collagen as well as matrix metalloproteinases among others. Several combinations of indirect and/
or direct markers have been put forth for the diagnosis of fibrosis. These include combinations of laboratory tests (e.g. the
AST to platelet ratio index - APRI score), patented proprietary
panels (e.g. enhanced liver fibrosis - ELF score) and combinations of clinical characteristics along with serum markers,
often an end product of multivariable analysis (e.g. FibroTest
and NAFLD fibrosis score). Across several studies, the area
under the receiver operating curve (AUROC) for detection of
advanced fibrosis (usually defined as presence of stage 3 or 4
fibrosis) ranges from 0.74-0.87. Most of these markers have
a high negative predictive value suggesting that such tests are
helpful to identify patients that do not have advanced fibrosis.
Limitations of the tests include generalizability of the results,
costs, wide applicability based on local availability as well as
an inability to discriminate between intermediate stages of fibrosis.
Radiologic markers
Elastography is a non-invasive measure of liver stiffness that

examines the physical properties of the liver. In this technique,
the velocity (in kilopascals, kPa) of an elastic shear wave is
captured as it propagates through the liver. The stiffer the
tissue, the faster the propagation. Several iterations based
on this principle are currently available. These include single
mode examinations (e.g. transient elastography, FibroScan),
ultrasound-based examinations (e.g. acoustic radiation force

imaging, Shear Wave elastography) and MRI-based examinations (e.g. MR elastography).
Transient elastography is uni-dimensional and measures
the velocity (in kPa) of a low frequency 50Hz elastic shear
wave propagating through the liver. The region of interest is
a 1x4cm cylinder, 2.5-6.5cm below skin which is 100x bigger
than liver biopsy. In a healthy liver, the stiffness is approximately 5.5kPa and in a cirrhotic liver it is approximately 11.514.5kPa.
In MR elastography, transmitting mechanical waves are

transmitted into the parenchyma and stiffness is quantified
based on wave propagation. This is achieved by the placement of a pneumatic passive driver over the right lobe with
an active driver sending mechanical waves at 60 Hz through a
7.6 m long plastic tube to the passive driver. Shear waves are
imaged and the mean stiffness values (kPa) are measured in
larger regions of interest within the liver. In a healthy liver,
the stiffness is approximately 2.9kPa and in a cirrhotic liver
it is approximately 5.2kPa. The shear modulus is 1/3 the
Youngs modulus obtained through transient elastography.
Across several studies and techniques, the AUROC for detection of cirrhosis ranges from 0.93-0.98. All of the radiologic
studies are excellent at the extremes in identifying the presence of normal tissue or cirrhosis. However, association of
absolute liver stiffness values with intermediate stages of
fibrosis is suboptimal. Further, many of the techniques are
limited by incomplete or unreliable examinations, especially
among obese subjects. Finally, liver stiffness may be falsely
elevated by the presence of passive congestion, obesity, biliary obstruction or active inflammation.
Recently, several studies have examined the role of liver stiffness or high risk baseline serum markers (e.g. high NAFLD fibrosis scores) and development of subsequent complications
of liver disease. As an example, in a study involving subjects
with biopsy proven NAFLD (median follow-up period of 104.8
months), subjects with intermediate and high risk baseline
NAFLD fibrosis scores had a significantly elevated hazard
for liver related complications, hazard ratio HR 7.7 (95% CI
1.4-42.7) and HR 34.2 (95% CI: 6.5-180.1), respectively.(4)
Similarly, in a recent meta-analysis, elevated liver stiffness
at baseline was associated with a significant risk of hepatic
decompensation (RR, 1.07; 95% CI, 1.03-1.11), hepatocellular cancer (RR, 1.11; 95% CI, 1.05-1.18), and death (RR, 1.22;
95% CI, 1.05-1.43).(5)
In summary, non-invasive markers play an important role in
the diagnosis of fibrosis and provide important prognostic information. The translation of non-invasive markers into clinical practice is limited by generalizability and applicability to a
population skewed towards non-alcoholic fatty liver disease.
Non-Invasive Markers of Liver Fibrosis: Can They Replace Biopsy? Which to Use and When?
Further work is needed to examine whether sequential or

concomitant administration of serum and radiologic markers may improve our assessment of presence of fibrosis and
potentially avoid liver biopsies for the assessment of fibrosis.
References
1. Bedossa P, Dargre D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003 Dec;38(6):1449-57.
2. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, Feng ZZ, Reddy KR, Schiff ER. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002 Oct;97(10):2614-8.
3. Castera L. Noninvasive methods to assess liver disease in patients
with hepatitis B or C. Gastroenterology. 2012 May;142(6):12931302.
4. Angulo P, Bugianesi E, Bjornsson ES, Charatcharoenwitthaya P, Mills
PR, Barrera F, Haflidadottir S, Day CP, George J. Simple noninvasive
systems predict long-term outcomes of patients with nonalcoholic
fatty liver disease. Gastroenterology. 2013 Oct;145(4):782-9.
5. Singh S, Fujii LL, Murad MH, Wang Z, Asrani SK, Ehman RL, Kamath
PS, Talwalkar JA. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol
Hepatol. 2013 Dec;11(12):1573-84.
Non
o invasive
as e markers
a eso
of liver
e fibrosis:
b os s
Can they replace biopsy? Which to use
and when?
Sumeet Asrani MD MSc
Baylor University Medical Center, Dallas
Greg and Jim: Chronic liver disease

in the community
Farmer
from rural
Texas
Lives iin
Li
downtown
Dallas,
Reads the
WSJ
Who has advanced fibrosis?
Cli i l questions
Clinical
ti
iin practice
ti
Can I reliably diagnose advanced
fibrosis or reassure the patient/myself of

the lack thereof?
Can I predict which patient with
advanced fibrosis will do well/ do poorly

p
y
over the ensuing years?
Can non invasive markers replace liver

biopsy?
Non
Non Invasive
Invasive
History
and
physical
Ser m
Serum
Imaging
HVPG
Invasive
Availability
Biops
Biopsy
Sampling?
Interobserver
variability?
Gold standard?
Morbidity?
Friedman Nat. Rev. Gastroenterol. Hepatol 2010
The cirrhotic patient: A new face
netterimages.com
Non invasive markers of liver fibrosis
DIAGNOSIS: DOES MY
PATIENT HAVE CIRRHOSIS OR
ADVANCED FIBROSIS?
S
Serum
M
Markers
k
S
Scores
E.g. APRI
Patented panels and
Serum
S
Markers
Indirect
Hepatic
function
Platelets, INR
-2
macroglobulin
Direct
Liver
Structure
Hyaluronic acid
Type III collagen
TIMP-1
g
modeling
E.g. FibroTest
Combination of pt
characteristics and
markers
E.g. NAFLD
Fibrosis score
Selected serum markers:

Ad
Advanced
d Fib
Fibrosis
i iin NAFLD
NAFLD
Components
AUROC
FIB-4
FIB
4 platelet,
platelet ast,
ast alt,
alt age
08
0.8
APRI platelet, ast
0.85
NON SPECIFIC
Indirect
FibroTest age, sex, alpha-2 macroglobulin, alpha2-globuin, gammaglobulin, apoA1, GGT,

total bilirubin
0.81-0.9
Direct
ELF hyaluronic acid, TIMP-1,
type III collagen
0.93
SPECIFIC
Indirect
NAFLD Fibrosis Score platelet, ast, alt, age
BMI, glucose, platelet, albumin
BARD score BMI, ast, alt, DM
0.88
S
Serum
T
Tests
t
Depends
p
on local availability
y
AUROC F4: 0.74-0.87
Usually high negative predictive value for relevant
cutoffs
Identify who does NOT have advanced fibrosis
No single test in isolation

Limitations
Li it ti
Unable to discriminate between intermediate
stages of fibrosis
Cost, turn around time
Indeterminate examinations
Castera et al. Gastro 2005

Cassinotto et al. J Hep 2014
El t
Elastography
h
Non-invasive measure of liver stiffness
Physical property: between a rock and a soft
place
Velocity (in kilopascals,

kilopascals kPa) of an elastic
shear wave (picture) propagating through liver

stiffer the tissue the faster the progression
Single mode: Transient elastography

Ultrasound: Acoustic radiation force imaging,
ShearWave elastography
MRI: MR elastography
T
Transient
i t El
Elastography
t
h
Fib S
FibroScan
Low stiffness
normal liver
High Stiffness
Cirrhosis
Sandrin US in Med and biol 2003
Laurent Liver Biopsy 2011
Shear Wave Elastography
Sh W
ShearWave
F0
F3
F2
F4
M
Magnetic
ti resonance elastography
l t
h
Courtesy R Ehman
MRE animation
i ti
El t
Elastography
h and
d stage
t
off fibrosis
fib i
~15
~5.2
~2.9
~5
TE/Fibroscan
MRE
Castera Gastroenterology 2005
Asrani et al. J Hep 2014
Summary of Meta-analyses
F2**
AUROC
Sen
F4**
Spe
p
AUROC
TE
0.87
78-79
78-84
0.93
ARFI
SWE*
MRE
0.85
0.92
0.97
74-76
90
87-94
80-83
88
94-95
0.92
0.98
0.97
*not Meta-analysis
y
**variable cutoffs
# Cochrane summary for ALD patients
Sen
Spe
p
83-87
0.95#
88-89
88
92-93
87-89
0.71#
83-87
97
91-96
Tsotchatzis J Hep 2011

Wang Hepatology 2012
Bota Liver Int 2013
Nierhoff Eur Radiol2013
Guo 2014
Ad
Advantages
t
Strength
ROI
Ease
Addition
TE
Ease
5 min
1x4cm
Clinic
European
guidelines
SWE
Ease
Real time
i
imaging
i
5 min
Larger,
operator
chosen
Clinic
US
Sig. fibrosis
longer
Largest
operator
chosen
MRI facility
MRI
MRE
Limitations
Limit
Incomplete
Intermediate
Stages
TE
Obese,
inflammation
inflammation,
operator
experience
p
Incomplete or
unreliable
No
SWE
Obese,
inflammation,
a
at o ,
operator
experience
Lower
incomplete?
co p ete
B-mode US:
training
N
No
MRE
inflammation?
passive
congestion, iron
Lowest
incomplete
Non GI office
?Better
C
Caveats
t
Great at the extremes: normal or not
not, cirrhosis or not
50% pretest probability of cirrhosis90%
probability of correct diagnosis

Absolute intermediate staging unknown
False elevation in stiffness

Acute inflammation, passive congestion
Extrahepatic cholestasis, ascites, obese
Absolute cutoff for cirrhosis?: 11.5-14.8kPa (US)
NAFLD
Unreliable results 3-50%: No measurement in 3
4%,, unreliable in 11-17%

Related to operator experience, obesity
Non invasive markers of liver fibrosis
PROGNOSIS: CAN I PREDICT

WHICH CIRRHOTIC PATIENT
WILL DECOMPENSATE?
Greg and Jim: Stiff Liver
Stiff Liver
25 kPa
kP (US)
7 kPa (MR)
Higher APRI
Stiff Liver
14 kPa
kP (US)
5.4 kPa (MR)
Intermed APRI
Can we predict decompensation?
Indirect marker panels and prognosis:

NAFLD
Outcome
NAFLD-FS
APRI
FIB-4
BARD
7.7
8.8
6.2
34.2
20.9
14.6
6.6
Intermediate
4.2
1.1
2.3
1.8
High
98
9.8
31
3.1
69
6.9
16
1.6
Liver events
Low
Intermediate
High
M t lit
Mortality
Low
Hazard ratios
Angulo et al Gastro 2013
El t
Elastography
h and
dd
decompensation
ti
21.1
5.8
MRE
TE
Robic Hep 2011

Asrani J Hep 2014
Elastography and decompensation
RR
Liver Stiffness
Hepatic
Decompensation
p
1.07
HCC
1.11
Mortalityy
1.22
Composite
1.32
Meta-analysis
Corpechot Hepatology 2012

Singh CGH 2013
Which strategy to choose?
I
Incorporation
ti into
i t clinical
li i l practice
ti
Cirrhosis
Most tests perform well
AUROC ~0.9 (elasto) vs. ~0.8 (serum)
Concomitant vs. sequential testing
Prognosis
Most tests perform well
Following
F ll i patients
ti t ((e.g. NAFLD)
?Serum Markers
Elastography every 2-3 years?
I
Incorporation
ti into
i t ((our)) clinical
li i l practice
ti
3 groups: normal,
normal intermediate or cirrhosis
Triage HCV therapy: >90% SVR
Identify
Id tif cirrhotics
i h ti versus non cirrhotics
i h ti
NAFLD
Identify cirrhotics versus non cirrhotics
Use to follow: e.g. TE/MRE every 2-3 years?
Cirrhotics
Prediction of decompensation: Singular value vs.
change
h
Testing in active vs. quiescent disease

Roulot Gut 2011
E l i IIssues
Evolving
Not addressed
Role of biomarkers: combination, sequential
Spleen stiffness
Elasto + something
Reliability of current standards
Reimbursement: active consideration
FDA Approval:
pp
TE, SWE
0346T: Elastography (2014)
MRE: billed as non contrast MRI
SWE: limited abdominal US (76705) + TE
(eventually)
TE 91299 ((other
TE:
th GI procedure)
d )
Charge: 150-500?
Non
o invasive
as e markers
a eso
of liver
e fibrosis:
b os s
Can they replace biopsy? Which to use
and when?
Sumeet Asrani MD MSc
Baylor University Medical Center, Dallas
The Failing Liver in an Outpatient:

When to Refer Whom, Changes to MELD,
Pre-transplant Management
Lorna Dove, MD, MPH

Columbia University Medical Center
The F
Th
Failing
ili Liver
Li
in
i an Outpatient:
O
i
When
Wh to refer
f whom,
h
changes to MELD, pre-transplant management
Lorna M. Dove, MD MPH
Associate Professor of Medicine at Columbia
University Medical Center
Outline
Indications for Liver Transplantation

Allocation of Organs
Proposed Changes in MELD Score
Accepted Guidelines for Advanced Liver Care
Controversies in the management of ESLD
Indications for Adult Liver Transplant-2012 &2002

1800
1600
1400
1200
1000
800
600
400
200
0
Acute Hepatic
Necrosis
SRTR, 2012
HCV
ALD
Cholestatic
Metabolic
Malignancy
Other
Indications for Transplantation

Fulminant Hepatic Failure
Life threatening Complication of Liver Failure
Hepatorenal Syndrome*
Ascites*
Hepatocellular Carcinoma**
Hepatic Encephalopathy
Bleeding from Portal Hypertension
Liver Based Metabolic Defect
*Captured by MELD
*MELD Changes
Whom to Refer
MELD=9
MELD=9
MELD Score
What Makes the Difference?

Score= 15
Score= 27
52 y.o. man with hx. Of NAFLD who

presents to the
h Emergency
E
Department with hematemesis, EGD
demonstrates Grade 3 Varices
Labs:
b
52 y.o. man with hx. Of NAFLD who

presents to the
h Emergency
E
Department with hematemesis, EGD
demonstrates Grade 3 Varices
Labs:
b
Hgb-9, PLT-48, Na-131, BUN-13, Cr-0.6

Alb-2.5, Tb-5, AST-98, ALT-60, INR-1.2
Exception Points!!!
Hgb-9, PLT-48, Na-131, BUN-13, Cr-3.5

Alb-2.5, Tb-5, AST-98, ALT-60, INR-1.2
Median Model for EndStage Liver Disease (MELD)

Score at Transplantation,
2011.
Lamas D, Rosenbaum L. N Engl J Med 2014;371:2447-2450.
Hepatocellular Carcinoma Patients Are Advantaged in the

Current Liver Transplant Allocation System
American Journal of Transplantation

pages 1643-1648, 10 MAY 2010 DOI: 10.1111/j.1600-6143.2010.03127.x
Access to Transplant
Year of Transplant
Calculated MELD (%)
HCC Exception (%)
2010
62.7
25.2
0
2011
61.4
6
27.4
2012
59.9
28.9
Heimbach, SRTR,2013
Proposal: HCC MELD Cap

there
h
are candidates
did
with
i h multiple
l i l HCC exception
i
extensions who are now receiving regional offers .These
candidates
ca
d dates aaree likely
e y to have
ave a much
uc lower
owe risk
s o
of d
disease
sease
progression or dropout (i.e., removal from the waiting list
for death or being too sick) than candidates with calculated
MELD/PELD scores of 35 and higher.
higher This proposal would
cap the HCC exception score at 34, in effect giving
candidates with calculated MELD/PELD scores of 35 and
higher a better opportunity to receive regional offers under
the new policy.
Hyponatremia and Survival
Jenq C et al. J. Clin Gastroenterology, 2010
MELD-NA
MELD Na
N [0.025
[0 025 MELD (140 Na)]
N )] + 140
Example
. Pt 1
1- INR-1.8,
INR 1 8 TB-7.6,Creatinine-1.4,
TB 7 6 C ti i 1 4 Na-136
N 136
MELD: 24
MELD-NA: 26
Patient 2- INR-1.8, TB-7.6, Creatinine-1.4, Na-125

MELD: 24
MELD-NA:
MELD NA 30
End-Stage Liver Disease
STANDARD CARE AND CONTROVERSIES IN

MANAGEMENT
Esophageal
Varices
AASLD/Baveno VRecommendations
Screening EGD is recommended when diagnosis of

cirrhosis is made
In p
patients with compensated
p
cirrhosis and no
varices on initial EGD, EGD should be repeated in 3
years
If there is evidence of hepatic decompensation, EGD
should be done at that time and repeated
p
annually
y
until therapy is instituted
In patients with with small varices but have criteria
for risk of bleeding, non-selective beta blockers
should be used
Medium to large varices with no bleeding but high
risk, nonselective beta blockers or EVL. If not high
risk, non-selective beta blocker is preferred
Nitrates (either alone or with beta blockers
blockers, shunt
therapy or sclero) should not be used for primary
prophylaxis
Beta Blockers and SBP
Beta Blockers and Refractory

y Ascites
Single Center Case study
151 patients
Mean MELD 18.8
LVP and albumin
Median Survival was 10 months
20 no propranolol
5 On propranolol
Risk Factors Mortality
CPC
Hyponatremia
Renal Failure
Beta Blocker Therapy
Serste et al. Hepatology 2010
When to Stop ??
Single Center
607 patients after first paracentesis
Mean MELD 17.5
Minimal initial effects on
hemodynamics
After 1s SBP episode,
proportion with SBP < 100 higher in those

on NSBB
Among patients with SBP, NSBB reduced
transplant-free survival
NSBB increased nonelective
hospitalization
Higher
Hi h proportion
ti with
ith HRS
Higher proportion with ARI
Mandorfer et al. Gastroenterology, 2014
Predictors of Death in Multivariate Analysis

1.76
Class C of Child-Pugh
HCC
1.94
2 61
2.61
Treatment with Beta Blockers
2.57
Etiology of refractory ascites

Renal Impairment
3.27
Hyponatremia
7.07
1
Serste et al,Hepatology 2010
Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites
S t ett al.l H
Serste
Hepatology
t l
2010
1 year survival 19 vs. 64 %
Up until the development of SBP, NSB had beneficial effect on transplant free survival .
After SBP, lower transplant free survival , 58% increase in mortality
Mandorfer, et al. Gastroenterology, 2014
Hepatic
Encephalopathy
2014 Practice
Guideline by AASLD
and EASL
The diagnosis of HE is through exclusion

The diagnosis and grading of minimal HE
and covert HE can be made using several
neurophysiological and psychometric
t t
tests
Stroop Test (mobile-EncephalApp)
Increased blood ammonia does not add
any diagnostic, staging or prognostic
value. A normal value calls for diagnostic
reevaluation
l ti
Hepatic
Encephalopathy
2014 Practice
Guideline by
y AASLD
and EASL
P
Primary
i
prophylaxis
h l i iis not required
i d
Recurrent intractable HE is an
indication for OLT*
Approach
A
h to HE
Initiation of care for AMS

Look for alternative causes
Id if precipitating
Identify
i i i factors
f
Empiric Treatment
Lactulose is the first choice

Rifaximin
f
is an effective
ff
add-on*
dd *
*Class 1- Conditions for which there is evidence and or agreement that a given diagnostic
evaluation procedure or treatment is beneficial, useful and effective
Hepatic
Encephalopathy
2014 Practice Guideline by
AASLD and EASL
Oral branched chain amino acids

(leucine, isoleucine and valine) can be
used as an alternative or additional
agent*
L-ornithine
ornithine L
L-aspartate
aspartate
Intravenous L
can be used as an alternative or
additional agent for patients not
responsive to traditional therapy
therapy*
Daily energy should be 35-40 kcal/kg
ideal body weight*
Daily
D il protein
t i intake
i t k should
h ld b
be 1
1.2-1.5
2 15
g/kg*
Inhibitors of
ammoniagenesis
Phenylbutyrate
Bioactive derivative, phenylacetate

complexes with glutamine to form
the renal excreted molecule
phenylacetylgutamine which
reduces the amount of nitrogenous
substrate available for ammonia
genesis
i
Glycerol Phenylbutyrate for HE- HALT-HE Study Group

Multi-center double blind RCT
Adults with cirrhosis who had at least two episodes of HE in the last 6 months
Exclusion
Other
O
h ammonia
i llowering
i agents
Active complications of cirrhosis(sepsis or bleeding)
TIPS
Drug or ETOH use within 6 months MELD>25
Creatinine >2
Na < 125
PLT <35k
Hgb <8,
8, HCT
HCT-< 25
Expected OLT within 6 months
If on rifaxmin, one episode of HE after taking this agent for 1 month
Rockey et. Al. Hepatology, 2014
Summary
Transplant is indicated for acute liver failure unlikely to recover as well
as chronic liver disease complicated by portal hypertension and loss of
synthetic function
Organ allocation is largely dictated by MELD Score
Two anticipated changes in the MELD Score and/or organ allocation
Addition
Additi off sodium
di
as a parameter
t in
i MELD score
Cap of additional points given to patients with HCC
Beta Blocker therapy remains a mainstay for both primary and

secondary bleeding prophylaxis
There may be a window period for beta blockers and discontinuation
should be considered in the setting of refractory ascites, SBP or HRS
Summary
The mainstay of therapy for HE continues to be
lactulose and rifaximin
There is some enthusiasm about IV L-ornithine Laspartate and oral branched chain amino acids
Research
R
h on Glycerol
Gl
l Ph
Phenylbutyrate
lb t t iis promising
i i
Infections in Cirrhosis: Prevalence,

Prognostication, and Proactive Management
Jasmohan Bajaj, MD, MS, FACG, AGAF

Associate Professor, Internal Medicine
Division of Gastroenterology, Hepatology and Nutrition
Virginia Commonwealth University and
McGuire VA Medical Center
Infections in Cirrhosis:
Prevalence, Prognostication, and Proactive
Management
Jasmohan S Bajaj, MD, MS, FACG, AGAF
Division of Gastroenterology, Hepatology and
Nutrition Virginia Commonwealth University and
Nutrition,
McGuire VA Medical Center, Richmond, VA
Outline
Definitions and impact of infections on the natural history
Association of infections with Acute on Chronic Liver Failure
(ACLF)
Goals of management
g
of inpatients
p
with infections
Prevention of nosocomial/second infections
Impact of concomitant medications on infections
Prevention of infections after discharge
Pathogenesis of infections in cirrhosis is multi-factorial
Definitions
Community-acquired: Within 48 hours of hospitalization or from the
community
Health-care
care associated: Infections in patients from the community
Health
who have had contact a health-care facility
Nosocomial (hospital-acquired): >48 hours after hospitalization
First Infection: Can be nosocomial/HCA or community-acquired
Second Infection: While patient is still hospitalized; most often
nosocomial
Subsequent Infection: Infections that occur after a patient has been
discharged
g after an index infection episode
p
Infections lead to high mortality in cirrhosis
30% die within 1 month
Additional 30% die by 1 year
Arvaniti V et al. Gastroenterology 2010; 139: 1246-1256
Infections in the natural history of cirrhosis

Infections
e o s can
a precipitate
pe p ae
Acute-on-Chronic liver failure
Death
Decompensated Cirrhosis
Compensated Cirrhosis
Ascites, variceal bleeding,

encephalopathy and jaundice
OLT
Damico et. Al. Natural history and prognostic indicators of survival in cirrhosis
Spectrum and causative organisms are evolving

Others
9%
Resp C diff
10% 4%
UTI
29%
Fungi
17%
No org
23%
Skin
12%
Bact
13%
SBP
23%
Gram
Pos
33%
Gram
Neg
27%
Bajaj JS et al (NACSELD) Hepatology 2014, Fernandez et al 2013 Hepatology
Acute On Chronic Liver Failure is often Precipitated by Infection

Jaundice
Ascites
Variceal bleeding
Hepatic encephalopathy
Chronic
Ch
i
liver disease
Precipitants
Infection
Viruses
Drugs
Alcohol
Ischemic
Surgery
Idiopathic
Type A
ACLF
Compensated cirrhosis
Type B
ACLF
Decompensated cirrhosis
Type C
ACLF
Hepatic and extrahepatic

organ failures
Jalan R et al ACLF WGO Consensus Gastroenterology 2014
ACLF is defined by organ failures and has a high mortality

Europe
North America
Moreau et al 2013 (CANONIC) Gastroenterology, Bajaj et al (NACSELD) 2014 Hepatology
ACLF
and
infections
We need to
prevent it
Levels at which Infections and subsequent ACLF can

be Prevented
1.
2.
3.
4.
Prevent decompensation or advancement of liver disease

Prompt recognition and appropriate treatment of infections
Prevent nosocomial infections and second infections
Reduce the use of medications that modulate the
development or prognosis of infections
5. Carefully monitor patients after discharge from the hospital
Levels at which Infections can be

managed
Prompt recognition and management
of infections in cirrhotic patients
Clues that can indicate infections in cirrhosis

Usual signs of infection may be absent due to impaired
immune response
Other
O h signs
i
and
d symptoms could
ld be
b relevant
l
Altered mental status or hepatic encephalopathy
Acute kidney injury
Asymptomatic patients with ascites can have silent SBP
Increase in WBC count may not be dramatic since cirrhotic
patients have a lower baseline
Judicious use of albumin prevents mortality and AKI in SBP but not
in other infections
SBP
Poca et al J Hepatol 2012, Sort et al N Engl J Med 1999, Thevenot et al J Hepatol 2014
Non-SBP
Inappropriate antibiotics increase mortality almost 10 fold

OR=9.5
Risk
Risk factor: Multidrug resistance organism
Arabi YM et al. Hepatology, 2012
Delay in antibiotics can impact survival
Arabi YM et al. Hepatology, 2012
Drug resistant organisms need to considered

Italy (%) Korea (%) France (%)
Spain (%)
Community-acquired infections
16
10*
13*
N
Nosocomial
i l infections
i f ti
33
41*
33*
35
*Gram-negative bacteria resistant to cefotaxime
Risk
Ri
k factors
f t
for
f Multi-drug
M lti d
resistant
i t t organisms
i
- SBP prophylaxis
- MDR infections in the last 6 months
- Use of -lactams
lactams within the previous 3 months
Bert et al, Eur J Clin Microb Infect Dis 2003; 22: 105, Cheong et al, Clin Infect Dis 2009; 48: 12306, Merli et al, Clin
Gastroenterol Hepatol 2010; 8: 97985
979 85, Fernndez et al,
al Hepatology 2012
2012, Waidmann et al Gut 2015

Managed
Prevent ACLF by reducing
nosocomial and second infections
Nosocomial infection categories are different in cirrhosis

Non-Cirrhotic
Ci h i Patients
i
Ci h i Patients
Cirrhotic
i
Bloodstream infections
UTI
Spontaneous bloodstream
infections
UTI
Pulmonary
Pulmonary
Surgical Site
C Difficile
C.
Intervention-related infections
Bajaj, OLeary, Wong, Reddy, Kamath Gut 2012
Second/nosocomial infections are potentially preventable and the

one of the few modifiable factors to prevent ACLF
Development of infection
infection-associated
associated ACLF
Modifiable: Second infection, SBP as the first infection
Type:
Respiratory (28%): 42% associated with aspiration, 28% with
ventilation
Urinary (26%): 50% associated with urinary catheterization
C. difficile (12%): all were on antibiotics
Bajaj JS NACSELD 2012 Hepatology
Goals in inpatient management of infections

Diagnose them accurately and rapidly: significant infections can exist in
asymptomatic patients
Examine the skin and IV sites carefully
Initiate early and appropriate antibiotics
Prevent kidney injury
Carefully evaluate for nosocomial and second infections
Modify antibiotic regimens according to culture results
Re-evaluate need for urinary catheterization, central lines and prevent
aspiration

managed
Reduce the use of medications that
predispose or modulate the response
to infections
Association of PPIs with infections exists in most reports

A
Association
i i NO Study
d type
Association YES
Study
d type
Bajaj, et al
Choi,, et al
Northup, et al
Bulcewicz, et al
Goel, et al
Waidmann et al
Bajaj et al
Oleary et al
(NACSELD)
Merli et al
Sargenti et al
Case-control (SBP/C.diff)
Campbell et al
Case-control
Mandorfer et al
Retro cohort
Terg et al
Retro cohort
Case-control
Retro cohort
Propensity-matched cohort
Prosp cohort
Prosp cohort
Prosp cohort
Case control
Retro Cohort
Prosp Cohort
Most cirrhotic patients are on PPI for unknown reasons

There are only limited FDA-approved indications for PPI use
Most studies have shown that almost 50-70% of cirrhotic
patients are on PPI for
f non-recommended
d d reasons
Even short-term PPI use can radically alter gut microbiota in
cirrhotic patients
All patients with cirrhosis should undergo an extensive
evaluation to see if they
y need their current PPI
Consider discontinuing PPIs if they are not required or
question the need to continue this therapy
Bajaj JS Am J Gastro 2009, Goel et al CGH 2011, Kalatzaikis et al 2008, Bajaj et al AJ Physiol 2014
Beta-blockers and infections in cirrhosis: jury is still out

Study
Study type
Sample size
BB Risk
association
C l i
Conclusions
Bajaj et al
Propensity
matched
database study
Case-control
Hospitalized
1836 1:1 early

and 1462 1:1
advanced pts
400
hospitalized
cirrhotics
607 patients
requiring
paracentesis
HR for infections
crossed 1
No association
Hazard Ratio
0.46
P t ti
Protective
In SBP BBreduced
survival and HRS
H
Harmful
f l
Merli et al
Mandorfer Retrospective
et al
analysis

managed
Carefully monitor patients after
discharge from the hospital
Prophylactic strategies for SBP are usefulbut

Therapy
Diagnosis
Survival
Other outcomes
t b ot c
Antibiotic
Prophylaxis
No
op
previous
e ous
episode of SBP
Decreased
ec eased SBP
S
occurrence (Needs
replication)
Antibiotic
Prophylaxis
GI bleed
Decreased probability of
infection
Antibiotic
prophylaxis
h l
Previous episode
off SBP
Less recurrence of SBP
Antibiotics studied are daily norfloxacin or ciprofloxacin; if allergic, can use

trimethoprim-sulphamethoxazole
trimethoprim
sulphamethoxazole
Cochrane review 2009 and 2010
Infections after discharge (subsequent infections) are

often unrelated to the original infection
After discharge for an index infection
Within 6 months
Determinants
- Age
- PPI U
Use
- SBP Prophylaxis
OLeary NACSELD et al Clinical Gastro Hep 2015
Summary: Infections in Cirrhosis

Infections profoundly affect the natural history of cirrhosis
The epidemiology and bacteriology of infections is changing
radically, in part due to medications and prophylaxis
Ah
high
h index
d off suspicion, fl
flexible,
bl rapid
d and
d appropriate
antibiotics and prevention of acute kidney injury is required
to improve survival
Prevention of further infections remains a challenge
Acknowledgements: NACSELD PIs and coordinators
Acknowledgements: NACSELD PIs and coordinators
VCU: JS Bajaj, Melanie White, Nicole Noble, Ariel Unser

Ri h
Richmond
d VA:
VA JS Bajaj,
B j j Edith
Edi h Gavis,
G i James
J
H
Hovermale
l
Baylor Dallas: Jacqueline Oleary
U Penn: Rajender Reddy, Sam Brayer
U Toronto: Florence Wong,
Wong M Khokar
Mayo Rochester: Patrick Kamath, Siddharth Singh
U Texas Houston: Michael Fallon, Sachin Batra
Yale: Guadalupe Garcia-Tsao
U Rochester: Benedict Maliakkal, K Doyle
Mercy Medical Center, Baltimore: Paul Thuluvath, A Poonia
Emory University: Ram Subramanian
MUSC: David Koch
U California San Diego: Heather Patton
Beth Israel Deaconess: Raza Malik
U Alberta,, Edmonton: Puneeta Tandon
The Family History Conundrum: What to Test,

When to Bring Back and When to Refer?
Sapna Syngal, MD
Dana-Farber/Brigham and Womens Cancer Center
The Family
y History
y Conundrum
What to Test and When to Refer for Genetic Evaluation?
Emergence from Esoterica to Standard of Care
Sapna Syngal, MD, MPH

Dana-Farber/Brigham and Women
Womenss Cancer Center
Hereditary Syndromes in GI Cancer

Hereditary Colorectal Cancer
H
Hereditary
dit
N
Nonpolyposis
l
i Colorectal
C l
t lC
Cancer (HNPCC) / Lynch
L h
Syndrome
Adenomatous Polyposis Syndromes (FAP, Attenuated FAP and MAP)
Hamartomatous Polyposis Syndromes
Hereditary Pancreatic Cancer

Hereditary Gastric Cancer
GI cancers associated with other hereditary syndromes
How is management of hereditary cancers different

than sporadic cancers?
Surgical
g
management
g
of cancer
Screening and surveillance post treatment of primary
cancer
Surveillance for associated cancers
Screeningg and surveillance of family
y members
Reproductive counseling
URL: http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
SUMMARY STATEMENTS & RECOMMENDATIONS

Summary Statements Mother
Mother and Apple Pie
Pie
Recommendations
Evidence-based
Graded by strength of recommendation and quality of evidence
Primarily deal with management
Still limited by paucity of data
SUMMARY STATEMENT: STANDARD FOR MINIMAL

CANCER FAMILY HISTORY ASSESSMENT
A family history of cancer and premalignant
ggastrointestinal conditions that p
provides sufficient
information to develop a preliminary determination of
the risk of a familial predisposition to cancer should be
obtained
STANDARD FOR MINIMAL CANCER FAMILY HISTORY

ASSESSMENT
Essential elements of a family history include presence and
type of cancer diagnoses in first- and second-degree
relatives, and presence and (ideally) type of polyps in firstdegree relatives
First-degree relatives parents, siblings, children
Second-degree relatives grandparents, grandchildren, aunts,
uncles nephews
uncles,
nephews, nieces or half siblings
Age and lineage should be noted for each diagnosis.
Causes of Hereditary Susceptibility to CRC
Sporadic
((65%85%))
Familial
(10%20%)
Rare CRC syndromes

(<0.1%)
Adenomatous Polyposis
(FAP, Attenuated FAP and MAP) (1-2%)
Lynch
y
Syndrome
y
(2-5%)
Clinical Features of HNPCC (Lynch Syndrome)

Early but variable age at CRC
diagnosis (~45 years)
Multiple
M lti l primary
i
cancers
Accelerated carcinogenesis
Tumor site in proximal colon
predominates
Extracolonic cancers: endometrium,
ovary, stomach, urinary tract, small
bowel, bile ducts, sebaceous skin
tumors1
LYNCH SYNDROME
Summary Statements
All newly
y diagnosed
g
colorectal cancers (CRCs)
(
) should be
evaluated for mismatch repair deficiency
Analysis may be done by immunohistochemical testing (IHC) for the
MLH1/MSH2/MSH6/PMS2 proteins and/or testing for
microsatellite instability (MSI)
Tumors that demonstrate loss of MLH1 should undergo BRAF
testing or analysis for MLH1 promoter hypermethylation
LYNCH SYNDROME
Summary Statements
Analysis may be done by immunohistochemical testing for
the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for
microsatellite instability
instability. Tumors that demonstrate loss of
MLH1 should undergo BRAF testing or analysis for MLH1
promoter hypermethylation.
Who should undergo

g g
genetic evaluation for Lynch
y
syndrome?
Individuals who have a tumor showing MMR
deficiency (and no BRAF mutation)
Known family mutation
Risk of >5% of LS based on risk prediction models
Subsumes Amsterdam and Bethesda Guidelines
Prediction Models for the Identification of

Lynch Syndrome
MMRpredict
MMR
di
MMRpro
PREMM1,2
PREMM1,2,6
Development of models based on proband and family history

phenotypes
h
+// tumor testing
i
Barnetson et al. N Engl J Med 2006; 354: 2751-63
Chen et al. JAMA 2006; 296:1479-87
Balmana et al. JAMA 2006; 296:1469-78
K
Kastrinos
i
et al.l Gastroenterology
G
l
2011 140:73-81
2011;
140 73 81
Prediction of MLH1/MSH2/MSH6 Mutations

(PREMM1,2,6
1 2 6) Model
Proband history
Presence of colon cancer,

cancer other HNPCC cancer and/or adenomas
Age of onset
Family history
Presence of colon or other HNPCC cancer
Youngest age at diagnosis

Predicted probability of mutation in
MLH1/MSH2/MSH6
www.dfci.org/premm
Google
g premm
p
Balmana et al. JAMA 2006

Kastrinos et al Gastro 2011
LYNCH SYNDROME
Summary Statements
Genetic testing of patients with suspected Lynch
syndrome should include germline mutation genetic
testing for the MLH1, MSH2, MSH6, PMS2 and/or EPCAM
genes, or the altered gene(s) indicated by
immunohistochemical testing.
LYNCH SYNDROME - Recommendations

Colonoscopy at least every 2 years, beginning between ages 20 and 25.
Consider annual colonoscopy in confirmed mutation carriers
Colectomy with ileorectal anastomosis (IRA) for colon cancer or colonic
neoplasia not controllable by endoscopy
Hysterectomy and bilateral salpingo-oophorectomy for mutation carriers who
h
have
finished
fi i h d child
hild bearing,
b i optimally
ti ll att age 40-45
40 45
Screening for endometrial cancer and ovarian cancer by endometrial biopsy
and transvaginal ultrasound annually starting at age 30 to 35 years
Screening
S
i ffor gastric
t i and
d duodenal
d d
l by
b baseline
b li EGD with
ith gastric
t i bi
biopsy att age
30-35 years; consider repeating every 3-5 years
Consider aspirin chemoprevention 600 mg per day
Who should undergo evaluation for Adenomatous

P l
Polyposis
i (FAP,
(FAP AFAP
AFAP, MAP)?
Individuals who have a personal history of >10 cumulative colorectal adenomas or
A ffamily
l history
h
off one off the
h adenomatous
d
polyposis
l
syndromes
d
or
A history of adenomas and FAP-type extracolonic manifestations
duodenal/ampullary adenomas
desmoid tumors (abdominal > peripheral)
papillary thyroid cancer
congenital hypertrophy of the retinal pigment epithelium (CHRPE)
epidermal cysts
osteomas
FAMILIAL ADENOMATOUS POLYPOSIS/MUTYH-ASSOCIATED

POLYPOSIS/ATTENUATED POLYPOSIS - Genetic Testing
Genetic testing of patients with suspected adenomatous

polyposis syndromes should include APC and MUTYH gene
mutation analysis
analysis.
FAMILIAL ADENOMATOUS POLYPOSIS/MUTYH-ASSOCIATED

POLYPOSIS/ATTENUATED POLYPOSIS - SURVEILLANCE
Annual colonoscopy or flexible sigmoidoscopy beginning at
puberty. In families with AFAP or MAP, surveillance should be by
colonoscopy
Screening for gastric and proximal small bowel tumors should be
done using upper endoscopy including duodenoscopy starting at
age 25-30 years. Surveillance should be repeated every 0.5-4 years
Annual thyroid screening by ultrasound
Who should be evaluated for PEUTZ-JEGHERS

J
SYNDROME
(PJS)?
Individuals with perioral or buccal pigmentation and/or
Two or more histologically characteristic gastrointestinal
hamartomatous polyp(s) or
A family history of Peutz-Jeghers syndrome
Peutz-Jeghers Syndrome
Incidence: unknown
Autosomal dominant inheritance

STK11 gene
Cancer
PJS Risk
General Population Risk
Breast
Colorectal
Stomach
Pancreas
Small Intestine
Lung
Ovary-sex cord tumors (women)
Cervix (women)
Uterus (women)
Testes (men)
45-50%
39%
29%
11-36%
13%
15-17%
18-21%
10%
9%
Low, but increased
12%
5-6%
<1%
<1%
<1%
7%
1-2%
<1%
2-3%
<1%
NCCN 2012
Hearle N. et al. Clin Cancer Res 2006;12:32092006;12:3209-3215
Slide courtesy of Dr.Huma Rana
Peutz-Jeghers syndrome- Surveillance

Site
Age to begin
Surveillance Surveillance procedures and comments
surveillance
interval
a Start
Colon
8,
18a
Colonoscopya
Stomach
8, 18a
Esophagogastroduodenoscopya
Small bowel
8, 18a
Video capsule endoscopya
Pancreas
30
1-2
1
2
MRI and/or EUS
Breast
25
Annual self-exam starting age 18, annual breast MRI and/or
at age 8; if polyps
present, repeat every 3
years; if no polyps repeat
at age 18, then every three
years, or earlier if
symptoms occur
mammogram starting at age 25

Ovarian, Endometrial
25
Pelvic exam and pelvic or transvaginal ultrasound
Cervix (adenoma malignum)
25
Pap smear
Testicular (Sertoli cell tumor)
Birth to teenage 1
Testicular exam, ultrasound if abnormalities palpated
Lung
Provide education about symptoms and smoking cessation
NCCN 2014
Who should be evaluated for JUVENILE POLYPOSIS

SYNDROME (JPS)
Individuals with five or more juvenile polyps in the
colorectum or
Any juvenile polyps in other parts of the GI tract
Family history of Juvenile Polyposis
Juvenile Polyposis Syndrome
Incidence: 1/16,000
1/16 000-1/100
1/100,000
000
Autosomal dominant transmission
Genetics: BMPR1A, SMAD4
Risks
Colorectal cancer (50%), Gastric (20%),
Small Intestine,
- Association with HHT
Management
Endoscopic, colonoscopic surveillance every 2 years
SMAD4 alteration, follow screening guidelines for HHT including:
annual evaluation for symptoms of AVMs
periodic complete blood counts with treatment of anemia
routine testing for pulmonary AVMs
screening for cerebral AVMs in children
COLORECTAL CANCER RISK ASSESSMENT TOOL

Patients who answer yes to any question should have more comprehensive family
history evaluations.
1
1.
Do you have a first-degree

first degree relative (mother
(mother, father,
father brother,
brother sister,
sister or child) with
any of the following conditions diagnosed before 50?
1. Colon or rectal cancer
2. Cancer of the uterus, ovary, stomach, small intestine, urinary tract (kindey,
ureter bladder),
ureter,
bladder) bile ducts,
ducts pancreas
pancreas, or brain
2. Have you had any of the following conditions diagnosed before age 50 years?
1. Colon or rectal cancer
2. Colon or rectal polyps
p yp
3. Do you have three or more relatives with a history of colon or rectal cancer?
(This includes parents, brothers, sisters, children, grandparents, aunts, uncles,
and cousins)
Kastrinos Allen et al
Kastrinos,
al. Am J Gastroenterol 2009; 104:1508-18
104:1508 18
GI Cancers in the Genetics Era

Personal and family
y history
y are still the best screeningg tool for
inherited diseases
Hallmark features include
E l age off onsett off cancer or polyps
Early
l
Rare histologies ie Peutz-Jegher type polyp, desmoid tumor
Multiple
p relatives affected in the family
y
GI Cancers in the Genetics Era

Need to systematize family history assessments in clinical practice
Refer for genetic counseling and testing when necessary
Genetic testing easy to do (blood test), but a send out test
Covered by insurance in most cases
Increasingly going to be done in panels
panels
Address surveillance of multiple cancers based on syndrome
Incorporate (and document) recommendations for family members
The spectrum of genetic diseases is likely to keep expanding in future
years and is likely more common than previously thought
Attenuated versions of many syndromes likely exist
Th k you
Thank
Evolving Truths About Diverticular Disease:

Roles of Diet (fiber), NSAIDs, 5-ASA Agents, and
Antibiotics
Neil Stollman MD, AGAF, FACP, FACG

LEARNING OBJECTIVES
able to:
1. Advise patients about the most recent evidence on risk
factors for developing diverticular disease or its complications, such as fiber, diet, and medications.
2. Recognize patients within the spectrum of diverticular
disease, particularly Symptomatic Uncomplicated
Diverticular Disease (SUDD)
3. Appropriately utilize the newest therapies in diverticular
disease, including mesalamine, rifaximin, and probiotics.
4. Apply newer data suggesting a more conservative
approach to both systemic antibiotic use and surgical
resection in acute diverticulitis.
INTRODUCTION
Diverticular disease is the sixth leading outpatient GI diagnosis in the United States, accounting for over 2 million outpatient visits annually, and is the most common GI indication
for hospitalization, accounting for $2.7 billion in costs. (1) It
is also the most commonly reported finding at colonoscopy,
identified in over 40% of all exams and in more than 70% of
patients older than 80 years. Further, both the incidence of,
and rate of hospitalization for, seem to be increasing in both
Europe and the United States. (1) This lecture will briefly review the recently published literature and new developments
concerning the pathogenesis, risk factors and treatments of
diverticular disease.
DIETARY FIBER: Role in Pathogenesis and Treatment
The conception of diverticulosis as a fiber-deficiency disease

was originally suggested in seminal work by Burkitt and Painter, and has remained a widely accepted thesis for over forty
years. Supportive observations included a lower rate of diverticulosis in populations with higher dietary fiber intake, eg Africa, compared with westernized populations that were consuming lower fiber diets over time, coincident with increasing
diverticular disease. Further, vegetarians with higher dietary
fiber intake have lower rates of diverticulosis, and experimentally, rodents fed a very low fiber diet develop diverticulosis as
well. The thesis is also intuitively appealing, and has become
fairly accepted dogma, despite shortcomings in the data available, including the assumption of uniform regional dietary
habits, and the lack of control for regional differences in lifespan.
A recent study challenging this fiber deficiency hypothesis

was published by Peery et al (2) who performed an observational cross-sectional study of over 2000 patients undergoing colonoscopy, who underwent a telephone dietary history
within three months after their colonoscopy. They observed
that a high-fiber diet was actually associated with a greater,
and not lower, prevalence of diverticulosis, as might have been
expected. The relationship was dose-dependent, and strongest in those with more diverticula. Also surprisingly, they also
reported that subjects with more frequent bowel movements
had a great risk, although standard thinking would have suggested a greater risk in more constipated patients. No association with dietary fat or red meat intake, nor physical activity,
was demonstrated. The validity of these conclusions has been
questioned, due to a number of methodological considerations,
including that the authors only assessed current dietary history, which may not be reflective of dietary intake years or even
decades earlier, when diverticulosis was developing. Further,
subjects were aware of their diagnosis of diverticulosis, and
could certainly have been instructed to increase their dietary
fiber intake, and/or may have reported that theyve been doing what theyve been told. Finally, they may also have learned
over time that increasing their dietary fiber intake, even if it

had been low decades earlier, resulted in symptomatic improvement in subtle diverticular symptoms.
While this important study calls into question the standard

theory of low fiber diets causing diverticular disease, a related,
and likely more clinically relevant, question relates to dietary
fiber as a treatment for patients with known diverticulosis.
To this point, two large prospective cohort studies have been
reported with highly consistent and favorable results. The
Health Professionals Follow-up study (3) followed >43,000
men for four years and reported a relative risk for symptomatic disease in highest vs lowest fiber quintiles of 0.63 (95%
CI 0.44-0.91). The Oxford-EPIC cohort (4), following >47,000
men and women in Europe, with 12 years of follow up, reported an adjusted relative risk for complications (hospitalizations
or death) of 0.59 (95% CI 0.46-0.78). The relative risk for vegetarians vs meat eaters was similar: 0.69 (95% CI 0.55-0.86).
Given the consistent and high quality evidence from both cohort studies that fiber likely diminishes diverticular complications, and that it is the complications, rather than the mere
occurrence of diverticulosis that accounts for morbidity and
costs, we should likely not yet be advising patients to avoid a
higher dietary fiber intake, which likely has other salutatory
health benefits as well.
NSAIDs
The recognition that NSAIDs are an important risk factor for

upper GI bleeding has been well established. Multiple investigations and meta-analyses have also confirmed a consistent
association between NSAID use and diverticular bleeding,
with ORs generally between 2 and 3. More recently, a large
meta-analysis (5) evaluating 23 studies has confirmed the established bleeding risk with NSAIDs (OR 2.69), but has also
described an increased risk of perforation or abscess with
NSAIDs (OR 2.49), steroids (OR 9.08) and opioids (OR 2.52).
GENETICS
Consistent with the prevailing fiber deficiency hypothesis,

the generally accepted belief was that diverticular disease was
acquired largely due to environmental factors, mainly inadequate dietary fiber. However, two recent twin registries, one
from Denmark and the other from Sweden, have reported consistent results, with relative risk of diverticular disease in one
twin, when the other had diverticular disease, ranging from
7-15. These studies have suggested that 40-53% of susceptibility to diverticular disease results from genetic factors.
RISK OF ACUTE DIVERTICULITIS
For many years, reviews articles, book chapters, and society

guidelines have generally quoted a risk of developing diverticulitis in patients with incidentally diagnosed diverticulosis
Evolving Truths About Diverticular Disease: Roles of Diet (fiber), NSAIDs, 5-ASA Agents, and Antibiotics
ranging from 10-25%. This consensus was based, however,

on very limited and quite dated studies, many over 50 years
old. Recently, a large (albeit retrospective) study has reported
data from the Los Angeles VA system, evaluating patients who
underwent colonoscopy and were found to have diverticulosis.
Over 11 year follow up, only about 4% of patients developed
diverticulitis based on fairly loose criteria; if stringent criteria were utilized (with CT or surgical confirmation), only 1%
developed diverticulitis. The ideal prospective study to answer this question will be challenging to perform, but available
evidence suggests that patients should be quoted a lower risk
than weve previously thought.
RISKS OF SEEDS/NUTS
For decades, patients with diverticular disease have been advised to avoid seeds and nuts, for fear that these particulates
would clog diverticula and foster diverticulitis. With no evidence in support of this popular tenet, the ACG Practice Guidelines in 1999 suggested that given that controlled studies that
support this belief are lacking.there is no role for any elimination diet in this disorder. In a subsequent landmark report,
Strate et al (6) reported on 47,000 men in the US Health Professionals Follow-up Study and found that nuts and popcorn, rather than increasing risk of diverticulitis, were either unrelated,
or perhaps even protective, with OR 0.72-0.80.
SUDD (Symptomatic Uncomplicated Diverticular
Disease)
Historically, diverticular disease has generally been conceptualized as either being asymptomatic or presenting as clinically
overt acute diverticulitis. More recent evidence suggests the
presence of low-grade chronic inflammation in patients with
symptomatic disease, who do not manifest severe or acute
symptoms, but rather subtle and indolent complaints, a condition that has been termed Symptomatic Uncomplicated Diverticular Disease (SUDD). The true prevalence of SUDD is unclear,
likely because of the clinical similarities to (and perhaps similar pathophysiology between) SUDD and irritable bowel syndrome (IBS). A recent retrospective study, for example, reported that in patients without prior diagnosed functional bowel
disease, IBS was 4.7 times more likely to develop after an index
episode of diverticulitis. Subsequent mood disorders were also
2.2 times more likely to develop, and the authors posit a postdiverticular IBS (PDV-IBS), akin to postinfectious IBS In a direct comparison, however,
fecal calprotectin was shown to be higher in patients with
SUDD compared with normal controls and patients with IBS,
suggesting that SUDD may have more of an inflammatory component.
Possible mechanisms to explain SUDD pathophysiology include a) inflammatory damage to enteric nerves (and aberrant
re-innervation leading to hypersensitivity), b) altered neuropeptides, c) subacute obstruction secondary to fibrosis and/or
d) muscle hypertrophy with increased intraluminal pressure.
There is modest evidence in support of all, but none has been
shown to be dominant at this point. There is now extensive
evidence exploring markers of inflammation in patients with
SUDD, including fecal calprotectin, Substance P, VIP, neuropeptides, neurokinins, as well as motility indices, and visceral sensitivity, all demonstrating increased markers of inflammation
(or motility or sensitivity) in SUDD patients compared with
asymptomatic diverticulosis patients.
The conception of subclinical inflammation underlying SUDD
has led to numerous trials recently, exploring the roles of antiinflammatory strategies in either diminishing the risk of acute
diverticulitis, or in treating SUDD. The main agents studied
include mesalamine (5-ASA), non-absorbable antibiotics, particularly rifaximin, and probiotics.
Mesalamine has been the most extensively studied agent over

the past years, with multiple small and non-randomized European studies demonstrating efficacy. More recently, two randomized double blind placebo-controlled Italian trials have
demonstrated improved symptoms at 12 and 24 months. The
first US randomized trial of mesalamine after a CT-confirmed
case of acute diverticulitis (the DIVA trial) also demonstrated
symptomatic improvement at 12 months, although like the
other two trials, did not demonstrate reduced acute diverticulitis (7). A much larger trial this year, with over 1000 subjects,
failed to demonstrate any reduction in acute diverticulitis (8).
Cyclic rifaximin, a non-absorbable oral antibiotic, has also been
fairly well studied in this arena, with two recent meta-analyses
suggesting improvements in symptoms, although modest benefit, if any, in reducing acute diverticulitis. Results for probiotics are similarly preliminary, and also suggest symptomatic
benefit in small series.
ROLE OF ANTIBIOTICS IN ACUTE DIVERTIUCULITS
Historically, systemic antibiotics have been felt to be obligate

for clinically evident acute diverticulitis, although now data
from Europe is questioning this dogma. An initial retrospective
case control study reported no difference in outcomes with a
selective use approach. This was followed by a large prospective study in Sweden of over 600 patients, in which the withholding of antibiotics did not seem to lead to worse outcomes
(9). Whether and for whom antibiotics should be prescribed
is still in flux, but its conceivable that a more conservative approach would be reasonable for patients with mild disease.
ROLE OF SURGERY IN ACUTE DIVERTICULITIS
Prior guidelines from both the American Society of Colorectal

Surgery and the American College of Gastroenterology have
both previously recommended consideration of an elective,

prophylactic surgical resection after a second confirmed attack of acute diverticulitis. Newer data question this assumption, with a recent Markov Model from a WA State database
suggesting that surgical intervention after a 4th (rather than
2nd) episode led to 0.5% fewer deaths and >$1000 saved. The
most recent ASCRS recommendations have echoed this, now
advocating that the number of attacks of uncomplicated diverticulitis is not necessarily an overriding factor in defining
the appropriateness of surgery and suggesting this discussion be made on a more individualized case-by-case basis.
REFERENCES:
1. Mosadeghi S, Bhuket T, Stollman N. Diverticular disease: Evolving concepts in classification, presentation,

and management. Curr Opin Gastroenterol 2015;31:5055.
2. Peery AF, Barrett PR, Park D et al. A high-fiber diet does
not protect against asymptomatic diverticulosis. Gastroenterology 2012;142:266-272.
3. Aldoori WH, Giovannucci EL, Rockett HR et al. A prospective study of dietary fiber types and symptomatic
diverticular disease in men. J Nutr 1998;128:714-719.
4. Crowe FL, Appleby PN, Allen NE et al. Diet and risk
of diverticular disease in Oxford cohort of European
Prospective Investigation into Cancer and Nutrition
(EPIC): Prospective study of British vegetarians and nonvegetarians. BMJ 2011;343:d4131.
5. Kvasnovsky CL, Papagrigoriadis S, Bjarnason I et al.
Increased diverticular complications with nonsteriodal anti-inflammatory drugs and other medications: a
systematic review and meta-analysis. . Colorectal Dis
2014;16:189-96.
6. Strate LL, Liu YL, Syngal S, Aldoori WH, Giovannucci EL.
Nut, corn, and popcorn consumption and the incidence
of diverticular disease. .JAMA 2008;300:907-14.
7. Stollman N, Magowan S, Shanahan F, Quigley EM et
al. A randomized controlled study of mesalamine after
acute diverticulitis: results of the DIVA trial. J Clin
Gastroenterol 2013; 47;621-9.
8. Raskin JB, Kamm MA, Jamal MM et al. Mesalamine did
not prevent recurrent diverticulitis in phase 3 controlled
trials. Gastroenterology 2014;147:793-802.
9. Chabok A, Pahlman L, Hjern et al. Randomized clinical
trial of antibiotics in acute uncomplicated diverticulitis.
Br J Surg 2012;99:532-9.
Evolving Truths About Diverticular Disease:

Roles of Diet ((fiber),
) NSAIDs, 5-ASA Agents,
g
Antibiotics and Surgery
Neil Stollman MD, AGAF, FACP, FACG
Oakland, CA
What we thought
g we knew..
Diverticulosis is caused by low dietary

fiber intake
intake
The Fiber Deficiency Hypothesis

1960s, Burkitt and Painter
g fiber diet,, high
g stool weights,
g , shorter transit
Africans: high
times, decreased pressures decreased diverticulosis.
British: low fiber diet, lower stool weights, longer transit
time, higher pressures increased diverticulosis.
Supported by rodent data (lifelong low fiber diet tics)
and lower rates in vegetarians (with higher fiber intake)
Popular thesis, but evidence supporting is poor.
Cross-sectional colonoscopy study: dietary risks for tics

2100 colonoscopies 1998-2010, post-exam telephone dietary history
Dose dependent increase in tics with increased fiber
APR: 1
1.30
30 (1.13-1.50)
(1 13 1 50) for highest vs lowest fiber quartile
Also, increased BMs associated with increased tics
No association with fat, red meat or physical activity
Problems: diet assessed decades after development of tics, and patients aware
of diagnosis, and might have learned (or been told) that fiber helps symptoms.
Post-facto association does not p
prove causality.
y
And even if high-fiber doesnt prevent, may still be effective in TREATMENT of
patients with diverticulosis (and have other health benefits as well)
Peery AF et al. Gastroenterology 2012;142:266-272
Can dietary fiber prevent complications?

2 large prospective cohort studies showing inverse relationship between
fiber intake and diverticular complications
study >43K men,
men US,
US 1988
1988-1992
1992, no prior colonic disease
HPFU study,
RR for symptomatic disease (highest vs lowest fiber quintiles)
0.63 (.44-.91) (insoluble fiber, esp cellulose)
EPIC-Oxford
f d Study,
d 47K M & F, United
d Kingdom,
d
12 year follow
f ll
up
812 cases (806 hospitalizations, 6 deaths)
Adjusted Relative Risk
Highest vs lowest fiber intake: 0.59 (.46-.78)
Vegetarians vs meat eaters:
0.69 (.55-.86)
Aldoori WH et al. J Nutr 1998;128:714-19
Crowe FL et al. BMJ 2011;343:
NSAIDs as risk factor
Many studies and meta-analyses consistently show NSAID

use as significant risk factor for diverticular bleeding.
Recent meta-analysis (23 studies):
Increased
d risk
k bleeding
bl d
with
h NSAIDs
SA
(O
(OR 2
2.69),
69) ASA (O
(OR 3
3.24)
24)
But also increased risk of perforation or abscess with NSAIDs (OR
2.49), steroids (OR 9.08) and opioids (OR 2.52)
Kvasnovsky CL, Papagrigoriadis S, Bjarnason I et al. Colorectal Dis 2014;16:189-96.
Genetics as risk factor

Swedish Twin Registry linked to Swedish Inpatient Registry1
>100K twins; 2300 had diagnosis of diverticular disease
OR for developing DD if monozygotic twin affected=7.15 (4.8-10.6) (3.2 for same
gender dizygotic twins)
Estimate hereditability
y at 40%
Danish Registry2, >10K siblings, 900+ twins

RR for developing
p g DD if monozygotic
yg
twin affected = 14.5 ((8.9-23)) (5.5
(
for
dizygotic twins)
Estimated hereditability at 53%
1. Granlund J et al. Aliment Pharmacol Ther 2012; 35:1103-07
2. Strate LL et al. Gastronenterology 2013;144:736-742.
What we thought
g we knew..
10-25% of patients with diverticulosis

will develop diverticulitis
diverticulitis
Risk of Acute Diverticulitis (AD)

( )
Estimates based on older data, true denominator unknown

p
review LA-VAMC 1996-2011
Retrospective
2222 pts with baseline diverticulosis (97% men)
Diverticulitis during 11 year follow up:
Liberal criteria:
Strict criteria:
4.3%
1.0% (CT or surgery confirmed)
Median time to event (AD): 7.1 years

g
in y
younger
g p
patients
Risk highest
Shahedi K, Fuller G, Bolus R et al. Clin Gastroenterol Hepatol 2013;11:1609-13.
What we thought
g we knew..
Patients with diverticular disease

should avoid seeds and nuts
nuts
Risk of seeds / nuts

ACG Practice Guidelines 19991
Controlled studies that support this belief are lacking.no role
for elimination
elimination diet
diet
Strate et al 20082 [US Health Professionals Study follow-up]
47,000 men free of DD on entry, followed 18 years
801 incident cases of diverticulitis
Hazard ratio for highest vs lowest consumption
Nuts:
N t
Popcorn:
0.80
0
80 (0.63
(0 63 1.01),
1 01) P = 0.04
0 04
0.72 (0.56 0.92), P = 0.007
Not only
y no association but may
y actually
y have protective
p
effect
1. Stollman NH, Raskin JB. Am J Gastroenterol. 1999;94(11):3110.
2. Strate LL et al. JAMA. 2008;300(8):907.
What we thought
g we knew..
Diverticulosis
Diverticulosis is binary (all or none),
none)
either incidental asymptomatic finding,
or causes acute diverticulitis
d
l
Asymptomatic
SUDD
Acute diverticulitis
Symptomatic Uncomplicated Diverticular Disease (SUDD)

SUDD: lower abdominal symptoms in absence of overt
inflammation. (by vital signs, labs, CT)
Now recognizing a continuum of inflammation in SUDD patients
Possible mechanisms of subclinical inflammation:
Inflammatory damage to enteric nerves (and aberrant re-innervation
re innervation
leading to hypersensitivity, enhanced afferent response to stimuli)
Altered neuropeptides
Subacute obstruction secondary
y to fibrosis
Muscle hypertrophy with increased intraluminal pressure
Microbiota alterations
Inflammatory markers in SUDD
Fecal calprotectin
Mucosal lymphocytes
Galanin
Substance P
Neuropeptide K
TNF
TNF-
VIP
PACAP
Neurokinin 1
Barostat pain threshold
Post-cibal
Post
cibal motility
60
50
40
30
20
10
0
No tics Asx tics SUDD
AD
Is SUDD a postdiverticulitis IBS?

Retrospective review 1100 pts with
AD LAVAMC (1996-2011), no prior Dx
of IBS (96% men, mean 64 years)
1100 controls, f/u 6 years
Hazard Ratio for subsequent:
-IBS=4.7
IBS 4.7 (CI 1.6
1.6-14.0,
14.0, P=0.006)
P 0.006)
-Mood disorder=2.2 (1.4-3.5, P<.001)
Suggests that AD might trigger longterm IBS and/or functional GI Sxs
Same group has just validated a SUDD
DV-QOL measure
Cohen E, Fuller G, Bolus R et al. Clin Gastroenterol Hepatol 2013;11:1614-9.
Treatment with mesalamine

Many studies, mainly European, have evaluated 5-ASA
either after acute diverticulitis or in SUDD patients
Generally favorable results, but ..
Data very heterogeneous
Most not double blinded or placebo controlled
Subjective endpoints
Dose / regimen unclear
Higher quality European data emerging

RDBPCT 96 pts 1st episode AUD
/
5ASA 800mgg BID 10d/month
vs PBO x 24 months
Diverticulitis 24 months:
5ASA:
PBO:
13%
28% (NS)
Statistically sign decrease in:

Symptoms at 24 months (p=0.02)
Additional GI drug use (p<0.03)
Parente F et al. Int J Colorectal Dis 2013;28:1423-31

Tursi A et al. Aliment Pharacol Ther 2013;38:741-51
RDBPCT 210 patients with SUDD

5ASA 1.6gm/day vs PBO with or
without Lactobacillus casei (LC)
(LC),
10d/month x 12 months
Recurrence of SUDD 12 months:
5ASA + LC:
5ASA + PBO:
PBO + LC:
PBO + PBO:
0%
14%
15%
46%
DIVA Trial
RDBPC proof-of-concept study (first in US)
Required CT scan confirmed acute diverticulitis, excluded IBS Dx
Patients randomized to:
Standard care (abx, dietary advice as per local MD)
Standard care, plus mesalamine 2.4gm QD
Standard care, plus mesalamine 2.4gm QD plus B. infantis QD
12 week Rx with 40 week additional f/u (one year total)

Lower (but NS) GSS at all time points with 5ASA (no effect probiotics)
Significant increase in responders (GSS=0 or 1) at some (not all) time points
No effect on diverticulitis recurrence rates or surrogate markers
Stollman N et al. J Clin Gastroenterol 2013; 47;621-9.
Global Symptom Score Responders

Pe
ercent R
Responders
(IITT)
80
# Significant difference vs. placebo

#
60
40
Placebo
20
0
Day 10 Week 12 Week 26 Week 39 Week 52

Responder = score of 0 or 1 for all symptoms
5ASA: The final answer?

Phase III RDBPCTs (PREVENT 1 and 2)
>1000 patients with >1 episode of acute
uncomplicated diverticulitis
Randomized to receive mesalamine (1.2, 2.4,
or 4.8 g/d) or placebo
Primary endpoint: proportion of patients free
of recurrent diverticulitis, defined as surgical
intervention or positive CT scan
No dose of 5ASA superior to placebo for
reducing diverticulitis at 104 weeks
No decrease in symptoms or time to
recurrence
Raskin JB, Kamm MA, Jamal MM et al. Gastroenterology 2014;147:793-802
Cyclic Rifaximin in SUDD (400mg BID, 7 d/month)

Meta-analysis: 4 PRCTs, 1660 pts
Pooled Rate Difference
Sx relief (1 year)
29% (CI 24 - 34%)

p<0.0001 NNT=3
All C
Complications
li i
2% (CI -3.2
3 2 - -0.1%)
0 1%)
p=0.03 NNT=59
Diverticulitis
2% (CI -3.4 - -0.6%)
p=0.0057 NNT=50
Bianchi M et al. Aliment Pharmacol Ther 2011;33:902-10

Maconi G. Dis Colon Rectum 2011;54:1326-38.
Systematic Review 31 studies (6 PC)

Significant improvement in Sxs and
greater prevalence of Sx
Sx-free
free patients
at 1 year with fiber plus rifaximin in
comparison with fiber alone.
Cumulative data from 11 RCTs:
significant benefit of rifaximin and
fiber for 1-year rate of AD:
11/970 (1.1%) vs 20/690 (2.9%); P = .012)
NNT of 57
Probiotics for SUDD and diverticulitis

Protocol
DD Stage
Follow up (N)
Lactobacillus paracasei F19 with fiber
SUDD
6 mos (50)
L. casei, 5-ASA, or both2
SUDD
12 mos (210)
Increased remission rate SUDD
L. casei plus 5-ASA3
SUDD
24 mos (75)
Increased remission rate
VSL#3 plus balsalazide4
SUDD
2 mos (30)
Improved symptoms
L. Acidophilus plus L.
L
L helviticus plus
5
Bifidobacterium
SUDD
6 mos (45)
Prevented recurrence
recurrence, improved
symptoms
B. infantis6
AD
12 mos (40)
Outcome
Improved symptoms
No effect + 5-ASA
1. Annibale B et al. Minerva Gastroenterol Dietol 2011 Mar;57:13-22. 2. Tursi A et al.Aliment Pharmacol Ther 2013;380:741-51. 3. Tursi A et al. Hepatogastroenterology.
2008;55:916-920. 4. Tursi A et al. Int J Colorectal Dis. 2007;22:1103-1108. 5. Lamiki P et al. J Gastrointestin Liver Dis. 2010;19:31-36. 6. Stollman N et al. J Clin
Gastroenterol 2013; 47;621-9.
What we thought
g we knew..
Antibiotics (with activity against

anareobes and GNR) are required in
acute diverticulitis
Retrospective, case-controlled study

272 patients with mild AD, CT confirmed admitted to two
different Dutch Hospitals with different tx regimens re Abx
191 patients: no Abx
81 patients: with Abx (higher temp on admit, o/w no diff)
Treatment failure: 4% vs 6% (NS)
NSAIDs: OR 7.25 (CI 1.22-46.9, P=0.037) for recurrence
Abx can be omitted in selected patients with mild colonic
diverticulitis
De Korte N et al. Colorectal Dis 2012;14:325-30.
Are Antibiotics Obligate?

First PRCT: 623 Swedish
d h patients (but
(b unblinded)
bl d d)
CT-confirmed acute diverticulitis without complications
No antibiotics vs antibiotics at MDs discretion for >7 days
Abscess, perforation
(P = 0.3)
Recurrent diverticulitis
(P = 0.88)
No antibiotics
6 (1.9%)
47 (16.2%)
Antibiotics
3 (1.0%)
46 (15.8%)
Chabok A et al. British Journal of Surgery 2012;99:532.
What we thought
g we knew..
Elective prophylactic / curative surgery

should be considered after a second
attack of confirmed diverticulitis
When to consider surgery?

Prior guidelines, including ASCRS and ACG recommended
considering prophylactic surgical resection after 2nd attack
1
Most
M
recent ASCRS recommendations
d i
The decision to recommend elective sigmoid colectomy after recovery from
uncomplicated acute diverticulitis should be individualized.
Routine elective resection based on young age (<50 years) is no longer
recommended.
Markov Model (WA State database)2

Colectomy after fourth (rather than 2nd) episode 0.5% fewer deaths and
saved $1,035/patient.
1. Feingold D et al. Dis Colon Rectum 2014;57:284-294. 2. Salem L et al. J Am Coll Surg 2004;199:904-12
Summary / Take home points

Fiber deficiency may not be as important a CAUSE of
diverticulosis as previously thought.
Adequate
Ad
fiber
fib intake
i k lik
likely
l IS effective
ff i at d
decreasing
i
complications of diverticulosis
NSAIDS significant risk factor for diverticular bleeding AND
diverticulitis/abscess
Genetics may
y play
p y a significant
g
role in susceptability
p
y
Acute Diverticulitis is probably less common than thought
Nuts and seeds: no need to avoid
Summary / Take home points

SUDD likely reflects a subclinical inflammatory state
y be a form of PI-IBS
PDV-IBS may
Mesalamine likely doesnt prevent diverticulitis, but MAY
improve symptoms
Rifaximin and probiotics: role TBD, may improve Sxs
g not be obligate
g
in mild AUD
Antibiotics: might
Surgery: recommended later, case-by-case
Mastering the Difficult Colonoscopy and

Polypectomy: What Are the Best Evidence-based
Methods? Should I Try Something New?

Director of Endoscopy
Indiana University Medical Center
Mastering the Difficult

Colonoscopy and
P
Polypectomy
l
t
Douglas K Rex
Indiana University Health
Indianapolis, Indiana
Difficult colonoscopy and

polypectomy
What are the best evidence based
methods?
Should I try something new?
4 Key Colonoscopy Quality

Measures
Adenoma detection rate
Males: 30%
Females: 20%
Cecal intubation rate

Overall 90%
Screening: 95%
Adherence to screening
g and surveillance
intervals: 90%
% of cases with adequate bowel
preparation: 85%
Keys to optimal bowel

preparation in colonoscopy
S
Split
lit or same d
day d
dosing
i (A)
Adjust the prep strength for predictors of failure (C)
Opioids, tricyclics, chronic constipation, prior colon
resection, diabetes, obesity, prior failed prep
Rate
R t the
th preparation
ti after
ft clean-up
l
Boston or Chicago scales
If the
th prep is
i adequate
d
t follow
f ll
the
th screening
i and
d
surveillance guidelines
Target for success of 85%
Technical Performance of
Water--Assisted Colonoscopy
Water
C
Water immersion
Turn
T
off
ff the
th gas att the
th source
Fill the colon with sufficient water to tell the
luminal direction
Remove the water during
g withdrawal
Water exchange
Fill the colon with water and remove during
insertion
Water assisted colonoscopy

Roles for water assisted insertion
Reduce pain and sedation requirements (A)
Improved preparation quality (A)
Detection of more adenomas (C)
Cecal intubation in redundant colon (C)
Passing
P
i the
th angulated
l t d sigmoid
i
id (C)
Prevention of barotrauma perforation (C)
Role of CO2 in colonoscopy

Use in all cases: reduced post
post-procedural
procedural
pain (A)
For intraprocedural pain water immersion is
more effective (A)
Selective use:
EMR and ESD
Severe diverticular disease (prevention of
d l
delayed
db
barotrauma)
t
)
Decompression
Stent placement
Difficult colonoscopy has 3

basic causes
Redundant colon
Standard colonoscope and good technique
Water immersion
4 handed pressure
Overtubes
Angulated sigmoid
Pediatric colonoscope, Ultrathin colonoscope, narrow push
enteroscope balloon enteroscope (single or double)
enteroscope,
4 handed pressure
Water immersion
Ineffective sedation
Propofol
Detection
What doesnt work or isnt

practical
For seeing behind folds
170 angle
g of view ((A))
Short caps* (A)
y Retroscope
p ((A))
Third-Eye
*benefit is minor
For detection of flat

lesions
NBI ((A))
FICE (A)
i-scan ((A))
Autofluorescence (A)
What does work

For seeing behind folds
Endocuff ((A))
Endorings (A)
G-EYE ((A))
Full Spectrum Endoscopy
(FUSE) (A)
For seeing flat lesions

Chromoendoscopy
py (p
(pancolonic dye-spraying)* (A)
*effective in both IBD and
routine screening and
surveillance
ill
Endocuff
Endocuff
EndoRing
Endorings
Pentax G Eye

Endoscopy
Full Spectrum
FDA cleared & CE Mark
330 Field of View
Full Spectrum Endoscopy

(FUSE)
( S )
Polypectomy
Cold snare polypectomy

R
Reduced
d
d risk
i k off d
delayed
l
dh
hemorrhage
h
(B)
More effective and more efficient than cold
forceps for polyps 5 mm (A)
Mixed
Mi d results
lt on effectiveness
ff ti
compared
d
to hot snaring for polyps 5-10 mm
Key is to anchor the snare tip away from the
polyp
p
yp and strip
p normal mucosa from around
the polyp
Predictors of ineffective
polypectomy
Endoscopist
Large size
Piecemeal (vs en bloc)
Ablation of flat portions
p
Serrated histology
Keys to effective EMR

Stop injecting with saline (hydroxyethyl starch A)
Include contrast agent
Use stiff snare
Use cap
p on ICV,, medial wall of cecum ((for
access)
Use short cap technique for very flat polyp
Limit thermal injury
The
Th very new:
Avulsion (Haber)
Underwater EMR (Binmoeller)
Olympus distal attachment
Dealing with flat

short cap on the tip
Cap for access
Limiting Thermal Injury
Avulsion
Underwater EMR
New tricks in colonoscopy

Difficult colonoscopy
Water immersion
CO2
Difficult polypectomy
Hydroxyethyl starch with contrast agent
Short cap
p on scope
p
Underwater EMR
Avulsion
Constipation and Colon Motility:

How to Diagnose? How to Manage?

Saint Louis University School of Medicine
GI Quality Indicators: What Should I Do in My

Practice? What are the Requirements?

Director of Health Services Research, Cedars-Sinai Health System
Director, Cedars-Sinai Center for Outcomes Research and Education (CS-CORE)
Professor of Medicine and Public Health in Residence
University of California, Los Angeles
GI Q
Quality
lit Indicators:
I di t
What Should I Do in My Practice?
What are the Requirements?
Cedars-Sinai Medical Center
Cedars-Sinai Center for Outcomes Research and Education (CS-CORE)
In the Beginning
Institute of Medicine. JAMA 1998;280:1000
Quality:
The degree
g
to which health services for
individuals and populations increase the likelihood
of desired health outcomes and are consistent
with current professional knowledge.
- Institute of Medicine. JAMA 1998;280:1000
Four IOM Conclusions

1
2
3
4
- Institute of Medicine. JAMA 1998;280:1000
The Reports
p
1999
2001
Painful academic theory
Whyy Should We Care?
Our
Our target is to have 30% of Medicare payments tied
to quality or value through alternative payment
models byy the end of 2016,, and 50% of p
payments
y
byy
the end of 2018..This is the first time in the history
of the program that explicit goals for alternative
payment models and value-based payments have
been set for Medicare.
NEJM. 2015;372:897
Three Bigg Pitfalls
Proportion
p
of Crohns Patients on Biologics
g byy Zip
p Code
David G, et al. Geographic variation in care of patients with IBD

suggests unequal quality of care in the United States. Presented at
DDW 2013, Orlando, FL
Spiegel BM et al. Clin Gastroenterol Hepatol. 2009 Feb;7(2):168-74
After Reading Textbook Vignette of IBS Patient

Survey Question: Does this Patient have IBS?
Believes patient probably
has IBS
Prepared to confidently
affirm diagnosis with
patient
Spiegel et al. Amer J Gastroenterol 2010;105:848-58
Diagnostic Testing in IBS-D: Huge Variation

(Especially among the experts)
experts )
Spiegel et al. Amer J Gastroenterol 2010;105:848-58
Measuring Adenoma Detection Rate (ADR)

in Teaching vs
vs. Non-Teaching
Non Teaching Sites
p=0 053
p=0.053
30
28.9%
25.9%
ADR (%))
A
25
20
15
10
5
0
Teaching
Non-Teaching
N=1216
N=2086
Wang et al. Gastrointest Endosc. 2013 Jan;77(1):71-8.
Comparing Total Adenomas Removed

Teaching
Ca
ase Freq
quency (%
%)
Non-Teaching
Number of Adenomas Detected by Case
Four Potential Endoscopist Behaviors
Total
Adenomas
ADR
ADR
All or None
Optimal
Total
None and done
Adenomas
One and Done
Wang et al. Gastrointest Endosc. 2013 Jan;77(1):71-8.
Four Quadrants of Behavior
All or None
None and Done
Optimal
One and Done
Addressingg Variation in Q
Qualityy
1 Standardize quality indicators ((QIs)
1.
QIs )
2 Measure achievement of QIs
2.
3 Report performance back to payers
3.
4 Get
4.
G t paid
id for
f reporting
ti QIs
QI (and
(
d penalized
li d for
f not)
t)
5 Think
5.
Thi k long
l
and
d hard
h d about
b
lapses
l
in
i quality
li
6. Improve performance
P hysician
Q uality
li
R eporting
S ystem
i e too late
i.e.
late
read
d for
f the
h d
details
il
PQRS
Q Performance Calculation
PQRS
Q GI Measures
1. Polyp surveillance (10 measures)
2. GERD (5 measures)
3. Hepatitis C (12 measures)
4. Inflammatory Bowel Disease (10 measures)
IBD Example:
p Flu Vaccination
GERD Example:
p Biopsy
p y for Barretts
Value-Based Care: The Bigg Picture

e.g. EGD for uncomplicated
dyspepsia
e.g. Choosing Wisely
((thou shouldnts))
(thou shall nots)
Cost
e.g. EGD for

complicated dyspepsia
((thou
thou shoulds
shoulds))
Low Yield
e.g. PQRS Metrics
Effectiveness
(thou shalls)
How to Report
p
Take Home Points

Times have changed and were not turning back
Get on board the quality train, or get left behind
Variation is okay, but extreme variation is not
Know your PQRS and Choosing Wisely metrics
Report, report, report (or get paid less)
Practical GI Practice: Top Take Home Points

From the Meeting to Bring to Your Practice

Gastroenterologist
Kaiser Permanente San Francisco Medical Center
Research Scientist III
Kaiser Permanente Division of Research

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2 0 1 5 A G A S p r i n g P o s t g r a d u at e C o u r s e r e s o u r c e s

Evidence That Will Change Your Practice:

New Advances for Common Clinical Problems

Examine the latest in clinical

Learn on the go and at your own pace with

Watch the presentations when your

Review comprehensive details of all sessions

* Does not offer CME.

Order online at www.gastro.org/spgcresources.

SYLLABUS 2015 AGA Spring Postgraduate Course

One Course, Four Options

Evidence That Will

May 16 & 17, 2015

AGA SpriSpringng Postgraduate

Orange County Convention Center

Walter E. Washington Convention Center

Course Director: Brennan Spiegel, MD, MSHS, AGAF, FACG

AGA Spring Postgraduate Course, May 16-17, 2015

Douglas Corley, MD, PhD, MPH

Accreditation and Designation

Presentation Summaries Saturday, May 16, 2015

AGA Spring Postgraduate Course, May 16-17, 2015

Session III Esophagus / Upper GI

Presentation Summaries Sunday, May 17, 2015

Evidence That Will Change Your Practice

Luncheon Breakout Sessions

AGA Spring Postgraduate Course, May 16-17, 2015

Gastroparesis, Nausea and Vomiting.

Clinical Challenge Sessions

Evidence That Will Change Your Practice

Endoscopic Management of Obesity.

Evidence That Will Change Your Practice

Lin Chang, MD, AGAF

Anna Mae Diehl, MD

Bruce Sands, MD, MS, AGAF

Maria Abreu, MD, AGAF

AGA Spring Postgraduate Course, May 16-17, 2015

11:45 a.m.12:45 p.m.

Luncheon Breakout Sessions

Neena Abraham, MD, MSc, AGAF,

Edward Livingston, MD, AGAF,

Ciaran Kelly, MD, AGAF

Brennan Spiegel, MD, MSHS

Lauren Gerson, MD, MSc, AGAF

Michael Camilleri, MD, AGAF

Bruce Bacon, MD, AGAF

Kris Kowdley, MD, AGAF, FASGE

William D. Chey, MD, AGAF

Scott Friedman, MD, AGAF

Douglas K. Rex, MD, AGAF, FASGE

Ronnie Fass, MD, AGAF, FASGE

Sunanda Kane, MD, MSPH, AGAF

Jacqueline OLeary, MD, MPH,

Evidence That Will Change Your Practice

Session III Esophagus / Upper GI

Nicholas J. Shaheen, MD, MPH,

Rhonda Souza, MD, AGAF, FASGE

AGA Spring Postgraduate Course, May 16-17, 2015

Case Studies in Microscopic